2019, Vol. 15, Number 2 ISSN 2450–1654

ISSN 2450–16542019, Vol. 15, Number 2

Oncology in Clinical Practice 2019, Vol. 15, N

umber 2, 85–138

Beata Hryciuk, Bartosz Szymanowski, Michał Bieńkowski, Adrian Perdyan, Aleksandra Korwat, Kamil Winnik, Barbara Radecka, Jolanta Żok, Natalia Cichowska, Katarzyna Sosińska-Mielcarek, Rafał Pęksa, Renata DuchnowskaConsistency in biomarkers expression between matched tissue microarray cores from primary gallblader and ovarian cancers

Marcin Kaczor, Rafał Wójcik, Joanna Połowinczak-Przybyłek, Piotr PotemskiCritical appraisal of clinical trials in oncology — part I

Monika Konopka-Filippow, Ewa Sierko, Marek Z. WojtukiewiczBenefits and difficulties during brain radiotherapy planning with hippocampus sparing

Ewa Cedrych, Ida CedrychNeratinib in adjuvant treatment of patients with HER2-positive breast cancer — less is more?

Katarzyna Kozak, Piotr RutkowskiWhy do we need a new BRAF-MEK inhibitor combination in melanoma?

Małgorzata Flis, Paweł Krawczyk, Izabella Drogoń, Katarzyna Kurek, Robert Kieszko, Janusz MilanowskiThe effectiveness of chemotherapy in small cell lung cancer patients with BRCA2 gene mutation and Schwartz-Bartter syndrome

Piotr Tomczak, Zuzanna SynowiecNivolumab in the treatment of advanced renal cell carcinoma

Aneta Lebiedzińska, Dawid Sigorski, Maciej Michalak, Zygmunt Kozielec, Anna Doboszyńska, Dariusz Zadrożny, Paweł Różanowski Complete pathological remission after palliative therapy with sorafenib in hepatocellular carcinoma — case report

Kamila Kaźmierczak, Joanna Kufel-Grabowska, Tomasz Kozłowski, Błażej Nowakowski When to say “no” to a patient with an ovarian tumour and in poor general condition?

Maciej KaweckiCurrent literature review

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https://journals.viamedica.pl/oncology_in_clinical_practice 2019, Vol. 15, Number 2

ORIGINAL ARTICLE

Consistency in biomarkers expression between matched tissue microarray cores from primary gallblader and ovarian cancersBeata Hryciuk, Bartosz Szymanowski, Michał Bieńkowski, Adrian Perdyan, Aleksandra Korwat, Kamil Winnik, Barbara Radecka, Jolanta Żok, Natalia Cichowska, Katarzyna Sosińska-Mielcarek, Rafał Pęksa, Renata Duchnowska ......................................................................................................................... 85

REVIEW ARTICLES

Critical appraisal of clinical trials in oncology — part IMarcin Kaczor, Rafał Wójcik, Joanna Połowinczak-Przybyłek, Piotr Potemski .................................................... 89

Benefits and difficulties during brain radiotherapy planning with hippocampus sparingMonika Konopka-Filippow, Ewa Sierko, Marek Z. Wojtukiewicz ........................................................................ 104

Neratinib in adjuvant treatment of patients with HER2-positive breast cancer — less is more?Ewa Cedrych, Ida Cedrych .................................................................................................................................. 111

Why do we need a new BRAF-MEK inhibitor combination in melanoma?Katarzyna Kozak, Piotr Rutkowski ....................................................................................................................... 115

CASE REPORTS

The effectiveness of chemotherapy in small cell lung cancer patients with BRCA2 gene mutation and Schwartz-Bartter syndromeMałgorzata Flis, Paweł Krawczyk, Izabella Drogoń, Katarzyna Kurek, Robert Kieszko, Janusz Milanowski ............................................................................................................................................... 120

Nivolumab in the treatment of advanced renal cell carcinomaPiotr Tomczak, Zuzanna Synowiec ..................................................................................................................... 124

Complete pathological remission after palliative therapy with sorafenib in hepatocellular carcinoma — case reportAneta Lebiedzińska, Dawid Sigorski, Maciej Michalak, Zygmunt Kozielec, Anna Doboszyńska, Dariusz Zadrożny, Paweł Różanowski .............................................................................. 127

When to say “no” to a patient with an ovarian tumour and in poor general condition?Kamila Kaźmierczak, Joanna Kufel-Grabowska, Tomasz Kozłowski, Błażej Nowakowski ............................... 132

CURRENT LITERATURE REVIEWMaciej Kawecki .................................................................................................................................................... 135

O f f i c i a l J o u r n a l o f t h e P o l i s h S o c i e t y o f C l i n i c a l O n c o l o g y

ONCOLOGYIN CLINICAL PRACTICE

85

ORIGINAL ARTICLE

Address for correspondence:

Dr hab. n. med. Renata Duchnowska,

prof. nadzw. WIM

Wojskowy Instytut Medyczny CSK MON

ul. Szaserów 128, 04–141 Warszawa

e-mail: [email protected]

Beata Hryciuk1*, Bartosz Szymanowski2*, Michał Bieńkowski3, Adrian Perdyan4, Aleksandra Korwat3, Kamil Winnik5, Barbara Radecka6, Jolanta Żok7, Natalia Cichowska8, Katarzyna Sosińska-Mielcarek8, Rafał Pęksa3, Renata Duchnowska2*

1Mazovian Centre for Lung Diseases and Tuberculosis, Division III, Otwock, Poland2Oncology Clinic Military Institute of Medicine, Warsaw, Poland3Chair and Department of Pathomorphology, Medical University of Gdansk, Poland4Medical Faculty, Medical University of Gdansk, Poland5Department of Pathomorphology, of Janusz Korczak Provincial Specialist Hospital in Slupsk, Poland6Institute of Medicine, Opole University, Opole, Poland7Provincial Centre of Oncology in Gdansk, Poland8Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland*On co-authorship rights

Consistency in biomarkers expression between matched tissue microarray cores from primary gallblader and ovarian cancers

ABSTRACTIntroduction. Tissue microarray (TMA) technique has been widely used, especially in immunohistochemical assays

of new prognostic and predictive markers. The main objections raised by its opponents are the small amount of

sampled material and the associated risk of inadequate assessment of analysed expression, resulting from the

potential heterogeneity of tumour tissue.

Material and methods. This study evaluated the compatibility of biomarker expression in two independent tissue

cores, 1.5 mm in diameter, obtained by TMA technique from patients with gallbladder cancer (ERb, cytoPgR, HER2,

CTGF) and ovarian cancer (PTEN, BCL2, PIK3CA, IGF1R). Comparison of the expression of individual biomark-

ers between cores was performed using the intraclass correlation coefficient (ICC), assuming a kappa < 0.4 as

a weak, ≥ 0.4 as sufficient, ≥ 0.6 as good, and ≥ 0.75 as optimal correlation, and Kendall’s tau test — ICC package.

Results. Evaluation of biomarker expression in the primary tumour was performed in 60 patients with gallbladder

cancer and in 64 patients with high-grade serous ovarian cancer. Additionally, in patients with follicular cancer,

the expression of the tested markers was assessed in the epithelium free from neoplastic malignancy. In both

tumours, a good or sufficient level of homogeneity was observed in the expression of the analysed biomarkers

between tissue cores. The correlation coefficient for the expression of individual markers in gallbladder cancer

and adhering healthy tissue was: 0.68 (95% CI: 0.53–0.79)/0.62 (95% CI: 0.39–0.78) for ERb, 0.44 (95% CI:

0.23–0.61)/0.77 (95% CI: 0.61–0.87) for cytoPgR, 0.77 (95% CI: 0.65–0.85)/0.66 (95% CI: 0.44–0.80) for HER2,

and 0.68 (95% CI: 0.53–0.79)/0.62 (95% CI: 0.39–0.78) for CTGF. In patients with ovarian cancer, the correlation

coefficient within the primary tumour was 0.82 (95% CI: 0.71–0.89) for PTEN, 0.84 (95% CI: 0.75–0.90) for BCL2,

0.71 (95% CI: 0.56–0.81) for PIK3CA, and 0.77 (95% CI: 0.65–0.85) for IGF1R.

Conclusions. Tissue microarray technique allows reliable assessment of the expression of tissue biomarkers

within the primary tumour of gallbladder cancer and ovarian cancer.

Key words: tissue microarrays, biomarkers, gallbladder cancer, ovarian cancer

Oncol Clin Pract 2019; 15, 2: 85–88

Oncology in Clinical Practice

2019, Vol. 15, No. 2, 85–88

DOI: 10.5603/OCP.2019.0011

Translation: dr n. med. Dariusz Stencel


ISSN 2450–1654


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OncOlOgy in clinical practice 2019, Vol. 15, No. 2

Introduction

The technique of tissue microarray (TMA) was first described in the 1980s [1]. In the following years, a modified method has been widely used, especially in immunohistochemical studies on new prognostic and predictive markers [2, 3]. It enables tissue material from tens or even hundreds of patients to be placed on a single microscope slide. In the first stage, the pathologist makes a microscopic evaluation of the whole specimen stained with haematoxylin and eosin to determine the most representative necrosis-free tumour area for further analysis. In the second stage, from a paraffin tissue block (the so-called “donor”) containing a formalin-fixed fragment of the tumour, a small, cylindrical core with a diameter of 0.6 to 2 mm is collected using a special needle. This core is then placed in a pre-prepared hole located in another paraffin block called the “recipient”. To increase the representativeness of the material being tested and to reduce the risk of tissue loss in the staining process, at least two cores are usually taken for each case. In addition, a map is created containing information about the location of the material, which allows it to be quickly identified in the block. After completion of the material collection process, sections are obtained for examination using the microtome; one microscopic slide usually contains of 50 to 150 cases [4]. The main objection raised by the opponents of this method is the small amount of material tested and the associated risk of inadequate assessment of analysed biomarker expression resulting from the potential heterogeneity of tumour tissue. Data on the reliability of TMA in gallbladder and ovarian cancer are scarce. This study evaluated the compatibility of biomarker expression between two tissue cores obtained by TMA in both tumours.

Material and methods

Characteristics of the assessed biomarkers (proteins)

The analysis included patients in whom the expres-sion of a panel of tissue biomarkers was examined as part of two retrospective clinical studies. Proteins for immu-nohistochemical analysis were selected on the basis of available literature, taking into account the availability of antibodies and technical feasibility of assessment on archived formalin-fixed paraffin-embedded (FFPE) tissue. In the project concerning gallbladder cancer, the expressions of following receptors were analysed: steroid hormones receptors: estrogen a (ERa) and b (ERb), progesterone (PgR), human epidermal growth factor 2 (HER2), and connective tissue growth factor (CTGF). In turn, in ovarian cancer, the expression of the following proteins was determined: human protein

encoded by the PTEN suppressor gene (phosphatase and tensin homolog deleted on chromosome 10) on the long arm of chromosome 10, proteins belonging to the BCL2 family (B-cell CLL/lymphoma 2), protein of the catalytic subunit a phosphatidyl inositol 3-kinase (PI3K-CA), and insulin-like growth factor-1 receptor (IGF1R).

Preparation of tissue microarrays

In the analysed group, sections stained with haema-toxylin and eosin were subjected to histopathological reassessment, which allowed verification of the diagnosis and determination of the most representative fragments of cancer and healthy tissues. Selected samples together with the corresponding paraffin blocks were used to determine the tumour areas from which the sections for tissue microarray were taken using a 1.5 mm diameter needle. Biopsy specimens of tumour-containing frag-ments were placed in previously prepared, tissue-free paraffin blocks — “recipients”. Tissue microarrays were performed using a Manual Tissue Arrayer I by Beecher Instruments (MTAI, K7 BioSystems). Two fragments (biopsies) of primary tumours were collected in both groups, and in the gallbladder cancer project, additionally, excisions from adjacent healthy tissues. Im-munohistochemistry was performed on tissue sections of microarrays with a thickness of 4 μm. Table 1 presents a list of the antibodies used in the study along with the methodology of performing immunohistochemical staining.

Statistical analysis

Statistical analysis was performed using the statistical environment R, version 3.4.3 [5] on the basis of data contained in a specially prepared database. A compar-ison of the expression of individual biomarkers between the “tissue cores” was performed using the intraclass correlation coefficient (ICC), assuming kappa < 0.4 as weak, ≥ 0.4 as sufficient, ≥ 0.6 as good and ≥ 0.75 as opti-mal correlation, and Kendall tau test — ICC package [6].

Results

In the gallbladder cancer project, biomarker expres-sion was evaluated in tissue material from cholecystec-tomy in 60 patients treated between 2004 and 2016 in four oncology centres in Poland: The Military Institute of Medicine in Warsaw, the University Clinical Centre of the Medical University of Gdansk in Gdansk, Professor Tadeusz Koszarowski Opole Oncology Centre in Opole, and Janusz Korczak Provincial Specialist Hospital in Slupsk. In the ovarian cancer project, the analysis was carried out in the primary tumour, in the postoperative material in 64 patients diagnosed with high-grade serous

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Beata Hryciuk et al., Consistency in biomarkers expression between matched tissue microarray cores from primary gallblader and ovarian cancers

Table 1. Antibodies tested and immunohistochemical methods

Antibody Manufacturer Catalogue No.

Concentration Epitope recovering

Exposure time

Control tissue

Assessment method

ERa DAKO; anti-human; rabbit clone EP1

RU HIER; DAKO PT-link, high pH

20’ Breast cancer Semiquantitative

ERb Abcam; anti-human; rabbit clone EPR3778;

ab133467

1:70 HIER; DAKO PT-link, high pH

Night incubation

Breast cancer Semiquantitative

PgR DAKO; anti-human; mouse clone 636

RU HIER; DAKO PT-link, high pH

20’+linker mouse 15’

Breast cancer Semiquantitative

HER2 Ventana; rabbit clone 4B5

RU Epitope recovering in the machine


CTGR Santa Cruz, California;

goat sc-14939

1:100 HIER, DAKO PT-link, high pH

60’ Smooth muscles Semiquantitative

PTEN DAKO; clone 6H2.1 1:50 HIER, DAKO PT-link, high pH

30’ Placenta Semiquantitative

BCL2 DAKO monoclonal mouse clone 124

RU HIER, DAKO PT-link, high pH

20’ Lymph node Semiquantitative

PIK3CA Cell signalling Rabbit monoclonal

1:50 HIER, DAKO PT-link, low pH


IGF1R Roche Rabbit Monoclonal (G11)

RU Epitope recovering in the machine

30’ Placenta Semiquantitative

cancer, treated surgically between 2010 and 2016 at the Military Institute of Medicine in Warsaw.

In both tumours, a good or sufficient level of homo-geneity was observed in the expression of the analysed biomarkers between tissue cores. ERa expression was not demonstrated in gallbladder and healthy tissue. The correlation coefficient for the expression of other bio-markers in gallbladder carcinoma and adhering healthy tissue was: 0.68 (95% CI: 0.53–0.79)/0.62 (95% CI: 0.39–0.78) for ERb, 0.44 (95% CI: 0.23–0.61) 0.77 (95% CI: 0.61–0.87) for cytoplasmic PgR, 0.77 (95% CI: 0,65–0.85)/0.66 (95% CI: 0.44–0.80) for HER2, and 0.68 (95% CI: 0.53–0.79)/0.62 (95% CI: 0.39–0.78) for CTGF. In patients with ovarian cancer, the correlation coefficient within the primary tumour was 0.82 (95% CI: 0.71–0.89) for PTEN, 0.84 (95% CI: 0.75–0.90) for BCL2, 0.71 (95% CI: 0.56–0.81) for PIK3CA, and 0.77 (95% CI: 0.65–0.85) for IGF1R (Table 2 and 3).

Discussion

Neoplasms are heterogeneous in nature, which means that there may be significant genotype differences in the primary tumour or its distant lesions, resulting from the selection of cell clones [7–9]. Therefore, the heterogeneity of tumours is spatial and temporal. In turn, in diagnostics and qualifications for treatment, especially molecularly targeted, there is a need to deter-

Table 2. Compatibility analysis for ERb, cytoPgR, HER2, and CTGF expression between tissue cores in gallbladder cancer and adherent healthy tissue (intraclass correlation coefficient [ICC], assuming kappa: < 0.4 as weak, ≥ 0.4 as sufficient, ≥ 0.6 as good, and ≥ 0.75 as optimal correlation, and Kendall tau test — ICC package)

HER2

In total 0.74 (95% CI: 0.64–0.82)

Gallbladder cancer 0.77 (95% CI: 0.65–0.85)

Healthy tissue 0.66 (95% CI: 0.44–0.80)

cytoPgR

In total 0.80 (95% CI: 0.73–0.86)



CTGF

In total 0.66 (95% CI: 0.55–0.76)



ERb

In total 0.66 (95% CI: 0.55–0.76)



mine reliable prognostic and predictive factors — bio-markers. Undoubtedly, intra-tumour heterogeneity in

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Table 3. Compatibility analysis for PTEN, BCL2, PIK3CA, and IGF1R expression between tissue cores in ovarian cancer (intraclass correlation coefficient [ICC], assuming kappa: < 0.4 as weak, ≥ 0.4 as sufficient, ≥ 0.6 as good, and ≥ 0.75 as optimal correlation, and Kendall tau test — ICC package)

PTEN

In total 0.82 (95% CI: 0.71–0.89)

BCL2

In total 0.84 (95% CI: 0.75–0.90)

PIK3CA

In total 0.71 (95% CI: 0.56–0.81)

IGF1R

In total 0.77 (95% CI: 0.65–0.85)

neoplastic disease can lead to erroneous conclusions and hinder the development of personalised medicine [7–9]. For this reason, validation of diagnostic methods used in scientific research is very important. The technique of tissue microarray, due to the gathering of material from different patients on one slide, significantly shortens the time of staining and evaluation, saves tissue material and the amount of reagents used, and allows testing in uniform conditions and with the same dilutions of the antibodies used. On the other hand, the evaluation of such small fragments of tissue raises doubts as to their rep-resentativeness in relation to the whole tumour. Previous studies on this issue, carried out in various cancers, indi-cate high consistency of results evaluated in microarrays and in full tumour sections [10–18]. In individual studies, the discrepancy in the number of cores needed to obtain an acceptable sample representation could be due to the heterogeneity of the expression of antigens in tumours [14, 16, 17, 19]. In a breast cancer study it was found that one or two TMA cores in each case yielded results that were 95% similar to those obtained using tumour sections [10]. However, most validation studies have shown that analysis of two to three cores with a diameter of 0.6 mm gives higher compliance rates than using one core [10, 14–16]. Therefore, two cores, 1.5 mm in diameter, were used in this work. High homogeneity in the expression of the analysed biomarkers with the use of tissue microarray technology in tumours has been demonstrated, which until now have not been the subject of a similar assessment. The reliability and usefulness of this method in the diagnosis of other cancers requires similar research.

Conclusions

In immunohistochemical studies on new prognostic and predictive biomarkers in gallbladder and ovarian

cancer, the tissue microarray technique is a reliable diagnostic method.

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REVIEW ARTICLE


Dr n. med. Marcin Kaczor

II Katedra Chorób Wewnętrznych

im. prof. Andrzeja Szczeklika

Uniwersytet Jagielloński

Collegium Medicum w Krakowie


Marcin Kaczor1, 2, Rafał Wójcik2, Joanna Połowinczak-Przybyłek3, Piotr Potemski3

1Jagiellonian University Medical College, Krakow, Poland2Aestimo, Krakow, Poland3The Department of Chemotherapy, Copernicus Memorial Multidisciplinary Centre for Oncology and Traumatology, Lodz; Chemotherapy Clinic, Medical University of Lodz, Poland

Critical appraisal of clinical trials in oncology — part I

ABSTRACTThe main concept of evidence-based medicine is that all therapeutic decisions should be based on results from

relevant, credible, and up-to-date clinical trials. Availability of a publication presenting a description of a clinical trial

conducted with reliable methods and its high-quality results seems to be an ideal situation from the practitioner’s

point of view. However, reading only the abstract or just the author’s conclusions may not always be sufficient

to make the right clinical decision. For this purpose, several aspects of the clinical trial should be put under as-

sessment, namely the methodology, its quality, internal and external credibility, clinical and statistical significance,

as well as consistency of the results. The ability to perform the proper assessment of clinical trials may prove

to be very helpful for practicing oncologists, especially in the case of new, emerging therapies, specific clinical

situations, or when salvage treatment is necessary. It is also worth emphasising that the outcome assessment

in oncology trials is specific, mainly due to the role of the survival analysis, which is relatively difficult to interpret.

In this paper we tried to present in a clear and intelligible way the theoretical basis and subsequent steps in the

critical appraisal of methods and results of clinical trials in oncology.

Key words: oncology, randomised clinical trial, critical appraisal, statistical analysis, survival analysis

Oncol Clin Pract 2019; 15, 2: 89–103


2019, Vol. 15, No. 2, 89–103

DOI: 10.5603/OCP.2018.0057



ISSN 2450–1654

Introduction

Decisions regarding the choice of treatment are made based on correctly performed and reliable clinical trials. The results of clinical trials are used to develop the current guidelines for clinical practice in accord-ance with the principles of evidence-based medicine (EBM). To assess whether the conclusions from the study are appropriate, first of all it should be critically analysed for internal credibility. In order to do this, it should be assessed whether the study has been carried out correctly (an appropriate methodology ensuring reliable and undistorted inference and proper statistical analysis) and whether there is internal consistency of conclusions in a range of individual endpoints. External consistency assessment can be also helpful, determining whether a similar effect was observed in other clinical trials. Then an assessment of external credibility should

be made, to find out whether the results of a clinical trial recognized as internally reliable can be extrapolated to the population subjected to treatment under real clinical practice, and whether similar clinical effects could be expected in these circumstances (patients’ characteristics, additional medical procedures, appro-priate comparator, compliance of study participants). Finally, clinical significance of the results should be assessed to answer the question of whether the magni-tude of the observed effect indicates significant clinical benefit (taking into account the prognosis in a given patient population) and whether it really should lead to a change in clinical practice [1].

The individual elements of critical appraisal of clinical trials are discussed below. In addition, taking into account the specifics of clinical trials in oncology, the analysis of “time to event” endpoints is presented in more detail.


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Clinical trial methodology

Correctly designed and conducted, blinded, ran-domised clinical trials (RCTs) provide evidence with the highest level of credibility [2]. These are experimental tests that assess at least two therapeutic interventions, and their use in patients is strictly controlled according to a previously developed study protocol. In oncology these studies usually have the character of trials with parallel groups. In some populations of oncological patients it is difficult to carry out a randomised trial, which may be due to the low prevalence of some cancers or small numbers of patients in specific clinical stages or treat-ment lines. It these cases it is necessary to conduct the study without a control group (single-arm). However, the methodological quality of such studies is initially lower than that of randomised trials. The same applies to cohort studies, which include a control group, but, due to the lack of randomisation, the non-random dis-tribution of disturbing factors is a burden, and inference about the observed differences in the effectiveness of therapy is limited [1].

Randomisation

Randomisation (random allocation of patients to respective groups) is used to obtain as similar as possible or almost identical baseline clinical and demographic characteristics of patients, which, with an appropriately large population, ensures balanced distribution of all po-tential, as well as unknown, confounding factors. There-fore, the randomisation procedure cannot be carried out on the basis of simple assumptions, such as a medical history number or date of birth, because it allows the pre-diction of which group a patient will be allocated (this is called pseudorandomisation). Randomisation methods providing full randomness, i.e. unpredictability, include those in which the lists of random numbers are created with use of a computer or special tables (such a method is called simple randomisation). In the case of a small target number of patients (sample size) in the study the probability of unbalanced number and distribution of patients’ characteristics in individual groups is higher; in this case more complex randomisation methods can be used. Examples of these include: block randomisa-tion (patients are assigned to individual interventions in blocks, or groups with a specific sequence of subsequent patients allocation), stratified randomisation (independ-ent stratification in any previously defined layer, such as country origin, gender, or type of previously used treatment, especially when differences in the effective-ness of assessed intervention between these subgroups are expected), or adaptive randomisation (in which the probability of allocation to a given group changes during the study, allowing the control of distribution of indi-vidual features in particular groups) [3]. In some studies

unequal distribution to the studied groups is used, e.g. in a 2:1 ratio, which may increase the amount of informa-tion about a new therapy, especially regarding safety as well as recruitment capacity (patients are more willing to participate in the study due to a greater chance of receiving experimental therapy), but it adversely affects the statistical power and requires a higher sample size compared to allocation with a 1:1 ratio [3].

Allocation concealment and blinding

With random assignment of patients to study arms the process of allocation concealment is very impor-tant, to prevent access to information about the group to which the patient was assigned — which is possible with use of central randomisation, performed regard-less of the individuals participating in the study. Ad-ditionally, allocation concealment allows elimination of influence of the researcher on patient assignment to particular groups, thereby reducing the risk of selec-tion bias. The second step that ensures greater cred-ibility is the introduction of blinding; therefore, the patient (single-blinded) or the patient and investigator (double-blinded) or patient, investigator, and team analysing the results (triple-blinded) are not aware of which intervention is received by each patient. It pro-vides higher credibility of the study due to elimination of some confounders — a terminally ill patient, who knows that he/she was assigned to a placebo group instead of an active intervention group, may present much worse results than a patient who is unaware of the study assignment [4, 5]. In the case of medicines blind-ing is ensured through their preparation in the same form (e.g. in visually identical vials), and for different routes of administration or collation of different treat-ment methods an additional important role is played by proper masking (dummy) of intervention, e.g. simulta-neous administration of two interventions that differ by administration routes, but in each study arm a dif-ferent intervention is replaced with a placebo. In some cases, e.g. different medical procedures it is difficult to ensure blinding or it is associated with high burden to the patients. It should be remembered that the lack of blinding significantly affects primarily the evaluation of the subjective endpoints, independently assessed by patients (PRO, patient-reported outcome; e.g. scoring of symptom severity, quality of life) or safety analysis, but does not disturb unambiguously objective endpoints, such as death (and hence survival outcomes) [3]. During endpoint evaluation with use of pathological or imag-ing examination, or standardised criteria (e.g. RECIST — Response Evaluation Criteria in Solid Tumours) the risk of systematic error is ambiguous. On the other side, in oncology studies, despite the blinding of imaging tests assessing a progression (response to treatment), they are centrally confirmed by an independent and

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Marcin Kaczor et al., Critical appraisal of clinical trials in oncology — part I

blinded committee. However, there is a risk, especially in placebo-controlled trial with crossover after disease pro-gression, that a lack of blinding will result in performing imaging examinations faster than planned, even upon mild symptoms. There are also clinical trials in which blinding of all researchers or patients is not required, but instead analysts evaluate the endpoints — these are referred to as PROBE (prospective, randomised, open, blinded-endpoint evaluation).

Evaluation of study quality

The simplest assessment of study credibility is pos-sible with the use of the Jadad five-point scale [6]. It assesses whether the study was described as randomised, whether double blinding was used, and provides infor-mation on how many patients discontinued the study and for what reasons. Additional points can be granted or deducted depending on whether randomisation and blinding were or were not performed correctly. However, this scale allows only for very general assessment of study quality and does not take into account other factors that could result in systematic error (bias). A more compre-hensive method is use of the Cochrane Collaboration recommendations [7], according to which the following aspects are assessed:

— selection bias — whether the correct method of randomisation and allocation concealment was used;

— blinding of patients and medical staff (perfor-mance bias);

— blinding of assessment of results (detection bias) — whether investigators were blinded or whether the authors of the publication justified that the lack of such blinding does not affect the assessment of a given endpoint; in the case of assessment of end-points with different susceptibility to bias resulting from the lack of blinding, it is necessary to carry out the evaluation for each of them separately;

— incompleteness of results and loss of patients from the study (attrition bias) — the low risk of this type of error is when the data lost does not interfere with the assessment of endpoints, investigators have applied the right method of imputation of missing data (e.g. LOCF [last observation carried forward], in which for patients lost from observation, the individual values of assessed endpoints recorded during the last control visit are imputed for each subsequent time point until the end of the study), and the percentage of patients excluded is not different between the groups; in practice, it is assumed that if more than 10% of patients have been lost from the study, the risk of systematic error resulting from data incom-pleteness is high, unless the frequency of individual causes of exclusion is similar and the percentage of patients lost to follow-up is small;

— selective presentation of results (reporting bias) — whether the study protocol is available, and the publication presents the results for all prede-fined endpoints;

— other factors (other bias) — whether no other po-tential sources of reduced reliability of presented results were found (such as incorrect study design or the allegation of dishonesty).It is worth noting that currently multicentre trials are

preferred with appropriate representation of different geographical regions [8], although they are associated with the risks of lowering the standardisation of the interventions used as well as the results [1].

Defining the studied population

The target study population should be described in details and defined based on inclusion criteria. They are analysed to conduct an external credibility assess-ment, e.g. determining the characteristics of patients for whom the conclusions of the study may be generalised. Too narrow and detailed inclusion criteria may limit the possibilities of recruiting patients to the study and the possibility of generalisation of conclusions, but too general inclusion criteria can cause dispersion of the as-sessed effect in subgroups with different characteristics, making it difficult to randomly distribute confounders and preventing subgroup analysis [3].

Defining the comparator

Another key element is the choice of a proper compa rator (control group), which determines the pos-sibility of further extrapolation of results on the target population and the study’s external reliability. The optimal and desirable comparator is the current clinical practice, consistent with widely accepted recommenda-tions and guidelines [9]. However, placebo is often used in the control group. This is justified when new therapy is an add-on treatment to the current standard (then placebo is used only for blinding, and it's the current prac-tice that is in fact the comparator) or when there is no other therapeutic option available in real-life conditions except symptomatic treatment, e.g. when the evaluated intervention is the very last treatment line. A compari-son with placebo is usually aimed at demonstrating the superiority of the new treatment. The choice of an active intervention as a comparator always brings additional challenges, also in the context of sample size, but use of placebo would be simply unethical. In the case of comparison with active treatment, testing of the non-in-feriority hypothesis may be considered [3]. The rationale for the selection of active intervention as a comparator should also be assessed in the context of changing clini-cal recommendations, especially in the case of clinical

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trials planned a few years before. In oncology, in view of diversified chemotherapy regimens and treatment methods, the investigator’s choice of therapy is often accepted as a comparator. In such a situation, it should be assessed which interventions were used in the com-parator group and how they were distributed, especially when symptomatic treatment is an option, and whether they reflect clinical practice and possible extrapolation of conclusions (external credibility).

Defining the endpoints

Endpoints (outcomes) should be accurately defined in the study protocol, with the specification of primary (for which sample size and statistical power are esti-mated) and additional/secondary endpoints. Evaluation of clinically relevant endpoints, such as overall survival (OS) and quality of life (general and aimed at evalua-tion of symptoms associated with a given type of cancer) is also desirable. The possibilities to assess the impact of interventions on overall survival will depend on the type of cancer and its clinical stage. This analysis will undoubtedly be difficult in the case of assessment of early stages of therapy with curative intent (e.g. neo- and adjuvant treatment), when the expected further survival could last for decades, and additional effects of subsequent treatment lines, implemented after later recurrences or progression, will have an impact on the observed differences in survival. In such cases, surrogate endpoints may include disease-free survival (DFS), event-free survival (EFS), relapse-free survival (RFS), e.g. the time since the date of inclusion to the study to the date of occurrence the first documented clinical event or death (whichever occurs earlier), for therapies used in the early stages of cancer, or progression-free survival (PFS), e.g. the time from the date of randomisation until the date of progression or death, in the advanced stages. Clinical events included in PFS/DFS definition are observed earlier than death, therefore the observa-tion period necessary to show a statistically significant difference between the interventions is usually shorter than for OS. Hence, the PFS assessment is preferred for example when high clinical needs exist (no other effec-tive treatment available), because the registration of the drug in a given indication can be obtained much faster (even by several years) than if it would be necessary to wait for OS outcome. In addition, the observed differ-ences in PFS are not affected by successive treatment lines and possible cross-over because further treatment is not usually introduced before disease progression. Progression-free survival is assessed in the majority of studies with the treatment of advanced cancer stages; nevertheless, it is considered as a surrogate endpoint. There are many publications assessing the correlation between PFS and OS regarding PFS usefulness as OS

predictor, although so far the conclusions presented by many authors are ambiguous [10]. There are other commonly used endpoints such as objective response rate (ORR) based on imaging tests for solid tumours or haematological remission for haematological malig-nancies together with the time of duration of response (DoR). As the alternative to PFS time to disease pro-gression (TTP) is sometimes used. It differs from PFS in that, that it comprises only events of progression, while observation of patients who died before its occurrence are censored at the time of death. Related endpoints, although much less frequently used in the assessment of palliative care effectiveness, include time to treatment failure (TTF) and time to next treatment (TTNT).

Considering the diversity of evaluated endpoints, the internal coherence of presented results should be highlighted, i.e. demonstrating a significant impact of the studied intervention on ORR, PFS, and then on OS. However, the following should always be remem-bered: the differentiation of studied populations in terms of type and stage of cancer, prognosis and time of expected survival, and even the type of intervention used, e.g. demonstration of the impact of immuno-therapy on OS, in the absence of effects on PFS due to pseudoprogression [11]. Regarding studies in oncology, particular attention should be paid to safety assessment, including undesirable or fatal adverse reactions, which in turn should include toxicity specific to the interven-tion. Finally, the benefit-risk ratio should be evaluated, taking into account the prognosis in a specific patient population [12, 13].

Information about planned statistical analysis

The scope and type of statistical analysis in a cor-rectly performed clinical trial should be predefined as part of a previously accepted protocol, together with predefined matching factors and subgroup analysis.

The initial estimation of sample size (statistical power of the study) is one of the key elements of the statistical analysis. It allows assessment of whether the sample is large enough to confirm or exclude differ-ences between interventions. The assessment of the sample size refers to the main (primary) endpoint (or endpoints). It requires the determination of the expected frequency of events in the control group, the magnitude of the intervention effect that the study is aimed to detect (an alternative hypothesis), the assumption of the ability to detect the real effect (statistical power of the study), and the selection of the statistical significance level. In oncological studies with a long observation period the expected discontinuation rate should also be taken into account. Because statistical power depends on the number of patients experiencing a given event during observation, in oncological studies it is often assumed

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that patients will be observed until the occurrence of an expected number of events (e.g. deaths or deaths and disease progressions in evaluation of OS or PFS) [3].

In the statistical analysis the researchers may adopt different analytical approaches — the hypothesis of superiority is tested most often, especially in the early stages of clinical trials and in placebo-controlled tri-als. The second approach is based on the assessment of whether the intervention is not inferior in terms of clini-cal efficacy to currently used methods (non-inferiority), especially with a better safety profile. In this case, there is a need to establish a clinically acceptable variability of effectiveness in terms of primary endpoint, and if the appropriate confidence interval (CI) for the difference between interventions does not exceed the set level, the intervention is considered to be no worse than the control. The use of the non-inferiority approach reduces the required sample size [14, 15]. There are also studies assessing the equivalence of interventions, where accept-able variability is assumed in both directions, but they are rarely used to assess clinical endpoints — laboratory parameters or pharmacokinetics are used instead. The population included in the analysis is also important — it may vary depending on the assessed endpoint. The ITT (intention-to-treat) population is included in the analysis of the results of all randomised patients, regardless of whether they received an assigned inter-vention and regardless of how long they remained in the observation (this usually applies to the assessment of OS or PFS). Sometimes a modified ITT (mITT) population is defined, i.e. randomised patients who have received at least one dose of the study drug — a safety analysis is usually performed in this population. Population PP (per-protocol) refers to patients who additionally did not discontinue the treatment, did not violate the protocol, and for whom a complete set of information is avail-able — it is often used to compare the effectiveness of interventions in non-inferiority trials [14]. ITT analysis is more conservative because it tends to underestimate the beneficial clinical effect, whereas PP analysis allows a comparison of therapeutic options in conditions of a complete observation. If the results obtained in ITT and PP analysis clearly differ, this may indicate reduced reliability of the study. The evaluation of objective response rate is often carried out in the population of patients for whom additional imaging results are avail-able, i.e. there is a possibility to assess the progression.

Evaluation of results

The analysis of results of a clinical study begins with a detailed assessment of the description of the popula-tion included and tables with baseline chara cteristics, which should include basic demographic data, disease

severity, previous treatment, and other factors that may affect the effectiveness of the assessed therapy — their scope and type depend on the type of cancer and should also be adapted to disease severity. The analysis of these parameters can be used to assess the correctness of ran-domisation and eliminate the influence of confounders (analysis of such a table can refer only to those known factors, but at the same time it could be assumed that random assignment to groups with appropriate sample sizes also ensures equal distribution of other, unknown prognostic factors). It is necessary to distinguish sub-groups defined for randomisation with stratification and subgroups, within which predefined analysis or possible unplanned post-hoc analysis will be performed. This information is also helpful in determining the external validity of study results. It allows also the assessment of whether the analysed population is close to the one in which the evaluated intervention is to be applied [8].

Study outcomes in the form of categorical (nominal) variables are usually presented as numbers and percent-ages, while continuous variables are usually presented by means of a measure of central tendency and dispersion — usually mean and standard deviation (SD) values, and in the case of variables that present the normal distribution, median and range, possibly interquartile range (IQR), are used (see below). In addition, some continuous variables can be transformed into ordinal variables (e.g. the percentage of patients above a given age). Referring to the previously mentioned assessment of the accuracy of randomisation, it should be checked that there are no significant differences in baseline characteristics between the groups — the authors should provide P-values in the table or declare no significant differences in the publication text [8].

The study should also include detailed informa-tion (usually on the appropriate diagram) on patient flow from the screening period (i.e. from consent to participation in the study to inclusion) until a possible additional follow-up period. As was already mentioned, this is an important element of assessment of study reli-ability — the size of the loss of patients from observation should be assessed, as well as how it can affect reliable analysis of results, and the occurrence of differences between groups.

The next step involves quantifying the differences between interventions, exposing the uncertainty of these estimates by means of confidence intervals, and evaluating the strength of evidence, i.e. confirming by means of P-value (statistical significance test) that the observed difference is true and not by chance [8, 16–18].

Because, for obvious reasons, it is not possible to test all patients in the considered clinical conditions, a sam-ple should be selected (a group included into the clini-cal trial), and, based on observed effects, conclusions should be drawn with some approximation about the

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real overall effectiveness of treatment. In the language of statistics, it is said that, based on the selected meas-ure of the effect determined in a random sample from this population, a parameter in the general population could be estimated, which in this approach comprises all possible results of the experiment.

At the beginning a research hypothesis should be precisely formulated and then tested with statistical methods for its acceptance or rejection. By default, it is assumed that evaluated interventions influence the health effect in a similar way (so-called null hypothe sis), and the observed differences are a result of random variation derived from the limitations of the experiment (e.g. the group of patients being too small). An alternative hypothesis is that the observed differences are true and not just a random observa-tion. The role of statistics is to indicate which of these hypotheses is more likely.

But how will we know that the groups do not differ from each other? It could be intuitively said that the lack of differences between these groups will be surely confirmed by the same percentage of patients with a re-sponse in the intervention group as in the control group. However, if there are any differences, the probability is estimated — designated as a P-value — to obtain a dif-ference in treatment at least as high as that observed (in both directions, i.e. in favour or not of the intervention being analysed) in a situation in which a null hypothesis were real. If the probability of the lack of differences between groups is below the statistical significance threshold of 5% adopted in the biomedical sciences (P < 0.05), it is assumed that these differences exist and are not the result of chance, so the null hypothesis is rejected with conclusions of significant differences between the groups. In other words, this means that the probability of obtaining at least such a difference as demonstrated is less than 0.05. Thus, the lower the P-value for a given estimate, the stronger the evidence against the hypothesis of the lack of differences and the greater the conviction about the effectiveness of the intervention. Obviously, the statistical significance of the result indicates only that the observed reliance is more likely than would result from a simple random case, but it does not mean that the observed effect is real. Critical appraisal should also take into account internal reliability and the influence of confounders related to study methodology and conduction (including randomisation, blinding, and loss of patients). In addi-tion, it is important to distinguish the difference between statistical and clinical significance and to further assess the magnitude of the observed effect in the context of prognosis in a specific population.

The uncertainty of estimates can be assessed by analysing the 95% confidence interval (CI), assuming there is a 2.5% probability that the real effect is below

and a 2.5% probability that it is above this range (such a confidence interval results from the assumption of P-value < 0.05). The accuracy of the estimation increases with the sample size: the larger the study, the more accurate the estimate and the narrower the confidence interval for the assessed parameter. With many repeated tests for effect measurement CI can be calculated in each of these tests, and 95% of them should contain a true value. The designated CI may also be used to assess the statistical significance of the result if the entire interval indicates a coherent effect, i.e. it does not contain a value indicating no differences (0 in the case of difference in continuous variables or probabilities and 1 when considering the hazard or pro-bability ratio in both groups). The intervals that exclude these values indicate significant differences between compared groups.

Usually, a statistical evaluation will assess the three types of variables in clinical studies: dichotomous (bina-ry) (e.g. response to treatment/no response), continuous (e.g. average body weight), and time-to-event variables used in survival analysis (e.g. OS).

Evaluation of dichotomous variables

One of the most common types of variables is the number of patients in whom the assessed event occurred or not. Usually it is expressed in the form of numbers and percentages. It should always be remembered that this is the number of cases with the first event being assessed, which is not a problem if they are unique (e.g. death) or rare. However, if they can be repeated many times, such as febrile neutropaenia, assessment of the overall number of events can be more informative, preferably calculated per observation period (incidence rate per patient-year). The number of events can therefore be analysed as a continuous or dichotomous variable.

Let us assume that patients in the study were randomly assigned to two groups of 100 patients, one receiving the active drug and the other placebo. After a year of observation, a clinical response was observed in 80 patients in the group with active treatment (80%) and only 40 (40%) patients in the control group. The authors of this illustrative publication presented four parameters, reflecting the differences between both groups in the frequency of response rate (it should be remembered that the event probability is 0.8 in the in-tervention group and 0.4 in the control group):

— RB = 2.00 (95% CI: 1.54–2.59); P < 0.0001; — OR = 6.00 (95% CI: 3.19–11.29); P < 0.0001; — RD = 0.40 (95% CI: 0.28–0.52); P < 0.0001; — NNT = 3 (95% CI: 2–4).The question is how many times the probability (risk)

of a given event is higher in the intervention group com-pared to the control group; the answer is then a relative

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parameter that in the case of a negative event is called relative risk (RR), while in case of a positive event it is called relative benefit (RB). If the frequencies of events (probabilities of their occurrence) are the same in both groups, their ratio will be 1 — this is therefore a neutral value, indicating lack of differences between interventions. Values greater than 1 indicate an increase in the probability in the intervention group, while less than 1 — the probability being lower. In the presented example the RB value is 2, so the probability of response is two times higher after using the study drug than with the placebo. It is also shown that the confidence interval constructed for this value ranges from 1.54 to 2.59 and does not contain the value 1, so it could be concluded that the differences are statistically significant, which is also confirmed by the quoted P-value (< 0.0001).

Instead of probability, the so-called chance of occur-rence of a given event in each group can be calculated. Odds are defined as the ratio of the number of patients in whom the event was observed to the number of pa-tients without such an event and hence determines how many times an event could be more frequently observed than could not. In the presented example, 80 patients responded in the intervention group and 20 did not, so the odds is 80/20 = 4 (it could be said that the chance of a response in this group is like 4 to 1). On the other side, in the control group, the chance of obtaining a response was much lower and amounted to 40/60 = 0.67. Then, by analogy with the relative benefit, the ratio of these odds values in the analysed groups could be calculated. Such a parameter is called the odds ratio (OR), and in the presented case it was shown that the chance of get-ting a response was six times higher in the intervention group than in the control group, which was statistically significant, as shown by the P-value and confidence interval not containing a neutral value of 1. Although the RR/RB values are more intuitive in interpreta-tion, the publications often present calculation results in the form of ORs, which are a natural result of the statistical methods commonly used in the assessment of dichotomic endpoints (logistic regression, often also taking into account adjusting factors). It is worth noting that in the case of very high frequencies of any event in both compared arms, the OR calculation may have an advantage over RR, which in such situations will be close to 1 and will not accurately illustrate the actual difference between the groups.

In addition to the relative parameters presented above, absolute parameters can also be estimated, which are considered more informative, because they addition-ally show the real frequency of events — whether they are extremely rare or occur in a significant percentage of the population. Risk difference (RD) or absolute risk reduction (ARR) — in the presented case it could be called absolute benefit increase (ABI) — is a simple

difference between probabilities in particular groups. In the presented example this difference is 0.40, and it could be concluded that the probability increases by 40 percentage points in the intervention group in rela-tion to the control group. In practice, this means that for every 100 patients receiving intervention a response to treatment will be recorded in an additional 40 patients compared to the control treatment. In the presented example a confidence interval constructed for the calculated risk difference and P-value is also provided. Hence, the range (0.28–0.52) does not contain the value 0, so it could be assumed that the observed differences between groups are statistically significant.

This relationship can be also reversed, and the ques-tion could be asked, for how many treated patients one more event will occur. Such a parameter is called the number needed to treat (NNT) in respect of beneficial effect of treatment, and number needed to harm (NNH) when the event is unfavourable. The ratio shows that this number will be 1/0.40 (NNT = 1/RD), i.e. 2.5; because it refers to a number of patients, the result should be rounded up to the total number, so it shows that pro-viding three patients with an intervention instead of control for a given time (year), one additional response could be expected [16–18]. Interpreting the results for dichotomous variables, in particular the values of ab-solute parameters, the observation period for a given endpoint should be taken into account. For example, NNT obtained in studies of different duration may not be directly comparable because the NNT value may vary with the observation period.

Evaluation of continuous variables

In clinical trials, the parameters determining the severity of disease symptoms, laboratory tests, or quality of life on a certain scale are often assessed. In each of these situations, the obtained results have a continu-ous nature, i.e. they take any value expressed in a real number from a given range. For example, patients may be asked to indicate their well-being on a scale from 0 to 100, from the worst to the best. We also have continu-ous results when measuring body mass, height, blood pressure, average white blood cell count, haemoglobin concentration, etc.

Such results for the studied groups of patients are usually summarised by presenting the central measure — mean or median value — as a reminder, the mean (arithmetic) is the sum of the results obtained for each patient in the group divided by the number of patients in this group, while the median is the middle value that divides a group of patients into half (i.e. half of the patients have a score below the median value and the other half, above). The set of results of a given effect expressed in a continuous variable is also characterised

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by a certain variability that can be represented graphi-cally as a spread of observed values around the mean. The parameter indicating the magnitude of this variation is the standard deviation (SD) — lower values indicate a small spread of results around the mean, while higher values indicate a large variability and large differences between the results and the mean value.

As in the case of event frequency analysis, also in the analysis of continuous data, the overall effect is assessed based on a sample from the general popula-tion. Because such sampling results in different mean values distributed around the mean value in this general population, an additional measure of this distribution can be introduced, precisely defining the distribution of the mean values from samples around the mean value in the general population; this parameter is called the standard error (SE) and is equal to the standard de-viation in the sample divided by the square root of the sample size. Standard error decreases with increased sample size, and the lower its value, the better the ap-proximation of the true value in the general population by the given sample.

If the study results are presented in the form of medi-ans, the range in which the observed results are found is also usually given. As already mentioned, the “median” is a median value, i.e. which divides a series of data into two equal parts. However, we can determine several such “aliquots” of the data set, depending on the adopted criteria — in general they are called quantiles, and the median is a special case of such a quantile. The set can be also divided into four parts — then the “aliquots” are called quartiles (it is worth noting that the median is also the second quartile of the set), and in the case of dividing the set into 100 equal parts — percentiles (the median is the 50th percentile of the set). Sometimes the authors present median values along with the so-called interquartile range (IQR), i.e. the distance between the first and third quartiles.

The reasoning when assessing the statistical sig-nificance of differences between groups for continuous variables is analogous to that carried out when describ-ing the difference in the frequency of events in two groups — in general, average values of a given param-eter should be determined in the analysed groups, and then their difference and the confidence intervals or P-value should be calculated. In case of variables with a normal distribution (also after the appropriate data transformation), Student’s t- or ANOVA test is usually used to assess the differences, and in other cases, one of the non-parametric tests is used, e.g. U Mann-Whitney. Because in patients with higher values of a given param-eter major changes can be expected during the test, an analysis of covariance (ANCOVA) is also used, which compares the mean values adjusted with the baseline values. As in the case of the risk difference described

earlier, statistical significance can be assessed based on confidence intervals, where “0” is a value indicating no differences between groups.

The parameter most often presented in the study is the mean difference (MD) between the analysed groups. Assessment of the results should be carried out carefully because the authors of the study can present them in several ways. For example, when assessing the quality of life, the average score can be determined at the end of the observation period in both groups, and then the difference in mean values between them can be calculated (it is important always to make sure that no significant differences in the measurements were initially observed). It is also possible to assess the mean score change during treatment with respect to the baseline and to calculate the mean differences for such changes — this approach is used more often because it allows assessment of the effect of treatment with matching in regard to an already existing effect.

In clinical trials the least square mean (LSM) is also commonly used; this is simply an average adjusted for additional factors. For example, in a given group of people the average age can be calculated by summing the years of life of each person and dividing this amount by the number of persons in the sample; a simple mean value is then obtained. However, if there are many older women in this group, it could lead to overestimation of the average — in this case, the average age can be calculated first among women, then among men, and only averaging the age value for both groups the aver-age value in the whole cohort could be obtained, with matching for gender [16–18].

Evaluation of “time-to-event” variables — survival analysis

Analysis of time-to-event data (e.g. death from any cause in OS analysis, death or tumour progression in PFS analysis) is associated with several problems. In general, the survival analysis is performed because during a sufficiently long period of observation the clinical events (progression/death) will occur in all or almost all patients. In this case, estimation of a sim-ple parameter like RR will be useless (probabilities of events will be close to 100% in both groups). Ad-ditionally, in the long-term observation, apart from the cases marked as “with an event” or “without an event”, there will also be patients who will be lost to follow-up during the study, whose state will remain unknown, or at statistical analysis they are still in observation but their future status is hard to predict. Finally, taking into account the different recruitment periods and the dates of inclusion of patients in the study, the observation will include patients with dif-ferent periods of study [18–22].

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The solution to these limitations is the survival analysis, considering not only the occurrence of an event, but also the time to its occurrence, and ena-bling the cutting-off (censoring) of patients lost to follow-up or with unknown further fate at the time of data analysis. It should be noted that the term “survival analysis” is not reserved exclusively for the assessment of overall survival (i.e. time to death) but applies also to all time-to-event endpoints (e.g. time to response, progression-free survival).

The simplest form of survival analysis is plotting of the Kaplan-Meier curves, based on which the probabilities of survival to a given time point and the median survival could be assessed. Then, by means of an appropriate statistical test (usually a log-rank test), a comparative assessment of time differences to the occurrence of an event between groups takes place. More advanced analysis, allowing us to take into ac-count the matching factors (independent explanatory) affecting the survival time, is carried out using regres-sion models, most often the Cox proportional hazard model (it should be remembered that Kaplan-Meier curves, as well as median time-to-event are still not adjusted in this situation). In general, the analysis of the magnitude and direction of differences in survival is based on the assessment of hazard ratio (HR), median survival time (until an event), and survival probability at a specific time point (e.g. 12-month survival). The HR value summarises the relative differences in survival between groups over the entire observation period. The assessment of differences in survival, consisting only of a simple comparison of median survival time in groups, is not sufficient to depict differences in the horizon of the entire study and can be quite misleading, especially in the case of lack of hazard proportionality (this issue is discussed later in this article).

The Kaplan-Meier curve is drawn based on the results of the study for individual patients, e.g. whether and when death occurred. However, it should be remem-bered that some patients “fall out” from the study for other reasons, and information about how long they live is lost. So, at the time of statistical analysis, it includes patients who live, patients who have died, and those who left the study some time ago and it is not known whether they are still alive, which is called censored observation.

The risk (hazard) determines the probability of an event occurring at a given time, assuming that the event has not occurred so far. The ratio of the hazard values estimated for the intervention and control group at a given time is called the hazard ratio (HR). Conceptu-ally, in a simplified interpretation the HR is close to the RR, but it should be remembered that the HR includes data from the entire period of observation for survival in the study and censored cases, while the RR is car-ried out at a predefined time point (e.g. deaths after

12 months of treatment). Interpreting the HR value presented in the study, it is assumed that this ratio is approximately constant at any time point during the observation (assuming proportionality of hazards), i.e. if, for example, the HR value is 0.61, it is assumed that for patients in the intervention group the risk of death is approximately 39% lower than in the control group at each time point during the follow-up. This relationship can also be presented as the average prolongation of survival time by 64% (1/0.61 = 1.64) in the interven-tion group compared to control [18–22]. It should be noted that HR values cannot easily be translated into absolute differences in survival time — for example, in a population with low mortality, a 30% reduction of the risk of death (i.e. HR = 0.70) may be accompanied by an increase in the average survival time of 12 months, while the same relative reduction in death risk (HR = 0.70) in a high-mortality population may be associated with a much lower absolute effect (e.g. three months).

The simplest way to confirm the assumption about the proportionality of hazards is visual analysis of the course of Kaplan-Meier curves, assessing whether the difference between them is approximately constant and persists over time. Small deviations (decrease or increase in time differences in the course of curves) are acceptable (Fig. 1). With sufficiently long observation, especially in the final lines of treatment of advanced can-cers, when events occur in all patients (with very mature data, when only a few patients remain in observation), after the initial period of maintaining differences in the course of curves their convergence can be observed (Fig. 2A). The opposite situation may occur in a population with low risk of death and expected long-term survival, when the curves can reach a flat course (plateau) due to very few deaths (Fig. 2D). Sometimes, at the very beginning of the observation, the curves intersect, which may happen because in the intervention group in the initial period the risk of complications may increase (especially if there is a significant difference between the observed procedures — e.g. surgery with chemotherapy vs. conservative treatment and chemotherapy), and the expected clinical benefit is only observed in the further period when the curves separate (Fig. 2B). In general, if the variability of the course of curves during the obser-vation relates to the magnitude of the effect, but not its direction, it could be considered that the deviation from the assumption of hazard proportionality is insignificant, and the presented interpretation of HR could remain. However, if there is a significant change in the direction of action (Fig. 2C), the calculated HR value cannot be interpreted because it changes significantly over time. One solution is an attempt to perform subgroup analysis in order to detect the cause of differences in effective-ness over time, with some objections related to such an analysis (see below) [18–22].

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Figure 1. The Kaplan-Meier chart is located on the plane bordered by the Y-axis describing the probability of overall survival and the X-axis, on which the time from the beginning of treatment (observation) in the study is presented. While constructing the Kaplan-Meier curve, the subsequent time intervals take into account the number of patients with the possibility of measurement at the beginning of the interval (at-risk), the number of patients with the event, and the number of patients lost to observation. The graph shows the cumulative probability at a given time. At the start of observation ( ) all patients are alive (OS = 100%). In fact, this is not the same moment in time (date of randomisation) for each of the participants, because they enter the study in different centres at different times. Then a decrease in the likelihood of overall survival in both arms over time is observed; however, it is always higher in group A (despite some variability in the size of differences between groups, the direction of the effect is consistent and it could be concluded that the deviation from the assumption of proportionality is slight — see text). Below the graph the number of patients in the observation at regular intervals should be given (at-risk) at the beginning of the given time interval ( ). If at the end of the graph they are small (< 10% of the baseline value), the inference from the curves is limited in this section. Looking at the Kaplan-Meier graph, values from both curves can be compared horizontally, looking for a difference in time when the cumulative probability of survival reaches 50% — ( ) and ( ), and they provide median survival values for groups A and B, respectively (median OS in the A group, median OS in the B group), and the median difference is 8.7 months. Differences in survival can also be assessed vertically, comparing the survival values at a given time point. In our example, the two-year survival rate (rate of overall survival at 24 months) is 79.7% in the intervention group and 69.5% in the control group ( ). This is the cumulative probability for this period; often its value is given with the confidence interval (which allows us to assess the accuracy of the estimation), and in the text a statistical evaluation of the result will usually find (P-value for differences in cumulative survival at this time point). Concluding the differences in survival throughout the observation period gives the relative hazard ratio ( ); it can be seen that at a given time point the risk of an event (death) is lower in the group with intervention, and the result is statistically significant (looking at both the confidence interval and the given P-value)

It should be remembered that HR is a relative value that allows the assessment of the statistical significance of observed differences in survival, but, as mentioned, when making a therapeutic decision it is also necessary to assess the clinical relevance, also in relation to prog-nosis in a given population. The absolute impact of the intervention compared to the control can be assessed by analysing the differences in the medians or by comparing the probability of survival at a given time (e.g. an annual or two-year survival).

During the RCT, especially with a long period of observation, preliminary (interim) analyses carried out by independent researchers in an unblinded but confidential manner are necessary. An independent, committee with no affiliation to the study may decide to prematurely terminate the study, e.g. due to safety con-cerns or the spectacular effect of the new intervention (in this situation the decision to stop should be assessed carefully, because the clear effect is often overestimated in the short period of observation and the differences

No. at Risk:

A 298 280 267 248 231 215 199 186 170 146 129 114 96 81 68 52 32 16

B 301 275 257 233 218 205 192 172 152 133 118 97 82 65 47 17 8 5

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Median OS in the A group

Hazard ratio (HR)

Median OS in the B group

34,7 mo (95% CI: 32.3; 37.2)

43.4 mo (95% CI: 40.8; 45.9)

B: 69.5% (95% CI: 63.8%; 75.2%)

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Figure 2 B. Early intersection of the Kaplan-Meier curves. In the initial period of observation, the curves intersect, and for a short period the survival is lower in the group with intervention compared to the control — e.g. when the intervention is associated with higher risk of complications ( ), but then there are clear differences in survival in further observation ( ). In this situation, it is also a permissible deviation from the assumption about the proportionality of hazards

Figure 2 A. Kaplan-Meier curves converging at the end of the observation period. From the very beginning of the observation, there are differences in survival ( ). The curves clearly “separate”, but at the end of the observation period ( ) the cumulative probability of death is practically the same in both arms of the study. Such a situation may occur, for example, at the terminal stages of cancer, where ultimately, regardless of the treatment used, an event (death) will occur in almost all patients. This is a permissible deviation from the assumption about the proportionality of hazards. Convergence of curves in the final observation period may also be caused by a high percentage of censored observations (i.e. a small number of at-risk patients), as a consequence of which the Kaplan-Meier estimation in the “tail” of the curve is impaired

between interventions become less visible in the longer period of observation) [14]. In statistical protocols of oncology studies further interim analyses are also prede-fined (when the statistical power calculation depends on the occurrence of a given number of events). Because of repeatedly testing the hypothesis, the risk of accidentally observed “statistically significant” results increases (the greater, the more pre-planned interim analyses, e.g. ac-cording to the O’Brien-Fleming criteria); it is worth noting that significant results will not refer to P-values of < 0.05, but assume a much lower threshold, e.g. < 0.001.

Finding significant OS differences between interven-tions according to the assumed statistical power may enable patients after disease progression to move from a control to an intervention group (cross-over, treat-ment switching), which acts in a conservative direction, overestimating the effectiveness of control intervention and reducing the estimated effect of the study drug. Obviously, this only matters for OS assessment, and PFS assessment itself is unaffected. In this case, it is possible to use appropriate methods of correction of the cross-over impact on OS, the simplest of which is

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Figure 2 D. Kaplan-Meier curves for an observation period that was too short. Mortality persists at a relatively low level, and it is difficult to conclude about the fate of patients and differences between groups (assessment in the early stages of cancer, with expected long-term follow-up). Despite the initial differences with a longer observation period, when more observed events accumulate, the course of these curves may approach any of the previously described situations

Figure 2 C. Kaplan-Meier curves intersecting in the later period of observation. The initial advantage of intervention ( ) disappears unexpectedly during the observation ( ), and the survival remains higher in the comparator arm until the end of the observation period. In this case, the proportionality of hazards criterion is not met, and no differences can be indicated between the groups. Probably there was an unknown confounder in the study that reversed the inference, and a detailed subgroups analysis is needed to identify it

the censoring of observations in patients changing the treatment [24, 25].

Adjusted results and subgroup analysis

Analysis of results with adjustment to baseline characteristics within logistic regression (when OR values are presented as adjusted or multivariate) or Cox proportional hazard model (in the case of survival analysis) can be presented as primary or sensitivity analysis. It is worth noting that the adjustment should primarily include prognostic factors and — unless it usually affects the accuracy of the estimate — can

modify the central measure of the estimate. However, taking into account the characteristics not related to the prognosis, although even including stratification factors (e.g. geographical location), does not significantly affect the results. Post-hoc selection of matching factors (not defined in the statistical plan) may raise the suspicion of purposeful data selection to achieve the desired ef-fect; in this case it should always be expected to display adjusted and not adjusted results [23].

Subgroup analysis should also be predefined in the statistical plan. Considering the diversity of the general study population, it allows the assessment of whether the general results refer to all patients or whether there

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are differences in the effectiveness of the interven-tion. If it is the case, it should be remembered that reliable evaluation of statistical differences leads to loss of statistical power. On the other hand, multiple defined subgroups and repeated testing increase the risk of completely random occurrence of statistically significant results. Above all, statistical significance or lack thereof in one of the subgroups is not sufficient to conclude real differences in the effectiveness of intervention. Usually a coherent effect is observed in individual subgroups, although with some variability of the central measure, and in smaller groups the confi-dence intervals become wider and, in some cases, may exceed the value of 1 (loss of statistical significance). In this situation attention should be paid to the sig-nificance of the interaction test (statistical analysis of whether the impact of interventions on an observed result depends on other factors) to assess whether there is a difference in the effectiveness of the intervention in a given subgroup (remembering, however, the pos-sibility of obtaining false results in repeated testing). Subgroup analysis may also be helpful in seeking a nar-rowing target population with no significant result in the general cohort. However, it should be remembered that subgroup analysis is more exploratory and serves to create further hypotheses rather than make final conclusions [23].

Summary

Translating the results of clinical trials into clinical daily practice is the established method of EBM. For this purpose, however, many elements should be assessed, which together provide evidence of the reliability of the study and significance of its results (Fig. 3). It is not easy, especially since most of the publications are written in English, and the authors often assume in advance that the recipient is fluent in terms of statistics and detailed explanations are unnecessary. In addition to assessment of the methodology and the reliability of the clinical study, it must be ensured that the population being evaluated is representative, i.e. it has characteristics similar to those for which a therapeutic decision is to be made, and if there are discrepancies (e.g. different age of patients or presence of comorbidities), what is their meaning. Then, if the comparator in the study is not widely used or not available but has a similar mechanism of action to the current treatment stand-ard, it should be assessed whether there is evidence of similar effectiveness, which would allow transferral of the inference from the study to clinical practice in this aspect. The sample size of the study is significant — if it was small and it was not due to the low prevalence of the disease, then it should be assessed whether the study had statistical power to indicate the differences.

Methodology Primary results Additional analysis Others

• Baseline characteristics

• Allocation, intervention, con-trol

• Comparator and local clinical practice

• Research hypothesis

• Randomization method, blind, open label, unmasked

• Drop-out, discontinuation

• Internal credibility

• Statistical significance, hazard ratio for progression-free sur-vival, overall survival — P-value and confidence interval

• Course of Kaplan-Meier curves

• Median OS and PFS

• Other end points

— convergence of inference with primary endpoints

— internal consistency (time to treatment discontinu-ation, objective response, complete response)

• Quality of life, safety, adverse event

• Intention-to-treat, per protocol analysis

• Subgroup analysis

— convergence of inference

with the ITT population

• Statistical significance in sub-populations (interaction test)

• Interim analysis, cross-over

• Subsequent treatment

• The authors’ conclusions — unambiguous or conservative

• Consistency of results with other tests (external coherence)

• The possibility of transferring conclusions to clinical practice (external credibility)

Figure 3. Aspects to which attention should be paid, making a critical evaluation of the methodology and results of a clinical trial in oncology

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It is also necessary to pay attention to possible differenc-es in baseline characteristics between groups — if they were significant, they may indicate a selection bias. An incorrect randomisation method can cause imbalanced distribution of confounders. In the absence of blinding, the assessment of differences in subjective endpoints is subject to the limitations. In the case of significant dif-ferences in the lost patient rate, it is important to know whether this could be related to the treatment applied. It is also worth checking the type of the research hypo-thesis tested. In oncology the primary endpoint will be the survival analysis — PFS and OS. If consistent, statis-tically significant, and clinically relevant differences are observed in favour of the intervention, there are strong premises about the superiority of the evaluated therapy. If, however, the significance of the results was observed only for PFS, it should be decided whether a further (final) assessment of the OS is planned, in which, with more matured data, the result could reach statistical significance. For some cancers, especially when assessing their early stages, it may be difficult to show differences in survival due to the expected follow-up, sometimes even decades. Such a long observation is an additional challenge, because during this time patients may be subjected, for example, to many different lines of further treatment, and the evaluation of ultimate survival dif-ferences is limited (in this situation, such endpoints as DFS or pathological response are of higher importance). It is important whether the possibility of changing the treatment after the progression (cross-over) was al-lowed, which could lead to OS overestimation in the control group. When HR for both OS and PFS didn't reach the significance level, the question should be asked whether this is not due to the lack of study statistical power, immaturity of published results (interim analy-sis), or high lost-patient rate. If none of these factors is relevant, there are probably no differences between the interventions. Assessing the consistency of results with other publications for a similar population may be very helpful. If PFS/OS medians differ from similar studies, the characteristics of the population should be carefully analysed. A valuable source of information is also subgroup analysis. Sometimes the result for the subpopulation becomes statistically significant, despite the lack of significance in the total population — this may be a premise of higher treatment effectiveness only in a specific subgroup, but on the other hand, one should bear in mind the exploratory nature of such analysis. If a similar trend in the results is observed depending on the presence or absence of a given criterion, but one of the subgroups lacks relevance, it is worth checking whether the size of this subgroup is not too small, as well as checking the result of the interaction test. If any therapeutic options are available in the analysed indica-tion, the safety issues of the therapy being evaluated are

extremely important. In oncology, treatment with higher efficacy is often associated with increased toxicity; this situation may be acceptable with clear clinical profit, such as prolonged survival.

In conclusion, the evaluation of a clinical trial con-sists of many elements discussed briefly in this paper. The authors hope, however, that they have addressed the most important aspects of the evaluation of clinical trial results and the terminology used, and that the article managed to show the complexity of the interpretation process. In the second part of the work, examples of clinical trials will be presented along with an assessment of their credibility and impact on clinical practice.

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REVIEW ARTICLE


Dr hab. n. med. Ewa Sierko

Klinika Onkologii

Uniwersytet Medyczny w Białymstoku

ul. Ogrodowa 12, 15–027 Białystok

Phone: +48 85 66 46 827


Monika Konopka-Filippow1, 2, Ewa Sierko1, 2, Marek Z. Wojtukiewicz1

1Oncology Clinic, Medical University of Bialystok, Poland2Department of Radiotherapy, Białystok Centre of Oncology, Poland

Benefits and difficulties during brain radiotherapy planning with hippocampus sparing

ABSTRACTRadiotherapy (RT) is frequently used in the treatment of primary and secondary brain tumours, as well as in

prophylactic cranial irradiation (PCI). The hippocampus plays a key function in the process of remembering,

relaying information from short-term to long-term memory as consolidation, and spatial orientation. Sparing the

hippocampus during brain radiotherapy aims to prevent hippocampal-dependent cognitive function deterioration.

This procedure requires a good knowledge of the brain’s radiological anatomy and use of modern radiotherapy

techniques.

This article presents the validity of hippocampus sparing during brain radiotherapy, the potential benefits of using

this procedure, available clinical premises regarding patient qualification, and technical difficulties in the brain’s

RT planning with hippocampus avoidance.

Key words: hippocampus sparing, brain radiotherapy, cognitive function

Oncol Clin Pract 2019; 15, 2: 104–110


2019, Vol. 15, No. 2, 104–110

DOI: 10.5603/OCP.2019.0019



ISSN 2450–1654

Hippocampus

The hippocampus was first described by Arantius in 1587 as a grey matter brain zone resembling a creature from Greek mythology drawing the chariot of the god of the sea, Poseidon. It consists of the head with the appear-ance of a horse’s head and a curved body like a sea wave. Hence the name of this organ is derived from hippo (horse) and campi (turn) [1]. It is difficult to depict the shape of the hippocampus in a two-dimensional plane due to its long, curved body (Fig. 1A, 1B).

Anatomically, the hippocampus is an even organ located in telencephalon region, in the temporal lobes of the cerebral cortex of the right and left hemispheres of the brain. Within the hippocampus, in the vicinity of the dentate gyrus, there is a cluster of neural stem cells (NSCs) grouped in two niches: the subventricular zone (SVZ) and the subgranular zone (SGZ) [2, 3] (Fig. 2). These NSCs are responsible for the key functions of this structure. It is worth noting that they are very sensitive to

damaging factors such as ischaemia, stress, and ionising radiation [4]. An analysis of brain magnetic resonance imaging (MRI) of 58 patients with nasopharyngeal car-cinoma performed three and six months after completed brain RT revealed atrophy of the hippocampal area [5]. Depopulation of NSCs by apoptosis, which occurs after the activation of the damaging factor, appears already after 12 hours and leads to the manifestation of deficits in cognitive functions for which the hippocampus cor-responds, and in particular to disorders in memorising and reproduction of information from working memory [6–8]. It was shown that irradiation of the hippocampus area with doses close to 30 Gy and higher, given in conventional fractionation, causes a decrease in NSCs proliferation by 93–96% after 48 hours [7]. Deficits in cognitive functions appear about two months after the activation of the damaging factor, and the peak of inten-sity falls around the fourth month [9–12]. Importantly, the consequences of NSC apoptosis are irreversible and usually progressive over time.


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Monika Konopka-Filippow et al., Benefits and difficulties during brain radiotherapy planning with hippocampus sparing

A B

Hippocampi, dentate gyrus

Figure 2. Localisation of neural stem cell (NSC) compartment in the region of dentate gyrus of hippocampi (author: M. Filippow)

Figure 1. The anatomical shape of the hippocampi (A) and a sketch of the creation from Greek mythology (B) (author: M. Filippow)

The rationale of hippocampus contouring during brain CT planning

The majority of patients with malignant neoplasms within the brain manifest cognitive dysfunction even be-fore the implementation of any causative treatment. They may result from the presence of malignant disease within the brain, its progression, the use of supportive treatment (e.g. opioids, steroids), comorbidities, or advanced age [13, 14]. Sudden/acute deterioration of cognitive functions may appear just after the brain’s RT due to the presence of brain metastases accompanied by extensive oedema zones around changes [15]. In turn, it was demonstrated that patients with small-cell lung cancer (SCLC) without metastases in the brain may show deterioration of cogni-

tive functions based on a previously unknown mechanism, presumably as a paraneoplastic effect [16]. The progress in oncological treatment is reflected both in the quality of therapy and in its effectiveness, which translates into longer survival time. Recently, attention has been paid to the patient’s quality of life after the use of anti-cancer treat-ment, and attempts are being made to reduce the negative effects of the therapy. Irradiation of the brain, particularly the area of the hippocampus, may lead to further cognitive deficits, which as a result significantly affects patients’ quality of life. Described cognitive functions relate to the thought processes used to process information coming from the outside world into the mind and contain basic aspects such as memory, attention, and association and complex ones, which include thinking and imagination [17].

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The most frequently described deficits of cognitive functions after brain CT are losses in short-term memory and less frequently in delayed memory, and problems with information recall and learning [18, 19]. There are also described verbal memory disorders, necessary to understand reading text, as well as inhibition of the higher cognitive processes necessary to behave in new and difficult situations [20, 21]. It is worth noting that any deterioration of cognitive functions in oncological patients significantly affects the quality of life after the completion of anticancer treatment and can contribute to the deepening of lowered mood, and even the occur-rence of depressive episodes [22, 23].

It should be noted that the hippocampus is a very rare location of cancer metastases [24, 25]. Researchers from the University of Wisconsin documented that only 3.3% of intracranial metastatic lesions were located up to 5 mm from the hippocampus, and over 86% were located at least 15 mm from this structure [26]. In another retrospective study analysing the location of 697 intracranial metastases, only 2.2% of lesions were found in the direct location of the hippocampus, and in patients with oligometastatic disease (one to three brain metastases) the rate of hippocampal metastases was below 1% [25].

Clinical assessment of impaired cognitive functions

Evaluation of the cognitive deficit after brain CT is methodically difficult and ambiguous. Until now, researchers have used subjective methods in the form of psychological tests, e.g. MMSE (mini-mental stage examination), HVLT (Hopkins verbal learning test), and AVLT (auditory verbal learning test) [10, 12, 27]. An example is the RTOG 0914 study conducted in a group of 445 patients with brain metastases (BM), who underwent whole brain radiotherapy (WBRT), which proved that both hypofractionated (30 Gy/10 frac-tions) and conventional (40 Gy/20 fractions) RT lead to a significant reduction in cognitive function, and the results of the MMSE test revealed a marked deteriora-tion in cognitive functions in both groups two and three months after completion of RT [9]. Another multicentre phase III trial based on 401 patients with BM treated with WBRT (30 Gy/10 fractions) revealed a significant decrease in cognitive functions assessed on the basis of the verbal fluency test (COWA, controlled oral word association) four months after RT, and then their improvement 15 months after completion of RT [28]. Preliminary results of the phase II RTOG 0933 study, using Hopkins’ verbal learning test (HVLT) showed that the use of hippocampal sparing in patients with BM during WBRT resulted in lower intensity of early

cognitive deficits within the first four months of treat-ment versus the state before treatment, as compared to RT without the cover of this structure [10, 12]. Another study, using the HVLT test, showed a smaller loss of cog-nitive functions in the field of learning and short-term memory in patients with 1–3 BM, who underwent only stereotactic brain radiotherapy (SRT), in comparison to patients with WBRT [12]. In turn, the AVLT auditory test revealed a decrease in verbal memory 6–8 weeks after completion of WBRT in patients with BM, in com-parison to baseline status [12]. In the phase III RTOG 0214 study conducted in a group of patients with stage III non-small cell lung cancer (NSCLC) subject to PCI, a marked decrease in cognitive function was seen after three months of brain RT evaluated with the MMSE test [27]. Research is ongoing to find an objective biomarker used alone or in fusion with MRI to detect early damage in the hippocampal region [5].

Hippocampus contouring techniques

Manual contouring of the hippocampus

This is the most popular technique in the daily practice of a radiotherapist; however, it requires a good knowledge of anatomy in the planned area. Correct contouring of the hippocampus is the most important process during the preparation of an irradiation plan with a procedure for the protection of this structure. In any case of contouring of the hippocampus, it is neces-sary to fuse locational computed tomography images with a current T2-weighted MRI brain examination at a scan density of min. every 1.5 mm [1]. The atlas created by the RTOG group is an assistance in the pro-cess of contouring the hippocampus during brain RT planning [29]. The necessity of training in contouring is emphasised, which allows practice of the technique of contouring of the most important area within the hippocampus: the dentate gyrus [30]. It was shown that without “contouring learning” of this structure there are large discrepancies in the exact location of this region between radiotherapists, and hence inconsequence in planning the brain RT and suboptimal results of treat-ment. The biggest discrepancies during manual contour-ing of the hippocampus occur in the area of the horn of the anterior lateral ventricle, while the smallest are in the area of the brain stem [31].

Automatic contouring of the hippocampus

Automatic methods of brain segmentation are usu-ally based on MRI images obtained on 1.5 T, 3 T, and even 7 T cameras, for better imaging and contrast of individual structures [32]. The first group includes pro-

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grams based on atlases, i.e. Atlas-Based Segmentation, Multi-Atlas-Based Methods [33, 34]. The second group of methods are modern computer programs analysing voxels, such as the Auto-Context Model (ACM) [35]. The automatic program for contouring the hippocampus during RT planning has advantages and disadvantag-es. The advantages undoubtedly include the minimum contribution of the “radiotherapist’s hand” and the ac-curacy of contouring on MRI images. However, it should be remembered that such contouring should always be verified and approved by a radiotherapist, which is connected with the requirement of his/her knowledge not only of the radiological anatomy of the brain, but also of the influence of various pathologies on its mor-phology [36, 37]. Automatic atlases for contouring of structures are becoming more common; however, most radiotherapy departments still do not have such software that is optimally integrated with the RT planning system. Importantly, this is also associated with the additional costs of purchasing such software.

It is worth noting that the brain often has various pa-thologies that disturb the anatomy of its structures, such as microcalcifications, the number of which increases with age, states after strokes, seizures, after brain infec-tions or Alzheimer’s disease [38–40]. In such cases, the automatically contoured structures of the hippocampus may turn out to be incorrect.

Clinical situations in which hippocampal protection should be considered during RT planning

In clinical practice, an appropriate group of patients should be selected in which there is a need for avoiding of the hippocampus during brain RT planning. The above procedure is a technical challenge regarding application of highly specialised RT techniques. It can be considered for patients with primary cerebral tu-mours, where the use of intensity-modulated radiation therapy (IMRT) allows us to reduce the dose within the hippocampus by 56.8% in relation to the classical 3D technique, i.e. from 36.6 Gy to approx. 15 Gy in the case of irradiation of part of the brain in the aforementioned group of patients [41]. In certain clinical situations, i.e. in the presence of an extensive oedema or central tu-mour location, especially around the brain stem, many authors suggest shielding only one hippocampus — on the opposite side of the tumour site [20, 42, 43]. It is worth adding that in children primary brain tumours are diagnosed much more frequently than in adults, and the procedure of hippocampal protection in these cases has a special clinical value during RT planning [44, 45].

Patients with SCLC represent another population. Elective brain radiotherapy — PCI with hippocampal

sparing may be considered in patients with radical ra-dio-chemotherapy or in patients undergoing palliative chemotherapy, who have achieved a clinical response within the chest after this treatment with no disease progression [46, 47]. The most frequently recommended PCI regimen is whole brain irradiation to a total dose of 25 Gy in 10 fractions of 2.5 Gy [48]. It has also been demonstrated that PCI may contribute to the impair-ment of cognitive functions as a result of post-radiation depopulation of NSCs within the hippocampus [49, 50]. Research results indicate that the use of a cover of both hippocampi could reduce or even prevent cognitive complications after PCI [49, 51].

Patients with secondary brain tumours (BM) consti-tute the most controversial group in terms of application of hippocampal protection procedure, due to the short-est expected overall survival, and therefore a relatively short time of expected potential benefit. On the other hand, the majority of research on the hippocampus pro-tection procedure during cerebral irradiation concerns patients with BM. Unfortunately, the current results of the study do not allow us to clearly define the eligibi-lity criteria for the hippocampus protection procedure during brain RT in the above group of patients [52–54].

There is a need to select specific criteria for the qualification of patients for hippocampus protection procedure during brain RT and to develop practical rec-ommendations during this procedure within brain RT.

“Protective” doses of ionising radiation in the area of the hippocampus

In current research it has been shown that even small doses of ionising radiation cause radiation-induced inflammation of the areas of neurogenesis within the hip-pocampus [6, 7]. In the phase II RTOG 0933 study a dose of ionising radiation was initially proposed that should not be exceeded in the hippocampal area during PCI and WBRT planning (Table 1) [54]. The above recommendations may prevent deterioration in terms of memory, especially short-term memory and verbal memory, or the reproduction of freshly-stored information after application of RT to the cerebral region [58]. The proposed doses refer to conven-tional radiotherapy in which the fractional dose oscillates between 2 and 3 Gy. The problem arises in the case of hypofractionated RT and in particular stereotactic RT, although there are newer reports of “protective” doses in the hippocampus region in such cases [59, 60].

Summary

Brain radiotherapy is a recognised method of on-cological treatment in patients with primary and meta-

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Table 1. Ionising radiation doses (Gray — Gy) recommended for hippocampal sparing brain irradiation (WBRT, PCI) procedure, according to the RTOG 0933 study compared to other authors. The ranges of standards are given in brackets

RTOG 0933 [54, 58]

Gondi et al. [55]

Nevelsky et al. [53]

Wang et al. [37]

Krayenbuehl et al. [56]

Zhao et al. [57]

PTV D98% (Gy) ≥ 25 25.7 (25.4–25.9)

25.8 (25.0–27.1)

≥ 25*

PTV V95% (%) 96.9 (96.1–97.5)

96.9 (96.0–97.5)

96.4 (95.2–97.8)

PTV D2 (Gy) ≤ 37.5 37.2 (36.9–37.6)

35.1 (34.8–35.6)

33.5 (32.8–34.6)

PTV V30Gy (%) = 90 92.1 (90.5–93.2)

92 (92.0–92.0) < 23.75

Hippocampus D100% (Gy) ≤ 9 8.4 (7.7–8.9) 9.3 (8.3–10.0) 8.1 (7.8–8.5) ≤ 9

Hippocampus Dmean (Gy) 7.3 (7.2–7.6) 7.3 (6.0–7.9)

Hippocampus Dmax (Gy) ≤ 16 15.3 (14.3–15.9)

14.3 (13.5–15.4)

16 (14.6–16.9) 14.1 (12.0–15.3)

≤ 16

Lens Dmax (Gy) 3.8 (3.1–4.3) 5.8 (4.5–6.5) 4.6 (3.7–5.6)

Crossing of the optic nerves (optic chiasm) Dmax (Gy)

≤ 37.5 36.2 (33.9–37.2)

34.7 (33.1–36.8)

32.9 (31.7–35.1)

Optic nerve Dmax (Gy) ≤ 37.5 32.5 (28.3–35.7)

32.0 (23.7–36.1)

33.1 (32.5–33.8)

*PCI-PTV — planning target volume with 3 mm margin excluding the hippocampal region (hippocampus expanded by 5 mm); PCI — prophylactic cranial irradiation; WBRT — whole brain radiation therapy; PTV — planning target volume; Dmax — maximal point dose; Dmin — minimal point dose; Dmean — mean point dose; D100% — dose to 100% of the volume; D98% — dose to 98% of the volume; V95% — volume covered by 95% of the prescribed dose; D2% — dose to 2% of the volume; V30Gy — volume covered by 30% of the prescribed dose

static cerebral lesions, although cognitive impairment appearing after this treatment may contribute to the deterioration of patients’ quality of life. Occurrence of these complications is associated with post-radiation damage to the hippocampus, a structure particularly sensitive to ionising radiation, and especially the NSCs within it. Cognitive deficits mainly concern problems with memorising and reproducing information, and problems with short-term, delayed, and verbal memory. Application of the hippocampus protection procedure during brain RT may significantly reduce or even pre-vent the above complications.

Modern RT techniques provide the ability to protect the hippocampus during brain RT, although there is a need for further research to establish clinical indications, qualify the appropriate group of patients, and develop technical recommendations for the imple-mentation of this procedure, which could translate into clinical benefits and improve the quality of radiotherapy (quality assurance).

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111

REVIEW ARTICLE


Lek. Ewa Cedrych

Oddział Onkologii, Uniwersyteckie

Centrum Kliniczne im. prof. K. Gibińskiego

Śląskiego Uniwersytetu Medycznego

w Katowicach


Ewa Cedrych1, Ida Cedrych2

1Department of Oncology, Uniwersyteckie Centrum Kliniczne im. prof. K. Gibińskiego, Medical University of Silesia, Katowice, Poland2University Hospital Reykjavik, Iceland

Neratinib in adjuvant treatment of patients with HER2-positive breast cancer — less is more?

ABSTRACTNeratinib is a new small molecule aimed at HER2 receptor. It has recently been approved in the United States of

America and Europe for adjuvant treatment of patients with early, HER2-positive breast cancer, who underwent

surgical resection followed by at least one year of adjuvant trastuzumab treatment. Despite initial enthusiasm,

several factors limit the implementation of neratinib in clinical practice. These include: modest reduction of recur-

rence rate; limited data regarding the effect on overall survival; and a significant rate of adverse events. Thus,

neratinib should be considered mainly in patients with high-risk HER2-positive breast cancer, because its clinical

benefit might outweigh the side effects in this population. In the following article, we discuss the controversies

regarding the pivotal phase III trial that eventually led to neratinib approval.

Key words: neratinib, breast cancer, HER2

Oncol Clin Pract 2019; 15, 2: 111–114

Introduction

Recent years have brought significant improvement in systemic treatment of breast cancer. Recognition of the biological mechanisms responsible for breast cancer development and growth have led to the introduction of personalised treatment that bases on the immunological phenotype of cancer cells. Systemic treatment arma-mentarium for breast cancer in the USA includes over 30 agents nearly half of which are molecularly targeted drugs. Neratinib is one of the most recent additions to this list and acts as a molecularly targeted drug [1].

Phase II clinical trials

Neratinib is a small molecule oral tyrosine kinase inhibitor. It irreversibly blocks human epidermal growth factor receptor 2 (ERBB2, HER2) and epidermal growth factor receptor (EGFR) [2]. The mechanism of action relies on the suppression of ErbB and autophos-phorylation of EGFR family receptor proteins, leading

to the impairment of cell proliferation. In a phase II trial published in 2010, neratinib was evaluated in patients with metastatic, HER2-positive breast cancer. The patients were divided into two cohorts — the first included patients with a confirmed progression during trastuzumab treatment, and the second only patients naïve to trastuzumab. Neratinib was used at a dose of 240 mg per day. The primary end point was the rate of progression-free survival (PFS) after 16 weeks of treatment. The rate of PFS was 56% in the first cohort and 78% in the second cohort, with a median PFS of 22.3 and 39.6 weeks, respectively. The response rate was 24% in patients who progressed on trastuzumab and 56% in trastuzumab-naïve patients. The most common treatment-related adverse events were diarrhoea, nau-sea, vomiting, and fatigue. Diarrhoea usually occurred in the first week of treatment and was present in 93% of patients, with grade 3 and 4 intensity (according to National Cancer Institute Common Terminology Criteria for Adverse Events v.3.0, CTCAE) in 21% of patients. Grade 3 and 4 diarrhoea was more prevalent in the cohort of patients with prior trastuzumab exposure


2019, Vol. 15, No. 2, 111–114

DOI: 10.5603/OCP.2019.0014

Translation: lek. Maciej Kawecki


ISSN 2450–1654

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(30%) compared to the cohort of trastuzumab-naïve patients (13%). Dose reduction was required in nearly one-third of patients in cohort one (29%), in contrast to only 4% of patients who needed dose reductions in cohort two [3]. The next phase II trial, the results of which were published three years later, aimed at proving non-inferiority of neratinib monotherapy to a combina-tion of lapatinib and capecitabine in patients with locally advanced or metastatic HER2-positive breast cancer after prior trastuzumab treatment. Patients in the experi-mental arm received neratinib 240 mg per day continu-ously (n = 117), and patients in the control arm received lapatinib 1250 mg per day continuously and capecitabine 2000 mg/m2 daily on days 1–14 of every 21 day cycle (n = 116). The trial failed to show non-inferiority of neratinib. Median PFS in patients receiving neratinib was 4.5 months versus 6.8 months in patients receiving lapatinib and capecitabine, with a median overall sur-vival (OS) of 19.7 and 23.6 months, respectively. The response rate was lower in the experimental arm (29%) compared to the control arm (41%) (p = 0.067), as was the rate of clinical benefit (44% vs. 64%, respectively) (p = 0.003). Patients receiving neratinib experienced more diarrhoea (85%) compared to patients receiving lapatinib and capecitabine (68%) (p = 0.002) [4]. Several other phase I/II trials evaluated neratinib combined with different cytotoxic agents (vinorelbine, capecitabine, and paclitaxel) in the treatment of patients with breast cancer, with a modest signs of activity [5–7].

Phase III clinical trial

Results of a prospective, randomised, multicentre, double-blinded, placebo-controlled trial evaluat-ing neratinib in adjuvant treatment of patients with HER2-positive breast cancer, who underwent surgery followed by at least one-year of trastuzumab treatment, were published in 2016 in „The Lancet Oncology”. The trial included patients from 495 oncological centres from all continents. Initially, the trial included patients over 18 years old with stage I–III HER2 breast cancer, who finished 12-months of adjuvant trastuzumab treat-ment within the last two years. Patients whose tumours expressed oestrogen receptors were recommended to receive endocrine therapy simultaneously. Hormonal receptor expression was evaluated locally and was not verified by a central laboratory. No homogenous method of receptor evaluation was required. Inclusion criteria included only typical factors: adequate performance sta-tus (ECOG 0–1); no clinical or laboratory contraindica-tions arising from liver, kidneys, or heart; no diagnosis of mental diseases; and no difficulties with oral ingestion. Neratinib was administered at a daily dose of 240 mg continuously for 12 months. Dose reductions or inter-

ruptions for no longer than three weeks were allowed. No diarrhoea prophylaxis was included; treatment was initiated if necessary. Besides routine clinical and ra-diological assessment, the trial included quality-of-life evaluation, using EuroQoL Five Dimensions (EQ5D) and Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaires. Quality of life evaluation was undertaken every three months. The primary end-point was invasive disease-free survival (iDFS) assessed 24 months after randomisation. Secondary end-points were: DFS including incidence of preinvasive breast cancer, distant recurrence-free survival, cumulated in-cidence of central nervous metastases incidence, overall survival, and treatment safety.

In February 2010 the protocol was modified, nar-rowing the inclusion criteria to patients with stage II and III disease and to those who finished trastuzumab therapy within a year. The amendment was justified by the results of two other published clinical trials (BCIRG 006), which showed excellent survival parameters of patients with HER2 overexpressed breast cancer with-out involvement of local lymph nodes, who received adjuvant trastuzumab. Additionally, most of the recur-rences occurred within one year of completing adjuvant treatment [8]. In October 2011 subsequent amendments were implemented. The trial finished recruitment after only 2842 patients from 3850 initially planned, and the observation period was limited to two years instead of a previously accounted five years. Those amendments, as described with published results, were due to the spon-sor’s doubts regarding safety [9]. Moreover, a previous sponsor withdrew financial support for the trial, which was continued by a small pharmaceutical company with limited experience in oncology.

The next amendment was implemented in January 2014. The decision revived some of the initial study assumptions and prolonged the period of observa-tion, again, to five years, with an additional efficiency analysis in the whole study population after 24 months from randomisation. The aforementioned analysis was undertaken in June 2014. In the neratinib arm, there were 70 events of invasive breast cancer in comparison to 109 events in the placebo arm (HR 0.67; 95% CI 0.50–0.91; p = 0.0091). The difference was even more clear in a subgroup of patients with positive hormone receptors (HR 0.51; 95% CI 0.53–0.77; p = 0.0013). No difference in iDFS was seen in patients without expres-sion of hormonal receptors. There were no differences regarding the metastasis-free survival (HR 0.75; 95% CI 0.53–1.04; p = 0.089) or the distant recurrence-free survival (HR 0.71; 95% CI 0.50–1.0; p = 0.054). The cu-mulative incidence of central nervous system metastases was similar in both arms (0.91% [95% CI 0.49–1.59] and 1.25% [95% CI 0.75–1.99]; p = 0.44). Quality of life as-sessment showed impaired scores in the neratinib group

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Ewa Cedrych, Ida Cedrych, Breast cancer treatment with neratinib

during the first month of treatment, with a subsequent diminishment of difference between both arms.

The restitution of a five-year period of observation required renewal of informed consent, which was ob-tained from 2117 patients (74.4% of the primary group). Data regarding patients who refused re-consent were censored at the date of last control. Results from the five-year observation were published in „The Lancet Oncology” [10] and were comparable to the results published after the 24-month analysis. The median treatment time was 353 days in the neratinib group and 360 days in the placebo group. Among patients with hormonal-receptor-positive cancer, 93% of patients in the experimental arm and 94% of patients in the placebo arm received simultaneous hormonal treatment, but at the time of final analysis only 52% and 47%, respectively, continued endocrine treatment. The difference between arms might be attributed to the higher rate of disease recurrence in the control arm, which forced hormonal therapy withdrawal. Long-term analysis showed a sig-nificantly lower rate of invasive breast cancer in the neratinib group compared to the control group (116 and 163 events, respectively; HR 0.73; 95% CI 0.57–0.92; p = 0.0083). The rate of five-year recurrence-free survival was 90.2% (95% CI 88.3–91.8) in the neratinib arm and 87.7% (95% CI 85.7–89.4) in the placebo arm. There were no significant differences between rates and medians of distant recurrence-free survival as well as cumulative five-year risk of central nervous system metastasis development. Again, the greatest difference in recurrence-free survival was seen in a sub-group of patients with a cancer expressing hormonal receptors (HR 0.60; 95% CI 0.43–0.83; p = 0.063), and no differ-ence was seen in patients without receptor expression (HR 0.95; 95% CI 0.66–1.35). No long-term toxicities attributed to neratinib were observed, including rates of cardio-vascular diseases and rates of secondary ma-lignancies. During the five-year observation, there were 121 incidences of death, 102 of which can be attributed to cancer and 19 to other causes. The results regarding overall survival have not been published yet because such analysis is planned for the third quarter of 2019 [10].

Adverse events

The most common adverse event during neratinib treatment is diarrhoea, with all grade incidents present in over 70% of patients (33% grade 2, 40% grade 3, and less than 1% grade 4 diarrhoea). Treatment emergent adverse events were responsible for a 28% rate of treat-ment withdrawal in the neratinib group (compared to 2% in the placebo group) and a 31% rate of dose ad-justment (compared to only 2% patients in the placebo group). Serious adverse events were reported in 7% and 6% of patients, respectively, with the most common be-

ing diarrhoea (22 vs. one event/s), vomiting (12 vs. one event/s) and dehydration (nine vs. one event/s). Grade 2, 3, and 4 diarrhoea usually emerged during the first week of treatment, with an increased risk during the subsequent few weeks. The presented trial did not include diarrhoea prophylaxis. However, conclusions arising from the trial suggest that this kind of prophylaxis should be encouraged in patients receiving neratinib. The prophylaxis should be initiated concurrently with neratinib and continued for the first two treatment cycles and as clinically indicated thereafter [10, 11]. Quality of life assessment is an essential factor during evaluation of novel drugs, especially when applied as part of adjuvant treatment. Results regarding quality of life in the Ex-teNet trial were published as a conference paper during the European Society for Medical Oncology Congress in 2017. The presented results included evaluation of health-related quality of life (HRQoL) assessment with two properly validated questionnaires: EuroQol Five Dimensions (EQ5D) and Functional Assessment of Cancer Therapy-Breast (FACT-B). The assessment was undertaken every three months for 12 months. Similar patterns of HRQoL changes were detected in both FACT-B and EQ-5D questionnaires: the quality of life scores in the neratinib group worsened in the first month of treatment but improved thereafter [11].

Discussion

Neratinib used as part of adjuvant treatment in patients with early-stage HER2-positive breast cancer improves invasive disease-free survival and non-invasive disease-free survival, especially in patients with tumours expressing hormonal receptors. No improvement with neratinib was seen regarding distant metastasis-free survival and rate of central nervous system metastasis incidence. Additionally, we currently lack data re-garding survival parameters. Better results obtained with neratinib in hormonal-positive patients might be explained by an interaction of HER2 and oestrogen receptors. Inhibition of the former leads to an overex-pression of the latter, sensitising cancer cells to hormo-nal treatment. It should be emphasised that improved effectiveness in the hormonal-positive population has not been observed in a trial with other HER2 inhibi-tors: trastuzumab, pertuzumab, or lapatinib. A possible explanation might be that neratinib itself can interact with oestrogen receptors. However, as the central as-sessment evaluated only HER2 receptor status and not hormonal receptor expression, the differences between multiple local standards might bias correct interpreta-tion of data. Several controversies arise due to the few protocol amendments undertaken during the trial and due to the change of sponsorship. The decision regard-ing limitation of the number of participants correlated

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with a primary analysis of a different small molecule HER2 inhibitor — lapatinib — used as a monotherapy in adjuvant treatment of HER2-positive breast cancer. The inferiority of lapatinib compared to trastuzumab led to an early trial suspension, and patients receiv-ing lapatinib were offered to continue their treatment with trastuzumab [12]. Because the neratinib trial was modified at the same time that the lapatinib trial results were made available, the sponsor might have limited recruitment only to reduce costs due to a high risk of obtaining negative results. Despite the lack of overall survival data, on 17 June 2017 the Food and Drug Ad-ministration (FDA) approved neratinib as an adjuvant treatment in adult early-stage HER-2 positive breast cancer patients who received at least 12 months of tras-tuzumab treatment [13]. Initially, in February 2018 the European Committee for Medicinal Products for Hu-man Use (CHMP) did not recommended registration of neratinib due to uncertainties whether the clinical benefit outweighs the increased toxicity [14]. However, four months later, on 28 June 2018 the CHMP revised its position and recommended registration of neratinib, but only in the population of patients with HER2-positive and hormone receptor-positive tumours. Since then, neratinib can be considered as an option for extended adjuvant treatment of HER2-positive and hormonal receptor-positive early-stage breast cancer [13].

The monthly cost of neratinib therapy in the USA is estimated at about 10,000 dollars, and, considering a standard 12-month regimen, a single neratinib treatment requires expenditure of 120,000 dollars. Unfortunately, toxicities related to neratinib occur commonly, add a sub-stantial burden, require intensive prophylaxis, and can impair quality of life (at least temporarily during the first months of treatment). Valuable insights might come with the data regarding survival parameters, but they will not be available until late 2019. Additionally, quality of life analy-sis of neratinib has been published only as a conference paper, which limits the ability to draw proper conclusions.

Conclusions

Recent advances in systemic therapy of solid tu-mours are limited mostly to targeted therapies and drugs aimed at the immune system (mostly immune checkpoint inhibitors). The last cytotoxic drug for breast cancer was registered in the USA in 2012. Since then, all drugs registered were molecularly targeted thera-pies. Trials evaluating immune checkpoint inhibitors in triple-negative breast cancer are underway. Strong pres-sion from millions of breast cancer patients around the globe, as well as technological development, has led to the introduction of novel and promising therapies. The exponentially growing body of evidence regarding can-cer genetics, supported by more precise technological

advancements, has shortened the cycle of drug develop-ment and allows rapid introduction of novel compounds to the market.

Still, it should be remembered that the daily prac-ticing oncologist, who meets patients and their needs, is the one responsible for the final recommendation of certain treatment for a certain patient. Knowledge about the full process the development of a novel drug offers a valuable insight into its clinical utility and supports precise and accurate therapeutic decisions [15].

References

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2. National Cancer Institute Drug Dictionary. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/neratinib-maleate (2018–12–01).

3. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2--positive breast cancer. J Clin Oncol. 2010; 28(8): 1301–1307, doi: 10.1200/JCO.2009.25.8707, indexed in Pubmed: 20142587.

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10. Martin M, Holmes FA, Ejlertsen B, et al. ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, pla-cebo-controlled, phase 3 trial. Lancet Oncol. 2017; 18(12): 1688–1700, doi: 10.1016/S1470-2045(17)30717-9, indexed in Pubmed: 29146401.

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12. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol. 2016; 34(10): 1034–1042, doi: 10.1200/JCO.2015.62.1797, indexed in Pubmed: 26598744.

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REVIEW ARTICLE


Lek. Katarzyna Kozak

Klinika Nowotworów Tkanek Miękkich,

Kości i Czerniaków

Centrum Onkologii — Instytut

im. Marii Skłodowskiej-Curie

ul. Roentgena 5, 02–781 Warszawa

Phone: 22 546 21 84

Fax: 22 643 93 75


Katarzyna Kozak, Piotr RutkowskiDepartment of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute — Oncology Centre, Warsaw, Poland

Why do we need a new BRAF-MEK inhibitor combination in melanoma?

ABSTRACTDespite the increasing role of immunotherapy, BRAF/MEK inhibitor combinations have still a central role in the

treatment of BRAF V600-mutant melanoma. Encorafenib-binimetinib is the third BRAF-MEK inhibitor combination ap-

proved for the metastatic melanoma with BRAF V600 mutation. Data from phase III trial demonstrated high antitumor

efficacy and good tolerability of encorafenib-binimetinib. Compared to other combinations (dabrafenib-trametinib,

vemurafenib-cobimetinib) the new combination showed favourable results in terms of the low rates of pyrexia

and photosensitivity. Trials with triplet regimens that combine encorafenib-binimetinib with immunotherapy or

a third targeted agent in an effort to overcome mechanisms of resistance to BRAF/MEK inhibition are ongoing.

Key words: advanced melanoma, BRAF mutation, encorafenib, binimetinib

Oncol Clin Pract 2019; 15, 2: 115–119

In the last few years, treatment of patients with BRAF-mutant advanced melanoma has changed radi-cally, not only in terms of new therapeutic options, but also in terms of the number of available drugs. Mo-lecularly targeted therapies (dabrafenib with trametinib, vemurafenib with cobimetinib) and immunotherapy (nivolumab, pembrolizumab, nivolumab with ipili-mumab) have significantly improved overall survival in this group of patients [1–9]. Currently, a registered combination of BRAF/MEK inhibitors (encorafenib with binimetinib) is being added to this group.

Similarly to dabrafenib and vemurafenib, en-corafenib is an ATP-competitive BRAF V600 kinase inhibitor. It differs from other drugs in this group by a more than 10 times longer dissociation half-life (> 30 h), which results in extended inhibition of mito-gen-activated protein kinase (MAPK) signalling path-way [10]. It probably results in more potent anti-cancer activity, with a smaller paradoxical upregulation of MAPK pathway in healthy tissues responsible for the development of side effects [10, 11]. In turn, binimetinib

is a selective inhibitor of MEK1 and MEK2 kinases, which are components of MAPK signalling pathway. Its effectiveness was also evaluated in patients with melanoma with a rare NRAS mutation (phase III NEMO study). However, the progression-free survival (PFS) improvement compared to dacarbazine (median 2.8 vs. 1.5 months) was too small to allow registration of a drug in this indication [12].

The activity of the combination of encorafenib with binimetinib in patients with metastatic BRAF-mutant melanoma was evaluated for the first time in a phase Ib/II study. The doses selected for phase II were 400, 450, or 600 mg daily for encorafenib and 90 mg daily for binimetinib. Response was observed in 72–78% of patients, and median PFS was 11.3 months [13]. These encouraging results led to a phase III trial (COLUM-BUS) comparing the efficacy of encorafenib + bini-metinib combination with vemurafenib and encorafenib in monotherapy. In the first part of this study, the patients were randomly assigned (1:1:1) to one of three arms, receiving: encorafenib at a dose of 300 mg/day,


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Table 1. Summary of treatment outcomes according to COLUMBUS protocol

COMBO450 n = 192

COMBO300 n = 258

ENCO300 (part 1+ 2) n = 280

WEMURAFENIB n = 191

Centrally assessed

Locally assessed

Centrally assessed

Locally assessed

Centrally assessed

Locally assessed

Centrally assessed

Locally assessed

Median PFS (months; 95% CI)

14.9 (11.0–18.5)

14.8 (10.4–18.4)

12.9 (10.1–14.0)

12.9 (10.9–14.8)

9.2 (7.4–11.0)

9.2 (7.4–11.1)

7.3 (5.6–8.2)

7.3 (5.7–8.5)

ORR (%; 95% CI) 63 (56–70)

75 (68–81)

66 (60–72)

73 (67–78)

50 (44–56)

56 (50–62)

40 (33–48)

49 (42–57)

CR (%) 8 16 8 11 5 8 6 7

PR (%) 55 59 58 62 45 49 35 42

Median DOR (mo.; 95% CI)

16,6 (12.2–20.4)

16.2 (11.1–20.4)

12.7 (9.3–15.1)

13.1 (10.8–16.6)

12.9 (8.9–15.5)

13.0 (9.5–15.0)

12.3 (6.9–16.9)

8.4 (5.8–11.0)

Cl — confidence interval; CR — complete response; ORR — overall response rate; PR — partial response; DOR — duration of response

vemurafenib at a dose 1920 mg/day or, encorafenib at a dose of 450 mg/day in combination with binimetinib at a dose of 90 mg/day. In total 577 patients were enrolled with unresectable/metastatic BRAF-mutant melanoma without prior systemic treatment or after one prior im-munotherapy line. At median follow-up of 16.6 months, independently assessed median PFS was 14.9 months in the encorafenib + binimetinib arm (95% confidence interval [CI]: 11.0–18.50), 7.3 months in the vemurafenib monotherapy arm (95% CI: 5.6–8.2), and 9.6 months (95% CI: 7.5–14.8) in the encorafenib monotherapy arm. Locally assessed median PFS values were similar. Hazard ratio (HR) was 0.54 for combination therapy vs. vemu-rafenib (p = 0.001) and 0.75 for combination therapy vs. encorafenib (p = 0.051) in independent assessment [14]. Of note, it is the first study showing a difference in efficacy of individual BRAF inhibitors in monotherapy (encorafenib vs. vemurafenib), which confirms the high specificity of BRAF kinase inhibition by encorafenib.

In October 2018 the overall survival (OS) data of patients treated in the first part of the COLUMBUS study were published [15]. Treatment with encorafenib at a dose of 450 mg/day in combination with binimetinib at a dose of 90 mg/day (COMBO450) reduced the risk of death compared to vemurafenib at a dose of 1920 mg/day (HR 0.61 [95% CI: 0.47–0.79], p < 0.001). Median OS was 33.6 months (95% CI: 24.4–39.2) for the patients treated with COMBO 450 vs. 16.9 months (95% CI: 14.0–24.5) for patients receiving vemurafenib. The three-year OS rate for the combination of encorafenib with binimetinib was 47%.

In the second part of the COLUMBUS study mono-therapy with encorafenib at a dose of 300 mg/day was compared with a combination of encorafenib at a dose of 300 mg/day with binimetinib at a dose of 90 mg/day (COMBO300). Median PFS for combinations with encorafenib at a dose of 300 mg was 12.9 months (95% CI: 10.1–14.0) and was significantly longer compared

to encorafenib monotherapy (HR 0.77, p = 0.029) but shorter compared to the combination COMBO450 [16]. This confirms the relationship between encorafenib dose and the effectiveness of combined therapy. Table 1 sum-marises the treatment outcomes in the COLUMBUS study, and Table 2 summarises the results of clinical trials with encorafenib and binimetinib.

The higher effectiveness of combination treatment is accompanied by better tolerance. Grade 3/4 adverse events (AEs) were observed less frequently in patients receiving encorafenib with binimetinib (combination therapy — 58%, vemurafenib — 63%, encorafenib — 66%), similarly to AEs requiring treatment inter-ruptions or dose modification. The maximum dose of encorafenib used as monotherapy, determined based on previous research, is 300 mg/day [10]. The addition of binimetinib improved tolerance of encorafenib to the extent that the dose of encorafenib used in the combina-tion was increased to 450 mg/day, which contributed to higher treatment effectiveness. However, it should be remembered when modifying treatment to reduce the dose of encorafenib to 300 mg/day in case of an inter-ruption or withdrawal of binimetinib.

The most common AEs observed in patients receiv-ing combination therapy are gastrointestinal tract disor-ders (app. 30–40%), increased creatine kinase activity (23%), and fatigue (29%). Whilst gastrointestinal tract disorders occurred more often than in patients receiving monotherapy, muscle and joint pains, skin complications (such as rash, hyperkeratosis, hand-foot syndrome, and hypersensitivity to light), as well as hair loss were less frequent. AEs specifically related to MEK inhibition, such as exudative serous chorioretinopathy (20–23%) and left ventricle functional disorders (2%), occurred more frequently during combination treatment [14, 15].

The nature of AEs is similar in all BRAF/MEK inhibitor combinations; only their prevalence is dif-ferent. Fever, which is a typical AE of dabrafenib with

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Katarzyna Kozak, Piotr Rutkowski, Why do we need a new BRAF-MEK inhibitor combination in melanoma?

Table 2. Summary of clinical trials of encorafenib and binimetinib

Study (year) Study design Efficacy outcomes Safety outcomes

Ascierto et al. (2013) [9]

Multicentre, open phase II study, BINI 45 mg twice daily in melanoma patients with NRAS (n = 30) and BRAF (n = 41) mutation

Investigator-assessed RR: 20% in patients with NRAS and BRAF mutations (6/30 and 8/41 patients)

PR confirmed in only 3 and 2 patients, with no CR

SD in 13 (42%) NRAS+ patients and 13 (32%) BRAF+ patients

Survival:

— median PFS for NRAS+: 3.7 months (95% CI: 2.5–5.4)

— median PFS for BRAF+: 3.6 months (95% CI: 2.0–3.8)

Common AE (NRAS+ and BRAF+; n = 71): acne-like dermatitis (46%), peripheral oede-ma (34%), diarrhoea (32%), elevated CPK activity (28%), ocular toxicity (18%)

Grade 3/4: 4 (5.6%) patients

Treatment discontinuation due to AE: 15 (21%) patients

Dose reduction due to AE: 33 (46%) patients

Dummer et al. (2017) NEMO [12]

Multicentre, open phase III study, ran-domisation 2:1: BINI 45 mg twice daily (n = 269) vs. DTIC 1000 mg/m2 IV every 3 weeks (n = 133) in melanoma patients with NRAS mutations

Confirmed RR: 15.2% for BINI (95% CI: 11.2–20.1) vs. 6.8% for DTIC (95% CI: 3,1–12,5); p = 0.015

SD: 40.5% (BINI) vs. 17.3% (DTIC)

Survival:

— median PFS: 2.8 months (95% CI: 2.8–3.6) for BINI vs. 1.5 months (95% CI: 1.5–1.7) for DTIC (HR: 0.62; p < 0.001)

Common AE (BINI): increased CPK activity (42%), diarrhoea (40%), peripheral oedema (36%), rash (36%), acne-like dermatitis (35%), ocular toxicity (17%)

Severe AE: 91 (33.8%) patients, treatment discontinuation due to AE: 66 (24.5%) patients

Dose reduction due to AE: 163 (60.6%) patients

Dummer et al. (2018) COLUMBUS [14]

Multicentre, open phase III study, randomisation 1:1:1 (n = 577): ENCO 450 mg once daily + BINI 45 mg twice daily (COMBO) vs. VEM 960 mg twice daily vs. ENCO 300 mg once daily (part 1) in melanoma patients with BRAF mutations

COMBO vs. VEM vs. ENCO

Confirmed RR: 63% (56–70) vs. 40% (33–48) vs. 51% (43–58)

Survival:

— median PFS: 14.9 months (11.0–18.5) vs. 7.3 months (5.6–8.2) vs. 9.6 months (7.5–14.8); HR: 0.54 for COMBO vs. VEM (p = 0.001) and 0.75 for COM-BO vs. ENCO (p = 0.051)

— median OS for COMBO: 33.6 months

Common AE (COMBO only): nausea (41%), diarrhoea (36%), vomiting (30%), fatigue (29%), arthralgia (26%), elevated CPK activity (23%), headache (22%), fever (18%), ocular toxicity (13%)

Grade 3/4 AE: 58% of patients

Treatment discontinuation due to AE: 16 (8%) patients

Dose reduction due to AE: 21 (11%) patients

Dose interruption due to AE: 88 (46%) patients

BINI — binimetinib; RR — response rate; PR — partial response; CR — complete response; SD — stable disease; PFS — progression-free survival; AE — adverse event; CPK — creatine phosphokinase; DTIC — dacarbazine; IV — intravenously; HR — hazard ratio; ENCO — encorafenib; VEM — vemurafenib

trametinib (> 50% of patients), occurs less frequently in patients receiving combinations of encorafenib with binimetinib (18%) and is not recurrent. Phototoxicity, also called photoirritation, which in turn occurs in half of the patients treated with vemurafenib with cobimetinib, affects only 5% of patients treated with encorafenib and binimetinib. Table 3 presents detailed data regarding therapy tolerance in the COLUMBUS study.

The results of the COLUMBUS study led to the registration of a combination of encorafenib with binimetinib by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of patients with unresectable/metastatic melanoma with BRAF mutation.

As combinations of BRAF/MEK inhibitors have been used in daily clinical practice for several years, attempts to modify the treatment in order to extend the response duration or breaking the resistance to molecularly targeted drugs has become more interest-

ing. There are a few clinical trials ongoing at the present time: IMMU-TARGET (NCT02902042), assessing the effectiveness of combination of encorafenib and binimetinib with anti-PD1 antibody, pembrolizumab; SECOMBIT (NCT02631447), assessing the optimal treatment sequence — encorafenib + binimetinib in the first line, nivolumab + ipilimumab in the second line — in comparison with the reverse sequence; EBIN (NCT03235245), assessing the effectiveness of im-munotherapy (nivolumab + ipilimumab) preceded by a 12-week induction phase with the use of encorafenib and binimetinib; and LOGIC2, in which patients after failure of treatment with encorafenib and binimetinib receive further combinations of drugs based on the assessment of molecular disorders in cancer tissue col-lected after disease progression. Activity of encorafenib and binimetinib is also evaluated in patients with meta-static colorectal cancer with BRAF mutation (phase III BEACON CRC study, NCT02928224).

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Table 3. The most frequent adverse events in the arms containing encorafenib in the phase III COLUMBUS study

COMBO300

n = 257

ENCO300 (part 1 + 2)

n = 276

COMBO 450

n = 192

Median duration of treatment exposure (weeks)

52.1 31.5 51

Adverse events (%) Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4

Diarrhoea 28 2 12 1 36 3

Nausea 27 2 36 3 41 2

Joint pain 22 1 43 8 26 1

Fatigue 22 1 26 1 29 2

Elevated creatine kinase activity 20 5 1 0 23 7

Vomiting 15 < 1 25 4 30 2

Elevated GGTP activity 14 5 11 4 15 9

Muscle pain 14 < 1 27 8 14 0

Alopecia 13 0 49 < 1 14 0

Headaches 12 < 1 26 3 22 2

Elevated ALT activity 11 5 4 1 13 6

Skin hyperkeratosis 10 0 39 3 14 1

Dry skin 8 0 28 0 14 0

Rash 15 1 43 5 23 1

Palmoplantar keratoderma 7 < 1 24 1 9 0

Palmar-plantar erythrodysesthesia syndrome

4 < 1 47 11 7 0

Fever 17 0 16 0 18 4

Left ventricle malfunctions 6 1 3 1 8 2

GGTP — gamma-glutamyl transpeptidase; ALT — alanine aminotransferase

Table 4. Phase III studies with BRAF or MEK inhibitors alone or in combination in the treatment of advanced melanoma

Authors Long et al. 2014 [8] Long et al. 2017 [1]

Robert et al. 2015 [5]

Larkin et al. 2014 [9] Ascierto et al. 2016 [6]

Dummer et al. 2018 [14, 15]

Drug Dabrafenib Dabrafenib

+ trametinib

Vemura-

fenib

Dabrafenib

+ trametinib

Vemura-

fenib

Vemurafenib

+ cobimetinib

Encorafenib

+ binimetinib

COMBO 450

Encorafenib

+ binimetinib

COMBO 300

ORR (%) 53 69 51 64 50 70 63 66

Median PFS (months)

8.8 11 7.3 12.6 7.2 12.3 14.9 12.9

Median OS (months)

18.7 25.1 18.0 25.6 17 22.3 33.6

2-/3-year OS rate

43/32% 52/44% 39/31% 53/45% 2-year OS rate: 57.6%

ORR — overall response rate; PFS — progression-free survival; OS — overall survival

Conclusions

Encorafenib with binimetinib is already the third registered combination of BRAF/MEK inhibitors. Re-sults of a phase III study showed very good tolerance of this treatment and the best survival among all available

combinations of targeted therapies in terms of both PFS and OS. Table 4 summarises the results of clinical trials with various BRAF/MEK inhibitors. Undoubtedly, it is difficult to directly compare the survival of partici-pants in these clinical studies, so a randomised clinical trial is needed. The better results of treatment with

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Katarzyna Kozak, Piotr Rutkowski, Why do we need a new BRAF-MEK inhibitor combination in melanoma?

encorafenib and binimetinib can be explained by slightly different patient populations (e.g. a lower percentage of patients with elevated lactate dehydrogenase activity) or better access to immunotherapy in subsequent treat-ment lines. On the other hand, median PFS and OS in patients treated with vemurafenib in the COLUMBUS study are very close to those observed in the coBRIM or COMBI-v studies. Higher efficacy of therapy can therefore result simply from better pharmacological properties of encorafenib. In conclusion, a combination of encorafenib with binimetinib is a valuable distinctive alternative to other drug combinations.

References

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10. Delord JP, Robert C, Nyakas M, et al. Phase i dose-escalation and -ex-pansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017; 23(18): 5339–5348, doi: 10.1158/1078-0432.CCR-16-2923, indexed in Pubmed: 28611198.

11. Adelmann CH, Ching G, Du L, et al. Comparative profiles of BRAF inhibitors: the paradox index as a predictor of clinical toxicity. Onco-target. 2016; 7(21): 30453–30460, doi: 10.18632/oncotarget.8351, indexed in Pubmed: 27028853.

12. Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dac-arbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017; 18(4): 435–445, doi: 10.1016/S1470-2045(17)30180-8, indexed in Pubmed: 28284557.

13. Sullivan RJ, Weber JS, Patel SP, et al. A phase Ib/II study of BRAF inhibi-tor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. J Clin Oncol. 2015; 33(15 (Suppl)): 9007, doi: 10.1200/jco.2015.33.15_suppl.9007.

14. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018; 19(5): 603–615, doi: 10.1016/S1470-2045(18)30142-6, indexed in Pubmed: 29573941.

15. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018; 19(10): 1315–1327, doi: 10.1016/S1470-2045(18)30497-2, indexed in Pubmed: 30219628.

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CASE REPORT


Lek. Małgorzata Flis

Oddział Chorób Płuc i Gruźlicy

Samodzielny Publiczny Szpital Kliniczny

nr 4 w Lublinie

ul. Jaczewskiego 8, 20–954 Lublin

Phone: 507 824 113


Małgorzata Flis1, Paweł Krawczyk2, Izabella Drogoń1, Katarzyna Kurek1, Robert Kieszko2, Janusz Milanowski2

1Independent Public Teaching Hospital No 4 , Lublin, Poland2Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Poland

The effectiveness of chemotherapy in small cell lung cancer patients with BRCA2 gene mutation and Schwartz-Bartter syndrome

ABSTRACTSmall cell lung cancer (SCLC) currently comprises 15–20% of all lung cancers. It is characterised by rapid growth

and early appearance of distant metastases. It is closely related to smoking. A characteristic feature of this type

of cancer is the frequent coexistence of paraneoplastic syndromes (about 50% of patients). Paraneoplastic

syndromes are clinically important because they can be the first sign of cancer. Early diagnosis of disturbing

symptoms is an important factor in increasing the effectiveness of treatment and the patient’s chance for longer

survival. The most frequent and important paraneoplastic syndromes in the course of SCLC are primarily the

syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), paraneoplastic cerebellar degeneration,

and Lambert-Eaton syndrome. This paper presents the case of a patient who came to the hospital with symptoms

of hyponatraemia. Looking for the causes of hyponatraemia, the syndrome of abnormal secretion of antidiuretic

hormone (Schwartz-Bartter syndrome) in the course of small cell lung cancer was confirmed. The fact that the

patient was genetically burdened with the family history of breast cancer and was a carrier of the BRCA2 gene

mutation was also significant. According to the latest research, mutation in the BRCA2 gene significantly affects

the chemosensitivity of cancer cells, and thus increases the body’s response to treatment. The patient received

chemotherapy with carboplatin and etoposide, resulting in partial remission of cancer after two treatment cycles.

Key words: small cell lung cancer, BRCA2 mutation, Schwartz-Bartter syndrome

Oncol Clin Pract 2019; 15, 2: 120–123

Introduction

Lung cancer is currently the most frequently di-agnosed malignant tumour in the world. There are around 1.8 million new cases of disease per year, and this number is constantly increasing. In Poland, the incidence of lung cancer is estimated at approximately 23,000 new cases per year. Lung cancer is the leading cause of cancer deaths among men and women around the world. High mortality is caused by, among others, late diagnosis of the cancer process. Lung cancer does not show characteristic early-stage symptoms, and no effective screening methods have been developed so far that would reduce the number of deaths due to this

disease. Therefore, in the majority of patients at the time of qualification for oncological treatment, there are present features of significant advanced local or distant metastases. Another factor conditioning high cancer mortality is a relatively poor response to chemotherapy.

Small cell lung cancer (SCLC) accounts for 15–20% of lung cancer cases, but is characterised by an extremely aggressive course, the presence of metastases at the time of diagnosis, and the lack of surgical treatment options. The basic method of treatment of patients with small cell lung cancer is chemoradiotherapy or chemo-therapy. Significant antitumour activity is demo nstrated by alkylating drugs (cisplatin, carboplatin), anthra-cyclines (doxorubicin, epirubicin), topoisomerase in-


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hibitors (etoposide, topotecan), followed by antimitotic drugs (vincristine, paclitaxel) and some antimetabolites (methotrexate). Higher efficacy of therapy was noted after the application of multidrug regimens. Response to treatment and its duration is still unsatisfactory. Median survival in patients with limited stage of small cell lung cancer (stages I–IIIA) is 14–20 months, and in patients in the generalised stage (stages IIIB–IV) it is 9–11 months. The search for new factors that influence the effectiveness of chemotherapy is ongoing [1–3].

Due to the development of genetic tests, it was observed that the presence of mutations in the BRCA2 gene, in addition to an increased risk of breast and ovarian cancer, significantly contributes to the increase of chemosensitivity [4–6]. The subject of the study is the case of a 67-year-old patient with small cell lung cancer with BRCA2 mutation and Schwartz-Bartter syndrome, in which a significant regression of advanced SCLC was obtained as a result of carboplatin chemo-therapy with etoposide.

Case report

The 67-year-old patient had been under the care of the oncological surgery clinic for many years due to the presence of breast cancer in the family (her mother was ill). At one of the follow-up visits, the need for genetic testing for the possible presence of mutations in the BRCA1 or BRCA2 genes was suggested. In December 2016, confirmation of the presence of the N372H muta-tion in the BRCA2 gene was obtained. The patient was informed about the increased risk of cancer, followed the doctor’s instructions, and set the time limits for periodic examinations.

In March 2018, the patient came to the hospital be-cause of severe weakness, nausea, and dizziness, which had been intensifying for several days. After the basic tests, hyponatraemia was found. The serum sodium level was 116 mmol/l. No abnormalities were observed in the X-ray of the chest (Fig. 1). After symptomatic treatment, the patient was referred for further ambula-tory diagnosis.

Two weeks later, the diagnostics of electrolyte disturbances began. During hospitalisation, moderate hyponatraemia was observed despite the treatment being used. Adrenal insufficiency and inadequate substitution of thyroid hormones was excluded (the patient suffered from post-operative hypothyroidism). The study revealed reduced osmolality of the plasma with normal osmolality of urine, and the urinary ex-cretion of sodium remained > 30 mmol/l. In addition, normal daily diuresis, and decreased urea and uric acid levels were found. The overall clinical picture indicated a syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). The occurrence

Figure 1. Chest review picture taken in March 2018. No irregularities were found

Figure 2. Infiltrative changes of the right lung (April 2018)

of Schwartz-Bartter syndrome, or syndrome of inad-equate secretion of vasopressin, without any under-lying cause, should always arouse oncological alert-ness, especially in smokers. This patient had smoked cigarettes for over 30 years. Paraneoplastic syndromes sometimes precede the symptoms of the cancer that they accompany. That was also the case with this pa-tient. The diagnosis of computed tomography of the neck, chest, and abdomen was extended, which re-vealed the presence of infiltrative changes in the upper lobe of the right lung (Fig. 2) as well as the presence of a mediastinal lymph node with 20–30-mm disinte-gration with right bronchus pressure, causing a sig-nificant obstruction of the high-lobe bronchi (Fig. 3).

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Figure 4. Regression of infiltrative changes of the right lung (June 2018)

Figure 5. Regression of mediastinal node changes (June 2018)

Figure 3. Lymph node pack with disintegration (April 2018)

In addition, the presence of the node of supra and subclavian nodes was revealed.

Oncological diagnostics of the disclosed changes has begun. Bronchofiberoscopy and endobronchial ultra-sound — thin needle aspiration (EBUS-TNA) — were performed, collecting a fragment of bronchi and lymph nodes for pathomorphological examination. From the collected material a diagnosis of small cell carcinoma with expression of Ki-67 in 90% of tumour cells (high mitotic capacity) was obtained.

Due to the advanced degree of SCLC, the patient was qualified for chemotherapy. The need to reduce the amount of fluids taken (SIADH syndrome) led to the selection of chemotherapy with carboplatin (instead of cisplatin) and etoposide. The patient tolerated the treat-ment well (no side effects were reported). During onco-logical treatment, the patient required periodic sodium supplementation. After two treatment cycles, the response to treatment was assessed. In computed tomography, a significant regression of pathological lymph nodes of the mediastinum was observed (maximum size up to 13 mm within the lymph node bundle of the right cavity, the size of the remaining nodes did not exceed the limit values, Fig. 4). In addition, there was almost complete regression of pathological foci in the upper right lobe (only residual lesions with fibrotic features were visualised, Fig. 5). There were no metastases to the central nervous system.

Anxiety was, however, caused by two osteosclerotic lesions visible in the thoracic vertebrae 3 and 11, not described in the previous study. Bone scintigraphy was performed, which revealed increased bone metabolism within the thoracic vertebra of the third, which may raise suspicion of a metastatic focus. It should be noted,

however, that bone metastases are often unnoticed in radiological descriptions because of their initially osteolytic nature. Only the action of chemotherapy or molecular-targeted therapies leads to osteosclerotic outbreaks visible in computed tomography.

Oncological treatment continued. The patient received another two cycles of chemotherapy with car-boplatin and etoposide. Due to CTC (common toxicity criteria) and CTC grade III thrombocytopaenia after the fourth cycle of chemotherapy, filgrastim injections, fludrocortisone, and antibiotic cover were used.

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Małgorzata Flis et al., The effectiveness of chemotherapy in small cell lung cancer patients with BRCA2 gene mutation and Schwartz-Bartter syndrome

An imaging assessment was made after the fourth cy-cle of treatment. In computed tomography, the changes were stationary and were comparable with the previous study. Stability of the disease was obtained.

Summary

BRCA2 is a suppressor gene that acts as a negative regulator of the cell cycle and has an effect on maintain-ing the stability of genetic material. The BRCA2 gene encodes the BRCA2 protein, whose main function is to participate in DNA repair. BRCA proteins (the most important of them is the BRCA1 protein) together with the protein kinase associated with ataxia-telangiectasia and Rad family proteins are involved in the repair of single-strand DNA damage (caused by the formation of platinum compounds adducts to DNA) and damage to both DNA strands (caused inter alia by radiotherapy). If immediate DNA repair is not possible due to the extent of damage, BRCA proteins participate in the activation of cell cycle checkpoint kinase 1/2, which results in cell cycle arrest and prolongation of the time necessary for DNA repair. This effect is enhanced by the involvement of BRCA proteins in the process of activating transcription of other genes related to DNA repair and cell cycle control and cell direction on the pathway of apoptosis [4–6].

Accordingly, cells with a mutation causing loss of BRCA1 or BRCA2 protein activity have increased sen-sitivity to DNA damaging agents, e.g. ionising radiation or cytostatic drugs that cause DNA strand breaks. The basic DNA repair process is stopped, and the cell enters the alternative DNA repair pathways [4–6].

Previous observations and studies reveal the dual nature of the BRCA2 gene mutation. On the one hand, mutations in the BRCA2 gene significantly increase the risk of breast cancer (up to 56%) and ovarian cancer (up to 27%). At the same time, other studies based on the evaluation of the effectiveness of oncological treatment reveal a significant effect of the presence of mutations in the BRCA2 gene on positive response to chemotherapy, especially with the participation of platinum compounds and other alkylating cytostatics. Yang et al. [4] analysed data from The Cancer Genome Atlas (TCGA) obtained from 316 women with low-differential serous ovarian cancer subjected to chemotherapy. In 35 women the BRCA1 mutation was found, and in 27 women the BRCA2 mutation was found, while in 219 none of the two mutations was noted. The patients underwent

chemotherapy with platinum compounds. The occur-rence of BRCA2 mutation was associated with high sensitivity to chemotherapy. Response to treatment was reported in 100% of patients with BRCA2 muta-tion, 82% of patients with BRCA1 mutation, and 80% of patients with mutations in these genes. Median progression-free survival was 18 months in carriers of the BRCA2 mutation, 11.7 months in patients with BRCA1 mutation, and 12.5 months in patients without BRCA gene mutations (statistically significant differ-ences) [4].

The above observations can be justified by the increased efficacy of cell chemotherapy with higher DNA instability and impaired remedial function. Most cytostatics work by inhibiting the effect of mitosis (cell division) mainly through DNA damage and structures responsible for cell division. DNA damage ultimately drives cells to the path of apoptosis. In the present case, the presence of the BRCA2 gene mutation, in addition to the obvious effect on tumour development, appears to have a simultaneous effect on the efficacy of cytostatic drugs through a synergistic effect on cell cycle disorder and DNA repair leading to cancer cell damage.

All authors have read and approved the final one working version to be submitted. Małgorzata Flis was the main co-creator in writing the manuscript. Malgorzata Flis, Izabella Drogoń and Katarzyna Kurek participated in collecting and interpreting data. Paweł Krawczyk, Ro-bert Kieszko and Janusz Milanowski contributed to data analysis and interpretation.

References

1. Tyczynski JE, Bray F, Parkin DM. Lung cancer in Europe in 2000: epidemiology, prevention, and early detection. Lancet Oncol. 2003; 4(1): 45–55, doi: 10.1016/s1470-2045(03)00960-4, indexed in Pub-med: 12517539.

2. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer Res. 2008; 68(21): 8643–8653, doi: 10.1158/0008-5472.CAN-07-6611, indexed in Pubmed: 18974103.

3. Krzakowski M, Orłowski T, Roszkowski K, et al. Polska Grupa Raka Płuca. Drobnokomórkowy rak płuca — zalecenia diagnostyczno-tera-peutyczne Polskiej Grupy Raka Płuca. Onkol Prakt Klin. 2007; 3: 1–7.

4. Yang Da, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011; 306(14): 1557––1565, doi: 10.1001/jama.2011.1456, indexed in Pubmed: 21990299.

5. Xia F, Taghian DG, DeFrank JS, et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomol-ogous end joining. Proc Natl Acad Sci U S A. 2001; 98(15): 8644–8649, doi: 10.1073/pnas.151253498, indexed in Pubmed: 11447276.

6. Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. 2010; 12(5): 245–259, doi: 10.1097/GIM.0b013e3181d38f2f, indexed in Pubmed: 20216074.

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CASE REPORT


Dr n. med. Piotr Tomczak

Szpital Kliniczny Przemienienia Pańskiego

Oddział Chemioterapii

ul. Szamarzewskiego 82/84, 60–568 Poznań

Phone: 61 854 90 38

Fax: 61 854 90 72


Piotr Tomczak1, 2, Zuzanna Synowiec2

1Department of Oncology, Poznan University of Medical Sciences, Poland2Chemotherapy Department, University Hospital of Lord’s Transfiguration in Poznan, Poland

Nivolumab in the treatment of advanced renal cell carcinoma

ABSTRACTNivolumab is a programmed death receptor-1 (PD-1) blocking antibody approved for the treatment of advanced

and metastatic renal cell carcinoma. Treatment with nivolumab is characterised by favourable toxicity profile. The

occurrence of grade 3 and 4 toxicity during the therapy is low. This article describes a medical history of a patient

with metastatic renal cell carcinoma treated with nivolumab.

Key words: renal cell carcinoma, immunotherapy, nivolumab

Oncol Clin Pract 2019; 15, 2: 124–126

Introduction

The occurrence rate of kidney cancer is about 2–3% of all human malignancies. In 90% of cases renal cell carcinoma (RCC) occurs [1]. The drugs used so far in the therapy of advanced renal cell carcinoma included tyrosine kinase inhibitors (TKI) and mTOR inhibitors (mammalian target of rapamycin inhibitors) [2].

Nivolumab is a monoclonal antibody that binds to the programmed cell death-1 receptor on the T lym-phocyte and blocks its connection to the PD-L1 ligand present on cancer cells or other cell types present in the tumour microenvironment [3]. As a result of this inhibition, the activity of effector lymphocytes is not inhibited, which leads to the intensification of their cy-totoxic effect on cancer cells. The CheckMate 025 study showed a 27% reduction in the hazard ratio (HR) of death (HR 0.73; p = 0.002) in the group of patients receiving nivolumab compared to patients treated with everolimus. Median overall survival (mOS) was 25 and 16. 9 months, respectively, in the studied groups [4]. In 2015 with accordance to the results of this study, the Food and Drug Administration (FDA) and the Euro-

pean Commission registered nivolumab for treatment of advanced clear cell renal cell carcinoma (ccRCC) after failure of an earlier antiangiogenic therapy [5].

Case report

A 55-year-old man was admitted to the Depart-ment of Oncology in July 2015 with the diagnosis of stage IV kidney cancer. In June 2015 he underwent radical left-sided nephrectomy, and histopathological examination confirmed the diagnosis of ccRCC, G3, pT3b, pNx. At the time of admission to the hospital, the patient was in good general condition; his perfor-mance status (PS) was 1 in the Eastern Cooperative Oncology Group (ECOG) scale. He was treated for hypertension, type 2 diabetes mellitus, and Parkinson’s disease. Complete blood count showed mild anaemia (Hb 7.8 mmol/l). Prognosis of the patient in Memo-rial Sloan Kettering Cancer Centre scale (MSKCC) [6] was moderate. Computed tomography (CT) of the abdominal cavity revealed presence of a 48 × 33 mm lymphadenopathy in the left paraaortic region, 22 mm


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Piotr Tomczak, Zuzanna Synowiec, Nivolumab in the treatment of advanced renal cell carcinoma

foci in the right kidney, and thrombosis in the left renal vein stump. On the basis of CT imaging, an embolism in the LS10 artery was found. The patient received anticoagulant therapy and was qualified for first-line treatment with pazopanib.

The patient started the therapy on July 17, 2015. Dur-ing the first 14 days of therapy, stage II inflammation of the oral mucosa was diagnosed according to common toxicity criteria for adverse events (CTCAE) v. 4.0. In ad-dition, the patient reported reduced appetite, headaches, muscle aches, and increased blood pressure. During the next 14 days of treatment, blood pressure increased even more up to 220/110 mm Hg, and the patient required medical assistance in the hospital emergency department, where the treatment of hypertension was modified. Pazo-panib therapy was stopped to normalise blood pressure, and it was decided to return to treatment at a reduced dose of 600 mg once a day. However, due to persistently high blood pressure values, despite the intensification of hypotensive treatment, it was necessary to further reduce the dose of pazopanib to 400 mg once daily. During fur-ther therapy, the patient remained in good condition and the blood pressure values remained normal.

According to Response Evaluation Criteria in Solid Tumours (RECIST) v. 1.1, in imaging studies performed after three months of treatment, the presence of partial response (PR) was noted, which lasted for the next six months. In May 2016 the progression of the disease in the form of numerous new metastases in the liver (the largest with a diameter of 17 mm) and a metastatic focal point in the vertebral body L1 was found. The first line of treatment lasted for 11 months.

At the beginning of June 2016, according to the pro-gram of the National Health Fund (NFZ), the patient was qualified for a second line of treatment with axitinib. During the therapy, hoarseness and second-degree diar-rhoea occurred. Due to coexisting arterial hypertension, increasing the drug dose was not possible, the patient continued therapy at a dose of 2 × 5 mg/day. At the

first radiological assessment carried out in September 2016 progression of the disease was observed. There was an increase in metastases in the liver; the largest at that time had a diameter of 23 mm. In addition, progression of the metastatic focus in the L1 vertebra with spinal muscle infiltration and tumour penetration into the spinal canal was observed. The second line of treatment was carried out for three months. Due to the pain, the patient was referred to lumbar radiotherapy and later received 4 mg of zoledronic acid every four weeks. Since September 2016 he has not been treated systemically due to the lack of available therapeutic options in the third line of treatment.

In December 2016 the patient was qualified for treat-ment with nivolumab under the Early Access Programme. A CT examination performed before starting the patient on the third line of treatment showed further progression of metastatic lesions in the liver, with the largest diameter 42 mm. In addition, the scan showed reduction of spinal muscle infiltration at L1 level, probably due to radio-therapy (8 Gy/T). At the beginning of immunotherapy, the patient was in good general condition with well con-trolled blood pressure and sugar levels. Treatment with nivolumab was carried out at a dose of 3 mg/kg starting from January 4, 2017 and then from May 2018 at a con-stant dose of 240 mg every two weeks [7].

During the treatment, first-degree diarrhoea epi-sodes occurred and a first-degree creatinine level in-crease was observed but did not exceed that level. These did not require additional interventions [8]. In the CT examination performed after three months of treatment, metastases in the liver were reduced to 24 mm in the largest diameter, and in the next evaluation — to 10 mm. Partial response to treatment (according to RECIST 1.1 criteria) has been maintained from June 2017 until now (October 2018). The patient has been continuing the treatment for 22 months, all the time with good tolerance and quality of life.

Table 1 presents the results of all lines of treatment.

Table 1. Course of treatment of the patient

Line of treatment I II III

Drug Pazopanib Axitinib Nivolumab

Best response PR PD PR

Treatment time, PFS (months) 11 3 > 22

The cause of ending of the treatment Progression Progression Treatment is continued

Treatment interruption Yes No No

Dose reduction Yes (twice) No, and without dose increasing

Does not apply

Adverse effects Yes Yes Yes

Adverse effects 3/4 Yes No No

Quality of life Quite good Good Very good

PD — progression of the disease; PR — partial response; PFS — progression-free survival

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Discussion

Treating the vascular endothelial growth factor receptors (VEGFR) with tyrosine kinase inhibitors is as-sociated with the occurrence of class-specific side effects such as arterial hypertension, hypothyroidism, inflam-mation of the oral mucosa, or chemotherapy-induced acral erythema [9]. In the course of immunocompetent treatment with PD-1 receptor inhibitors, a different pro-file of side effects is observed. Typical adverse reactions associated with anti-PD-1 treatment include pneumonia, nephritis, diarrhoea, and hypothyroidism, which require appropriate management depending on the severity [8].

In the CheckMate025 studies, 79% of patients treated with nivolumab had adverse reactions of all de-grees, compared to 88% treated with everolimus, while third- and fourth-degree adverse effects were observed in 19% vs. 37% of these patients, respectively. The qual-ity of life in the group of patients receiving nivolumab was also better compared to the group of patients treated with everolimus [4]. In this case, it is worth noting that the patient remains in good general condition during immunotherapy, with minor side effects.

The benefit of nivolumab treatment in the Check-Mate 025 study was reported in patients in all prognostic categories. Prognosis of patients was evaluated on the basis of the scale consisting of three factors (presence of anaemia, hypercalcaemia, and reduced efficiency). Pa-tients without the above-mentioned factors were a group with favourable prognosis, with one unfavourable factor — a group with moderate prognosis, and finally with two or three factors — a group with poor prognosis. In this study, considering the group with favourable prog-nosis, the median overall survival (OS) for patients treated with nivolumab was not achieved compared to 19.6 months in patients treated with everolimus (HR 0.80). In the group with moderate prognosis the median OS was 21.8 vs. 18.4 months (HR 0.81), and in the group with poor prognosis 15.3 vs. 7.9 (HR 0.48) [4, 10].

Benefit of treatment was also noted among patients with metastases to the bones and liver, i.e. those belong-ing to the group with worse prognosis. In patients with liver metastases the median OS was 18.3 vs. 16.0 months (HR 0.81), whereas in the group with bone metastases it was 18.5 vs. 13.8 months (HR 0.72). In the group of patients with pulmonary metastases better results were obtained — the median OS was 25 vs. 18.7 months (HR 0.72) [10].

The percentage of objective response rate (ORR) in the group of patients treated with nivolumab was 25% compared to 5% in patients receiving everolimus; the dif-

ference was statistically significant (p < 0.001). A large proportion of the objective responses obtained in the CheckMate 025 study during treatment with nivolumab were permanent [4]. In the presented case, partial re-sponse with the third line of treatment was observed in a patient with moderate prognosis, with metastases to the bones and liver, which lasted for 16 months. The re-sults of treatment with immunotherapy are better in the presented case in comparison to treatment with previous therapies in which tyrosine-kinase inhibitors were used.

Conclusions

Nivolumab is an anti-PD-1 drug with proven ef-fectiveness in the treatment of patients with RCC and a favourable toxicity profile. In Poland it is currently available for use in the second line of treatment of advanced ccRCC and is a valuable therapeutic option in this indication.

Reference

1. Wysocki P, Borkowski T. Nowotwory układu moczowo-płciowego. In: Krzakowski M. ed. Onkologia kliniczna, t. 2. Via Medica, Gdańsk 2015: 751–760.

2. Escudier B, Porta C, Schmidinger M, et al. ESMO Guidelines Com-mittee. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016; 27(Suppl 5): 58–68, doi: 10.1093/annonc/mdw328, indexed in Pubmed: 27664262.

3. Krawczyk P, Wojas-Krawczyk K. Immunoterapia ukierunkowana na immunologiczne punkty kontroli. In: Wysocki P. ed. Immunoonkologia. ViaMedica , Gdańsk 2016: 47–57.

4. Motzer R, Escudier B, McDermott D, et al. Nivolumab versus everoli-mus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373(19): 1803–1813, doi: 10.1056/nejmoa1510665.

5. Xu JX, Maher VE, Zhang L, et al. FDA approval summary: nivolumab in advanced renal cell carcinoma after anti-angiogenic therapy and exploratory predictive biomarker analysis. Oncologist. 2017; 22(3): 311–317, doi: 10.1634/theoncologist.2016-0476, indexed in Pubmed: 28232599.

6. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratifi-cation of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999; 17(8): 2530–2540, doi: 10.1200/JCO.1999.17.8.2530, indexed in Pubmed: 10561319.

7. Zhao X, Suryawanshi S, Hruska M, et al. Assessment of nivolumab bene-fit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann Oncol. 2017; 28(8): 2002–2008, doi: 10.1093/annonc/mdx235, indexed in Pubmed: 28520840.

8. Brahmer J, Lacchetti C, Schneider B, et al. American Society of Clinical Oncology. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018; 36(17): 1714–1768, doi: 10.1200/jco.2017.77.6385.

9. Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst. 2012; 104(2): 93–113, doi: 10.1093/jnci/djr511, indexed in Pubmed: 22235142.

10. Escudier B, Sharma P, McDermott D, et al. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017; 72(6): 962–971, doi: 10.1016/j.eururo.2017.02.010.

http://dx.doi.org/10.1093/annonc/mdw328


http://dx.doi.org/10.1056/nejmoa1510665

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http://dx.doi.org/10.1200/JCO.1999.17.8.2530


http://dx.doi.org/10.1093/annonc/mdx235


http://dx.doi.org/10.1200/jco.2017.77.6385

http://dx.doi.org/10.1093/jnci/djr511


http://dx.doi.org/10.1016/j.eururo.2017.02.010

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CASE REPORT


Lek. Aneta Lebiedzińska

Oddział Onkologii i Immunoonkologii

Szpital MSWiA w Olsztynie


Aneta Lebiedzińska1, 2, Dawid Sigorski1, Maciej Michalak3, Zygmunt Kozielec4, Anna Doboszyńska2, Dariusz Zadrożny5, Paweł Różanowski1 1Clinical Department of Oncology and Immuno-Oncology, The Ministry of Interior and Administration’s Hospital with Warmia and Mazury Cancer Centre in Olsztyn, Poland 2Department of Pulmonology, Faculty of Health Sciences, University of Warmia and Mazury in Olsztyn, Poland 3Department of Radiology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland4Department of Pathomorphology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland 5Department of General and Oncological Surgery, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Poland

Complete pathological remission after palliative therapy with sorafenib in hepatocellular carcinoma — case report

ABSTRACT Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver cancer. The five-year overall survival

(OS) in men diagnosed with HCC does not exceed 9%. Patients (pts) with advanced disease are treated with

sorafenib (multikinase inhibitor). In randomised trials the OS advantage was within the range of three months

for sorafenib. Stabilisation of disease was achieved in 71% of patients, and no case of CR was reported. We

present a case of 60-year-old patient with locally advanced cT3aN0M0 (stage IIIA according to seventh TNM)

bifocal HCC (12 × 10 cm and 10 × 8 cm). The diagnosis was confirmed by pathologic examination. Due to the

clinical stage, palliative treatment with sorafenib was administered from January 2016 to February 2017. A clini-

cal partial response (cPR) enabled surgery. In May 2017, left-sided liver bisegmentomy and resection of residual

lesion in segment 6 were performed. The pathological report revealed ypCR. Subsequently, pathology verifica-

tion changed the primary diagnosis to PR. In September 2017 thermoablation of lesion in segment 5 of the liver

was performed. The increased AFP (alpha-fetoprotein) level at baseline was normalised during treatment. The

sorafenib therapy was completed after one year. The patient remains in follow-up with no evidence of relapse.

Treatment with sorafenib in the presented case enabled radical therapy, so the palliative treatment turned out to

be an induction treatment. Clinical CR (especially pCR) in advanced non-operable solid tumours after systemic

treatment is quite rare (3–15%), and even less common in HCC. So far, only a few cases of achievement of CR

during sorafenib therapy in HCC have been described.

Key words: hepatocellular carcinoma, sorafenib, complete response

Oncol Clin Pract 2019; 15, 2: 127–131


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Introduction

Hepatocellular carcinoma (HCC) is the most com-mon primary liver malignant tumour. There are more than 600,000 new cases per year in the world (in Poland about 1–2 thousand cases are diagnosed annually). Hepatocellular carcinoma is the third cause of can-cer-related death [1–4]. The five-year overall survival (OS) in male patients diagnosed with HCC does not exceed 9% [5]. The most common aetiological factors

leading to increased incidence include alcoholic liver cirrhosis or caused by hepatitis C or B virus (HCV or HBV) infection, diabetes, obesity, exposure to aflatox-ins, genetic factors associated with congenital metabolic disorders such as haemochromatosis, tyrosinaemia (type I), galactosaemia, porphyria, or alpha 1-anti-trypsin deficiency. Hepatocellular carcinoma is several times more frequent in male than in female patients, and the median of morbidity occurs around the age of 50–60 years [6, 7].


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Figure 1. Baseline status before treatment — 04/01/2016. Tumours in the right and left liver lobe, examination in the venous phase after intravenous administration of iodine contrast medium

Standard chemotherapy is not used in the treatment of patients with advanced and inoperable HCC. The most scientific evidence concerns the use of doxoru-bicin, which produce remissions in approximately 10% of patients. Multidrug regimens do not increase the response rate but are associated with higher toxicity [8]. A breakthrough in systemic treatment of HCC has been the use of sorafenib, a multi-tyrosine kinase inhibitor.

Case report

In January 2016, a 60-year-old male patient diag-nosed with HCC was admitted to the oncology depart-ment. The diagnosis was established on the basis of core needle biopsy (CNB) of hepatic lesions described in imaging studies performed in the course of routine internal diagnostics due to increased exercise intoler-ance in the last few months.

At admission, the patient was in a good general condition, the ECOG (Eastern Co-operative Oncology Group) performance status (PS) was 1, and the patient did not report clinically significant complaints. Concomi-tant diseases included well-controlled hypertension, type 2 diabetes, obesity, and mixed hyperlipidaemia.

Computed tomography (CT) imaging of the chest, abdomen, and pelvis was performed in January 2016 (Fig. 1) — it revealed hypervascular tumours with a wash-out effect and central disintegration. There were two lesions identified: in segment 6 with transverse dimensions 120 × 100 mm and in segments 2/3 with size 100 × 82 mm. No metastases outside the liver were found. Clinical stage was defined as cT3aN0M0 (IIIA according to TNM, seventh edition).

Infection with hepatitis B and C viruses (HBV and HCV) was excluded. The hepatic efficiency was assessed as Child-Pugh A (5 points), with no cirrhosis, and base-line alpha-fetoprotein (AFP) level before treatment was 83.88 IU/mL (N 0–5.8 IU/mL).

The patient was qualified for first-line palliative treatment with sorafenib in a daily dose of 800 mg orally.

From January 12, 2016 to February 6, 2017 the patient received 15 courses of treatment with good initial tolerance. Fatigue syndrome (Common Toxicity Criteria [CTC] 1) and hand–foot syndrome (CTC 1) were observed. The patient did not required reduction of initial sorafenib dose.

In subsequent imaging studies, a gradual decrease in the size of liver lesions was noted. In the follow-up CT study in February 2017 (Fig. 2, 3), two lesions were visible: in segment 6 (55 × 43 mm) and in segment 3 (55 × 37 mm). Clinical partial remission (cPR) was described, according to the RECIST (Response Evalu-ation Criteria in Solid Tumours) classification 1.1. Nor-malisation of AFP level was obtained after 12 weeks of treatment.

Due to a very good treatment response, the patient was qualified for radical surgical treatment. In May 2017, left-sided liver bisegmentomy with resection of residual segments 2 and 3 and resection of liver segment 6 were performed. Complete remission (ypCR) was found — no cancer cells were detected in postoperative histological evaluation. Due to the fact that CR is an extremely rare phenomenon in this type of cancer, and because of the preoperative radiological response at the level of partial remission, re-evaluation of histological preparations was performed. It was found that HCC islands were visible in the postoperative material, surrounded by fibrosis and lymphocytic infiltrates, which corresponds to partial remission (ypPR) in response to preoperative treatment rather than complete remission as described in the primary material.

The follow-up CT imaging performed in June 2017 (Fig. 4) showed the state after resection of left-sid-ed lobe segments — the presence of a tumour-resection bed in the right lobe, without features of local recur-rence. In contrast, in the right lobe a new hypervascular nodule with wash-out effect was described (Fig. 5). In September 2017, thermoablation of the focal area, vis-ible in imaging studies in segment 5 was performed. Due to the lack of lesions that can be monitored (measurable) in imaging studies and a very good effect of local treat-ment, the patient was considered cured and excluded from treatment within the drug program. The patient has not received systemic therapy with sorafenib since February 2017. He has been observed since then. The last CT scan was performed in September 2018 — the picture remained stable and there were no signs of recurrence or dissemination of the disease. AFP level

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Aneta Lebiedzińska et al., Complete pathological remission after palliative therapy with sorafenib in hepatocellular carcinoma

Figure 3. Status after sorafenib treatment — 02/02/2017. Shrinkage of lesion in the right lobe, venous phase

Figure 2. Status after sorafenib treatment — 02/02/2017. Shrinkage of lesion in the left lobe, venous phase

Figure 5. Status after surgery — 23/06/2017. The control shows the metastasis in the right lobe

Figure 4. Status after resection of the lateral segments (2 and 3) of the left lobe together with the tumour and segment 6 — 23/06/2017

remained within normal limits. The patient has reached over 12 months of disease-free survival (DFS). The use of sorafenib in the described case allowed us to conduct a radical procedure, and the treatment, assumed to be palliative, became a remission-inducing and ena-bling resection.

Discussion

Patients with inoperable HCC are qualified for therapy with sorafenib, an inhibitor of tyrosine kinase of membrane receptor and serine/threonine kinases of the intracellular RAS/MAPK signalling pathway. Sorafenib is the first drug to be used in the prospective

randomised SHARP study and extended the median OS in patients with HCC by three months; 71% of patients achieved stabilisation of the disease, no CR was reported. Only 2% of patients achieved a clinical response at the PR level [9]. The results obtained were confirmed in the ASIA-PACIFIC study; however, the small sample size (226 compared to 602 patients in the SHARP study) requires caution in the interpretation of its conclusions [10].

To date, only a dozen CR cases have been described in the literature in patients with HCC during sorafenib treatment, and pCR has been found only in a few cases in the world [11].

In the recent years, several clinical trials have been completed with drugs that can be used in HCC systemic

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treatment (e.g. sunitinib, erlotinib, everolimus, bri-vanib), but none of them has yet proved its effectiveness in HCC patients [12–15].

In 2016, a study with regorafenib (RESORCE) was completed, which showed a positive effect of the drug on progression-free survival (PFS) prolongation by ap-proximately three months in comparison with placebo in second-line treatment [16].

The results of other studies have been published — in reference to the first-line treatment REFLECT study with lenvatinib compared to sorafenib, in further treatment lines in the CELESTIAL study with cabozan-tinib, and in the REACH-2 study with ramucirumab, which proved the effect of these drugs on extended survival versus placebo [17].

In 2018, very interesting results of a retrospective analysis were published on the basis of sorafenib treat-ment of over 800 patients diagnosed with HCC, among which a subgroup of 81 patients (10%) was identified receiving the drug for more than 12 months. In the group with long-term treatment 11 patients (13.7%) achieved radiological PR, and another five (6.3%) patients clinical CR. Two patients underwent liver transplantation, and three others underwent resection of a primary tumour. The authors of the study suggest that patients receiving sorafenib for over one year can have significant benefit in terms of long-term survival [18].

To date, predictive factors of response to treatment have not been identified in HCC patients receiving multi-kinase inhibitors. In the majority of patients, the results of treatment are not satisfactory. Currently, only sorafenib treatment in the first line is generally available in Poland (drug program). Treatment may be provided to patients without extrahepatic metastases, in good general condition, and without signs of liver failure. Due to the lack of availability of subsequent treatment lines, it was extremely difficult to decide about discontinuation of sorafenib treatment in the present case. Maintenance therapy with sorafenib after surgical intervention and thermoablation is a therapeutic option; nevertheless, its course is so non-standard that there are no guidelines for further treatment or evidence of the efficacy of continuing systemic treatment.

It is noteworthy that, based on previous experience, the results of adjuvant treatment with sorafenib in pa-tients who underwent radical surgical treatment did not improve DFS or OS [19]. At present, the patient has been under observation for almost 1.5 years without the need to receive treatment — he lives in a sense of health and has returned to normal life and social roles.

New molecular targets that might be useful in the treatment of HCC patients are still being sought. The results were published of studies with anti-PD-1 (nivolu-mab, pembrolizumab), anti-PD-L1 (durvalumab), and anti-CTLA-4 (tremelimumab) drugs as well as

anti-PD-L1 (atezolizumab) in combination with beva-cizumab [17]. These drugs are tested both in palliative and in adjuvant treatment. It may also be possible to identify the predictors of treatment response in patients with HCC undergoing immunotherapy.

There are first reports on the impact of PD-L1 ex-pression level, baseline AFP concentration, and CD8+ T cell infiltration, which may corelate with response to immune checkpoint-targeted cancer immunotherapies [20, 21]. The correlations of immune response with mi-crobiota or monocyte level in peripheral blood that are the subject of many ongoing studies are noteworthy [22].

Based on the aforementioned case report, the im-portance of the quality of histological evaluation results should also be underlined. In the presented case, the pCR described in another centre was questioned and, after consultation, finally described as pPR. Complete pathological remissions in HCC after using sorafenib should now be treated as anecdotal, and each of them should undergo independent histological evaluation in the reference centre.

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CASE REPORT


Lek. Kamila Kaźmierczak

Oddział Ginekologii Operacyjnej,

Onkologicznej i Endoskopowej

Wielkopolskie Centrum Onkologii

ul. Garbary 15, 61–866 Poznań


Kamila Kaźmierczak1, Joanna Kufel-Grabowska1, 2, Tomasz Kozłowski3, Błażej Nowakowski1, 4 1Department of Surgical, Oncological and Endoscopic Gynaecology, Greater Poland Cancer Centre, Poznan, Poland2Department of Electroradiology, Poznan University of Medical Sciences, Poznan, Poland3Department of Anaesthesiology and Intensive Care, Greater Poland Cancer Centre, Poznan, Poland4Department of Cancer Pathology and Prophylaxis, Poznan University of Medical Sciences, Poznan, Poland

When to say “no” to a patient with an ovarian tumour and in poor general condition?

ABSTRACT Neuroendocrine tumours (NET) originating from the ovary are very rare, constituting about 0.52–1.7% of all

NETs. Primary carcinoids constitute about 0.1% of ovarian tumours and 0.3% of all carcinoids. They rarely show

hormonal activity. They are most often diagnosed post-operatively, based on pathomorphological examination

using immunohistochemical methods. Due to the small number of cases, most information on the management

of patients with this diagnosis comes from retrospective studies and case reports.

This paper presents a case report of a 63-year-old woman who was admitted to the department of surgical

gynaecology with the diagnosis of a 15-cm right ovary tumour. Her general condition was poor due to severe

respiratory failure and severe tricuspid valve insufficiency. The clinical picture and the performed echocardiographic

examination aroused the suspicion of carcinoid heart disease (Hedinger syndrome — a cardiological syndrome

of carcinoids). Due to the determination and cooperation of a multidisciplinary medical team, despite a very bad

prognosis, the patient underwent surgery. Immediately after the operation, the patient’s condition was critical, but it

gradually improved. In the postoperative pathomorphological examination, a highly differentiated neuroendocrine

tumour (grade 1 – G1) was diagnosed at stage IA according to the FIGO classification. The patient was referred

to the endocrinology department, where receptor scintigraphy was performed without revealing other tumour

changes. The patient did not require adjuvant therapy. Making a decision about surgical treatment of a patient in

poor physical condition with a possibly reversible cause of heart failure was the right thing to do, and it allowed

her to return to normal physical activity.

Key words: neuroendocrine tumour, carcinoid syndrome, carcinoid heart disease, Hedinger syndrome

Oncol Clin Pract 2019; 15, 2: 132–134


2019, Vol. 15, No. 2, 132–134

DOI: 10.5603/OCP.2019.0018

Translation: dr Elżbieta Stelmaszczyk


ISSN 2450–1654

Introduction

Neuroendocrine tumours (NET) of the ovary occur very rarely, constituting 0.52–1.72% of all NETs [1]. Primary carcinoids constitute about 0.1% of ovarian tumours and 0.3% of all carcinoids [2]. Among primary neuroendocrine ovarian tumours, there are carcinoids, large-cell carcinomas, and small-cell carcinomas of the hypercalcaemic and lung type [3]. These diseases are divided based on the FIGO classification. In over half of these cases, carcinoids are diagnosed at an early stage

and the prognosis is very good at that time with five-year survival of over 90% [4]. At more advanced stages, survival is much worse, and only 33% of the patients survive for over five years [5].

Neuroendocrine tumours are usually located in the digestive tract (75–85%), and more rarely pertain to the respiratory system (15–25%). Most of them show no clinical symptoms and are diagnosed incidentally. In 20–30% of the patients, the first symptoms are re-lated to the production of hormones, which enables the diagnosis of carcinoid syndrome. The most common

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Kamila Kaźmierczak et al., When to say “no” to a patient with an ovarian tumour and in poor general condition?

symptoms of carcinoid syndrome include flushing and diarrhoea, along with symptoms of bronchospasm and heart damage. These symptoms are related to the hy-persecretion of serotonin, and other active substances, and occur in the case of significantly advanced disease in patients with liver metastases [6]. In the case of liver failure due to the presence of metastases, an excess of serotonin flows into the right heart directly with venous flow. The precise pathomechanism of serotonin-induced valve damage is not known — the visible effect is the appearance of lesions mainly in the endocardium and the endothelial layer of large vessels, which manifest as sharply delineated fibrous thickening. These lesions cause morphological, and subsequently mechanical, damage to the valves, mainly those of the right heart, which leads, most often, to regurgitation (and less often to tricuspid stenosis). Cardiological damage is seen in 50% of patients with carcinoid syndrome and it significantly worsens their prognosis due to progressive right-heart failure.

Cardiological carcinoid syndrome (Hedinger syn-drome) without other clinical symptoms exists unusu-ally seldom. In the case of the presented patient with a tumour of the right ovary, venous blood flows directly from the inferior vena cava, omitting the portal circula-tory system, due to which an excess of serotonin is not metabolised by the hepatocytes, causing “right heart” damage.

Case report

In November 2017, a 63-year-old patient with diag-nosis of a tumour of the right ovary, with a diameter of 15 cm, was referred to the Gynaecology Clinic of the Greater Poland Oncology Centre to be qualified for surgical treatment. The patient was in intermediate overall condition, and peripheral cyanosis along with ab-dominal swelling and swelling of the limbs was notable. The patient complained of dyspnoea on exertion, and increased concentration of CA-125 (cancer antigen-125; 88.66 u/ml) as well as HE4 (human epididymis protein; 159.50 pmol/l) was found. On gynaecological and vaginal sonographic examination, the presence of a right ovar-ian tumour was confirmed, with a diameter of 15 cm, which, due to its size, constituted an absolute indication for surgical treatment. Sonographic examination of the uterus and left adnexa was insignificant. The patient was referred to a cardiology ward for a full evaluation of the cardiovascular system. Within three weeks of the gynae-cological consultation, the patient’s overall condition deteriorated significantly — respiratory insufficiency, lower body oedema, and peripheral cyanosis worsened and central cyanosis appeared. The patient was unable

to function independently and spent most of her days in a half-sitting position. An echocardiogram revealed severe tricuspid regurgitation, a lack of flap coaptation, and normal ventricular systolic activity. Peripheral blood saturation was 80%. The general clinical picture raised suspicion of carcinoid heart disease. A rise in markers was also observed, with the values being — Ca--125 (133 u/ml) and HE4 (496 pmol/l). Bilateral renal retention was found, with ureteral widening, and the presence of free fluid in the lesser pelvis.

The most likely cause of worsening right ventricular insufficiency was pressure on the inferior vena cava cause by a massive tumour of the right ovary; due to this, the patient was transferred to the oncological gynaeco-logy ward. The patient was qualified for a life-saving procedure, having been informed of the high risk of perioperative complications. Anaesthesia and perio-perative care for this patient constituted a complex medical problem, because — as well as right ventricular insufficiency — symptoms resulting from pressure on the inferior vena cava were present. Before the procedure, a detailed risk assessment according to the NSQIP (National Surgical Quality Improvement Program) was done — the risk of serious complications, includ-ing death, was estimated at 22.7%. The results were discussed during a meeting of the team of gynaecologists and anaesthesiologists, the patient and her family were also informed on the above results. When making the decision to ope rate, the fact that the planned surgical procedure, despite a high risk of complications, was the only possibility of treating the cause, and ultimately made a final diagnosis possible. The removal of the pressure on the vena cava caused by the tumour was a condition for any possible cardiosurgical treatment.

After the procedure, the patient’s overall condition was severe — she spent 16 days in the intensive care unit, including nine days of sedation, she was intubated, ventilated mechanically — with an oxygen concentration up to 65% — and also required pharmacological support of the cardiovascular system, as well as diuresis stimula-tion. A gradual improvement of overall condition was observed. At the time of transfer to the gynaecological ward, the patient was cardiovascularly stable, breathed without dyspnoea even in supine position, was supported with passive oxygen therapy only at times, and had a blood oxygen saturation of 95%. In the final pathologi-cal testing, a highly-differentiated (G1) NET of the right ovary was found. On the 20th day after surgery, the pa-tient was transferred to the endocrinology department, where imaging was performed. An octreoscan did not reveal the presence of NET focal lesions, the patient did not require adjuvant treatment. The patient’s general condition improved significantly, and the symptoms of inferior vena cava syndrome withdrew.

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Discussion

The average lifespan of patients with cardiac car-cinoid syndrome, with symptoms of moderate and severe cardiac insufficiency (NYHA III/IV), is about 11 months. Most patients die due to progressive heart failure due to tricuspid valve regurgitation. The aver-age delay in cardiosurgical treatment due to the lack of clear guidelines for invasive treatment of Hedinger syndrome amounts to 24 months, which significantly worsens the prognosis [7]. Currently, based on a 20-year observation of over 200 patients with cardiac carcinoid syndrome at the Mayo Clinic in the USA, it is thought that early surgical intervention in this group of patients may increase their chances of survival [8]. Three-year survival is noted amongst 31% of patients with cardiac carcinoid syndrome, compared to 60% for those without cardiological involvement [9].

The main clinical symptoms in the patient discussed here were those of severe right-heart failure and inferior vena cava syndrome, which made surgical intervention a high-risk path. The echocardiographic imaging could have suggested carcinoid heart disease; however, a lack of general symptoms caused by an excess of serotonin suggested a different cause for “right heart” damage. According to the latest guidelines by the Polish Neu-roendocrine Tumour Network (Polska Sieć Guzów Neu-roendokrynnych) from 2017 regarding the diagnostics and treatment of patients with neuroendocrine tumours, chromogranin concentration is no longer recommended as routine testing, and the serial assessment of chro-mogranin may be useful for monitoring the course of the disease. In carcinoid syndrome, 5-hyrdoxyindoloacetic acid concentration is used [10].

The symptoms of carcinoid syndrome were not present in our patient, and the rise of CA-125 and HE4 markers, along with the presence of free fluid in the pelvic cavity, suggested a malignant tumour typical of the ovary. Imaging tests showed no traits of dissemi-nation, which was an argument for taking on the risk of surgery. Considering the possibility of cardiosurgical treatment after the symptoms of inferior vena cava syndrome have subsided, it was decided that an excision of the tumour would be performed. This decision was extremely risky, but an attempt at the procedure gave

a chance for remission, or a prognosis improvement, while further symptomatic treatment would have ended up in a rapid death. Although symptomatic treatment with diuretics, digoxin, and limiting the intake of fluids and sodium may alleviate the symptoms of right-heart failure at first, they do not improve the final progno-sis. Removal of the primary tumour may be associated with the patient’s complete recovery but will not undo the valve damage [11, 12]. The only effective treatment of valve defects due to carcinoid syndrome is cardiosur-gical treatment consisting of valve replacement surgery, which decreases the symptoms and increases quality of life. In the case of the presented patient, an active ap-proach caused significant improvement in her overall condition, and thanks to the pathological diagnosis further cardiosurgical treatment is possible. The patient is currently awaiting cardiac surgery.

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CuRRENT LITERATuRE REVIEW

Maciej KaweckiDepartment of Oncology and Radiotherapy, Maria Sklodowska-Curie Institute of Oncology, Warsaw

Modern oncology relies not only on the advances in cancer treatment, but also on the optimization of sup-portive care. Proper pain management, intensive nutri-tional care and appropriate identification and treatment of adverse events results improve outcomes in the both palliative and radical setting. Venous thromboembolic disease, including its’ most dangerous form — pulmo-nary embolism, has direct effect on patient’s survival and quality of life. Thromboembolic disease affect not only cancer patients in the in-patient setting, who nearly always require primary prophylaxis for thromboembolic disease, but also patients treated in the out-patient set-ting, who present various risk of thromboembolic com-plications depending on a cancer type and the specific risk factors (Khorana scale [1]) Depending on the num-ber of risk factors, Khorana scale stratify patients into low, intermediate or high risk group. Achieved result may provide physician with guidance on whether specific patient may benefit from primary venous thromboem-bolic prophylaxis with low-molecular weight heparin (LMWH) administered subcutaneously. Currently, no guidelines recommend routine venous thromboembolic prophylaxis during chemotherapy, leaving this decision to the leading physician. Unfortunately, mostly due to the way of administration, primary prophylaxis with LMWH presents a major burden for cancer patients and can be unacceptable, especially if used long-term. Considering this burden, application of direct oral anti-coagulants (DOAs) instead of LMWH offers attractive alternative. However, due to the increased risk of bleed-ing events and potential drug interactions, introduction of DOAs into clinical practice had had to be preceded by clinical trials dedicated specifically to the cancer pa-tients. Currently, we can refer to the results of two trials assessing effectiveness of DOAs in primary prophylaxis of venous thromboembolic diseases. The results, as often in medicine, are not fully convergent.

The results of first trial were published by Carrier et al. in “The New England Journal of Medicine” on the 21 of February 2019 [2]. The AVERT trial was randomized, double-blinded, phase III clinical trial that compared apixaban, administered orally at a dose of 2.5 mg twice daily, with placebo in cancer patients who

initiated chemotherapy and had intermediate or high risk of thromboembolic events (2 or more point in the Khorana scale). No screening for asymptomatic venous thrombotic disease was performed before treatment initiation. The intervention was planned for 180 days in both trial arms. The trial’s primary endpoint was ob-jective occurrence of venous thromboembolic event in 180-day observation. The primary safety endpoint was occurrence of major bleeding episode. Additionally, safety analysis included also outcomes regarding rate of clinically relevant non-major bleeding (CRNMB) episodes and overall survival. The trial included 574 pa-tients, randomized in 1:1 ratio to both arms, from all 1809 patients screened for eligibility. The primary analysis included 563 patients who received at least one dose of allocated treatment. Median treatment time and rate of treatment discontinuation before planned 180 days was similar between arms. Primary endpoint occurred in 12 patients (4.2%) in the apixaban arm and 28 patients (10.2%) in the placebo arm (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.26–0.65; p < 0.001). During active treatment period the primary endpoint occurred in 3 (1%) patients receiving apixa-ban and in 20 (7.3%) patients receiving placebo. In the safety analysis, major bleeding episode was detected in 10 patients (3.5%) patients in the apixaban arm and in 5 patients (1.8%) in the placebo arm, which resulted in HR of 2.0 (95% CI 1.01–3.95; p = 0.046). Most bleeding episodes were mild, without critical organ bleedings or bleeding-related deaths. During the active treatment period, major bleeding episodes were seen in 6 patients (2.1%) receiving apixaban and in 3 patients (1.1%) receiving placebo. Rate of adverse events were similar between both arms. During observation, 35 patients (12.2%) in the apixaban arm and 27 patients (9.8%) in the placebo arm died, with 87% of deaths related to cancer. As the primary endpoint was met, AVERT study is clearly a positive one. It confirmed value of apixaban in the primary prophylaxis of venous thromboembolic diseases in cancer patients receiving chemotherapy.

The results of second trial were published by Khora-na et al. in the same issue of “The New England Journal of Medicine” from the 21 of February 2019 [3]. CASSINI

Oncology in Clinical Practice 2019, Vol. 15, No. 2, 135–138. DOI: 10.5603/OCP.2019.0020, copyright © 2019 Via Medica, ISSN 2450–1654

Safety and effectiveness of direct oral anticoagulants in the primary prophylaxis of venous thromboembolic disease among cancer patients initiating chemotherapy

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was randomized, double-blinded, phase III trial that compared rivaroxaban 10 mg orally per day with placebo in cancer patients who were initiating chemotherapy, had intermediate or high risk of venous thromboem-bolic disease according to Khorana scale and who had no asymptomatic venous thrombosis. The intervention period was 180 days. Every 8 weeks participants under-went ultrasonographic screening to exclude presence of thrombotic changes in lower extremities. Primary endpoint was composite and consisted from objective occurrence of proximal deep-vein thrombosis in lower extremities, symptomatic deep-vein thrombosis in up-per extremities or distal deep-vein thrombosis in lower extremities, symptomatic or asymptomatic pulmonary embolism and death due to venous thromboembolism as assessed up to 180 days from the treatment initiation. Additional analysis assessing primary endpoint dur-ing active treatment was pre-planned. The primary safety endpoint was the occurrence of a major bleed-ing episode, with the rate of CRNMB as a secondary safety endpoint. The trial included 1080 patients, among whom 49 (4.5%) were excluded due to the presence of asymptomatic thrombosis, and 190 (17.5%) were not randomised due to other reasons. In the end, 841 pa-tients who underwent randomisation (in a 1:1 ratio) represented the intention-to-treat population assessed in efficacy analysis, and 809 patients who received treat-ment represented the safety-analysis population. About 43.7% of patients receiving rivaroxaban and 50.2% of patients receiving placebo discontinued the intervention before reaching the planned 180 days (with similar rates of reasons for discontinuation and mean intervention time of 4.3 months). The primary composite endpoint occurred within the 180-day observation period in 25 pa-tients (6.0%) receiving rivaroxaban and in 37 patients (8.8%) receiving placebo (HR 0.66; 95% CI 0.40–1.09; p = 0.1), with nearly 39% of all events occurring after the treatment discontinuation. In a pre-planned analysis limited to the active treatment period, primary endpoint was noted in 11 patients (2.6%) in the rivaroxaban arm and 27 patients (6.4%) in the placebo arm (HR 0.40; 95% CI 0.20–0.80). Lower rate of thromboembolic com-plications within the arterial system and visceral organs was also noted in the patients receiving rivaroxaban. Additionally, a lower number of deaths was observed in the rivaroxaban arm compared to the placebo arm (20% vs. 23.8%). This was confirmed by a pre-planned composite analysis that included primary endpoint combined with death from all-causes, which occurred in 23.1% of patients receiving rivaroxaban compared to 29.5% of patients receiving placebo (HR 0.75; 95% CI 0.57–0.97). Major bleeding episodes were noted in eight patients (2.0%) receiving rivaroxaban and in four pa-tients (1.0%) receiving placebo, with a HR of 1.96 (95% CI 0.59–6.49). Rates of CRNMB were similar (2.7% in

the rivaroxaban group and 2.0% in the placebo group; the difference did not reach statistical significance). Rates of all adverse events also did not differ between both arms. One case of bleeding-associated death was observed in the rivaroxaban arm. Generally, the CASSINI trial is a negative study, because the primary endpoint was not met. Nevertheless, in contrast to the AVERT trial, no statistically significant increase of rivaroxaban-associated bleeding was observed, and the numerical outcomes achieved during active treatment were clearly superior in the rivaroxaban arm, which argues in favour of rivaroxaban activity in the primary prophylaxis of venous thromboembolic disease.

The presented trials bring important data allow-ing for better understanding of cancer-related venous thromboembolic disease. However, it is difficult to pre-dict their impact on routine clinical practice. Despite the fact that according to the AVERT trial every cancer pa-tient initiating chemotherapy with intermediate or high risk according to Khorana scale should receive primary prophylaxis for venous thromboembolic disease with apixaban, we must be aware of the details that hinder extrapolation of AVERT data to the general population. Firstly, the AVERT trial included only 574 patients from all 1809 screened for eligibility, which indicates significant patient selection. Secondly, despite the reduc-tion of risk of venous thromboembolic events, not even a numerical reduction of deaths was seen in the apixaban arm. In contrast, a marginal trend for improved survival was seen in the placebo arm (HR 0.98–1.71). The deci-sion regarding initiation of apixaban prophylaxis should include the fact that no impact on mortality should be expected. Nevertheless, we may currently reco - gnise apixaban as an oral alternative to LWMH in the primary prophylaxis of venous thromboembolic disease. Concurrently, independently of the negative results of the CASSINI trial, data regarding rivaroxaban activity can be considered interesting. Rivaroxaban prophylaxis numerically reduced the risk of thromboembolic events, with low rates of bleeding complications. Moreover, even though the CASSINI trial was too underpowered to detect differences in survival, a lower rate of deaths was seen among patients receiving rivaroxaban (with number-needed-to-treat [NNT] of only 26). Both trials bring valuable data regarding the safety of DOAs in cancer patients, confirming their acceptable and man-ageable toxicity profile. We currently dispose evidence regarding DOA safety not only in the primary prophy-laxis of venous thromboembolic disease (AVERT and CASSINI trials) but also in treatment and secondary prophylaxis (SELECT-D and Hokusai VTE Cancer trials). If further research provides better tools for patient selection in terms of safety, we may soon expect DOAs to fill in for LMWH as the basic anticoagulants in oncology.

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Maciej Kawecki, Current literature review

It is not a change; it is a revolution — novel options in the first-line treatment of clear cell renal cell carcinoma

Recent years have brought tremendous changes in the treatment of patients with renal cell carcinoma, comparable only with the introduction of tyrosine kinase inhibitors (TKIs) over a decade ago. Renal cell carci-noma, like melanoma or lung cancer, are an example of cancers in which modern immunotherapy shows greatest potential. Currently, nivolumab is an option in second-line treatment after TKI failure and a combina-tion of nivolumab and ipilimumab can be considered as the standard of care in the first-line treatment of patients with intermediate and poor prognosis accord-ing to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Promising data coming from other trials assessing combinations of immunotherapy with other molecularly driven agents suggest further changes in the field of renal cell carci-noma. With the recent results of two phase III trials it is becoming increasingly clear that we should forget about monotherapy in the first-line treatment of patients with advanced clear cell renal cell carcinoma.

The results of the first aforementioned trial, KEY-NOTE-426, were published by Rini et al. in “The New England Journal of Medicine” of 21 March 2019 [4]. KEYNOTE-426 was a randomised, non-blinded, phase III trial that compared standard first-line treatment with sunitinib (50 mg orally per day for four weeks with a two-week break) with an experimental combination of pembrolizumab (200 mg intravenously every three weeks) and axitinib (5 mg orally two times per day con-tinuously, with dose titration if applicable). The trial included patients with previously untreated advanced clear cell renal cell carcinoma and performance of at least 70 according to the Karnofsky scale. The primary endpoint was overall survival (OS) and progression-free survival (PFS). The presented data came from the first interim analysis. From 1062 screened patients, 861 were randomised in a 1:1 ratio to both trial arms. After a me-dian observation time of 12.8 months, the trial met its primary endpoint at statistical significance predicted for first interim analysis. The rate of 12-month survival was 89.9% (95% CI 86.4–92.4) in the combined treat-ment arm compared to 78.3% (95% CI 73.8–82.1) in the sunitinib arm. Median OS was not reached in either of the arms, but the risk of death was 47% lower in patients receiving pembrolizumab with axitinib (hazard ratio for death 0.53; 95% CI 0.38–0.74; p < 0.0001). Median PFS reached 15.1 months (95% CI 12.6–17.7) in the combination group vs. 11.1 months (95% CI 8.7–12.5) in the sunitinib group, with HR reaching 0.69 (95% CI 0.57–0.84; p < 0.001). Benefit in OS and PFS was confirmed in all analysed subgroups, includ-ing all IMDC prognostic groups, and PD-L1 expression

status. The objective response rate was also higher in the pembrolizumab and axitinib arm — 59.3% (95% CI 54.5–63.9) as compared to 35.7% (95% CI 31.1–40.4) in the sunitinib arm (p < 0.001). The rates of all adverse events were similar in both arms — 98.4% in patients receiving combination vs. 99.5% in patients receiving sunitinib. Rates of adverse events grade 3 and were, respectively, 75.8% and 70.6%. Rates of patients who re-quired treatment discontinuation reached 10.7% in the combination arm and 13.9% in the sunitinib arm. Rates of treatment-related adverse events that led to death were 0.9% (four patients) in the pembrolizumab-axitinib group and 1.6% (seven patients) in the sunitinib group. The toxicity profile of the pembrolizumab and axitinib combination was similar to previous studies except for the increased incidence elevated liver enzymes of grade 3 and higher. About 50% of patients who progressed on pembrolizumab and axitinib received subsequent treatment, as compared to 60.7% of patients who progressed on sunitinib (including 37.6% who received PD-1/PD-L1 inhibitors). Based on the results of KEY-NOTE-426 we can currently recognise the combination of pembrolizumab with axitinib as a novel option in the first-line setting for patients with advanced clear cell renal cell carcinoma, irrespective of IMDC prognostic group or PD-L1 expression.

The results of a second trial were published in the same issue of “The New England Journal of Medicine” from 21 March 2019 by Motzer et al. [5]. JAVELIN Re-nal 101 was randomised, unblinded phase III trial that compared standard first-line treatment with sunitinib (50 mg orally per day for four weeks with a two-week break) with an experimental combination of avelumab (10 mg/kg of bodyweight every two weeks) and axitinib (5 mg orally two times per day continuously, with dose titration if applicable) in patients with advanced renal cell carcinoma with a clear cell component, who did not receive prior systemic treatment. The trial included pa-tients with very good (ECOG 0) or good (ECOG 1) per-formance status irrespective of IMDC prognostic group. The primary endpoint was PFS, but an amendment im-plemented before data unblinding introduced two new, independent primary endpoints: PFS and OS in patients with present expression of PD-L1. Secondary endpoints included, among others, PFS and OS in the overall population and response rate. Altogether, 886 patients were recruited and randomised in a 1:1 ratio to both trial arms. A group of 560 patients with PD-L1-positive tumours constituted the primary endpoint population. After a median follow-up in PD-L1-positive population of 9.9 months in combination arm and 8.4 months in su-nitinib arm, statistically significant improvement in PFS

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was seen in the combination arm: 13.8 months (95% CI 11.1 to not reached) vs. 7.2 months (95% CI 5.7–9.7) in the sunitinib arm (stratified HR for progression or death 0.61; 95% CI 0.47–0.79; p < 0.001). The difference in PFS was significant in all analysed subgroups. Due to the low number of deaths in the PD-L1-positive population (13.7% in the combination arm vs. 15.2% in the sunitinib arm), evaluation of overall survival difference did not show statistically significant differences, but the wide range of confidence intervals should be noticed. Benefit in term of PFS was also seen in the general popula-tion: 13.8 months (95% CI 11.1 to not reached) in the patients receiving avelumab and axitinib vs. 8.4 months (95% CI 6.9–11.1) in the patients receiving sunitinib (stratified HR for progression or death 0.69; 95% CI 0.56–0.84; p < 0.001). Similarly to the PD-L1-positive population, low death rates in the general population (14.3% in the combination arm vs. 16.9% in the sunitinib arm) hindered evaluation of overall survival and only showed a trend towards benefit from avelumab and axitinib (stratified HR for death 0.78; 95% CI 0.55–1.08; p = 0.14). The response rate in the PD-L1-positive population was 55.2% (95% CI 49.0–61.2) in the com-bination arm vs. 25.5% (95% 20.6–30.9) in the sunitinib arm. Similar response rates were achieved in the general population (51.4% vs. 25.7%, respectively). Rates of all adverse events were 99.5% in patients receiving combi-nation vs. 99.3% in patients receiving sunitinib. Rates of adverse events grade 3 and higher were, respectively, 71.2% and 71.5%. Adverse events that led to treatment discontinuation occurred in 7.6% of patients in the combination arm and 13.4% of patients in the sunitinib

arm. Deaths related to adverse events occurred in three patients receiving avelumab with axitinib and in one patient receiving sunitinib. After disease progression, 20.8% of patients in the combination arm and 39.2% of patients in the sunitinib arm received subsequent treatment. Most of the patients (66.7%) in the sunitinib arm received therapies aimed at PD-1 or PD-L1 after study discontinuation. Results of the JAVELIN Renal 101 trial suggest that a combination of avelumab and axitinib provides benefit over standard treatment for patients with advanced clear cell renal cell carcinoma in the first line of treatment. Considering the increase in overall survival seen in the KEYNOTE-426 trial, it cur-rently seems that pembrolizumab-based combinations are more promising, at least until publication of further results of the JAVELIN Renal 101 trial.

Both described trials are examples of revolution-ary changes in the first-line treatment of renal cell carcinoma. Although standard treatment for a long time, monotherapy with TKIs is now outdated. Cur-rently important clinical questions include the choice, which patients should receive immunotherapy doublet (nivolumab + ipilimumab) and which combination of im-munotherapy with TKIs or another antiangiogenic agent. Moreover, including only advanced trials, the nearest future may provide us with at least four immunotherapy combinations with proven benefit on overall survival. In perfect conditions, the decision regarding treatment in each individual is becoming more difficult. In Poland, we are left with technology that should be called obsolete. From a bitter, ironic perspective, one must admit that the decisions are a lot simpler if there is no choice.

References

1. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008; 111(10): 4902–4907, doi: 10.1182/blood-2007-10-116327, indexed in Pubmed: 18216292.

2. Carrier M, Abou-Nassar K, Mallick R, et al. AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019; 380(8): 711–719, doi: 10.1056/NEJMoa1814468, indexed in Pubmed: 30511879.

3. Khorana AA, Soff GA, Kakkar AK, et al. CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019; 380(8): 720–728, doi: 10.1056/NEJMoa1814630, indexed in Pubmed: 30786186.

4. Rini BI, Plimack ER, Stus V, et al. KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019; 380(12): 1116–1127, doi: 10.1056/NEJMoa1816714, indexed in Pubmed: 30779529.

5. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019; 380(12): 1103–1115, doi: 10.1056/NEJMoa1816047, indexed in Pubmed: 30779531.

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2019, Vol. 15, Number 2 ISSN 2450–1654

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