UNIVERSITY OF MEDICINE AND PHARMACY „GRIGORE … · UNIVERSITY OF MEDICINE AND PHARMACY...
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UNIVERSITY OF MEDICINE AND PHARMACY „GRIGORE T. POPA” IAȘI PhD Thesis Summary HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY ASSOCIATED WITH CYTOREDUCTIVE SURGERY IN PERITONEAL CARCINOMATOSIS OF GASTROINTESTINAL ORIGYN SCIENTIFIC COORDINATOR, PROFESSOR DR. SCRIPCARIU Viorel PhD STUDENT HUŢANU Ionuţ 2013
Transcript of UNIVERSITY OF MEDICINE AND PHARMACY „GRIGORE … · UNIVERSITY OF MEDICINE AND PHARMACY...
UNIVERSITY OF MEDICINE AND PHARMACY „GRIGORE T. POPA” IAȘI
PhD Thesis
Summary
HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY ASSOCIATED
WITH CYTOREDUCTIVE SURGERY IN PERITONEAL
CARCINOMATOSIS OF GASTROINTESTINAL ORIGYN
SCIENTIFIC COORDINATOR,
PROFESSOR DR. SCRIPCARIU Viorel
PhD STUDENT
HUŢANU Ionuţ
2013
Research funded by the project “Burse doctorale pentru creşterea
competitivităţii în domeniul medical şi farmaceutic” POSDRU/88/1.5/S/63117,
cofounded from the European Social Fund through the Operational Program for
Human Resources Development 2007-2013
Main intervention field: 1.5 „Doctoral and post-doctoral program
supporting the research”
Project title: „Doctoral fellowships for the increase of competitiveness in
the medical and pharmaceutical field”
Beneficiary: “Gr. T. Popa” University of Medicine and Pharmacy of Iasi
Partner : University of Medicine and Pharmacy of Timişoara
The thesis consists of:
- theory (40 pages )in four Chapters
- personal research (95 pages) in five Chapters
- 352 references
- 63 pictures
- 25 tables
- 2 B+ aticles and 5 ISI indexed published or accepted
In this abstract, the table of contents and the number for each figure is the same as in
the thesis
Key words
Peritoneal carcinomatosis, HIPEC, peritonectomy, cytoreduction,
pseudomyxoma peritonei, diffuse malingnant mesothelioma
Table of contents
Personal motivations 9
General Part.Level of acknowledge 11
CHAPTER 1 Considerations on peritoneal carcinomatosis
Anatomy and psysiopathology 13
1.1.I. Ultrastructure of peritoneum 13
1.1.II. Molecular biology of peritoneal carcinomatosis 14
1.2. Clinical aspects in peritoneal carcinomatosis 16
1.3. Imaging of peritoneal carcinomatosis 16
CHAPTER 2 Hyperthermic intraperitoneal chemotherapy 19
2.1. Intraperitoneal assessment of the extent of peritoneal carcinomatosis 19
2.2. Hyperthermic intraperitoneal chemotherapy (HIPEC) 20
2.3. The evolution of the treatment of peritoneal carcinomatosis 21
2.4. Peritonectomy procedures – technique 22
CHAPTER 3 Role of HIPEC in the treatment of peritoneal carcinomatosis 25
3.1. Colorectal cancer 25
3.1.I. The incindence of colorectal peritoneal carcinomatosis 25
3.1.II. Survival after systemic chemotherapy 27
3.1.III. Survival after systemic chemotherapy associated with biologic agents 28
3.1.IV. Survival after HIPEC 29
3.1.V. Peritoneal carcinomatosis associated with liver metastases 33
3.1.VI. Strategy in incidental findins of peritoneal carcinomatosis of colorectal origin 33
3.1.VII. Cytoreductive surgery without HIPEC 33
3.1.VIII Tumor relapse after HIPEC 34
3.2. Gastric cancer 34
3.3. Ovarian cancer 37
3.4. Pseudomyxoma peritonei 39
3.4.I. Pathology os pseudomyxoma peritonei 39
3.4.II. Clinical aspects of pseudomyxoma peritonei 42
3.4.III. Treatment of pseudomyxoma peritonei 42
3.5. Diffuse malignant peritoneal mesothelioma 44
CHAPTER 4 Considerations on HIPEC 48
4.1. Patient selection for HIPEC 48
4.2. Morbidity and mortality after HIPEC 49
4.3. Quality of life after HIPEC 53
4.4. Costs of HIPEC procedure 56
4.5. Learning curve in cytoreductie surgery 59
Personal contributions 61
CHAPTER 5. Morbidity and mortality after HIPEC for peritoneal carcinomatosis of colorectal
cancer and pseudomyxoma peritonei. Experience of National Cancer Institute of Milano, Italy
61
5.1. Aims of the study 61
5.2. Material and methods 62
5.3. Results 83
5,4. Discussions 93
CHAPTER 6 The role of circulating tumor markers in pseudomyxoma peritonei 99
6.1. Aims of the study 99
6.2. Material and Methods 100
6.3. Results 105
6.4. Discussions 127
CHAPTER 7. Treatment of peritoneal carcinomatosis of gastro-intestinal origin-a retrospective
study of 203 cases 131
7.1. Introduction. Aim of the study 131
7.2. Material and methods 132
7.3. Results 132
7.4. Discussions 137
7.5. Conclusions 138
CHAPTER 8 The role of perioperative systemic chemotherapy in diffuse malignant peritoneal
mesothelioma patients treated with cytoreductive surgery associated with hyperthermic
intraperitoneal chemotherapy (HIPEC) 141
8.1. Introduction. Aims of the study 141
8.2. Material and methods 141
8.3. Results 147
8.4. Discussions 154
CHAPTER 9 Discussions and conclussions 157
9.1. Discussions 157
9.2. Conclusions 163
References 165
Addenda 185
Abbreviations 185
Informed Consent for HIPEC treatment 186
List of scientific papers issued during PhD studies 191
Personal Motivations
Peritoneal carcinomatosis (PC) is a disease with a dismal prognosis, difficult
to treat wich represent a permanent problem for surgeons, medical oncologists, and
other specialities.
Overall survival of the patiens with peritoneal carcinomatosis is very poor.
It‘s natural history is very unpredicteble with long hospitalisation, low quality of life, ,
palleative surgery to treat various complications, ascites, and finally death.
Primary peritoneal carcinomatosis is a very rare disease wich include diffuse
malignant peritoneal mesothelioma and serous peritoneal carcinomatosis. Secondary
pesitoneal carcinomatosis is more frecquent and coul be found in advanced intra or
extraperitoneal disease. The most frecquent cancers are gastric, colorectal, pancreatic
and ovarian. Rare cancers are billiary, prostatic, renal and breast cancer and a very
rare appendicular cancer - pseudomyxoma peritonei.
EVOCAPE study on 370 patients with PC of gastrointestinal origyn revealed
aoverall survival of 3 to 9 month for the patients with 3 months for those with nodules
greater than 2 cm and 9 months for those with nodules less tan 5 mm. [1].
Hiperthermic intraperitoneal chemotherapy (HIPEC) has become during the
last 30 years standard therapy fost PC of colorectal origun and for pseudomyxoma
peritonei and peritoneal mesothelioma. There are reports favoring the complex
procedure for other entities like ovarian, gastric carcinomatosis.
One of the concerning of this complex procedures reguard the lack of high
evidence base medicine with only one randomised prospective study comparing the
survival of patients with peritoneal carcinonamtosis of colorectal origyn with or
without HIPEC. Other concernings are high morbidity and mortality, costs, quality of
life, learning curve.
In Romania HIPEC procedure is not performed. The aim of this study is to
investigate the morbidity and mortality of this procedure, the morbidity and mortality
of „traditionally treated patient‖ with carcinomatosis and various aspects of the
treattment of pseudomyxoma peritonei and peritoneal diffuse mesothelioma.
Level of aknowledge
CHAPTER 1. Peritoneal carcinomatosis
Mechanisms of peritoneal carcinomatosis
Nowadays the mechanism of CP is incompletely understood. It is considered
that it‘s different from the hematogenous or lymphatic pathways involved in the
development of distant metastases in parenchymal organs or lymph nodes. In order to
explain the occurrence of CP, there have been proposed several theories. One
hypothesis suggests that the tumor cells once they are infiltrating the serous and once
they are free into the peritoneal cavity, then they are able to generate the appearance
of CP. In this process may be involved also the tumor manipulation during surgery or
biopsy[10]. This theory can not explain, however, a rare occurrence of CP in T1 or T2
tumors [1]. It has been described the presence of free tumor cells in colorectal cancer
in stage I before their surgical manipulation [11].
I.2. Clinical aspects in peritoneal carcinomatosis
The clinical aspects in CP usually overlaps with the primary tumor signs and
symptoms. To those pacients where the primitive tumor hasn‘t been diagnosed, it may
occure signs as ascites, enlargement of the abdomen, weight, physical or intellectual
ability loss, irritability, changes in eating habits, flatulence, presence of palpable
tumors. Often, especially in pseudomixoma peritonei and ovarian cancer, the palpation
of the abdomen reveals a central tumor mass because of the tumoral implants on the
great omentum, also known as "omental-cake". In advanced cases, the patients
become cachectic, and the clinical picture may be complicated by the appearance of
intestinal obstruction because of the invasion of the small or large bowel, local
peritonitis in case of tumor invasion or diastatic perforation, bleeding.Sometimes
clinical signs and symptoms may be lesions to other secondary (metastatic) sites: liver,
lung, bone, brain.
.
CHAPTER 2. Hyperthermic intraperitoneal chemotherapy (HIPEC) treatment of
peritoneal carcinomatosis
2.2. Hiperthermic intraperitoneal chemotherapy (HIPEC)
Hiperthermic intraperitoneal therapy belongs to locoregional therapies. With
other procedures like locoregional treatment of unresectable liver metastases [50-51],
isolated limb perfusion for advanced tumors with the goal to preserve the function
[52-53], intraoperative radiotherapy for advanced breast cancer [54] HIPEC provides
high dose of chemotherapic agents locally avoiding systemic complications. In the last
3 decennia HIPEC proved its efficacity in various loaclly advanced tumors like
colorectal cancer [55], ovarian [56], gastric [57-58] and has became golden standard
for rare tumors like pseudomyxoma peritonei (PMP) [59-60] and peritoneal
mesothelioma (MP) [61].
2.3. The evolution of the surgical treatment of peritoneal carcinomatosis
The evolution of intraperitoneally administred chemotherapy [69]:
Weisberger and col. in 1955 [70] administred nitrogen mustard for the threatment of
ascites of in advanced ovarian cancer. Authors observed a good palliation of ascites
but no improvements in survival pentru tratamentul ascitei neoplazice.
1980 Spratt and col. [71] suggested intraperitoneal hiperthermic chemotherapy after
animal studies.Then they performed for the first time the procedure in a 37 years old
male with pseudomixoma peritonei
1981 Spreyer and col. [72] described the farmacology of intraperitoneally
adminiustred 5-florouracyl in liver cancer patients
1984 Hamazoe and col. [73] first study of hiperthermic intraperitoneal chemotherapy
with Mitomicin C in patients with gastric and colorectal carcinomatosis proving the
efficacity of the method
1985 Sugarbaker and col. [74] published the results of a randomized study
(systemic chemotherapy vs intraperitoneal chemotherapy) for advanced colorectal
cancer with no macroscopic carcinomatosis. Authors observed a low incidence of
peritoneal carcinomatosis in patients treated with intraperitoneal chemotherapy.
1988 Koga and col. [75] reported first study of prophylactic intraperitoneal
chemotherapy with Mitomicin C in advanced gastric cancer (T3). The authors
observed an improvement of survival.
1988 Kiuchi and col. [76] reported an overall survival of 380 days and 62%-one
year survival in a population of pacients with gadvanced gastric cancer treated with
HIPEC and overall survival of 160 days and 16% one years survival in patients
traditionally treated.
1995 Sugarbaker [77] described peritonectomy procedure
2003 Verwaal and col. [78] published the results of the first randomized study on
HIPEC in peritonel carcinomatosis of colorectal cancer. The authors observed an
overall survival of 22 monts in patients treated with hiperthermic intraperitoneal
chemotherapy and 12 month in patients treated with surgery plus systemic
chemotherapy.
CHAPTER 3. The role of HIPEC in the treatement of peritoneal carcinomatosis
3.1.The Colorectal cancer
Colorectal cancer in Europe has estimated an incidence of 415 000 cases per
year. It is estimated that approximately 210 000 patients die because of this
neoplasia[105].CP is one of the most common ways of dissemination in colorectal
cancer having symptoms which may overlay on the primary tumor condition, only if
it‘s limited. It‘s diagnosed in 7-10% of patients who had surgery for colorectal
cancer, it develops in 4-19% of patients who underwent surgery with curative visa and
occurs in approximately 44% of patients with postoperative tumor recurrence.In a
retrospective study of 3019 patients [106] , 349 of them (13%) developed CP of which
214 (61%) had a CP synchronous and 135 (39%) CP metachronous.
Treatment of metastatic colorectal cancer is multimodal,surgery is the only curative
intent, despite the new class of chemotherapy which significantly improved survival.
3.1.IV.Results in CP‘s multimodal treatment (cytoreduction + HIPEC) of colorectal
etiology.
In 1995, Sugarbaker et al. [81] published the first results of multimodal
therapy including tumor cytoreduction associated with hyperthermic intraperitoneal
chemotherapy in a group of 181 patients, who uderwent surgery for colo-rectal CP (51
patients), and for apendicular etiology for CP (130 patients). The authors identified
colonic origin, nods status, tumor differentiation and extent of CP as negative
prognostic factors. In those colo-rectal patients with incomplete cytoreduction,
authors have reported a 3-year survival of 20%, significantly lower than those with a
full cytoreductive (60%).
There is only one study [119] randomized and completed so far on the colo-
rectalCP treated by HIPEC. In this study, between february 1998 - august 2001, 105
patients were randomized into two groups. All 105 patients had histological diagnosis
of colo-rectal CP and no liver or extra-abdominal metastases, age under 71years old,
with acceptable performance status and good renal, liver and bone marrowfunction.
The patients were randomized to standard therapy or experimental treatment. The
patients in the standard group (51 patients after randomization) went surgery only if
there were casesof complications and in that situation they performed bypass, stenting
and exceptional resection. Otherwise, in a total of 44 patients, there were performed
standard chemotherapies from that that period in Netherlands, after a schema
containing 5-Fluorouracil and Leucovorin. In the experimental group (54 patients after
randomization) 49 patients wentsurgerypracticing tumor cytoreduction and
hyperthermic intraperitoneal chemotherapy for a period of 90 minutes with mitomycin
C.Subsequently these patients (33 patients) had systemic chemotherapy following the
same pattern as those in the standard arm.All patients were subsequently re-evaluated
every 3-6 months. Study results showed a median survival of 12 months in arm with
systemic chemotherapy and 22 months in the experimental arm so a benefit of about
10 months
3.4. Pseudomixoma peritonei
Pseudomixoma peritonei (PMP) is localized or generalized progressive
accumulation of a gelatinous consistency ascite in the abdominal cavity, usually a
consequence of chistadenoma appendix rupture.PMP is a generic term used to
describe clinical and radiological syndrome, but not a histopathologic diagnosis.
Rokitansky was the first to describe an appendix mucocel, he named it hydrops
vermiform process [185]. In 1884 [186], Werth introduced the PMP term describing
the first case in a patient with an ovarian tumor.In 1901 Frankel had described a case
ofPMP associated with an appendicular cyst.
PMP prevalence in the general population is difficult to assess. It is estimated
at 1-2 cases per 1 million inhabitants.In a retrospective study [187] for a period of 10
years from 167 744 appendectomies carried out in Holland in 1482 were found
appendix tumors (0.9%) of which 574 were epithelial tumors. Because it is a rare
condition there is no prospective study on the treatment of this heterogeneous
disease.Nowadays,in the world are 8 reference centers with more than 100 patients
[59], the greatest casework of 500 cases being reported in Basingstoke.
CHAPTER 4. Considerations about HIPEC
4.1. Patient selection for HIPEC
Patient selection for HIPEC is not easy. Surgical treatment decision should
not belong to a single physician, it should be taken in consensus by a multidisciplinary
team [222].Piso et al. [224] have sketched some indicative criteria for selection of
patients with CP proposed for surgery by identifying factors related to tumor and
patient: factors related tumors: primary tumor location, histological type and grading;
presence of extra-abdominal metastatic disease, the presence of para-aortic lymph
nodes metastasis, Peritoneal Cancer Index, bowel and hepatogastric
ligamentinvolvement, bladder or ureteral stenosis, response to prior systemic
chemotherapy. Other factors: ECOG performance status,patient comorbidities, the
learning curve of the surgeon, the patient's informed consent, quality of life expected
postoperatively.
4.2. Morbidity and mortality after HIPEC
The complications, such as fistula or the perforation, are at a rate of 7-17%
[88, 237-238]. Compared to the 2-4% incidence of fistula in elective colorectal
surgery [239] the relatively large number of anastomotic anastomotic fistulas is
justified by thepatients‘status, often with a history of multiple interventions with
postoperative adhesions that make dissection difficult,but also by the fact that in some
cases, in order to obtain anproper cytoreductive result, we actually increase the risk of
complications by performing a large number of anastomosis. Often we practice serous
tumor cytoreduction in bowel or mesentery, which increase the risks of bowel necrosis
and devascularisation.
4.5. The learning curve in cytoreductive surgery.
Smeenk et al. [223] believes that learning curve peak is reached after
approximately 130 cases.The authors have noticeda decreaing morbidity from 71 to
34%, a decrease in the length of stay for 24 to 17 days and an increased proportion of
patients with complete cytoreductive from 35 to 65% in a group of 323 patients who
went for surgery for colo-rectal CP or PMP, dividing the patients into 3 groups
according to the period in which they were operating.
In the group of patients the ultimate complications of gastrointestinal
complications have been observed (32%), infection (20%), lung (13%), bone marrow
suppression (12%).Post-operative mortality decreased from 8% to 4% for the first 75
patients operated on.One of the authors explanations for better results over time is
related to a more rigorous selection of patients excluding patients with extensive
abdominal CP (6-7 regions), becausecomplete citoreduction is difficult and because of
thepostoperator riscks and complications, due to large excision necessary for optimal
cytoreduction.Yan et al. [271] in a group of 140 patients operated by cytoreduction
combined with HIPEC has been a net improvement in the parameters of the last 70
patients from the first 70 patients.
PERSONAL PART
CONTRIBUTIONS
CHAPTER 5. Morbidity and mortality in patients operated after HIPEC with
peritoneal carcinomatosis of colorectal etiology and Pseudomixoma peritonei at
National Tumor Institute in Milan, Italy
5.1. The purpose of the study
The main objective of this study is to identify the main risk factors for the occurrence
of severe postoperative complications in patients with CR and PMP peritoneal
carcinomatosis. The second objective is to evaluate the oncological outcome of
patients with CR CP, when performind peritonectomie associated with intraperitoneal
chemotherapy.
5.2.I. The group of patients
The study was conducted on a group of patients operated at the National
Cancer Institute (INT) in Milan between june 1996 - march 2012.In this period went
for surgery a total of 473 patients with various diseases of the peritoneum.All patients
were operated by a single surgical team, having as principal surgeon the same surgeon
(Marcello Deraco) who also performed patient selection for curative intervention visa.
The decision was taken after surgery consent multidisciplinary team consisting of a
surgeon, oncologist, pathologist, anesthesiologist and nutritionist.
All patients were operated after a protocol developped by INT and met the
following criteria: CR CP or PMP, good renal function, hepatic and hematopoietic,
age under 75 years old, ECOG performance status less than 3, the absence of distant
metastases and retroperitoneal lymphadenopathy blocks, imaging investigations that
suggest the possibility of an optimal citoreductive surgery, signed informed consent of
patients.
Fig. 5.7 Right upper quadrant peritonectomy
Collection of Dr. Marcello Deraco
Fig. 5. 14 Parietal and pelvic peritonectomy
Collection of Dr. Marcello Deraco
TABLE 5.IV
Risk factors for postoperative high grade mororbidity after HIPEC in PMP and
colorectal peritoneal carcinomatosis patients
Factors Morbidity Grade 3-5
Univariate analysis*
Multivariate**
p Odds Ratio
Confidence interval P
Tumor (Colon vs PMP) 0,91 - - -
Sex (Male vs Female) 0,51 - - -
Age >52 years 0,30 - - -
Body mass index <22
( yes vs no)
0,14 - - -
Performance status (0 vs 1-2) <0,01 3,73 1,50-9,30 <0,01
Charlson morbidity index > 3 (da vs nu) 0.600 - - -
Histologic subtype (Colon + PMCA vs
DPAM)
0,12 - - -
Prior surgical score 0-1 vs 2-3 0,40 - - -
Preoperative chemotherapy
(yes vs no)
0,20 - - -
Preoperative albumin
(<3,5 vs >3,5)
0,09 - -
Preoperative lymphocite count < 1500 (da vs nu)
0,02 - -
Preoperative platelets count > 400.000
( da vs nu)
0,48 - - -
Peritoneal Cancer Index (> 20 vs < 20) <0,01 - - -
Anastomoses( yes vs no) 0,04 - - -
Anastomoses > 2 (yes vs no) <0,01 - -
Ttransfusions > 2 units ( yes vs no)
1 - - -
Transfusion ( yes vs no) 0,70 - - -
Duration of procedure > 600 minutea ( yes vs no)
0.23 - - -
Splenectomy (yes vs no) 0,06 - - -
Colectomy ( yes vs no) 0,09 - - -
Enterectomy ( yes vs no) 0,01 2,49 1,16-5,31 0,02
Histerectomy 0,14 - - -
Number of procedures > 8
(yes vs no)
0,31 - - -
Complete cytoreduction
(yes vs no)
0,46 - - -
CDDP intraperitoneal > 220 mg
( yes vs no)
<0,01 2,96 1,31-6,67 <0,01
TABEL 5.V Risk factors fost postoperative fistulas after HIPEC in PMP and colorectal carcinomatosis
patients
Risk factors Fistulae
Univariate
analysis*
Multivariate analysis**
p Odds
Ratio
Confidence interval P
(Colon vs PMP) 0,69 - - -
Sex (male vs female) 0,31 - - -
Age >52 (yes vs no) 0,59 - - -
BMI <22 ( yes vs no) 0,17 - - -
Performance status (0 vs 1-2) 0,046 - -
Charlson comorbidity index
> 3 (yes vs no)
0,94 - - -
(Colon + PMCA vs DPAM) 0,83 - - -
Prior surgical score 0-1 vs 2-3 0,21 - - -
Preoperative chemotherapy (da vs nu) 0,58 - - -
Preoperative albumin (<3,5 vs >3,5) 0,61 - -
Preoperative lymphocitic count < 1500
(da vs nu)
<0,01 3,90 1,45-10,46 <0,01
Preoperative platelets > 400.000
( da vs nu)
0,45 - - -
Peritoneal Cancer Index >20
(yes vs < no)
<0,01 4,57 1,40-14,56 0,01
Anastomoses ( yes vs no) 0,31 - - -
Anastomoses > 2 (yes vs no) <0,01 - - -
Intraoperative blood units > 2 unităti
( yes vs no)
1 - - -
Blood transfusion ( yes vs no) 0,70 - - -
Durata operaţiei > 600 minute ( da vs
nu)
0.23 - - -
Splenectomy (yes vs no) 0,08 - - -
Colectomy ( yes vs no) 0,09 - - -
Enterectomy (yes vs no) <0,01 2,94 1,18-7,34 0,02
Histerectomie (yes vs no) 0,14 - - -
Nomber of procedures
> 8 ( yes vs no)
0,14 - - -
CC score >1 (yes vs no) 0,09 - - -
Cisplatin dose > 220 mg
( yes vs no)
<0,05 - - -
5.4. Discussions
Univariate analysis showed the following factors: ECOG performance status,
preoperative lymphocyte count, Peritoneal Cancer Index> 20, enterectomy,
colectomy, splenectomy, CDDP dose and complete cytoreduction. After performing
multivariate analysis (logistic regression - backward conditional) only Peritoneal
Cancer Index >20, enterectomy and preoperative lymphocytic count remained as
independent factors. One explanation for Peritoneal Cancer could be : more
involvement of peritoneal cavity implies more procedures and thus higher risk for
bleeding, fistulas, anastomotic leak. Preoperative albumin, number of procedures,
perioperative blood transfusion were not amongst the independent factors.
CHAPTER 6. Circulating tumor markers: predictors of incomplete
cytoreduction and powerful determinants of outcome in pseudomyxoma
peritonei
6.1. Introduction Pseudomyxoma peritonei (PMP) is a rare condition characterized by
a slow accumulation of peritoneal deposits of mucinous tumors and mucin. With
systemic chemotherapy and palleative surgery overall survival is limited.
The aim of this study is to evaluate the ability of preoperative serum markers (Ca125,
CEA, and Ca19-9) to predict incomplete cytoreduction in patients PMP patients
elected eligible to cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy deemed for hyperthermic intraperitoneal chemotherapy associated with
peritonectomy.The secondary aim of this study is to evaluate their prognostic role for
oncologic outcome .
6.3. Results
Mean follow up was 42 months (1-170). 30 patients died (mean follow-up 31
months range 1-132. 34 patients were alive (mean follow-up 46 months range 13-
143). Five year overall survival was 73%. Mean age was 53 years (±13,6). There were
60 males and 96 females. Mean Charlson comorbidity index was 3,6 (±1).
Preoperative serum albumin was 4.3 g/dl (±0,7). PSS was 0 to1 in 47% patients and
was > 2 in 53% of patients. 23% patients underwent preoperative systemic
chemotherapy. 34% patients had PMCA/PMVA-I histologic type. Mean Peritoneal
Cancer Index was 22,6 (±11,1). Most frecquent procedure was omentectomy.
(TABLE 6.I) 14 patients (9%) underwent incomplete cytoreduction. Mean operative
time was 600 minutes (75-1260 minute). During the intervention were recquired 3
units of blood (range 0-37) Mean lenght of stay was 18 days (7-101). One patient
presented postoperative leukopenia ( TABLE 6.II)
6.4. Discussions
Univariate analysis revealed the following negative prognostic factors:
Charlson comorbidity index >4, male gender, ECOG performance status >2
preoperative systemic chemotherapy, histologic subtype PMCA, preoperative albumin
< 3,5mg/dl, Peritoneal Cancer Index >20, incomplete cytoreduction, Ca125>125
U/ml, Ca19,9 >89 U/ml. After multivariate analysis (multivariate logistic regression)
only the following factors remained: ECOG performance status, serum albumin < 3,5
mg/dl, Ca125 >125 and Ca19.9 > 89
TABLE 6.II.
Changes in laboratory values after HIPEC
Creatini >1,3mg/dl 36
Creatin > 3mg/dl 5
TGO 276 (38-1157)
TGP 311 (35-1503)
Total bilirubin 1 (0,4-4,49)
Amilase 239 (46-1226)
Leukopenia <3000 /mmc 1
Anemia <8 gHb/dl 31
Platelets count < 120.000mmc 9
TABLE 6.V
Risk factors for death in PMP patients after HIPEC Factors Univariate analysis
(Log-Rank)
Cox regression
p HR ( p
Gender (Male vs Female) 0,03 NS
Age ( > 52 vs 52) 0,8 -
Preoperative chemotherapy (Yes vs No)
0,03 NS
Histologic subtype ( DPAM vs
PMCA)
<0,01 NS
Serum albumin (≤3,5mg/dl vs >3,5
mg/dl)
<0,01 3,9 (1,45-10,49) <0,01
Ca 125 ( Ca125 >125U/ml vs ≤125
U/ml
<0,01 4,56 (1,98-10,51) <0,01
CA 19.9 ( CA19.9 > 89U/ml vs ≤
89 U/ml)
0,04 2,82 (1,17-6,71) 0,02
ACE ( > 18ng/dl vs ≤18 ng/dl) 0,35 -
Performance status ECOG (1-2 vs
0)
0,03 NS
Charlson Index ( >3 vs ≤3) 0,30 -
Preoperative platelets (>450.000 vs
≤ 450.000)
0,89 -
Prior Surgical Score ( 2-3 vs 0-1) 0,75 -
Peritoneal Cancer Index ( >20 vs ≤ 20)
<0,01 NS
No procedures ( >8 vs ≤ 8) 0,38 -
Cytoreduction (CC0-1 vs CC2-3)
<0,01 8,15 (2,73-23,86) <0,01
Postoperative morbidity (grade III-IV vs 0-II)
0,19 -
The following variables were proven to be independently associated with
shorter PFS: charlson comorbidity index >4, preoperative systemic chemotherapy,
incomplete cytoreduction, morbidity G3-5, and Ca125>125 U/ml. On the other hand,
variables independently associated with shorter OS were as follows: ECOG
performance status >2, serum preoperative albumin<3.5 g/dl, CC, Ca125>125U/ml,
and Ca19-9>89U/ml.
Neither the histological subtype nor the PCI>20 were proven to be
independent predictors of survival.
Despite presenting a reasonable discriminant power in predicting incomplete
cytoreductive surgery others clinicopathlogic data are more important. On the other
hand preoperative Ca125 and Ca19.9 were proven to be important oncological
prognostic markers of poor prognosis in operated PMP patients.
CHAPTER 7. Treatment of peritoneal carcinomatosis of gastro-intestinal
origin a retrospective study on 203 cases
7.1. Introduction.Aim of the study
Peritoneal carcinomatosis of gastrointestinal origin (PC-GI) is an advanced
digestive tumor and is found in 10-30% of patients (P) with primary surgery for
cancer (C) and up to 50% of C recurrences.
Patients with peritoneal carcinomatosis of gastrointestinal origyn have a very
poor prognosis. With systemic therapy the overall survival is limited to 3 to 9 months.
New drugs improved the survival of colorectal patients to 22 monts.
The aim of this studz is to evaluate the main characteristics, ethio-pathogenesis,
prognosis and imaging to track of P with PC-GI admitted to the Third Surgical Clinic,
"St. Spiridon" Hospital, Iaşi.
7.2. Material and methods
A retrospective study was carried out on series of 203 patients admitted in the
period June 2006 - March 2011. The patients were aged between 27-80 years (average
62), with a women/men ratio of 95/108. The duration of hospitalization was between 1
and 61 days, with an average of 13.5 days for emergency cases and 15 days for
elective cases. The data from observation files, the operating protocols, pathology
reports and follow-up files were collected and analyzed.
7.3. Results
136 patients were hospitalized with synchronous PC (the most common
gastric N = 60) and 67 with metachronous PC (the most common colon N = 29).
Imaging investigations consisted of ultrasound and computer tomography that showed
a sensibility and specificity of 80% and 73% respectively, mainly in regard to ascites
but less in assessing the presence of peritoneal deposits. The most common
complication was septic shock and mortality was 9.5% (17 patients). Average survival
was 5.7 months.
The ethiology of sincronous peritoneal carcinomatosis is summarised in TABLE 7.II
TABLE 7.II
Ethiology of syncronous carcinomatosis 136 patients with syncronous carcinomatosis
Stomac 60
Colon 31 Right 14
Trasverse 4
Left 13
Pancreas 19 Head 5
Body and tail 14
Rectum 8
Esophagus 6
Duodenum 2
Liver 4
Billiary tree 7
Small bowell 1
Others 6
The ethiology os metacronous carcinomatosis is summarised in TABLE 7.III 53
patients with metacronous carcinomatosis were operated
TABLE 7.III
Ethiology of metacronous carcinomatosis 67 patients metacronous carcinomatosis
Stomac 13
Colon 29 Right 10
Transverse 5
Left 14
Pancreas 7 Head 5
Body and tail 2
Rectum 8
Esophagus -
Duodenum 3
Liver -
Billiary tree -
Others 7
7.4. Discussions
Intraperitoneal normothermic chemotherapy was performed only in 5 patients
2 with right colon cancer with sincronous peritoneal carcinomatosis and 3 with
metactonous carcinomatosis). One patient presented a transitory renal failure. Two
patient were lost to follow-up and the other three survived between 6 to 9 months.
Conclusion
PC-GI is a disease with a poor prognosis, posing difficulties in early
diagnosis, establishing the surgical indication and protocol. Consistent advances in
systemic and locoregional chemotherapy, surgical techniques, intraoperative
radiotherapy, as well as immunotherapy are expected to improve prognosis.
CHAPTER 8. The role of perioperative systemic chemotherapy in diffuse malignant
peritoneal mesothelioma patients treated with cytoreductive surgery and hyperthermic
intraperitoneal chemotherapy
8.1.Introduction. Aim of the study
Peritoneal mesothelioma is a rare disease with an incidence of 1-2 cases per
million in western countries.70% of all mesotheliomas arises from pleura, 20-25%
from peritoneum and in very rare cases the disease arises from pericardum or from
tunica vaginalis testis. It is a disease with a poor prognosis- overall survival with
systemic chemotherapy is one year [327]. There is no gold standard therapy for this
disease. Best systemic chemotherapy includes cisplatin and doxorubicin.
HIPEC has became in the last 30 years standard therapy for diffuse malignat
mesothelioma with 5 years survival exceeding 50% [328].
Despite good results this aggresive method is still performed in only a few
centers. High costs, high morbidity and mortality long learning curve are arguments
for the centralisation of this procedure[329] .
The aim of this study was to evaluate the effects of perioperative systemic
chemotherapy on short-term surgical and long-term oncologic results in diffuse
malignant peritoneal patients treated with HIPEC at National Cancer Institute of
Milan.
8.3. Results
There were 116 with diffuse malignant peritoneal mesotheliomapatients
operated between February 1995 and October 2011, 60 males and 56 females. Main
characteristics are summarized in TABLE 8.I. Main procedures during the
intervention are summarized in TABLE 8.II
Fig. 8.2 Diffuse malignant mesothelioma. Peritoneal Cancer Index 36. Operative time 870 minutes.
Collection of dr. Marcello Deraco
TABLE 8.I.
Clinicopathologic characteristics of DMPM patients
Characteristics
Agexx 58 (22-76)
Sex (m\f) 60\56
BMIxx 24 (15-56)
ECOG 0-1 vs >2 105\11
Hystological type epitelial \byphasic + sarcomatos 104\12
Albumin (g/dl)xx 4,03 (2,5-5,7)
Total Proteins (g/dl)xx 7,2 (5,7-8,8)
Preoperative platelets /mmcxx 373000 (87000-1400000)
Hospitalisationxx 25 (9-110)
Morbiditz grade III-Vx 47 ( 40,5%)
Mortality ( grade V)x 3 (2,5%)
Follow-up (months)xx 39 (1-119)
TABLE 8.IV.
Univariate and multivariate analysis of risk fators for severe morbidity and incomplete
cytoreduction in patients operated for diffuse malignant peritoneal mesothelioma Factor Morbidity (Grade III-V) Optimal cytoreduction vs incomplete
cytoreduction
Univariatex Multivariatexx Univariatex
Multivariatexx
p OR p p OR p
Age
0,53 0,47
Sex 0,28 0,57
ECOG 0,03 5,29
(1,27-22,6)
0,02 <0,01 4,25
(1,03-
17,47)
0,045
Charlson index (> 3 vs <4)
0,9 0,7
Prior surgical score ( > 2 vs < 2)
0,72 0,34
( epiteliod vs
biphazic/sarcomat
os)
0,71 0,07 NS
Platelet
preoperatice
>400.000
Yes vs no
0,39 0,08 NS
Preoperative chemotherapy (da
vs nu)
0,41 0,14
Peritoneal cancer
index > 20 (Yes vs
No)
0,06 NS 0,01 5,64
(1,45-
21,89)
0,1
Anastomosis (yes vs no)
0,02 3,49 (1,51-8,2)
<0,01 0,87
No. Procedures > 7
(Yes vs no)
0,01 4,25 (1,43-12,6)
<0,01 0,26
Optimal
cytoreduction (Yes vs No)
0,44
X – chi-square test/ Fisher exact test xx- multivariate logistic regression
8.4.Discussions
With the setting up of the division for peritoneal diseases at INT Milano,
patients form all Italy have been examined and treated.
After the finalizations of the investigations the patients are put on waiting
lists. The waiting time is approximately 6 months. Some of them have received
therapeutic schemes before arriving at INT and smaller percentage underwent
chemotherapy between first medical evaluation and the surgical intervention time.
The analysis of risk factors in the studied patient group for postoperative
complications and incomplete cytoreduction reveals together with the disease
extension through the peritoneum (Peritoneal Cancer index) the role of the ECOG
performance status.
The disease extension quantified by the peritoneal cancer index usually
translates in patients with high values, a diffuse involvement of the peritoneal cavity,
therefore the necessity of complex surgical gesture with the possibly of visceral
multiple resection. Other important complications are the prolonged intraoperative
time, intra and postoperative bleeding, fistula, due to intestinal serosa peritonectomy
or due to the necessity of anastomosis creation after intestinal or colic resection.
ECOG performance status role is most obvious for low performance status patients,
which means limited organism resources and deficient nutritional status.
On the studied group of patients preoperative chemotherapy did not influence
the optimal cytoreduction possibilities and post operative morbidity. Unlike the
ovarian cancer or the hepatic metastasis originating in colorectal cancer, where
neoadjuvant chemotherapy might lead to diminishing tumor dimensions and therefore
raise the cytoreduction possibilities, chemotherapy didn‘t influence the optimal
treatment possibilities. One of the explanations might be the relative chemoresistence
of PM.[336].
CHAPTER 9. Discussions and conclusions
9.1. Discussions
The survival of cancer patients already found in the metastatic phase has been
reported taking into consideration all types of metastasis. Therefore there is a lack of
data regarding the survival of the peritoneal metastatic disease patients. Tumor
biological variety and different evolutionary paths can lead to cerebral, hepatic,
pulmonary, bone, retroperitoneal and quite frequent peritoneal metastasis. Due to ease
of management the general therapeutic approach has been that of treating all these
entities as metastatic disease. In reality all these locations can have a different impact
over survival rate. The existence of 1 cm cerebral metastasis can significantly
influence the patient survival, sometimes limited to only a few weeks in the absence of
a surgical gesture. One, a few centimeters large, hepatic metastasis can evolve without
any clinical symptoms for several years. Due to intestinal lumen proximity PC can
also have an unforeseeable evolution. Occasionally a small singular nodule located on
the small bowel serosa can cause serious complications, whereas sometimes patients
can present multiple intraperitoneal nodules that do not concern the intestinal
peritoneum. Apparently these do not generate transit changes and sometimes even the
imagistic diagnosis is challenging.
There is no standard treatment for PC. It is a disease with a poor prognosis and for a
long time patients underwent treatment only for palliative purposes. Once new
chemotherapeutic agents were introduced the ovarian and colorectal PC prognosis has
been improved. In spite of a good initial response most patients present cancer
recurrence and five year survival cases are extremely rare. The idea of bringing
tumorous cells into contact with the chemotherapeutic agent had to undergo several
stages before being accepted by most surgeons. The first data concerning the
cytoreduction benefits in ovarian cancer drew interest for further research regarding
the PC‘s biology and made possible the development of new techniques designed to
achieve the maximum therapeutic benefits for patients [341]. Another goal of the
conducted studies has been indentifying patients that could best benefit from surgical
interventions.
Few I and II phase and only one III phase study that were carried out
according to Spratt intraperitoneal chemotherapy scheme in the case of a young
patient with PMP have shown obvious benefits as far as survival and life quality in
patients suffering from PC RC and PMP is concerned, using the complex procedure
that includes both cytoreduction and HIPEC. Intraoperative chemotherapy initially
normothermic and afterwards done hyperthermicly in association or not with
postoperative intaperitoneal chemotherapy has become a complex multidisciplinary
treatment method in PC. This change represents an alternative to systemic
chemotherapy used with palliative purposes.
Numerous retrospective studies have shown the advantages of the method for
PMP, peritoneal malignant mezothelioma, primary peritoneal tumors. Unfortunately
the complex treatment method has not yet been proven through prospective
randomized or multicentric studies. The majority of the studies are in reference to
personal experience which is rarely constituted by more than 100 cases of operated
patients. Furthermore most of them are not considered high reference points.
Wervaal and col‗s [119] randomized prospective study is the only EBM first
class study that has yet been published. Numerous systematic reviews [231,342] have
shown the method‘s advantages in comparison to systemic chemotherapy associated
with palliative surgical intervention.
In the retrospective study „Treatment of peritoneal carcinomatosis of gastro-
intestinal origin--a retrospective study of 203 cases” (Rev Med Chir Soc Med Nat
Iasi. 2012 Jan-Mar;116(1):150-6 PMID:23077888) [343] conducted at III Surgical
Clinic of Sf Spriridon Hospital Iaşi, data about morbidity and mortality has been
assessed after the admission of 203 patients over a period of 5 years. There have been
numerous problems in conducting the study. The patient lot has been heterogenic –
electively admitted patients or as emergencies with PC of different etiology but with
GC and RC predominance with or without preoperative chemotherapy. The
retrospective nature of the study didn‘t allow the evaluation of some clinical and
epidemiological factors such as nutritional and performance status, postoperative
complications in CTCAE classification and tumor markers.
The relatively small patient lot with a heterogenic pathology has not
permitted uni/multivariate analysis to identify the risk factors for postoperative
complications.
During hospitalization patients were not given life quality questionnaires.
Also the postoperative follow up has not been done actively therefore data about life
quality, undertaken chemotherapy and other possible surgeries, is missing. Patient or
family compliance to the sent questionnaires and also the difficulties in the
collaboration process with the Population Evidence Bureau have not allowed survival
estimation with Kaplan Meier curve.
Due to patient group heterogeneity and lacking data we could not make a
comparison with the witness group. In the absence of a regional or national register for
cancer patients and in the absence of a proactive systematic follow up, the
retrospective recuperation of data was deficitary.
One of the observations made after the study regarded the mortality during
patient hospital admission which was rather high 9,5% and did not include 30 or 60
days mortality according to recommendations for accurately done estimations over
postoperative mortality.
One of the reasons for high mortality could be the specific of the department
that has many emergencies cases. For occlusive RC and cephalic cancer the absence
of minimally invasive palliative treatment through stent implantation has probably
influenced the immediate survival of these patients.
Many of these patients underwent surgery regardless of the performance
status which may have lead to discrepancies between the high mortality rate and the
reported rate for ample interventions such as HIPEC.
The patient group cannot be compared to a witness group treated with
intaperitoneal chemotherapy because of data inconsistency due to the small number of
intraperitoneal chemotherapy conducted (5 patients).
During the time spent at the National Institute for Tumors in Milano as part
as the Doctoral scholarship I have conducted several studies, most of them
retrospective.
The Circulating tumor markers: Predictors of incomplete cytoreduction and
powerful determinants of outcome in pseudomyxoma peritonei”. [344] (J Surg Oncol.
2013 May 29. doi: 10.1002/jso.23329) evaluates the role of the tumoral markers in the
management of the patients that underwent surgery for PMP. There is little
mentioning in medical literature of the tumoral markers in PMP.
In 2007 Barrati and col. [345] published a retrospective study on a 62 patient
group that underwent surgery at INT underlining the preoperative role of Ca125 in
optimal cytoreduction possibility prediction and prognostic role of Ca 19.9. In the
present study there were included 156 patients with PMP treated at INT. With the help
of ROC curve –un useful instrument in evaluating the diagnosis capacity of a test we
have established threshold limits of the main tumor markers CEA ca 125 and Ca19.9.
The analysis on a larger group of patients highlighted the minor preoperative role of
tumoral markers in the prediction of optimal cytoreduction possibility.
The preoperative value of tumoral markers didn‘t significantly influence the
tumoral cytoreduction possibilities. In the group of patients with optimal
cytoreduction, a value of the Ca 125 and Ca 19.9 markers over the threshold limit
represented a negative prognosis factor with a precocious apparition of tumoral
recurrence and also a shorter survival rate. Even though the patient group is small and
patient subgroups with histological different subtypes are small, the study shows the
importance of tumoral markers in the oncologic prognosis of PMP patients operated
by HIPEC.
Even if some patients had an optimal cytoreduction they had tumoral
recurrence and a continuously evolving disease. One of the possibilities for future
research might be the role of neoadjuvant chemotherapy in patients with high levels of
tumor markers at the moment of diagnosis. The study could not follow the tumoral
markers dynamic through the pre and post operative period nor could it follow the
impact of perioperative chemotherapy in these patients.
Although MP is not a digestive disorder, this rare pathology is one of the
HIPEC beneficiaries. The low incidence of the disorder in the Western countries is
probably underrated due to the lack of diagnosis of all types of the disorder and to
confusing it with other disorders whose starting point are the abdominal parts.
Between 2003 and 2011, while I was working within the III Surgical Clinic of Sfantul
Spiridon Hospital of Iasi only 2 MP patients have been diagnosed and treated. This
slightly low number of patients treated in a surgical clinic with addressability from a
region with more than 4 million people contradicts the incidence of the illness for our
country. Considering that in real life a high number of MP patients receive an
inaccurate diagnosis, I was interested in this pathology during my external traineeship
with INT Milano. The department of peritoneum disorders within INT is a reference
centre in Italy for this disorder and probably one of the first four centres in the world
in terms of number of operated patients.
In the research ―The role of perioperative systemic chemotherapy in diffuse
malignant peritoneal mesothelioma patients treated with cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy‖ (Ann Surg Oncol, 2013 Apr; 20(4):1993-
100, two: 10.1245/s10434-012-2845-x) [2013] on a batch of 150 operated patients I
assessed the role of chemotherapy in MP patients subject to HIPEC. Considering that
the role of perioperative chemotherapy has not been studied before, the research data,
under the limitation caused by the low number of cases, showed a small impact of
chemotherapy on the survival rate of the patients, but there was highlighted a survival
rate of approximately 50% in patients with optimal cytoreduction. The low incidence
of the disorder in general population, namely 1-2 cases in one million of inhabitants,
should not be a counter-argument to the utility of setting up a HIPEC programme in
Romania. At least in theory, this disorder has an incidence that equals those in the
Western countries, where it is estimated that the incidence peak will be reached in
2030. In Romania, by dropping the use of asbestos materials later, the peak of this
incidence will probably occur after this year. Between the period May 2012 and
March 2013 in the I Surgical Clinic of the Regional Institute of Oncology Iasi 2 MP
patients were operated. A 70-year-old patient was investigated for undetermined
etiology ascites. The laparascopic examination diagnosis with biopsy of peritoneal
nodules raised the suspicion of CP with digestive, maybe pancreatic starting point.
Under the paliative treatment applied with Gemcitabina, the condition of the patient
improved after 2 chemotherapy sessions. A re-assessment of the biopsy parts revealed
suggestive aspects of peritoneal mesothelioma biphasic type. Three months after the
surgery, the patient was undergoing systemic chemotherapy. Another patient, aged 56
years, operated in another service for a right retroperitoneal tumour with
anatomopathologic examination suggested an extra digestive neuroendocrine tumour,
under chemotherapeutic treatment, has been assessed in the I Clinic for a relapse
retroperitoneal tumour. The patient was suggested for surgical intervention taking into
consideration the tumour cytoreduction in order to facilitate the systemic
chemotherapy. Due to the surgery, there were revealed a large retroperitoneal tumour
that was making common block with the ascending colon and the last ileal ansa, as
well as several peritoneal nodules located on the great epiploon and on the mesentery
serosa. It was applied an expanded right hemicolectomy and an epiplonectomy, and
the anatomopathologic examination revealed an epithelioid mesothelioma aspect with
a low degree of differentiation. Four months after the surgery, the patient undergoes
systemic chemotherapy.
In the 6th
chapter of the paper there were investigated the post-surgery
morbidity and mortality on the patients operated at the National Institute of Tumours
in Milano for CP of CR and PMP etiology. Although there had been concerns in the
CP treatment of gastric etiology, they were abandoned at the end of 2000 because of
the unsatisfactory results of the operated patients. Intraperitoneal chemotherapy for
gastric cancer should be reserved according to the opinion of the doctors responsible
of experimental trials within INT. Another suggestion of the European research is that
once CP occurs in a case of gastric cancer, chemotherapy would have limited benefits.
Intraperitoneal chemotherapy should be practised when there are no peritoneal
tumours, when there is no tumour residue, but patients have an increased risk of
relapsing with localisation in the peritoneum only (T3, T4, N+ tumours).
The two types of pathologies included in the research are chiefly different.
The PMP diagnosis is different from the CP CR one. On the other hand, within PMP
there are also histological subtypes with different diagnoses – PMCA has a reserved
diagnosis similar to the CP CR one. The two entities were included in the research
because the batches with CP CR or PMP patients were similar from point of view of
the clinical-epidemiological features, the number of intra-operative procedures being
similar in both cases. It would have been impossible to carry out a study only on the
batch of patients with CP CR because of the low number of patients.
Although it is a more complex intervention, the tumoral cytoreduction
associated to intraperitoneal chemotherapy for the batch of patients from INT has not
been followed in the postoperative period by increased morbidity or mortality. The
data is comparable to the data available in literature for HIPEC [233, 346-347], with
severe morbidity of 23% and intrahospital mortality of 3.5%. The multi-varied
analysis of the risk factors for the postoperative severe morbidity identified a factor
related to the patient and to the physician that carries out the selection for the patient –
ECOG performance status, a factor that is related to the extension of the peritoneal
affectation – the number of performed enterectomies and a physician-related factor –
the dosage of the chemotherapy used. The performance status during the preoperative
period is highly important since it probably reflects the duration of the illness
evolution, functional reserves and the ability of the patient to recover during the
postoperative period. It is arguable whether a patient who needs recovery in bed for
more than 12 hours or a patient who is incapable of taking care of himself can be
submitted to a large intervention. In relation to the number of anastomoses carried out
it is obvious in every surgical intervention that every anastomosis with various
localisations can increase the occurrence risk of the anastomotic fistula. There is not
much data known about the role of chemotherapy applied intraoperatively on
anastomoses. Research conducted on animals revealed a more difficult recovery of
anastomoses under hyperthermia [348]. All anastomoses are carried out at INT before
performing regular chemotherapy on the small intestine, generally mechanic suture in
cases of ileotransverse, colocolical and colorectal or ileorectal anastomosis, with
protective ileostomy in the last case.
In the research The Importance of the Learning Curve and Surveillance of
Surgical Performance in Peritoneal Surface Malignancy Programs (Surg Oncol Clin N
Am, 2012 Oct; 21 (4):559-76, two: 10.1016/j.soc.2012.07.011) [244] the assessment
was retrospectively on the cases operated within the National Institute for Tumours in
Milano between 1995 and 2011. The learning curve is a concept that appeared almost
30 years ago in medical practice and mainly refers to the stages necessary to reach
expertise in a field when starting from scratch. It is a rough guide, but it has a
subjectivity degree. It is hard to believe that a surgeon does only a certain type of
surgeries in order to gain experience. While earning experience, the surgeon assists
other colleagues as well or performs other interventions and thus he always makes
progress. There are few studies related to the learning curve in cytoreductive surgery.
Since in most retrospective cases the learning curve is assessed by dividing the batch
into periods or sub-batches selected arbitrarily, there can be discrepancies between the
capacity of the surgeon reflected on his position on the learning curve and the
postoperative results. The classical method of assessing the learning curve, by
dividing the patients into batches does not take into account other factors, such as
patient-dependent factors. The performance of the surgeon must also be adjusted on
the patient. The patients‘ selection is highly important and depends on the qualities of
the surgeon, but patients who could benefit from HIPEC should at least be assessed
for surgery. It is obvious that if a surgeon selected for a complex intervention only
young patients, with a high probability of favourable postoperative evolution, he
would probably reach the peak of the learning curve faster than a surgeon that would
select patients with increased probabilities of complications. A 70-year-old patient
with multiple co-morbidities that has a Peritoneal Cancer Index of 30 and might
undergo cytoreduction would need a complex intervention and would have a higher
probability of developing postoperative complications as compared to a 40-year-old
patient, who has not important co-morbidities and has a limited affectation of the
peritoneum. If a surgeon operates the 2 patients successively, the impact on the
surgeon‘s performance is different if patients have a postoperative severe
complication. For the patient with important co-morbidities the occurrence of a
postoperative complication reflects least the surgeon‘s performances and more his
performance status. On the same patient, the simple postoperative evolution is mainly
due to the surgeon‘s performances. The situation is rather opposite in the case of the
young patient. Therefore, in order to assess the performances of a surgeon in carrying
out an intervention the patient should also be taken into consideration. It is likewise
for other objectives aimed at during surgery (optimal cytoreduction etc.).
Severe morbidity was 29% in the study group. The mortality rate was 2.4%. RA-
SPRT curve showed a peak reaching the learning curve in the control of severe
postoperative complications after approximately 150 cases. For incomplete
cytoreduction learning curve peak is reached after 140 cases. The most common
disorders included in the study were PMP and MP. The RA-SPRT curve indicates an
improvement of performances after approximately 80 PMP cases operated and for
approximately 100 operated MP cases.
In the study "Learning Curve for cytoreductive Surgery and Hyperthermic
Intraperitoneal Chemotherapy in Peritoneal Surface malignancies: Analysis of Two
Centres (J Surg Oncol. 2013 Mar, 107 (4) :312-9. Doi: 10.1002/jso.23231. Epub 2012
August 23) [350]" we evaluated the mentor‘s role in the learning curve of a surgeon
who has initiated, under supervision, a treatment program for peritoneal diseases.
From 2003 to 2006 the main surgeon from INT oversaw the development of a new
center of peritonectomy at Bentivoglio Hospital from Bologna. Through repeated trips
from Bologna to INT and assisting the surgeon at INT, and then by initiating at
Bologna the peritonectomy program + HIPEC by the surgeon here, assisted in the
operations by the surgeon from INT, from 2003 to 2006 the Bologna center
peritonectomy was founded.
The goal of the study was to examine whether the support of the experienced
doctor influenced the surgeon's learning curve from the new center. 628 patients were
included in the study, operated at two hospitals: 67.4% at INT and 32.6% at the
Hospital in Bologna. With pre-operative risk factors for both groups of patients a
multivariate regression logistic pattern was created. With this pattern were then
evaluated and compared learning curves (RA-SPRT) for the two doctors - the
experienced and the initiated. After comparing the two curves RA-SPRT the
conclusion was that the initiated doctor has shortened the learning period with about
20 cases for optimal cytoreduction, severe morbidity and postoperative mortality. The
determining factor in this difference probably lies in the different ways of initiating a
HIPEC program. The initiated surgeon from Milan witnessed at the beginning of his
career a few interventions in the service where cytoreduction was sporadically used
and then visited the Cancer Institute in Washington, and then initiated the program
HIPEC unassisted by any experienced surgeon. The initiated surgeon after witnessing
a numerous interventions made in Milan was then assisted by an experienced surgeon.
The main conclusion is that in order to improve the results of HIPEC in the early
initiation of a program, the best solution is that the initiated surgeon is attended by an
experienced surgeon during his first operations. This is the only study that compares
the learning process through two different ways of initiation in the cytoreduction
tumors.
In Diffuse malignant peritoneal mesothelioma: Long-term survival with complete
cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy
(HIPEC)( Eur J Cancer. 2013 Jul 4. pii: S0959-8049(13)00435-8. doi:
10.1016/j.ejca.2013.05.027. [Epub ahead of print]) 108 patients were operated for
malignant peritoneal mesothelioma at INT where HIPEC was used. In the group of
patients studied postoperative mortality was 1.9%, and the severe morbidity was 39%.
Survival and disease free interval were 63 and 25 months. Survival reached a plateau
after about 84 months for 19 patients after that these patients were disease free.
Multivariate analysis revealed a direct correlation between survival and histological
subtype, nodal status, Ki67 positive presence in more than 10% of cells, and a
correlation between disease-free interval and the positive staining at podoplanin.
The absence of randomized multicentre prospective studies and of met analyses
is responsible for the skepticism that HIPEC is viewed. The rarity of PMP and MP are
making almost impossible the conduction of prospectively randomized studies. It
gradually imposed the necessity of specialized treatment centers [351]. The reason for
these centers is that more cases benefit the expertise of a surgical team involved in a
complex procedure.
In 2008, RC incidence (GLOBOCAN International Agency for Research on
Cancer) was approximately 1.2 million, representing 10% of all newly diagnosed
cancers. In Romania in the same year almost 9000 patients were diagnosed with RC.
Transposing Jayne's study results at Romanian's population results that about 1,000
patients are diagnosed with CP and of these, approximately 250 have limited HP.
They are a subgroup of patients in which systemic chemotherapy / possibly associated
with biological agents and HIPEC would make a superior survival rate compared to
other patients.
In an article published in 2003 Bayon and col [352] revealed several necessary
factors to create a HIPEC center : implementation in progressive stages under institute
tutelage with permanent evaluation and improvement of the human and material
resources, the creation of multidisciplinary support, training the involved staff and
starting a program through a feasibility study.
Technical difficulties and high costs are the reasons why the HIPEC technique is
used in a limited number of centers. It is almost impossible for a surgeon to reach the
peak of the learning curve after 10-20 cases. Probably the best option would be that
after being instructed in an experienced center to be then helped by doctors who have
reached the curve's peak and then to operate by themselves on the easier cases.
9.2 Conclusions
The classical surgical treatment of peritoneal carcinomatosis is difficult with
a high postoperative morbidity and mortality rate that goes up to 10% when unselected
patients are included.
Careful patient selection and treatment opportunities in specialized centers
provided by experienced physicians in peritoneum disease may limit morbidity and
mortality to 30 and respectively 3%
Common tumor markers play a limited part in patient selection for tumor
cytoreduction associated with HIPEC but are associated with negative prognosis when
high levels are reached in the preoperative stage.
Preoperative chemotherapy does not bring significant advantages over the
surgical approach in patients with peritoneal mezotelioma who are treated by
cytoreduction associated with HIPEC. A 50% survival rate after 5 years in patients
operated in reference centers validates the aggressive treatment protocol of this poor
prognostic malignancy.
The learning curve in cytoreductive surgery is a long one of over 130 cases
needed for efficient management in the selection, surgical treatment and postoperative
care of patients with peritoneal disease that require peritonectomy associated with
HIPEC.
This learning curve can be shortened with the help of a mentor that is initially
assisted and then assists the one that wishes to specialize in cytoreduction surgery.
Through the setting up of peritonectomy centers in Romania for a number of
patients with peritoneal carcinomatosis of peritoneal mesothelioma, apendicular and
colorectal etiology, the oncologic prognosis may be improved.
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List of scientific papers issued during PhD studies
1. Tratamentul carcinomatozei peritoneale de etiologie digestivă - studiu retrospectiv pe un lot de 203
pacienţi.
I. Huţanu, D. Timofte, V. Scripcari , C. Diaconu Rev Med Chir Soc Med Nat Iasi. 2012 Jan-Mar;116(1):150-6.
http://www.revmedchir.ro/uploads/1/5/7/2/15722076/22_hutanu.pdf
2. Learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal
surface malignancies: Analysis of two centres†
Shigeki Kusamura, Dario Baratti, Salvatore Virzì, Serena Bonomi, Domenico Rosario Iusco ,Antonio Grassi, Ionut Hutanu ,Marcello Deraco
J Surg Oncol., Online first
http://onlinelibrary.wiley.com/doi/10.1002/jso.23231/abstract
3.The importance of the learning curve and surveillance of surgical performance in peritoneal surface
malignancy programs.
Kusamura S, Baratti D, Hutanu I, Rossi P, Deraco M.
Surg Oncol Clin N Am. 2012 Oct;21(4):559-76. doi: 10.1016/j.soc.2012.07.011
http://www.surgonc.theclinics.com/article/S1055-3207(12)00060-9/abstract
4. Circulating tumor markers: predictors of incomplete cytoreduction and powerful determinants of outcome in pseudomyxoma peritonei
Kusamura S, Hutanu I, Baratti D, Deraco M.
J Surg Oncol. 2013 May 29. doi: 10.1002/jso.23329. [Epub ahead of print]
5. The role of perioperative systemic chemotherapy in diffusemalignant peritoneal mesothelioma patients treated withcytoreductive surgery and hyperthermic intraperitoneal Chemotherapy
Marcello Deraco, Dario Baratt, Ionut Hutanu, Rossella Bertuli, Shigeki Kusamura MD PhD.1
Ann Surg Oncol. 2013 Apr;20(4):1093-100. doi: 10.1245/s10434-012-2845-x. Epub 2013 Mar 2.
6. Chimioterapia hipertermică asociată citoreducţiei tumorale (CHIP) - opţiune în tratamentul
carcinomatozei peritoneale de etiologie colorectală I. Huțanu, R.Iulian, B. Filip, Mihaela Buna, Marcello Deraco, V.Scripcariu Jurnalul de Chirurgie NR. 1, VOL. 9, 2013
7. Diffuse malignant peritoneal mesothelioma: Long-term survival with complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC).
Baratti D, Kusamura S, Cabras AD, Bertulli R, Hutanu I, Deraco M.
Eur J Cancer. 2013 Jul 4. pii: S0959-8049(13)00435-8. doi: 10.1016/j.ejca.2013.05.027. [Epub ahead of print]
List of submitted papers
1.Neutrophil-lymphocyte ratio and Onodera index: new prognostic markers in pseudomyxoma peritonei
Shigeki Kusamura, Dario Baratti, Ionut Hutanu, Cecilia Gavazzi, Alessandro Sironi, Haeusler Edward,
Daniele Morelli, Marcello Deraco Annals of Surgical Oncology
2. Diffuse malignant peritoneal mesothelioma: seven-year actual survival after surgical cytoreduction and
hyperthermic intraperitoneal chemotherapy (HIPEC) defines cure D. Baratti, S. Kusamura, A. D. Cabras, R. Bertulli, I. Hutanu, M. Deraco Annals of Surgical Oncology
List of papers presented in national and international congresses National congresses
1. Conferinţa Naţională de Chirurgie Sibiu 19-21 Mai 2011
Carcinomatoza peritoneala cu punct de plecare digestiv . studiuretrospectiv pe un lot de 64 de pacienti ai
Clinicii III Chirurgie Iasi I.Hutanu, G. Anitei, R. lulian, C. Diaconu, V. Scripcariu, D. Timofte
http://chirurgie2011.eventernet.ro/images/program_final.pdf
2.Simpozionul Doctoranzilor 8 septembrie 2011, Timişoara
Experienta clinicii III Chirurgie Iaşi în tratamentul carcinomatozei peritoneale de etiologie digestiva -
studiu retrospectiv pe o perioadă de 5ani.
I.Hutanu
3.Simpozionul National"Contribuţii ale tinerilor cercetatori la dezvoltarea cercetării in domeniul medico-farmaceutic",sectiunea studentilor - doctoranzi.
Iaşi, 7 - 9 Noiembrie 2012
The evaluation of risk factors for complications after cytoreductive surgery associated with hipec for colorectal and appendicular carcinomatosis patients
Hutanu Ionut , ScripcariuViorel, Shigeki Kusamura , Dario Baratti, Marcello Deraco
4.Confer 2012 Conferinţele institutului regional de oncologie iaşi zilele oncologiei ieşene, ediţia a VIII-A
22‐24 NOIEMBRIE 2012, IAŞI Chimioterapia hipertermică intraperitoneală asociată citoreducţiei tumorale. Experienţa Institutului
Naţional pentru Tumori din Milano, Italia I. Huţanu, V. Scripcariu, Shigeki Kusamura, D. Baratti, M. Deraco
http://oncologieiasi.ro/atdoc/Program_detaliat.pdf
5. Congresul Naţional al Societăţii Române de Coloproctologie
ediţia a III-a 18 – 20 aprilie 2013 Iaşi, Centrul de Conferinţe Palas Carcinomatoza peritoneală de etiologie colorectală - prezent şi viitor
I. Huţanu
International congresses
The role of preoperative albumin and lymphocytes in predicting severe complications and survival in patients with appendiceal neoplasms submitted to cytoreduction and hyperthermic intraperitoneal
chemotherapy
Kusamura S, Baratti D, Gavazzi C, Hutanu I, Sironi A, Gil Gomes E, Deraco M Eighth International Symposium on Regional Cancer Therapies February 16—18, 2013
Hyatt Grand Champion Resort & Spa - Indian Wells, California
http://www.regionaltherapies.com/pdf/2013_brochure.pdf
The role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients
treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Kusamura S, Baratti D, Hutanu I, Deraco M
11th International Conference of the International Mesothelioma Interest Group (iMig 2012), September 11
– 14, 2012, Seaport Hotel and World Trade Center in Boston, Massachusetts, USA. http://www.imig2012.org/scientific-program/documents/iMig2012_OnsiteProgram_vFF_lowres.pdf
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