Patient Information

German Hodgkin Lymphoma Study Group (GHSG)

Chairman: Prof. Volker Diehl, MD University Clinics of Cologne University

Klinikum der Universitaet zu Koeln Studienzentrale der DHSG 50924 Koeln Germany

1 von 8 GHSG Patient information (HD15 - 12/2006-V05)

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Sponsored by Deutsche Krebshilfe

Sponsored by BMBF

Information for Patients

- HD15 for advanced stages - Quality assurance protocol for reduction of toxicity and for the prognostic

relevance of FDG-PET in the first-line treatment of advanced stage Hodgkin lymphoma

(8 x escalated BEACOPP vs. 6 x escalated BEACOPP vs. 8 x BEACOPP-14 followed by RT to PET positive PR)

Dear Patient,

We would like to ask for your consent to your participation in a clinical trial. The following pages are to inform you fully about the planned trial and to help you to decide whether to participate. Please read this information carefully. You will have the opportunity to ask questions in a subsequent talk with your doctor. Your doctor has explained to you that you are suffering from Hodgkin's lymphoma, a cancer of the lymphatic system. Hodgkin's lymphoma is one of the best treatable cancers in adults and can be cured in most cases. However, since not all patients with this disease can be cured yet, and the treatment is moreover often associated with side-effects and long-term toxicity, it is currently being attempted to improve the effectiveness of the treatment and, most importantly, to reduce side effects. In the present scientific study, the physicians under the direction of Prof. Dr. V. Diehl cooperating in the German Hodgkin Lymphoma Study Group (GHSG) have developed new treatment strategies which aim to improve upon the current standard treatment. With this aim, studies involving several countries are being performed. Within this so-called quality assurance protocol, various treatment strategies, involving exclusively drugs that have been authorized, are compared.

Aims of the HD15 Study The study aims to reduce through the new treatment strategies the side effects of chemotherapy and to improve quality of life, as well as to maintain effectiveness at the level of the standard therapy. Furthermore, the reliability of a new medical examination technique (PET examination) will be evaluated. A further aim is to investigate the effectiveness of a supportive drug for avoidance of anemia, a frequent side-effect of chemotherapy. The documentation of late toxicities is also important. The aim is to involve 1500 patients in the HD15 Study.

Documentation of quality of life within the HD15 Study In the assessment of the new treatment strategies, your quality of life before, during and after treatment is also to be examined. We therefore ask you to take part in the quality of life investigations.


Clinical-scientific co-investigations within the HD15 Study Besides this, we ask for your participation in two studies using blood samples through which it is hoped that information on the biological background to the illness will be gained.

In the following sections, the treatment of your illness within the framework of the HD15 Study, the quality of life investigation and the clinical-scientific co-investigations will be described in greater detail.

Treatment procedure in the HD15 Study Chemotherapy Treatment for Hodgkin's lymphoma consists of a combination of chemotherapy and radiotherapy. In certain cases, chemotherapy is used alone. The type and extent of treatment depend upon the severity of the disease, which is subdivided into early, intermediate and advanced stages. In your case, an advanced stage of Hodgkin's lymphoma was diagnosed. The standard treatment for advanced stages consists of the so-called escalated BEACOPP regimen, a combination of seven high-dose chemotherapy drugs (cyclophosphamide, Adriamycin, etoposide, procarbazine, prednisone, vincristine, bleomycin). This BEACOPP regimen is applied in the present trial in three versions, which differ in terms of the duration and number of cycles (treatment phases). In one treatment group, 6 cycles each lasting 21 days are given, in another group 8 cycles also lasting 21 days each, and in the third group 8 cycles each lasting 14 days. The component drugs of this chemotherapy are administered as an infusion or in the form of tablets at precisely scheduled time-points. In order to avoid side effects, not all drugs are given at once. After a treatment cycle has been completed, there follows a pause in treatment before the next treatment cycle begins. If these 6 or 8 cycles can be administered without delay, the full chemotherapy lasts between 4 and 6 months. Slight delays are however not exceptional, and usually do not represent a risk to a successful outcome

PET examination In the present trial, if residual tumor persists after chemotherapy, an additional positron emission tomography examination (PET) is performed to decide whether a consolidatory radiotherapy is needed (PET study). This PET examination detects whether the remaining tissue after chemotherapy is still metabolically active, which indicates that residual tumor is present. If the examination shows increased density (thus indicating the presence of metabolically active tissue), radiation therapy will be performed. In the case of residual tumor existing, your examination images after chemotherapy and your PET images will be forwarded to a particularly highly qualified specialist in nuclear medicine, named by the trial direction of the DHSG, for review of the PET examination results.

Radiotherapy Should the PET examination show an increased density in the area of the residual tissue, radiation therapy of the residual tumor follows at a dosage of 30 Gy. Irradiation should begin within 6 to 8 weeks after the end of chemotherapy. In most cases, it will take place daily on weekdays over a period of 2 to 4 weeks. After completion of radiotherapy, the treatment outcome will be re-evaluated. If the PET examination shows no increased density no radiation therapy will be given. In this case, frequent monitoring will follow.

Outpatient treatment schedule or hospitalization Since administration of the drugs and patient care take place mainly in an outpatient setting, long periods of hospitalization directly due to therapy are not expected. In the two treatment groups with a cycle duration of 21 days, only the first cycle of BEACOPP will be administered


in hospital. You must visit your doctor for the scheduled treatment appointments. Blood for determination of blood values will be sampled weekly until the end of treatment. The PET examination will be carried out in an out-patient setting without costs being incurred to you. However, the costs of traveling there must be borne by the patient.

Randomization Each patient who decides to participate in the trial will be allocated by chance through the principle of randomization to one of the three chemotherapeutic treatment groups (randomization). The trial will compare the three treatment schemes and determine the optimal treatment. The probability of allocation is in each case equal for all treatment groups By means of the quality assurance protocol at hand the various treatments are to be compared and the optimal therapy determined. The incorporation of the chance principle ensures comparability among the treatment groups.

Investigations within the framework of the trial Within these trials, a series of examinations will be performed in order to assess, as far as possible, the physical status of the patient before, during and after treatment. Without these examinations, appropriate treatment is not possible and the effectiveness of the treatment cannot be adequately assessed.. It should be stressed that the extent and frequency of these examinations and samples taken, as described below, do not exceed that which would in any case be necessary outside of the trial. Without your consent to these examinations and tissue sampling, no treatment can take place within the trial.

Examinations prior to therapy (diagnosis) The treating doctor records your case history and performs the physical examination before treatment. Please tell your doctor of any medicines which you take regularly. Extensive laboratory diagnostics (using a blood sample) and tests for possible viral diseases such as hepatitis B, hepatitis C and HIV (human immunodeficiency virus) are carried out. Tissue samples will be sent to a particularly highly qualified specialist pathologist (review pathologist) named by the trial directors of DHSG to confirm the diagnosis, in order that the selection of an optimal treatment for you is ensured. Without your consent to these tests, no treatment can take place within the trial. After the removal of a lymph node, a bone marrow biopsy (i.e. a bone tissue puncture) is needed to estimate the extent of disease. The bone marrow biopsy is performed under local anesthetic, usually on the pelvis. Further, it is necessary to check certain other organ functions before starting treatment. Such examinations allow possible side-effects of treatment to be assessed more effectively. They include: ECG (electrocardiograph), echocardiograph (ultrasound examination of the heart), lung function test and the measurement of thyroid function via a blood sample. The function of the genitalia (ovaries and testes) will be assessed by recording the menstrual history in women and by laboratory tests in men. Various imaging techniques will be used to describe the extent of the disease precisely: X-rays of the chest (from the front and from the side), ultrasound of the abdomen and computed tomography of the neck, chest and abdomen. A nuclear magnetic resonance examination can be needed in individual cases. A bone scintigraphy, which portrays the skeleton, is also necessary. Treatment can be started promptly after completion of all diagnostic examinations, which usually takes about two weeks.

Accompanying examinations and treatments during therapy Treatment is accompanied by regular blood tests in order to detect possible side-effects as early as possible. You are required to visit your doctor on the appointed treatment dates. For determination of laboratory values, your blood will be sampled weekly until the end of treatment.


Besides chemotherapy drugs, further medication will be administered in order to prevent possible side-effects. These may include antibiotics, medicines to avoid nausea and vomiting, medicines to protect the kidney and bladder, blood, blood products and medicines to support the natural production of blood cells. Should an iron deficiency be detected, you will also receive, according to the judgement of your doctor, up to 200 mg daily of an iron preparation. This is necessary because an adequate supply of iron to the body is important for the production of blood. Close contact between doctor and patient is necessary for good treatment. Therefore, it is essential that you discuss any complaints you may have with your treating doctor.

Assessment of treatment success (Restaging) A restaging is always performed after the end of chemotherapy or (if given) radiotherapy. An additional restaging (interim restaging) takes place between the 4th and 5th chemotherapy cycle. These assessments again include a physical examination, blood tests, X-ray examinations and computed tomography. In particular, all initially involved sites will be reexamined.

Examination after treatment (Follow-up) Regular follow-up is essential after any treatment for cancer. This follow-up aims at early detection of any reappearance of the disease (relapse), detection and treatment of accompanying and subsequent diseases and at providing support for the patient in physical, emotional and social matters (quality of life). After the end of chemotherapy and/or radiotherapy, regular follow-up examinations should be performed. Checks are planned beginning four times per year, later twice and then once per year, which include physical examination, blood tests, X-ray examinations and ultrasound. Computed tomography will be scheduled individually, depending on the outcome of the chemotherapy. The accompanying follow-up examinations concerning late toxicities/adverse effects (damage to other organs which might occur due to chemotherapy or radiotherapy) are also essential. These examinations include ECG, echocardiography and lung function. The quality of life questionnaire is to be completed before starting treatment, during treatment and especially during follow-up. Appointments for follow-up examinations are arranged either with the hospital where treatment took place or with your own doctor. They should continue regularly over the following years. The examinations monitor treatment success and are chiefly for your own safety.

Side-effects / risks Both chemotherapy and radiotherapy have side-effects. Since chemotherapy drugs and radiation attack not only the tumor but also healthy tissues, the following side-effects may occur: Loss of hair from the head is often observed. The hair grows again after treatment. Nausea and vomiting can occur particularly on treatment days, but can in almost all cases be well treated by medicines. Likewise, loss of appetite, sleep disturbances, fever, influenza-like symptoms, skin rash, mucal inflammation in the mouth, throat and gullet and allergic reactions can occur. Further, temporary or even permanent damage to organs such as lung, kidney, spinal cord, peripheral nerves, liver, heart and bone marrow can arise. However, these toxicities are rare. For the low-dose Involved Field Irradiation employed in this trial, only minor side-effects are expected. Immediately after irradiation, occasional changes to the mucus and problems in swallowing are experienced: skin reactions are rare. Very rarely, irradiation can cause late toxicities such as lung fibrosis (scar-like changes to the lung tissues causing restrictions to breathing), heart damage or second cancers.


The chemotherapy employed in this trial can affect male or female fertility temporarily or permanently. In women, particularly after the age of 35, menstruation can cease, and menopause symptoms are possible. Sexual desire is often reduced temporarily in both men and women. Recognized contraception methods must always be used during treatment. If you plan to have children, please consider before beginning treatment whether to employ a technique such as freezing of sperm in a sperm-bank or artificial insemination. Certain drugs can cause tingling and a furry feeling in the hands and feet. The digestive system can also be affected in the form of diarrhea or constipation. You are highly susceptible to infections during the entire chemotherapy. This applies particularly between the 8th and 16th day of each chemotherapy cycle, when the concentration of leukocytes (white blood cells) falls. Therefore, thorough hygiene, especially in the mouth, is important during the entire treatment period. Avoid petty mucal infections by using a soft toothbrush. The scarcity of red blood cells can lead to shortness of breath during exertion and general tiredness. Blood transfusions might be needed in certain cases. Fever should always be examined since it could be a danger to life. If you develop fever during treatment, please visit your doctor. The ingestion of iron tablets can lead to complaints concerning the stomach and intestine and to changes to stools such as constipation or dark colouring of the faeces. If adverse effects or unexpected symptoms occur, please contact your doctor immediately. Although PET is performed with the help of a radioactive drug (fluorine-18 radioactive marked sugar), the drug has only short-lived radioactivity. After a few hours, most of the radioactivity has decayed, and so there is negligible long-term activity. The radiation exposure of PET means less radioactive burden for the patient than a CT examination.

Most patients suffering from Hodgkin's disease today can be cured. The necessary treatment components lead to the side-effects described above. In addition, however, treatment is burdened with the risk of late toxicities. Chemotherapy and radiotherapy increase the risk of so-called secondary malignancies (second cancers) such as leukemia and solid tumors. Further, late toxicities can still arise months or years after the disappearance of the acute side-effects on the heart, lungs and sex organs. Furthermore, supportive medication which may become necessary during your treatment can cause further side-effects. You doctor will brief you on these effects.

Other treatment methods If you decide not to take part in this trial, your doctor will explain which other possible treatments are available, for example, treatment with other chemotherapy drugs or a modified form of radiation therapy. At present there is no alternative method to the administration of Epoetin alpha for influencing or avoiding anemia. Blood concentrates are prescribed only in case of extreme anemia in order to alleviate serious symptoms already present such as shortness of breath or racing heartbeat. Despite intensive tests, the possibility of transmission of certain infectious diseases by such blood transfusions cannot be entirely excluded.

Investigation of quality of life within the HD15 trial Additionally, we request you to complete questionnaires on quality of life before, during and after treatment. The aim of this survey is to assess whether and how your physical, emotional and social state have been affected by the disease and by treatment, also in the long-term. The first questionnaire will be handed to you by the doctor treating you prior to the therapy. Further questionnaires will be sent to you by the trial coordination center (if you consented to this before treatment). This will also continue into the period of follow-up care. Please return the completed questionnaires to the trial coordination center as soon as possible or give them to the doctor treating you. Even if you would like to participate in the trial concerning treatment regimens, you can still refuse the history taking concerning your quality of life at any time.


Clinical-scientific investigations accompanying the HD15 trial The two blood samples taken within the clinical-scientific accompanying investigations are taken purely for clinical research purposes. Within the treatment trial, genetic factors and proteins in the blood are to be identified with the help of which it will, in future, be possible for the course of the disease to be predicted more reliably and for treatment to be individually optimized. For this evaluation, it is necessary for a blood sample to be taken exclusively for the above-mentioned clinical research purposes before and after the treatment. The risks involved in the clinical-scientific accompanying investigations are limited to the risks of the blood collection. Even if you would like to participate in the trial concerning treatment regimens, you can still refuse to take part in the clinical scientific accompanying investigations at any time without any disadvantage for your treatment.

Further information This trial protocol was reviewed by the ethics committee and assessed positively. Participation in this clinical trial, in the investigation of quality of life and in the clinical-scientific accompanying investigations is of course voluntary. If you agree to participate, you can withdraw this consent at any time without incurring any disadvantage. Should you decide to take part, your doctor will ask you to sign a statement of consent and thereby confirm that you are fully informed about the trial and understand its aims. If you withdraw early from treatment within the trial, for reasons of safety, restaging and follow-up examinations should take place. You will then be further treated outside the trial according to the best available medical expertise. Furthermore, please note that your treatment can be amended when necessitated by medical reasons. In this case, you will be further treated outside the trial according to best medical knowledge. Should findings become known during the course of the trial that could have an impact on your decision regarding continued participation in the trial, you will be informed of them at once. If you withdraw from the trial treatment early, your personal data will continue to be stored for purposes of clinical consultation with the trial direction. Should you withdraw your consent to further collection of data, the data already collected will be anonymized thereby removing any connection of the data with your person.

The benefit of your participation lies in the possibility of successful treatment through a new treatment scheme. The results of the trial may provide valuable knowledge for the future treatment of your disease. However, it cannot be guaranteed that you will benefit from participation in this trial. Participation involves you in no extra trial-associated costs.

Since the drugs used in this trial may possibly damage the fetus, pregnant women are excluded from participating. Women of childbearing age must guarantee through the use of safe contraception that a pregnancy cannot occur during treatment. We also recommend avoiding pregnancy for a period of one year after treatment. If necessary, your doctor will advise you with respect to contraceptive methods that are sufficiently reliable.

Patient insurance Patients not resident in Germany are excluded from the insurance scheme described below, and should ensure that they are adequately covered. For the duration of the treatment, a patient insurance (Contract No. 37.907.546.060 Deutsche Krebsgesellschaft e.V.) has been arranged with the Gothaer Allgemeine Versicherung AG (Kln, Tel.: 0221-308-1336). The maximum value per insured person is 512 000 Euro. The general conditions can be obtained from your doctor or the secretariat of


the Deutsche Hodgkin Lymphom Studiengruppe (DHSG), Clinic of the University of Kln, 50924 Kln (Tel: 0221 4786032). There is however the precondition that any other medical treatment, except in emergencies, may only be performed with the agreement of the doctor who is responsible for you in the trial. Otherwise the insurance cover is endangered. Any damage to health which might be a consequence of the trial must be reported immediately to the insurers. No insurance cover exists with respect to accidents occurring on the way to examinations occasioned by the trial.

Information concerning data protection rights Within this trial, your individual treatment data i.e. clinical data with name, given name and date of birth will be collected and transferred to the trial coordination center in Cologne, Germany. This ensures that consultation on treatment between the trial coordination center of the DHSG and the doctor treating you can take place speedily. For your own safety and in order to guarantee the quality of treatment, the study organisation center of the DHSG will establish contact with the review institutions (review pathology, review nuclear medicine), Data collection serves exclusively the aims of the trial as given above. For the investigation of quality of life, we require that a questionnaire is filled out by you personally. Thus your data with respect to quality of life will be stored in the trial center in Cologne with reference to your person. In processing this data, the data protection regulations will be observed. Your data will be stored electronically. The regulations with regard to data protection will be observed in the processing of the data. Only trial personnel have access to your data, and these persons are committed to secrecy. Due to legal regulations, certain persons (authorized third parties) have a right to view your personal case files. These persons include persons who, acting on the instruction of the DHSG, check the correctness of the data (monitors, auditors), other persons appointed by the DHSG, representatives of the responsible regulatory or national authorities. This access is permitted only according to the legally regulated tasks of these persons, namely, to check the data. These persons, too, are committed to secrecy. You may demand information concerning your stored data at any time. You have the right to correct erroneous personal data or to have data deleted, and you have the right to withdraw your consent to the processing of your data related to your person at any time. You can contact the following address as necessary: Studienzentrale der DHSG, Klinikum der Universitt zu Kln, 50924 Kln (Tel.: 0221-478-6032 or -3555, e-mail: [email protected]). Data analysis is carried out without direct reference to your name (pseudonymized) by persons employed by the DHSG These persons are also committed to secrecy. Publication of trial results will not reveal from the data who has participated in the trial. No connection can be made with your person under any circumstances. Your data will remain in the trial coordination center of the DHSG. In the treatment of the Hodgkin Lymphoma, follow-up monitoring continuing over a period of years is important for your safety. A risk of solid tumors continues to exist even after many years which could perhaps make it necessary that clinical consultation with the trial direction is carried out. In order to make this possible for you, the data related to your person will be stored in the trial coordination center or the DHSG for the entire duration of your life. After the end of your life, the personal connection to your clinical data will be deleted. The antibody analysis involved in the clinical scientific examinations accompanying the trial will be carried out by a laboratory under contract with the Medical Clinic I of the Klinikum der Universitt zu Kln using anonymized blood samples only, i.e. without any reference to your personal data. Likewise, the genetic factors will be examined in the course of the clinical scientific investigation accompanying the trial at


the Klinikum der Universitt zu Kln using only anonymized blood samples. The data protection officer of the Klinikum der Universitt zu Kln guarantees the anonymization of the data. If need arises, you can get in touch with the Data Protection Officer of the Klinikum der Universitt zu Kln through the trial coordination center of the DHSG or on the telephone number 0221-478-3385.

If over a long period of time the trial coordination center receives no information from you, it will write to you asking you to arrange a follow-up examination with a doctor of your choice or to inform us of the address of your doctor, assuming that you have agreed beforehand to being written to. Further, you will receive quality of life questionnaires regularly from the trial coordination center, which you should complete at the next follow-up examination and return or hand to your doctor. If the trial coordination center receives no quality of life questionnaire from you over a long time period, the trial coordination center will send you a reminder.

Further questions If you have further questions concerning the trial or your rights and duties as a participant, please contact your doctor at any time.

Name: ........................................ Tel..........................................................

Fax: ..

or contact the trial coordination center of the German Hodgkin Lymphoma Study Group (Tel. +49-221-478-6032; -3555).

If you decide to participate in this trial, we would like to thank you warmly for your support.

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