Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Meyer RM, Gospodarowicz MK, Connors JM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin s lymphoma. N Engl J Med 2012;366: DOI: /NEJMoa

2 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: REVISED: REVISED: REVISED: REVISED: 94-AUG OCT JUN DEC JUL-16 NATIONAL CANCER INSTITUTE OF CANADA CLINICAL TRIALS GROUP (NCIC CTG) A PHASE III STUDY OF RADIOTHERAPY OR ABVD PLUS RADIOTHERAPY VERSUS ABVD ALONE IN THE TREATMENT OF EARLY STAGE HODGKIN'S DISEASE NCIC CTG Protocol Number: HD.6 ECOG: JHD06 NATIONAL CANCER INSTITUTE OF CANADA, CLINICAL TRIALS GROUP (NCIC CTG) STUDY CHAIR: TRIAL COMMITTEE: PHYSICIAN COORDINATOR: BIOSTATISTICIAN: QUALITY OF LIFE COORDINATOR: STUDY COORDINATOR: DR. R. MEYER DR. J. CONNORS DR. MARY GOSPODAROWICZ DR. ROBERT PEARCEY DR. WOODROW WELLS DR. LOIS SHEPHERD DR. BENNY ZEE DR. ANDREA BEZJAK MARINA DJURFELDT EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) ECOG STUDY CO-ORDINATOR: DR. JANE WINTER

3 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 TREATMENT SCHEMA Patients with Clinical Stage I or IIA previously untreated Hodgkin's Disease, excluding patients who might be treated with involved-field only irradiation (section 5.2.3) or patients with bulky adenopathy (section 5.2.4), are eligible for this study. Eligible patients will be divided into 2 cohorts based on the following risk factors: Patients will be assigned to Cohort 1 if all of the following criteria are met: Lymphocyte predominant (LP) or nodular sclerosing (NS) histology Age < 40 years Erythrocyte sedimentation rate (ESR) < 50 plus: Supradiaphragmatic disease with < 4 disease sites or: Pelvic disease (ileofemoral, inguinal, parailiac) with < 4 disease sites All other eligible patients will be assigned to Cohort 2. Stratification: by Centre ABVD: Doxorubicin - 25 mg/m 2, days 1 and 15 Bleomycin - 10 units/m 2, days 1 and 15 Vinblastine - 6 mg/m 2, days 1 and 15 Dacarbazine mg/m 2, days 1 and 15 Chemotherapy must begin within 7 days, and radiation therapy within 4 weeks, of randomization.

4 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 TABLE OF CONTENTS SCHEMA... Frontispiece 1.0 OBJECTIVES BACKGROUND AND STUDY RATIONALE Staging and Management of Hodgkin's Disease Prognostic Factors in Limited Stage Hodgkin's Disease Long-term Mortality and Treatment of Hodgkin's Disease Chemotherapy For Limited Stage Hodgkin's Disease Rationale For Current Study Quality of Life BACKGROUND THERAPEUTIC INFORMATION Doxorubicin (NSC ) Bleomycin Vinblastine Dacarbazine (DTIC) TRIAL DESIGN Stratification Randomization STUDY POPULATION Eligibility Criteria Ineligibility Criteria PRE-TREATMENT EVALUATION ENTRY/RANDOMIZATION PROCEDURES Entry Procedures BSA Calculation... 16a 7.3 Stratification... 16a 7.4 Randomization... 16a 8.0 TREATMENT PLAN ARM A - (STANDARD) ARM B - (EXPERIMENTAL) Chemotherapy Treatment Plan Radiation Therapy Concomitant Therapy EVALUATION DURING STUDY Evaluation During Protocol Treatment Evaluation After Protocol Treatment i

5 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS Evaluable Definitions Response Definitions Freedom from progression ADVERSE EVENT REPORTING PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING Criteria for Discontinuing Protocol Treatment Therapy After Protocol Treatment is Stopped Follow-up Off Protocol Treatment CENTRAL REVIEW PROCEDURES Pathology Review Central Radiotherapy Review Final Review STATISTICAL CONSIDERATIONS Objectives and Study Design Primary Endpoints and Analysis Sample Size and Duration of study Interim Analysis PUBLICATION POLICY Authorship of Papers, Meeting Abstracts, Etc Responsibility for Publication Submission of Material for Presentation or Publication ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES REB (Research Ethics Board) Approval for Protocols Informed Consent Centre Performance Monitoring On-site Monitoring Case Report Forms REFERENCES SAMPLE CONSENT FORM ii

6 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 TABLE 1 - TREATMENT OF LIMITED-STAGE HODGKIN'S DISEASE: RANDOMIZED TRIALS TABLE 2 - RANDOMIZED TRIALS COMPARING MOPP AND ABVD TABLE 3 - STATISTICAL CONSIDERATIONS FOR ACCRUAL APPENDIX I - PATIENT EVALUATION FLOW SHEET APPENDIX II - ANN ARBOUR STAGING CRITERIA APPENDIX III - MEASUREMENT OF MEDIASTINAL MASS LESIONS AND CALCULATION OF TREATMENT RESPONSE OF MEDIASTINAL AND ABDOMINAL LYMPH NODES APPENDIX IV - DOCUMENTATION FOR STUDY APPENDIX V - NCIC CTG EXPANDED COMMON TOXICITY CRITERIA APPENDIX VI - LIST OF "CONTACTS" APPENDIX VII - QUALITY OF LIFE ASSESSMENT iii

7 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD OBJECTIVES 1.1 To compare the twelve year survival in patients with early stage I, II A Hodgkin's disease (Ann Arbor Staging criteria - Appendix II) excluding patients who might be treated with involved field only irradiation (section 5.2.3) or patients with bulky adenopathy (section 5.2.4)), treated with chemotherapy alone (ABVD) versus patients given standard treatment that includes radiotherapy (radiotherapy alone in low risk and combined modality in higher risk patients). 1.2 To assess freedom from progression (FFP) in these patients at 5 and 10 years. 1.3 To assess additional secondary endpoints including: - proportion of patients entering complete remission - proportion of patients free from 2 nd disease progression at 5 and 10 years - cause-specific survival (survival from Hodgkin's disease at 5, 10, and 15 years) - treatment related toxicity both short and long term 1.4 To assess quality of life in these patients over the duration of the study. Description of quality of life during therapy (intra-group comparisons). Comparison of patients treated by chemotherapy alone with patients receiving standard therapy during treatment and during long-term follow-up (intergroup comparisons) 1

8 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD BACKGROUND AND STUDY RATIONALE 2.1 Staging and Management of Hodgkin's Disease Optimum treatment of patients with Hodgkin's disease requires determination of the pretherapy extent of disease (stage). The prognostic significance of the Ann Arbor staging system 1 has been well validated and use of stage-specific therapies considered standard practice. Disease control is anticipated in more than 80% of patients with limited-stage disease 2 and 60% of those with advanced-stage disease 3. Management of patients with limited-stage disease (Ann Arbor stage I/II) remains controversial. Problems of disease control must be balanced against risks of treatment toxicity. Radiation therapy as a single modality, with reservation of chemotherapy for high-risk patients or relapse, was previously considered a standard approach. However, many management options have been studied including: i) the role of surgical staging (laparotomy) 4 ; ii) the extent of the radiation field ; iii) the choice of chemotherapy regimen 8 ; iv) the use of a single treatment modality (radiation or chemotherapy) versus combined modalities 6, ; and, v) the choice of chemotherapy or radiation A literature review of randomized trials treating adult patients with stage I/II Hodgkin's disease demonstrates that measures of disease-free survival (DFS) can be improved by adding chemotherapy to radiation therapy (see Table 1) 6, 9-12 However, no survival advantage is seen with this or any other of the above strategies. Improved DFS may not confer a survival advantage for three reasons: prolonged disease control can be achieved with second-line therapy (thus "salvaging" patients not cured with first line therapy); patients with residual disease may have an indolent course necessitating long follow-up periods; and, the toxic "late-effects" of initial therapy may result in premature death from causes not perceived to be due to Hodgkin's disease. Further investigation is required to determine which treatment produces optimum long-term outcome. 2.2 Prognostic Factors in Limited Stage Hodgkin's Disease Factors predictive for outcome within the spectrum of limited-stage Hodgkin's disease have been used to modify therapy. Reports from large series show that patient age, gender, histological subtype, presence of systemic ("B") symptoms, erythrocyte sedimentation rate (ESR), number of disease sites, and disease bulk are independently predictive of outcome. The prognostic importance of tumour bulk (specifically the presence of a mediastinal tumour mass measuring more than one-third the chest wall diameter on a standard chest radiograph) and systemic ("B") symptoms have lead to treatment practices that include chemotherapy paralleling that used for advanced-stage disease. Age Patient age is a continuous variable predictive of disease-free and overall survival. The prognostic importance of age persists even after accounting for potential biases resulting in less aggressive staging and treatment in older patients. Inferior survival has been attributed to differences in disease biology, increased treatment toxicity due to comorbid conditions, and inability to salvage patients who fail first line-therapy. A variety of age cut-off values ranging between years have been used to differentiate outcome patterns. For instance, Sutcliffe has described inferior DFS in patients greater than age 50 treated at the Princess Margaret 2

9 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Hospital 16. An analysis of 9,090 patients compiled by the European Organization for Treatment and Research of Cancer (EORTC), showed that age 40 predicts for response and response duration 17. ESR Of the remaining factors, ESR, number of disease sites, histology, and gender have been used to formulate treatment practices. The ESR is also a continuous prognostic variable. Data from the EORTC show that the optimum cutoff point is linked to systemic symptoms; an ESR of 50 appears to best discriminate good from poor prognosis in stage I/II patients who do not have "B" symptoms 17. Other studies have ascribed prognostic significance to values of 40 or 45. Number of Disease Sites Number of disease sites is also a continuous variable. Most studies have either attributed prognostic importance to stage (one vs more than one disease site) or number of sites of stage II disease. The EORTC has demonstrated that patients with more than two sites of disease who receive single modality radiation therapy have inferior relapse-free and overall survival in comparison to those with two or fewer disease sites even when treatment policies include subdiaphragmatic radiation and/or pathological staging 18. Data from Stanford however, suggest that more than three versus three or fewer sites best predicts for a positive staging laparotomy 19 and may provide a more acceptable cut-off point for North American investigators. Histology Patients with limited-stage disease who have mixed cellularity or lymphocyte depleted histology have a higher incidence of a positive staging laparotomy and eventual disease relapse 20. Treatment strategies that do not include laparotomy will likely fail to detect subdiaphragmatic disease in more than 30% of these patients. Gender The independent prognostic importance of patient sex appears to be less important after correcting for histology. Treatment practices based on combinations of prognostic factors have been described. The EORTC has used number of disease sites (>2) and a combination of ESR and systemic symptoms (>30 if "B", >50 if "A") to define a poor-risk group of limited-stage patients 4. Current practice at the Princess Margaret Hospital includes use of age, ESR and histology to determine whether radiation or combined modality therapy is administered. These practices are believed to result in superior disease control with first-line therapy while minimizing late treatment-related toxicities. A poorrisk group of limited-stage patients for this study will use the Princess Margaret Hospital criteria as well as the number of disease sites < 4 versus > 4 based on the Stanford data. 2.3 Long-term Mortality and Treatment of Hodgkin's Disease Although Hodgkin's disease and immediate treatment-related toxicity remain the most frequent causes of death within the first decade following diagnosis, cumulative mortality from other causes, most notably fatal secondary cancers and cardiovascular events, will outnumber deaths 3

10 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 from Hodgkin's disease during the second and subsequent decades of follow-up. An increased risk of second malignancies, especially acute leukemia, has been firmly established. Data quantifying these risks have been reviewed by Kaldor and Lasset and suggest a 100-fold increase in the relative risk of developing acute leukemia in patients treated with chemotherapy (alkylating agent based) 21. An increased risk of leukemia was not seen in patients treated with radiation alone. However, patients receiving radiation were at increased risk of developing a solid tumour (relative risk 2.43 for radiation alone; 4.87 for combined modality therapy) 21. This risk was not seen in patients receiving chemotherapy alone. Kaldor has also analyzed data from 11 tumour registries from Canada and Europe 22, and again demonstrated an increased risk of acute leukemia and several solid tumours. Of note, almost all of the solid tumours occur in the supradiaphagmatic region included in a standard mantle radiation field. Analysis of data compiled at the 1989 Paris International Workshop allowed for similar conclusions. The components of therapy responsible for tumour development have been most comprehensively assessed in studies of secondary leukemia. Leukemia results from chemotherapy rather than from radiation treatment; a contributing role of radiation as part of combined modality treatment remains uncertain. The development of leukemia is associated with use of regimens that include an alkylating agent, especially nitrogen mustard, and procarbazine. Case-control data show this risk correlates with cumulative drug dose, further strengthening the association for causation 23. Other factors implicated with leukemogenesis include older age and prior splenectomy. The independent importance of these factors remains uncertain. An increased risk of leukemia has not been observed with non-alkylating regimens such as ABVD. Two retrospective analyses that include a large inception cohort have associated treatment of Hodgkin's disease with cardiovascular mortality 20, 25. The largest of these studies includes 1,660 patients with early-stage disease treated on four successive EORTC studies. All patients received mediastinal irradiation 20. Cardiac causes accounted for 8% of deaths representing and 8-fold increase over that expected. The relative risk was increased in males and inversely correlated with patient age. Boivin reported a study of 957 patients showing no increase in cardiac mortality except in a subset analysis of patients treated with mediastinal irradiation 24. Two smaller series (326 and 340 patients) have not demonstrated an increased incidence of cardiac deaths 25 26, although one of these did show an increase in "intercurrent" deaths (those not due to Hodgkin's disease, immediate treatment toxicity, or other cancer) 26. Data implicating radiation therapy in non-fatal cardiac toxicity come from Cosset et al who compared outcomes of 499 patients whose treatment included mediastinal irradiation to 138 patients not receiving radiation to this site 27. The incidence of pericarditis and myocardial infarction were increased in patients receiving mediastinal irradiation. Finally, two large data bases (the combined experience of four EORTC early stage trials and the 1989 Paris International Workshop data) clearly demonstrate that treatment for Hodgkin's disease increases the relative risk of death from other causes This relative risk progressively increases after the first decade of follow-up and is seen across all age groups. In fact, because of the reduced proportion of deaths in younger versus older controls, the increased relative risk of death from causes other than Hodgkin's disease is inversely correlated with age. This risk is increased in patients with limited- as opposed to advanced-stage disease, likely due to the reduced risk of death from Hodgkin's disease in limited-stage patients. 4

11 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Chemotherapy For Limited Stage Hodgkin's Disease Chemotherapy as a sole treatment modality for patients with limited-stage Hodgkin's disease was initially described in small case series from disadvantaged health care systems. As radiation facilities were unavailable, chemotherapy, using MOPP, was administered to small cohorts in Uganda 29, Algeria 30, and Brazil 31. Long-term survival was seen in 36-75% of patients. Lack of controls and potential differences in supportive care limit the interpretation of these results. More comprehensive data have been reported by Ekert et al describing results of treating children with MOPP or ChlVPP 32. Because of concerns of radiation induced bone growth retardation, chemotherapy was used as a single modality; long-term survival was seen in 94% of limited-stage patients. Three randomized trials in adult patients with limited-stage disease have compared single modality chemotherapy to either radiation alone (two trials) or combined modality therapy (one trial) 13 (see Table 1). Longo et al have reported the outcomes of 106 patients (104 pathologically staged) who were randomized to receive MOPP or radiation (field according to disease pattern) 15. This study initially included patients with bulky mediastinal and limited Stage IIIA disease. Ten year relapse free survival (86% v 60%; p =.009) and overall survival (92% v 76%; p =.051) were superior in patients treated with MOPP. However, when patients with bulky mediastinal or limited Stage IIIA disease were excluded from the analysis, differences were no longer observed (10 year relapse-free survival 82% with MOPP and 67% with radiation, p =.27; survival 90% with MOPP v 85% with radiation, p =.68). Biti et al have reported quite different results in comparing MOPP to subtotal nodal irradiation in pathologically-staged patients 14. Freedom from disease progression at 8 years appeared superior in patients treated with radiation (76% v 64%); there was insufficient power to achieve statistical significance. Survival was superior in the radiation group (93% v 56%, p <0.001) as MOPP treated patients were not as effectively salvaged with second-line therapy for relapse disease and also suffered an increased number of deaths from other causes. The third trial, reported by Pavlovsky et al, compared CVPP to CVPP plus radiation to sites of known disease 13. Combined modality therapy resulted in a superior 7 year DFS (71% v 62%; p = 0.01); a difference in overall survival was not observed (89% v 82%; p = 0.3). The interpretation of this study is limited because of use of a chemotherapy regimen that included onehalf the standard doses of cyclophosphamide and vinblastine. These three trials have used MOPP or MOPP-derived regimens and give inconclusive results. No comparative trials have tested a non-alkylating based regimen, such as ABVD, as a single treatment modality in patients with limited-stage disease. Consideration of using ABVD is important when one considers that: i) three randomized trials have shown ABVD to be superior to MOPP with respect to DFS (one trial also shows superior survival with ABVD; see Table 2) ; and, ii) ABVD has not been associated with leukemogenesis. Furthermore, ABVD has the additional advantage of not inducing infertility. 2.5 Rationale For Current Study This study is based on the rationale that optimum therapy for patients with limited-stage Hodgkin's disease is that which best produces disease control with front-line therapy and has the lowest risk of long-term toxicity. Current data suggest that low-risk patients with Stage I-II disease can be treated with radiation alone. Laparotomy staging provides marginal, if any, effect on disease-free survival and no survival benefit. Randomized trials have repeatedly shown that disease-free survival is superior with combined modality therapy as opposed to 5

12 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 radiotherapy alone and that this benefit particularly applies to high-risk Stage I-II patients. Factors allowing separation of low from high-risk patients have been identified. Therefore, among the currently available options, a standard practice of radiation therapy for good prognosis patients and combined modality therapy for poorer risk patients is reasonable. Such an approach would however mean that all patients receive radiation and would be susceptible to the long-term toxicities including second malignancies and cardiovascular complications. This trial is based on the hypotheses that optimum chemotherapy, consisting of ABVD, will produce disease-free survivals that are at least equal to standard therapy and will be associated with a reduced risk of death due to late treatment related toxicity. If this hypothesis is correct, superior survival should ultimately be seen. The primary outcome of this trial is overall survival at 12 years. By comparing the overall survivals of the two treatment groups, the effects of disease control and treatment-related toxicity will be included. The potential indolent nature of Hodgkin's disease, and the lead time required for fatal toxicities necessitate comparison of survival after long-term follow-up. It is expected that important differences in survival may take 12 years to become apparent. 2.6 Quality of Life A quality of life component will be used to evaluate differences in the two arms of the study which may add additional information that routine treatment-related toxicity may fail to identify. It will be important to evaluate quality of life over the duration of the study as delayed toxicity such as cardiovascular disease or second malignancies may be the sole difference in outcome between the two arms. In addition quality of life related to original treatment modalities may be the only outcome difference and should be evaluated. The EORTC-QLQ-C30+3 and a trial-specific checklist for Hodgkin's Disease will be used to assess quality of life. The QLQ-C30+3 is a "core" questionnaire consisting of 33 items that assess five functional dimensions (physical, role, cognitive, emotional and social), three symptom dimensions (e.g. fatigue, pain, nausea/vomiting, etc.) and global quality of life. The core questionnaire, known as the QLQ-C30, has been psychometrically validated in patients with lung cancer. Three items have been added which are of a developmental nature. The Hodgkin's Disease checklist consists of additional items that provide additional details on symptom-related distress and was specifically designed for this study. Five additional questions (the "subjective significance" module) were designed to elicit the patient's opinions about the perceived significance of changes in physical function, emotional state, social interactions, overall physical discomfort, and overall quality of life. 6

13 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT BACKGROUND THERAPEUTIC INFORMATION 3.1 Doxorubicin (NSC ) Mechanism of Action Doxorubicin is a derivative of the antitumour antibiotic daunorubicin, and differs by the presence of a hyroxyl group in the C-14 position. Its mechanism of action is thought to be the binding of nucleic acids, preventing DNA and possibly RNA synthesis Human toxicology P Hematologic: Leukopenia (dose limiting) and granulocytopenia, also thrombocytopenia and anemia. Nadir days, recovery in 21 days, generally permits an every-three week schedule. Patients with obstructive liver disease have more myelosuppression due to impaired drug excretion. Thus patients with hepatic dysfunction may need to have reduced dosage or be excluded from therapy. P Dermatologic: Alopecia, usually complete, but always reversible, hyperpigmentation of nailbeds and dermal creases, radiation recall. P Gastrointestinal: Nausea and vomiting, sometimes severe, which develops shortly after drug administration and occasionally persists 2-3 days, anorexia, diarrhea, mucositis, especially with daily x 3 schedule. P Cardiovascular: Arrythmias, ECG changes, rarely sudden death. Severe cardiomyopathy has been reported but appears related to total cumulative dose; risk is greater with total doses > 550 mg/m 2, mediastinal irradiation, pre-existing cardiac disease, advanced age; risk is reduced with weekly or continuous infusion regimens. P Other: Fever on day of administration, renal excretion of doxorubicin is minimal, but enough to colour the urine red, thus impaired renal function does not appear to increase the toxicity of doxorubicin. P Local effects: Phlebitis at site of drug injection. Vesicant if extravasated (leading to soft tissue necrosis); flush along vein, facial flush Pharmaceutical Data Doxorubicin is supplied as a 2 mg/ml solution in 25 ml and 100 ml vials. Refrigerated vials may be used for up to 30 days following initial use Storage and Stability Doxorubicin solution is stored under refrigeration Administration Doxorubicin may be further diluted in 50 to 100 ml of D5W or Normal Saline and infused intravenously over 15 to 30 minutes. Avoid extravasation. 7

14 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT Bleomycin Mechanism of Action Bleomycin is thought to inhibit DNA synthesis, with lesser evidence of RNA and protein synthesis Human Toxicology P Hematologic: Myelosuppression, nadir of WBC and platelet depression occurs approximately days after treatment. P Dermatologic: Alopecia, facial flushing (redness), mouth ulcers, hyperpigmentation, thickening, ulceration, hyperkeratosis, nail changes, rash, vesiculation and other skin changes are the most commonly observed side effects of treatment with bleomycin. These may develop in the second to third week of treatment, and are, in general, related to cumulative dose. Extravasation may result in severe pain but has not resulted in tissue damage. Rapid IV push may result in pain along injection site or thrombophlebitis. There have been infrequent reports of pain at tumour site and other local reactions. P Gastrointestinal: Severe nausea and vomiting, which characteristically lessens with each subsequent daily dose. P Hepatic: Increased ALT, AST. P Renal: Increased serum creatinine, BUN. P Neurologic: Facial parasthesia. P Pulmonary: The most potentially severe side effect, occurring in about 10% of patients is pulmonary, usually manifesting as pneumonitis, occasionally progressing to pulmonary fibrosis, which may result in death. It is usually, though not always, dose and age related. P Other: Flu-like syndrome (with fever, malaise, myalgia) rarely occurs about 7 days and last 1-3 weeks. Rarely anaphylaxis (in about 1% of patients a hypersensitivity reaction may occur) Pharmaceutical Data Each vial of bleomycin contains 15 units as bleomycin sulfate in dry powder form, stable for at least 18 months if unopened, at 2-8 C. Potency is retained for 14 days after reconstitution, when refrigerated. Bleomycin is reconstituted with sterile water for injection to yield a solution of 3 or 5 mg/ml Administration When given by the I.V. route, bleomycin can be injected directly over 2 to 3 minutes or by smallvolume infusion over 15 to 30 minutes. 8

15 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Vinblastine REVISED: 95-OCT Mechanism of Action Vinblastine is an alkaloid derived from the periwinkle, Cantharanthus roseus. It enters cells rapidly and binds to tubulin thus interfering with the microtubular systems responsible for maintaining cell shape and surface mobility and, most importantly, mitosis since it cause dissolution of the mitotic spindle. Cells are arrested at the G2-M interface. Vinblastine also interferes with the energy-generating metabolism of the cell and inhibits RNA synthesis via RNA polymerases. It is highly bound to plasma proteins and degraded to active metabolites which are mostly excreted in the bile Human Toxicity P Hematologic: Leukopenia (dose limiting toxicity is granulocytopenia), thrombocytopenia, anemia. P Dermatologic: Alopecia, epilation, and soft tissue damage if extravasated (the manufacturer recommends subcutaneous injection of hyaluronidase and application of heat to help disperse the drug), rash, photosensitivity. P Gastrointestinal: Nausea, vomiting (preventable), constipation (see neurologic side effects), which are moderately common, abdominal pain (cramps), anorexia, diarrhea, mucositis, gastrointestinal hemorrhage. P Neurologic: peripheral neuropathy (loss of deep tendon reflexes, paresthesias or paralysis), autonomic neuropathy (constipation, paralytic ileus, urinary retention, orthostasis); vocal cord paralysis; myalgias, Raynaud's phenomenon; headache, seizures, depression, dizziness, malaise; may be enhanced by concomitant use of interferon. P Pulmonary: Bronchospasm (acute shortness of breath), more common when administered with mitomycin; pulmonary edema. P Other: Severe pain in the jaw, pharynx, bones, back or limbs following injection, syndrome of inappropriate antiduiretic hormone (SIADH), fever, ischemic cardiotoxicity, enhanced interferon toxicity Pharmaceutical Data Each sterile vial contains 10 mg of the drug in 10 ml of solution. The correct dose of the solution should be injected into the tubing of a running intravenous infusion over 1 to 3 minutes. 3.4 Dacarbazine (DTIC) Mechanism of Action Dacarbazine itself is probably inactive and undergoes demethylation to metabolites exhibiting alkylating properties. The exact mechanism of cytotoxicity is not clearly established and inhibition of purine synthesis may also contribute to the effect. The drug can alter the immunogenicity of mouse tumour cells. There is no established schedule dependency. Fifty percent of the drug is eliminated unchanged by the kidneys. 9

16 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT Human Toxicology P Hematologic: Leukopenia, thrombocytopenia, anemia is dose related with the white cell and platelet nadirs about day Thus cycles of the single agent can be given every 3 to 4 weeks. P Dermatologic: Alopecia, facial flushing, extravasation may result in severe pain but has not resulted in tissue damage. Rapid IV push may result in pain along injection site or thrombophlebitis. Skin photosensitivity has been reported after high doses. P Hepatic: Increased ALT, AST. P Renal: Increased serum creatinine, BUN. P Neurologic: Facial parasthesia. P Other: Flu-like syndrome (with fever, malaise, myalgia) rarely occurs about 7 days after treatment and last 1-3 weeks. Rarely anaphylaxis Pharmaceutical Data Dacarbazine is supplied in 200 mg vials and should be stored at 2-8 C, protected from light Administration The 200 mg/vial is reconstituted with 19.7 ml of Sterile Water for Injection, USP. the resulting solution contains an equivalent of 10 mg/ml of dacarbazine. Dacarbazine may be further diluted in 100 ml to 250 ml D5W and administered over 30 to 60 minutes. Any solution remaining in the vial may be stored at 4 C for 96 hours. At 20 C the solution is not stable for more than 24 hours. 9a

17 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD TRIAL DESIGN This is a multi-centre, non-blinded, randomized trial of the NCIC Clinical Trials Group. 4.1 Stratification Patients will be stratified by centre. 4.2 Randomization Patients will be randomized to receive one of the following treatments: Standard treatment (radiation or combined modality therapy according to defined risk factors - see cohort assignment below) or experimental treatment (ABVD), to a planned sample size of 450 patients. Patients will be randomized to one of the following two arms: RANDOMIZATION AGENTS/ DOSE SCHEDULE Cohort 1 Supradiaphragmatic disease Sub-total nodal irradiation (STNI) cgy/fraction Mantle - 20 fractions over 4 wks Rest 4 wks UA - 20 fractions over 4 wks Cohort 1 Pelvic disease Inverted Y cgy/fraction Inverted Y - 20 fractions over 4 wks Doxorubicin mg/m 2 ARM A (Standard) Cohort 2 All patients Bleomycin units/m 2 Vinblastine... 6 mg/m 2 Dacarbazine mg/m 2 Days 1 and 15 Give TWO cycles IV q 28 days followed by radiation (see below) Cohort 2 Supradiaphragmatic disease Sub-total nodal irradiation (STNI) cgy/fraction Long mantle - 20 fractions over 4 wks or Mantle - 20 fractions over 4 wks Rest over 4 wks UA - 20 fractions over 4 wks Cohort 2 Pelvic disease Inverted Y cgy/fraction Inverted Y - 20 fractions over 4 wks Doxorubicin mg/m 2 ARM B (Experimental) Cohort 1 and 2 Bleomycin units/m 2 Vinblastine... 6 mg/m 2 Dacarbazine mg/m 2 Give TWO cycles IV q28 days followed by restaging; Days 1 and 15 Two to four more cycles (4-6 total) will be given depending upon results of restaging 10

18 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Cohort Assignment Patients will be assigned to Cohort 1 if all of the following criteria are met: Lymphocyte predominant (LP) or nodular sclerosing (NS) histology Age < 40 years Erythrocyte sedimentation rate (ESR) < 50 plus: Supradiaphragmatic disease with < 4 disease sites or: Pelvic disease (ileofemoral, inguinal, parailiac) with < 4 disease sites All other patients meeting eligibility criteria and who do not fulfill all the criteria above will be assigned to Cohort 2. 11

19 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD STUDY POPULATION REVISED: 97-JUN-12 Patients with newly diagnosed clinical Stage IA or IIA Hodgkin's Disease. 5.1 Eligibility Criteria There will be no exceptions to eligibility requirements at the time of randomization. Questions about eligibility criteria should be addressed prior to calling for a randomization. Patients must fulfill all of the following criteria to be eligible for admission to the study: Note: Patients in whom all evidence of Hodgkin's Disease has been removed (i.e. at biopsy) are eligible for this study. The presence of measurable/evaluable disease is not a requirement Histologically proven Hodgkin's Disease. A needle aspirate specimen will not be considered sufficient for diagnosis Pathologic material must have been reviewed by a designated local reference pathologist (LRP) prior to randomization. Histologic subtype determined by the LRP will be used for patient cohort assignment Patients must have clinical stage I - IIA disease according to Ann Arbor staging criteria (see Appendix II). Clinical stage must be based on at least one tissue biopsy. The following aspects are to be considered in determining patient stage: i) Splenic Enlargement: Splenic enlargement determined by imaging studies only should not be considered evidence of splenic involvement with Hodgkin's disease. Patients should be considered as having splenic involvement if the spleen is palpable on physical examination and enlarged on imaging studies, or imaging studies show focal abnormalities consistent with Hodgkin's disease. These patients, if presenting with supradiaphragmatic disease would therefore be assessed as having Stage III disease and would be ineligible. ii) Bone Disease: Lytic or blastic lesions seen on plain radiographs or abnormalities on bone scan consistent with Hodgkin's disease will be considered as bone involvement with Hodgkin's disease. These patients would therefore be assessed as having Stage IV disease and would be ineligible. iii) Pleural Effusion and Ascites: The presence of a pleural effusion or ascites will be considered as evidence of Hodgkin's disease even if cytological examination is negative. These patients would be assessed as having probable Stage IV disease and therefore would be ineligible. Patients assessed on Xray as having pleural thickening or "blunting" of the costophrenic angle only may be eligible. iv) Extra-nodal vs. Stage IV Disease: Patients with disease involving a single extra-nodal site may be considered as "limited-stage" provided all disease can be included in a standard radiation field. Patients with extra-nodal disease that cannot be included in such a field (eg, lung, bone) or with multiple sites of extra-nodal disease are not eligible for this trial. 12

20 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16; REVISED: 97-DEC Pulmonary function tests must be done in patients with symptomatic lung disease. FVC, FEV -1 and DLCO must be > 60% of predicted value. Patients with asthma controlled by medication are eligible if the above criteria are met Patient's age is > 16 years. (Note that the lower age limit at each centre will be determined by that centre's policy regarding the age at which an individual may sign their own consent.) Patient must not have received previous chemotherapy or radiotherapy Laboratory requirements: granulocytes > 1.5 x 10 9 /L (S.I.) or > 1.5 x 10 3 /:L (U.S.) platelets > 125 x 10 9 /L (S.I.) or > 125 x 10 3 /:L (U.S.) bilirubin < 2.5 x UNL (unless due to hemolytic anemia) serum creatinine < 2 x UNL Patient must have been seen by both a radiation oncologist and medical oncologist who agree the patient is able to receive protocol radiation therapy Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Clinical Trials Coordinator that such clearance has been obtained, before the trial can commence in that centre. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given in section The patient must sign the consent form prior to randomization. Please note that the consent form for this study must contain a statement which gives permission for the NCIC CTG and monitoring agencies to review patient records (see section 16.2 for further details) Availability of patient for follow-up and quality of life (QoL) assessments. Patients must be accessible for treatment and follow-up. Investigators must assure themselves that patients registered on this trial will be available for complete documentation of the treatment, toxicity and follow-up. Comparison of quality of life is an end-point of this study. Patients must have completed the prerandomization quality of life assessment and be willing to complete future assessments. The only exceptions will be patients who are unable to read english or french. Patients on study are expected to complete all the quality of life assessments but, should this not prove possible, they will be retained in the study for all other analyses. 5.2 Ineligibility Criteria Patients who fulfill any of the following criteria are not eligible for admission to the study: Prior or concurrent malignancies, except adequately treated basal cell carcinoma of the skin. (Patients with prior carcinoma-in-situ of the cervix are not eligible.) 13

21 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Cardiac disease defined as symptomatic congestive heart failure or coronary artery disease, known valvular (other than asymptomatic mitral valve prolapse) or congenital heart disease (other than asymptomatic atrial septal defects) or need for cardiac medications. Hypertension controlled with drug therapy is not an exclusion criterion Other major medical illness judged likely by the local investigator to preclude safe administration of protocol treatment or required follow-up Patients with stage IA disease (who might be treated with involved-field only irradiation) defined by meeting all of the following criteria: i) lymphocyte predominant or nodular sclerosing histology ii) disease bulk < 3 cm iii) erythrocyte sedimentation rate (ESR) < 50 iv) unilateral high - neck only disease, defined as disease located above the upper border of the thyroid cartilage or isolated epitrochlear adenopathy Patients with very unfavourable clinical stage I-IIA disease defined as bulky adenopathy. Bulky adenopathy is defined as a palpable nodal mass greater than 10 cm. in diameter or a mediastinal mass with a maximum mass diameter measuring greater than or equal to 1/3 the maximum chest wall diameter (see Appendix III) Patients with intra-abdominal disease. (Patients with pelvic disease: ileofemoral, inguinal or parailiac nodes are eligible for this study.) Patients with B symptoms Patients known to have a positive antibody test for the human immunodeficiency virus (HIV) or who have a clinical diagnosis of acquired immunodeficiency syndrome. HIV testing is not a requirement for study entry Patients who have undergone a staging laparotomy Female patients who are pregnant. Note: men and women of childbearing age must be advised in the use of adequate contraception. 14

22 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 94-AUG-02; REVISED: 97-DEC PRE-TREATMENT EVALUATION (See Appendix I) INVESTIGATIONS TIMING History and Physical Exam including: Hematology Biochemistry Height and weight, performance status Presence/absence of "B" symptoms Presence/absence (and dimensions) of palpable adenopathy, and hepato-splenomegaly CBC, WBC differential, platelets ESR (Westergren method should be used) Serum creatinine AST or ALT Alkaline phosphatase LDH Total Bilirubin Pregnancy test (if clinically indicated) within 21 days prior to randomization Radiology* Chest Xray PA and lateral within 28 days prior to randomization Other Investigations CT of chest CT of abdomen and pelvis Bipedal lymphangiogram (if CT of abd/pelvis is negative) is strongly recommended. (It will not be mandatory if a local centre's practice is not to do LAGs.) Other studies as indicated i.e. sinus, skeletal, gastro-intestinal Gallium scan** Bone marrow aspirate and biopsy is recommended but must be done if blood counts abnormal*** Pulmonary function tests (if indicated - see section 5.1.3) within 8 weeks prior to randomization within 8 weeks prior to randomization Quality of Life EORTC QLQ-C30+3 within 14 days prior to Toxicity Baseline "toxicity" evaluation (to document baseline symptoms) randomization * To ensure compatibility baseline and subsequent xrays/scans to assess response must be performed using identical techniques ** Gallium scans are optional but if a disease site is identified by gallium, this must be indicated. *** Abnormal defined as hemoglobin < 100 g/l women (< 10.0 g/dl U.S.) < 120 g/l for men (< 12.0 g/dl U.S.) WBC < 4.0 x 10 9 /L (< 4.0 x 10 3 /:L U.S.) 15

23 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT ENTRY/RANDOMIZATION PROCEDURES 7.1 Entry Procedures NCIC CTG Institutions: All eligible patients enrolled on the study by a participating treatment centre will be entered into a patient registration log provided by the NCIC CTG. This will automatically provide a serial number for that patient which should be used on all documentation and correspondence with the NCIC CTG. All randomizations will be done centrally by the NCIC CTG and will be obtained by calling the NCIC Clinical Trials Assistant at (613) or faxing the eligibility checklist to (613) At the time of randomization, a copy of the completed and signed eligibility checklist must be available. The following information will be required: P trial code (NCIC CTG Trial HD.6) P treatment centre and investigator P patient's initials, hospital number and NCIC CTG serial number P confirmation of the requirements listed in Section 5.0, including dates of essential tests and actual laboratory values P completed and signed eligibility checklist P BSA and calculated starting doses Registration, ECOG Investigators: A signed HHS 310 Form, a copy of the institution's IRB-approved informed consent document, and written justification for any changes made to the informed consent for this protocol must be on file at the ECOG Coordinating Center before an ECOG institution may enter patients. The signed HHS 310, institution informed consent, and investigator's justification for changes will be submitted to the following address: ECOG Coordinating Center, Frontier Science, 303 Boylston Street, Brookline MA, Patients must not start protocol treatment prior to registration. To register eligible patients on study, the investigator will telephone the Central Randomization Desk at the ECOG Coordinating Center at (617) Monday-Friday between the hours of 9 a.m. and 5:30 p.m. EST, to allow time to call NCIC CTG that same day. ECOG members should not call NCIC CTG directly. The following information will be requested: Protocol Number; Investigator Identification (including institution name and/or affiliate and investigator's name); Patient Identification (including patient's name or initials and chart number, patient's social security number, patient demographics [sex, birth date, race, nine-digit zip code and method of payment]); Eligibility Verification. Patients must meet all of the eligibility requirements listed in Section 5.1. The randomization specialist will verify eligibility by asking questions from the checklist. In addition, the Randomization Desk will verify IRB approval. The ECOG Randomization Desk will then contact NCIC CTG to enter the patient, after which the 16

24 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16 ECOG Office will contact the institution to relay the treatment assignment for that patient. The NCIC CTG will forward a confirmation of treatment assignment to the ECOG Randomization Desk for routing to the ECOG participating institution. If a patient does not receive protocol therapy, the patient MAY NOT be cancelled. 7.2 BSA Calculation In calculating surface areas, actual heights and weights should be used, that is, there will be no downward adjustment to "ideal" weight. This principle applies to individuals whose calculated surface area is 2.2 m 2 or less. In those rare cases where a patient's surface area is greater than 2.2, the actual surface area or 2.2 may be used. 7.3 Stratification: Patients will be stratified by centre. 7.4 Randomization: Randomization will be given by telephone and confirmed by mail. NOTE: The validity of results of the trial depends on the authenticity of and the follow-up of all patients entered into the trial. Under no circumstances, therefore, may an allocated patient be withdrawn prior to final analysis, except on disclosure of initial ineligibility. All eligible patients admitted to the trial will be followed by the coordinating centre. It is the responsibility of the physician in charge to satisfy himself or herself that the patient is indeed eligible before requesting randomization. All randomized patients are to be followed until death. The minimal follow-up requirement for ineligible patients is annual follow-up using a Form 5(m) and Form 6. 16a

25 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD TREATMENT PLAN Although the National Cancer Institute of Canada Clinical Trials Group acts as the coordinating agency for the trial, the responsibility for treatment of patients rests with the individual investigator. Patients allocated to commence treatment with chemotherapy (Arm A - Cohort 2; Arm B - all patients) should commence therapy within 7 days of randomization. Patients allocated to treatment with radiation therapy alone (Arm A - Cohort 1) should commence therapy within 4 weeks of randomization. The overall treatment strategies are as follows: ARM A - (STANDARD) Cohort 1 (supradiaphragmatic disease): These patients will be treated with radiation therapy consisting of 35 Gy given in 20 daily fractions to supradiaphragmatic lymph node areas (mantle region) and 35 Gy given in 20 daily fractions to the spleen and para-aortic lymph nodes. Radiation therapy will not be given to liver or lungs. Cohort 1 (pelvic disease): Patients with pelvic disease will receive radiotherapy consisting of 35 Gy given in 20 fractions to an "inverted Y" field. The spleen will not be irradiated. Cohort 2: These patients will receive initial treatment with 2 cycles of ABVD (see section 8.1). Radiation treatment will commence not earlier than 4 weeks and no later than 6 weeks after completion of chemotherapy. This delay will minimize any undue cardiovascular toxicity related to doxorubicin. Neutrophil and platelet counts must have recovered prior to the start of radiation (defined as a neutrophil count of > 1.5 x 10 9 /L and a platelet count of > 125 x 10 9 /L). If this recovery requires > 6 weeks, radiation treatment should be delayed. Radiation therapy will consist of 35 Gy given in 20 daily fractions administered to supradiaphragmatic lymph node areas (mantle region) and simultaneously to the upper abdomen to the level of L2. Alternatively, radiation therapy can be given consisting of mantle (35 Gy in 20 fractions) followed by upper abdomen to the level of L2 (35 Gy 20 fractions). Specific details of radiation planning and administration are indicated in section 8.2. ARM B - (EXPERIMENTAL) These patients will receive initial treatment with 2 cycles of ABVD (see 8.1) followed by restaging of all disease parameters which were initially positive. Patients in complete remission will then receive 2 further cycles of ABVD (total 4 cycles) after which therapy will be discontinued. Those patients assessed as achieving a partial remission and not demonstrating progressive disease will receive 4 further cycles of ABVD (total 6 cycles) after which therapy with ABVD will be discontinued. Patients achieving an unconfirmed/uncertain CR (CRu) will receive 2 further cycles of ABVD and undergo repeat reassessment. If a CR is confirmed no further treatment will be given. If 17

26 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 however there is continuing resolution of abnormalities, 2 further cycles of ABVD will be given (total 6 cycles). Patients with progressive disease will be taken off-study. Treatment must not be interrupted or delayed for the disease assessment after cycle Chemotherapy Treatment Plan Arm A (standard) patients (Cohort 2 only) and Arm B (experimental) patients will receive ABVD chemotherapy as follows: Drug Administration Patients will be randomized to one of the following two arms: ARM AGENTS/DOSE SCHEDULE ROUTE ARM A - Standard Cohort 1 Radiation - see section 8.2 Doxorubicin mg/m 2 ARM A - Standard Cohort 2 Bleomycin units/m 2 Days 1 and 15 IV Vinblastine... 6 mg/m 2 Dacarbazine mg/m 2 Give TWO cycles q28 days plus radiation - see section 8.2 Doxorubicin mg/m 2 ARM B - Experimental Cohorts 1 & 2 Bleomycin units/m 2 Vinblastine... 6 mg/m 2 Dacarbazine mg/m 2 Days 1 and 15 Give TWO cycles q28 days followed by restaging: P if CR, give two more cycles (4 total) P if PR, give 4 more cycles (6 total) P if CRu, give 2 further cycles, and repeat assessment. If this indicates CR, give no further treatment, if abnormalities continue to resolve, give 2 more cycles (total 6) P if PD, patient is off-study IV Premedication Anti-emetic premedication for chemotherapy will be left to the discretion of the treating physician. Use of corticosteroids is permitted if deemed appropriate. Premedication prior to administration of bleomycin (to prevent fever and rigors) will be left to the discretion of the treating physician. 18

27 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Dose Adjustments (for ABVD) Doses will be reduced for hematologic and other toxicities. Dose adjustments for ABVD are to be made according to the system showing the greatest degree of toxicity. Toxicities will be graded using the NCIC CTG Expanded Common Toxicity Criteria (see Appendix V). The major toxic effects of ABVD which limit dose are myelosuppression and mucositis. The guidelines which follow outline dose adjustments for several of these toxic effects. IF A PATIENT EXPERIENCES SEVERAL TOXICITIES AND THERE ARE CONFLICTING RECOMMENDATIONS, PLEASE USE THE RECOMMENDED DOSE ADJUSTMENT THAT REDUCES THE DOSE TO THE LOWEST LEVEL Hematologic Toxicity (both arms, for patients receiving ABVD) Doses will not be adjusted for nadir counts or for an episode of fever/neutropenia. DAY 1 AND DAY 15 DOSE ADJUSTMENTS (both arms, for patients receiving ABVD) TREATMENT DAY COUNTS (i.e. days 1 and 15): Granulocytes (x10 9 /L) Platelets (x10 9 /L) Dose This Cycle > 1.5 AND > 125 treat on time; give full protocol doses of all drugs > 0.8 but < 1.5 OR < 125 but > 75 treat on time, give 50% of doxorubicin and vinblastine (full doses of bleomycin and dacarbazine) < 0.8 OR < 75 delay all drugs for one week, then re-assess and continue treatment according to this table Information regarding the use of growth factors is given in section Non-hematologic Toxicity (both arms, for patients receiving ABVD) TREATMENT DAY: Total Bilirubin Dose this Cycle x UNL Treat on time. Give 50% doses of doxorubicin and vinblastine (full doses of bleomycin and dacarbazine). 2.5 and <4.0 x UNL Treat on time. Give 25% doses of doxorubicin and vinblastine (full doses of bleomycin and dacarbazine). Note: Dose attenuations are not required for hyperbilirubinemia due to hemolytic anemia. 19

28 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 GASTROINTESTINAL Stomatitis/mucositis* > grade 3 Delay further therapy until < grade 1 * Infectious etiologies such as Herpes simplex should be considered. Vinblastine ileus > grade 3 Delay treatment until recovery. Give 75% dose of vinblastine. Discontinue for recurrent > grade 3 ileus despite dose reduction. Note: Treatment should proceed despite nausea/vomiting, with appropriate antiemetics to be used. CARDIAC DYSFUNCTION If features of congestive heart failure are evident, a radionuclide angiocardiogram should be performed. If an ejection fraction result of < 50% is obtained, doxorubicin should be discontinued. The patient should be withdrawn from the trial and treated at physician discretion. PULMONARY DYSFUNCTION If features of interstitial lung disease are evident, and not attributable to an infectious process, bleomycin should be discontinued Patient Compliance As therapy consists of intravenous medications and/or radiation therapy, compliance is readily evaluable. Patients who experience treatment delays, or withdraw from therapy, for reasons assessed as failure to comply will be analyzed on an intention-to-treat basis. 8.2 Radiation Therapy The goal of radiation therapy is to obtain permanent local control of the disease in the irradiated area. Patients randomized to radiation therapy alone will start radiation treatment within 4 weeks of randomization. Patients receiving combined modality therapy will commence radiation treatment not earlier than 4 weeks and no later than 6 weeks after the completion of chemotherapy. Note: Patient's blood counts should recover from previous chemotherapy (see section 8.0: Standard Arm, Cohort 2) prior to commencing radiation. If this recovery requires > 6 weeks radiation treatment should be delayed Quality of Radiation - Equipment Patients should be treated with a minimum allowed energy of 4 MV photons, using linear accelerator at a minimum SSD/SAD of 100 cm. 60 Co equipment is acceptable, providing extended SSD ( cm) is used. 20

29 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Number and Arrangements of the Beams REVISED: 97-JUN-12 Patients will be treated supine and prone or supine, where an isocentric technique is available. Patients will be treated with parallel pair of anterior/posterior opposed beams. Immobilization devices such as plaster shells and alpha cradles are optional Target Volume Mantle Field Target volume should include submandibular, cervical, supraclavicular, infraclavicular, axillary, mediastinal and pulmonary hilar nodes. Upper Abdomen Target volume should include celiac nodes, paraaortic nodes, splenic hilar nodes and spleen. Inverted Y Target volume should include celiac nodes, paraaortic nodes, bilateral iliac nodes and bilateral inguino-femoral nodes Radiation Fields (portals) - Treatment Volume The guidelines listed below may be modified if required to cover clinical extent of the disease. Mantle Field In view of the fact that one of the endpoints of the study is delayed toxicity, including the induction of second malignancies, consideration should be given to minimizing the unnecessary exposure of normal tissues (especially the lung and the female breast) to primary and scattered radiation. In almost all cases the axillary portions of the mantle field can safely be blocked inferior to the points where the fifth and sixth ribs cross each other at the chest wall as seen on anteriorposterior planning films. Superior border: line from the mentum of the chin to the external auditory meatus with neck in extended position. Inferior border: superior extent of the dome of left diaphragm (usually T8-9 or T9-10 disc space) Lateral borders: lateral borders of the axillae at the surgical neck of the humerus (arms abducted with hand resting on the hips) Shielding: Mandatory: Optional: Margins: divergent blocks are preferable, but not essential individually shaped lung shields (partial transmission lung blocks may NOT be used) subcarinal shield (5 cm below carina) at 3000 cgy bilateral humeral head shields posterior cervical cord shield (1.5-2 cm wide midline posterior shield extending from the upper border down to the C7-T1 vertebral disc level - the dose to the cord should not be < 2500 cgy) anterior larynx shield (maximum 2x2 cm anterior shield); larynx shield should not be used in patients with medially placed neck nodes mouth shield minimum margin of 2 cm from the palpable lymph nodes should be maintained minimum margin of 1 cm from the mediastinum to the lung shield should be maintained 21

30 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Upper Abdominal Field REVISED: 97-JUN-12 In order to limit renal damage when planning the left kidney shielding, it should be noted that the protocol requests that the kidneys be visualized in each patient, either by CT or with and IVP during planning. Superior border: lower border of the mantle with appropriate junction Inferior border: Left border: Right border: Shielding: L4-L5 vertebral interspace in Cohort 1, L2-L3 level in Cohort 2 (combined modality treatment) outer aspect of lateral abdominal wall (lower ribs) lateral edge of the right transverse process left kidney shield - individually outlined with CT plan or simulation with IVP (8-10 cm width of the paraaortic field should be preserved) Field Matching - Mantle and Upper Abdomen The method of matching mantle and upper abdomen should be described in detail on treatment prescription. The dose to the spinal cord at the junction should be < 3800 cgy. The two methods listed below are acceptable: 1. Mantle and upper abdominal field will be matched at T8-9 or T9-10 vertebral disc space. A junction spinal cord shield 2 x 2 cm should be placed posteriorly throughout the upper abdomen treatment. 2. The mantle and upper abdominal field matched by individual calculations of the skin gap for either SAD or SSD setup. Inverted Y Fields Superior border: upper border of L hemidiaphragm or T10-T11 vertebral disc space Inferior border: Lateral borders: Shielding: 5 cm below obturator foramen or 5 cm below clinically palpable inguinal lymph nodes 3 cm lateral of the medial bony margin of the pelvis or 3 cm lateral to the palpable inguinal nodes bilateral lateral abdominal shields, maintain 2 cm margin on the paraaortic and pelvic lymph nodes central pelvic shield to maintain 2 cm margin on pelvic and inguinal lymph nodes Treatment Technique Treatment Position Supine for isocentric technique; supine and prone in other situations. Head rest and immobilizing devices should be used according to institutional practice. 22

31 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Planning and Treatment Verification The treatment volume should be simulated in treatment position. Shielding should be drawn individually on simulator films. Port films (anterior and posterior) should be obtained and verified by the radiation oncologists before beginning of therapy. Beam Modifying Devices Compensation and/or attenuation should be used as per institutional practice to achieve a uniform dose distribution within + 10% of the tumour dose. Shielding should be with blocks with a minimum 5 HVL Dose Prescription Total treatment dose is defined at central transverse plane. Preferable dose variation is + 10%. The minimum dose within the treatment volume should not be less than 3000 cgy. Attention should be paid so that the dose delivered to gross disease is > 3500 cgy. Small field boost RT is allowed to achieve dose > 3500 cgy to the gross disease. Bolus should be used for superficial nodes, especially if higher energies are used. Radiation treatment will be delivered to the daily TD of 175 cgy per fraction for the large fields. Small field boost dose will be delivered to the daily fraction of < 200 cgy. Both anterior and posterior fields will be treated daily, five days per week. Total treatment time should be 4-5 weeks allowing for boost RT, equipment maintenance days and holidays. Patients receiving radiation therapy to the mantle and upper abdomen will have 4 weeks rest between treatment to the mantle and to the abdomen, except where mantle and upper abdomen are treated concurrently in one extended field. For patients treated with XRT alone (cohort 1) Mantle: 3500 cgy in 20 fractions over 4 weeks + boost of < 600 cgy Upper abdomen: 3500 cgy in 20 fractions over 4 weeks Inverted Y: 3500 cgy in 20 fractions over 4 weeks For patients treated with combined modality therapy (cohort 2) Mantle: 3500 cgy in 20 fractions over 4 weeks Upper abdomen: 3500 cgy in 20 fractions over 4 weeks or Mantle and upper abdomen: 3500 cgy in 20 fractions over 4 weeks Inverted Y: 3500 cgy in 20 fractions over 4 weeks The dose to the spinal cord should be less than 3800 cgy in 20 daily fractions, treating 5 days per week over 4 weeks. 23

32 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Dose Distribution REVISED: 95-OCT-16 Dose calculations should be performed using treatment planning computer with program for irregular field calculations (e.g. Theraplan - Irreg). The mantle calculations should itemize the doses at following points: mediastinum (T5-T6 vertebral interspace) at midplane separation, axilla (1.5 cm lateral to the third rib at midaxillary space) at midplane separation, left supraclavicular fossa (1 cm above the clavicle, 5 cm from midline), right neck (superior border of the thyroid cartilage, 2 cm lateral from midline). The dose to the upper abdomen or inverted Y should be specified at midplane separation Radiotherapy Toxicity NCIC CTG Common Toxicity Criteria will be used to record acute toxicity experienced over the course of treatment Real-time Review The copy of radiation treatment prescription, simulator films, together with extent of disease diagram and CT chest and copy of dose calculation data should be sent to Dr. Woodrow Wells for review before patient commences treatment course. Any corrections to the treatment volume should be faxed to the investigator within 48 hours. The copy of port films should be sent for review within 3 days of patient commencing therapy. See section 13.2 (central radiotherapy review) for further details. 8.3 Concomitant Therapy Permitted Patients will receive ongoing supportive and palliative care (nutritional support, pain control) as indicated throughout the study. Use of prophylactic antimicrobial therapy will be left to the discretion of the attending physician. The use of growth factors is permitted in this study, but should be used according to institutional or provincial guidelines. They must not be used in the first cycle of chemotherapy. The use of growth factors to increase chemotherapy dose beyond that prescribed, or to shorten cycle intervals is not permitted. Use of a hematologic growth factor as a supportive measure in a severely ill patient (due to sepsis and neutropenia) is permitted but must be recorded as a concomitant medication on the case report forms Not Permitted Use of other anti-cancer therapy is not allowed unless documentation of disease progression (including relapse from remission) has occurred. 24

33 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Treatment Contamination Treatment contamination refers to situations in which patients receive therapy meant to be provided for the other study arm. This could occur with mistakes in patient allocation. In such a situation, a major protocol violation would be recorded and the patient considered non-evaluable. Patients whose therapy is contaminated by receiving additional therapy (e.g., additional chemotherapy for patients of the standard arm; radiation therapy for patients of the experimental arm) will be analyzed on an intention-to-treat basis and will be considered to have had resistant or progressive disease at the time of administration of the contaminating therapy. 25

34 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD EVALUATION DURING STUDY REVISED: 95-OCT-16 All patients entered on study must be evaluated according to the schedule outlined below and summarized in Appendix I with documentation submitted according to the schedule in Appendix IV. 9.1 Evaluation During Protocol Treatment History and Physical Exam including: INVESTIGATION Tumour measurements TIMING After 2 cycles ABVD (Arm B only), possible additional assessments, (see schema) and one month after treatment completion. Hematology CBC and differential Day 1, 15 during chemotherapy, day 1 and one month after treatment completion. Weekly counts may be done during radiotherapy at investigator discretion, but are not required. Biochemistry Bilirubin (total) (if clinically indicated) Day 1 of each chemotherapy cycle. Radiology* Chest Xray (PA and lateral) CT of chest CT of abdomen and pelvis Gallium scan (if done initially and used to identify a disease site) Other studies as indicated i.e. sinus, skeletal, gastro-intestinal Studies positive prior to therapy are to be repeated as follows: Arm A - cohort 1 & 2. One month after completion of radiation therapy, and if PR or CR(u), again 2 months later (i.e. at 3 month follow-up) Arm B - cohort 1 & 2. After 2 cycles of ABVD. If CR(u), after 4 cycles of ABVD. After completion of all chemotherapy (i.e. 1 month after day 28 of cycle 4 or 6). If CR(u) after 6, re-assess again 2 months later (i.e. at 3 month follow-up). Quality of Life EORTC QLQ-C30+3 See Appendix VII. Toxicity ** Continuously * To ensure compatibility baseline and subsequent xrays/scans to assess response must be performed using identical techniques ** Patients must be evaluated after each chemotherapy cycle for toxicity and following radiation therapy. Toxicities will be recorded and graded according to the NCIC CTG Expanded Toxicity Criteria (Appendix V). 26

35 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT Evaluation After Protocol Treatment INVESTIGATION TIMING History and Physical Exam With each follow-up visit for first 3 years post treatment. Hematology Biochemistry CBC and differential AST or ALT, alkaline phosphatase Bilirubin (total) Thyroid stimulating hormone (TSH) level at investigator discretion Annually Radiology Chest Xray PA and lateral Every 6 months for 1 year, then annually for years 2 and 3 CT of chest, abdomen or pelvis if symptomatic Quality of Life EORTC QLQ-C30+3 See Appendix VII. Toxicity * Specific notation of cardiac events and development of second malignancies Continuously * Toxicities will be recorded and graded according to the NCIC CTG Expanded Toxicity Criteria (Appendix V). Follow-up evaluations and reporting, for the purposes of this protocol should take place on the following schedule, commencing after the evaluation of final response to protocol treatment. YEARS SINCE COMPLETING TREATMENT EVALUATION INTERVAL 0-1 at 3, 6 and 12 months 1-15 yearly 27

36 10.0 CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 10.1 Evaluable Definitions PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment (chemotherapy or radiation therapy) Evaluable for response. All patients with initially measurable disease (uni or bi-dimensionally measurable) who have received any protocol treatment will be considered evaluable for response Evaluable for survival. All patients who have been randomized will be considered evaluable for survival. Overall survival will be defined as the time from randomization to the time of death from any cause or last follow-up Response Definitions - Cotswold Criteria 34 Complete Response (CR). The patient has no clinical, radiological, or other evidence of Hodgkin's disease. Changes consistent with the effects of previous therapy (i.e., radiation fibrosis) may be present. Complete Response (unconfirmed/uncertain) (CR[u]). This category (CR[u]) of response has been included to denote patients in whom remission status is unclear. The patient is in normal health with no clinical evidence of Hodgkin's disease but some radiological abnormality, not consistent with the effects of therapy, persists at a site of previous disease. Implicit in this designation is considerable uncertainty about the significance of such abnormalities, it being well known that abnormal widening of the mediastinum or architectural distortion of lymphographic studies may persist for many years without therapy and without evidence of recurrent Hodgkin's disease. Attempts to resolve the dilemma of persistent disease versus residual anatomic distortion not indicative of Hodgkin's disease should include investigations such as radiological imaging, MRI, and/or gallium scanning. Within the bounds of acceptable morbidity, pathological examination may be appropriate, although the difficulties of 'sampling' artifacts are acknowledged. Unusual lesions or highly suspicious lesions should be rebiopsied. Persistent elevation of the erythrocyte sedimentation rate, while not diagnostic of active Hodgkin's disease is an indication for very close surveillance. Partial Remission (PR). Partial remission is defined as a decrease by at least 50% in the sum of the products of the largest perpendicular diameters of all measurable lesions. There should also be an objective improvement in nonevaluable but clinically evident malignant disease. Stable Disease (SD). Steady state of response less than partial response or progression less than progressive disease. There may be no appearance of new lesions in this category. Progressive Disease (PD). Progressive disease is defined as a 25% or more increase in the size of at least one measurable lesion, or the appearance of a new lesion, or occurrence of "B" symptoms which cannot be explained otherwise Freedom from progression will be measured from the time of randomization until disease progression is objectively documented. Patients who die without demonstrating evidence of disease progression will be censored /at the time of death. 28

37 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT ADVERSE EVENT REPORTING 11.1 NCIC CTG Institutions This protocol does not contain investigational agent(s) and toxicities occurring as a result of this commercially available treatment, should be reported to NCIC CTG in the manner described below. In addition, your local Research Ethics Board (REB) should be notified Any death (ie. grade 5 toxicity) which occurs while a patient is receiving protocol treatment or any death which occurs at any time after protocol treatment has ended, but which is felt to be treatment related, must be reported on an AER form to NCIC CTG within 10 working days of the event. This form must be signed by the responsible investigator All grade 4 unexpected reactions (not reported in the literature or package insert) must be reported on an AER form to NCIC CTG within 10 working days of the event. This form must be signed by the responsible investigator Grade 4 expected reactions to commercially available agents need not be reported. Note: Mailing address for NCIC CTG is: NCIC Clinical Trials Group Barrie Street Queen's University Kingston, Ontario K7L 3N ECOG Institutions GUIDELINES FOR REPORTING OF ADVERSE DRUG REACTIONS (ADR'S) OCCURRING WITH COMMERCIAL AGENTS: ADR reporting should be based on the NCIC CTG Common Toxicity Criteria (Appendix V). Written Adverse Drug Reaction reports are to be submitted ONLY on the Adverse Reaction (ADR) Form for Investigational Drugs (Form 391RF), and the form must be signed by the treating investigator. NCIC CTG will accept this form in lieu of the 2 page NCI Adverse Drug Reaction (ADR) form and the 1 page FDA Adverse Drug Reaction (ADR) form (1639). All ADR reports sent to ECOG are to be accompanied by copies of all available and updated study data (on-study forms, follow-up forms, etc.) as well as evidence of notification to the institutional IRB. This protocol does not contain IND agents; toxicities occurring on treatment arms are to be considered commercial. 29

38 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16 Guidelines for reporting of toxicities occurring with commercially available agents: P Any ADR which is BOTH serious (Grade 3) or life-threatening (Grade 4) AND unexpected P Any Grade 4 event while on treatment if CLEARLY related to the commercial agent(s) P Any increased incidence of a known ADR Submit original written ADR form to the IRB and a copy to the ECOG Coordinating Center within 5 working days of the event. The ECOG Coordinating Center will call the NCIC CTG Operations Office to report the telephone ADR calls. The ADR forms will be forwarded to the NCIC CTG Operations Office by the ECOG Coordinating Center. NCI Telephone Number: (301) NCI Mailing Address: Investigational Drug Branch P.O. Box Bethesda, MD ECOG Telephone Number: (617) ECOG Address: ECOG Coordinating Center Frontier Science ATTN: ADR 303 Boylston Street Brookline, MA Non-Treatment Related Toxicities: If a toxicity is felt to be outside the definitions listed above and unrelated to the protocol treatment, this must be clearly documented on the forms which are submitted to the ECOG Coordinating Center according to the Data Submission Schedule. This does not in any way obviate the need for reporting the toxicities described above. 29a

39 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 12.1 Criteria for Discontinuing Protocol Treatment Patients may stop protocol treatment in the following instances: Intercurrent illness which would, in the judgment of the investigator, affect assessments of clinical status to a significant degree, and require discontinuation of protocol therapy Unacceptable toxicity as determined by the attending physician Tumour progression or disease recurrence as defined in section Request by the patient Completion of therapy as outlined in section 8.0. Efforts should be made to maintain the investigations schedule and continue follow-up, even if patients discontinue protocol treatment prematurely and/or no longer attend the participating institution Therapy After Protocol Treatment is Stopped If patients fail to respond to their assigned protocol treatment or are removed from therapy because of toxic effects or disease progression, further treatment, if any, is at the discretion of the investigator. Patients evaluated after 2 cycles of ABVD as demonstrating progressive disease will not have received radiotherapy, and therefore consideration could be given to using radiotherapy as second line therapy Follow-up Off Protocol Treatment See sections 9.0 and

40 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD CENTRAL REVIEW PROCEDURES REVISED: 95-OCT-16; REVISED: 01-JUL Pathology Review The central pathology review process was completed for the first 100 patients randomized. This process is now no longer required. Each participating institution will designate a local reference pathologist (LRP). All patients will be entered on this study on the basis of the LRP's diagnosis and pathology review. A copy of the surgical pathology report should be sent to NCIC CTG as supporting documentation with the Form 1 Initial Evaluation. This will include the reports of both the original pathologist and the local reference pathologist. Histological examination of the tumour specimen should be carried out by a pathologist experienced in the diagnosis of Hodgkin's Disease. Each participating centre will identify a local reference pathologist with expertise in the diagnosis of Hodgkin's Disease who will review and confirm the diagnosis. Cohort assignment will be based on this pathologic diagnosis at the time of randomization. In addition central pathology review will be conducted to confirm patient eligibility for the first 100 cases. Subsequent to this, central pathology review will be carried out for cases for which histology (determined by local reference pathologist) is lymphocyte depleted; diffuse lymphocyte predominant, or the cellular phase of nodular sclerosing. The review will be conducted by: Dr. Bruce Burns, MD FRCPC Assistant Director Canadian Reference Centre for Cancer Pathology Clinical Studies Unit Building 60 Ruskin Street, Ottawa, Ontario K1Y 4M9 A request for 3 unstained slides of the original blocks used to make the diagnosis will be initiated by the central reference pathology coordinator. The slides/blocks and surgical pathology report will be forwarded to the reviewer, who will report the result using a Form 7. Copies of this report will be sent to the local pathologist and to NCIC CTG. NCIC CTG will forward a copy to the investigator. ECOG Investigators The central pathology review process was completed for the first 100 patients randomized. This process is now no longer required. Three (3) unstained slides of the original blocks are required. The slides, along with the completed ECOG Pathology Material Submission Form 050 -Part B and the institutional pathology report, should be submitted within one month of study entry. The slides and forms should be sent to: ECOG Coordinating Center, Frontier Science, ATTN: Pathology, 303 Boylston Street, Brookline, MA Do not send blocks. Any blocks received will be returned. 31

41 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT Central Radiotherapy Review Patients allocated to receive radiotherapy (Arm A, cohorts 1 and 2) will require central radiotherapy review. NCIC CTG Institutions Usually before treatment has commenced or no later than 3 days after the onset of radiotherapy the following should be sent for real-time review. See section 8.2 for descriptive details. 1. The radiation treatment prescription sheet with all dose calculation data. 2. Form 1 page 1 (to provide patient identifiers), and page 4 to provide description of extent of disease. A notation made here of cohort assignment (cohort I versus II) would be helpful in allowing reviewer to determine whether prior chemotherapy has been received. 3. Simulator films. 4. CT chest or abdomen/pelvis (as applicable) plus radiologist's report of the original scan. These films will be reviewed within hours of receipt and will be couriered back to referring radiotherapist. Any corrections to the treatment volume should be faxed to the investigator within 24 hours. Please note that in cases which are scheduled to receive mantle followed by upper abdomen radiation therapy, the above information must be submitted for both mantle and upper abdomen treatment plans. This should be sent to: Dr. Woodrow Wells Phone no.: (416) Dept. of Radiation Oncology The Princess Margaret Hospital Fax no.: (416) Att: Dr. W. Wells 600 University Avenue Toronto, Ontario M5G 2M9 ECOG Institutions ECOG institutions will send materials directly to Dr. Woodrow Wells as outlined in Section 13.2 and The use of courier mail is recommended to expedite the real-time review process Final Review After completion of radiotherapy, all completed prescription sheets should be sent for review. They will be checked to ascertain that the treatment was delivered according to protocol in respect to: all fields treated at every fraction, adherence to correct fraction-size and what degree of compliance was attained with regard to total treatment time. 32

42 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD STATISTICAL CONSIDERATIONS 14.1 Objectives and Study Design The primary objective of this study is to compare the efficacy of treatment with chemotherapy (ABVD) alone versus standard treatment that includes radiotherapy with respect to overall survival in patients with clinical stage I-IIA Hodgkin's disease. Patients eligible in this study will be classified into two prognostic groups. Patients classified into the good-prognostic group (cohort 1) have to meet all of the following criteria: 1) lymphocyte predominant or nodular sclerosing histology 2) age < 40 3) ESR < 50 4) supradiaphragmatic disease with less than 4 disease sites or pelvic disease with less than 4 disease sites All other eligible patients will be classified into the poor-prognostic group (cohort 2). Patients in cohort 1 will be randomized with equal probability to either chemotherapy alone or radiation therapy alone. Patients in cohort 2 will be randomized to either chemotherapy alone or radiation therapy plus chemotherapy. Patients will be stratified by centre prior to randomization. Secondary outcomes of this study include time to disease progression, proportion of patients entering complete remission, second malignancy, incidence of toxicities and quality of life. The major analysis will be comparisons of all patients randomized to receive chemotherapy alone versus all patients randomized to receive radiation therapy with or without chemotherapy Primary Endpoints and Analysis The primary endpoint for this study is overall survival, defined as the time from randomization to the time of death from any cause or last follow-up. Progression-free survival will also be compared between treatment arms. Patients who die without demonstrating evidence of disease progression will be censored at the time of death in this analysis. Log-rank statistics will be used to compare overall survival and progression-free survival experiences between the two arms stratified by prognostic groups. A stratified Cox proportional hazards model will be used to assess other prognostic factors, and the treatment effect will be tested after controlling for important prognostic variables. Treatment-related toxicity will be assessed using the NCIC CTG Expanded Common Toxicity Criteria. Complete remission rates, proportions of second malignancies and toxicities between the two treatment arms will be compared by Pearson chi-square statistic and Fisher's exact test where appropriate. Logistic regression will be used to assess and adjust for prognostic factors with 33

43 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 respect to binary outcomes. The causes of deaths will also be compared between treatment arms. The following are potential classifications of causes of deaths in this study: 1) Hodgkin's disease 2) immediate treatment-related toxicity 3) neoplasia other than Hodgkin's disease 4) myocardial infarction or congestive heart failure 5) other Patients' health related quality of life will be assessed using the EORTC quality of life questionnaire. The EORTC quality of life questionnaire is a self-administered cancer specific questionnaire with multi-dimensional scales. The validity and reliability of this instrument have been studied by the EORTC Study Group on Quality of Life 35. Since quality of life will be assessed longitudinally, the method of analysis of variance for repeated measures 36 will be used for domains represented by aggregate scores. The domains represented by single items are in the form of repeat categorical data. They will be analyzed using the generalized least squares method proposed by Koch et al 37. The profiles of the quality of life scores will be displayed and compared between the two treatment arms Sample Size and Duration of study The overall survival at 12 years for all patients receiving radiation therapy is about 80%. In order to have 80% power to detect a 10% improvement assuming exponential lifetimes, we need to observe a total of 56 deaths in the study using a two-sided 5% level test. If we enter 60 patients per year, a total of 450 patients in 7.5 years are needed for the study. The required number of events will be obtained with another 7 years of follow-up after the end of the accrual period. If the proportion of good-prognostic patients is higher so that the 12-year survival for the standard arm becomes 85%, we will have 80% chance to detect the same 10% improvement by observing a total of 24 events with a two-sided 5% test. With the same accrual rate assumption, 450 patients will be accrued in 7.5 years and need only 5 years of additional follow-up for the study Interim Analysis The original accrual plan is to enter patients in this study for 7.5 years and perform an interim analysis when we have a total of 28 events. The estimated calender time is about one year after the end of the accrual period. The result of this interim analysis has no effect on early termination of the study. However, if we do not have other study planned for this patient population by the end of the accrual period, the committee may consider an extension of the accrual for another year so that the results of the interim analysis can be used to make an informative decision to either continue or stop accrual. The results of the interim analysis will be presented to the monitoring committee, early publication of the results may be considered when a significance level of is obtained in the survival comparison. This significance level is based on the type I error spending function of Lan and DeMets 38 such that the overall significance level will be maintained at 5%. 34

44 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD PUBLICATION POLICY 15.1 Authorship of Papers, Meeting Abstracts, Etc Prior to trial activation, the chair will decide whether to publish the trial under a group title, or with naming of individual authors. If the latter approach is taken, the following rules will apply: P The first author will generally be the chair of the study. P A limited number of the members of the NCIC Clinical Trials Group may be credited as authors depending upon their level of involvement in the study. P Additional authors, up to a maximum of 15, will be those who have made the most significant contribution to the overall success of the study. This contribution will be assessed, in part but not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the study chair In an appropriate footnote or at the end of the article the following statement will be made: "A study coordinated by the Clinical Trials Group of the National Cancer Institute of Canada. Participating investigators included: (a list of the individuals who have contributed patients and their institutions)." 15.2 Responsibility for Publication It will be the responsibility of the study chair to write up the results of the study within a reasonable time of its completion. If after a period of six months following the analysis of study results the draft is not substantially complete, the central office reserves the right to make other arrangements to ensure timely publication Submission of Material for Presentation or Publication Material may not be submitted for presentation or publication without prior review by the NCIC Clinical Trials Group and approval of the trial chair. Individual participating centres may not present outcome results from their own centres separately. Supporting groups and agencies will be acknowledged. 35

45 16.0 ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 16.1 REB (Research Ethics Board) Approval for Protocols PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REB Composition: Research Ethics Boards will be constituted according to local interpretation of the Canadian Medical Research Council (MRC) Guidelines. Initial Approval Member centres wishing to participate in a trial are required to obtain local ethics approval of the protocol by the appropriate research ethics board (REB), and to forward this approval and consent to NCIC CTG. Continuing Approval Annual re-approval is required for as long as the trial is open to patient accrual. Amendments Protocol amendments will be circulated in standard format with clear instructions regarding REB review Informed Consent Process: Before recruitment and enrolment into the study, each prospective candidate will be given a full explanation of the study. The informed consent form will be submitted for approval to the Research Ethics Board, Institutional Review Board or Ethics Committee that is responsible for review and approval of the study. Each consent form must include all of the relevant elements required by Canadian authorities. Once this essential information has been provided to the patient and the investigator is assured that they understand the implications of participating in this study, the patient will be asked to give consent to participate in the study by signing an informed consent. Patients who cannot give informed consent (ie. mentally incompetent, or physically incapacitated such as comatose patients), are not to be recruited into the study. Patients competent but physically unable to sign the consent form may have this signed by their nearest relative or legal guardian. Consent Form Content: The following elements must appear in the consent form: a description of the purpose of the study (indicating, if appropriate, that the drug is investigational); potential side effects; potential benefits; study design; voluntary participation; and confidentiality. This consent form may be modified to satisfy local REB requirements. However, please note that the consent form for this and all other NCIC CTG studies must contain a statement which gives permission for the NCIC CTG and other sponsoring and monitoring agencies to review patient records. 36

46 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Sample Consent: A sample consent is provided in section 18.0 which may be modified to local needs. Please note that all required elements as described above must remain. A French translation is available on request Centre Performance Monitoring Ineligibility and timeliness are monitored for all centres and the results are reported in the Centre Performance Index. This index is generated twice a year and there are minimum standards for performance. Centres are required to submit Eligibility Checklist/Form 1 Initial Evaluation Forms and Form 5 Follow-up Reports within the time guidelines specified in Appendix IV - DOCUMENTATION FOR STUDY On-site Monitoring In addition to the routine review of case report forms and supporting documents sent to the central office, NCIC CTG site monitoring may be conducted at participating centres in the course of the study as part of the overall quality assurance programme. The monitors will require access to patient medical records to verify the data Case Report Forms A list of forms to be submitted as well as expectation dates are to be found in Appendix IV. 37

47 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD REFERENCES 1. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 1971; 31: Hoppe RT, Coleman CN, Cox RS, Rosenberg SA, Kaplan HS. The management of stage I-II Hodgkin's disease with irradiation alone or combined modality therapy. Blood 1982; 59: Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992; 327: Carde P, Hagenbeek A, Hayat M, et al. Role of laparotomy and splenectomy in the staging of early stages Hodgkin's disease (HD): The H6F randomized trial from the EORTC lymphoma cooperative group. Blood 1992; 80: 259a (abstr). 5. Rosenberg SA, Kaplan HS. The evolution and summary results of the Stanford randomized clinical trials of the management of Hodgkin's disease: Int J Radiat Oncol Biol Phys 1985; 11: Carde P, Burgers JM, Henry-Amar M, Hayat M, et al. Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors. J Clin Oncol 1988; 6: Zittoun R, Audebert A, Hoerni B, Bernadou A, et al. Extended versus involved fields irradiation combined with MOPP chemotherapy in early clinical stages of Hodgkin's disease. J Clin Oncol 1985; 3: Tubiana M, Henry-Amar M, Carde P, Burgers JM, et al. Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: Blood 1989; 73: Tubiana M, Henry-Amar M, Hayat M, et al. Long-term results of the E.O.R.T.C. randomized study of irradiation and Vinblastine in clinical stages I and II of Hodgkin's disease. Eur J Cancer 1979; 15: Nissen NI, Nordentoft AM. Radiotherapy versus combined modality treatment of stage I and II Hodgkin's disease. Cancer Treat Rep 1982; 66: Anderson H, Deaken DP, Wagstaff J, et al. A randomized study of adjuvant chemotherapy after mantle radiotherapy in supradiaphragmatic Hodgkin's disease PS IA-IIB: A report from the Manchester lymphoma group. Br J Cancer 1984; 49: Horning SJ, Hoppe RT, Hancock SL, Rosenberg SA. Vinblastine, bleomycin, and methotrexate: an effective adjuvant in favorable Hodgkin's disease. J Clin Oncol 1988; 6: Pavlovsky S, Maschio M, Santarelli MT, Muriel FS, et al. Randomized trial of chemotherapy versus chemotherapy plus radio-therapy for stage I-II Hodgkin's disease. J Natl Cancer Inst 1988; 80: Biti GP, Cimino G, Cartoni C, et al. Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study. J Clin Oncol 1992; 10:

48 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Longo DL, Glatstein E, Duffey PL, et al. Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial. J Clin Oncol 1991; 9: Sutcliffe SB, Gospodarowicz MK, Bergsagel DE, et al. Prognostic groups for management of localized Hodgkin's disease. J Clin Oncol 1985; 3: Meerwaldt JH, Van Glabbeke M, Hudson BV. Prognostic factors for stage I and II Hodgkin's disease. In Treatment Strategy in Hodgkin's Disease. Eds Somers ER, Henry-Amar M, Meerwaldt JH, Carde P. Colloque INSERM/John Libbey Eurotext Ltd 1990; 196: Tubiana M, Henry-Amar M, van der Werf-Messing B, Henry J, et al. A multivariate analysis of prognostic factors in early stage Hodgkin's disease. Int J Radiat Oncol Biol Phys 1985; 11: Leibenhaut MH, Hoppe RT, Efron B, Haplern J, Nelsen T, Rosenberg SA. Prognostic indicators of laparotomy findings in clinical stage I-II supradiaphragmatic Hodgkin's disease. J Clin Oncol 1989; 7: Henry-Amar M, Somers R, for the EORTC Lymphoma Cooperative Group. Long term survival in early stages Hodgkin's disease: the EORTC experience. In Treatment Strategy in Hodgkin's Disease. Eds Somers ER, Henry-Amar M, Meerwaldt JH, Carde P. Colloque INSERM/John Libbey Eurotext Ltd. 1990; 196: Kaldor JM, Lasset C. Second malignancies following Hodgkin's disease. In Treatment Strategy in Hodgkin's Disease. Eds Somers ER, Henry-Amar M, Meerwaldt JH, Carde P. Colloque INSERM/John Libbey Eurotext Ltd. 1990; 196: Kaldor JM, Day NE, Band P, et al. Second malignancies following testicular cancer, ovarian cancer, and Hodgkin's disease: an international collaborative study among cancer registries. Int J Cancer 1987; 39: Kaldor JM, Day NE, Clarke EA, et al. Leukemia following Hodgkin's disease. N Engl J Med 1990; 322: Boivin JF, Hutchison GB. Coronary heart disease mortality after irradiation for Hodgkin's disease. Cancer 1982; 49: Hancock SL, Hoppe RT, Horning SJ, Rosenberg SA. Intercurrent death after Hodgkin disease therapy in radiotherapy and adjuvant MOPP trials. Ann Intern Med 1988; 109: van Rijswijk REN, Verbeek J, Haanen C, Dekker AW, van Daal W, van Peperzeel HA. Major complications and causes of death in patients treated for Hodgkin's disease. J Clin Oncol 1987; 5: Cosset JM, Henry-Amar M, Pellae-Cosset B, et al. Pericarditis and myocardial infarctions after Hodgkin's disease therapy. Int J Radiat Oncol Biol Phys 1991; 21: Henry-Amar M, Somers R. Survival outcome after Hodgkin's disease: a report from the international data base on Hodgkin's disease. Semin Oncol. 1990; 17: Olweny CLM, Katongole-MBidde E, Kiire C, Lwanga SK, MaGrath I, Ziegler JL. Childhood Hodgkin's Disease in Uganda: A ten year experience. Cancer 1978; 42:

49 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD Colonna P, Andrieu JM. MOPP chemotherapy alone: a suitable treatment for early stages of Hodgkin's disease. Lancet 1985; 1: 1224 (letter). 31. Bubman I, Kirchhoff LV, Morioka H, debellis N. Treatment of Hodgkin's disease stages I and II with chemotherapy alone. Med Ped Oncol 1986; 14: Ekert H, Waters KD, Smith PJ, Toogood I, Mauger D. Treatment with MOPP or ChIVPP chemotherapy only for all stages of childhood Hodgkin's disease. J Clin Oncol 1988; 6: Santoro A, Bonadonna G, Valagussa P, Zucali R, et al. Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 1987; 5: Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds Meeting. J Clin Oncol 1989; 7(11): Aaronson N, Ahmedzai S, Bullinger M, el at. The EORTC Core Quality of Life Questionnaire: Interim Results of an International Field Study. In: The Effect of Cancer on Quality of Life, Ed. Osoba D, Ch. 14, CRC Press, Zee B. and Pater J. Statistical analysis of trials assessing quality of life. In: The Effect of Cancer on Quality of Life, Ed. Osoba D, Ch. 9, CRC Press, Koch GG, Landis JR, Freeman JL, Freeman DH, Lehnen RG. A general methodology for the analysis of repeated measurement of categorical data. Biometrics 1977; 33: Lan G. and DeMets D. Discrete sequential boundaries for clinical trials. Biometrics 1983; 70:

50 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD SAMPLE CONSENT FORM REVISED: 95-OCT-16 Please note: this consent form may be modified to satisfy local REB requirements. However, please note that the consent form for this and all other NCIC CTG studies must contain statements which give permission for patient data to be sent to the NCIC CTG and other sponsoring and monitoring agencies, and for the NCIC CTG and those agencies to review patient records. Other required elements are: description of the purpose of the study; potential side effects; potential benefits; study design; voluntary participation; and confidentiality. A Phase III Study of Radiotherapy Or ABVD Plus Radiotherapy Versus ABVD Alone in the Treatment of Early Stage Hodgkin's Disease Purpose and Description of Study I have been told by my doctor that I have Hodgkin's Disease. My disease has been diagnosed at an early stage. Hodgkin's Disease at this stage is usually treated with radiation therapy alone, or in combination with chemotherapy. About 85% of patients remain free of disease 5 years after treatment. The purpose of this study is to determine which of the treatments is more effective in 1) prolonging my life and 2) reducing premature death from long term side effects of the treatment. Long term effects of the radiation therapy and chemotherapy used to treat Hodgkin's Disease can include risks of developing other medical problems including other cancers and heart disease. I have been asked to take part in a research study. About 450 patients across Canada and the United States will participate. This study will compare two different forms of treatment for my disease. One of the treatments will be radiation therapy alone or the same radiation therapy with a very short course of chemotherapy. The alternative treatment would be chemotherapy alone. Background It has been known for a long time that radiation treatment alone can produce long disease free intervals in patients with early stage Hodgkin's Disease. The disease free intervals can be further improved by adding chemotherapy to the radiation treatment. The majority of patients treated this way will be cured of their Hodgkin's Disease. Some people treated this way will relapse (disease returns) but usually respond to second line therapy. There are "late effects" of the initial treatment that cause other diseases and premature death such as heart disease or other forms of cancer. Treatment Selection No one knows which treatment is better for me. For this reason the treatment I get will be decided by chance (like the flip of a coin). This is called randomization. My doctor will call a central statistical office, which will assign one of the treatments to me. My chances of getting either of the treatments are about equal. The chances of my receiving any of the treatments described below are approximately equal. I will be told which treatment I can get. 41

51 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16 Description of Treatment If I am assigned to Arm 1, I will receive one of two possible treatments. If my disease is of a more favourable type, I will receive radiation therapy only. This treatment will normally be given over 4-8 weeks (Monday to Friday each week). If my disease is of a less favourable type, I will receive two cycles of chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), given every two weeks for two months. All of these drugs will be given by vein over a period of 5-30 minutes. This treatment will be followed by radiation treatment given over 4-8 weeks. If I am assigned to Arm 2, I will receive only chemotherapy. This will consist of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) given every 2 weeks for 4-6 months. All of these drugs will be given by vein over a period of 5-30 minutes. The duration of this treatment will depend on how my disease responds. Possible Side Effects and Risks Side effects that may occur as a result of treatment with radiation therapy include the following:! a lowering of my blood counts, which may result in an increased risk of infection or bleeding! fatigue, nausea and vomiting, and loss of appetite! difficulty in swallowing, dry mouth, or a sore throat! diarrhea! loss of hair at the nape of the neck! increased redness and sensitivity over the neck! shortness of breath, cough Side effects that may occur as a result of treatment with chemotherapy (ABVD) include the following:! a lowering of my blood counts, which may results in an increased risk of infection or bleeding (all drugs)! nausea and vomiting (all drugs)! hair loss which is reversible (all drugs)! constipation (vinblastine)! numbness and tingling in my hands and feet (vinblastine)! skin changes including mouth ulcers (bleomycin)! flu-like symptoms (dacarbazine)! other side effects which occur more rarely include heart damage (adriamycin), lung damage (bleomycin), jaw pain (vinblastine) My doctor will watch me closely to see if I have side effects. Side effects usually disappear after the treatment has stopped. My doctor may prescribe medicine to help prevent or lessen these side effects. 42

52 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Possible Benefits REVISED: 95-OCT-16 Current standard therapy for my condition is radiation therapy alone, or radiation therapy with a short course of chemotherapy. This study may show that chemotherapy alone will provide similar disease free intervals and cure rates as current standard therapy. After many years of follow-up it may be possible to find out whether chemotherapy alone has fewer long term side effects or complications. Information from this study may help other cancer patients in the future. I have been told that should my disease progress, if side effects become very severe, if new information indicates that this treatment is not in my best interest, or my doctor feels that this treatment is no longer in my best interest, the treatment will be stopped. Further treatment would be discussed. No one knows if I will benefit from taking part in this study. My cancer may shrink or disappear. There may be less chance on my cancer coming back. I may live longer and the quality of my life may be better. These things cannot be predicted for me. Other Treatment Choices If I do not take part is this study, other treatment choices are available. The usual treatment for disease like mine is one of the treatments described in this study. It would be given in the same way, but I would not be part of a study. Tests A number of tests (blood tests, x-rays) will be done while I am on the study. These tests are of the same type that would be done if I was not taking part in the study. I understand that at specified intervals while on the study, I will be asked to fill out a questionnaire asks me about how I am feeling. It takes about 10 minutes to complete. It may remind me of unpleasant things about my treatment or disease. Some of the questions are personal and I can refuse to answer these if I wish. Length of Study Treatment with radiation therapy or chemotherapy will be stopped if: P my disease becomes worse P side effects are very severe P new scientific research shows that this treatment is not the best for me P my doctor feels that this is no longer the best treatment for me. If new side effects or information about my disease or treatment are discovered during the study, I will be told. 43

53 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16 Confidentiality, Access to Medical Records Information from my medical record, about my treatment and disease, will be sent to the National Cancer Institute of Canada, Clinical Trials Group (which is organizing this study). This information may include: P test results P reports of operations P x-rays, other body scans P tissue samples Histopathologic material including slides, and radiologic materials (e.g. x-rays) may be sent to a central office for review. Even after my treatment is complete, information will still be sent on my progress so that it is clear how well the treatment worked. This may go on for years (from my start of treatment and possibly for the rest of my life). If I stop taking part in the study, information will also still be sent because it is important to follow the progress of all people who started out on the study. Representatives for the organization above may wish to see my hospital or clinic records to make sure the information sent was correct. My records may also be inspected by representatives of: P The Food and Drug Administration of the U.S. government P the National Cancer Institute of the U.S. The organizations listed will keep information about me confidential: P my name will not be given to anyone except the researchers doing the study, who have pledged an oath of confidentiality P my name will not be used in any reports about the study P I will be identified only by a code and my initials P identifying information will be kept in locked cabinets. Voluntary Participation I have discussed the information above with my doctor and he/she has answered my questions. I can ask my doctor questions any time in the future. I am taking part is this study of my own free will. I can refuse to take part right now or can stop taking part at any time. If I refuse or withdraw, my doctor will continue to treat me with the best means available. My doctor will discuss any further treatment with me. 44

54 Whom do I call if I have questions or problems? PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16; REVISED: 01-JUL-16 If I have questions about taking part in this study I can talk to my doctor. Or, I can meet with the doctor who is in charge of the study at this institution. That person is: Name Telephone If I suffer a research-related injury or would like advice regarding my rights as a patient, I can talk to someone who is not involved in the study at all. That person is: Name Telephone My signature on this consent form means that I agree to take part in this study. Signature of Patient Signature of Doctor Signature of Witness Signature of Translator (if applicable) Date Date Date Date Note: This consent form is available in French upon request. 44a

55 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 TABLE 1 - TREATMENT OF LIMITED-STAGE HODGKIN'S DISEASE: RANDOMIZED TRIALS Author/Group (ref) Patients Laparotomy RTx CTx Studies of Radiation Field Rosenberg/Stanford (5) CS I/II A+B No IF None No EF None Rosenberg/Stanford (5) PS I/II A+B Yes IF None Yes STNI None Carde, Tubiana/EORTC (6) PS I/II Yes M None "favourable" Yes M+PA None Zittorin/France (7) CS I/II A+B, IIIA No IF MOPP No EF MOPP Studies of Radiation vs Combined Modality Therapy Tubiana/EORTC (9) CS I/II A+B No M None No M VLB Nissen/Dutch (10) PS I/II A+B Yes (S)TNI None Yes M MOPP Anderson/Manchester (11) PS I/II A+B Yes M None Yes M MVPP Horning/Stanford (12) PS I/II A+B, IIIA Yes (S)TNI None Yes IF VBM Carde, Tubiana/EORTC (6) CS I/II No (S)TNI None "unfavourable" No M MOPP Studies of Radiation vs Chemotherapy Biti/Italy (14) PS I/II A Yes M + PA None Yes None MOPP Longo/NCI (15) PS II A+B, III A Yes M None Yes None MOPP Studies of Chemotherapy vs combined Modality Therapy Pavlovsky/Argentina (13) CS I/II A+B No None CVPP No IF CVPP Studies of Chemotherapy Type Tubiana/EORTC (8) CS I/II Unfavourable Studies of Laparotomy as Diagnostic/Treatment Strategy Carde/EORTC (4) CS I/II Favourable No No No Yes M M STNI M(+PA ) MOPP ABVD None (MOPP or ABVD ) F/U (yrs) DFS (%) * * 68 95* 69 93* 72 97* 66 83* * 62 71* * p # 0.05 Survival reported as actuarial 5 year survival ( ) Brackets denote received by some patients Radiation Terms: IF - involved field EF - extended field M - mantle M+PA - mantle and para-aortic (S)TNI - (sub) total nodal irradiation Chemotherapy Terms: VLB - vinblastine MOPP - nitrogen mustard, vincristine, prednisone, procarbazine MVPP - nitrogen mustard, vinblastine, prednisone, procarbazine VBM - vinblastine, bleomycin, methotrexate CVPP - cyclophosphamide, vinblastine, prednisone, procarbazine ABVD - Doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine Survival (%) * *

56 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 TABLE 2 - RANDOMIZED TRIALS COMPARING MOPP AND ABVD Author/Group (ref) Patients RTx CTx F/U (yrs) DFS (%) p Survival (%) p Santoro/Milan (33) CS IIB + III A/B M M MOPP ABVD < Tubiana/EORTC (8) CS I/II Unfavourable M M MOPP ABVD >.5 Canellos/CALGB (3) CS III 2 A+ and RTx relapse None None MOPP ABVD NS TABLE 3 - STATISTICAL CONSIDERATIONS FOR ACCRUAL Standard 12-YEAR SURVIVAL Experimental Hazards ratio (ª) Accrual per year Accrual (years) Follow-up (years) Total number 80% 90% % 92%

57 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 APPENDIX I - PATIENT EVALUATION FLOW SHEET REVISED: 95-OCT-16 REQUIRED STUDIES PRE- STUDY ON CHEMO ON RT AFTER 2 CYCLES DAY 1 EACH CYCLE DAY 15 DAY 1 WKLY ABVD (ARM B ONLY) ONE MONTH AFTER TREATMENT COMPLETION Physical History & physical x x Height, weight x x x Performance status x x B-symptoms x x Tumour measurements ++ x x x Toxicity Evaluation Laboratory continuous evaluation CBC, WBC, diff., platelets x x x x x ESR LDH, AST or ALT Alkaline phosphatase Serum creatinine Total bilirubin x x Pregnancy test (if clinically indicated) x x x x x Xrays and Scans Chest x-ray x x CT chest CT abdomen/pelvis Gallium scan * Bipedal lymphangiogram ** Other Bone marrow aspirate and biopsy *** Pulmonary function test+ x x x x x x Quality of life assessment x see Appendix VII Repeat any other studies positive prior to therapy * Gallium scan required only if chest x-ray and CT chest are negative. ** LAG, if CT abdomen/pelvis is negative, is strongly recommended, but not mandatory *** Bone marrow aspirate/biopsy required only if blood counts abnormal, as defined in section Only to be done in patients with symptomatic lung disease. ++ See also schema. x Repeat any other studies positive prior to therapy 47

58 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 APPENDIX II - ANN ARBOUR STAGING CRITERIA Stage I: Stage II: Stage III: Stage IV: Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE). Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE). Involvement of lymph node regions on the both sides of the diaphragm (III) which may be accompanied by localized involvement of an extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS), or both (IIISE). Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement. Each stage is divided into A and B categories: A: No systemic symptoms B: Unexplained weight loss greater than 10% of the body weight in the previous 6 months and/or, Unexplained fever with temperatures above 38 C and/or Night sweats 48

59 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 APPENDIX III - MEASUREMENT OF MEDIASTINAL MASS LESIONS AND CALCULATION OF TREATMENT RESPONSE OF MEDIASTINAL AND ABDOMINAL LYMPH NODES NOTES: 1. use a 6 foot PA film taken at end inspiration. 2. the composite width of the mediastinal mass is the sum of a+ b, that is the maximum extension of the mass to the left of midline plus maximum extension to the right of midline; a and b may or may not be at the same level for an individual patient. 3. hilar lymphadenopathy is excluded when measuring the composite width. 4. c is the greatest transthoracic diameter measured rib to rib not including soft tissues. 5. the mediastinal mass ratio is defined as mediastinal mass ratio = a + b c 6. mediastinal mass lesions will be grouped as 0 = no mass, < 1/3, $ 1/3 depending on the mediastinal mass ratio. 7. Calculation of percent response when residual abnormalities are present. 1. Mediastinal mass The abnormal extra width of the mediastinal widening will be taken as that amount by which the composite width of the mediastinal mass exceeds 7.0 cm. Thus a patient who starts with a composite width of 14 cm (extra width = = 7.0) and, after 6 cycles of chemotherapy has a composite width of 8.0 cm (extra width = = 1.0), has had an 86% (6.0/7.0) reduction in the mediastinal mass. 49

60 2. Abnormal abdominal lymph nodes by lymphangiogram or CT scan. PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 The abnormal enlargement of the lymph node will be taken as that amount by which the longest dimension of the measured lymph node exceeds 1.5 cm. Exactly analogously to the calculation for mediastinal mass, the response in abdominal lymph nodes will be determined by comparing the extend by which the measured lymph node mass exceeds 1.5 cm before and after treatment. Thus a node which shrinks from 6.0 to 3.0 cm has had a 67% reduction (from 4.5 to 1.5 cm greater than 1.5 cm). 50

61 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 APPENDIX IV - DOCUMENTATION FOR STUDY REVISED: 95-OCT-16; REVISED: 01-JUL-16 Follow-up is required for patients from the time of randomization and will apply to all eligible patients. FORM Eligibility Checklist/Form 1 Initial Evaluation Form 3 Systemic Therapy/ Toxicity Report Form 4 Radiotherapy Report Form 5 Follow-up Report Form 6 Final Report Form 9 Relapse/Progressive Disease Report Adverse Event Report ECOG Institutions TO BE COMPLETED prior to calling NCIC CTG to randomize patient after cycles 2, 4 and 6 of chemotherapy after completion of subtotal nodal RT DUE IN CENTRAL OFFICE within 6 weeks of randomization within 2 weeks of the end of cycles 2, 4 and 6 within 6 weeks of the completion of RT within 8 weeks of clinic visit within 8 weeks of the patient's death SUPPORTING DOCUMENTATION REQUIRED P operative and pathology reports P signed copy of patient consent P chest x-ray P bone marrow biopsy/aspirate (if done) P CT scan chest, and abdomen/pelvis P lymphangiogram, gallium scan (if done) P pulmonary function tests (if done) P baseline quality of life questionnaire any radiology/pathology done to document response (required if initially abnormal) completed treatment sheets after each scheduled follow-up visit to clinic at time of patient's autopsy report (if done) death at first evidence of relapse/progression and within 4 weeks of all subsequent the event relapse/progressions See section 11.0 Adverse Event Reporting for details. any radiology/pathology done to document relapse/progression Forms submission: The original data forms as listed in Appendix IV should be submitted at the required intervals to the ECOG Coordinating Center. Include the NCIC CTG and ECOG study numbers and patient numbers on each sheet. The Coordinating Center will forward the forms to NCIC CTG. In addition, ECOG Pathology Material Submission Form No Part B must be completed within one month of on study. The required forms are attached to the protocol. Additional forms packets will not be supplied when patients are randomized. It is the responsibility of the participating institution to maintain a supply of available forms for data submission. 51

62 APPENDIX V - NCIC CTG EXPANDED COMMON TOXICITY CRITERIA NCIC CTG EXPANDED COMMON TOXICITY CRITERIA Explanatory Notes 1. Toxicities are grouped into the following categories based on body system: Allergy Blood/Bone Marrow Cancer-related Symptoms Cardiovascular Coagulation Dentition (teeth) Endocrine Flu-Like Symptoms Gastrointestinal Genitourinary Hepatic Infection Metabolic Neurologic Ocular Osseous (bone) Other Pulmonary Skin Weight PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 2. Protocols requiring detailed hyposensitivity reaction reporting will include a Hypersensitivity Reaction Module. 3. Categories are listed alphabetically, with toxicity variables (eg. dysrhythmia, nausea, dizziness) listed alphabetically within each category. 4. Toxicity codes are composed of a 2-character "prefix" based on toxicity category, and a 3-character "description" based on variable name. For example: (cardiovascular) dysrhythmia = CD DYS (gastrointestinal) nausea = GI NAU (neurologic) dizziness = NE DIZ 5. Some conventions: H = hyper (or high) (eg. CD HBP = hypertension) L = hypo (or low) (eg. MT LCA = hypocalcemia) 6. Codes are usually derived from the first 3 letters of the toxicity variable (eg. nausea = GI NAU). Exceptions to this rule have been made in the following cases: 6 where the first 3 letters are not particularly helpful or descriptive (eg. mouth dryness has been coded GI DRY instead of GI MOU) 6 where the first 3 letters are potentially confusing (eg. flushing, facial has been coded SK FAC instead of SK FLU) 6 where a "common" 3 letter abbreviation already exists (eg. hemoglobin has been coded BL HGB instead of BL HEM) 7. For toxicities which do not have an existing code, but do fit into an existing toxicity category, use "other" variable in the appropriate toxicity category (eg. code pathologic fracture OSSEOUS OTHER (OS OTH)). For toxicities which do not have existing codes, and do NOT fit into existing categories, code OTHER OTHER (OT OTH). 8. Please note that ONLY the codes listed in the criteria may be used. Data managers should not "create" new toxicity codes. If a new toxicity is identified which doesn't have an existing code or doesn't fit an existing category, use OTHER and OTHER OTHER variables as outlined above. If you're unsure how to code a particular toxicity, please record toxicity type only on the form. A coding decision will then be made at the NCIC CTG central office. Explanatory Notes Revised 94-Dec-21 52

63 NCIC CTG EXPANDED COMMON TOXICITY CRITERIA REVISED: 94-DEC-21 Grade AL LER Allergy none transient rash, fever < 38 C, F ALLERGY urticaria, fever=38 C, F, mild bronchospasm serum sickness, bronchospasm, req parenteral meds anaphylaxis Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergic drug fever (eg. as from biologics) should be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only (IN FEC or IN NEU). NB: Protocols requiring detailed reporting of hypersensitivity reactions, will include a Hypersensitivity Reaction module. AL OTH Other* none mild moderate severe life threatening BLOOD/BONE MARROW (SI UNITS) BL WBC White Blood Count (WBC) > /L <1.0 BL PLT Platelets WNL 10 9 /L 75.0-normal <25.0 BL HGB Hemoglobin (Hgb) WNL g/l 100-normal <65 BL GRA Granulocytes > /L <0.5 (i.e. neuts + bands) BL LYM Lymphocytes > /L <0.5 BL HEM Hemorrhage resulting from thrombocytopenia (clinical) none mild, no transfusion (incl bruise/hematoma, petechiae) gross, 1-2 units transfusion per episode gross, 3-4 units transfusion per episode massive, >4 units transfusion per episode BL OTH Other* none mild moderate severe life threatening CANCER RELATED SYMPTOMS CA DEA Death from malignant disease within 30 days of treatment* (grade=5) CA PAI Cancer pain* none pain, but no treatment pain controlled with nonopioids pain controlled with uncontrollable pain req opioids CA SEC Second malignancy* none present -- CA OTH Other* none mild moderate severe life threatening CD ART Arterial* (non myocardial) CARDIOVASCULAR none transient events (eg. transient ischemic attack) deep vein thrombosis not deep vein thrombosis req anticoagulant therapy req anticoagulant CD VEN Venous* none superficial (excl IV site reaction6code SK LTO) CD DYS Dysrhythmias none asymptomatic, transient, req no therapy CD EDE Edema* (eg. peripheral edema) none 1+ or dependent in evening only CD FUN Function none asymptomatic, decline of resting ejection fraction of > 10% but < 20% of baseline value CD HBP Hypertension none or no change asymptomatic, transient increase by >20mm Hg (D) or to >150/100 if previously WNL. No trt req CD LBP Hypotension none or no change changes req no therapy (incl transient orthostatic hypotension) recurrent or persistent, no therapy req 2+ or dependent throughout day asymptomatic, decline of resting ejection fraction by >20% of baseline value recurrent or persistent increase by >20mm Hg (D) or to >150/100 if previously WNL. No trt req req fluid replacement or other therapy but not hospitalization therapy req trt permanent event (eg. cerebral vascular accident) pulmonary embolism req monitoring, or hypotension, or ventricular tachycardia, or fibrillation 3+ 4+, generalized anasarca mild CHF, responsive to therapy req therapy req therapy & hospitalization; resolves within 48hrs of stopping agent severe or refractory CHF hypertensive crisis req therapy & hospitalization for >48hrs after stopping agent * denotes NCIC CTG specific criteria Any toxicity which causes death should be given grade 5. 53

64 NCIC CTG EXPANDED COMMON TOXICITY CRITERIA REVISED: 94-DEC-21 Grade CD ISC Ischemia (myocardial) none non-specific T wave flattening CD PAI Pain (chest)* none pain, but no treatment req CD PER Pericardial none asymptomatic, effusion, no intervention req asymptomatic, ST & T wave changes suggesting ischemia pain controlled with nonopioids pericarditis (rub, chest pain, ECG changes) angina without evidence for infarction pain controlled with opioids symptomatic effusion; drainage req acute myocardial infarction uncontrollable pain tamponade, drainage urgently req; or constrictive pericarditis req surgery CD TAC Sinus tachycardia* none mild moderate severe life threatening CD OTH Other* none mild moderate severe life threatening COAGULATION CG FIB Fibrinogen WNL x N x N x N <0.24 x N CG PT Prothrombin time WNL x N x N x N >2.00 x N CG PTT Partial thromboplastin time WNL x N x N x N >3.00 x N CG OTH Other* none mild moderate severe life threatening DENTITION (TEETH) DE DEC Tooth decay* none mild moderate severe - DE PAI Toothache* none pain, but no treatment req pain controlled with nonopioids pain controlled with opioids uncontrollable pain DE OTH Other* none mild moderate severe life threatening ENDOCRINE * EN AME Amenorrhea none irregular menses > 3 mths EN CUS Cushingoid normal mild pronounced EN FLA Hot flashes none mild or <1/day moderate & >1/day frequent & interferes -- with normal function EN GYN Gynecomastia normal mild pronounced or painful EN IMP Impotence/ Libido normal decrease in normal function -- absence of function -- EN OTH Other none mild moderate severe life threatening FL FEV Fever in absence of infection* (incl drug fever) FL HAY Hayfever* (incl sneezing, nasal stuffiness, post-nasal drip) FL JOI Arthralgia* (joint pain) FL LET Lethargy* (fatigue, malaise) FL MYA Myalgia* (muscle ache) FL RIG Rigors/Chills* (Gr 3 incl cyanosis) FL SWE Sweating* (diaphoresis) FLU-LIKE SYMPTOMS none C F C F >40.0 C >104.0 F for <24hrs >40.0 C (104.0 F) for >24hrs or fever accompanied by hypotension Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergic drug fever (eg. as from biologics) should be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only (IN FEC or IN NEU). none mild moderate severe -- none mild moderate severe -- none mild, or fall of 1 level in performance status moderate, or fall of 2 levels in perf. status severe, or fall of 3 levels in perf. status none mild moderate severe -- none mild or brief pronounced and/or cyanosis -- prolonged none mild moderate severe -- FL OTH Other* none mild moderate severe life threatening GASTROINTESTINAL GI ANO Anorexia* none mild moderate severe dehydration GI APP Appetite-- increased* none mild moderate GI ASC Ascites (nonmalignant)* none mild moderate severe life threatening -- * denotes NCIC CTG specific criteria Any toxicity which causes death should be given grade 5. 54

65 NCIC CTG EXPANDED COMMON TOXICITY CRITERIA REVISED: 94-DEC-21 Grade GI DIA Diarrhea none increase of 2-3 stools/day; or mild increase in loose watery colostomy output compared to pre-trt GI DPH Esophagitis/ dysphagia/ odynophagia* (incl recall reaction) GI DRY Mouth, nose dryness* GI FIS Fistula (intestinal, esophageal, rectal)* none dys. or odyn. not req trt, or painless ulcers on esophagoscopy increase of 4-6 stools/day, or nocturnal stools; or moderate increase in loose watery colostomy output compared to pre-trt dys. or odyn. req trt increase of 7-9 stools/day, or incontinence, malabsorption; or severe increase in loose watery colostomy output compared to pretrt dys. or odyn. lasting >14 days despite trt increase of>10 stools/day or grossly bloody diarrhea; or grossly bloody colostomy output or loose watery colostomy output req parenteral support; dehydration dys. or odyn. with 10% loss of body wt, dehydration, hosp. req none mild moderate severe -- none req intervention req operation GI GAS Flatulence* none mild moderate severe -- GI HEA Heartburn* none mild moderate severe -- (incl dyspepsia) GI HEM Gastrointestinal bleeding* none mild, no transfusion gross, 1-2 units transfusion per episode gross, 3-4 units transfusion per episode massive, >4 units transfusion per episode Bleeding resulting from thrombocytopenia should be coded under BL HEM, not GI GI NAU Nausea none able to eat reasonable intake significantly no significant intake -- intake decreased but can eat GI OBS Small bowel obstruction* none -- intermittent, no intervention req intervention req operation GI PAI Gastrointestinal pain/cramping* (incl rectal pain) GI PRO Proctitis (rectal) none none pain, but no treatment req perianal itch, hemorrhoids GI STO Stomatitis/oral none painless ulcers, erythema, or mild soreness pain controlled with nonopioids tenesmus or ulcerations relieved with therapy, anal fissure painful erythema, edema, or ulcers but can eat pain controlled with opioids tenesmus or ulcerations or other symptoms not relieved with therapy painful erythema, edema, or ulcers, and cannot eat uncontrollable pain mucosal necrosis with hemorrhage or other life threatening proctitis mucosal necrosis and/or req parenteral or enteral support, dehydration GI TAS Taste, sense of none mild moderate severe -- smell altered* GI ULC Gastritis/ulcer* none antacid req vigorous medical management or nonsurgical trt uncontrolled by medical management; req surgery for GI ulceration perforation or bleeding GI VOM Vomiting none 1 episode in 24hrs 2-5 episodes in 24hrs 6-10 episodes in 24hrs >10 episodes in 24hrs or req parenteral support, dehydration GI OTH Other* none mild moderate severe life threatening GU BLA Bladder changes* none light epithelial atrophy, or minor telangiectasia GENITOURINARY generalized telangiectasia severe generalized telangiectasia (often with petechiae) or reduction in bladder capacity (<150ml) necrosis, or contracted bladder (capacity <100ml), or fibrosis GU CRE Creatinine WNL <1.5 x N x N x N >6.0 x N GU CYS Cystitis* (non-bacterial) none mild symptoms req no intervention symptoms relieved completely with therapy symptoms not relieved despite therapy severe (life threatening) cystitis Urinary tract infection should be coded under infection, not GU. GU FIS Fistula* (vaginal, vesicovaginal) none req intervention req operation * denotes NCIC CTG specific criteria Any toxicity which causes death should be given grade 5. 55

66 NCIC CTG EXPANDED COMMON TOXICITY CRITERIA REVISED: 94-DEC-21 Grade GU FRE Frequency* none freq of urination or nocturia twice pre-trt habit freq of urination or nocturia <hourly freq with urgency and nocturia >hourly GU HEM Hematuria, neg micro only gross, no clots gross + clots req transfusion bleeding per vagina Bleeding resulting from thrombocytopenia should be coded under BL HEM not GU. GU INC Incontinence* none mild moderate severe -- GU OBS GU PAI Ureteral obstruction* Genito-urinary pain* (eg: dysuria, dysmenorrhea, dyspareunia) none unilateral, no surgery bilateral, no surgery req not complete bilateral, but stents, nephrostomy tubes or surgery req none pain, but no treatment req GU PRT Proteinuria no change 1+ or <0.3 g% or <3g/L GU VAG Vaginitis* (+/- vaginal discharge) (non-infectious) pain controlled with nonopioids or or g% 3-10g/L none mild, no trt req moderate, relieved with trt pain controlled with opioids 4+ or >1.0g% or >10g/L severe, not relieved with trt -- complete bilateral obstruction uncontrollable pain nephrotic syndrome life threatening GU OTH Other* none mild moderate severe life threatening HEPATIC HP ALK Alk Phos or WNL <2.5 x N x N x N >20.0 x N 5'nucleotidase HP ALT Transaminase WNL <2.5 x N x N x N >20.0 x N SGPT (ALT) HP AST Transaminase SGOT (AST) WNL <2.5 x N x N x N >20.0 x N HP BIL Bilirubin WNL -- <1.5 x N x N >3.0 x N HP CLI Liver (clinical) no change from baseline precoma hepatic coma HP LDH LDH* WNL <2.5 x N x N x N >20.0 x N HP OTH Other* none mild moderate severe life threatening Viral Hepatitis should be coded as infection rather than liver toxicity. INFECTION IN FEC Infection none mild, no active trt moderate, localized infect req active trt IN NEU Febrile neutropenia* Absolute gran. count <1.0x10 9 /L, fever >38.5 C treated with (or ought to have been treated with) IV antibiotics severe, systemic infect req parenteral trt, specify site life threatening sepsis, specify site none present -- Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergic drug fever (eg. as from biologics) should be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only (IN FEC or IN NEU). METABOLIC (SI UNITS) MT AMY Amylase WNL <1.5 x N x N x N >5.1 x N MT HCA Hypercalcemia <2.64 mmol/l >3.37 MT LCA Hypocalcemia >2.10 mmol/l <1.50 MT HGL Hyperglycemia <6.44 mmol/l >27.8 or ketoacidosis MT LGL Hypoglycemia >3.55 mmol/l <1.66 MT LKA Hypokalemia* no change or >3.5 mmol/l <2.0 MT LMA Hypomagnesemia >0.70 mmol/l <0.29 MT LNA Hyponatremia* no change <120 or >135 mmol/l MT OTH Other* none mild moderate severe life threatening * denotes NCIC CTG specific criteria Any toxicity which causes death should be given grade 5. 56

67 NCIC CTG EXPANDED COMMON TOXICITY CRITERIA REVISED: 94-DEC-21 Grade NE CER Cerebellar none slight incoordination, dysdiadochokinesis NEUROLOGIC intention tremor, dysmetria, slurred speech, nystagmus locomotor ataxia cerebellar necrosis NE CON Constipation none or no change mild moderate severe, obstipation ileus >96hrs NE COR Cortical none mild somnolence moderate somnolence severe somnolence, confusion, disorientation, hallucinations (incl drowsiness) NE DIZ Dizziness* (incl lightheadedness) NE EXT Extrapyramidal/ none mild agitation (incl moderate agitation Involuntary restlessness) movement* NE HED Headache none mild moderate or severe but transient coma, seizures, toxic psychosis none mild moderate severe (incl fainting) -- NE HER Altered hearing none or no change asymptomatic, hearing changes on audiometry only tinnitus, symptomatic hearing changes not req hearing aid or trt torticollis, oculogyric crisis, severe agitation unrelenting & severe -- hearing changes interfering with function but correctable with hearing aid or trt -- hearing changes or deafness not correctable NE INS Insomnia* none mild moderate severe -- NE MOO Mood no change mild anxiety or moderate anxiety or severe anxiety or suicidal ideation depression depression depression NE MOT Motor none or no change subjective weakness; no objective findings mild objective weakness without significant impairment of function objective weakness with impairment of function paralysis NE PAI Neurologic pain* (eg: jaw pain) NE PER Personality Change* none no change pain, but no treatment req change, not disruptive to pt or family NE SEN Sensory none or no change mild paresthesias, loss of deep tendon reflexes (incl tingling) pain controlled with nonopioids disruptive to pt or family mild or moderate objective sensory loss; moderate paresthesias pain controlled with opioids harmful to others or self sensory loss or paresthesias that interfere with function uncontrollable pain psychosis NE VIS Vision none or no change blurred vision -- symptomatic subtotal loss of vision blindness NE OTH Other* none mild moderate severe life threatening OCULAR OC CAT Cataract* none mild moderate severe -- OC CJN Conjunctivitis/ none erythema or chemosis req trt with steroids or corneal ulceration or -- Keratitis not req steroids or antibiotics antibiotics visible opacification OC DRY Dry eye normal mild req artificial tears severe req enucleation OC GLA Glaucoma no change yes -- OC PAI Eye pain* none pain, but no treatment req OC TEA Tearing* (watery eyes) pain controlled with nonopioids pain controlled with opioids -- uncontrollable pain none mild moderate severe -- OC OTH Other none mild moderate severe life threatening OSSEOUS (BONE) OS PAI Bone pain* none pain, but no treatment req pain controlled with nonopioids pain controlled with opioids uncontrollable pain OS OTH Other* (eg: avascular necrosis) none mild moderate severe life threatening OTHER OT OTH Other none mild moderate severe life threatening For toxicities which do not have an existing code, but do fit into an existing toxicity category, use "other" variable in the appro-priate toxicity category. Only toxicities which do not fit into existing categories should be coded OTHER OTHER (OT OTH). * denotes NCIC CTG specific criteria Any toxicity which causes death should be given grade 5. 57

68 NCIC CTG EXPANDED COMMON TOXICITY CRITERIA REVISED: 94-DEC-21 Grade PU CMD Carbon Monoxide Diffusion Capacity (DLCO)* >90% of pretreatment value decrease to 76-90% of pre-trt PULMONARY decrease to 51-75% of pre-trt decrease to 26-50% of pre-trt decrease to <25% of pre-trt PU COU Cough* none mild moderate severe -- PU EDE Pulmonary Edema* none -- out-pt management in-pt management req intubation PU EFF Pleural effusion* (non-malignant) none mild moderate severe life threatening PU FIB Pulmonary Fibrosis* normal radiographic changes, no symptoms -- changes with symptoms -- PU HEM Hemoptysis* none mild, no transfusion gross, 1-2 units transfusion per episode gross, 3-4 units transfusion per episode massive, >4 units transfusion per episode Bleeding resulting from thrombocytopenia should be coded under BL HEM, not PU PU HIC Hiccoughs* none mild moderate severe -- PU PAI Pulmonary pain* none pain, but no treatment req pain controlled with nonopioids pain controlled with opioids uncontrollable pain PU PNE Pneumonitis* (non-infectious) PU SOB Shortness of breath (SOB) (incl wheezing) PU VOI Voice changes* (incl hoarseness, loss of voice) normal none or no change radiographic changes, symptoms do not req steroids asymptomatic, with abnormality in PFT's steroids req oxygen req req assisted ventilation dyspnea on significant exertion dyspnea at normal level of activity, apnea without cyanosis dyspnea at rest, apnea with cyanosis none mild moderate severe -- PU OTH Other* none mild moderate severe life threatening Pneumonia is considered infection and not graded as pulmonary toxicity unless felt to be resultant from pulmonary changes directly induced by treatment. SKIN SK ALO Alopecia no loss mild hair loss pronounced or total head hair loss SK CHA Skin changes* (eg: photosensitivity) none localized pigmentation changes generalized pigmentation changes or atrophy total body hair loss -- subcut. fibrosis or localized shallow ulceration generalized ulcerations or necrosis SK DES Desquamation* none dry desquamation moist desquamation confluent moist -- desquamation SK DRY Dry skin* none mild moderate severe -- SK FAC Flushing* (eg: facial) none mild moderate severe -- SK HEM Bruising/bleeding none mild, no transfusion gross, 1-2 units transfusion per episode gross, 3-4 units transfusion per episode massive, >4 units transfusion per episode Bleeding resulting from thrombocytopenia should be coded under BL HEM, not SK SK LTO Local Toxicity (reaction at IV site) none pain pain & swelling, with inflammation or phlebitis ulceration plastic surgery indicated SK NAI Nail changes* none mild moderate severe -- SK PAI Skin pain* (incl scalp pain) none pain, but no treatment req pain controlled with nonopioids pain controlled with opioids uncontrollable pain SK RAS Rash/Itch* (not due to allergy) (incl recall reaction) none or no change scattered macular or papular eruption or erythema that is asymptomatic scattered macular or papular eruption or erythema with pruritus or other associated symptoms generalized symptomatic macular, papular, or vesicular eruption exfoliative dermatitis or ulcerating dermatitis SK OTH Other* none mild moderate severe life threatening WEIGHT WT GAI Weight Gain <5.0% % % >20.0% -- WT LOS Weight Loss <5.0% % % >20.0% -- * denotes NCIC CTG specific criteria Any toxicity which causes death should be given grade 5. 58

69 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT-16; REVISED: 01-JUL-16 APPENDIX VI - LIST OF "CONTACTS" PATIENT RANDOMIZATION: All patients MUST be registered by telephone with NCIC CTG. ELIGIBILITY CHECKLIST MUST be completed prior to the telephone call to request an allocation STUDY SUPPLIES Forms, Protocols CONTACT TEL. # FAX # Amy Hawkins Clinical Trials Assistant NCIC CTG ahawkins@ctg.queensu.ca Marina Djurfeldt Study Coordinator NCIC CTG (613) (613) GENERAL PROTOCOL- RELATED QUERIES ADVERSE EVENT REPORTING See protocol Section 11.0 for details of reportable events marina@ctg.queensu.ca OR: Dr. Lois Shepherd Physician Coordinator NCIC CTG shepherl@ctg.queensu.ca OR: rmeyer@octrf.on.ca Dr. Ralph Meyer Study Chair OR: Dr. Jane Winter ECOG Study Coordinator Northwestern University Medical School Wesley Pavilion, Rm. 1456A 250 East Superior St. Chicago, IL OR: Dr. Michael Chen ECOG Radiation Oncologist Mayo Clinic/Rochester Division of Radiation Oncology Rochester, MN (416) (416) (312) (312) (507) (507) Marina Djurfeldt Study Coordinator NCIC CTG (613) (613)

70 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 APPENDIX VII - QUALITY OF LIFE ASSESSMENT INSTRUCTIONS FOR DATA MANAGERS (DM) QoL questionnaires will be available in English and French. The brief instructions given below are intended as a guide for the quality of life (QoL) questionnaire. 1. Please note that for this trial, there are two versions of the quality of life assessment. Both are included in this protocol. The first, printed on blue paper, should be given to the patient at randomization and during the active treatment phase of the study. The second, printed on yellow paper, contains questions pertaining to long-term effects of treatment and/or disease, and should be given to the patient at the 3-month post-treatment follow-up visit, and all subsequent follow-up visits. 2. The QoL assessment is in the form of a self-report questionnaire. Therefore, it must be completed by the patient only, without coaching or suggestions as to the "correct" answer by relatives or health care personnel. 3. The DM should give the questionnaire directly to the patient before the patient is seen by the physician at the clinic visits indicated in the protocol. (Generally, there is a brief waiting period to see the physician and this is a good time to fill out the questionnaire, since it only takes minutes to complete). 4. The DM should explain that the purpose of the questionnaire is to obtain information which is additional to the information usually gathered at clinic visits and state that the DM will be in the vicinity should the patient have questions about the questionnaire. The DM may provide clarification, but should not rephrase the questions, suggest answers or discuss the answers. (An explanation of the purpose will likely be required on the first occasion that the questionnaire is presented). 5. The DM should collect the questionnaire as soon as it has been completed, check the answers to see that each question has been answered and gently remind the patient to answer any questions that may not have been answered in case they were omitted inadvertently. If the patient states that he/she prefers not to answer some questions despite a reminder from the DM, the DM should not encourage the patient to provide an answer, but subsequently should note "prefers not to answer questions " and sign at the end of the questionnaire. 6. Each completed questionnaire should be sent within seven days of completion to the coordinating group office. 7. Questionnaires should not be mailed to patients, except in very exceptional circumstances such as: (a) failure to give the questionnaire to the patient during a clinic visit, (b) when a patient decides not to keep an appointment for follow-up and is unlikely to return for future follow-up because of: (i) a wish to go off study, (ii) move to another locale where the patient will not be followed on study, (iii) recurrent cancer and unlikely to return to clinic, or (iv) some similar reason. If one of these circumstances were to occur, the completed questionnaire should be accompanied by a note from the DM explaining why the questionnaire was mailed to the patient. 60

71 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 REVISED: 95-OCT The patient should be encouraged to complete questionnaire in clinic, preferably before seeing the physician, and should not take the questionnaire home for return (in person or by mail) at a later time (except as noted in 7 above). (Varying the environment in which the questionnaire is completed by allowing completion at times other than at the time of the clinic visit introduces unnecessary variables into the study). Should the patient insist on taking the questionnaire home, and failure to comply with the patient's wishes is likely to result in the questionnaire not being completed at all, then the patient may take the questionnaire home with the instructions that it is to be completed the same day. When the questionnaire is returned, the DM should check the date on which the questionnaire was completed and attach a note to it stating why the patient took it away from the clinic before completion. 9. The information provided by the patient in the completed questionnaire is confidential and should not be discussed with or shown to anyone who is not mentioned in the consent form signed by the patient. Schedule for Quality of Life Assessment Arm A, cohort I (mantle + upper abdomen): blue "on-treatment" questionnaire yellow "aftertreatment" questionnaire P within 14 days prior to randomization P day 1 of radiotherapy (mantle) P final day of radiotherapy (mantle) P day 1 of radiotherapy (upper abdomen) P final day of radiotherapy (upper abdomen) P 4 weeks after completion of all radiotherapy P 3 months after completion of all radiotherapy P 6 months P 1 year P annually for years 2-10 after completion of all radiotherapy Arm A, cohort I (inverted Y) blue "on-treatment" questionnaire yellow "aftertreatment" questionnaire P within 14 days prior to randomization P day 1 of radiotherapy (long mantle or inverted Y) P final day of radiotherapy (long mantle or inverted Y) P 4 weeks after completion of all radiotherapy P 3 months after completion of all radiotherapy P 6 months P 1 year P annually for years 2-10 after completion of all radiotherapy Continued next page 61

72 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 Schedule for Quality of Life Assessment Arm A, cohort II blue "on-treatment" questionnaire P within 14 days prior to randomization P day 1 of each 28 day cycle of chemotherapy (2 cycles - baseline questionnaire may be used for day 1 cycle 1) After chemotherapy is complete, follow schedule below: Arm A, cohort II blue "on-treatment" questionnaire yellow "aftertreatment" questionnaire (mantle + upper abdomen): OR (long mantle or inverted Y): P within 14 days prior to randomization P day 1 of radiotherapy (mantle) P final day of radiotherapy (mantle) P day 1 of radiotherapy (upper abdomen) P final day of radiotherapy (upper abdomen) P 4 weeks after completion of all radiotherapy P 3 months after completion of all radiotherapy P 6 months P 1 year P annually for years 2-10 after completion of all radiotherapy P within 14 days prior to randomization P day 1 of radiotherapy (long mantle or inverted Y) P final day of radiotherapy (long mantle or inverted Y) P 4 weeks after completion of all radiotherapy Arm B, cohorts I and II blue "on-treatment" questionnaire yellow "aftertreatment" questionnaire P within 14 days prior to randomization P day 1 of each 28 day cycle of chemotherapy (baseline questionnaire may be used for day 1 cycle 1) P 4 weeks (i.e. day 28) after day 1 final cycle of chemotherapy P 8 weeks after day 1 of final cycle of chemotherapy P 3 months after completion of chemotherapy P 6 months P 1 year P annually for years 2-10 after completion of chemotherapy * A quality of life assessment should also be completed within one week following time of relapse. 62

73 PROTOCOL DATE: 93-DEC-16 NCIC CTG TRIAL: HD.6 NCIC CTG TRIAL HD.6 A PHASE III STUDY OF RADIOTHERAPY OR ABVD PLUS RADIOTHERAPY VERSUS ABVD ALONE IN THE TREATMENT OF EARLY STAGE HODGKIN'S DISEASE EORTC COOPERATIVE GROUP - QUALITY OF LIFE QUESTIONNAIRE L To be administered during treatment phase of study. 7 DATE: PATIENT INITIALS: (first, middle, last) PATIENT NCIC CTG SERIAL #: PATIENT HOSPITAL #: CENTRE: INVESTIGATOR: # OF WEEKS SINCE RANDOMIZATION: WAS QUESTIONNAIRE ADMINISTERED? YES NO IF NO: REASON: WERE ALL QUESTIONS ANSWERED? YES NO IF NO: REASON: NOTE: THIS PAGE TO BE COMPLETED BY NURSE/DATA MANAGER/INVESTIGATOR NCIC CTG USE ONLY Logged: Study Coord: Data Ent'd: Verified: (scan) NCIC CTG Trial HD.6. EORTC QOL Core 30+3 (Core 30 Questionnaire copyright 1992 EORTC Study Group on Quality of Life. All rights reserved.) 63

74 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: EORTC QUALITY OF LIFE QUESTIONNAIRE (HD.6) We are interested in some things about you and your health. Please answer all the questions yourself by circling the number that best applies to you. There are no 'right' or 'wrong' answers. The information that you provide will remain strictly confidential. Please fill in your initials: Your birthdate (Year, Month, Day): Today's date (Year, Month, Day): No Yes 1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase? Do you have any trouble taking a long walk? Do you have any trouble taking a short walk outside of the house? Do you have to stay in a bed or a chair for most of the day? Do you need help with eating, dressing, washing yourself or using the toilet? Are you limited in any way in doing either your work or doing household jobs? Are you completely unable to work at a job or to do household jobs? 1 2 DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 8. Were you short of breath? Have you had pain? Did you need to rest? Have you had trouble sleeping? Have you felt weak? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 1 of 6 PLEASE GO ON TO THE NEXT PAGE L

75 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 13. Have you lacked appetite? Have you felt nauseated? Have you vomited? Have you been constipated? Have you had diarrhea? Were you tired? Did pain interfere with your daily activities? Have you had difficulty in concentrating on things like reading a newspaper or watching television? Did you feel tense? Did you worry? Did you feel irritable? Did you feel depressed? Have you had difficulty remembering things? Are you limited in doing either your work or household jobs? Are you limited in pursuing your hobbies or other leisure time activities? Has your physical condition or medical treatment interfered with your family life? Has your physical condition or medical treatment interfered with your social activities? Has your physical condition or medical treatment caused you financial difficulties? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 2 of 6 PLEASE GO ON TO THE NEXT PAGE L

76 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: FOR THE FOLLOWING QUESTIONS PLEASE CIRCLE THE NUMBER BETWEEN 1 AND 7 THAT BEST APPLIES TO YOU. 31. How would you rate your overall physical condition during the past week? 1 Very Poor Excellent 32. How would you rate your overall health during the past week? 1 Very Poor Excellent 33. How would you rate your overall quality of life during the past week? 1 Very Poor Excellent PATIENTS SOMETIMES REPORT THAT THEY HAVE THE FOLLOWING SYMPTOMS. PLEASE INDICATE THE EXTENT TO WHICH YOU HAVE EXPERIENCED THESE SYMPTOMS. DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 34. Were you bothered by a dry mouth? Were you bothered by a sore mouth? Were you bothered by a change in taste? Were you bothered by trouble swallowing solid food? Were you bothered by trouble swallowing liquids? Were you bothered by skin itchiness or irritation? Were you bothered by a cough? Were you bothered by a fever? Were you bothered by numbness of your hands or feet? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 3 of 6 PLEASE GO ON TO THE NEXT PAGE L

77 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 43. Did you have any difficulty doing up your buttons? Were you bothered by muscle aches or cramps? Were you bothered by hair loss? Were you bothered by weight loss? Were you bothered by weight gain? Were you bothered by procedures that involved needles (for example in starting IV or taking blood from you)? Were your usual activities outside your home disrupted because of the treatments you were receiving? Were your usual activities outside your home disrupted because you were not feeling well? Were your usual activities in your home disrupted because of the treatments you were receiving? Were your usual activities in your home disrupted because you were not feeling well? How much overall difficulty did you have with the treatments you have been receiving? Did your medical condition make you feel less interested in physical intimacy? Did your treatments make you feel less interested in physical intimacy? Did your medical condition affect your feeling of being "in control" over what is happening to you? Did you worry about your health in the future? If yes, what were you worried or concerned about? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 4 of 6 PLEASE GO ON TO THE NEXT PAGE L

78 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: WE WOULD LIKE TO KNOW IF THERE HAVE BEEN ANY CHANGES SINCE THE LAST TIME YOU FILLED OUT THE QUESTIONNAIRE. PLEASE CIRCLE YOUR ANSWER. 1. Since the last time I filled out the questionnaire, my physical condition is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 2. Since the last time I filled out the questionnaire, my emotional state is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 3. Since the last time I filled out the questionnaire, my ability to enjoy social life is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 4. Since the last time I filled out the questionnaire, my symptoms in general...that is, overall physical comfort is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 5. Since the last time I filled out the questionnaire, the overall quality of my life is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 5 of 6 PLEASE GO ON TO THE NEXT PAGE L

79 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: PLEASE CHECK TO MAKE SURE YOU HAVE ANSWERED ALL THE QUESTIONS Can you think of other issues or concerns that we didn't ask about, that you feel are important? Please indicate which ones, and use the space below for any additional comments. THANK YOU. NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 6 of 6

80 NCIC CTG TRIAL HD.6 A PHASE III STUDY OF RADIOTHERAPY OR ABVD PLUS RADIOTHERAPY VERSUS ABVD ALONE IN THE TREATMENT OF EARLY STAGE HODGKIN'S DISEASE EORTC COOPERATIVE GROUP - QUALITY OF LIFE QUESTIONNAIRE L To be administered after treatment completion. 7 DATE: PATIENT INITIALS: (first, middle, last) PATIENT NCIC CTG SERIAL #: PATIENT HOSPITAL #: CENTRE: INVESTIGATOR: # OF WEEKS SINCE RANDOMIZATION: WAS QUESTIONNAIRE ADMINISTERED? YES NO IF NO: REASON: WERE ALL QUESTIONS ANSWERED? YES NO IF NO: REASON: NOTE: THIS PAGE TO BE COMPLETED BY NURSE/DATA MANAGER/INVESTIGATOR NCIC CTG USE ONLY Logged: Study Coord: Data Ent'd: Verified: (scan) NCIC CTG Trial HD.6. EORTC QOL Core 30+3 (Core 30 Questionnaire copyright 1992 EORTC Study Group on Quality of Life. All rights reserved.)

81 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: EORTC QUALITY OF LIFE QUESTIONNAIRE (HD.6) We are interested in some things about you and your health. Please answer all the questions yourself by circling the number that best applies to you. There are no 'right' or 'wrong' answers. The information that you provide will remain strictly confidential. Please fill in your initials: Your birthdate (Year, Month, Day): Today's date (Year, Month, Day): No Yes 1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase? Do you have any trouble taking a long walk? Do you have any trouble taking a short walk outside of the house? Do you have to stay in a bed or a chair for most of the day? Do you need help with eating, dressing, washing yourself or using the toilet? Are you limited in any way in doing either your work or doing household jobs? Are you completely unable to work at a job or to do household jobs? 1 2 DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 8. Were you short of breath? Have you had pain? Did you need to rest? Have you had trouble sleeping? Have you felt weak? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 1 of 6 PLEASE GO ON TO THE NEXT PAGE L

82 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 13. Have you lacked appetite? Have you felt nauseated? Have you vomited? Have you been constipated? Have you had diarrhea? Were you tired? Did pain interfere with your daily activities? Have you had difficulty in concentrating on things like reading a newspaper or watching television? Did you feel tense? Did you worry? Did you feel irritable? Did you feel depressed? Have you had difficulty remembering things? Are you limited in doing either your work or household jobs? Are you limited in pursuing your hobbies or other leisure time activities? Has your physical condition or medical treatment interfered with your family life? Has your physical condition or medical treatment interfered with your social activities? Has your physical condition or medical treatment caused you financial difficulties? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 2 of 6 PLEASE GO ON TO THE NEXT PAGE L

83 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: FOR THE FOLLOWING QUESTIONS PLEASE CIRCLE THE NUMBER BETWEEN 1 AND 7 THAT BEST APPLIES TO YOU. 31. How would you rate your overall physical condition during the past week? 1 Very Poor Excellent 32. How would you rate your overall health during the past week? 1 Very Poor Excellent 33. How would you rate your overall quality of life during the past week? 1 Very Poor Excellent PATIENTS SOMETIMES REPORT THAT THEY HAVE THE FOLLOWING SYMPTOMS. PLEASE INDICATE THE EXTENT TO WHICH YOU HAVE EXPERIENCED THESE SYMPTOMS. DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 58. Were your usual activities outside your home disrupted because of not feeling well? Were your usual activities in your home disrupted because of not feeling well? Were you limited in any way in doing your work because of not feeling well? Were you limited in any way in doing your household duties because of not feeling well? Was your marriage/relationship affected by your health? Have you felt less interested in physical intimacy because of your health? NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 3 of 6 PLEASE GO ON TO THE NEXT PAGE L

84 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: DURING THE PAST WEEK: Not at All A Little Quite a Bit Very Much 64. Did your health affect your feeling of being "in control" over what is happening to you? Did you experience any other problems that you felt were related to your health? If yes, what were they? 66. Did you worry about your health in the future? If yes, what were you worried about? 67. Are there any positive results from your experience with Hodgkin's disease? If yes, what were they? If you had planned to have children, please answer questions 68 and 69. If no, please tick off here and proceed directly to question Did Hodgkin's disease interfere with your plans to have children? Did the treatment that you received for Hodgkin's disease interfere with your plans to have children? If you were still in school or university when you were diagnosed with Hodgkin's disease did you feel that your education or career plans were affected because of Hodgkin's disease and/or its treatment? If you had completed your education by then, please tick off here, and do not answer question 70. NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 4 of 6 PLEASE GO ON TO THE NEXT PAGE L

85 This box to be completed by the clinic nurse or data manager: Pt. Serial #: Pt. Initials: WE WOULD LIKE TO KNOW IF THERE HAVE BEEN ANY CHANGES SINCE THE LAST TIME YOU FILLED OUT THE QUESTIONNAIRE. PLEASE CIRCLE YOUR ANSWER. 1. Since the last time I filled out the questionnaire, my physical condition is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 2. Since the last time I filled out the questionnaire, my emotional state is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 3. Since the last time I filled out the questionnaire, my ability to enjoy social life is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 4. Since the last time I filled out the questionnaire, my symptoms in general...that is, overall physical comfort is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better 5. Since the last time I filled out the questionnaire, the overall quality of my life is: Very much worse Moderately worse A little worse About the same A little better Moderately better Very much better NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 5 of 6 PLEASE GO ON TO THE NEXT PAGE L

86 PLEASE CHECK TO MAKE SURE YOU HAVE ANSWERED ALL THE QUESTIONS Can you think of other issues or concerns that we didn't ask about, that you feel are important? Please indicate which ones, and use the space below for any additional comments. THANK YOU. NCIC CTG Trial HD.6. EORTC QOL Core 30+3 Page 6 of 6

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