ALTE04N1 Activated: Closed: 10/18/2004 Version Date: Amendment 04/14/2010 #4 CHILDREN'S ONCOLOGY GROUP ALTE04N1 HEALTH-RELATED OUTCOMES FOR HODGKIN DISEASE SURVIVORS A Limited Non-Therapeutic Study Children’s Hospital Regional Medical Center –Coordinating Center The Fred Hutchinson Cancer Research Center University of Minnesota University of California Los Angeles Children’s Hospital of Philadelphia Columbia University Rhode Island Hospital Memorial Sloan Kettering Cancer Center Rochester University St. Jude Children’s Research Hospital Stanford University Texas Children’s Hospital, Baylor University Hackensack University Medical Center (Tomorrow Children's Med Ctr) Cincinnati Children’s Hospital Medical Center University of Chicago University of Texas Southwestern Vanderbilt Children’s Hospital Yale University THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY OTHER PURPOSE. STUDY CHAIR Debra L. Friedman, MD, MS Associate Professor of Pediatrics E. Bronson Ingram Chair in Pediatric Oncology Division Director, Pediatric Oncology/Hematology Co- Leader, Cancer Epidemiology, Control and Prevention Program Vanderbilt-Ingram Cancer Center 397 Preston Research Building 2220 Pierce Ave. Nashville, TN 37232 Phone: 615-322-9397 Fax: 615-936-1767 Email: [email protected] Statistical and Data Center Contact: http://members.childrensoncologygroup.org Page 1 ALTE04N1 TABLE OF CONTENTS SECTION STUDY COMMITTEE PAGE 3 ABSTRACT 5 EXPERIMENTAL DESIGN SCHEMA 6 1.0 SPECIFIC AIMS 8 2.0 BACKGROUND AND RATIONALE 2.1 Introduction 2.2 Pediatric Hodgkin disease treatment: Paradigm shift over time 2.3 Late Effects of Hodgkin Disease therapy 2.4 Screening Hodgkin disease survivors for adverse health-related outcomes 8 8 8 9 11 3.0 ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 3.1 Study Enrollment 3.2 Patient Eligibility Criteria 11 11 12 4.0 MATERIALS AND METHODS 4.1 Required Procedures 4.2 Additional Data 4.3 Specimen Collection and Submission 4.4 Laboratory Analysis 13 13 16 16 16 5.0 STATISTICAL CONSIDERATIONS 5.1 Statistical Design 5.2 Accrual (and Expected Duration of Accrual) 5.3 Statistical Analysis Methods 16 16 16 17 REFERENCES 21 SAMPLE INFORMED CONSENT 28 Page 2 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 STUDY COMMITTEE STUDY CHAIR Debra Friedman, MD,MS Associate Professor of Pediatrics Vanderbilt Children's Hospital Ingram Cancer Center 397 Preston Research Building 2220 Pierce Ave. Nashville, TN 37203 Phone: (615) 332-93974 Fax: (615) 936-1767 E-mail: [email protected] STUDY COMMITTEE MEMBERS Wendy Hobbie Nurse Children’s Hospital of Philadelphia Oncology 34th & Civic Center Blvd. Philadelphia, PA 19104 Phone: (215) 590-4562 Fax: (215) 590-4183 E-mail: [email protected] STUDY VICE CHAIR Cindy Schwartz, MD Hematology/Oncology Rhode Island Hospital Pediatrics/Hematology/Oncology 593 Eddy Street Providence, RI 02903 Phone: (401) 444-5171 Fax: (401) 444-8845 E-mail: [email protected] Kathy Ruble Nurse Johns Hopkins Hospital Pediatric Oncology 6215 Leithwalk Baltimore, MD 21239 Phone: (410) 955-2457 Fax: (410) 955-0028 E-mail: rubleka@jhmi STUDY STATISTICIAN Lu Chen, Ph.D Children's Oncology Group - Operations Center Statistics 440 E. Huntington Drive; 4th Floor Arcadia, CA 91006 Phone: (626) 241-1520 Fax: (626) 445-4334 E-mail: [email protected] Barbara “Bobbi” Stansfeld, CRA III Clinical Research Associate (CRA) Seattle Children's Hospital 1900 Ninth Ave. Mailstop C9S-9C Seattle, WA 98101 Phone: (206) 884-1018 Fax: (206) 729-3062 E-mail: [email protected] Melissa Maria Hudson, MD Pediatric Oncologist St. Jude Children's Research Hospital Memphis Hematology/Oncology 262 Danny Thomas Place MS 735 Memphis, TN 38105 Phone: (901) 595-3445 Fax: (901) 595-3045 E-mail: [email protected] Louis S. Constine, MD Radiation Oncology University of Rochester Medical Center 601 Elmwood Avenue Box 647 Rochester, NY 14642 Phone: (585) 275-5622 Fax: (585) 275-1531 E-mail: [email protected] Page 3 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 Doojduen Villaluna, MS Statistics Children's Oncology Group - Operations Center Group Operations Center 440 E. Huntington Drive; 4th Floor Arcadia, CA 91006 Phone: (626) 241-1525 Fax: (626) 445-4334 E-mail: [email protected] RESEARCH COORDINATOR Smita G. Subramanian, MS Children's Oncology Group - Operations Center Statistics & Data Center 440 E. Huntington Drive Arcadia, CA 91006 Phone: (626) 241-1623 Fax: (626) 445-4334 E-mail: [email protected] Kevin Charles Oeffinger, MD Pediatric Oncologist Memorial Sloan-Kettering Cancer Center Pediatrics 1275 York Avenue Box 396 New York, NY 10065 Phone: (212) 639-8469 Fax: (212) 717-3239 E-mail: [email protected] PROTOCOL COORDINATOR Lanie Lindenfeld, MA Children's Oncology Group - Operations Center Group Operations Center 440 E. Huntington Drive; 4th Floor Arcadia, CA 91006 Phone: (626) 241-1575 Fax: (626) 447-4293 E-mail: [email protected] Lonnie Zeltzer, MD UCLA David Geffen School of Medicine Department of Pediatrics--UCLA 10833 Le Conte Avenue Los Angeles, CA 90095-1752 Phone: (310) 825-0731 Fax: (310) 794-2104 E-mail: [email protected] For Group Operations (GOC) and Research Data Center (RDC) contacts see: http://members.childrensoncologygroup.org Telephone: (626) 447-0064 Page 4 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 The Children's Oncology Group has received a Ce rtificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of inform ation about y our subjects collected during the course of our covered studies. The researchers involved in the studi es cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are crim inal, administrative, or le gislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected information under certain circumstances. For example, if the subject or his/her guardian requests the release of inform ation in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. ABSTRACT Survival from pediatric Hodgkin disease now exceeds 85%, resulting in a growing cohort of survivors who are at risk for adverse long-term health-related outcomes. With changes in multi-modality therapy over time, the prevalence, incidence and spectrum of such outcomes is likely to change. While there are data on long-term adverse health-related outcom es for patients treated in the 1960’s through the early 1980’s, there is little systematically collected information regarding similar outcomes for patients treated in the m ore contemporary era from 1987 to the present. This latter period was notable for therapeutic changes that included reductions in the use of alkylating agents, anthracy clines and radiotherapy , specifically to decrease adverse long-term outcomes in areas of cardiopulmonary, endocrine, reproductive and psychological health and to decrease the inciden ce of secondary malignant neoplasms. Current late effects screening criteria are largely based on studi es of Hodgkin disease survivors treated in the earlier era of chemotherapy and radiotherapy, and may not be applicable to more contemporarily treated patients. The spectrum and incidence of late effects experienced by these patients can inform us with respect to the design of future risk-adapted therapeutic trials. The study will utilize two unique resources in a collaborative m anner: The Childhood Cancer Survivor Study (CCSS), an NCI-supported 25-institution cohort study tracking the outcom es of 14,000 childhood cancer survivors, and the Children’s Oncology Group. With de dicated investigators in long-term outcomes, and a clinical infrastructure that supports risk-directed clinical studies, in a group of Hodgkin disease survivors treated on or in parallel to cooperative group and consortium studies after 1986, we will seek to evaluate the health-related outcomes of Hodgkin disease survivors treated with risk-adapted therapy. This cohort study will evaluate by 1) patient self-report and 2) clinical evaluation and m edical record review, the incidence, prevalence and spectrum of the following targeted a dverse long-term outcomes. In eligible Hodgkin disease survivors, diagnosed from 1987 until the present, who are at least 5-years from diagnosis, treated or currently followed at any one of the participating institutions we will: 1. Conduct risk-based clinical evaluations and identify selected phy siologic and psy chologic long-term sequelae of treatment. The spectrum of adverse out comes will be characterized and the cum ulative incidence will be determined. 2. Compare the self-reported selected phy siologic and psychologic long-term sequelae of treatment from this contem porary cohort with the Hodgkin disease survivors from the CCSS treated between 1976 and 1986, with data collected at a comparable point following diagnosis. 3. Compare and validate the self-reported phy siologic and psy chologic long-term sequelae of treatment with those determined by clinical evaluation and m edical record review in the contemporary cohort, and validate selected phy siologic complications with medical review in the CCSS cohort. Page 5 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 EXPERIMENTAL DESIGN SCHEMA 1. All COG center study participants Completion of CCSS baseline questionnaire Consent and enrollment on study Survivors return to a treating or participating institutions or PMD for clinical evaluation Characterization of prevalence, spectrum and cumulative incidence of cardiac, pulmonary, gonadal, thyroid, psychosocial outcomes and SMN Medical record review and risk-based clinical evaluation 2. Data to be obtained from CCSS participants treated 1976 –1986 only Review of replies for targeted outcomes from CCSS baseline questionnaire already completed Medical record review for selected positive responses Page 6 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 3.Comparsion of outcomes Contemporary cohort selfreport data Contemporary cohort data from medical records and clinical evaluation 1. Compare self-reported cardiac, pulmonary, gonadal, thyroid outcomes, SMN and BSI at same time point from diagnosis CCSS cohort self report data CCSS cohort medical record review 3. Compare self-reported cardiac, pulmonary, gonadal, thyroid, complications and SMN with medical record review Page 7 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 1.0 ALTE04N1 SPECIFIC AIMS 1.1 To determine the cumulative incidence and characterize the spectrum of targeted adverse physiologic and psychosocial outcomes, using self -report and clinical evaluation. 1.2 To compare the cum ulative incidence and spectru m of self-reported adverse outcomes with Hodgkin disease survivors from the CCSS, with data collected at a comparable time period following diagnosis 1.3 To compare self-reported health-related outcom es with t hose detected by clinical evaluation and m edical record review in the contemporary cohort, and by medical record review in the CCSS cohort. 2.0 BACKGROUND AND RATIONALE 2.1 Introduction The very therapy that has resulted in im proved long-term survival in Hodgkin disease can also lead to longterm morbidity and mortality. Specifically, survivors of Hodgkin disease are subject to excess risk of cardiopulmonary dysfunction, thyroid disease, infer tility, second malignancies and im paired psychosocial functioning and general health-related quality of life [1]. Priority areas of research for this and other survivor cohorts include descriptive and analy tic epidemiologic studies to 1) define incidence of adverse phy siologic and psychologic long-term sequelae that may be altered by changes in therapy over time; 2) develop standards for best practices for screening and early intervention to ameliorate these late effects and 3) develop preventive strategies to avoid these late effects [2-4]. Research to date has focused on ther apeutic advances, physiologic or psychologic outcomes, often targeting a single research domain. In addition, outcom es studies have largely examined late effects of therapies of the 1960s through the early 1980s. There has been a paucity of similar research for patients treated from 1987 onward, when risk-adapted studies were conducted to re duce long-term morbidity and mortality. The lack of such research has many implications. Cancer survivors are often unaware of potential long-term health problem s for which they may be at risk. Conversely, health-care providers are unable to provide a quantitative estimate of that risk, especially for those who are now 5 to 15 years from diagnosis. Current late effects screening guidelines are largely based on longterm toxicities experienced by Hodgkin disease survivors treated with different therapies in the 1960’s through the early 1980’s. These guidelines may not be applicable to more contemporarily treated patients, who may be subject to inappropriate screening, if indeed, the risk profile has changed. Moreover, the quality of their lives may be compromised by the concerns engendered in them by currently recommended screening guidelines. In an era of health cost containment, the cost-benefit ratio remains unclear. 2.2 Pediatric Hodgkin disease treatment: Paradigm shift over time Over the past 25 y ears, there has been a paradigm shift in the approach to pediatric Hodgkin disease, largely due to the recognition that long-term toxicity from treatment was enhanced in children and adolescents, and may have adverse outcomes that exist and potentially worsen over a longer life span. As a result, therapeutic trials have evolved over tim e from those with cure as the primary aim to those with dual aim s of maximum cure with minimum long-term toxicity. Page 8 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 Donaldson first introduced the concept of combined modality therapy for pediatric patients using the MOPP backbone and low-dose radiation therapy [5]. To decrease the dose of mechlorethamine, subsequent therapies then built upon the MOPP backbone in the 1980’s, such as the MOPP/ABVD hybrid therapies [6-10]. Starting in 1987, pediatric cooperative treatment groups further developed risk-adapted therapies designed to reduce late effects with reducti ons in therapy based on a combination of rapid early response, risk stratum and gender-specific late effects. These included reductions in alkylating agent dose and use, radiotherapy use and dose and anthracycline dose [11-23]. 2.3 Late Effects of Hodgkin Disease therapy 2.3.1 Cardiac toxicity Survivors of Hodgkin disease are at risk of cardiotoxi city from both radiotherapy and doxorubicin. Risk factors for doxorubicin-related cardiom yopathy include female sex, cumulative doses greater than 200 300mg/m2, younger age at tim e of exposure and increased time from exposure. Thoracic radiotherapy further increases this risk, in a dose-dependent manner. Cardiomyopathy rates range widely across studies from 0.5% to 30 % at 30 y ears, and the spectrum and cumulative incidence has not been docum ented for contemporary survivors of pediatric Hodgkin disease [ 24-31]. The only published guidelines for monitoring cardiotoxicity in survivors of childhood can cer are greater than a decade old, reflect risk conferred by higher doses of anthracy cline combined with higher doses of radiotherapy , and have not been universally applied [32, 33]. Early mortality from cardiac causes in Hodgkin disease survivors has been prom inent in several studies [25, 34, 35]. In a recent review, Donaldson and colleagues state that 14% of Hodgkin disease survivors will die prem aturely from cardiovascular causes [ 36]. Little is known about the clinical spectrum of nonfatal toxicity, or about the functional or psychosocial implications of this toxicity. In recognition of these risks, in the recent CCG, POG and PHC studies, we have attem pted to reduce toxicity with reduction in radiotherapy dose, tailoring of ra diotherapy fields, reduction in doxorubicin dose based on stage and response to initial therapy , and use of dexr azoxane, (DZR), a chelating agent, shown to prevent anthracycline-induced cardiotoxicity [16, 20-23, 37-41] . Long-term cardiac outcom es research in patients treated on these newer risk-adapted studies has been limited by small sample size, inadequate follow-up, selection bias and the lack of consistent m ethodology for assessing risk. Therefore, findings of little long-term cardiotoxicity must be viewed with some caution [9, 42, 43]. 2.3.2 Pulmonary toxicity Pulmonary fibrotic disease and abnormal pulmonary diffusion are seen as late com plications, occurring 5 to 20 y ears following thoracic radiotherapy and the use of bleomycin [44-48]. A few pediatric studies, limited by size and selection bias, have found rat es of 55 – 75% for abnorm al pulmonary diffusion, although the functional significance of these findings has not been evaluated [ 42, 49, 50]. In the CCSS cohort, pulmonary disease resulted in excess early mortality, with a standardized mortality ratio (SMR) of 9.2 [35]. A further analy sis of self-reported pulm onary complications in the CCSS revealed statistically significant associations for lung fibrosis and supplem ental oxygen use with thoracic radiotherapy or bleomycin exposures [51]. Page 9 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 2.3.3 Thyroid disease Hypothyroidism is well docum ented in survivors of Hodgkin disease with a peak incidence 3-7 y ears following treatment. A radiotherapy dose-response re lationship has been dem onstrated [52-54]. The incidence of other thy roid abnormalities such as hy perthyroidism and thy roid nodules are less well documented, and thyroid nodules are often not seen until 7 or m ore years post treatm ent [54, 55]. The largest study of thy roid disease in Hodgkin disease survivors com es from the self-report data of the CCSS, where 34% of Hodgkin disease patients reported at least one thyroid abnormality [55]. 2.3.4 Gonadal toxicity For males, there is evidence that Hodgkin disease itself m ay result in abnorm ality of sperm number and function [56, 57]. Spermatogenesis is then highly sensitive to alkylating agents, a mainstay of Hodgkin disease therapy. Cyclophosphamide causes dam age to sperm atogonia in a dose-dependent m anner. This gonadal toxicity is enhanced by co-administration of other alkylating agents, such as procarbazine [58-64]. Reduction of alkylating agent therapy in multiagent protocols has resulted in reduction of the risk for male infertility [19, 59, 61, 62, 65]. The degree and permanency of radiotherapy-induced damage to the male reproductive system is dose, field, schedule and age dependent [ 66-68]. Some males treated with chem otherapy and radiotherapy may recover gonadal function after a period of infertility. [69]. While short term follow-up reveals that the m ajority of females have retained norm al menstrual function [69], later risk of prem ature menopause is of concern. Two large studies of childhood cancer survivors treated through the 1980’s have shown elevated rates for infertility and elevated relative risks for early menopause for Hodgkin disease survivors treated with abdominopelvic radiotherapy and alkylating agents [70, 71]. Mechlorethamine and procarbazine together are the most damaging chemotherapeutic agents to the gonads. Substitution of cy clophosphamide for mechlorethamine appears to have reduced the risk of ovarian dysfunction [72]. However, the overall risk and incidence of prem ature menopause is still unknown, as survivors treated with cyclophosphamide are only now approaching the age where premature menopause was previously reported with m echlorethamine use. The ovary is also sensitive to the effects of ionizing radiation, with age and dose effects evident [66, 67, 73]. 2.3.5 Second malignant neoplasms Second malignant neoplasms (SMN) following Hodgkin disease occur m ore frequently than after any other pediatric cancer, with the exception of hereditary retinoblastoma, where a tumor suppressor gene is known to play an essential role. Second m alignancies also contribute significantly to early mortality in survivors of pediatric Hodgkin disease [25, 34, 35, 74] . Follow-up from a num ber of large cohorts demonstrates a rising incidence and a changing spect rum of second m alignancies with increased elapsed time from treatment. Within the first 5 to 15 years from diagnosis, leukemia is predominant with a plateau in incidence seen at 10 to 15 y ears from diagnosis. The risk of solid tumors starts to rise at 7 to 10 y ears post diagnosis, and continues to rise with incr eased elapsed tim e from diagnosis, with no plateau identified. Breast cancer is now the most common second primary malignancy following Hodgkin disease [75-88]. The increased risk for second prim ary malignancies has been a clear im petus to changes in therapy for children with Hodgkin disease. Leukem ia risk in Hodgkin disease has been associated with alky lating agent exposure in a dose-dependent m anner. Mechlorethamine was found to be m ore leukemogenic than cyclophosphamide [89, 90]. Therefore, in the early 1990’s, mechlorethamine was deleted from pediatric cooperative group and consortium therapeutic protocols. Exposure to thoracic radiotherapy has been identified as the major treatment risk factor for breast cancer. Knowledge of this association has, in turn, lead to a reduction in the doses and fields of thoracic radiotherapy , especially for females [1, 16, 23, 91] . Due to the longer latency periods for solid tumors, more time has yet to elapse before it can be determined Page 10 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY that the risk and incidence of strategies. ALTE04N1 breast and other solid organ cancers will indeed be reduced by these 2.3.6 Psychosocial outcomes Decreased health-related quality of life, increased fatigue, depression and post-traumatic stress are reported in adult survivors of pediatric Hodgkin disease and other hem atologic malignancies [92-104], and can m anifest five to twenty years following tr eatment. However, the full spectrum of psy chosocial outcomes remains largely unknown. Furthermore, the im pact of the changing spectrum of phy siologic morbidities on psychologic outcome has not been studi ed. The CCSS has published the largest study of psychological health in pediatric Hodgkin disease. Survi vors were more likely than sibling controls to report symptoms of depression and som atic distress, with fem ales at higher risk than males. The only treatment variable that predicted scores indicating depressive symptomatology was exposure to intensive chemotherapy [97]. These findings will be im portant to re-examine in our contem porary cohort, where, over time, we have developed shorter, but more dose-intensive regimens for pediatric Hodgkin disease. 2.4 Screening Hodgkin disease survivors for adverse health-related outcomes Using a thorough review of the literature, as well as the collective clinical experience of clinicians and researchers with expertise in long-term health-related outcomes, the COG Late Effects com mittee has developed late effects screening guidelines to assist surv ivors and health care providers with risk-based longterm follow-up. However, m uch of the literature utilized in that review largely reflects long-term outcomes from therapies utilized through the early 1980s, which ar e no longer used. Therefore, it is unclear whether these guidelines reflect changes in therapy over time. The guidelines may recommend excessive screening in some areas and inadequate screening in others. In the clin ical evaluations that will be conducted in this study , we will use these guidelines in a standardized and form alized manner and obtain some exploratory data about their use in contemporarily treated survivors. 3.0 ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 3.1 Study Enrollment 3.1.1 IRB Approval Upon receipt of local IRB approval for a COG study , fax the officially signed IRB approval to the Group Operations Center (GOC) at: (626) 445-6715. The COG IRB Approval Fax Cover Sheet is required to be faxed with the official approval. A copy of this cover memo can be obtained from the protocol links area of the COG website. After this approval is recorded by GOC staff, the institution will have access to the eRDE enrollment screens. 3.1.2 Patient Registration Prior to study enrollment, all patients m ust have b een registered via the eR DE system into the COG Cancer Registry (Diagnosis/Registry). The patient re gistration application is available 24 hours a day , 7 days a week. The assigned COG patient identification number will be used to identify the patient in all future interactions with the COG. If you have problems with registration, please refer to the online help in the eRDE area of the COG website. Page 11 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 3.1.3 Study Enrollment Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study enrollment is accom plished by going to the Enrollment application in the eRDE sy stem. If y ou have problems with enrollment, refer to the online help in the Applications area of the COG website. 3.2 Patient Eligibility Criteria Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per COG policy posted 5/11/01). 3.2.1 Case Criteria Eligibility for participation includes: Treatment for primary Hodgkin disease at any one of the participating institutions 1987 – onward, or patients otherwise eligible and cu rrently followed at one of the participating institutions Age < 21 years at time of diagnosis Alive without evidence of disease at time of study entry At least 5 years from diagnosis at time of study entry Initial treatment on or in parallel to the following protocols: Children’s Cancer Group (CCG) 5942, 59704; Pediatric Oncology Group (POG) 8625, 8725, 9226, 9225, 9425, 9426; Pediatric Hodgkin’s Consortium : VAMP, VEPA, VAMP/COP, Stanford V, and the following institutional protocols: COPP/ABV, COPP/ABVD, MOPP/ABV, MOPP/ABVD, ABVD. Patients treated with radiotherapy alone as initial therapy are not eligible, nor are patients treated with radiotherapy for initial treatm ent at doses of >30Gy as part of multimodal therapy Patients who m eet above criteria and subsequently relapsed, and received additional therapy, are eligible, provided their initial th erapy consisted of the eligible protocols above. 3.2.2 Control Criteria For comparison of outcom es, the self-report data from the COG participants will be com pared with that previously reported by participants with Hodgkin disease who are pa rticipants in the Childhood Cancer Survivor Study (CCSS). This will include Hodgkin disease survivors as follows: Current enrollment in the CCSS 3.2.3 Diagnosed 1976 – 1986 Completed baseline questionnaire at com parable time points following diagnosis as contemporary cohort Regulatory 3.2.3.1 All patients and/or their parents or legal guardians must sign a written informed consent. 3.2.3.2 All institutional, FDA, and NCI requirements for human studies must be met. Page 12 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 4.0 MATERIALS AND METHODS 4.1 Required Procedures ALTE04N1 4.1.1 Subject ascertainment All eligible participants will be inv ited to 1) participate in the study and 2) return to their participating institution for the com plete clinical evaluation. For those desiring participation, but who no longer live near their institution, they will be provided the contact for the closest participating institution. For those who wish to participate, but cannot or will not return to any of the participating institutions, the clinical evaluation can be com pleted by their community health care provider (CHCP). The institutional PI will work with the survivors to facilitate the clinical evaluation at the treating institution, another participating institution, or through the community health care provider. As we are aware that inability or unwillingness to return to one’s treatment center is one of the reasons for lack of appropriate long-term monitoring for Hodgkin disease survivors, we will collect inform ation on participating and non-participating eligible survivors as outlined in Table 1 below. Table 1: Categories of participation Unable to contact for participation: Lost-to-follow-up despite tracing attempts Full active refusal Passive refusal Participation with clinical evaluation at treating institution with cancer survivorship program Participation with clinical evaluation at participating institution with cancer survivorship program Participation with clinical evaluation at CHCP Due to inability to return to treating or participating institutions with cancer survivorship program Due to refusal to return to treating or participating institutions with cancer survivorship program (Reasons for inability or refusal to return to treating or participating institutions will be collected) Completion of self-report questionnaire with refusal for clinical evaluation Completion of self- report questionnaire with expressed desire to participate in clinical evaluation but unable due to: Lack of insurance CHCP referral required for treating or participating center evaluation and refused Refusal to return to treating or participating institutions with late effects program and Do not have CHCP CHCP refuses to conduct evaluation 4.1.2 Targeted long-term health-related outcomes for study The targeted outcomes to be investigated in this proposal are: 1. CARDIAC: Cardiomyopathy, valvular insufficiency, arrhythmia, coronary artery disease, myocardial infarction, invasive cardiac procedures 2. PULMONARY: Pulmonary fibrosis, decreased pulmonary diffusion 3. ENDOCRINE: Hyperthyroidism, hypothyroidism, thyroid nodules 4. GONADAL: Primary or secondary ovarian failure, azoospermia, oligospermia 5. SECOND MALIGNANCIES: Secondary leukemia, second primary solid tumors 6. PSYCHOSOCIAL: Health-related quality of life, sexual quality of life, fatigue, sleep, post traumatic stress, post traumatic growth, symptoms of depression or somatic distress Page 13 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 4.1.3 ALTE04N1 Specific study required procedures 4.1.3.1 Self report questionnaire Upon study entry, after signing inform ed consent and release of personal heath inform ation documents, each participant (or parent, if under 18 y ears of age) will complete the self-report study instrument, based upon the CCSS Baseline Questionnaire (See Data Form s on COG’ s website) and will return it to the treating institution in the provided postage-paid mailer. The institution will forward a copy of the consent and the completed questionnaire to the coordinating center in Seattle. If participants so desire, the questionnaire can also be completed via telephone interview. This telephone interview will be conducted by trained interviewers at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, Washington, working in collabor ation with the study chair and the coordinating center for the study, Children’s Hospital and Regional Medical Center. If participants wish to com plete the questionnaire by telephone, a m ember of the research team at the participating institution will get consent from the patient and will complete the “ALTE04N1: Request for Telephone Administration of HD Patient Questionna ire” and fax to Barbara Stansfeld and to Collaborative Data Services at the institution. Collaborative Data Services Collaborative Data Services (CDS) is a shared resour ce, physically located in FHCRC Division of Public Health Sciences (PHS), and is made up of two research support units: the Survey Research Unit and the Institutional Review Board policies Programming Unit. All CDS staff receives ongoing training in including specific modules addressing the Health Insurance Portability and Accountability Act (HIPAA) privacy and security rules in addition to Human Subjects Training. The Survey Research Unit specializes in survey design, developm ent, and testing; survey coding, batching, key entry, and verificati on; and development and processing of optically scanned surveys. It also offers interviewing by telephone including co mputer-aided telephone interviewing that can be directly linked to autom ated sample management or random digit dialing software applications. Other services in this unit include data m anagement; mail assembly and tracking, and overall project coordination. The Programming Unit provides software developm ent and programming support for CDS key-entry, optical scanning, tracking sy stems and te lephone interviewing services, and also for outside customers. 4.1.3.2 Medical record abstraction For all participating patients, the institutional prin cipal investigator will be responsible for providing treatment data (cumulative chemotherapy doses, radiotherapy doses, fields and volumes) to correlate with health outcomes. In addition to abstraction of treatm ent data, the institutional principal investigator will abstract the m edical record for any prevalent m edical conditions that fall within the spectrum of the targeted outcomes (See Data Forms on COG’s website). 4.1.3.3 Clinical evaluation After completion and return of the CCSS self-report questionnaire, and a m edical record review, all subjects will receive a single com prehensive risk-based clinical evaluation, with specific exam inations and studies based upon recom mendations contained within the COG Late Effects Screening Guidelines, as appropriate for Hodgkin disease, and the participants ’ specific therapeutic exposures. This clinical evaluation will be recorded on a uniform entry form (See Data Form s on COG’s website). The specific study are based upon therapeutic exposures and are derived directly from the COG Late Effects Screening Guidelines [105]. Page 14 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 Specified Clinical Evaluations from COG Late Effects Screening Guidelines Targeted outcome Cardiomyopathy Arrhythmia Hyperlipidemia Pulmonary fibrosis Interstitial pneumonitis Thyroid function Thyroid nodule Female Gonadal evaluation Male Gonadal evaluation Therapy-related leukemia Bladder malignancy Thyroid cancer Breast cancer Gastrointestinal malignancy General cancer screening Any psychosocial problem Associated exposure therapeutic CARDIAC Doxorubicin, chest radiotherapy Doxorubicin, chest radiotherapy Doxorubicin , chest radiotherapy PULMONARY Bleomycin, chest radiotherapy Neck radiotherapy Neck radiotherapy ENDOCRINE GONADAL Cyclophosphamide, Mechlorethamine Dacarbazine, Procarbazine Pelvic radiotherapy Cyclophosphamide, Mechlorethamine Dacarbazine, Procarbazine Pelvic radiotherapy Screening tests (in addition to routine health history and physical examination Echocardiogram Electrocardiogram Fasting lipid profile Pulmonary function tests Chest X Ray TSH and Free T4 Palpation of thyroid gland; Imaging if abnormal For patients age 11 years or older: LH, FSH, estradiol For patients who have failed to proceed through puberty Gynecology or reproductive endocrinology consultation for consideration of hormonal replacement therapy For post-pubertal patients who have unsuccessfully tried to become pregnant, who have irregular menses, signs or symptoms of premature menopause: Gynecology or reproductive endocrinology consultation for, infertility consultation For patients age 11 years or older: Testicular volume by Prader orchiometry LH, FSH, testosterone For postpubertal males: Semen analysis Reproductive endocrinology consultation for infertility evaluation SECOND MALIGNANT NEOPLASMS Cyclophosphamide, Mechlorethamine CBC with differential Doxorubicin, Etoposide Cyclophosphamide Urinalysis yearly Pelvic radiotherapy Neck radiotherapy Thyroid palpation – imaging study if abnormal Chest radiotherapy Self breast-examination monthly Mammogram annually to start 8 years following radiotherapy or at age 25 years, whichever occurs last Abdominal radiotherapy > 25 Gy To start at 15 years post radiotherapy or at age 35 years, whichever occurs last: One of 3 options: 1. Fecal occult blood (3 samples) yearly and flexible sigmoidoscopy every 5 years OR 2. Double contrast barium enema every 5 years OR 3. Colonoscopy every 10 years No specific risk factors Follow American Cancer Society Recommendations PSYCHOSOCIAL Any therapy for cancer Clinical interview yearly Referral to mental health professional as clinically indicated Abbreviations of screening tests: TSH: thyroid stimulating hormone; T4: thyroxine; LH: luteinizing hormone; FSH: follicular stimulating hormone; CBC: complete blood count. For those survivors, who have had an evaluation in the 6 months prior to study entry, with their consent, that evaluation will be used for the study examination, or they may elect to wait an additional 6 m onths when another clinical evaluation would be clinically indicated. Results from any screening m easures that were collected previously, and not medically indicated to repeat during the study period, will be used for the study purposes, with the consent of the participant. For ex ample, if a survivor is recom mended to have an echocardiogram every 5 years, and one was done within a y ear of the study , it will not be repeated for study purposes during the 4-year study period. Page 15 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 For a m ore in-depth assessm ent of psy chosocial problems, participants also will com plete a self-report psychologic assessment, which is em bedded in the study questionnaire, with questions regarding sleep, fatigue, depression and symptoms of psychologic distress, quality of life, post traumatic growth and stress, and sexual quality of life (See Data Forms on COG’s website). 4.2 Additional Data Children’s Hospital and Regional Medical Center will be the coordinating institution for the study . All data should be sent to Barbara Stansfeld (see contact information below). 4.3 Specimen Collection and Submission The following data forms should be completed for each enrolled patient: 1. Registration form 2. Level of participation form 3. Completed patient CCSS and psychosocial questionnaires 4. Medical record abstraction form 5. Clinical evaluation form All forms should be sent to: Barbara “Bobbi” Stansfeld Clinical Research Associate (CRA III) Seattle Children's Hospital 1900 Ninth Ave. Mailstop C9S-9C Seattle, WA 98101 Phone: (206) 884-1018 Fax: (206) 729-3062 E-mail: [email protected] 4.4 Laboratory Analysis Laboratory studies should be perform ed as indicated in the Late Effects Guidelines. Results should be recorded on the clinical evaluation form. 5.0 STATISTICAL CONSIDERATIONS 5.1 Statistical Design This is a cohort study with a comparison to historical controls. 5.2 Accrual (and Expected Duration of Accrual) Contemporary subjects will be accrued from participating institutions and the study will be coordinated by Children’s Hospital & Regional Medical Center in Seattle (CHRMC). Using the tumor registries and divisional databases at the participating institutions , together with COG and PHC databases, we have identified all eligible Hodgkin disease survivors, treat ed on or in parallel to the following protocols: Children’s Cancer Group (CCG) 5942, 59704; Pediatric Oncology Group (POG) 8625, 8725, 9425, 9426; Pediatric Hodgkin’s Consortium: VAMP, VEPA, VAMP/ COP, and the following institutional protocols: COPP/ABV, MOPP/ABVD, ABVD. Page 16 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 At the start of the first y ear, and throughout the study period, as needed, institutional principal investigators will identify all currently eligible patients who are known lost to follow-up. They will submit demographic data on those patients directly to the Tracking Resour ce Center (TRC) at Fred Hutchinson Cancer Research Center (FHCRC), with whom they will contract in a business arrangem ent, for the purpose of tracking patients. The TRC will procure current contact information for as many eligible patients as possible, using the methodology described previously. The same methodology will be used for any eligible participants who are found lost to follow-up during the research period. No demographic information that contains personal health information will be released to the coordinating center at CHRMC until the participant has signed appropriate informed consent. Institutions who require assistan ce with using the TRC should contact Barbara “Bobbi” Stansfeld 206-884-1018 or [email protected]. We expect at least 1000 eligible HD patients in the cont emporary cohort and, with late relapse, loss to follow up and refusals of as high as 20%, we will be able to study a minimum of 800 contemporary-cohort patients in this study. Power calculations are therefore, conservatively based on 800 participants. However, given current follow-up patterns and tracking, we will likely study more patients. In the earlier cohort treated in 1976-1986, we have 1272 HD patients who participated in the CCSS. The total number of person-years among the 1272 patients during 5-15 years from the first cancer diagnosis was 10,275.79: we focus on the 5-15 y ears from the diagnosis since this is the tim e period of observati on for the contem porary cohort. Our power calculations below are tailored specifically to each of the three specific aims. 5.3 Statistical Analysis Methods 5.3.1 Data Analysis Part 1: To characterize the incidence and spectrum of adverse physiological and psychological outcomes in Hodgkin disease survivors treated with contemporary chemotherapy with or without involved field radiotherapy, and compare with a cohort of patients treated from 1976 to 1986. The first part will investigate each of adverse phy siological conditions (i.e., cardiac toxicity , pulmonary toxicity, thyroid dysfunction, gonadal dysfunction, and second malignant neoplasm as defined in Section D.3) and psychological conditions (sy mptoms of depression or somatic distress, health-related quality of life, sexual quality of life, fatigue, sleep, post traum atic stress, post traumatic growth) as separate outcom es. The incidence rates of each condition will be com puted by the number of new occurrences, counting only the first event of the adverse condition of interest, divided by the total number of person-years at risk. Each individual will be considered to be at risk for a specific adver se condition until the earliest of death, developm ent of the adverse condition, loss to follow up, or completion of questionnaire. The calculation of the incidence rates will be done in two ways: (a) using the self-report incidence of adverse conditions; and (b) using the incidence of adverse conditions validated by clinical evaluation. Confidence intervals for the incidence rates will be calculated using the bootstrap m ethod via resampling of survivors [106]. Cumulative incidence curves will also be produced to show the tim e of occurrence of each condition after the entry to the study regarding mortality as the competing risk [107]. We will compare the incidence rates between survivors treated from 1987 to 2000 with those treated from 1976 to 1986. Note that this com parison will be based on self-report incidence of adverse conditions since the earlier cohort will not have had uniform clinical evaluations. The ratio of the incidence rates for the contemporary cohort over the earlier cohort will y ield a relative rate (RR) estim ate of each adverse condition for the contemporary cohort. Specifically, we will use Cox proportional hazards modeling with time from the 5 th-year survival to an occurrence of the event of interest as the failure time to be analyzed. The regression will adjust for age at diagnosis, sex, and treated institutions in assessing the RR of m ain Page 17 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 interest, i.e., the adjusted RR for the contem porary cohort com pared to the earlier cohort (1976-1986). Since the set of study institutions differs between the earlier cohort and the contem porary cohort, we will conduct a secondary sensitivity analysis by restricting the analysis to the institutions with both cohorts’ data and assessing the consistency in the contem porary-versus-earlier RR estim ate. Specifically , the model will take the proportional hazard form: (t) = o(t) exp (XT + ZT) where (t) is the hazard of an adverse condition at time t from the 5-y ear survival of Hodgkin disease (i.e., the entry to the CCSS study ), o denotes the baseline hazard, X is the indicator of contem porary cohort membership, and Z is a vector of adjustm ent variables. and are parameters associated with X and Z, respectively, of which our m ain focus will be on , the log hazard rate ratios of the adverse condition of interest in the contem porary cohort relative to the earlier cohort, adjusting for Z. Standard large-sample inference methods for a Cox regression parameter, , will be used to construct its confidence limit and perform significance tests [108]. To investigate the factors that m odify the risk fo r the adverse conditions in the contem porary treatment cohort, we will tabulate the incidence rates by various demographic and treatm ent categories. We will explore variables such as sex, age, race/ethnicity, primary treatment modality, treatment with alkylating agents, treatment with doxorubicin, treatment with bleomycin, and treatment with radiotherapy, and doses of these therapies. For the exploratory tabulation, we will use Poisson regression models to summarize the rates and their modification by the significant demographic and treatment characteristics, simultaneously. Specifically, the model takes the following log-linear form with an offset term: log E[Yij] = log PYij + XijT, Yij’s are independent Poisson random variables with means E[Yi]’s, where Yij, PYij, and Xij are the indicator of an adverse condition occurrence, person-tim e at risk, and a vector of dem ographic/treatment factors, respectively, in ith survivor’s j th time segment, and is the parameter vector of interest, log relative rates associated with covariates X. Note that the piece-wise constant hazards for time segments permit the use of time-dependent covariates in this analysis. Standard large-sample inference methods for generalized linear m odels will be used to construct interval estim ates and perform significance tests for [109]. Part 2: To validate self-reported health-related outcom es of Hodgkin disease survivors, including both new cohort and CCSS cohort, with clinical evaluation. For the CCSS cohort (the earlier cohort), we will obtai n medical records to validate 700 positive responses for targeted conditions reported between 5 and 15 years from diagnosis. For the contemporary cohort, we will use a combination of medical records and clinical eval uations to validate all sel f-reported positive and negative responses for targeted conditions. For purposes of assessing validity, medical records and clinical evaluation will be used as the 'gold standard'. If a condition is mentioned in the medical record or clinical evaluation, it is assigned a ' yes' value, otherwise it is assigned a ' no' value. Similarly, each response in the self-report questionnaire is recorded as a 'yes' value for a positive r esponse and a 'no' value for a negative response in the corresponding categories. Page 18 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 Sensitivity and specificity validity measures of the qu estionnaire will be calculated for binom ial categorical variables. The term 'sensitivity' is defined as the propor tion of those with the com plication (as defined by the medical records/clinical evaluations) who are correctly classified by the questionnaire. ' Specificity' is the proportion of the study population that truly does not have the complication and is correctly reported in the questionnaire. We will also obtain validation statisti cs such as positive predictive value (PPV) of self report, defined as the proportion of true positives among those reported as positives in the questionnaire, and negative predictive value (NPV), defined as proportion of tr ue negatives among those reported as negatives in the questionnaire. For the earlier cohort (1976-1986), our medical-record-based validation will be limited to those who self reported adverse events (i.e., negative self reports will not be validated). For this reason, we will calculate PPV only for the earlier cohort. Our statisti cal inference regarding sensitivity, specificity, PPV, and NPV will be based on the standard binomial-based methods for evaluating medical diagnostic tests discussed by Pepe [110]. 5.3.2 Power calculations: Aim 1. Descriptive incidence rates In the contemporary cohort of 800 survivors, we expect approximately 6,000 person-years based on the total person-years observed in the earlier cohort in the peri od of 5-15 y ears from the first cancer diagnosis. The precision of a descriptive rate can be represented by its expected width of confidence intervals. Under the standard Poisson assumption of event occurrences, the e xpected width of a 95% confidence interval for the incidence rate per 10,000 person-years will be 1.96()0.5 x 10/6, where 10/6 is the underlying incidence rate per 10,000 person-y ears. Thus, the expected widths (i.e., the precision of our incidence estimates) are as follows: Incidence rates per 10,000 person-years Precision (CI width) 50 100 150 200 250 300 350 400 450 500 17.9 25.3 31.0 35.8 40.0 43.8 47.3 50.6 53.7 56.6 Aim 2. Earlier vs. contemporary comparison This will be a com parison of two independent groups with respect to adverse condition incidence using Cox regression. The reference group is the earlie r cohort of 1272 HD survivors with approxim ately 10,000 person-years of follow-up and the com parison group is the contemporary cohort of 800 survivors with approximately 6,000 person-y ears of follow-up. Our calculation of power for this com parison is based on the method proposed by Lachin and Foulkes for failure-time data analysis. With the type I error probability of 0.05 and a two-sided test, we will have the following power [111]: Cumulative incidence of an adverse condition in the earlier cohort 5% 10% 15% Rate ratio (contemporary vs. earlier) 0.5 0.3 62% 94% 91% >99% >96% >99% Thus, if the cumulative incidence of an adverse condition in the earlier cohort is greater than 10%, we will have sufficient power to detect a rate ratio of 0. 5 or smaller comparing the contemporary cohort to the earlier cohort. If the cumulative incidence of an adverse condition in the earlier cohort is 5%, we will not have sufficient power to detect a rate ratio of 0.5 but have sufficient power to detect a rate ratio of 0.3 or smaller. Page 19 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 Aim 3. Validity of self-report against medical record/clinical evaluation With 800 survivors and a cum ulative incidence of 100%, we will have 800 true positives and 800(1-) true negatives. T he precision of sensitivity estimate, approximated by the width of a 95% confidence interval, will be 1.96{p(1-p)}0.5/(800), where p is the true sensitivity . Sim ilarly, the precision of specificity estimate will be 1.96{p*(1-p*)}0.5/{800(1-)}, where p* is the true specificity . Thus, the precision of our sensitivity/specificity estimates will be as follows: Cumulative incidence of an adverse condition 5% 10% 30% 50% Sensitivity / Specificity 70% 2.2% / 0.1% 1.1% / 0.1% 0.4% / 0.2% 0.2% / 0.2% 80% 2.0% / 0.1% 1.0% / 0.1% 0.3% / 0.1% 0.2% / 0.2% 90% 1.5% / 0.1% 0.7% / 0.1% 0.2% / 0.1% 0.1% / 0.1% 95% 1.1% / 0.1% 0.5% / 0.1% 0.2% / 0.1% 0.1% / 0.1% Page 20 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ALTE04N1 REFERENCES 1. Schwartz CL. The management of Hodgkin disease in the y oung child. Curr Opin Pediatr, 2003. 15(1): 10-6. 2. Aziz NM, Rowland JH. Cancer survivorship research am ong ethnic m inority and m edically underserved groups. Oncol Nurs Forum, 2002. 29(5): 789-801. 3. Meadows AT, Varricchio C, Crosson K, Harlan L, McCorm ick P, Nealon E, Sm ith M, Ungerleider R. Research issues in cancer survi vorship: report of a workshop sponsored by the Office of Cancer Survivorship, National Cancer Institute. Cancer Epidem iology, Biomarkers & Prevention, 1998. 7(12): 1145-51. 4. Rowland JH, Aziz N, Tesauro G, Feuer EJ. The changing face of cancer survivorship. Sem inars in Oncology Nursing, 2001. 17(4): 236-40. 5. Donaldson SS, Glatstein E, Rosenberg SA, Kaplan HS. Pediatric Hodgkin's disease. II. Results of therapy. Cancer, 1976. 37(5): 2436-47. 6. Behrendt H, Brinkhuis M, Van Leeuwen EF. Treatment of childhood Hodgkin's disease with ABVD without radiotherapy. Med Pediatr Oncol, 1996. 26(4): 244-8. 7. Fryer CJ, Hutchinson RJ, Krailo M, Collins RD, Constine LS, Hay s DM, Heller RM, Davis PC, Nachman J, O'Brien RT, . Efficacy and toxicity of 12 courses of ABVD chem otherapy followed by low-dose regional radiation in advanced Hodgkin' s disease in children: a report from the Children's Cancer Study Group. J Clin Oncol, 1990. 8(12): 1971-80. 8. Hutchinson RJ, Fryer CJ, Davis PC, Nachman J, Krailo MD, O'Brien RT, Collins RD, Whalen T, Reardon D, Trigg ME, Gilchrist GS. MOPP or radia tion in addition to ABVD in the treatm ent of pathologically staged advanced Hodgkin' s disease in children: results of the Children' s Cancer Group Phase III Trial. Journal of Clinical Oncology, 1998. 16(3): 897-906. 9. Hunger SP, Link MP, Donaldson SS. ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin's disease: the Stanford experience. J Clin Oncol, 1994. 12(10): 2160-6. 10. Oberlin O, Leverger G, Pacquement H, Raquin MA, Chompret A, Habrand JL, Terrier-Lacom be MJ, Bey P, Bertrand Y, Rubie H.. Low-dose radiation therapy and reduced chem otherapy in childhood Hodgkin's disease: the experience of the Fren ch Society of Pediatric Oncology. J Clin Oncol, 1992. 10(10): 1602-8. 11. Donaldson SS, Hudson MM, Lamborn KR, Link MP, Kun L, Billett AL, Marcus KC, Hurwitz CA, Young JA, Tarbell NJ, Weinstein HJ. VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: results of a prospective clinical trial. J Clin Oncol, 2002. 20(14): 3081-7. 12. Donaldson SS. Pediatric Hodgkin' s disease--up, up, and bey ond. Int J Radiat Oncol Biol Phy s, 2002. 54(1): 1-8. 13. Hudson MM, Donaldson SS. Treatment of pediatric Hodgkin's lymphoma. Semin Hematol, 1999. 36(3): 313-23. 14. Hudson MM, Weinstein HJ, Donaldson SS, Greenwald C, Kun L, Tarbell NJ, Hum phrey WA, Rupp C, Marina NM, Wilim as J, . Acute hy persensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease. J Clin Oncol, 1993. 11(6): 1080-4. 15. MacKenzie RG, Franssen E, Wong R, Sawka C, Berinstein N, Cowan DH, Senn J, Poldre P. Risk-adapted therapy for clinical stage I-II Hodgkin's disease: 7-y ears results of radiotherapy alone for low-risk disease, and ABVD and radiothe rapy for high-risk disease. Clinical Oncology (Royal College of Radiologists), 2000. 12(5): 278-88. 16. Nachman JB, Sposto R, Herzog P, Gilchrist GS, Wolden SL, Thom son J, Kadin ME, Pattengale P, Davis PC, Hutchinson RJ, White K. Random ized comparison of low-dose involved-field radiotherapy and no radiotherapy for childre n with Hodgkin' s disease who achieve a com plete response to chemotherapy. J Clin Oncol, 2002. 20(18): 3765-71. Page 21 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. ALTE04N1 Reuss K, Engert A, Tesch H, Diehl V. Current clinical trials in Hodgkin' s disease. Annals of Oncology, 1996. 7 Suppl 4: 109-13. Schellong G. Pediatric Hodgkin's disease: treatment in the late 1990s. Ann Oncol, 1998. 9 Suppl 5: S115-9. Schellong G, Potter R, Bramswig J, Wagner W, Prott FJ, Dorffel W, Korholz D, Mann G, Rath B, Reiter A, Weissbach G, Riepenhausen M, Thiemann M, Schwarze EW. High cure rates and reduced long-term toxicity in pediatric Hodgki n's disease: the Germ an-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin' s Disease Study Group. J Clin Oncol, 1999. 17(12): 3736-44. Schwartz C, Constine L, London W, Kam ps W, Marcus R, Chauvenet A. Intensive responsebased therapy with or without dexrazoxane for intermediate/high-stage (I/HS) pediatric Hodgkin's disease (HD): A Pediatric Oncology Group (POG) Study. in Fifth International Symposium on Hodgkin's Lymphoma. 2001. Koln, Germany: Harwood Academic. Tebbi C, Mendenhall N, Schwartz C. Respon se dependent treatm ent of stages IA, IIA and IIIA1micro Hodgkin's disease with DBVE and low dose involved field irradiation with or without dexrazoxane. in Fifth International Sy mposium on Hodgkin's Lymphoma. 2001. Koln, Germany: Harwood Academic. Weiner MA, Leventhal B, Brecher ML, Marcus RB, Cantor A, Gieser PW, Ternberg JL, Behm FG, Wharam MD, Jr., Chauvenet AR. Random ized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study . J Clin Oncol, 1997. 15(8): 2769-79. Kelly KM, Hutchinson RJ, Sposto R, Weiner MA, Lones MA, Perkins SL, Massey V. Feasibility of upfront dose-intensive chem otherapy in ch ildren with advanced-stage Hodgkin' s lymphoma: preliminary results from the Children's Cancer Group Study CCG-59704. Ann Oncol, 2002. 13 Suppl 1: 107-11. Giantris A, Abdurrahm an L, Hinkle A, A sselin B, Lipshultz SE. Anthracycline-induced cardiotoxicity in children and y oung adults. Cr itical Reviews in Oncology -Hematology, 1998. 27(1): 53-68. Green DM, Hyland A, Chung CS, Zevon MA, Hall BC. Cancer and cardiac mortality among 15year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol, 1999. 17(10): 3207-15. Lipshulltz S, Schwartz C, Fajardo L, Coen V, Hardenberg P, Constine L. Radiation Associated Cardiovascular Disease: Manifestations and management. Sem Rad Onc, In Press. Lipshultz S, Lipsitz S, Sallan S. Chronic progressive left ventricular sy stolic dysfunction and afterload excess years after doxorubicin therapy for childhood acute lymphoblastic leukemia. in Proceedings of American Society of Clinical Oncology. 2000. Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP, Orav EJ, Gelber RD, Colan SD. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer.. New England Journal of Medicine, 1995. 332(26): 1738-43. Nysom K, Holm K, Lipsitz SR, Mone SM, Colan SD, Orav EJ, Sallan SE, Olsen JH, Hertz H, Jacobsen JR, Lipshultz SE. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. Journal of Clinical Oncology , 1998. 16(2): 545-50. Silber JH, Jakacki RI, Larsen RL, Goldwein JW , Barber G. Increased risk of cardiac dy sfunction after anthracyclines in girls.. Medical & Pediatric Oncology, 1993. 21(7): 477-9. Steinherz LJ, Steinherz PG, Tan C. Card iac failure and dy srhythmias 6-19 y ears after anthracycline therapy: a series of 15 patients. Medical & Pediatric Oncology , 1995. 24(6): 35261. Page 22 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. ALTE04N1 Steinherz LJ, Graham T, Hurwitz R, Sondhe imer HM, Schwartz RG, Shaffer EM, Sandor G, Benson L, William s R. Guidelines For Cardiac Monitoring Of Children During and After Anthracycline Therapy: Report Of the Cardiol ogy Committee Of the Childrens Cancer Study Group. Pediatrics, 1992. 89(5 Pt 1): 942–9. Lipshultz SE, Sanders SP, Goorin AM, Kri scher JP, Sallan SE, Colan SD. Monitoring for anthracycline cardiotoxicity.. Pediatrics, 1994. 93(3): 433-7. Hudson MM, Poquette CA, Lee J, Greenwald CA, Shah A, Luo X, Thom pson EI, Wilimas JA, Kun LE, Crist WM. Increased m ortality after successful treatm ent for Hodgkin's disease. J Clin Oncol, 1998. 16(11): 3592-600. Mertens AC, Yasui Y, Neglia JP, Potter JD, Nesbit ME, Jr., Ruccione K, Smithson WA, Robison LL. Late mortality experience in five-y ear survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study.. Journal of Clinical Oncology, 2001. 19(13): 3163-72. Donaldson SS, Hancock SL, Hoppe RT. Th e Janeway lecture. Hodgkin' s disease--finding the balance between cure and late effects. Cancer J Sci Am, 1999. 5(6): 325-33. Wexler LH. Ameliorating anthracycline cardiotoxicity in children with cancer: clinical trials with dexrazoxane. Seminars in Oncology, 1998. 25(4 Suppl 10): 86-92. Herman EH, Zhang J, Rifai N, Lipshultz SE, Hasinoff BB, Chadwick DP, Knapton A, Chai J, Ferrans VJ. The use of serum levels of cardiac troponin T to com pare the protective activity of dexrazoxane against doxorubicin- and m itoxantrone-induced cardiotoxicity. Cancer Chem other Pharmacol, 2001. 48(4): 297-304. Lipshultz SE. Dexrazoxane for protection ag ainst cardiotoxic effects of anthracy clines in children.. Journal of Clinical Oncology, 1996. 14(2): 328-31. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelm an A, Reddy S, Pendergrass K, Velez-Garcia E, Ewer MS, Bianchine JR, Gams RA. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.. Journal of Clinical Oncology, 1997. 15(4): 1318-32. Venturini M, Michelotti A, Del Mastro L, Gallo L, Carnino F, Garrone O, Tibaldi C, Molea N, Bellina RC, Pronzato P, Cy rus P, Vinke J, Testore F, Guelfi M, Lionetto R, Bruzzi P, Conte PF, Rosso R. Multicenter random ized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in wo men receiving epirubicin chem otherapy for advanced breast cancer. Journal of Clinical Oncology, 1996. 14(12): 3112-20. Mefferd JM, Donaldson SS, Link MP. Pediatric Hodgkin's disease: pulm onary, cardiac, and thyroid function following combined modality therapy. Int J Radiat Oncol Biol Phy s, 1989. 16(3): 679-85. Hamilton VM, Norris C, Bunin N, Goldwein JW, Bunin GR, Lange B, Meadows AT. Cyclophosphamide-based, seven-drug hybrid and low-dose involved field radiation for the treatment of childhood and adolescent Hodgkin disease. J Pediatr Hem atol Oncol, 2001. 23(2): 84-8. Allavena C, Conroy T, Aletti P, Bey P, Lederlin P. Late cardiopulmonary toxicity after treatment for Hodgkin's disease. Br J Cancer, 1992. 65(6): 908-12. Dubray B, Henry-Amar M, Meerwaldt JH, Noordijk EM, Dixon DO, Cosset JM, Tham es HD. Radiation-induced lung damage after thoracic irradiation for Hodgkin' s disease: the role of fractionation. Radiother Oncol, 1995. 36(3): 211-7. Horning SJ, Adhikari A, Rizk N, Hoppe RT, Olshen RA. Effect of treatm ent for Hodgkin' s disease on pulm onary function: results of a prospective study . J Clin Oncol, 1994. 12(2): 297305. Pohjola-Sintonen S, Totterm an KJ, Salm o M, Siltanen P. Late cardiac effects of mediastinal radiotherapy in patients with Hodgkin's disease. Cancer, 1987. 60(1): 31-7. Page 23 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. ALTE04N1 Villani F, Viviani S, Bonfante V, De Maria P, Soncini F, Laffranchi A. Late pulmonary effects in favorable stage I and IIA Hodgkin's disease treated with radiotherapy alone. Am J Clin Oncol, 2000. 23(1): 18-21. Marina NM, Greenwald CA, Fairclough DL, Thompson EI, Wilimas JA, Mackert PW, Hudson MM, Stokes DC, Bozem an PM. Serial pulm onary function studies in children treated for newly diagnosed Hodgkin's disease with m antle radiotherapy plus cy cles of cy clophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleom ycin, vinblastine, and dacarbazine. Cancer, 1995. 75(7): 1706-11. Nysom K, Holm K, Hertz H, Hesse B. Risk factors for reduced pulmonary function after malignant lymphoma in childhood. Medical & Pediatric Oncology, 1998. 30(4): 240-8. Mertens AC, Yasui Y, Liu Y, Stovall M, Hutc hinson R, Ginsberg J, Sklar C, Robison LL. Childhood Cancer Survivor S. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer, 2002. 95(11): 2431-41. Hancock SL, Cox RS, McDougall IR. Thy roid diseases after treatment of Hodgkin's disease. N Engl J Med, 1991. 325(9): 599-605. Constine LS, Donaldson SS, McDougall IR, C ox RS, Link MP, Kaplan HS. Thy roid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer, 1984. 53(4): 878-83. Bhatia S, Ramsay NK, Bantle JP, Mertens A, Robison LL. Thy roid Abnormalities after Therapy for Hodgkin's Disease in Childhood. Oncologist, 1996. 1(1 & 2): 62-67. Sklar C, Whitton J, Mertens A, Stovall M, Green D, Marina N, Greffe B, Wolden S, Robison L. Abnormalities of the thy roid in survivors of Hodgkin' s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab, 2000. 85(9): 3227-32. Rueffer U, Breuer K, Josting A, Lathan B, Sieber M, Manzke O, Grotenhermen FJ, Tesch H, Bredenfeld H, Koch P, Nisters- Backes H, Wolf J, Engert A, Diehl V. Male gonadal dysfunction in patients with Hodgkin's disease prior to treatment. Ann Oncol, 2001. 12(9): 1307-11. Fitoussi, Eghbali H, Tchen N, Berjon JP, S oubeyran P, Hoerni B. Sem en analysis and cryoconservation before treatment in Hodgkin's disease. Ann Oncol, 2000. 11(6): 679-84. Ben Arush MW, Solt I, Lightm an A, Linn S, Ku ten A. Male gonadal function in survivors of childhood Hodgkin and non-Hodgkin ly mphoma. Pediatric Hem atology & Oncology , 2000. 17(3): 239-45. Hill M, Milan S, Cunningham D, Mansi J, Sm ith I, Catovsky D, Gore M, Zulian G, Selby P, Horwich A. Evaluation of the efficacy of the VEEP regim en in adult Hodgkin's disease with assessment of gonadal and cardiac toxicity. Journal of Clinical Oncology, 1995. 13(2): 387-95. Dhabhar BN, Malhotra H, Joseph R, Garde S, Bhasin S, Sheth A, Advani SH. Gonadal function in prepubertal boys following treatment for Hodgkin' s disease. Am erican Journal of Pediatric Hematology Oncology, 1993. 15(3): 306–10. Kulkarni SS, Sastry PS, Saikia TK, Parikh PM, Gopal R, Advani SH. Gonadal function following ABVD therapy for Hodgkin's disease. American Journal of Clinical Oncology , 1997. 20(4): 3547. Muller U, Stahel R. Gonadal function afte r MACOP-B or VACOP-B with or without dose intensification and ABMT in y oung patients with aggressive non-Hodgkin' s lymphoma. Ann Oncol, 1993. 4: 399-402. Pryzant RM, Meistrich ML, Wilson G, Brown B, McLaughlin P. Long-term reduction in sperm count after chem otherapy with and without radiation therapy for non-Hodgkin' s lymphomas. Journal of Clinical Oncology, 1993. 11(2): 239-47. Bokemeyer C, Schmoll HJ, van Rhee J, Kuczyk M, Schuppert F, Poliwoda H. Long-term gonadal toxicity after therapy for Hodgkin' s and non- Hodgkin's lymphoma. Ann Hem atol, 1994. 68(3): 105-10. Relander T, Cavallin-Stahl E, Garwicz S, Ol sson AM, Willen M. Gonadal and sexual function in men treated for childhood cancer. Medical & Pediatric Oncology, 2000. 35(1): 52-63. Page 24 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. ALTE04N1 Ash P. The influence of radiation on fertility in man. British Journal of Radiology, 1980. 53(628): 271-8. Lushbaugh CC, Casarett GW. The effects of gonadal irradiation in clinical radiation therapy : a review. Cancer, 1976. 37(2 Suppl): 1111-25. Kinsella T, Fraass B, Glatstein E. Late effects of radiation therapy in the treatm ent of Hodgkin's disease. Cancer, 1982. 69: 1241-7. Ortin TT, Shostak CA, Donaldson SS. Gonadal status and reproductive function following treatment for Hodgkin' s disease in childhood: the Stan ford experience.. International Journal of Radiation Oncology, Biology, Physics, 1990. 19(4): 873-80. Byrne J, Fears TR, Gail MH, Pee D, Connelly RR, Austin DF, Holm es GF, Holm es FF, Latourette HB, Meigs JW. Early menopause in long-term survivors of cancer during adolescence. American Journal of Obstetrics & Gynecology, 1992. 166(3): 788-93. Chiarelli AM, Marrett LD, Darlington G. Early menopause and infertility in fem ales after treatment for childhood cancer diagnosed in 1964-1988 in Ontario, Canada. American Journal of Epidemiology, 1999. 150(3): 245-54. Santoro A, Valagussa P. Advances in the treatm ent of Hodgkin's disease. . Current Opinion in Oncology, 1992. 4(5): 821–8. Thomson AB, Critchley HO, Kelnar CJ, Wallace WH. Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Practice & Research Clinical Endocrinology & Metabolism, 2002. 16(2): 311-34. Hudson MM, Jones D, Boy ett J, Sharp GB, Pui CH. Late m ortality of long-term survivors of childhood cancer. Journal of Clinical Oncology, 1997. 15(6): 2205-13. Meadows AT, Baum E, Fossati BF, Green D, Jenkin RDT, Marsden B, Nesbit M, Newton W, Oberlin O, . Second malignant neoplasms in children: an update from the late effects study group. Journal of Clinical Oncology, 1985. 3(4): 532-38. Meadows AT. Risk factors for second m alignant neoplasms: report from the Late Effects Study Group. Bull Cancer, 1988. 75(1): 125-30. Meadows AT, Obringer AC, Marrero O, Oberlin O, Robison L, Fossati-Bellani F, Green D, Voute PA, Morris-Jones P, Greenberg M. Second m alignant neoplasms following childhood Hodgkin's disease: treatment and splenectom y as risk factors. Medical & Pediatric Oncology , 1989. 17(6): 477-84. Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, Meadows AT. Breast cancer and other second neoplasm s after childhood Hodgkin' s disease. N Engl J Med, 1996. 334(12): 745-51. Bhatia S, Robison L, Meadows A. High ri sk of second m alignant neoplasms (SMN) continues with extended follow-up of childhood Hodgkin' s disease (HD) cohort: Report from the Late Effects Study Group (LESG). Blood, 2001. 98: 768a. Bhatia S, Meadows AT, Robison LL. Second cancers after pediatric Hodgkin's disease. J Clin Oncol, 1998. 16(7): 2570-2. Donaldson SS, Hancock SL. Second cancers after Hodgkin's disease in childhood. N Engl J Med, 1996. 334(12): 792-4. Metayer C, Ly nch CF, Clarke EA, Glim elius B, Storm H, Pukkala E, Joensuu T, van Leeuwen FE, van't Veer MB, Curtis RE, Holowaty EJ, Andersson M, Wiklund T, Gospodarowicz M, Travis LB. Second cancers among long-term survivors of Hodgkin' s disease diagnosed in childhood and adolescence. J Clin Oncol, 2000. 18(12): 2435-43. Tucker MA, Colem an CN, Cox RS, Varghese A, Rosenberg SA. Risk of second cancers after treatment for Hodgkin's disease. New England Journal of Medicine, 1988. 318(2): 76-81. Wolden SL, Lam born KR, Cleary SF, Tate DJ, Donaldson SS. Second cancers following pediatric Hodgkin's disease. J Clin Oncol, 1998. 16(2): 536-44. Page 25 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. ALTE04N1 Tucker MA. Solid second cancers following Hodgki n's disease. Hematology - Oncology Clinics of North America, 1993. 7(2): 389-400. Swerdlow AJ, Barber JA, Hudson GV, Cuni ngham D, Gupta RK, Hancock BW, Horwich A, Lister TA, Linch DC. Risk of second m alignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment. Journal of Clinical Oncology , 2000. 18(3):498509. Green DM, Hyland A, Barcos MP, Reynolds JA, Lee RJ, Hall BC, Zevon MA. Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence. Journal of Clinical Oncology, 2000. 18(7): 1492-9. Neglia JP, Friedm an DL, Yasui Y, Mertens AC, Ham mond S, Stovall M, Donaldson SS, Meadows AT, Robison LL. Second malignant neoplasms in five-y ear survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst, 2001. 93(8): 618-29. Mauch PM, Kalish LA, Marcus KC, Colem an CN, Shulman LN, Krill E, Com e S, Silver B, Canellos GP, Tarbell NJ. Second malignancies after treatment for laparotom y staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome. Blood, 1996. 87(9): 3625-32. Schellong G, Riepenhausen M, Creutzig U, Ritte r J, Harbott J, Mann G, Gadner H. Low risk of secondary leukemias after chem otherapy without m echlorethamine in childhood Hodgkin' s disease. German-Austrian Pediatric Hodgkin's Disease Group. Journal of Clinical Oncology , 1997. 15(6): 2247–53. Hudson MM. Pediatric Hodgkin's therapy: time for a paradigm shift. J Clin Oncol, 2002. 20(18): 3755-7. Cameron CL, Cella D, Herndon JE, 2nd, Kornb lith AB, Zuckerman E, Henderson E, Weiss RB, Cooper MR, Silver RT, Leone L, Canellos GP, Peterson BA, Holland JC. Persistent sy mptoms among survivors of Hodgkin's disease: an explanatory model based on classical conditioning. Health Psychol, 2001. 20(1): 71-5. Greil R, Holzner B, Kemmler G, Kopp M, Buchowski A, Oberaigner W, Fritsch E, Dirnhofer S, Rueffer U, Diehl V, Sperner-Unterweger B. Retrospective assessm ent of quality of life and treatment outcome in patients with Hodgkin' s disease from 1969 to 1994. Eur J Cancer, 1999. 35(5): 698-706. Hill JM, Kornblith AB, Jones D, Freem an A, Holland JF, Glicksman AS, Boyett JM, Lenherr B, Brecher ML, Dubowy R, Kung F, Maurer H, Holland JC. A com parative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation. Cancer, 1998. 82(1): 208-18. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonom i A, Silberm an M, Yellen SB, Winicour P, Brannon J . The Functional Assessm ent of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol, 1993. 11(3): 570-9. Zeltzer LK. Cancer in adolescents and y oung adults psychosocial aspects. Long-term survivors. Cancer, 1993. 71(10 Suppl): 3463-8. Zebrack BJ, Zeltzer LK, Whitton J, Mertens AC, Odom L, Berkow R, Robison LL. Psychological outcomes in long-term survivors of childhood leukem ia, Hodgkin's disease, and non-Hodgkin's lymphoma: a report from the Childhood Cancer Survivor Study . Pediatrics, 2002. 110(1 Pt 1): 42-52. Bleyer WA. The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. European Journal of Cancer, 1997. 33(9): 1439-47. Fobair P, Hoppe RT, Bloom J, Cox R, Va rghese A, Spiegel D. Psy chosocial problems among survivors of Hodgkin's disease. J Clin Oncol, 1986. 4(5): 805-14. Abrahamsen AF, Loge JH, Hannisdal E, Holte H, Kvaloy S. Socio-medical situation for longterm survivors of Hodgkin's disease: a survey of 459 patients treated at one institution. Eur J Cancer, 1998. 34(12): 1865-70. Page 26 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. ALTE04N1 Knobel H, Havard Loge J, Brit Lund M, Forfang K, Nom e O, Kaasa S. Late m edical complications and fatigue in Hodgkin's disease survivors. J Clin Oncol, 2001. 19(13): 3226-33. Kazak AE, Stuber ML, Barakat LP, Meeske K, Guthrie D, Meadows AT. Predicting posttraumatic stress symptoms in mothers and fathers of survivors of childhood cancers. Journal of the American Academy of Child & Adolescent Psychiatry, 1998. 37(8): 823-31. Kazak AE, Simms S, Barakat L, Hobbie W, Fo ley B, Golom b V, Best M. Surviving cancer competently intervention program (SCCIP): a cognitive-behavioral and family therapy intervention for adolescent survivors of childhood cancer and their fam ilies. Family Process, 1999. 38(2): 175-91. Hobbie WL, Stuber M, Meeske K, Wissler K, Rourke MT, Ruccione K, Hinkle A, Kazak AE. Symptoms of posttraum atic stress in y oung adult survivors of childhood cancer. Journal of Clinical Oncology, 2000. 18(24): 4060-6.. Hudson M, Landier W, Bhatia S, and the Late Effects Steering Committee. Late Effects Screening Guidelines. Version 1.0. March 2003, Children's Oncology Group. Eforn B, Tibshirani R. An introduction to the bootstrap. 1993, London: Chapman & Hall. Gooley TA, Leisenring W, Crowley JP, Storer BE, Why Kaplan-Meier fails and cum ulative incidence succeeds when estim ating failure probab ilities in the presence of com peting risks., in Handbook of Statistics in Clinical Oncology. 2000. p. 513-523. Therneau TM, P.M. G. Modeling Survival Data: Extending the Cox Model. 2001, New York: Springer. Breslow N, Day N. Statistical methods in cancer research, Volume II - The design and analysis of cohort studies. 1987, Lyon: IARC Scientific Publications. Pepe MS. The Statistical Evaluation of Medical Tests for Classification and Prediction. 2003, Oxford: Oxford University Press. Lachin JM, Foulkes MA. Evaluation of sam ple size and power for analy ses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics, 1986. 42(3): 507-19. Page 27 ALTE04N1 This model informed consent form has been reviewed by the DCT/NCI and is the official consent document for this study. Institutions should use the sections of this document which are in bold type in their entirety. Editorial changes to these sections may be made as long as they do not change information or intent. If the local IRB insists on making deletions or more substantive modifications to any of the sections in bold type, they must be justified in writing by the investigator at the time of the institutional audit. SAMPLE INFORMED CONSENT ALTE04N1: Health-Related Outcomes for Hodgkin Survivors If you are a parent or legal guardian of a child who may take part in this study, permission from you is required. The assent (agreement) of your child may also be required. When we say “you” in this consent form, we mean you or your child; “we” means the doctors and other staff. WHAT IS THIS STUDY ABOUT? This study is a clinical trial (a research study involving human patients). Clinical trials only include patients who choose to take part. Please take your time to make your decision. You may want to discuss your decision with your friends and family. This study is being carried out by the Children’s Oncology Group (COG). The COG is an international research group that consists of more than 200 hospitals that treat children with cancer in the United States, Canada, Australia, New Zealand, the Netherlands and Switzerland. Much is known about the late effects of treatment for Hodgkin Disease diagnosed before 1987. As a result of that knowledge, treatment was changed in the late 1980’s to decrease those effects. This study is an attempt to find out how survivors are doing after receiving these newer treatments in order to try and help patients treated for Hodgkin Disease after 1987 and future children who are diagnosed with Hodgkin Disease. You/your child are invited to participate in this research study because you/your child was diagnosed and treated for Hodgkin Disease at Children’s Hospital and Regional Medical Center. You/your child were/was treated on a Children’s Oncology Group, Children’s Cancer Group, Pediatric Oncology group or similar protocol between 1987 and 2000. WHY IS THIS STUDY BEING DONE? The purpose of this study is to learn how survivors are doing after receiving these newer treatments. The possible late effects of treatment that we will be looking for with this research study are: Heart problems. Lung problems. Endocrine (hormone) problems. Gonadal problems (problems having children). Second cancers. Psychological and social problems relating to health-related quality of life, sexual quality of life, fatigue, post-traumatic stress, post traumatic growth*, and depression. Page 28 ALTE04N1 * Post traumatic growth is the opposite of post traumatic stress. It refers to survivors, who after going through the "trauma" of cancer and its therapy, grow psychologically from the experience. HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? About 800 people will take part in this study. WHAT WILL HAPPEN TO ME ON THIS STUDY? If you/your child decide to take part in this research study you/your child will complete a questionnaire about your/your child’s current health, family medical history, and health behaviors. This will take 45 – 90 minutes to complete. This questionnaire can be completed by you/your child in written format or it can be administered by telephone interview, whichever is more convenient for you. You/your child will also be scheduled for a comprehensive risk-based evaluation. This evaluation will include examinations and testing recommended by the Children’s Oncology Late Effects Screening Guidelines. o Complete health history and review of systems. o Complete physical examination. o Laboratory tests: blood and urine evaluation. o Diagnostic imaging studies: tests to look at the function of your/your child’s heart, lungs, and hormones. There may also be cancer screenings, such as mammograms for women (to start 8 years after radiotherapy or by 25 years, whichever occurs last) and tests to look at your/your child’s stomach and colon (to start at 15 years post radiotherapy or at age 35, whichever happens last). o Age and gender (male or female) specific pubertal and reproductive evaluations. For girls older than 11, they may have their hormones tested if they failed to go through puberty. For girls who already went through puberty, they will be offered a chance to meet with an infertility specialist if they were unable to get pregnant and/or have irregular menstrual cycles. For boys older than 11, they may have their hormones evaluated. For boys who already have already gone through puberty, they will be offered a chance to have their sperm evaluated and they and/or their parents may meet with an infertility specialist if they are interested in having children. o Psychological evaluation. You will receive a written summary of your evaluation with recommendation for future care and observation. In addition, we will be reviewing your/your child’s medical record. We will be collecting information about past health problems that may have resulted from treatment for Hodgkin Disease. We will collect information on the results of routine tests done to check for late effects, such as blood tests, tests of heart function. We are only using results that are in your/your child’s medical record. We will ask you/your child to sign a Release of Information Form to obtain records from your/your child’s primary medical doctor. We will only gather information from your/your child’s primary medical doctor that may be related to late effects of treatment for Hodgkin Disease. HOW LONG WILL I (MY CHILD) BE IN THE STUDY? You will be on this study for as long as it takes to complete the questionnaires, usually 45-60 minutes. (The clinical evaluation tests are part of routine follow up and should not require an additional visit to your/your child’s treating institution). We would like to keep track of your medical condition for at least five years. Keeping in touch with you and checking on your condition every year helps us look at the long-term effects of the study. WHAT ARE THE RISKS OF THE STUDY? Page 29 ALTE04N1 Some of the questions in the questionnaires are of a personal nature and may make you/your child feel uncomfortable. For example, questions will be asked about smoking, alcohol use, and ability to have children. We will also be asking questions about your/your child’s emotions and feelings. The questionnaires that are being used for this research study have been used many times by many hospitals and clinics. To the best of our knowledge they have not caused anyone serious problems. You/your child do not have to answer any question that you/your child don’t want to. Simply leave the answer blank on the questionnaire. The participant/family may experience distress as they learn about potential health risks of treatment of which they were not previously aware. If a participant/family experiences distress, we can make a referral to an experienced social worker to help resolve distress or discomfort. All of the blood work is standard of care so there is no added risk from a blood draw since you/your child will already having blood drawn for routine follow up. ARE THERE BENEFITS TO TAKING PART IN THE STUDY? Each participant will receive a comprehensive risk-based evaluation, along with appropriate health education. This may result in an improved quality of life and improved future health. We hope that the information gained from this research study will help other patients with Hodgkin Disease in the future. WHAT OTHER OPTIONS ARE THERE? You have (your child has) the option of choosing not (to have your child) participate in this study. You may want to discuss this option with your (child’s) regular doctor as well as other trusted personal and family advisors. WHAT ABOUT CONFIDENTIALITY? Efforts will be made to keep your personal information confidential. We cannot guarantee absolute confidentiality. Your personal information may be disclosed if required by law. The Children’s Oncology Group has received a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. Information about the certificate is included in Attachment #1. Organizations that may inspect/or copy your (child’s) research records for quality assurance and data analysis include: The Children’s Oncology Group (COG); The National Cancer Institute (NCI); The Food and Drug Administration (FDA); The Institutional Review Board of this hospital (IRB); and Children’s Hospital and Regional Medical Center, University of Washington WHAT ARE THE COSTS? The evaluations recommended as part of this study are considered standard of care for longterm survivors of Hodgkin disease. You and/or your health plan/ insurance company will need to pay for some or all of the evaluation costs. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out Page 30 ALTE04N1 what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. If you/your insurance cannot pay for the recommended evaluations, please discuss this with your physician. You will not be paid for taking part in this study For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy. WHAT ARE MY (AND MY CHILD’S) RIGHTS AS A PARTICIPANT? Taking part in this study is voluntary. You may choose (for your child) not to participate in this study. If you decide not to (let your child) participate, you (your child) will not be penalized and you (your child) will still receive treatment as agreed upon with your (child’s) primary doctor. If you choose to (allow your child to) participate, you may discontinue your (child’s) participation in the study at any time. If you discontinue participation in the study, physicians and hospital personnel will still take care of you (your child). Whether you participate or not, you (your child) will continue to get the best medical care this hospital can provide. WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? For questions about the study or if you have a research related problem or if you think you have been injured, contact Dr. XXXX or your doctor at XXXXX If you have any questions about your rights as a research participant or any problems that you feel you cannot discuss with the investigators, you may call XXXX IRB Administrator at (XXXX If you have any questions or concerns that you feel you would like to discuss with someone who is not on the research team, you may also call the Patient Advocate at XXXX WHERE CAN I GET MORE INFORMATION? The COG Family Handbook for Children with Cancer has information about specific cancers, tests, treatment side effects and their management, adjusting to cancer, and resources. Your doctor can get you this Handbook, or you can get it at www.curesearch.org/ Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/ If you are in the United States, you may call the NCI's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 Information about long term follow-up http://www.survivorshipguidelines.org/ after cancer treatment can be found at: You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). SIGNATURE Page 31 ALTE04N1 I have been given a copy of all _____ pages of this form. The form includes one (1) attachment. I have reviewed the information and have had my questions answered. I agree to take part in this study. Participant Date Parent/Guardian Date Parent/Guardian Date Physician/PNP obtaining consent Date IRB# Page 32 ALTE04N1 Attachment #1 Certificate of Confidentiality The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of information about subjects collected during the course of our covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected information under certain circumstances. For example, if the subject or his/her guardian requests the release of information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against the required reporting by hospital staff of information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others. Page 33
© Copyright 2024