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© 2002 American Society for Clinical Oncology
Cancer Survivorship Research: The Best Is Yet to ComeAbramson Family Cancer Research Institute, at the University of Pennsylvania Cancer Center; The Children’s Hospital of Philadelphia, Philadelphia, PA AN ESTIMATED 7.2 million Americans, or nearly 4% of the population, are adult survivors of cancer.1 Although it is well known that cancer survivors confront a myriad of challenges as a result of the physical and psychosocial effects of cancer and its treatment, research in this area has been limited. The ultimate goal of cancer survivorship research is to enable cancer patients to have the best chance for a long and healthy life. Advances in our understanding of the deleterious effects of cancer and its treatment have led to modification of treatment regimens to minimize long-term risks without sacrificing the chance for cure. Important examples include the reduction or elimination of radiation in childhood acute lymphoblastic leukemia2 and the development of nonalkylating agent chemotherapy for Hodgkin’s disease.3 Cancer survivorship research may also result in the identification of adverse effects in certain populations and in the development of effective prevention or intervention strategies for these patients. Infertility is one of the most distressing of all the adverse effects of cancer therapy. Many cancer patients require treatments that carry the potential for long-term gonadal failure. For example, patients with germ cell tumor (GCT) may have azoospermia related to the disease itself or to the sterilizing effects of chemotherapy.4,5 Fertility is an important predictor of long-term health-related quality of life in GCT survivors.6 GCT patients undergoing chemotherapy are usually counseled concerning the risks of infertility and offered the opportunity for sperm banking before commencing therapy. However, for some patients this is not possible due to subfertile sperm counts, the emergent need to initiate treatment, or lack of resources. For the azoospermic GCT survivor, donor insemination and adoption have historically been the main reproductive options. In this issue of the Journal of Clinical Oncology, Damani et al report on 23 men, including 12 GCT survivors, with postchemotherapy nonobstructive azoospermia who underwent testis sperm extraction (TESE).7 This assisted reproductive technology, initially developed for conditions such as congenital absence of the vas deferens, resulted in successful retrieval of sperm in approximately two thirds of the patients. In 12 couples, retrievable testis sperm was used for fertilization by intracytoplasmic sperm injection (ICSI) for a total of 26 cycles. Nearly one third of these ICSI cycles led to successful pregnancies, resulting in 10 healthy offspring born to these couples. These data compare favorably with TESE/ICSI in other settings.8 The authors are correct in recommending that TESE should not be considered an alternative to pretreatment sperm banking, a simpler and more established procedure. Rather, it should be considered a reproductive option for the male azoospermic cancer survivor without banked sperm. Whether the results will appear as favorable when TESE/ICSI is applied to a larger pool of azoospermic cancer survivors or is performed at other centers needs to be determined. The authors also offer a cautionary note concerning the need for longer follow-up on the health of children born as a result of this approach. These limitations not withstanding, the report by Damani et al is an important achievement. TESE/ICSI represents the development of an effective intervention for an established treatment-related adverse effect with the potential to improve the long-term well being of the cancer survivor.
For many of the other physiologic adverse effects of cancer treatment, the situation is not so clear. The prevalence and time course for development of certain late effects have not been well defined. In a 1992 editorial in this journal, Bosl wrote "the late complications of GCT therapy are likely to be vascular, subtle, and slow to develop."9 GCT chemotherapy has been associated with Raynaud’s phenomenon,10 and serious vascular complications, including myocardial infarction, stroke, and thromboembolic disease, have been reported.11-13 Some, but not all, studies have suggested that after GCT chemotherapy, patients may be at increased risk for the premature development of hypertension and lipid abnormalities, major cardiovascular risk factors.14-17 However, does GCT chemotherapy result in an increased risk for early cardiovascular events? In one study of GCT patients treated with surgery or surgery plus chemotherapy, no increase in cardiovascular events was noted in the chemotherapy group at a median follow-up of 5 years.18 A more recent study reported an increased risk of cardiovascular events for GCT survivors There are major problems with survivorship research, especially research that evaluates interventions for late effects that may take years to develop. Who will be following the cancer survivor when these adverse effects become manifest? While the oncologist might be the most knowledgeable about the potential late adverse effects of cancer treatment, many survivors may not regularly see an oncologist once the risk of tumor recurrence is unlikely. We suspect (but we know of no available data to prove) that many of these patients are followed by primary care physicians, who may not be fully aware of the details of the patient’s oncologic history and may not be familiar with the long-term sequelae of cancer and its treatment. Other patients may exit the health care system altogether. For uncommon cancers such as GCT, few centers will have enough patients to define a large enough long-term cohort for study, and unless that cohort is complete, biased results will limit the applicability of the research findings. Despite these difficulties, there is a need for the development of effective strategies for late effects research. The approach that has proven somewhat successful in pediatrics is the establishment of centers for the clinical care and research of cancer survivors. In a recent survey, approximately half of respondent members of the pediatric oncology cooperative groups reported that their institution had a long-term follow-up clinic for childhood cancer survivors.19 However, only 15% of the institutions responding to the survey had a formal database for adult survivors. Pediatric oncologists staffed most of these survivorship programs; few programs had adult oncology or primary care physicians involved. The successful development of interdisciplinary clinical and research programs for adult cancer survivors will best result from the collaboration of many institutions, including the cooperative groups, and will require funding by governmental and private organizations. Other promising alternatives for the recruitment of adequate numbers of patients for survivorship research include accessing the tumor registries of the Surveillance, Epidemiology, and End-Results program, the Comprehensive Cancer Centers,20 or consortia such as the Childhood Cancer Survivor Study. The Childhood Cancer Survivor Study is a retrospective cohort study of more than 14,000 long-term survivors of childhood cancer from 25 institutions. Late mortality and second neoplasms in this large cohort have recently been reported.21,22 Since many long-term cancer survivors will be followed by primary care physicians, relationships with primary care colleagues for collaborative research and educational efforts need to be established. Cancer survivorship research that could have an impact on clinical care represents an opportunity for interdisciplinary collaboration between oncologists, primary care physicians, and other subspecialists. The report by Damani et al7 is one example of how research advances can positively change the lives of cancer survivors. However, larger scale research efforts with a special focus on long-term adult survivors of cancer are needed. If we are successful in this endeavor, the best is yet to come for our patients. REFERENCES
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Hewitt M, Breen N, Devesa S: Cancer prevalence and survivorship issues: Analyses of the 1992 National Health Interview Survey. J Natl Cancer Inst 91: 1480-1486, 1999 2. Nachman J, Sather HN, Cherlow JM, et al: Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: A report from the Children’s Cancer Group. J Clin Oncol 16: 920-930, 1998[Abstract] 3. Valagussa P, Santoro A, Bellanni, et al: Absence of treatment-induced second neoplasms after ABVD in Hodgkin’s disease. Blood 59:488-494, 1982
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Petersen PM, Skakkebaek NE, Vistisen K, et al: Semen quality and reproductive hormones before orchiectomy in men with testicular cancer. J Clin Oncol 17: 941-947, 1999
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Stephenson WT, Poirier SM, Rubin L, et al: Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J Clin Oncol 13: 2278-2280, 1995 6. Rudberg L, Nilsson S, Wikblad K: Health-related quality of life in survivors of testicular cancer 3 to 13 years after treatment. J Psychosoc Oncol 18: 19-31, 2000[CrossRef] 7. Damani MN, Masters V, Meng MV, et al: Postchemotherapy ejaculatory azoospermia: Fatherhood with sperm from testis tissue with intracytoplasmic sperm injection. J Clin Oncol 19: 930-936, 2001 8. Gil-Salom M, Romero J, Minguez Y, et al: Testicular sperm extraction and intracytoplasmic sperm injection: A chance of fertility in nonobstructive azoospermia. J Urol 160: 2063-2067, 1998[CrossRef][Medline]
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Bosl GJ: The late effects of germ cell tumor chemotherapy: More data are needed. J Clin Oncol 10: 1375-1376, 1992 10. Vogelzang NJ, Bosl GJ, Johnson K, et al: Raynaud’s phenomenon: A common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med 95: 288-292, 1981 11. Vogelzang NJ, Frenning DH, Kennedy BJ: Coronary artery disease after treatment with bleomycin and vinblastine. Cancer Treat Rep 64: 1159-1160, 1980[Medline] 12. Doll DC, List AF, Greco FA, et al: Acute vascular ischemic events after cisplatin-based combination chemotherapy for germ cell tumors of the testis. Ann Intern Med 105: 48-51, 1986 13. Lederman GS, Garnick MB: Pulmonary emboli as a complication of germ cell cancer treatment. J Urol 137: 1236-1237, 1987[Medline] 14. Gietema JA, Sleijfer DT, Willemse PHB, et al: Long-term follow-up of cardiovascular risk factors in patients given chemotherapy for disseminated nonseminomatous testicular cancer. Ann Intern Med 116: 709-715, 1992
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Raghavan D, Cox K, Childs A, et al: Hypercholesterolemia after chemotherapy for testicular cancer. J Clin Oncol 10: 1386-1389, 1992
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Ellis PA, Fitzharris BM, George PM, et al: Fasting plasma lipid measurements following cisplatin chemotherapy in patients with germ cell tumors. J Clin Oncol 10: 1609-1614, 1992
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Nichols CR, Roth BJ, Williams SD, et al: No evidence of acute cardiovascular complications of chemotherapy for testicular cancer: An analysis of the Testicular Cancer Intergroup Study. J Clin Oncol 10: 760-765, 1992 19. Oeffinger KC, Eshelman DA, Tomlinson GE, et al: Programs for adult survivors of childhood cancer. J Clin Oncol 16: 2864-2867, 1998[Abstract] 20. Pakilit AT, Kahn BA, Petersen L, et al: Making effective use of tumor registries for survivorship research. Cancer 92: 1305-1314, 2001[CrossRef][Medline]
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Mertens AC, Yasui Y, Neglia JP, et al: Late mortality experience in five-year survivors of childhood and adolescent cancer: The Childhood Cancer Survivor Study. J Clin Oncol 19: 3163-72, 2001
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Neglia JP, Friedman DL, Yasui Y, et al: Second malignant neoplasms in five-year survivors of childhood cancer: Childhood Cancer Survivor Study. J Natl Cancer Inst 93: 618-629, 2001 This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50 years of age who had received chemotherapy and were in remission for 10 or more years.
