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Originally published as JCO Early Release 10.1200/JCO.2005.11.951 on February 28 2005 © 2005 American Society of Clinical Oncology.
Hidden by HIPAA: The Costs of CureCleveland Clinic Taussig Cancer Center, Cleveland, OH In the second half of the last century, there were dramatic improvements in the management of advanced cancers of the genitourinary tract, with particular progress in the management of germ cell tumors. The management of metastatic testicular germ cell tumors has become one of the paradigms of successful cancer treatment, reflecting progress in the development of chemotherapy and an improved understanding of the principles of tumor biology, and of the importance of multidisciplinary management. With increasing experience, we have come to recognize that these approaches to treatment have some flaws, particularly with respect to the creation of late iatrogenic effects, and this has become the focus of intense scrutiny. An increased understanding of risk factors has allowed us to tailor our treatments to the level of risk, such as reducing the number of cycles of chemotherapy required for good-risk metastatic disease, based on randomized trial data. We have attempted to avoid some of the late complications of treatment by modifying some treatment approaches. However, some of these attempts to improve treatment outcomes by reducing toxicity have failed, largely because of a reduction in the initial cure rate—for example, the attempt to avoid the nephrotoxicity of cisplatin by the introduction of carboplatin, or the attempt to omit bleomycin from standard treatment because of concerns about late pulmonary effects. This serves to illustrate simply a critically important principle—when effective treatment is available, modifications must be introduced with a thoughtful and structured approach that ensures that there are no hidden costs associated with the innovations under consideration. The acute toxicities of chemotherapy have been well defined, and include the potential for nausea and vomiting, myelosuppression, alopecia, allergic phenomena, pneumonitis, infection, anorexia, and a range of relatively uncommon complications, as reviewed elsewhere.1 Most of these can be controlled by modern supportive techniques. As noted by Nuver et al in this issue of the Journal of Clinical Oncology,2 the chronic or delayed adverse effects of treatment are now becoming increasingly recognized, especially as the medical community has become used to the concept of germ cell tumors as a curable entity, and the focus is now shifting to the avoidable costs of such cure. Of particular concern is an emerging recognition of an apparent increase in the prevalence of cardiovascular and cerebrovascular disease, hypercholesterolemia, hypertension, Raynaud's phenomenon, and a range of subtle metabolic abnormalities after cisplatin-based chemotherapy.1-10 The so called metabolic syndrome, a combination of hypertension, central obesity, and dyslipidemia, is associated with an increased risk of cardiovascular disease, and seems to provide a unifying mechanism for the various vascular phenomena that occur after chemotherapy for testis cancer. This is potentially of particular importance in subjects without smoking histories, perhaps providing a unique model of the evolution of vascular disease. Furthermore, this syndrome may provide a mechanism to explain the increased prevalence of osteoporosis in cured patients with germ cell tumors (Raghavan et al, submitted for publication). Another area of concern is the emerging prevalence of second malignancies, including leukemia, soft tissue sarcoma, malignant melanoma, and other solid tumors.8,11-16 The basis of this phenomenon is not completely clear, but may include carcinogenicity of some chemotherapy drugs, such as alkylating agents,11 outgrowth from pluripotential stem cells or evolution from teratomatous elements, and the association of premalignant lesions of other tissues with the presence of germ cell tumors (for example, the association of multiple atypical nevi with germ cell tumors).17 This is further complicated by the relatively recent documentation of the phenomenon of late germ cell tumor relapse, with outgrowth from elements of metastatic immature teratoma that have not been surgically resected. As some of these problems have been identified in surveys of patients only 5 to 10 years after treatment, it is possible that the reported prevalence figures are low, and will increase with the duration of follow-up, or that other unsuspected problems will emerge even later. As a consequence, the continuation of careful and focused follow-up will be essential for these patients, despite the efforts of many health insurance organizations to reduce structured specialist follow-up by returning the care of these patients to their general practitioners and internists. As the population of cured patients after chemotherapy and radiotherapy is rapidly growing, the health care system will have to create vehicles that will provide optimal care for them, including rationalized programs of surveillance for likely late complications (Table 1)18 and the formal assessment of whether early diagnosis and intervention will improve mortality and morbidity of these conditions. Similarly, government will need to prepare itself for this situation. In the current climate, there are clear disincentives for "well" patients to seek screening programs for fear that they will be labeled as "unwell" and bear the consequences imposed by health insurance payers. Similarly, the complexities and uncertainties of interpreting the Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations are already interfering with our ability to monitor and screen patients for late effects. In our recent study, supported by the Surveillance, Epidemiology, and End Results (SEER) program and the Lance Armstrong Foundation, final resolution of on-treatment information was inhibited by failure to disclose information regarding management of survey patients by numerous hospitals and medical practices, despite availability of written informed consent, thus precluding final analysis and publication.
We must be gratified by the extraordinary progress in the management of germ cell tumors that has been achieved in just 25 years. We must not withhold life-saving treatment simply because of the theoretical risks of late complications. However, it does behoove us to study our management paradigms very closely, to identify risk factors for late complications, and to make structured decisions about treatment modification that do not reduce the initial cure rate, but which may ameliorate the pattern of late effects. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
REFERENCES 1. Horvath L, Boyer MJ: Acute toxicity of chemotherapy,.in Raghavan D (ed), American Cancer Society Atlas of Clinical Oncology: Germ Cell Tumors. London, United Kingdom, BC Decker, Hamilton, Canada, 2003, pp 340-348 2. Nuver J, Smit AJ, Wolffenbuttel BH, et al: The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 23:10.1200/JCO.2005.02.176
3. Raghavan D, Cox K, Childs A, et al: Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol 10:1386-1389, 1992
4. Boyer M, Raghavan D, Harris PJ, et al: Lack of late toxicity in patients treated with cisplatin-containing combination chemotherapy for metastatic testicular cancer. J Clin Oncol 8:21-26, 1990 5. Bokemeyer C, Berger CC, Kuczyk MA, et al: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14:2923-2932, 1996[Abstract] 6. Nord C, Fossa SD, Egeland T: Excessive annual BMI increase after chemotherapy among young survivors of testicular cancer. Br J Cancer 88:36-41, 2003[CrossRef][Medline] 7. Gietema JA, Meinardi MT, van der Graaf WT, et al: Syndrome X in testicular cancer survivors. Lancet 357:228-229, 2001
8. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000
9. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003
10. Bosl GJ, Leitner SP, Atlas SA, et al: Increased plasma renin and aldosterone in patients treated with cisplatin-based chemotherapy for metastatic germ-cell tumors. J Clin Oncol 4:1684-1689, 1986 11. Pedersen-Bjergaard J, Daugaard G, Hansen SW, et al: Increased risk of myelodysplasia and leukemia after etoposide, cisplatin and bleomycin for germ-cell tumours. Lancet 338:359-363, 1991[CrossRef][Medline]
12. Van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout A, et al: Second cancer risk following testicular cancer: A follow-up study of 1909 patients. J Clin Oncol 11:415-424, 1993 13. Segelov E, Raghavan D, Coates A, et al: Acute leukemia following chemotherapy including etoposide for testicular carcinoma. Aust N Z J Med 23:718-719, 1993[Medline]
14. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89:1429-1439, 1997 15. Boyer MJ, Roth BJ: Toxicity of treatment of germ cell tumors, in Raghavan D, Scher HI, Leibel S, et al (eds): Principles and Practice of Genitourinary Oncology. Philadelphia, PA, Lippincott, 1997, pp 754-764 16. Kaldor JM, Day NE, Band P, et al: Second malignancies following testicular cancer, ovarian cancer and Hodgkin's disease: An international collaborative study among cancer registries. Int J Cancer 39:571-585, 1987[Medline]
17. Raghavan D, Zalcberg J, Grygiel JJ, et al: Multiple atypical nevi: A cutaneous marker of germ cell tumors. J Clin Oncol 12:2284-2287, 1994 18. Raghavan D: Follow up of the patient with testicular cancer, in Johnson FS, Virgo K (eds): Cancer Patient Follow Up. St Louis, MO, Mosby-Year Book, 1995
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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