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Originally published as JCO Early Release 10.1200/JCO.2004.06.923 on August 9 2004 © 2004 American Society of Clinical Oncology.
Early Identification of Therapeutic Failure in Nonseminomatous Germ Cell Tumors by Assessing Serum Tumor Marker Decline During Chemotherapy: Still Not Ready for Routine Clinical UsePeter MacCallum Cancer Center, Melbourne, Australia Serum tumor markers play a vital role in the excellent outcomes now expected for men with testicular cancer. The relative survival for all cases of testicular cancer is approximately 96% at 5 years.1 Serum tumor markers contribute to these excellent outcomes by aiding diagnosis, permitting surveillance alone after orchiectomy as a principal strategy for early-stage nonseminoma, determining prognosis (and therefore optimal treatment) for patients requiring chemotherapy, and allowing early identification of relapse in the post-treatment setting. In this issue of the Journal of Clinical Oncology, Fizazi et al report an analysis of predicted time to normalization of serum tumor markers during the first cycle of chemotherapy in men with metastatic nonseminomatous germ cell tumors (NSGCT).2 The major serum tumor markers, alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG), were considered individually and jointly. Based on a marker value measured before and after the first cycle of chemotherapy, the expected time to reach normal marker levels was predicted, assuming an exponential decline. Patients who had a prolonged predicted time to normal marker values (AFP > 9 weeks or HCG > 6 weeks) had inferior progression-free and overall survival compared with the remaining patients. These differences were predominantly seen in those patients with a poor prognosis as classified by the International Germ Cell Consensus Classification (IGCCC).3 The prognostic value was confirmed in multivariate analyses in this poor-prognosis subgroup. The authors conclude that estimating predicted time to marker normalization is a valuable prognostic tool and could potentially be used to determine an early change in therapy for those patients with poor expected outcomes with initial standard therapy. Indeed, the authors report that this methodology will be incorporated into a multi-institutional clinical trial for poor-prognosis NSGCT, in which patients with a prolonged predicted time to normalization will be randomly assigned to either continue standard chemotherapy or switch to a more intensive regimen.2 Failure of marker values to return to normal after orchiectomy or chemotherapy indicates residual or refractory malignancy (unless another cause is identified). Conversely, values that rapidly return to normal portend a good prognosis. The analysis of Fizazi et al2 aims to further refine our ability to use marker values during chemotherapy to improve identification of patients destined to experience treatment failure. This is potentially of greatest utility in cases that do not fit into either of the categories above, ie, those with marker values that reach normal levels greater than 2 to 3 weeks after starting therapy. A brief review of marker biology is warranted. After complete resection of germ cell tumors, marker levels reduce in an exponential fashion with a half-life for clearance of AFP and HCG from the circulation of approximately 5 to 7 days and 1 to 2 days, respectively.4 After chemotherapy, an increase in marker levels may be seen in the first 7 to 10 days, presumably because of release of marker proteins from lytic neoplastic cells. This increase, or marker surge, is unpredictable, as it only occurs in some cases and the degree of increase is variable.5 A number of studies of marker decline after chemotherapy have suggested that AFP values should halve every 5 to 7 days and HCG values should halve each 2 to 3.5 days after any marker surge has occurred.6,7 After chemotherapy, measured values of AFP and HCG should represent the sum of production of marker by viable malignancy and the amount of marker still present from the original tumor (and any marker surge). Assuming a simple tumor growth kinetic concept in which a similar proportion of viable cells are destroyed by each cycle of chemotherapy,8 and given that three cycles of therapy commonly cure patients with metastatic disease, each cycle of therapy would be expected to remove at least 99.99% of viable tumor (and 99.99% of marker production). Therefore, in the majority of cases, the tumor marker levels after day 10 of the first cycle of chemotherapy should simply reflect biologic clearance of pre-existing levels. How much viable malignancy would need to be present to change this normal pattern of marker decline? If we assume that the marker levels are highest at day 7 of the first cycle and decay with a half-life of 7 days and 3.5 days, then AFP and HCG values will be 2–2 and 2–4, respectively, of their day 7 values at the end of the first 21-day cycle, and 2–5 and 2–10, respectively, of their day 7 values at the end of cycle 2. Using these calculations, to increase AFP values by 30%, at least 8% of the original tumor would need to be viable at the end of cycle 1 and at least 1% at the end of cycle 2. To increase HCG values by 30%, at least 2% of the original tumor would need to be viable at the end of cycle 1 and at least 0.03% by the end of cycle 2. These simplistic calculations indicate that monitoring marker decline is unlikely to be a highly sensitive tool to identify failure of treatment, as the amount of viable tumor needed to impact on the marker levels is much greater than the amount expected to be present in cases destined for cure. The calculations also suggest that monitoring HCG is likely to be more sensitive than AFP. Therefore, it is difficult to explain the findings by Fizazi et al2 on the basis of identification of ongoing marker production by resistant neoplastic cells. A possible alternative explanation for the results is the potential prognostic impact of the marker surge. No assessment for the presence of a marker surge was undertaken in this analysis, as only two values were measured: one before chemotherapy and the second at approximately day 22. De Wit et al5 have separately reported that an increase in AFP, but not HCG, at day 7 after starting chemotherapy had a negative prognostic impact. If a marker surge occurred in cases in Fizazi’s analysis, this would have the effect of prolonging the predicted time to normalization and may be associated with a worse prognosis. This is a potential explanation for Fizazi’s findings, at least for AFP, but, if so, it would suggest that the finding is an epiphenomenon. How do the findings of Fizazi et al2 fit with other published literature in this area? The concept of monitoring the rate of decline of marker values to assess the effectiveness of chemotherapy for NSGCT therapy was reported as early as 1979.9 Since then, numerous reports have been published using varying methodologies and with conflicting conclusions.4,6,7,10-19 Investigators at Memorial Sloan-Kettering Cancer Center (including this author) assessed the half-life of AFP and HCG values between day 7 and the end of the second cycle of chemotherapy and found it was prognostic.7,14,15 The Memorial Sloan-Kettering group have used marker half-life in clinical trials to select patients for high-dose chemotherapy with stem-cell support.20,21 Their most recent analysis was similar to earlier reports, but also took into consideration the IGCCC prognostic category.7 The finding that the prognostic significance was greatest in the IGCCC poor-prognosis group is similar to the result of Fizazi et al. The major criticism of many of these analyses, including the present study, is that they have not adequately demonstrated the discriminative value of the marker decline. If a change in therapy is proposed on the basis of such an assessment, then the appropriate statistical assessment is the same as for a diagnostic test. By including cases in which the early postchemotherapy marker values are normal within the satisfactory group and those with stable or increasing marker levels in the unsatisfactory group, the analyses produce highly significant P values without providing adequate information about which method of analysis or cutoff values are optimal.2,7,14,15,19 In the current report by Fizazi et al,2 cases in which the second measured marker value was normal made up a significant proportion of the satisfactory group and had better survival outcomes than those cases in the satisfactory group with an abnormal second marker value and calculated time to normalization. When other analyses were confined to only abnormal marker values, the ability to predict outcome has been much weaker, and some have failed to show a significant difference in outcome.6,14,16-18 Other criticisms of the methodologies used to analyze marker values during chemotherapy in the published literature include the lack or the inadequacy of multivariate analyses. In the present study, the authors have demonstrated that predicted time to marker normalization and baseline marker values are independently prognostic. However, it is difficult to imagine that there is not a significant interaction between these variables. The baseline marker values were considered as categoric variables in the multivariate analysis, but inclusion as continuous variables may have been more appropriate. In addition, all of the published analyses have been retrospective and fail to provide adequate information about the time interval between the identification of failure by markers analyses as compared with failure by conventional monitoring. Could these methodologic concerns be the sole explanation for the phenomena described by Fizazi et al2 and others in the past? At present, we lack adequate information to be sure, although it seems most likely that monitoring marker decline will be useful, at least in some cases. The optimal methodology to assess marker decline remains unclear. Given our understanding of marker biology, it seems likely that monitoring over two cycles is likely to be better than a single cycle. This is supported by analyses of marker half-life using similar methodology over one or two cycles and finding greater prognostic impact in the latter.6,16,17 A comparison of early versus late AFP half-life was more sensitive than a single best-fit half-life in the postsurgery setting,22 but this methodology has not been reported in a large series after chemotherapy. Hopefully, prospective data collected as part of a recently completed trial for intermediate and poor-prognosis patients (National Cancer Institute Trial T94-0086D) will clarify the issue. If these data are to be conclusive, they should exclude cases in which outcome can be predicted clinically, such as those that have normal marker values soon after the start of chemotherapy. The analysis should report the positive and negative predictive value as well as the sensitivity and specificity of the method used to predict failure, rather than a P value for differences in outcome. If adequate numbers are available, the analysis should compare differing methods to assess marker decline and different cutoff values used to distinguish satisfactory from unsatisfactory decline. Finally, the report should include information about the time interval between prediction of failure and the diagnosis of failure by conventional means. If the results are positive, they may need to be compared with other promising methods of assessment of early response, including functional imaging.23,24 What conclusions can the practicing clinician draw from these complex data to improve management decisions? As has been recommended for many years, it remains valuable to monitor marker levels regularly during chemotherapy. Many experienced clinicians measure marker values at least weekly while they remain abnormal and find it easiest to follow changes by plotting the values on a semi-logarithmic graph. In this way, a plateau in the decrease of marker values or an increase in levels can be detected early; these incidents generally indicate treatment failure and warrant a change in treatment. Changes in therapy based only on the predicted time to normalization described by Fizazi et al2 or other previously reported methods to assess marker decline are not yet warranted in clinical practice outside a clinical trial setting. Hopefully, further clarity about this issue will occur with prospective data from clinical trials. In the meantime, the practicing clinician should be aware that the available evidence suggests that a potentially more important intervention for patients with high marker levels (and an attendant worse prognosis) is to ensure treatment at a center where a large number of similar cases are managed.25,26 Author’s Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Ries LAG, Eisner MP, Kosary CL, et al: SEER cancer statistics review, 1975-2001. Bethesda, MD, National Cancer Institute. http://seer.cancer.gov/csr/1975_2001/
2. Fizazi K, Culine S, Kramar A, et al: Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis non-seminomatous germ-cell tumors. J Clin Oncol 22:3868-3876, 2004
3. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594-603, 1997 4. Lange PH, Vogelzang NJ, Goldman A, et al: Marker half-life analysis as a prognostic tool in testicular cancer. J Urol 128:708-711, 1982[Medline] 5. de Wit R, Collette L, Sylvester R, et al: Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance. Br J Cancer 78:1350-1355, 1998[Medline] 6. Gerl A, Lamerz R, Clemm C, et al: Does serum tumor marker half-life complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors. Clin Cancer Res 2:1565-1570, 1996[Abstract]
7. Mazumdar M, Bajorin DF, Bacik J, et al: Predicting outcome to chemotherapy in patients with germ cell tumors: The value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy. J Clin Oncol 19:2534-2541, 2001 8. Skipper HE: Kinetics of mammary tumor cell growth and implications for therapy. Cancer 28:1479-1499, 1971[CrossRef][Medline] 9. Thompson DK, Haddow JE: Serial monitoring of serum alpha-fetoprotein and chorionic gonadotropin in males with germ cell tumors. Cancer 43:1820-1829, 1979[CrossRef][Medline]
10. Vogelzang NJ, Lange PH, Goldman A, et al: Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors. Cancer Res 42:4855-4861, 1982 11. Picozzi VJ Jr, Freiha FS, Hannigan JF Jr, et al: Prognostic significance of a decline in serum human chorionic gonadotropin levels after initial chemotherapy for advanced germ-cell carcinoma. Ann Intern Med 100:183-186, 1984 12. Horwich A, Peckham MJ: Serum tumour marker regression rate following chemotherapy for malignant teratoma. Eur J Cancer Clin Oncol 20:1463-1470, 1984[CrossRef][Medline]
13. Carl J: Drug-resistance patterns assessed from tumor marker analysis. J Natl Cancer Inst 81:1631-1639, 1989
14. Toner GC, Geller NL, Tan C, et al: Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous germ cell tumors. Cancer Res 50:5904-5910, 1990 15. Murphy BA, Motzer RJ, Mazumdar M, et al: Serum tumor marker decline is an early predictor of treatment outcome in germ cell tumor patients treated with cisplatin and ifosfamide salvage chemotherapy. Cancer 73:2520-2526, 1994[CrossRef][Medline]
16. Stevens MJ, Norman AR, Dearnaley DP, et al: Prognostic significance of early serum tumor marker half-life in metastatic testicular teratoma. J Clin Oncol 13:87-92, 1995 17. de Wit R, Sylvester R, Tsitsa C, et al: Tumour marker concentration at the start of chemotherapy is a stronger predictor of treatment failure than marker half-life: A study in patients with disseminated non-seminomatous testicular cancer. Br J Cancer 75:432-435, 1997[Medline] 18. Gerl A, Lamerz R, Mann K, et al: Is serum tumor marker half-life a guide to prognosis in metastatic nonseminomatous germ cell tumors? Anticancer Res 17:3047-3049, 1997[Medline] 19. Inanc SE, Meral R, Darendeliler E, et al: Prognostic significance of marker half-life during chemotherapy in non-seminomatous germ cell testicular tumors. Acta Oncol 38:505-509, 1999[CrossRef][Medline]
20. Motzer RJ, Mazumdar M, Gulati SC, et al: Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst 85:1828-1835, 1993
21. Motzer RJ, Mazumdar M, Bajorin DF, et al: High-dose carboplatin, etoposide and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Clin Oncol 15:2546-2552, 1997 22. See WA, Cohen MB, Hoxie LD: Alpha-fetoprotein half-life as a predictor of residual testicular tumor: Effect of the analytic strategy on test sensitivity and specificity. Cancer 71:2048-2054, 1993[CrossRef][Medline]
23. Spaepen K, Stroobants S, Dupont P, et al: Early restaging positron emission tomography with 18F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 13:1356-1363, 2002
24. Kostakoglu L, Coleman M, Leonard JP, et al: PET predicts prognosis after 1 cycle of chemotherapy in aggressive lymphoma and Hodgkin’s disease. J Nucl Med 43:1018-1027, 2002
25. Collette L, Sylvester RJ, Stenning SP, et al: Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma: European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 91:839-846, 1999
26. Feuer EJ, Sheinfeld J, Bosl GJ: Does size matter? Association between number of patients treated and patient outcome in metastatic testicular cancer. J Natl Cancer Inst 91:816-818, 1999
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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