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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

From the Department of Epidemiology and Biostatistics and the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Weill Medical College, Cornell University, New York, NY.

Address reprint requests to Madhu Mazumdar, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 44, New York, NY 10021; email: mazumdar{at}biost.mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The prognostic significance of the rate of decline of the serum tumor marker alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) during the first two cycles of chemotherapy in germ cell tumor (GCT) patients was initially reported by us, but its value has been debated. We re-examined this issue in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system and investigated the role of including in the analysis patients whose markers normalized early.

PATIENTS AND METHODS: One hundred eighty-nine GCT patients with elevated AFP/HCG marker values treated with platinum-based chemotherapy between 1986 and 1998 were included in this analysis. Patients were classified as good, intermediate, or poor risk by the IGCCCG criteria and as having satisfactory or unsatisfactory marker decline. Risk and marker decline were correlated with response, event-free survival, and overall survival.

RESULTS: Satisfactory marker decline predicted improved complete response (CR) proportion and event-free and overall survival (P < .0001). The CR proportion, 2-year event-free, and 2-year overall survival rates for patients with a satisfactory and unsatisfactory marker decline were 92% versus 62%, 91% versus 69%, and 95% versus 72%, respectively. Marker decline remained a significant variable for all three end points when adjusted for risk (P < .01) with the outcome differences most pronounced in the poor-risk group.

CONCLUSION: The rate of marker decline during chemotherapy has prognostic value independent of risk and may play a significant role in the management of poor-risk patients. It is appropriate to include patients whose markers normalized early.

	INTRODUCTION

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GERM CELL tumors (GCT) in men are cured in more than 90% of previously untreated patients and in 70% to 80% of patients with advanced disease requiring initial chemotherapy.¹ Clinical research over the last 15 years has attempted to identify the 20% to 30% of patients with advanced GCT who do not achieve complete remission (CR) and ultimately die of disease. Several classification algorithms^2-11 have been developed and used to group patients into good- and poor-risk categories and target therapy accordingly. The most recent and comprehensive risk classification system was developed by the International Germ Cell Cancer Collaborative Group (IGCCCG).¹²

The IGCCCG classification allocates patients into three risk groups based on the likelihood of achieving a CR. Risk stratification strategies have allowed the study of therapies directed to reducing toxicity without compromising efficacy in good-risk patients, and to increasing efficacy with tolerable toxicity in intermediate- and poor-risk patients. However, in approximately 10% of good-risk patients, 20% of intermediate-risk patients, and 50% of poor-risk patients, treatment fails to achieve a durable CR. Therefore, it is essential to identify those patients in whom therapy is likely to fail, especially for the intermediate- and poor-risk groups, to allow the treating physician the option of changing to a more intensive therapy when a patient’s tumor is not responding, instead of completing the standard treatment course.

The serum concentrations of alpha-fetoprotein (AFP) and/or human chorionic gonadotrophin (HCG) are elevated in 80%¹³ of patients with metastatic GCT; therefore, serial monitoring of serum levels is important in patient management. Persistently elevated levels of either AFP or HCG or both at the conclusion of chemotherapy are recognized to represent residual viable disease, even in the absence of radiographic or clinical evidence. Effective treatment is expected to cease marker production with some initial abrupt increase.^14-16 Half-lives of AFP and HCG after complete surgical excision are approximately 5 days and 1 to 2 days, respectively.¹⁷ A significant deviation in the expected half-lives of AFP and HCG is considered to be approximately 7 days and 3 to 3.5 days, respectively.^13,17-25 Half-lives greater than these values are indicative of treatment failure.

Others and we have previously reported that the posttherapy rate of decline in marker concentration is predictive of outcome in studies of GCT surgical patients¹⁷ and previously untreated^18,21,22,26 and previously treated¹⁹ patients with GCT receiving chemotherapy. The significance was maintained after adjusting for risk categorization defined by Memorial Sloan-Kettering Cancer Center (MSKCC)² or Medical Research Council criteria.¹⁰ However, this observation has failed to be confirmed by others or has found marginal significance.^20,23,24 The current study provides strong evidence of the independent prognostic value of marker decline in the presence of the IGCCCG classification system using a data set independent of our previous publications. The question of whether to include in analyses patients whose markers normalize early is addressed.

	PATIENTS AND METHODS

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Eligibility Criteria
Between 1986 and 1998, 415 patients with testicular/retroperitoneal or mediastinal GCT were treated with conventional dose, platinum-based chemotherapy at MSKCC. Of these 415 patients, 202 did not have an elevated baseline HCG level ( > 10 miu/mL) or an elevated baseline AFP level ( > 15 ng/mL). This resulted in the selection of 213 patients who had at least one marker elevated from four prospective MSKCC good- and poor-risk protocols^27-29 (173 patients), including patients in a small randomized trial of cisplatin + etoposide (EP) versus carboplatin + etoposide for good-risk patients that was stopped early, or those who had received standard chemotherapy with EP alone (40 patients). All patients’ chemotherapy regimen contained etoposide, except for four who received vinblastine.

The serum tumor marker values between day 7 and day 56 (approximate completion day of cycle two) were used for these analyses. Markers between day 1 and day 7 were excluded because of the possibility of an unpredictable increase in serum tumor marker levels during the initial days of chemotherapy.^14-16 Restriction of the data to two cycles was required because the purpose of the analysis was to assess the rate of decline as an early indicator of treatment outcome with the intent to change treatment, if such a change was indicated. This criterion reduced the total number of patients to 189. Therefore, these 189 patients met the following eligibility criteria: (1) an elevated serum HCG level ( > 10 miu/mL) or an elevated serum AFP level ( > 15 ng/mL) at the time of initiation of chemotherapy, (2) assessable for response and survival, and (3) had a sufficient number of post-treatment marker values to determine marker regression (a minimum of two elevated serum tumor marker values was needed for half-life calculation). Of the 189 patients, there were 140 patients for whom AFP was elevated and AFP marker decline could be determined and 105 patients in which this was true for HCG.

The treatment regimens for the 189 patients were as follows: four cycles of EP in 101 patients; four cycles of carboplatin + etoposide in 70 patients; three cycles of vinblastine, cyclophosphamide, dactinomycin, bleomycin, and cisplatin in four patients; and four cycles of etoposide, ifosfamide, and cisplatin in 14 patients.

IGCCCG Classification
The IGCCCG classification was retrospectively used to classify patients into three risk groups based on histology (seminoma v nonseminoma), primary site (mediastinal v gonadal/retroperitoneal), presence of nonpulmonary visceral metastases (liver, brain, or bone), and levels of the serum tumor markers AFP, HCG, and lactate dehydrogenase.¹² The data set consisted of 55% good-risk, 33% intermediate-risk, and 12% poor-risk patients.

Serum Tumor Marker Assay
HCG was assayed using a modification of the double-antibody radioimmunoassay procedure.³⁰ The standard HCG for this assay was obtained from the National Institute of Arthritis, Metabolism and Digestive Disease (standard CR117). The antiserum against the purified beta subunit was prepared in rabbits. Minimally elevated values of HCG can be false-positive in patients who are disease free;³¹ a value of greater than 10 ng/mL was considered elevated. AFP was assayed using a sandwich-enzyme immunoassay method from Hybritech (San Diego, CA). Both the capture and signal antibodies were monoclonal. An AFP of greater than 15 ng/mL was considered elevated.

Definition of Marker Decline
The marker half-life was calculated using the method previously described.¹⁷ A logarithmic transformation (natural log to the base e) of all elevated marker values between days 7 and 56 were regressed over time and the slope coefficient (M) from the linear regression was obtained. The slope was then used to calculate the serum tumor marker half-life as follows: T_1/2 = -0.693/M. A calculated satisfactory (CS) marker decline was defined as a half-life 7 days for AFP or 3.5 days for HCG. Those patients in whom the first or second postchemotherapy marker value was normal were categorized as automatically satisfactory (AS). A patient was considered to have satisfactory AFP or satisfactory HCG marker decline if they were categorized as either AS or CS for that marker. An unsatisfactory (US) decline was defined as a calculated half-life of more than 7 days for AFP or more than 3.5 days for HCG. In addition, those for whom marker values were increasing were considered to have US decline. AFP half-life calculations were performed in 53 patients, 22 of whom had two marker values measured and 31 had more than two. HCG half-life calculations were performed in 13 patients, seven of whom had two marker values measured and six had more than two. AFP and HCG marker values were increasing for one patient each. Overall marker decline was defined as satisfactory if both markers demonstrated satisfactory decline (AS or CS) or if one marker had a satisfactory decline and the other was not elevated at baseline, and as US if one or both markers demonstrated a slow decline. Overall marker decline status could not be determined for eight patients because no AFP values were measured and their HCG decline was satisfactory.

Outcome Definitions
Standard MSKCC response criteria were used. Response was categorized as either a complete response (CR) or incomplete response (IR). CR to chemotherapy alone was defined as complete disappearance of all clinical, radiographic, and biochemical findings of GCT after either chemotherapy alone or chemotherapy and surgical resection of residual tumor with the pathologic analysis revealing only necrotic debris, fibrosis, or mature teratoma. CR to chemotherapy plus surgery required complete resection of a postchemotherapy tumor mass with viable malignant GCT (other than teratoma) in one or more specimens and negative markers and margins. All responses less than CR were considered IR. Overall survival was calculated from the time the patient had satisfactory markers or a prolonged half-life to the last day of follow-up or death. Event-free survival was calculated from this same time point until the first event. An event was defined as a relapse or death for patients achieving a CR and death for patients achieving an IR. In the analysis of overall marker decline, if both AFP and HCG were elevated, event-free and overall survival were calculated from the later of the two dates.

Statistical Methods
The relationship between response (CR versus IR) and AFP, HCG, and overall marker decline (satisfactory v US) were investigated using Fisher’s exact test.³² Survival and event-free survival curves were estimated by the Kaplan-Meier method³³ and univariate comparisons were made using the log-rank test³⁴ or the Wilcoxon rank sum test.³⁵ A permutation test based on the log-rank statistic was used when the total sample size was less than 30.³⁶ Logistic regression³⁷ was used to study whether satisfactory overall marker decline was an independent prognostic factor for response and the Cox proportional hazards model³⁸ was used to study the same issue for event-free and overall survival. All analyses were performed using SAS (SAS/STAT User’s Guide [ed 4]; Cary, NC, SAS Institute, 1990).

	RESULTS

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Patient characteristics for the whole group as well as for the three risk groups are presented in Table 1. The overall proportion of CR was 85% and the median follow-up for the survivors was 71 months (range, four to 145). Of the 189 patients treated with cisplatin-based therapy, 148 (78%) had an elevated AFP, 105 (56%) had an elevated HCG, and 64 (34%) had an elevation in both markers. Of the 140 patients in the AFP analysis, 116 (83%) had satisfactory AFP decline, 86 of whom had a normal first or second AFP value (AS). Of the 105 patients in the HCG analysis, 99 (94%) had satisfactory HCG decline, 91 of whom had a normal first or second HCG value (AS). The overall marker decline was satisfactory in 152 out of 181 (84%) and US in 29 (16%) patients.

View larger version (19K): [in this window] [in a new window]   Fig 1. Survival of patients according to satisfactory or unsatisfactory (A) AFP, (B) HCG, and (C) overall marker decline. Tick mark (1) indicates last follow-up.

View larger version (20K): [in this window] [in a new window]   Fig 2. Survival for (A) good-, (B) intermediate-, and (C) poor-risk patients according to satisfactory or unsatisfactory overall marker decline. Tick mark (1) indicates last follow-up.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The current study confirms our previous work in which we showed that, in addition to risk group defined by MSKCC criteria,² a satisfactory marker decline during the first two cycles of platin-based chemotherapy is predictive of an improved complete response and overall survival.¹⁸ Several smaller but methodologically weak studies in the 1980s also suggested this phenomenon.^15-17,26 Other trials in the 1990s showed mixed results.^18-24 Possible explanations for these differences are small sample size, the various patient populations considered, the time span in which markers were measured, and a variety of definitions of satisfactory marker decline.

It has been suggested that those patients whose markers have normalized by the second measurement point should not be included in a marker decline analysis,^20,23 because they are an inherently better group of patients. It is our goal to use the concept of marker decline as an additional tool for directing treatment strategies for the entire cohort of patients treated with an active chemotherapy. Hence, we feel that the tool needs to be developed from the data collected on the whole cohort of patients and not from a subgroup of patients. We have addressed this issue, however, by including an analysis that divides patients with a satisfactory decline into two categories: those whose markers have declined to normal by their second measurement, and those whose marker decline was determined to be satisfactory according to a half-life calculation. We found that, although there is a statistically significant difference between these two groups in terms of survival, after adjusting for risk group, this difference dissipates. This observation prompts us to conclude that if the patient population is treated with the appropriate treatment regimen according to the IGCCCG risk classification, there is no need to distinguish between the patients with normalizing markers and those with a satisfactory decline based on a calculated half-life when making further treatment decisions.

The time frame in which markers should be collected and analyzed to determine marker decline status has been debated. Some studies have used only the marker values in the first cycle. We feel that it is important to include marker values from the first two cycles of chemotherapy. This interval allows the treatment an adequate amount of time to be effective so that the marker values are an accurate assessment of the patient’s residual disease. In addition, an appropriate evaluation of marker decline requires a sufficient number of samples to be certain that the half-life marker assessment is reliable. It is suggested that markers be evaluated at weekly intervals to estimate half-life accurately. In some patients, there is an unpredictable increase in serum marker levels (surge effect) immediately after the start of the therapy, perhaps due to tumor cell death and intracellular protein release into the systemic circulation.^14-16 Therefore, the marker values in the first week of treatment should be excluded from the marker decline analysis.

Observation of US marker decline after two cycles of chemotherapy can be used for directing treatment strategies. If a patient’s marker decline is found to be prolonged, a change to a more intensive therapy could prove beneficial. This strategy was used in two prospective clinical trials using marker decline as an eligibility criterion. In these phase II trials of first-line therapy for patients with poor-risk GCT,^28,39 levels of AFP and HCG were obtained frequently during the first two cycles of the chemotherapy regimen. If the marker decline was prolonged, therapy was changed to two cycles of high-dose chemotherapy and autologous bone marrow transplant. Otherwise the patient completed standard therapy. These trials^28,39 found that when serum tumor marker half-life was used to predict resistance to standard therapy, a better outcome was achieved compared with historical controls by including high-dose chemotherapy in the regimen. Moreover, the toxicity of the high-dose therapy was less when administered as part of first-line therapy, compared with the toxicity observed when the same or similar high-dose therapy was administered as third-line salvage therapy. The results of these two trials provided the preliminary data for an ongoing, randomized, multi-institutional, phase III trial of two cycles of bleomycin, etoposide, and carboplatin (commonly referred to as BEP), followed by two cycles of high-dose chemotherapy versus four cycles of BEP alone for previously untreated patients with poor- and intermediate-risk GCT (National Cancer Institute T94-0086; Southwest Oncology Group 94-42; Eastern Cooperative Oncology Group 38-94; Cancer and Leukemia Group B 99-812; and MSKCC 94-76). One of the objectives of the trial is to evaluate prospectively the rate of decline of AFP and HCG drawn weekly. This data set will be used for prospective validation of the results of the current study.

In the current study, the separation of outcomes was most pronounced in the poor-risk group. Specifically, there were 51%, 23%, and 40% differences in response proportion, 2-year event-free survival, and 2-year overall survival, respectively, between the satisfactory and US poor-risk patients. Caution should be practiced when interpreting these differences, because they are based on limited sample sizes. Despite this issue, the use of marker decline for directing treatment could be of great consequence, because therapy fails in 50% of these patients.

A weakness of the study is its retrospective nature. Data obtained from the above-mentioned ongoing phase III trial will resolve that issue. It is important to note that the results reported herein are not applicable to patients who do not have elevated baseline markers. Even though a normal marker level is generally a good prognostic feature, a small proportion of these patients succumbs to disease. New markers based on protein expression assayed by immunohistochemistry or molecular markers are needed to better identify drug resistance.

In conclusion, this study provided significant evidence of the prognostic importance of serum tumor marker decline. Our results were further strengthened by the continued significance of marker decline after adjustment for risk status defined by the most comprehensive IGCCCG risk criteria.

	ACKNOWLEDGMENTS

 
Supported in part by grant nos. CA-05826 and CA-60126 from the Cancer Chemotherapy Program Project and the Byrne Foundation.

We thank Linda Marks and Elyn Riedel for sharing their in-depth knowledge of the structure of the database and their skills in data extraction.

	NOTES

 
Presented at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

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Submitted July 5, 2000; accepted February 7, 2001.

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