A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ-cell tumors: final results of a phase III randomized trial

K. Fizazi1,+,§, K.-A. Do1, X. Wang1, L. Finn1, C. J. Logothetis1 and R. J. Amato2

1Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 2Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA

Received 6 April 2001; revised 2 August 2001. accepted 24 August 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: This prospective randomized clinical trial was designed to compare the efficacy of a low-dose regimen of cisplatin, doxorubicin and cyclophosphamide alternated with vinblastine and bleomycin (CISCA/VB) with the original CISCA/VB regimen in patients with disseminated non-seminomatous germ-cell tumors (NSGCT) and a predicted favorable outcome.

Patients and methods

One hundred and twenty-five patients with disseminated NSGCT and a predicted favorable outcome according to the M.D. Anderson Cancer Center classification [testicular primary and human chorionic gonadotropin (hCG) serum level <50 000 mIU/ml] were randomized to receive the original CISCA/VB regimen (100% dose) or a low-dose CISCA/VB regimen (80% dose).

Results

Among the 124 eligible patients, there was no significant difference in the number of patients in the two treatment arms who achieved a complete response to therapy: 53 of 65 patients (82%) on the original CISCA/VB regimen and 53 of 59 patients (90%) on the low-dose CISCA/VB regimen (P = 0.29). Overall, the original CISCA/VB regimen resulted in a significantly higher relative dose intensity (P <0.0001). After a median follow-up of 6.8 years (range 0.37 to 12.94 years), there was no significant difference in disease-free survival (P = 0.87) or in overall survival (P = 0.88) between the two treatment arms. The 5-year overall survival rate was 93.7% [95% confidence interval (CI) 88% to 100%] and 94.1% (95% CI 84% to 100%) in the original CISCA/VB arm and the low-dose CISCA/VB arm, respectively. The 5-year overall survival rate for the entire study population was 98% (95% CI 94% to 100%) and 88% (95% CI 76% to 100%) in the good- and intermediate-prognosis groups, respectively, as defined by the International Germ Cell Consensus Classification Group (IGCCCG). The low-dose CISCA/VB regimen resulted in significantly less neutropenic fever (P <0.001), grade 4 thrombocytopenia (P <0.03) and severe mucositis (P <0.01) than the original CISCA/VB regimen.

Conclusions

CISCA/VB is highly efficient in patients with good or intermediate prognosis NSGCT according to the IGCCCG criteria. Although equivalent antitumor efficacy cannot be claimed, the low-dose CISCA/VB regimen appears to be a better mode of delivery than the original CISCA/VB regimen with respect to toxicity, since survival is comparable.

Key words: chemotherapy, germ-cell tumors, randomized trial


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The cure rates of disseminated germ-cell tumors have improved dramatically since the early 1970s [1, 2]. The curative potential of chemotherapy in patients with this disease was first established with the introduction of vinblastine–bleomycin combination therapy [3], and later with the advent of cisplatin. It is currently recognized that ~80% of patients with disseminated non-seminomatous germ-cell tumors (NSGCT) will eventually be cured. Refinements in prognostic staging lead to the emergence of the International Germ Cell Consensus Classification Group (IGCCCG) in 1997, and this staging system enables researchers to compare clinical trials and is now widely accepted [4]. In patients with NSGCT, assignment to a prognostic group takes into account the primary site (mediastinal versus testicular or retroperitoneal), the degree of tumor marker elevation, and the presence of extra-pulmonary visceral metastases. Treatment of patients assigned to the IGCCCG poor prognosis group remains a challenge for oncologists, and recent studies have focused on the use of high-dose [5] and dose-dense [6] chemotherapy regimens. The dose-dense strategy was developed at M.D. Anderson Cancer Center with promising preliminary results [7]. In contrast, the emphasis of clinical trials in the last 15 years has been reducing the toxicity of chemotherapy in patients with good-risk NSGCT [1, 2].

In the early 1980s, a cyclical chemotherapy regimen was developed at M.D. Anderson Cancer Center that combined two independently effective regimens, cisplatin, doxorubicin and cyclophosphamide (CISCAII) [8] and vinblastine and bleomycin (VBIV) [3]. Initial results obtained with the CISCA/VB regimen in 48 patients indicated a 92% complete response rate [9]. These encouraging results were subsequently confirmed in 1986, in a large study of 100 unselected patients with advanced NSGCT in which an 89% continuous disease-free long-term survival rate was achieved [10]. A stepwise logistical regression analysis showed that patients with human chorionic gonadotropin (hCG) serum level >50 000 mIU/ml and those with an extragonadal primary NSGCT had a poor outcome. These features partially match those of the IGCCC poor-prognosis group. However, with a 73% long-term, disease-free, survival rate, the presence of extra-pulmonary visceral metastases was not found to be an independent factor for poor outcome in this multivariate analysis, in contrast to the IGCCCG. The acute toxicity associated with this regimen is substantial and includes mainly febrile neutropenia and stomatitis [912]. In order to improve tolerance, a randomized study was designed to compare the original CISCA/VB regimen with one with a 20% dose reduction in patients with a good chance for cure according to the M.D. Anderson Cancer Center criteria. Here, we report the final results of this study.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Patients were enrolled in this study between May 1987 and January 1993. Men with a diagnosis of non-seminomatous germ-cell tumor of the testis, evidence of disseminated disease (clinical stage II to stage III-B5 according to Samuels’ modified classification; Table 1), and a serum hCG level <50 000 mIU/ml were eligible. They were retrospectively classified according to the IGCCCG criteria [4]. Excluded from this study were patients infected by the Human Immunodeficiency Virus (HIV) (they are the subject of a separate report), patients with extragonadal NSGCT, patients with pure seminomas with a normal serum {alpha}-fetoprotein (AFP), and patients who had previously undergone chemotherapy. There was no exclusion criterion based on performance status or life expectancy. Signed informed consent forms approved by the Internal Review Board of the M.D. Anderson Cancer Center were obtained from all patients before enrollment.


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Table 1. Modified Samuels’ staging criteria for advanced NSGCT
 
Baseline assessment
Patients were assessed by a review of the histological tumor type and by serum tumor marker assays for hCG, AFP and lactate dehydrogenase (LDH) (both absolute and isoenzymes). Radiographical studies included a chest X-ray, a bipedal lymphangiography and a computed tomography (CT) scan of the pelvis and abdomen. A chest CT scan was performed in cases of suspicious thoracic lesions. Other baseline studies included an audiogram, a gallium scan and an echocardiogram, in addition to a complete blood count with platelet count, and an assessment of electrolytes, testosterone level, and renal and liver function. Additional studies were obtained as warranted by the patient’s clinical presentation.

Treatment
Patients were randomly assigned to receive either the original CISCA/VB regimen (arm A) or the low-dose CISCA/VB regimen (arm B). The dose schedules for the two arms were the same except that the doses of CISCA and VB were reduced by 20% in arm B compared with the doses of arm A. Dose schedules are summarized in Table 2.


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Table 2. Original versus low-dose chemotherapy schedule for CISCA/VB
 
Cyclophosphamide and doxorubicin were given on days 1 and 2 by a rapid intravenous infusion. Cisplatin was delivered over a period of 2 h on day 3 with a simultaneous forced mannitol diuresis, as described previously [13]. Patients were prehydrated and their hydration status was evaluated prior to the initiation of cisplatin. Patients received magnesium sulfate and potassium phosphate supplementation, and other electrolytes were given as required. Calcium was not routinely replaced. The forced mannitol diuresis was continued for 25 h.

After 3 weeks from the start of CISCA and upon recovery from the acute hematological and non-hematological toxicity, patients were readmitted to the hospital and VB was delivered. Vinblastine was delivered for five consecutive days as a continuous infusion via a centrally placed catheter; simultaneously, bleomycin, 30 U/day for five consecutive days, was infused through a separate peripheral Y line as a continuous intravenous infusion. Patients were treated liberally with laxatives in order to reduce constipation and ileus.

Criteria for the initiation for each course of chemotherapy included: (i) absence of active infection; (ii) no mucositis; (iii) absolute granulocyte count >1500/mm3 and a platelet count >100 000/mm3. The minimum interval between courses of chemotherapy was 3 weeks. Prior to each course of CISCA, the following additional criteria were required: no evidence of doxorubicin-induced cardiac toxicity, a creatinine clearance >60 ml/min or a serum creatinine level of less 2 mg/dl. Spirometry was performed before each course of VB. Patients with a reduction in forced-vital-capacity of >10% over baseline did not receive bleomycin. Dose modification due to hematological toxicity was not permitted. In this study, patients did not receive hematological growth factors. Dose reduction was discussed in cases of renal function impairment defined by a creatinine clearance of <60 ml/min.

All patients were scheduled to receive a minimum of four courses of induction chemotherapy. The total number of chemotherapy courses was individualized based on tumor response. Patients received two courses beyond the one in which complete remission was achieved or in which a radiographically stable mass and negative serum biomarkers were established. The disease was staged again after normalization of serum hCG, AFP and LDH. When disease stabilization and tumor marker normalization were obtained, two additional courses of chemotherapy were given, followed by exploratory surgery to remove residual masses. Patients who were found to have viable carcinoma received two courses of salvage chemotherapy.

Response
Patients in whom tumor markers normalized and for whom there was no clinical or radiological evidence of disease were classified as having achieved complete response to chemotherapy (cCR). Patients with normal tumor markers and in whom completely resected residual masses contained only necrosis or mature teratoma were classified as having achieved pathological complete response (pCR). Patients with normal tumor markers and in whom completely resected masses contained viable cancer were classified as having achieved surgical complete response (sCR). Patients in whom tumor markers failed to normalize, although a plateau was reached, were classified as having achieved incomplete response (IR) and were proposed for surgery or salvage chemotherapy. All other responses were considered incomplete responses. Progressive disease (PD) was defined as rising tumor markers confirmed at least twice or the appearance of new lesions, except when pathological evidence of a growing teratoma syndrome [14, 15] was provided.

Dose intensity
The received dose intensity was defined as the ratio of the received dose over time. It was calculated based on the number of cycles actually received. In order to allow comparison between the two arms, the relative dose intensity was calculated as the ratio between the received dose intens-ity and the theoretical dose intensity of arm A (100% dose).

Statistical analysis
The primary endpoint of this study was the proportion of patients having complete response to therapy and being alive and disease-free at 18 months. Based on the previous experience [10] with the original CISCA/VB regimen in patients with stage II to III-B5 disease according to Samuels’ modified classification, it was expected that 90% to 95% of patients randomized to arm A would be alive and disease-free at 18 months. It was considered that the low-dose CISCA/VB arm (arm B) would be an acceptable regimen if it could be demonstrated with 95% confidence that it was, at worst, 15% inferior to arm A, with respect to the primary endpoint of the study. According to the sample-size calculation method of Makuch and Simon [16], it was estimated that a total of 60 patients should be recruited on each arm. The power of the test was pre-determined to be at least 80%.

Patients were stratified according to histology, tumor volume (as defined by the Samuels’ modified classification) and levels of serum tumor markers. By histology, patients were stratified into those with and those without choriocarcinoma in their histology. By tumor volume, patients were stratified into those with minimal disease (stage II to IIIB3) and those with advanced disease (stage III-B4 and III-B5). Tumor marker stratification was performed as follows: serum LDH defined two strata (cut-off = 2.5 x normal value), serum hCG defined two strata (cut-off = 20 000 IU/ml) and serum AFP defined two strata (cut-off = 1000 IU/l).

Comparisons of complete response and toxicity rates between the two arms were made using the Chi-square and the Fisher’s exact tests. Survival curves were generated by the method of Kaplan–Meier. The log-rank test was performed to compare the difference between survival curves. P values <0.05 were considered significant. All analyses were performed using Splus statistical software (Insightful Corporation, Seattle, WA, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
One hundred and twenty-five patients were entered in this study between August 1987 and April 1992. One patient who had a pure seminoma and a false-positive AFP was ineligible. Therefore, 124 patients were considered eligible. Sixty-five and 59 were randomly assigned to arm A and B, respectively. Table 3 lists the characteristics of these patients. The two arms were well balanced with respect to serum tumor marker level, performance status and clinical stage. Sufficient information was available to retrospectively classify all but one patient (due to the lack of an LDH value) using the IGCCCG system. Overall, 76 (61%) patients fell into the IGCCCG good-prognosis group. There was no significant difference between the two arms with respect to the prognosis status based on the IGCCCG classification (P = 0.37).


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Table 3. Patient characteristics
 
Toxicity
Table 4 shows the worst toxicities observed during the whole treatment. Overall, toxicity occurred more often and was more severe in arm A than in arm B. Grade 4 granulocytopenia was universal (100% in arm A and 98% in arm B) and resulted in neutropenic fever in 91% of patients in arm A. In contrast, 37% of patients in arm B did not experience febrile neutropenia (P <0.001). Severe thrombocytopenia (P <0.03) and severe mucositis (P <0.01) also occurred less frequently in arm B compared with arm A. Likewise, severe anemia and a number of non-hematological toxicities, including nausea or vomiting, peripheral neurological toxicity and renal failure, occurred less often in patients who received the low-dose CISCA/VB regimen, although the difference did not demonstrate statistical significance.


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Table 4. Toxicity
 
There was one toxicity-related death (one patient in arm A died of pulmonary toxicity related to bleomycin after three courses of therapy). Seven other patients discontinued therapy because of severe toxicity, including six in arm A and one in arm B [rectal abcess requiring surgical drainage (two), acute renal failure in the context of neutropenic fever (two), phlebitis associated with neutropenic fever (one), pulmonary toxicity (one) and severe exacerbation of a known peptic ulcer of the duodenum (one)]. Moreover, one patient in arm B developed an acute myocardial infarction after two courses of chemotherapy.

Dose intensity
Insufficient hematological status and/or non-hematological toxicity resulted in a significant delay in recycling of chemotherapy in both treatment arms. The median time between courses was 25.1 days (range 21–65 days) in arm A and 23.75 days (range 21–49 days) in arm B. The intervals between courses led to a reduction in relative dose intensity, as shown in Table 5. Overall, the relative dose intensity was significantly higher arm A than in arm B: 0.83 (0.62–0.98) versus 0.71 (0.56–0.78), respectively (P <0.0001).


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Table 5. Relative dose-intensity (DI)
 
Response
Response to therapy is illustrated in Table 6. Eleven patients were not assessable for response. Eight of these unassessable patients were in arm A, and the reasons they were not assessable included severe toxicity (six), toxicity-related death (one) and patient decision to discontinue therapy (one). The remaining three patients were in arm B, and the reasons for which they were unassessable included toxicity (one), myocardial infarction (one) and patient decision to discontinue therapy (one).


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Table 6. Response to therapy
 
Complete response to therapy (cCR, pCR or sCR) was obtained in 53 (82%) patients in arm A and in 53 (90%) patients in arm B. This difference in complete response between the two arms was not significant (P = 0.29).

Survival
All eligible patients were assessable for survival. The median follow-up was 6.8 years (range, 0.37–12.94 years). Disease-free and overall survival curves are shown in Figures 1 and 2, respectively. The 5-year disease-free survival rates were 89.1% (95% CI 82% to 97%) and 89.5% (95% CI 77% to 100%) in arm A and arm B, respectively. The 5-year overall survival rates were 93.7% (95% CI 88% to 100%) and 94.1% (95% CI 84% to 100%) in arm A and arm B, respectively. There was no significant difference in either disease-free survival, which was the primary endpoint of the study (P = 0.87), or overall survival (P = 0.88), between treatment arms. Results of survival by arm and by IGCCCG subgroups are shown in Table 6. Subgroup analysis by IGCCCG allocation showed no statistically significant difference in survival between the two arms (data not shown). The 5-year overall survival rates in the overall population were 98% (95% CI 94% to 100%), 88% (95% CI 76% to 100%) and 83% (95% CI 58% to 100%) with regards to the IGCCCG good-, intermediate and poor-prognosis groups, respectively.



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Figure 1. Disease-free survival.

 


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Figure 2. Overall survival.

 
Only one patient had a late relapse of NSGCT. This patient developed a lombo-aortic relapse 10 years after receiving CISCA/VB and had obtained a pCR teratoma. The patient is currently receiving salvage therapy.

Three patients developed a second neoplasm during the follow-up period. One patient had an adenocarcinoma of the kidney 10 years after therapy for the NSGCT and was rendered disease-free after 2 years of follow-up. Another patient had a metachronous left testicular NSGCT 3 years after therapy for a right NSGCT and was again rendered disease-free with a follow-up of 7 years. The third patient had refractory anemia with excess blasts in transformation 5 years after receiving four courses of the arm A CISCA/VB regimen. Cytogenetic analysis showed a hyperploid clone (51 XY, +2, +8, +9, +14, +21). The patient was rendered disease-free by chemotherapy, and he was still disease-free 4 years after his last follow-up.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study is the largest experience reported to date of the use of CISCA/VB for the treatment of NSGCT. Overall, our data confirm that CISCA/VB is a highly efficient regimen in patients with good or intermediate prognosis according to the IGCCCG, with an overall survival rate of 98% (95% CI 94% to 100%) and 88% (95% CI 76% to 100%), respectively. Previous clinical studies have identified CISCA/VB as a highly efficient regimen and have suggested that this regimen is more efficient than the cisplatin, vinblastine and bleomycin (PVB) regimen, which was developed at approximately the same time [9, 10]. The present trial also clearly indicates that the low-dose CISCA/VB achieves a comparable survival, while substantially reducing the acute morbidity of the regimen.

Since the identification of prognostic factors in NSGCT, many trials have attempted to reduce acute and long-term toxicity in good-risk patients [1729]. The results of these trials have suggested that: (i) cisplatin, etoposide and bleomycin (BEP) has equivalent activity when compared with PVB, but is associated with lower toxicity in good-risk patients [17]; (ii) the number of cisplatin-based courses of therapy can be safely reduced from four to three [18, 19]; (iii) prolonged maintenance chemotherapy (more than four cycles) is not useful in this subset of patients when a complete response has been obtained [20]; and (iv) cisplatin cannot be replaced by carboplatin outside a clinical trial [2123]. A number of randomized trials have also addressed the question of the deletion of bleomycin in regimen targeting good-risk patients [2429]. Although a trend for a higher efficacy was reported in some of these trials in the bleomycin-containing arms [25, 27, 28], some authors recommend restricting bleomycin in patients classified on the IGCCC poor-prognostic group and in some patients who are classified on the intermediate-prognostic group [30]. Preliminary results of the only randomized study that compares three courses of BEP with four courses of EP suggested an equivalent efficacy, although a longer follow-up will be required to make a firm conclusion [29].

On the other hand, concerns about the limitations of a therapeutic de-escalation strategy in a highly curative setting such as NSGCT have been expressed [31]. If a small benefit in survival is indeed related to bleomycin, it is obvious that identification of the benefit may be difficult and would require the accrual of a high number of patients in a randomized trial. Taken together with the fact that disseminated NSGCT is a rare neoplasm, it is likely that a definitive answer will not be provided. With respect to this point, the CISCA/VB regimen provides a relatively safe way to deliver bleomycin. In this regimen, bleomycin is given as a continuous infusion, and both preclinical models and clinical experience have suggested that it might reduce the risk of pulmonary injury [3235]. Indeed, none of 100 patients previously treated with the original CISCA/VB regimen died of bleomycin-related toxicity [10]. In the present trial, although one lung toxicity-related death occurred in the original CISCA/VB arm, none occurred in the low-dose arm. To our knowledge, there has been no report of lung toxicity-related death in patients who received the low-dose CISCA/VB regimen [12], nor was there in a French prospective trial of low-dose CISCA/VB in 90 patients with advanced NSGCT [36]. This latter randomized trial assesses low-dose CISCA/VB in poor-risk patients. Its accrual is closed and preliminary results were shown recently at the 2001 ASCO meeting in San Francisco. So far, there is no significant difference in survival between the two arms. There were two lung toxicity-related deaths in the BEP arm versus none in the CISCA-VB arm. Since the present study was completed, low-dose CISCA/VB has been routinely used in intermediate-volume NSGCT at M.D. Anderson Cancer Center. From 1992 to 1998, 43 consecutive patients received this regimen, and no pulmonary-related death occurred [37]. Therefore, the overall experience accounts for more than 200 patients treated with low-dose CISCA/VB worldwide, and there has been no case of pulmonary-related death so far. The pulmonary-related death rate associated with short-infusion bleomycin-based regimens has been typically 1% in the literature [17, 26, 28, 31]. One may argue that the hematological toxicity of this regimen is too high to justify its use in this population of patients. However, the use of a regimen with less acute hematological toxicity may not be of great advantage if repeated dose of bleomycin and cisplatin is required, since this may result in an increased incidence of long-term toxicity. Philosophically, we have viewed toxicity in highly curable disease differently than settings where palliation is the principal objective of chemotherapy. In this study we may have succeeded in avoiding the potentially severe long-term side effects of chemotherapy such as pulmonary toxicity, cardiac toxicity or nephrotoxicity.

The development of a common staging system by the IGCCCG has provided investigators with a method for comparing results of patients treated in clinical studies [4]. In contrast to risk classification systems developed previously [3, 3840], the IGCCCG identifies three prognostic groups in NSGCT instead of two. So far, there has been no consensus on the most appropriate regimen to be used in the intermediate-risk patient group, although most investigators would probably recommend four cycles of chemotherapy, including cisplatin and bleomycin. In the original publication of the IGCCCG, the 5-year overall survival rate was 91% and 79% in the good- and in the intermediate-risk prognosis groups, respectively, and the results of the CISCA/VB regimen in the present study compare favorably with these results. Indeed, the results of the large prospective experience reported here with the CISCA/VB regimen parallel strikingly those of the POMB/ACE regimen, another alternate multidrug regimen developed at the Charing Cross Hospital, London, UK [41]. In a report of 339 consecutive patients, the overall survival rate stratified by the IGCCCG groups also compared favorably with that expected. However, to date, the POMB/ACE regimen has not been assessed prospectively in a randomized clinical trial. Other alternate and/or dose-dense regimens have been developed in NSGCT, but their results in the IGCCCG intermediate-prognostic group have not been published so far [6]. Only one randomized trial has compared a dose-dense, multidrug regimen with the BEP regimen in a population of poor-risk patients that included some IGCCCG intermediate-risk patients, and no survival difference between the two arms was found [42]. Final results of the French study comparing the CISCA/VB regimen versus 4 BEP are awaited and will be of importance in determining whether the higher hematological toxicity of the CISCA/VB regimen is worthwhile, especially in patients with an intermediate prognosis.

Based on this experience we conclude that the low-dose CICA/VB regimen has a less acute toxicity than the original CISCA/VB regimen. Antitumor efficacy is comparable in the two arms, although equivalence cannot be claimed because this trial was designed to detect a difference of 15% with a power of 80%. In addition, survival rates achieved with CISCA/VB compare favorably with those achieved with other regimens in IGCCCG good- and intermediate-prognostic groups. However, the results of this study do not permit direct comparisons to be made with other regimens. Our results also illustrate the challenges for detecting the modest advances in therapy that will result in a universal cure for these patient groups. The available methodology and the relatively rare occurrence of this disease are such that clinical studies designed in the traditional manner are unlikely to be able to detect modest differences. Therefore, a challenge for investigators in the future to reach a universal cure of patients in these categories will be to develop novel trial designs that may allow detection of modest advances. There is also a need for improved methods to integrate therapies based on objective criteria. Such an approach may result in the codification of the multidisciplinary care of patients with advanced NSGCT.


    Acknowledgements
 
We thank Thelondia N. Wiltz-Everett and Cherie Perez for their excellent assistance in collecting the data.


    Footnotes
 
+ Correspondence to: Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France. Tel: +33-(1)-42-11-42-11; Fax: +33-(1)-42-11-52-30; E-mail: fizazi@igr.fr Back

§ Present address: Institut Gustave Roussy. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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