Fédération Nationale des Centres de Lutte Contre le Cancer, 101 rue de Tolbiac, 75 013 Paris, France
Departments of Medical Oncology, 1Hôpital Tenon, Paris, 2 Institut Bergonié, Bordeaux, 4 Institut Gustave Roussy, Villejuif, 5 Centre Oscar Lambret, Lille, 6 Institut Paoli-Calmette, Marseille, 7 Centre Paul Papin, Angers, 8 Centre François Baclesse, Caen, 9 Centre Paul Strauss, Strasbourg, 10 Hôpital d'Instruction des Armées, Clamart, 11 Centre Jean Perrin, Clermont-Ferrand, 12 Centre Léon Bérard, Lyon, 13 Centre Val d'Aurelle, Montpellier; 3 Biostatistical Unit, Centre Léon Bérard, Lyon, France
* Correspondence to: Professor J.-P. Lotz, Hôpital Tenon, Assistance PubliqueHôpitaux de Paris, 4 rue de Chine, 75 970 Paris cedex 20, France. Tel: +33-1-56-01-60-58; Fax: +33-1-56-01-68-75; Email: jean-pierre.lotz{at}tnn.ap-hop-paris.fr
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Abstract |
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Materials and methods: Patients with relapsed poor-prognosis GCTs were scheduled to receive two cycles combining epirubicin and paclitaxel (Taxol) followed by three consecutive HD-CT supported by stem cell transplantation [one course combining cyclophosphamide, 3 g/m2 + thiotepa, 400 mg/m2, followed by two ICE regimens (ifosfamide, 10 g/m2, carboplatin, AUC 20, etoposide, 1500 mg/m2)].
Results: From March 1998 to September 2001 (median follow-up, 31.8 months), 45 patients (median age, 28 years) were enrolled in this phase II study. Twenty-two patients received the complete course. Twenty-five patients died from progression and five from toxicity. The overall response rate was 37.7%, including an 8.9% complete response rate. The median overall survival was 11.8 months. The 3-year survival and progression-free survival rate was 23.5%. The Beyer prognostic score predicted the outcome after HD-CT.
Conclusion: Although our results warrant further studies on HD-CT in relapsed poor prognosis GCTs, patients with a Beyer score >2 did not benefit from this approach and should not be enrolled in HD-CT trials. Better selection criteria have to be fulfilled in forthcoming studies.
Key words: germ-cell tumors, high-dose chemotherapy
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Introduction |
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Materials and methods |
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Initial evaluation
Each patient underwent clinical evaluation that included measurements of tumor marker levels, and an imaging work-up. The tumor marker levels were determined throughout the sequence of treatment (normal level <10 ng/ml for alpha-fetoprotein and <2 mIU/ml for HCG). The tumor mass was measured after the first two cycles of induction/mobilization therapy and at the end of the treatment.
Chemotherapy
Patients were scheduled to receive two courses of front-line mobilization CT followed by 3 HD-CT supported by PBSCT. The front-line treatment consisted of a combination of epirubicin (100 mg/m2 in a 30-min infusion), and paclitaxel (Taxol®, Bristol Myers Squibb, Princeton, NJ, USA; 250 mg/m2 given in a 3-h infusion), administered on days 1 and 14. These two cycles were supported by filgrastim (Neupogen®), 5 µg/kg, twice a day from days 2 and 15, respectively, until apheresis was carried out on days 1013 and 2427. Apheresis was stopped when at least 9 x 106 CD34+ cells/kg of body weight was obtained for the three grafts. A third cycle was permitted if the number of CD34+ cells was not achieved after the first two cycles, provided the patient was responsive to CT, or for any reason decided upon by the investigator.
The first HD-CT regimen consisted of an association of thiotepa, 400 mg/m2 and cyclophosphamide, 3 g/m2, both administered in a continuous infusion over 2 days (D34 and D35). The first pack of CD34+ cells was infused on day 39. The second and the third courses (ICE) scheduled on days 6266 and 9094, respectively, consisted of a combination of etoposide (150 mg/m2 twice a day, in a 2-h infusion, for 5 days), ifosfamide (2000 mg/m2/day in a 3-h infusion, for 5 days) supported by sodium mercaptoethanesulfonate (mesna, in a 30-min infusion every 3 h, during a 12-h period, initiated at the same time as the ifosfamide infusion), and carboplatin (AUC 4/day, in a 6-h infusion, for 5 days). Infusion of PBSCs was planned on days 71 and 99. During the three high-dose therapies, G-CSF was administered at a daily dose of 5 µg/kg, from the day of PBSC infusion until PMN recovery (i.e. PMN >1.5 x 109/l). Each of these ICE regimens was delayed if the PMN level was less than 1.5 x 109/l and/or the platelet level was less than 100 x 109/l.
Evaluation of toxicity, response to therapy and survival
This phase II study was initially designed as a Gehan method [30]. The main objective of the study was the CR rate. With this aim in view, we planned to enroll 14 patients in a first phase to ensure that if no CR was observed, the study would be stopped for inefficacy (i.e. a CR rate lower than 20%). If one or more CR were observed, the protocol specified that up to 45 patients could be included in order to reduce the confidence interval (CI) of the CR rate. Secondary objectives were the overall (complete plus partial) response rate (RR), overall survival (OS) and progression-free survival (PFS) rates, toxicity and toxic death rate. The statistical analysis was done in terms of intention-to-treat. Toxicity and response to therapy were evaluated according to the ECOG and WHO criteria [31
, 32
].
The duration of response was calculated from the date of documented response to the date of progression. Whenever possible, patients in clinical partial response (PR) with normal tumor markers (PRm) underwent surgery of residual masses at the end of the whole procedure. Sequential procedures were proposed in the case of multiple metastatic sites. If surgery was complete and the pathological examination did not show any viable tumor, patients were considered as complete responders. If surgery was complete and the pathological examination showed persistent viable tumor, they were considered as surgical CR [20]. Progression, death from treatment and withdrawal from protocol for whatever reason were considered as treatment failures.
The duration of PFS and OS was calculated from the date of inclusion to the date of progression, or death if no progression (PFS), and the date of death (OS), according to KaplanMeier's method [33]. The patients were stratified into good-, intermediate-, and poor-risk categories on the basis of a cumulative score calculated using a prognostic index proposed by Beyer et al. [20
]. One point each was given for progressive disease before HD-CT and non-seminomatous mediastinal primary or refractory disease before HD-CT. Two points were given for HCG levels greater than 1000 mIU/ml before HD-CT or absolute refractory disease. Patients with a cumulative score greater than 2 were in the poor-prognosis group and those with a score of 0 were in the good-prognosis group.
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Results |
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Administration of chemotherapy (Table 2)
Four out of the 45 patients who had received the first cycle were excluded before the second cycle of CT: one died from therapy-related toxicity, three from progressive disease. Hence, 41 patients were eligible to receive the second mobilization course. Following this second course, eight patients were excluded (six for progression, one for harvest failure, and one who died from toxicity). Thirty-three patients underwent the first HD-CT course. Four were excluded after this third cycle, three for hematologic toxicity, one for toxic death. Twenty-nine patients were eligible to receive the first ICE regimen. Seven supplementary withdrawals were due to various reasons: two for progression, two toxic deaths, two for toxicity including one hemorrhagic cystitis and one hematologic toxicity, and one refusal. Finally, 22 patients (49%) were eligible to receive the complete course of treatment.
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Toxicity
The 45 patients included in the study were assessable for toxicity.
Hematologic toxicity. One hundred and seventy-four cycles of chemotherapy were assessable for hematologic toxicity, with 89 for epirubicinpaclitaxel and 85 for cycles of HD-CT. One hundred and seven courses (61.5%) were complicated by grade IV neutropenia and 79 (45.4%) by grade IV thrombocytopenia. Seven cases of grade IV anemia occurred during the therapy. The median number of red blood cell unit transfusions per patient was 15 (range: 626) and the median number of platelet unit transfusions per patient was 13 (range: 124).
Extra-hematologic toxicity. Two grade IV toxic effects consisting of cerebral hemorrhage occurred in two patients among the four exhibiting cerebral metastases. Twenty-one patients suffered from grade IV vomiting despite the use of 5-HT3 antagonists. Two reversible grade III liver toxic effects occurred, one related to the use of thiotepa and carboplatin. Four grade III and three grade IV episodes of fever were reported. One reversible IFM-related grade IV central neuropathy occurred. One patient suffered from CPM-related hemorrhagic cystitis. Finally, no grade III or IV renal toxicity was observed in this trial.
Treatment-related deaths. Five patients died from therapy-related complications: one after each of the two mobilization cycles, one after the first HD-CT cycle, and two after the first ICE cycle. The treatment-related death rate in this poor-prognosis population was 11%. Among the four patients with cerebral metastases, two died from cerebral hemorrhage, one after the first mobilization cycle and one during the first ICE regimen. Three patients (6.6%) died from non-hematologic toxicity: one from acute respiratory syndrome, one from a toxic shock syndrome during the first HD-CT course, and one from multi organ failure during the first ICE regimen.
Response to therapy (Table 3)
Two CR were observed among the first 14 patients. With a median follow-up of 31.8 months (range: 5.157.1), 17 patients achieved a response (overall RR 37.7%; 95% CI, 23.753.4). Nine patients (20%; 95% CI: 9.634.6) obtained a PR with negative tumor markers, four patients (8.9%; 95% CI: 2.521.2) obtained a PR with positive tumor markers, and four patients (8.9%; 95% CI: 2.521.2) obtained a clinical CR.
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Survival (Figures 13)
Twenty-five patients (55.5%) died from disease progression. The median OS for the whole population was 11.8 months (95% CI: 8.313). The 3-year survival rate was 23.5% (95% CI: 15.242.4) with a plateau starting at 17 months. The median PFS time was 6 months (95% CI: 4.87.5) and the 3-year PFS rate was 23.5% (95% CI: 13.838.1), with a plateau starting at 13 months. The median time to progression was 6 months (Figure 1). According to the Beyer classification, OS and PFS were better in patients graded as 0 than in patients graded as 12 or more (Figures 2 and 3). The 3-year PFS rate of patients graded as 0 was 62%, compared with 13% for patients graded as 12 and 0% for patients graded as >2.
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Discussion |
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The prognostic score predicts the outcome after HD-CT. Analysis of survival has shown that no long-term survivors were observed among the patients graded with a Beyer score greater than 2. These results confirm that highly refractory patients and particularly patients with resistant/refractory primary mediastinal GCTs, clearly did not benefit from HD-CT. Selection of patients who could benefit from HD-CT should be respected (Beyer score 02) whereas new drugs (gemcitabine, oxaliplatin and paclitaxel) should be proposed within clinical trials for patients with a score greater than 2 [35]. Prognosis of patients graded 12 certainly remains poor, but these patients should however be treated within HD-CT clinical trials.
Vaena et al. [36] have published similar results in their retrospective study. In a population of 80 patients who received salvage HD-CT between 1988 and 2001 and exhibited at least one poor-prognosis characteristic (platinum-refractory or absolutely platinum-refractory GCT, primary mediastinal NSGCT, HCG 1000 mIU/ml or alpha-fetoprotein
1000 ng/ml before HD-CT), the authors reported a median OS of 14.7 months, a 2-year PFS of 32%, and no relapse had occurred 2 years after HD-CT [36
]. The optimal salvage treatment for patients with relapsed or refractory disease remains controversial [37
]. In the 1990's, a series of HD-CT for previously treated patients yielded 1525% lasting CR rates. These poor results have been attributed to various factors, including poor PS, refractory disease and high treatment-related death rates [38
]. Improved results in terms of toxicity and response or survival have been observed with an earlier administration of HD-CT [14
, 38
41
]. Bhatia et al. obtained a 57% relapse-free rate (RFR) at 39 months in a population of 65 patients treated in first relapse with one or two cycles of VeIP followed by two HD cycles of carboplatinetoposide [14
]. In this study, patients with EGCTs were excluded and only two patients were in progression during initial cisplatin-based treatment. Response to VeIP chemotherapy before HD-CT as well as response to HD-CT itself predicted long-term DFS. Likewise, Rodenhuis et al. obtained a RFR of 54% at 37 months in a population of 35 previously CR patients treated with conventional induction and two high-dose regimens combining carboplatin, thiotepa and CPM [41
]. However, the results of the first prospective randomized study were disappointing. The EBMT-IT-94 study failed to demonstrate the superiority of a single course of HD-CT (CARBOPEC), administered after three courses of conventional CT (VeIP or VIP) versus four courses of conventional VeIP or VIP protocols for patients with advanced GCTs, who had relapsed after previous CR or achieved an incomplete remission or failed to normalize tumor markers after first-line therapy [42
]. Overall CR and PRm rates were 41 and 17% in the standard arm and 44 and 18% in the HD arm, respectively. The 1 year event-free survival (EFS) rates were 48 and 52%, respectively (P= n.s.). Finally, the 3-year OS rate was 53% in the two arms.
In our study, we have tried to optimize the concept of salvage therapy. First, in view of its efficacy in controlling the progression of the disease and its ability to mobilize PBSC, we proposed to combine epirubicin and paclitaxel [2125
, 43
, 44
]. Secondly, we decided to give two consecutive courses of epirubicin and paclitaxel. Indeed, several studies have investigated the use of multiple paclitaxel-based salvage therapy [43
46
]. Motzer et al. obtained a RFR of 41% at 30 months in a population of 37 patients treated in first relapse [43
]. Several important differences should be underlined in this single center study: patients with brain metastases were ineligible, the only patient who developed brain metastases during induction therapy was excluded from the HD sequence, only 3% of the patients were pre-treated with more than two lines of CT, compared with 13.5% in our trial, and finally, no toxic deaths were observed during the whole sequence. Moreover, the surgical approach differed between the two studies. In our study, only nine out of the 22 patients who received the whole sequence of treatment underwent surgery; three were in PR, four had stable disease, and two were in progression. Only two of these achieved a pathological CR. In Motzer's study, 21 patients (57%) achieved a CR, of whom 18 required resection of residua; 14 patients were in CR to chemotherapy alone, defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease for at least 4 weeks, and four achieved the status of CR after completing surgery. These results emphasize the role of surgery in increasing the CR rate. Shamash et al., in a small cohort of 13 relapsed or refractory patients, obtained a relapse-free survival rate of 46% at 40 months [45
]. Rick et al. obtained a RFR of 34% at 36 months in a population of relapsed or refractory patients, but no long-term survivors were observed among the prognostically worst group of patients [46
]. Recently, McNeish et al., using the HD carboplatinetoposidecyclophosphamidepaclitaxel (225 mg/m2) regimen in a population of 36 GCT patients, reported a 1 year OS and a 1 year EFS rate of 88 and 64%, respectively, in 24 sensitive patients [47
]. In our trial, the dose of paclitaxel was increased to 250 mg/m2 and two cycles were administered on a day 1 to 14 regimen to improve dose-intensity. A 34.1% RR was observed after these two cycles. Thirdly, considering the efficacy and availability of thiotepa in HD regimens, we introduced this drug in the first HD-CT course of our multiple program [48
]. Fourthly, considering the therapeutic potential of multiple carboplatin-based courses, the principle of tandem HD therapy was maintained, and the second and third cycles were derived from our previously described tandem ICE protocol [13
, 36
, 37
, 49
]. The rational for a sequential approach was based on the assumption that the use of multiple semi-intensive cycles as front-line therapy may be more efficient before drug resistance develops. Moreover, several phase II studies have explored the potential role of tandem HD-CT, more likely to eradicate residual cancer cells than a single application of HD-CT [36
, 43
, 49
, 50
]. If the concept of multiple cycles of HD-CT seems promising, we can expect that its application as front-line therapy would enhance the results. It is in this spirit that Hartmann et al. have reported their experience with sequential HD VIP-chemotherapy with PBSCT as first-line treatment in 28 patients with primary mediastinal GCT. With a median follow-up of 22 months, 61% achieved a CR/PRm status. Two-year PFS and OS rates were 54% and 64%, respectively. For the authors, these results may indicate that the use of intensive first-line treatment leads to an approximately 10% improvement in survival in patients with mediastinal GCTs [50
].
In conclusion, these results support further studies on multiple HD-CT courses in relapsed poor prognosis GCTs. Earlier intervention should allow us to improve the results and decrease the toxicity of these sequential high dose approaches, notably the toxic death rate, which remains too high [36, 44
]. Better selection criteria have to be fulfilled. The role of surgery for residual tumors after HD-CT must be recalled [51
]. With this in mind, the Groupe d'Etudes des Tumeurs Uro-Génitales (Genito-Urinary Tract Tumor Study Group) have started the TAXIF-II protocol, targeting non-refractory patients, and in which CPM is replaced by higher dose paclitaxel (360 mg/m2), combined with higher doses of thiotepa (720 mg/m2) as reported by Fields et al. [52
] and in which a 12 g/m2 dose of IFM is proposed, as in the original ICE regimen [13
, 52
]. The time has come to apply new and more intensive treatments in populations of patients who could clearly benefit from HD-CT.
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Acknowledgements |
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Received for publication July 14, 2004. Revision received October 12, 2004. Accepted for publication October 25, 2004.
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References |
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