A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours

J.-L. Pico1, G. Rosti2, A. Kramar3,*, H. Wandt4, V. Koza5, R. Salvioni6, C. Theodore1, G. Lelli7, W. Siegert8, A. Horwich9, M. Marangolo2, W. Linkesch10, G. Pizzocaro6, H.-J. Schmoll11, J. Bouzy1, J.-P. Droz12, P. Biron12 for the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG-FNCLCC), France and the European Group for Blood and Marrow Transplantation (EBMT)

1 Institut Gustave Roussy, Villejuif, France; 2 Ospedale Santa Maria Delle Croci, Ravenna, Italy; 3 CRLC Val d'Aurelle, Montpellier, France; 4 Klinikum Nord U. Inst. F. Onkologie, Nuremberg, Germany; 5 Charles University Hospital, Pilsen, Czech Republic; 6 Istituto Nazionale Tumori, Milan, Italy; 7 Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy; 8 Universitatklinikum Rudolf Virchow, Berlin, Germany; 9 The Royal Marsden Hospital, London, UK; 10 Medizinische Universitatklinik, Graz, Austria; 11 Martin Luther Universität, Halle, Germany; 12 CAC Léon Bérard, Lyon, France

* Correspondence to: Dr. A. Kramar, CRLC Val d'Aurelle, Biostatistics Unit, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France. Tel: +33-4-6761-3161; Fax: +33-4-6761-3718; Email: akramar{at}valdorel.fnclcc.fr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients. This phase III randomised trial compares conventional salvage to high-dose-intensification chemotherapy.

Patients and methods: Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries, were randomly assigned to receive either four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) (arm A), or three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support (arm B).

Results: Similar complete and partial response rates were observed in both treatment arms (56%; 95% CI 50% to 62%). There were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with CarboPEC were observed in either 3-year event-free survival (35% versus 42%, P=0.16) or overall survival (53%; 95% CI 46% to 59%). Complete responders with CarboPEC had a significant improvement in disease-free survival (55% versus 75% at 3 years, P <0.04).

Conclusions: The single cycle of high-dose salvage chemotherapy after three cycles of standard dose chemotherapy had no effect on treatment outcomes. These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a randomised trial.

Key words: CarboPEC, germ cell tumours, high-dose chemotherapy, randomised trial


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Since the introduction of cisplatin into combination chemotherapeutic regimens, the chemo-sensitive nature of germ cell tumours has made it possible to attain durable complete remissions in 70%–90% of newly diagnosed patients, even when disseminated [1Go, 2Go]. Among the 10%–30% of patients who fail to achieve a durable disease-free status, approximately 25% may be cured by standard salvage chemotherapy regimens containing cisplatin and ifosfamide, with or without subsequent surgery [3Go]. For the remainder, however, prognosis is poor, and most patients requiring salvage treatment die of their disease.

The optimal salvage chemotherapy remains to be defined, but investigations have proceeded along the lines of both conventional-dose [3Go] and high-dose chemotherapy with autologous bone marrow or peripheral blood haematopoietic stem cell support [4Go, 5Go]. Conventional salvage regimens used to date are reviewed by Nahleh et al. [6Go]. The current standard salvage regimen of a four-course 5-day cycle with vinblastine-etoposide-cisplatin (VeIP) repeated every 3 weeks, resulted in disease-free status 1 month after treatment in almost 50% of patients, with a 1-year progression-free survival rate of 28% [3Go].

The chemotherapeutic dose–response relationship displayed by germ cell tumours, predominantly in young, otherwise healthy individuals with good performance status, suggests that they are particularly suited to dose escalation strategies, an approach which has provided an alternative line of investigation. Dose escalation in this setting is further assisted by the rarity of bone marrow involvement, which allows the provision of haematopoietic stem cell support, and the availability of recombinant growth factors such as granulocyte colony-stimulating factor (G-CSF) that both enhance haematopoietic stem cell production and ameliorate the haematological toxicity of chemotherapeutic agents. Following moderately promising results in early studies utilising high-dose chemotherapy in the salvage treatment of patients with refractory or relapsing germ cell tumours [4Go, 5Go], and on the conceptual basis that a final cycle of high-dose chemotherapy might eliminate residual disease, in 1994 the Genito-Urinary Group (GETUG) of the French Federation of Cancer Centres and the European Group for Blood and Marrow Transplantation planned a randomised, prospective comparative study, the IT94 study. The aim of this study was to determine whether the replacement of a fourth cycle of conventional PEI/VeIP chemotherapy by a high-dose carboplatin-etoposide-cyclophosphamide (CarboPEC) cycle with haematopoietic stem cell support would provide enhanced clinical benefit to patients. The findings of this study, which have been presented in preliminary form [7Go], are detailed below.


    Patients and methods
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 Introduction
 Patients and methods
 Results
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Eligibility criteria included males at least 16 years old, performance status 0–2, and relapsing germ cell tumours who had achieved a complete or partial remission from platinum combination chemotherapy as first-line treatment. Patients with elevated tumour markers, metastases, or seminoma failing cisplatin combination chemotherapy were also included.

Exclusion criteria included refractoriness to first-line platinum-containing chemotherapy, defined as a documented increase of tumour burden and/or serum tumour marker level within 1 month of treatment; pure seminoma pretreated with carboplatin; HIV-positive status; concurrent severe cardiac, pulmonary, neurological or metabolic disease that could interfere with treatment or life expectancy.

All patients were required to provide written informed consent prior to randomisation. The protocol was subjected to independent ethical review according to national regulatory requirements.

Treatment
Patients were randomised between arm A, four 21-day cycles of PEI or VeIP, and arm B, three cycles of PEI or VeIP followed by CarboPEC. Both regimens included ifosfamide (1200 mg/m2, i.v.), mesna (400 mg/m2, i.v.), and cisplatin (20 mg/m2, i.v.), days 1–5. Each cycle included either etoposide (75 mg/m2, i.v., days 1–5) (PEI); or vinblastine (0.11 mg/kg, days 1–2) (VeIP), depending on which drug had previously been used as first-line treatment. Patients considered refractory 21 days after the start of the second cycle, were withdrawn from the study and treated at the investigator's discretion. The CarboPEC regimen included a 1 or 2 h carboplatin infusion day 1, etoposide (450 mg/m2/day, i.v.), cyclophosphamide (1600 mg/m2/day, i.v.) and mesna (3600 mg/m2/day; 1 h infusion) on days 1–4, followed on day 7 by either bone marrow or stem cell autologous haematopoietic re-infusion. Carboplatin dosages of 0, 250, 400 and 550 mg/m2/day were determined on the basis of EDTA clearance: <30, <60, <100 and ≥100 ml/min, respectively.

Expected relative dose intensities for patients in arm B relative to arm A were 1.75 mg/m2/week for platin, 1.95 for etoposide and 1.55 for oxazaphosphorines [9Go–11Go].

In case of haematological toxicity, a maximum 3-day PEI/VeIP cycle delay was allowed, with haematological support as necessary in the form of haematopoietic growth factors or platelet transfusions. In case of extra-haematological toxicity, cycle delay was recommended rather than dose deductions, with the proviso that the total treatment duration should not exceed 6 months.

Response to chemotherapy was evaluated 21 days from cycle 2 according to standard WHO criteria (CR, PR, SD, PD). Patients with incomplete response with residual disease were candidates for surgery. Patients considered non-evaluable for response at cycle 3 were retrospectively assigned to the response category observed at cycle 2 if the results at cycle 2 and cycle 4 were the same. Overall response after chemotherapy alone or after surgical excision of residual masses was evaluated according to the following criteria: complete disappearance by all lesions and serum marker normalisation for at least 1 month from chemotherapy alone (cCR); normal tumour markers, complete resection of non-viable malignancies (necrosis, fibrosis, teratoma) (pCR); no evidence of disease after complete resection of viable malignancy and normal tumour markers (sCR); partial remission with elevated tumour markers (PRm+); partial remission or >90% reduction of elevated tumour markers for at least 1 month (PRm–); response not qualifying as either partial response nor progressive disease (SD); progressive disease from chemotherapy, or >10% increase in elevated tumour markers (PD). Subsequent treatment options were left to the discretion of the investigator.

Patients were followed-up at 4-monthly intervals for 2 years.

Statistical methods
Based on estimated 1-year event-free survival rates of 25% and 40% for arms A and B, respectively, 280 patients were required to provide a two-sided {alpha}=5% and a ß=20%, assuming 20% refractory patients after two cycles.

Patient characteristics and maximum grade toxicities were compared by the chi-squared test. Response rates were estimated with 95% confidence intervals (CI). Survival rates were estimated according to Kaplan–Meier and compared by the log-rank test, stratified on the a priori prognostic classification. Cox's proportional hazards regression model was used to identify potential confounding prognostic factors. Differences were considered significant if P <0.05. Event-free survival defined as time to disease progression, relapse or death, whatever the cause, was the main end point. Disease-free survival (DFS), defined as the time to failure after achieving a complete response, was considered a secondary end point. All survival times were calculated from the date of the start of the first chemotherapy cycle, since 26% of patients were randomised after the start of the first chemotherapy cycle.

A 1:1 stratified randomisation treatment allocation ratio was performed centrally by fax after verification of eligibility criteria. Randomisation was stratified according to three prognosis categories, which were defined from a combination of the following prognostic factors: complete response to first-line therapy, presence of lung metastases and primary site [8Go]. This stratification classified patients with none or one of the first two unfavourable characteristics into the good prognostic group, and two unfavourable characteristics into either the intermediate or poor prognostic group depending on the primary site. Data was collected on standardised case report forms and entered into and verified with the database management system used at the Biostatistics Department of the Gustave Roussy Institute in Villejuif. Statistical analyses were performed with STATA 7.0.


    Results
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 Abstract
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 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries were randomly assigned to either arm A (4PEI/VeIP) or arm B (3PEI/VeIP followed by CarboPEC). Randomisation after the start of the PEI/VeIP regimen was tolerated, since the first three cycles were similar in both arms and concerned 26% of patients. Seventeen patients were considered ineligible: renal insufficiency (one patient), progressive disease (four), stable disease (one), complete remission (one), complete response according to surgical criteria after first-line treatment (one), tumour marker positive (seven), and no data (two). Thus 263 patients, 128 and 135 in treatment groups A and B, respectively, were used in the analysis.

Most patients (85%) received standard BEP or EP regimens as first-line treatment. Characteristics of the 263 eligible patients showed no significant imbalances between the two arms with respect to initial diagnosis and disease characteristics at salvage except for significantly more patients with mediastinal lymph nodes in arm A (Table 1). This imbalance is probably due to chance. No significant difference in the histology of patients with or without mediastinal lymph nodes was noted.


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Table 1. Characteristics of the study population and disease status at diagnosis

 
The IGCCCG [12Go] classification had not been established when this study started, and insufficient data were available to allow retrospective categorization.

Treatment delivery
Thirty-one patients received less than three cycles of PEI/VeIP: 27 refractory (13 in A and 14 in B), three toxic deaths (two in A and one in B) and one toxicity in arm B. Overall 232 (88%) patients received at least three cycles of PEI/VeIP. Thirty-one patients did not receive a fourth cycle of chemotherapy: 19 refractory (seven in A and 12 in B), five refusals in arm B, one toxic death on day 15 in arm A, four toxicity (two each in A and B) and two other reasons in arm B. Overall 103 (80%) patients in arm A and 98 (73%) patients in arm B received a fourth cycle of chemotherapy, and 96 patients (81%) received CarboPEC. One patient received a fourth cycle of PEI/VeIP before CarboPEC. Twenty-three patients did not commence CarboPEC: progressive disease (12), haematological toxicity (two), infection and diabetes (one), bacterial contamination of stem cell harvest (one), and withdrawal of consent (five). Two other patients also received a fourth cycle of PEI/VeIP in arm B but did not go on to receive CarboPEC chemotherapy: one due to toxicity, and one because of a complete response. These two patients, although scheduled to receive CarboPEC but who received the treatment plan of arm A, were kept in arm B for analysis.

Mean relative dose intensities (mg/m2/week) were 1.65 for platin, 1.43 for oxazaphosphorine and 1.96 for etoposide for arm B relative to arm A. Median doses of carboplatin (n, range) were 1000 (15, 882–1210), 1600 (32, 1166–2200) and 2200 (49, 1279–2465) mg/m2 for patients with EDTA clearance <60, 60–100 and ≥100 ml/min, respectively.

Adverse effects
All but four randomised patients were evaluable for toxicity, with PEI/VeIP administered in 503 and 398 cycles for patients in arms A and B, respectively. These four patients were found to be ineligible. No data had been collected from these four patients.

During the first three cycles, significant differences were observed for neutropenia, febrile neutropenia and thrombocytopenia (Table 2). There were significantly more cycles with growth factors in arm B (58% versus 65% cycles) related to the need for the mobilisation of stem cells for autologous transplantation. However, no differences were observed between arms A and B, as far as the use of growth factors during PEI/VeIP was concerned with 50%, 65%, 72% and 67% of patients during cycle 1, 2, 3 and 4, respectively.


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Table 2. Toxicity

 
During all cycles, significant differences were observed for febrile neutropenia (A versus B) (49% versus 78%; P <0.001) and thrombocytopenia (56% versus 85%; P <0.001), essentially due to the patients in arm B undergoing CarboPEC. All CarboPEC patients experienced grade 4 neutropenia and grade 3+ thrombocytopenia, and 95% of patients experienced febrile neutropenia. The corresponding cycle 4 proportions for patients in arm A were 70%, 47% and 26%, respectively (Table 2).

Toxic effects of CarboPEC were longer lasting than PEI/VeIP. Duration (median) of severe neutropenia and thrombocytopenia during cycle 4 were: 3.5 (range 1–11) and 10 days (range 3–24) in arm A, and 3 (range 1–15) and 9 days (range 1–41) in arm B Peripheral blood stem cells (PBSC) and autologous bone marrow transplantation (ABMT) stem cell support was administered to 81% and 12% of patients, respectively. Seven per cent received both PBSC and ABMT.

Significant differences were observed in grade 3+ GI toxicity concerned (A versus B): nausea and vomiting (12% versus 41%; P <0.0001), diarrhoea (2% versus 14%; P <0.001) and mucositis (2% versus 36%; P <0.001) (Table 3).


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Table 3. Response to chemotherapy and overall response

 
No significant differences between arms A and B was observed concerning PEI/VeIP cycle delay with 27%, 34% and 47% of patients with more than a 3-day delay for cycles 2, 3 and 4, respectively.

Four toxic deaths were reported in arm A: septic shock (two), pneumonia on day 7 of cycle 1, neutropenia and thrombocytopenia on day 16 of cycle 4, septic pneumonia on day 18 of cycle 1, and heart failure on day 15 of cycle 3. This 43-year-old patient had had cardiotoxicity recorded in his baseline clinical status, but had refused urgent hospital admission and died at home. Nine toxic deaths were reported in arm B: four from sepsis, renal failure and adult respiratory distress syndrome 5 weeks after cycle 1, and septic pneumonia (CarboPEC days 13, 18 and 75), two from multi-organ failure (CarboPEC days 9 and 30), one from brain haemorrhage (CarboPEC day 10), one from diffuse alveolar haemorrhage 2 days after the end of CarboPEC, and one as a result of progression of complications arising from surgery for residual masses, 6 months post-surgery. This patient had normal pre-operative marker levels, but happened to be the patient with the largest body surface area.

Response
The objective response (OR) rates after three PEI/VeIP cycles were similar in groups A (n=99) and B (n=109): 65.7% (95% CI 56% to 75%) versus 67.9% (95% CI 59% to 77%), respectively (Table 3), the estimated difference being 2.2% (95% CI 10.7% to 15.2%). The overall complete response rate was 16.3% (95% CI 11% to 21%).

Among evaluable patients, the cycle 4 OR rates were 67% versus 75% (Table 3, P=0.23) with a 27% (95% CI 20% to 34%) complete response rate. The provision of high-dose CarboPEC provided no advantage over conventional PEI/VeIP chemotherapy in terms of response to chemotherapy.

Forty (31%) and 38 (28%) patients had surgery after four PEI/VeIP cycles, and four and two patients had surgery before four cycles in arms A and B, respectively. Surgical exeresis was considered complete in 75% versus 68% of patients (P=0.45), and with non-viable histology in 50% and 67% of patients (P=0.10). Also, there was no imbalance in pre-operative tumour marker levels between the two groups.

Sixteen patients were not evaluable for overall response: six toxic deaths (three and three), five withdrawals for toxicity (one and four), three refusals (two and one), and two other causes (none and two) in arms A and B, respectively. An overall complete response was observed for 51 (42%) and 53 patients (43%) in arms A and B, respectively (Table 3). A further 21 patients (17%) versus 23 patients (18%) achieved a tumour marker-negative partial remission. The replacement of a fourth cycle of PEI/VeIP by a cycle of high-dose CarboPEC, provided no clinical benefit (P=0.71).

Survival
Median follow-up was 45 months (22 days to 7.5 years) and 83 and 75 patients failed treatment in arms A and B, respectively (35% versus 42% at 3 years; Figure 1, P=0.16). Fifty-six (44%) and 53 (39%) patients progressed after chemotherapy, 20 (16%) and 11 (8%) relapsed after a complete remission, four (3%) and nine (7%) patients died from toxicity, and three and two patients died from other causes. These results are similar when considering all randomised patients.



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Figure 1. Event-free survival.

 
In a subgroup analysis of the 104 patients who achieved a complete response, the 3-year DFS rates were 55% and 75% in arms A and B, respectively (Figure 2, P=0.04). Among the 84 patients who had surgery, patients with a complete resection and non-viable cells (38 patients) had a 3-year event-free survival rate of 79% (overall survival 91%) compared with 45% (overall survival 66%) and 8% (overall survival 30%) for patients with an incomplete resection or viable cells (33 patients), and incomplete resection and viable cells (13 patients), respectively. Tumour marker levels at surgery had no statistically significant impact on event-free nor overall survival.



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Figure 2. Disease-free survival from time of overall treatment evaluation among patients in complete remission.

 
Fifty-seven and 57 patients died in arms A and B, respectively (53% versus 53%; Figure 3). These results are similar when considering either the ITT population (53% versus 54%) or ITT patients randomised before the first chemotherapy cycle [45 deaths among 104 patients (53%) in arm A versus 45 deaths among 103 patients (51%) in arm B].



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Figure 3. Overall survival.

 
Univariate event-free and overall survival for important prognostic factors, were significantly different for the following variables: initial stratification prognostic group, including complete response to first-line treatment, primary site, presence of lung metastases; as well as Indiana disease status, {alpha}-fetoprotein (AFP) and lactate dehydrogenase (LDH) (Table 4). Time to relapse among first-line CR patients was at the limit of statistical significance for both event-free survival (P=0.09) and overall survival (P=0.052).


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Table 4. Prognostic factors for event-free (EFS) and overall survival (OS)

 
Cox's proportional hazard's regression model identified the Indiana University staging classification system, AFP and LDH markers as important discriminators for both event-free and overall survival. Treatment effect was not significant either in a univariate analysis or when adjusted for these prognostic factors.


    Discussion
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 Abstract
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 Patients and methods
 Results
 Discussion
 References
 
A number of studies, published during the course of the IT94 study, showed that a durable complete remission might be obtainable in as few as 15%–25% of patients treated with high-dose carboplatin-based salvage chemotherapy with autologous bone marrow or peripheral blood stem cell transplantation in relapsed or refractory germ cell tumors [4Go–6Go], which is not markedly different from what could be achieved by conventional salvage chemotherapy. Each of these studies, however, was limited by the inclusion of a relatively small number of patients, and the absence of a control arm for comparison. Also, the Vaena study [5Go] was limited to a specific group of patients who were defined as having poor prognostic variables by the previously published study by Beyer [13Go]. Subsequently, a retrospective matched-pair analysis of 193 patients with relapsed or refractory non-seminomatous germ cell tumours who had undergone either conventional or high-dose salvage chemotherapy, concluded that the benefit provided by high-dose salvage chemotherapy might be even lower, reporting estimated absolute improvements of as little as 6%–12% in event-free survival and 9%–11% in overall survival at 2 years [13Go]. The IT94 study remains the sole randomised study comparing conventional and high-dose chemotherapy in these patients, but the findings demonstrate clearly that late dose-intensification of a salvage regimen provides no clinical benefit to a heterogeneous population of patients in terms of either response or survival.

Significant differences were observed in both event-free and overall survival between the Indiana disease stage classification, as well as the risk groups into which the patients had been stratified even though one of the individual components was only revealed to be significant for overall survival [8Go]. Furthermore, among patients who achieved a complete response to salvage chemotherapy, there was a significant difference towards improved 2-year disease-free survival for patients in the high-dose arm. However, this subgroup analysis was not planned in advance, and these results should be interpreted with caution. This nevertheless suggests that any future strategy for the optimisation of high-dose salvage chemotherapy should focus on a multivariate prognostic evaluation.

From a review of more than 200 patients with recurrent germ cell cancer treated with cisplatin/ifosfamide-based conventional dose salvage chemotherapy in three institutions between 1984 and 1990, Droz et al. [8Go] identified four independent adverse prognostic factors: incomplete response to first-line chemotherapy; an extra-gonadal tumour origin; the presence of lung metastases; and elevated tumour markers (serum HCG or AFP). In a subsequent retrospective analysis of more than 300 patients with relapsed or refractory germ cell tumours treated with high-dose chemotherapy with haematopoietic stem cell support at four centres in the United States and Europe, Beyer et al. [14Go] identified progressive disease before high-dose chemotherapy, a mediastinal non-seminomatous primary tumour, refractoriness or absolute refractoriness to conventional dose cisplatin, and pretreatment HCG levels >1000 U/l as independent adverse prognostic variables for failure-free survival. These results in terms of survival were prospectively confirmed in a further group of 46 patients treated in one of the centres participating in the former analysis [16Go]. Given projected 2-year failure-free survival rates of approximately 50%, 25% and 0%–5% for patients in the three risk categories, it would clearly make sense to concentrate the administration of high-dose salvage chemotherapy, as currently conceived, to those most likely to benefit from it. Furthermore, other forms of high-dose chemotherapy consolidation treatment should be investigated. The possible role of sequential high-dose chemotherapy must be stressed in future trials [16Go]. The single cycle of high dose salvage chemotherapy after three cycles of standard dose chemotherapy has no effect on treatment outcomes. However, in different studies, mainly in the United States, tandem high-dose chemotherapy is performed after one or two cycles of standard salvage regimen [17Go]. This hypothesis may be also tested in further trials.


    Acknowledgements
 
Contributing investigators alphabetically (by country): Mme Dr Jitka Abrahamova, Thomayer Memorial Teaching Hospital, Prague, Czech Republic; Dr Cetkovsky, Charles University Hospital, Pilsen, Czech Republic; Pr Kiss, Masaryk University Hospital, Brno, Czech Republic; Mme Dr Katerina Kubackova, University Hospital, Prague, Czech Republic; Pr Pont, Keiser Franz Josef-Hospital, Vienna, Austria; Pr Newslands, Charing Cross Hospital, London, England; Dr Sweetenham and Dr Mead, University of Southampton, Southampton, England; Dr Bui, Institut Bergonié, Bordeaux, France; Mme Dr A. Caty, Centre Oscar Lambret, Lille, France; Mme Dr C. Chevreau, Institut Claudius Regaud, Toulouse, France; Dr Delva, Centre Paul Papin, Angers, France; Dr Facchini and Mme Dr S. Walter, Centre Hospitalier Bon Secours, Metz, France; Dr Geoffrois, Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France; Pr Heron, Centre François Baclesse, Caen, France; Pr Kerbrat, Centre Eugéne Marquis, Rennes, France; Dr Kohser/Dr Audhuy, Centre Hospitalier L. Pasteur, Colmar, France; Dr Linassier, Hopital Bretonneau, Tours, France; Mme Dr C. Martin, C.H.R. Annecy, Annecy, France; Dr Merrouche, Hopital Jean Minjoz, Besançon, France; Mme Pr M. Mousseau, C.H.U Grenoble, Grenoble, France; Dr Platini, Hopital Bel Air, Thionville, France; Pr Thyss, Centre Antoine Lacassagne, Nice, France; Dr Elling, Klinikum Minden II, Minden, Germany; Dr Hafner, University of Ulm, Ulm, Germany; Mme Dr Anna Efremedis, Hellenic Cancer Institute, Athens, Greece; Dr Battista, A.O.R.N. Cardarelli, Naples, Italy; Dr Berruti, Ospedale San Luigi, Torino, Italy; Mme Dr Sophie Fossa, Norvegian Radium Hospital, Oslo, Norway; Dr Ptushkin, Cancer Research Center, Moscow, Russia; Dr Garcia Conde, Universitat de Valencia, Valencia, Spain; Mme Dr Ana Montes, Institut Catalá d'Oncologia, Barcelona, Spain; Dr Ramon de las Penas, Complejo Hospitalario de Leon, Leon, Spain; Dr Matthey, Centre Hospitalier Univers. Vaudois, Lausanne, Switzerland.

Financial support for this study was obtained from a 1994 PHRC grant from the French Ministry of Health (JPD), and a grant from Institut Gustave Roussy (AK and JB)

Received for publication December 2, 2004. Revision received March 21, 2005. Accepted for publication March 30, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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