Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(2):275-281; doi:10.1093/annonc/mdl384
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© 2006 European Society for Medical Oncology
gynecologic tumors |
Phase II study of bleomycin, vindesine, mitomycin C and cisplatin (BEMP) in recurrent or disseminated squamous cell carcinoma of the uterine cervix
1 EORTC Datacenter, Brussels, Belgium
2 Erasmus MC, Rotterdam, The Netherlands
3 Medical University, Gdansk, Poland
4 Centre Antoine Laccasagne, Nice
5 Institut Gustave Roussy, Villejuif, France
6 Clinica Universita de Torino, Torino
7 Ospedale S. Gerardo, Monza, Italy
8 Department of Oncology, University Hospital Antwerp, Edegem, Belgium
* Correspondence to: Prof J. B. Vermorken, Department of Oncology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel: +32-3-8213954; Fax: +32-3-8250564; E-mail: jan.b.vermorken{at}uza.be
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Abstract |
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Objective: We carried out a phase II trial with BEMP [bleomycin, vindesine (Eldisine®), mitomycin C and cisplatin] in patients with recurrent and/or metastatic squamous cell carcinoma of the uterine cervix with the specific aim to assess whether BEMP was of particular interest when certain disease sites were involved.
Patients and methods: Eligible patients received four cycles of E 3 mg/m2, day 1 + 8; P 50 mg/m2, day 1; B 15 mg/day (continuous infusion), day 2–4 and M 8 mg/m2, day 5 (on alternate cycles), every 3 weeks during an induction phase. Thereafter, those without progression continued with MEP every 4 weeks in a maintenance phase. MEP consisted of E 3 mg/m2, day 1 + 8, M 6 mg/m2 (on alternate cycles) and P 50 mg/m2, both on day 1. All drugs were given i.v. Both response evaluation and toxicity grading were assessed according to World Health Organization criteria.
Results: Of the 161 eligible patients, 143 were assessable for survival, 148 for toxicity and 131 for response. Overall response rate was 45% [complete (CR) 14.5%, partial response (PR) 30.5%]. Most responsive disease sites were lung, lymph nodes and skin metastases (>60% response, CR rate >25%). Median duration of response was 7.6 months. Survival was significantly better in patients with only distant metastases: 12.9 months versus 8.6 months in those with other disease sites involved (P = 0.002). In a multivariate analysis, patients with a good performance status yielded a better prognosis (P = 0.0017), as did the patients with only metastatic disease compared with those who had pelvic disease also or solely (P = 0.045). There were two toxic deaths and 21% of patients stopped treatment because of excessive toxicity.
Conclusions: Patients with a good performance status and only distant metastases seem optimal candidates to receive the BEMP regimen. This benefit should be balanced against the expected serious toxic effects.
Key words: BEMP, cervical cancer, chemotherapy, metastatic, recurrent
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Treatment for recurrent or metastatic cervical cancer remains mainly palliative when local treatments have failed or deemed inappropriate. In such circumstances, the only reasonable option is systemic therapy, primarily chemotherapy. Results of such chemotherapy are usually inferior to those in patients treated with upfront chemotherapy as certain cofactors such as a reduced exposition of drugs to the tumor due to prior local therapies and a reduced sensitivity to drugs due to prior use of chemotherapeutic agents are present [1–3]. Over the last 20 years >50 single agents have been studied and >20 have displayed significant clinical activity defined as inducing a response rate of 15% or more, in tumors of squamous origin [4, 5]. Also many two- to four-drug combinations have been under investigation. These more aggressive combination chemotherapy regimens induce higher response rates than single agents do, but these still have to prove that they substantially prolong survival or improve quality of life [6, 7]. Cisplatin is the most intensively studied drug and has proven to be the most effective cytotoxic agent in this disease, also for histological cell types other than squamous cell carcinoma. Response rates with cisplatin, however, remain around 20%–30% (of which 10% are complete) and responses are usually of short duration. Combinations of cisplatin with some newer agents include those with paclitaxel [8], topotecan (TP) [9], vinorelbine [10, 11] and gemcitabine [12]. The most interesting data have come forward from the recent randomized phase III studies using such agents, indicating that we are at the brink of changing our concept of preferring single-agent cisplatin [8, 9]. In the last two decades of the last century, the Gynecological Cancer Group (GCG) of the European Organization for Research and Treatment of Cancer (EORTC) conducted studies in patients with disseminated cervical cancer to determine the efficacy of different combination chemotherapy regimens, most of them containing at least the combination of bleomycin and mitomycin C, as promising results had been reached with these agents [13]. After the completion of the VBMP (vincristine, bleomycin, mitomycin C, and cisplatin) and MP (mitomycin C plus cisplatin) studies [14, 15], the role of vincristine in the VBMP regimen was questioned, and replaced by vindesine after a straightforward phase II trial had shown activity of this agent as a single agent [16]. In 2001, the EORTC–GCG published their results of the four-drug regimen bleomycin/vindesine (Eldisine®) mitomycin C/cisplatinum (BEMP) versus single-agent cisplatin obtained in a multicenter randomized phase III trial. Results demonstrated that the BEMP regimen indeed produced more responses than cisplatin alone did, but at the cost of more experienced toxicity and without a significant impact on survival [7]. Here we present the results of the phase II trial preceding that trial and focus on the disease site in relation to response to BEMP. Moreover, we tried to specify subgroups of patients who might benefit more than others from more aggressive cisplatin-based combination chemotherapy regimen.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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eligibility criteria
Eligible patients were those with histologically confirmed squamous cell carcinoma of the uterine cervix and evidence of disseminated disease, not suitable for curative therapy in the form of surgery or radiotherapy. Patients had to have measurable disease outside previously irradiated areas (associated or not with recurrence in pre-irradiated areas) and had to give informed consent to be treated with BEMP. Age had to be <75 years, life expectancy >3 months, World Health Organization (WHO) performance status 2 or less, patients had to be chemotherapy naive and prior radiotherapy was only allowed when not given within 8 weeks before study entry. Organ function had to be within acceptable limits defined as WBC >4.0 x 109/l, platelets >100 x 109/l, creatinine clearance >60 ml/min/1.73 m2 and serum bilirubin <1.5 mg/dl (<25 µmol/l). Patients with symptomatic brain or leptomengeal involvement, neurologic conditions which could interfere with neurologic toxicity or a condition of impaired mobility in which neurological toxicity might cause an unacceptable degree of incapacity, were considered ineligible. Also, severe pulmonary dysfunction [maximal breath capacity (MBC) <30 l/min, forced expiratory volume in 1 second (FEV1) <1000 ml] or psychiatric disorder were not permitted. Finally, patients were not allowed to have a previous or concurrent malignancy at another site with the exception of adequately treated basal cell carcinoma of the skin. Bone lesions only detectable on bone scans, sclerotic bone metastases and serous effusions were not permitted as single-tumor response parameters, and index lesions had to be situated outside previously irradiated areas and had to be measurable and evaluable by chest X-ray, computed tomography (CT) scan and/or ultrasound.
Investigations at baseline consisted of a complete physical and pelvic examination, complete blood counts, blood chemistry, creatinine clearance, urinanalysis, electrocardiography, measurement of indicator lesions by CT, clinical examination, ultrasound or X-ray and pulmonary function tests. Optional examinations carried out on indication were cystoscopy, a bone scan and audiometry. During the induction phase, complete blood counts were taken weekly, thereafter on day 1 and day 8 of each cycle. All laboratory tests were repeated before each treatment cycle. Tumor measurements were carried out after two and four treatment cycles. Thereafter, this was done every 3 months or sooner to confirm any late beneficial effect [complete response (CR) or partial response (PR)] or when progression was suspected.
treatment schedule
Treatment consisted of an induction phase of four cycles of BEMP and a maintenance phase where bleomycin was deleted from the treatment regimen. During the induction phase, the BEMP schedule was given as follows: after adequate hydration and check of sufficient diuresis, vindesine 3 mg/m2 was given first by i.v. push into a running i.v. infusion of dextrose 5% or normal saline. After this, cisplatin 50 mg/m2 diluted in 500 ml of normal saline was given over 3–4 h. Post-hydration continued for 18 h with an infusion rate of 500 ml/3 h. Diuresis was closely monitored and if this was <100 ml/h, 100 ml of a 20% mannitol solution was given with or without a small dose (5–10 mg) of furosemide. Thereafter, an infusion of bleomycin 15 mg/day was given for 3 days on days 2–4 followed by mitomycin C 8 mg/m2 as an i.v. bolus injection on day 5. Mitomycin C was given on alternate cycles (1, 3). On day 8 of each cycle, vindesine was repeated at a dose of 3 mg/m2. The BEMP regimen was repeated every 3 weeks for four cycles.
After the four cycles of BEMP, responding patients and those with stable disease (SD) continued treatment with MEP after an interval of 4 weeks. MEP differed from BEMP in that bleomycin was deleted from the schedule and both vindesine and mitomycin C were given before cisplatin on day 1. If so wished, patients could receive MEP on an outpatient basis. In that case, an adapted hydration schedule was used. Doses of the three drugs in MEP were as follows: vindesine 3 mg/m2 day 1 and 8, mitomycin C 6 mg/m2 on alternate cycles and cisplatin 50 mg/m2 day 1. Contrary to the use of BEMP during the induction phase, the MEP regimen during this maintenance phase was given once every 4 weeks.
dose modifications and evaluability
Dose modifications were determined by the severest toxicity and specified for hematologic, neurologic, hepatic, renal and pulmonary toxicity or other observed dysfunctions.
Toxicity was graded according to WHO criteria. In case of myelosuppression, all modifications were carried out referring to counts measured on day 1 (with exception of the vindesine dose in the MEP regimen given on day 8 which was adjusted according to the counts on that day). If WBC were <2.0 x 109/l and/or platelets <50 x 109/l on day 1, the schedule was postponed for 1 week. If the delay was longer than 2 weeks, the patient went off study. In case the WBC and platelets had recovered before that time to the abovementioned levels, the given dose was modified according to prespecified criteria. Prophylactic use of hematopoietic growth factors was not planned. Regarding neurotoxicity, in case of moderate paresthesia, the vindesine was reduced by 50%. In case of other grade II or III neurologic symptoms, vindesine and cisplatin were stopped. In case of hepatic toxicity, if bilirubin values were 25–50 µmol/l the vindesine and mitomycin C doses were reduced by 50%. If bilirubin values exceeded 50 µmol/l, the vindesine and mitomycin C doses were reduced by 75%. When creatinine clearance dropped below 45 ml/min bleomycin, mitomycin C and cisplatin were stopped and treatment continued with vindesine alone at a dose of 3 mg/m2 i.v. once every 2 weeks until disease progression. In case of severe pulmonary dysfunction during therapy (MBC reduced >25%) both bleomycin and mitomycin C were deleted from the regimen, and treatment was to be continued with vindesine/cisplatin, in which case vindesine (3 mg/m2) had to be given on day 1 and 8 and cisplatin (50 mg/m2) on day 1, once every 4 weeks.
Patients who were in CR were supposed to continue for 1 year with the protocol treatment after the complete remission was achieved or to stop earlier in case excessive toxicity occurred. Those with SD or partial remission were to continue until disease progression or excessive toxicity occurred, whatever came first. Patients were considered assessable for response if they had received at least two cycles of BEMP and had had no delay between these cycles of >2 weeks whatever the reason. If at any time during treatment it was believed that protocol treatment was detrimental to the health of a patient, this patient could be withdrawn from the study, with the reasons specified in the clinical record forms.
criteria for response
Responses were assessed according to WHO criteria [17]. CR was defined as complete disappearance of all clinically detectable tumor together with a return of relevant blood chemistries to normal values for at least 4 weeks. PR was defined as a 50% or more decrease in total tumor size of the lesions which was measured or evaluated to determine the effect of therapy by two observations not <4 weeks apart. This was to be found in the absence of progression of any lesion or any appearance of new lesions. SD (no change) was defined as a change of <50% reduction or <25% increase in the size of one or more measurable lesions for the duration of at least twelve weeks. Progression was defined as a >25% increase of lesions. Response was evaluated every two cycles during the induction phase and every three months (or sooner when indicated) during the maintenance phase. Responses were assessed after two and four treatment cycles. If there was progression after two cycles, BEMP was discontinued and patients went off study. In the maintenance phase, response to treatment was assessed every 3 months, or sooner if indicated.
statistical considerations
The main end points of this trial were response rate and toxicity. Originally, for this observational phase II study, a minimum number of 20 patients was planned. Once this number, however, was reached, it was decided to keep the trial open to include more patients in order to create larger subgroups of specific disease recurrence sites to be able to make a more reliable estimation of the chance of response in these sites. For any response comparison, use was made of the Fisher's exact test for 2 x 2 contingency table. Survival curves were constructed according to Kaplan–Meier and compared with a two-sided log-rank test [18]. For the multivariate analysis, a Cox proportional hazards model was used [19].
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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From April 1985 until September 1988, a total of 208 patients entered this study of which 161 patients were eligible and 114 patients were fully assessable. Forty-seven patients were ineligible for the following reasons: 10 patients had an inadequate disease stage or histopathology, seven were in a poor physical condition (WHO performance status >2), eight patients had prior treatment not allowed by the protocol, five patients had no measurable lesions, 11 patients started treatment before the trial was opened and for six patients no data were retrieved. Of 161 eligible patients, 114 were considered fully assessable (70%) and another 41 (26%) were partially assessable. Altogether, 143 patients were assessable for survival, 148 patients for toxicity and 131 for response. Six patients were not assessable at all for the following reasons: one patient never started treatment, one patient refused treatment, two patients had major protocol violations, i.e. one received an inadequate dosage, and the second received chemotherapy with incorrect intervals. No data were available for two patients. Although 31 institutions took part in the study, 70% of the included patients were accrued by 10 centers. The characteristics of all eligible patients are summarized in Table 1. The median number of cycles administered was 5 (range 0–12). It should be noted that most patients (138/161) had received radiotherapy, so most of the locoregional relapses occurred in pre-irradiated areas.
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response and survival.
The overall response rate in the 131 patients assessable for response was 45%. CR was observed in 19 patients (14.5%) and PR in 40 patients (30.5%). The median duration of response was 7.6 months from the start of treatment and 4.9 months from the onset of response. Maximal responses during the induction phase were obtained after the fourth cycle (see Table 2). Most responsive to BEMP were lung, lymph node and skin metastases (>60% response rate, CR rate >25%). Patients with only distant metastases, independent of the site, showed a higher response rate than those who had locoregional disease also (63.2% versus 34.1%; P = 0.002), most probably because lesions in the pelvic area (primary tumor, regional nodes and pelvic mass) responded less well. Taking the first three sites in Table 2 together (i.e. all pelvic disease sites), a CR rate of 8.5% and a PR rate of 22% were observed. Contrary to these data are those of patients with only distant metastases, in whom a CR rate of 26.5% and a PR rate of 36.7% were obtained. This translated also into a longer survival for these patients. Median survival for patients with only metastatic disease was 12.9 months [95% confidence interval (CI) 9.4–18.2 months] versus 8.6 months (95% CI 7.6–9.8 months) in those with other tumor sites also involved [hazards ratio (HR) 0.55, 95% CI 0.37–0.81; P = 0.002]. Median progression-free survival (PFS) for patients with only metastatic disease was 6.2 months (95% CI 4.8–10.2 months) versus 4.7 months (95% CI 3.5–6.6 months) in those with other disease sites (HR 0.71, 95% CI 0.5–1.02). There was no significant difference in survival between patients with only lung and/or lymph node metastases (n = 8) and those with only metastatic disease elsewhere (n = 44): 14.0 months versus 12.9 months. The median PFS of these two groups was 5.8 and 6.6 months, respectively. As mentioned earlier, disease in the pelvic area responded poorly. This is also evident from Table 3, showing the response rate by extent of disease. The difference that could be observed was in overall survival (OS) between patients with only distant metastases and those who also had locoregional disease (Figure 1). The difference in PFS was of borderline significance (HR 0.35, 95% CI 0.11–1.16, P = 0.09). In a multivariate analysis of prognostic factors (on all eligible patients), the following variables were incorporated in the model: performance status, prior treatment, International Federation of Gynecology and Obstetrics stage, age, only lung and/or lymph node metastases and extent of disease. The analysis showed that patients with a good performance status yielded a better prognosis (P = 0.0017), as did those with only metastatic disease, compared with the group including either only locoregional disease, or distant metastases and locoregional disease also (P = 0.045).
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toxicity
With respect to non-hematologic toxicity, all types of toxicity that were observed in >10% of the patients can be found in Table 4. Alopecia (91.1%) and nausea and vomiting (97.3%) occurred most frequently. Also, taking into account only severe toxic effects (WHO grade 3 and 4), alopecia and nausea and vomiting were the most frequently observed toxic effects. Nevertheless, considerable numbers of patients had drug fever (55%), diarrhea (48%) and peripheral neuropathy (41%). Regarding hematologic toxicity, the median lowest nadir values for platelets occurred in cycle 2 and for WBC in cycle 3. Further details on nadir values and grade 3 and 4 hematologic toxic effects can be found in Table 5. Of notice, nearly 50% of the patients experienced grade 3–4 leucopenia. This led to severe complications in two patients: one patient died of a candida sepsis during bone marrow aplasia after the first cycle of BEMP. A second patient died of a sepsis due to myeloid aplasia before the second BEMP cycle. A third patient died of acute renal failure, probably treatment related, after the seventh treatment cycle (MEP). A total of 28 (19%) of the 144 patients assessable for WBC toxicity developed infections. During the induction phase, doses were reduced in 6.2%, 33.1%, 41.7% and 41.7% of cycles 1, 2, 3 and 4, respectively. During the whole treatment program, 274 out of 821 cycles were reduced in dose (33.4%). With respect to dose delays: during the induction phase 21.3%, 26.7% and 25.0% of cycles 2, 3 and 4 were delayed, respectively. During the whole treatment program, 138 out of 675 follow-up cycles were delayed (20.4%). Most patients stopped chemotherapy because of tumor progression (n = 65, 44%). It should, however, be stressed also that 31 out of 148 stopped treatment because of excessive toxicity (21%).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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In this extensive phase II study, we demonstrated that patients with only distant metastases are the candidates who most likely benefit from a more aggressive chemotherapy regimen such as the BEMP we described in the present report. The overall results of this phase II trial are in line with the results found in the phase III study comparing treatment with BEMP with P [7]. This is illustrated in Table 6. As demonstrated in the phase III trial, a response rate of 42% for the BEMP arm versus 25% for the P arm did not translate into a longer PFS or OS for the combination chemotherapy arm. This is in agreement with many other studies testing cisplatin-based combination regimens in cervical cancer in the past. So far, they never showed any superiority in terms of prolonging survival, although in one Gynecologic Oncology Group (GOG) trial some benefit in PFS was observed with the addition of ifosfamide [6]. Only in two more recent phase III studies, the experimental combination was considered superior to cisplatin alone, with only one of the two showing an OS benefit. The first study, undertaken by the GOG, compared cisplatin, with or without paclitaxel in 264 eligible patients [8]. The experimental arm showed a higher response rate (36% versus 19%) and a higher CR rate (15% versus 6%) than the cisplatin-alone arm and a longer PFS (4.8 months versus 2.8 months in the cisplatin arm, P <0.001) with sustained quality of life. The second study, also carried out by the GOG, was a phase III trial in which 364 patients with stage IVB, recurrent or persistent cervical cancer were randomized between treatment with either cisplatin alone, cisplatin with topotecan (TP) or a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC). The latter arm stopped early due to excessive toxicity. The TP arm, however, yielded a survival benefit over cisplatin alone, a unique observation. The median PFS was 4.6 months versus 2.9 months (adjusted HR 0.78, P = 0.0075), and the median OS 9.4 months versus 6.5 months (HR 0.77, P = 0.021) [9]. No final conclusion in that study could be obtained about response by site (as pelvic only or extrapelvic with or without pelvic involvement) and its impact on survival. The large number of patients included into our trial was the result of an attempt to achieve considerable subgroups of patients with different disease sites. The goal was to determine whether patients with specific disease sites in particular might benefit from treatment with BEMP in terms of survival. As already demonstrated in previous studies, patients with only metastatic disease do better and have the highest response rates [2, 7]. In the present trial, these patients also had a better survival compared with patients with locoregional disease only or those with locoregional disease plus distant metastases. In those with only distant metastases, we were not able to indicate a specific disease site that corresponded with a better survival. In particular, patients with only lung and/or lymph node metastases, the group with the highest response rates (Table 2) did not do better than those with distant metastases elsewhere. This might be partly explained by the fact that although the trial was kept open for a longer period of time, the number of patients with only lung and/or lymph node metastases assessable for survival was extremely low (n = 8). It has to be stressed, however, that in a previous study on VBMP in the EORTC–GCG, a longer PFS was found, and survival benefit was suggested for those patients with only lung and/or lymph node disease [14]. In order to identify more favorable subgroups with respect to survival, larger numbers of the specific categories are needed. We are now preparing a combined analysis of EORTC–GCG trial 55851 (this report) and 55863 [7] with the hope that we might be able to find such categories.
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In conclusion, this is yet another trial where an increase in response rate goes hand in hand with increased morbidity. In this trial, 21% of patients stopped treatment because of excessive toxicity. Therefore, the search for better chemotherapeutic regimens should continue. It is clear that an individual approach towards patients with this stage of disease is necessary to provide the most optimal care balancing the use of only palliative measures versus more aggressive treatment with a curative intent.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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We acknowledge the following colleagues as co-authors: C. F. de Oliveira, Servicio de Ginecologia, Hospitais da Universidade de Coimbra, Coimbra Portugal; S. Pecorelli, Universita da Brescia, Brescia, Italy; B. Lund, Rigshospitalet Copenhagen, Denmark; W. W ten Bokkel Huinink, Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands; J. Wils, St. Laurentius Ziekenhuis Roermond, The Netherlands; L. V. A. Beex, St Radboud University Hospital, Nijmegen, The Netherlands; H. Bonnefoi, Hopital Cantonal Universitaire de Geneve, Geneve, Switzerland; J. P. Guastalla, Centre Leon Berard, Lyon, France; C. H. N. Veenhof, Amsterdam Medical Centre, Amsterdam, The Netherlands; S. Tumolo, Centro di Referimento Oncologico, Aviano, Italy; J. B. M. Z. Trimbos, Leids Universitair Medisch Centrum, Leiden, The Netherlands.
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Present address: Medical Center Haaglanden, Lijnbaan 32, 2512 VA Den Haag, The Netherlands 
Received for publication April 12, 2006. Revision received August 12, 2006. Accepted for publication September 11, 2006.
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References |
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