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© 1999 American Society for Clinical Oncology Cisplatin, Gemcitabine, and Vinorelbine Combination Therapy in Advanced Non–Small-Cell Lung Cancer: A Phase II Randomized Study of the Southern Italy Cooperative Oncology GroupFrom the Division of Medical Oncology A, National Tumor Institute, Naples; Divisions of Medical Oncology and Pneumology, Cardarelli Hospital, Naples; Division of Medical Oncology, San Carlo Hospital, Potenza; Division of Medical Oncology, Oncology Institute, Bari; Division of Thoracic Surgery, San Paolo Hospital, Bari; Division of Pneumology, General Hospital, Caserta; Unit of Medical Oncology, Da Procida Hospital, Salerno; Unit of Medical Oncology, San Gennaro Hospital, Naples; and Department of Respiratory Diseases, School of Medicine, Second University of Naples, Italy; email pcomella@sirio-oncology.it. Address reprint requests to Pasquale Comella, MD, Division of Medical Oncology A, via M. Semmola 80131, Naples, Italy.
PURPOSE: In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non–small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen.
PATIENTS AND METHODS: One hundred eleven chemotherapy-naive patients, age RESULTS: Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms. CONCLUSION: The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.
ALTHOUGH NOTABLE progress has been made in the field of chemotherapy of solid tumors, advanced non–small-cell lung cancer (NSCLC) has remained relatively refractory to cytotoxic chemotherapy.1 A cisplatin (CDDP)-based chemotherapy is considered the standard front-line treatment in patients with advanced NSCLC, considering the small but significant survival gain when compared with regimens that do not contain CDDP,2 but more effective cytotoxic agents are needed to substantially modify the fate of these patients. Among the new agents, taxanes, vinorelbine (VNR), irinotecan, and gemcitabine (GEM) seem the most promising in view of their particular mechanism of action, favorable toxicity profile, good activity level, and, finally, the synergism with CDDP shown both in vitro and in vivo.3,4 VNR has been shown to have a very promising activity as a single agent, with negligible neurotoxicity. Moreover, the CDDP-VNR combination showed a clear therapeutic advantage over CDDP or VNR as single agents and in comparison with the CDDP-vindesine combination in two large phase III randomized trials.5,6 GEM is a new anticancer drug with novel metabolic properties and mechanisms of action.7,8 GEM has been shown to synergize with drugs that play a role in the treatment of lung cancer, such as CDDP, VNR, ifosfamide, and mitomycin, and may also synergize with radiation.9,10 Several phase II and, more recently, phase III trials have been conducted in the last few years to test GEM as a single agent in patients with advanced NSCLC, with a response rate almost always exceeding 20% and a median survival duration longer than 8 months.11-14 Interestingly, GEM as a single agent gave a similar response rate and overall survival and better quality of life when compared with CDDP-etoposide.13,14 The GEM-CDDP combination has already been tested in several phase II and III trials, with response rates of approximately 40% and a median survival duration ranging from 10 to 13 months.15-18 In view of these considerations, we previously tested the combination of both VNR and GEM with CDDP in a phase I study. We kept the dose of CDDP fixed and attempted to escalate the doses of the other two drugs. Taking into account the previous toxicity data reported by the investigators15,16 who had tested the CDDP-GEM regimen, we chose to administer all drugs on days 1 and 8 of a 3-week cycle. We found that GEM 1,000 mg/m2 and VNR 25 mg/m2 could be safely added to CDDP 50 mg/m2 on days 1 and 8. Moreover, this combination yielded encouraging results in terms of both response rate and overall survival.19 In view of these considerations, we started this phase II trial to better define the activity and toxicity of this regimen in patients with advanced NSCLC at the doses selected in the previous phase I study. To avoid selection biases, we decided to randomize our patients and chose the combination of CDDP, epirubicin, vindesine plus lonidamine (PEV-LND), with which several investigators who participated in the present trial were already familiar, as standard treatment. In a previous randomized study,20 this regimen had obtained an overall response rate (ORR) of 43% and a median survival duration of 11 months.
Eligibility Criteria Chemotherapy-naive patients  70 years of age were eligible if they had histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic NSCLC. No prior chemotherapy or thoracic radiotherapy was allowed. Patients were required to have adequate bone marrow function (absolute neutrophil count  2 x 109/L, platelet count 100 x 109/L, and hemoglobin level 100 g/L), liver function (bilirubin level < two times the upper limit of normal, AST and/or ALT < three times the upper limit of normal, prothrombin time < 1.5 times control), and creatinine clearance 60 mL/min. The presence of CNS metastases, severe cardiac arrhythmia or heart failure, second- or third-degree heart block, and acute myocardial infarction within 4 months before study entry were considered exclusion criteria. A performance status 1 on the World Health Organization (WHO) scale (Karnofsky score 70) and a life expectancy of at least 12 weeks were also required. All patients gave written informed consent, and the trial was approved by the Ethical Committee for the Biologic Research of the National Tumor Institute of Naples.
Diagnostic Procedures Physical examination, laboratory tests, and chest radiograph were performed at each chemotherapy course, and all diagnostic procedures required to evaluate response to treatment were performed after the third and sixth course. A complete blood cell count was performed weekly.
Treatment Regimens A short-term hyperhydration (2 L of normal saline over 4 hours) was performed in both arms on the day of chemotherapy administration. All patients received an antiemetic prophylaxis consisting of hydroxytryptamine-3–receptor antagonists plus 20 mg of dexamethasone.
In patients who received the experimental treatment, full doses of chemotherapy were given if neutrophil and platelet counts on the day of treatment were In patients who received the standard regimen, treatment was delayed by 1 week if grade 1 or more neutropenia or thrombocytopenia occurred. Chemotherapy was delivered at 75% if grade 1 myelotoxicity persisted after a 1-week delay. The doses of each drug were reduced in both arms by 25% if WHO grade 4 neutropenia or thrombocytopenia or grades 3 or 4 nonhematologic toxicity had occurred in the previous cycle. CDDP was reduced by 50% for creatinine serum levels of 131 to 180 mmol/L and suspended for levels greater than180 mmol/L. The use of granulocyte colony-stimulating factor was allowed in the presence of grade 4 neutropenia that lasted more than 7 days or neutropenic fever, or if grade 2 or more neutropenia persisted after 2 weeks from the scheduled time of chemotherapy administration. The treatment was definitively discontinued if more than grade 1 neutropenia or thrombocytopenia or major nonhematologic toxicity persisted 3 or more weeks after the scheduled time of recycling.
Response and Toxicity Evaluation The WHO grade scale21 was also used to record toxicity. Toxicity was assessed before each cycle of chemotherapy, and hematologic assessments were also performed weekly to determine the toxicity at the nadir. For toxicity analysis, the worst data for each patient in all cycles of chemotherapy were used. Performance status (according to either Eastern Cooperative Oncology Group or Karnofsky scale) and symptom assessments were performed before each cycle of chemotherapy. Quality of life, although not an end point of this study, was assessed in patients at two participating centers by analyzing a 10-item questionnaire completed by patients at diagnosis, after three and six cycles, and thereafter every 3 months until death. This questionnaire was derived from the Lung Cancer Symptom Scale.22 In the first section, we included the five most frequent disease-related symptoms (cough, loss of appetite, dyspnea, fatigue, and pain), whereas the other five-item section concerned psychologic, social and emotional aspects and general well-being. Compared with the Lung Cancer Symptom Scale, we expanded the number of items concerning the social and emotional aspects to obtain a better evaluation of the subjective aspects of quality of life. Each item was scored according to a five-step scale ranging from zero (absence of any symptom, or any impairment of quality of life) to four (the worst symptom grade possible). A decrease of the summation score (ranging from zero to 40) was required to define the achievement of improved quality of life. We had already used this questionnaire to evaluate the quality of life in a previous study in elderly patients with NSCLC. It had proven to be an easy and reliable way to determine the subjective status of the patients, and there was a strict correlation between the quality-of-life score and both the objective response achievement and the performance status changes.23 The same score used in the questionnaire for the five disease-related symptoms (cough, dyspnea, pain, loss of appetite, and fatigue) was adopted for the physician-performed assessment of symptom improvement. A decrease of any grade of the total score was required to define symptom relief achievement.
Statistical Methods and Study Design Randomization was performed centrally at the Division of Medical Oncology A of the National Tumor Institute in Naples, Italy. Stage (IIIB v IV) and center were used as stratifying variables. Patients not assessable for response (because of treatment refusal or early treatment discontinuation for reasons other than progression) were considered as nonresponding in the calculation of the objective response rate; we also calculated the 95% exact confidence intervals (CIs) for response rates. Patients who received at least one cycle of chemotherapy were considered eligible for quality-of-life evaluation. For survival analysis, the day of randomization was considered the date of entry. Analysis was conducted on the basis of randomization (intent to treat) and on the follow-up data available as of February 28, 1998. Progression-free survival was defined as the time elapsed from the date of entry to the date of progressive disease or death without progression. Overall survival was measured from the date of entry to the date of death or last follow-up evaluation. Survival curves were estimated by the Kaplan-Meier product-limit method.25 A Cox model26 was used for multivariate analysis of assigned treatment, as well as of the effect on survival of pretreatment variables, including sex (male v female), age (< 60 years v others), performance status (0 v 1), stage (IIIB v IV), and histotype (squamous v others) as covariates.
Demographics Between October 1995 and March 1997, a total of 145 patients, of whom 141 were eligible (63 stage IIIB and 78 stage IV disease), were entered onto the study. Two patients in each arm were excluded because of major protocol violations (performance status of 2 in three patients, hemoglobin level < 100 g/L in one). Overall, 87 patients were assigned to experimental treatment (arm A), compared with 54 patients assigned to control treatment (arm B). This unequal distribution occurred because randomization was stopped in December 1996 (57 and 54 patients had been enrolled, respectively). At that time, we had performed a second interim analysis to verify whether at least 17 objective responses had been recorded in the first 46 patients treated with the experimental regimen. Unexpectedly, we observed that the minimum number of responses31 required on the whole study population to consider the experimental treatment worth further evaluation in phase III had already been reached at that time. Therefore, the study could be considered virtually closed, but we decided to treat more patients with the experimental regimen to better estimate its activity, and stopped the accrual in arm B because we considered it unethical to keep treating patients with a regimen that showed an activity rate remarkably lower than that of the experimental treatment. Although the last 30 patients who received the experimental treatment were not randomized, the two arms were fairly well balanced for the main pretreatment characteristics (Table 1). A slightly lower prevalence of stage IIIB disease occurred in arm B, in which more patients showed a squamous histology compared with those in arm A. However, these differences were not statistically significant.
Response
We analyzed separately the data concerning the first 57 patients randomly allocated to the experimental arm. The ORR was even higher in this subgroup (60%). Stage IIIB disease was associated with a higher response rate in both arms (63% and 41% in the experimental and control arms, respectively), compared with stage IV disease (52% and 34%, respectively), but these differences did not reach the level of statistical significance. A slightly higher response rate, although not statistically significant, was also observed in the experimental arm for patients with an Eastern Cooperative Oncology Group performance status of 0 (67% v 54% for those with a performance status of 1) and squamous histology (63% v 50% for those with other histology), whereas the ORR did not vary according to performance status and histology in the control arm. Performance status improved in 48 (55%) and 20 (37%) patients in the experimental and control arms, respectively. Forty-nine (60%) of 81 patients who received CDDP-GEM-VNR and who had at least one symptom at diagnosis showed complete10 or partial39 symptom relief during the course of the treatment. Symptom improvement was observed in 20 (38%) of 51 assessable patients who received PEV-LND (Table 3). Quality of life was evaluated in 74 of 141 patients (51 in the experimental arm and 23 in the control arm). The quality-of-life score improved in 30 (59%) of 51 patients and nine (39%) of 23 patients, respectively. The improvement of quality-of-life score was very much related to the achievement of the objective response and symptom relief. In fact, among the 39 patients with improved quality-of-life score, 35 had an objective response and 37 showed symptom relief (Table 4).
After a median follow-up duration of 82 weeks (range, 52 to 121 weeks), 31 patients were still alive and 25 were progression-free in the experimental arm, for median progression-free and overall survival durations of 32 weeks (95% CI, 27 to 38 weeks) and 50 weeks (95% CI, 41 to 58 weeks), respectively. Median time to progression and overall survival were 18 weeks (95% CI, 11 to 26 weeks) and 33 weeks (95% CI, 24 to 41 weeks), respectively, in the control arm. The 1- and 2-year survival probabilities were 48% and 19% in the experimental arm, compared with 29% and 0% in the control arm, respectively (Fig 1). Median survival was substantially longer in patients with stage IIIB than stage IV disease (61 v 47 weeks and 42 v 29 weeks in the two arms, respectively; Fig 2), and in those with a performance status of 0 compared with 1 (62 v 46 weeks and 36 v 22 weeks in the experimental and control arms, respectively). The Cox analysis performed on the whole population failed to identify any pretreatment features that significantly affected survival.
Response to treatment was associated with a longer survival duration in both arms (62 v 39 weeks and 41 v 26 weeks in the experimental and control arms, respectively). Interestingly, median survival of nonresponders who had received the CDDP-GEM-VNR regimen was similar to that of responder patients treated with the PEV-LND combination (Fig 3). When response to treatment was included into the Cox model as a time-dependent covariate after stratification for treatment, it was strongly predictive of a longer survival outcome. The relative risk of dying was 1.98 (range, 1.26 to 3.12) in nonresponders compared with responders (P = .004).
Toxicity Both regimens were associated with a manageable toxicity. No toxic deaths occurred. Only five patients (three in the experimental and two in the control arm) discontinued treatment early because of severe toxicity. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of the patients in the experimental arm and in 22% and 11% of those of the control arm, respectively (Table 3). Nine patients in the experimental arm were hospitalized because of neutropenic fever, compared with two patients in the control arm. Overall, three patients (two in the experimental and one in the control arm) required platelet transfusions because of symptomatic thrombocytopenia. The occurrence of severe anemia, requiring packed RBC transfusions, was similar in the two arms (almost 10% of patients). Hematologic toxicity was more frequent and severe after the third cycle, and as a consequence of delay and/or dose reductions, the median delivered dose-intensity of all drugs in the experimental arm was 78% in the last three cycles, compared with 93% in the first three cycles. Chemotherapy was reduced at least once in 58 of 87 patients in the experimental arm, and this reduction was permanent in 23 patients because of the occurrence of grade 4 hematologic or grade 3/4 nonhematologic toxicity. 
Severe nonhematologic toxicity was uncommon in both arms. Grade 3 to 4 nausea/vomiting occurred in four (5%) of 87 patients who received CDDP-GEM-VNR treatment, compared with seven (13%) of 54 of those treated with PEV-LND. Grade 1 to 2 peripheral neuropathy occurred in 17 patients (11 who received the CDDP-GEM-VNR regimen and six treated with PEV-LND). A mild or moderate increase of the serum levels of creatinine was observed in five patients in the experimental arm and four patients in the control arm. The administration of CDDP-GEM-VNR was associated with a transient increase of the hepatic enzymes in seven patients and caused thrombocytosis in five. Lonidamine-related arthralgias and abdominal pain were observed in 10 and 12 patients, respectively, resulting in the discontinuation of lonidamine administration in only two cases.
In the last decade, the introduction into the clinical practice of several new drugs with proven antitumor activity in patients with NSCLC has renewed the interest of clinical oncologists in the treatment of this disease. As a consequence, the number of clinical trials testing new drugs or combinations in this field has increased dramatically. Recently, the combination of GEM and CDDP has become popular in view of its high therapeutic activity and good tolerance.15-17 Although GEM administration on days 1, 8, and 15 every 4 weeks (with platinum given on days 1, 2, or 15) has been used initially, there are some concerns about the third dose of GEM, which was frequently omitted because of the occurrence of myelotoxicity at the scheduled time. Therefore, a modified regimen has been proposed, in which GEM administration on day 15 is deleted, and recycling is shortened by 1 week. These changes do not seem to cause an impairment of antitumor activity.18,19,27 Although the number of clinical trials testing the GEM-CDDP combination is still growing, it is a bit surprising to note that the addition of GEM to standard chemotherapy regimens has not yet been attempted. We believed that it could be worthwhile to include GEM in a three-drug regimen containing CDDP and VNR because we were interested in putting together a non–phase-specific drug, such as CDDP, with two phase-specific agents that affect two different steps of the cell cycle. The results of our previous phase I study showed that it was possible to give this three-drug combination at full doses of all drugs, with very manageable toxicity.19 In fact, the compliance to the treatment was excellent in the majority of patients, given the negligible proportion that complained of severe hematologic, gastrointestinal, renal, or neurologic toxicity. In our opinion, the schedule we adopted (all drugs were administered on days 1 and 8 every 3 weeks) played a major role in producing this result and also permitted easy outpatient administration of treatment. The aim of the present phase II study was to define the activity of this new regimen in advanced disease. Our results show that our combination has very promising antitumor activity. Indeed, the ORR in patients who received the CDDP-GEM-VNR combination was 20% higher than that observed in those treated with the regimen of PEV-LND. In view of the large number of patients treated, there is a 95% probability that the true activity rate of our experimental regimen exceeds 45%. Even in stage IV disease, the CDDP-GEM-VNR combination seems able to yield a more than 50% ORR. The 50-week median survival duration does not seem particularly impressive, but such a long median survival time has never been reported in randomized trials. Median survival durations longer than 1 year were previously reported in phase II trials that tested GEM-CDDP,15,16 or carboplatin and paclitaxel28 regimens, but confirmatory randomized trials are still awaited. It must be noted that the median potential follow-up was substantially longer in our study than in those by Crinò et al15 and Abratt et al,16 making our survival data much more mature. Evidence of an approximately 20% 2-year survival probability is particularly encouraging, especially if we take into account the fact that 25 of the 31 patients who are still alive are also progression-free. The median survival time of patients with stage IV disease (47 weeks) was also promising, in comparison with the figures generally reported with other chemotherapy regimens in this subpopulation.1 Another result that should be stressed is the substantial quality-of-life gain obtained with the CDDP-GEM-VNR treatment. In fact, almost 60% of patients experienced a performance status improvement and symptom relief. A formal assessment of the quality-of-life changes, by means of a patient-completed questionnaire, was performed in only a subgroup of patients, but a strict correlation between objective response achievement, symptom relief, overall survival, and improvement of quality-of-life score seemed evident. It could be objected, on the basis of the promising response and survival data reported by several investigators with the GEM-CDDP combination,15,16 that the addition of VNR to this regimen does not produce a substantial therapeutic gain. We freely admit that it is still unproven whether the addition of a third drug to CDDP-GEM results in a substantial advantage in survival outcome and quality of life. However, we would like to make the following remarks on this matter. First, our results were obtained in a randomized study. Although randomization was not performed in the last 30 patients, it is clear that no selection bias occurred that could have overestimated the activity rate of the experimental regimen, considering that the activity of the PEV-LND regimen in this trial was slightly lower than that previously reported,20 and taking into account the even higher response rate observed in the first 57 randomized patients randomly allocated to the experimental arm. Another result that must be stressed is the fact that nonresponding patients treated with CDDP-GEM-VNR had a median survival time similar to that of responding patients who received PEV-LND. The duration of response, of course, strongly affects the survival length. In the past, the achievement of a higher response rate with more aggressive treatments often failed to translate into a significant survival advantage, probably because of the excessively short duration of the response in most patients. In our study, many patients who received the CDDP-GEM-VNR regimen were still progression-free after 6 months from the end of chemotherapy, and the median time to progression (34 weeks) observed in the whole population was impressive, especially considering that it was only 18 weeks in the control arm. The prognostic relevance of the response achievement seems to be confirmed by the results of a recent retrospective landmark analysis conducted by the European Lung Cancer Working Party. Among patients who were alive at 12 weeks from the beginning of chemotherapy, the survival duration (starting from that point on) was more than double in those who showed a complete or partial tumor regression compared with the others.29 Furthermore, the toxicity associated with our regimen was quite mild, despite the much higher amount of drugs delivered, in comparison with that used by the other investigators who tested the two-drug CDDP-GEM regimen. In fact, the occurrence of grade 4 neutropenia and thrombocytopenia was lower in our study than in studies by Crinò et al15 and Abratt et al.16 The occurrence of life-threatening toxicity was completely unknown in our patients, and among nonhematologic toxicities, gastrointestinal, neurologic, and renal side effects were mild, perhaps also because we used a split dose of CDDP. Finally, even if it is still to be demonstrated that "more is better" in patients with metastatic NSCLC, the development of more aggressive combinations could be of some utility in the treatment of patients with less advanced disease. There is an increasing body of evidence that suggests a substantial increase in long-term survival with the combination of chemotherapy with radiotherapy or surgery, in stage IIIA or IIIB disease.30-33 It is reasonable to believe that the optimization of chemotherapy (ie, the use of multidrug combinations, including agents with a different mechanism of action) could translate into a further improvement of the efficacy of this multidisciplinary approach. In view of these considerations, we believe that our regimen deserves to be compared with those regimens considered more effective in the treatment of patients with NSCLC with either operable or advanced disease. Therefore, in April 1997, the Southern Italy Cooperative Oncology Group started a three-arm phase III trial to compare the CDDP-GEM-VNR regimen with both the CDDP-GEM and CDDP-VNR combinations in locally advanced inoperable or metastatic NSCLC. The design of this phase III trial should clarify whether a substantial difference in antitumor activity exists between GEM and VNR when added to CDDP and whether the combination of both drugs with CDDP is of any advantage when compared with the addition of only one of them. In conclusion, the combination of CDDP with both GEM and VNR has been shown to be feasible, well tolerated, and highly active in patients with advanced-stage NSCLC. The randomized nature of this trial and the large series of treated patients makes us confident that both ORR and survival associated with this treatment will be confirmed in future phase III trials. Properly designed phase III trials are required to define the role of this new regimen in the treatment of patients with operable or inoperable NSCLC.
Study Participants The Southern Italy Cooperative Oncology Group conducted this study with the cooperation of the following institutions and investigators: Division of Medical Oncology A (Pasquale Comella, Giuseppe Frasci, Adriano Gravina, John Perchard, and Giuseppe Comella) and Division of Thoracic Surgery (Pasquale Ruffolo, Tindaro Gatani, and Raimondo Di Giacomo), National Tumor Institute of Naples. Division of Medical Oncology (Nicola Panza, Gianpaolo Nicolella, Carmen Pacilio, and Giovanni Pacilio) and Division of Pneumology (Michele Natale), Cardarelli Hospital, Naples. Division of Medical Oncology (Luigi Manzione and Domenico Bilancia), San Carlo Hospital, Potenza. Division of Medical Oncology (Vito Lorusso and Mario De Lena), Oncologic Institute of Bari, Bari. Division of Thoracic Surgery (Franco Carpagnano and Gaetano Di Rienzo), San Paolo Hospital, Bari. Division of Pneumology (Riccardo Cioffi), City Hospital of Caserta, Caserta. Division of Pneumology (Giuseppe De Cataldis and Pietro Carnicelli), Daprocida Hospital, Salerno. Unit of Medical Oncology (Luigi Maiorino), San Gennaro Hospital, Naples. Chair of Respiratory Diseases (Enrico Micillo, Andea Bianco, and Paolo Marcatili) and Chair of Medical Oncology (Giuseppe Catalano and Michele Della Vittoria), School of Medicine, Second University of Naples, Naples. Division of Pneumology (Franco Piantedosi), Monaldi Hospital, Naples. Unit of Medical Oncology (Giovanni Ianniello), Rummo Hospital, Benevento. Unit of Medical Oncology (Mario Belli and Filomena Del Gaizo), City Hospital, Avellino.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
—, control arm, stage IIIB; – –
