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© 1999 American Society for Clinical Oncology Cisplatin, Gemcitabine, and Paclitaxel in Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: A Phase I-II StudyFrom the Southern Italy Cooperative Oncology Group, National Tumor Institute of Naples, Naples, Italy. Address reprint requests to Dr. Giuseppe Frasci, Division of Medical Oncology A, via M. Semmola 80131, Naples, Italy; email gifrasei{at}sirio-oncology.it
PURPOSE: Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non–small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS: From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m2) and gemcitabine (1,000 mg/m2) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS: Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m2 in pretreated patients, whereas it continued to 150 mg/m2 in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m2 was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patient's disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION: The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.
OVER THE LAST few decades, advances in cancer chemotherapy have produced a remarkable prognostic improvement for several neoplasms, but advanced non–small-cell lung cancer (NSCLC) has remained relatively refractory to cytotoxic chemotherapy.1 In view of the results of a meta-analysis of randomized trials, platinum-based chemotherapy is today considered to be the standard front-line treatment in patients with advanced NSCLC, but there is still much debate about the best drugs to be combined with cisplatin.2 Recently, several new agents have been shown to have a level of single-agent activity against NSCLC that is greater than the 15% threshold.3 Among them, the taxanes, vinorelbine, irinotecan, and gemcitabine seem to be the most promising, because of their peculiar mechanism of action, good activity level, and, last but not least, their synergism with cisplatin as shown both in vitro and in vivo.4 Two phase II studies5,6 using paclitaxel alone showed response rates of 21% and 24%, respectively, which wereamong the highest ever recorded with single-agent therapy in NSCLC. In combination with platinum compounds, paclitaxel has again shown promising results in terms of both response rate and overall survival.7-9 Two recent phase III trials10,11 conducted in the United States and Europe, have compared cisplatin-paclitaxel with either cisplatin-etoposide or cisplatin-teniposide, and this first combination is now considered to be the standard therapy for both the Eastern Cooperative Oncology Group [ECOG]10 and the European Organization for Research and Treatment of Cancer.11
Gemcitabine is a new anticancer drug with novel metabolic properties and mechanisms of action. Several phase II trials have been conducted in the last few years testing gemcitabine as a single-agent mode of therapy in advanced NSCLC patients. In almost all of these trials, gemcitabine produced a response rate exceeding 20%, with a median survival of more than 8 months.12-14 On the basis of the drugs' single-agent activities, nonoverlapping toxicities, and preclinical data suggesting synergy between them, clinical trials combining gemcitabine and cisplatin have been carried out.15-18 An overall response rate (ORR) In view of these considerations, we have undertaken this phase I-II study with the aim of determining the maximum-tolerated dose (MTD) of paclitaxel when it is given in combination with fixed doses of cisplatin and gemcitabine on days 1 and 8 every 3 weeks, and we aimed to define the antitumor activity of this new regimen in advanced NSCLC patients.
Eligibility Criteria Chemotherapy-naive or pretreated patients  75 years of age were eligible if they had histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic NSCLC. Patients who had received previous treatment with gemcitabine or paclitaxel were not eligible. Patients were also 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), adequate liver function (bilirubin level < two times the upper limit of normal, AST and/or ALT levels < three times the upper limit of normal, prothrombin time < 1.5 times control), and a creatinine clearance rate 60 mL/min. The presence of severe cardiac arrhythmia or heart failure, second- or third-degree heart block, or acute myocardial infarction within 4 months before entry onto the study were considered exclusion criteria. The presence of CNS metastases was not considered as an exclusion criterion, provided that a good control of the symptoms had been obtained with corticosteroids. A performance status 2 on the World Health Organization (WHO) scale and a life expectancy of at least 12 weeks were also required. All patients gave their written informed consents, and the protocol was approved by the Ethical Committee for the Biologic Research of the National Tumor Institute of Naples.
Diagnostic Procedures The physical examination and routine laboratory tests were performed at the time of each chemotherapy course, and all of the diagnostic procedures required to evaluate response to treatment were performed after the third and sixth courses. In the phase I study, a complete blood cell count was performed twice a week during the first treatment cycle and weekly thereafter.
Treatment Cisplatin and gemcitabine were each suspended in 500 mL of 0.9% sodium chloride and infused over 30 minutes. Paclitaxel was supplied by Bristol-Myers Squibb Co. (Rome, Italy). It was administered in 500 mL of 0.9% sodium chloride over 1 hour, soon after the administration of cisplatin and then followed by gemcitabine. The antiemetic prophylaxis consisted of hydroxytryptamine-3–receptor antagonists plus 20 mg of dexamethasone. All patients received premedication to prevent hypersensitivity reactions. Dexamethasone 20 mg intravenously, ranitidine 50 mg intravenously, and promethazine 50 mg intramuscularly were administered 1 hour before the start of the paclitaxel treatment.
Full doses of chemotherapy were given if the neutrophil and platelet counts on the day of treatment were
Study Design Phase II study. A Simon two-stage minimax design19 was chosen for definition of the total number of patients required for the phase II study. We set an overall response rate of 50% as the target activity level and chose 30% as the lowest overall response rate (ORR) of interest. At least 17 objective responses among 39 patients were required for this new combination to be considered worthy of further evaluation.
Response Evaluation Criteria
Quality of Life Evaluation We had previously used this questionnaire to evaluate QOL. It proved to be an easy and reliable way to determine the subjective status of the patients, and there was a very strict correlation between the QOL score and both the objective response achievement and the performance-status changes.23,24 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 the symptom improvement.
Characteristics of Patients A total of 75 patients entered onto this study through five dose escalations. Ten pretreated patients entered onto the first two cohorts (paclitaxel 50 mg/m2 and 75 mg/m2). Because three of six patients showed DLT at the second step, the accrual of pretreated patients was stopped, and the study was continued by our enrolling only chemotherapy-naive patients. The fourth paclitaxel dose level (125 mg/m2) was recommended for phase II, and 39 patients were included in this cohort overall. Thirty-three of these 39 patients were entered onto the trial in a randomized fashion. Indeed, from December 1997, after which the paclitaxel dose advisable for phase II had been selected (six patients had already been treated at that level), an additional 33 patients were included in this cohort, after a preliminary randomization between the cisplatin-gemcitabine-paclitaxel regimen and the inclusion in a three-arm phase III trial (cisplatin-gemcitabine-vinorelbine v cisplatin-gemcitabine v cisplatin-vinorelbine), which had started in May 1997. The baseline characteristics of the patients in the study presented here are listed in Table 1. There was a total of 64 men and 11 women, with a median age of 62 years (range, 40 to 73 years). Twenty-eight patients had stage IIIB disease and 47 had stage IV disease. Asymptomatic CNS involvement was present in nine patients. Among the 39 patients treated at the paclitaxel MTD, 13 had stage IIIB disease and 26 (13 of whom had two or more metastatic sites) had stage IV disease. Eight had an ECOG performance status of 2, and five had brain metastases.
Dose Escalation Results
An additional 26 chemotherapy-naive patients were treated through three increasing paclitaxel dose levels (100 mg/m2, five patients; 125 mg/m2, six patients; 150 mg/m2, 15 patients). Only one episode of DLT occurred at the dose of 100 mg/m2 and one at that of 125 mg/m2, consisting in each case of neutropenia on day 8 (of grade 2 and 3, respectively), which precluded the chemotherapy administration. At the paclitaxel dose of 150 mg/m2, 15 patients were enrolled, because the initial toxicity results after the first cycle suggested that this dose level could be used for phase II. Indeed, only one episode of DLT at the first cycle was observed in the first six patients recruited. A total of five of 15 patients showed DLT, which consisted of neutropenic fever in one case, grade 2 thrombocytopenia on day 8 in one case, severe fatigue and loss of appetite in two cases, and severe diarrhea in the last case. Nevertheless, as the number of delivered cycles increased, a dramatic increase in cumulative toxicity became evident. Almost all patients had to reduce the drug doses (or omit day 8 treatment) at least once because of neutropenia or thrombocytopenia or because of frequently occurring severe nonhematologic toxicity (nausea/vomiting, diarrhea, fatigue). The dose intensity of chemotherapy actually delivered in all cycles was 69% at this dose level, compared with 91% in the preceding cohort. Therefore, we decided to adopt the lower dose of 125 mg/m2 for phase II, and an additional 33 patients were included in this cohort.
Toxicity
The nonhematologic toxicities that occurred are listed in Table 4. These toxicities were only a minor problem in the majority of patients treated at doses lower than 150 mg/m2. Overall, 20 patients experienced severe nonhematologic toxicity at least once in the course of their treatment. In particular, this happened in seven of the 39 (18%) patients treated at the paclitaxel 125 mg/m2 dose, compared with eight of 15 (53%) of those who received a dose of 150 mg/m2. Severe diarrhea, vomiting, and fatigue occurred in eight patients (14 cycles), 13 patients (21 cycles), and 15 patients (23 cycles), respectively, most of whom had been treated at the 150 mg/m2 dose level.
Mild or moderate nephrotoxicity occurred in a total of seven patients. Grade II neurotoxicity occurred in eight patients (14 cycles), and an additional patient treated at the 150 mg/m2 dose level showed a sensory and motor grade 3 neuropathy after two cycles. All of these patients had an improvement in their symptoms after a temporary suspension of the treatment; in two of them, chemotherapy was resumed at reduced doses, whereas in the remaining patients, it was definitively suspended because of disease progression. Fifteen patients complained of moderate musculoskeletal pain, and 12 of moderate rhinorrhagia. Five patients showed constipation, and seven patients had a moderate transient elevation of hepatic enzyme levels. An episode of congestive heart failure occurred after two chemotherapy cycles in a patient who received the 150 mg/m2 dose. He had stage IV disease with hepatic involvement and a poor performance status. The treatment was discontinued, but the patient did not recover from his cardiac toxicity. Among the 39 patients treated at the 125 mg/m2 dose level, severe diarrhea, vomiting, and fatigue occurred in four, five, and four patients, respectively. One patient refused to continue the treatment after one cycle because of severe vomiting, loss of appetite, and fatigue. Mild paresthesias occurred in approximately 40% of the patients, but only in three cases was a grade 2 peripheral neuropathy observed. Moderate musculoskeletal pain occurred in five patients, and three patients had a moderate transient elevation of hepatic enzyme levels.
Response
Thirty-nine objective responses, four of which were complete responses, occurred in the 64 chemotherapy-naive patients with measurable disease, for a 61% (95% CI, 48% to 73%) to ORR, The four complete responses occurred in two patients with stage IIIB disease and two with stage IV disease for bone or adrenal involvement who had been treated with three different paclitaxel doses (75 mg/m2, 100 mg/m2, and 125 mg/m2). In all cases, the response was documented after three cycles, responses lasted for 3+, 5, 8, and 13 months. No shrinkage of brain lesions with chemotherapy was observed.
Regarding the cohort of patients treated at paclitaxel 125 mg/m2, 38 of 39 were assessable for response. One patient had nonmeasurable disease. Four patients discontinued the treatment early because of early disease progression (two patients) or refusal (two patients). Two complete and 24 partial responses were recorded in this group, for a 68% (95% CI, 51% to 82%) ORR. One of the two complete responses occurred in a patient with stage IV disease for adrenal involvement and the other in another patient with stage IIIB disease. Fifteen of the 24 patients who showed a partial response achieved a
The QOL score improved in 27 of 38 (71%) of these patients. In particular, cough, dyspnea, pain, and fatigue improved in 72%, 69%, 65%, and 75% of patients, respectively. Twenty-four of the 27 patients who showed a QOL improvement had also achieved an objective major tumor regression. Eighteen of 24 patients who showed weight loss at the beginning of treatment showed a clear gain in body weight, and 25 of 34 (73%) patients with a Karnofsky score below 100 at diagnosis had a definite increase in the score after three chemotherapy cycles. After a 13-month median potential follow-up period (range, 1 to 23 months), none of the ten pretreated and 49 of the 65 chemotherapy-naive patients are still alive (and 28 are progression-free). The median survival time was 15 months in the 65 chemotherapy-naive patients. Among the 39 patients treated at the 125 mg/m2 dose, 12 have shown disease progression and five have died. The median follow-up period was 7 months (range, 1 to 13 months) in this group, with only six patients observed for 1 year or longer. Median survival has not yet been reached, and the 1-year projected survival probability is 70% (Fig 1). The median survival has also not yet been reached in the 26 patients with stage IV disease, with 6-month and 12-month survival probabilities being 79% and 61%, respectively.
Our data show that a total paclitaxel dose of 250 mg/m2 every 3 weeks (split on days 1 and 8) can be delivered together with full doses of cisplatin and gemcitabine in chemotherapy-naive NSCLC patients, at a price of a manageable hematologic and a nonhematologic toxicity. A much lower paclitaxel dose proved to be feasible in pretreated patients, although the presence of massive liver involvement in some of them could have substantially altered the pharmacokinetics of paclitaxel, so reducing the tolerance to the treatment. Both hematologic and nonhematologic toxicities were very mild until the paclitaxel dose level of 125 mg/m2 was reached. The compliance to treatment became substantially worse at the last dose level because of the frequent occurrence of severe hematologic and nonhematologic toxicities. The substantial cumulative hematologic and nonhematologic toxicities observed in this cohort also caused a reduction of the dose intensity actually delivered (69 mg/m2/wk), which was even lower than that delivered in the preceding dose level. In view of this, the paclitaxel dose of 125 mg/m2 on days 1 and 8 was used in the phase II study. The evidence of moderate hematologic and nonhematologic toxicities in patients who received a total paclitaxel dose of 250 mg/m2 together with 100 mg/m2 of cisplatin and 2,000 mg/m2 of gemcitabine over 3 weeks seems quite surprising, if we take into account that in previous studies using a standard once-every-3-weeks schedule, the MTD of paclitaxel was always lower than 250 mg/m2 when combined with the platinum compound alone or even when administered alone.7-9 It is difficult to compare our toxicity data with those of other trials testing paclitaxel given in a similar three-drug combination. There is only one other study, which was published in an abstract form, that has tested the cisplatin-gemcitabine-paclitaxel combination. All three drugs were given every 2 weeks, and the intended cumulative dose over 3 weeks was substantially lower in this trial (cisplatin, 90 mg/m2; paclitaxel, 165 mg/m2; gemcitabine, 1,200 mg/m2). Moreover, the toxicity was more severe, with grades 3 to 4 neutropenia occurring in 80% of patients. Despite the modest cumulative doses delivered, the response rate observed in that study (52%) was, however, very promising.25 A carboplatin-paclitaxel-gemcitabine combination was recently tested by both US and Italian authors.26-28 The paclitaxel dose recommended for their phase II study was 175 to 200 mg/m2, together with carboplatin given at an AUC of 5 or 6 on day 1 and gemcitabine at 1,000 mg/m2 on days 1 and 8. Despite the substantially lower dose intensity of paclitaxel and carboplatin, these authors reported higher hematologic and nonhematologic toxicities than those observed in our study. The combination of gemcitabine and paclitaxel without a platinum compound has recently been tested by several authors. Giaccone et al29 tested this regimen in a phase I/II study. Gemcitabine was given at a dose of 1,000 mg/m2 on days 1 and 8, and paclitaxel was safely escalated up to 200 mg/m2 on day 1, with a recycling of this schedule every 3 weeks. The ORR was 30% in this trial. In a US phase I study, the recommended gemcitabine and paclitaxel doses were 150 mg/m2 and 3,000 mg/m2 every 2 weeks.30 The gemcitabine-paclitaxel combination was also tested in pretreated NSCLC patients by Androulakis et al.31 Gemcitabine was given at a dose of 900 mg/m2 on days 1 and 8, and paclitaxel was given at a dose of 175 mg/m2 on day 8, with filgrastim support from days 9 to 15 of each cycle. As a consequence of the granulocyte colony-stimulating factor support, the hematologic toxicity was moderate, with only 12% of patients experiencing grade 3 to 4 neutropenia and only one hospitalization for neutropenic fever. However, nonhematologic toxicity was relevant in this study, with grade 2 to 3 fatigue and neurotoxicity occurring in 51% and 32% of patients, respectively. The particular schedule we chose for both cisplatin and paclitaxel could, in our opinion, explain the better tolerance of our regimen, in comparison with these other authors' experiences in using the standard single-day administration for the platinum compound and paclitaxel. The possibility for a weekly schedule to improve the toxicologic profile of paclitaxel was confirmed by Einhorn et al,32 who administered paclitaxel and gemcitabine weekly for 3 of 4 weeks. Weekly doses of paclitaxel 130 mg/m2 and gemcitabine 1,000 mg/m2, respectively, proved to be safe in this study. In a Rhode Island study,33 weekly administration of paclitaxel resulted in an astonishing increase in its dose intensity of when given as a single agent, at doses up to 175 mg/m2, with only mild hematologic toxicity. Cisplatin and paclitaxel doses of 70 mg/m2 and 90 mg/m2, respectively, were safely given on days 1, 8, and 15 of an every-4-week cycle in ovarian cancer patients, resulting in moderate toxicity and very high antitumor activity.34 It should be remarked, however, that as in the Rhode Island study,33 our study saw an unpredictable dose-toxicity relationship at the last dose level. In fact, the increase in the paclitaxel dose from 125 mg/m2 to 150 mg/m2 in our study, and from 175 mg/m2 to 200 mg/m2 in the Akerley et al study,33 dramatically altered the tolerance of the treatment, with a high proportion of patients experiencing life-threatening hematologic and nonhematologic toxicities. This unpredictable increment of toxicity observed at the highest dose level could be the consequence of nonlinear pharmacokinetics, which can be much more evident when paclitaxel is given as a short-term infusion. In fact, the elimination of paclitaxel from the body is mediated by a saturable system, according to which low plasma concentrations (associated with a longer infusion time) are cleared at a relatively faster rate than high concentrations.35 The evaluation of the therapeutic activity of this new regimen in both chemotherapy-naive and pretreated advanced NSCLC patients was another primary end point of this study. The small number of pretreated patients enrolled makes it difficult for conclusions to be drawn about the efficacy of this approach in pretreated patients. However, the evidence of definite and durable regressions of the tumor in some patients who have been refractory to standard cisplatin-based chemotherapy would seem to confirm the roles of both gemcitabine and paclitaxel in platinum-resistant NSCLC patients. However, the similar antitumor activity shown in pretreated patients by the gemcitabine-paclitaxel combination would suggest that the addition of a platinum compound may not be useful in this subgroup. With regard to chemotherapy-naive patients, the 61% ORR looks very promising, especially if we take into account that four different paclitaxel doses were used (the highest being double the lowest) and that a relevant proportion of patients had poor prognostic features at diagnosis (stage IV, poor performance status, brain involvement). The survival data also seem interesting. In fact, a 15-month median survival time has been observed in chemotherapy-naive patients.
A more detailed analysis of the outcome of the 39 patients treated in phase II at the 125 mg/m2 dose would permit, in our opinion, a better evaluation of the role of this combination in the management of this subset of NSCLC patients. We had planned that at least 17 of 39 (44%) major responses were required for this new regimen to be considered worthy of being evaluated in phase III. The analysis of the response data permits us to claim that this combination has completely fulfilled the chosen activity requirements for it to be pursued in phase III. The ORR we recorded (68%) is absolutely remarkable, especially if we take into consideration that in the majority of these patients, a It is too soon to draw definite conclusions about the impact of this regimen on survival, because the median follow-up period is too short (7 months) and too small a number of patients have a longer than 1-year potential follow-up. However, the evidence of a 6-month death risk of 14% (with 20 of 39 patients at risk at that time) and of a 70% 1-year projected survival are very promising and suggest that this new approach could at least substantially reduce the risk of death within 1 year. Moreover, it is worth noting that median survival has not yet been reached in the 26 patients with stage IV disease, with the 6-month and 12-month probabilities of remaining alive being 79% and 61%, respectively. Only a well-designed, large, randomized trial will determine whether the combination of both gemcitabine and paclitaxel with cisplatin or carboplatin provides a meaningful therapeutic advantage when compared with the combination of cisplatin with only one of the two other agents or with other standard regimens. The cisplatin/carboplatin-paclitaxel and the cisplatin-gemcitabine regimens showed very high antitumor activity in the initial phase II trials, with ORRs even approaching 60% and median survival being longer than 1 year.7-9,15,16 Unfortunately, the enthusiasm about these two combinations has cooled down as a consequence of the quite disappointing results of the most recent phase III trials. Indeed, the ORRs fell below 50% and median survival was stuck at 8 to 10 months in these studies.10,11,36-38 The almost 70% ORR and the much longer than 12 months median survival time that was observed in the study presented here in the 39 patients treated at the paclitaxel dose of 125 mg/m2 appear to be worth noting in comparison with the above-mentioned figures and also because almost all of these patients (33 of 39) have been included in this study in a randomized fashion. In view ofthis, we are reasonably confident that our regimen will show similar activity in the future phase III studies. Even if the future phase III trials conclude that the aggressive therapeutic approach adopted by our institutions does not provide a substantial therapeutic advantage in patients with metastatic disease, when compared with less aggressive treatments, its role in other NSCLC patient subgroups deserves to be addressed. Indeed, the particularly impressive ORR observed in our study in patients without distant metastases (78%) might suggest that the cisplatin-gemcitabine-paclitaxel regimen could have a more relevant impact on the outcome of patients with less-advanced tumors. Using this proposal, it could be interesting to test this regimen as adjuvant or neoadjuvant treatment in stage I-IIIAN2 disease or as induction chemotherapy followed by concomitant chemoradiotherapy in stage IIIB disease. In conclusion, the combination of cisplatin, gemcitabine, and paclitaxel given at full doses on days 1 and 8 every 3 weeks is feasible and well tolerated. It has a very promising therapeutic activity in chemotherapy-naive NSCLC patients. Although the phase II evaluation may be considered concluded, the accrual of patients still continues for a phase III study.
The following institutions (and investigators) participated in this study: The Division of Medical Oncology A, National Tumor Institute, Naples (Giuseppe Frasci and Pasquale Comella); Divisions of Medical Oncology (Nicola Panza and Gianpaolo P. Nicollela) and Pneumology (Michele Natale), Cardarelli Hospital, Naples; Division of Medical Oncology, San Carlo Hospital, Potenza (Luigi Manzione and Domenico Bilancia); Division of Pneumology, City Hospital, Caserta (Riccardo Cioffi); Division of Medical Oncology, San Gennaro Hospital, Naples (Luigi Maiorino); Division of Medical Oncology, Da Procida Hospital, Salerno (Giuseppe De Cataldis); Division of Medical Oncology, City Hospital, Avellino (Mario Belli); Chair of Respiratory Disease, Second University School of Medicine, Naples (Enrico Micillo); Division of Medical Oncology, Oncology Hospital, Cagliari (Vittorio Mascia); Chair of Medical Oncology, University School of Medicine, Cagliari (Bruno Massidda); Division of Medical Oncology, Oncology Institute, Bari (Vito Lorusso and Mario De Lena); Division of Thoracic Surgery, San Paolo Hospital, Bari (Francesco Carpagnano); Division of Medical Oncology, City Hospital, Sassari (Antonio Contu); and Division of Pneumology, Binaghi Hospital, Cagliari (Guido Pusceddu), Italy.
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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
