1 Operative Unit of Medical Oncology, Oncology Institute of Bari, Bari; 2 Medical Oncology, Caldarelli Hospital, Naples; 3 Thoracic Surgery Department, San Paolo Hospital of Bari, Bari, Italy
Received 18 February 2002; revised 7 May 2002; accepted 7 June 2002
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Abstract |
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The aim of our study was to determine the maximum tolerated dose of paclitaxel combined with a fixed dose of gemcitabine and vinorelbine in the treatment of non-small-cell lung cancer (NSCLC) and to evaluate in a phase II trial the efficacy of this combination.
Patients and methods:
Sixty-two patients with stage IIIB/IV NSCLC were treated with paclitaxel in escalating doses from 4080 mg/m2 combined with gemcitabine and vinorelbine at fixed doses of 1000 mg/m2 and 25 mg/m2, respectively. All drugs were given intravenously on day 1 and 8 every 3 weeks.
Results:
In a phase I trial, carried out on 21 patients, grade 4 neutropenia, as dose-limiting toxicity, occurred at the dosage level of paclitaxel 80 mg/m2. In a phase II trial, with paclitaxel administered at 70 mg/m2, 27 out of 41 (66%) assessable patients responded (10% complete responses and 56% partial responses). Objective response was observed in 13 of 16 patients (81%) with stage IIIB disease and in 14 of 25 (56%) with stage IV disease. The median time to treatment failure was 26 weeks (range 372 weeks; 32 weeks and 20 weeks for stages IIIB and IV, respectively) and median survival 62 weeks (range 4176 weeks; 72 weeks and 56 weeks for stages IIIB and IV, respectively). One-year survival was 64% for all patients (72% for patients with stage IIIB and 52% for those with stage IV). Grade 3 and 4 neutropenia were observed in 11 (27%) and seven (17%) cases, respectively; grade 3 thrombocytopenia was observed in three patients (7%) and grade 3 anemia in four patients (10%). The most relevant non-hematological toxicity was grade 2/3 asthenia, which was observed in 12 patients (29%). Alopecia was almost universal, whereas nausea and vomiting were absent.
Conclusions:
The combination of paclitaxel, gemcitabine and vinorelbine is effective and tolerable in the treatment of NSCLC. The high activity and low toxicity of this regimen warrant randomized studies with platinum-containing combinations.
Key words: chemotherapy, gemcitabine, non-small-cell lung cancer, paclitaxel, vinorelbine
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Introduction |
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In recent years, a number of new non-platinum agents have demonstrated significant activity in advanced NSCLC. Among them there are the taxanes (paclitaxel and docetaxel), vinorelbine and gemcitabine [9]. Along with activity, in general the novel agents have a toxicity profile that is superior to that of platinum. This is highly important in this setting in which overall quality of life is a major consideration, along with control of lung cancer symptoms. Combinations of these new drugs in doublets have yielded results comparable with those achievable with cisplatin-containing regimens. In particular, the combination of gemcitabine and vinorelbine proved feasible with myelosuppression being the most frequent toxicity. Most phase II trials reported response rates of 2040% and median survival duration of 711 months [1013]. The combination of vinorelbine plus paclitaxel showed promising results (32% response) in previously treated patients with small-cell lung cancer [14]. The efficacy and toxicity of combined paclitaxel and gemcitabine was evaluated in a phase II study on chemotherapy-naïve patients with advanced NSCLC [15]. The response rate observed was 36%, the median survival 51 weeks, and the toxicity negligible. Moreover, these results have recently been confirmed in a phase III trial comparing the combination of paclitaxel/gemcitabine with paclitaxel/carboplatin [16]. With regard to the first experiences with a three drug combination without cisplatin, Masters et al. [17] obtained disappointing results with the combination of paclitaxel, ifosfamide and vinorelbine plus granulocyte colony-stimulating factor (G-CSF) support. In fact, this combination appeared only to exacerbate toxicity, with no increase in efficacy, as compared with the commonly used platinum-containing combinations. In our study we have employed a combination of paclitaxel, gemcitabine and vinorelbine which had never been tested before. The aim of this study was to determine the maximum tolerated dose (MTD) of paclitaxel (T) when combined with a fixed dose of gemcitabine (G) and vinorelbine (V) in the treatment of advanced non-small-cell-lung cancer and subsequently to evaluate in a large phase II study the efficacy of this combination (TGV).
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Patients and methods |
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Treatment plan
Escalating doses of paclitaxel were administered intravenously by 3-h infusion followed by a fixed dose of gemcitabine 1000 mg/m2 over 30 min and vinorelbine 25 mg/m2 over 20 min on days 1 and 8. The starting dose of paclitaxel was 40 mg/m2 (dose level 1), and the subsequent dose levels were 50, 60, 70 and 80 mg/m2 (dose levels 2, 3, 4 and 5, respectively). The chemotherapy cycle was administered every 3 weeks to a maximum total of eight cycles for patients with complete response (CR), partial response (PR) or stable disease (SD). Whenever disease progression occurred, patients were treated with a platinum-containing regimen as second-line chemotherapy.
Patients with stage IIIB disease suitable for radiotherapy received the chemotherapy program as a part of a combined treatment that consisted of induction chemotherapy (six cycles) followed by radical radiotherapy (50.4 Gy, given in daily fractions of 1.8 Gy).
With regard to dose reduction, no dose modifications were allowed in the phase I study. On the other hand, in the phase II study dose reductions were allowed as follows: full doses of chemotherapy were given if the neutrophil and platelet counts on the day of treatment were >2 x 109 /l and 100 x 109 /l, respectively. If neutropenia or thrombocytopenia of WHO grade 1 or higher occurred on day 1, the administration of chemotherapy was delayed for 1 week. If, after this delay, grade 1 neutropenia or thrombocytopenia persisted, the treatment was given at doses reduced to 75% of that originally planned. If grade 1 neutropenia or thrombocytopenia occurred on day 8, chemotherapy was given without any delay at doses reduced to 75%. In the presence of grade 2 or greater neutropenia or thrombocytopenia on either day 1 or 8, the treatment was omitted. Finally, if grade 4 neutropenia or thrombocytopenia lasted longer than 7 days or if grade 3 or 4 non-hematological toxicity occurred at any time during the treatment, the doses of each drug were resumed at a 75% dose level in all subsequent chemotherapy administrations. The treatment was definitely discontinued if neutropenia or thrombocytopenia, greater than grade 1, or major non-hematological toxicity, persisted for 3 or more weeks after the planned time for the schedule to be recycled.
Toxicity and evaluation of response
Clinical monitoring was performed twice weekly with a complete blood cell count. Toxicity was scored using WHO criteria [18]. In the phase I part of the study, where no dose reductions were allowed, a minimum of three patients were treated at each dose level. To determine the MTD of this combination, toxicity was assessed by one of the following events: (i) grade 4 thrombocytopenia for 1 day or grade 4 leukopenia for 4 days; (ii) grade 2 renal or liver dysfunction; (iii) any other non-hematological, non-hepatic and non-renal grade 3 toxicity, excluding alopecia; or (iv) inability to deliver full doses of both drugs on day 8 of the cycle of chemotherapy because of grade 24 leukopenia or thrombocytopenia. If any of these side-effects developed in one of three patients, one patient was added. If dose-limiting toxicity was observed in two out of three or four patients, a fifth patient was added. If dose-limiting toxicity was observed in none of three patients, one out of four patients, or two out of five patients at a single dose level, the dose of paclitaxel was increased by 10 mg/m2. If dose-limiting toxicity was observed in three out of three, four or five patients, the MTD was reached, thus the previous dose level was that recommended for the phase II trial (best-of-five schedule). Antitumor activity was evaluated every two courses (i.e. 6 weeks) on all measurable lesions, and all patients were scheduled for at least two cycles to be eligible for assessment of tumor response. In patients with tumor responses or SD, treatment was continued to a maximum of eight cycles. Tumor response was classified according to WHO criteria [18] and documented by two investigations at least 6 weeks apart.
The KaplanMeier method was used to analyze time to disease progression and overall survival. Confidence intervals for the response rates were calculated using the method described by Simon [19]. P values were calculated by Fisher exact tests.
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Results |
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Dose escalation phase
Twenty-one patients, not previously submitted to chemotherapy, were enrolled into the phase I portion of the study in five cohorts. Patients received a total of 88 courses of chemotherapy. The median age was 58 years (range 3967) and most patients were male (86%). Performance status was 0, 1 and 2 in seven (33%), five (24%) and nine (43%) patients, respectively. Fourteen patients (67%) had stage IV disease and seven (33%) stage IIIB. Nine patients (43%) had adenocarcinoma, eight (38%) squamous and four (19%) undifferentiated histological type. Characteristics of patients are listed in Table 1.
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Phase II
Forty-one patients were enrolled into this trial and all were assessable for response and toxicity. Patients received a total of 189 courses of chemotherapy. The median age was 60 years (range 4369). Male:female ratio was 34:7. Moreover, performance status was 0 or 1 in 31 patients (76%) and 2 in 10 patients (24%). Twenty-five patients (61%) had stage IV disease and 16 (39%) stage IIIB. Twelve patients (29%) had adenocarcinoma, 26 (64%) squamous and three (7%) undifferentiated histological types. Fourteen patients (34%) complained of weight loss >10% in the last 6 months. Patient characteristics are reported in Table 2.
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Non-hematological toxicity
For the non-hematological toxicity, asthenia was observed in 12 patients (29%) (grade 1 or 2 in nine patients and grade 3 in three patients) (Table 4). Alopecia was almost universal whereas nausea and vomiting virtually absent. One patient had a hypersensitivity reaction after the first paclitaxel administration and continued to be treated without this drug.
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Second-line therapy
With regard to second-line therapy, all patients primarily refractory to TGV were submitted to a platinum-containing chemotherapy if, after two cycles, at first disease re-evaluation, progressive disease was detected. On the other hand, out of 27 patients responding to TGV, only in 12 was it possible to administer a platinum-containing therapy. In fact, most of these patients progressing after a long therapy-free interval refused second-line therapy, or were in poor performance status condition, not allowing platinum therapy.
It is also worth noting that no patient primarily refractory to TGV responded to a platinum-containing combination administered as second-line therapy (generally a combination of cisplatin, ifosfamide and etoposide or cisplatin, vinblastine and mitomycin). Conversely, out of 12 patients who had responded to TGV, eight responded again when treated with cisplatin combinations at the time of relapse, prolonging their survival by 612 months.
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Discussion |
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In recent years, a number of new agents have demonstrated high single-agent activity and low-toxicity profiles in the treatment of advanced NSCLC. The next step, consisting of the combination of these new non-platinum agents together was the natural evolution of the treatment process. Gemcitabine and vinorelbine, because of the same administration schedule and compatible toxicity, were combined in a number of phase II studies. These trials reported response rates of 2040%, myelosuppression as the major toxicity and median survival duration of 711 months [1013].
The efficacy and toxicity of combined paclitaxel and gemcitabine have recently been evaluated in 54 chemotherapy-naïve patients with metastatic NSCLC [15]. Gemcitabine 1000 mg/m2 was administered on days 1 and 8 and paclitaxel 200 mg/m2 as a continuous 3-h infusion on day 1. Treatment was repeated every 21 days. Two patients (4.3%) achieved a CR and 15 (31.9%) achieved a PR, giving an overall response rate of 36.2%. The median survival time was 51 weeks, with a 1-year survival probability of 0.48. Grade 3/4 neutropenia and febrile neutropenia occurred in 15.2 and 2.2% of courses, respectively. Grade 3/4 thrombocytopenia was rare (1.8% of courses). Among non-hematological toxicities, grade 1 or 2 peripheral neurotoxicity developed in 25 patients (47.2%) and grade 1 or 2 arthalgia/myalgia was observed in 30 patients (56.6%). Similar results were confirmed by Isla et al. [21] with a fortnightly regimen. Moreover, the combination of paclitaxel/gemcitabine was directly compared with paclitaxel/carboplatin, a platinum-containing regimen considered as the gold standard in the USA. In this randomized study of 329 patients, no significant efficacy difference between the two arms was demonstrated, despite a trend toward a slightly higher response rate for the gemcitabine arm when compared with the carboplatin arm (36.5 versus 28.7, respectively; P = 0.17). The median survival for the gemcitabine arm was 12.3 months compared with 10.7 months for the carboplatin arm. Grade 3 or 4 neutropenia was also comparable in both arms, with a 10.5% incidence for gemcitabine/paclitaxel and 9.6% incidence for carboplatin/paclitaxel [16].
Our data show that paclitaxel, gemcitabine and vinorelbine can be delivered together in chemotherapy-naïve NSCLC patients with manageable hematological and non-hematological toxicity. The overall response rate of 66% achieved in the phase II study in 41 assessable patients is superior to the results achievable with any cisplatin-containing doublet and substantially comparable with the response reported with a three-drug platinum-containing combination [22]. The survival data also seem encouraging. In fact, a 14.5 month median survival has been observed in our series. No response to second-line platinum-containing chemotherapy was achieved in the 14 patients (three SD and 11 progressive disease) not responding to TGV, whereas all the responses to second-line platinum were recorded in patients who had already responded to TGV. This would suggest that the addition of a platinum compound, in front-line treatment, would not have been useful in this subgroup of patients. It is also worth noting that with TGV there was evidence of clear improvement of cancer-related symptoms and performance status in more than 70% of our patients. In fact, the only remarkable side-effect observed was asthenia in 29% of cases, but only in three patients (7%) as grade 3. However, a similar toxicity profile had already been observed with the combination of paclitaxel and gemcitabine [15, 16]. Thus the addition of vinorelbine to these two agents did not seem to worsen neurotoxicity.
In conclusion, in view of the favorable safety profile of paclitaxel, gemcitabine and vinorelbine combination, coupled with encouraging response and survival rates, further comparative randomized trials are warranted in order to define the possible advantage of treating patients in the first-line with a non-platinum triplet, keeping platinum, as salvage therapy, in reserve.
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Acknowledgements |
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Footnotes |
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