1Chest Department, Taipei Veterans General Hospital, National Yang-Ming University; 2Division of Cancer Research, National Health Research Institute, Taiwan
Received 20 April 2001; revised 9 July 2001; accepted 16 August 2001.
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Abstract |
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Paclitaxel (Taxol) plus carboplatin (PC) has shown activity in the treatment of advanced non-small-cell lung cancer (NSCLC). Non-platinum-containing combination chemotherapy, such as paclitaxel plus gemcitabine (PG), has also demonstrated reasonable efficacy. Our aim here was to evaluate the clinical efficacy and cost-effectiveness of PC versus PG in chemo-naive, advanced NSCLC patients.
Patients and methods
Ninety (68 male, 22 female) patients were enrolled from August 1999 to August 2000. The performance status was one in 29 patients and two in 16 patients of the PC group, and one in 24 patients and two in 21 patients of the PG group. Seventeen patients had stage IIIb disease and 28 patients stage IV disease in the PC group; 18 patients had stage IIIb disease and 27 patients stage IV disease in the PG group (New International Staging System). Treatment consisted of P 175 mg/m2 and C at AUC = 7 (predicted using measured clearances and the Calvert formula) intravenous infusion (i.v.) on day 1, or P 175 mg/m2 i.v. on day 1 and G 1000 mg/m2 i.v. on days 1 and 8, every 3 weeks.
Results
In all, 175 cycles of PC and 184 cycles of PG were given in the PC and PG groups, respectively. The median treatment cycle was four cycles in both groups. All the patients were assessable for toxicity and response measurement. There were three complete responses and 15 partial responses (overall 40%) in the PC group, and no complete response, but 18 partial responses (overall 40%) in the PG group. WHO grades 3/4 leukopenia, anemia and thrombocytopenia occurred in six (13.3%), seven (15.5%) and five patients (11.1%) in the PC group; and in four (8.9%), six (13.3%) and 0 patients in the PG group, respectively. Two patients in each group suffered from grade 3 peripheral neuropathy. Other non-hematological toxicities were mild and few. Median survival time was 14.1 months in the PC group and 12.6 months in the PG group. One-year survival was 50.7% in the PC group and 53.3% in the PG group. The PG group had a higher total expense and expended more days undergoing treatment than the PC group (P = 0.034 and 0.069, respectively).
Conclusions
Both PC and PG combination chemotherapy produce a similar efficacy in the treatment of NSCLC. However, PC is more cost-effective than PG.
Key words: carboplatin, gemcitabine, non-small-cell lung cancer, paclitaxel
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Introduction |
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In the past two decades, cisplatin in combination with second- or third-generation chemotherapeutic agents has been found to effectively, although modestly, increase patient survival, in randomized trials and/or meta-analyses [19]. However, the gastrointestinal and bone marrow toxicities induced by cisplatin with/without other agents can be significant and lead to a perceived negative impact on the quality of life, and thus are still a major concern of both physicians and patients. Among the new anticancer drugs, paclitaxel (Taxol; Bristol-Myers Squibb Co., Princeton, NJ 08543, USA) or gem-citabine in combination with cisplatin treatment has yielded better patient survival but similar toxicities, compared with cisplatin with or without etoposide, in recent phase III clinical trials [8, 9]. However, some studies have not shown better survival in comparison with standard chemotherapy [1012]. Nevertheless, paclitaxel plus cisplatin has replaced etoposide plus cisplatin as the reference regimen in phase III trials [13]. Carboplatin is another platinum drug with a different toxicity profile from that of cisplatin. In a previous five-arm Eastern Cooperative Oncology Group (ECOG) study, patients receiving single agent carboplatin treatment were found to have the best 1-year survival and least toxicity [14]. The replacement of cisplatin with carboplatin or other non-platinum drugs has been evaluated more frequently in recent years in an attempt to decrease cisplatin-induced toxicity while keeping or even improving drug efficacy.
Relative to paclitaxel-based combination chemotherapy, paclitaxel plus carboplatin has been evaluated to be efficacious against NSCLC [15]. The dose-limiting toxicity of carboplatin is thrombocytopenia. Many studies have demonstrated the platelet-sparing effect of paclitaxel used together with carboplatin [16]. Among the non-platinum combinations, paclitaxel and gemcitabine are certainly of particular interest due to their essentially non-overlapping toxicities and single-agent activities, which compare favorably with single-agent cisplatin. Another study has found, in a phase I/II pharmacokinetic and pharmacodynamic investigation of paclitaxel plus gemcitabine treatment, that paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This increment of dFdCTP might enhance the antitumor activity of gemcitabine [17]. A phase I/II study of paclitaxel plus gemcitabine, using paclitaxel 200 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 of every three weeks in the phase II period, revealed a response rate of 24% in 49 evaluable patients. This regimen proved to be safe and easy to administer in an out-patient setting [18]. The combination of paclitaxel with gemcitabine probably represents a new and promising regimen for the treatment of NSCLC and other tumor types.
Based on the high activity, relatively good safety profiles and superior 1-year survival rates of NSCLC patients treated with paclitaxel plus carboplatin, and possibly paclitaxel plus gemcitabine, we conducted a phase II randomized trial using both regimens in NSCLC patients with inoperable stage III and IV disease, to investigate the efficacy, toxicity and cost-effectiveness of these regimens.
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Patients and methods |
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Initial work-up included the documentation of the patients history, a physical examination, and a performance score. A complete blood cell count, urinalysis, serum biochemistry profile, electrocardiogram (ECG), chest roentgenography, whole body bone scan, brain computed tomgraphy (CT) scan, and chest CT scan (including liver and adrenal glands), were also performed. All pretreatment laboratory work was obtained within 7 days of study entry, whereas CT and whole body bone scans were obtained within 2 weeks of study entry.
Study design
Eligible patients were randomized into either the paclitaxel plus carboplatin regimen or paclitaxel plus gemcitabine regimen by a statistical office not involved in the trial, using a computer-generated list of random numbers. Paclitaxel 175 mg/m2 was given as a 3-h intravenous infusion (i.v.), followed by carboplatin at AUC = 7 (predicted using measured clearances and the Calvert formula) i.v. for 1 h on day 1 every 3 weeks in the paclitaxel plus carboplatin (PC) treatment group, or paclitaxel 175 mg/m2 i.v. on day 1 and gemcitabine 1000 mg/m2 i.v. for 30 min on days 1 and 8 every 3 weeks in the paclitaxel plus gemcitabine (PG) treatment group. All patients received dexamethasone (10 mg i.v. at 12 and 6 h), cimetidine (300 mg i.v.), and diphenhydramine (50 mg i.v.) before paclitaxel administration. Metoclopramide (40 mg i.v.) was given before the paclitaxel plus carboplatin or gemcitabine as an antiemetic prophylaxis. Dexamethasone (10 mg i.v.) and metoclopramide (20 mg i.v.) were given before gemcitabine treatment (day 8) as an antiemetic prophylaxis.
With regard to dose modifications within a cycle, the dose of gemcitabine was reduced by 50% if the absolute neutrophil count (ANC) was from 1.5 to 1.0 x 109/l and/or platelet count 99 to 75 x 109/l on the day of the scheduled chemotherapy. Gemcitabine was omitted if the ANC was <1.0 x 109/l, or the platelet count was <75 x 109/l. For dose adjustments in the subsequent cycle, a 50% reduction in paclitaxel and carboplatin or gemcitabine were instituted when the patient suffered from grade 4 neutropenia or thrombocytopenia. Subsequent dose escalation to the original dosage was allowed providing the patient tolerated the doses given at the 50% level. For non-hematological toxicities, paclitaxel and carboplatin or gemcitabine were reduced to a 75% dose if there were grade 3 toxicities, and the patient went off study with grade 4 toxicities, excluding those due to nausea/vomiting or alopecia. Patients were withdrawn from the study if they suffered from grade 3 or worse neuropathy.
After maximal effective chemotherapy, radiotherapy was given to all stage IIIb patients, excluding those with malignant pleural effusion.
Response evaluation
Before and after each injection of the chemotherapeutic agent, the patients vital signs and temperature were recorded. Performance status was documented weekly throughout therapy. A complete blood cell count was repeated before every injection. Serum biochemistry was performed before every course of chemotherapy, and during the course, if clinically indicated. A chest roentgenography and ECG were performed before every course of chemotherapy. Disease-related symptoms, e.g. pain, dyspnea, cough and hemoptysis, were recorded at study entry and before each course of chemotherapy.
Response and study drug-related toxicities were evaluated according to WHO criteria [19]. Patient responses were re-evaluated after every two cycles. Complete response was defined as the disappearance of all known disease, determined by two observations not less than 4 weeks apart. A partial response was defined as that greater than a 50% decrease in the total tumor size of the measurable lesions by two observations not less than 4 weeks apart, with no appearance of new lesions or progression of any lesion. In responding patients and patients with stable disease, a maximum of six cycles of chemotherapy was given. Those patients whose tumors progressed were withdrawn from the study as soon as this finding was documented clinically and/or radiographically. All adverse events, whether thought to be due to chemotherapy or not, were recorded.
Statistical methodology
The study was designed to enroll 90 qualified patients, including 45 patients in each arm of the treatment. The primary objective was to determine whether there exists a significant difference in the cost and time required for treatment in these two regimens, and to make sure the lower limit of the 95% confidence interval (CI) was higher than 20% for the response rates of these two regimens. The width of the CI would vary according to the actual observed response rate, but a response rate of 40% would produce a 95% CI of 54.3% to 25.7%.
Overall survival and time-to-disease progression were analyzed using the KaplanMeier estimation method. Time-to-disease progression was calculated from the date of initiation of treatment to the date of disease progression or death. If disease progression had not occurred by the time of this analysis, progression-free survival was considered censored at the time of last follow-up. Survival time was measured from the date of initiation of treatment to the date of death. If death had not occurred, survival time was considered censored at the last follow-up time. All comparisons of response rates and toxicity incidences were performed by means of Pearsons 2 test. An independent-samples t test [20] was used for comparisons of the cost and time expended in undergoing different regimens of chemotherapy.
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Results |
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Response
After two cycles of treatment, three patients achieved a complete response and 15 patients achieved a partial response in the PC arm, and 18 patients achieved a partial response in the PG arm. Both groups had an overall response rate of 40% (95% CI 25.7% to 54.3%, Table 2). Eight of 17 stage IIIb patients and 10 of 28 stage IV patients in the PC arm had a complete or partial response to the treatment; and 10 of 18 stage IIIb patients and eight of 27 stage IV patients in the PG arm had a partial response to the treatment. Complete response occurred only in the PC group, while more patients in the PG group suffered from progressive disease. The response rate did not correlate to the patients performance status and staging in either arm.
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There was an improvement in pain control in 7/22 patients, dyspnea abated in 14/21 patients, cough decreased in 15/24 patients, and hemoptysis was resolved in 4/5 patients in the PC arm; and in 13/29 patients, 15/31 patients, 12/20 patients, and 2/3 patients in the PG arm, respectively.
Toxicity
All patients enrolled into the study were eligible for toxicity evaluation. All the toxicities were mild and reversible, except for some patients who were left with grade 1 peripheral neuropathy which lasted for several months. The main toxicities were hematological in both arms of treatment (Table 3). The incidence of WHO grade 3 or 4 hematological toxicity per patient was: leukopenia 13.3%, anemia 15.5% and thrombocytopenia 11.1% in the PC group, and leukopenia 8.9%, anemia 13.3% and thrombocytopenia 0% in the PG group. The incidence of grade 3 thrombocytopenia was significantly higher in the PC arm (P = 0.021). The incidence of WHO grade 3 or 4 hematological toxicity per cycle was: leukopenia 4%, anemia 5.1% and thrombocytopenia 4% in the PC group, and leukopenia 2.7%, anemia 3.3% and thrombocytopenia 0% in the PG group. No febrile neutropenia occurred in the present study, nor did a treatment-related death occur. There were several other non-hematological toxicities (Table 4). Most of the non-hematological toxicities were mild and tolerable in both groups.
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Discussion |
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It has been reported that overall survival may be affected by second-line chemotherapy containing newer agents, and thus it may be important to gather information regarding the use of salvage therapy in NSCLC trials. A recent study reported on a group of patients who had been treated with cisplatin chemotherapy and who were then treated with docetaxel or supportive care only; the median survival was longer in patients who were treated with docetaxel (7.5 versus 4.6 months; P = 0.01) [28].
Recent phase III randomized trials of first-line chemotherapy against NSCLC revealed that either paclitaxel or gemcitabine plus cisplatin is superior to cisplatin alone or with etoposide, in terms of response rate, time to disease progression, and/or overall survival [8, 9, 29]. A preliminary report of the ECOG randomized phase III trial of four chemotherapy regimens in NSCLC revealed there was no significant difference in survival with different treatment regimens [13]. It is very likely that the effectiveness of these new anti-cancer drugs in combination with a platinum drug is overwhelmingly the same. The only difference in these drugs is the slightly different proportion of toxicities and the drug cost.
Paclitaxel/non-platinum combinations may prove to be reasonable alternatives for NSCLC patients who cannot tolerate cisplatin, and for patients with a compromised performance status. The different mechanisms of action of both paclitaxel and gemcitabine, and the lack of overlapping toxicities, make the combination of these drugs appealing in the treatment of NSCLC. A variety of phase I studies have evaluated gemcitabine plus paclitaxel, with response rates ranging from 22% to 30% [30]. Another common non-cisplatin containing combination chemotherapy was gemcitabine plus vinorelbine. The response rate and median survival of phase I and/or II studies ranged from 2572.5% and 3354 weeks, respectively [3135]. There has been no randomized trial comparing non-cisplatin containing combination chemotherapy, such as paclitaxel plus gemcitabine versus gemcitabine plus vinorelbine, up to the present. Which is the better combination is still unknown.
The schedule and doses of paclitaxel and carboplatin we used were based on a previous phase I study by Belani et al. [36], and a phase II study by Kosmidis et al. [25]. The authors found that this combination of paclitaxel and carboplatin is active and well-tolerated in patients with inoperable non-small-cell lung cancer. The Hellenic Cooperative Oncology Group also has recently performed a phase III randomized study comparing paclitaxel plus carboplatin treatment with paclitaxel plus gemcitabine treatment [37]. The paclitaxel dose they used (200 mg/m2 every 3 weeks) was slightly higher than ours; however, the carboplatin dose was lower (AUC = 6). The gemcitabine dose was the same in both studies. Their preliminary results indicated that both combinations are effective and have comparable activity and toxicity in patients with non-operable NSCLC. However, they did not report the cost-effectiveness and the number of days patients needed for the treatment.
All costs were higher in the study patients undergoing paclitaxel plus gemcitabine treatment as compared with those receiving paclitaxel plus carboplatin therapy. The difference in the two treatments was the drug cost and the eighth day of treatment with gemcitabine. Chemotherapy drug costs were significantly higher in the paclitaxel plus gemcitabine treatment group. The mean chemotherapy drug cost difference per patient between these two regimens was NT 57 907 dollars (US$ 1755). The mean total cost difference per patient was NT 73 042 dollars (US$ 2214). Total days stay or days visiting the hospital were also greater in the paclitaxel plus gemcitabine treatment group. The main difference was that the paclitaxel plus gemcitabine treatment group required more admission days. The reason for the extended hospital stay in this group, more than 5 days longer than the paclitaxel plus carboplatin treatment group, was due partly to the refusal of some patients to receive gemcitabine treatment in the out-patient clinic. If we excluded the days in hospital for gemcitabine administration related to the patients refusal to receive out-patient therapy, mean admission days would decrease by 2 days. However, out-patient clinic visit days would also increase by 2 days. The toxicity of both regimens was modest and easily managed in our study. Forty-one of the 90 patients in this study were older than 70, and they went through treatment as uneventfully as those younger than 70. Very few patients suffered from severe nausea/vomiting or myelosuppression, and no patient suffered from febrile neutropenia, which was more likely to occur in those patients receiving cisplatin-based combination chemotherapy.
Objective response rate is not a particularly good surrogate marker of treatment efficacy in NSCLC. Survival is the only endpoint truly reflective of treatment efficacy. Thus, one may argue that it is difficult to conclude from this study that these two regimens are truly equally efficacious, as the trial is under-powered to provide therapeutic equivalency based on survival results. Nevertheless, treatment expenses were significantly higher in the paclitaxel plus gemcitabine group while the toxicity profile, response rate and survival were similar in both groups of patients, indicating that paclitaxel plus carboplatin treatment is more cost-effective.
Because of the similar efficacy and good toxicity profiles of both groups, but greater expense and length of treatment time in the paclitaxel plus gemcitabine treatment arm, paclitaxel plus carboplatin should be considered for NSCLC patients instead of non-platinum chemotherapy with a paclitaxel plus gemcitabine regimen.
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Acknowledgements |
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Footnotes |
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