Japanese Journal of Clinical Oncology 30:494-498 (2000)
© 2000 Foundation for Promotion of Cancer Research
Phase II Study of Regimen of Gemcitabine and Cisplatin in Advanced Non-small Cell Lung Cancer
1First Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taipei and 2Division of Hematology–Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Many novel drugs, including gemcitabine, navelbine, paclitaxel and docetaxel have been used in combination with cisplatin. Of these drugs, gemcitabine is reported to have a high response rate and acceptable toxicity. The aim of this study was to evaluate the efficacy and safety of the combination of gemcitabine and cisplatin.
Methods: Thirty-two patients with NSCLC, who met the selection criteria from June 1998 to January 1999, were enrolled. All of them were confirmed by histology and were in an advanced stage, i.e. stage IIIB with pleural effusion or stage IV. Cisplatin at a dose of 80 mg/m2 was given monthly on day 15, in combination with gemcitabine at a dose of 1000 mg/m2 administered on days 1, 8 and 15 of the 28-day cycle.
Results: Of the 32 assessable patients, two showed complete remission and 11 achieved partial remission. The overall response was 40.6% (95% CI, 24.8–56.4%). The median time to disease progression was 7.2 months (95% CI, 4.87–9.53 months). The major hematological toxicity was neutropenia. Seven patients (22.9%) developed grade 3 and 4 neutropenia, but none developed febrile neutropenia. One patient (3.1%) had grade 3 thrombocytopenia. One patient (3.1%) developed grade 3 anemia. Nausea and vomiting were seen in 12 patients (37.5%).
Conclusions: The regimen of combined gemcitabine with cisplatin is safe and effective. With this combination, a lower dose of cisplatin seems to have an efficacy similar to that in previous reports.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is the most common cause of cancer-related death worldwide. It ranks second among males and first in females in the leading causes of death from cancer and causes more than 5000 deaths every year in Taiwan (1). Non-small cell lung cancer (NSCLC) comprises 80% of the patients with lung cancer in Taiwan. The majority of the patients present with locally advanced cancer, either stage IIIB or distal metastasis, stage IV, which cannot be cured by current therapy; thus, prolongation of life and palliation of symptoms are the aims of treatment. Cisplatin-containing regimens have long been used and they have been shown to be of some benefit compared with the best palliative care used (2). A recent meta-analysis comparing cisplatin-based chemotherapy with the best supportive care had shown that chemotherapy can yield a 27% reduction in death risk, a 10% survival benefit at 1 year and an increase in median survival of 1.5 months (3). Although the cisplatin-based regimens are considered an effective treatment for advanced NSCLC, they have only modest benefits. Recently, a number of novel agents for NSCLC, with different mechanisms of action and lower toxicity profiles, have been used, such as paclitaxel, docetaxel, vinorelbine and gemcitabine. Gemcitabine, a nucleoside analogue (2', 2'-difluorodeoxycytidine) acts as a competitive nucleotide for incorporation into DNA, where it leads to chain termination (4). Single-agent treatment with gemcitabine achieved response rates of 20% or more in some phase II trials (5–8). Synergistic interaction was found, both in vitro and in vivo, between gemcitabine and cisplatin (9). The NSCLC cell lines that express a high level of HER-2/neu are thought to have greater power for DNA repair. The gemcitabine and cisplatin combination was found to be more effective than etoposide and cisplatin against these cell lines (10). In this prospective study, we evaluated the efficacy and safety of a combined regimen of gemcitabine and cisplatin. Gemcitabine was administered on days 1, 8 and 15 and cisplatin was given on day 15 of a 28-day cycle. Although some published studies had reported valuable results, there has been little work with Asians receiving gemcitabine and cisplatin in the treatment of NSCLC.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria and Pretreatment Evaluation
Patients with histologically confirmed NSCLC, stage IIIB or IV, who met the eligibility criteria below were enrolled. Patients were required to have complete medical history records, a physical examination, complete blood cell count, biochemical analysis profile, chest radiographs, computed tomographic (CT) scan of the thorax and a whole-body radionuclide bone scan. Eligibility criteria included a performance status scale (ECOG scale) of 0–2, a life expectancy of more than 12 weeks, no previous chemotherapy or radiotherapy for the assessable lung tumor, at least a two-dimensionally measured lesion, a granulocyte count
1500/µl, platelet count 100 000/µl and hemoglobin level 10 g/dl, a serum creatinine level <1.6 mg/dl, a serum bilirubin level <1.5 times the upper normal limit, no history of other malignancy, no severe concomitant disease and no brain metastasis. Before this study was begun, the regimen of gemcitabine plus cisplatin was approved by the Cancer Committee of Chang Gung Memorial Hospital and was agreed to be used in treatment of NSCLC. The approval of the IRB was not necessary in this situation in Chang Gung Memorial Hospital. Informed consent was obtained verbally from all the patients before they were enrolled. All of the patients who met the eligibility criteria were registered in the study after informed consent had been given.
Treatment Regimens and Dose Modification
Gemcitabine at a dose of 1000 mg/m2 (i.v. 30 min) was administered weekly on days 1, 8 and 15 of each 28-day cycle. Cisplatin at a dose of 80 mg/m2 was given on day 15 of each 28-day cycle. Parenteral administrations of 5-HT3 receptor antagonists plus corticosteroids preceded cisplatin infusion. Treatment was discontinued if disease progression or unacceptable side effects occurred. In those patients who responded, a maximum of six cycles were given. The dose of gemcitabine and cisplatin was reduced by 75% if the granulocyte count was between 1000 and 1500/µl and/or the platelet count was between 75 000 and 50 000/µl. Chemotherapy was delayed until recovery if the granulocyte count was <1000/µl and/or the platelet count was <50 000/µl. Granulocyte-colony stimulation factor (G-CSF) was applied in patients who had suffered from neutropenic fever after chemotherapy.
Response and Toxicity Evaluation
The treatment response was recorded according to World Health Organization (WHO) criteria for the assessment of chemotherapy efficacy. A complete response was defined as the complete disappearance of all evidence of tumor. Partial response was defined as a 50% reduction in the sum of the products of the largest perpendicular diameters of all measured lesions for at least 4 weeks. Stable disease was defined as a decrease of <50% or an increase of <25% in well-outlined lesions for at least 4 weeks. Progressive disease was defined as an increase of >25% in the cross-sectional area of one or more lesions or the occurrence of new lesions. Toxicity was evaluated using the WHO toxicity grading scale. To evaluate and confirm the efficacy, all patients received chest X-ray examinations before each cycle of chemotherapy. Chest CT scans were performed 2 and 6 weeks after the third and sixth courses of chemotherapy. The chest X-ray films were reviewed by one pulmonary physician and one radiologist independently and showed agreement. The response was evaluated after three and six cycles of chemotherapy. Those patients with stable or responsive disease received further treatment until disease progression and a maximum of six cycles were given. After completion of six cycles of treatment, complete physical and chest X-ray examinations were done at each month and a chest CT scan was performed if there was any change in the chest X-ray film. A brain CT scan or bone scan was done if a patient had symptoms of brain or bone metastasis.
Statistical Methods and Designs
According to Simon’s two-stage optimal design (11), we chose a lower activity (p0) of 0.10 and a target activity level (p1) of 0.30. A total of 29 patients were required to test this hypothesis (type I error 0.05, type II error 0.20). At the end of the first stage, at least one response had to be found in 10 patients. Time to disease progression was defined as the time from the date of initial treatment to the date of disease progression. Overall survival was estimated by method of Kaplan and Meier.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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From June 1998 to January 1999, 32 consecutive previously untreated patients with NSCLC who met the selection criteria were enrolled. Their characteristics are listed in Table 1. The median age of the patients was 62 years. Just over half of the patients were male (53.1%).
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Response
Of the 32 assessable patients, two showed CR and 11 achieved PR. The overall response was 40.6% (95% CI, 24.8–56.4%). The median time to disease progression for all patients was 7.2 months (95% CI, 4.9–9.5 months). The median survival was 13.5 months. The Kaplan–Meier curve for survival is shown in Fig. 1. The 1-year survival probability was 58.8%. After a median follow-up time of 54 weeks, three patients showed no disease progression, 11 patients were still alive and 21 patients had died.
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Compliance with Treatment
A total of 141 cycles of chemotherapy were given to the patients. The median number of cycles was three (range 2–6 cycles). Seven cycles were delayed owing to leukopenia and one cycle was delayed owing to thrombocytopenia. The chemotherapy dose was reduced to 75% in 14 cycles: 10 cycles owing to leukopenia, two cycles owing to thrombocytopenia and two cycles owing to combined leukopenia and thrombocytopenia.
Toxicity
Tables 2 and 3 show the hematological and non-hematological toxicities of the treatment. The major hematological toxicity was neutropenia. Five patients (15.6%) developed grade 3 neutropenia and two patients (6.3%) developed grade 4 neutropenia, but there was no febrile neutropenia. One patient (3.1%) had grade 3 thrombocytopenia. One patient (3.1%) developed grade 3 anemia. Grade 3 and 4 nausea and vomiting were observed in 12 patients (37.5%). Eight patients (25%) developed grade 3 constipation. Skin rash was mild, only one patient developed grade 3 toxicity. No grade 3 or 4 neuropathy was noted. Hepatic and renal impairment was mild.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cisplatin is a cycle-specific agent, whereas gemcitabine is a phase-specific agent. They have different anti-cancer activities in NSCLC, and their toxicity profiles do not overlap. The major toxicities of cisplatin are nephrotoxicity and neurotoxicity (12), but these side effects are rarely seen in treatment with gemcitabine. A regimen containing these two drugs would yield a better therapeutic result than either of them alone. Cisplatin kills tumor cells by binding to DNA and forming intra- and inter-strand DNA–DNA cross-links. The damaged DNA could undergo excision repair, causing the occurrence of resistance to cisplatin (13). The addition of gemcitabine offers many benefits. When gemcitabine is incorporated on the end of an enlongating DNA strand, it masks the chain termination after a further deoxynucleotide is added. Gemcitabine blocks new DNA repair by depleting the deoxyribonucleotide and ribonucleotide pools (9).
Table 4 shows the results of some phase II studies using a combined regimen of gemcitabine and cisplatin in different schedules. Different schedules of the combined regimen may offer different efficacy and side effects. Shepherd et al. (14) first gave gemcitabine 1000 mg/m2 and cisplatin 30 mg/m2 weekly on days 1, 8 and 15 of a 28-day cycle. They described a low response rate of 26% and a median survival of 9.1 months. Interestingly, with the same schedule, but with a higher dosage of cisplatin (35 mg/m2), Lippe et al. (15) reported a higher response rate of 40% and a longer median survival of 11.8 months.
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In two studies, gemcitabine was given 1000 mg/m2 weekly for 3 weeks on days 1, 8 and 15 and cisplatin 100 mg/m2 on day 15 of a 28-day cycle. The results were comparable in both studies with an overall response rate of 42%. The median survival was 10.2 months in a total of 43 patients described by Steward et al. (16) and the overall response rate was 52% and median survival was 13 months in a total of 50 patients studied by Abratt et al. (17). In this study, we used the same dose of gemcitabine, 1000 mg/m2, on days 1, 8 and 15, but a lower dose of cisplatin, 80 mg/m2, on day 15 of a 28-day cycle. Our results were similar to those described in the above two studies, with an overall response rate of 40.6%, median survival of 13 months and a 1-year survival of 59.2%.
Cisplatin may also be given in differing schedules. In two studies, gemcitabine 1000 mg/m2 was given on days 1, 8 and 15 and cisplatin 100 mg/m2 on day 1 or day 2 in a 28-day cycle. Einhorn (18) administered cisplatin on day 1 and achieved a response rate of 37% and a median survival of 8.4 months in 30 evaluable patients. Crino et al. (19) gave cisplatin on day 2 in 48 patients and got a higher response rate at 54% and a median survival of 15 months.
A re-evaluation report (20) reviewing the data from previous phase II studies concluded that cisplatin given on day 15 rather than weekly is more beneficial. When cisplatin is administered on day 15, it provides the patient with a longer exposure to gemcitabine. Besides, it can be accompanied with the optimal dose intensity. Although no randomized study has been carried out comparing the efficacy and toxicity when cisplatin is used in differing schedules (weekly or on day 15), the regimen of weekly gemcitabine and monthly cisplatin on day 15 is now more commonly used. Some authors also administered cisplatin on day 1 or day 2.
In this study, the major hematological toxicity was neutropenia. The incidence of grade 3 and 4 neutropenia was 21.9%. Otherwise, the incidence of grade 3 and 4 thrombocytopenia, 3.1%, was lower than those in other reports (16, 19), at 58, 36% and 21, 52%, respectively. The lower incidence of hematological toxicity in our patients than in previous reports may be due to a lower dose of cisplatin and better performance status of our patients. Nausea or vomiting is mainly due to the adverse effects of cisplatin and grade 3 and 4 nausea/vomiting occurred in 37.5% of our patients. Similarly to previous reports, these side effects cause many to withdraw from treatment and incur further medical care problems.
In conclusion, in the 32 NSCLC patients treated with a combined regimen of gemcitabine with cisplatin, the response rate was 40.6%, the median survival was 13.5 months and the 1-year survival probability was 58.8%. The regimen of weekly gemcitabine and monthly cisplatin on day 15 is safe and effective in the treatment of NSCLC. In this combination, a lower dose of cisplatin seems to have an efficacy similar to previous reports.
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FOOTNOTES |
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+ For reprints and all correspondence: Thomas Chang-Yao Tsao, Chief, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan. E-mail: drtsao@adm.cgmh.com.tw
Abbreviations: NSCLC, non-small cell lung cancer; CT, computed tomography; G-CSF, granulocyte-colony stimulating factor; WHO, World Health Organization; CR, complete remission; PR, partial remission
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Received May 30, 2000; accepted August 30, 2000.
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