Japanese Journal of Clinical Oncology 32:43-47 (2002)
© 2002 Foundation for Promotion of Cancer Research
Phase I/II Study of 3-Week Cycle Cisplatin–Gemcitabine in Advanced Non-small Cell Lung Cancer
Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The combination of cisplatin and gemcitabine is one of the most active chemotherapy regimens against non-small cell lung cancer. However, the optimum schedule for this combination has not been determined. This study was performed to determine the maximum tolerated dose of gemcitabine combined with cisplatin in a 3-week cycle regimen and to observe safety and efficacy for Japanese patients with advanced non-small cell lung cancer.
Methods: 80 mg/m2 of cisplatin on day 1 and escalated doses of gemcitabine on days 1 and 8 were administered every 3 weeks to patients with previously untreated, advanced non-small cell lung cancer. The initial dose of gemcitabine was 1000 mg/m2 and was escalated in 250 mg/m2 increments.
Results: Twenty-four patients were enrolled between March and December 2000. In total, 64 courses were given. The main toxicities were neutropenia, thrombocytopenia and hepatotoxicity. The maximum tolerated dose was determined to be 1500 mg/m2 of gemcitabine combined with 80 mg/m2 of cisplatin. Nine of 24 patients (37.5%) achieved a partial response.
Conclusion: This study demonstrates that the combination of cisplatin and gemcitabine repeated every three weeks is tolerable for Japanese patients with advanced non-small cell lung cancer. We determined 1250 mg/m2 of gemcitabine combined with 80 mg/m2 of cisplatin to be the recommended dose.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although many clinical studies have been performed, the role of chemotherapy in advanced non-small cell lung cancer (NSCLC) remains controversial. Among the active agents examined for advanced NSCLC, cisplatin (CDDP) has been considered the most important. A meta-analysis of CDDP-containing regimens showed a benefit with an increase in the survival rate of 10% at 1 year and with an increase in the median survival time (MST) of 1.5 months, compared with the best supportive care in advanced NSCLC (1). Based on these results, CDDP-containing regimens are currently the recommended treatment for advanced NSCLC.
In the last few years, several new drugs have shown promising activity against advanced NSCLC. Among these drugs, a novel nucleoside analog, gemcitabine, has demonstrated superior activity against solid tumors, including lung, ovarian and pancreatic cancers (2). In phase I studies, it was evaluated for various dosages and schedules (3,4) and weekly administration of gemcitabine was recommended as a 30 min intravenous infusion (5). In phase II studies of single-agent gemcitabine, weekly administration at doses of 800–1250 mg/m2 achieved response rates of 20–26% (6–8). Several investigators have administered CDDP on day 1 or 15 and 1000 mg/m2 of gemcitabine on days 1, 8 and 15 every 4 weeks, with response rates of 20–54% and MST of 8–14 months in advanced NSCLC (9–14). The main toxicity was myelosuppression and grade 3 or 4 thrombocytopenia was frequent in these studies. The combination delivered as a 4-week cycle was associated with a high incidence of grade 3 or 4 myelotoxicity during the third week of the cycle, which required a dose reduction or omission of gemcitabine on day 15. This occurred in almost 50% of the total courses (13). To obtain a higher dose intensity than 4-week cycle regimens, 3-week cycle regimens were examined in clinical studies. Cardenal et al. (15) conducted a randomized phase III study to compare a 3-week cycle regimen of CDDP and gemcitabine with the combination of CDDP and etoposide in advanced NSCLC. They administered 100 mg/m2 of CDDP on day 1 and 1500 mg/m2 of gemcitabine on days 1 and 8 every 3 weeks. They reported that the combination of CDDP and gemcitabine provided a significantly higher response rate than CDDP and etoposide (40.6 vs 21.9%; P = 0.02).
In Japan, Kurita et al. conducted a phase I/II study and reported 80 mg/m2 of CDDP and 1000 mg/m2 of gemcitabine to be the optimum doses in a 4-week cycle regimen (16). Although a 3-week cycle regimen has been regarded as promising, there have been no studies in Japan. This study was therefore designed to determine the maximum tolerated dose (MTD) and the recommended dose of gemcitabine combined with cisplatin in a 3-week cycle regimen for Japanese patients with advanced NSCLC. The secondary objectives were to evaluate the safety and efficacy of this regimen.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Selection
Patients with histologically or cytologically confirmed unresectable stage IIIB/IV or postoperative recurrent NSCLC were enrolled in this study after giving written informed consent. Other eligibility criteria included the following: no prior chemotherapy or radiotherapy; 20–74 years of age; Eastern Cooperative Oncology Group performance status (PS) of 0 or 1; measurable disease; adequate organ function: 12 000/µl
WBC count 4000/µl, absolute neutrophil count (ANC) 2000/µl, hemoglobin level 9.0 g/dl, platelet count 100 000/µl, serum bilirubin level 
1.5 mg/dl, AST level 66 IU/l, ALT level 56IU/l, serum creatinine level 1.5 mg/dl, 24 h creatinine clearance 60 ml/min, PaO2 60 mmHg. Exclusion criteria included the following: a serious pre-existing medical condition such as infection, severe heart disease, uncontrolled diabetes mellitus, interstitial pneumonia or pulmonary fibrosis, pericardial or pleural effusion requiring drainage, symptomatic brain metastasis, pregnancy or lactation. The protocol was approved by the Institutional Review Board of the National Cancer Center.
Pretreatment Evaluation
Pretreatment evaluation included a complete history, physical examination, electrocardiogram, chest X-ray, chest computed tomography (CT), CT or magnetic resonance imaging (MRI) of the brain, ultrasonography or CT of the abdomen and a radionuclide bone scan. Laboratory investigations included a complete blood cell count, full chemistry profile and urinalysis. A physical examination and chest X-ray (or chest CT) were performed just before the administration of all courses of chemotherapy. Hematological and biochemical studies were repeated weekly.
Drug Administration
Cisplatin was administered on day 1 for 60 min. Gemcitabine was administered on days 1 and 8 for 30 min. Prophylactic antiemetics were routinely administered. Drugs were administered intravenously as follows. On day 1, patients were given intravenous hydration with 1000 ml of normal saline. Gemcitabine in 100 ml of normal saline was administered for 30 min. A 3 mg dose of 5-HT3 receptor antagonist and 16 mg of dexamethasone in 100 ml of normal saline were given before the administration of CDDP. Cisplatin was administered over 1 h with 500 ml of 0.9% sodium chloride solution and 1000 ml of 5% glucose solution for hydration.
On day 8, initially 3 mg of 5-HT3 receptor antagonist in 100 ml of normal saline were administered for 30 min. Then, gemcitabine in 100 ml of normal saline was administered for 30 min. The vein was washed out with a further 100 ml of normal saline. The administration of gemcitabine on day 8 was omitted if the WBC count was <2000/µl, platelet count <75 000/µl, AST and/or ALT levels 2.5 times normal or serum creatinine >2.0 mg/dl. Treatment was repeated if the WBC, ANC and platelet counts had recovered to more than 4000, 2000 and 100 000/µl, respectively. If the patients experienced grade 4 leukopenia, neutropenia or febrile neutropenia, the use of G-CSF was permitted.
Dose Escalation
The dose escalation scheme is presented in Table 1. We planned three incremental dose levels of gemcitabine and the dose of cisplatin was fixed at 80 mg/m2. The starting dose of gemcitabine was 1000 mg/m2. The rationale for selection of the initial dose was as follows: in several studies of the combination of CDDP and gemcitabine, the recommended doses were reported to be 1000 mg/m2 of gemcitabine on days 1, 8 and 15 with 80 mg/m2 of cisplatin on day 1 every 4 weeks (10–13) or 1250 mg/m2 of gemcitabine on days 1 and 8 with 80 mg/m2 of cisplatin on day 1 every 3 weeks (14). The expected main toxicity was myelosuppression with our regimen and we considered 1000 mg/m2 of gemcitabine to be appropriate as the initial dose.
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DLT and MTD
Six patients were entered at each dose level. When dose-limiting toxicity (DLT) was observed in more than three of six patients at the same level, this level was defined as the MTD. Dose escalation was undertaken based on the toxicity encountered in the first cycle and intrapatient dose escalation was not permitted. DLT was defined as follows: (1) grade 4 neutropenia lasting 5 days or more, (2) febrile neutropenia (>38°C), (3) platelet count <20 000/µl or platelet transfusion, (4) any grade 3 or 4 non-hematological toxicity (excluding nausea, vomiting, asthenia, alopecia, transient elevation of serum bilirubin and transient hyponatremia or hypokalemia), (5) interstitial pneumonia and (6) omission of gemcitabine on day 8. Toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria. A recommended dose of gemcitabine was regarded as one level below the MTD.
Criteria for Response
Responses were evaluated according to WHO criteria (17). Tumors were measured from the sum of the products of the two-dimensional diameter on a CT scan or a chest X-ray. A CT scan or a chest X-ray assessed responses in all patients after each cycle of chemotherapy.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Twenty-four patients were enrolled between March and December 2000; their characteristics are summarized in Table 1. There were 17 men and seven women, with a median age of 60 years (range: 38–70 years). Four patients had stage IIIB disease and 20 patients had stage IV disease. Three patients had postoperative recurrent disease.
Treatment Administered
A total of 64 courses were given. The median number of courses administered was four, three and three at levels 1, 2 and 3, respectively (Table 2). One patient at level 1 and two at level 2 required the omission of gemcitabine on day 8 in the first course because of toxicity. Two patients at level 1, four at level 2 and four at level 3 required delay of the second course because their WBC count or neutrophil count did not recover to the eligibility criteria, which were WBC count >4000/µl, ANC >2000/µl and platelet count >100 000/µl. The median delay interval was 10 days. Then, the criteria to start the second course were changed to WBC count >3000/µl, ANC >1500/µl and platelet count >100 000/µl. Six more patients were enrolled at level 2, none of whom required delay of the second course under the new criteria. The actual dose intensities in the first course were 546, 660 and 741 mg/m2/week of gemcitabine and 24.1, 24.5 and 19.7 mg/m2/week of cisplatin.
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Toxicity
Hematological toxicities in the first course are summarized in Table 3. The main toxicities were leukopenia, neutropenia and thrombocytopenia. Grade 3 or 4 leukopenia was observed in 25%, neutropenia in 29% and thrombocytopenia in 17%. Although G-CSF was required in five of 64 courses and platelet transfusion was required in one course, neutrophil and platelet counts recovered in a few days and no serious hematological events occurred. Non-hematological toxicities are also summarized in Table 3. Grade 3 elevation of hepatic enzymes was seen in two patients (8%). One patient at level 1 had serum anti-HCV antibody, but another patient at level 2 had neither hepatic disease nor liver metastasis. Liver enzymes were elevated on day 8 and normalized in a few weeks. Asthenia was seen in 50%, with grade 3 asthenia in one patient at level 1. Serious hair loss, nausea/vomiting and nephrotoxicity were not observed. Cumulative toxicity, except anemia, was not observed (Table 4).
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DLT are summarized in Table 5. The DLT at level 1 was grade 3 elevation of serum ALT in a patient with anti-HCV antibody. At level 2, DLT were observed in four of 12 patients. Omission of gemcitabine on day 8 because of grade 3 leukopenia or grade 2 elevation of serum ALT was defined as DLT in this study. At level 3, DLT were observed in three of six patients, fibrile neutropenia in one and grade 4 thrombocytopenia requiring platelet transfusion in one. The third patient could not receive the second course of treatment within 6 weeks from the start of treatment because of prolonged neutropenia. Although this toxicity was not defined as DLT, we considered it to be dose-limiting and included it in DLT. Therefore, at level 3, 1500 mg/m2 of gemcitabine combined with 80 mg/m2 of CDDP was determined to be the MTD.
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Response
All patients were assessable for response (Table 6). Five of six patients at level 1 and four of 12 patients at level 2 achieved a partial response, but no patient showed a response at level 3. There were no complete responses. The overall response rate was 37.5%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The present study demonstrated the combination of CDDP and gemcitabine in a 3-week cycle regimen to be well tolerated, showing a promising response in advanced NSCLC. The main toxicities were leukopenia, neutropenia, thrombocytopenia, hepatotoxicity and asthenia, which were profiles similar to those in other studies. These toxicities were thought to be tolerable.
A phase III study was conducted by the Eastern Cooperative Oncology Group to compare CDDP plus docetaxel, CDDP plus gemcitabine, CDDP plus paclitaxel and carboplatin plus paclitaxel (14). The combination of CDDP and gemcitabine produced a response rate of 21%, MST of 8.1 months, 1-year survival rate of 36% and time to progression (TTP) of 4.5 months. It was therefore established as the recommended regimen. However, the combination of CDDP and gemcitabine in 4-week cycles has frequently required dose reduction or omission of gemcitabine on day 15 (10–14), resulting in a decreased dose intensity.
In this study, the actual dose intensities of both drugs in level 2 were almost the same as the scheduled dose intensities achieved by the 4-week cycle regimen, which contained 1000 mg/m2 of gemcitabine and 100 mg/m2 of CDDP. We speculated that a 3-week cycle regimen could obtain a higher dose intensity than 4-week cycle regimens because of the aforementioned dose reduction or omission of gemcitabine often occurring in 4-week cycle regimens (10–14). Three-week cycle treatment could be repeated safety and efficiently, when the starting criteria were WBC count >3000/µl, ANC >1500/µl and platelet count >100 000/µl. We determined 1250 mg/m2 of gemcitabine combined with 80 mg/m2 of CDDP to be the recommended dose. This was considered comparable to the doses in the previous study of a 3-week cycle regimen. Although the number of patients in each cohort of this study was small, the response rate was promising. These results should be further evaluated in a phase II or III study.
In conclusion, the current study demonstrated the combination of CDDP and gemcitabine in Japanese patients with advanced NSCLC to be well tolerated. These agents can be given at the same doses as those in the previous study of a 3-week cycle regimen.
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FOOTNOTES |
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+ For reprints and all correspondence: Tomohide Tamura, Division of Internal Medicine, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Received August 17, 2001; accepted November 2, 2001.
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