| Japanese Journal of Clinical Oncology | Pages |
Phase I Study of Cisplatin and Docetaxel Plus Mitomycin C in Patients with Metastatic Non-small Cell Lung Cancer
Introduction
Patients And Methods
Patient Selection and Pretreatment Evaluation
Treatment Plan
Study Design
Results
Patients' Characteristics
Toxicity
Discussion
Acknowledgments
References
Phase I Study of Cisplatin and Docetaxel Plus Mitomycin C in Patients with Metastatic Non-small Cell Lung Cancer
Background: Docetaxel, cisplatin and mitomycin C are some of the active drugs used in the treatment of patients with metastatic non-small cell lung cancer (NSCLC). The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose of the three drugs in combination for such patients. Methods: Chemotherapy-native patients with metastatic NSCLC were enrolled in this study. The doses of docetaxel and cisplatin were fixed at 60 and 80 mg/m2, respectively. It was planned to increase the dose of mitomycin C from 4 to 6 and 8 mg/m2. All drugs were administered on day 1 and repeated every 3-4 weeks. Results: All six patients received 60 mg/m2 of docetaxel and 80 mg/m2 of cisplatin, three of them with 4 mg/m2 of mitomycin C (level 1) and the other three with 6 mg/m2 of mitomycin C (level 2). Two of the three level 2 patients experienced dose-limiting toxicities (DLTs) in first cycle: febrile neutropenia and grade 3 hyponatremia. Based on these data, the MTD was concluded to be 60 mg/m2 for docetaxel, 80 mg/m2 for cisplatin and 6 mg/m2 for mitomycin C. Evaluation of the data from all of the cycles, however, showed that four of the six patients experienced DLTs. Conclusions: The addition of mitomycin C to docetaxel and cisplatin resulted in relatively high toxicities. It was impossible to use a high enough dose of mitomycin C to improve the survival of NSCLC patients. We therefore concluded that further evaluation of this combination is unwarranted.
Key words: non-small cell lung carcinoma - mitomycin C - cisplatin - docetaxel - phase I
INTRODUCTION
The prognosis of patients with metastatic non-small cell lung cancer (NSCLC) is still very poor. Cisplatin-based combination chemotherapy in such patients produces only a small survival benefit and long-term survival cannot be expected (1). Development of effective new combination chemotherapy for patients with metastatic NSCLC obviously must improve patient survival.
Many investigators have reported that the active drugs against NSCLC are cisplatin, ifosfamide, vinca alkaloids and mitomycin C, with response rates of 15-25% (2,3). Recently, several new active drugs, such as irinotecan, paclitaxel, docetaxel, vinorelbin and gemcitabin, have also been tested in NSCLC and response rates of 15-33% have been reported (4). These agents have been combined into multidrug regimens with substantial activity.
Docetaxel has been widely used to treat patients with advanced NSCLC (5-15) and 100 mg/m2 of docetaxel has generally been given every 3-4weeks. The response rates in the trials ranged from 21 to 38% and the median survival time was 7-14 months. Docetaxel is one of the most active drugs against NSCLC as a single agent.
The efficacy of combination chemotherapy with docetaxel and cisplatin as a first line treatment for patients with advanced NSCLC has been evaluated in many trials (16-21); the response rates were 33-51%, with median survival times of 8-13 months. These results seem more favorable than those obtained with old generation combination chemotherapy, such as cisplatinandvindesine or cisplatin and etoposide, which have been widely used as regimens for NSCLC.
Phase II trials of cisplatin and docetaxel for NSCLC have been conducted in Japan (22); 60 mg/m2 of docetaxel and 80 mg/m2 of cisplatin on day 1 every 3-4weeks were used in both studies. However, in most non-Japanese combination studies of docetaxel and cisplatin the recommended dose of docetaxel has been 75-100 mg/m2 and that of cisplatin 75-100 mg/m2. The dose of docetaxel in Japanese studies was decided without identifying the MTD, because the recommended dose of docetaxel as a single agent in the phase II trial was 60 mg/m2 on day 1 every 3-4 weeks (23,24). Since the addition of another drug to the docetaxel plus cisplatin combination might improve the survival of NSCLC patients, we designed a phase I trial of mitomycin C in combination with docetaxel and cisplatin.
The aims of the phase I trial were to determine the MTD and recommended dose of mitomycin C to add to docetaxel and cisplatin in chemotherapy-native NSCLC patients.
PATIENTS AND METHODS
Patient Selection and Pretreatment Evaluation
The eligibility criteria for this trial required a histologically or cytologically proven diagnosis of metastatic NSCLC. No previous chemotherapy was permitted and no radiation therapy within 4 weeks prior to the study. Other criteria included measurable disease, age 20-75 years, performance status (ECOG) 0 or 1, leukocyte count <12,000/mm3 and [ge]4000/mm3, absolute neutrophil count [ge]2000/mm3, platelet count [ge]100×103/mm3, hemoglobin [ge]9.5 g/dl, serum GOT and serum GPT level <2 times the upper limit of the normal range, serum bilirubin level <upper limit of normal range, serum creatinine <upper limit of normal range, 24 h creatinine clearance [ge]60 ml/min, O2 pressure of arterial blood [ge]70 mmHg and written informed consent.
Pretreatment evaluation consisted of a complete history, physical examination and a laboratory evaluation including a complete blood cell count and full range of blood chemistry studies. Staging procedures in all patients included chest X-ray, computed tomography (CT) of the thorax, CT and/or ultrasonography of the upper abdomen, bone scintigraphy and CT or magnetic resonance imaging of the whole brain.
Treatment Plan
Each patient received cisplatin, docetaxel and mitomycin C at one dose level, with courses repeated every 3-4 weeks. A 60 mg/m2 dose of docetaxel was chosen because it was the recommended dose of docetaxel combined with 80 mg/m2 of cisplatin in Japanese phase II and phase III trials. The dose of mitomycin C chosen was 50% of the mitomycin C dose in commonly used combination chemotherapy regimens, such as cisplatin and vindesin plus mitomycin C. All patients received granisetron hydrochloride 3 mg intravenously and dexamethasone 16 mg intravenously. Antiemetic treatment was allowed, if needed and G-CSF (granulocyte colony-stimulating factor) was allowed if the leukocyte count dropped below 2000/mm2 and/or the absolute neutrophil count dropped below 1000/mm2.
Patients who responded continued to receive treatment until disease progression or the development of serious toxicity. Patients who developed progressive disease at any time were removed from the study.
Study Design
DLT was defined as one or more of the following: febrile neutropenia or leukocytopenia (fever >38.0 °C with grade 4 neutropenia or leukocytopenia), grade 4 neutropenia or leukocytopenia lasting more than 5 days, grade 4 thrombocytopenia or grade 3 or 4 non-hematological toxicity except vomiting/nausea, anorexia, general fatigue and elevated serum bilirubin. The Japan Clinical Oncology Group has drawn up a scale for evaluating the severity of toxicity and it was used in this study.
Three patients were enrolled at each of the two levels. If DLT was observed in two or more patients in the first cycle, the dose at that level was concluded to be the MTD. If DLT was observed in one patient, an additional three patients were enrolled. If three or more of the six patients experienced DLT, then the dose at that level was concluded to be the MTD. The recommended dose was decided on the basis of the results of all of the cycles of this treatment.
Dose reductions for toxicity were as follows: grade 4 neutropenia or leukocytopenia lasting more than 4 days, reduce all drugs by 25%; grade 2 peripheral neuropathy, reduce docetaxel and cisplatin by 25%; grade 3 stomatitis, reduce cisplatin and mitomycin C by 25%.
History, physical examination, chest X-ray and a laboratory evaluation including a complete blood cell count and full range of blood chemistry studies were repeated weekly. Complete blood cell counts were obtained twice a week and every 2 or 3 days in the case of febrile neutropenia.
RESULTS
Patients' Characteristics
Six patients were enrolled in this study and their characteristics are given in Table 1. All patients were eligible. Their median age was 62 years; all six patients were in performance status 1; the histological types of their cancers were adenocarcinomas in four and squamous cell carcinomas in two. All patients had metastatic disease and had not received any prior treatment.
Table 1. Patients' characteristics (n = 6)
| Characteristic | No. |
| Age (years) | |
| Median | 62 |
| Range | 53-71 |
| Gender | |
| Male | 4 |
| Female | 2 |
| Performance status | |
| 0 | 0 |
| 1 | 6 |
| Histology | |
| Squamous cell carcinoma | 2 |
| Adenocarcinoma | 4 |
| Clinical stage | |
| IV | 6 |
Toxicity
The toxicities in the first cycle at each level are given in Table 2. At level 1, no patients experienced DLT. However, one patient could not continue this treatment because of prolonged leukocytopenia with a WBC count <4000/mm3 at 6 weeks after the first treatment. At level 2, two of the three patients experienced DLT: febrile neutropenia in one and grade 3 hyponatremia (122 mEq/l) in the other. The first patient required antibiotics and G-CSF. The second patient was scored as PS 3 and required intravenous fluid replacement. However, both patients recovered from the toxicities within 2 weeks. In any event, level 2, consisting of 80 mg/m2 of cisplatin, 60 mg/m2 of docetaxel and 6 mg/m2 of mitomycin C, was concluded to be the MTD.
Table 2. Toxicity in the first cycle
| Level | Toxicity | Grade (JCOG) | ||||
| 0 | 1 | 2 | 3 | 4 | ||
| 1 | WBC | 0 | 1 | 1 | 1 | 0 |
| Neutrophils | 0 | 0 | 2 | 1 | 0 | |
| Platelets | 3 | 0 | 0 | 0 | 0 | |
| Hemoglobin | 2 | 1 | 0 | 0 | - | |
| Nausea/vomiting | 1 | 0 | 1 | 1 | - | |
| Diarrhea | 2 | 0 | 1 | 0 | 0 | |
| Infection | 2 | 0 | 1 | 0 | 0 | |
| Hyponatremia | 3 | 0 | 0 | 0 | 0 | |
| Hypokalemia | 3 | 0 | 0 | 0 | 0 | |
| 2 | WBC | 0 | 0 | 1 | 1 | 1* |
| Neutrophils | 1 | 0 | 0 | 1 | 1 | |
| Platelets | 3 | 0 | 0 | 0 | 0 | |
| Hemoglobin | 3 | 0 | 0 | 0 | - | |
| Nausea/vomiting | 2 | 0 | 1 | 0 | - | |
| Diarrhea | 1 | 0 | 2 | 0 | 0 | |
| Infection | 2 | 0 | 1 | 0 | 0 | |
| Hyponatremia | 1 | 0 | 1 | 1* | 0 | |
| Hypokalemia | 3 | 0 | 0 | 0 | 0 | |
The recommended dose was decided on the basis of the results of all of the cycles of this treatment. The toxicities in all the cycles at each level are given in Table 3. DLT was seen at both levels. At level 1, one patient experienced febrile neutropenia in the second cycle and another experienced febrile neutropenia and grade 3 hypokalemia (2.5 mEq/l) in the second cycle. At level 2, two patients experienced DLT, hence only one patient could receive a second cycle. This third patient did not experience DLT. There were no treatment-related deaths in this study.
Table 3. Toxicity in all the cycles
| Level (total cycles) | Toxicity | Grade (JCOG) | ||||
| 0 | 1 | 2 | 3 | 4 | ||
| 1 (5) | WBC | 0 | 1 | 2 | 1 | 1 |
| Neutrophils | 0 | 0 | 2 | 1 | 2* | |
| Platelets | 4 | 0 | 1 | 0 | 0 | |
| Hemoglobin | 2 | 2 | 1 | 0 | - | |
| Nausea/vomiting | 1 | 0 | 2 | 2 | - | |
| Diarrhea | 3 | 0 | 2 | 0 | 0 | |
| Infection | 3 | 0 | 1 | 1[dagger] | 0 | |
| Hyponatremia | 4 | 1 | 0 | 0 | 0 | |
| Hypokalemia | 3 | 1 | 0 | 1[dagger] | 0 | |
| 2 (4) | WBC | 0 | 0 | 2 | 1 | 1[dagger] |
| Neutrophils | 1 | 0 | 0 | 2 | 1 | |
| Platelets | 3 | 1 | 0 | 0 | 0 | |
| Hemoglobin | 4 | 0 | 0 | 0 | - | |
| Nausea/vomiting | 3 | 0 | 1 | 0 | - | |
| Diarrhea | 2 | 0 | 2 | 0 | 0 | |
| Infection | 3 | 0 | 1 | 0 | 0 | |
| Hyponatremia | 1 | 1 | 1 | 1[dagger] | 0 | |
| Hypokalemia | 4 | 0 | 0 | 0 | 0 | |
[dagger]DLT.
All patients were evaluable for response. At level 1 one patient achieved a partial response (PR), there was no change (NC) in two and progressive disease (PD) in three.
DISCUSSION
Several new active drugs for NSCLC have recently been developed. Docetaxel is one of them and its combination with cisplatin is more efficacious against NSCLC. Many combination chemotherapy studies have reported a higher response rate for docetaxel and cisplatin in combination. In Japan, the recommended doses for phase II studies of docetaxel and cisplatin on day 1 are 60 and 80 mg/m2, respectively. However, studies in other countries have often used higher doses of docetaxel and the recommended dose in Japan was decided without identifying the MTD. We therefore thought that another drug could be added to the combination regimen. Mitomycin C is active against NSCLC and some studies have reported that addition of mitomycin C had a tendency to result in a higher response rate (25,26). Sekine et al. (4) reported that the response rate was significantly correlated with MST in single-agent phase II trials for NSCLC.
The major toxicities of this combination are hematological and metabolic. Many investigators have reported that the most frequent non-hematological toxicities of the combination of docetaxel and cisplatin are diarrhea and nausea/vomiting (16-22). Diarrhea and nausea/vomiting also occurred in this study, but they were at acceptable levels. All patients who experienced severe metabolic toxicities had diarrhea and nausea/vomiting and thus metabolic toxicities might be reduced if patients received more replacement fluid intravenously or electrolyte supplements. However, it cannot be ruled out that the patients may have experienced metabolic toxicities for unknown reasons or as a direct effect of chemotherapy.
In this study, we decided the MTD in this combination on day 1 to be 60 mg/m2 of docetaxel, 80 mg/m2 of cisplatin and 6 mg/m2 of mitomycin C. However, these doses were inappropriate for further study, because an additional 4 mg/m2 of mitomycin C was not expected to improve the survival of NSCLC patients. Furthermore, two cycles of this combination would produce relatively severe toxicities.
In conclusion, addition of mitomycin C to the combination of docetaxel and cisplatin produced severe toxicities. It was impossible to use a high enough dose of mitomycin C to improve the survival of NSCLC patients.
Acknowledgments
This work was supported in part by a grant from the Ministry of Health and Welfare for the Second Term Comprehensive Strategy for Cancer Control and a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.
References
Received June 11, 1999; accepted July 26, 1999
For reprints and all correspondence: Yukio Hosomi, Division of Thoracic Oncology, National Cancer Center Hospital East, 5-1 Kashiwanoha 6-chome, Kashiwa, Chiba 277-8577, Japan. E-mail: yhosomi{at}east.ncc.go.jp
Abbreviations: MTD, maximum tolerated dose; DLT, dose-limiting toxicities; CT, computed tomography; G-CSF, granulocyte colony-stimulating factor
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Copyright© 1999 Foundation for the Promotion of Cancer Research.
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