Japanese Journal of Clinical Oncology 30:542-546 (2000)
© 2000 Foundation for Promotion of Cancer Research
A Phase II Study of VP-16–Ifosfamide–Cisplatin Combination Chemotherapy Plus Early Concurrent Thoracic Irradiation for Previously Untreated Limited Small Cell Lung Cancer
Departments of 1Internal Medicine and 2Therapeutic Radiology, College of Medicine, Hallym University and Departments of 3Internal Medicine and 4Therapeutic Radiology, College of Medicine, Sungkyunkwan University, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: At present the addition of thoracic irradiation to combination chemotherapy is a standard treatment for limited staged small cell lung cancer. However, there is still controversy about the optimum timing of chest irradiation. We conducted a phase II study of etoposide (VP-16)–ifosfamide–cisplatin (VIP) combination chemotherapy plus early concurrent thoracic irradiation for the patients with previously untreated limited small cell lung cancer in order to assess if the treatment modality could improve the response rate and the toxicity.
Methods: Forty-four patients with limited small cell lung cancer were treated with etoposide–ifosfamide–cisplatin and concurrent thoracic irradiation. Combination chemotherapy consisted of etoposide 100 mg/m2 (on days 1–3), ifosfamide 1000 mg/m2 (on days 1 and 2) and cisplatin 100 mg/m2 (on day 1). Concurrent thoracic irradiation consisted of a total of 4000 cGy over 4 weeks starting on the first day of the first chemotherapy. All patients who showed a complete response were given prophylactic cranial irradiation for 2.5 weeks.
Results: Forty-four of the 49 patients who entered the study from May 1994 to August 1998 were evaluable. The median age was 59 years and 40 patients had a performance status of 0 or 1. The median survival time was 22.5 months. Twenty-eight patients (62%) showed a complete response and 16 (38%) a partial response. Twenty-four patients (54%) developed grade 3 or 4 neutropenia; there was a 9% RTOG score 3 or 4 esophagitis.
Conclusion: VIP combination chemotherapy and early concurrent thoracic irradiation for patients with limited stage small cell lung cancer revealed excellent antitumor response with tolerable toxicity.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The combination chemotherapy of etoposide (VP-16) and cisplatin is often chosen for concurrent chemoirradiation therapy for the treatment of small cell lung cancer because of the weak radiosensitizing effect of cisplatin. Ifosfamide is effective for small cell lung cancer even as a single agent (1) and has a moderate myelosuppressive effect. According to a previous report, an etoposide (VP-16)–ifosfamide–cisplatin (VIP) regimen was more effective than an etoposide-cisplatin regimen in extensive small cell lung cancer (2). Meta-analysis of thoracic irradiation for limited small cell lung cancer showed that thoracic irradiation helps in improving survival and local control in limited small cell lung cancer patients (3). However, the optimum timing and the dose of thoracic irradiation have not been clearly defined. In the conceptual model of limited small cell lung cancer according to the presence or absence of chemoresistant stem cells and their location (4), many showed a resistant clone of cells at the primary site. Early thoracic irradiation may reduce chemoresistant clones within primary tumors from the beginning and prevent resistant tumors from spreading to distant sites during the treatment. Even though severer toxicity with concurrent chemoirradiation, based on the premise that early would be more efficient than late radiotherapy, was expected, we conducted a phase II study of etoposide, ifosfamide and cisplatin (VIP) combination chemotherapy plus early concurrent thoracic irradiation for previously untreated limited small cell lung cancer.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
Patients with previously untreated, histologically documented small cell lung cancer were entered in this study. The eligibility criteria for patient entry included no active second malignancy and an Eastern Cooperative Oncology Group performance status of 0–2. Patients also needed adequate hematological function, defined as a WBC count >4000/mm3 and a platelet count >100 000/mm3, adequate renal function with serum creatinine level <1.5 mg/dl and adequate cardiac function defined as no symptomatic heart disease and no significant arrhythmia or myocardial infarction within the past 3 months. Patients with pleural effusions, chest wall involvement and pericardial effusion were excluded. The study was approved by the institutional review boards of the participating institutions and all patients gave written informed consent before they participated.
Pretreatment Examinations
Patients underwent staging evaluation before the initiation of treatment. We noted their history and performed a physical examination, complete blood cell count with differential serum chemistry examination and urine analysis. Imaging studies included chest X-ray, computed tomography of chest and liver and radionuclide bone scan. They also underwent fiber-optic bronchoscopy, bone marrow aspiration and biopsies. Brain CT scan or MRI was not performed routinely unless they complained of CNS symptoms or demonstrated CNS signs. We consulted with radiation oncologists about their suitability for combined modality therapy. Limited disease was defined as a tumor confined to one hemithorax and hilar, mediastinal and supraclavicular nodes and encompassable within a tolerable radiotherapy portal after completion of staging evaluation.
Chemotherapy
All patients received chemotherapy consisting of etoposide 100 mg/m2 (on days 1–3), ifosfamide 1000 mg/m2 (on days 1 and 2) and cisplatin 100 mg/m2 (on day 1). Mesna was administered at a dose of 300 mg/m2 as an intravenous bolus before the first dose of ifosfamide and was continued as a continuous intravenous infusion at a dose of 600 mg/m2/day over 24 h on days 1 and 2. Patients were hydrated with 5% dextrose in 9% normal saline infused at a rate of 125–150 ml/h during treatment. The combination chemotherapy was repeated every 3 weeks from the start of treatment concurrently with thoracic irradiation and a total of six cycles were applied. Dosage modifications of chemotherapy were as follows: if theWBC was 3000–4000/mm3, etoposide and ifosfamide were reduced to 75% of the original dose, if the WBC was <3000/mm3 on day 22, chemotherapy was delayed 1 week and when serum creatinine was 1.5–2.0 mg/dl, a 75% dose of cisplatin was administered.
Thoracic Irradiation
Concurrent chest irradiation was started on the first day of cycle 1 and consisted of 40 Gy in 20 fractions over 4 weeks using 6 MV linear accelerator photons. Anterior and posterior opposed fields were used. The dose was prescribed at the central axis and calculated at the midplane. Radiation portals to the primary tumor included the complete extent of visible tumor as defined radiographically with a 2 cm margin around the tumor. The lymph nodes included in the treatment volume were bilateral supraclavicular nodes and ipsilateral hilar nodes (5 cm below the carina). For lower lobe lesions, the radiation portals were extended down the diaphragm.
Radiation therapy was delayed only if the platelet count was <40 000/mm3 or the granulocyte count was <1000/mm3 before the start of the second chemotherapy. If there was grade 3 or worse non-hematological toxicity, treatment was delayed for 1 week. If toxicity had recovered to grade 1 or better after a 1-week treatment delay, then treatment was resumed. The patients who achieved a complete response were given 2400 cGy of prophylactic cranial irradiation in 12 fractions over 2.5 weeks. Patients were examined at the end of the treatment, every month for 6 months (after completion of therapy), every 2 months for 2 years thereafter and every 4 months after that.
Follow-up
History, physical examination, assessment of performance status, weight, chest radiography and urine analysis were repeated before each cycle during treatment. After three and six cycles of combination chemotherapy, the response was determined by fiber-optic bronchoscopy with washings and biopsies, computed tomographic scans of chest and liver and radionuclide bone scan.
Response Criteria
The responses were assessed according to WHO criteria (5). A minimum duration of 4 weeks was required to document a response and the best response was recorded for each patient. Complete response (CR) was defined as complete disappearance of all measurable malignant lesions for at least 4 weeks. Partial response (PR) was a reduction of at least 50% in the sum of the products of the greatest perpendicular diameters of all measurable lesions for at least 4 weeks without any new malignant lesion. No response was defined as stabilization or <50% reduction in measurable or evaluable disease. Progression was defined as an increase of >25% of at least one lesion or the appearance of a new malignant lesion.
Statistical Analysis
A fixed-sample-size design was used. Employing 
= 0.05 and ß = 0.20, the target number of cases would be 44. The sample size calculation of George and Desu was used (6). Radiation-induced effects on normal tissue were assessed according to the criteria of the Radiation Therapy Oncology Group (7). Duration of response was measured from the start of treatment to the date of disease progression in patients who achieved a CR or PR. Response rates were calculated as the proportion of assessable cases. The confidence interval was calculated based on a binomial distribution. Survival time was calculated from the date of treatment initiation until the date of the last follow-up evaluation or death. A survival curve was generated using the Kaplan–Meier method (8). Survivors were censored on the date they were last known to be alive.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Characteristics and Administration of Treatment
Between May 1994 and October 1998, 49 patients were registered at two participating institutions. Of these, five patients were later excluded; three of them were found to have extensive disease, one was enrolled but was never treated and two received one cycle and were lost to follow-up. Forty-four patients (33 men and 11 women) were eligible for toxicity and response studies. The median age was 59 years (range 42–79 years) and 40 patients were fully ambulatory with a performance status of 0 or 1. Twenty-four patients revealed normal LDH and 14 patients elevated LDH (Table 1); an LDH test was not performed on the other six patients.
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Table 2 gives the percentages of prescribed doses of chemotherapy and irradiation actually delivered to the patients. The relative dose intensities of etoposide, ifosfamide and cisplatin were 0.876, 0.819 and 0.878 (9,10) and the average dose intensity of the combination chemotherapy was 0.857. The median follow-up time was 27 months (range, 2–43 months).
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Response and Survival
Twenty-eight patients (62%) had a complete response (95% CI = 58.6–65.4%) and 16 (38%) had a partial response (95% CI = 31.9–44%). All 28 patients who had a complete response received prophylactic cranial irradiation. The median duration of response was 8.5 months (Fig. 1) and the median survival time was 22.5 months (Fig. 2).
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Toxicity
Twenty-four patients (55%) were hospitalized for febrile neutropenia; these patients were febrile for a median of 2 days (range, 1–12 days) and received a median of 7 days of antibiotics. There were 11 (25%) anemia cases (WHO grade >3) and 26 patients required transfusion of blood products, with a median of 5 U (range, 2–16 U) of packed RBCs, and three patients received platelet transfusions. Nausea and vomiting were generally acceptable, frequently observed and typical for cisplatin use (Table 3). One patient showed increased GOT/GPT (grade 1). With regard to nephrotoxicity, gross hematuria (more than WHO grade 2) was not observed. There were 18 patients with serum creatine elevated (WHO grade 1). Radiation toxicities were generally tolerable and reversible. Four patients developed RTOG grade 3 esophagitis, which required an NG feeding tube, i.v. fluids and hyperalimentation. The patients received a median of 6 days (range, 2–14 days) of i.v. fluids. No patients had esophageal obstruction, ulceration or perforation. There were two cases of severe radiation pneumonitis, with seven patients having moderate pulmonary toxicity and six patients having mild toxicity that was present with mild symptoms, such as dry cough and slight radiographic appearance (Table 4).
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Fourteen of twenty-eight patients who showed a complete response (50%) had relapsed at the time of analysis, with the lung being the most common area in 11 patients. Seven patients showed infield recurrence. Three of these patients had relapsed multiple sites. Two of the patients had CNS metastasis at the time their small cell lung cancer relapsed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cisplatin and etoposide produce response rates and survival comparable or superior to CAV for small cell lung cancer (11). For the combined modality of chemotherapy and chest irradiation for lung cancer, cisplatin and etoposide have been widely used because of the weak radiosensitizing properties of cisplatin, apart from doxorubicin and cyclophosphamide. Also, there has not been any implication of radiation recall toxicity with cisplatin and etoposide. The combination chemotherapy of cisplatin and etoposide has been widely administered in patients with non-small cell lung cancer with doses of cisplatin 60–120 mg/m2 for 1 day and etoposide 100–120 mg/m2 for 3 days (12,13).
In a randomized trial comparing cisplatin (120 mg/m2, day 1) plus etoposide (100 mg/m2, days 1–3) with carboplatin (325 mg/m2) plus etoposide (100 mg/m2, days 1–3) in advanced non-small cell lung cancer, the cisplatin plus etoposide regimen was more toxic than the carboplatin-containing regimen (14). Ifosfamide, known to be effective for small cell lung cancer as a single agent (1,15) and less myelotoxic, can be combined with other myelosuppressive drugs and it was synergistic with cisplatin in preclinical studies (16). Considering these data, we planned VIP combination chemotherapy consisting of etoposide (100 mg/m2 on days 1–3), ifosfamide (1 g/m2 on days 1 and 2) and cisplatin (100 mg/m2 on day1). According to other studies that evaluated the effectiveness of VIP in small cell lung cancer patients, the VIP combination chemotherapy produced overall response rates of 71–100%, with a 27–100% CR rate in SCLC patients (17,18). In a randomized study by the Hoosier Oncology Group, VIP combination chemotherapy was associated with an improved time to progression and overall survival compared with etoposide–cisplatin in patients with extensive small cell lung cancer (2).
Thoracic radiotherapy may improve the rate of local control, but it cannot change the fatal outcome for all these patients. The probability of cure progressively decreases as thoracic irradiation is delayed because of the cumulative probability of metastatic events. There have been three published randomized studies of early versus late thoracic irradiation (19–21). The CALGB group reported that 399 patients were randomized to receive thoracic radiation starting on day 1 (arm I), on day 64 of chemotherapy (arm II) and chemotherapy alone (arm III). With 10 years of follow-up, the combined modality with thoracic irradiation improved both complete response rate and survival compared with chemotherapy alone. However, the difference between the radiation arms (arms I and II) was not stastically significant (p = 0.238). The NCIC reported higher incidences of CNS relapse in the late than in the early irradiation group and the overall survival rates were slightly better in the NCIC trial, especially the early thoracic irradiation group. With regard to the local control, no significant differences were observed in the three trials. We started concurrent chest irradiation on the first day of cycle 1 consisting of 40 Gy in 20 fractions over 4 weeks. The results showed complete response 62%, partial response 38% and overall response rate 100%, but the response duration was just 8.5 months, which was never prolonged. Also, there was no gain in survival compared with others. Even though the dose of ifosfamide was about half that in the Hoosier Oncology Group study, our data showed grade 3 and 4 neutropenia of 41% and 14%, respectively, and all patients experienced febrile neutropenia and needed antibiotics. If they could not be controlled with empirical antibiotics, we administered growth factor. We were not able to observe the mortality associated with neutropenia. Pulmonary toxicity that required corticosteroid therapy was noted in two of 44 patients (4.5%). NCIC reported a 3% incidence of severe pulmonary toxicity in the early irradiation arm, which is not statistically significant, compared with the late arm. Even though, with developing supportive care, we could expect more improvement in the results of combined modality and life quality of the patients, we need to develop other new systemic therapeutic regimens to overcome the evolution of drug resistance and more effective chemotherapeutic drugs and establish the optimum timing and dose of chest irradiation.
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FOOTNOTES |
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+ For reprints and all correspondence:Young Suk Park, Department of Internal Medicine, Hallym University, KangDong Sacred Heart Hospital, 445, Gil-dong, Kangdong-ku, Seoul, Korea 134-701. E-mail: pys27hmo@yahoo.com
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Received June 29, 2000; accepted September 19, 2000.
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