Phase I-II study of high dose epirubicin plus cisplatin in unresectable non-small-cell lung cancer: searching for the maximal tolerated dose.

The purpose of this study was to search for the maximal tolerated dose of cisplatin in the cisplatin plus high-dose epirubicin combination for patients with non-small-cell lung cancer. The following range of cisplatin dosages were tested in a phase I study: 75, 90, 105, and 120 mg/m2 in combination with epirubicin 120 mg/m2 every 3 weeks. Eligibility consisted of previously untreated stage IIIb or IV non-small-cell lung cancers, Eastern Cooperative Oncology Group Performance Status less than or equal to 2, age less than or equal to 70 years, measurable disease, adequate blood counts, chemistry, cardiac function, and no brain metastasis. The maximal tolerated dose was defined as the dose level of cisplatin for which two of three patients or three of six patients developed one or more limiting toxicities during the first course of therapy. Afterward, the maximal tolerated dose of cisplatin was adopted in a subsequent phase II study. Three centers enrolled 42 patients: 18 in phase I and 24 in phase II. The maximal tolerated dose was almost reached at the last dose level (i.e., 120 mg/m2). Taking into account the total duration of the treatment, the real dose intensity for patients treated at the fourth dose level (120 mg/m2) did not differ from that of the third dose level (105 mg/m2). The latter dosage was therefore considered as the maximal tolerated one. In the subsequent phase II study, the median number of cycles received per patient was three (range: one to eight). Fifty percent required a dose reduction of either epirubicin, cisplatin, or both. The main toxicity was neutropenia, resulting in 10 episodes of febrile grade IV neutropenia requiring readmission. Other toxicities were mild to moderate. There was no toxic-related death. On intent-to-treat analysis, 10 patients (33%) achieved an objective response. Among them were three complete responders. Median survival was 8 months. We observed neither detraction nor improvement of quality of life as assessed using the European Organization for Research and Treatment of Cancer QLQ-C30-LC13. Given every 3 weeks in combination with epirubicin 120 mg/m2, the maximal tolerated cisplatin dose is 105 mg/m2. This combination yields activity in non-small-cell lung cancer.

Concomitant brain radiotherapy and vinorelbine-ifosfamide-cisplatin chemotherapy in brain metastases of non-small cell lung cancer.

AIM: To determine whether or not brain radiotherapy and concomitant three-drug chemotherapy is feasible and yields anti-tumour activity in patients with non-small cell lung cancer and brain metastases at time of presentation. PATIENTS AND METHODS: Twenty-three previously untreated patients suffering from non-small cell lung cancer and brain metastasis were prospectively included in this feasibility study. Most of the patients had neurological symptoms and an Eastern Collaborative Oncology Group (ECOG) performance index over 2. Treatment consisted of three courses of whole brain radiotherapy (18 Gy in 10 fractions) and vinorelbine, 30 mg/m2 on days 1 and 8, ifosfamide, 1.5 g/m2 daily from day 1 through day 3 with uromitexan uroprotection, and cisplatin, 100 mg/m2 on day 2. A cycle restarted every 28 days. RESULTS: Eighteen patients completed the three-cycle programme. All patients were affected by a grade 4 neutropenia and 14 of them experienced a febrile episode. Other toxicities were mild to moderate and manageable. Received-dose intensities of vinorelbine, ifosfamide and cisplatin were 80, 90 and 90%, respectively. Overall response rate was 30%. Specific evaluation of brain response demonstrated complete response for seven patients, and partial response in six (objective brain response rate, 56%). All responders benefited by a remission of symptoms and improvement of performance index. Median survival from start of protocol was 7.6 months. CONCLUSION: Although the high rate of toxicity requiring re-admission, concomitant brain radiotherapy plus vinorelbine, ifosfamide and cisplatin chemotherapy is feasible in patients suffering from brain metastasis, and demonstrates an anti-tumour activity for this particular subset of stage IV non-small cell lung cancer. The development of such an aggressive approach needs further comparative evaluation.

Neoadjuvant etoposide, ifosfamide, and cisplatin followed by concomitant thoracic radiotherapy and continuous cisplatin infusion in stage IIIb non-small cell lung cancer.

OBJECTIVE: To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. RESULTS: Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. CONCLUSION: Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.

Concomitant brain radiotherapy and high-dose ifosfamide in brain relapses of lung cancer.

PATIENTS AND METHODS: Twenty patients with lung cancer and brain metastasis were prospectively included in this feasibility study (four small-cell and 16 non-small-cell lung cancers). There were two previously untreated patients and 18 pretreated patients for whom brain metastases constituted the first relapse after a treatment-free interval following chemotherapy for the primary lung cancer. Most of the patients had neurological symptoms and an ECOG performance index over 2. Treatment consisted of three courses of whole brain radiotherapy (18 Gy in 10 fractions) and ifosfamide: 3 g/m2 daily from day 1 through day 4, i.e., during the first four days of radiotherapy with uromitexan uroprotection and haematopoietic support (r-HuG-CSF). RESULTS: Seventeen patients completed the three-cycle programme. Sixteen patients had grade 4 neutropenia and six of them experienced a febrile episode. Other toxicities were mild to moderate and manageable. The received dose-intensity of ifosfamide was 90%. Response evaluation demonstrated stable disease for two patients, partial response for eight, complete response for six and progression for four. All responders benefited by a remission of symptoms and improvement of performance index. Median survival from start of protocol was 13 months. CONCLUSION: Brain radiotherapy plus high-dose ifosfamide is feasible in patients suffering from brain recurrences of lung cancer.