Mitomycin C in combination with vinorelbine or cisplatin and erythropoietin in pretreated patients with in field relapse after radiation therapy of non-small cell lung cancer: a phase II trial of the AIO
BACKGROUND: Cisplatin-based chemotherapy in combination with thoracic radiotherapy is frequently used as a standard treatment for patients with unresectable NSCLC stage IIIA/IIIB disease. Within three years up to 70% of these patients develop a disease recurrence and a subgroup relapses within the radiation field. Therapy is challenging for this patient group, since a high degree of tumour hypoxia often makes these tumours resistant to chemotherapy, even if small portions of normoxic regions, in particular in the outer regions of the tumour, might still exist. As Mitomycin is known to be effective under hypoxic conditions, a combination of Mitomycin with Vinorelbine or Cisplatin was used to treat relapses that occur in the radiation field. Simultaneously, erythropoietin was applied to decrease tumour hypoxia. METHODS: Fifteen patients pretreated with definitive radio- or radio-chemotherapy who developed a symptomatic relapse within the radiation field were enrolled in the study: 5 patients with stage IIIB and 10 with stage IV. Patients received Mitomycin 8 mg/m2 on day 1 with either Vinorelbine 25 mg/m2 (in case of Cisplatin pretreatment) on days 1 and 8 or Cisplatin 40 mg/m2 on days 1 and 8 of a 21-day cycle to a maximum of 4 cycles. 40,000 IE Erythropoietin was administered s.c. every 7 days to maintain Hb levels between 12 and 13.0 g/dl. Response (WHO criteria), time to progression, survival, toxicities and Hb values were evaluated. RESULTS: A median of 2 cycles was administered (1–4). Fourteen patients were assessable for clinical response, one died before first tumour response evaluation. One patient achieved a partial response, stable disease was observed in 6 patients. Median time to progression was 2.3 months (95% CI, 1.20–5.60 months) and median survival was 4.6 months (95% CI, 3.42–6.54 months). Main Grade 3/4 toxicities included leucocytopenia (4/15) and neutropenia (4/15). One patient died of a pulmonary fibrosis probably due to Mitomycin medication. Median Hb levels were maintained above 11 g/dl. CONCLUSION: This is the first trial investigating a standardised treatment of pretreated patients with a relapse within the radiation field. The therapeutic concept including Mitomycin for the treatment of recurrent disease in the radiation field offers an active regimen with modest toxicity. Stable disease was observed in 43%, partial response in 7% of the patients and reaches a similar rate as known from chemotherapy results of pretreated patients. Median survival was poor, but may be due to the limited prognosis of this selected patient cohort. There was a trend to better results in patients with performance status 0 or 1 and response to previous radio-chemotherapy. Further studies for patients with radiation field relapses are warranted.