Dose-finding study of irinotecan and cisplatin plus concurrent radiotherapy for unresectable stage III non-small-cell lung cancer

Abstract

Summary Irinotecan hydrochloride shows marked anti-tumour activity alone and in combination with cisplatin in non-small-cell lung cancer (NSCLC). It is necessary to investigate combined-modality therapy including novel effective anti-cancer agents to improve long-term survival of patients with unresectable stage Ill NSCLC. A phase I/ll study of concurrent chemoradiotherapy with CPT-11 and cisplatin was conducted to determine the maximum tolerated dose (MTD) and efficacy in this group of patients. Thirteen previously untreated patients with unresectable stage IIIA/B NSCLC were enrolled and efficacy and toxicity was evaluated in 12 of them; one patient was ineligible. Chemotherapy was repeated every 4 weeks for three courses. Radiation therapy was started on day 2 of the first course of chemotherapy and 60 Gy in 30 fractions was given over 6 weeks. Four of six patients enrolled at level 1 completed the scheduled treatment. Another two received only one and two courses of chemotherapy as a result of persistent leucopenia and neutropenic fever respectively. Three of six patients given level 2 therapy completed the scheduled treatment. Another three received only one and two courses of chemotherapy, two refused treatment because of diarrhoea and one died of pneumonia. Radiation therapy was inadequate in these three patients. As the CPT-11 dose intensity in this trial was low, because of the necessity of omitting CPT-11 administration on days 8 and/or 15 as a result of leucopenia or diarrhoea, and the low radiation therapy completion rate, the trial was discontinued at level 2. Five patients at level 1 and three at level 2 showed partial responses, an overall response rate of 67%. Although neither MTD nor dose-limiting toxicity could be identified, chemotherapy with CPT-11 and cisplatin plus concurrent radiation therapy was deemed unacceptable. We are now conducting a phase I/Il study of chemotherapy using CPT-11 as a single agent in combination with radiation therapy.Keywords: non-small-cell lung cancer; irinotecan; radiation therapy; combined-modality therapy Approximately 25-30% of non-small cell lung cancer (NSCLC) is already unresectable stage III disease by the time it is diagnosed and, therefore, about 7000 such patients are seen in Japan per year. Traditionally, the standard treatment is radiation therapy, but the 5-year survival rate is 10% or less in patients treated with radiation therapy alone and the majority of patients experience extrathoracic recurrence (Perez et al, 1987). It is important to control distant metastases, as well as local tumours, in order to improve long-term survival. The efficacy of chemotherapy in such patients has long been a controversial issue. Recently, several randomized trials (Dillman et al, 1990(Dillman et al, , 1996Le Chevalier et al, 1991;Sause et al, 1995) and meta-analysis (Non-small Cell Lung Cancer Collaborative Group, 1995) showed that chemotherapy followed by radiation therapy was more effective than radiation therapy alone. However, survival was still only prolonged...

Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer

“…When the irinotecan/ cisplatin regimen was used, ordinary concurrent CRT was deemed unacceptable (Yokoyama et al, 1998), and unexpectedly poor results of the sequential CRT in LD-SCLC with a MST of 14.3 Irinotecan and carboplatin in SCLC A Kinoshita et al months and 2-year survival rate of 17.5% (Kudoh et al, 1998) may even suggest unsuitableness of irinotecan/platinum for radiotherapy. To resolve this issue, we administered a split-course early concurrent radiotherapy combined with irinotecan/cisplatin (Oka et al, 2001(Oka et al, , 2002Nagashima et al, 2004).…”

“…Tumour response and toxicities were classified according to World Health Organization criteria (WHO, 1979). A CR represented the disappearance of any evidence of tumours for at least 4 weeks.…”

Where to go with new expensive treatments in NSCLC

“…The study was stopped early but even at these low doses, a response rate of 67% was obtained (Yokoyama et al, 1998). This has important implications for the use of irinotecan with radiotherapy in both lung and bowel cancer (Yokoyama et al, 1998).Where do we take these new treatments and how do we make progress in the treatment of non-small-cell lung cancer? We now have five new drugs with activity in non-small-cell lung cancer and all of them priced in the range of between 6 and 30 times the cost of any of our previous regimens.…”

“…This chemoradiotherapy combination was not tolerated because of a number of toxicities, but in particular leucopenia. The study was stopped early but even at these low doses, a response rate of 67% was obtained (Yokoyama et al, 1998). This has important implications for the use of irinotecan with radiotherapy in both lung and bowel cancer (Yokoyama et al, 1998).…”

“…The results of larger studies are keenly awaited before this approach can become standard. Furthermore, care must be taken when introducing these new agents with concomitant radiotherapy, as demonstrated in this month's journal (Yokoyama et al, 1998).…”