Clinical Investigation
Induction Chemotherapy and Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Patients With Locally Advanced Inoperable Non–Small-Cell Lung Cancer: The MRC INCH Randomized Trial

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Purpose

Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non–small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART.

Methods and Materials

Patients with histologically confirmed, inoperable, Stage I–III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone.

Results

Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31–1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients.

Conclusions

This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study.

Introduction

Patients with locally advanced or medically inoperable non–small-cell lung cancer (NSCLC) may be suitable for radical radiotherapy, but the 5-year survival rate after conventional radiotherapy (with a total dose of around 60 Gy given in 2 Gy daily fractions) is only 5–10% 1, 2, 3.

Several clinical trials have looked at various options for improving patient outcomes. Two modifications that seemed to offer increased survival were continuous hyperfractionated accelerated radiation therapy (CHART), and the addition of chemotherapy to conventional radical radiotherapy.

During a conventional (once a day, 5 days a week) course of radiotherapy, proliferation of the surviving cells may lead to repopulation of the tumor and local failure. Theoretically this may be combated by reducing the overall duration of the course and by delivering several fractions per day in an accelerated schedule that continues treatment over the weekend. This was the rationale behind the development of CHART in the 1980s in the United Kingdom, which delivered a total dose of 54 Gy in 36 fractions (three times per day) over 12 consecutive days including the weekend (4). A randomized trial of 563 patients compared CHART with conventional radical radiotherapy (60 Gy/30 f) given over 6 weeks and suggested that CHART offered a 9% improvement in 2-year survival (5).

The addition of chemotherapy prior to (or concurrently with) conventional radical radiotherapy, has been explored in meta-analyses that suggested that this offered a 4–7% improvement in 2-year survival 3, 6.

The obvious question raised by these results was whether the survival improvements seen with CHART and chemotherapy separately were additive. Initially a dose escalation study (7) was set up for patients to receive two cycles of carboplatin and vinorelbine before CHART. However, the study was closed when 2 of the first 3 patients developed respiratory failure from widespread pulmonary fibrosis and died, although in both of the patients who died at postmortem there was evidence of preexisting pulmonary fibrosis in addition to more acute changes related to treatment. Nevertheless, the concern was that CHART was given too soon after chemotherapy and there should be a gap of at least 4 weeks between treatments. This was confirmed by Bell et al. (8), who treated 29 patients with platinum/vinorelbine chemotherapy followed by CHART with a median time from the first day of the last chemotherapy cycle to the start of radiotherapy of 41 days (range, 18–64). The only patient who had a treatment-related death (bronchopneumonia 13 days after completing radiotherapy) started CHART 24 days after chemotherapy.

A multicenter randomized controlled trial (INCH) was therefore set up to assess the value of adding chemotherapy to CHART, randomizing patients to CHART alone or induction chemotherapy followed by CHART.

Section snippets

Patients and study design

Patients had to have histologically or cytologically confirmed, inoperable, Stage I-III NSCLC. They had to be previously untreated with chemotherapy or radiotherapy, have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, have a life expectancy of at least 3 months, be free of any malignancy likely to interfere with protocol treatment or comparisons, have adequate respiratory function (forced expiratory volume in 1 second or transfer factor of greater than 50% predicted), and

Results

Between August 2005 and September 2007, 46 patients were enrolled (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Because of the early termination of the trial, there were too few patients and events to conclusively answer all the hypotheses, and all analyses are underpowered. Therefore, the results presented here must be seen as hypothesis generating.

Discussion

The theoretical biological benefits of CHART have been translated into improved patient survival. Between 1990 and 1995, a total of 563 patients with Stage I–III NSCLC were entered into a multicenter randomized controlled trial comparing CHART with conventional (60 Gy/30 f) radiotherapy (5). The 2-year survival rate was improved from 20% with conventional radiotherapy to 29% with CHART. In addition, there was no evidence of a difference in morbidity and quality of life (13). The success of this

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  • Cited by (0)

    Funded by Medical Research Council and Cancer Research UK. Pierre Fabre provided funds and support for the running of promotional educational meetings. R.S. has received honoraria from Pierre Fabre Oncology for giving talks.

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