Altered fractionation of radical radiaton therapy in the management of unresectable non-small-cell lung cancer

Question: Do any altered fractionation radiation schemes prolong survival in the treatment of locally advanced, unresectable stage III non-small-cell lung cancer (NSCLC) compared with the North American standard of 60 Gy in 30 fractions? Perspective: Evidence was selected and reviewed by three radiation oncologists who are members of the Lung Cancer Disease Site Group (Lung DSG) of the Cancer Care Ontario Practice Guidelines Initiative. This document has been reviewed and approved by the Lung DSG. The Lung DSG is comprised of medical and radiation oncologists, pathologists, surgeons, a psychologist, and a medical sociologist. Two community representatives participated in the discussion of this practice guideline. Outcomes: Survival was the primary outcome of interest. Toxicity was also considered. Results: Quality of Evidence One published meta-analysis, eight randomised controlled trials, one comparative cohort study, and two randomised phase I/II trials evaluating altered fractionation (including continuous hyperfractionated, accelerated, Continuous Hyperfractionated Accelerated Radiation Therapy [CHART], Hyperfractionated Accelerated Radiation Therapy [HART], Continuous Hyperfractionated Accelerated Radiation Therapy Weekendless [CHARTWEL], or hypofractionated and splitcourse radiotherapy) were selected for review. Benefits: The published meta-analysis demonstrated a significant survival benefit for hyperfractionated over standard radiotherapy (odds ratio: 0.69; 95% Confidence Interval [CI]: 0.51-0.95; p = 0.02). The Cancer Care Ontario Practice Guidelines Initiative's Resource Group conducted an (unpublished) meta-analysis of the same trials as the published meta-analysis, which did not demonstrate a significant survival benefit for hyperfractionated over standard radiotherapy (odds ratio: 0.67; 95% CI: 0.42-1.07; p = 0.091). Three of four randomised controlled trials demonstrated a survival benefit for hyperfractionation compared with standard radiotherapy, although not all results were statistically significant (data from one of the three trials were not statistically significant; data from the second trial demonstrated a 3-year survival rate of 22% for hyperfractionated versus 0% for standard radiotherapy, but no significance level was given; and the third trial demonstrated a statistically significant 2-year survival benefit [p < 0.05]). A phase I/II study demonstrated a survival benefit for hyperfractionated compared with standard radiation therapy, with a 1-year survival rate of 58% versus 30% and a 3-year survival rate of 20% versus 7% (p = 0.002 logrank). With respect to hyperfractionated accelerated radiotherapy, one randomised controlled trial demonstrated a 2-year survival benefit for CHART of 29% versus 20% for standard radiotherapy (hazard ratio: 0.76; 95% CI: 0.63-0.92; p = 0.004) and one comparative cohort study demonstrated a 3-year survival benefit for HART of 28% versus 6% for standard radiotherapy (p < 0.001). No survival data were cited in the full report of one phase I/II study of CHARTWEL; the authors state that there was no survival difference between the two groups at 18 months after radiotherapy. One randomised controlled trial showed that hypofractionation improved 3-year survival (19% vs. 9% for standard radiotherapy), but no significance was reported. Acute treatment toxicity was reduced in the hypofractionation patients (30% experienced no oesophagitis compared with 70% of standard radiotherapy patients). Harms: Hyperfractionation, CHART, and hypofractionated radiotherapy demonstrated no significant differences in late toxicity compared with standard radiotherapy. Oesophagitis was more severe (p = 0.004) and of longer duration (p < 0.0001) in patients receiving accelerated radiotherapy compared to the standard radiotherapy group. Oesophagitis was experienced by 87% of HART patients versus 44% of standard radiotherapy patients (p < 0.05). Accelerated radiotherapy was shown to increase acute toxicity over standard radiotherapy. It is unclear whether toxicity was monitored for split-course radiotherapy. Practice Guideline: The current standard treatment for unresected stage III NSCLC is combined modality therapy (Practice Guideline Report no. 7-3: Unresected Stage III Non-Small Cell Lung Cancer). There is evidence from one randomised controlled trial demonstrating that Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) improves survival over standard radiotherapy of 60 Gy in 30 fractions, in patients with locally advanced, unresectable stage III NSCLC. Therefore, selected patients (with ECOG performance status ≤ 1 who do not fit the criteria for induction chemotherapy and radiotherapy or patients who prefer radiotherapy only) may be considered for CHART. Evidence from a comparative cohort study suggests that Hyperfractionated Accelerated Radiation Therapy (HART) also improves survival over standard radiotherapy. On the other hand, there is insufficient data of high quality to recommend non-accelerated hyperfractionated radiotherapy over standard radiotherapy of 60 Gy in 30 fractions. Further randomised controlled trials are necessary to confirm the benefits, if any, of non-accelerated hyperfractionation radiotherapy. The main adverse effect associated with these altered fractionation treatments is acute oesophagitis. Trials examining therapies which provide greater convenience to patients with locally advanced, unresectable stage III NSCLC did not show evidence of a survival benefit for either hypofractionation or split-course radiotherapy. If symptom palliation is the main concern, patients may consider participating in clinical trials examining the role of hypofractionation or split-course radiotherapy. The effect of treatment on quality of life was not reviewed in most of these trials. Therefore, if quality of life is the main issue of concern, there is insufficient evidence at this time to draw any conclusions on the value of altered fractionation.