Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

Abstract

PurposeThe optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy.Methods and MaterialsEligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled.Results3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2).ConclusionsIn trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.

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“…5 Elevated radiation doses during radiotherapy may improve the local control of resistant tumors located in the lung, but it increases the risk of side effects in the lungs and heart. 6 A safer and more effective methodology, which can either elevate the radiation dose to the tumor or improve the damage to the tumor while sparing the organs at risk, is needed for advanced NSCLC treatment.…”

Local Radiotherapy Intensification for Locally Advanced Non–small-cell Lung Cancer – A Call to Arms

“…A recent meta-analysis concluded that dose escalation above 60 Gy with conventional fractionation did not benefit patients receiving concurrent chemotherapy. 22 Alternative fractionation regimens have been examined, but direct comparisons to 60 Gy chemoradiotherapy are lacking. 23 The randomized trials continuous hyperfractionated accelerated radiotherapy (CHART) and CHART weekend-less (CHARTWEL), which used hyperfractionated/accelerated fractionation regimens, showed some improvement in overall survival relative to radiotherapy alone, but with increased toxicity.…”

“…59 Such high doses delivered in short time periods have the potential to provide better tumor control above the limited effects seen in conventionally fractionated dose escalation regimens for stage III NSCLC. 22 Several institutions have taken the tools of lung SBRT and applied them to locally advanced disease. 60 Four prospective studies have examined SBRT to boost residual disease or treat isolated recurrences [61][62][63][64] (Table 5).…”

The dosimetric effect of electron density overrides in 3DCRT Lung SBRT for a range of lung tumor dimensions

“…For patients whom surgery is not an option, conventional or stereotactic radiotherapy is frequently used . One of the main toxicities stemming from radiation therapy in NSCLC is Radiation Pneumonitis (RP) .…”