High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC

Abstract

Introduction: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation.

Methods: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients.

Results: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3-25.1), median progression free survival (PFS) was nine months (range 4.5-16), and median loco-regional control (LRC) was 12.1 months (range 6.5-20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033).

Conclusion: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

Keywords: NSCLC; immunotherapy; lung cancer; re-irradiation; stage III.

Figure 1

Study selection process.(This review was not registered with PROSPERO).

Figure 2

The median overall survival was 18.1 months (dashed red line). Although most studies presented the range, a 95% confidence interval was given only in two analyses. The black squares indicate the median OS (mOS).

Figure 3

(a). Total dose at re-irradiation correlates to median loco-regional control (mLRC) (Pearson correlation, p-value = 0.012). (b). Total dose at re-irradiation correlates to median overall survival (Pearson correlation, p-value = 0.007). (c). Median OS correlates with median loco-regional control (Pearson correlation, p-value = 0.006).

Figure 3

(a). Total dose at re-irradiation correlates to median loco-regional control (mLRC) (Pearson correlation, p-value = 0.012). (b). Total dose at re-irradiation correlates to median overall survival (Pearson correlation, p-value = 0.007). (c). Median OS correlates with median loco-regional control (Pearson correlation, p-value = 0.006).

Figure 4

The occurrence of acute toxicity grade 1 to 4 versus PTV size at re-irradiation: patients who experienced acute toxicity grade 1 to 4 had a larger PTV compared with those without (Pearson correlation, p-value = 0.033). The studies by Kilburn and Ohguri could not be included in this calculation since they did not contain information on PTV size, hence the number of patients was reduced to 458.