Which fractionation of radiotherapy is best for limited-stage small-cell lung cancer?
Authors: Rainer Fietkau
Journal: The Lancet Oncology (2017)

The role of radiotherapy in the treatment of small-cell lung cancer has been established through a series of clinical trials and meta-analyses during the past 20 years, which showed that local radiotherapy in addition to chemotherapy1Pignon JP Arriagada R Ihde DC et al.A meta-analysis of thoracic radiotherapy for small-cell lung cancer.N Engl J Med. 1992; 327: 1618-1624Google Scholar and whole-brain radiotherapy2Auperin A Arriagada R Pignon JP et al.Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.N Engl J Med. 1999; 341: 476-484Google Scholar can improve patient prognosis. Moreover, use of radiotherapy with concurrent chemotherapy3De Ruysscher D Lueza B Le Péchoux C et al.Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.Ann Oncol. 2016; 27: 1818-1828Google Scholar in the early stages of disease has been shown to further improve treatment outcomes. Results from the Intergroup 0096 trial4Turrisi 3rd, AT Kim K Blum R et al.Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.N Engl J Med. 1999; 340: 265-271Google Scholar showed that a radiotherapy dose of 45 Gy given twice daily led to improved prognosis when compared with once-daily fractionation regimens employing the same total radiotherapy dose. This study was criticised because the dose (45 Gy) in the conventional treatment group was regarded as insufficient, since some studies have shown that a 60 Gy dose can achieve better results than 45 Gy in conventionally fractionated schedules.5Choi NC Herndon 2nd, JE Rosenman J et al.Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.J Clin Oncol. 1998; 16: 3528-3536Scopus (151) Google Scholar In The Lancet Oncology, Corinne Faivre-Finn and colleagues report results from the CONVERT trial,6Faivre-Finn C Snee M Ashcroft L et al.Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.Lancet Oncol. 2017; (published online June 17.)http://dx.doi.org/10.1016/S1470-2045(17)30318-2Google Scholar which compared a twice-daily radiotherapy regimen (45 Gy delivered in 30 twice-daily fractions of 1·5 Gy) with a once-daily radiotherapy regimen (66 Gy delivered in 33 once-daily fractions of 2 Gy), both given in combination with chemotherapy, in patients with limited-stage small-cell lung cancer. The authors found no difference between the treatment groups in the primary endpoint of overall survival (median overall survival 30 months [95% CI 24–34] in the twice-daily group vs 25 months [21–31] in the once-daily group; hazard ratio 1·18 [95% CI 0·95–1·45], p=0·14). They also reported no differences between the groups in local or metastatic progression-free survival. In the CONVERT trial, the authors were able to address an important radio-oncological question concerning the superiority of a fractionation schedule in a large patient population. The trial is remarkable for several other reasons. Unlike the Intergroup trial 0096, this study shows no significant disadvantage of once-daily fractionation schedules, but the use of a high radiation dose (66 Gy) was necessary with this regimen. This fact underlines that not only is the radiotherapy dose crucial for the effects of treatment, but so also is the time in which this dose is applied (19 days in the twice-daily group vs 45 days in the once-daily group). A shorter duration of radiotherapy delivery might reduce the dose required. 5-year overall survival results for both regimens (31% in the once-daily group and 34% in the twice-daily group) were higher than those reported by other trials so far (eg, 16–26% in Intergroup trial 0096).5Choi NC Herndon 2nd, JE Rosenman J et al.Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.J Clin Oncol. 1998; 16: 3528-3536Scopus (151) Google Scholar Remarkably, this outcome was achieved with lower than anticipated acute and long-term toxicity in both groups (eg, acute grade 3–4 pneumonitis 2% and grade 4 oesophagitis 19%, in both groups). This outcome was achieved by modifying two steps of the treatment protocol: 312 (57%) of 547 patients were staged by PET/CT and the radiotherapy dose was limited to areas definitely involved by tumour, without any elective irradiation. Moreover, all patients received modern 3D planning or intensity-modulated radiotherapy. These approaches should be regarded as standard in the treatment of small-cell lung cancer. The data presented beg the question of which fractionation schedule should now be used in daily practice. The authors conclude from their results that twice-daily radiotherapy (45 Gy) should continue to be regarded as standard of care. This statement could be questioned, however. The study shows that life-threating grade 4 neutropenia in particular was significantly higher in the twice-daily radiotherapy group. However, radiotherapy was delivered over the planned treatment time more often in the twice-daily group than in the once-daily group (63% vs 48%; p=0·0004); unfortunately, the authors do not give more information about this finding. Additionally, more patients received the full dose of radiotherapy in the twice-daily group (98% twice-daily vs 83% once-daily; p<0·0001). The authors speculate that dose constraints for lung and spinal cord in particular were easier to meet because of the lower total dose in the twice-daily radiotherapy group. Additionally, more patients did not receive treatment as originally prescribed in the once-daily group (39 [14%] of 270) than in the twice-daily group (26 [10%] of 273). Since there were no significant differences in survival outcomes, twice-daily radiotherapy up to a total dose of 45 Gy will remain the standard treatment for small-cell lung cancer. However, for patients for whom this regimen is not feasible for logistical reasons, or in whom there is an increased risk of grade 4 neutropenia, a regimen using once-daily radiotherapy in combination with an increased total dose could be seen as an acceptable alternative. I declare no competing interests. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trialSurvival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Full-Text PDF Open Access