Radiotherapy and chemotherapy remain the mainstay of treatment for SCLC patients. Regarding to LS-SCLC, a meta-analysis indicates that integration of radiotherapy into etoposide/platinum chemotherapy gives rise to a reduction of 14% in mortality and an improvement of 5.4% in 3-year survival of LS-SCLC patients.(18) At a certain extent, powerful locoregional control by thoracic radiotherapy contributes to this process. As documented, the local control rate of thoracic radiation achieves to 25.3%, thus benefiting the survival of LS-SCLC patients.(19) This case can be translated into ES-SCLC as well. A meta-analysis of two randomized trials indicates that thoracic radiation can improve OS and progression-free survival of ES-SCLC patients.(20) As mentioned above, HyperRT of 45 Gy and conventionally fractionated radiotherapy of 66 Gy perform well in controlling primary tumors of SCLC. Besides, although HypoRT regimens for SCLC were rarely investigated in past years, but an existing evidence still revealed the therapeutic efficacy of HypoRT on SCLC as well. (14) As advancing in radiation technology and our insights into the radiobiology related to malignant tumors, HypoRT is increasingly being used to treat early-staged tumors or metastatic tumors. In fact, HypoRT commonly gives rise to higher BED than conventional RT. In theory, it is widely accepted that a high BED will give rise to increased tumor control rate across cancers. In addition, shortening RT period is another benefit of HypoRT, and a previous study found that shortening RT period will cause increased local control and survival of SCLC patients.(21) On this basis, we carried out this study, and retrospectively analyzed the toxicity and efficacy of HypoRT in the treatment of SCLC.
In the present study, we assessed the toxicity of patients after receiving HypoRT in the first place. Herein, we observed that the most common grade 3 or more acute toxicity was myelosuppression. Besides, radiation pneumonitis and radiation esophagitis were also presented in a portion of enrolled patients. Comparing to the published data, HyperRT was reported to cause a high risk of leukopenia and esophagitis.(6) Moreover, patients treated with conventional RT of 70 Gy also developed severe leukopenia and esophagitis as well.(4) In our study, one-third of patients experienced severe leukopenia, and incidence of Grade 3 radiation esophagitis was 6.67%. Intriguingly, most of patients developed their radiation esophagitis at 7-10 days post-HypoRT. Another toxicity that we paid close attention was radiation pneumonitis. In INT0096 study, the incidence of severe pneumonitis with HyperRT was reported as 4%.(6) In our study, two patients were diagnosed as grade 3 radiation pneumonitis at 3-6 months post-HypoRT, and no grade 4 or pneumonitis-related deaths were observed. In addition, a retrospective study reported that the incidences of severe radiation esophagitis and radiation pneumonitis related to conventional RT was 24.0% and 6.0%, respectively, and the incidence by HyperRT was 20.0% and 4.0%, respectively. (22) Additionally, no significant difference was found in the incidence of severe radiation pneumonitis and radiation esophagitis between sIMRT and VMAT groups. Thus, most of enrolled patients in our study can tolerate HypoRT. We believe several reasons can be attributed to this notion. Foremost, in this study, all LS-SCLC patients received 3-4 cycles of induction chemotherapy, and all ES-SCLC patients received 6 cycles of chemotherapy. The reduction in tumor size due to induced chemotherapy may result in a smaller radiation range and radiation dose to surrounding normal tissues, potentially reducing the incidence of acute toxicity.(23) A study also showed that the incidence of radiation pneumonitis is related to the volume of high-dose radiation in the lungs.(24) Another study showed a significant correlation between acute esophageal toxicity and esophageal D5cc and Dmax.(25) A Dmax of 56 Gy EQD210 and a D 5cc of 35.5 Gy EQD210 were observed without severe radiation esophagitis.(25) In this study, dose limit of D5cc<30 Gy and Dmax<45 Gy may explain the esophageal tolerance. Moreover, the duration of HypoRT was only 2 weeks and could be completed in the interim between 2 cycles of chemotherapy, which was also considered to contribute to fewer toxicities.
The preliminary results showed that this new HypoRT regimen achieved a ifRR of 6.67% (2/30), which was better than the results in the literature. In this study, the locoregional failure rate of 10% was observed, which was lower than that of daily RT of 70 Gy over 7 weeks in the CALGB studies (28%),(4) confirmed that the prolonged total radiotherapy time may be one of the reasons for the local treatment failure. In Radiation Therapy Oncology Group protocol 0239, the local failure rate was observed to be lower of 20%. And in that study, the accelerated RT with a relatively shorter total radiation time was used.(26) Although the median follow-up time was only 6 months and the median ifRFS of 15 months currently, the local control rate was very high, with only 6.67% of patients failing in the field of HypoRT.
In our study, the adverse reactions are acceptable, indicating that the regimen is well tolerable and clinically feasible. Notablely, the local control of HpoRT is very high. Additionally, such a RT schedule slashes the total duration of treatment. We are continuing to collect eligible SCLC patients and continue to follow current patients. Based on these results, a multicenter prospective trial is being conceived. Limitations of this study include retrospective studies, insufficient sample size, and differences in the total cycles of chemotherapy, which may affect the objectivity of the results. Approximately 70% (21/30) of patients did not receive PCI, possibly due to the compliance of patients (most patients lived out of city). In addition, previous study showed that the use of PET/CT improves the accuracy of SCLC staging, which has a potential impact on the delineation of targets and the assessment of isolated nodule failure and distant failure.(27)However, only a few of patients in this study underwent PET/CT staging, which also caused limitations.