Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses—reply

Thank you for your interest in our study and we appreciate your constructive editorial comments on our recent publication: “Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses” (1).

We agree with the editorial authors that in the domain of drug therapy for small cell lung cancer (SCLC), except for two recently published landmark studies using immunocheckpoint inhibitors (2,3), there has been little substantive progress in the past two decades.

However in the field of radiotherapy, some progresses have been made, such as the confirmation of the importance of thoracic radiotherapy (TRT) (4-6) and prophylactic cranial irradiation (7), these achievements changed the comprehensive treatment mode, and significantly improved the prognosis of patients with this stubborn disease.

On the basis of these masterpieces, the follow-up studies mainly focused on the optimization of TRT and radio-chemotherapy.

The study of the optimal target volume for TRT has been within this context. Of course, it is much easier to design the target volume for patients with simultaneous TRT and 1^st cycle of chemotherapy. While the starting point of our study was for limited-stage SCLC patients who had received several cycles of induction chemotherapy. This is not uncommon in China, especially for patients with large tumor burden or with atelectasis or extensive mediastinal lymph node metastasis, induction chemotherapy can effectively reduce tumor volume thus facilitate the implementation of radiotherapy. As for the design of target volume in these patients, however, two main questions are prominent, namely, should we treat the pre-chemotherapy tumor volume or the post-chemotherapy residual tumor? Should we prophylactically treat the non-metastatic lymph node regions (elective nodal irradiation, ENI)?

Up till now, this is the only prospective randomized study on these issues. We used contemporary radiotherapy techniques, i.e., 3-dimentional conformal radiotherapy (3DCRT) or intensity modulated radiotherapy (IMRT). Eligible patients were randomized to receive TRT to the post-chemotherapy or pre-chemotherapy tumor volume, and involved-field radiotherapy (IFRT) was applied (no ENI) for both arms. The results showed neither mediastinal lymph nodes nor primary tumor developed out-field recurrence. Moreover, treatment related toxicities were reduced in patients received radiotherapy to the post-chemotherapy tumor volume.

As TRT in our study was administered concurrently with cycle 3 chemotherapy, the editorial authors have raised the question of the timing of TRT. For our study was launched in 2002, when there was still controversy about the timing of radiotherapy. With the accumulation of evidences, we also advocate earlier initiation of TRT (with the 1^st or 2^nd cycle of chemotherapy), because that could improve prognosis (8-11), provided the patients could tolerate the potential treatment related toxicities. In CONVERT study (12), TRT was administered concurrently with cycle 1 chemotherapy, the authors reported 5-year survival rates of 34% and 31% respectively in patients who received twice daily and once daily radiotherapy, higher than that of our study. However, we have noticed that 15.7% (86/547) of patients in this study were in stage I-II. In contrast, 92.9% (287/309) of our patients were in stage III, and the proportion of patients with IIIB disease, in particular, was 63.4% (196/309). Consequently, the 5-year overall survival (OS) rate of about 25% in our study was still satisfactory. A South Korea phase III study (13) randomized 222 patients to receive TRT administered concurrently with cycle 1 (early TRT) or cycle 3 (late TRT) chemotherapy. The 5-year OS rates were not significantly different between the early or late TRT groups (24.3% vs. 24.0, P=0.69). While significantly more patients of the early TRT arm developed neutropenic fever than the late TRT arm (21.6% vs. 10.2%, P=0.02), which the investigators attributed to the larger radiotherapy volume in the early TRT arm. At present, it is acceptable to start TRT simultaneously with cycle 3 chemotherapy in the Chinese Society for Radiation Oncology guidelines for SCLC, but TRT should not be postponed any longer (to be published).

The editorial authors have addressed the important role of PET/CT in target volume definition. In two studies, PET/CT was applied in target volume definition for limited-stage SCLC (14,15). The results showed that only 1.7–3% of patients experienced isolated out-field nodal recurrences. The authors of the CONVERT study have also conducted a secondary analysis to investigate the role of PET/CT (16). Although there were no significant differences in terms of survival in patients staged with or without PET/CT, lower radiation doses to normal organs and lower incidence of late esophagitis was observed in the PET/CT arm. In our study, only 19.1% of (59/309) patients received PET/CT examination because it was not mandatory. Even though, the overall isolated out-field recurrence rate was low (3.3%, 10/300). One possible explanation is, by comparing lymph node size before and after chemotherapy, we could indirectly determine whether it was a metastatic lymph node or not so as to decide whether it should be included into target volume for irradiation. Moreover, after the interim analysis (17), all eligible patients received supraclavicular ultrasound examination and fine-needle aspiration was performed when any suspected lymphadenopathy was detected. Anyway, we agree with the editorial authors and PET/CT examination has already been listed as a routine item in our clinical studies and daily practice.

In their editorial, Jeremic et al.raised an open question of whether PET / CT metabolic imaging could be used for adaptive target delineation at some time during TRT to enable dose escalation. In a study of 42 patients with locally advanced non-small cell lung cancer, Kong et al. (18) adaptively escalated radiotherapy to the residual tumor, which was defined on mid-treatment PET/CT up to a total dose of 86 Gy in 30 fractions, and the risk of radiation induced lung toxicity was individualized to a fixed level. The 2-year rate of infield failure was 18%, with median OS time of 25 months and 5-year OS rate of 30%. Although the phase III prospective randomized CONVERT study showed that 66 Gy high-dose conventional fractionated radiotherapy was not superior to 45 Gy hyperfractionated radiotherapy in terms of both overall and progression-free survival, the PET/CT-adapted dose escalation have yet been investigated in SCLC patients.

As the editorial authors noted, lower rate of severe acute esophagitis in our study was reported compared with the recently published CONVERT study. One possible explanation is more patients in our study received IMRT (49.7% vs. 17.4% in CONVERT). Two retrospective studies have also indicated that compared with 3DCRT, IMRT was associated with a lower incidence of severe acute esophagitis (19,20). The mean esophagus dose and V5 through V40 of esophagus also predict acute esophagitis (20). Actually, our dosimetric study has shown that in patients who received IMRT, the incidental radiation doses delivered to mediastinal lymph node regions were significantly lower (in regions 1R, 9L, 9R, 10L, 10R) or tend to be lower (in regions 4L, 4R, 5, 6, 8) than that of the patients received 3DCRT. This also indirectly indicated that IMRT could reduce the dose to the tissues around the target volumes. Unfortunately, we did not conduct dosimetric study on acute esophagitis.

We acknowledge that there are limitations in this study, as pointed out by the editorial authors. However, because patients with limited-stage SCLC who have received induction chemotherapy before TRT are ubiquitous in our clinical practice, this study provided a higher level of evidence for standardized and reasonable target design. In addition, the results of this study will also contribute to unify the definition of target volumes and improve the homogeneity when conducting multicenter clinical trials in this specific patient cohort in the future.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (grant numbers 81402540, 81401911 and 81672972), the National Health Commission of the People’s Republic of China scientific research funds-Zhejiang Province Major Science and Technology Project on Medicine (grant number WKJ-ZJ-1701), co-cultivation project of National Health Commission of the People’s Republic of China and Zhejiang province (grant number 2014PYA003) and Zhejiang Science and Technology Plan on Medicine and Health (grant number 2019KY046).

Footnote

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3841). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hu X, Bao Y, Xu Y, et al. Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses. Cancer 2020;126:840-9. [Crossref] [PubMed]
2. Horn L, Mansfield AS, Szczęsna A, et al. First-line Atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220-9. [Crossref] [PubMed]
3. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39. [Crossref] [PubMed]
4. Pignon JP, Arriagada R, Idhe D, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-24. [Crossref] [PubMed]
5. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell lung cancer? A meta-analysis. J Clin Oncol 1992;10:890-5. [Crossref] [PubMed]
6. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 1999;17:2092-9. [Crossref] [PubMed]
7. Aupérin 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;341:476-84. [Crossref] [PubMed]
8. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004;22:4837-45. [Crossref] [PubMed]
9. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057-63. [Crossref] [PubMed]
10. De 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;27:1818-28. [Crossref] [PubMed]
11. Hu X, Xia B, Bao Y, et al. Timing of thoracic radiotherapy is more important than dose intensification in patients with limited-stage small cell lung cancer: a parallel comparison of two prospective studies. Strahlenther Onkol 2020;196:172-81. [Crossref] [PubMed]
12. Faivre-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, randomized, superiority trial. Lancet Oncol 2017;18:1116-25. [Crossref] [PubMed]
13. Sun JM, Ahn YC, Choi EK, Ahn MJ, et al. Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited-disease small-cell lung cancer. Ann Oncol 2013;24:2088-92. [Crossref] [PubMed]
14. van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2010;77:329-36. [Crossref] [PubMed]
15. Shirvani SM, Komaki R, Heymach JV, et al. Positron emission tomography/computed tomography-guided intensity-modulated radiotherapy for limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2012;82:e91-7. [Crossref] [PubMed]
16. Manoharan Prakash, Salem Ahmed, Mistry Hitesh, et al. 18F-Fludeoxyglucose PET/CT in SCLC: Analysis of the CONVERT Randomized Controlled Trial. J Thorac Oncol 2019;14:1296-305. [Crossref] [PubMed]
17. Hu X, Bao Y, Zhang L, et al. Omitting elective nodal irradiation and irradiating postinduction versus preinduction chemotherapy tumor extent for limited-stage small cell lung cancer: interim analysis of a prospective randomized noninferiority trial. Cancer 2012;118:278-87. [Crossref] [PubMed]
18. Kong FM, Ten Haken RK, Schipper M, et al. Effect of midtreatment PET/CT-adapted radiation therapy with concurrent chemotherapy in patients with locally advanced non-small-cell lung cancer: a phase 2 clinical trial. JAMA Oncol 2017;3:1358-65. [Crossref] [PubMed]
19. Shirvani SM, Juloori A, Allen PK, et al. Comparison of 2 common radiation therapy techniques for definitive treatment of small cell lung cancer. Int J Radiat Oncol Biol Phys 2013;87:139-47. [Crossref] [PubMed]
20. Grant JD, Shirvani SM, Tang C, et al. Incidence and predictors of severe acute esophagitis and subsequent esophageal stricture in patients treated with accelerated hyperfractionated chemoradiation for limited-stage small cell lung cancer. Pract Radiat Oncol 2015;5:e383-91. [Crossref] [PubMed]