Dose-escalated twice daily radiotherapy for limited stage small cell lung cancer: an implementation strategy in the Netherlands

With great interest we read the editorial commentary by Miccio et al. on dose-escalated twice daily (BID) chemoradiotherapy for limited stage small cell lung cancer (LS-SCLC) (1). The authors discuss radiation technical factors of high dose twice daily radiotherapy, as studied by Grønberg et al., and how these affect efficacy and toxicity outcomes (2). Differences in dose-volume parameters for organs at risk (OAR) and planning target volume (PTV) are compared between standard BID radiotherapy 45 Gy/30 fractions over 3 weeks and high-dose BID radiotherapy 60 Gy/40 fractions over 4 weeks. Overall, mean and max dose to OARs are higher in the 60 Gy BID group, but similar grade 3 or higher toxicity was observed in both arms. PTV coverage was not defined in the study protocol, but the median V95 was approximately 95% in both arms.

The authors state that, if dose-escalated BID radiotherapy gains further support, shorter regimens like the regimen studied by Yu et al. may be preferred (3). This regimen consists of BID radiotherapy over 3 weeks with 1.5 Gy to the PTV and a simultaneous integrated boost of 1.8 Gy to the gross tumor volume (GTV). In a randomized phase 3 trial, this strategy resulted in a 21.2 month increase in median overall survival (OS) compared to standard BID radiotherapy. A survival benefit in the same order of magnitude as the addition of adjuvant Durvalumab in the ADRIATIC trial (median OS difference 22.5 months) (4). In the recent ESTRO-EORTC expert guideline on treatment of LS-SCLC, high dose BID radiotherapy is not yet adopted as standard of care, amongst others due to limited radiotherapy quality assurance in both studies (5). Miccio et al., however, suggest that a high dose regimen may be reasonable in selected patients in which careful attention is placed on not exceeding safe and tolerable doses and volumes of OAR including the spinal cord, lung, heart and esophagus and with critical attention to target coverage.

Currently, in the Netherlands, 75% of all patients with LS-SCLC are treated with a BID regimen, of which 40% are 70 years or older (6). In our real-world cohort of more than 700 patients, 97% of patients started with BID concurrent chemoradiation finish treatment with low acute toxicity (13% esophagitis grade ≥3; 2% pneumonitis grade ≥2). Given the impressive survival benefit of high-dose BID 54 Gy/30 fractions and our extensive experience with a BID 3-week schedule, we implemented this regimen in the Netherlands in June 2025 in multiple radiotherapy centers as routine clinical care. Using the integrated boost strategy, there is no increase in hospital visits or linear accelerator occupancy and there are no additional costs. The Dutch protocol was developed with careful attention for OAR constraints and adequate GTV and PTV coverage (Table 1). Staging and target delineation is recommended according to ESTRO-EORTC expert guidelines (5). Constraints on mean lung dose, lung V20 and V5 are equal to, or slightly stricter than the CONVERT trial and CALGB/RTOG trial (Table 1) (5,7,8). Mean esophagus dose should be below 34 Gy, similar to the CALGB/RTOG trial. Although the study by Grønberg et al., showed no difference in maximum esophagus dose and late esophagitis toxicity between the 60 Gy (7.9%) and 45 Gy (7.4%) arm, the maximum esophagus dose is a known risk factor for late toxicity (9). Therefore, for maximum esophagus dose (0.5 cc) we use a conservative planning organ at risk volume (PRV) of 5 mm around the esophagus where the maximum dose should be ≤54 Gy. If an acceptable esophagus dose cannot be met, a GTV edit may be generated to meet acceptable dose constraints. In case of a GTV edit, 98% of the unedited GTV is required to receive at least 45 Gy. Constraints for heart and spinal cord are generally accepted constraints and depicted in the Table 1.

One surprising result in the study by Yu et al. was that both severe acute toxicity and OAR doses were similar, and in some cases even lower, in the integrated boost arm (3,10). While preparing the Dutch protocol in clinical daily practice we performed a treatment planning study in 7 patients. In these treatment plans we also observed no meaningful difference in mean lung dose, V20 and V5, mean esophagus dose and mean heart dose for 45 Gy and 54 Gy plans (Table 1). In fact, mean V5 was slightly lower in the 54 Gy plans. A possible explanation could be that the 54 Gy plans are accompanied with a steeper dose fall-off due to heterogeneous dose distribution within the PTV with two different dose levels. As expected, we did see higher max dose to the esophagus (mean difference 5.9 Gy) and spinal cord (mean difference 2.9 Gy). The maximum esophagus + 5 mm dose was below the dose constraint of 54 Gy in 6 of 7 patients. One patient had a max dose of 56.6 Gy on the esophagus + 5 mm. For this patient, according to our protocol, a GTV edit would be made to reduce the area that receives 54 Gy while maintaining a dose of 45 Gy on the un-edited GTV.

This protocol has currently been adopted by 10 of the 19 radiotherapy centers in the Netherlands. Toxicity and survival outcomes in patients treated with this regimen, including the impact of adding adjuvant durvalumab, will be prospectively evaluated using data from the Dutch Lung Cancer Audit-Radiotherapy (DLCA-R). This national quality registry collects detailed information on patient and tumor characteristics, treatment data, radiotherapy parameters, and clinical outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1231/coif). M.P. reports taking part in an advisory committee regarding immunotherapy in small-cell lung cancer and presenting data on adjuvant immunotherapy at an organised lung cancer conference (advisory committee in April and ‘Zwolse longkankeravond’ in June 2025, respectively). For both events, a market-based financial compensation for the invested time was provided. The other 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/.

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