Definitive radiotherapy practices for small-cell lung cancer in Japan: a national survey (JROSG 23-3)

ABSTRACT

This survey examined the real-world practice of radiotherapy for small-cell lung cancer (SCLC) in Japan, focusing on treatment strategies for limited-disease SCLC (LD-SCLC) and extensive-disease SCLC (ED-SCLC). This study aimed to identify inter-institutional differences, optimize treatment strategies and explore opportunities for standardization. A questionnaire was distributed to members of the Japanese Radiation Oncology Study Group, and responses were collected from 15 December 2023 to 14 March 2024. Responses to 11 questions specifically related to SCLC treatment strategies were analyzed. Among the 112 institutions, 38.3% did not set an upper age limit for concurrent chemoradiotherapy in LD-SCLC, whereas 31.3% set the limit at 80 years. The most commonly used chemotherapy regimen was cisplatin plus etoposide (79.5%), and the predominant radiotherapy fractionation schedule was twice-daily 45 Gy in 30 fractions (97.3%). Elective nodal irradiation (ENI) was ommited in 30.4% of institutions, while 17.9% reported performing ENI in all cases. Intensity-modulated radiation therapy (IMRT) was introduced in 71.4% of institutions, with D_50% as the most frequently used dose-prescription method (47.5%). After achieving complete response, 16.1% of institutions routinely perform prophylactic cranial irradiation (PCI) in all patients. Hippocampus-sparing PCI was not widely used at the time of the survey (13.3%). In conclusion, this Japanese nationwide survey highlighted the SCLC treatment patterns and differences compared with non-small lung cancer (NSCLC). ENI omissions and IMRT have become increasingly adopted for SCLC, whereas clinical target volume margin definitions show some variation compared with NSCLC. Regular surveys are essential to monitor the evolution of treatment strategies.

INTRODUCTION

Lung cancer is among the most prevalent malignancies worldwide. Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases and is characterized by rapid progression and a high propensity for early metastasis [1]. For limited-disease SCLC (LD-SCLC), the standard treatment has remained largely unchanged for decades following the intergroup trial, which established twice-daily radiotherapy (45 Gy in 30 fractions) as the standard regimen [2]. Attempts to improve outcomes through dose escalation using once-daily radiotherapy have not demonstrated superiority [3, 4]; therefore, 45 Gy in 30 fractions of chemoradiotherapy (CRT) remains the current standard. However, recent studies have suggested that dose escalation using twice-daily radiotherapy may yield promising results and could potentially change future standards of care [5, 6].

Historically, elective nodal irradiation (ENI) was widely employed in LD-SCLC treatment [2]. With the increasing use of PET/CT for staging, the ability to accurately detect previously occult micrometastases has improved, leading to a gradual shift toward involved-field radiotherapy (IFRT) [5–7]. Although IFRT has become more common, optimal clinical target volume (CTV) margins have not yet been fully established [8], and different institutions employ varying approaches.

Additionally, the ADRIATIC trial is expected to establish immunotherapy as a standard post-CRT adjuvant treatment for LD-SCLC [9], similar to its role in non-small cell lung cancer (NSCLC) [10]. The introduction of immune checkpoint inhibitors (ICIs) may also influence future radiotherapy strategies, necessitating optimization of radiotherapy approaches in the era of ICIs.

Previous trials have demonstrated that prophylactic cranial irradiation (PCI) after a complete response (CR) to CRT improves overall survival in LD-SCLC [11]. However, concerns regarding neurotoxicity have led to PCI omission in selected cases [12] and the development of hippocampal-sparing techniques to mitigate cognitive impairment [13].

For extensive-disease SCLC (ED-SCLC), where chemotherapy alone has traditionally been the standard of care, recent studies suggest that the addition of thoracic irradiation may improve survival outcomes [14–18].

Given these evolving treatment considerations, we conducted a nationwide survey to examine current radiotherapy strategies for SCLC in Japan, assess inter-institutional variations and identify areas requiring further investigation.

MATERIALS AND METHODS

The study protocol and methodology were based on the NSCLC survey and have been described in the first part of this paper. This study was approved by the Clinical Trials Review Committee of the Japanese Radiation Oncology Study Group (JROSG) (approval number: JROSG 23-3). The requirement for written informed consent was waived due to the survey-based design.

The questionnaire survey was designed by N.K., N.I. and S.T. approved by all members of the JROSG Lung and Mediastinal Cancer Committee. It consisted of 33 questions, including general institutional information, treatment strategies for locally advanced NSCLC (LA-NSCLC), and treatment strategies for SCLC. The original questionnaire in Japanese is provided in Supplementary Document 1, and its English translation is provided in Supplementary Document 2. Responses were collected from 15 December 2023 to 14 March 2024. This study analyzed 11 questions specifically related to SCLC and compared survey responses between patients with SCLC and NSCLC. Statistical analyses and graphical representations were performed using the R software (version 4.3.0).

RESULTS

Survey response rate and general information of the institutions

Details of the survey response rate and general institutional characteristics are reported in the NSCLC survey [19]. A total of 120 responses were received from 112 institutions. Of the 145 JROSG institutional members, 89 (61.4%) responded, while the remaining 23 responses were from individual JROSG members. After removing duplicates, 112 unique responses from 112 institutions were analyzed.

The annual number of patients receiving radiation therapy (RT) varied widely, with 53.6% of institutions treating more than 600 patients per year. For definitive RT or CRT in NSCLC, most institutions treated 11–20 patients annually (27.7%), followed by 21–30 patients per year (25.9%); in total, 34.8% treated more than 20 patients annually [14]. In this survey, we assessed the annual number of LD-SCLC patients receiving definitive RT or CRT. The most common range was 2–5 patients per year (49.1%), followed by 6–10 patients (34.8%). Eleven or more patients were treated annually in 10.7% of institutions, whereas 5.4% reported treating one or fewer patients. These results indicate that, compared with NSCLC, most institutions manage a smaller number of LD-SCLC cases annually. Regarding irradiation techniques, 99 institutions (88.4%) adopted intensity-modulated radiation therapy (IMRT), of which 87 (77.7%) incorporated respiratory motion management techniques. The distribution and utilization of these techniques are detailed in the NSCLC survey [14].

Indications and contraindications

General upper age limits for definitive CRT in LD-SCLC were as follows: no upper limit in 43 institutions (38.3%), 75 years in 22 institutions (19.6%), 79 years in 3 institutions (2.7%), 80 years in 35 institutions (31.3%) and 85 years in 8 institutions (7.1%). Other indications and contraindications for locally advanced lung cancer are described in our NSCLC report [14]. Key findings include: the most common absolute contraindication was active interstitial pneumonia (60.7%), followed by contralateral hilar lymph node metastasis (42.0%). The most frequently cited relative contraindication was the dose-volume index of the normal lung (70.5%).

Chemotherapy regimens and fractionations for chemoradiotherapy

For concurrent CRT, the most common chemotherapy regimens were cisplatin (CDDP) plus etoposide (ETP) in 79.5% of institutions and carboplatin (CBDCA) plus ETP in 18.8%. When considering the second most common regimen, CBDCA + ETP was reported by 76.8% of institutions and CDDP + ETP by 16.1%.

The most frequently used radiotherapy fractionation schedule was twice-daily 45 Gy in 30 fractions (97.3%). Other fractionation schedules included twice-daily 54 Gy in 36 fractions, twice-daily 54 Gy in 30 fractions and once-daily 60 Gy in 30 fractions, each administered at one institution.

ENI and CTV definitions

For ENI, 30.4% of institutions reported no use in any case, whereas 17.9% reported using ENI in all cases. The distribution of institutions by ENI use was as follows: 0% (30.4%), 1–20% (7.1%), 21–40% (8.0%), 41–60% (9.8%), 61–80% (11.6%), 81–99% (15.2%) and 100% (17.9%) (Fig. 1).

Fig. 1.

Distribution of institutions by the percentage of patients with LD-SCLC receiving ENI.

Regarding CTV definitions in cases without ENI, 45.7% of institutions included lymph node stations with metastasis, while an equal proportion applied margins to metastatic lymph nodes. The remaining 8.7% did not respond or used alternative methods.

Irradiation techniques and dose prescription in IMRT

For LD-SCLC, 28.6% of institutions reported using only three-dimensional conformal radiotherapy (3D-CRT), whereas 12.5% used IMRT in all cases. IMRT utilization was distributed as follows: 0% (28.6%), 1–20% (23.2%), 21–40% (8.0%), 41–60% (3.6%), 61–80% (8.9%), 81–99% (15.2%) and 100% (12.5%). Among institutions using IMRT, the most common dose prescription method was D_50% (48.8%), followed by D_95% (38.8%); the remaining 12.5% used other methods or did not respond. Stratified analysis by institutional size indicated that IFRT was introduced in a substantial proportion of LD-SCLC patients receiving CRT, regardless of size (Fig. 2a). Institutions treating more LD-SCLC patients annually tended to adopt IMRT more frequently, suggesting that experience and patient volume influence adoption rates (Fig. 2b). Figure 2c shows that institutions with higher IMRT utilization also had higher IFRT adoption rates. Figure 3 illustrates the proportion of IFRT performed and CTV margin application methods among the 86 institutions performing IFRT. Institutions treating a higher proportion of patients with IFRT were more likely to use margin-based approaches.

Fig. 2.

Heatmaps of (a) IFRT adoption rates categorized by the annual number of patients with LD-SCLC RT, (b) IMRT adoption rates categorized by the annual number of patients with LD-SCLC receiving RT and (c) IFRT adoption rates categorized by IMRT adoption rates. Note: The numbers in the heatmaps represent percentages per column.

Fig. 3.

Methods of CTV margin definition categorized by the institutional IFRT adoption rate for LD-SCLC.

Comparison of irradiation techniques between SCLC and NSCLC

Figure 4a illustrates the relationship between IFRT adoption rates in LA-NSCLC and LD-SCLC. A substantial number of institutions with lower IFRT adoption rates for LD-SCLC adopted IFRT at higher rates for LA-NSCLC. Additionally, the adoption rate of IMRT was higher for NSCLC than for SCLC (Fig. 4b). Regarding CTV margin definition for IFRT, among the 86 institutions that adopted IFRT for both LA-NSCLC and LD-SCLC, 48.8% reported using a margin expansion method for both, whereas 31.4% included metastatic lymph node regions for both. Notably, 17.4% of institutions used a margin expansion method for NSCLC but adopted a station-based method for SCLC (Fig. 4c).

Fig. 4.

Heatmaps of (a) IFRT adoption rates and (b) IMRT adoption rates for LD-SCLC and LA-NSCLC and (c) methods of CTV margin definition for IFRT in both LD-SCLC and LA-NSCLC among institutions implementing IFRT for both diseases. Note: The numbers in the heatmaps represent percentages per column.

PCI for LD-SCLC

Among patients achieving CR after initial treatment for LD-SCLC, PCI was performed in varying proportions: 0% in 8.9%, 1–20% in 14.3%, 21–40% in 11.6%, 41–60% in 17.0%, 61–80% in 16.1%, 81–99% in 16.1% and 100% in 16.1% of institutions.

Among the 102 institutions performing PCI, the most commonly used fractionation schedule was 25 Gy in 10 fractions (98.0%), with 2.0% using alternative schedules. Hippocampal-avoidance PCI was performed in 15.7% of institutions, while 84.3% did not implement this technique.

Thoracic radiotherapy for ED-SCLC

For extensive-disease SCLC (ED-SCLC), 27.7% of institutions reported performing thoracic radiotherapy in nonclinical trial settings with the goal of improving prognosis, whereas 72.3% did not.

PCI for ED-SCLC

Regarding PCI following initial treatment for ED-SCLC, only 7.1% of the institutions reported performing PCI, whereas 92.9% did not.

DISCUSSION

This survey, conducted at 112 institutions across Japan, collected data on real-world practices for treating patients with SCLC who received definitive RT. Key findings included indications, chemotherapy regimens, fractionation schedules, CTV definitions, irradiation techniques and PCI trends. The results indicate a gradual shift toward omission of ENI and increased adoption of IMRT for LD-SCLC, although IMRT adoption remained slightly lower than that for NSCLC. These findings clarify standardized treatment strategies in Japan and may reduce inter-institutional disparities in both clinical practice and clinical trials.

Nearly all participating institutions (97.3%) employed the standard regimen of 45 Gy in 30 fractions with twice-daily irradiation. Although the surveyed institutions were large-scale centers with high patient volumes, the survey confirmed that 45 Gy in 30 fractions remains widely implemented. Multiple clinical trials have failed to demonstrate the superiority of dose-escalated once-daily RT over this regimen [3, 4], reinforcing its long-standing status as the standard of care [2, 20]. Recent studies suggest promising results with dose escalation using twice-daily RT [5, 6], warranting reassessment of optimal standard treatment.

IMRT has been widely adopted for LD-SCLC, with 71.4% of the institutions implementing this technique, slightly lower than for LA-NSCLC (88.4%). Regarding primary use, 53.8% of institutions reported mainly using IMRT for NSCLC [19], whereas 36.6% used it primarily for LD-SCLC. One potential factor influencing this difference is Japan’s insurance reimbursement system; at the time of the survey, IMRT reimbursement for twice-daily treatment was not available, but it is now allowed, potentially increasing IMRT use for LD-SCLC. In NSCLC, normal lung dose-volume constraints were the most common reason for ineligibility for definitive RT (70.5%) [19]. IMRT may reduce the risk of radiation pneumonitis [21, 22], potentially increasing eligibility for definitive CRT in LD-SCLC.

Survey results demonstrate a shift from ENI to IFRT in patients with LD-SCLC. Historically, ENI including the mediastinal and ipsilateral hilar lymph nodes was commonly used [2]. However, widespread PET/CT use and toxicity concerns have prompted a move toward IFRT [7, 20, 23]. Clinical trials show that IFRT does not increase uninvolved nodal recurrence and reduces treatment-related toxicity [7, 23], supporting its future predominance. Given these considerations, the European Society for Medical Oncology Clinical Practice Guidelines recommend omitting ENI in the treatment of LD-SCLC [20]. In institutions utilizing IFRT, there were variations in the CTV margin definitions. The European Society for Radiotherapy and Oncology guidelines propose two primary methods: geometric expansion and lymph node station-based margin definition [8]. Our survey found that station-based and margin expansion methods were used in equal proportions. Given that the margin expansion method is more commonly adopted for NSCLC, the comparable use of the station-based method for SCLC may reflect a historical preference for broader nodal coverage. Importantly, even when the same margin definition is applied, the incidental irradiation to surrounding regions [24] and the dose to normal organs may differ between IMRT and 3D-CRT. It is also important to recognize that different CTV margin definitions result in varying doses to normal organs [25]. Future studies should optimize CTV margins to balance risk and toxicity.

Cisplatin plus etoposide remains the standard chemotherapy regimen for LD-SCLC; carboplatin plus etoposide is administered in select cases, particularly in patients intolerant of cisplatin. This aligns with recent clinical trials [3–6, 26]. Carboplatin use likely reflects toxicity management in elderly patients or those with comorbidities. Our survey did not include questions regarding the timing of concurrent RT. Meta-analyses suggest early RT initiation improves survival [27], though the optimal timing remains unclear. RT is traditionally initiated during the first chemotherapy cycle [2], though some trials start in the second cycle [3–6, 26]. Second-cycle initiation may allow target volume reduction [28] and reduce toxicity [23] while maintaining outcomes [29].

Other findings from this survey revealed several notable trends in clinical practice. In the first part of this study on NSCLC [19], eligibility criteria for definitive CRT, including exclusion criteria, were thoroughly examined. In this survey on SCLC, we specifically investigated the upper age limit for CRT eligibility. Our results suggest that the upper age limit for CRT in SCLC may be slightly lower than that for NSCLC. While past clinical trials have included patients over 80 years old [2–4], our survey found that 38% of institutions had no upper age limit for CRT, while 31% set the limit at 80 years and 20% at 75 years. With the continued adoption of IMRT and IFRT, which reduce treatment toxicity, the number of elderly patients eligible for CRT may increase. Recent retrospective studies have demonstrated that selected elderly patients, including those aged 80 years or older, may benefit from chemoradiotherapy with acceptable toxicity profiles [30, 31].

Additionally, 16% of the institutions routinely administered PCI to all patients achieving CR after initial treatment. Although PCI improves overall survival, neurotoxicity concerns may lead to its omission by some institutions. Similar trends in clinical practice have been reported worldwide. In the United States, large single-institutional studies have shown that only about half of patients with LD-SCLC receive PCI, mainly due to concerns about neurocognitive toxicity, and it is less frequently administered in patients of advanced age or with poor performance status [32, 33]. In Europe, a nationwide registry analysis from the Netherlands demonstrated a gradual decline in PCI implementation in recent years, possibly reflecting increased awareness of neurocognitive side effects [34]. Hippocampal-sparing PCI was performed in only 15.7% of institutions, likely influenced by insurance policies at the time that restricted IMRT reimbursement to ‘limite solid tumors.’ Advances in imaging and systemic therapies have raised questions regarding the necessity of PCI for all patients, warranting further investigation [12]. In ED-SCLC, PCI remains controversial and is not commonly performed in routine practice. The European randomized trial demonstrated an overall-survival benefit of PCI [35], whereas a subsequent Japanese phase III trial incorporating MRI surveillance failed to confirm this benefit, showing no survival advantage over observation [36]. These conflicting results suggest that the effectiveness of PCI for ED-SCLC has not yet been established. Thoracic RT, suggested to improve the prognosis of ED-SCLC, was not widely adopted. The efficacy of thoracic RT in ED-SCLC was demonstrated in the past European clinical trials [15, 16]; however, these trials were conducted before ICIs were introduced into the treatment of ED-SCLC. As ICIs have shown clinical benefit in ED-SCLC [37, 38], further improvement in survival is anticipated with their combined use. Ongoing trials [18, 39], including JCOG2002, are currently evaluating the efficacy of this approach.

This study has several limitations. First, respondents were primarily from JROSG-affiliated institutions, mostly high-volume centers, potentially introducing a selection bias. Second, responses reflect clinical practice as of March 2024; recent changes, such as insurance reimbursement for twice-daily IMRT, may influence practice patterns. Third, based on the ADRIATIC trial results [9], the introduction of ICIs in SCLC treatment is expected to further alter strategies in the near future.

In conclusion, this Japanese nationwide survey reveals evolving trends in RT for SCLC. Regular surveys are essential to monitor evolving practices and to refine treatment strategies for SCLC.

CONFLICT OF INTEREST

N.I.: Honoraria for lectures from AstraZeneca K.K.; N.K.: Honoraria for lectures from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., MSD K.K. and Varian Medical Systems; S.T.: Honoraria for lectures from AstraZeneca K.K.; M.N.: Research grant paid to affiliated institution from Illumina, honoraria for presentations from AstraZeneca K.K. and honoraria for lectures from Sumitomo Heavy Industries; Y.H.: Honoraria for lectures from AstraZeneca K.K.; N.K.: Honoraria for lectures from AstraZeneca K.K.; T.K.: Honoraria for lectures from AstraZeneca K.K. and Canon medical systems; Y.K.: Nothing to disclose; K.T.: Honoraria for lectures from AstraZeneca K.K.; M.K.: Honoraria for lectures from AstraZeneca K.K. and Varian Medical Systems; T.T.: Nothing to disclose; T.E.: Nothing to disclose; Y.S.: Honoraria for moderating from Hitachi, Ltd. and Hitachi High-Tech Corporation and honoraria for lectures from Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K. and AstraZeneca K.K.; K.S.: Nothing to disclose; H.O.: Research grant paid from Accuray Japan K.K. and Hitachi, Ltd., royalties from APEC Medical, Inc. and honoraria for lectures from AstraZeneca K.K.; K.H.: Nothing to disclose; Y.N.: Honoraria for lectures from AstraZeneca K.K., Varian Medical Systems and Hitachi High-Tech Corporation; Y.M.: Honoraria for lectures from Varian Medical Systems, AstraZeneca K.K., BrainLAB, Chugai Pharmaceutical Co.Ltd., Accuray Inc., Daiichi Sankyo Co.Ltd. and Hitachi Ltd.; T.K.: Nothing to disclose.

PRESENTATION AT A CONFERENCE

The results of this survey were partly presented orally at the 37th Annual Meeting of the Japanese Society for Radiation Oncology, held from 21–23 November 2024, in Yokohama, and at the 65th Annual Meeting of the Japan Lung Cancer Society, held from 31 October to 2 November 2024, in Yokohama.

CREDIT AUTHOR STATEMENT

Nobuki Imano: Conceptualization, methodology, formal analysis, investigation, software, validation and writing—review and writing—original draft; Noriko Kishi: Data curation, formal analysis, investigation, software, visualization and editing; Shigeo Takahashi: Conceptualization, formal analysis, investigation, funding acquisition, project administration, methodology, software and writing—review & editing; Masaki Nakamura: Resources and writing—review & editing; Yasuhito Hagiwara: Resources and writing—review & editing; Nobuteru Kubo: Resources and writing—review & editing; Takafumi Komiyama: Resources and writing—review & editing; Yoshizumi Kitamoto: Resources and writing—review & editing; Kayoko Tsujino: Resources and writing—review & editing; Masaki Kokubo: Resources and writing—review & editing; Tsuyoshi Takanaka: Resources and writing—review & editing; Takeshi Ebara: Resources and writing—review & editing; Yoshiyuki Shioyama: Resources and writing—review & editing; Keiko Shibuya: Resources and writing—review & editing; Hiroshi Onishi: Resources and writing—review & editing; Kazushige Hayakawa: Resources and writing—review & editing; Yasushi Nagata: Supervision and writing—review & editing; Yukinori Matsuo: Supervision and writing—review & editing; Tomoki Kimura: Supervision and writing—review & editing.