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High-dose versus standard dose twice-daily thoracic radiotherapy in limited stage small-cell lung cancer: final survival data, long-term toxicity and relapse patterns in a randomised, open-label, phase II trial

Bjorn Henning Gronberg, Kristin Toftaker Killingberg, Oystein Flotten, Maria Moksne? Bjaanas, Odd Terje Brustugun, Tesfaye Madebo, Seppo Wang Langer, Signe Lenora Risumlund, Tine Schytte, Nina Helbekkmo, Kirill Neumann, yvind Yksnoy, Jens Engleson, Sverre Fluge, Thor Naustdal, Liv Ellen Giske, Jan Nyman, Georgios Tsakonas, Tarje Onsgien Halvorsen

PII: S1556-0864(25)00696-3
DOI: https://doi.org/10.1016/j.jtho.2025.04.007
Reference: JTHO 3329

To appear in: Journal of Thoracic Oncology

Received Date: 14 February 2025

Revised Date: 9 April 2025

Accepted Date: 14 April 2025

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High-dose versus standard dose twice-daily thoracic radiotherapy in limited stage small-cell Iung cancer: final survival data, long-term toxicity and relapse patterns in a randomised, open-label, phase II trial

Bjorn Henning Gronberg a,b, Kristin Toftaker Killingberg a,b, ystein Flotten , Maria Moksnes Bjaanaes d, Odd Terje Brustugun e.f, Tesfaye Madebo 9, Seppo Wang Langer h, Signe Lenora Risumlund h, Tine Schytte i, Nina Helbekkmo i, Kirill Neumann k, yvind YksnoyI, Jens Engleson m, Sverre Fluge , Thor Naustdal o, Liv Ellen Giske P, Jan Nyman 4r, Georgios Tsakonas s, Tarje Onssien Halvorsen a,b

a Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
b Department of Oncology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway c Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway
d Department of Oncology, Oslo University Hospital, Oslo, Norway
e Section of Oncology, Drammen Hospital, Vestre Viken HF, Drammen, Norway
f Institute of Clinical Medicine, University of Oslo, Oslo, Norway
9 Department of Pulmonary Medicine, Stavanger University Hospital, Stavanger, Norway
h Department of Oncology, Copenhagen University Hospital - Rigshospitalet, Denmark
' Department of Oncology, Odense University Hospital, Odense, Denmark
j Departments of Pulmonology and Oncology, University Hospital of North Norway, Tromso, Norway K Department of Pulmonology, Akershus University Hospital, Lorenskog, Norway.
' Department of Pulmonology, Alesund Hospital, Alesund, Norway
m Department of Oncology, Skane University Hospital, Lund University, Sweden
n Department of Pulmonology, Haugesund Hospital, Haugesund, Norway
Levanger Hospital, Levanger, Norway, Levanger, Norway
P Department of Oncology, Innlandet Hospital Trust, Gjovik, Gjovik, Norway
Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
' Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
s Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
Corresponding author:
Bjorn H. Gronberg
Department of Cancer Research and Molecular medicine
NTNU, Norwegian University of Science and Technology
PO Box 8905, 7491 Trondheim, Norway
Email: bjorn.h.gronberg@ntnu.no
Phone: + 4 7 47297878
Conflicts of interest: None to declare
Keywords: chemoradiotherapy, BID, radiotoxicity, accelerated, dose escalation, LS SCLC

This trial is registered at ClinicalTrials.gov, NCT02041845

Abstract

Introduction: Chemoradiotherapy is standard treatment for limited stage (LS) smallcell lung cancer (SCLC). A majority of patients relapse and there is a need for better treatment. We investigated whether twice-daily thoracic radiotherapy (TRT) of 60 Gy/40 fractions improve survival compared with the established schedule of 45 Gy/30 fractions. Here we report final survival data and long-term toxicity.

Methods: Randomised, open-label, phase Il trial. Eligible patients had PS 0-2, were >= 1 8 years, underwent FDG-PET/CT and brain MRI for staging and were randomised 1:1 to TRT of 60 or 45 Gy. Patients were to receive four courses of platinum/etoposide chemotherapy and responders were offered prophylactic cranial irradiation.

Results: 170 patients were randomized (60 Gy: n = 8 9 45 Gy: \scriptstyle \mathsf { n } = 8 1 ). Median age was 65, 3 1 % >= 7 0 years, 57 % women, 8 9 % had PS 0-1, 8 3 % stage III disease, median planning target volume was 3 0 5 \mathsf {cm } ^ { 3 } , and 67 % were treated with threedimensional conformal radiotherapy (3D CRT). Median OS in the 60 Gy group was significantly longer (43.5 vs. 22.5 months, HR 0.68, 9 5 % CI 0.48-0.98, \mathsf { p } { = } 0 . 0 3 7 ). The 60 Gy group did not experience more acute grade 3-4 esophagitis (60 Gy: 2 1 % , 45 Gy: 1 8 % 5 \mathsf { p } { = } 0 . 8 3 ) or pneumonitis (60 Gy: 3 % , 45 Gy: 0 % 1 \mathsf { p } { = } 0 . 3 9 ). Two patients, both in the 60 Gy group, developed oesophageal strictures, while eleven patients (60 Gy: \scriptstyle \mathsf { n } = 5 45 Gy: \scriptstyle \mathsf { n } = 6 developed severe long-term eating and swallowing dysfunction.

Conclusion: Twice-daily TRT of 60 Gy/40 fractions was well tolerated and prolonged survival compared with 45 Gy/30 fractions in LS SCLC patients.

Funding: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.

Introduction

Concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCl) to those who respond to chemoradiotherapy (CRT) has been standard treatment for LS SCLC since the 1990's. Twice-daily TRT of 45 Gy in 30 fractions has been recommended since the Intergroup 0096 trials showed superiority compared with once-daily TRT of 45 Gy in 25 fractions, but population based studies show that a majority of patients still receive once-daily TRT due to concerns about oesophagitis and logistical challenges. 1,2 Five-year survival rates of 2 3 - 3 6 % have been reported, 3-7 but although some patients are cured, there is a large and unmet need for better treatment. Many treatment failures are due to intrathoracic relapses, 3,8 and it has been proposed that higher TRT doses improve local control and consequently survival. However, high-dose once-daily TRT of 66-70 Gy does not prolong survival compared with the twice-daily schedule of 45 Gy in 30 fractions. 5,6

Due to the high radiosensitivity of SCLC cells, tumor control can be achieved even at low fraction-doses, and accelerated TRT prevents the rapid repopulation of tumor cells that can occur after approximately three weeks of treatment. 10 Thus, escalating the TRT dose using a hyper-fractionated accelerated schedule might be an effective approach. We performed a randomised phase II trial investigating whether escalating the TRT dose using a hyper-fractionated accelerated schedule prolongs survival and have previously reported that patients receiving 60 Gy in 40 fractions twice-daily had a significantly higher 2-year survival rate (primary endpoint) than those receiving the standard 45 Gy schedule ( 7 4 . 2 % vs. 4 8 . 1 % , OR 3.09 [ 9 5 % CI 1.62-5.89]; \scriptstyle \mathsf { p } = 0 . 0 0 0 5 ). 11 Importantly, the higher dose did not cause more acute toxicity. 11.12 Here we present final survival data, relapse patterns, post-progression treatment, long-term toxicity and patient-reported health-related quality of life (HRQoL) after five years of follow-up.

Methods

Study design and participants

The design of our open label randomised phase II trial (NCT02041845) has been described previously. 11 Briefly, patients were >= 1 8 years, had performance status (PS) 0-2, confirmed SCLC, and LS according to the IASLC definition13 (lymph node metastases to contralateral hilum was also accepted). One negative cytology was required if pleural effusion was present.

Brain Magnetic Resonance Imaging (MRI) and whole body FDG-PET/CT scan were mandatory for staging (pathological lesions assessed according to local routines) and TRT target volumes were limited to pathological lesions. Radiotherapy planning techniques included 3D CRT, volumetric modulated arc therapy (VMAT) and intensity-modulated RT (IMRT). Prophylactic cranial irradiation (PCI) of 25-30 Gy in 10-15 fractions (once daily, without hippocampus sparing technique) was offered to those who had at least stable disease according to RECIST 1.1 after chemoradiotherapy. Relapses were treated according to each hospital's routine.

No independent Data and Safety Monitoring Board was considered necessary for this phase Il trial with a limited number of participants, since the experience from Swedish colleagues was that the 60 Gy schedule was feasible and tolerable. 14 The trial was performed in agreement with Declaration of Helsinki and approved by the Regional Committee for Medical Research Ethics (Central Norway, Norway), the Regional Ethics Board in Gothenburg (Sweden), and the National Committee on Health Research Ethics (Denmark). All patients gave written informed consent.

Randomization

Patients were randomly allocated (1:1) to receive twice daily TRT of 60 Gy in 40 fractions or 4 5 \mathsf { G y } in 30 fractions stratifying for ECOG performance status (0-1 vs. 2), disease stage (I-II vs. IIl), and presence of pleural effusion (yes vs. no).

Procedures

Patients were to receive four courses of intravenous cisplatin ( 7 5 m g / m ^ { 2 } ) or carboplatin (AUC 5-6 mg/mL/min) day 1 and etoposide ( 1 0 0 ~ { m g / m ^ { 2 } } ) days 1-3 every three weeks. TRT was to start 20-28 days after the first day of the first chemotherapy-course. All patients received two fractions per day (minimum 6 hours between fractions), ten fractions per week. The gross tumour volume (GTV) included the primary lung tumour and lymph node metastases. GTV-volumes were defined on TRT treatment planning CT scans performed after the first chemotherapy course (approximately one week before TRT commenced).

Stage of disease was assessed according to TNM 7, toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and treatment response according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1). CT scans were used for response evaluation, follow-up and assessing relapses. Patients reported health-related quality of life (HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the QLQLC13. Raw scores were transformed to a 0-100 scale following the EORTC scoring manual. 15 Mean scores for each item were compared across treatment groups and timepoints, with a difference of 10 or more considered clinically significant. Patients completed the paper-based questionnaires at each visit, with mean scores reported at baseline (week 0), week 8 (end of TRT), week 22 (first follow-up after CRT), and annually from years 1 to 5. Patients who did not complete the final 5-year questionnaire were sent a reminder.

Treatment related deaths was defined as all deaths considered related to treatment occurring at any time during the study period, or any death occurring within 4 weeks after completing study treatment. All patients were followed for at least 5 years or until death.

Outcomes

The primary endpoint was 2-year overall survival. Secondary endpoints were overall survival, progression free survival, toxicity, response rates, thoracic relapse rates and HRQoL. The main HRQoL endpoints were dysphagia and dyspnea reported on the LC-13, secondary endpoints were global quality of life, physical and cognitive function reported on the QLQ-C30. Exploratory analyses of relapse patterns and outcomes of patients with intrathoracic relapse or brain metastasis as first relapse were performed.

Statistical analyses

To show an improvement in 2-year overall survival from 5 3 % to 6 6 % with a onetailed a of 0.1 and β of 0.2, 73 evaluable patients were required in each group. The main efficacy analyses included the intention-to-treat population, patients who

commenced TRT were included in the toxicity analyses, and patients who completed at least one QLQ were included in the HRQoL analyses.

All survival analyses were calculated form the first day of the first course of chemotherapy. Overall survival (OS) was calculated until death of any cause. Progression free survival (PFS) until progression was detected or death of any cause. Patients without events were censored at the time of the last observation alive for OS, and at the time of the last CT scan for PFS. Time to progression was defined until the date of radiological progression. Post progression survival was defined as time from the date of radiological progression until death of any cause. Survival was estimated using the Kaplan-Meier method and compared using Cox proportional hazards regression for both uni- and multivariable models. Multivariable models were adjusted for TRT-schedule, age (continuous variable), sex, performance status (0-1 vs. 2), stage of disease (I-II vs. IlI), and the presence of pleural fluid (yes vs. no). Pearson's x ^ { 2 } test or Fishers exact test were used to compare toxicity and response rates. Overall response rate was defined as the sum of complete and partial responses.

While sample size calculations were based on one-tailed a of 0.1, we have applied a significance level of \mathsf { p } { < } 0 . 0 5 for this report. All tests are two-sided. Analyses were performed using SPSS version 29.

Role of the funding source

The funders of the study had no role in the study design, data collection, data interpretation or writing of the report.

Results

Participants

Between July 8 ^ { { t h } } 2014 and June 6 ^ { { { t h } } } 2018,176 patients were enrolled at 22 hospitals in Norway, Sweden and Denmark; six were ineligible due to extensive disease ( n = 3 ) A withdrawn consent ( n = 2 ) , and previous TRT \scriptstyle ( \mathsf { n } = 1 ) , therefore 170 patients were randomly assigned (89 to 60 Gy, 81 to 4 5 \mathsf { G y } ) and included in the efficacy analyses (Figure 1). Four patients (all in the 45 Gy group) withdrew from the study before TRT started due to renal failure \scriptstyle ( \mathsf { n } = 1 ) , cerebral infarctions ( n = 2 ) and death from myocardial infarction ( n = 1 ) . The 166 patients who commenced TRT were included in the toxicity analyses (60 Gy: n = 8 9 , 45 Gy \scriptstyle { \mathsf { n } } = 7 7 ), patients that commenced TRT and completed at least one HRQoL questionnaire were included in the HRQoL analyses (60 Gy: n = 6 4 45 Gy \scriptstyle \mathtt { n = 5 6 } ) (Figure 1).

Median age was 65 years, 3 1 % were >= 7 0 years, 57 % women, 8 9 % had PS 0- 1, 84 % stage III disease, 8 % pleural effusion, and 20 % had a 2 5 % weight loss last three months before enrolment. Charlson Comorbidity Index total score was 0 for 42 % , 1 for 2 9 % and >= 2 for 2 9 % of the patients. Median planning target volume (PTV) was 3 0 5 \mathsf {cm } ^ { 3 } , and 67 % of the patients were treated with three-dimensional conformal radiotherapy (3D CRT). Baseline patient and disease characteristics, TRT planning technique and target volumes were well balanced between treatment groups (Table1). Completion rates of all four chemotherapy courses (60 Gy: 9 2 % , 45 Gy: 8 8 % ), TRT (60 Gy: 9 7 % , 45 Gy: 91 % ), PCI (60 Gy: 8 1 % , 45 Gy: 8 4 % ) and overall response rates (60 Gy: 78 % , 45 Gy: 7 7 % ) were similar between treatment groups (Table 1).

At the time of the final efficacy analyses (September 15th, 2023), 53 of 89 patients ( 5 9 . 6 % ) in the 60 Gy group and 58 of 81 patients ( 7 1 . 6 % ) in the 45 Gy group had died. Disease progression was detected in 99 patients, 60 Gy: 48/89 ( 5 4 % ) , 45 Gy: 51/81 ( 6 3 % ) . Four patients (two in each group) were still alive after disease progression. Median follow-up time for overall survival was 86 months IQR 19 (94-75), and median follow-up time for PFS was 62 months IQR 18 (76-58).

Overall survival

For the whole cohort, median OS was 33.3 months, and 58/170 patients ( 3 4 . 1 % ) were alive after 5 years. The 2-year survival rates remained unchanged from our previous report (60 Gy: 7 4 . 2 % , 45 Gy: 4 8 . 1 % , OR 3.09 [ 9 5 % CI 1.62-5.89]; \scriptstyle \mathsf { p } = 0 . 0 0 0 5 . Median OS in the 60 Gy group was significantly longer than in the 45 Gy group (60 Gy: 43.5 months [ 9 5 % CI 30.4-56.6], 45 Gy: 22.5 months [ 9 5 % CI 17.2- 28.0], HR 0.68 [ 9 5 % CI 0.48-0.98]; \mathsf { p } { = } 0 . 0 3 7 . Five-year survival rates were 3 9 . 3 % ( 6 0 \mathsf { G y } ) and 2 8 . 4 % ( 4 5 \mathsf { G y } )

Post-hoc analyses of patients who commenced ( n = 1 6 6 ) and those who completed TRT per protocol ( n = 1 6 0 ) ) are included in the Supplement Figure 5. Among patients who commenced TRT, median OS was 43.5 months 9 5 % CI 30.4- 56.6) in the 6 0 ~ \mathsf { G y } group and 24.0 months ( 9 5 % CI 15.8-32.1) in the 45 Gy group (HR 0.73, 9 5 % CI 0.50-1.05, \scriptstyle \mathsf { p } = 0 . 0 8 5 . Among those who completed TRT per protocol, median OS was 43.6 months ( 9 5 % Cl 29.9-57.2) in the 60 Gy group and 24.0 months ( 9 5 % Cl 15.1-32.9) in the 45 Gy group (HR 0.71, 9 5 % CI 0.49-1.03, \mathsf { p } { = } 0 . 0 7 1 1

TRT treatment technique was not associated with overall survival (3D CRT: 34.2 months [ 9 5 % CI 24.5-43.9], IMRT/VMAT: 33.2 months [ 9 5 % Cl 20.2- 46.32], HR 1.2 9 5 % CI 0.85-1.83), { \sf p } = { \sf 0 } . 2 6 ) (Supplementary Figure 4).

The survival difference between the 60 Gy and the 45 Gy groups remained significant in the multivariable analysis \scriptstyle \mathtt { \mathtt { p } } = 0 . 0 3 1 ). In addition, increasing age was an independent negative prognostic factor for survival (HR 1.03 [ 9 5 % CI 1.00-1.06], \mathsf { p } { = } 0 . 0 2 1 ) while female sex was a positive prognostic factor for survival HR 0.68, [ 9 5 % CI 0.47-0.97], \mathsf { p } { = } 0 . 0 3 5 ) (Supplementary Table 1). Subgroup survival analyses including a forest plot are provided in Supplementary Figure 1.

Progression free survival

Overall, median PFS was 15.0 months; 18.6 months ( 9 5 % Cl 11.6-25.6) in the 60 Gy group, and 10.9 months 9 5 % 0 . 1 8 . 7 \substack { - 1 3 . 2 } ) in the 45 Gy group (HR 0.76, 9 5 % CI 0.53-1.08; { \mathsf { p } } { = } 0 . 1 3 (Figure 2B). In multivariable analyses of PFS there were no significant difference between treatment groups (HR 0.75 9 5 % CI 0.53-1.07, { \mathsf { p } } { = } 0 . 1 2 Female sex was the only baseline characteristic significantly associated with PFS (HR 0.61, 9 5 % CI 0.43-0.87, \mathsf { p } { = } 0 . 0 0 7 -

Toxicity

Acute and long-term toxicity are listed in Table 2. No more acute toxicity was reported than in our previous publication, and there were no significant differences in the proportions who experienced acute grade 3-4 toxicities. Patients in the 60 Gy group did not experience more acute grade 3-4 esophagitis (60 Gy: 2 1 % , 45 Gy: 1 8 % .. \mathsf { p } { = } 0 . 8 3 ) or pneumonitis (60 Gy: 3 % , 45 Gy: 0 % .. \mathsf { p } { = } 0 . 3 9 ). As previously reported, there were six fatal events during the study treatment period, three in each treatment group. There were no differences in proportions with acute esophagitis or pneumonitis, or long-term adverse effects according to TRT treatment technique (Supplementary table 2).

Eleven patients (60 Gy \scriptstyle \mathsf { n } = 5 , 45 Gy \scriptstyle \mathsf { n } = 6 ) developed persistent, severe longterm eating and swallowing dysfunction lasting more than 4 weeks after completing CRT. Two patients, both in the 60 Gy group, developed oesophageal strictures which required blocking and/or stenting. One of these experienced grades 3 esophagitis during TRT, reported maximum dysphagia at week 8, and received parenteral nutrition. The other patient did not experience acute esophagitis and did not complete the QLQ at the end of TRT. These patients lived for 29.4 and 15.3 months, respectively, did not experience intrathoracic relapse, but developed brain metastases and died from their SCLC.

Long term cognitive dysfunction was reported for eight patients, and significantly more in the 45 Gy group (60 Gy \mathsf { n } { = } 1 , 45 Gy \mathsf { n } { = } 7 1 _ { \mathsf { p } = 0 . 0 2 5 } ), of whom six had received PCI. None of these were ever diagnosed with brain metastases (Table 2).

Health-Related Quality of life

Mean scores for the primary and secondary HRQoL endpoints are shown in Supplementary Figure 2. As previously described, patients reported maximum dysphagia at week 8, and there was no clinically significant difference between treatment groups (mean scores 60 Gy: 51, 45 Gy: 44), though patients that received 60 Gy reported slightly more dysphagia after one year (difference in mean scores of 9 points). There was no difference in the mean scores for dyspnea across treatment arms and scores remained stable over time. Mean scores for physical- and cognitive function declined from baseline until year 5, (physical function: -10 points in both groups, cognitive function: 60 Gy: -21 points, 45 Gy: -18 points), while global quality of life remained stable. There were no clinically significant differences between treatment groups for these last three items at any timepoint (Supplementary Figure 2), and mean scores were stable and similar between treatment groups for remaining HRQoL items (data not shown).

Relapse

Relapse locations are shown in Table 3. At the time of the final analyses, 99 patients had progressed (60 Gy: 54 % , 45 Gy: 6 3 % ). The proportions which experienced

distant metastasis were similar across treatment groups (60 Gy: 42 % , 45 Gy 4 6 % 1 \mathsf { p } { = } 0 . 6 0

Overall, there were fewer intrathoracic relapses in the 60 Gy group (60 Gy: 23 % , 45 Gy: 3 7 % 5 \mathsf { p } \mathsf { = } 0 . 0 3 7 , and 1 5 % of patients had intra-thoracic relapse at first relapse (60 Gy: 12 % , 45 Gy: 1 7 % 5 \mathsf { p } { = } 0 . 3 7 ) (Table 3). We did not detect a significant difference between treatment groups in median time to progression for patients with isolated relapse in the thorax as first progression (60 Gy: 13.1 months [ 9 5 % CI 7.8- 18.5], 45 Gy: 10.1 months 9 5 % Cl [9.6-10.6], \mathsf { p } { = } 0 . 1 0 ) (Figure 3A). Nor did we detect a significant difference in median post-progression survival (60 Gy: 22.9 months [ 9 5 % Cl 13.96-31.90], 45 Gy: 11.1 months [ 9 5 % CI 3.76-18.60], \mathsf { p } { = } 0 . 1 1 ) (Figure 3B), though there was a difference in overall survival among these patients (60 Gy: 43.5 months [ 9 5 % Cl 22.4-64.6], 45 Gy: 21.6 months [ 9 5 % CI 12.4-30.6], { \sf p } = 0 . 0 2 7 -

The most common site of distant metastasis was the brain (60 Gy: 20 % , 45 Gy: 12 % { \mathsf { p } } \mathbf { = } \mathbf { 0 } . 1 7 . Among the 143 patients who received PCI 24 ( 1 7 % ) developed brain metastasis, while among the 30 patients who did not receive PCl, 4 ( 1 3 % ) developed brain metastases.

Median OS for patients that developed brain metastases was 29.2 months 9 5 % CI 23.8-34.7). Among patients who developed brain metastases as first relapse, the median time to progression was 11.8 months ( 9 5 % CI 7.0-16.6) and median post progression survival was 13.5 months ( 9 5 % CI 7.8-19.1).

Fewer patients in the 60 Gy group had multiple distant metastases at the time of first relapse (60 Gy: 3 % , 45 Gy: 1 3 % 7 \mathsf { p } { = } 0 . 0 2 ) (Table 3). Otherwise, there were no significant differences in relapse patterns.

Post-progression therapy

Post-progression therapy among those with relapse is shown in Table 3. Similar proportions received second-line chemotherapy (60 Gy: 8 5 % , 45 Gy: 7 6 % A { \sf p } = { \sf 0 } . 2 6 I most commonly re-introduction of platinum/etoposide. More patients in the 60 Gy group received any radiotherapy as second line therapy (60 Gy: 54 % , 45 Gy: 3 1 % 5 \scriptstyle { \mathsf { p } } = 0 . 0 2 2 { { \ } } , this includes RT for thoracic relapse (60 Gy: 10 % 7 4 5 \ : \mathsf { G y } { : 8 % } ) ,bone metastasis ( 6 0 \mathsf { G y } { : } 4 % 5 4 5 \ : \mathsf { G y } { : } 6 % ) and SRS for brain metastases ( 6 0 \mathsf { G y } { : 2 7 % } , 45 Gy: 1 9 % ) (Table 3). Of the 19 patients (60 Gy: \mathsf { n } = 7 , 45 Gy: n = 1 2 ) who did not receive chemotherapy after first relapse, five patients received radiotherapy (60 Gy:

\mathsf { n } { = } 1 , 45 Gy: \scriptstyle \mathsf { n } = 4 , of which four received stereotactic radiosurgery (SRs) for brain metastases.

Of the 25 patients with isolated intrathoracic relapse at first progression, 18 received chemotherapy, one underwent surgery, and five re-irradiation (30-42 Gy or SBRT), while one did not receive any treatment.

Of the 28 patients who developed brain metastases, 18 (60 Gy: n = 1 3 , 45 Gy: \scriptstyle \mathsf { n } = 5 ) received SRS (Table 3). Median time to progression for these patients was 11.8 months ( 9 5 % CI 8.9-14.7), median post progression survival was 17.4 months ( 9 5 % CI 16.2-18.6) and median OS from baseline was 32.8 months ( 9 5 % CI 20.3-45.4) (Supplementary Figure 3A-C).

For the whole cohort, post progression survival was significantly longer for the 60 Gy group (60 Gy: 14.0 months [ 9 5 % Cl 9.2-18.8], 45 Gy: 8.2 months [ 9 5 % CI 6.0- 10.4], \scriptstyle \mathsf { p } = 0 . 0 0 8 P

Discussion

These final efficacy analyses confirm that twice-daily TRT of 6 0 ~ \mathsf { G y } in 40 fractions was superior to the established schedule of twice-daily 4 5 \mathsf { G y } in 30 fractions in our study cohort. The median OS in the 60 Gy group is almost twice as long as in the 45 Gy group (43.5 vs. 22.5 months) and there was a clinically relevant increase in 5- year survival rate from 2 8 . 4 % to 3 9 . 4 % . We have previously reported that the higher dose did not cause more acute toxicity, and here we report that the higher dose did not cause more late toxicity. Importantly, few participants experienced long-term adverse effects. Patients reported a decline in physical and cognitive function from baseline until 5 years. Otherwise, they did not report impaired long term HRQoL.

This was the first randomised controlled trial to demonstrate a survival benefit from escalating the TRT dose in LS SCLC. Two phase III trials have investigated whether TRT of 66-70 Gy in once-daily fractions of 2 Gy improve survival compared to twice-daily 45 Gy in 30 fractions, but there was no survival benefit of the higher TRT dose in neither. 5,6 Qiu and colleagues have shown that accelerated TRT of 65 Gy in 25 fractions improve PFS compared with twice-daily 45 Gy in 30 fractions (17.2 vs. 13.4 months, \mathsf { p } { = } 0 . 0 3 1 ), though in that trial, the acceleration was done by hypofractionation, i.e. one daily dose of 2 . 6 \mathsf { G y } 16 Another recently published Chinese trial by \mathsf { Y u } and colleagues shows that twice daily TRT of 54 Gy in 30

fractions utilizing simultaneous integrated boost RT to GTV/IGTV prolongs survival compared to 4 5 \mathsf { G y } in 30 fractions (60.7 vs 39.5 months, HR 0.55, \mathsf { p } { = } 0 . 0 0 3 ). 17 These, and our trial, strongly indicate that dose-escalation prolongs survival in LS SCLC when TRT is accelerated, and that accelerated TRT is superior to standard fractionated schedules, supporting previous reviews concluding that a shorter treatment time is positively associated with survival time in this setting. 18

Another important observation is that more patients appear to complete TRT when the treatment time is shorter. In the CALGB 30610/RTOG058 and CONVERT trials, 2 1 % and 20 % of patients in the high-dose groups did not complete TRT as planned. 5,6 By contrast, 3 . 4 % in the 60 Gy group in our trial, 0 . 9 % in the 54 Gy group of the study by \mathsf { Y u } and colleagues, and 2 . 3 % in the 65 Gy group of the study by Qiu and colleagues discontinued TRT. 16,17 Possible explanations might be that significant radiotoxicity occur more often before TRT is completed among patients who receive normo-fractionated TRT, 19 and that patients need to receive more chemotherapy courses during TRT.

Median overall survival in our 45 Gy group (22.5 months) is somewhat shorter than in other recent trials (28.7-39.5 months), 5,6,16,17,20 but the main reason for the positive result of our trial is that survival in the experimental arm was much longer than expected. Furthermore, median overall survival in our control arm was within the range observed in most population-based studies and our previous LS SCLC trial (21.5-27.0 months) 21-23 and the 5-year survival rate quite similar to what other recent trials report ( 2 9 % - 3 4 % . 5,6 Comparisons across trials are always challenging, but it seems that we applied a more liberal definition of LS than other recent trials, allowed PS 2 patients, and had fewer other exclusion criteria than the CONVERT and CALGB 30610/RTOG058 trials, 5,6 though patients with N0 disease were not eligible for the latter. Patients in the trial by Qiu and colleagues were younger (median age 58), and patients > 7 0 years were excluded from the trial by Yu and colleagues, 16,17 older patients have worse survival compared to younger . 24,25 Furthermore, more patients in the Chinese trials were never smokers16,26 who might have better survival than former/current smokers. 27

As hypothesized, there were fewer intrathoracic relapses in the 60 Gy group, and the local failure rate in the 45 Gy group was similar as in previous reports. 3,28,29 Still, 23 % of patients in the high-dose group experienced such relapses. Little is known about where they occur or whether they are preventable, and we will assess

Iocations of intrathoracic relapses and TRT doses delivered to these locations. We believe that these data provide important information on whether the survival benefit was truly due to higher TRT dose and potentially clarify whether intrathoracic control can be improved by adapting TRT target volumes or escalating TRT doses further.

The most common site of distant metastases was the brain ( 1 6 % of patients). There are few other reports on the frequency of brain metastases after CRT and PCI in the modern treatment setting, but the proportion is similar to that in a Canadian retrospective single institution study ( 1 9 % ) .29 Interestingly, 18 of the 28 patients who developed brain metastases were treated with SRS and median survival time after such treatment was 17.4 months, supporting previous studies suggesting that SRS has a role for selected SCLC patients with intracranial recurrence, especially after PCI, when whole brain radiotherapy is not an obvious choice. 30,31

In these final analyses, the survival difference is still larger than the difference in PFS between our study groups, for which we do not have any evident explanation. There was no imbalance in baseline characteristics, and we did not find any differences in radiotherapy planning target volumes or primary tumour locations. 32 Molecular analyses of tumour and blood samples including subtyping are ongoing. There were no obvious imbalances in relapse treatment and only one patient received immunotherapy after relapse, though we did not collect data on systemic therapy beyond second-line. One possible explanation is that there was no central radiological review. It can sometimes be diicult to separate relapses from radiation induced fibrosis. Furthermore, PET CT or biopsy was not mandatory for confirming relapses. Notably, more patients in the 45 Gy group developed metastases in multiple organs at the time of first relapse, and even if there was no difference in post-progression therapy, post-progression survival was significantly longer in the 60 Gy group. Thus, it might be that the tumour biology in relapsing disease was less aggressive after TRT of 60 Gy.

Importantly, the higher TRT dose did not cause more toxicity. The proportion who experienced severe acute esophagitis ( 2 0 % ) was within the same range as in other recent trials ( 1 1 % - 1 9 % ) .5,6,16,17 A previous phase I study concluded that the maximum tolerated twice-daily TRT dose was 4 5 \mathsf { G y } 33 but later trials, 5,6,11,16,17 including ours, show that a higher dose is tolerable, especially when using FDGPET/CT for staging and target volume definition and applying modern radiotherapy techniques. It has been questioned that there might have been a potential imbalance between our treatment groups with respect to extent of disease and tumor burden, but no such differences were detected in a recently published, detailed analyses of the radiotherapy plans. 32

We are only aware of three other trials reporting late toxicity in this setting. 5,7,17 Few participants ( 1 . 5 % ) in the CONVERT trial experienced long-term grade ^ { \ge 3 } esophagitis. 7 All were in the once daily group, and 0 . 8 % developed stricture or fistulation of the esophagus. 7 In the trial by \mathsf { Y u } and colleagues, none developed esophagitis grade >=slant 3 or strictures after 3 months. 17 Patient reports from the CALGB 30610/RTOG058 and our trial support these findings since reported dysphagia had returned to baseline 6 months after completing TRT. 12,34 The long term HRQoL in our study indicate that radiation induced esophagitis is transient in most cases and rarely leads to long term sequela and there are no reasons to believe that twice-daily TRT causes more toxicity than once-daily schedules. Furthermore, older patients in our trial tolerated treatment as well as the younger ones. 25

Few patients experienced severe pneumonitis (60 Gy: 3 . 4 % , 45 Gy: 0 . 0 % .. \mathsf { p } { = } 0 . 3 9 ) . They were all in the 60 Gy group, and one died even though TRT was discontinued at 45 Gy. Similarly, few patients in the CONVERT trial developed severe radiation pneumonitis (twice-daily \scriptstyle \mathsf { n } = 5 QD \scriptstyle \mathsf { n } = 6 ), of whom three died (twicedaily \mathsf { n } { = } 1 , QD \scriptstyle { \mathsf { n } } = 2 ^ 7 \mathsf { Y } \mathsf { u } and colleagues reported grade 3 pneumonitis in 2 patients in the 54 Gy arm and 3 patients in the 45 Gy, whereas none developed grade 3 pulmonary fibrosis. 17 The CALGB 306010/RTOG058 trial did not report pneumonitis, but 12 patients in the twice-daily group and 22 patients in the QD group experienced grade 3-4 dyspnea. 5 Thus, severe pneumonitis remains a major complication for an important minority of patients. The challenge is that we are currently not able to discern which patients are at risk. Not surprisingly, 35 we have found that higher mean doses, V2ogy and \mathsf { V } _ { 5 \mathsf { G y } } increase the risk of severe pneumonitis, while increased PTV volume (and mean dose to the esophagus) increases the severity of acute esophagitis. 32

Overall, there was a significant decline in patient reported cognitive function from baseline until year five, possibly due to PCI, 36 since 8 2 % of patients received such irradiation. The proportions of patients who received PCI was similar between treatment groups (60 Gy 8 1 % , 45 Gy 8 4 % 7 { \mathsf { p } } { = } 0 . 7 2 -

Unfortunately, our study was not designed to assess causality, and the only measure was patient reports on the QLQ C30, which contains only one question for cognitive function, and the number of completed QLQs the last years of follow-up was limited.

The main limitation of our trial is the sample size. On the other hand, we report more comprehensive data on relapse patterns, post-progression treatment and long-term toxicity than most previous studies of LS SCLC, and we are not aware of other studies including patient reported HRQoL for 5 years in this setting.

Considering that the 60 Gy schedule did not cause more toxicity, we believe that it is a promising alternative to established schedules, but the survival benefit should be confirmed. Recently, the ADRIATIC trial has shown that durvalumab immunotherapy after chemoradiotherapy improves survival in LS SCLC, 37 and we are planning a phase Ill trial investigating whether the 60 Gy schedule improves survival compared with 45 Gy when patients receive durvalumab after CRT.

In conclusion, hyper-fractionated, accelerated twice daily TRT of 60 Gy prolonged survival compared to the established 45 Gy schedule, without increasing the risk of acute or long-term toxicity, or negatively impact long term patient reported HRQoL.

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Figure legends

Table 1 Baseline characteristics, planning target volume, treatment planning techniques, treatment completion rates and response to chemoradiotherapy

Table 2 Acute severe radiotherapy related adverse effects and long-term adverse effects in patients who commenced thoracic radiotherapy

Table 3 Relapse locations and treatment

Figure 1 Trial profile

Figure 2 A) Overall survival (OS), and B) progression free survival (PFS)

Figure 3 Patients who developed intrathoracic relapse: A) Time to first intrathoracic relapse and B) postprogression survival for these patients

Figure legends supplemetary

Supplementary Table 1 Multivariable survival analyses

Supplementary Figure 1 Subgroup survival analyses

Supplementary Figure 2 HRQoL mean scores at baseline, week 8 (end of TRT), week 22, and years 1-5. A) physical functioning, B) global quality of life, C) cognitive function
reported on the EORTC QLQ C30, and D) dyspnea and E) dysphagia reported on the EORTC LC13. A higher score on the functional scales indicates a better function, while a
higher score on the symptom scales indicates more symptoms. Number of completed questionnaires at each timepoint is listed in F) (y=year, w=week).

Supplementary Figure 3 A) Time to progression (TTP), B) post-progression survival (PPS), and C) overall survival (OS) for patients with brain metastasis treated with SRS ( n = 1 8 )

Supplementary Figure 4 Survival according to radiation treatment technique

CRediT Statement:

Bjorn Henning Gronberg: Conceptualization, Funding acquisition, Project administration, Methodology, Data curation, Writing - review & editing, supervision

Kristin T Killingberg: Project administration, Data curation; Validation, Formal analysis, original draft, Writing - review & editing

Tarje Onssien Halvorsen: Project administration, Methodology, Data curation; Validation Formal analysis, Writing - review & editing, and Validation.

Oystein Flotten: Data curation, Writing - review & editing

Odd Terje Brustugun: Conceptualization, Data curation, Writing - review & editing

Maria M. Bjaanxs: Data curation, Writing - review & editing

Tesfaye Madebo: Data curation, Writing - review & editing

Seppo W Langer: Conceptualization, Data curation, Writing - review & editing

Tine Schytte: Project administration, Data curation, Writing - review & editing

Jan Nyman: Conceptualization, Project administration, Data curation, Writing - review & editing

Signe Leonora Risumlund: Data curation, Writing - review & editing

Georgios Tsakonas: Data curation, Writing - review & editing Jens Engelson: Data curation, Writing - review & editing Nina Hellbekkmo: Data curation, Writing - review & editing Oyvind Yksnoy: Data curation, Writing - review & editing Thor Naustdal: Data curation, Writing - review & editing Liv Ellen Giske: Data curation, Writing - review & editing Sverre Fluge : Data curation, Writing - review & editing Kirill Neumann: Data curation, Writing - review & editing

Figure 2 A) Overall survival (OS), and B) progression free survival (PrS) ournal

Number at risk (number censored)

0 Gy 89 (0) 81 (0) 66 (0) 30 (0) 24 (0) 23 (0)
5 Gy 81 (0) 65 (0) 39 (0) 49 (0) 41 (0) 36 (0)
60 Gy 89 (0) 54 (0) 40 (0) 35 (0) 28 (4) 17 (1:
45 Gy 81 (0) 38 (0) 28 (0) 24 (0) 22 (1) 15 (6)

Number at risk (number censored)