Radiol Oncol 2024; 58(3): 432-443. doi: 10.2478/raon-2024-0054 432 research article A retrospective evaluation of therapeutic efficacy and safety of chemoradiotherapy in older patients (aged ≥ 75 years) with limited- disease small cell lung cancer: insights from two institutions and review of the literature Ayako Shiono1, Hisao Imai1,2, Satoshi Endo2, Kazuki Katayama1, Hideaki Sato1, Kosuke Hashimoto1, Yu Miura1, Shohei Okazaki3, Takanori Abe4, Atsuto Mouri1, Kyoichi Kaira1, Ken Masubuchi2, Kunihiko Kobayashi1, Koichi Minato2,5, Shingo Kato4, Hiroshi Kagamu1 1 Department of Respiratory Medicine, International Medical Center, Saitama Medical University, Saitama, Japan 2 Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Gunma, Japan 3 Division of Radiation Oncology, Gunma Prefectural Cancer Center, Gunma, Japan 4 Department of Radiation Oncology, International Medical Center, Saitama Medical University, Saitama, Japan 5 Division of Health Evaluation and Promotion, SUBARU Health Insurance Society, Ota Memorial Hospital, Gunma, Japan Radiol Oncol 2024; 58(3): 432-443. Received 9 December 2023 Accepted 26 August 2024 Correspondence to: Hisao Imai, M.D., Ph.D., Department of Respiratory Medicine, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-City, Saitama 350-1298, Japan. E-mail: m06701014@gunma-u.ac.jp Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreo- ver, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC. Patients and methods. From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT. Results. A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The me- dian ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75–81) years and 79 (range: 76–92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1–5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference (p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively (p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group. Conclusions. Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group. Key words: chemoradiotherapy; chemotherapy; older patients; efficacy; limited disease; radiotherapy; safety; small cell lung cancer Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients 433 Introduction Lung cancer is the leading cause of cancer-related deaths worldwide.1 Small cell lung cancer (SCLC) accounts for 10–15% of all lung cancers and is an aggressive tumor characterized by early develop- ment of extensive metastases and rapid growth.2,3 Limited-disease SCLC (LD-SCLC) is restricted to one hemithorax and its regional lymph nodes, and it can be treated with a single radiotherapy field. Furthermore, LD-SCLC accounts for one-third of all SCLCs cases at the time of diagnosis.1 The pro- portion of older patients with SCLC continues to increase with the growing geriatric population.4,5 Approximately 30–40% of patients with SCLC are ≥ 70-years-old at their diagnosis6, and it is becom- ing increasingly crucial to understand how SCLC therapy should be tailored for older patients. The standard treatment for patients with LD- SCLC in good general condition is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT), followed by prophylactic cra- nial irradiation (PCI) for those who respond to chemoradiotherapy (CRT).7,8 However, many clini- cal studies on LD-SCLC have precluded the enroll- ment of older patients for reasons such as a decline in organ function or comorbidities.9,10 For example, a previous study demonstrated that a cisplatin plus etoposide combination regimen and concur- rent TRT are more effective for the treatment of LD-SCLC than a cisplatin plus etoposide combina- tion and sequential TRT11; however, it is notewor- thy that patients aged ≥ 75 years were precluded from enrolling in the study. Retrospective subset studies of patients with LD- SCLC treated with cisplatin, along with etoposide and concurrent early CRT, in randomized phase III studies have demonstrated that severe hemato- logical adverse event, pneumonitis of Grade 4 or more, and treatment-related deaths were observed more frequently in older patients aged ≥ 70 years than their younger counterparts.12,13 Although the objective response rate and 5-year event-free sur- vival rate were not significantly different between these two subgroups, there was a trend for them to be worse in older patients. Notably, a signifi- cant difference in the 5-year overall survival rate was observed in patients < 70 years of age in one trial.12,13 These results imply that the combination of cisplatin and etoposide is toxic to older patients with LD-SCLC, and that the most suitable treat- ment remains unclear. However, the therapeutic efficacy and toxicity of CRT in older patients with LD-SCLC have not yet been fully examined. In particular, as men- tioned above, older patients with LD-SCLC aged ≥ 75 years are excluded from clinical trials11 or stud- ies focusing on patients aged ≥ 75 years are scarce. Thus, the aim of our analysis was to retrospec- tively evaluate the safety and treatment efficacy of CRT and to explore the most suitable therapy for older patients with LD-SCLC aged ≥ 75 years. We assessed patient backgrounds, treatment compli- ance, treatment efficacy, and toxicity between pa- tients who underwent concurrent and sequential CRT. Patients and methods Patients We retrospectively analyzed the medical records of consecutive patients with Stage I–III LD-SCLC, aged ≥ 75 years, whose treatment plan involved concurrent or sequential CRT between April 2007 and June 2021 at two Japanese institutions (International Medical Center, Saitama Medical University and Gunma Prefectural Cancer Center). The requirement for written informed consent was waived by the Ethics Committee of Saitama Medical University owing to the retrospective na- ture of the study. All procedures complied with the tenets of the Declaration of Helsinki. The study design was approved by the Institutional Ethics Committee of the International Medical Center at Saitama Medical University (approval number 2023-033). The inclusion criteria were as follows: (i) older patients aged ≥ 75 years with cytologically or histologically diagnosed SCLC; (ii) patients with involvement of one hemithorax and its regional lymph nodes that could be treated with a single radiotherapy field; and (iii) patients that under- went first-line CRT (concurrent or sequential). The clinical stage of SCLC was determined based on the Union for International Cancer Control tumor- node-metastasis (TNM) Classification, Seventh Edition.14 The inclusion criteria for concurrent or sequential CRT at our institutions are as follows: patients with a performance status (PS) of 0–2; neutrophil count, ≥ 1.5 × 103/mm3; platelet count, ≥ 1.0 × 105/mm3; serum creatinine, ≤ 1.5 mg/dl; total bilirubin, ≤ 2.0 mg/dl; and a transaminase level ≤ 100 U/L. All patients underwent pretreatment physi- cal examinations, chest radiography, computed tomography (CT) scans of the chest/abdomen, CT or magnetic resonance imaging of the brain, Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients434 and bone scintigraphy/18F-fluorodeoxyglucose positron-emission tomography to assess the TNM disease stage. Data of each patient were extracted from the electronic medical records. Treatment Chemotherapy A combination of etoposide (60–100 mg/m2) on days 1–3 plus cisplatin (60–80 mg/m2) on day 1 or carbo- platin (area under the curve [AUC] 3–5) on day 1 was administered intravenously every 3–4 weeks. The chemotherapeutic agent and its dose were de- termined by an attending physician. The chemo- therapeutic administration cycles were repeated every 3–4 weeks. At our institution, the criteria for initiating subsequent cycles of chemotherapy were the same as the criteria for the inclusion of concur- rent or sequential CRT as described in the Patient subsection. If these criteria were not met, subse- quent cycles were withheld until the dosing crite- ria were met. If the dosing criteria were not met seven weeks after the first day of the cycle, chemo- therapy was discontinued. Generally, the doses of etoposide and platinum (cisplatin or carboplatin) are reduced or chemotherapeutic regimens are altered in the adverse event of Grade 4 decreased platelet count, prolonged Grade 4 decreased white blood cell count / decreased neutrophil count, or Grade 3 or more severe non-hematological toxic- ity during the previous chemotherapeutic cycle. For neutropenia, a granulocyte colony-stimulating factor was administered as prophylaxis at the dis- cretion of the attending physician. Treatment was terminated when disease progression was ob- served, intolerable toxicity occurred, or when the patient withdrew consent for treatment. Radiotherapy Generally, TRT is started concurrently in the first cycle of chemotherapy or sequentially after four cycles of chemotherapy in older patients with LD- SCLC. The prescribed dose was 45 Gy in 30 frac- tions (1.5 Gy twice-daily) for the concurrent case and 60 Gy in 30 fractions (2 Gy daily) for the se- quential case. All the patients underwent chest CT to facilitate treatment planning. The primary tumor (gross tumor volume [GTV] primary) was delineated in the pulmonary windows, and nodal involvement (GTV node) was delineated in the me- diastinal windows. A clinical target volume (CTV) margin of 5 mm was added to the GTV primary and node. To plan the target volume margin, 5 mm was added to the CTV to ensure that the dose reached the target volume. The initial field in the sequential arm was based on pretreatment tumor volume. Regarding dose constraints, for normal lung volume receiving > 20 Gy (V20), the dose was ≤ 35% of the total lung volume and maximum spinal cord dose was < 45 Gy in a once-daily frac- tion regimen or < 36 Gy in twice-daily fractions regimen. Additionally, TRT was suspended if the patient experienced a decrease in Grade 4 plate- let count, radiation pneumonitis, fever caused by infection, decrease in arterial oxygen pressure ex- ceeding 10 mmHg, or if the patient had difficulty swallowing a liquid diet. After TRT, PCI was administered to patients with a complete or near-complete response rep- resented by a scar-like shadow on chest CT if the physician in charge judged that the patient would benefit from PCI, which consisted of 25 Gy/10 frac- tions for the entire brain. Evaluation of treatment response and adverse events The best overall response and maximum tumor shrinkage were evaluated as tumor responses. Radiographic tumor responses were classified based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.15 Tumor responses were defined as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not evaluated (NE). If treatment failure occurred, the patients were permitted any subsequent treatment based on their preferences. Treatment CRT-related adverse events were grad- ed according to the Common Terminology Criteria for Adverse Events (version 4.0). Statistical analysis Categorical variables were analyzed using Fisher’s exact test, and continuous variables were analyzed using Welch’s t-test. Progression-free survival (PFS) was calculated from the start of treatment until PD or death from any cause, and overall survival (OS) was calculated from the first day of treatment until death or censored on the date of the last follow-up. Survival curves were calculated using the Kaplan–Meier method and compared between the two groups using the log-rank test. Differences were considered statistically signifi- cant at a two-tailed p-value of < 0.05. All statistical analyses were performed using the JMP statistical Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients 435 software, version 11.0, for Windows (SAS Institute, Cary, NC, USA). Results Patient characteristics The patient selection process is illustrated in Supplementary Figure 1. Thirty-two patients were treated with CRT between April 2007 and June 2021 at both institutions (concurrent CRT group, n = 19; sequential CRT group, n = 13) and were as- sessed for response, survival, and safety of the treatments. Table 1 shows the patient characteris- tics in the concurrent/sequential CRT group. Men comprised a majority of the patients (n = 27, 84.3%), and the median age of the entire group was 78 (range, 75–92) years. A total of 96.8% of patients had a PS of 0 or 1, and the remaining patients had a PS of 2. All the patients were smokers, and 71.8% had a disease stage of III. No significant differ- ences were observed in the baseline patient char- acteristics between the concurrent and sequential CRT groups. The median number of chemothera- peutic treatment cycles was four (range 1–4) in the concurrent CRT group and four (range 2–5) in the sequential CRT group. Most patients (28, 87.5%) were treated with car- boplatin and etoposide in combination with ra- diotherapy. Supplementary Table 1 lists the treat- ment delivery. The most frequently administered doses in the concurrent CRT group were AUC 4 for carboplatin and 80 mg/m2 for etoposide (n = 9 patients, 47.3%), and in the sequential CRT group, they were AUC 5 for carboplatin and 80 mg/m2 for etoposide (n = 4 patients, 30.7%). Treatment response and survival Table 2 shows the results of the treatment re- sponse. The response rate was 94.7% in the concur- rent CRT group (CR, n = 3; PR, n = 15; SD, n = 0; and PD, n = 0) and 100.0% in the sequential CRT group (CR, n = 0; PR, n = 13; SD, n = 0; and PD, n = 0). No significant differences in treatment response were observed between the concurrent and sequential CRT groups. Regarding survival, median PFS was 11.9 (95% CI: 8.2–15.2) months (Figure 1A) and median OS was 21.1 (95% CI: 13.0–39.5) months (Figure 1B) for all patients. No significant differences were ob- served in the PFS or OS between concurrent and sequential CRT groups. Median PFS was 13.0 (95% CI: 7.8–18.2) months in the concurrent group and 9.0 (95% CI: 6.0–not reached) months in the sequen- tial group (p = 0.67; Figure 2A). Median OS was 19.2 (95% CI: 11.0–37.1) months in the concurrent CRT group and 23.5 (95% CI: 11.0–not reached) months in the sequential CRT group (p = 0.46; Figure 2B). Toxicity Treatment-related adverse events of all the patients are presented in Table 3. Toxicity was evaluated in all 32 patients. Myelosuppression was the most fre- quent treatment-related adverse event—decreased neutrophil counts (Grade 3 or 4) were seen in 71.9% patients and decreased white blood cell counts (Grade 3 or 4) in 62.5% patients. Febrile neutrope- nia was observed in three patients (9.4%). Grade 3 or 4 anemia occurred in six patients (18.8%), and decreased platelet counts (Grade 3 or 4) in seven patients (21.9%). The incidence of non-hemato- logical toxicities was low, and the most frequent Grade 3 or 4 non-hematologic toxicity was infec- tion (12.5%). Grade 3 or 4 pneumonitis was seen in two patients. Adverse events leading to treatment discontinuation occurred in 6/19 (31.6%) patients in the concurrent CRT group and 1/13 (7.7%) patients A B FIGURE 1A. Kaplan-Meier analysis of the progression-free survival of the 32 patients. The median progression-free survival was 11.9 months. FIGURE 1B. Kaplan-Meier analysis of the overall survival of 32 patients. The median overall survival was 21.1 months. A B FIGURE 2B. The overall survival (OS) of the concurrent and sequential chemoradiotherapy groups. The median OS was 19.2 months in the concurrent group and 23.5 months in the sequential group (p = 0.46). FIGURE 2A. Progression-free survival (PFS) of the concurrent and sequential chemoradiotherapy groups. The median PFS was 13.0 months in the concurrent group and 9.0 months in the sequential group (p = 0.67). Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients436 TABLE 1. Baseline patient characteristics Characteristic Total(N = 32) Concurrent CRT group (n = 19) Sequential CRT group (n = 13) p a Sex Male / female 27 / 5 16 / 3 11 / 2 > 0.99 Age (years) Median 78 77 79 0.05b Range 75–92 75–81 76–92 ECOG-PS, n 0 / 1 / 2 / 3 / 4 12 / 19 / 1 / 0 / 0 6 / 12 / 1 / 0 / 0 6 / 7 / 0 / 0 / 0 Smoking status, n Yes / no 32 / 0 19 / 0 13 / 0 > 0.99 Histology, n Small cell carcinoma / combined small cell carcinoma 29 / 3 18 / 1 11 / 2 0.55 Disease stage, n I / II / III / postoperative recurrence 5 / 4 / 23 / 0 4 / 2 / 13 / 0 1 / 2 / 10 / 0 History of postoperative adjuvant chemotherapy, n Yes / no 0 / 32 0 / 19 0 / 13 > 0.99 Number of cycles chemotherapy administered, n Median 4 4 4 0.19b Range 1–5 1–4 2–5 Chemotherapy regimen, n CBDCA+etoposide / CDDP+etoposide 28 / 4 16 / 3 12 /1 0.63 With or without G-CSF prophylaxis, n Yes / no 27 / 5 17 / 2 10 / 3 0.37 Radiation irradiation method, n Conventional / accelerated hyperfractionated radiotherapy 26 / 6 14 / 5 12 / 1 0.36 Completion of chemotherapy, n Yes / no 21 / 11 11 / 8 10 / 3 0.45 Completion of radiotherapy, n Yes / no 31 / 1 18 / 1 13 / 0 > 0.99 Prophylactic cranial irradiation, n Yes / no 2 / 30 2 / 17 0 / 13 0.50 Reason for discontinuation of chemotherapy administrationb, n Progressive disease 1c 0 1 Adverse events 7 6 1 Others 3 2 1 Alive at data cutoff, n Alive / death 8 / 24 4 / 15 4 / 9 0.68 CBDCA = carboplatin; CDDP = cisplatin; CRT = chemoradiotherapy; ECOG-PS = Eastern Cooperative Oncology Group - Performance Status; G-CSF = granulocyte colony- stimulating factor a Comparison between the concurrent and sequential chemoradiotherapy groups b Welch’s t-test c The clinical progressive disease after two courses of chemotherapy, followed by definitive radiotherapy and partial response (PR) Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients 437 in the sequential CRT group and were more fre- quent in the concurrent CRT group, although the difference was not significant (p = 0.06). Treatment- related deaths occurred in two patients, one in each group. One patient suffered from pneumo- nitis in the sequential group and another patient suffered from acute coronary syndrome in the concurrent group. Analysis of myelosuppression revealed that he- matological toxicities occurring with sequential CRT were milder than those with concurrent CRT (Table 3). The frequencies of Grade 3 or 4 hema- tologic toxicities in patients receiving sequential CRT versus those receiving concurrent CRT were as follows: white blood cell count decreased by 30.8% versus 84.2%, respectively (p = 0.004); neu- trophil count decreased by 61.5% versus 78.9%, respectively (p = 0.43); anemia decreased by 7.7% versus 26.3%, respectively (p = 0.36); and platelet count decreased by 15.4% versus 26.3%, respective- ly (p = 0.67). Febrile neutropenia occurred in 7.7% of patients receiving sequential CRT and in 10.5% of patients receiving concurrent CRT. Other non- hematologic toxicities, such as Grade 3 or higher diarrhea, dermatitis, radiation, infection, pneumo- thorax, hypotension, generalized muscle weak- ness, and acute coronary syndrome, were more common in the concurrent CRT group; however, this was not statistically significant. Subsequent treatment after CRT Subsequent treatment administered after CRT is presented in Table 4 and recurrence was observed in 27/32 patients. The best supportive care was of- ten the treatment of choice for patients with recur- rence after CRT, with a post-relapse chemotherapy conversion rate of 13/27 (48.1%) patients. The most common subsequent chemotherapy was a combi- nation of carboplatin and etoposide, followed by amrubicin monotherapy. Six patients received up to third-line treatment; however, no patients re- ceived chemotherapy beyond the fourth-line treat- ment. Discussion This retrospective study assessed the efficacy and safety of CRT in older patients with LD-SCLC. Concurrent and sequential CRT groups demon- strated similar efficacy in the treatment of older patients with LD-SCLC; however, the toxicity pro- files tended to be higher in the concurrent CRT group. These safety profiles should be considered when using CRT to treat older patients with LD- SCLC. Meta-analyses and prospective and retrospec- tive studies specifically focused on older patients with LD-SCLC have shown conflicting results re- garding the survival benefits and tolerability of CRT.16-27 In the CONVERT trial, Christodoulou et al. reported the treatment outcomes of a subgroup of patients aged ≥ 70 years with LD-SCLC com- pared to those of younger patients.26 Concurrent CRT was found to be feasible in selected, fit old- er patients with LD-SCLC. Findings of previous studies on CRT in older patients with LD-SCLC are TABLE 2. Treatment response Response Total (N = 32) Concurrent CRT (n = 19) Sequential CRT (n = 13) pa Complete response 3 3 0 Partial response 28 15 13 Stable disease 0 0 0 Progressive disease 0 0 0 Not evaluated 1 1 0 Response rate (%) (95% CI) 96.9 (82.9–100) 94.7 (73.5–100) 100 (-) > 0.99 Disease control rate (%) (95% CI) 96.9 (82.9–100) 94.7 (73.5–100) 100 (-) > 0.99 CRT = chemoradiotherapy; 95% CI = 95% confidence interval a Comparison between the concurrent and sequential chemoradiotherapy groups Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients438 summarized in Table 5, along with our findings. Considering the findings of previous prospective trials evaluating CRT in older patients (≥ 70 years) with LD-SCLC, we infer that the response rate, PFS, and OS obtained in our study were satisfacto- ry.17,23,24,26,27 In meta-analyses and prospective and retrospective studies of older patients with LD- SCLC, the response rates in both the concurrent and sequential CRT groups generally ranged from 70–100%, with PFS ranging from 9–14 months and OS from 17–29 months. Moreover, the therapeutic efficacies were similar, except for those reported by Jeremic et al. and Corso et al. in which the OS was 15 months and 15.6 months, respectively. To the best of our knowledge, only a few stud- ies on CRT have been conducted to date in older patients aged ≥ 70 years, and only three studies have been conducted on patients aged ≥ 75 years (two retrospective and one prospective study18,20,23, both with small numbers of cases; Table 5). A com- parison of toxicities between concurrent and se- quential CRT groups showed that the frequency of Grade 3 or higher myelosuppression (particularly leukopenia) was higher in the concurrent than in sequential CRT group. However, Kubo et al. re- ported that in the sequential CRT group, Grade 3 or higher neutropenia, thrombocytopenia, fe- brile neutropenia, and pneumonia were relatively common, which may have been influenced by the chemotherapeutic regimen of cisplatin and topote- can therapy.23 In general, except in the study by Jeremic et al., concurrent CRT was associated with a higher rate of Grade 3 or higher levels of leukope- nia, neutropenia, and thrombocytopenia. TABLE 3. Adverse events Adverse event All patients (N = 32) Concurrent CRT (n = 19) Sequential CRT (n = 13) Any Grade % Grade≥3 % Any Grade % Grade≥3 % Any Grade % Grade≥3 % p a Led to discontinuation 7 21.9 6 18.8 6 31.6 6 31.6 1 7.7 0 0.0 0.06 Led to death - 2 6.3 - - 1 5.3 - - 1 7.7 > 0.99 Treatment relatedb White blood cell decreased 28 87.5 20 62.5 18 94.7 16 84.2 10 76.9 4 30.8 0.004 Neutrophil count decreased 26 81.3 23 71.9 18 94.7 15 78.9 8 61.5 8 61.5 0.43 Anemia 28 87.5 6 18.8 16 84.2 5 26.3 12 92.3 1 7.7 0.36 Platelet count decreased 27 84.4 7 21.9 16 84.2 5 26.3 11 84.6 2 15.4 0.67 Febrile neutropenia 3 9.4 3 9.4 2 10.5 2 10.5 1 7.7 1 7.7 > 0.99 Diarrhea 3 9.4 1 3.1 2 10.5 1 5.3 1 7.7 0 0.0 > 0.99 Constipation 14 43.8 1 3.1 9 47.4 0 0.0 5 38.5 1 7.7 0.41 Dermatitis radiation 8 25.0 1 3.1 2 10.5 1 5.3 6 46.2 0 0.0 > 0.99 Pneumonitis 29 90.6 2 6.3 18 94.7 1 5.3 11 84.6 1 7.7 > 0.99 Infection 7 21.9 4 12.5 4 21.1 3 15.8 3 23.1 1 7.7 0.63 Pneumothorax 2 6.3 2 6.3 2 10.5 2 10.5 0 0.0 0 0.0 0.50 Hypotension 1 3.1 1 3.1 1 5.3 1 5.3 0 0.0 0 0.0 > 0.99 Generalized muscle weakness 1 3.1 1 3.1 1 5.3 1 5.3 0 0.0 0 0.0 > 0.99 Acute coronary syndrome 1 3.1 1 3.1 1 5.3 1 5.3 0 0.0 0 0.0 > 0.99 CRT = chemoradiotherapy. Bold text indicates statistically significant differences. aComparison between the concurrent cohort and sequential chemoradiotherapy groups of Grade ≥ 3. bTreatment-related adverse events reported as Grade ≥ 3 in ≥ one patient. Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients 439 In our study, the major adverse events in the concurrent CRT group were hematological tox- icities, including decreased white blood cell and neutrophil counts. Gastrointestinal toxicities, in- cluding anorexia, nausea, vomiting, and consti- pation, were relatively mild. However, Grade 3 or higher infection and pneumothorax occurred in three (15.8%) and two (10.5%) patients, respec- tively. Moreover, there was one treatment-related death. The main adverse events in the sequential CRT group were hematologic toxicities, includ- ing decreased white blood cell counts; however, there were significantly fewer cases showing Grade 3 or higher white blood cell decreases, a relatively small proportion of other hematologic and non-hematologic toxicities, including he- matocytopenia, and one treatment-related death. In this study, the incidence of Grade 3 or higher adverse events was also higher in the concurrent CRT group than that in the sequential CRT group, except for pneumonitis. Despite prophylactic ad- ministration of G-CSF in 27 of 32 patients (84.3%), more than 70% of the total patient, 78.9% of pa- tients in the concurrent CRT group, and 61.5% of patients in the sequential CRT group had Grade 3 or higher neutrophil count decreased. All patients who received G-CSF administered it prophylac- tically during chemotherapy and not during ra- diotherapy. Neutrophil count decrease occurred at high rate, but febrile neutropenia occurred in 9.4% of overall patients. Although routine prophy- lactic administration of G-CSF is not usually rec- ommended, clinical guidelines recommend that patients with risk factors for febrile neutropenia who are treated with chemotherapeutic regimens associated with a ≥ 20% risk of febrile neutrope- nia should be administered G-CSF as primary prophylaxis.28,29 Routine prophylactic adminis- tration of G-CSF during chemotherapy in CRT in older patients with LD-SCLC is not recommend- ed. However, one report suggests considering pri- mary prophylaxis with G-CSF to prevent febrile neutropenia in male patients with SCLC who are treated with platinum plus etoposide and have a history of radiation therapy, which is a risk fac- tor for febrile neutropenia.30 Primary prophylaxis with G-CSF may be considered aggressively dur- ing chemotherapy in certain situations. However, it should be noted that when evaluat- ing toxicity, the criteria for determining the Grade of adverse events may not be consistent across dif- ferent studies. Table 5 shows that treatment discon- tinuation mainly occurred owing to failure to com- plete chemotherapy. In studies evaluating concur- rent CRT and this study, the proportion of patients who did not complete treatment was > 30%. In this study, of the 19 patients who received concurrent CRT, 6 did not complete a full cycle of chemother- apy owing to toxicity and 1 discontinued TRT. Of the 13 patients who received sequential CRT, one did not complete a full cycle of chemotherapy ow- ing to toxicity. Regarding treatment completion, the concurrent CRT group had a higher rate of toxicity discontinuation than the sequential CRT group in this study. We speculate that patients in good general condition were treated with concur- rent CRT and frail patients were treated with se- quential CRT. Therefore, as our findings suggest, TABLE 4. Overview of subsequent chemoradiotherapy treatments Second-line Third-line ≥ Fourth-line Carboplatin+etoposide 7 0 0 Carboplatin+etoposide+atezolizumab/durvalmab 2 0 0 Carboplatin+irinotecan 0 1 0 Carboplatin+paclitaxel 0 1 0 Amurubicin 4 2 0 Nogitecan 0 0 0 Irinotecan 0 0 0 Others 0 2 0 Best supportive care 14 - - No recurrence 5 Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients440 TABLE 5. Findings of previous studies on chemoradiotherapy in older patients with limited-disease small cell lung cancer Report [ref] Year Region Age (years) Study type Sample size PS Stage Treatment Response rate (%) (All, con CRT vs. seq CRT) PFS (months) (All, con CRT vs. seq CRT) OS (months) (All, con CRT vs. seq CRT) Interruption of treatment Grade 3 or higher a Jeremic et al.17 1998 Yugoslavia ≥ 70 Prospective, Phase 2 72 KPS≥60 Limited disease concurrent CRT (CBDCA+ETP) 75 NR 15 NR Leukopenia 8.3%, Thrombocytopenia 11%, Infection 4.2%, Pneumonitis 18% Shimizu et al.18 2007 Japan ≥ 75 Retrospective 7 0–1 II–III concurrent CRT (CBDCA+ETP or CDDP+ETP) 100 NR 24.7 Imcompleted intent cycles of chemotherapy 3/7 (42.8%) Leukopenia 100%, Neutropenia 100%, Thrombocytopenia 57.1%, FN 42.8%, Pneumonitis 28.5% Okamoto et al.19 2010 Japan ≥ 70 Retrospective 12 0–1 II–III concurrent CRT (CDDP+ETP) 100 14.2 24.1 Imcompleted intent cycles of chemotherapy 5/12 (41.7%) Leukopenia 100%, Neutropenia 100%, Thrombocytopenia 33%, FN 67%, Pneumonitis 8% Shukuya et al.20 2013 Japan ≥ 75 Retrospective 20 0–1 II–III concurrent CRT (CBDCA+ETP or CDDP+ETP); n=5, sequential CRT (CBDCA+ETP or CDDP+ETP); n=15 NR, 100 vs. 80 NR, 208 days vs. 216 days 601 days (seq CRT with CBDCA+ETP) Con vs. seq CRT; Imcompleted intent cycles of chemotherapy 2/5 (40%) vs., 2/15 (13.3%) Con vs. seq CRT; Leukopenia 100% vs. 53%, Neutropenia 100% vs. 93%, Thrombocytopenia 20% vs. 27%, FN 60% vs. 13%, Infection 0% vs. 7%, Pneumonitis 0% vs. 27% Okamoto et al.21 2014 Japan ≥ 70 Prospective, Phase 1 12 0–1 Limited disease concurrent CRT (split CDDP+ETP) 91.6 11.5 17 Imcompleted intent cycles of chemotherapy 5/12 (41.6%) Leukopenia 100%, Neutropenia 100%, Thrombocytopenia 33%, FN 33%, Pneumonitis 16% (level 2 cohort) Corso et al.22 2015 U.S.A ≥ 70 Retrospective 4362 b NR I–III concurrent CRT; n=3472, sequential CRT; n=1136 NR NR 15.6, 17.0 vs. 15.4 NR NR Kubo et al.23 2016 Japan ≥ 76 Prospective, Phase 2 22 0–2 I–III sequential CRT (CDDP+TOP) 68 9.1 22.2 Imcompleted intent treatment course of CRT 41% Neutropenia 96%, Thrombocytopenia 50%, FN 32%, Pneumonitis 18% Misumi et al.24 2017 Japan ≥ 70 Prospective, Phase 1/2 35 c 0–2 I–III sequential CRT (CBDCA+CPT11) 88.6 11.2 27.1 Imcompleted intent cycles of chemotherapy 7/35 (20.0%) Neutrophils 51%, Platelets 11.4%, FN 5.7%, Pneumonitis 5.7% Stinchcombe et al.25 2019 USA ≥ 70 Pooled analysis 254 NR Limited disease concurrent CRT (CBDCA+ETP or CDDP+ETP) NR 10.6 17.8 Imcompleted intent treatment course of CRT 135/250 (54%) Neutropenia 56%, Pneumonitis 2% Christodoulou et al.26 2019 Europe ≥ 70 Prospective, Phase 3 (subgroup) 67 0–2 I–III concurrent CRT (CDDP+ETP) NR 18 29 Imcompleted intent cycles of chemotherapy 25/67 (37.3%) Neutropenia 84%, Thrombocytopenia 28%, Infection 13%, Pneumonitis 3% Killingberg et al.27 2023 Norway ≥ 70 Prospective, Phase 2 (subgroup) 53 0–2 I–III concurrent CRT (CBDCA+ETP or CDDP+ETP) 70 12.2 24 Imcompleted TRT as planned 8%, Imcompleted four cycles of chemotherapy 15% Neutropenia 80%, Thrombocytopenia 30%, Infection 4%, Pneumonitis 4% Current study Japan ≥ 75 Retrospective 32 0–2 I–III concurrent CRT (CBDCA+ETP or CDDP+ETP); n=19, sequential CRT (CBDCA+ETP or CDDP+ETP); n=13 96.9, 94.7 vs. 100 11.8, 13.0 vs. 9.0 21.1, 19.2 vs. 23.5 Con vs. seq CRT; Imcompleted intent cycles of chemotherapy 6/19 (31.6%) vs. 1/13 (7.7%) Con vs. seq CRT; White blood cell decreased 84.2% vs. 30.8%, Neutrophil count decreased 78.9% vs. 61.5%, Platelet count decreased 26.3% vs. 15.4%, FN 10.5% vs. 7.7%, Infection 15.8% vs. 7.7%, Pneumonitis 5.3% vs. 7.7% CBDCA = carboplatin; CDDP = cisplatin; con CRT = concurrent chemoradiotherapy; CPT11 = irinotecan; ETP = etoposide; FN = febrile neutropenia; KPS = Karnofsky performance status; NR = not reported; OS = overall survival; PFS = progression-free survival; PS = performance status; seq CRT = sequential chemoradiotherapy a Some studies use different versions of the Common Terminology Criteria for Adverse Events. b Patients receiving CRT with survival of at least 4 months after diagnosis c Phase 2 cohort Radiol Oncol 2024; 58(3): 432-443. Shiono A et al. / Therapeutic efficacy and safety of chemoradiotherapy in older patients 441 it may not be possible to perform concurrent CRT in all older patients (> 75 years) with LD-SCLC. Furthermore, radiation pneumonitis should be considered with caution, as Grade 3 or higher se- vere pneumonitis occurred in 2/32 patients (6.3%) in our study. To reduce the frequency and sever- ity of radiation pneumonitis, it may be appropriate to set the irradiation field according to the tumor volume after the induction of chemotherapy in the case of sequential CRT.31 Older patients with good PS and normal organ function, including those with extensive SCLC, tend to be treated using the same regimens as younger patients undergoing chemotherapy. However, some studies have suggested that these older patients may be at greater risk of severe tox- icity as compared to their younger counterparts.4,32 Regarding whether chemotherapy regimens based on cisplatin or carboplatin, in combination with TRT, are superior, a meta-analysis demonstrated that both cisplatin-based and carboplatin-based chemotherapy regimens are equally effective in SCLC.33 In addition, the studies shown in Table 5 have shown that carboplatin-based combination regimens are relatively more common in older patients. Thus, non-cisplatin chemotherapeutic regimens such as carboplatin and etoposide have become the favored chemotherapy regimens for older patients with SCLC.34 Our study population included patients en- rolled from 2007–2021, during which time im- provements in supportive care, such as antiemetic drugs, and developments in radiation methods and devices may have affected the efficacy and safety of the treatment. As shown in Table 4, ap- proximately half of the patients who relapsed re- ceived subsequent chemotherapy. Kasahara et al. reported that treatments administered after first- line CRT might affect OS.35 In this study, two pa- tients were treated with chemotherapy combined with immune checkpoint inhibitors (ICIs), which may have affected OS. In the future, the use of more active ICIs in older patients with LD-SCLC who relapse after CRT may have a significant im- pact on the long-term prognosis. This study had some limitations. First, this study had a retrospective design and a small sample size, thereby limiting the generalizability of the findings. A retrospective study design de- pends on subjective physician examinations, lead- ing to variabilities in tumor response and PFS data. Second, the intervals between lesion evaluations in this study were not as consistent as those in a prospective trial. Thus, the potential significance of the sources of bias must be considered when in- terpreting our data. In particular, the severity of non-hematological adverse events may have been underestimated owing to the retrospective na- ture of this study. Third, patients were treated as inpatients for most of the treatment duration, and data on treatment toxicities were recorded in de- tail in the patients’ medical records. This explora- tory analysis could not be considered definitive. Nevertheless, because it is difficult to collect data on a large number of older patients with LD-SCLC who have received CRT, our findings may be help- ful for physicians in determining the optimal treatment choice for this patient group. In summary, although hematological toxicities, particularly decreased neutrophil counts, were severe, CRT showed favorable efficacy not only in the concurrent CRT group, but also in the sequen- tial CRT group. However, concurrent CRT may not be feasible for all older patients with LD-SCLC, and sequential CRT should be considered as a treatment choice for this patient group. Further prospective trials are warranted to develop and evaluate optimal treatment strategies for older pa- tients with LD-SCLC. Acknowledgements The authors thank Ms. Kyoko Nakagawa for her assistance in preparing this manuscript. No fund- ing was received for this study. Author contributions All the authors have read and approved the final manuscript. Conceptualization and methodology, A.S. and H.I.; Formal analysis and data curation, H.I. and K. Kaira; Project administration, visuali- zation, and writing—original draft preparation, A.S. and H.I.; Supervision, K. Kaira. and H.K.; Investigation and resources, S.E., K. Katayama, H.S., K.H., Y.M., S.O., T.A., A.M., K. Masubuchi, K. Minato, K. Kobayashi, and S.K.; writing, review, and editing, all authors. 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