Abstract
Objective
This study assessed the outcomes of elderly patients with limited‐stage small cell lung cancer (LS‐SCLC), which may be linked to the timing of thoracic radiotherapy (TRT) following chemotherapy.
Methods
Elderly patients (n = 78) with LS‐SCLC were divided into three groups depending on the timing of radiotherapy. The patients in the TRT group were stratified into early (TRT after 1–2 cycles of chemotherapy, n = 29), medium‐term (TRT after 3–4 cycles of chemotherapy, n = 33), and late (TRT after 5–6 cycles of chemotherapy, n = 16) TRT groups. The overall survival (OS) and progression‐free survival (PFS) were assessed and compared.
Results
The medium‐term TRT group demonstrated significantly longer mPFS (20.12 months) and better mOS (35.97 months) than those in the other groups (PFS: P = 0.021;OS: P = 0.035). A pairwise comparison of the three groups revealed that those who received medium‐term TRT exhibited significantly improved PFS than the early (mPFS: 20.12 vs. 10.36 mouths, P = 0.018) and late (mPFS: 20.12 vs. 9.17 months, P = 0.016) TRT. The medium‐term TRT group demonstrated significantly improved OS than the early TRT (mOS: 35.97 vs. 25.22 months, P = 0.007) but not in comparison with the late TRT (mOS: 35.97 vs. 21.63 months, P = 0.100).
Conclusion
In elderly patients with LS‐SCLC, the addition of TRT after 3–4 cycles of chemotherapy appears to be a viable and potentially beneficial treatment approach.
Keywords: elderly patients, intensity modulated radiation therapy, limited‐stage small cell lung cancer, prognosis, radiotherapy timing, thoracic radiotherapy
1. INTRODUCTION
Small‐cell lung cancer (SCLC) is a histologically aggressive tobacco‐induced tumor that accounts for approximately 15% of all lung cancer diagnoses. 1 The incidence of limited‐stage SCLC (LS‐SCLC) is increasing, potentially due to better staging techniques, which include the more frequent utilization of brain magnetic resonance imaging (MRI) and 18‐fluorodeoxyglucose positron emission tomography (PET). Approximately 45% of patients with the disease are over the age of 70 years, whereas approximately 10% of diagnoses are made in individuals aged 80 years or older. 2 In the context of the remarkably aging population worldwide, the need for evidence to guide treatment decisions in elderly group is apparent.
The first‐line treatment of LS‐SCLC is chemo‐radiotherapy (CRT). 3 Two meta‐analysis showed the advantage for CRT compared with chemotherapy alone. 4 , 5 Although there is general agreement on the management of LS‐SCLC using a combination of therapies, debate persists regarding the most effective configuration of concurrent CRT, particularly with respect to the scheduling of thoracic radiotherapy (TRT). 6 Several clinical trials aimed at tackling this issue have yielded discrepant outcomes. 7 , 8 , 9 , 10 , 11 , 12 , 13 Some studies have reported a survival benefit with early TRT, 7 , 9 , 13 whereas others have not. 8 , 10 , 11 , 12
Elderly patients constitute a unique demographic group due to their typically compromised overall health and reduced capacity to withstand rigorous treatment regimens. Therefore, we conducted a retrospective review of patients with LS‐SCLC who underwent CRT at our institution to highlight the importance of optimizing the combination of TRT with chemotherapy for improved treatment outcomes.
2. PATIENTS AND METHODS
2.1. Patient characteristics
In this retrospective study, elderly patients (aged ≥ 60 years) with LS‐SCLC who were initially diagnosed at the Weihai Municipal Hospital between January 1, 2016, and October 31, 2022, were enrolled. The definition of elderly was based on the World Health Organization criteria (2021 version). The inclusion criteria were as follows: (a) LS‐SCLC stage, (b) aged ≥ 60 years, and(c) availability of complete patients’ medical records. The exclusion criteria were as follows: (a) patients who did not receive TRT, (b) TRT administered in the disease progression, (c) radiotherapy underdose (radiation dose < 35 Gy), and (d) performance status (PS) score > 2. Neoplasm staging included computed tomography (CT) of the chest and abdomen, MRI of the head, and whole‐body bone scans.
2.2. Data extraction
Patient baseline characteristics, including sex, age, PS score, smoking status, family history of lung cancer, presence or absence of initial symptoms, fractionation, dose, and prophylactic cranial irradiation (PCI) were extracted using a standard data extraction system. Patients were categorized into three groups based on when TRT was initiated in relation to chemotherapy. Early TRT was defined as starting TRT after 1–2 rounds of chemotherapy, medium‐term TRT referred to commencing TRT after 3–4 cycles of chemotherapy, and late TRT indicated that TRT was administered after 5–6 chemotherapy sessions.
2.3. Treatment modalities
All patients received platinum‐based chemotherapy. Most patients preferred the etoposide (ETP) plus cisplatin (CDDP) scheme, and a small number utilize the etoposide plus carboplatin (CBDCA) scheme. The detailed chemotherapy regimen was CDDP (25 mg/m2 on days 1–3) and ETP (100 mg/m2 on days 1–3), or CBDCA (AUC = 5–6 on day 1) and ETP (100 mg/m2 on days 1–3) q3w for up to 4–6 cycles. The radiotherapy fractionation scheme was once‐daily (standard fractionation) or twice‐daily (hyperfractionated radiationtherapy) with 45 Gy in 30 fractions. The radiotherapy technique used was intensity modulated radiation therapy (IMRT).
2.4. Follow‐up
Follow‐up information was obtained directly from electronic medical record system documents or via telephone. Patient medical records, including sex, age, smoking history, family history of lung cancer, radiological imaging, pathological diagnosis, and treatment, were collected. The long‐term endpoints were progression‐free survival (PFS) and overall survival (OS). PFS was defined as the time elapsed from the date of pathological diagnosis to the date of the CT scan confirming disease progression. OS was defined as the interval between the date of pathological diagnosis and the time of death or last follow‐up day. Follow‐up was conducted until October 31, 2022.
2.5. Statistical analysis
Statistical analyses were performed using SPSS version 27.0. Univariate analyses of PFS and OS were performed for elderly patients based on prognostic factors. Variables with P‐value < 0.1 in univariate analysis were introduced into the Cox regression model. The Cox proportional hazards model was used for multivariate survival analysis to assess prognostic factors. Differences between proportions were tested using the Fisher's exact test. Survival curves were plotted using GraphPad Prism 9.4.1, and log‐rank test was used to analyze between‐group survival differences. All tests were two‐sided, and a P‐value < 0.05 was considered statistically significant.
3. RESULTS
3.1. Patient characteristics
Between January 2016 and October 2022, 78 elderly patients (aged ≥ 60 years) with LS‐SCLC treated at the Weihai Municipal Hospital met the criteria and were included in the final analysis. The median age of the patients was 66 years (range, 60 to 79 years). The majority were male (n = 62, 79.5%), had no family history of lung cancer (n = 70, 89.7%), were smokers (n = 48, 61.5%), had a PS score of 0–1 (n = 74, 94.9%), and had initial symptoms (n = 68, 87.2%). Of the patients, 52 (66.7%) had the comorbid conditions, with cardiovascular disease (30, 38.5%) being the most prevalent, followed by respiratory (20, 25.6%), and endocrine (10, 12.8%) diseases. In terms of treatment, 29 (37.2%), 33 (42.3%), and 16 (20.5%) received early, medium‐term, and late TRT, respectively. The majority of the fractionation scheme was once‐daily (standard fractionation). However, only a small proportion of the patients underwent PCI (n = 4, 5.1%). Further details regarding patient characteristics stratified based on TRT timing are listed in Table 1.
TABLE 1.
Patient characteristics stratified based on TRT timing in 78 patients aged ≥60 years with LS‐SCLC.
| Factors | 1–2 cycles | 3–4 cycles | 5–6 cycles | ||
|---|---|---|---|---|---|
| n (%) | n (%) | n (%) | χ2 | P‐value | |
| Sex | |||||
| Female | 3 (10.3) | 10 (30.3) | 3 (18.8) | 3.809 | 0.145 |
| Male | 26 (89.7) | 23 (60.7) | 13 (81.2) | ||
| Age (years) | |||||
| ≥ 60 and < 75 | 27 (93.1) | 31 (93.9) | 16 (100.0) | 1.11 | 0.574 |
| ≥ 75 | 2 (6.9) | 2 (6.1) | 0 | ||
| PS score | |||||
| 0 | 5 (17.2) | 3 (9.1) | 0 | 3.574 | 0.467 |
| 1 | 23 (79.3) | 28 (84.8) | 15 (93.8) | ||
| 2 | 1 (3.5) | 2 (6.1) | 1 (6.2) | ||
| Smoking | |||||
| Never | 10 (34.5) | 16 (48.5) | 4 (25.0) | 2.820 | 0.267 |
| Current/ever | 19 (65.5) | 17 (51.5) | 12 (75.0) | ||
| Family history | |||||
| No | 26 (89.7) | 31 (93.9) | 13 (81.2) | 1.970 | 0.440 |
| Yes | 3 (10.3) | 2 (6.1) | 3 (18.8) | ||
| Initial symptom | |||||
| No | 4 (13.8) | 5 (15.2) | 1 (6.2) | 0.698 | 0.825 |
| Yes | 25 (86.2) | 28 (84.8) | 15 (93.8) | ||
| Complication | |||||
| No | 10 (34.5) | 11 (33.3) | 5 (31.3) | 0.048 | 0.976 |
| Yes | 19 (65.5) | 22 (66.7) | 11 (68.7) | ||
| Respiratory | 6 (30.0) | 9 (45.0) | 5 (25.0) | ||
| Cardiovascular | 11 (36.7) | 14 (46.7) | 5 (16.6) | ||
| Digestive | 2 (66.7) | 1 (33.3) | 0 | ||
| Endocrine | 6 (60.0) | 2 (20.0) | 2 (20.0) | ||
| Respiratory | 3 (42.9) | 3 (42.9) | 1 (14.2) | ||
| Fractionation | |||||
| Once daily | 25 (86.2) | 30 (90.9) | 15 (93.8) | 0.667 | 0.796 |
| Twice daily | 4 (13.8) | 3 (9.1) | 1 (6.2) | ||
| Dose (Gy) | |||||
| 35–55 | 16 (55.2) | 16 (48.5) | 9 (56.2) | 0.387 | 0.837 |
| 56–70 | 13 (44.8) | 17 (51.5) | 7 (43.8) | ||
| PCI | |||||
| No | 26 (89.7) | 32 (97.0) | 16 (100.0) | 2.032 | 0.417 |
| Yes | 3 (10.3) | 1 (3.0) | 0 |
Abbreviations: LS‐SCLC, limited‐stage small cell lung cancer; PCI, prophylactic cranial irradiation; PS, performance status; TRT, thoracic radiotherapy.
3.2. TRT timing efficacy in elderly patients
A total of 78 patients were classified into three groups according to the timing of TRT.
Improvements in PFS and OS were associated with the use of TRT after 3–4 cycles of chemotherapy (Figure 1). The mPFS (20.12 months) and mOS (35.97 months) were longer in the mid‐term TRT group (PFS: P = 0.021; OS: P < 0.035) than in the other two groups. In the pairwise comparison among the three groups, those who received medium‐term TRT exhibited significant improvement in PFS than those with early TRT (mPFS: 20.12 vs. 10.36 months, P = 0.018) and late TRT (mPFS: 20.12 vs. 9.17 months, P = 0.016). The medium‐term TRT group showed a statistically significant improvement in OS compared with early TRT (mOS: 35.97 vs. 25.22 months, P = 0.007) but not with late TRT (mOS: 35.97 vs. 21.63 months, P = 0.100). The comparison of TRT timing efficacy is shown in Table 2.
FIGURE 1.
Kaplan–Meier curve of the PFS and OS in different TRT timing in 78 patients aged ≥ 60 with SCLC. (A) overall survival (OS); (B) progression‐free survival (PFS).
TABLE 2.
Comparison of TRT timing efficacy in 78 patients aged ≥ 60 years with SCLC.
| 1–2 cycles | 3–4 cycles | 5–6 cycles | χ2 | P‐value | |
|---|---|---|---|---|---|
| mPFS | 10.36 | 20.12 a | 9.17 b | 7.71 | 0.021 |
| mOS | 25.22 | 35.97 a | 21.63 | 6.68 | 0.035 |
Significant at P < 0.05 vs. 1–2 cycle group
Significant at P < 0.05 vs. 3–4 cycle group.
Abbreviations: OS: overall survival; PFS: progression‐free survival; SCLC, small cell lung cancer; TRT, thoracic radiotherapy.
3.3. Analysis of prognostic factors for PFS
In terms of disease characteristics, the univariable analysis showed that female sex (P = 0.015), never smoking (P = 0.049) and PS 0–1 score (P <0.001) were associated with longer PFS. Additionally, medium‐term TRT (P = 0.018 and P = 0.016, respectively) and PCI (mPFS: 26.93 vs. 12.13 moths, P = 0.179) were associated with prolonged PFS; however, the difference was not statistically significant for PCI. In the multivariable analysis, early versus medium‐term TRT (HR = 2.02; 95%CI:1.09–3.73; P = 0.018), late versus medium‐term TRT (HR = 2.04; 95%CI:1.04‐4.03; P = 0.016) and PS 2 versus 0 (HR = 17.78; 95%CI:4.12‐76.69; P < 0.001) were independent risk factors. The univariate and multivariate analyses of PFS is shown in Table 3.
TABLE 3.
Univariate and multivariate analyses of the PFS in 78 patients aged ≥ 60 years with LS‐SCLC.
| Factors | Univariate (Log‐rank) | Multivariate (COX) | ||
|---|---|---|---|---|
| mPFS (m) | P‐value | HR (95% CI) | P‐value | |
| Sex | ||||
| Female | 22.52 | – | 1 | – |
| Male | 10.49 | 0.015 | 2.31 (0.91–5.84) | 0.077 |
| Age (years) | ||||
| ≥ 60 and < 75 | 12.13 | – | – | – |
| ≥ 75 | 9.86 | 0.391 | – | – |
| PS score | ||||
| 0 | 14.56 | – | 1 | – |
| 1 | 12.16 | 0.518 | 1.68 (0.69–4.10) | 0.255 |
| 2 | 4.54 | <0.001 | 17.78 (4.12–76.69) | <0.001 |
| Smoking | ||||
| Never | 17.52 | – | 1 | – |
| Current/ever | 10.49 | 0.049 | 1.05 (0.52–2.13) | 0.895 |
| Family history | ||||
| No | 12.13 | – | – | – |
| Yes | 7.09 | 0.870 | – | – |
| Initial symptom | ||||
| No | 15.16 | – | – | – |
| Yes | 11.64 | 0.561 | – | – |
| Fractionation | ||||
| Once daily | 12.16 | – | – | – |
| Twice daily | 11.64 | 0.916 | – | – |
| Dose (Gy) | ||||
| 35–55 | 12.13 | – | – | – |
| 56–70 | 12.20 | 0.951 | – | – |
| PCI | ||||
| No | 12.13 | – | – | – |
| Yes | 26.93 | 0.179 | – | – |
| Timing | ||||
| 1–2 cycles | 10.36 | 0.018 | 2.02 (1.09–3.73) | 0.025 |
| 3–4 cycles | 20.12 | – | 1 | – |
| 5–6 cycles | 9.17 | 0.016 | 2.04 (1.03–4.03) | 0.041 |
Abbreviations: PCI, prophylactic cranial irradiation; PFS, progression‐free survival; PS, performance status.
3.4. Analysis of prognostic factors for OS
Regarding disease characteristics, the univariable analysis showed that male sex (P = 0.082) and initial symptoms (P = 0.066) were associated with shorter OS. Regarding treatments, the univariable analysis showed that hyperfractionated radiotherapy (mPFS: 44.12 vs. 25.22 months, P = 0.339) was associated with prolonged OS; however, the difference was not statistically significant. The multivariate analysis indicated that early versus medium‐term TRT (HR: 2.03; 95%CI:1.03–4.02; P = 0.041) was an independent risk factor. The univariate and multivariate analyses of the OS is shown in Table 4.
TABLE 4.
Univariate and multivariate analyses of the OS in 78 patients aged ≥ 60 years with LS‐SCLC.
| Factor | Univariate (Log‐rank) | Multivariate (COX) | ||
|---|---|---|---|---|
| mOS(m) | P‐value | HR (95% CI) | P‐value | |
| Sex | ||||
| Female | – | – | 1 | – |
| Male | 25.22 | 0.082 | 1.89 (0.81–4.40) | 0.140 |
| Age (years) | ||||
| ≥ 60 and < 75 | 25.22 | – | ||
| ≥ 75 | 35.90 | 0.636 | ||
| PS score | ||||
| 0 | 29.03 | – | – | – |
| 1 | 25.61 | 0.413 | 1.85 (0.70–4.86) | 0.214 |
| 2 | 7.79 | 0.039 | 2.70 (0.71–10.27) | 0.146 |
| Smoking | ||||
| Never | 31.20 | – | – | – |
| Current/ever | 25.22 | 0.375 | – | – |
| Family history | ||||
| No | 26.70 | – | – | – |
| Yes | 22.92 | 0.314 | – | – |
| Initial symptom | ||||
| No | 59.61 | – | 1 | – |
| Yes | 25.22 | 0.066 | 2.60 (0.92–7.35) | 0.073 |
| Fractionation | ||||
| Once daily | 25.22 | – | – | – |
| Twice daily | 44.12 | 0.339 | – | – |
| Dose(Gy) | ||||
| 35–55 | 25.61 | – | – | – |
| 56–70 | 25.68 | 0.940 | – | – |
| PCI | ||||
| No | 25.61 | – | – | – |
| Yes | 31.60 | 0.498 | – | – |
| Timing | ||||
| 1–2 cycles | 25.22 | 0.007 | 2.03 (1.03–4.02) | 0.041 |
| 3–4 cycles | 35.97 | – | 1 | – |
| 5–6 cycles | 21.63 | 0.100 | 1.78 (0.84–3.79) | 0.136 |
Abbreviations: LS‐SCLC, limited‐stage small cell lung cancer; OS, overall survival; PCI, prophylactic cranial irradiation; PS, performance status.
3.5. Adverse events
Among these patients, the common grades 1–2 treatment‐related adverse events (TRAEs) were bone marrow suppression (n = 17, 21.8%) and gastrointestinal reactions (n = 15, 19.2%). The incidences of bone marrow suppression (10.3% vs. 7.7% vs. 3.8%) and gastrointestinal reactions (8.9% vs. 5.1% vs. 5.1%) were comparatively higher in the early TRT group. Other grades 1–2 TRAEs included airway mucosal reactions (n = 15, 19.2%), radioactive dermatitis (n = 3, 3.8%), and radiation pneumonia (n = 5, 5.1%). TRAEs of grade 3 and above included bone marrow suppression (n = 19, 24.4%), gastrointestinal reactions (n = 2, 2.6%), and radiation pneumonia (n = 1, 1.3%). A comparison of adverse events is shown in Table 5.
TABLE 5.
Adverse events in 78 patients aged ≥ 60 years with SCLC.
| Adverse Events | Grades 1–2, n(%) | Grade≥3, n(%) | ||||
|---|---|---|---|---|---|---|
| 1–2 cycles | 3–4 cycles | 5–6 cycles | 1–2 cycles | 3–4 cycles | 5–6 cycles | |
| Bone marrow suppression | 8 (10.3) | 6 (7.7) | 3 (3.8) | 9 (11.5) | 8 (10.3) | 2 (2.5) |
| Gastrointestinal reaction | 7 (8.9) | 4 (5.1) | 4 (5.1) | 0 | 1 (1.3) | 1 (1.3) |
| Airway mucosal reaction | 2 (2.5) | 4 (5.1) | 1 (1.3) | 0 | 0 | 0 |
| Radioactive dermatitis | 0 | 2 (2.5) | 1 (1.3) | 0 | 0 | 0 |
| Radiation pneumonia | 1 (1.3) | 1 (1.3) | 2 (2.5) | 1 (1.3) | 0 | 0 |
4. DISCUSSION
SCLC is a highly malignant neuroendocrine tumor prone to extensive metastasis. 14 The treatment regimen has not changed significantly over the years, and the standard regimen includes 4–6 cycles of cisplatin and etoposide chemotherapy (EP) with TRT, followed by PCI. However, the optimal timing of radiotherapy has not yet been determined. A key finding of this study was the association between TRT timing and survival, which favored medium‐term TRT. Compared with the other two groups, the mPFS (20.12 months) and mOS (35.97 months) were longer in the mid‐term TRT group (PFS: P = 0.021;OS: P = 0.035) than in the other two groups. Meanwhile, medium‐term TRT was an independent prognostic factor in multivariate analysis for PFS and OS.
Several randomized trials 11 , 15 , 16 and meta‐analyses 17 , 18 , 19 have evaluated the effects of the timing of TRT on the survival of patients with LS‐SCLC. In a retrospective analysis evaluating the impact of 1–2 cycles of chemotherapy followed by early TRT or 3–6 cycles of chemotherapy followed by late TRT on survival in patients with LS‐SCLC, the 3‐year OS rate was superior for late TRT (31%) than for early TRT (17%). 15 The CALGB 8083 study divided patients with LS‐SCLC into early radiotherapy (day 1 of chemotherapy) and late radiotherapy (day 64 of chemotherapy) groups. The results showed that the mOS in the late TRT group was better than that in the early TRT group (14.54 vs. 13.04 months). 11 In addition, Sun et al. 16 conducted a phase III trial of TRT with concurrent first or third cycle chemotherapy and showed no significant difference in mOS (24.1 vs. 26.8 months) and PFS (12.4 vs. 11.2 months) between early and late TRT groups. However, multiple meta‐analyses have shown that early TRT improves patients'survival. 17 , 18 , 19
Although most guidelines and practice patterns recommend initiating TRT after the first or second cycle of chemotherapy, no consensus has been reached in studies involving older patients. 3 , 20 , 21 Elderly patients may experience greater toxicity due to severe comorbidities, polypharmacy, functional limitations, or reduced organ function, resulting in their exclusion from clinical trials. 21 , 22 , 23 Our study retrospectively analyzed the optimal timing of radiotherapy in elderly patients and found that after the start of first‐line chemotherapy, TRT can prolong PFS and OS in elderly patients with LS‐SCLC. Initiating TRT after 3–4 cycles has significant prognostic benefits. Compared to the addition of radiotherapy after 1–2 cycles of chemotherapy, the tumor shrinkage effect after 3–4 cycles of chemotherapy is more conducive for radiotherapy intervention. This may be related to the physiological changes in organ function and aging in elderly patients, which may alter the pharmacokinetics of drugs and affect their tolerance to cytotoxic chemotherapy. 24 Meanwhile, the dose distribution becomes more precise and the incidence of radiation pneumonitis is lowered by reducing the target area. In contrast, compared to the addition of radiotherapy after 5–6 cycles of chemotherapy, 3–4 cycles of chemotherapy is more favorable for patient survival. This may be attributed to the shorter duration for the development of resistant tumor clones after initiating systemic therapy, suggesting that earlier TRT could potentially yield better results. 25
Our study has several strengths, including the classification of the timing of TRT into three groups (early, medium‐term, and late TRT), with medium‐term TRT defined as initiating with 3–4 cycles of chemotherapy. Moreover, since elderly patients are often excluded from study designs due to their generally poor condition and low tolerance, we retrospectively analyzed elderly patients aged ≥60 years to facilitate the selection of optimal timing of TRT in this population. However, this study has some limitations. First, this was a single‐center study with a small number of patients. Second, the number of patients aged > 75 years was relatively small. Finally, the retrospective nature of the study led to a partial loss of objectivity, and the treatments were not randomized. In the future, more prospective or retrospective studies with larger sample sizes should be conducted to confirm the accuracy of these results.
5. CONCLUSIONS
Initiating TRT after–3–4 cycles of chemotherapy may be an acceptable regimen for elderly patients with LS‐SCLC. However, additional cohort and randomized controlled trials are required to improve the sample size and increase the reliability of the results.
CONFLICT OF INTEREST STATEMENT
All the authors declare that they do not have any conflicts of interest in this work.
ETHICS STATEMENT
Retrospective analysis was performed using data from Weihai Municipal Hospital. A written patient consent form was waived due to the retrospective nature.
ACKNOWLEDGMENTS
This research was supported by funding from Medical and Health Technology Development Program in Shandong Province (202203100273).
Zhao H, Qi Y, Zhang L, Xing M, Yang F. Thoracic radiotherapy timing and prognostic factors in elderly patients with limited‐stage small cell lung cancer. Prec Radiat Oncol. 2024;8:14–21. 10.1002/pro6.1223
Huan Zhao, Yue Qi and Lanfang Zhang Contributed equally.
REFERENCES
- 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small‐cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539‐4544. [DOI] [PubMed] [Google Scholar]
- 2. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol. 2007;25(35):5570‐5577. [DOI] [PubMed] [Google Scholar]
- 3. Ganti AKP, Loo BW, Bassetti M, et al. Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(12):1441‐1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited‐stage small‐cell carcinoma of the lung? A meta‐analysis. J Clin Oncol. 1992;10(6):890‐895. [DOI] [PubMed] [Google Scholar]
- 5. Pignon JP, Arriagada R, Ihde DC, et al. A meta‐analysis of thoracic radiotherapy for small‐cell lung cancer. N Engl J Med. 1992;327(23):1618‐1624. [DOI] [PubMed] [Google Scholar]
- 6. Barros JM, Rizzo MM, Chiozza JO, Couñago F. Is there a place for optimizing thoracic radiotherapy in limited‐stage small cell lung cancer after twenty years? World J Clin Oncol. 2021;12(1):1‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited‐stage small‐cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002;20(14):3054‐3060. [DOI] [PubMed] [Google Scholar]
- 8. Work E, Nielsen OS, Bentzen SM, Fode K, Palshof T. Randomized study of initial versus late chest irradiation combined with chemotherapy in limited‐stage small‐cell lung cancer. Aarhus Lung Cancer Group. J Clin Oncol. 1997;15(9):3030‐3037. [DOI] [PubMed] [Google Scholar]
- 9. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited‐stage small‐cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1993;11(2):336‐344. [DOI] [PubMed] [Google Scholar]
- 10. Gregor A, Drings P, Burghouts J, et al. Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited‐disease patients with small‐cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study. J Clin Oncol. 1997;15(8):2840‐2849. [DOI] [PubMed] [Google Scholar]
- 11. Perry MC, Herndon JE 3rd, Eaton WL, Green MR. Thoracic radiation therapy added to chemotherapy for small‐cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol. 1998;16(7):2466‐2467. [DOI] [PubMed] [Google Scholar]
- 12. Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small‐cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2001;12(9):1231‐1238. [DOI] [PubMed] [Google Scholar]
- 13. Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small‐cell lung cancer: a randomized study. J Clin Oncol. 1997;15(3):893‐900. [DOI] [PubMed] [Google Scholar]
- 14. Yang FJ, Zhao H. Progress in radiotherapy for small‐cell lung cancer.Prec Radiat Oncol.2023;7(3):207‐217 [Google Scholar]
- 15. Bayman E, Etiz D, Akcay M, Ak G. Timing of thoracic radiotherapy in limited stage small cell lung cancer: results of early versus late irradiation from a single institution in Turkey. Asian Pac J Cancer Prev. 2014;15(15):6263‐6267. [DOI] [PubMed] [Google Scholar]
- 16. Sun JM, Ahn YC, Choi EK, et al. Phase III trial of concurrent thoracic radiotherapy with either first‐ or third‐cycle chemotherapy for limited‐disease small‐cell lung cancer. Ann Oncol. 2013;24(8):2088‐2092. [DOI] [PubMed] [Google Scholar]
- 17. Huncharek M, McGarry R. A meta‐analysis of the timing of chest irradiation in the combined modality treatment of limited‐stage small cell lung cancer. Oncologist. 2004;9(6):665‐672. [DOI] [PubMed] [Google Scholar]
- 18. Pijls‐Johannesma MC, De Ruysscher D, Lambin P, Rutten I, Vansteenkiste JF. Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev. 2005;2004(1):CD004700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. De Ruysscher D, Lueza B, Le Péchoux C, et al. RTT‐SCLC Collaborative Group . Impact of thoracic radiotherapy timing in limited‐stage small‐cell lung cancer: usefulness of the individual patient data meta‐analysis. Ann Oncol. 2016;27(10):1818‐1828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Simone CB 2nd, Bogart JA, Cabrera AR, et al. Radiation Therapy for Small Cell Lung Cancer: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2020;10(3):158‐173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Chun SG, Simone CB 2nd, Amini A, et al. American Radium Society Appropriate Use Criteria: Radiation Therapy for Limited‐Stage SCLC 2020. J Thorac Oncol. 2021;16(1):66‐75. [DOI] [PubMed] [Google Scholar]
- 22. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer‐treatment trials. N Engl J Med. 1999;341(27):2061‐2067. [DOI] [PubMed] [Google Scholar]
- 23. McMurdo ME, Roberts H, Parker S, et al. Comprehensive Clinical Research Network. Improving recruitment of older people to research through good practice. Age Ageing. 2011;40(6):659‐665. [DOI] [PubMed] [Google Scholar]
- 24. Pallis AG, Shepherd FA, Lacombe D, Gridelli C. Treatment of small‐cell lung cancer in elderly patients. Cancer. 2010;116(5):1192‐2000. [DOI] [PubMed] [Google Scholar]
- 25. Bogart JA, Waqar SN, Mix MD. Radiation and Systemic Therapy for Limited‐Stage Small‐Cell Lung Cancer. J Clin Oncol. 2022;40(6):661‐670. [DOI] [PMC free article] [PubMed] [Google Scholar]