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

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 development 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 proportion 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 becoming 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 cranial irradiation (PCI) for those who respond to chemoradiotherapy (CRT).^7,8 However, many clinical studies on LD-SCLC have precluded the enrollment 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 concurrent TRT are more effective for the treatment of LD-SCLC than a cisplatin plus etoposide combination and sequential TRT¹¹; however, it is noteworthy 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 hematological 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 survival rate were not significantly different between these two subgroups, there was a trend for them to be worse in older patients. Notably, a significant 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 treatment 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 mentioned above, older patients with LD-SCLC aged ≥ 75 years are excluded from clinical trials¹¹ or studies focusing on patients aged ≥ 75 years are scarce. Thus, the aim of our analysis was to retrospectively 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 compliance, treatment efficacy, and toxicity between patients who underwent concurrent and sequential CRT.

This retrospective study assessed the efficacy and safety of CRT in older patients with LD-SCLC. Concurrent and sequential CRT groups demonstrated similar efficacy in the treatment of older patients with LD-SCLC; however, the toxicity profiles 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 retrospective studies specifically focused on older patients with LD-SCLC have shown conflicting results regarding the survival benefits and tolerability of CRT.^{16,17,18,19,20,21,22,23,24,25,26,27} In the CONVERT trial, Christodoulou et al. reported the treatment outcomes of a subgroup of patients aged ≥ 70 years with LD-SCLC compared to those of younger patients.²⁶ Concurrent CRT was found to be feasible in selected, fit older patients with LD-SCLC. Findings of previous studies on CRT in older patients with LD-SCLC are 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 satisfactory.^{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 studies 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 study^18,20,23, both with small numbers of cases; Table 5). A comparison of toxicities between concurrent and sequential 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. reported that in the sequential CRT group, Grade 3 or higher neutropenia, thrombocytopenia, febrile neutropenia, and pneumonia were relatively common, which may have been influenced by the chemotherapeutic regimen of cisplatin and topotecan 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 leukopenia, neutropenia, and thrombocytopenia.

In our study, the major adverse events in the concurrent CRT group were hematological toxicities, including decreased white blood cell and neutrophil counts. Gastrointestinal toxicities, including anorexia, nausea, vomiting, and constipation, were relatively mild. However, Grade 3 or higher infection and pneumothorax occurred in three (15.8%) and two (10.5%) patients, respectively. Moreover, there was one treatment-related death. The main adverse events in the sequential CRT group were hematologic toxicities, including 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 hematocytopenia, 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 administration of G-CSF in 27 of 32 patients (84.3%), more than 70% of the total patient, 78.9% of patients 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 prophylactically during chemotherapy and not during radiotherapy. Neutrophil count decrease occurred at high rate, but febrile neutropenia occurred in 9.4% of overall patients. Although routine prophylactic administration of G-CSF is not usually recommended, clinical guidelines recommend that patients with risk factors for febrile neutropenia who are treated with chemotherapeutic regimens associated with a ≥ 20% risk of febrile neutropenia should be administered G-CSF as primary prophylaxis.^28,29 Routine prophylactic administration of G-CSF during chemotherapy in CRT in older patients with LD-SCLC is not recommended. However, one report suggests considering primary 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 factor for febrile neutropenia.³⁰ Primary prophylaxis with G-CSF may be considered aggressively during chemotherapy in certain situations.

However, it should be noted that when evaluating toxicity, the criteria for determining the Grade of adverse events may not be consistent across different studies. Table 5 shows that treatment discontinuation mainly occurred owing to failure to complete chemotherapy. In studies evaluating concurrent 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 chemotherapy owing to toxicity and 1 discontinued TRT. Of the 13 patients who received sequential CRT, one did not complete a full cycle of chemotherapy owing 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 concurrent CRT and frail patients were treated with sequential CRT. Therefore, as our findings suggest, 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 severe pneumonitis occurred in 2/32 patients (6.3%) in our study. To reduce the frequency and severity 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 toxicity 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 enrolled from 2007–2021, during which time improvements 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, approximately half of the patients who relapsed received subsequent chemotherapy. Kasahara et al. reported that treatments administered after first-line CRT might affect OS.³⁵ In this study, two patients 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 impact 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 depends on subjective physician examinations, leading 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 interpreting our data. In particular, the severity of non-hematological adverse events may have been underestimated owing to the retrospective nature of this study. Third, patients were treated as inpatients for most of the treatment duration, and data on treatment toxicities were recorded in detail in the patients’ medical records. This exploratory 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 helpful 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 sequential 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 patients with LD-SCLC.