In the present population-based study, we investigated the efficacy of definite CCRT using real-world data for patients with LD-SCLC. The results revealed that the survival outcomes patients who received EP-CCRT were better than those patients who received IP-CCRT. As second-line treatment in cases of CCRT failure or progression during treatment, the EP regimen resulted in better OS than did the IP regimen; however, the IP regimen was more effective in patients with PFS of <6 months after CCRT, i.e., platinum-resistant relapsed patients. This study provides evidence that the EP combination should be the gold standard for CCRT in Korean patients with LD-SCLC. To the best of our knowledge, this analysis included the largest study population till date.
Previous studies have provided sufficient evidence for the advantages of the EP regimen over other regimens for CCRT [2, 5, 9]. EP-based chemotherapy, combined with concurrent thoracic radiotherapy, has been considered the standard of care for patients with LD-SCLC, with lesser toxic effects on intrathoracic organs and the ability for radiosensitization [9]. Previous randomized trials have suggested that concurrent thoracic radiotherapy and EP-based chemotherapy is better than older regimens such as doxorubicin-based or cyclophosphamide-based ones [9, 18]. Despite a better response to chemotherapy alone, doxorubicin-based or cyclophosphamide-based CCRT showed a median OS period of just 15 months in patients with LD-SCLC. These unsatisfactory results may be partially attributed to significant toxic effects such as more myelosuppression, weight loss, esophagitis, and pulmonary dysfunction [9, 19, 20].
In a recent randomized trial including a Korean population, IP-based chemotherapy had significantly favorable effects on survival outcomes when compared to EP-based chemotherapy for previously untreated ED-SCLC [17]. Similar findings were reported in a meta-analysis of six trials involving 1,476 patients [21]. In addition to having cytotoxic effects on SCLC, irinotecan is known to be a potent radiosensitizing agent [22], and the IP combination has been adopted as the chemotherapy regimen in CCRT for LD-SCLC. Although it has been shown that IP-based chemoradiotherapy is effective and tolerable in Asian and Western populations, there has been no direct comparison between EP-CCRT and IP-CCRT. Table 3 summarizes the results of previous studies on EP-CCRT and IP-CCRT for LD-SCLC. In a nutshell, the efficacy of IP-CCRT was comparable to that of EP-CCRT in patients with untreated LD-SCLC. The results of phase II trials showed that median survival with IP-based CCRT was 12.4–44.5 months, which was comparable to the survival time with EP-CCRT; however, there were considerable discrepancies in results among different studies [4, 8, 10-15, 23]. In a phase II study in Japan, IP-based chemotherapy with concurrent split-course radiotherapy showed a remarkable survival benefit, with a median time to progression of 14.5 months and a median OS duration of 44.5 months [11]. However, in a phase II trial in Korean patients with LD-SCLC, median OS was 20.0 months, with 1-year and 2-year OS rates of 85% and 35%, respectively [23]. Similarly, in a western phase II trial, the overall radiographic response rate was 67%, median OS was 19 months, and the 1-year and 2-year OS rates were 60% and 44%, respectively [10].
However, these substantial differences in efficacy among studies on IP-based CCRT may be explained by differences in the timing of radiotherapy and its optimal dose, fractionation of thoracic radiotherapy, and consolidation chemotherapy. Pneumonitis and neutropenia were the main toxicities caused by IP-CCRT. Of note, pneumonitis is an important problem associated with IP-based chemoradiotherapy [20]. A study by Ohe et al. showed that pulmonary fibrosis identified on plain chest X-rays was a very strong risk factor for thoracic radiotherapy-related death [19], and that CCRT-related deaths occurred in 25 of 926 (2.7%) patients, including seven (28%) with radiation pneumonitis [19]. In the real-world setting, the rate of poor prognostic factors, the proportion of elderly patients, or the presence of comorbidities may be higher. Furthermore, patient compliance may be poorer, and routine medical practice may differ from protocol-specific patient care provided in clinical trials [24]. In the present study, patients who received EP-CCRT showed significantly better PFS and OS than did those who received IP-CCRT. Thus, treatment-related toxicities, including pulmonary toxicities, may have an unfavorable impact on the patients’ clinical outcomes. Taken together, the EP regimen should be strongly considered as a concurrent chemotherapeutic regimen in definite CCRT for LD-SCLC.
Recently, Horn et al. demonstrated better PFS and OS when atezolizumab was added to chemotherapy for ED-SCLC than when only chemotherapy was used (OS, 12.3 vs. 10.3 months; PFS, 5.2 vs. 4.3 months) [6]. Of note, xenograft models have proved the synergistic effects of radiotherapy with immune checkpoint inhibitors [25], which are expected to have promising clinical efficacy through low toxicity and abscopal effects in several ongoing studies [NCT03811002, NCT02402920] regarding LD-SCLC.
Concerning the strategy of using cytotoxic chemotherapy as a second-line treatment for LD-SCLC, there is no consensus on the most effective regimen. In the present study, patients who received combination chemotherapy as a second-line treatment showed significantly better OS than did those who received single agents as second-line treatment; this finding is consistent with that of a previous study [26]. Multi-agent chemotherapy has historically demonstrated response rates higher than those shown by single-agent chemotherapy in cases of relapsed SCLC. However, these better rates have often been achieved with an increase in toxicities. A recent Japanese phase III trial demonstrated the superiority of the cisplatin, irinotecan, and etoposide combination over topotecan alone as a second-line regimen for platinum-sensitive relapsed SCLC (OS: 18.2 vs. 12.5 months, HR: 0.67, 95% CI: 0.51–0.88; P = 0.0079) [26]. However, it has been emphasized that this combination should be administered only in select patients, such as those with platinum-sensitive relapsed SCLC, because of associated toxicities.
Clinically, the differentiation of platinum-sensitive and platinum-resistant SCLC patients is essential. Although there are some reports about the association between the platinum sensitivity status and clinical outcomes in patients with relapsed SCLC, the role of the platinum sensitivity status remains controversial [27]. In a previous study, cross-administration of chemotherapy was effective in the platinum-resistant relapsed group [27]. In the present analysis, we could confirm that IP-based chemotherapy resulted in better OS than did EP-based chemotherapy in platinum-resistant relapsed patients, defined by PFS of <6 months after CCRT.
Poor prognostic factors for patients with LD-SCLC included older age, the male sex, the absence of hypercholesterolemia, and the use of IP-CCRT as definite treatment. There are many conflicting reports about the prognostic role of lipidemia in cancer patients. Some studies have shown that malignant aerobic glycolysis, or the Warburg effect, leads to efficient biomass synthesis, including lipid synthesis, which is required for malignant cell proliferation [28]. In contrast, adipose tissue modulates the storage of extrinsic potential carcinogens such as benzo(a)pyrene, which induces DNA adduct formation and prevents the accumulation of carcinogen-DNA adducts in target organs, resulting in reduced cancer risk [29]. Hypocholesterolemia is often observed in patients with advanced-stage cancer, probably because of increased demand for cholesterol by neoplastic cells, which results in increased low-density lipoprotein cholesterol removal. This dynamicity is involved in the prognosis of SCLC, regulating the metabolism of lipids as dynamic organelles [30].
This study has several limitations that must be considered when interpreting the results. First, several potential information biases might exist. The HIRA data were retrospectively analyzed, and there was no information regarding the radiation dose, chemotherapy dose intensity, frequency of adverse treatment-related reactions, and causes of death. Second, identification of LD-SCLC or ED-SCLC patients as per the operational definition may be associated with bias. However, to overcome such bias, we used a strict multistep approach, and the Kaplan–Meier curves for LD-SCLC and ED-SCLC showed results similar to those in recent studies. Moreover, the clinical implications were validated through single-institute pooled analysis.
The results of this study suggest that the effects of EP-CCRT on OS and PFS are significantly more favorable than those of IP-CCRT in Korean patients with LD-SCLC. In cases where CCRT fails, combination chemotherapy provides a better survival benefit than does single-agent chemotherapy. Moreover, in CCRT failure cases with PFS of <6 months (platinum-resistant relapsed patients), IP-based chemotherapy has significantly better effects on OS and PFS than does EP-based chemotherapy.