In this study, we examined the relationship between OS and the occurrence of severe CIN to identify prognostic factors for patients with ED-SCLC that were treated with standard IP or EP as first-line therapy. A multivariate analysis revealed that pretreatment LDH levels ≥ 245 and grade 4 CIN were two significant independent factors that influenced the OS of patients treated with IP. LDH has long been reported to be a prognostic factor in solid tumors and it has also been reported to be a prognostic factor in SCLC. This finding was consistent with the results of the current study and confirmed LDH as an important prognostic factor. We also showed that in addition to LDH, the occurrence of severe CIN was an independent factor affecting the prognosis of patients with ED-SCLC treated with IP.
In recent years, an integrated analysis of 6 randomized clinical trials in non-SCLC revealed that the occurrence of severe CIN has a positive impact on prognosis. CIN is not just an adverse event, but may serve as a marker of improved patient outcome. The development of grade 4 neutropenia in patients treated with IP was also associated with longer OS in our study. Although the detailed mechanism of the association between the development of severe CIN and favorable prognosis is unclear, it is believed that the hematological toxicity associated with the administration of cytotoxic drugs may be a surrogate marker for the biological activity of anticancer drugs. Since hematologic toxicity, such as neutropenia, is a dose-dependent adverse event, patients who do not develop CIN may have received inadequate doses of the anticancer drugs or may be resistant to treatment. Currently, the dose of anticancer drugs is administered to the patient based on body surface area (BSA) or creatinine clearance, however, it has been suggested that BSA-based dosing calculations may be inadequate. In two randomized trials of gastric and breast cancer, a trend toward improved progression-free and recurrence-free survival were observed in the latter group compared with the BSA-based dosing chemotherapy group and the group in which the dose of anticancer drugs was adjusted based on the incidence of adverse reactions, such as CIN. Although no studies have been conducted in SCLC, this retrospective study revealed that grade 4 CIN may be an indicator of IP response. In other words, low grade CIN results from an underdose of IP therapy, and prognosis may be improved by increasing the dose of the anticancer drugs. However, there is currently insufficient evidence for dose escalation for IP therapy in patients with SCLC, thus it is necessary to conduct prospective clinical trials to evaluate dose escalation and safety.
In contrast, there was no association between the development of CIN and prolonged survival in patients who received EP therapy as opposed to IP therapy. A high incidence of grade 3 or higher CIN was associated with EP therapy (92.2%) in a phase III trial of Japanese patients with ED-SCLC. In the present study, we found that grade 3 or higher CIN occurred more frequently in the EP therapy (87.2%) group, in particular, 61.7% of the patients had grade 4 CIN. The incidence of FN in the group of patients who received EP therapy was 19.1% (9/47), which was higher compared with that of patients who received IP therapy (4.9%, 5/102). Thus, the occurrence of FN may have had a significant effect as a poor prognostic factor in patients treated with EP. In fact, the MST was 473 days (95% CI, 371–599) for the group without FN and 367 days (95% CI, 219–443) for the group with FN (log-rank, P = 0.040).
To our knowledge, there have been no studies on the relationship between the occurrence of CIN and ED-SCLC patient survival. This study showed for the first time that the occurrence of CIN is not associated with prognosis following EP therapy and the development of severe CIN is associated with a favorable prognosis following IP therapy. Irinotecan is converted to its active metabolite, SN-38, by carboxylesterases. SN-38 is inactivated and excreted into the bile by glucuronidation, which is catalyzed by UDP-glucuronosyltransferases. Since irinotecan and SN-38 are both substrates for the ABC transporters, polymorphisms in these transporter genes may affect the pharmacokinetics of irinotecan and irinotecan-associated toxicity. The association between the development of CIN and polymorphisms in the UGT1A1 and ABCB1 genes is becoming clearer.[26–28] It is anticipated that the prediction of response to IP therapy will be possible by examining these genetic polymorphisms prior to chemotherapy.
Recently, a three-drug combination chemotherapy regimen consisting of platinum and etoposide plus an immune checkpoint inhibitor (ICI) has been recommended as a standard regimen for ED-SCLC. The results of two phase III trials indicated the efficacy of triplet chemotherapy with atezolizumab or durvalumab, showing a median OS time of 12.3 and 12.9 months, respectively, for patients treated with ICIs., The median OS of all patients treated with IP in this study was 423 days (approx.14.1 months), whereas the median OS of patients who developed grade 4 CIN was 555 days (approx. 18.5 months). Although a simple comparison cannot be made, the median survival time of patients treated with IP therapy is comparable to that of combined therapy with platinum, etoposide, and ICI. Moreover, there appears to be a clear trend toward improved median survival time, particularly in patients who developed grade 4 CIN. Combination chemotherapy regimens with ICI and anticancer drugs have been implemented worldwide for multiple cancer types, however, combination therapy with atezolizumab or durvalumab has been estimated to be less cost effective compared with conventional chemotherapeutic regimens for first-line treatment of patients with ED-SCLC., In addition, biomarkers for predicting the effect of ICIs, such as PD-L1 expression and tumor mutational burden, have not been established in ED-SCLC. Therefore, the selection of responders may be an important therapeutic strategy in conventional chemotherapy, in which the cost of treatment is relatively low.
There are several limitations to the current study. First, this was a retrospective study and the sample size was not determined. Also, the patients were Japanese and it has been suggested that there are differences in the development of CIN based on race. Thus, the findings of this study may not be applicable to patients in other countries or regions of Japan. Despite these limitations, the results of this study are important because they are the first to show that the occurrence of severe CIN with IP therapy is a prognostic factor for ED-SCLC and revealed that median OS is extremely long in patients exhibiting severe CIN.