Comparison of irinotecan/platinum versus etoposide/platinum chemotherapy for extensive-stage small cell lung cancer: A meta-analysis

Han, Dong; Wang, G.; Li, Sun; Ren, Xin; Shang, W.; Xu, Li‐Yan; Li, S.

doi:10.1111/ecc.12723

Cited by 22 publications

(24 citation statements)

References 18 publications

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“…[4] However, discrepancies exist in the comparative efficacy of these treatments: recent meta-analyses of randomized controlled trial (RCT) data have shown that platinum chemotherapy in combination with irinotecan increases overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and 1-year survival in ED-SCLC, compared to platinum/etoposide regimens. [8, 9] In contrast, a similar meta-analysis did not report any ORR or disease control rate improvements with the same regimen, providing little conclusive data on the clear superiority of one treatment over the others. [10] Despite these results, the survival benefit reported in RCTs remains modest regardless of the treatment type used.…”

Section: Introductionmentioning

confidence: 99%

Real-world effectiveness and tolerability of small-cell lung cancer (SCLC) treatments: A systematic literature review (SLR)

et al. 2019

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Objectives SCLC makes up approximately 15% of all lung carcinomas and is characterized by relatively aggressive spread and poorer prognosis compared to other lung cancers. Treatment options are limited, and their efficacy in randomized trials is poor, whilst outcomes in clinical practice remain unclear. The aim of this study was to assess the real-world effectiveness and tolerability of SCLC treatments. Methods An SLR was conducted across nine databases accessed through OVID, capturing observational, non-randomized studies published between 01/2006–11/2018. In total, 554 abstracts were retrieved and systematically screened for eligibility. The eligible publications included effectiveness and tolerability data from adult SCLC patients (at any line of therapy). Additional grey literature searches were conducted. Results Forty-three publications were included in this review—data from first-line therapies were captured most often (n = 32), while data from second (n = 14) and third line (n = 7) and beyond (n = 7) were less frequent. The publications reported primarily on chemotherapy/radiotherapy. The majority of publications lacked robustness and only 14/43 conducted statistical analyses or controlled for bias. Median OS for the largest SCLC populations were 9.6 months at first line (n = 23,535) and 4.9 months at second line (n = 254) for treatment with chemotherapy, and 4.7 months at third line (n = 120) for predominantly platinum-based chemotherapy or cyclophosphamide/adriamycin/vincristine. Hematologic toxicities (such as neutropenia, thrombocytopenia and anemia) were the most frequently reported TRAEs (n = 9). Conclusions Real-world treatment effectiveness and tolerability data were fragmented and inconsistently reported, and available publications were primarily of poor quality and lacked statistical analyses. This SLR showed limited treatment options and poor OS in SCLC, with no treatment option being clearly superior. TRAEs additionally increased the burden of this already challenging disease. Recent data suggest real-world outcomes are even poorer that those reported in clinical trials, and that novel therapies are needed to offer new treatment options for patients.

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Section: Introductionmentioning

confidence: 99%

Real-world effectiveness and tolerability of small-cell lung cancer (SCLC) treatments: A systematic literature review (SLR)

et al. 2019

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“…Irinotecan, a topoisomerase 1 inhibitor, is a chemotherapeutic agent widely used for the treatment of a variety of cancers, including small cell lung cancer, gastrointestinal cancer, and breast cancer [ 8 – 11 ]. However, the role of irinotecan in the tumor–immunity cycle has not yet been investigated and there are few clinical studies evaluating the combination of irinotecan with PD-L1/PD-1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Iwai¹,

Sugimoto²,

Wakita³

et al. 2018

Oncotarget

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Anti-PD-L1 antibodies inhibit interactions between PD-L1 and PD-1 and interactions between PD-L1 and B7-1, thereby reinvigorating anticancer immunity. Although there are numerous ongoing clinical studies evaluating combinations of standard chemotherapies and anti-PD-L1 antibodies, irinotecan has not yet been investigated in this context so there is little information about its compatibility with anti-PD-L1 antibodies. Here we investigated the efficacy of anti-PD-L1 antibody in combination with irinotecan and the role of irinotecan in the tumor–immunity cycle in an FM3A murine tumor model. Despite a transient decrease in lymphocytes in the peripheral blood after irinotecan treatment, the antitumor activity of anti-PD-L1 antibody plus irinotecan was significantly greater than each agent alone. Irinotecan in combination with anti-PD-L1 antibody enhanced proliferation of CD8+ cells in both tumors and lymph nodes, and the number of tumor-infiltrating CD8+ cells was higher than either irinotecan or anti-PD-L1 antibody monotherapy. Irinotecan was found to decrease the number of Tregs in lymph nodes and tumors, and specific depletion of Tregs by anti-folate receptor 4 antibodies was found to enhance the proliferation of CD8+ cells in this model. In addition, irinotecan augmented MHC class I expression on tumor cells and concurrently increased PD-L1 expression on tumor cells and tumor-infiltrating immune cells. These results indicate that irinotecan may enhance the effect of T cell activation caused by anti-PD-L1 treatment by reducing Tregs and augmenting MHC class I–mediated tumor antigen presentation, and concurrent upregulation of PD-L1 expression can be blocked by the anti-PD-L1 antibody. These interactions may contribute to the superior combination effect.

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“… 2 – 6 Other groups argued that relying on significance based on p value alone was not scientific, 22 , 23 and preferred to accept “the trend” and the result from meta-analyses. 11 – 13 Schmittel et al claimed that the CBDCA+ETP regimen remained the standard treatment because the CBDCA+CPT11 regimen could not demonstrate statistically significant superiority in OS of patients with ED-SCLC (HR 1.29, 95% CI 0.96–1.73, p = 0.095; median OS 10.0 month versus 9.0 months, p = 0.06). 24 Although the pooled HRos calculated using data from Hermes and Schmittel was 0.72 (95% CI 0.59–0.90, p = 0.002) without heterogeneity (P for heterogeneity = 0.2, I 2 = 0%) at the time of the publication of the study Schmittel ( Figure 4B ), 11– 13 , 24 , 25 several groups agreed with the results of the Schmittel and continued to use CBDCA+ETP as the standard reference treatment ( Table 1 , Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Systematic review of first-line chemotherapy for chemo-naïve extensive-stage small-cell lung cancer: network meta-analysis

et al. 2020

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Background: Our goal was to organize the data from randomized controlled trials that evaluated first-line chemotherapy for chemo-naïve extensive disease small-cell lung cancer (ED-SCLC). Methods: The protocol following PRISMA methodology was submitted as PROSPERO 154049. We included individually randomized trials comparing two or more chemotherapy regimens as the first-line treatment for chemo-naïve ED-SCLC regardless of the age, sex, performance status, co-morbidities, and organ functions written in the English language since 2000. Molecular targeted agents and immune checkpoint inhibitors were considered chemotherapy along with cytotoxic medications. We pooled the logarithm of hazard ratio (HR) and its standard error using the frequentist weighted least squares approach random-model network meta-analysis. Results: A total of 46 eligible trials that involved 11,987 patients were included. The primary endpoint, HR of overall survival (OS, HRos) of the selected comparisons was as follows: carboplatin+amrubicin (HRos 0.56, 95% confidence interval (CI) 0.33–0.96), carboplatin+etoposide+atezolizumab (HRos 0.70, 95% CI 0.53–0.92), and carboplatin+irinotecan (HRos 0.73, 95% CI 0.58–0.91) were compared with carboplatin+etoposide. The carboplatin+etoposide+atezolizumab regimen was compared with carboplatin+irinotecan (HRos 0.97, 95% CI 0.68–1.37) and cisplatin+irinotecan regimen (HRos 0.87, 95% CI 0.58–1.31). “Selective carboplatin or cisplatin (CBDCA/CDDP)”+etoposide+durvalumab was compared with CBDCA/CDDP+etoposide (HRos 0.73, 95% CI 0.59–0.91). Platinum+etoposide+durvalumab was compared with platinum+irinotecan (HRos 0.88, 95% CI 0.67–1.15). Cumulative meta-analysis suggested that platinum+irinotecan was associated with better OS than platinum+etoposide as of 2010 through 40 out of 46 trials in our review that used platinum+etoposide as a reference regimen. Conclusion: Patients treated with carboplatin+amrubicin, carboplatin+etoposide+atezolizumab, CBDCA/CDDP+etoposide+durvalumab, and platinum+irinotecan showed better HRos than those treated with platinum+etoposide, one of the standard regimens.

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Comparison of irinotecan/platinum versus etoposide/platinum chemotherapy for extensive-stage small cell lung cancer: A meta-analysis

Cited by 22 publications

References 18 publications

Real-world effectiveness and tolerability of small-cell lung cancer (SCLC) treatments: A systematic literature review (SLR)

Real-world effectiveness and tolerability of small-cell lung cancer (SCLC) treatments: A systematic literature review (SLR)

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Systematic review of first-line chemotherapy for chemo-naïve extensive-stage small-cell lung cancer: network meta-analysis

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