Comparison of Irinotecan/carboplatin versus Etoposide/carboplatin for extended disease small cell lung cancer (ED-SCLC): A systematic review and meta-analysis of randomized controlled trials

Comparison of Irinotecan/carboplatin versus Etoposide/carboplatin for extended disease small cell lung cancer (ED-SCLC): A systematic review and meta-analysis of randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of Irinotecan/carboplatin versus Etoposide/carboplatin for extended disease small cell lung cancer (ED-SCLC): A systematic review and meta-analysis of randomized controlled trials ZEESHAN AFZAL, Sara Hira, Xia Song, Na Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3908903/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Platinum-based chemotherapy in addition to the non-platinum agent Etoposide is the standard of care for ES-SCLC. However, the front-line chemotherapy regimen is not known. Therefore, we aimed to perform this review comparing irinotecan/carboplatin and etoposide/carboplatin in the patients of ED-SCLC. Methods We searched three databases i.e. PubMed, Embase and Cochrane library. We evaluated the outcomes for complete response, median overall survival, and progression free survival. In addition to that adverse events such as leukopenia, thrombocytopenia, anemia, diarrhea, and infections were also assessed. RevMan 5.4.1 was used to perform the statistical analysis. Results Three RCTs with 676 patients were included. There was a significant difference among IC and EC arms in terms of complete response (RR 2.52; 95% CI 1.20–5.32; p = 0.02, I 2 = 0%), Leukopenia (RR = 0.47; 95% CI 0.23 to 0.97; P = 0.04; I 2 = 90%), Anemia (RR = 0.55; 95% CI 0.38 to 0.78; P = 0.0008; I 2 = 0%), Thrombocytopenia (RR = 0.51; 95% CI 0.39 to 0.68; P = 0.00001; I 2 = 0%); and Diarrhea (RR = 4.88; 95%CI 1.64 to 14.49; P = 0.004; I 2 = 33%). There was no statistically significant difference among IC and EC arms in terms of Median Overall survival (HR = 1.16; 95%CI 0.84 to 1.62; P = 0.37; I 2 = 74%), Progression-free survival (HR = 1.04; 95% CI 0.69 to 1.56; P = 0.85; I 2 = 77%), Nausea (RR = 1.70; 95%CI 0.76 to 3.81; P = 0.19; I 2 = 0%), Infection (RR = 0.97; 95%CI 0.64 to 1.48; P = 0.89; I 2 = 0%) and Treatment-related Deaths (RR = 0.58; 95%CI 0.24 to 1.42; P = 0.23; I 2 = 0%). Conclusions In conclusion, this meta-analysis provides valuable evidence supporting the superiority of IC regimens over EC regimens in terms of complete response and toxicity profile for ED-SCLC. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 1. Introduction Small-cell lung cancer is the leading cause of cancer-related fatalities worldwide, it comprises 15% of total lung cancers [ 1 ]–[ 3 ]. Due to rapid progression and the tendency to metastasize to lymph nodes and various organs, approximately 70–80% of cancer patients arrive at an extended disease stage [ 4 ]. With a 5-year OS rate of less than 5%, ES-SCLC is still an incurable illness [ 5 ], [ 6 ]. Initially, ED-SCLC is sensitive to chemotherapy in most cases, but due to local or distal relapse, the overall prognosis is very low. The inclusion of immune checkpoint inhibitors in platinum-based chemotherapy in recent years has considerably improved patient survival rates [ 7 ]. Over the past 20 years, Cisplatin/carboplatin in addition to Etoposide (topoisomerase-II inhibitor) has been the preferred treatment for ED-SCLC [ 8 ]. In 2001, the J9511 trial showed the initial evidence supporting that Irinotecan/cisplatin is superior to etoposide/cisplatin [ 9 ]. Following this study, further trials were conducted to compare carboplatin/irinotecan and carboplatin/etoposide (Hermes 2008; Schmittel 2011; and Shimokawa 2023) [ 10 ]–[ 12 ]. A prior meta-analysis compared Platinum/Irinotecan and Platinum/Etoposide regimens [ 13 ]. Subsequent to this earlier analysis, new studies have emerged, notably the work of Shimokawa in 2023. However, there has been no systematic meta-analysis comparing the treatment effectiveness of only carboplatin/irinotecan and carboplatin/etoposide regimens. A meta-analysis and systematic review were done to assess the efficacy of carboplatin/irinotecan and carboplatin/etoposide regimens as first-line therapies for ED-SCLC. 2. Methods 2.1. Search strategy Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Cochrane Collaboration's recommendations were followed for this review [ 14 ], [ 15 ]. The study protocol was submitted in PROSPERO with the ID CRD42023468968. We conducted a thorough search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials inception from September 17, 2023, for the following search terms: ‘Carboplatin’, ‘Platinum’, ‘Irinotecan’, ‘etoposide’, ‘Topoisomerase’, ‘SCLC’, and ‘Small cell lung cancer’. 2.2. Eligibility Criteria We chose studies that met the following criteria for inclusion: (1) randomized controlled trials (RCTs); (2) patients with extended disease small cell lung cancer; (3) comparing irinotecan/carboplatin with etoposide/carboplatin; and (4) providing at least one significant clinical outcome. Exclusion criteria: (1) Non-randomized trials; (2) patients with limited-stage small-cell lung cancer; (3) comparisons of different platinum regimens; and (4) animal studies. 2.3. Endpoints We carried out a systematic review and meta-analysis on these endpoints (1) Median Overall survival; (2) Median Progression-free survival; (3) Complete response; (4) Anemia; (5) Thrombocytopenia; (6) Leukopenia; (7) Diarrhea; (8) Infection; and (9) Treatment-related Death. 2.4. Study screening and selection Two authors Z.A. and S.H. independently conducted the primary screening based on titles and abstracts. Articles selected after the primary screening were read in full text. The final studies to be included in the meta-analysis were chosen based on the eligibility criteria. The authors compared the final results of the secondary screening. Disagreements were clarified by discussion and consultation with senior author S.X. 2.5. Data Extraction A standard Excel sheet was used to extract data from the selected studies. We gathered all relevant data from the included studies' tables, texts, and figures, such as the author's name, publication year, ages, number of patients, chemotherapeutic drugs, dose, metastatic locations, number of cycles, second-line treatment, and performance status. We retrieved data on median overall survival (OS), median progression-free survival (PFS), complete response, and toxicity, including anemia, thrombocytopenia, leukopenia, diarrhea, nausea, infections, and treatment-related mortality. 2.6. Statistical and sensitivity analysis Pooled HR, and risk ratio with 95% CI were used to compare the treatment effect. Der Simonian and Laird's random-effects model was used. Cochrane Q test and I 2 statistics were used to analyze heterogeneity; p 25% were accounted significant for heterogeneity. The statistical analysis was conducted using Review Manager 5.4.1, and the Leave-one-out sensitivity analysis was carried out using R 4.3.1 software. 2.7. Quality assessment The risk of bias in each randomized trial was evaluated using the ROB-2 tool [ 16 ]. Each study was assigned a score corresponding to low, some concerned, or high risk of bias in each of the following five dimensions of reporting bias: selection, performance, detection, attrition, and reporting bias (Fig. 12 ). 3. Results 3.1. Characteristics of included studies As shown in Figure. 1, the initial search extracted 2569 results. Duplicate studies were excluded and ineligible studies were removed on the base of title/abstract, the remaining 126 studies were thoroughly analyzed for inclusion and exclusion criteria. Finally, 683 patients from 3 RCTs were included, 339 were assigned to irinotecan/carboplatin treatments, and 344 to etoposide/carboplatin regimens. Table 1 highlights the baseline characteristics of the selected studies. Focusing on age, gender, dosage, regimen, and specific comorbidities. 3.2. Pooled analysis 3.2.1 Clinical outcomes A significant difference in Complete response was observed between the two arms favoring the IC group (Risk Ratio 2.52; 95% CI 1.20 to 5.32; p = 0.02; I 2 = 0%; Fig. 2 ). No significant differences were found between the IC and EC arms in median overall survival (Hazard Ratio = 1.16; 95% CI 0.84 to 1.62; p = 0.37; I 2 = 74%; Fig. 3 ); and Progression-free Survival (Hazard Ratio = 1.04; 95% CI 0.69 to 1.56; p = 0.85; I 2 = 77%; Fig. 4 ). 3.2.2 Hematological Adverse Outcomes There was a statistically significant difference between the IC and EC arms in Anemia (Risk Ratio = 0.55; 95% CI 0.38 to 0.78; P = 0.0008; I 2 = 0%; Fig. 5 ); Thrombocytopenia (Risk Ratio = 0.51; 95% CI 0.39 to 0.68; P = 0.00001; I 2 = 0%; Fig. 6 ); and Leukopenia (Risk Ratio = 0.47; 95% CI 0.23 to 0.97; P = 0.04; I 2 = 90%; Fig. 7 ) favoring IC group. 3.2.3 Gastrointestinal adverse outcomes A statistically significant difference was found in Diarrhea between the IC and EC arms favoring the EC group (Risk Ratio = 4.88; 95%CI 1.64 to 14.49; P = 0.004; I 2 = 33%; Fig. 8 ). No significant differences were found between the IC and EC arms in Nausea (RR = 1.70; 95%CI 0.76 to 3.81; P = 0.19; I 2 = 0%; Fig. 9 ). 3.2.4 Infections and Treatment-related Death: No significant differences were found between IC and EC arms with regards to infections (Risk Ratio = 0.97; 95%CI 0.64 to 1.48; p = 0.89; I 2 = 0%; Fig. 10 ) and treatment-related death (Risk Ratio = 0.58; 95%CI 0.24 to 1.42; P = 0.23; I 2 = 0%; Fig. 11 ). 3.3 Risk of Bias assessment and sensitivity analysis All of the selected trials had a minimal risk of bias in all the domains resulting in an overall low risk of bias (Fig. 12 ). The heterogeneity reduced from 74–0% omitting Shimokawa in Overall survival (Fig. 13 ), 90–38% omitting Hermes in Leukopenia (Fig. 14), and 33–0% omitting Schmittel in Diarrhea (Fig. 15 ). Discussion This meta-analysis compared irinotecan/carboplatin (IC) and etoposide/carboplatin (EC) regimens for extended disease small cell lung carcinoma (ED-SCLC). It revealed that IC arm exhibited superior treatment response rates and fewer hematological adverse events compared to the EC arm. Conversely, the EC arm demonstrated a reduced incidence of gastrointestinal adverse events, particularly in relation to diarrhea. We observed that the OS and PFS in the IC arm were slightly longer than EC arm. However, statistically speaking, the differences were insignificant. Before the introduction of immunotherapy, chemotherapy was the primary choice of treatment for ED-SCLC and the treatment varied from person to person. In the literature, there is no clear significant difference in the efficacy of IP and EP regimens for small-cell lung cancer [ 17 ]–[ 20 ]. J9511 trial compared Irinotecan/Cisplatin (IP) vs Etoposide/Cisplatin (EP) which showed that the IP arm has longer survival benefits with a median OS of 12.8 months (1-year 58% and 2-year 19%), and a median PFS of 6.9 months (1-year 13% and 2-year 8%) [ 18 ]. Another phase III trial (Zatloukal et al) showed similar results, the IP arm with a median OS of 10.2 months (1-year 41.9% and 2-year 16.3% survival rate)[ 20 ]. Although the IP arm has comparatively longer OS and PFS than EP, but there is no significant difference between the IP and EP regimens. However, carboplatin in addition to cisplatin, is also commonly used platinum-based chemotherapy. The three trials included in our meta-analysis exclusively compared Irinotecan/Carboplatin and Etoposide/Carboplatin. Hermes 2008 showed that the IC arm increases QoL and overall survival in ED SCLC patients [ 10 ]. Schmittel's 2006 Phase II trial showed that the IC arm is effective, less toxic, and appears to improve progression-free survival (PFS) [ 21 ]. However, the extended phase III trial of Schmittel 2011 did not establish the superiority of irinotecan over etoposide when combined with carboplatin [ 11 ]. Shimokawa 2023 suggests favorable efficacy in the IC arm, although it did not significantly differ from the EC arm [ 12 ]. Leave-one-out sensitivity analysis revealed that Shimokawa, Hermes, and Schmittel are responsible for high heterogeneity in the outcomes of overall survival, leukopenia, and diarrhea respectively. On exploring the reasons for heterogeneity, Shimokawa only had patients > 75 years of age in their study, Hermes reported the use of corticosteroids which resulted in Leukopenia in their study participants and Schmittel reported more prevalence of diarrhea than would normally be observed despite the controlled environment. Irinotecan/cisplatin and Etoposide/cisplatin regimens in ED-SCLC were compared in a prior meta-analysis by Han et al. (2017), which showed differences in the two regimens' overall response and survival, especially in the eastern grouping. [ 22 ]. A different prior meta-analysis conducted by Jiang et al. (2010) examined the effects of Irinotecan/cisplatin regimens vs Etoposide/cisplatin regimens in ED-SCLC and found that the first regimen had a greater overall response and survival rate than the second [ 23 ]. However, the carboplatin trial was excluded after the subgroup, and sensitivity analysis because it was unable to exhibit benefit in IP regimens. Although the results of toxicities were the same in our meta-analysis as compare to the previous meta-analysis. The toxicity profile of the regimens is a critical consideration, as the study found that IC regimens were associated with significantly less severe anemia, leukopenia, and thrombocytopenia, compared to EC regimens. Whereas, EC regimens were associated with less frequent severe nausea, and diarrhea, compared to IC regimens. Notably, the optimum role of chemotherapy in ED-SCLC patients is palliative, its impact on the patient’s QoL is a crucial flaw in concluding the true value of therapy [ 22 ]. A study showed that Chemoimmunotherapy may be used in real-world settings and is beneficial in treating unselected ES-SCLC patients, such as those who had corticosteroid usage, poor performance status, and untreated brain metastases. Comparable to the outcomes seen in clinical trials, the CT-IO group's median overall survival was 11.4 months [ 24 ]. This result highlights the encouraging survival rates of Chemoimmunotherapy in clinical use. According to ACSO Guidelines 2023, Patients with untreated or previously treated ES-SCLC receiving chemotherapy or chemo-immunotherapy may be administered Trilaciclib or granulocyte colony-stimulating factor (G-CSF) as a myeloid-supportive drug and is recommended to be given to adult patients before receiving a platinum/etoposide-containing regimen or a topotecan-containing treatment for extensive-stage small cell lung cancer in order to reduce the incidence of myelosuppression during chemotherapy[ 25 ], [ 26 ]. Although our study indicates a statistically significant difference in terms of complete response (CR), due to the limited sample size and the limited amount of related research, the advantage of IC over EC may not be proven in this study. Further clinical trials and real-world data are needed to verify whether IC can bring benefits to patients acquiring ED-SCLC. In conclusion, the meta-analysis provides valuable evidence supporting the superiority of IC regimens over EC regimens in terms of complete response and toxicity profile for ED-SCLC. Given the implications for clinical practice and the need for further research. The study's comprehensive approach, robust methodology, and clinically relevant findings make it a valuable contribution to the field of ED-SCLC treatment. Declarations Author Contribution The authors confirm their contribution to the meta-analysis as follows: study conception, design, data collection, analysis, and draft manuscript preparation: Z.A, S.H; interpretation of results and discussion: X.S, N.W. All authors reviewed the results and approved the final version of the manuscript. References Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021, CA Cancer J Clin , vol. 71, no. 1, pp. 7–33, Jan. 2021, https://doi.org/10.3322/caac.21654 . Toyoda Y, Nakayama T, Ioka A, Tsukuma H. Trends in Lung Cancer Incidence by Histological Type in Osaka, Japan, 10.1093/jjco/hyn072 . Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward, Nat Rev Cancer , vol. 17, no. 12, pp. 725–737, Dec. 2017, 10.1038/NRC.2017.87 . Simon GR, Wagner H. Small Cell Lung Cancer*, Chest , vol. 123, no. 1, Supplement, pp. 259S-271S, 2003, https://doi.org/10.1378/chest.123.1_suppl.259S . 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Ann Oncol. 2006;17(4):663–7. 10.1093/ANNONC/MDJ137 . Han D et al. Nov., Comparison of irinotecan/platinum versus etoposide/platinum chemotherapy for extensive-stage small cell lung cancer: A meta-analysis, Eur J Cancer Care (Engl) , vol. 26, no. 6, 2017, 10.1111/ECC.12723 . Jiang J, et al. A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol. 2010;5(6):867–73. 10.1097/JTO.0B013E3181D95C87 . Porte M et al. Nov., A Multicenter Study Assessing the Real-World Use and Effectiveness of First-Line Chemotherapy Plus Immunotherapy in Advanced Small-Cell Lung Cancer (SCLC) Patients, Clin Lung Cancer , 2023, 10.1016/J.CLLC.2023.11.009 . Khurshid H, et al. Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline. J Clin Oncol. Dec. 2023;41(35). 10.1200/JCO.23.01435 . G1 Therapeutics’ COSELA® (trilaciclib) Recommended in Updated Small Cell Lung Cancer Guidelines from the American Society of Clinical Oncology (ASCO). - G1 Therapeutics, Inc. Accessed: Dec. 16, 2023. [Online]. Available: http://investor.g1therapeutics.com/news-releases/news-release-details/g1-therapeutics-coselar-trilaciclib-recommended-updated-small . Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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of IC and EC on Complete Response\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/747ad6d459c5fcf4caa5f83e.png"},{"id":52184382,"identity":"1ff1a9c5-4fb3-45be-983b-69052e1fe094","added_by":"auto","created_at":"2024-03-07 18:19:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":64432,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Median Overall Survival\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/1721ddf95c2d352c38558bcc.png"},{"id":52184388,"identity":"ed0d54ae-3a12-4732-9664-e4993b8f02ff","added_by":"auto","created_at":"2024-03-07 18:19:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":141717,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Median Progression-free-Survival\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/12a89ff2956e605ab8ca4418.png"},{"id":52184381,"identity":"a5fc52f2-ca6d-45fb-9ae1-81e862b6f923","added_by":"auto","created_at":"2024-03-07 18:19:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":72524,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Anemia\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/c1d2e08f2b2337cb761048d8.png"},{"id":52184383,"identity":"354594c9-01ad-4bd5-b16a-50761f2d06b9","added_by":"auto","created_at":"2024-03-07 18:19:27","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":73074,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Thrombocytopenia\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/8cc1ecb771a9eaac0159d683.png"},{"id":52183362,"identity":"d136df98-1eb8-42f6-a5c3-e2899c32eb0b","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":73069,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Leukopenia\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/738de975b6b39656fb8c91d0.png"},{"id":52183365,"identity":"2d4c62a3-46f2-4ed2-97bd-e8efa14e794e","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":73318,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Diarrhea\u003c/p\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/9649eed08bb6e77eee508cc4.png"},{"id":52184385,"identity":"8315dbd0-c85c-4679-88ac-d5bd5159a245","added_by":"auto","created_at":"2024-03-07 18:19:27","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":116460,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Nausea\u003c/p\u003e","description":"","filename":"image9.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/3bec8260b2f420f16b84cd12.png"},{"id":52183370,"identity":"527b207b-a604-409e-93ec-4f6982dc7731","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":73719,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Infection\u003c/p\u003e","description":"","filename":"image10.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/65aecb8b2d2f7eca08dc097d.png"},{"id":52183368,"identity":"56090fe0-d08b-494f-aba8-ce188c5ef839","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":72160,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of IC and EC on Treatment-related Death\u003c/p\u003e","description":"","filename":"image11.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/d0d542df381fb17f97def26d.png"},{"id":52186428,"identity":"c7eadd47-3f55-4bc7-925e-873400142268","added_by":"auto","created_at":"2024-03-07 18:27:27","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":173365,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of Bias in included studies\u003c/p\u003e","description":"","filename":"image12.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/02613c7435b97e7bc59a9e2d.png"},{"id":52183366,"identity":"e196cb91-a327-4267-9e40-107d50a5d556","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":122176,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis of Median overall survival\u003c/p\u003e","description":"","filename":"image13.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/67517bf68b8e8d6b48e5435b.png"},{"id":52184387,"identity":"61fc8b98-d60f-418f-a998-be7afd968ee0","added_by":"auto","created_at":"2024-03-07 18:19:27","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":114576,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis of Leukopenia\u003c/p\u003e","description":"","filename":"image14.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/da74f815ce21328f0ae5559d.png"},{"id":52183372,"identity":"47db54f1-f34f-47ec-a851-bf94bb58e9dc","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"png","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":34689,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis of Diarrhea\u003c/p\u003e","description":"","filename":"image15.png","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/70ce5aca8154bb2b4d4c37d5.png"},{"id":52262819,"identity":"5c94859b-a1d4-4ff7-9d65-3437ee89f74c","added_by":"auto","created_at":"2024-03-08 11:20:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1389779,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/12040022-2a39-407c-8ac1-f4936bcd80c6.pdf"},{"id":52183375,"identity":"3f7d36ce-3857-4f19-8b91-a25186301cf7","added_by":"auto","created_at":"2024-03-07 18:11:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":42818,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3908903/v1/2e22c9c9856f8434f964f3c4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Irinotecan/carboplatin versus Etoposide/carboplatin for extended disease small cell lung cancer (ED-SCLC): A systematic review and meta-analysis of randomized controlled trials","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSmall-cell lung cancer is the leading cause of cancer-related fatalities worldwide, it comprises 15% of total lung cancers [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u0026ndash;[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Due to rapid progression and the tendency to metastasize to lymph nodes and various organs, approximately 70\u0026ndash;80% of cancer patients arrive at an extended disease stage [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. With a 5-year OS rate of less than 5%, ES-SCLC is still an incurable illness [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInitially, ED-SCLC is sensitive to chemotherapy in most cases, but due to local or distal relapse, the overall prognosis is very low. The inclusion of immune checkpoint inhibitors in platinum-based chemotherapy in recent years has considerably improved patient survival rates [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Over the past 20 years, Cisplatin/carboplatin in addition to Etoposide (topoisomerase-II inhibitor) has been the preferred treatment for ED-SCLC [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2001, the J9511 trial showed the initial evidence supporting that Irinotecan/cisplatin is superior to etoposide/cisplatin [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Following this study, further trials were conducted to compare carboplatin/irinotecan and carboplatin/etoposide (Hermes 2008; Schmittel 2011; and Shimokawa 2023) [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u0026ndash;[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A prior meta-analysis compared Platinum/Irinotecan and Platinum/Etoposide regimens [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Subsequent to this earlier analysis, new studies have emerged, notably the work of Shimokawa in 2023. However, there has been no systematic meta-analysis comparing the treatment effectiveness of only carboplatin/irinotecan and carboplatin/etoposide regimens.\u003c/p\u003e \u003cp\u003eA meta-analysis and systematic review were done to assess the efficacy of carboplatin/irinotecan and carboplatin/etoposide regimens as first-line therapies for ED-SCLC.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Search strategy\u003c/h2\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Cochrane Collaboration's recommendations were followed for this review [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The study protocol was submitted in PROSPERO with the ID CRD42023468968.\u003c/p\u003e \u003cp\u003eWe conducted a thorough search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials inception from September 17, 2023, for the following search terms: \u0026lsquo;Carboplatin\u0026rsquo;, \u0026lsquo;Platinum\u0026rsquo;, \u0026lsquo;Irinotecan\u0026rsquo;, \u0026lsquo;etoposide\u0026rsquo;, \u0026lsquo;Topoisomerase\u0026rsquo;, \u0026lsquo;SCLC\u0026rsquo;, and \u0026lsquo;Small cell lung cancer\u0026rsquo;.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Eligibility Criteria\u003c/h2\u003e \u003cp\u003eWe chose studies that met the following criteria for inclusion: (1) randomized controlled trials (RCTs); (2) patients with extended disease small cell lung cancer; (3) comparing irinotecan/carboplatin with etoposide/carboplatin; and (4) providing at least one significant clinical outcome. Exclusion criteria: (1) Non-randomized trials; (2) patients with limited-stage small-cell lung cancer; (3) comparisons of different platinum regimens; and (4) animal studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Endpoints\u003c/h2\u003e \u003cp\u003eWe carried out a systematic review and meta-analysis on these endpoints (1) Median Overall survival; (2) Median Progression-free survival; (3) Complete response; (4) Anemia; (5) Thrombocytopenia; (6) Leukopenia; (7) Diarrhea; (8) Infection; and (9) Treatment-related Death.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Study screening and selection\u003c/h2\u003e \u003cp\u003eTwo authors Z.A. and S.H. independently conducted the primary screening based on titles and abstracts. Articles selected after the primary screening were read in full text. The final studies to be included in the meta-analysis were chosen based on the eligibility criteria. The authors compared the final results of the secondary screening. Disagreements were clarified by discussion and consultation with senior author S.X.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Data Extraction\u003c/h2\u003e \u003cp\u003eA standard Excel sheet was used to extract data from the selected studies. We gathered all relevant data from the included studies' tables, texts, and figures, such as the author's name, publication year, ages, number of patients, chemotherapeutic drugs, dose, metastatic locations, number of cycles, second-line treatment, and performance status. We retrieved data on median overall survival (OS), median progression-free survival (PFS), complete response, and toxicity, including anemia, thrombocytopenia, leukopenia, diarrhea, nausea, infections, and treatment-related mortality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Statistical and sensitivity analysis\u003c/h2\u003e \u003cp\u003ePooled HR, and risk ratio with 95% CI were used to compare the treatment effect. Der Simonian and Laird's random-effects model was used. Cochrane Q test and I\u003csup\u003e2\u003c/sup\u003e statistics were used to analyze heterogeneity; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;25% were accounted significant for heterogeneity. The statistical analysis was conducted using Review Manager 5.4.1, and the Leave-one-out sensitivity analysis was carried out using R 4.3.1 software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Quality assessment\u003c/h2\u003e \u003cp\u003eThe risk of bias in each randomized trial was evaluated using the ROB-2 tool [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Each study was assigned a score corresponding to low, some concerned, or high risk of bias in each of the following five dimensions of reporting bias: selection, performance, detection, attrition, and reporting bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Characteristics of included studies\u003c/h2\u003e \u003cp\u003eAs shown in Figure. 1, the initial search extracted 2569 results. Duplicate studies were excluded and ineligible studies were removed on the base of title/abstract, the remaining 126 studies were thoroughly analyzed for inclusion and exclusion criteria. Finally, 683 patients from 3 RCTs were included, 339 were assigned to irinotecan/carboplatin treatments, and 344 to etoposide/carboplatin regimens.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e highlights the baseline characteristics of the selected studies. Focusing on age, gender, dosage, regimen, and specific comorbidities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Pooled analysis\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1 Clinical outcomes\u003c/h2\u003e \u003cp\u003eA significant difference in Complete response was observed between the two arms favoring the IC group (Risk Ratio 2.52; 95% CI 1.20 to 5.32; p\u0026thinsp;=\u0026thinsp;0.02; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No significant differences were found between the IC and EC arms in median overall survival (Hazard Ratio\u0026thinsp;=\u0026thinsp;1.16; 95% CI 0.84 to 1.62; p\u0026thinsp;=\u0026thinsp;0.37; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;74%; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e); and Progression-free Survival (Hazard Ratio\u0026thinsp;=\u0026thinsp;1.04; 95% CI 0.69 to 1.56; p\u0026thinsp;=\u0026thinsp;0.85; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;77%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2 Hematological Adverse Outcomes\u003c/h2\u003e \u003cp\u003eThere was a statistically significant difference between the IC and EC arms in Anemia (Risk Ratio\u0026thinsp;=\u0026thinsp;0.55; 95% CI 0.38 to 0.78; P\u0026thinsp;=\u0026thinsp;0.0008; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e); Thrombocytopenia (Risk Ratio\u0026thinsp;=\u0026thinsp;0.51; 95% CI 0.39 to 0.68; P\u0026thinsp;=\u0026thinsp;0.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e); and Leukopenia (Risk Ratio\u0026thinsp;=\u0026thinsp;0.47; 95% CI 0.23 to 0.97; P\u0026thinsp;=\u0026thinsp;0.04; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;90%; Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e) favoring IC group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.2.3 Gastrointestinal adverse outcomes\u003c/h2\u003e \u003cp\u003eA statistically significant difference was found in Diarrhea between the IC and EC arms favoring the EC group (Risk Ratio\u0026thinsp;=\u0026thinsp;4.88; 95%CI 1.64 to 14.49; P\u0026thinsp;=\u0026thinsp;0.004; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;33%; Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). No significant differences were found between the IC and EC arms in Nausea (RR\u0026thinsp;=\u0026thinsp;1.70; 95%CI 0.76 to 3.81; P\u0026thinsp;=\u0026thinsp;0.19; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.2.4 Infections and Treatment-related Death:\u003c/h2\u003e \u003cp\u003eNo significant differences were found between IC and EC arms with regards to infections (Risk Ratio\u0026thinsp;=\u0026thinsp;0.97; 95%CI 0.64 to 1.48; p\u0026thinsp;=\u0026thinsp;0.89; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e) and treatment-related death (Risk Ratio\u0026thinsp;=\u0026thinsp;0.58; 95%CI 0.24 to 1.42; P\u0026thinsp;=\u0026thinsp;0.23; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of Bias assessment and sensitivity analysis\u003c/h2\u003e \u003cp\u003eAll of the selected trials had a minimal risk of bias in all the domains resulting in an overall low risk of bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e12\u003c/span\u003e). The heterogeneity reduced from 74\u0026ndash;0% omitting Shimokawa in Overall survival (Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e13\u003c/span\u003e), 90\u0026ndash;38% omitting Hermes in Leukopenia (Fig.\u0026nbsp;14), and 33\u0026ndash;0% omitting Schmittel in Diarrhea (Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis meta-analysis compared irinotecan/carboplatin (IC) and etoposide/carboplatin (EC) regimens for extended disease small cell lung carcinoma (ED-SCLC). It revealed that IC arm exhibited superior treatment response rates and fewer hematological adverse events compared to the EC arm. Conversely, the EC arm demonstrated a reduced incidence of gastrointestinal adverse events, particularly in relation to diarrhea. We observed that the OS and PFS in the IC arm were slightly longer than EC arm. However, statistically speaking, the differences were insignificant.\u003c/p\u003e \u003cp\u003eBefore the introduction of immunotherapy, chemotherapy was the primary choice of treatment for ED-SCLC and the treatment varied from person to person. In the literature, there is no clear significant difference in the efficacy of IP and EP regimens for small-cell lung cancer [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u0026ndash;[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eJ9511 trial compared Irinotecan/Cisplatin (IP) vs Etoposide/Cisplatin (EP) which showed that the IP arm has longer survival benefits with a median OS of 12.8 months (1-year 58% and 2-year 19%), and a median PFS of 6.9 months (1-year 13% and 2-year 8%) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another phase III trial (Zatloukal et al) showed similar results, the IP arm with a median OS of 10.2 months (1-year 41.9% and 2-year 16.3% survival rate)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough the IP arm has comparatively longer OS and PFS than EP, but there is no significant difference between the IP and EP regimens. However, carboplatin in addition to cisplatin, is also commonly used platinum-based chemotherapy. The three trials included in our meta-analysis exclusively compared Irinotecan/Carboplatin and Etoposide/Carboplatin.\u003c/p\u003e \u003cp\u003eHermes 2008 showed that the IC arm increases QoL and overall survival in ED SCLC patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Schmittel's 2006 Phase II trial showed that the IC arm is effective, less toxic, and appears to improve progression-free survival (PFS) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, the extended phase III trial of Schmittel 2011 did not establish the superiority of irinotecan over etoposide when combined with carboplatin [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Shimokawa 2023 suggests favorable efficacy in the IC arm, although it did not significantly differ from the EC arm [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLeave-one-out sensitivity analysis revealed that Shimokawa, Hermes, and Schmittel are responsible for high heterogeneity in the outcomes of overall survival, leukopenia, and diarrhea respectively. On exploring the reasons for heterogeneity, Shimokawa only had patients\u0026thinsp;\u0026gt;\u0026thinsp;75 years of age in their study, Hermes reported the use of corticosteroids which resulted in Leukopenia in their study participants and Schmittel reported more prevalence of diarrhea than would normally be observed despite the controlled environment.\u003c/p\u003e \u003cp\u003eIrinotecan/cisplatin and Etoposide/cisplatin regimens in ED-SCLC were compared in a prior meta-analysis by Han et al. (2017), which showed differences in the two regimens' overall response and survival, especially in the eastern grouping. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A different prior meta-analysis conducted by Jiang et al. (2010) examined the effects of Irinotecan/cisplatin regimens vs Etoposide/cisplatin regimens in ED-SCLC and found that the first regimen had a greater overall response and survival rate than the second [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, the carboplatin trial was excluded after the subgroup, and sensitivity analysis because it was unable to exhibit benefit in IP regimens.\u003c/p\u003e \u003cp\u003eAlthough the results of toxicities were the same in our meta-analysis as compare to the previous meta-analysis. The toxicity profile of the regimens is a critical consideration, as the study found that IC regimens were associated with significantly less severe anemia, leukopenia, and thrombocytopenia, compared to EC regimens. Whereas, EC regimens were associated with less frequent severe nausea, and diarrhea, compared to IC regimens. Notably, the optimum role of chemotherapy in ED-SCLC patients is palliative, its impact on the patient\u0026rsquo;s QoL is a crucial flaw in concluding the true value of therapy [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA study showed that Chemoimmunotherapy may be used in real-world settings and is beneficial in treating unselected ES-SCLC patients, such as those who had corticosteroid usage, poor performance status, and untreated brain metastases. Comparable to the outcomes seen in clinical trials, the CT-IO group's median overall survival was 11.4 months [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This result highlights the encouraging survival rates of Chemoimmunotherapy in clinical use. According to ACSO Guidelines 2023, Patients with untreated or previously treated ES-SCLC receiving chemotherapy or chemo-immunotherapy may be administered Trilaciclib or granulocyte colony-stimulating factor (G-CSF) as a myeloid-supportive drug and is recommended to be given to adult patients before receiving a platinum/etoposide-containing regimen or a topotecan-containing treatment for extensive-stage small cell lung cancer in order to reduce the incidence of myelosuppression during chemotherapy[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough our study indicates a statistically significant difference in terms of complete response (CR), due to the limited sample size and the limited amount of related research, the advantage of IC over EC may not be proven in this study.\u003c/p\u003e \u003cp\u003eFurther clinical trials and real-world data are needed to verify whether IC can bring benefits to patients acquiring ED-SCLC.\u003c/p\u003e \u003cp\u003eIn conclusion, the meta-analysis provides valuable evidence supporting the superiority of IC regimens over EC regimens in terms of complete response and toxicity profile for ED-SCLC. Given the implications for clinical practice and the need for further research. The study's comprehensive approach, robust methodology, and clinically relevant findings make it a valuable contribution to the field of ED-SCLC treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eThe authors confirm their contribution to the meta-analysis as follows: study conception, design, data collection, analysis, and draft manuscript preparation: Z.A, S.H; interpretation of results and discussion: X.S, N.W. All authors reviewed the results and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel RL, Miller KD, Fuchs HE, Jemal A. 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Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://investor.g1therapeutics.com/news-releases/news-release-details/g1-therapeutics-coselar-trilaciclib-recommended-updated-small\u003c/span\u003e\u003cspan address=\"http://investor.g1therapeutics.com/news-releases/news-release-details/g1-therapeutics-coselar-trilaciclib-recommended-updated-small\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3908903/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3908903/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePlatinum-based chemotherapy in addition to the non-platinum agent Etoposide is the standard of care for ES-SCLC. However, the front-line chemotherapy regimen is not known. Therefore, we aimed to perform this review comparing irinotecan/carboplatin and etoposide/carboplatin in the patients of ED-SCLC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe searched three databases i.e. PubMed, Embase and Cochrane library. We evaluated the outcomes for complete response, median overall survival, and progression free survival. In addition to that adverse events such as leukopenia, thrombocytopenia, anemia, diarrhea, and infections were also assessed. RevMan 5.4.1 was used to perform the statistical analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThree RCTs with 676 patients were included. There was a significant difference among IC and EC arms in terms of complete response (RR 2.52; 95% CI 1.20\u0026ndash;5.32; p\u0026thinsp;=\u0026thinsp;0.02, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), Leukopenia (RR\u0026thinsp;=\u0026thinsp;0.47; 95% CI 0.23 to 0.97; P\u0026thinsp;=\u0026thinsp;0.04; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;90%), Anemia (RR\u0026thinsp;=\u0026thinsp;0.55; 95% CI 0.38 to 0.78; P\u0026thinsp;=\u0026thinsp;0.0008; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), Thrombocytopenia (RR\u0026thinsp;=\u0026thinsp;0.51; 95% CI 0.39 to 0.68; P\u0026thinsp;=\u0026thinsp;0.00001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%); and Diarrhea (RR\u0026thinsp;=\u0026thinsp;4.88; 95%CI 1.64 to 14.49; P\u0026thinsp;=\u0026thinsp;0.004; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;33%). There was no statistically significant difference among IC and EC arms in terms of Median Overall survival (HR\u0026thinsp;=\u0026thinsp;1.16; 95%CI 0.84 to 1.62; P\u0026thinsp;=\u0026thinsp;0.37; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;74%), Progression-free survival (HR\u0026thinsp;=\u0026thinsp;1.04; 95% CI 0.69 to 1.56; P\u0026thinsp;=\u0026thinsp;0.85; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;77%), Nausea (RR\u0026thinsp;=\u0026thinsp;1.70; 95%CI 0.76 to 3.81; P\u0026thinsp;=\u0026thinsp;0.19; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), Infection (RR\u0026thinsp;=\u0026thinsp;0.97; 95%CI 0.64 to 1.48; P\u0026thinsp;=\u0026thinsp;0.89; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) and Treatment-related Deaths (RR\u0026thinsp;=\u0026thinsp;0.58; 95%CI 0.24 to 1.42; P\u0026thinsp;=\u0026thinsp;0.23; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn conclusion, this meta-analysis provides valuable evidence supporting the superiority of IC regimens over EC regimens in terms of complete response and toxicity profile for ED-SCLC.\u003c/p\u003e","manuscriptTitle":"Comparison of Irinotecan/carboplatin versus Etoposide/carboplatin for extended disease small cell lung cancer (ED-SCLC): A systematic review and meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-07 18:11:22","doi":"10.21203/rs.3.rs-3908903/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"44a3a217-06b3-458f-aa39-ec0dd6b480c0","owner":[],"postedDate":"March 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-08T11:17:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-07 18:11:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3908903","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3908903","identity":"rs-3908903","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}