Chemotherapy For Extensive-stage Small-cell Lung Cancer Research Articles

Assessment of hospitalizations and cytopenia events among patients with extensive stage small cell lung cancer (ES-SCLC) receiving chemotherapy with trilaciclib.

531 Background: Prior studies have reported that that nearly 75% of patients receiving chemotherapy for small cell lung cancer present a hospitalization associated with myelosuppression. Trilaciclib is a myeloprotective agent indicated for use prior to chemotherapy in ES-SCLC. Given the relative recency in trilaciclib approval (2/12/2021), this study assessed real-world outcomes associated with trilaciclib among patients with ES-SCLC. Methods: This study was a retrospective analysis of adult ES-SCLC patients diagnosed between 2020 and 2023 using the 100% Medicare Fee-for-Service and MORE2 Registry claims databases. Eligible patients met literature-based criteria for ES-SCLC using International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes, received platinum/etoposide- or topotecan-based chemotherapy regimens after diagnosis, and were continuously enrolled ≥ 30 days preceding and following chemotherapy initiation. Patients were categorized into 2 mutually exclusive cohorts: 1) trilaciclib administered at chemotherapy initiation and with no granulocyte colony stimulating factor (G-CSF) received during chemotherapy, and 2) no trilaciclib administered during chemotherapy. Chi-square tests and student’s t-tests were used to assess statistically significant differences between groups on cytopenia events (based on the appearance of an ICD-10 diagnosis code) and all-cause hospitalizations during the post-index period. Data use agreements prohibit reporting of categorical outcomes of < 11 patients. Results: 132 trilaciclib (mean age 70.6, male 50.8%) and 12,305 non-trilaciclib patients (age 68.0, male 48.2%) were eligible for the study; median follow-up was 202 days. Compared to the non-trilaciclib cohort, patients receiving trilaciclib had a lower rate of hospitalizations per patient per month during follow-up (0.14±0.25 vs. 0.19±0.27; p <0.001). Within 90 days post-chemotherapy initiation, trilaciclib was associated with lower rates of hospitalization (21.2% vs. 32.4%; p <0.01) and febrile neutropenia (< 3% vs. 5.7%, p=0.01). Anemia (44.7% vs. 52.6%, p=0.07), neutropenia (9.1% vs. 14.9%, p=0.06) and thrombocytopenia (5.3% vs. 8.4%, p=0.2) were numerically lower for trilaciclib patients in the 90-day post-index period. Results were similar when the non-trilaciclib group was stratified by prophylactic G-CSF usage. Conclusions: This real-world study demonstrated that receiving trilaciclib prior to chemotherapy treatment was associated with a lower rates of hospitalizations and cytopenia events, suggesting trilaciclib may prevent adverse events associated with treatment for ES-SCLC.

Extensive-Stage Small-Cell Lung Cancer: Current Landscape and Future Prospects.

Small-cell lung cancer (SCLC) is characterized by aggressive disease progression and tendency to metastasize. Although chemotherapy for extensive-stage SCLC (ES-SCLC) has remained unchanged for decades, immune checkpoint inhibitors have become the primary therapy for ES-SCLC. However, the number of patients benefiting from immunotherapy is limited, and the treatment outcomes remain unsatisfactory. In addition, predictive biomarkers for immunotherapy have not yet been identified. Recent reports have shed light on the genomics of SCLC and defined four distinct molecular subtypes based on transcription factor expression. This may increase our understanding of the biology of SCLC and identify novel therapeutic targets and drugs. In this article, we review the current standard management of ES-SCLC and present the most recent reports to further our understanding of molecular classification, predictive biomarkers, and prospective therapies, including immunotherapy, chemotherapy, and targeted therapy.

Cost-effectiveness of the combination of immunotherapy and chemotherapy for extensive-stage small-cell lung cancer: a systematic review

BackgroundThe combination of immunotherapy and chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC) was primarily carried out with a combination of immune checkpoint inhibitors (ICIs) and platinum-etoposide (EP). It is likely to be more effective in treating ES-SCLC than EP alone, but could result in high healthcare costs. The study aimed to investigate the cost-effectiveness of this combination therapy for ES-SCLC.MethodsWe searched literature from the following databases: PubMed, Embase, Cochrane Library, and Web of Science for studies on cost-effectiveness of immunotherapy combined with chemotherapy for ES-SCLC. The literature search period was up to April 20, 2023. The quality of the studies was evaluated using the Cochrane Collaboration's tool and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist.ResultsA total of 16 eligible studies were included in the review. All studies met CHEERS recommendations, and all randomized controlled trials (RCTs) in these studies were rated as having low risk of bias using the Cochrane Collaboration's tool. The treatment regimens compared were ICIs plus EP or EP alone. All studies mainly used incremental quality-adjusted life year and incremental cost-effectiveness ratio as outcomes. Most ICIs plus EP treatment regimens were not cost-effective based on corresponding willingness-to-pay thresholds.ConclusionsAdebrelimab plus EP and serplulimab plus EP were probably cost-effective for ES-SCLC in China, and serplulimab plus EP was probably cost-effective for ES-SCLC in the U.S. Lowering the price of ICIs and selecting ES-SCLC patients who were sensitive to ICIs could improve the cost-effectiveness of the ICIs-combined treatment.

Efficacy and safety of anlotinib as maintenance therapy after induction chemotherapy in extensive-stage small-cell lung cancer.

Anlotinib has been approved as the third-line or beyond treatment regimen for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, it is indistinct whether there are survival benefits of anlotinib in the maintenance therapy of ES-SCLC. Therefore, this study aims to evaluate the efficacy and safety of anlotinib monotherapy as maintenance therapy after induction chemotherapy for patients with ES-SCLC. The median progression-free survival (mPFS) was considered to be the pivotal symbol as the primary endpoint. The median overall survival (mOS) and safety were recognized as the second endpoints. Eligible patients in stable status after first-line chemotherapy would subsequently accept oral anlotinib (12 mg/d, d1-d14, every 21 days as a course). The maintenance method was continued until disease progression or unmanageable toxicity occurred. The mPFS was 7.7 months (95% CI, 7.20-8.20 months) and the mOS was 11.0 months (95% CI, 9.19-12.82 months), respectively. The most common treatment-related adverse events were hypertension ( n = 9; 64.3%), fatigue ( n = 6; 42.9%), followed by decreased appetite ( n = 5; 35.7%), nausea ( n = 5; 35.7%), weight decrease ( n = 4; 28.6%), and rash ( n = 4; 28.6%). There were no patients who required dose reduction because of severe adverse events. Anlotinib achieved prospective efficacy and manageable safety in the maintenance treatment of ES-SCLC. These above outcomes demonstrated that anlotinib was a tolerable and potent maintenance treatment option after induction chemotherapy in ES-SCLC.

Chemo-Immunotherapy in First Line Extensive Stage Small Cell Lung Cancer (ES-SCLC): A Systematic Review and Meta-Analysis.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with early metastatic potential. The standard-of-care treatment has not changed in years. Recent studies report improved progression-free survival (PFS) and overall survival (OS) with combined ICI and chemotherapy in ES-SCLC. We conducted a systematic review and meta-analysis to assess the magnitude of survival benefits. We searched MEDLINE, EMBASE, and Cochrane between 1 January 2010 and 15 July 2022 and conference proceedings from 2018 to 2022, for randomised controlled trials, evaluating chemo-ICI compared with platinum-doublet chemotherapy in untreated ES-SCLC. Outcomes assessed were PFS, OS, objective response rate (ORR), duration of response (DoR), toxicity, and health-related quality of life (HRQoL). The search identified 8061 studies, with 8 (56 publications) included in the final analysis. PFS and OS were significantly improved for patients randomised to chemo-ICI (PFS hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.70-0.80) and (OS HR 0.79, 95% CI 0.73-0.85). Subgroup analysis demonstrated a differential effect between PD-1/PD-L1 and CTLA-4 inhibitors. There was no difference in ORR and DoR. All-grade adverse events (RR 1.06, 95% CI 1.00-1.12) were similar. The addition of ICI to chemotherapy in untreated ES-SCLC results in a 22% risk reduction in death, and a 25% risk reduction in disease progression with a minimal increase in toxicity. These improvements are modest but represent progress beyond the standard of care.

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

P48.18 Chemo-Immunotherapy in First Line Extensive Stage Small Cell Lung Cancer (ES-SCLC): A Systematic Review and Meta-Analysis

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with early metastatic potential. Standard of care with platinum-etoposide chemotherapy has not changed in 30 years. Immune checkpoint inhibitors (ICI) have recently demonstrated significant improvement in non-small cell lung cancer (NSCLC) patients. There is evidence for increased benefit of ICI in mutagenic cancers, such as SCLC, caused by exposure to carcinogens (i.e. smoking). There are now several studies that report improved progression free survival (PFS) and overall survival (OS) with combined ICI and chemotherapy in ES-SCLC. We aimed to assess the magnitude of the survival benefit of combined chemo-ICI in the first line systemic treatment of ES-SCLC as compared to standard of care chemotherapy. MEDLINE, EMBASE and the Cochrane library were systematically searched, along with abstracts from relevant major conferences (i.e. ASCO, ESMO, WCLC). We searched databases between January 1, 2010 and June 10, 2020 and limited the search of relevant meeting and conference proceedings to 2018 to 2020. Studies were included if they met the following criteria: randomized controlled trials, patients with untreated ES-SCLC treated with combined chemo-ICI as compared to standard of care chemotherapy. Any chemo-ICI pairings were eligible including PD-1 inhibitors, PD-L1 inhibitors and CTLA-4 inhibitors, combined with platinum-etoposide or platinum-paclitaxel chemotherapy. Trials were excluded if patients were being treated in the second or further line. Relevant outcomes of interest were survival outcomes (PFS and OS), measures of response (objective response rate (ORR), duration of response (DoR)), and toxicity (Grade 1-4 toxicity, Grade 3-4 toxicity). A total of 2705 studies and abstracts were identified in our initial search, with 6 studies (33 publications) included in the final analysis. PFS was significantly improved for patients randomized to chemo-ICI compared with chemotherapy alone (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.75-0.87). Similarly, OS was significantly improved (HR 0.82, 95% CI 0.76-0.89). The between-study heterogeneity was low (I2 0%) for both outcomes. A prespecified subgroup analysis demonstrated no evidence of any significant differential effect between PD-1/PD-L1 inhibitors and CTLA-4 inhibitors. The pooled ORR as expressed as a risk ratio comparing chemo-ICI with chemotherapy alone was 1.04 (95% CI 0.98-1.10) and the pooled duration of response demonstrated a mean difference of 0.09 months (95% CI -0.13-0.32) in favor of chemo-ICI. There were no significant increases in either all grade adverse events (pooled risk ratio of 1.03, 95% CI 1.01-1.06), or grade 3-4 adverse events (risk ratio of 1.06, 95% CI 0.99-1.13). Multiple trials have assessed the efficacy of combined chemo-ICI regimens. They consistently demonstrate survival improvements in both PFS and OS with combined chemo-ICI. This review demonstrates an approximate18% risk reduction in death, and 19% risk reduction in disease progression. The pooled analysis suggests a minimal increase in toxicity with chemo-ICI regimens though clinically relevant toxicity (Grade 3-4 toxicity) crossed null. Chemo-ICI appears to offer survival benefit with potentially equivalent toxicity profile in the setting of first line ES-SCLC regardless of the class of ICI.

Cost-effectiveness of adding durvalumab to first-line chemotherapy for extensive-stage small-cell lung cancer in China

ABSTRACT Objectives Durvalumab plus chemotherapy could significantly improve overall survival compared with chemotherapy alone in the first-line treatment of extensive-stage small-cell lung cancer (SCLC). However, its long-term economic outcomes remain unclear yet. This study aimed to evaluate the cost-effectiveness of adding durvalumab to first-line chemotherapy for extensive-stage SCLC from the perspective of the Chinese health-care system. Methods A decision-analytic model with 10-year horizon was developed to estimate the health and economic outcomes of adding durvalumab to first-line treatment for extensive-stage SCLC. The primary outcomes included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Costs and utility values were obtained from the published literature. A scenario analysis for a patient assistance program (PAP) was conducted. Sensitivity analyses were performed to explore the robustness of the model outcomes. Results Durvalumab plus chemotherapy yielded additional 0.25 QALYs, with incremental costs of 76,354 USD, resulting in an ICER of 302,051 USD/QALY compared with chemotherapy alone, when PAP was available, the ICER was 192,591 USD/QALY. Sensitivity analyses confirmed the robustness of model outcomes. Conclusion Adding durvalumab to first-line chemotherapy for extensive-stage small-cell lung cancer is unlikely to be cost-effectiveness in China.

Myelopreservation and reduced use of supportive care with trilaciclib in patients with small cell lung cancer.

12096 Background: Chemotherapy (CT) is a mainstay of cancer treatment; however, its side effects, notably myelosuppression, cause significant suffering. Trilaciclib (T) is an IV CDK4/6 inhibitor that protects hematopoietic stem and progenitor cells by preventing proliferation during CT administration. Results from three randomized, double-blind, placebo (P)-controlled phase II trials in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) have previously been reported. Data from these studies were pooled to understand the effects of T on specific myelosuppression endpoints with greater statistical precision. Methods: All pts received standard CT (etoposide/carboplatin [E/C], E/C/atezolizumab, or topotecan) plus T or P. Analyses were conducted on pooled intent-to-treat datasets from three ES-SCLC studies (NCT02499770; NCT03041311; NCT02514447). Results: 123 pts were treated with T and 119 with P. Median age in both groups was 64 years. Addition of T decreased measures of myelosuppression and the need for supportive care interventions (Table). From the pooled dataset, median OS and PFS (months [95% CI]) were comparable between pts treated with T vs P (OS: 10.6 [9.1, 11.7] vs 10.6 [7.9, 12.8]; PFS: 5.3 [4.6, 6.1] vs 5.0 [4.4, 5.5], respectively). Fewer pts on T had grade 3/4 hematologic events (54 [44.3%]) vs P (91 [77.1%]). Among pts who continued after cycle 1, 11 pts (9.2%) treated with T had ≥1 CT dose reduction vs 36 (30.8%) with P. Conclusions: T significantly and meaningfully reduced both CT-induced myelosuppression and its consequences, with no detrimental effect on PFS or OS, thus improving the patient experience with CT in ES-SCLC. T has potential to become a new standard of care for preventing myelosuppression in SCLC. [Table: see text]

Atezolizumab and platinum-based chemotherapy in extensive-stage small cell lung cancer: A single center experience.

e21110 Background: In extensive stage small-cell lung cancer (ES-SCLC) immune check-point inhibitors, atezolizumab and durvalumab, when combined with chemotherapy in the first-line setting show better efficacy than chemotherapy alone with safety profile similar as the adverse events of individual agents. Methods: We administered atezolizumab, etoposide and platinum, either carboplatin or cisplatin, in the first-line treatment in 24 newly diagnosed patients with ES-SCLC. Patients were treated until disease progression or unacceptable toxicity. Results: Out of 24 treated patients 13 were males and 11 were females, median age 61 (ranging from 44 to 80). Majority of patients were ECOG 1. Median number of atezolizumab doses was 8 (ranging from 2 to 11). We observed median progression free survival of 6 months (95%CI 4,28-7,72), while median overall survival was not reached. 10 patients (41%) are still undergoing treatment and 9 patients (37%) have died. Immune-related adverse events occurred in 6 patients (25%). Four patients developed pneumonitis (all of them CTCAE grade 2), two patients colitis (CTCAE grade 2 and 3) and one patient rash, CTCAE grade 3. Median treatment pause was 5 weeks (ranging from 3 to 12 weeks). There were no treatment discontinuations due to adverse events nor treatment related deaths. Conclusions: Atezolizumab combined with chemotherapy in ES-SCLC showed good tolerability and effectiveness in real world setting. Our data are consistent with published clinical trial data. There was no new safety signal in our patient cohort. Limitations of our report are small sample size and short follow-up time.

Irinotecan-platinum combination therapy for previously untreated extensive-stage small cell lung cancer patients: a meta-analysis

BackgroundThere is still a debate regarding whether regimens combining irinotecan with platinum could replace regimens combining etoposide with platinum, as first-line chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). We performed a meta-analysis to compare these regimens as first-line chemotherapy for ES-SCLC.MethodsA literature search for randomized controlled trials was performed using the Cochrane Library, PubMed, and Embase. The inverse variance method was used to estimate summary hazard ratios and their 95% confidence intervals for overall survival and progression free survival. Relative risk was used to estimate the overall response rate, disease control rate, 1-year survival, 2-year survival, and adverse event data.ResultNine randomized controlled trials (2451 patients) were included. Regimens combining irinotecan and platinum improved overall survival, progression-free survival and overall response rate compared to combination etoposide and platinum regimens. Meanwhile, superior progression-free survival and overall response rate outcomes were observed in the Asian subgroup of patients. These patients receiving a combination irinotecan and platinum regimen experienced grade 3–4 diarrhea more frequently and experienced less hematologic toxic events than the non-Asian groups.ConclusionsOur data suggest that a combination irinotecan and platinum regimen can prolong overall survival, progression-free survival and overall response rate for patients with ES-SCLC as compared to a combination etoposide and platinum regimen. And the Asian patients could benefit from irinotecan combined with platinum easier.

Irinotecan-Based Regimen as Second-Line Chemotherapy for Extensive- Stage Small Cell Lung Cancer

Purpose: This study evaluates the clinical outcomes of extensive-stage small-cell lung cancer (SCLC) patients who received Irinotecan-based second-line chemotherapy after platinum-based first-line therapy, especially focused on efficacy and toxicity between single-agent and doublet chemotherapy. Patients and methods: We retrospectively reviewed 83 patients who given irinotecan-based second-line chemotherapy for extensive-stage SCLC. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis. Results: Fifty-nine patients received doublet chemotherapy and 24 with single-agent treatment. The objective response rate (ORR) was 23.7% in the doublet group and 25% in the single-agent group (P=0.90). The disease control rate (DCR) was 65.7% and 58.3%, respectively, (P=0.71). The Progression-free survival (PFS) was 3.10 months in the doublet group and 2.10 months in the single-agent group (P=0.35). In the sensitive recurrence group, 27 patients were with doublet chemotherapy and 10 with single-agent treatment. The Median PFS was 4.73 months (95% CI: 4.37-5.09) and 3.83months (95% CI: 2.65-5.02), respectively (P=0.543). In the refractory recurrence group, there were 32 patients with doublet chemotherapy and 14 with single-agent treatment. The median PFS was 2.57 months (95% CI: 2.19-2.93) and 1.40 months (95% CI: 1.13-1.64), respectively (P=0.048). The grade III/IV toxicity in single-agent group is lower than doublet group (45.8% vs.71.2%, P=0.029). No difference was found in cancerrelated symptoms improvement between the doublet and single group (P=0.36). Conclusion: Patients with extensive-stage SCLC could benefit from irinotecan-based second-line treatments. The refractory recurrence patients with doublet treatment obtain a moderate PFS advantage than single-agent chemotherapy.

Retrospective study of irinotecan/cisplatin followed by etoposide/cisplatin or the reverse sequence in extensive-stage small cell lung cancer.

BackgroundMuch research has confirmed the favorable effect of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) on extensive-stage small cell lung cancer (E-SCLC). This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC.MethodsNinety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS), ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP.ResultsMedian overall survival was 15.4 months in group A (IP followed by EP) versus 15.7 months in group B (EP followed by IP; P=0.483). The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361). As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256). Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as second-line treatment developed grade 3/4 neutropenia than those who received the IP regimen as first-line therapy.ConclusionThere were no statistically significant differences in between the two sequences of IP and EP in the treatment of E-SCLC. Except EP regimen, IP may be another reserved regimen in the first-line treatment of E-SCLC.

Phase I study of dose-dense chemotherapy (DDC) alternating cisplatin (CDDP), topotecan (TPT), and paclitaxel (PTX) with CDDP, amrubicin (AMR), and PTX under granulocyte colony-stimulating factor support for extensive-stage small-cell lung cancer (ES-SCLC).

e18553 Background: Platinum-based combination is the mainstay of chemotherapy for ES-SCLC, with limited recent fruit of new agent development. In terms of treatment modality, dose-intensive chemoth...

Second-line Chemotherapy and Its Survival Analysis of 181 Patients with Extensive-stage Small Cell Lung Cancer in a Single Institute

背景与目的小细胞肺癌（small cell lung cancer, SCLC）是恶性程度极高的神经内分泌肿瘤，对放化疗敏感，但大多数接受一线化疗的患者在1年-2年内复发。一旦疾病复发，预后不良。目前，广泛期SCLC的一线标准化疗方案为铂类联合依托泊苷方案，二线化疗方案尚无定论。该研究分析二线化疗预后的影响因素；比较不同二线化疗方案的近期疗效、不良反应和远期生存情况的差异。方法回顾性分析接受二线化疗的181例广泛期SCLC患者的临床资料。根据不同化疗方案分为6组，采用χ2检验比较计数资料和各组组成差异。采用Kaplan-Meier法分析总生存时间（overall survival, OS）和无进展生存时间（progression-free survival, PFS）。采用单因素和Cox回归多因素分析方法分析生存期的影响因素。结果二线化疗的中位OS为7.0个月，单因素和多因素的分析结果表明吸烟情况（P=0.004）、ECOG评分（P < 0.001）、肝转移（P=0.019）和骨转移（P=0.028）是影响二线化疗OS的独立影响因素；二线化疗的中位PFS为3.0个月，吸烟（P=0.034）、ECOG评分（P=0.011）和骨转移（P=0.005）是二线化疗PFS的独立影响因素。6组有效率有明显差异（χ2=12.413, P=0.017），两两比较各组无明显差异；副反应方面，伊立替康组胃肠道反应的发生率明显高于其它组；6组的OS和PFS无统计学差异（χ2=1.491, P=0.914; χ2=6.133, P=0.293）。结论ECOG评分是影响广泛期SCLC二线化疗预后的最重要因素。广泛期SCLC的二线化疗尚无疗效确切的最优方案。

Single-agent chemotherapy compared with combination chemotherapy as second-line treatment in extensive-stage small cell lung cancer: a retrospective analysis

This retrospective analysis evaluates the clinical outcomes of extensive-stage small cell lung cancer (SCLC) patients who received second-line chemotherapy after platinum-based first-line chemotherapy, especially focusing on efficacy and toxicity between single-agent and combination chemotherapy. We retrospectively reviewed 193 patients who received second-line chemotherapy for extensive-stage SCLC. Patients relapsing or progressing beyond 90 days were defined as sensitive recurrence patients, and below 90 days as refractory recurrence patients. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. 138 patients received combination chemotherapy and 55 received single-agent treatment. The objective response rate (ORR) was 25.4 % in the combination group and 9.1 % in the single-agent group (p = 0.012). The disease control rate (DCR) was 65.2 and 34.5 %, respectively, (p < 0.001). The progression-free survival (PFS) was 3.80 months in the combination group and 2.13 months in the single-agent group (p = 0.001). In the sensitive recurrence group, the median PFS was 3.80 months in combination group and 3.23 months in single-agent group (p = 0.092). In the refractory recurrence group, the median PFS was 2.83 and 1.30 months, respectively (p = 0.001). The grade III/IV toxicity in single-agent group is much lower than the combination group (56.4 vs. 74.6 %, p = 0.013). Our retrospective data suggest a potential role of prolonging the PFS for combination treatment in extensive-stage SCLC second-line treatment, especially for the refractory recurrence patients, but with more toxicity as compared to single-agent.

Progress in Small-Cell Lung Cancer: The Lowest Common Denominator

Progress in the therapy of small-cell lung cancer (SCLC), commonly viewed at initial presentation as one of the most highly chemotherapy-sensitive solid tumors, has been painfully slow. In fact, it could be argued that little to no therapeutic advances have been made for extensive stage patients in more than 20 years. In a disease uniquely positioned from its causal biology and growth kinetics to be vulnerable to both new chemotherapeutic drug classes and the wealth of targeted therapeutic agents which have entered clinical development within the last decade, why has so little progress been made? In this issue of Journal of Clinical Oncology, Hermes et al present a randomized trial in extensive SCLC comparing oral etoposide plus carboplatin (EC) to a newer chemotherapeutic regimen of considerable interest: irinotecan and carboplatin (IC). The authors conclude that IC prolongs survival over EC, without compromising quality of life, supporting the use of this regimen as a new standard in SCLC. Viewed from a North American perspective, the Hermes et al trial clearly raises as many questions as it answers. Are the conclusions warranted? Does the regimen share a common denominator with other recent reports in the literature, or is it a one-of-a-kind experience? Finally, does this study truly represent progress in SCLC? To address these questions, we first must consider current treatment perspectives for extensive-stage SCLC. Although regional differences exist, in North America and worldwide, first-line chemotherapy for extensive stage SCLC most commonly consists of a platinum agent (cisplatin or carboplatin) combined with multiday intravenous etoposide. Attempting to build on this platform, several randomized phase III trials, all published in JCO, have disappointingly shown no survival advantage with the addition of topotecan consolidation, paclitaxel, Bec-2 vaccination, or thalidomide to a platinum-etoposide backbone. However, in 2002, the Japan Clinical Oncology Group published the striking results of J9511, a small phase III trial demonstrating the superiority of irinotecan and cisplatin (IP) over etoposide and cisplatin (EP) in response rate, progression-free survival (PFS) and survival, both overall and at 1 and 2 years. Was this the advance we had been waiting for? In view of pharmacogenomic considerations for irinotecan in Japanese populations and the limited patient sample size in J9511 due to Data Safety Monitoring Board–mandated early closure, confirmatory studies were launched. Using a modified dose schedule of IP, Hanna et al were unable to demonstrate superiority over EP. Most recently, at the 2008 Annual Meeting of the American Society of Clinical Oncology, the Southwest Oncology Group reported results of S0124, a large phase III study comparing IP to EP, in which the treatment regimens utilized in J9511 were exactly duplicated. While there were no significant efficacy differences observed between IP and EP in this North American population, a patient-level toxicity comparison of S0124 and J9511 confirmed greater toxicity in the Japanese study. Table 1 compares key parameters regarding patient demographics and end points of the four phase III trials comparing irinotecan and platinum to etoposide and platinum regimens. Clearly, the study by Hermes et al stands out in several ways: eligibility criteria (performance status [PS] 0 to 4 and brain metastases), use of oral etoposide, dose of carboplatin (area under the curve, 4), and age-mandated cycle 1 dose reductions, to name some of the most obvious. These differences in study design and patient characteristics may explain differences in survival outcomes; the Hermes et al trial reports the shortest overall survival times; response rates and PFS were not reported. Moreover, arbitrary dose reductions for patients older than age 70 may also have adversely affected survival times in the Hermes et al study. More than half of all new lung cancer patients are older than 70 years of age. The rationale for empiric age-related dose reductions in the Hermes et al study is unclear because older patients appear to tolerate chemotherapy as equally well as younger patients with similar PS and equal degrees of comorbidities. Potential pharmacogenomic variability in irinotecan metabolism due to genetic polymorphisms of uridine diphosphateglucuronosyltransferase is another dimension worth considering. Both interindividual and population-related differences are well recognized. While this factor was not assessed in the Hermes et al trial, other recent studies suggest it is of clinical significance in predicting the therapeutic index of this agent, including a preliminary report from the S0124 study. In addition, the treatment regimens selected for the Hermes et al trial may have contributed to reduced efficacy in both arms of the study. For example, despite initial enthusiasm, use of oral etoposide has fallen substantially in the United States. This is in part due to interpatient differences in bioavailability and pharmacodynamics, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 26 SEPTEMBER 1

Chemotherapy versus best supportive care for extensive small cell lung cancer.

Combination chemotherapy has been the mainstay of treatment for extensive stage small cell lung cancer (SCLC) over the last 25 years even though it only gives a short prolongation in median survival time. The main goal for these patients, if their survival prognosis is limited, should be adequate palliation with the aim of improving their quality of life. To evaluate the effectiveness of chemotherapy in extensive SCLC compared with best supportive care (BSC) or placebo treatment. Medline (1966-Jan 2003), Embase (1974-Jan 2003), Cancerlit (1993-Jan 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2002) were searched. In addition experts in the field were contacted to identify further studies not found by electronic searches. Randomised controlled trials in which any chemotherapy treatment was compared with a placebo group or best supportive care in patients with extensive stage SCLC. Data extraction and quality assessment were undertaken independently by two reviewers and disagreements were resolved by a third author. Additional information on the included studies was obtained from the author of the original studies. Only two studies (the first published in 1977 and the second in 1982) met the inclusion criteria of the review. A total of 65 patients with extensive disease (33 in the first study and 32 in the second) were randomised to received either placebo treatment or ifosfamide. In the second study a third arm of comparison included ifosfamide plus CCNU. Ifosfamide gave an extra 78.5 days survival (mean survival time) compared with the placebo group. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group. Pooled analysis was not possible because only mean survival time was reported in both studies for patients with extensive disease. Chemotherapeutic treatment prolongs survival in comparison with placebo in patients with advanced SCLC. Nevertheless the impact of chemotherapy on quality of life and in patients with poor prognosis is unknown. Well-designed, controlled trials are needed to further evaluate the risks and benefits of different chemotherapeutic schedules in patients with advanced small cell lung cancer.