Treatment of Small Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians (ACCP) Guideline Table of Contents Data Supplement 1: Summary of included studies from updated search Data Supplement 2: Original recommendations with qualifying statements Data Supplement 3: ACCP Grade of Recommendation table Data Supplement 4: Search Strategy String and Dates
Data Supplement 1: Summary of included studies from updated search Table 1: Included studies from updated search Author/ year Study design Population Intervention Primary Outcome Summary of findings Fink et al., 2012 Phase III RCT Chemo-naive patients with ED- SCLC Topotecan-Cisplatin (TP) (n=346) Cisplatin-Etoposide (PE) (n=343) OS (superiority of TP compared with PE, with the possibility to switch to a noninferiority test) Median survival was similar in TP compared to PE (44.9 versus 40.9 weeks; p = 0.40). One-year survival rate was 39.7% for TP versus 36.1% for PE (p = 0.29). Median time to progression was significantly longer with TP compared to PE (27.4 versus 24.3 weeks, p=0.01). Overall response rates were significantly higher for TP compared to PE (55.5% versus 45.5%, p = 0.01). Hematologic toxicity was slightly higher for TP compared to PE: G 3/4 neutropenia (35.7/35.8%), G 3/4 thrombocytopenia (18.7/4.8%), G 3/4 anemia (11.6/6.7%), febrile neutropenia (2.0/2.7%), sepsis (1.7/1.2%), and toxicity-related deaths (5.2/2.7%). Authors conclusions: TP is noninferior to PE in overall survival and superior in time to progression and overall response rates. Because of slightly worse toxicity profile TP is not a first-line standard treatment for patients with ED-SCLC. Satouchi et al., 2014 Phase III RCT Chemo-naive patients with ED- SCLC Amrubicin + Cisplatin (AP) (n=142) OS The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. Irinotecan + Cisplatin (IP) Updated analysis: median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85) Median PFS was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was
Author/ year Study design Population Intervention Primary Outcome Summary of findings (n=142) 72.3% (IP) versus 77.9% (AP; P=.33). Adverse events: IP vs AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). Authors conclusions: AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan Jotte et al., 2011 Phase II RCT LS or ES-SCLC patients that were sensitive to first-line platinum-based chemotherapy. Amrubicin (n=50) ORR Amrubicin treatment showed significantly higher ORR than topotecan (44% v 15%; P=.021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. Topotecan (n=26) Grade 3 or worse neutropenia and thrombocytopenia was more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively). Authors conclusions: Amrubicin showed promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Schmittel et al., Phase III RCT Chemo-naive patients with ED- Irinotecan-carboplatin (IP) PFS Median PFS was 6.0 months [95% confidence interval (CI) 5.0 7.0] in the IP arm and 6.0 months
Author/ year Study design Population Intervention Primary Outcome Summary of findings 2011 SCLC (n=106) Etoposide-carboplatin (EP) (n=110) (95% CI 5.2 6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4 11.6) and 9.0 months (95% CI 7.6 10.4) in the IP and EP arm (P = 0.06), respectively. HR for disease progression and OS were 1.29 (95% CI 0.96 1.73, P = 0.095) and 1.34 (95% CI 0.97 1.85, P = 0.072), respectively. Response rates were similar in both groups. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. Authors conclusion: This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin. Spigel et al., 2011 Placebocontrolled, double-blind, Chemo-naive patients with ED- SCLC Placebo + chemotherapy (n=50) PFS Median PFS was higher in the bevacizumab group (5.5 months) than in the placebo group (4.4 months; hazard ratio [HR], 0.53; 95% CI, 0.32 to 0.86). phase II RCT Median OS was similar for both groups (9.4 v 10.9 months for bevacizumab and placebo groups, respectively), with an HR of 1.16 (95% CI, 0.66 to 2.04). Bevacizumab + Chemotherapy (n=52) ORR were 58% (95% CI, 43% to 71%) for the bevacizumab group and 48% (95% CI, 34% to 62%) for the placebo group. Median duration of response was 4.7 months for the bevacizumab group and 3.2 months for the placebo group. In the bevacizumab and placebo groups, 75% versus 60% of patients, respectively, experienced one or
Author/ year Study design Population Intervention Primary Outcome Summary of findings more grade 3 or higher adverse events. Authors conclusions: The addition of bevacizumab to cisplatin or carboplatin plus etoposide for treatment of ED- SCLC improved PFS, with an acceptable toxicity profile. However, no improvement in OS was observed. Von Pawel et al., 2014 Phase III RCT Patients with refractory or sensitive LS or ES-SCLC Amrubicin (n=424) OS Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (HR, 0.880; P=.170). In refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P=.047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P=.018). Topotecan (n=213) ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P <.001). Grade 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P =.004), thrombocytopenia (21% v 54%; P<.001), anemia (16% v 31%; P<.001), infections (16% v 10%; P=.043), febrile neutropenia (10% v 3%; P =.003), and cardiac disorders (5% v 5%; P=.759); transfusion rates were 32% and 53% (P <.001), respectively. Authors conclusions: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin. Radiotherapy
Author/ year Study design Population Intervention Primary Outcome Summary of findings Kubota et al., 2014 Phase III RCT Patients with LS- SCLC Etoposide + cisplatin + AHTRT OS In the etoposide plus cisplatin group, median OS was 3.2 years (95% CI 2.4 4.1). (n=129) In the irinotecan and cisplatin group, median OS was 2.8 years (95% CI 2.4 3.6); OS did not differ between the two groups (HR 1.09 [95% CI 0.80 1.46], onesided stratified log-rank p=0.70). Irinotecan + cisplatin (n=129) The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group. Authors conclusions: Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for LS-SCLC. Slotman et atl., 2015 Phase III RCT Patients with ES-SCLC who responded to chemotherapy Thoracic radiotherapy (30 Gy in ten fractions) (n=247) OS All patients underwent prophylactic cranial irradiation. OS at 1 year was not significantly different between groups: 33% (95% CI 27 39) for the thoracic radiotherapy group versus 28% (95% CI 22 34) for the control group (HR 0.84, 95% CI 0.69 1.01; p=0.066). No thoracic radiotherapy (n=248) In secondary analysis, 2-year OS was 13% (95% CI 9 19) versus 3% (95% CI 2 8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61 0.87; p=0.001). At 6 months, PFS was 24% (95% CI 19 30) versus
Author/ year Study design Population Intervention Primary Outcome Summary of findings 7% (95% CI 4 11; p=0.001). No severe toxic effects were reported. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (3 vs 4). Authors conclusion: Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. Wolfson et al., 2011 Phase II RCT Patients with LD- SCLC who achieved a complete response following chemotherapy and thoracic irradiation PCI 2.5 Gy 10 (Arm 1) (n=131) Neuropsychological test batteries (NPTB) and QoL There are 112 (42.2%) pts alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding QoL measures and one of the NPTB, namely the Hopkins Verbal Learning Test. There was a significant increase in the occurrence at 12 months post-pci of CNt in the 36 Gy cohort (p=0.02). 2.0 Gy 18 (Arm 2) (n=67) Logistic regression analysis revealed increasing age was the most significant predictor of CNt (p=0.005). Authors conclusions: Due to the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a CR to initial chemoradiation. 1.5 Gy 24 (Arm 3) (n=66) Abbreviations: LS, Limited stage; ES, Extensive stage, SCLC, Small cell lung cancer; OS, Overall Survival; ORR, Overall response rate; PFS, Progression free survival; PCI, Prophylactic cranial irradiation; CNt, Chronic neurotoxicity
Other clinical practice guidelines picked up from the search: 1. Fruh M, De Ruysscher D, Popat S, et al: Small-cell lung cancer (SCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 24:vi99-vi105, 2013 2. Kalemkerian GP, Akerley W, Bogner P, et al: Small cell lung cancer: Clinical practice guidelines in oncology. JNCCN Journal of the National Comprehensive Cancer Network 11:78-98, 2013
Data Supplement 2: Original recommendations with qualifying statements ACCP Recommendations 2.4.1: In patients with SCLC (proven or suspected), a staging evaluation is recommended consisting of a medical history and physical examination, CBC and comprehensive chemistry panel with renal and hepatic function tests, CT of the chest and abdomen with intravenous contrast or CT scan of the chest extending through the liver and adrenal glands, MRI or CT of the brain, and bone scan (Grade 1B) Qualifying statements If PET is obtained, then bone scan may be omitted. 2.4.2: In patients with clinically limited-stage (LS)-SCLC, PET imaging is suggested (Grade 2C). Remark: If PET is obtained, then bone scan may be omitted. PET scan will also be applicable to ES-SCLC 2.4.3: In patients with SCLC, it is recommended that both the Veterans Administration system (LS vs extensive stage [ES]) and the American Joint Committee on Cancer/International Union Against Cancer seventh edition system (TNM) should be used to classify the tumor stage (Grade 1B). 3.1.1: In patients with clinical stage I SCLC, who are being considered for curative intent surgical resection, invasive mediastinal staging and extrathoracic imaging (head MRI/CT and PET or abdominal CT plus bone scan) is recommended (Grade 1B). 3.1.2: In patients with clinical stage I SCLC after a thorough evaluation for distant metastases and invasive mediastinal stage evaluation, surgical resection is suggested over non-surgical treatment (Grade 2C). 3.1.3: In patients with stage I SCLC who have undergone curative-intent surgical resection, platinum-based
adjuvant chemotherapy is recommended (Grade 1C). 4.3.1: In patients with LS-SCLC, early chemoradiotherapy, with accelerated hyper-fractionated radiation therapy (twice-daily treatment) concurrently with platinum-based chemotherapy, is recommended (Grade 1B). Comparison of accelerated hyperfractionated radiotherapy with an extended course of daily radiation at standard fractionation is currently being investigated. 4.3.2: In patients with LS- or ES-SCLC who achieve a complete or partial response to initial therapy, prophylactic cranial irradiation is recommended (Grade 1B). Remark: The regimen of 25 Gy in 10 daily fractions has the greatest supporting data for safety and efficacy. The panel notes that a recent Japanese study failed to demonstrate survival advantage with PCI in patients with extensive stage SCLC. Upon publication of the mature data from this study, the recommendation for PCI in extensive stage SCLC might be subject to revision 4.3.3: In patients with ES-SCLC who have completed chemotherapy and achieved a complete response outside the chest and complete or partial response in the chest, a course of consolidative thoracic radiotherapy (TRT) is suggested (Grade 2C). Further evaluation of this question is required before a treatment recommendation can be made. 6.1.1: In patients with either LS- or ES-SCLC, four to six cycles of platinum-based chemotherapy with either cisplatin or carboplatin plus either etoposide or irinotecan is recommended over other chemotherapy regimens (Grade 1A). Clinical trials in the US and Europe have not demonstrated a benefit for the Irinotecan regimen over the etoposide. In LS disease four cycles may be preferred. 7.1.1: In patients with relapsed or refractory SCLC, the administration of second-line, single agent chemotherapy is recommended (Grade 1B). Remark: Reinitiation of the previously administered first-line chemotherapy regimen is recommended in patients who relapse. 6 months from completion of initial chemotherapy. Enrollment in a clinical trial is encouraged.
8.1.1: In elderly patients with LS-SCLC and good performance status (PS) (Eastern Cooperative Oncology Group [ECOG] 0-2), treatment with platinum-based chemotherapy plus TRT is suggested, with close attention to management of treatment-related toxicity (Grade 2B). 8.1.2: In elderly patients with ES-SCLC and good PS (ECOG 0-2), treatment with carboplatin-based chemotherapy is suggested (Grade 2A). 8.1.3: In elderly patients with SCLC and poor PS, treatment with chemotherapy is suggested if the poor PS is due to SCLC (Grade 2C).
Data Supplement 3: ACCP Grade of Recommendation table
Data Supplement 4: Search Strategy String and Dates Ovid Medline strategy Search Date: 04 Mar 2015 1 Carcinoma, Non-Small-Cell Lung/ or NSCLC.tw. or (non adj small).tw. or nonsmall.tw. 2 ((small adj cell adj lung adj3 (tumo?r$ or adenocarcinoma$ or cancer$ or carcinoma$ or neoplasm$)) or SCLC).tw. or (oatcell or oat-cell or oat cell).af. 3 2 not 1 [non-small-cell taken out of TW search] 4 Small Cell Lung Carcinoma/ 5 3 or 4 [All SCLC] 6 1 and 5 [NSCLC and SCLC citations] 7 5 or 6 [SCLC or NSCLC and SCLC] 8 clinical trial.pt. 9 random.mp. 10 (clinical trial or clinical trials).mp. 11 (tu or th or ad or ae or dt or rt).fs. 12 exp Treatment Outcome/ 13 (treatment adj2 (effectiv$ or efficacy)).mp. 14 or/8-13 [All Therapy] 15 7 and 14 16 limit 15 to humans 17 limit 15 to animals 18 15 not 16 not 17 19 16 or 18 20 limit 19 to (english and yr= 2011-Present") 21 (case reports or comment or editorial or in vitro or letter).pt. 23 20 not 21