Refractory Relapsed Small-cell Lung Cancer Research Articles

Safety and efficacy of amrubicin with primary prophylactic pegfilgrastim as second-line chemotherapy in patients with small cell lung cancer.

Amrubicin (AMR) regimens have shown efficacy as second-line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P-PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P-PEG as second-line chemotherapy for SCLC. We retrospectively reviewed patients with SCLC who received AMR as second-line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P-PEG in their regimen, patients (n = 60) were divided into P-PEG (n = 21) and non-P-PEG groups, and their clinical outcomes were evaluated. Median of AMR treatment cycles was five (range: 1-39 cycles) in P-PEG group and four (range: 1-15 cycles) in non-P-PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P-PEG group than in the non-P-PEG group. The objective response rates were 52.4% and 30.8%, and median progression-free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P-PEG and non-P-PEG groups, respectively. AMR with P-PEG as second-line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P-PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Impact of nab-paclitaxel plus PD-1/PD-L1 inhibitor on chemorefractory relapsed small-cell lung cancer.

Background: The present study evaluated the efficacy and safety of nab-paclitaxel (nab-PTX) with a concurrent PD-1/PD-L1 inhibitor in patients with refractory relapsed small-cell lung cancer (SCLC). Patients & methods: We retrospectively analyzed 240 patients with refractory relapsed SCLC: 40 patients were treated with nab-PTX plus PD-1/PD-L1 inhibitor, and 200 received traditional chemotherapy. Results: Median progression-free survival in the nab-PTX plus PD-1/PD-L1 inhibitor and traditional chemotherapy groups was 3.6 and 2.5months (p=0.0021), respectively. The median overall survival was 8.0 and 5.2months (p=0.0002), respectively. No new safety issues were identified. Conclusion: Nab-PTX plus PD-1/PD-L1 inhibitor significantly improved survival in patients with refractory relapsed SCLC compared with traditional chemotherapy.

Analysis of the Efficacy of Irinotecan in the Second-line Treatment of Refractory and Relapsed Small Cell Lung Cancer

背景与目的肺癌死亡率在恶性肿瘤中高居首位，小细胞肺癌（small cell lung cancer, SCLC）是肺癌恶性程度最高的一种，其倍增时间短，患者在治疗过程中易发生迅速耐药，且复发后病情迅速恶化。目前除拓扑替康外，缺乏有效的二线单药化疗方案。本研究旨在探究伊立替康（irinotecan, CPT-11）二线单药治疗难治性复发SCLC的疗效及安全性。方法收集吉林国文医院肿瘤内科2012年4月-2020年3月确诊的一线治疗后6个月内复发的经单药CPT-11二线化疗的SCLC患者107例，末次随访至2020年11月。记录患者的无进展生存时间（progression free survival, PFS）和总生存时间（overall survival, OS），观察单药CPT-11化疗效果以及不良反应发生情况。结果患者的中位PFS为3.8（3.4-4.4）个月，中位OS为8.1（6.5-10.9）个月，客观缓解率（objective response rate, ORR）为16.82%（18/107），DCR为55.14%（59/107），3级-4级不良反应发生率较低，其中中性粒细胞减少为13.08%，迟发性腹泻为7.48%，恶心呕吐为17.76%，肝功能受损为6.54%。影响单药CPT-11二线化疗患者PFS的因素有性别（P=0.001）、NSE（P=0.029）以及积液状态（P=0.040），影响OS的因素仅为NSE水平（P=0.033）。结论针对于难治性复发的SCLC患者，CPT-11单药二线化疗方案有一定疗效，耐受较好，值得推广应用。

Efficacy of second-line chemotherapy in poor-risk patients with refractory-relapsed small-cell lung cancer.

The treatment efficacy of second-line chemotherapy in poor-risk patients with refractory-relapsed small-cell lung cancer is unclear. We defined refractory relapse as treatment-free interval <90 days and poor-risk as Eastern Cooperative Oncology Group Performance Status ≥2. We retrospectively examined the medical record data of patients who were treated at our hospital between September 2002 and December 2014. Twenty-three poor-risk patients with refractory-relapsed small-cell lung cancer were treated in our hospital. The characteristics of patients at the time of first-line treatment were as follows: median age (range) 71 (57-83) years; male 74%; extensive disease 96%; proportion of patients with PS 0 or 1 and those with 2-4 was 43 and 57%, respectively; median treatment-free interval 26 days. Amrubicin was the most commonly used drug and was administered in 15 patients (65%). The overall response rate of all patients was 22%. Median progression-free survival and overall survival was 2.2 and 3.7 months, respectively. Among patients treated with amrubicin, overall response rate was 13%, median progression-free survival was 2.2 months, and median overall survival was 3.9 months. The most common grade 3 or worse adverse events were hematologic toxicities, including leukopenia (66%), neutropenia (69%), thrombocytopenia (9%) and anemia (22%). Febrile neutropenia was observed in two patients (9%). Second-line chemotherapy might have poor efficacy to poor-risk patients with refractory-relapsed small-cell lung cancer.

Phase II study of amrubicin (AMR) combined with carboplatin (CBDCA) for refractory relapsed small cell lung cancer (SCLC): North Japan Lung Cancer Group 0802.

7086 Background: AMR, a new anthracycline agent, has achieved some promising results for advanced SCLC both in the first-line and the second-line setting. However the efficacy of AMR alone against refractory relapsed SCLC was relatively low in previous studies. This study was conducted to evaluate the safety and efficacy of the combination of AMR plus CBDCA in patients with refractory relapsed SCLC. Methods: Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30 mg/m2, day1-3) and CBDCA (AUC 4.0, day 1) every 3 weeks. The primary endpoint of this study was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 45% in eligible patients would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.10, at least 24 patients were required. Results: From September 2008 to May 2011, 30 patients were enrolled from 10 institutions. One patient was excluded because of ineligible histology. Patient characteristics were: Male/Female 26/3; median age 67 (range 50-81); Performance status 0/1/2 9/16/4. The median number of treatment cycles were 4 (range 1-7). The objective responses evaluated by RECIST were: CR 0, PR 10, SD 14, PD 5. The ORR was 34% and the disease control rate was 83%. Median PFS was 3.5 months and median survival time was 7.3 months. Grade 3-4 neutropenia was observed in 23 patients (79%) and grade 3-4 thrombocytopenia was observed in 7 patients (24%). One patient (3%) suffered from grade 3-4 febrile neutropenia. Other grade 3 non-hematological toxicities such as infection, interstitial lung disease, hyponatremia, hypoglycemia, were observed in 7 patients (24%). No treatment related death was observed. Conclusions: This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. Further investigation of this treatment is warranted.

Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy

While more elderly patients are being diagnosed with lung cancer every year, no anti-lung cancer therapy designed specifically for the elderly has been established yet. This is the first retrospective study to examine the efficacy and safety of amurubicin (AMR) for elderly patients with refractory relapsed small cell lung cancer (SCLC) as second or third-line chemotherapy. Thirty-six patients were eligible for analyzing the frequency of hematologic and non-hematologic toxicities and effectiveness of AMR for refractory relapsed SCLC in both elderly (≥ 70 years) and non-elderly (<70 years) groups. Among these patients as third-line chemotherapy, the response rate and the disease control rate of refractory relapsed cases were 44.4 and 55.6%, respectively. The median of progression-free survival time was 3.0 months and the median of overall survival time was 5.1 months. There were no significant differences in the frequency of the grade 3-5 hematologic or non-hematologic toxicity between the elderly (≥ 70 years) and non-elderly (<70 years) patients or second and third-line chemotherapies. AMR could be one of the effective tools in the treatment of elderly patients with refractory relapsed SCLC as third-line chemotherapy, and the recommended dose is 30 mg/m 2 for three consecutive days.

A Phase II Study of Higher Dose Weekly Topotecan in Relapsed Small-Cell Lung Cancer

BackgroundFive-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m2 intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) < 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. Patients and MethodsThis multicenter phase II trial sought a 25% ORR (α = 0.04; β = 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m2 I.V. for 6 weeks) and were restaged every 8 weeks. ResultsBaseline characteristics were N = 38, enrolled 5/2006-10/2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (> 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths. ConclusionWeekly topotecan (6 mg/m2 I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC.

Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer

Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55–73 years). Patients received the combination of amrubicin (30mg/m2 on days 1–3) plus carboplatin (with a target area under the concentration-versus-time curve of 4mgmin/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0–57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7–84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9–15.4%; p=0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1–42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p=0.004). The median progression-free survival (PFS) time was 3 months (range: 1–14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p=0.01). The most frequent grade 3–4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3–4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC.

Review of the management of relapsed small-cell lung cancer with amrubicin hydrochloride.

Lung cancer is the leading cause of cancer death, and approximately 15% of all lung cancer patients have small-cell lung cancer (SCLC). Although second-line chemotherapy can produce tumor regression, the prognosis is poor. Amrubicin hydrochloride (AMR) is a synthetic anthracycline anticancer agent and a potent topoisomerase II inhibitor. Here, we discuss the features of SCLC, the chemistry, pharmacokinetics, and pharmacodynamics of AMR, the results of in vitro and in vivo studies, and the efficacy and safety of AMR monotherapy and combination therapy in clinical trials. With its predictable and manageable toxicities, AMR is one of the most attractive agents for the treatment of chemotherapy-sensitive and -refractory relapsed SCLC. Numerous studies are ongoing to define the applicability of AMR therapy for patients with SCLC. These clinical trials, including phase III studies, will clarify the status of AMR in the treatment of SCLC.

Phase II trial of vinflunine (VFL) in sensitive and refractory relapsed small-cell lung cancer (SCLC): Updated results

19028 Background: VFL is a new microtubule inhibitor with preclinical activity in SCLC. In this multicenter, community-based phase II trial, we evaluated VFL in patients (pts) with sensitive and re...

Prognostic factors for response and survival of second-line chemotherapy in patients with relapsed small cell lung cancer (SCLC)

18023 Background: Despite high response rates to initial chemotherapy, the majority of patients with SCLC experience tumor progression. Previous studies showed that both the response to initial chemotherapy and the response duration are important for predicting the efficacy of second-line chemotherapy. Therefore, relapsed SCLC is commonly classified into two groups: sensitive relapse (respond to initial chemotherapy and relapse more than 3 months after the completion of initial chemotherapy) and refractory relapse (not respond to initial chemotherapy or respond but relapse within 3 months). However, prognostic factors of the second-line chemotherapy have not been fully understood. Methods: From July 1992 to December 2003, four hundred and seventy-four patients with SCLC received chemotherapy as initial treatment, subsequently 229 patients received second-line chemotherapy (144 sensitive relapse and 85 refractory relapse) in our hospital. We analyzed the association of patients’ clinical factors with response and survival of second-line chemotherapy in sensitive relapsed patients and refractory relapsed patients, separately. For sensitive relapsed patients, analyzed clinical factors were as follows: age (&lt;70/=70), gender (M/F), response to initial chemotherapy (CR/PR), PS at relapse (&lt;2/=2) and the extent of disease at relapse (LD/ED). For refractory relapsed patients, analyzed clinical factors were as follows: age (&lt;70/=70), gender (M/F), response to initial chemotherapy (responder/non-responder), PS at relapse (&lt;2/=2) and the extent of disease at relapse (LD/ED). Results: Response to second-line chemotherapy was significantly correlated with PS in sensitive relapsed patients, however, no significant factor was detected in refractory relapsed patients. For survival, PS was the only significant prognostic factor in both sensitive and refractory relapsed patients. The median survival time was 328 days (PS&lt;2) and 128 days (PS=2) in sensitive relapsed patients (p&lt;0.0001), while 195 days (PS&lt;2) and 113 days (PS=2) in refractory relapsed patients (p=0.0001), respectively. Conclusions: PS was the only significant prognostic factor for survival both in sensitive and refractory relapsed SCLC. No significant financial relationships to disclose.

Phase II study of weekly cisplatin, etoposide and irinotecan (PE/CPT) for refractory relapsed small cell lung cancer (SCLC)

7088 Background: There is no standard treatment for relapsed SCLC. Irinotecan and etoposide has been studied in several phase II trials as active agents for relapsed SCLC. We reported the efficacy and tolerability of irinotecan combined with weekly cisplatin and etoposide (PE) in patients (pts) with sensitive relapsed SCLC (Goto, et al. Br J Cancer 2005). Methods: We conducted a phase II study to evaluate the efficacy and toxicity of PE/CPT regimen in pts with refractory relapsed SCLC, who had relapsed within 8 weeks after completion of first-line therapy. Pts must have measurable or assessable disease, age of 75 years or younger, performance status of 0 to 2 (ECOG), and adequate organ function. PE/CPT regimen consisted of cisplatin 25 mg/m2 on day 1 at one-week intervals for 9 weeks (at least 6 weeks), etoposide 60 mg/m2 on days 1–3 on week 1, 3, 5, 7, 9 (at least on week 1, 3, 5), and irinotecan 90 mg/m2 on day 1 on weeks 2, 4, 6, 8 (at least on week 2, 4, 6). After day 1 on week 2, G-CSF was administered on days when cytotoxic drugs were not given. Results: From May 2000 to January 2005, 30 pts were enrolled in this study. Pt characteristics were median age 64 years (range 44–75); 23 male and 7 female; 3 LD and 27 ED. Prior chemotherapy included PE in 13 pts, cisplatin and irinotecan in 7, carboplatin and etoposide in 5, and others in 5. 23 pts (77%) completed 6 or more weeks of chemotherapy. 2 CR and 19 PR were observed and the overall response rate was 70% (95% CI 50.6–85.3%). Grade 3/4 neutropenia, anemia and thrombocytopenia were observed in 60%, 73% and 47%, respectively. Grade 3/4 diarrhea was observed in only 7%. Coclusions: PE/CPT regimen was active and well tolerated for refractory relapsed SCLC. No significant financial relationships to disclose.

The evolving role of pemetrexed (Alimta) in lung cancer

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.