Extensive-disease Small-cell Lung Cancer Research Articles

Phase II study of nedaplatin and irinotecan in patients with extensive small-cell lung cancer

The standard chemotherapy for Japanese patients with extensive disease of small-cell lung cancer (ED-SCLC) is cisplatin and irinotecan. Patients with untreated ED-SCLC were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan (CPT) at 50 mg/m(2) on days 1 and 8 every 4 weeks for four cycles. Twenty-five patients were registered. Nineteen patients were male and six female, with a median age of 64 years (50-79 years). Two patients had a performance status of 2. Nineteen of them were able to receive 4 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 8.0, 68.0, and 36.0 % of patients, respectively. Other grade 3 toxicities were SGOT, hyponatremia, fatigue, vomiting, diarrhea, hypotension, febrile neutropenia, oral hemorrhage, and pneumonia. Grade 4 fatigue occurred in one patient. There was no treatment-related death. The overall response rate was 100 %. The median progression-free and overall survivals were 6.6 and 16.0 months, respectively, and the 2-year survival rate was 28 %. NP with CPT is effective and safe for patients with ED-SCLC.

Potential toxicities of prophylactic cranial irradiation.

Prophylactic cranial irradiation (PCI) with total doses of 20-30 Gy reduces the incidence of brain metastasis (BM) and increases survival of patients with limited and extensive-disease small-cell lung cancer (SCLC) that showed any response to chemotherapy. PCI is currently not applied in non-small-cell lung cancer (NSCLC) since it has not proven to significantly improve OS rates in stage IIIA/B, although novel data suggest that subgroups that could benefit may exist. Here we briefly review potential toxicities of PCI which have to be considered before prescribing PCI. They are mostly difficult to delineate from pre-existing risk factors which include preceding chemotherapy, patient age, paraneoplasia, as well as smoking or atherosclerosis. On the long run, this will force radiation oncologists to evaluate each patient separately and to estimate the individual risk. Where PCI is then considered to be of benefit, novel concepts, such as intensity-modulated radiotherapy and/or neuroprotective drugs with potential to lower the rates of side effects will eventually be superior to conventional therapy. This in turn will lead to a re-evaluation whether benefits might then outweigh the (lowered) risks.

Topotecan/Cisplatin Compared with Cisplatin/Etoposide as First-Line Treatment for Patients with Extensive Disease Small-Cell Lung Cancer: Final Results of a Randomized Phase III Trial

This phase III study compared efficacy and safety of topotecan-cisplatin (TP) versus topotecan-etoposide (TE) versus cisplatin-etoposide (PE) in chemo-naïve extensive disease small-cell lung cancer patients. Seven hundred and ninety-five previously untreated patients were randomly assigned to TP (topotecan 1mg/m IV, d1-5; cisplatin 75 mg/m IV, d5; n = 358), PE (cisplatin 75 mg/m IV, d1; etoposide 100 mg/m IV, d1-3; n = 345) or TE (topotecan 1mg/m IV, d1-5; etoposide 80 mg/m IV, d3-5; n = 92). Primary endpoint was superiority of TP compared with PE, with the possibility to switch to a noninferiority test. The TE arm was closed after recommendations by the Independent Data Safety Monitoring Board. Median survival was similar and met the predefined endpoint of noninferiority of TP to PE (44.9 versus 40.9 weeks; p = 0.40). One-year survival rate showed 39.7% for TP versus 36.1% for PE (p = 0.29). Median time to progression was significantly longer with TP (27.4 versus 24.3 weeks, p = 0.01). Overall response rates were significantly higher for TP (55.5% versus 45.5%, p = 0.01).Hematologic toxicity was slightly higher for TP regarding 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%). 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 extensive disease small-cell lung cancer.

Angiogenesis Inhibitors in Lung Cancer: Beyond VEGF?

‘Angiogenesis’ refers to the formation of new blood vessels, a tightly controlled process regulated by multiple factors in vivo. Proangiogenic molecules include VEGF, HIF-1a, PDGF, bFGF angiopoietins and IL-8 (reviewed in [1]). On the other hand, antiangiogenic molecules include thrombo spondin, angiostatin and collagen type XVIII (the precursor of endostatin; reviewed in [1]). Without the induction of angiogenesis, diffusion of nutrients and oxygen are thought to limit the survival of proliferating cells in growing tumors. Therefore, perturbation of physiological regulation of angiogenesis is hypothesized to be necessary to sustain tumor growth. This has sustained interest in exploitation of angiogenesis as a therapeutic target in cancer over the past few decades, including in lung cancer, which remains the most common cause of cancer-related death in the western world. Building on outcomes with VEGF pathway antagonist therapy, we discuss some strategies to further exploit the potential of antiangiogenic therapy in lung cancer. Evidence from two large Phase III trials suggests that in nonsquamous metastatic non-small-cell lung cancer (NSCLC), bevacizumab (a VEGF-A inhibitor) led to significantly increased response rates and improved progression-free survival (PFS) [2,3]. One of the trials reported improved overall survival (OS) [2]. While antiangiogenic therapy is less studied for small-cell lung cancer, a recent Phase II trial of bevacizumab in combination with chemotherapy for extensive disease smallcell lung cancer suggested prolonged PFS and OS compared with historical controls [4]. However, Phase III data are awaited. Overall, the bevacizumab trials have confirmed the safety and tolerability of VEGF inhibitor therapy in combination with chemotherapy for nonsquamous NSCLC. Despite concerns for squamous tumors, significant bleeding episodes were rare, even in patients on full-dose anticoagulant therapy who had nonsquamous tumors [5]. Allergies and proteinuria were rare, while hypertension was conveniently managed in the minority who developed this side effect [2,3]. Nevertheless, the median OS benefit for the addition of bevacizumab to chemo therapy was only 2 months [2]. The

Effect of thoracic radiotherapy in extensive-disease small cell lung cancer on progression-free and overall survival: A retrospective review.

e17519 Background: Extensive-disease small cell lung cancer (ED-SCLC) carries a poor prognosis. The current standard practice of 4-6 cycles of a platinum based chemotherapy (PC) leads to a median survival of only 9-11 months. The role of thoracic radiotherapy (TRT) in ED-SCLC remains controversial. We report patient outcomes with ED-SCLC with respect to whether they received TRT or not. Methods: The practice of two oncologists from 2005-2009 was retrospectively reviewed. Patient age, performance status (PS) at presentation and site of progression were recorded. Progression-free survival (PFS) and overall survival (OS) were calculated with respect to the patient receiving 4-6 cycles of PC or not and then again in this subgroup with respect to whether or not they had TRT at any time after chemotherapy. Survival data was compared using the log-rank test. Results: 141 patients age 42-86 years old (mean 67.4 years) were identified. 58% were PS 0-2. 56 patients (40%) completed 4-6 cycles of PC with a median PFS of 8.4 months compared to 2.4 months in those that did not (p<0.001), median OS was 8.9 and 3.1 months (p<0.001). Of the 45 who had the site of progression recorded - 49% progressed within the thorax. Of 87 patents who received any chemotherapy, 43 received TRT and 44 did not with median PFS of 7.8 and 5.4 months respectively (p= 0.003) and median OS of 8.9 and 5.9 months (p=0.002). In the 56 patients who received 4-6 cycles of PC, median PFS was 9.2 with and 7.7 months without TRT (p=0.02). Median OS was 10.2 months with and 7.7 without TRT (p=0.02). Conclusions: Patients who received TRT at some point in their treatment demonstrated improved median PFS and OS. The role of TRT in ED-SCLC warrants further evaluation. The results of the REST trial are eagerly anticipated.

Phase II trial of huKS-IL2 with cyclophosphamide (CTX) in patients with extensive disease small-cell lung cancer (ED-SCLC).

7090 Background: huKS-IL2 immunocytokine is a humanized antibody specific for EpCAM, fused at its Fc end to two molecules of IL2. Results of a phase 1b study of huKS-IL2 plus low-dose CTX, and preclinical data, provided a rationale to evaluate this combination in SCLC, which is often EpCAM-positive. Methods: Patients (pts) with ED-SCLC responding (PR/CR) to 4 cycles of first-line Pt-based chemotherapy were randomized 1,5:1 to receive huKS-IL2/CTX or best supportive care (BSC). Pts in the huKS-IL2/CTX arm received six 21-day cycles of CTX 300 mg/m2 on day (d) 1, and 1.5 mg/m2/d huKS-IL2 on d2–4, followed by 21-d cycles of CTX on d1 and huKS-IL2 on d2 until progression. Pts were stratified for prophylactic cranial irradiation (PCI) and response to chemotherapy. Primary endpoint was PFS rate at 6 months (mo). Secondary endpoints included OS rates at 12 and 18 mo from start of Pt-based chemotherapy, median PFS and OS, safety, and immunogenicity. Results: 108 pts (64 huKS-IL2/CTX arm, 44 BSC arm) were randomized and treated. Baseline characteristics were balanced between arms; however, higher % of males (75 vs 61.4%) and of ECOG PS 0 (45.3 vs 38.6%) were observed in the active arm. Median age was 61.7 (32; 81) and 59.2 (45; 74) years in the active and BSC arm, respectively. Most pts were in PR at randomization (2 pts – 1 in each arm – had CR). PCI was used in 15 (23.4%) and 11 (25%) pts in the active and BSC arm, respectively. No significant differences in PFS or OS were observed in the active vs BSC arm: PFS rate was 6.4 vs 12.2%; median PFS was 1.5 vs 1.4 mo; OS rates at 12 and 18 mo were 52 vs 61% and 24 vs 29%, respectively; median OS was 12.3 vs 14.1 mo. One PR (45% reduction vs randomization baseline) was observed in the active arm. In a subset of pts who received PCI, median PFS was 1.7 vs 1.5 mo, median OS 21.5 vs 14.3 mo in the active vs BSC arm, respectively. AEs observed more frequently in the active arm were flu-like symptoms, rash, hypotension, lymphopenia, LFT and creatinine elevations; all Grade 3/4 AEs related to huKS-IL2 were reversible/manageable. Conclusions: HuKS-IL2/CTX was well tolerated, but showed no benefit in pts with ED-SCLC in PR/CR after chemotherapy. A trend for improved PFS and OS was observed in pts who received prior PCI.

Genome-wide association study of survival in small cell lung cancer patients treated with irinotecan and cisplatin chemotherapy.

7089 Background: The prognosis of patients with extensive-disease small-cell lung cancer (ED-SCLC) remains poor. Despite a high initial response rate to chemotherapy, most patients die from rapid recurrence. We conducted a genome-wide analysis study (GWAS) to examine whether germline genetic variations are prognostic factors in ED-SCLC patients treated with irinotecan and cisplatin (IP) chemotherapy. Methods: We prospectively collected blood samples from 139 patients who participated in two phase II studies of IP chemotherapy as first-line therapy and conducted a GWAS using overall survival (OS) as the endpoint. Germline DNA was genotyped using the Affymetrix 5.0 or 6.0 array sets. Associations between OS and single nucleotide polymorphisms (SNPs) were investigated using multivariate Cox regression analysis. Adjustments for age, performance status (PS) and gender were made. We selected most promising SNPs with p<1×10−6 in the GWAS allelic association analyses. Results: A total of 426,019 SNPs were genotyped and 343,530 SNPs passed quality control (HWE, p<10-7, minor allele frequency>1%). We found 7 SNPs showing a significant association with OS. Patients harboring rs16950650 CT, rs7186128 AG or GG, rs17574269 AG, rs8020368 CC, rs4655567 CC, rs2166219 TT and rs2018683 TT genotypes showed shorter OS compared to patients with control alleles. Hazards ratios of death for each risk variants were 30.2 (95% CI, 8.3-109.0, p=2.1X10-7), 2.5 (95% CI, 1.7-3.5, p=3.8X10-7), 7.6 (95% CI, 3.4-16.6, p=4.5X10-7), 3.4 (95% CI, 2.1-5.5, p=3.5X10-7), 4.9 (95% CI, 2.7-9.0, p=3.1X10-7), 5.8 (95% CI, 2.9-11.7, p=8.4X10-7) and 7.8 (95% CI, 3.4-17.7, p=8.0X10-7), respectively. Among these SNPs, rs4655567, rs8020368, rs2018683 and rs17574269 were significantly associated with a refractory relapse. In multivariate logistic analysis including age, gender and PS, rs8020368 CC genotype showed higher risk of refractory relapse than patients with TT or TC genotype (HR=14.9 [95% CI, 1.9-114.8], p=0.010). Conclusions: This exploratory GWAS identified several candidate SNPs that might predictive for the outcome of patients with ED-SCLC receiving IP chemotherapy.

Prophylactic cranial irradiation for small-cell lung cancer: how, when and for whom?

Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases and improves overall survival in both limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC), in complete and good responders to initial chemo(radio)therapy. In LD-SCLC, a standard dose of 25 Gy given in ten fractions is recommended, whereas in ED-SCLC a shorter schedule of 20 Gy in five fractions could be used. The issues of acute neurotoxicity (NT) and the potential impact of PCI on quality of life are of particular concern in ED-SCLC patients, as their expected survival is short. In LD-SCLC late neurologic sequelae may worsen quality-adjusted life expectancy for long-term survivors, as the pronounced effect of NT becomes apparent after several years. Some novel potential approaches to reduce the PCI-related late NT have recently been investigated. Despite the growing incidence of lung cancer in elderly people, there are no established standards of treatment for this subset of the population.

A Weekly Combination of Carboplatin and Irinotecan for Previously Untreated Extensive Disease Small-cell Lung Cancer, Results of a Minimum Follow-up of 3 Years: A Multi-center Phase II Trial JMTO LC02-02

We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease small-cell lung cancer. Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m(2)) were administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if >45 responses were observed in the 55 patients. Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6-87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8-18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9-7.4). This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial.

Hyponatremia as prognostic factor in small cell lung cancer – A retrospective single institution analysis

The aim of this retrospective study is to present data on clinical significance of hyponatremia in an unselected contemporary patient population with small cell lung cancer (SCLC) with limited disease (LD) and extensive disease (ED). Our electronic database was searched for patients with newly diagnosed SCLC from June 2004 to December 2008. 395 cases were identified. We collected data on patient characteristics including clinical performance status, serum sodium values, serum LDH values, metastatic sites, chemotherapy regimens and response, radiotherapy and survival. Hyponatremia (sodium <135 mmol/l) was present in 18.9% of all cases. Severe hyponatremia (sodium <129 mmol/l) was detected in 8.8%. Hyponatremia was present in 58 out of 241 (24%) patients with ED SCLC and 17 of 154 (11%) patients with LD SCLC. Hyponatremia was associated with significantly shorter median survival (SCLC all patients: 9.0 vs. 13.0 months, p < 0.001, LD SCLC: 9.0 vs. 17.0, p = 0.050, ED SCLC 9.0 vs. 10.0, p = 0.135). After adjustment for age, gender, LDH and performance status hyponatremia was an independent predictor of mortality in patients with ED and LD SCLC. According to the extensive statistical analyses in our comprehensive unselected patient population, hyponatremia seems to constitute an independent prognostic factor in patients with SCLC.

Management of Small Cell Lung Cancer

Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and the incidence has reduced over the last 20 years. Treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease. Chemotherapy remains the cornerstone of treatment for limited (LD) and extensive disease (ED), with concurrent chemotherapy and radical thoracic radiotherapy representing the best treatment option for fit patients with LD. Platinum-based chemotherapy is the treatment of choice in fit patients with good organ function, and the radiosensitizing effect of cisplatin is critically important for concurrent chemoradiotherapy in LD. Anthracycline-containing regimens represent a viable alternative for patients where platinum-based chemotherapy is contraindicated. Patients who relapse or progress after first-line chemotherapy have a very poor prognosis. Second-line therapy may produce a modest clinical benefit. Maintenance chemotherapy has not been shown to convincingly improve outcomes for SCLC. A number of targeted agents have been investigated in LD and ED, mostly in unselected populations, with disappointing results. Prophylactic cranial irradiation has been shown to reduce the incidence of brain metastases and prolong survival for both LD and ED without negative impact on quality of life (QOL) and cognitive function. Ongoing trials will shed some light on the impact of thoracic radiotherapy on QOL, symptom control and survival in ED SCLC patients who benefitted from first-line chemotherapy.

166 Thoracic radiotherapy in extensive-disease small cell lung cancer: a retrospective review

166 Thoracic radiotherapy in extensive-disease small cell lung cancer: a retrospective review

Insulin-Like Growth Factor Receptor

The insulin-like growth factor (IGF) signaling axis plays an essential role in the balance between cellular proliferation and apoptosis. Higher levels of IGF receptor are seen in lung tumor cells than normal tissue. IGF-1 receptor (IGFR-1R) and its ligand IGF-2 is overexpressed in non-small cell lung cancer (NSCLC). Elevated levels of IGF-1 in plasma are associated with an increased risk of developing lung cancer, and IGF-1R has been shown to promote the proliferation of lung cancer cells in vitro. 1 IGF-1R can hybridize with other membrane receptors leading to the activation of different tyrosine kinase domains. 2 The central role that the IGFR pathway plays in various signaling pathways in tumor cells makes the IGF axis an attractive target for therapeutic intervention. Dr. Pollak presented an overview of the science of the IGFR to establish the rationale for the development of this class of drugs for the treatment of NSCLC. There are a number of possible avenues through which the effects of IGF can be inhibited. These strategies include antibodies directed against IGF ligand, IGF-1R tyrosine kinase inhibitors, and antibodies targeting the IGF-1R. The approach of blocking the IGF-1 receptor tyrosine kinase pathway and the insulin receptor (IR) via signal transduction inhibitors is also undergoing clinical evaluation. IMC-A12 IMC-A12 is a fully humanized IgG1 monoclonal antibody with a half-life of 15 to 21 days that targets the IGF-1 receptor. 3 Both weekly and q21-day schedules are being explored. There are three ongoing randomized phase II trials with differentfirst-line platinum-based regimens including a trial that is comparing gemcitabine, carbopatin with the addition of IMC-A12, cetuximab, or both, and another evaluating carboplatin, paclitaxel bevacizumab with or without IMC-A12 in nonsquamous NSCLC. There is one randomized first-line trial of etoposide, cisplatin with or without either IMC-A12 or the hedgehog inhibitor GDC-0449 in extensive disease small cell lung cancer (EDSCLC). The combination of erlotinib plus A12 was closed due to toxicity of the combination. Currently, no additional toxicity or efficacy data are available. AMG-479 Phase I studies established thrombocytopenia as the dose-limiting toxicity of AMG-479, a fully human monoclonal antibody to IGF-1R. 4 AMG-479 is being evaluated in the front-line setting in combination with etoposide and carboplatin or cisplatin in a randomized phase I/II trial in patients with EDSCLC. Patients will receive up to six cycles of the combination then single-agent AMG 479 as maintenance therapy until disease progression. Preliminary results indicate that AMG-479 can be safely combined with etoposide and cisplatin (or carboplatin) in this patient population without impact on the delivery of AMG-479 or the chemotherapy. Activity in the phase I portion was similar to reported with chemotherapy alone. 5 The phase II portion of the trial has completed accrual and results are pending. MK-0646 MK-0646 is a fully humanized monoclonal IgG1 antibody that selectively binds to the IGF-1 receptor and not to the insulin receptor. 6 The recommended phase II dose is 10 mg/kg weekly. An overview of the compound and the design of several clinical trials were presented. In the randomized phase II IMPACT study, MK-0646 is being evaluated in combination with pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) as first-line therapy in patients with stage IIIB or IV nonsquamous NSCLC. The phase I/II design of MK-0646 plus cisplatin and etoposide in patients with treatment-naive EDSCLC was also presented. Both studies are ongoing but not actively recruiting participants.

A German multicenter, randomized phase III trial comparing irinotecan–carboplatin with etoposide–carboplatin as first-line therapy for extensive-disease small-cell lung cancer

BackgroundThis trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer. Patients and methodsPatients were randomly assigned to receive carboplatin area under the curve 5 mg ·min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1–3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity. ResultsOf 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0–7.0] in the IP arm and 6.0 months (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. Hazard ratios 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. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. ConclusionThis trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.

A Phase II Study of Carboplatin and Irinotecan in Extensive Stage Small-Cell Lung Cancer

ObjectivesOur study set out to determine the antitumor efficacy of carboplatin and irinotecan as assessed by response rate in persons with chemotherapy-naive extensive-disease, small-cell lung cancer (ED-SCLC). Secondary objectives included progression-free survival (PFS), overall survival, and toxicity findings. MethodsPatients with previously untreated ED-SCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, life expectancy ≥ 3 months, and adequate organ function were eligible. Patients were treated with carboplatin AUC 5 intravenously over 30-60 minutes on day 1, followed by CPT-11(irinotecan) 50 mg/m2 intravenously over 30-90 minutes on days 1 and 8 every 3 weeks for 4-6 cycles at the discretion of the treating physician. ResultsFifty-six patients were enrolled, and 50 patients were eligible. The median age of patients was 60.1 years. The most common toxicities were neutropenia, thrombocytopenia, nausea/vomiting, and dehydration. The overall response rate was 58%. Median PFS was 5.3 months, median overall survival was 9.7 months, and 1-year overall survival was 28.7%. ConclusionsCarboplatin and irinotecan is a safe and reasonable combination for the treatment of patients with ED-SCLC.

Prognostic significance of metabolic parameters measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with small cell lung cancer

The aim of this study was to evaluate the prognostic significance of some metabolic parameters measured by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in patients with small cell lung cancer (SCLC). We retrospectively reviewed 98 patients with pathologically proven SCLC who underwent pre-treatment (18)F-FDG PET/CT. Metabolic tumor volume (MTV), integrated standardized uptake value (iSUV) and average SUV (SUV(mean)) of all malignant lesions, and maximum SUV (SUV(max)) of the primary tumor were measured by (18)F-FDG PET/CT. We determined the relationship between overall survival (OS) and progression free survival (PFS) and these PET metabolic parameters. The estimated median OS and PFS for the entire cohort were 16.7 months and 9.8 months. The patients with larger MTV had significantly shorter median OS (9.6 months vs 23.2 months, P<0.001) and PFS (6.9 months vs 15.5 months, P<0.001) than the patients with smaller MTV. On multivariate analysis, MTV, iSUV, tumor stage and LDH were the significantly prognostic factors with OS and PFS. SUV(max) did not show correlation with OS and PFS. In subgroup analysis, limited disease (LD) with larger MTV showed significantly shorter median OS and PFS than LD with smaller MTV. Extensive disease (ED) with larger MTV also had significantly shorter median OS and PFS than the same stage with smaller MTV. MTV and iSUV are important independent prognostic factors for survival in patients with SCLC. Either MTV or iSUV may identify subgroups of patients at higher risk of progression or death in both LD and ED SCLC.

A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401

Backgrounds Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. Methods Amrubicin (35 mg/m 2) and topotecan (0.75 mg/m 2) were administered on days 3–5 and 1–5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases. Results Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths. Conclusion This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.

Vergleich von Behandlungsergebnissen in zwei Patientengruppen (2004–2005 und 2007–2008) mit einem kleinzelligen Bronchialkarzinom im begrenzten und metastasierten Krankheitsstadium

The aim of this retrospective study was to compare patient characteristics, treatment patterns and treatment results in two groups of patients with limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC) in 2004 - 2005 vs. 2007 - 2008. We included all patients with LD or ED SCLC in this retrospective analysis who were diagnosed in our department in the periods 2004 - 2005 and 2007 - 2008. We collected data on patient characteristics, chemotherapy, radiotherapy, treatment response and median survival. Statistical analyses were separately performed for patients in LD and ED SCLC. 109 patients had LD SCLC. The response rate on first-line therapy was 74 %. More than half of the cases had recurrent disease. Second-line treatment was given to about two thirds of these patients. Third-line therapy was administered in around 15 % of all cases. Prophylactic cranial irradiation was performed more frequently from 2007 - 2008. The median survival was 17 months. There were no statistically significant differences regarding patient characteristics and treatment results. ED SCLC was present in 188 patients. The response rate was around 68 %. All patients relapsed, second-line therapy was administered in half of these cases; third-line therapy in 10 % of all cases. No statistically significant differences were detected between the two time frames. Median survival was 10 months. Overall, no statistically significant differences were present for patients with LD and ED SCLC in 2004 - 2005 vs. 2007 - 2008. Prophylactic cranial irradiation was employed more frequently in LD SCLC from 2007.

A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive‐disease small cell lung cancer

The objective of this study was to investigate the efficacy of simvastatin in combination with irinotecan and cisplatin in chemotherapy-naive patients with extensive-disease small-cell lung cancer (ED-SCLC). In this phase 2 study, 61 patients received treatment with irinotecan (65 mg/m(2) ) and cisplatin (30 mg/m(2) ) on Days 1 and 8 every 3 weeks until either death or disease progression occurred. Patients also received oral simvastatin (40 mg daily) during the course of chemotherapy. The primary endpoint was 1-year survival. Secondary endpoints included the response rate (RR), progression-free survival (PFS), and toxicity. The 1-year survival rate was 39.3%. The median overall survival (OS) was 11 months, and the median PFS was 6.1 months. Overall, the RR was 75%. The most common grade 3/4 toxicity was neutropenia (67%). Efficacy of the treatment was associated significantly with smoking status. Compared with never-smokers, ever-smokers had a better RR (40% vs 78%; P = .01), a longer PFS (2.5 months vs 6.4 months; P = .018), and had a trend toward an improved OS (9.0 months vs 11.2 months; P = .095). The effect of smoking on survival was apparent when ever-smokers were subdivided according to pack-years (PY) of smoking. Ever-smokers who had smoked >65 PY had a significantly longer OS compared with ever-smokers who had smoked ≤65 PY or never-smokers (20.6 months vs 10.6 months vs 9.0 months, respectively; log-rank P = 0.032). In multivariate analysis, PY >65 was predictive of longer survival (hazard ratio, 0.280; 95% confidence interval, 0.113-0.694). The current results indicated that simvastatin in combination with irinotecan and cisplatin did not improve the survival of patients with ED-SCLC. Although the subgroup analysis by smoking status was exploratory, the addition of simvastatin to irinotecan and cisplatin may improve the outcome of heavy smokers with ED-SCLC.

Treatment of Cranial Metastases Following Prophylactic Cranial Irradiation (PCI) for Small Cell Lung Cancer (SCLC)

PCI is associated with a survival advantage in both limited (LD) and extensive disease (ED) SCLC. This retrospective population-based study aims to determine the percentage of patients developing cranial metastasis (CM) following PCI, the median time from diagnosis to CM and the median survival post CM. Treatment patterns will be examined to establish guidelines for the treatment of post PCI CM.