bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I dose escalation study of sunitinib in combination with gemcitabine + cisplatin for advanced non-small cell lung cancer (NSCLC)
Authors: Reck M. , Frickhofen N. , Gatzemeier U. , Fuhr H. , Lanzalone S. , Lechuga M. J. , Wang E. , Chao R. , Felip E.
Published: March 2020

18057

Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m2 + C 80 mg/m2, and 7 pts with SU 50 mg + G 1000 mg/m2 + C 80 mg/m2. No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m2) and C (80 mg/m2) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m2 or with SU administered on a CD schedule is ongoing.

No significant financial relationships to disclose.
Activity of patupilone for the treatment of recurrent or progressive brain metastases in patients (pts) with non-small cell lung cancer (NSCLC): An open-label, multicenter, phase II study
Authors: Abrey L. , Wen P. Y. , Govindan R. , Reimers H. J. , Rigas J. R. , Robins H. I. , de Bedout S. , O’Connell C. , Li X. , Johri A.
Published: March 2020

18058

Background: Advances in systemic chemotherapy have improved overall survival for patients with advanced NSCLC; unfortunately, CNS metastasis is common and limits survival benefits with current therapies. Unlike taxanes, preclinical findings suggest that the novel epothilone, patupilone, crosses the blood-brain barrier in 3 animal species and also has antitumor effects in brain tumor models. Results of an ongoing phase I/II study of patupilone as second-line therapy in pts with NSCLC are encouraging. The present study is evaluating the efficacy of patupilone in pts with brain metastases from NSCLC who have failed or recurred after previous chemotherapy, surgery, and/or radiation to the brain. Methods: This open-label, single-arm, multicenter, phase II study has a 2-stage design (25 pts per stage). Eligible pts have histologically confirmed NSCLC and = 1 recurrent, bidimensionally measurable intracranial lesion = 2 cm. Patupilone was administered IV at 10 mg/m2 as a single 20-min IV infusion every 3 weeks until disease progression, satisfactory response, or unacceptable toxicity. The primary multinomial endpoint was a combination of early progression (disease progression or death before cycle 1, day 21) and response rate (alive without progression at cycle 4, day 1). Results: An interim analysis of 13 pts with a median age of 62 years (range, 40–67 years) is reported. The most common adverse events (AEs) related to study drug were NCI CTC grade 1/2 diarrhea in 7 (54%) pts, nausea in 3 (23%), and fatigue in 2 (15%). Only 2 serious AEs (grade 4 colitis and grade 3 diarrhea) and 2 additional grade 3 AEs (diarrhea, neutropenia) were reported in 1 pt each. Three (23%) pts experienced early disease progression. Five (38%) pts responded, receiving a median 10 cycles (range, 5 to 12 cycles) and were alive without progression on cycle 4, day 1. Conclusions: Patupilone has activity in patients with CNS metastases from advanced NSCLC and is well tolerated. Additional investigation of patupilone as a treatment for brain metastases from NSCLC is warranted.

[Table: see text]
A randomized phase II study of carboplatin and paclitaxel (CP) versus gemcitabine and vinorelbine (GV) in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): West Japan Thoracic Oncology Group 00
Authors: Iwamoto Y. , Saito H. , Nakagawa K. , Kashii T. , Katakami N. , Nakano T. , Kurata T. , Ando M. , Fukuoka M.
Published: March 2020

18060

Background: Although doublet chemotherapy is a standard treatment regimen for PS 0–1 patients with advanced non- small cell lung cancer (NSCLC), the optimal chemotherapy for PS 2 patients with advanced NSCLC still remains to be established. We conducted a randomized phase II study to compare the efficacy and safety of a platinum-doublet regimen (CP) versus a non-platinum doublet regimen (GV) in PS 2 patients with advanced NSCLC. Methods: Chemotherapy-naive patients with stage IIIB (malignant effusion) and IV NSCLC were eligible for this study. The patients were randomly assigned to carboplatin area under the curve of 6 plus paclitaxel 200 mg/m2 on day 1 every 3 weeks (the CP arm) or gemcitabine 1000 mg/m2 plus vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks (the GV arm). The primary endpoint was the 1-year survival rate while the secondary endpoints were the response rate, the time to progression and the quality-of-life (QOL). The sample size was 41 assessable patients in each arm. Results: Of the 89 patients enrolled, 84 were assessable for efficacy and toxicity: 41 patients (median age 65 years, male/female 30/11, stage IIIB/IV 7/34) in the CP arm and 43 patients (median age 67 years, male/female 31/12, stage IIIB/IV 7/36) in the GV arm. The overall response and 1-year survival rates were 29.3% (95% CI, 16.1 to 45.5%) and 22% (95% CI, 9.3 to 34.6%) for the CP and 20.9% (95% CI, 10 to 36%) and 27.9% (95% CI, 14.5 to 41.3%) for the GV arm, respectively. The median survival time and time to progression were 5.9 and 2.9 months, respectively, for the CP arms and 6 and 2.6 months for the GV arm. The selected Grade 3/4 toxicity in the CP and GV arms included neutropenia (67.5% vs 65.1%, respectively), anemia (12.5% vs 30.2%), thrombocytopenia (7.5% vs 11.6%), febrile neutropenia (17.1% vs 11.6%), infection (29.3% vs 23.3%), pneumonitis (4.9% vs 11.6%), liver dysfunction (2.5% vs 9.3%), and neuropathy (5.1% vs 0%). The QOL improved after each treatment and it was similar between the two arms. Conclusions: Both CP and GV appear to be active in PS 2 patients with advanced NSCLC . The toxicity profiles were different between the two arms.

[Table: see text]
Phase II study of TS-1 (S) plus cisplatin (P) with concurrent thoracic radiotherapy for unresectable stage III non-small cell lung cancer (NSCLC)
Authors: Ohyanagi F. , Yamamoto N. , Horiike A. , Horai T. , Gomi K. , Murakami H. , Harada H. , Takahashi T. , Nakamura Y. , Nishio M.
Published: March 2020

18070

Background: Although combined chemoradiotherapy is the standard of care in stage III NSCLC, the optimal chemotherapy regimen is not established. S-1, a fourth-generation oral fluoropyrimidine is an active new agent for NSCLC and the combination with cisplatin has a favorable toxicity profile. The objective of this study was to evaluate feasibility and efficacy of S plus P with concurrent radiation for unresectable stage III NSCLC. Methods: Patients with histologically or cytologically confirmed NSCLC, 20 to 75 years in age, performance status 0–1, with no prior chemotherapy were eligible for the study. Patients were treated with P (60 mg/m2 on day 1) and S (orally at 40 mg/m2/dose bid (80 mg/m2/d), on days 1 to 14) repeated every 3–4 weeks for 4 cycles and TRT (60 Gy/30 fr over 6 weeks starting on day 2). The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 28 patients (Simon’s two-stage minimax design, P0=70%, P1=90%, a =0.1, β = 0.1). Results: Of 28 patients enrolled between August 2005 and October 2006, 28 were evaluable. There were 24 males and 4 females, median age of 63 (range 40–74) and 11 IIIA and 17 IIIB. Chemoradiotherapy was well tolerated; 2 cycles of SP and 60 Gy of TRT were administered in all patients and 24 (86%) patients received 4 cycles of SP. During concurrent chemoradiotherapy, grade 3 toxicities were neutropenia (8 pts), leukopenia (6 pts), fatigue (6 pts), anorexia (5 pts), febrile neutropenia (4 pts) and, esophagitis (4 pts). Only one grade 4 leukopenia were observed. During consolidation therapy, grade 3–4 neutropenia, anemia, esophagitis, and pneumonitis were developed in 4, 1, 1 and 2 patients, respectively. No toxic deaths have occurred. Overall RR was 85.7% (95% CI: 79.1- 98.7%) with 4 SDs and 24 PRs. The median progression-free survival and median survival is not mature enough to estimate as only 4 progression and no deaths have occurred. Conclusions: This chemoradiotherapy regimen produced promising response rate in patients with stage III NSCLC and it seems to be well-tolerated.

No significant financial relationships to disclose.
Phase II trial of irinotecan plus cisplatin with concurrent thoracic radiotherapy (TRT) in patients with previously untreated locally advanced non-small cell lung cancer (NSCLC)
Authors: Fukuda M. , Soda H. , Nakamura Y. , Fukuda M. , Kinoshita A. , Nagashima S. , Nakano H. , Yamaguchi H. , Kohno S. , Oka M.
Published: March 2020

18071

Background: The combined modality of the third generation new agent plus cisplatin with concurrent TRT is considered ideal for locally advanced non-small cell lung cancer. However, it is difficult to conduct because of severe toxicities. Methods: Patients fulfilling the following eligibility criteria were enrolled: previously untreated, good performance status (PS 0–2), age <75, stage III, and adequate organ function. The patients received irinotecan 60 mg/m2 i.v. on days 1, 8 and 15, and cisplatin 80 mg/m2 i.v. on day 1 in the first group. The doses were reduced to 50 and 60 mg/m2 in the second group, respectively. Two cycles of chemotherapy were repeated every 4 weeks. Thoracic radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle, with 28 and 32 Gy administered in the first and second cycles, respectively. Primary endpoint and objective sample size were response rate and 45 patients, respectively. Results: Fifty patients were eligible and 48 (16 in the 1st, 32 in the 2nd group) patients were assessable for response, toxicity and survival. The overall response (OS) was 83% (95% confidence interval (CI), 70–93%). Grade 4 leukopenia, neutropenia, grade 3 or 4 diarrhea, pneumonitis, esophagitis and fatigue occurred in 21%, 48%, 19%, 10% and 19%, respectively. The median time to progression was 8.2 months. The median overall survival time (MST), and the 2- and 5-year survival rates were 20.1 months, 47.1% and 17.1%, respectively. In subgroup analysis, the OS of 1st and 2nd groups were 75% and 88% (not significant), respectively. The MST of 1st and 2nd groups were 13.1 and 33.4 months, respectively, and significant favor with 2nd group (p=0.011). The execution rates of irinotecan on day 15 were significant higher in 2nd (22% vs. 48%) groups (p=0.032), and the survival separated by execution times on day 15 were significantly favor with higher execution time group (p=0.026). Conclusions: This therapy is active and further investigations are warranted at the 2nd group dose level. High execution of chemotherapy on day 15 may be important for the achievement of concurrent chemoradiotherapy.

No significant financial relationships to disclose.
Radiation dose is significantly associated with overall survival in patients with stage III non-small cell lung cancer treated with combined radiation and chemotherapy
Authors: Wang L. , Zhao L. , Hayman J. , Kalemkerian G. , Kong F.
Published: March 2020

18074

Background: Radiation dose is an independent prognostic factor for survival in patients with early stage non-small cell lung cancer (NSCLC). We hypothesized that radiation dose is also a significant independent factor associated with survival in patients with stage III disease treated with combined radiation and chemotherapy. Methods: This is an Institutional Review Board approved retrospective study. Eligible subjects included those with stage III NSCLC registered in the radiation oncology database at University of Michigan Hospital between January 1992 and July 2004. Radiation was given using 3-dimensional conformal technique with doses ranging from 30 to 102.9 Gy, corresponding to a bioequivalent dose (BED) of 39 to 124.5Gy. Median age was 65 years (range, 36–89). There were 80 males and 67 females. Median follow-up was 13.0 months (range, 2.7–145.9). Results: For patients treated with radiation alone (n=40), sequential chemoradiation (n=42), and concurrent chemoradiation (n=65), median survival was 8.6 (95% CI: 5.7–11.5), 12.8 (95% CI: 9.5–16.0) and 15.4 (95% CI: 12.7–18.0) months, respectively (P =0 .011). Multivariate Cox-regression analysis showed that BED (HR=0.96, 95% CI: 0.95–0.97, P<0.001) and administration of chemotherapy (HR=0.44, 95% CI: 0.28–0.70, P=0.001) were independent prognostic factors associated with the risk of death. T stage was marginally significant (P=0.065). Age, gender and N stage were not independent factors (P>0.05). To isolate the BED effect, multivariate analysis was performed separately in patients treated with and without chemotherapy: the hazard ratios of BED for the risk of death were 0.97 (95% CI: 0.95–0.99, P=0 .013) and 0.95 (95% CI: 0.93–0.98, P=0.001), respectively. BED also remained a significant independent prognostic factor in patients treated with chemotherapy and radiation in the dose range of 60–66 Gy (HR=0.91, 95% CI: 0.84–0.99, P=0.041). Conclusions: Radiation dose is significantly associated with survival in patients with stage III NSCLC treated with combined radiation and chemotherapy.

No significant financial relationships to disclose.
Covariates of efficacy and safety in four trials of pemetrexed gemcitabine (PG) in advanced stage IIIB (with pleural effusion) or stage IV non-small cell lung cancer (NSCLC)
Authors: Van Doren B. A. , Ye Z. , Treat J. A.
Published: March 2020

18076

Background: P and G have demonstrated antitumor activity as a first-line treatment in pts with locally advanced or metastatic NSCLC. The impact of covariates such as age and gender on the activity and toxicity of this doublet has not been elucidated. Methods: A total of 220 pts with Stage IIIB (with pleural effusion) or IV NSCLC were treated with PG in four Phase 2 clinical trials. Three trials used G 1250 mg/m2 D 1,8 and P 500 mg/m2 on D 1 or D 8, and one used a 14-d regimen of G 1500 mg/m2 D 1 and P 500 mg/m2 D 1. Two types of analyses were performed to determine covariates’ relationship to variables of response (CR+PR), disease control (CR+PR+SD), and toxicity. Using logistic regression, odds ratios (ORs) were calculated by comparing pt covariates to outcomes. In a separate analysis, pt populations were stratified by baseline covariates, which were treated as categorical variables. Results: Conclusions: Neither age nor gender were statistically significant prognostic factors for activity or toxicity using either analysis, although older pts may have had a slightly better response rate and disease control rate when compared with younger pts. Complete analyses will be presented at the meeting.

[Table: see text]

No significant financial relationships to disclose.
Long-term effect of COPD on patients with lung cancer
Authors: Panwalkar A. , Kessinger A. , Loberiza F. , Ganti A.
Published: March 2020

18077

Background: Despite the association between chronic obstructive pulmonary disease (COPD) and lung cancer, their inter-relationship has not been studied. Their pathogenesis suggests that they may be a continuum of a single disease. The effect of COPD on outcomes in lung cancer has been primarily studied in surgical candidates in the peri-operative period, however long-term effects are unclear. We proposed to study the influence of COPD on overall survival in this patient population. Methods: After IRB approval a retrospective chart review was performed on patients with stage I and II, non-small cell lung carcinoma (NSCLC) diagnosed from 1994 through 2005. Data including demographics, smoking, treatment given, pulmonary function tests (PFTs) and survival were collected. Patients were classified as having COPD based on FEV1/FVC ratio of < 70%, and further graded by the percentage of predicted FEV1 value. Overall survival was computed by multiple linear regression and the p-value was calculated using the chi-square test. Results: Of the 399 patients with early stage NSCLC, 107 had PFTs evaluated before treatment of the cancer. Of these 42 (39%) did not have COPD, while 65 (61%) had COPD. Patients with COPD presented with a later stage (IB or II) as compared to those without COPD. After adjusting for age, stage, histology, treatment or smoking history, there was no difference in the overall survival among the two groups. The probability of 2-year overall survival for patients with mild, moderate, severe and very severe COPD was 100%, 79%, 77% and 62% respectively, compared with 72% for those without COPD. (p = 0.64). Conclusions: Patients with COPD presented with a later stage (IB or II) as compared to those without COPD. Despite this there was a trend toward an improvement in overall survival in patients with mild to moderate COPD that underwent surgical resection. This may be related, in part, to the beneficial effects of volume reduction of the diseased lung. The data are limited by low power that may have led to insignificant results. Further larger studies are required to better assess the relationship between COPD and lung cancer and its long term effects.

No significant financial relationships to disclose.
A prospective phase II study of gefitinib in non-small cell cancer patients with epidermal growth factor receptor gene (EGFR) mutations
Authors: Sugio K. , Uramoto H. , Oyama T. , Onizuka T. , Ichiki Y. , Yasuda M. , Sugaya M. , Nozoe T. , Takenoyama M. , Hanagiri T. , Yasumoto K.
Published: March 2020

18081

Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to gefitinib, a tyrosine kinase inhibitor that targets EGFR, especially in patients with adenocarcinoma, females, and/or never/light smokers. In our retrospective study, cases with EGFR mutations (exon19del or L858R) showed a high sensitivity to gefitinib, and the patients with sensitive EGFR mutations also tended to have a more favorable prognosis than those with wild-type after gefitinib treatment (Uramoto, et al. Lung Cancer 2006;51:71). In the present study, we prospectively assessed the efficacy of gefitinib and the survival benefit for patients with EGFR mutations. Methods: Patients with either recurrent disease after undergoing surgery or advanced disease (IIIB or IV) of NSCLC which demonstrated EGFR mutations were eligible for this study. EGFR mutations in exons 19–21 were examined by our previously described screening method (Sugio, et al. Br J Cancer 2006;94:896) and confirmed by direct sequencing after informed consent was obtained from all patients. The patients with EGFR mutations were enrolled in this study after obtaining informed consent a second time, and they were thereafter treated with gefitinib. Results: Between 2005 and 2006, 16 patients (10 males/6 females, all adenocarcinoma) who had EGFR mutations were enrolled onto this study. Six pts had a deletion in exon 19, 8 pts had a missense mutation in exon 21 (L858R), 1 pt had both an exon 19 del and L858R, and 1 pts had an exon19 del and missense mutation in exon 20 (G796A). The overall response rate was 50%, and the disease control rate was 88%. In patients with exon19 del and L858R, the response rates were 83% and 25%, respectively. A case with a deletion in exon19 and a missense mutation in exon20 (G796A) showed resistance to gefitinib. The median progression-free survival time was 8.8 months, and the median survival time was 15.4 months. No life-threatening toxicity was observed. Conclusions: EGFR mutations in exons 19 or 21 are therefore considered to a good predictor of the efficacy of gefitinib, and the treatment with gefitinib was also found to achieve a prolonged survival.

No significant financial relationships to disclose.
A phase II study to determine if sensory neuropathy of nab-paclitaxel can be reduced by prolonging infusion in patients with non-small cell lung cancer (NSCLC)
Authors: James L. P. , Kris M. G. , Heelan R. T. , Ng K. K. , Chia G. H. , Gomez J. E. , Krug L. M. , Moore E. , Hawkins M. J. , Rizvi N. A.
Published: March 2020

18087

Background: We have previously reported that nab-paclitaxel (ABI-007; Abraxane) administered at 125 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days has a response rate (RR) of 30% and median survival of 11 months [Rizvi, Proc. ASCO 2006]. We also observed 15/40 (38%) patients developed grade 2/3 sensory neuropathy with a 30 minute infusion. We hypothesize that a longer infusion with nab-paclitaxel may reduce peak plasma levels and accordingly reduce sensory neuropathy. Methods: After enrollment of 40 patients at 125 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days, we amended the protocol to study an additional 25 patients with chemotherapy naïve stage IV NSCLC with a 2 hour infusion. The enrollment criteria and treatment schedule otherwise remained the same. Our goal was to detect 1 to 2 grade improvement of peripheral neuropathy with 80% power at the two sided p=0.10 significance level compared to the 40 patients treated with this dose given over 30 minutes. Results: To date, 22 of 25 planned patients have been treated with a 2 hour infusion. The mean number of doses administered was 11 for the initial 40 patients treated with a 30 minute infusion and 10 for the 22 patients treated with the 2 hour infusion. We observed 9/40 grade 2 and 6/40 grade 3 sensory neuropathy with the 30 minute infusion and 2/22 grade 2 and 1/22 grade 3 sensory neuropathy with the 2 hour infusion. The combined grade 2 and 3 toxicities were less with the 2 hour infusion (3/22, 14%) compared with the 30 minute infusion (15/40, 38%; p=0.078, Fisher’s exact test). Conclusions: Prolonging the infusion rate of nab-paclitaxel from 30 minutes to 2 hours is associated with a significant decrease in grade 2 and 3 sensory neuropathy. Efficacy data is presently being evaluated.

[Table: see text]
Phase II study of bevacizumab in combination with docetaxel and carboplatin in patients with metastatic non-small cell lung cancer (NSCLC)
Authors: William W. N. , Kies M. S. , Fossella F. V. , Gladish G. , Heymach J. V. , Glisson B. S. , Tse W. H. , Liu D. , Herbst R. S. , Lippman S. M.
Published: March 2020

18098

Background: The combination of bevacizumab, paclitaxel and carboplatin has been recently shown to increase response rates and survival in patients (pts) with untreated, metastatic, non-squamous, NSCLC and is currently FDA-approved for this indication. However, there are limited data on the safety and efficacy of bevacizumab in combination with other widely used chemotherapy doublets for NSCLC. This is a single-arm, open-labeled, phase II trial of bevacizumab, docetaxel and carboplatin for pts with NSCLC. Methods: Eligibility criteria included chemotherapy-naïve stage IIIB or IV incurable NSCLC of non-squamous cell histology, PS 0–1, no brain metastases, no history of hemoptysis, no cavitation, stable cardiac condition and no full dose anticoagulation. Treatment consisted of docetaxel 75 mg/m2, carboplatin AUC 6, and bevacizumab 15 mg/kg IV on day 1 every 3 weeks for up to 6 cycles followed by bevacizumab 15 mg/kg alone every 3 weeks until progression. The primary endpoint was progression-free survival. Results: 20 pts (12 females) have been enrolled with a planned sample size of 50 pts. Baseline characteristics were: median age 66 years old (37–77), PS 0 (6 pts) or 1 (14 pts), stage IIIB (1 pt) or IV (19 pts). 19 pts are evaluable for response and toxicity at this time. Severe adverse events (SAEs) included: 4 pts with neutropenia (2 febrile neutropenias), mild hemoptysis in 2 pts (treated with radiotherapy), 1 pt with peritoneal perforation (who had a history of diverticula), 1 pt with pulmonary embolism, and 1 pt with grade 3 hypertension. Partial responses by RECIST have been observed in 14 pts (74%, 13 confirmed), and stable disease in 5 pts (26%, 4 confirmed). Disease control rate (PR+SD) was 100% after 4 cycles of therapy. 9/20 pts are off treatment (3 progressions, 5 SAEs, 1 maximal benefit). Progression-free survival will be reported at the completion of the trial. Conclusions: The combination of bevacizumab, docetaxel and carboplatin appears to be efficacious and tolerable for the first-line treatment of metastatic NSCLC.

No significant financial relationships to disclose.
Symptom assessment in small cell lung cancer (SCLC) in a randomized trial: A psychometric analysis of Patient Symptom Assessment in Lung Cancer (PSALC)
Authors: Chen L. , Antras L. , Duh M. , Neary M. , Dharan B. , O’Brien M. E.
Published: March 2020

18101

Background: Lung symptoms may be very burdensome for patients (pts) with SCLC. PSALC is a symptom scale that was developed for use in pts with SCLC for assessment of 9 symptoms (shortness of breath, cough, chest pain, hemoptysis, appetite loss, sleep interference, hoarseness, fatigue, interference with daily activities) scored from 1 (not at all) to 4 (very much), but has not been formally validated. The objective of this study is to evaluate the validity of the PSALC through a psychometric analysis of trial data. Methods: Data were analyzed from a randomized, open-label, multicenter trial with 141 pts with SCLC receiving either oral topotecan with best supportive care (BSC) or BSC alone. PSALC and EQ-5D were administered to pts at baseline and at 3-week intervals at subsequent visits. Endpoints for psychometric analysis included statistics for internal consistency, construct validity, reliability, and responsiveness to change in clinical status. Results: Factor analysis (n=131) indicated that there was only one factor, therefore PSALC total score (PSALC-TS) could be used for psychometric analysis. Weighted Cronbach’s alpha from all visits was 0.78. Construct validity was supported by association with established measures: higher baseline PSALC-TS (worse symptoms) was associated with worse ECOG (12.31, 16.37, 17.49 for ECOG score=0, 1, 2, respectively, p=0.0002); baseline PSALC-TS was significantly correlated with EQ-5D utility index (Pearson correlation coefficient [CC] =-0.493, p<0.0001, n=125) and EQ-5D VAS score (Pearson CC=-0.495, p<0.0001, n=122). Reliability was supported by intraclass CC of 0.68 for PSALC-TS evaluated before any change in clinical status, and concordance CC of 0.65, calculated using PSALC-TS at baseline and before first visit. PSALC-TS was responsive to change in clinical status from baseline to tumor response (responsiveness statistic (RS) =-0.99) and to tumor progression (RS=0.94). Conclusions: Retrospective analysis of trial data suggests that PSALC is a reliable, valid, and responsive scale for measuring SCLC symptoms. If feasible in SCLC population, a prospective validation study could be used to further evaluate the validity of this symptom scale.

No significant financial relationships to disclose.
Phase II trial of irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) given weekly on alternating weeks with granulocyte colony-stimulating factor support in the treatment of extensive-stage small cell lung cancer
Authors: Uyeki J. , Johnson F. M. , Feng L. , Peeples B. O. , Blumenschein G. J. , Fossella F. V. , Karp D. D. , Pisters K. M. , Stewart D. J. , Glisson B. S.
Published: March 2020

18119

Background: Irinotecan has significant activity in small-cell lung cancer. Randomized trials comparing IP to EP have yielded conflicting results. Our phase I study of alternating weekly therapy with IP and EP with granulocyte colony-stimulating factor (G-CSF) support found this regimen to be tolerated and active in untreated small cell lung cancer.(Johnson et al Clin Lung Cancer 2003) Methods: Based on these findings we conducted a phase II study to estimate the efficacy of weekly combination therapy in previously untreated patients with extensive disease small-cell lung cancer (ED-SCLC). Patients received 12 weeks of therapy with cisplatin (20 mg/m2) on day 1 and irinotecan (100 mg/m2) on day 1 and G-CSF days 2–5 (IP) alternating with cisplatin (20 mg/m2) on day 1 and etoposide 60 mg/m2 on days 1–3 with G-CSF on days 4–7 (EP). Patients with asymptomatic brain metastases were included. The primary end point was overall survival. Results: 38 patients were enrolled from 7/2001 to 7/2006. The median age was 60 years (range 37–73) and 55% were female. ECOG performance was 0 in 11 patients, 1 in 25 patients and 2 in 2 patients. 87% of patients completed 12 weekly cycles of chemotherapy (range 1–12) with 90% of the planned dose intensity of irinotecan delivered. The objective response rate in 33 evaluable patients was 87% (0 CR, 30 PR). Median follow-up time was 43.7 months. Median progression free survival was 6.4 months (95% CI 5.16–7.59 months). The median survival was 10.9 months (95% CI 8.61–13.5 months). The 2 year survival rate was 19% (95% CI 5–31%). Grade 3–4 non-hematologic toxicities included diarrhea (8%), hyponatremia (5%), dehydration (3%), and neutropenic fever (5%).Grade 3–4 hematologic toxicities included anemia (13%), neutropenia (5%), and thrombocytopenia (3%). There was 1 therapy related death due to sepsis. Conclusions: Weekly therapy with IP alternating with EP with growth factor support was well tolerated in patients with untreated ED- SCLC, but did not show improved progression-free or overall survival when compared with historical controls at our institution.

No significant financial relationships to disclose.
Phase II study of docetaxel and S-1 combination therapy in patients with previously treated non-small cell lung cancer
Authors: Atagi S. , Kawahara M. , Kubo A. , Kawaguchi T. , Yumine K. , Okishio K. , Tomizawa Y. , Komatsu H. , Fukai S.
Published: March 2020

18122

Background: Docetaxel is active against chemotherapy-pretreated non-small-cell lung cancer (NSCLC). S-1 is a novel oral fluoropyrimidine, composed of tegafur, 5-chloro-2,4-dihydroxypyridine (dihydropyrimidinedehydrogenase inhibitor), and potassium oxonate (orotate phosphoribosyl transferase inhibitor). It has been commercially available and used for NSCLC in Japan. We conducted this study to evaluate the efficacy and safety of docetaxel combined with S-1 in NSCLC patients (pts) who were previously treated with one or more regimens. Methods: Eligible pts were required to have histologically or cytologically confirmed measurable or evaluable stage IIIB or IV NSCLC, age= 20 years, one or more previous chemotherapy, a performance status (PS) 0–1, and adequate organ function and bone marrow reserve. In this study, pts received S-1 (80 mg/m2 orally on days 1–14) and docetaxel (40mg/m2 IV on days 1). Treatment was repeated every 3 weeks. Results: Between January 2005 and May 2006, 30 pts were enrolled on this study. 29 pts were eligible and evaluable. Median age was 67 (48–79), male/female (23/6), PS 0/1 (9/20), stage IIIB/IV (7/22), and prior chemotherapy regimen 1/2/3 (23/4/2). 28 pts received a platinum-based chemotherapy. Response: PR=7(24%), SD=13, PD=7, NE=2. Median survival time was 10.2 months. Grade 3/4 toxicities (% of pts) were as follows: leukocytes 6/0 (20.6%), neutrophils 7/3 (34.4%), platelets 0/0, infection 0/1 (3.4%), fever 2/0 (6.9%), diarrhea 1/0 (3.4%), neurology 0/1 (3.4%), and mucositis 1/0 (3.4%). There were no treatment-related deaths. Conclusions: The combination of docetaxel and S-1 was effective with acceptable toxicity in pts with previously treated NSCLC. These results warrant further investigations of this regimen a randomized controlled trial as a second-line treatment for NSCLC.

No significant financial relationships to disclose.
CyberKnife high-dose fractionated stereotactic radiosurgery with tumor tracking: An effective non-surgical treatment alternative for single small peripheral lung tumors
Authors: Malik S. M. , Erickson K. , Collins S. , Reichner C. , Jamis-Dow C. , Banovac F. , Anderson E. D. , Smith F. P. , Hwang J. , Collins B. T.
Published: March 2020

18125

Background: We report preliminary outcomes using CyberKnife radiosurgery with tumor tracking to treat small (<4 cm) peripheral inoperable stage I lung cancers and single pulmonary metastases. Methods: Enrollment of eligible pts began in July 2004. Prior conventional thoracic irradiation and the incorporation of systemic therapy were permitted. Fiducials (3–5) were placed near tumors under CT guidance. Pts received 45–60 Gy in 3 equal 1–2 hour fractions delivered over a 5–9 day period. Results: The median follow-up period of survivors was 12 months (range = 3–24 months). A total of 24 lesions were treated, 15 clinical stage I lung cancers and 9 single lung metastases. Four patients had prior conventional thoracic radiation (17%) and 6 patients received systemic therapy in conjunction with radiosurgery (25%). Two received systemic doses of platinum based doublet chemotherapy, 3 received gefitinib and 1 received sunitinib. Pneumothorax was a complication of fiducial placement in 7 pts, requiring tube thoracostomy in 4. All pts completed treatment with few acute side effects. No unexpected additional toxicities were noted with systemic therapy except for one pt who developed Grade III radiation pneumonitis while receiving gefitinib. A second pt with Grade III radiation pneumonitis had prior extensive conventional thoracic radiation. All tumors responded to treatment at 3 months as seen by a decrease in gross tumor volume. At 12 months 14 CT scans were evaluable. Four lesions responded completely (33%), 2 exhibited a partial response and the remaining 8 were obscured by radiation fibrosis corresponding to the high-dose irradiated volume (57%). Local progression was seen in only 2 single lung metastases at 10 and 12 months. There have been no regional lymph node failures. Four patients have died, 1 of progressive metastatic disease and 3 of comorbid illnesses. Conclusion: CyberKnife high-dose fractionated stereotactic radiosurgery with tumor tracking is an effective well-tolerated treatment option for small peripheral lung tumors, both primary and metastatic. The integration of systemic therapy appears feasible but needs to be further evaluated in clinical trials.

No significant financial relationships to disclose.
Palliative radiotherapy versus palliative chemoradiotherapy in treatment of NSCLC stage IIIA and IIIB: Phase II randomized trial
Authors: Nawrocki S. , Krzakowski M. , Wasilewska-Teńluk E. , Kowalski D.
Published: March 2020

18128

Background: The optimal treatment for stage IIIA/IIIB NSCLC patients who do not qualify for radical treatment has not been identified. Different palliative radiotherapy regimens and chemotherapy are used but have not been compared. We decided to combine short chemotherapy and radiotherapy (CT-RT) in order to improve therapeutic index of radiotherapy (RT). Methods: Eligibility criteria: Locally advanced, inoperable patients (pts) in IIIA (N2 positive) -IIIB clinical stage with tumor larger than 8 cm in longest diameter or/and FEV1 smaller than 40%, PS: 0–2 (ECOG), non-eligible for radical CT-RT. Treatment: RT arm - 3-D radiotherapy, 30 Gy/3 Gy, 2 weeks. CT-RT arm - two cycles of CT (cisplatin: 80 mg/m2; d 1, 22; vinorelbine: 25 mg/m2 iv; d 1,8,22,29) followed by RT as in Arm 1 with concurrent third cycle of CT (cisplatin 80 mg/m2, d 43; vinorelbine 25 mg/m2 iv., d 43, 50). Study design: Phase II, two-center, randomized study, stratification IIIA vs. IIIB, PS 0–1 vs. 2, treating center (Warsaw vs. Olsztyn). Two-stage design, a and β errors = 0,1; p1 minus p0 = 0,20. Planned sample size - 46 pts/arm. Primary endpoint: response rate (RECIST). Secondary end-points: overall survival (OS), toxicity, progression free survival (PFS). Results: During 2 years 104 pts randomized, 98 eligible for toxicity and survival/progression analysis, 82 for response assessment. Demographics: median age - 65 (45–78), IIIA/IIIB: 27/71 pts. PS 0–1/2: 72/26. Well balanced between arms. Response rate: RT arm- 26%, CT-RT arm- 46%, median OS for RT arm - 195 days, CT-RT arm 2 - 385 days, log-rank test p=0,047, median PFS for RT arm - 140 days, CT-RT arm - 172 days, log-rank test p=0,16. Toxicity: deaths - 2 in RT arm, 2 in CT-RT arm; hematological G3–4 - 0 in RT arm, Arm CT- RT: anemia - 2, thrombocytopenia - 6, neutropenia - 11, esophagitis - 2. Other G3–4: RT arm -3, CT-RT arm -1. Conclusions: Palliative radiotherapy (30Gy) with chemotherapy postponed to progression is a suboptimal treatment for patients with locally advanced NSCLC. 2 cycles of cisplatin/vinorelbine plus RT concomitantly with 3 cycle increases clinical response rate and significantly prolongs survival at the cost of acceptable toxicity in palliative setting.

No significant financial relationships to disclose.
Combination chemotherapy with irinotecan and cisplatin in elderly patients (≥65 years) with extensive-disease small-cell lung cancer
Authors: Lee G. , Kim K. , Cho Y. , Kim H. , Hwang I. , Kim H. , Kang J. , Jang J. , Lee J.
Published: March 2020

18135

Background: Combination chemotherapy with irinotecan and cisplatin is one of the standard treatments for patients with small-cell lung cancer (SCLC). In elderly patients, however, its efficacy and toxicity has not been well documented. In this Phase II study, we assessed the efficacy and toxicity of combination chemotherapy with irinotecan and cisplatin and examined whether advanced age compromises it in elderly patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Methods: In this study, 43 previously untreated elderly patients (65 years or older) with ED-SCLC were given combination chemotherapy consisting of irinotecan 60mg/m2 on days 1, 8 and 15 and cisplatin 60mg/m2 on days 1. The treatment was repeated every four weeks until patients completed the maximum six cycles. Results: Patients consisted of 34 men and 9 women, whose median age was 70 years (range 65 - 81 years). A complete response and a partial response were observed in 23.3% (10/43) and 58.1% (25/43), respectively. The overall response rate was 81.4% (95% C.I; 69.7 - 93.0%). The overall median survival was 10.3 months (range 7.8 - 12.7 months). The 1-year and 2- year survival rates were 31.8% and 3.4%, respectively. The median progression-free survival was 8.32 months (range 6.8 - 9.8 months). Major toxicities included neutropenia (grade 3 to 4, 55.9%), leukopenia (grade 3 to 4, 46.5%), infection (grade 3 to 4, 37.3%) and diarrhea (grade 3 to 4, 30.3%). Incidence of febrile neutropenia was significantly higher in patients with ECOG performance status 2 compared with ECOG performance 1 (70.7% vs. 5.2%; p < 0.001). There were two treatment related deaths in patients ECOG performance status 2. Conclusions: Our results indicate that combination chemotherapy with irinotecan and cisplatin is an effective treatment for elderly patients with ED-SCLC. However, physicians should be aware of the mortality and morbidity due to myelosuppression following this treatment in elderly ED-SCLC patients with ECOG performance status 2.

No significant financial relationships to disclose.
Phase I/II study of oral TS-1 and gemcitabine in elderly patients with advanced non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group 0502
Authors: Seto T. , Yamanaka T. , Eguchi K. , Okamoto H. , Shibuya M. , Ogura T. , Shinkai T. , Takiguchi Y. , Masuda N. , Ichinose Y. , Watanabe K.
Published: March 2020

18137

Background: Optimal treatment for elderly patients with NSCLC has been under active investigation. This study evaluated the safety and initial efficacy of a novel combination regimen of oral fluoropyrimidine TS-1 plus gemcitabine (GEM) for elderly patients (pts) with advanced NSCLC. Methods: A phase I/II trial in 11 centers examined TS-1 and GEM in pts with age = 70, stage IIIB/IV previously untreated NSCLC. The starting dose was 60 mg/m2day (day 1–14) for TS-1 and 800 mg/m2 for GEM (day 8, 15). GEM was increased to 1,000 mg/m2 at dose level 2 and TS-1 was increased to 80 mg/mg2/day at dose level 3. Phase II portion of the study assessed the efficacy and tolerability of the combination regimen at the dose determined in the phase I portion. The primary endpoint was objective response rate. Results: Twenty two pts were enrolled in the phase I portion: 6 pts on dose level 1, 10 on dose level 2 and 6 on dose level 3. Median age of this group was 75 yrs (range 70–85). Dose limiting toxicities included Gr. 4 neutropenia (2 pts) and Gr.3 skin toxicity (4 pts). The recommended dose (RD) was TS-1 60 mg/day and GEM 1,000 mg/m2, with which 20 pts were subsequently treated in the phase II portion. The median age of 30 pts treated with the RD was 76 yrs (range 70–85). Grade (Gr) 3/4 toxicities include neutropenia (12 pts; 7 with Gr 4), thrombocytopenia (4 pts; 0 with Gr 4), skin toxicity (8 pts), thrombus (1 pt) and peumonitis (2 pts). Nine patients (30%, 95% confidence interval [CI] = 14 to 46%) had partial responses and 16 (53%, 95% CI = 35 to 71%) had stable disease. Conclusions: Encouraging antitumor activity and safety of TS-1 plus gemcitabine support further development of this combination therapy for elderly patients with advanced NSCLC.

No significant financial relationships to disclose.
Phase I study of bortezomib plus cetuximab in patients with tumors expressing epidermal growth factor receptor (EGFR)
Authors: Dudek A. , Gada P. , Mulamalla K. , Shehadeh N.
Published: March 2020

18143

Background: Bortezomib is a proteasome inhibitor that augments EGFR inhibitor activity (Cancer Research 2007; 67:(2),1–8). Cetuximab is a chimeric mouse-human antibody against EGFR that has been found to induce tumor responses in patients with colon cancer and head and neck cancer. The purpose of this study was to establish a maximum tolerated dose (MTD) for the combination of bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumors. Methods: A 21-day treatment cycle was given with a maximum of six cycles per patient. Bortezomib was administered intravenously on days 1 and 8 via dose escalation, beginning with a minimum dose of 1.3 mg/m2 and increasing in one-tenth increments to 2.0 mg/m2 for a total of eight dose levels. Cetuximab was delivered with an initial dose of 400mg/m2 on day 1 cycle 1, with subsequent doses of 250mg/ m2 on days 1, 8 and 15. Results: Twenty patients (13 male and 7 female) with an ECOG PS <2 were enrolled in this study from November 2005 to December 2006. The median age was 59.5 (range: 41- 68), and the median number of prior chemotherapy regimens was 5 (range 1–7). Primary tumor sites included lung (9), head and neck (4), kidney (3), pancreas (2), bladder (1), and ovary (1). A total of 54 cycles of chemotherapy were administered; the median number of cycles per patient was 2.5 (range 1–6). Thirteen patients discontinued therapy because of disease progression. Two patients completed all six cycles of therapy. One dose-limiting toxicity (DLT) was seen at dose level 4 (bortezomib 1.6 mg/m2), which included grade 3 nausea, vomiting and dysphagia based on evaluation using CTCAE (version 3.0). Level 4 was expanded to enroll 3 additional patients, and no further grade 3 or 4 toxicities were observed. Grade 3/4 non- hematological toxicities were observed in 14 patients after their first cycle of therapy. Nine patients had delay in treatment. Conclusions: MTD for bortezomib plus cetuximab was not achieved at dose levels 1–6. This combination therapy has shown limited clinical activity in our extensively pretreated group of patients with solid tumors. Complete results for all dose levels, including dose levels 7–8, will be reported at the 2007 meeting of the American Society of Clinical Oncology.

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Toxicity of g-csf given for neutropenia during chest radiotherapy in limited-stage small cell lung cancer (SCLC)
Authors: Karcznmarczyk A. , Nawrocki S.
Published: March 2020

18148

Background: There are concerns that use of white blood cell growth factors during radiotherapy, especially chest radiotherapy may lead to severe thrombocytopenia. Bunn P reported (J Clin Oncol 1995) that use of gm-csf during radical CT-RT of limited- stage SCLC is associated with life-threatening thrombocytopenia and did not reduce significantly neutropenia. On the other hand the prolongation of CT-RT total time in limited-stage SCLC has negative impact on survival. We have evaluated the safety of g-scf administration given for neutropenia (ANC<500/mm3) in limited-stage SCLC. Methods: 32 patients, 19 men, 13 women (median age 58,5 range 49–71, PS (WHO) = 0 or 1 - 30 patients, PS=2 - 2 patients. Chemotherapy during RT: cisplatin 60 mg/m2 d 1, etoposide 120 mg/m2 d 1–3, every 3 weeks. RT: 54 Gy/2 Gy/5 days a week together with 3rd and 4th CT cycle to gross tumor, ipsilateral hilar and bilateral lymph nodes planned in 3-D planning system, 6 MV photons. G-csf given for 3 to 10 days (median - 6 d) once (22 patients) or twice during RT-CT (10 patients) for G4 (CTC) neutropenia or febrile neutropenia, 30 mln u/d for 19 patients, 48 mln u/d for 13 patients. Toxicity was recorded (CTC v.2.0) Hematology tests done every 7 days during RT and every 7 days after RT till resolution of thrombocytopenia. No breaks in RT due to neutropenia, break if thrombocytopenia G3/G4. Results: G3-G4 thrombocytopenia was observed in 15 out of 32 patients during or after RT. In 2 patients platelet’s transfusions were given, in 1 patient haemoptysis was observed, no toxic deaths were noticed. Febrile neutropenia in 10 out of 32 patients. No breaks in RT in 20 out of 32 patients. 1 to 3 days’ breaks in 7 patients, 4 to 6 days breaks in 2 patients, longer breaks in 3 patients. Mean platelet count before RT - 221,000/mm3, after RT in 3 following weeks: 135,000/mm3, 149,000/mm3, 137,000/mm3. In 21 out of 32 patients clinical response (CR or PR) was observed after CT-RT. Thrombocytopenia was not associated (p>0,1) with age, PS or radiotherapy dose, associated with number of chemotherapy cycles (p=0.07). Conclusions: Use of g-csf during CT-RT in SCLC seems to be safe, regarding thrombocytpenia. G-csf given in lower doses for shorter times than in P. Bunn’s paper may be safer. Randomized study with g-csf in limited- stage SCLC is justified.

No significant financial relationships to disclose.