First-line CTX Research Articles

Prognostic impact of local recurrence and timing of palliative radiotherapy in patients with unresectable recurrent rectal cancer.

132 Background: The standard treatment for unresectable recurrent rectal cancer (URRC) is chemotherapy (CTx) regardless of local recurrence (LR). Approximately 80% of patients with LR experience LR-related pain, making these patients difficult to treat, especially the timing of radiotherapy (RT). However, the impact of LR and the appropriate timing of palliative RT on prognosis in patients with URRC remains unclear. Methods: This retrospective study included patients with URRC who had an ECOG Performance Status (PS) of 0–2 and received fluoropyrimidines plus oxaliplatin and/or irinotecan as first-line CTx between September 2006 and December 2020 at a single institution. Patients were divided into two groups: patients with LR (LR+) and patients without LR (LR−). Progression-free survival (PFS), overall survival (OS), and post-progression survival (PPS) after first-line CTx were compared between the two groups. The association between receiving palliative RT for LR-related symptoms until disease progression after first-line CTx and the proportion of patients receiving subsequent second-line CTx was also evaluated in the LR+ group. Multivariate Cox analysis, including variables with p < 0.10 in univariate analyses, was performed for PPS. Results: The LR+ and LR− groups included 49 and 99 patients, respectively. No significant differences in the baseline characteristics were detected between the two groups, except liver metastasis, which occurred less frequently in the LR+ group. OS and PPS were shorter in the LR+ group compared with the LR- group (median OS, 33.4 vs. 48.2 months; hazard ratio [HR], 1.52; p = 0.05; median PPS, 17.2 vs. 23.5 months; HR, 1.77; p = 0.01). PFS was similar between the two groups (median PFS, 13.0 vs. 15.8 months; HR, 1.18; p = 0.39). Fewer patients in the LR+ group received second-line CTx compared with the LR- group (68 vs. 83%, p = 0.06). The proportions of patients with PS ≥ 1 (78 vs. 52%, p = 0.007) and PS deterioration at progression after first-line CTx (59 vs. 27 %, p = 0.002) were higher in the LR+ group compared with the LR group-. The most common cause of PS deterioration in the LR+ group was LR-related pain (77%). Among patients with LR-related pain, the proportion of patients receiving subsequent second-line CTx was numerically lower in patients who did not receive palliative RT than in patients who did receive palliative RT until disease progression after first-line CTx (75 vs. 54%, p = 0.23). Multivariate analysis revealed that receiving subsequent second-line CTx was an independent prognostic factor for PPS in LR+ patients (adjusted HR, 4.77; p = 0.006). Conclusions: The presence of LR is associated with poor prognosis in URRC, which may be due to worsening PS caused by LR-related symptoms and the lower proportion of subsequent CTx. Thus, palliative RT should be recommended more actively when LR becomes symptomatic.

An observational study on treatment patterns and outcomes among patients with metastatic or recurrent esophageal cancer: Real-world data and empirical analyses in Japan (POME).

289 Background: There has been little information on treatment patterns and factors affecting outcomes of metastatic or recurrent esophageal cancer (EC) in clinical practice before the marketing of immune checkpoint inhibitors. This study aimed to investigate the treatment patterns and outcomes among patients (pts) with EC treated with systemic chemotherapy (CTx). Methods: This was a retrospective chart review study and included pts with histologically diagnosed esophageal squamous or adenosquamous carcinoma who started systemic CTx for metastatic or recurrent disease between January 1, 2013 and December 31, 2018 at 16 institutions in Japan. With a cutoff date of December 31, 2020, the treatment patterns and outcomes, including response rate (RR), progression-free survival (PFS), and overall survival (OS) for first through third CTx, were analyzed. Results: A total of 891 pts were included in this analysis. The median age (range) was 67 (23-90) years, 84.9% of pts were male, histological types were squamous cell carcinoma in 99.0% and adenosquamous carcinoma in 1.0%, and disease status was metastatic in 35.8% of pts. Most common first-, second-, and third-line regimens were fluoropyrimidine-based (72.4%), taxane-based (64.6%), and taxane-based (48.2%), respectively. Of the pts who received the first-line CTx, the second- and third-line CTx were administered in 51.2% and 21.4% of pts, respectively. The RR from first- to third-line CTx was 24.2%, 6.5%, and 2.2%, and mPFS was 4.1 months (mo) (95% CI 3.7-4.5), 3.1 mo (95% CI 2.8-3.6), and 3.0 mo (95% CI 2.5-4.2), respectively. The mOS from the first-, second-, and third-line CTx were 12.6 mo (95%CI 11.4-13.6), 8.3 mo (95% CI 7.7-9.6), and 8.0 mo (95% CI 7.1-9.5), respectively. As for OS from first-line CTx, a trend of improvement was shown before (median 11.9 mo, 95% CI 10.6-13.3) or after (median 13.2 mo, 95% CI 11.3-14.5) the median time of treatment initiation (March 2016). Pts with recurrent disease (mOS 26.6 mo, 95% CI 24.7-28.6) had a better prognosis than those with stage 4 disease at initial diagnosis (mOS 14.9 mo, 95% CI 13.2-16.3). Of the 293 pts who relapsed after esophagectomy with perioperative CTx or radical chemoradiotherapy, the time from the last day of CTx administration to relapse was less than 6 mo (early recurrence) in 123 (42.0%) pts and more than 6 mo (late recurrence) in 170 (58.0%) pts. The prognosis for pts with early recurrence (mOS 16.3 mo, 95% CI 13.7-20.2) was worse than for pts with late recurrence (mOS 32.9 mo, 95% CI 28.9-35.5). Conclusions: The results of this study revealed the actual treatment and prognosis of metastatic or recurrent EC in clinical practice. This real-world data might identify unmet needs and provide important information for the development of treatments in future.

Efficacy of first-line checkpoint inhibitors in combination with chemotherapy in high-grade extrapulmonary metastatic neuroendocrine carcinomas.

Poorly differentiated extrapulmonary neuroendocrine carcinomas (EP NECs) are aggressive cancers characterized by a high Ki-67 index, rapid tumor growth and poor survival, and are subdivided into small and large cell carcinoma. For small cell carcinoma of the lung, a pulmonary NEC, the combination of cytotoxic chemotherapy (CTX) and a checkpoint inhibitor (CPI) is considered standard therapy and superior to CTX alone. EP NECs are typically treated with platinum-based regimens, some clinicians have adopted the addition of a CPI to CTX based on data from trials in patients with small cell carcinoma of the lung. In this retrospective study of EP NECs, we report 38 patients treated with standard first-line CTX and 19 patients treated with CTX plus CPI. We did not observe any additional benefit of adding CPI to CTX in this cohort.

Durvalumab (D) plus tremelimumab (T) immunotherapy in patients (Pts) with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy (CTx): Interim results of the IMMUNOBIL GERCOR D18-1 PRODIGE-57 study.

4108 Background: D (anti-PDL1) plus T (anti-CTLA-4) combination immunotherapy showed encouraging results in hepato-biliary cancers. Its efficacy in non-Asian Pts with pretreated BTC is unknown. Methods: IMMUNOBIL GERCOR-D18-1 PRODIGE-57 was initially a 2-arm, open-label, randomized non-comparative phase II study. Pts with recurrent/advanced pathologically proven BTC (intrahepatic cholangiocarcinoma [iCCA]/extrahepatic CCA [eCCA]/gallbladder cancer [GC]), ECOG PS 0-1, pre-treated with platinum-based CTx were randomized (1:1) to D (1500 mg Q4W) plus T (75 mg Q4W x 4 cycles [T75]) (Arm A) or D plus T in combination with weekly paclitaxel (Arm B). Arm B was closed prematurely for toxicity after inclusion of 10 Pts. The study continued with Arm A only. It was further amended to modify the T schedule (300 mg at cycle 1 [T300], amended Arm A) due to higher efficacy reported in other tumors as compared to T75 mg x 4. The new primary endpoint was the overall survival (OS) rate at 6 months (M6) in amended Arm A (D + T300) with a Fleming two-stage design (H0: 50%, H1: 65%, one-sided alpha: 5%, power: 90%). A total of 100 evaluable Pts were required (efficacy threshold: 59%). We present here the efficacy data of Arm A (D + T75). Results: From 12/2018 to 12/2020, 106 Pts were included in Arm A; 103 were evaluable for OS at M6. Median age was 66 years, 47% were male, 46% had ECOG PS 0, 69%/18%/13% had iCCA/eCCA/GC, 76% had metastatic disease, and 28% had prior tumor resection. First-line CTx was GEMCIS/GEMOX/5-FU-based/other in 63%/22%/4%/11%. The M6-OS rate was 59.2%. With a median follow-up of 12 months (95% Cl 11.4-14.9), the median OS was 8.0 months (95% Cl 5.7-11.7) and median PFS was 2.5 months (95% Cl 2.0-3.2). Complete response (CR) was observed in 2 (1.9%) Pts, partial response (PR) in 8 (7.8%), and stable disease (SD) in 32 (31.1%), resulting in an objective response rate of 9.7% and a disease control rate of 40.8%. Absence of progression (PD, iRECIST) after 2 cycles (M6-OS rate: 84% vs 41%, median OS: 17.9 months vs 4.4 months) and CR/PR as a best overall response (M6-OS rate: 100% vs 84% and 39% for SD and PD, respectively) were associated with markedly prolonged OS. 65 (63.1%) Pts had ≥1 grade 3-4 (G3-4) adverse event (AE) and 22 (21.4%) had ≥1 G3-4 treatment-related AE (TRAE). The most commonly reported G3-4 AEs were fatigue (12.6%), abdominal pain (5.8%), and aspartate aminotransferase increase (5.8%) and G3-4 TRAEs were fatigue (4.9%) and diarrhea (2.9%). One death was possibly related to treatment. Conclusions: Although no statistical conclusions can be drawn from this exploratory analysis of Arm A, D+T75 reached the pre-defined threshold for efficacy, with no unexpected toxicity. Results from amended Arm A (D+T300, N = 106 additional Pts), quality of life, and ancillary studies are pending. Clinical trial information: NCT03704480.

Adapted physical activity in patients (Pts) with advanced pancreatic cancer (APACaP): Results from a prospective national randomized GERCOR trial.

4007 Background: The benefit of adapted physical activity (APA) on health-related quality of life (HRQoL) in Pts with advanced pancreatic ductal adenocarcinoma (aPDAC) treated by chemotherapy (CTx) has never been prospectively assessed. Methods: Pts with aPDAC and ECOG performance status (PS) 0–2 were randomized 1:1 to receive usual care (UC) including first-line CTx at the investigator’s choice (standard arm), or UC plus a home-based 16-week APA program (APA arm). The APA program consisted of personalized aerobic and resistance exercises, with a weekly remote supervision by an APA professional trainer, and unsupervised sessions with a family member or friend (APA partner). The primary objective was the effect on HRQoL at week 16 (W16) measured by 3 dimensions of the EORTC QLQ-C30, global health status (GHS), physical functioning (PF), and fatigue (FA), with a one-sided type I error of 0.016 for each dimension. The primary HRQoL analysis was performed in Pts with available baseline and W16 scores for the 3 targeted dimensions (mITT1). Secondary analyses of HRQoL changes by the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods included Pts with baseline and ≥1 follow-up score (mITT2). Differences > 5 points in scores were considered clinically significant. Results: A total of 313 Pts (median age: 64 years; men: 55%, ECOG PS 0-1: 93%; metastatic: 77%; FOLFIRINOX: 78%, gemcitabine-based: 13%) were included from 11/2014 to 10/2020 (standard arm: n = 157, APA arm: n = 156). In the mITT1 population (n = 172), mean differences in HRQoL at W16 adjusted from baseline were -0.98 (SD 23.87; p = 0.39), -2.08 (SD 21.34; p = 0.26), and 4.16 (SD 29.18; p = 0.18) for GHS, PF, and FA, respectively. In the mITT2 population (n = 259), APA was associated with significant improvements in 5 (GHS, PF, cognitive functioning [CF], social functioning [SF], appetite loss) and 8 (GHS, CF, emotional functioning [EF], SF, insomnia, constipation, pain, financial difficulties) dimensions of HRQoL by MMRM and TUDD, respectively (Table). Secondary endpoints, including overall survival, progression-free survival, and chemotherapy toxicity will be presented. Conclusions: APA in combination with usual care improved several dimensions of HRQoL in Pts with aPDAC receiving first-line CTx. Clinical trial information: NCT02184663. [Table: see text]

Plasma metabolomics to predict chemotherapy (CTX) response in advanced pancreatic cancer (PC) patients (pts) on enteral feeding for cachexia.

600 Background: We evaluated the potential of plasma metabolites as predictors of response to CTX in a prospective cohort of pts who received enteral feeding for cachexia and advanced PC. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for palliative CTX. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. As part of an exploratory analysis of the PANCAX-1 trial, serial blood samples were collected at 3 predefined timepoints over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. The mean AUC was used in pts with metabolites measured from > 1 timepoint of collection. Pts were stratified by stable disease (SD), partial response (PR), or progressive disease (PD) as best overall response to standard CTX. Results: Of 31 pts with advanced PC prospectively enrolled for enteral feeding, there were 55 blood samples collected from 28 pts available for plasma metabolomics. 20/28 (71%) pts received first-line CTX, the majority of whom (90%) received gemcitabine-based CTX. There were 2 PRs (7%) and 10 with SD (36%) as best response to CTX. Overall, there were statistically significant differences in levels of intermediates involved in multiple metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and nucleoside synthesis in pts with PR/SD vs. PD to CTX (all p < 0.05). When stratified by CTX regimen, PD to 5-fluorouracil-based CTX (e.g., FOLFIRINOX) was associated with decreased levels of essential amino acids (AAs, L-leucine, L-methionine, L-tryptophan) and non-essential AAs (L-arginine, L-serine, L-tyrosine, all p < 0.05). For gemcitabine-based CTX (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis (pyruvate), TCA cycle (L-glutamate), nucleoside synthesis (xanthine), and bile acid metabolism (taurocholic acid, all p < 0.05). Conclusions: We are the first to demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced PC pts on enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of response and warrant further study.

A randomized phase 2 trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma

Background No preferred first-line chemotherapy regimen exists for advanced esophagogastric adenocarcinoma. Addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has been shown to improve survival but is associated with increased toxicity. In this randomized, non-comparative phase 2 trial, we tested carboplatin, docetaxel, and capecitabine (CTX), a potentially useful modification of DCF (NCT02177552). Patients and methods Patients with advanced HER2-negative esophagogastric adenocarcinoma not previously treated in the first-line setting were randomized to intravenous docetaxel 60 mg/m2 and carboplatin AUC5 plus oral capecitabine 1000 mg/m2 bd days 1–14, q4w (CTX) or intravenous epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 625 mg/m2 bd days 1–21, q3w (epirubicin, oxaliplatin and capecitabine [EOX]). Treatment continued until progression, intolerance or for a maximum of nine cycles. The primary endpoint was 1-year survival for patients treated with CTX. Results Between June 2014 and January 2019, a total of 98 eligible patients were randomized. The 1-year survival rate was 34.7% (95% CI 21.8 − 47.9) with CTX and 36.7% (95% CI 23.6 − 50.0) with EOX. Progression-free survival and overall survival were 6.1 months (95% CI 5.5 − 7.1) and 9.8 months (95% CI 8.2 − 11.0) with CTX and 5.1 months (95% CI 4.3 − 7.0) and 10.2 months (95% CI 8.0 − 11.9) with EOX, respectively. Related grade 3 or 4 treatment-emergent adverse events (AEs) occurred in 86% of patients on CTX and 69% on EOX. Febrile neutropenia occurred in 31.4% of patients on CTX and 13.7% on EOX. Conclusions First-line CTX showed insufficient efficacy and caused a high rate of febrile neutropenia. CTX could not, therefore, be recommended for further study. This trial adds to current knowledge of docetaxel combined with platinum and 5-FU: that the combination is associated with increased toxicity and its use should be limited to fit patients in need of a response.

Efficacy of second-line chemotherapy after standard combination chemotherapy in patients with metastatic pancreatic cancer: The results from the NAPOLEON study.

661 Background: Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) have been established as standard first-line combination chemotherapy (CTx) for patients with metastatic pancreatic cancer (MPC). However, the efficacy of second-line CTx and the significance of combination CTx in clinical practice are unclear. We therefore investigated the efficacy of second-line CTx in patients with MPC. Methods: Data were collected from CTx-naive MPC patients treated with first-line combination CTx at 14 hospitals in the Kyushu area of Japan from December 2013 to June 2018. The median overall survival (mOS) from second-line treatment was compared between patients who received second-line CTx (CT group) and those who received best supportive care (BSC group). Furthermore, in the CT group, the mOS was compared between the patients who received combination CTx and those who received mono-CTx. To control potential bias in the selection of second-line treatment, we also conducted a propensity score-adjusted analysis. Results: A total of 255 patients received GnP or FFX as first-line CTx. Of these, there were 156 (61%) in the CT group and 77 (30%) in the BSC group. The number of patients who received FFX/GnP as first-line CTx was 79 (51%)/77 (49%) in the CT group and 15 (20%)/62 (80%) in the BSC group, respectively (P < 0.01). The mOS in the CT group was significantly longer than that in the BSC group (5.2 vs. 2.7 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.31-0.57; p < 0.01 and 5.2 vs. 2.6 months; adjusted HR 0.39; 95% CI 0.28-0.55; p < 0.01). In the CT group, 89 (57%) patients received combination CTx, and 67 (43%) received mono-CTx. There was no significant difference in the mOS between the combination CTx and mono-CTx patients (5.5 vs. 4.4 months; HR 0.88; 95% CI 0.62-1.26; p = 0.88 and 5.6 vs. 4.4 months; adjusted HR 0.85; 95% CI 0.56-1.30; p = 0.47). Conclusions: Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination CTx conferred no improvement in the survival duration compared with mono-CTx.

Efficacy of Chemotherapy Integrated With Traditional Korean Medicine in Patients With Metastatic Pancreatic Cancer: A Single-Center Retrospective Study.

Background:This retrospective study investigated the efficacy and safety of chemotherapy (CTX) integrated with Traditional Korean Medicine (TKM) in patients with metastatic pancreatic cancer, in a single Korean center.Methods:From January, 2014 to February, 2019, patients with metastatic pancreatic cancer who had received CTX were enrolled. Overall survival (OS), demographic characteristics, and adverse events were examined. Statistical analysis was utilized to evaluate the differences in characteristics and to compare the survival rates between the CTX group and CTX+TKM group. Kaplan-Meier curves were used to compare the differences in survival time. A Cox regression analysis was performed to determine the hazard ratio of the risk of mortality.Results:A total 37 participants were included and visited a TKM hospital 7.4 ± 8.3 months after being diagnosed with metastatic pancreatic cancer. The median age of the participants was 62 years; 26 patients (70.3%) had an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 2, and 23 patients (62.2 %) had first-line CTX failure. The median OS of all patients was 3.8 months (95% CI, 3.1-4.6). The CTX + TKM group showed longer survival (4.1 months; 95% CI, 2.4- .8) than the CTX group (2.4 months, 95% CI 0.2-4.6) but this was not statistically significant (P = .217). Chemotherapy with TKM treatment for more than 30 days (CTX + TKM ≥ 30) significantly prolonged median OS (9.1 months; 95% CI, 3.6-14.5; P = .025) compared to chemotherapy alone. Cox hazard ratio analysis revealed that CTX + TKM ≥ 30 and prior chemotherapy were significantly independent prognostic factors for OS. The main herbs in the TKM treatment were Rhus verniciflua Stokes and Astragalus. Severe adverse events with respect to TKM treatment were not reported.Conclusions:TKM treatment integrated with chemotherapy may prolong OS in patients with metastatic pancreatic cancer compared to chemotherapy treatment alone. More rigorous prospective clinical trials are needed to confirm this result.

Germline BRCA1and BRCA2 mutations in patients with HER2-negative metastatic breast cancer (mBC) treated with first-line chemotherapy: Data from the German PRAEGNANT registry.

1048 Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.

Abstract OT2-05-02: A phase II study of metronomic daily oral vinorelbine as first-line chemotherapy in advanced/metastatic hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to endocrine therapy - VinoMetro

Abstract Background Chemotherapy (CTx) is a cornerstone in HR+/HER2- advanced/metastatic breast cancer (a/mBC) after failure of endocrine treatment. In this indication, vinorelbine (VRL) is a well-established cytotoxic drug. There is a high medical need for new options that prolong the time between endocrine failure and intensive CTx, which is commonly associated with impaired quality of life and serious side effects. Metronomic CTx was shown to induce disease control in a/mBC with a favorable safety profile. This innovative approach involving continuous daily dosing of oral VRL, which could provide anti-angiogenic and immune-modulatory properties, has not been investigated so far in this indication. Trial Design VinoMetro is an open-label, single-arm, phase II study (Simon two-stage minimax) of metronomic daily oral VRL (30 mg/day) as first-line CTx. The study involves strict safety monitoring with an initial safety run-in. It is accompanied by a steering committee and supervised by an independent data safety and monitoring board (DSMB). The main objectives are to estimate efficacy in terms of clinical benefit rate after 24 weeks of treatment (primary endpoint) and the progression-free survival, amongst others, as well as the assessment of safety and quality of life. Patients with HR+/HER2- a/mBC having failed or being no candidate for endocrine therapy (targeted combinations allowed) and being naïve to palliative CTx are eligible, if they exhibit ECOG 0-1. The main exclusion criteria are prior vinca-alkaloids, aggressive disease requiring combination CTx and CNS involvement. Until 2017-05-31, 7 patients were enrolled. It is planned to include 45 (39 evaluable) patients at 8 German sites until 09/2018. Scheduled completion date is 09/2019. Two interim analyses are planned (first analysis: safety evaluation based on the 10 initial patients with predefined stopping rules). Depending on recruitment, it is planned to include the interim safety data in the congress presentation. VinoMetro is an investigator initiated trial (NCT03007992) sponsored by the University Medical Centre of Johannes Gutenberg-University Mainz, Germany, and supported by an unrestricted grant provided by Pierre Fabre Pharma GmbH (Freiburg, Germany). Citation Format: Schmidt M, Decker T, Fehm T, Fuxius S, Harbeck N, Juhasz-Böss I, Thomssen C, Seehase M, Schollenberger L, Ruckes C, Möbus V. A phase II study of metronomic daily oral vinorelbine as first-line chemotherapy in advanced/metastatic hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to endocrine therapy - VinoMetro [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-05-02.

MP88-02 EXPRESSION OF CLASS III BETA-TUBULIN PREDICTS PROGNOSIS IN CISPLATIN-RESISTANT BLADDER CANCER PATIENTS RECEIVING PACLITAXEL-BASED SECOND-LINE CHEMOTHERAPY

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-02 EXPRESSION OF CLASS III BETA-TUBULIN PREDICTS PROGNOSIS IN CISPLATIN-RESISTANT BLADDER CANCER PATIENTS RECEIVING PACLITAXEL-BASED SECOND-LINE CHEMOTHERAPY Tomohiro Matsuo, Yasuyoshi Miyata, Yuichiro Nakamura, Takuji Yasuda, Kojiro Ohba, and Hideki Sakai Tomohiro MatsuoTomohiro Matsuo More articles by this author , Yasuyoshi MiyataYasuyoshi Miyata More articles by this author , Yuichiro NakamuraYuichiro Nakamura More articles by this author , Takuji YasudaTakuji Yasuda More articles by this author , Kojiro OhbaKojiro Ohba More articles by this author , and Hideki SakaiHideki Sakai More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2727AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Class III beta-tubulin (TUBB3) is associated with malignant aggressiveness and prognosis, in addition, its expression is recognized as a predictive marker for taxane-based chemotherapy (CTx) in several cancers. In urothelial cancer (UC), standard first-line therapy for advanced disease is cisplatin (CDDP)-based CTx. On the other hand, although second-line regimen for CDDP-resistant tumor is not still established, several studies showed paclitaxel (PTX)-based regimens were effective to improve the prognosis. The main aim is to clarify the predictive value of TUBB3 expression for anti-cancer effect by first-line CDDP-based CTx and second-line PTX-based one in patients with UC. METHODS We reviewed 116 UC (bladder cancer = 90 and upper urinary tract cancer = 26) patients treated with CDDP-based regimen as first-line CTx. Among these patients, 53 patients were received PTX-based second-line CTx. As PTX-based CTx, the combination of gemcitabine and PTX were performed in 42 patients. TUBB3 expression was evaluated by immunohistochemical technique, and survival analyses were performed by using Kaplan-Meier survival curves and multivariate COX proportional hazard analysis. RESULTS Positively stained ratio of TUBB3 in grade 3 tumors (50 / 74 = 67.6%) was significantly higher (P < 0.001) than that in grade 1 (0 / 5 = 0.0%) and grade 2 (14 / 37 = 37.8%). A similar trend was found in T stage; however, it did not reach the significant level (P = 0.062). No significant relationship was found in age, sex, and metastasis. When the predictive value of TUBB3 expression for CDDP-based first-line CTx was investigated, it is not recognized as a significant predictive factor for progression-free survival (P = 0.796). On the other hand, high expression of TUBB3 is significantly associated with unfavorable overall survival from starting of second-line CTx (P = 0.013). Multivariate analysis model including all pathological features, part of a tumor, and regimen of second-line therapy showed that TUBB3 expression was identified as an independent predictor (hazard ratio = 5.18, 95% confidential intervals = 1.85 - 14.53, P = 0.002). CONCLUSIONS The TUBB3 expression is associated with malignant potential in UC. TUBB3 expression was identified as a useful predictive factor for anti-cancer effects of second-line PTX-based CTx in advanced UC patients with CDDP-resistant tumors. Out information is useful to discuss treatment strategies for patients with CDDP-resistant UC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1174-e1175 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Tomohiro Matsuo More articles by this author Yasuyoshi Miyata More articles by this author Yuichiro Nakamura More articles by this author Takuji Yasuda More articles by this author Kojiro Ohba More articles by this author Hideki Sakai More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effect of first-line molecular targeted agents on the efficacy of second-line bevacizumab-containing regimen for metastatic colorectal cancer.

748 Background: Bevacizumab (BV)-containing regimen is a standard second-line chemotherapy(CTX) for patients (pts) with metastatic colorectal cancer (mCRC) regardless of the prior use of BV in the first-line CTX. However, little is known about the efficacy of the second-line BV-containing regimen after first-line CTX with anti-EGFR agents. Methods: We retrospectively evaluated the efficacy of a BV-containing regimen as the second-line CTX for mCRC. The eligibility criteria for the pts included in the study were as follows: ECOG PS 0–2, KRAS wild-type tumors, and refractory to first-line CTX with fluoropyrimidine and oxaliplatin or irinotecan from March 2007 to March 2015. The Kaplan–Meier method with a log-rank test and Cox regression analysis were performed to evaluate the progression-free survival (PFS) of the pts. Results: A total of 123 pts were eligible. The pts’ characteristics were as follows: males/females 73/50, median age 59 years, PS 0-1/2 118/5, LDH levels &lt; 400IU/l / ≥ 400IU/l 91/32, second-line CTX regimen FOLFIRI+BV/FOLFOX+BV 111/12. The patients were categorized into the following 3 cohorts according to the prior use of molecular targeted agents: anti EGFR agents (cohort E, 35 pts), BV (cohort B, 58 pts), no molecular targeted agents (cohort C, 30 pts). There was hardly any difference in the baseline characteristics of the 3 cohorts; however, LDH levels in cohort E were higher than those in the other cohorts. Treatment efficacies were as follows (cohort E/B/C): response rate, 30%/10%/20%, with a significant difference between cohort E and B (OR = 1.50, p = 0.035) and median PFS, 8.6/5.9/6.9 months, with a significant difference between cohort E and B (p = 0.025). Multivariate analyses for PFS were adjusted for baseline characteristics such as histology, PS, chemotherapy regimen, presence of peritoneal metastasis, LDH levels, and duration of PFS in the first-line CTX. The PFS of cohort E was better than that of cohort B (HR = 2.180, p = 0.0025) and was not much different from that of cohort C (HR = 1.682, p = 0.64)in multivariate analyses. Conclusions: The second-line BV-containing regimen is effective regardless of the prior use of anti-EGFR agents.

Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184-162) of immunotherapy as a maintenance concept.

TPS4151 Background: First-line systemic CTX is standard-of-care for advanced gastric cancer. However, most pts relapse or have severe adverse events (AEs), creating a need for new therapies with better benefit/risk and toxicity profiles. Endogenous immune activity against tumor cells has been demonstrated in the human gastric cancer tumor microenvironment, supporting a role for immunotherapy. As a new maintenance concept, sequential administration of immunotherapy may prolong clinical benefit of first-line CTX before disease progression (PD). Ipi, a fully human monoclonal antibody which binds CTLA-4, augments the antitumor immune response. Ipi improved overall survival (OS) in patients with advanced melanoma with AEs managed using product-specific treatment guidelines.This global (32 sites among 10 countries), multicenter, randomized, open-label, phase II trial (ClinicalTrials.gov identifier NCT01585987) will compare the efficacy of Ipi and BSC after first-line CTX. Methods: Pts with good performance status (0 or 1) and histologically confirmed, unresectable locally advanced or metastatic gastric or GEJ cancer without PD after first-line CTX with a fluoropyrimidine (F) and platinum (P) doublet will be eligible. Pts with radiological evidence of brain metastases, autoimmune/immune-mediated disease, inadequate hematologic, renal, and hepatic function, or are HER2+ will be ineligible. Pts will be randomized to Ipi (4 doses [10 mg/kg, IV Q3W], followed by Q12W) until confirmed immune-related PD or unacceptable toxicity, or to BSC (continuing F used in lead-in CTX or no active systemic therapy). The primary objective is to compare immune-related progression-free survival (PFS): immune-related response criteria were derived from World Health Organization (WHO) criteria to better capture Ipi response patterns. Secondary objectives are to compare PFS per mWHO criteria and OS, and estimate immune-related best overall response rate. The study is planned to randomize 114 pts. Clinical trial information: NCT01585987.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. The National Institute for Health Research Health Technology Assessment programme.

Sequential chemotherapy with methotrexate and 5-fluorouracil for chemotherapy-naive advanced gastric cancer with disseminated intravascular coagulation at initial diagnosis

Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis before treatment with no current standard chemotherapy (CTx) regimen. However the prognosis is extremely poor without CTx. We investigated the effectiveness of sequential CTx with methotrexate and 5-fluorouracil (MF) in chemotherapy-naive AGC patients with DIC. We retrospectively examined AGC patients who received first-line CTx and selected those who were diagnosed with DIC before starting CTx to investigate clinical characteristics and responses. From July 1999 to January 2007, 1,365 patients with unresectable or recurrent AGC received first-line CTx at the National Cancer Center Hospital in Tokyo, Japan. DIC was diagnosed in 22 (1.6%) patients (16 men and 6 women; median age, 56 years) and the performance status of all the patients was 1/2/3 = 9/10/3. Nineteen patients (86%) had histologically diffuse-type adenocarcinoma and 18 (82%) had bone metastasis. Patients received sequential MF every week until progressive disease was confirmed, with DIC improving in 17 (77%) patients. The median time-to-treatment failure for AGC and overall survival were 98 days [95% confidence interval (CI), range 50-146 days] and 154 days (95% CI, range 126-180 days), respectively. Grade 3 or greater toxicities consisted of neutropenia (4 patients, 18%), anemia (9 patients, 40%), thrombocytopenia (4 patients, 18%), and bilirubinemia (1 patient, 5%). MF was an effective and well-tolerated regimen for improving DIC in chemotherapy-naive AGC patients with DIC; however, the prognosis of the patients remained poor even with improved DIC parameters.

Renal safety of sustained pemetrexed (P)/platinum treatment for advanced malignant mesothelioma (MM)

18106 Background: MM is a very rare and aggressive neoplasm with a short life expectancy. Standard care of MM is P + cisplatinum (DDP). The optimal duration of chemotherapy(ctx) for MM is undetermined. The feasibility of maintenance with P/DDP has not been reported. A major obstacle to sustained P/DDP for MM is renal safety beside neurotoxicity. At present, there are no data regarding renal safety in pts receiving ≥ 6 cycles of P/DDP in MM. Methods: We evaluated long term renal function of P(500 mg/m2)/DDP(75 mg/m2) for MM prospectively. Ctx on d1 was repeated on d22 until disease progression or toxicity. Pts with impairment of renal function (creatinine-clearance &lt;60 ml/min) switched to P/carboplatin (CP) AUC 5 for further ctx. P ctx was stopped if creatinine-clearance (CrCl) &lt;45 ml/min. Routine folinic acid and vitamine B12 was administered to prevent AE. Study endpoint was long term renal function for sustained therapy of P/DDP followed by P/CP and/or P-mono. Results: Between 12/02 and 05/06 86 consecutive MM pts were treated. Staging revealed peritoneal MM in 19, and pleural MM in 67 pts. Five pts did not receive ctx. First-line ctx was P/DDP in 66 pts (prior s-crea 0.85; SD 0.17) given a mean of 4.9 cyles (range 1–11) for a mean of 120 d (21–397 d) and a mean of 138 mg DDP/cycle. 28 pts received CP/P sequentially for further maintenance up to 27 cycles (mean 6.4). A change from P/DDP to P/CP was necessary due to a worsening renal function in all of those pts. Mean s-crea/CrCl prior to DDP ctx in those pts was 0.87 mg/dl (SD 0.17)/96.0 ml/min (SD 26) and 1.01 mg/dl (SD 0.29)/73.4 ml/min (SD 22) at the end of P/DDP. Mean given CP dose was 425 mg/cycle (range 175 - 725 mg). Pts subsequently receiving P/CP had a s-crea of 1.16 mg/dl (CrCl 73.4 ml/min) prior to ctx that did not change during P/CP (1.13 mg/dl/CrCl 73.2 ml/min). 13 pts received P- mono with a mean of 8 cycles (1–26) subsequently. Renal function showed a s-crea(CrCl) of 1.13 mg/dl (71.2 ml/min) prior and 1.11 mg/dl (70.8 ml/min) at the end of P ctx. Conclusions: Long term maintenance P/DDP of MM is limited by renal impairment due to DDP, while subsequent P/CP or P-mono was feasible and not associated with further deterioration of renal function. Further trials with sustained P/CP or P ctx for MM are warranted to evaluate the efficacy of maintenance for advanced MM. No significant financial relationships to disclose.