bluuebunny/crossref_metadata_2025 huggingface dataset:
Pattern of local-regional relapse and survival after bimodality therapy for esophageal cancer: Implications for the surveillance strategy.
Authors: Sudo Kazuki , Xiao Lianchun , Wadhwa Roopma , Taketa Takashi , Blum Mariela A. , Skinner Heath D. , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Komaki Ritsuko , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: March 2020

4083

Background: Evidence for definitive chemoradiotherapy (bimodality therapy [BMT]) has been established for patients with esophageal and gastroesophageal junction cancer (EGEJC) who do not qualify for surgery. Surveillance for these patients is often recommended but the literature lacks guidance for an evidence-based surveillance strategy after BMT. Methods: We analyzed 276 patients with EGEJC who underwent BMT and had pre- and postchemoradiation endoscopic biopsies and imaging studies available for review. Patients who underwent planned surgery or salvage surgery (SS) within 6 months from BMT were excluded. We reviewed the pattern of relapse over time. Local-regional disease (LRD) after BMT was classified as regional disease (RD) or luminal-only disease (LD). Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: For 276 patients, the median follow-up time was 53.0 months (95% confidence interval [CI], 47.3-58.7). A total of 184 (66.7%) patients had a persistent disease or relapse after BMT: 120 distant metastases (43.5% of 276) and 64 LRD (23.2% of 276). Of 64 LRD, 58 (91%) were diagnosed within 2 years of BMT and 63 (98%) were diagnosed within 3 years (see Table). Twenty-three of 64 LRD patients underwent SS. For patients with SS, the median OS time from diagnosis of LRD was 58.0 months (95% CI, not reached), and that for patients without SS was 9.0 months (95% CI, 7.3-10.7); this difference was highly significant (p < 0.001). Conclusions: Our data suggest that 91% of LRD occurred within 2 years after BMT and the OS with SS for LRD was better than that without SS. These data can contribute to the development of an evidence-based surveillance strategy. [Table: see text]
Phase II study of mFOLFOX with bevacizumab (Bev) in metastatic gastroesophageal and gastric (GE) adenocarcinoma (AC).
Authors: Li Jia , Kortmansky Jeremy S. , Fischbach Neal A. , Stein Stacey , Yao Xiaopan , Hochster Howard S. , Lacy Jill
Published: March 2020

4084

Background: The median survival for patients (pts) with metastatic GE AC in phase III studies is <12 mos. Bev has demonstrated promising activity in metastatic GE AC when used in combination with cisplatin-based regimens in studies with patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of Bev in combination with mFOLFOX6 in pts with metastatic GE AC. Methods: Pts with previously untreated metastatic GE AC (gastric, GE junction, distal esophagus) received mFOLFOX6 (LV 400 mg/m2, 5-FU 400 mg/m2 bolus and 2400 mg/m2 over 46 hr continuous infusion, Ox 85 mg/m2) and Bev 10 mg/kg q 2 wks. Response by RECIST was evaluated by CT q 8 wks. Primary objective was time to progression (TTP); secondary objectives were safety, response rate (RR), and overall survival (OS). Results: 39 pts were enrolled between 09/08 and 06/12. Pt characteristics are as follows: median age, 59 yo (range 27-79); M/F, 31/8; ECOG PS 0/1, 11/28; gastric/distal E and GEJ, 13/26; metastatic sites: lymph nodes 23, liver 19, lung 9, peritoneum 9; >2 metastatic sites, 20; prior gastrectomy or esophagectomy, 7. Nine pts remain on study, and 15 pts are alive. Median # of cycles administered is 11 (range 4 - >31). RR is 56.4% (4 CR, 18 PR). Median TTP is 8.2 mos. Median OS is 15.2 mos. Three pts survived >24 mos. Grade 3/4 toxicities include neutropenia (13, 33.3%), neuropathy (8, 20.5%), DVT/PE (5, 12.8%), thrombocytopenia (3, 7.7%), anemia (1, 2.6%), hypertension (1, 2.6%), and proteinuria (1, 2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. Conclusions: FOLFOX6/Bev is well tolerated and associated with increased TTP and OS in pts with metastatic GE AC compared to historical data from similar populations treated without Bev. Our findings validate previous studies with Bev in combination with cisplatin-based regimens in pts from the Americas with metastatic GE AC. This study is supported by Genentech. Clinical trial information: NCT00673673.
FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients: A randomized placebo-controlled multicentric AIO phase II trial.
Authors: Moehler Markus Hermann , Thuss-Patience Peter C. , Schmoll Hans-Joachim , Hegewisch-Becker Susanna , Wilke Hansjochen , Al-Batran Salah-Eddin , Weissinger Florian , Kullmann Frank , Von Weikersthal Ludwig Fischer , Siveke Jens T. , Kanzler Stephan , Schimanski Carl Christoph , Otte Melanie , Schollenberger Lukas , Koenig Jochem , Galle Peter Robert
Published: March 2020

4086

Background: Sunitinib is an receptor tyrosine kinase (RTK) inhibitor of VEGFR1-3, PDGFR-α-β, and other RTK. After we established Sunitinib (Sun) alone associated with limited response rate (RR) and good tolerability in refractory advanced esophagogastric cancer patients (Moehler et al. EUR J Cancer. 2011, 47: 1511), this double-blinded placebo-controlled phase II evaluated safety and efficacy of SUN as add-on in second-line or third-line FOLFIRI (ClinicalTrials.gov NCT01020630). Methods: Patients with failure of any prior docetaxel and/or platinum-based chemotherapy were randomized to receive 6-week cycles including FOLFIRI two weekly and SUN (25 mg) versus (vs) placebo (PLA) daily for 4 consecutive weeks followed by a 2-week rest. Primary endpoint was progression-free survival (PFS). Results: 91 randomized patients (ITT) had similar characteristics in both groups (SUN/PLA 45/46). Both groups had 2.7 treatment cycles. Objective RR was 20/29%, and tumor control rate was 58/56 % for SUN/PLA, respectively. Median PFS was similar for SUN vs. PLA with 3.6 vs. 3.3 months, respectively (HR 1.11; 95%CI 0.70-1.74, P = 0.66). Median overall survival (OS) was longer for SUN vs. PLA with 10.5 vs. 9.0 months, in ITT (HR 0.816; 95%CI 0.50 - 1.34, P = 0.42, one-sided 0.21) and in the per protocol population (HR 0.71; 95%CI 0.41 - 1.24, P = 0.23) respectively. No unexpected higher toxicities, SAE or SUSAR occurred with SUN. For SUN/PLA, all grade AEs (%) possibly related to study drug were nausea 49/47%, fatigue 36/29%, vomiting 27/29%, diarrhoea 36/38%, neutropenia 62/22%, stomatitis 27/20%, and palmar-plantar erythrodysaesthesia 13/3%, and Grade 3+ AEs (%) were neutropenia 56/20%, diarrhoea 2/13%, nausea 7/7%, fatigue 0/9% and pain 0/9%, respectively. Performed quality of life outcomes were mostly in favor of Sunitinib. Conclusions: In our phase II trial, Sunitinib added to FOLFIRI increased hematotoxicity and did not improve response rates or PFS in chemotherapy-resistant GC patients. Since the regimen was safe and patients had a trend to better OS, biomarker analyses will be performed to identify subgroups that benefit from add-on Sunitinib. Clinical trial information: NCT01020630.
Who benefits from radiotherapy for gastric cancer? A meta-analysis.
Authors: Ohri Nitin , Garg Madhur , Aparo Santiago , Kaubisch Andreas , Tome Wolfgang A. , Kennedy Timothy J. , Kalnicki Shalom , Guha Chandan
Published: March 2020

4093

Background: Randomized trials have demonstrated significant survival benefits with the use of adjuvant (including neoadjuvant) chemotherapy or chemoradiotherapy for gastric cancer. The importance of adjuvant radiotherapy (RT) remains unclear. Here we perform an up-to-date meta-analysis of randomized trials testing the use of radiotherapy for resectable gastric cancer. Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine if the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, and lymph node status. Results: Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR=0.78, 95% CI: 0.70 to 0.86, p<0.001) and DFS (HR=0.71, 95% CI: 0.63 to 0.80, p<0.001). In the five studies that tested adjuvant chemoradiotherapy against adjuvant chemotherapy, similar effects were seen for OS (HR=0.83, 95% CI: 0.67 to 1.03, p=0.087) and DFS (HR=0.77, 95% CI: 0.91 to 0.65, p=0.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusions: In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regards to patient selection and integration with systemic therapy.
Nomogram predicting long-term survival probability of thoracic esophageal squamous cell carcinoma after radical esophagectomy.
Authors: Mao Weimin , Zhou Xinming , Chen Qixun , Jiang Youhua , Yang Xun , Wu Jie , Tao Kaiyi , Zheng Weihui , Yan Zhen , Liu Liang , Wu Shaoyuan , Su Dan
Published: March 2020

4094

Background: Nomograms have been widely and successfully used for numerous cancers to obtain reliable prognostic information for each individual patient.To date, however, no studies have conducted survival estimates using nomograms for esophageal squamous-cell carcinoma (ESCC) in Chinese population.The purpose of this study is to develop a nomogram to predict the long-term survival probabilities in patients diagnosed with ESCC after radical esophagectomy. Methods: This study involves a dataset containing 1923 patients who underwent radical esophagectomy for ESCC at Zhejiang Cancer Hospital in Hangzhou, China. Among them, 1,578 patients with no missing data were used to build a prognostic nomogram based on Cox proportional hazard regression model. A multivariate survival analysis using Cox regression model was applied to identify significant variables with P-values <0.05. On the basis of the predictive model with the identified variables, a nomogram was constructed for predicting five-year and ten-year overall survival probabilities. The prediction model was internally validated using bootstrap resampling, assessing its optimism-corrected discrimination and calibration. Results: The median of overall survival times of 1578 ESCC patients was 35.6 months, and the 5-year and 10-year survival rate was 32% and 20%, respectively. The multivariate Cox model identified alcohol, tumor length, surgical approach, number of surgical removed lymph node, ratio of metastatic lymph nodes, region of lymph nodes dissection, depth of invasion, differentiation of tumor, postoperative complications as covariates significantly associated with survival. Across the 100 bootstrap replicates, the median optimism-corrected summary C-index for predicting survival was 0.713 (SE=0.011). Conclusions: A nomogram predicting 5- and 10-year overall survival after radical esophagectomy for ESCC in Chinese population was constructed and validated based on nine significant variables. The nomogram can be applied in daily clinical practice for individualized survival prediction of ESCC patients after potentially curative esophagectomy.
Result of clinical study on feasibility of laparoscopy-assisted D2 distal gastrectomy to treat advanced gastric cancer (COACT_1001).
Authors: Kim Young Woo , Park Young-Kyu , Yoon Hong Man , Nam Byung-Ho , Ryu Keun Won , Lee Young-Joon , Jeong Oh , Yoon Ki Young , Lee Jun Ho , Lee Sang Eog , Yu Wansik , Jeong Sang-Ho , Kim Taebong
Published: March 2020

4105

Background: Benefit of quality of life made laparoscopic gastric cancer surgery attractive, but there are still concerns about laparoscopic lymph node dissection. The aim of this study was to evaluate a feasibility of laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection compared with open distal gastrectomy (ODG) for advanced gastric cancer (AGC). Methods: Patients with cT2-T4a and cN0-2 (AJCC 7th staging system) distal gastric cancer were randomly assigned to LADG or ODG. The primary endpoint was the non-compliance rate of the lymph node dissection defined as rate of cases where there was more than one missing lymph node station according to the guidelines of the Japanese Research Society for Gastric Cancer lymph node grouping. Secondary endpoints were perioperative complications, changes of inflammatory and immunological parameters, postoperative hospital stay, and 3 year disease free survival. This trial was registered at ClinicalTrials.gov as NCT01088204. Results: Between Jun 2010 and Oct 2011,204 patients were randomly allocated and underwent either LADG (n=105) or ODG (n=99). 8 patients were excluded in the intention to treatment analysis because of protocol violation and patient’s withdrawal of permission, and finally 100 patients in LADG and 95 patients in ODG were analyzed. There were no significant differences of overall non-compliance rate of lymph node dissection between LADG and ODG groups; they were respectively 47.0% and 43.2%. (p=0.648). In the subgroup analysis according to the stratified risk groups, non-compliance rate in LADG was significantly higher than ODG (52.0% vs. 25.0%, p=0.043) for clinical stage III but it was not significantly different for stage II (46.2% vs. 48.9%, p=0.788). Intraoperative event rate was not significantly different between groups (LADG;6.0% and ODG;4.2%, p =0.748). Complications rate in early postoperative period up to 1 month was also not different between groups (LADG;17.0 %, ODG;18.8%, p=0.749). Conclusions: LADG was feasible in AGC compared with ODG, especially in clinical stage II in terms of non-compliance rate of D2 lymph node dissection and perioperative complications. Clinical trial information: NCT01088204.
Efficacy and safety of dose-dense modified TCF regimen (TCF-dd) in metastatic or locally advanced gastroesophageal cancer (GEC).
Authors: Toppo Laura , Tomasello Gianluca , Liguigli Wanda , Ratti Margherita , Poli Rossana , Negri Federica , Curti Alessandra , Vismarra Marco , Maltese Mariangela , Delfrate Roberto , Donini Maddalena , Colombi Chiara , Brighenti Matteo , Panni Stefano , Perrucci Bruno , Lazzarelli Silvia , Passalacqua Rodolfo
Published: March 2020

4112

Background: TCF is a standard first line option for GEC. The Norton-Simon hypothesis suggests that chemotherapy efficacy can be enhanced by decreasing intervals between cycles. We previously reported on the high activity of TCF-dd in GEC (Tomasello 2010). The aim of this study is to investigate the efficacy and safety of this intensified dose-dense regimen in a single-center large cohort of patients (pts). Methods: 150 pts with measurable or evaluable GEC, PS 0-2, with adequate organ function, treated in our center from 2004 to 2012 received TCF-dd: Docetaxel (60-85 mg/m2 d 1), Cisplatin (50-75 mg/m2 d 1), l-Folinic Acid (100 mg/m2 d 1-2), 5-FU (400 mg/m2 bolus d 1-2, and 600 mg/m2 as a 22 h continuous infusion d 1-2), plus Pegfilgrastim 6 mg d 3, every 14 days. Pts aged ≥ 65 years received the same schedule with a dose reduction by 30%. Analysis was based on the intention to treat population. Results: At a median follow-up of 44 months, 128 pts were evaluable for response, all for survival. Median age 65 (range 31-81), M:F 112:38. 17 pts (11%) with locally advanced inoperable GEC, 133 pts (89%) with metastatic GEC. Metastatic sites: liver 40%, peritoneum 31%, bone 14%, lung 12%. A median of 4 cycles (range 1-7) per patient was administered. 33% required a dose reduction. 33% were treated without any delay. 10 CR, 74 PR, 24 SD and 20 PD were observed, for an ORR of 66% (95% CI 57-74). Median OS was 13 months (95% CI 9.7-14.2). Most frequent grade 3/4 toxicities: neutropenia (34%), asthenia (28%), thrombocytopenia (17%), hypokalemia (16%), diarrhea (11%), febrile neutropenia (10%), anemia (9%), and stomatitis (4%). 11 pts (7%) [7 metastatic, 4 locally advanced] became operable after TCF-dd and underwent surgery. We identified 12 metastatic pts (8%) with overall survival > 3 years and 7 (5%) still maintaining a long lasting CR at the time of the current analysis. Conclusions: TCF-dd in GEC is very active and may be an option for conversion therapy. Toxicity can be relevant and requires a careful monitoring.
A nationwide cohort study of surveillance for stage I seminoma.
Authors: Mortensen Mette Sakso , Gundgaard Maria Gry , Lauritsen Jakob , Agerbaek Mads , Holm Niels Vilstrup , von der Maase Hans , Daugaard Gedske
Published: March 2020

4502

Background: The standard treatment for stage I seminoma remains a topic for discussion. Survival rates are excellent irrespective of treatment modality (radiotherapy, carboplatin or surveillance). However, late effects might differ between treatment options. Only smaller surveillance studies with limited follow-up have previously been published. We present data from a large nationwide cohort study on surveillance in stage I seminoma patients. Methods: A nationwide and population based clinical database covering germ cell cancer patients diagnosed 1984-2007 was constructed. The database included 4,683 cases. All stage I seminoma patients followed by surveillance were identified. Possible prognostic factors for relapse were collected from patient files and pathology reports. By merging our data with the national patient registry we were able to collect data on late relapses, vital status and cause of death on all patients up to December 2012. Results: 1,822 patients with stage I seminoma were followed on a surveillance program. The median follow-up time was 15.4 years. Ten year cancer specific survival (CSS) was 99.6%. A total of 355 (19.5%) patients had a relapse after a median time of 13.7 months (range 1.2-173.7 months). Within 2-5 years after orchiectomy, 72 patients (4.0 %) had a relapse and 26 patients (1.4 %) had a relapse more than 5 years after orchiectomy. Invasion of blood or lymphatic vessels, tumor size > 4 cm and serum human chorionic gonadotropin > 200 IU/L were all predictive factors for relapse in both univariate and multivariate analyses (p<0.01). Invasion of rete testis was significant in the univariate analysis but not in the multivariate analyses (p=0.53). Conclusions: We present the largest cohort ever published of stage I seminoma patients followed on a surveillance program. The prognosis was excellent with a 10 year CSS of 99.6%. Prognostic factors for relapse were identified. The relapse rate after 5-years of follow-up was 1.4%. Surveillance should be the preferred option of management in stage I seminoma patients. Several international guidelines are now in agreement with this statement.
A phase II study of intermittent sunitinib (S) in previously untreated patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Rini Brian I. , Wood Laura S. , Elson Paul , Zhu Hui , Chittoria Namita , Mittal Kriti , Dreicer Robert , Gilligan Timothy D. , Shah Shetal N. , Garcia Jorge A.
Published: March 2020

4515

Background: S as initial treatment in mRCC is limited by balancing acute and chronic toxicity with clinical benefit. Pre-clinical and retrospective clinical data support that extended treatment breaks are feasible without a reduction in efficacy. Methods: Pts with treatment-naïve clear cell mRCC were enrolled on a prospective phase II trial and initially treated with 4 cycles of S (50 mg 4/2). Pts with ≥ 10% reduction in tumor burden (TB) following 4 cycles had S held, with CT scans approximately every 10 weeks. S was re-initiated for 2 cycles in those pts with an increase in TB by ≥ 10% and again held with ≥ 10% TB reduction. This intermittent S dosing continued until RECIST-defined disease progression while on S. The primary objective was feasibility of intermittent S, defined as the proportion of eligible pts who underwent intermittent therapy. The alternative hypothesis was a feasibility of > 80% vs. a null hypothesis of < 50% (a=0.05; power 80%). Results: Thirty-six pts were enrolled; 70% male, median age 60, 95% PS 0/1 and 32% favorable/65% intermediate by Heng criteria. Twenty pts were eligible for intermittent therapy and all pts (100%) entered the intermittent phase. Pts were not eligible for intermittent S due to PD (n=13); toxicity (n=1) or w/d of consent (n=2) prior to end of cycle #4. Sixteen pts (80%) had ≥ 10% TB increase off S with a median (range) increase of 1.5 cm (1.1-2.5) compared to the TB immediately prior to stopping S, considering all off periods.Four pts did not have ≥ 10% TB increase off S (3 pts after the 1st off period; off for 12, 8 and 5 months to date and 1 pt after the 2nd off period; off for 8 months prior to restarting S). Most pts exhibited a stable saw tooth pattern of TB reduction on S and TB increase off S. No pt had RECIST-defined PD while on S, but 2 pts were taken off extended breaks due to gradual TB increase over time, and 1 pt developed new CNS mets during the 2nd off period.The objective response rate was 53%. Toxicity was typical for S and completely resolved during treatment breaks. Conclusions: S dosing with periodic extended time off drug is feasible and associated with reduction in toxicity during the off periods. Clinical efficacy does not appear to be compromised. Clinical trial information: NCT01158222.
A phase II clinical trial examining the impact of neoadjuvant axitinib on primary tumor response in patients with locally advanced clear cell renal cell carcinoma.
Authors: Karam Jose A. , Devine Catherine E , Lozano Marisa , Tannir Nizar M. , Ahrar Kamran , Tamboli Pheroze , Wood Christopher G.
Published: March 2020

4516

Background: Previous studies have shown minimal impact of TKIs on primary renal tumor downsizing. Axitinib is a VEGFR TKI that has been recently approved for use in patients with metastatic clear cell renal cell carcinoma (RCC). In this prospective phase II trial, we sought to investigate the safety and role of axitinib in downsizing tumors in patients with non-metastatic renal cell carcinoma, prior to undergoing surgical resection. Methods: Patients with locally advanced (clinical stage T2-T3b N0 M0) biopsy-proven clear cell RCC were eligible for this phase II clinical trial. The primary outcome was objective response rate (using RECIST) following the administration of axitinib for 12 weeks prior to undergoing radical nephrectomy. Secondary outcomes included safety, tolerability, and feasibility of administration of axitinib in this patient population. Patients were given axitinib 5mg PO BID, and dose titration was allowed. Axitinib was continued until 36 hours prior to surgery. A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: The study goal of enrolling 24 patients has been recently reached. At present, nineteen patients have completed the studies required for assessment of the primary outcome and are hereby reported. Fifteen patients were males, and four were females. Median age was 61 years (range 42-83 years). All patients had biopsy-proven clear cell RCC. All 19 patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. Adverse events of any grade were: arthralgia in 6, hypothyroidism in 14, fatigue in 15, and hypertension in 16 patients. No wound complications occurred after surgery. Nine patients (47%) experienced a partial response by RECIST, and 10 patients had stable disease. There was no progression of disease while on axitinib. Conclusions: Axitinib is well tolerated in the neoadjuvant setting in patients with planned surgery for locally advanced non-metastatic clear cell RCC. The drug showed tumor downsizing activity when given for 12 weeks prior to surgery. Adverse events of any grade were common and easily manageable with routine care. Clinical trial information: NCT01263769.
Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance).
Authors: Nixon Andrew B. , Halabi Susan , Shterev Ivo , Starr Mark , Brady John C , Dutcher Janice P. , Hopkins Judith O. , Hurwitz Herbert , Small Eric Jay , Rini Brian I. , Febbo Phillip G. , George Daniel J. ,   for the Alliance for Clinical Trials in Oncology
Published: March 2020

4520

Background: CALGB 90206 was a phase III trial of 732 pts with RCC comparing B+I versus I alone demonstrating no difference in OS. To date, there are no validated predictive biomarkers for B in RCC. For this reason, baseline plasma samples from CALGB 90206 pts were analyzed to identify and test predictive markers for B+I in RCC pts. Methods: Baseline EDTA plasma samples from 424 consenting pts were analyzed using an optimized multiplex ELISA platform for 32 candidate factors related to tumor growth, angiogenesis, and inflammation. The data were randomly split into training (n=286) and validation (n=138) sets. The proportional hazards model was used to test for treatment-marker interactions of OS. The estimated coefficients from the training set were used to compute a risk score (RS) for each pt in the validation set. The RS classified pts by risk in the validation set. The model was assessed for its predictive accuracy using area under the curve (AUC). Results: A statistically significant 3-way interaction between interleukin-6 (IL-6), hepatocyte growth factor (HGF) and treatment was observed in the training set (p<0.0001). The median levels of IL-6 and HGF in the training set were 8.4 pg/ml and 89 pg/ml, respectively. In the validation set, the RS was predictive of OS (p<0.001) with the high and low risk groups having a median OS of 10 months and 32 months, respectively. The AUC in the validation set was 0.82 (95% CI=0.77-0.88). The median OS (in months) by median levels of IL-6 and HGF stratified by treatment arm in the validation set is presented in the table with associated 95% CI (NR=not reached). Conclusions: IL-6 and HGF are predictive for OS in RCC patients treated with B+I and a RS based on these factors identified patients who benefitted most from B. If independently validated, this novel RS could guide clinical decisions and pt selection in future RCC trials. [Table: see text]
Pdl-1/pdl-3 (programmed death ligand-1/3) tissue expression and response to treatment with IL2 and antiangiogenic therapies.
Authors: Bailey Alexandra S. , Cheng SuChun , Kwon Eugene D. , Leibovich Bradley C. , Signoretti Sabina , Dutcher Janice P. , Appleman Leonard Joseph , Sosman Jeffrey Alan , Margolin Kim Allyson , Clark Joseph , Khushalani Nikhil I. , Curti Brendan D. , Ernstoff Marc S. , Pantuck Allan J. , Vaishampayan Ulka N. , Logan Theodore , McDermott David F. , Atkins Michael B. ,   Cytokine Working Group
Published: March 2020

4521

Background: Expression of PDL1 by RCC has been associated with aggressive histology and poor survival. Tissue obtained from the patients enrolled in the IL-2 Select Trial, a prospective, single arm, multicenter CWG study, was analyzed by IHC to determine if PDL1or PDL3 expression predicted for response to initial or subsequent therapy. Methods: Paraffin embedded tumor tissue was stained for PDL1 and PDL3 expression, and results were correlated with RECIST defined response to IL2 treatment. Tumor tissue was considered positive for PDL1 if >5% of the tumor membranes stained for the marker. A cutoff of 10% was used for PDL3. Duration of subsequent VEGFR/mTOR inhibitor therapy was also correlated with tissue PDL1/3 expression. Results: 120 eligible pts were enrolled; 115 had clear cell histology. The overall response rate (ORR) to IL2 was 25% (30/120) with a median OS of 40.6 months. 113 tumors were stained. 18 (16%) were PDL1+. ORR was 19% and 50% in the patients PDL1- and PDL1+ tumors, respectively (p=0.012). 85 (75%) tumors were PDL3+. ORR was 10.7% and 29.4% in the PDL3- and PDL3+ tumors, respectively (p=0.075). In the 17 patients who were positive for both PDL1 and PDL3, ORR was 52.9%. In the 27 pts who were negative for both PDL1 and PDL3, ORR was 11.1%. 69 patients received at least 1 dose of a VEGFR TKI as next therapy following IL2 treatment. 66 tumors were stained. Pts who were PDL1+/PDL3+ had a shorter duration on VEGFR TKI therapy compared to pts who were PDL1-/PDL3- (see Table). Conclusions: This small, retrospective analysis suggests that PDL1 and PDL3 tissue expression may predict for better response to IL2. PDL1 expression has been suggested as a possible predictor of response to anti-PD1 therapy. The current data suggests that its expression may predict for benefit to other immune therapies. PDL3 (+/- PDL1) expression appears to correlate to less benefit from subsequent VEGFR TKI therapy. Funded by NCI SPORE Grant # 5 P50 CA101942-08. [Table: see text]
Treatment patterns and outcomes in “real world” patients (pts) with metastatic urothelial cancer (UC).
Authors: Galsky Matt D. , Chowdhury Simon , Bellmunt Joaquim , Wong Yu-Ning , Recine Federica , Pal Sumanta Kumar , Moshier Erin L. , Ladoire Sylvain , De Giorgi Ugo , Yu Evan Y. , Niegisch Guenter , Crabb Simon J. , Mardones Mabel A , Necchi Andrea , Golshayan Ali Reza , Bamias Aristotelis , Mano Roy , Harshman Lauren Christine , Powles Thomas , Rosenberg Jonathan E. ,   RISC Investigators
Published: March 2020

4525

Background: Most studies reporting outcomes of pts with metastatic UC are derived from clinical trial data, potentially limiting the breadth/generalizability of the findings. To explore patterns of care/outcomes in “real world” pts, we initiated an international retrospective cohort study. Methods: Data were collected via an electronic data capture platform from 23 centers. Eligible pts had UC (at least muscle-invasive) and were initially evaluated from 1/1/2006-1/1/2011. Parameters were subjected to regression analysis to identify prognostic variables. Results: By 12/18/12, 1905 pts were enrolled. Among 1077 with metastatic UC, median age was 67 (IQR 60-75), 80% were male, 87% had bladder primary tumors, and 33% received perioperative chemotherapy. Only 758 (70%) received 1st-line chemotherapy for metastatic UC: cisplatin-based (51%), carboplatin-based (29%), non-platinum single-agent (16%), and non-platinum multi-agent (4%). The median survival from date of diagnosis of metastatic UC was 5.2 months (95% CI 4.4-6.5) and 16.1 months (95% CI 15.1-17.5) for pts who did and did not receive 1st-line chemotherapy, respectively [13.9 months (95% CI 12.78-14.98) from start of chemotherapy for latter group]. Among pts receiving 1st-line chemotherapy, univariable analysis revealed gender, primary tumor site, removal of primary, creatinine clearance, LDH, and hgb were not significantly associated with survival whereas smoking status, performance status, perioperative chemotherapy, metastatic sites, study site and chemotherapy regimen were. The multivariable analysis is shown in the Table. Conclusions: The current analysis identifies previously unrecognized prognostic factors in an international cohort of “real world” pts with metastatic UC treated with 1st-line chemotherapy. A large subset of pts with metastatic UC receives no chemotherapy. [Table: see text]
Randomized phase III trial of neoadjuvant chemotherapy (NAC) with methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by radical cystectomy (RC) compared with RC alone for muscle-invasive bladder cancer (MIBC): Japan Clinical Oncology Group study, JCOG0209.
Authors: Kitamura Hiroshi , Tsukamoto Taiji , Masumori Naoya , Shibata Taro , Kunieda Futoshi , Fujimoto Hiroyuki , Hirao Yoshihiko , Kitamura Yasuo , Tomita Yoshihiko , Tobisu Kenichi , Niwakawa Masashi , Naito Seiji , Eto Masatoshi , Kakehi Yoshiyuki
Published: March 2020

4526

Background: Cisplatin-based NAC for patients (pts) with MIBC is considered to provide a 5–8% overall survival (OS) advantage, although several studies failed to prove the survival benefit of NAC. Methods: Eligibility criteria included histologically proven urothelial carcinoma, MIBC (T2-4aN0M0) within 8 weeks from TURBT, PS 0-1, and age 20-75 years old. Patients were randomized to receive 2 cycles of neoadjuvant MVAC followed by RC (NAC arm) or RC alone (RC arm). The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), surgery-related complications, adverse events during NAC, the percent with no residual tumor in the RC specimens (pT0), and QOL. The sample size was 180 pts in each arm with a one-sided alpha of 5% and a power of 80% to detect a 7% difference in 5-year OS, 45% in the RC arm, and 57% in the NAC arm. Results: From March 2003 to March 2009, 130 pts were randomized to the NAC arm (n=64) and RC arm (n=66). Fifty-nine patients in the NAC arm and 65 in the RC arm underwent cystectomy. The patient registration was terminated early because of slow accrual. At the 2nd interim analysis conducted after the completion of patient accrual, OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19-2.18; one-sided log-rank p = 0.07). Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. PFS of the NAC arm was better than that of the RC arm (HR, 0.61; 95% CI, 0.35-1.06, one-sided log-rank p=0.04). No differences in perioperative complications, other than lymph leakage, were observed between the arms. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (p<0.01). In subgroup analyses, OS in almost all subgroups was in favor of NAC. Conclusions: Although NAC with GC is widely used for MIBC, NAC with MVAC can still be considered promising. Clinical trial information: C000000093.
Prognostics factors in previously untreated urothelial cancer patients ineligible for cisplatin-based chemotherapy: An external validation of the Bajorin risk groups.
Authors: Collette Sandra , Sylvester Richard , Bellmunt Joaquim , Mead Graham , Kerst Jan M. , Leahy Michael Gordon , Maroto Pablo , Gil Thierry , Marreaud Sandrine , Daugaard Gedske , Skoneczna Iwona Anna , De Wit Ronald , De Santis Maria ,   EORTC GU Cancers Group
Published: March 2020

4529

Background: In patients with urothelial cancer who are unfit for Cisplatin chemotherapy, EORTC phase II/III trial 30986 investigated two carboplatin-based chemotherapy regimens: Gemcitabine/Carboplatin (GC) and Methotrexate/Carboplatin/Vinblastine (M-CAVI). The trial did not show any significant differences in efficacy (response rate, OS, PFS) between the treatments; however the incidence of severe acute toxicity was slightly higher on M-CAVI. We now investigate the prognostic factors for survival. Methods: 238 patients with impaired renal function (Glomerular Filtration Rate (GF) <60 mL/min) or poor performance status (PS 2) were randomized by 29 institutions between GC and M-CAVI. The median follow-up was 4.5 years and, with 218 deaths reported (progression of malignant disease in 72%), the overall survival median was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm. Univariate and multivariate Cox prognostic factor regression models for overall survival were developed on the whole population stratified by treatment arm. Results: In the multivariate analysis, the risk of death significantly increased (p<0.10) with WHO-PS 2, hemoglobin ≤ 12 g/dl (women) or ≤ 13.6 g/dl (men), the presence of visceral metastases and even more with the presence of liver metastases. The risk of death was not influenced by the site of the primary tumour, white blood cell or platelet count. In addition, the prognostic factors had a stronger effect in the M-CAVI arm than in the GC arm. Conclusions: This prognostic factors analysis confirms the Bajorin classification based on visceral metastases and performance status. However, we were also able to show the importance of hemoglobin and that in the patients with visceral metastases, the subgroup of patients with liver metastases had a significantly worse prognosis than the patients with only other visceral metastasis. Clinical trial information: NCT00014274.
A randomized trial of 72-hour infusional bleomycin in BEP (cisplatin, etoposide, and bleomycin) versus conventional weekly bleomycin in patients with metastatic IGCCCG good prognosis disease.
Authors: Vinnicombe Sarah , Harland Stephen John , Joffe Johnathan K. , Huddart Robert , Mazhar Danish , Birtle Alison J. , White Jeff D. , Wilson Peter , Marshall Marita , Sarker Shah-Jalal , Shamash Jonathan
Published: March 2020

4535

Background: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary symptoms often dictate drug cessation and death occurs in 1-2% of patients. Circumstantial evidence suggests that continuous infusion may be less toxic. Methods: We conducted a randomized phase 3 study to see whether infusional bleomycin was associated with less pulmonary toxicity. Patients were stratified for smoking, renal dysfunction and age and were randomized to receive either conventional BEP with weekly bleomycin (3,0000 units /week iv over 30min) or the same doses but administered as a 90,000 unit infusion on day 1 over 72 hours. The primary endpoint was CT proven lung toxicity, secondary endpoints included PFS and changes in lung function testing. CT scans and lung function testing were conducted after 1 cycle, end of treatment and 1 year post treatment. Sample size of 210 was calculated to detect a difference of 16% Bleomycin damage with 80% power at the 5% level of significance using 2-sided test. Results: The median follow-up was 2.5 years. At day 21 of the treatment, 52% patients in the infusional arm had grade 1 or above toxicity compared to 55% in the conventional. At the end of treatment the results were 84% vs. 60% and at one year it was 65% vs. 59%. Repeated measures mixed effects model shows no significant difference in percentage of grade 1 and above toxicity between the two arms (Difference=1.63, P=0.09, 95% CI: -0.28, 3.54). However, there was a significantly higher level of grade 2 and above toxicity in patients in the infusion arm (difference=0.8; 95% CI 0.11 to 1.49). Toxicity level was the highest at the end of treatment and in older patients (Age>30). Lung function testing between the two arms failed to show any differences. Two-years PFS rate was 93% in both arms (hazard ratio infusion vs conventional was 0.91; 95% CI 0.33 to 2.52). There was an association between toxicity after 1 cycle and subsequent toxicity at end of treatment and at 1 year (p=0.003). Conclusions: Infusional bleomycin has no advantage over standard administration of bleomycin. Clinical trial information: 08648791.
Stomach cancer risk following radiotherapy for testicular cancer.
Authors: Morton Lindsay M , Fossa Sophie D. , Stovall Marilyn , van Leeuwen Flora E. , Johannesen Tom B. , Rajaraman Preetha , Aleman Berthe M , Dores Graca , Gilbert Ethel S. , Hall Per , Holowaty Eric J. , Joensuu Heikki , Kaijser Magnus , Lynch Charles , Pukkala Eero , Storm Hans H , Smith Susan A , Fraumeni Joseph F , Travis Lois B. , Hauptmann Michael
Published: March 2020

4536

Background: Testicular cancer (TC) is a highly curable malignancy occurring most commonly among men aged 15-34 years. Survivors are at increased risk for adverse late effects of therapy. Previous studies have reported more than 4-fold risks of stomach cancer after TC, although the potential role of radiotherapy and chemotherapy for TC in these associations is unclear. Methods: We evaluated stomach cancer risk in an international cohort of 23,982 men diagnosed with TC during 1959-1987. Using detailed radiotherapy records, doses to the stomach tumor location were estimated for 92 stomach cancer patients and 180 individually matched controls. Chemotherapy drugs and doses also were recorded. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Results: Fifty-seven percent of patients with stomach cancer were diagnosed with TC before age 40 years, 65% had seminoma, 95% had stage I or II disease, and 37% were diagnosed with stomach cancer ≥20 years after TC diagnosis. Patients who received radiotherapy [87 (95%) cases, 151 (84%) controls] had a 5.9-fold (95%CI 1.6-21.3) increased risk of stomach cancer compared with patients who did not receive radiotherapy. Risk increased with increasing radiation dose to the stomach (P-trend<0.001), with ORs of 3.6 (95%CI 1.3-10.6), 4.4 (1.2-16.4) and 13.3 (2.5-70.0) after 20-39.9 Gy, 40-49.9 Gy, and ≥50 Gy radiation to the stomach, respectively, compared with <10 Gy. Radiation-related stomach cancer risk did not vary by calendar year of treatment, age at exposure, or TC histology. The OR for having received any chemotherapy was 1.3 (14 cases, 23 controls, 95% CI 0.6-2.8). Stomach cancer risk was not significantly elevated among patients given cisplatin-based chemotherapy (7 cases, 10 controls, OR=1.7, 95% CI 0.6-5.1). Conclusions: Patients administered radiotherapy for TC in the past are at increased risk of developing stomach cancer, particularly those who received ≥20 Gy to the stomach. The study results warrant consideration in radiation risk assessment and long-term follow-up. Future studies should further investigate a possible role for chemotherapy in stomach cancer risk.
Impact of response to prior chemotherapy (RTPC) on outcomes in second-line therapy for advanced urothelial carcinoma (UC): Implications for trial design.
Authors: Pond Gregory Russell , Bellmunt Joaquim , Fougeray Ronan , Choueiri Toni K. , Qu Angela Q. , Salhi Yacine , Niegisch Guenter , Albers Peter , Di Lorenzo Giuseppe , Galsky Matt D. , Necchi Andrea , Sonpavde Guru
Published: March 2020

4539

Background: Performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) are significant prognostic factors in second-line therapy for advanced UC. Setting of prior chemotherapy, i.e., metastatic or perioperative, has not appeared significant. However, the impact of prior chemosensitivity is unclear, which may confound trial interpretation. Hence, we examined the prognostic impact of RTPC, when prior therapy was given for metastatic disease. Methods: Six phase II trials evaluating second-line chemotherapy and/or biologics (n=504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if data regarding Hb, LM, PS, and TFPC were available. Response by RECIST to first-line therapy was recorded. Progression-Free Survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan-Meier method. Results: 275 pts were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo or vinflunine (2 trials). Those with prior response (n=111) had a median (95% CI) OS of 8.0 (6.8-9.4) months (mo) and PFS of 3.0 (2.6-4.0), compared with OS and PFS of 5.9 (5.0-6.6) mo and 2.6 (2.0-2.8) for those without prior response (n=164). Multivariable analysis did not reveal an independent impact of RTPC on PFS or OS (Table). Conclusions: RTPC in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Patients who received prior chemotherapy in peri-operative or metastatic settings may be enrolled in the same second-line trial stratified for PS, anemia, LM and TFPC. [Table: see text]
Expression of PD-L1 in primary urothelial carcinoma (UC).
Authors: Zhang Jingsong , Dickinson Shohreh I , Clark Noel D , Flaherty Amber Lea
Published: March 2020

4541

Background: Engagement of programmed cell death-1 (PD-1), expressed on CD8+ T cells, with it ligand PD-L1(B7H1), expressed on tumor cells, results in T cell suppression and tumor protection. Antibodies against PD-1 or PD-L1 have reported impressive anti-tumor activities in phase I/II trials and are being tested in the phase 3 setting. Exploratory analysis indicated that expression of PD-L1 could be a predictive marker for response. Of note, urothelial carcinoma (UC) was not included in the early phase anti-PD1 or anti-PD-L1 studies. To explore anti-PD-L1 as a new treatment for this lethal disease, we assessed PD-L1 expression in UC. Methods: The relative mRNA abundance of PD-L1 mRNA in UC was studied in the Oncomine Bittner Multi-cancer dataset, which included a total of 1911 tumor samples. PD-L1 immunohistochemistry (IHC) was performed with rabbit monoclonal antibody against human PD-L1 on tissue microarrays with 83 formalin fixed paraffin embedded T1, T2 and T3 UC. IHC slides were reviewed by a genitourinary pathologist. A positive staining is defined when ≥ 5% of cancer cells had positive PD-L1 membrane and/or cytoplasmic staining. The IHC slides were scanned with the Aperio ScanScope XT and the immunopositivity of PD-L1 was quantitatively scored using commercial algorithms from the Aperio Toolbox and TissueStudio. The 1+, 2+, and 3+ score of each core was based on the dominant IHC staining intensity. Results: In the Bittner multi-cancer dataset, the log2 median mRNA intensities of PD-L1 in prostate cancer, clear cell renal cell carcinoma, colon cancer, UC of the bladder, ureter and squamous cell carcinoma of the bladder were 0.245, 0.528, 0.61, 0.81, 0.802, and 1.202 respectively. The overall PD-L1 IHC staining positivity was 45% in 83 primary UC samples. All six 3+ PD-L1 staining cores were grade 3 urothelial carcinomas and each core had more than 60% of cancer cells with 3+ PD-L1 membrane staining. Grade 3 cores also had the highest percentage of 2+ and 3+ PD-L1 positivity. No association was observed between T staging and PD-L1 staining intensity. Conclusions: PD-L1 is expressed in primary UC. We have obtained additional UC samples to correlate its expression with survival and its expression pattern with the pattern of tumor infiltrating lymphocytes.