bluuebunny/crossref_metadata_2025 huggingface dataset:
The need for a revised staging system of metastatic (M) colorectal cancer (CRC): Evidence from a national perspective on survival following surgically treated (HPX) liver metastases
Authors: Morris E. , Thomas J. , Forman D. , Quirke P. , Cottier B. , Poston G. J.
Published: August 2020

4099

Background: AJCC V.6 (2002) places all patients with MCRC beyond the lymph node basin of the primary tumor in a homogenous Stage 4. Patients with inoperable hepatic MCRC can be made operable with curative intent with chemotherapy yet remaining in Stage 4. Via the linkage of routine health datasets across England this population-based study sought to determine the impact of HPX for MCRC on stage-matched survival at initial presentation. Methods: All patients between 1998–2001 undergoing surgery for CRC in England were identified via the national-linked cancer registry HES dataset. All care episodes in the 3 years following initial colorectal surgery were examined to determine the frequency of subsequent HPX. Kaplan-Meier curves and log- rank tests were used to examine 5-year survival following HPX for MCRC compared to all Stage 3 and Stage 4 at presentation. Survival was calculated from the date of resection of each patient's primary colorectal tumor. Results: 68,307 individuals were identified as undergoing surgery for primary CRC over the study period. 20,298 were Stage 3 at presentation. 1,483 (2.2%) subsequently underwent HPX <3 years of their colorectal operation. 55 patients died within 30 days of HPX (mortality rate: 3.7%). Crude 5-year survival of patients who underwent HPX was 41.6% (95%CI 39.0–44.1%) from time of initial colectomy. This survival rate was significantly better than that for both Stage 3 (38.6% (95%CI 37.9%-39.2%, P<0.01) and 4 (6.1% 95%CI 5.3–6.9%, P<0.01) overall. Conclusions: 5-year survival following HPX for MCRC is better than that seen overall for all Stage 3 patients (with MCRC confined to the regional draining lymph node basin) following initial colectomy. Our data support the hypothesis that all MCRC that is potentially resectable with curative intent should be stratified within Stage 3, and Stage 4 should only contain those MCRC patients for whom surgery is not an option. If further evidence emerges to support this theory then a revision of the current staging system will be required.

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Does microsatellite instability predict the effect of adjuvant chemotherapy in stage III colorectal cancer? A meta-analysis
Authors: Des Guetz G. , Uzzan B. , Nicolas P. , Chouahnia K. , Perret G. , Zelek L. , Morere J.
Published: August 2020

4121

Background: Microsatellite instability (MSI) is a prognostic factor in colorectal cancer. Whether it predicts the effect of adjuvant chemotherapy (CT) on overall survival (OS) and relapse-free survival (RFS) is controversial. Methods: Studies were identified by an electronic search using online PubMed, with simultaneous keywords (colorectal neoplasm, microsatellite instability, chemotherapy, prognosis). Abstracts from ASCO and AACR proceedings were reviewed. Articles were obtained from cross-checking of references and from a previous prognostic meta-analysis (MA) (Popat, 2005). We used EasyMA software, available online. A Hazard Ratio (HR) < 1 for MSI-high (MSI-H) status compared with microsatellite stable (MSS) meant a better survival. Results: Our MA found 21 studies (4 abstracts). Statistical calculations were performed in 11 studies (5087 patients including 2879 receiving 5FU-based CT; mean age: 63 years; 1489 stage II, 2648 stage III (64%)). MSI-H was found in 644 patients (15% of total), MSS in 3624. Seven studies (2 randomized) assessed 2 cohorts receiving or not adjuvant CT, 4 studies only included patients receiving CT. Global HR OS (9 studies) was 0.79 (95% confidence interval or CI: 0.64–0.98; p = 0.03). Global HR RFS (8 studies) was 0.67 (95% CI: 0.54–0.83; p < 0.001). A MA on stage III patients (4 studies, 719 patients, 137 MSI-H) found a higher survival among MSI-H than MSS patients receiving CT (HR OS: 0.71, 95% CI 0.49–1.03; HR RFS 0.56, 95% CI 0.42–0.75). Interaction between MSI status and CT status was statistically significant on OS and RFS (4 studies). A MA among MSI-H patients (7 studies) found no survival difference between patients under CT or not: HR OS: 0.70 (95% CI 0.44–1.09), HR RFS: 0.96 (95% CI: 0.62–1.49). Conclusions: Adjuvant CT significantly improved survival in MSI-H compared with MSS patients. MSI-H stage III patients receiving CT survived more than MSS. MSI-H status did not predict response to CT compared with no treatment.

No significant financial relationships to disclose.
Placebo-controlled, double-blind, prospective, randomized study of the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group
Authors: Arnold R. , Müller H. , Schade-Brittinger C. , Rinke A. , Klose K. , Barth P. , Wied M. , Mayer C. , Aminossadati B. ,   PROMID Study Group
Published: August 2020

4508

Background: Octreotide is currently used for the control of symptoms in patients with gastroenteropancreatic neuroendocrine tumors (NETs). However, the ability of long-acting somatostatin analogues to control the growth of well-differentiated metastatic NETs is a matter of debate. The analysis of the first randomized, double-blind, placebo-controlled, multicenter, phase IIIb study of octreotide LAR in patients with metastatic NETs of the midgut is presented. Methods: Treatment-naïve patients with histologically confirmed locally inoperable or metastasized well-differentiated NETs and a Karnofsky index >60 were randomized to receive either octreotide LAR 30 mg/month (mo) or placebo for 18 mos, or until tumor progression or death. The primary endpoint was median time to tumor progression. Secondary endpoints included objective tumor response rate (WHO criteria), measured every 3 mos, as well as symptom control and overall survival. This was a planned interim analysis using the Lan-DeMets error spending approach. Results: Eighty-five patients (n=43 octreotide LAR; n=42 placebo) have been enrolled to date and data from 67 patients with tumor progressions and 16 deaths (n=7 octreotide LAR; n=9 placebo) are included here. Median time to tumor progression in the octreotide LAR and placebo groups were 14.3 mos and 6 mos, respectively (HR: 0.34; 95% CI: 0.20–0.59; P=0.000072). After 6 mos of treatment, stable disease was seen in 67% and 37.2% of patients treated with octreotide LAR and placebo, respectively. Due to the low number of observed deaths, median survival time could not be estimated. Conclusions: Octreotide LAR significantly lengthens median time to tumor progression compared with placebo in patients with metastatic NETs of the midgut. Patients treated with octreotide LAR had a 66% risk reduction of tumor progression compared with patients receiving placebo. Octreotide LAR demonstrates substantial tumor control and shows a more favorable antiproliferative response than placebo as two-thirds of patients treated with octreotide LAR achieved stable disease at 6 mos.

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A randomized phase II trial of irinotecan plus oxaliplatin versus oxaliplatin, fluorouracil (5 FU), leukovorin (LV) as first-line treatment in advanced gastric cancer
Authors: Boukovinas I. , Androulakis N. , Polyzos A. , Vardakis N. , Amarantidis K. , Bozionelou V. , Kouroussis C. , Giassas S. , Christophyllakis C. , Mavroudis D.
Published: August 2020

4536

Background: To compare the efficacy and tolerance of two oxaliplatin-based regimens as first-line treatment of advanced gastric cancer. Methods: Chemotherapy-naïve patients with measurable recurrent or metastatic gastric adenocarcinoma, PS (ECOG) 0–2 and adequate organ functions were randomly assigned to receive either irinotecan 200mg/m2 and oxaliplatin 80mg/m2 (IO), every 21 days or oxaliplatin 85mg/m2 on day 1, 5-FU 400 mg/m2 (over 1 hour infusion) + 600mg/m2 (over 22 hours infusion) on days 1 and 2, leucovorin (LV) 200mg/m2 on days 1 and 2 (FOLFOX4) every 2 weeks. Study endpoints: Overall Response Rate (ORR), Toxicity Time to Progression (TTP) and Survival (S). Results: 138 patients were enrolled and all were evaluable for response. Median number of cycles administered was 5.5 (range 1–10) for IO and 7 (range 1–18) for FOLFOX4. In an intent-to treat analysis the ORR (RR+CR) was 29.4% for IO arm and 34.3 % for FOLFOX4 arm (p= 0.587). The median response duration was 5.63 months (mo) for IO arm and 6,6mo for FOLFOX4 arm. Median TTP was 4.2mo and 6,1mo for IO and FOLFOX4 arm respectively (p= 0.012). Median OS was 9.4mo for IO and 11.97mo for FOLFOX4 (p= 0.456). Toxicity was acceptable, with one toxic death in each arm. Grade 3–4 vomiting (7.3%), diarrhea (11.8%), neutropenia (22%) and febrile neutropenia (5.9%) occurred more frequently in IO arm, while anaemia (4.3%) and grade II neurotoxicity (11.4%) was more frequent in FOLFOX4 arm. Conclusions: Both regimens are well tolerated and active in advanced gastric cancer. Based on the TTP and toxicity profile, the FOLFOX4 regimen merits to be further evaluated in prospective phase III trials.

No significant financial relationships to disclose.
Updated result on the 2.5-year follow-up of GC0301/TOP-002: Randomized phase III study of irinotecan plus S-1 (IRI-S) versus S-1 alone as first-line treatment for advanced gastric cancer (AGC)
Authors: Tsuburaya A. , Narahara H. , Imamura H. , Hatake K. , Imamoto H. , Esaki T. , Kato M. , Furukawa H. , Hamada C. , Sakata Y. ,   GC0301/TOP-002 Study Group
Published: August 2020

4544

Background: IRI-S had longer in median survival time (MST) than S-1 alone, and was well tolerated in previously untreated AGC, but not statistically significant. Considering 68 patients (pts) were censored, further follow-up was needed to confirm the OS with more precision (Imamura et al. ASCO-GI 2008). We now present updated results of OS and exploratory analysis with the prolonged 2.5 year follow-up data. Methods: Treatments Arm A (oral S-1 80 mg/m2/day from Day 1 to 28, q6w), or Arm B (IRI-S; oral S-1 80 mg/m2/day from Day 1 to 21 and intravenous irinotecan 80 mg/m2 on Days 1 and 15, q5w) were continued until disease progression or unacceptable toxicities were observed. The primary endpoint was to compare OS between groups. This updated result was regarded as exploratory position. Results: Although the MST of Arm A was 319 days (95%Cl: 286–395) and of Arm B was 389 days (95%Cl: 324–459), Arm B didn’t show statistically significant superiority to Arm A (log-rank test p=0.54; hazard ratio (HR) =0.93). The 1-year survival was 45.0% in Arm A and 52.0% in Arm B, and the 2-year survival was 22.5% and 18.0%, respectively. Response rate was significantly different (Arm A/B, 26.9%/41.5%; chi-square test p=0.04) in 187 patient evaluated by RECIST criteria. Time to treatment failure was also favored in Arm B (median=138 days) compared to Arm A (111 days; log-rank test p=0.16; HR=0.85). In subset analyses, two groups showed possibility of clinical benefit in Arm B. The HR of diffuse type group was 0.71 (95%Cl: 0.52–0.96), and of PS1, 2 group was 0.63 (95%Cl: 0.42–0.95). As post protocol treatment, 45.6% of Arm A patients received an irinotecan-based regimen, and the MST of them was 496 days (95%Cl: 395–573). Conclusions: IRI-S did not show statistically significant superiority to S-1 alone in OS with this follow-up data. Post protocol treatment, effective treatment after S-1 failure might have affected survival. According to exploratory analyses, IRI-S may have clinical benefit in early-term of treatment, group of the diffuse type and that of PS1, 2. We need more considering predictive factors, because the gastric cancer is heterogeneous adenocarcinoma.

[Table: see text]
The association of PET response with complete pathological response (CPR) and residual nodal disease (RND) after induction chemoradiotherapy (CRT) and resection of esophageal cancer: A review of 493 cases
Authors: Barnett S. A. , Rizk N. P. , Adusumilli P. S. , Park B. J. , Bains M. S. , Flores R. M. , Goodman K. A. , Ilson D. H. , Akhurst T. J. , Rusch V. W.
Published: August 2020

4552

Background: RND and lack of CPR of the primary tumor correlate with poor survival after induction CRT and resection of esophageal cancer. PET response to CRT (SUVmax change and post-induction SUVmax) is used by some clinicians as an indicator of CPR and RND in order to stratify patients after CRT to observation alone vs completion resection. We aimed to investigate the association of PET response with CPR and RND after induction CRT and resection of esophageal cancer. Methods: An IRB-approved retrospective review of an institutional surgical database identified patients who underwent resection of esophageal squamous cell (SCC) and adeno carcinoma (AC) following CRT. The database was locked on Sept 30, 2008. Categorical variables were analyzed by chi square, continuous variables by t-test, and survival by the Kaplan-Meier method. Results: From 1/96 to 3/08, 493 patients were identified, 82% were male. Median age was 62, chemotherapy cisplatin-based in 87%, mean radiation 50 Gy, in-hospital mortality 4.1% and R0 resection rate 88%. Pathology revealed AC in 80%, lack of CPR in 73% and RND in 35%. While in AC patients CPR and lack of RND were both associated with prolonged survival, PET response was not associated with either. In SCC patients, prolonged survival was associated with CPR but not with lack of RND. In SCC, PET response was associated with CPR but not RND. In these patients, reduction in SUVmax <50, 50–75 and >75% was associated with CPR rates of 29, 44 and 85% respectively (p=0.02). Conclusions: These results do not support the use of PET response to justify observation alone after CRT in esophageal AC. With respect to SCC, though exploratory, these provocative results support further study of the use of PET response to predict CPR.

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No significant financial relationships to disclose.
A phase II study of bevacizumab, docetaxel, and oxaliplatin in gastric and GEJ cancer
Authors: El-Rayes B. F. , Patel B. , Zalupski M. , Hammad N. , Shields A. , Heilbrun L. , Venkatramanamoorthy R. , Philip P.
Published: August 2020

4563

Background: VEGF (vascular endothelial growth factor) has a central role in angiogenesis, tumor growth and metastasis of gastric cancer. Bevacizumab, an anti-VEGF monoclonal antibody, has demonstrated anti-tumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin. Methods: The primary endpoint was time to progression (TTP) in patients with locally advanced or metastatic adenocarcinoma of the gastric or gastroesophageal junction treated with docetaxel, oxaliplatin and bevacizumab. Previously untreated patients with a performance status (PS) of 0–1 were eligible for this study. Patients received bevacizumab 7.5 mg/kg, docetaxel 70 mg/m2 and oxaliplatin 75 mg/m2 administered on day 1 of a 21 day cycle. Results: A total of 23 patients (median age 57, males 70%, gastric 52%) were enrolled on the study. Median PS was 1. The median number of cycles was 5. Ten patients are still receiving treatment on study. Partial responses were documented in 10 (59%) patients and stable disease in 7 (41%). No treatment related deaths were observed. The most commonly reported grade 3–4 toxicities were neutropenia (13%), leukopenia (4%), fever (4%), acute neuropathy (4%), and hypertension (4%). Gastrointestinal (GI) perforation occurred in 3 patients. Perforation was not found at the tumor site in the patient who required surgery. The site of perforation could not be ascertained in the second patient who was managed medically. Both patients had had no prior surgical resection of the primary tumor. The third perforation presented as a tracho-bronchial fistula. The patient had previously undergone surgical resection of his primary tumor after receiving chemoradiotherapy to the thoracic area. Conclusions: The regimen of docetaxel, oxaliplatin and bevacizumab appears to be very active. The development of GI perforations in 3 patients is of concern. At this time, bevacizumab should not be used in gastric or gastroesophageal junction cancers outside of a clinical trial until its safety is well established.

[Table: see text]
An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC)
Authors: Raoul J. L. , Finn R. S. , Kang Y. K. , Park J. W. , Harris R. , Coric V. , Donica M. , Walters I.
Published: August 2020

4577

Background: Brivanib is an orally available dual inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signaling. FGF pathway activation is of increasing importance in the setting of liver fibrosis and HCC. This phase II study aimed to assess the efficacy and safety of brivanib in patients (pts) with unresectable, locally advanced or metastatic HCC who had received either no prior systemic therapy (Cohort A) or one prior regimen of angiogenesis inhibitor (Cohort B). Methods: Eligible pts had biopsy-proven HCC or had radiological evidence of HCC and were serology positive for Hep B or C with alpha fetoprotein levels ≥ 400 μg/L. Pts received brivanib 800 mg qd. Efficacy endpoints included OS, PFS, TTP, ORR, and DCR. Safety was assessed throughout the study. Serum levels of a biomarker, Collagen IV (a component of the basement membrane of blood vessels), were measured on day 1, weeks 3 and 6, and at end of treatment. Results: Interim results are reported. From December 2006 to October 2008, 96 patients were enrolled (Cohort A: 55 pts; Cohort B: 41 pts). In Cohort B, 38 pts had failed sorafenib and 3 had failed thalidomide. In Cohort A, median OS (95% CI) was 10 (6.8,-) months. Most frequently reported grade 3/4 AEs were fatigue (16%), AST elevation (19%), and hyponatremia (41%) in Cohort A and hypertension (7.3%), diarrhea (4.9%), and headache (4.9%) in Cohort B. 24 pts died in Cohort A and 5 pts in Cohort B, none were considered treatment-related. Treatment-induced reductions in serum Collagen IV appear to correlate with long term outcome (PFS and OS). Conclusions: Brivanib has activity as both first-line and second-line post-sorafenib systemic treatment in HCC. Collagen IV, a novel serum angiogenic biomarker, appears to be associated with outcome.

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Phase II trial of erlotinib in advanced pancreatic cancer (PC)
Authors: Tang P. , Gill S. , Au H. J. , Chen E. X. , Hedley D. , Leroux M. , Wang L. , Moore M. J.
Published: August 2020

4609

Background: The epidermal growth factor receptor (EGFR) is a potentially important target in PC. Benefit from erlotinib (Tarceva), an oral EGFR tyrosine kinase inhibitor has been associated with the presence of a skin rash. The purpose of this study was to determine the efficacy of erlotinib, dosed to achieve a rash, in patients (pts) with PC. Methods: Erlotinib was given at an initial dose of 150 mg/day to eligible pts with locally advanced (LA) or metastatic PC who had progressed or were unable to tolerate gemcitabine-based chemotherapy. The dose of erlotinib was increased by 50mg every 2 weeks (maximum 300 mg/day) until > grade 1 rash (CTCAE v 3.0) or other dose-limiting toxicities occurred. Erlotinib pharmacokinetic (PK) studies were performed. Baseline tumor tissue was collected for analysis of Kras mutations, EGFR by IHC and FISH. The primary endpoint of this two- stage phase II trial was prolonged disease control (PR + SD > 8 wks) with a rate of >20% assumed to be significant . Results: Fifty pts were accrued (median age 61, M:F = 25:25, ECOG 0:1:2 = 5:41:4, LA:Metastatic = 5:45, prior gemcitabine none:adjuvant:palliative = 2:16:35). 47 and 40 pts were evaluable for toxicity and response, respectively. Dose-escalation to 200–300 mg of erlotinib was possible in 9 pts. Most common treatment adverse events (TAEs) of any grade were: rash (35 pts, 74.5%), diarrhea (18 pts, 38.3 %), and fatigue (8 pts, 17%). Grade 3+ TAEs were rash in 2 pts and diarrhea in 2 pts. Best response was SD in 14 pts, 0.35 (95% CI: 0.2–0.5). Prolonged disease control (SD > 8 wks) was observed in 10/40 evaluable pts, 0.25 (95% CI: 0.12–0.38), which met the primary study endpoint. Median TTP was 1.6 mo (95% CI:1.6–2.1), mOS 4.1 mo (95% CI:3.2–7.3), and 6 mo OS rate was 39% (95%CI: 24–61%). PK and correlative data are being analyzed and will be presented. Conclusions: Erlotinib is associated with prolonged stable disease in a subset of pts with advanced refractory PC. Dose escalation in the absence of toxicity is feasible and safe.

[Table: see text]
Use of a genome-wide association study to detect candidate polymorphisms associated with overall survival in stage IV pancreatic adenocarcinoma patients receiving gemcitabine monotherapy
Authors: Ueno H. , Okusaka T. , Furuse J. , Ishii H. , Saijo N. , Saito Y. , Sawada J. , Sakamoto H. , Yoshida T. , Sato Y.
Published: August 2020

4611

Background: Individual variations in overall survival time (OS) or antitumor effects may be partly explained by host genetic factors, which have not yet been identified. We performed a genome-wide association study (GWAS) in Japanese patients with stage IV pancreatic adenocarcinoma receiving gemcitabine (Gem) monotherapy. Methods: Metastatic pancreatic ductal adenocarcinoma patients who had previously received neither radiation nor chemotherapy were eligible in this study. Gem was administered as a 30-min i.v. infusion at either 800 or 1000 mg/m2. The peripheral blood leukocyte DNA samples were genotyped at 110,000 SNPs using Illuimina's Human-1 Genotyping BeadChip. Statistical analyses were performed by the log-rank test and Cox proportional hazards model in consideration of linkage disequilibrium. Results: From Jul 2002 to Jul 2006, 67 patients (male/female: 44/23, PS 0/1/2: 31/32/4, 36–78 (median: 62) years of age were enrolled. The median survival time (MST) of these 67 patients was 5.8 months. In the GWAS, we detected 11 candidate SNPs which were associated with significantly shortened OS. Eventually, 6 SNPs were MAF>5% and remained statistically significant even after multiple comparison adjustment: rs1861674 in the LOH12CR1 gene (MST for CC [n=60] and CT [n=7] + TT [n=0] were 6.4 and 1.6 months, respectively; P=1.0×10-7, HR=8.25 (3.3–20.9)), rs10504551 in the TCEB1 (MST for CT [n=28] + CC [n=36] and TT [n=3] were 5.8 and 1.0 months. P=1.1×10-7, HR=14.9 (3.9–56.1)), rs1132750 (MST for AC [n=18] + AA [n=45] and CC [n=4] were 6.3 and 1.1 months. P=4.6×10-11, HR=23.5 (6.1–91.7)), rs2055943 in the GABRA4 (MST for AC [n=27] + CC [n=36] and AA [n=4] were 6.3 and 1.2 months. 1.3×10-11, HR=26.1 (6.4–107), rs2589506 in the MAPK10 (MST for AG [n=29] + GG [n=31] and AA [n=7] were 6.4 and 1.1 months. P=3.2×10-6, HR=5.9 (2.6–14.1)) and rs2586404 in the DNM3 (MST for CT [n=30] + CC [n=33] and TT [n=3] were 5.8 and 0.62 months. P=3.4×10-9, HR=18.6 (4.9–71.5)). Conclusions: GWAS is a powerful tool to search for new prognostic biomarkers for patients with stage IV pancreatic adenocarcinoma receiving Gem monotherapy and may reveal as yet unexplored molecular pathways which correlate with drug response.

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A phase II study of radiation and docetaxel and cisplatin in the treatment of locally advanced pancreatic carcinoma. FNCLCC-ACCORD 09 /0201 trial
Authors: Viret F. , Ychou M. , Baey C. , Bennouna J. , Adenis A. , Peiffert D. , Mornex F. , Celier P. , Montoto-Grillot C. , Ducreux M.
Published: August 2020

4625

Background: Locally advanced pancreatic carcinoma remains a challenging tumor with no clear standard of care in terms of radio-chemotherapy. The purpose of this phase II trial was to determine the efficacy and the toxicity of radiotherapy and docetaxel and cisplatin in histologically proven adenocarcinoma of the pancreas. Methods: Patients (pts) received external beam radiotherapy (54 Gy in 1.8 Gy fractions, six weeks) and weekly chemotherapy regimen of association docetaxel and cisplatine (20 mg/m2/weeks each) for six weeks. Results: 51 pts (20 women and 31 men, with median age of 62 years) with disease considered to be unresectable but confined to pancreas area and celiac nodes were included between 06/10/2003 and 15/02/2008. Location of the tumor: head (33 pts), body (13 pts), and tail (5 pts). The median dose of radiotherapy received by the patients was 54 Gy. The median dose of docetaxel and cisplatin administered was 19.8 mg/m2/w (relative dose intensity 97%). Radiotherapy has to be interrupted in 7 pts. 30 pts experienced at least one episode of grade 3 or 4 toxicity (asthenia 12 pts, anorexia 11 pts, vomiting 10 pts, nausea 9 pts, abdominal pain 5 pts). No toxic death was observed. 6 pts underwent secondary pancreatic resection (4 compete resection and 1 pt with histological complete remission). The objective response rate (CR 5 pts, PR 3 pts), was 16% with a median duration of 7.6 months. At 6 months, 30 pts had progressed. Median progression free survival was 5.8 months. With a 21 months median follow up, median overall survival was 9.6 months and 18 months survival rate of 31%. Conclusions: The association docetaxel+cisplatin+radiotherapy has limited effect in patients with locally advanced pancreatic carcinoma but major objective responses have been observed allowing secondary resections. Grant by sanofi-aventis, Amgen, and Ligue Nationale Contre Le Cancer.

No significant financial relationships to disclose.
Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumors: Updated analysis of a randomized trial with 8 years follow-up
Authors: Grimison P. S. , Stockler M. R. , Thomson D. B. , Olver I. N. , Harvey V. J. , Gurney H. , Lewis C. R. , Gebski V. J. , Boland A. L. , Toner G. C. ,   Australia and New Zealand Germ Cell Trials Group
Published: August 2020

5016

Background: We performed a multicentre randomised trial for good-prognosis germ-cell tumours of two standard chemotherapy regimens containing bleomycin (B), etoposide (E) and cisplatin (P). Accrual was stopped early, after interim analysis with a median follow-up of 33 months found a survival benefit for the regimen similar to Indiana University BEP, compared with the less dose-intense regimen (Toner, Lancet 2001). Here we report on long-term outcomes and patterns of relapse. Methods: Patients with a good prognosis defined by modified Memorial Sloan-Kettering criteria were randomised to 3B90E500P (3 cycles every 21 days of B 30 kU on days 1, 8 and 15, E 100 mg/m2 on days 1–5, and P 20 mg/m2 on days 1–5); or 4B30E360P (4 cycles every 21 days of B 30 kU on day 1, E 120 mg/m2 on days 1–3, and P 100 mg/m2 on day 1). Overall survival was the primary endpoint. Progression-free survival (PFS) was a secondary endpoint. All analyses were by intention-to-treat and with 2-sided p-values. Results: 166 patients were randomised, 83 to each regimen. Median follow-up is now 8.5 years and all but 5 have been followed ≥ 5 years. Overall survival remains substantially better with 3B90E500P than 4B30E360P (8YS 92% vs 83%, hazard ratio 0.38, 95% CI 0.15 to 0.97, p=0.037), and remains significant when analyses were restricted to 138 patients with good prognosis by IGCCCG criteria (p=0.035). Trends for PFS favour 3B90E500P but are not statistically significant (8YPFS 86% vs 79%, hazard ratio 0.6, 95% CI 0.3 to 1.1, p=0.15). 7 of 15 relapses occurring within 2 years after randomisation were fatal, but all 4 relapses occurring > 2 years after randomisation were fatal. Conclusions: The survival benefit of 3B90E500P compared to 4B30E360P was maintained with long-term follow-up. The occurrence of relapses beyond 2 years affirms the importance of long-term follow-up. Late relapses in this study were associated with uniformly poor outcomes.

[Table: see text]

No significant financial relationships to disclose.
Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients
Authors: Gronwald J. , Byrski T. , Huzarski T. , Dent R. , Bielicka V. , Zuziak D. , Wisniowski R. , Lubinski J. , Narod S.
Published: August 2020

502

Background: Neoadjuvant chemotherapy is administered to control disease, make surgical resection possible and increase the possibility of breast tissue conservation. A further advantage of neoadjuvant therapy is that it helps to assess chemo-sensitivity to a particular agent. Induction of a pathological complete response (pCR) is one of the primary goals of neoadjuvant therapy in order to achieve a better disease-free and overall survival. Experimental data suggest that BRCA1 related breast cancer may have increased sensitivity to platinum-based chemotherapy, but clinical data are limited. The aim of this study was to evaluate the frequency of complete pathologic response after neo-adjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation. Methods: Twenty five women with breast cancer and a BRCA1 mutation with stage I, II, and III breast cancer between December 2006 and December 2008 were entered into this study. Patients were treated with cisplatin 75 mg/m2 intravenously every three weeks for four cycles. After chemotherapy, patients underwent surgery and were assessed for pathologic response in both the breast and axillary lymph nodes. Complete pathologic response was defined as no residual invasive disease in both the breast and axilla, however ductal carcinoma in situ was allowed. Results: Twenty five patients were enrolled in the study. Thirteen patients had tumors of greater than two centimeters (52%) and seven patients had positive lymph nodes at diagnosis (28%). Twenty two patients completed four cycles of cisplatin (88%) and three patients completed two cycles (12%). Clinical complete response was observed in eighteen patients (72%). Pathologic complete response was observed in eighteen patients (72%). Conclusions: Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers. Clinical trials are warranted to determine the optimum treatment for this subgroup of breast cancer patients.

No significant financial relationships to disclose.
A phase II trial of high-dose chemotherapy (HDCT) supported by haematopoietic stem cell transplantation (HSCT) in patients (pts) with disseminated germ-cell tumors (GCTs) failing chemotherapy and with adverse prognostic factors: The TAXIF II protocol
Authors: Lotz J. , Selle F. , Fizazi K. , Gravis G. , Bui B. , Delva R. , Bay J. , Baron A. , Robain M. , Biron P.
Published: August 2020

5028

Background: HDCT using the etoposide-carboplatin ± ifosfamide regimen is able to circumvent resistance in GCT pts, even when used as third-line or later therapy (Lotz, Ann Onco.l 2005 / Einhorn, N Eng J Med. 2007). Pts whose relapses occur more than 4 w after CDDP-based CT are probably the best candidates for HDCT. Epirubicine (E) and paclitaxel (P) possess interesting activity in GCTs. Thiotepa (TTP) and P can be safely combined at HD with good efficacy. The ICE regimen is a well-known worldwide used regimen. Methods: Non-resistant/refractory GCTs pts failing CT and with adverse prognostic factors were planned to receive 2 cycles combining (mg/m2) E (100) and P (250), given on day 1 and 14 supported by filgrastim (F), followed by 3 consecutive HDCTs [1 course combining a 3-d combination of P (360) + TTP (720), followed by 2 ICE regimens (IFM, 12 g/m2, CBDCA, AUC 20, VP16, 1,500 mg/m2), given on 5 days with HSCT and F]. Inclusion criterias were mainly: radiologically and/or biologically mesurable disease, seminomatous GCT in relapse after 2 lines of CT (BEP/VeIP), non-seminomatous GCT in relapse after 1 or 2 lines of CT or in PR after 1 line of CT, primary mediastinal GCT in first relapse. Resistant / refractory pts were excluded. PBSC were collected after the first ± the second courses of EP (aim: 9x10E6 CD34+/kg BW). We report herein on the preliminary results of this multicentric study. Results: From 09/04 to 12/07, 45 pre-treated (BEP ± VeIP) pts with gonadal (89%) or extra-gonadal T (11%) were treated in second-line (27%), 3rd-line (44 %) or more (29 %). Thirty-five pts received 1 HDCT, 29 two HDCTs and 21 pts could receive the whole protocol. At the time of analysis (12/08), the final overall response rate was 47%, 10 pts were in continuous CR (median time, 8 m; range, 1–18), and 37 pts (82%) were alive at a median F/U of 9 m (range, 1–26). The 1-y survival rate was 90%. The 1-y PFS rate was 62%. One pt died of multi-organ failure and 7 died of disease progression. Conclusions: This HDCT program preceded by 2 semi-intensive cycles of E-P is highly effective in non-resistant/refractory pts with disseminated GCTS failing CT and with adverse prognostic factors.

No significant financial relationships to disclose.
Phase II study of perifosine in metastatic renal cell carcinoma (RCC) progressing after prior therapy (Rx) with a VEGF receptor inhibitor
Authors: Vogelzang N. J. , Hutson T. E. , Samlowski W. , Somer B. , Richey S. , Alemany C. , Loesch D. , Richards P. , Gardner L. , Sportelli P.
Published: August 2020

5034

Background: Perifosine, a synthetic alkylphospholipid, inhibits or modulates a number of different signal transduction pathways (AKT, MAPK and JNK). In a prior trial, 15 RCC patients (pts) were enrolled in a randomized dose finding study, 9 were evaluable for response and 3 (33%) had a partial response (PR). Thus phase II trials were begun for pts who had been treated with one prior VEGFr inhibitor (Group A) or with a prior VEGFr inhibitor and prior mTOR inhibitor (Group B). We report the results of Group A (closed), and Group B (enrollment open). Methods: To measure the objective response rate (RECIST) and PFS to single agent perifosine (100 mg qhs with food) after 3 mos of Rx; Prior Rx with vaccine therapy, bevacizumab and/or cytokines was permitted. Normal organ/marrow function was required. Results: From 12/07–12/08, 46 pts (31 Group A/ 15 Group B) were treated at 13 sites. Median age 64 (range 46–80) and 36 were male; Median prior Rx was 2 (range 1 - 5); Clear cell = 37, non clear cell = 6, data n/a = 3. Prior sunitinib = 35, prior sorafenib = 10, 1 unknown due to blinded study. Prior mTOR; Tem = 9 and Rad001 = 6. As of 12/08, 44 pts were evaluable for response and PFS (two pts not eval; 1 withdrew consent, 1 toxicity < 5 days on Rx). Results listed in the table below. As of 12/08, 12/44 pts (5 Group A/ 7 Group B) remain on treatment. Median survival; not reached. Most common toxicity was grade 1 & 2 nausea (56%), arthralgia (47%), vomiting (36%), fatigue (33%) and cognitive changes (28%). Grade 3 & 4 toxicity was uncommon; arthralgia (14%) and hyperuricemia/gout (8%). Conclusions: Perifosine, similar to mTOR inhibitors, appears to have clinical benefit in mRCC as reflected by the PR rate and a 15 wk median overall PFS. This is most notably in patients who failed both a prior VEGFr and mTOR inhibitor where 7/14 remain on study as of 12/08. Randomized studies are under consideration to further evaluate perifosine's clinical benefit as 2nd or 3rd line therapy of mRCC.

[Table: see text]

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Prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF)-targeted agents: Results from a large multicenter study
Authors: Heng D. Y. , Xie W. , Regan M. M. , Cheng T. , North S. , Knox J. J. , Kollmannsberger C. , McDermott D. , Rini B. I. , Choueiri T. K.
Published: August 2020

5041

Background: Prognostic factors (PF) for OS have yet to be fully defined for patients with metastatic RCC in the era of VEGF-targeted therapy. This study identifies PFs in this population and updated survival and validation results are presented. Methods: Baseline characteristics and outcomes on anti-VEGF-naïve metastatic RCC patients were collected from three US and four Canadian centers. Using a Cox proportional hazards model, 3 risk categories for predicting survival were identified on the basis of 6 pretreatment clinical features. Results: Six-hundred forty-five patients were included. The median (m) OS was 22 months (95% CI: 20.0–24.8) with a median follow-up of 25 months. Patients were treated with sunitinib (n = 396), sorafenib (n = 200) or bevacizumab (n = 49); 33% had prior immunotherapy. Four of the five PFs previously identified by MSKCC were independent predictors of short survival, including hemoglobin below the lower limit of normal (LLN) (p < 0.0001), corrected calcium above the upper limit of normal (ULN) (p = 0.0006), Karnofsky performance status <80% (p < 0.0001) and time from initial diagnosis to initiation of therapy ULN (pULN (p = 0.012) were independent adverse PFs. Patients were assigned one point for each poor PF and were segregated into three risk categories: favorable-risk (0 PFs, n = 133) median OS (mOS) 37.0 months; intermediate-risk (1 - 2 PFs, n = 292) mOS 28.5 months; and poor-risk (3–6 PFs, n = 139) mOS 9.4 months (log rank p < 0.0001). This model produced a c-index of 0.74 and the bootstrap procedure confirmed good internal validity. The discriminatory ability of the model and its parameter estimates were not affected after adjusting for prior use of immunotherapy or the type of anti-VEGF drug used. Conclusions: These data validate components of the MSKCC model with the addition of platelet and neutrophil counts. This model derived from a large population can be incorporated into patient care and clinical trials of VEGF-targeted agents.

[Table: see text]
Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC)
Authors: Rixe O. , Dutcher J. , Motzer R. , Wilding G. , Stadler W. M. , Garrett M. , Pithavala Y. , Kim S. , Tarazi J. , Rini B. I.
Published: August 2020

5045

Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, 3. An association between dBP elevation and clinical outcome has been previously reported (Rini, ASCO. 2008). The objective of this pooled analysis of two phase II mRCC studies was to explore the relationship between PK, dBP, and clinical efficacy. Methods: PK data from two phase II studies in cytokine-refractory mRCC patients (pts) and 8 single-dose healthy volunteer (HV) studies were included (n = 109 mRCC pts and 240 HV) in the population PK analysis; the efficacy analysis included mRCC pts only. PK data was analyzed using nonlinear mixed-effects modeling to estimate population PK parameters (mean and inter-individual variability). Mean steady-state area under the plasma concentration-time curve (AUC) at the end of cycle 1 and the dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan-Meier analyses. Results: The median overall survival (mOS) for mRCC pts with at least 1 dBP measurement ≥90 mmHg (n = 59) during axitinib therapy was 130 weeks vs. 42 weeks (p < 0.01) for pts without any dBP ≥90 mmHg (n = 50). The mOS of pts with an AUC below the median (605 ng.hr/ml; n = 54) was 69 weeks vs. 88 weeks (p > 0.05) for pts with an AUC above the median (n = 55). Among pts with dBP ≥90 mmHg, mOS was 120 weeks and 131 weeks (p > 0.05) for pts with AUC below and above the median (n = 23 and 36), respectively. Among pts without dBP ≥90 mmHg, mOS was 42 weeks and 43 weeks (p > 0.05) for pts with AUC below and above the median (n = 31 and 19), respectively. An 82% increase in probability of a partial response was predicted for a 10 mmHg higher dBP during therapy. There was no apparent correlation between the AUC and maximum dBP during axitinib therapy. Conclusions: dBP ≥90 mmHg during axitinib therapy is a strong predictor of clinical efficacy in patients with mRCC, and is not merely a reflection of higher axitinib drug levels. These data support an ongoing pivotal phase III trial in previously treated mRCC that incorporates a dose-titration scheme based on patient tolerance and BP.

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Interaction of obesity and race in predicting recurrence rates after radical prostatectomy
Authors: Lee D. J. , Ritch C. , Desai M. , McKiernan J. M.
Published: August 2020

5070

Background: Black men are twice as likely to die from prostate cancer compared to white men. Obese men are known to have higher mortality rates and recurrence rates, and blacks are 1.4 times as likely to be obese than white Americans. However, the relative contribution of BMI and race to biochemical failure (BCF) after radical prostatectomy (RP) has not been well-characterized. We examined the interaction of BMI and race in predicting BCF after RP. Methods: A retrospective analysis of the Columbia Urologic Oncology Database found that 3,736 consecutive men underwent RP between 1988 and 2008. 1,461 men had BMI and race data available. 213 (14.6%) were black men, 1,004 (68.7%) were white, 162 (11.1%) were Hispanic, and 82 (5.6%) were Asian. Overweight and obese men were defined as having a BMI > 25 kg/m2 and a BMI > 30 kg/m2, respectively. BCF was defined as a post-surgery PSA level >0.2 ng/mL on > 2 measurements. Cox regression methods were used to model the relationship between race, BMI and BCF. Results: The 1,461 men had a median age of 60 years, and median pre-operative PSA of 5.5. There was no significant difference in BMI among the four races (p = 0.58). The 5 year disease-free survival for black obese men was the lowest at 69%, compared to non-obese black (71%), obese white (80%), and non-obese white men (80%, p < 0.001). BMI did not have a significant impact on BCF. After adjusting for preoperative PSA level, tumor stage, and Gleason sum, race remained an independent predictor of BCF (HR = 1.65, p = 0.04). An analysis assessing the effect of an interaction between race and BMI demonstrated that hazard ratios for increased BMI did not differ significantly by race. Black men who were normal, overweight and obese were 2.0, 3.0 and 2.5 times more likely than white men to have BCF in the respective weight categories, but the differences were not significant. Conclusions: Black race is an independent predictor of biochemical failure after adjusting for pathologic factors. The impact of BMI on BCF did not vary among different races. However, BMI does contribute to the accurate estimation of the risk of BCF. These findings suggest that elevated BMI does not affect the BCF rates of black men more than in other races, and that other factors may influence the racial variability in disease-free survival and BCF risk.

No significant financial relationships to disclose.
Independent validation of the 2002 UICC TNM staging system for papillary renal cell carcinoma in a multicenter cohort
Authors: Wulfing C. , Herrmann E. , Trojan L. , Schrader A. , Becker F. , Stähler M. , Haferkamp A. , Legal W. , Brenner W. , Hartmann A. ,   German Papillary Renal Cancer Study Group
Published: August 2020

5092

Background: Papillary renal cell carcinoma (pRCC) is the second most malignant histologic subtype in nephrectomy specimens. To date, the most recognized staging system to stratify renal cancer patients is the 2002 UICC TNM classification system. Its accuracy for predicting patient outcome for pRCC is unknown. Methods: From ten urologic institutions in Germany follow-up data on 675 patients with pRCC were collected. In most cases histologic slides were available and central pathologic review was performed. The Kaplan-Meier method was used to derive the cumulative cancer-specific survival. For multivariate analysis of prognostic factors, a Cox regression analysis was performed. Results: 498 (74.1%) patients had organ-confined tumor stages (≤pT2). Synchronous distant metastases in the entire group occurred in 58 (8.7%) patients and 69 (11.2%) others developed metastatic disease during follow-up. Cancer-specific survival (CSS) was significantly related to TNM stage and histologic grading in univariate as well as in multivariate analysis (all p < 0.0001). 5-year CSS in pT1b tumors (90.0%) was significantly shorter compared to pT1a tumors (98.3%) (p = 0.017). Patients with ≥pT3 were at high risk for metastases (50.6%), while metastatic disease associated with ≤pT2 tumors occurred in 7.8% (p < 0.0001). Once metastatic disease was present, prognosis was poor (5-year CSS: 7.2%). Age was associated with a worse prognosis in the subgroup of ≥pT3 tumors in univariate (p = 0.026), but not in multivariate analysis. Conclusions: The 2002 UICC TNM staging system is applicable for pRCC. Clinical and radiologic follow-ups should be offered in frequent intervals to patients with venous thrombus and/or locally advanced disease. The role of age remains unclear, but should not be underestimated at risk stratification after tumor resection.

No significant financial relationships to disclose.
Safety and efficacy analysis of sunitinib (S), bevacizumab (B), and M-Tor inhibitors in metastatic renal cell cancer (mRCC) patients (pts) with renal insufficiency (RI)
Authors: Gupta S. , Parsa V. , Heilbrun L. , Smith D. , Dickow B. , Heath E. , Vaishampayan U.
Published: August 2020

5108

Background: S, T (temsirolimus) and E (everolimus) are primarily metabolized in the liver, while the metabolism of B is unclear. There are limited data on the clinical toxicity profile and efficacy of these agents in pts with RI. Methods: The primary objective was to assess the safety and efficacy of S, B, T and E in pts with RI. Medical records of pts with mRCC at Wayne State University, treated on S, B, T or E were reviewed. Pts with a calculated creatinine clearance (CrCl) of ≤ 60ml/min [chronic kidney disease stage 3 or higher per K/DOQI guidelines by the National Kidney Foundation] were deemed to have RI. Data on safety and efficacy of the therapy were collected and analyzed with respect to renal function. Results: 19 of 51 (37%) pts had RI. Pts with RI had a higher median rise in blood pressure (BP) with S and B than pts with normal renal function. Patients with RI had an increased incidence of rash and higher dose interruption rates with m-TOR inhibitors. No major differences in toxicities including cardiac, thyroid, renal, lipid profile abnormalities or hyperglycemia were observed. Similar efficacy was seen in all groups. Conclusions: More than a third of pts with mRCC receiving targeted therapy have RI, hence highlighting the importance of evaluating tolerability of therapies in pts with RI. Therapy with S, B and T/E is well tolerated and efficacy appears to be maintained. Closer monitoring for hypertension is needed in pts receiving S and B.

[Table: see text]

No significant financial relationships to disclose.