bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumour activity of pemetrexed (Pem) and irinotecan (Iri) in second-line metastatic colorectal cancer (MCRC) patients: A multicenter phase II study
Authors: Louvet C. , Andre T. , Gamelin E. , Hebbar M. , Mabro M. , Bennamoun M. , De Gramont A.
Published: March 2020

4103

Introduction: 5FU + Iri (i.e. FOLFIRI) is a validated second line treatment after 5FU + Oxaliplatin (i.e. FOLFOX) induction in MCRC, with a response rate ranged from 10 to 15%. Pem is a multi-antifolate with wide range of target inhibition as compared to 5FU suggesting that Pem + Iri could have a better efficacy as compared to FOLFIRI. We then studied the antitumour activity and the safety of Pem + Iri combination in patients treated with FOLFOX for MCRC. Methods: Forty-six patients with measurable second line MCRC and no brain metastases were included in this trial. Pem 400 mg/m2 over 10min on d1 with folic acid and vitamin B12 supplementation followed by Iri 180 mg/m2 (90min) on the same day were given q2w for 12 cycles. Results: 44/46 patients (95%) received at least one cycle of the combination with median age: 63 yrs, baseline ECOG performance status = 2: 100%. Metastatic sites were: liver: 70%, lung: 41%, lymph node: 7% and peritoneum: 5%. The median number of administered cycles was 4.5. Seven out of 44 patients (16%) received at least 12 cycles of study therapy. The objective response rate (intent-to-treat, RECIST criteria, assessed by investigators) was 14% (95% CI [5.2; 27.4]), 41% had stable disease. Grade 3/4 toxicities were: neutropenia: 19%, anemia: 9%, elevated AST/ALT 10%, diarrhea: 16%, vomiting: 7%, nausea: 5% and fatigue: 20% which was the most limiting toxicity for this combination. Conclusion: The combination of Pem + Iri is active in second line MCRC. However, response rate seems to be in the same range as compared to historical data for FOLFIRI. Patients are still in the follow-up period. Data of PFS and OS will be presented at the meeting.

No significant financial relationships to disclose.
Intratumoral lactate dehydrogenase 5 (LDH5) protein expression is associated with expression of angiogenesis markers and hypoxia in patients with colorectal cancer (CRC)
Authors: Koukourakis M. I. , Giatromanolaki A. , Sivridis E. , Gatter K. C. , Harris A. L. , Trarbach T. , Folprecht G. , Shi M. M. , Meinhardt G.
Published: March 2020

4107

Background: Recent clinical trials (CONFIRM 1 and CONFIRM 2) have shown that metastatic CRC patients (pts) with high serum lactate dehydrogenase (LDH) derive the greatest therapeutic benefit from PTK787/ZK 222584 (PTK/ZK). PTK/ZK is a novel, oral tyrosine kinase inhibitor (TKI), which blocks all known VEGF receptors (VEGFR). From previous studies, total LDH and isoenzyme LDH5 have been associated with tumor aggressiveness and hypoxia. In the present study, we tested whether CRC pts with high levels of tumor LDH5 have increased expression of proteins involved with hypoxia (hypoxia inducible factors [HIF1a and 2a], pyruvate dehydrokinase [PDHK]), increased vessel density (VD), angiogenesis (VEGFA; phosphorylated VEGFR2 [pKDR]), acidity (carbonic anhydrase 9 [CA9]), and others. Methods: Baseline sections from either primary or metastatic tumor sites from 42 pts of the CONFIRM 1 and 2 trials were analysed with immunohistochemistry utilizing an established nominal scoring system. The degree of association between the scores of protein expressed was estimated by the phi-coefficient (correlation coefficient) and assessed by means of p-values from pairwise Fisher’s exact test (two- sided). Results: Associations were observed between LDH5 and the following: pKDR (Phi=.53; p<.001), VEGF (Phi=.41; p=.006), HIF-1a (Phi=.56; p<.001), VD (Phi=.34; p=.052), and PDHK (Phi=.58; p=.014), respectively. HIF-1a associated with pKDR (Phi=.38; p=.027), VD (Phi=.34; p=.045), and VEGFA (Phi=.33; p=.067). VEGFA associated with PDHK (Phi=.52; p=.035). Conclusions: Our results demonstrate that mCRC patients with high level of intratumoral protein expression of LDH5 have elevated HIF-1a, pKDR, VEGFA, PDHK expression and VD. These results support the concept that tumor hypoxia and angiogenesis are associated and that elevated LDH protein expression may serve as a surrogate marker for activated HIF-1a pathway.

No significant financial relationships to disclose.
Quantitative multiplex PCR analysis for large rearrangements in the MLH1 and MSH2 genes for hereditary non- polyposis colorectal cancer
Authors: Roa B. , Judkins T. , Hendrickson B. , Eliason K. , Schoenberger J. , Rajamani S. , Scholl T. , Colvin C.
Published: March 2020

4109

Background: Hereditary non-polyposis colon cancer (HNPCC) is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. HNPCC patients have ∼80% increased risk of colon cancer, and elevated risk for cancers of the endometrium, ovary, stomach, small intestine and upper urinary tract. Molecular genetic testing in HNPCC families showed that ∼90% of cases are due to MLH1 and MSH2, 7–10% to MSH6, and <5% to PMS2. The majority are point mutations detectable by sequencing; however, about 5% and 20% of mutations in MLH1 and MSH2, respectively, are large rearrangements that require other detection techniques such as Southern blot or multiplex ligation-dependent probe amplification (MLPA). Our laboratory had previously developed and implemented a quantitative multiplex PCR (QMPCR) endpoint assay for clinical testing for large rearrangements in the BRCA1 and BRCA2 genes. We have developed a similar assay for the MLH1 and MSH2 genes in HNPCC which we refer to as CART (Colorectal cancer Rearrangement Test). Methods: CART consists of 9 multiplexes of 8–12 amplicons each, with at least 2 amplicons targeting each coding exon, promoter, and 3’UTR of both genes. Copy numbers are normalized against MLH1, MSH2, and two unlinked control genes. Internally developed software provides automated analysis and statistical confidence levels for the presence or absence of large rearrangements. Results: Initial validation of CART has been performed on 14 MLH1 or MSH2 rearrangement-positive and 30 negative DNA samples. Results were 100% concordant with previous Southern blot data, as well as supplemental MLPA studies. CART has greatly improved turnaround time, accuracy, and consistency compared to Southerns and MLPA. Conclusions: QMPCR is a superior diagnostic tool for detecting large rearrangements in disease genes. Validation of CART for MLH1 and MSH2 rearrangements is underway on a larger set of previously genotyped samples in a blinded manner. In conjunction with sequencing of the MLH1 and MSH2 genes, the CART assay is expected to improve molecular diagnostic testing on individuals at risk for HNPCC.

No significant financial relationships to disclose.
Statin use is associated with a reduced risk of colon cancer recurrence
Authors: Anderson D. M. , Jackson J. , Butani A. , Asche S. , Rolnick C.
Published: March 2020

4114

Background: A significant body of data suggests that statin use reduces the risk of developing colon and other cancers, although other data have not confirmed these findings. We examined whether statin use helps prevent recurrence of colon cancer in patients with resected disease. Methods: We conducted a retrospective analysis of patients treated for stage I, II, and III colon cancer in a Minneapolis/St. Paul health system. Incident cases of colon cancer between 1995 and the present were identified through a hospital tumor registry. All identified cases were then cross-checked against an HMO membership database. Data regarding statin use was pulled from the HMO outpatient pharmacy database. For each patient all available data from a 5-year window prior to first diagnosis of cancer until either recurrence or most recent data available was obtained. Demographic data and survival data from the tumor registry were then combined with pharmacy data regarding statin use in a single database for analysis. Recurrence and time to recurrent disease were compared in statin users and non-users. Results: A total of 358 colon cancer cases were available for analysis. Median follow up of patients after diagnosis of colon cancer was 49 months. 89 patients (24.9%) used statin drugs for some period of time with a median of 780 days of use. Median age of all patients enrolled was 69 (range 24–95). Statin use was higher in patients ages 61–75 (33%) than in those aged 24–60 (22%) or those aged 76–95 (19%) (p=0.02). There was no association between statin use and stage at diagnosis. 6 of 89 patients (6.7%) with any statin use relapsed as opposed to 43 of 269 (16%) of patients with no statin use (Fisher’s exact p=0.03). Kaplan-Meier analysis of relapse curves found a significant difference in relapse between groups with a two year recurrence rate of 3.7% among statin users and 10.1% among non users (Log Rank p=0.03, using age stratification). Conclusions: Statin use was associated with a decreased risk of recurrence in patients diagnosed with stages I-III colon cancer in this study. Further study of statin use in the prevention of colon cancer recurrence is warranted.

No significant financial relationships to disclose.
Use of sex-specific genomic profile to predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5- fluorouracil/oxaliplatin
Authors: Gordon M. A. , Zhang W. , Yang D. , Nagashima F. , Chang H. , Lurje G. , Borucka E. , Lenz H. J.
Published: March 2020

4122

Background: There is increasing evidence that gender plays a significant role in the development and progression of colorectal cancer (CRC). Rates of CRC incidence are higher among males, and it has been shown that hormone replacement therapy in postmenopausal women reduces the risk of developing CRC, indicating a protective effect of female hormones. These findings indicate that physiological differences between the sexes may contribute to differential tumor development and progression. In the current study, we tested the hypothesis whether males and females would have different genomic profiles that would predict clinical outcome in 5-FU/oxal-treated mCRC. Methods: One hundred seventy-three patients were enrolled in this phase II study. One hundred fifty-two patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). Twenty-four polymorphisms in 12 genes involved in cancer progression were tested by PCR. CART analysis was used to test for association of polymorphisms with overall survival (OS), time to tumor progression (TTP), and tumor response. Separate regression trees were developed for males and females. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. CART analysis by gender generated significantly different regression trees for men versus women. For TTP, males carrying polymorphisms in the ER-β and SCN1A genes had improved TTP, while females carrying polymorphisms in the XPD and EGFR genes had improved TTP. For OS, male patients carrying ER-β and MTHFR polymorphisms had improved OS, while female patients carrying polymorphisms in SCN1A and PLA2 had improved OS. It is notable that analysis of males and females in combination produced a different regression tree than when separated by gender. Conclusions: Our results suggest for the first time that genomic profiling to predict clinical outcome of patients with mCRC depends on gender. Taking gender into account when examining the genetic profile of patients may help to more specifically identify those who will benefit from 5-FU/oxal chemotherapy.

No significant financial relationships to disclose.
Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor (EGFr), in patients (pts) with metastatic colorectal cancer (mCRC) across clinical trials
Authors: Peeters M. , Van Cutsem E. , Berlin J. , Hecht J. R. , Ruiz R. , Navale L. , Amado R. , Meropol N. J.
Published: March 2020

4138

Background: Panitumumab is indicated in pts with EGFr-expressing mCRC refractory to chemotherapy. We present a summary of safety with panitumumab monotherapy in mCRC pts across 10 clinical trials. Methods: Data were pooled from pts enrolled in 10 clinical trials (including 2 extension studies). Pts received at least 1 dose of panitumumab at 2.5 mg/kg QW, 6 mg/kg Q2W, or 9 mg/kg Q3W. Adverse events were graded using NCI-CTC or CTCAE criteria. Results: A total of 920 mCRC pts were included in this analysis: 60% were male; 88% were white; median age (range) was 61 (20, 88) years. All pts had prior therapy; 77% had failed prior fluoropyrimidine, irinotecan, and/or oxaliplatin. Most (80%) pts received panitumumab 6 mg/kg Q2W; 17% and 3% of pts received panitumumab 2.5 mg/kg QW and 9 mg/kg Q3W, respectively. Median (range) follow-up time was 21 (1–124) weeks. A total of 7264 panitumumab infusions were administered with a median (range) of 5 (1–94) infusions/pt. Treatment-related adverse events (AE) were experienced by 94% (grade = 3, 20%) of pts. All pts had = 1 AE. The most common AEs were skin-related and GI toxicities ( table ). Skin-related AEs resulted in discontinuation in 2% of pts. Overall, 12% of pts discontinued panitumumab due to toxicity. Four (0.4%) pts had grade = 3 infusion reactions. In pts with postdose samples (n = 613), increased and persistent postdose levels of anti-panitumumab antibodies were detected in 0.5% of pts by ELISA and in 4.6% of pts by Biacore assay. Conclusions: Skin toxicity was common, but rarely treatment-limiting. Most AEs were mild to moderate and infrequently resulted in discontinuation. Infusion reactions and formation of anti-panitumumab antibodies were rare. The safety profile of 9 mg/kg Q3W panitumumab appeared consistent with other dosages; however, because of the small pt size further evaluation is needed. Panitumumab at 2.5 mg/kg QW and 6 mg/kg Q2W was well tolerated across 10 clinical studies.

[Table: see text]

No significant financial relationships to disclose.
Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor receptor (EGF-r) : Eastern Cooperative Oncology
Authors: Burtness B. A. , Powell M. , Berlin J. , Liles D. , Chapman A. , Mitchell E. , Benson A. B. ,   Eastern Cooperative Oncology Group
Published: March 2020

4519

Background: Gemcitabine (G) is standard for metastatic pancreatic cancer (PC), with median survivals of 6 months (m). Second cytotoxic or biologic agents do not substantially advance survival. EGFR is expressed on PC and a phase II trial of G plus cetuximab (C) resulted in favorable 1 year survival. A phase II trial of irinotecan/docetaxel (I/D) chemotherapy reported a median survival for metastatic patients (pts) of 9 m. We conducted this randomized phase II trial to confirm the activity of this non-G regimen, and determine whether combining it with C was feasible and active. The primary endpoint was response. Methods: Pts required histologic confirmation of adenocarcinoma of the pancreas, evidence of distant metastases, ECOG PS 0–1, normal bilirubin, written informed consent, and were randomly assigned to Arm A (N=47) or B (N=45). Imaging with CT or MR within 4 weeks (wk) was used for tumor measurement. Dexamethasone was given 12 hours (h), 1 h before and 12 h after chemotherapy. Pts on Arm A received D 35 mg/m2 over 1 h and I 35 mg/m2 over 30 minutes weekly x 4 in a 6 wk cycle. Pts on Arm B received the same therapy, but C (loading dose 400 mg/m2 wk 1, 250 mg/m2 weekly thereafter) was given before D. Pts not receiving therapeutic anticoagulation received enoxaparin 40 mg per day. Pts were restaged (RECIST) after 2 cycles. Results: Median age Arm A: 59.9, Arm B: 60.2 years. Arm A 55% male, 32% PS 0, 97% EGFR immuno+. Arm B 84% male, 42% PS 0, 97% EGFR +. Median number of cycles for each arm 2 (1 -10). >4 cycles were delivered to 10.5% of pts Arm A, 20.9% Arm B. Grade ¾ neutropenia 26% Arm A, 33% Arm B. Grade 3 nausea 28% Arm A, 18% Arm B; Grade ¾ diarrhea 33% Arm A, 44.4% Arm B. 1 treatment-related death per arm. Median overall survival (OS), with 70.2% of pts known to have died, 6.5m [(95% CI (4.8, 8.6)] in Arm A. With 86.7% of pts known to have died in Arm B, OS 7.4 m [95% CI (4.4, 10.7)]. Response/progression data will be available at time of presentation. Conclusions: Weekly I/D ± C is associated with high rates of grade ¾ neutropenia/diarrhea. Median survival is 6.5m for I/D and 7.4m for I/D/C. Non-G containing therapy is active in metastatic PC.

[Table: see text]
Post-resection CA 19–9 predicts overall survival (OS) in patients treated with adjuvant chemoradiation: A secondary endpoint of RTOG 9704
Authors: Berger A. C. , Winter K. , Hoffman J. , Regine W. , Abrams R. , Safran H. , Konski A. , Benson A. , MacDonald J. , Willet C.
Published: March 2020

4522

Background: CA 19–9 is an important tumor marker in pancreatic adenocarcinoma. Several single institutional studies have demonstrated post-resection CA 19–9 to be an important prognostic factor. A secondary endpoint of RTOG 9704, a phase III adjuvant chemoradiation trial for pancreatic cancer, was to prospectively evaluate the ability of post-resectional CA 19–9 to predict survival. Methods: A total of 538 patients were accrued to this trial, of which 385 had evaluable CA 19–9 levels. These were analyzed using ELISA GI-MA kits provided by Diagnostic Products Corporation, a Siemens Company. CA 19–9 expression was analyzed as a dichotomized variable (<180 vs. =180). Cox proportional hazards models were utilized to characterize the contribution of CA 19–9 expression on OS. The following additional variables were included in the multivariate analysis: treatment, nodal involvement, tumor diameter (< or > 3cm), and margin status. Actuarial estimates for OS were calculated using Kaplan-Meier methods. Results: Most patients had CA 19–9 < 180 (n=220, 57%), while 34% were Lewis Antigen negative (unable to express CA 19–9) and 33 (9%) patients had levels >180. Survival was statistically significantly improved among patients with CA 19–9 <180 compared with those whose CA 19–9 =180 (HR=3.58(95% CI=2.40–5.34), p<0.0001) ( table ). This corresponds to a 72% reduction in the risk of death. This improvement was observed among patients with pancreas head and non-head tumors when analyzed separately. The multivariate analysis confirms that CA 19–9 is a highly significant predictor of OS in patients with resected pancreatic cancer. Conclusions: This prospective analysis of CA 19–9 in 385 patients treated with adjuvant chemoradiation definitively confirms the importance of post-resectional CA 19–9 in pancreatic cancer patients who have undergone resection. Patients with post-resection CA 19–9 >180 should be considered for additional therapy.

[Table: see text]

No significant financial relationships to disclose.
Impact of radiation (RT) regimen on palliative procedures (PP) for patients with resectable locally advanced esophageal cancer treated with exclusive chemoradiation (CRT) or preoperative chemoradiation (CRT+S): results from a phase III trial of the Federation Francophone de Cancerologie Digestive (FFCD 9102)
Authors: Crehange G. , Bonnetain F. , Seng S. , N'guyen T. , Mirabel X. , Marchal C. , Verrelle P. , Roullet B. , Maingnon P. , Bedenne L.
Published: March 2020

4531

Background: The FFCD 9102 trial demonstrated that CRT is an alternative to CRT+S for responding patients. We investigated the type of PP in the follow-up (FU) period, according to the RT scheme: protracted (P-RT) vs. split course (SC-RT). Methods: Resectable T3 N0–1 M0 thoracic esophageal carcinoma were included. First sequence : 2 cycles of cisplatin and 5-FU (day (d)1 - d22) combined with RT. Two schemes of RT were allowed: P-RT (46 Gy / 4.5 weeks (w), 2 Gy / f) or SC-RT (2 one-week courses of 15 Gy, 3 Gy / f). For CRT, the same chemotherapy was given on d43, d64 and d92 combined with 20 Gy / 2w (P-RT) or 15 Gy / 1w (SC-RT). Responding patients after the first sequence were randomized between CRT and CRT+S. The impact of SC-RT vs. P-RT on PP in the FU period was explored using a Mann-Whitney test. Results: From February 1993 to December 2000, 451 pts were registered and 446 were eligible. P-RT: 161 pts, SC-RT: 285 pts. After a median FU of 47.4 months, 2-year overall survival and local relapse-free survival were for P-RT vs. SC-RT: 37.1% vs. 30.5% (p = 0.25) and 76.7% vs. 56.8% (p = 0.002), respectively. P-RT vs. SC-RT: mean length of hospital stay: 48 d vs. 60.5 d (p= 0.0003). Mean number of dilatation sessions: 0.56 vs. 0.66 (p= 0.43). Mean number of stents: 0.21 vs. 0.34 (p= 0.03). Mean number of any PP: 1.01 vs. 1.50 (p= 0.001). Mean dysphagia grade: 2.99 vs. 3.12 (p= 0.21). In the CRT+S-group, P-RT vs. SC-RT: mean length of hospital stay 55.0d vs. 68.7d (p =0.051). Mean number of dilatation sessions: 0.74 vs. 0.74 (p= 0.77). Mean number of stents: 0.09 vs. 0.18 (p= 0.44). Mean number of PP: 1.00 vs. 1.37 (p= 0.054). In the CRT-group, P-RT vs. SC-RT, mean length of hospital stay: 42.6d vs 54.0d (p= 0.053). Mean number of dilatation sessions : 0.38 vs. 0.67 (p= 0.12). Mean number of stents: 0.31 vs. 0.50 (p= 0.03). Mean number of PP: 0.83 vs. 1.86 (p= 0.0005). Conclusions: Stents, rate of PP and length of hospital stay were significantly increased with SC-RT. Dysphagia score was similar between SC-RT and P-RT at last FU.

No significant financial relationships to disclose.
Predictive factors of transcatheter arterial chemoembolization for hepatocellular carcinoma
Authors: Ishii H. , Furuse J. , Nakachi K. , Suzuki E. , Shimizu S. , Yoshino M. , Satake M. , Hayashi T.
Published: March 2020

4541

Background/Aim: Although transcatheter arterial chemoembolization (TACE) has been widely used for the treatment of unresectable hepatocellular carcinoma (HCC), the optimal indication of the TACE has not been fully elucidated. Methods: The treatment outcomes after TACE were analyzed retrospectively to determine predictive factors of anti-cancer effect on HCC. The patient (pts) selection criteria were: 1) admission between 1992 and 2005, 2) diagnosis of fresh HCC, 3) no extrahepatic metastasis and 4) primary treatment with TACE. TACE was performed by selectively introducing a catheter into the hepatic artery and injecting gelatin sponge particles following an emulsion consisting of 2–5 ml of iodized oil (Lipiodol) and 20–50 mg doxorubicin hydrochloride. Lipiodol accumulation in tumors was regarded as an indication of necrosis. We defined complete response (CR) as disappearance or 100% necrosis of all tumors, and partial response (PR) as more than 50% reduction and/or more than 50% necrosis. Results: There were 270 pts who fulfilled the above criteria. According to Japan Integrated Staging, the number of T1, T2, T3 and T4 was 10, 59, 171 and 30, respectively. There were 52 CRs, 113 PRs, 77 who remained SD and 28 who showed PD/NE. The median survival months of CR, PR, SD and PD/NE were 50, 30, 15 and 5, respectively, and there was a significant differences between them. The logistic regression analysis revealed tumor multiplicity and vascular invasion (VI) were significantly associated with the objective response (CR or PR). The response probability of patients with solitary tumor without VI was 85%, that with multiple tumors without VI was 63%, that with solitary tumor with VI was 33% and that with multiple tumors with VI was 16%. The small tumor (<5 cm) was another favorable factor which was significantly associated with CR. Among 231 patients without VI, the CR probability of patients with a solitary tumor <5 cm or >5 cm was 46% or 40%, respectively; although that of those with multiple tumors <5cm or >5cm was 21% or 5%, respectively. Conclusion: TACE is recommended for HCC patients without VI, and is optimally indicated for those with a solitary tumor or those with multiple tumor <5 cm among them.

No significant financial relationships to disclose.
A phase II study of gemcitabine (GEM) given at fixed-dose rate (FDR) infusion, low-dose cisplatin (CDDP), and bevacizumab (BEV) for metastatic adenocarcinoma of the pancreas (PanCa): Update with completion of study accrual
Authors: Ko A. H. , Dito E. , Schillinger B. , Venook A. P. , Bergsland E. K. , Wong D. , Allen J. , Tempero M. A.
Published: March 2020

4548

Background: The objectives of this study are to determine safety and efficacy in pts with metastatic PanCa treated with a novel combination consisting of FDR GEM, low-dose CDDP, and BEV. We present here updated results on the full 53-pt study cohort. Methods: Chemotherapy-naive pts with histologically confirmed PanCa and documented extrapancreatic metastases received GEM 1,000 mg/m2 at FDR infusion (10 mg/m2/min), CDDP 20 mg/m2, and BEV 10 mg/kg, all administered on dd 1 and 15 of a 28-dd cycle. Pts were monitored by CT scans every 2 cycles and monthly serum CA19–9 measurements. Results: 53 pts (24M,29F; median age 60 y.o. [range 39–85]; ECOG PS 0–1) were enrolled betw 6/2004 and 9/2006 (med f/u, 513 dd; range, 93–885). 16 pts remain alive, with 9 still undergoing study rx. Pts received a median of 4.75 cycles of rx (range, 0.5–20). 29 pts discontinued study rx 2o to progressive dz (med # of cycles, 5; range, 0.5–20); 9 pts 2o to rx-assoc toxicity; 4 pts 2o to plateau in response with cumulative asthenia (after 8–12 cycles); and 2 pts 2o to prolonged rx delay from bowel obstruction. Major events include 2 bowel perforations, one associated with placement of a duodenal stent; 4 major GI bleeds; 7 DVT/PE; 1 stroke-like sxs; and 3 cardiac events (MI x 1, arrhythmias x 2). 4 pts (7.5%) developed grade 3/4 HTN. Gr 3/4 hematologic toxicities inc. neutropenia in 4 pts (7.5%) and thrombocytopenia in 1 pt (2.9%). 16 pts (20%) required dose reduction in gemcitabine during study rx and 4 required holding of cisplatin. There were 3 deaths potentially assoc with rx. 12 pts (22.6%) have had an unconfirmed response (1 CR, 11 PR) and 26 pts (49.1%) have had stable dz for >2 cycles, for an overall dz control rate of 71.7%. 20 of 35 pts (57.1%) with elev baseline CA19–9 levels (>2X ULN) had >50% biomarker decline during rx. Median TTP is 6.2 months. Median overall survival is 8.0 months with an est. 1-yr survival rate of 40%. Conclusions: The addition of BEV to FDR GEM/low-dose CDDP shows promising efficacy, particularly in TTP and 1-yr survival rate, with manageable toxicity. Further efforts are ongoing to identify which pts are most likely to benefit from BEV-based rx.

[Table: see text]
Final results from cohort 1 of a phase II study of volociximab, an anti-α5β1 integrin antibody, in combination with gemcitabine (GEM) in patients (pts) with metastatic pancreatic cancer (MPC)
Authors: Evans T. , Ramanathan R. K. , Yazji S. , Glynne-Jones R. , Anthoney A. , Berlin J. , Valle J. W.
Published: March 2020

4549

Background: A critical survival step for proliferating endothelial cells is the ligation of fibronectin in the extracellular matrix to integrin a5β1. Volociximab, a chimeric monoclonal antibody, blocks fibronectin binding to a5β1, and induces apoptosis of proliferating endothelial cells. Volociximab activity is independent of growth factor stimuli, suggesting that a5β1 signalling occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. The efficacy and safety of volociximab in combination with GEM was determined in pts with MPC. Methods: This is a multi-center, open-label, 2-cohort, single-arm Phase II study. Eligible pts had confirmed MPC, no prior chemotherapy for MPC, adequate hematologic, renal and hepatic function, and had measurable disease. Pts received volociximab 10mg/kg iv every 2 weeks (days 1 and 15) with GEM (1,000 mg/m2 iv) on days 1, 8, 15 of a 4- week cycle until disease progression (PD). Radiologic assessments of measurable disease were performed every 8 weeks. The primary endpoint was objective tumor response (RECIST criteria). Sample size was 20 pts per cohort. At least 1 confirmed response at 4 months (mo) or SD ≥ 4 mo was necessary in cohort 1 (n=20) before expansion to the second cohort. Results: 20 pts (male=11, female=9), median age = 59.8 years (range 34–74), were treated in cohort 1 and were evaluable for safety and efficacy. PS (ECOG) was 0–1 (n=19; 95%) or 2 (n=1; 5%). Pts received a median of 8 weeks’ (range 2–58) treatment. Most frequent toxicities included nausea in 14 (70%) pts, vomiting (12; 60%) and constipation (10; 50%). Overall response included 1 confirmed PR (5%), and stable disease in 10 (50%) pts. Median time to progression was 4.3 mo; 41% had not progressed at 6 mo. Overall survival was 5.4 mo, and at 6 and 8 mo was 45%, and 37% at 12 mo. 12 pts died in the study due to PD (10 pts), GI perforation (1), pulmonary embolism (1). Conclusions: Volociximab is well tolerated at 10mg/kg 2-weekly with GEM. Cohort 2 is currently recruiting at a higher dose of volociximab (15 mg/kg) administered weekly.

[Table: see text]
A randomized phase II study of axitinib (AG-013736) and gemcitabine versus gemcitabine in advanced pancreatic cancer, preceded by a phase I component
Authors: Spano J. , Chodkiewicz C. , Maurel J. , Wong R. P. , Wasan H. S. , Pithavala Y. K. , Bycott P. W. , Liau K. , Kim S. , Rixe O.
Published: March 2020

4551

Background: The current standard of care for patients (pts) with advanced pancreatic cancer (APC) is gemcitabine (GEM)- based chemotherapy. Axitinib (AG) is a potent inhibitor of vascular endothelial growth factor receptors. A phase I study of AG in solid tumors identified 5 mg BID as the therapeutic starting dose. The main objectives of this trial are to determine whether the overall survival (OS) of the combination of AG and GEM is superior to that of GEM alone as first-line therapy in pts with APC, and to determine doses of AG and GEM that can be safely administered together. Methods: 8 pts were treated on the phase 1 (P1) portion of this trial. For the phase 2 (P2) portion of the trial, 103 pts with locally advanced or metastatic disease, no prior GEM or VEGF/VEGFR inhibitors, PS 0–2 were randomized (2:1) to GEM 1,000 mg/m2 over 30 minutes on days (D) 1, 8, 15 every 28 D with or without AG at a starting dose of 5 mg po BID between Jan 06 and Aug 06. CT scans were performed every 2 cycles. Results: Data from the evaluable P1 pts (n=5) indicated that PK of GEM and AG appeared to be unchanged in combination. The GEM mean plasma exposure (AUC) was 11,348 alone vs 12,840 ng.h/mL with AG; similarly mean steady-state AG AUC was 250 alone vs 270 ng.h/mL with GEM. 3 of 8 pts had a PR. The median number of days on study drug was 158 days (range: 57–330 days) with 2 pts ongoing. Data from the randomized P2 pts: male 48%; median age 62 (36- 81); PS 0/1 vs 2: 91% vs 9%; 41% with locally advanced disease; 59% with metastatic disease. The most commonly reported adverse events are anemia (48%), alk phos elevations (48%), leukopenia (45%), neutropenia (42%), LFT elevations (39%), and thrombocytopenia (27%). The most common non-hematologic adverse events are nausea (24%), vomiting (20%), fatigue (19%), diarrhea (18%), anorexia (18%), constipation (13%), dyspnea (12%), and pyrexia (12%). 55 events have been reported in the 103 P2 pts. The pooled median OS is 203 days with a 95% CI of (158, not estimable). The median follow-up time is currently 223 days. Conclusions: AG can be safely administered at a starting dose of 5 mg BID in combination with standard dose GEM in patients with APC. Final safety and OS results by treatment arm will be presented.

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Impact of gene expression of orotate phosphoribosyl transferase for complete response to chemoradiotherapy in patients with squamous cell carcinoma of the esophagus
Authors: Kajiwara T. , Nishina T. , Hyodo I. , Moriwaki T. , Endo S. , Nasu J. , Hori S. , Iguchi H. , Hiasa Y. , Onji M.
Published: March 2020

4566

Background: Chemoradiotherapy (CRT) is a potential alternative to surgery in patients with squamous cell carcinoma of the esophagus. Complete response (CR) to CRT is essential for a good prognosis and there is a need for a predictive method of CR in CRT. Methods: The pretreatment formalin-fixed, paraffin-embedded endoscopic tumor biopsy material was obtained from 41 patients treated with a definitive concurrent CRT (5-FU/CDDP and 60 Gy) for esophageal cancer (cStage II or III). cDNA was derived from tumor cells of biopsy specimens by the laser capture microdissection and analyzed to determine mRNA expression relative to an internal reference gene (β-actin) using fluorescence-based, real-time reverse transcription PCR. Gene expression levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase (OPRT), metylenetetrahydrofolate reductase, dihydrofolate reductase (DHFR), excision repair cross-complementing gene 1, vascular endothelial growth factor, epidermal growth factor receptor and matrix metalloproteinase 9 (MMP-9) were measured. Results: Median gene expression levels of OPRT and DHFR were significantly higher in CR patients (p=0.0206 and 0.0191, respectively). MMP-9 was significantly lower in CR patients (p=0.0436). When the median values of the gene expression levels were selected as the cutoff values, CR rate was significantly higher in the high OPRT group and high DHFR group (p=0.0104 and 0.0104, respectively). However, there was no statistical difference in CR rate between the low MMP-9 group and the high MMP-9 group. Multivariate analysis, including clinical stage and biomarkers, revealed that high OPRT gene expression was an independent predictive factor of CR (p=0.0329, relative risk=6.65, 95% confidence interval, 1.17–37.89%). Conclusions: The measurement of OPRT gene expression in tumor biopsies may be a predictive factor of CR to CRT in patients with squamous cell carcinoma of the esophagus.

No significant financial relationships to disclose.
Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring
Authors: Malka D. , Dromain C. , Farace F. , Horn S. , Pignon J. , Ducreux M. , Boige V.
Published: March 2020

4570

Background: Effective therapy for pts with advanced HCC is still lacking. This phase II trial was designed to define efficacy of bevacizumab in HCC pts. Methods: Pts with unresectable HCC received bevacizumab at 5–10 mg/kg bimonthly. Prior treatment for HCC was allowed. Main ineligibility criteria included Child-Pugh score > 7; CLIP score > 3; recent (< 6 months) thromboembolic event; and anticoagulation or anti-platelet therapy. Propranolol had to be prescribed in case of large esogastric varices. CEC, identified by a CD45- CD31+CD146+7AAD- phenotype by four-color flow cytometry, were measured at day (D) 1,3,15 and 46 after start of treatment. Results: Overall, 30 pts (27 men; median age, 65.5 years [range, 23–84]; histologically proven cirrhosis, 20 pts [Child-Pugh A5/A6/B7: 12/15/3; CLIP 0/1/2/3/4: 1/6/14/6/3] received a median of 6 cycles (range, 2–25; total, 234). As progressive disease (PD) was observed within 16 weeks in 12 pts after inclusion of the first 23 pts treated at 5mg/kg, subsequent pts (n=7) were treated at 10 mg/kg as planned by the protocol design. Of the 30 pts treated at either dose, 6 (20%) discontinued bevacizumab because of variceal hemorrhage (variceal banding successful in every case) (n=3); grade 3 transient ischemic attack (n=1); grade 3 hemorrhagic ascites (n=1); and grade 3 proteinuria (n=1). Grade 1–2 toxicities included fatigue, epistaxis, hypertension, and proteinuria. Among the 24 pts evaluable for efficacy, 3 (12.5%) had partial response (PR), and 13 (54%) had stable disease (SD) (> 16 weeks in 7 pts) (disease control rate (DCR), 67%). Median baseline CEC level (n=21) was 14/ml (range, 0- 71), as compared to 5.5/ml (range, 0–15) in healthy subjects (n=20) and 16/ml (range, 0–179) in pts with various metastatic cancers (n=80). CEC levels increased more than two-fold at D3 in 11 (52%) among 21 pts; a dramatic drop was observed in all PR pts, as well as in a fraction (25%) of SD pts. Conclusions: Bevacizumab is relatively safe and provides an encouraging DCR in patients with HCC and compensated cirrhosis. Accrual is ongoing at the dose of 10 mg/kg. The predictive value of CEC will be presented at the meeting.

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Randomised prospective phase II study of combination chemotherapy epidoxorubicin, cisplatin, 5-FU (ECF) versus epidoxorubicin, cisplatin, capecitabin (ECX) in patients with advanced or metastatic gastric cancer
Authors: Ocvirk J. , Rebersek M. , Skof E.
Published: March 2020

4571

Background: In phase II studies ECF with 5- FU inf. resulted in response rates (RR) > 50 %. Despite high responses the potential drawback of ECF may be the poor patient’s (pts) acceptability of the indwelling catheter and external infusion pump and related complications: sepsis, catheter-related infections, shoulder pain, thrombosis and pneumothorax. Capecitabin can maintain a constant level of 5- FU without complications and inconvenience associated with central venous access. The aim was to compare the efficacy and safety ECF versus ECX. Secondary endpoint was overall survival. Methods: Pts with histological proven, previously untreated advanced or metastatic gastric cancer, >18 years, ECOG performance status 0- 2 and adequate organ and hematological function were randomized to ECF or ECX. In ECF epidoxorubicin 50 mg/m2 and cisplatin 60 mg/m2 were administrated on day 1 by i.v., 5- FU 200 mg/m2/day was administrated by cont. inf. day 1- 14 of each cycle. Cycle was repeated every 3 weeks. In ECX epidoxorubicin 50 mg/m2 and cisplatin 60 mg/m2 were administrated on day 1 by i.v., capecitabin 825 mg/m2 twd was administrated orally day 1- 14. Cycle was repeated every 3 weeks. Results: Seventy- one pts were enrolled in this study between Jan 03 to Dec 05. Male 80 %, median age 56 yrs (40- 77). Thirty pts received ECF and 41 pts received ECX . All pts were assessable for responses and toxicity. The overall clinical RR were 45 % including 12.9 % partial responses (PR) and 6.4 % complete responses (CR) in ECF group and 69 % including 21.4 % PR and 4.7 % CR in ECX group. Median OS and TTP were 8.8 months (mos) ± 7.8 and 6.0 mos ± 4.4 in ECF group and 10.5 mos ± 7.2 and 7.0 mos ± 4.6 in ECX group respectively. The most frequent grade ¾ side effects graded according to CTCAE - 3 were fatigue - 20 % in ECF group and 19.5 % in ECX group, hematological (neutropenia) - 16 % in ECF group and 4.8 % in ECX group, nausea - 10 % in ECF group and 7.3 % in ECX group, diarrhea - 2.4 % in ECX group, hand- foot syndrome - 2.4 % in ECX group. Conclusions: ECX is at least effective as ECF with less toxic pattern and more convenient for pts and could replace ECF in first- line therapy in pts with advanced or metastatic gastric cancer.

No significant financial relationships to disclose.
Immunological and clinical response after vaccination therapy of pancreatic carcinoma patients with autologous, tumor-lysate pulsed dendritic cells: Results of a phase II-study
Authors: Bauer C. , Dauer M. , Saraj S. , Schnurr M. , Jauch K. , Rüttinger D. , Bruns C. , Emmerich B. , Endres S. , Eigler A.
Published: March 2020

4579

Background: Multiple studies in the experimental and in the clinical setting have shown that vaccine therapy using dendritic cells can induce antitumor immunity. Here, we report about the results of a phase II-study using autologous, tumor-lysate pulsed dendritic cells for the treatment of patients with advanced pancreatic carcinoma. Methods: Pancreatic carcinoma patients receiving abdominal surgery were included into to the study protocol. Tumor-lysate was derived by freeze-taw-cycles from surgically derived tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were derived from PBMC according to a six-day protocol, loaded with tumor lysate and stimulated with TNF-a and PgE2. DC were applicated intracutaneously into the groin region every other week for three cycles, then monthly. All patients received standard chemotherapy with gemcitabine concomitantly. Immune response was controlled by DTH skin testing. Samples of non adherent cells were frozen for MLR and ELISPOT assays to monitor immune response ex vivo. Main study end point was partial or complete remission. Results: Ten patients have received dendritic cell vaccination so far. Of these, one patient developed a partial remission after a four-months course of vaccination therapy. Another patient showed stable disease after having received five vaccinations. Both patients showed immunological response. The patient with stable disease had a mean of 56 IFN-γ positive spots per 50E3 DC-stimulated non adherent cells prior to vaccination. After vaccination, this number increased to 191 spots per 50E3 cells (negative control: 5; positive control: 315). Both patients are alive 13 and 7 months after the start of vaccination therapy, respectively. Conclusions: Vaccination therapy with dendritic cells can be of clinical benefit in the setting of advanced pancreatic carcinoma. Clinical responses were associated with the induction of a stable immunological response.

No significant financial relationships to disclose.
First-line simplified GEMOX (D1-D1) versus classical GEMOX (D1-D2) in metastatic pancreatic adenocarcinoma (MPA). A GERCOR randomized phase II study
Authors: Andre T. , Afchain P. , Lledo G. , Nguyen S. , Paitel J. , Mineur L. , Artru P. , Selle F. , de Gramont A. , Louvet C.
Published: March 2020

4592

Background: GEMOX was defined as a D1-D2 schedule, based on preclinical data. In order to improve convenience for patients, we evaluated a simplified D1-D1GEMOX regimen (S-GEMOX) in MPA. Methods: Patients (pts) with MPA were 2:1 randomly assigned for first-line treatment to S-GEMOX (arm A : gemcitabine 1,000mg/m2, 100 min infusion D1 immediately followed by oxaliplatin 100 mg/m2, 120 min infusion) or to GEMOX (arm B : gem D1 and ox D2). Treatment was repeated in each arm every 2 weeks until disease progression. Stratification was performed on centre and PS. Results: Fifty-seven pts were enrolled, A = 37 (PS 2 : 22%), B = 20 (PS 2 : 20%). Populations were well balanced for age (64.9 yrs vs 66.6), gender (57% male vs 65), location of primary tumor (pancreas head 49% vs 50), and metastasic sites (liver 76% vs 85; peritoneum 24% vs 20; lung 16% vs 10; lymph nodes 14% vs 15; other 5% vs 5). Tumor differentiation significantly differed among the 2 groups (A : 8% poorly differentiated vs B : 36%). Response rate was 27% (95% CI : 12–42) in arm A and 10% (95% CI : 0 - 23) in arm B. Median PFS was 4.0 and 2.5 months in arm A and B, respectively. Median OS was 7.6 and 3.2 months in arm A and B, respectively. S-GEMOX was more toxic than GEMOX for gr 3–4 neutropenia (20% vs 0%) and thrombocytopenia (16% vs 10%). Other toxicities were comparable. However, since more cycles were administered in arm A (8.5 (1–29) vs 5.8 (2–12)), gr 3 oxaliplatin- induced neuropathy was higher in arm A (21.6% vs 0%). Conclusions: S-GEMOX is active in MPA. This activity is in the same range as compared to our previous experiences of GEMOX. The very bad outcome of pts randomized in arm B could be in part explained by the high rate of poorly differentiated tumors. This study emphazises one more time the limit of studies with small sample size of pts in MPA.

No significant financial relationships to disclose.
Gemcitabine, oxaliplatin (GEMOX) and cetuximab for treatment of hepatocellular carcinoma (HCC): Results of the phase II study ERGO
Authors: Louafi S. , Hebbar M. , Rosmorduc O. , Tesmoingt C. , Asnacios A. , Romano O. , Fartoux L. , Artru P. , Poynard T. , Taieb J.
Published: March 2020

4594

Background: A promising efficacy of the GEMOX combination was previously reported in HCC. Moreover, the EGFR signalling pathway is involved in hepatic carcinogenesis and tumor progression. This phase II study of GEMOX plus cetuximab was therefore undertaken in patients with unresectable HCC. Methods: 44 patients were included in the study between November 2005 and October 2006. All patients received cetuximab (initial dose 400 mg/m2 BSA then 250 mg/m2 weekly) combined with GEMOX (gemcitabine 1000 mg/m2, Day 1 and oxaliplatin 100 mg/m2, Day 2), repeated every 14 days until disease progression or limiting toxicity. Inclusion criteria were: histologically proven HCC or morphologically typical hepatic tumor with alpha-feto protein (AFP) level >250 ng/mL, ECOG performance status (PS) 0–2, age =18, measurable lesion, platelets >100.109 G/L, PNN >1.5.109 G/L, creatinine <120 μmol/L, non decompensated Child A or B cirrhosis, documented tumor progression (RECIST), informed consent. Results: 43 patients, including 22 with baseline AFP >400, were evaluable for safety and 35 for efficacy. Patients’ characteristics, toxicity and efficacy are summarized in the table below; 26% of patients received prior intra-arterial chemotherapy. Only one grade 4 toxicity was reported (thrombocytopenia). Grade 3 toxicities were: thrombocytopenia (21%) neutropenia (19%), acneiform rash (19%), asthenia (7%). Grade 2 and 3 neurotoxicity (specific scale) occurred in 16% and 5% of patients, respectively. No toxic death or other severe toxicity was reported. Conclusion: GEMOX plus cetuximab was well tolerated and induced a satisfactory control of disease in progressive HCC. Final results will be presented at the meeting.

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No significant financial relationships to disclose.
A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: Final results
Authors: Gruenwald V. , Wilkens L. , Gebel M. , Greten T. F. , Kubicka S. , Ganser A. , Manns M. P. , Malek N. P.
Published: March 2020

4598

Background: Hepatocellular carcinoma (HCC) express the epidermal growth factor receptor (EGFR), and EGFR-targeting therapies are known to block tumor growth. We tested the activity of cetuximab (CET) in HCC and evaluated serial tumor biopsies for biomarker analyses. Methods: Patients (pts) with advanced or metastatic HCC with ECOG = 2 and adequate organ function were eligible. Prior therapy was permitted. CET was given iv weekly (400 mg/m2 loading dose, 250 mg/m2 thereafter). The primary endpoint was the rate of progression-free survival (PFS) at 24 wks. Serial tumor biopsies were performed prior to treatment, after 4 wks and at time of progression. 32 pts were enrolled. 27 pts are evaluable for tumor response. Results: Stable disease (SD) was achieved in 44.4% (12 pts) for at least 8 weeks of treatment. 55.6% failed to respond to CET (15 pts). The median time to progression (TTP) for all pts was 8.0 wks. Pts, which were stable for more than 8 wks achieved a median TTP of 22.5 wks (11–48 wks) compared to a median TTP of 6.0 wks (3–8 wks) in progressive pts. No treatment-related severe adverse events were noted throughout the study. Preliminary evaluation of surrogate markers showed no correlation with cytogenetic abnormalities based on FISH analyses for chromosome 1 and 8. Furthermore, only 5 of 21 tumor specimens were positive for EGFR expression without gene amplification, evaluated by FISH analyses. Serial tumor specimens are available in 5 responding and in 7 non-responding pts for changes of p27 and p21 expression. p27 and p21 were upregulated simultaneously in 60% (3/5 pts) of responding pts, whereas in pts with treatment failure p27 and p21 expression was detectable in 14% (1/7 pts) only. Conclusions: Cytogenetic aberrations of chromosome 1 and 8 failed to predict response to CET. In a subgroup of pts with SD >8 weeks, induction of p21 and p27 were associated with prolonged TTP >20 wks. Further evaluation of p21 and p27 as early molecular tumor response is warranted to identify pts, which benefit from anti-EGFR therapies.

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No significant financial relationships to disclose.