bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I clinical trial of vorinostat in combination with sFULV2 in patients with refractory solid tumors
Authors: Fakih M. G. , Pendyala L. , Egorin M. J. , Fetterly G. , Espinoza-Delgado I. , Ross M. , Phelan J. , Kramer Z. , Yirinec B. , Diasio R.
Published: August 2020

4083

Background: Thymidylate synthase (TS) over-expression is associated with 5-FU resistance. Pre-clinical studies demonstrate that vorinostat down-regulates intra-tumor TS in a dose-dependent fashion and augments 5-FU antitumor activity in xenograft models. We conducted a phase I clinical trial of an intermittent schedule of QD x 3 vorinostat in combination with a fixed dose of fluorouracil (5-FU) and leucovorin (LV) in patients (pts) with refractory solid tumors. Methods: Vorinostat was escalated in a standard 3 x 3 design in combination with a fixed dose of 5-FU and LV (simplified de Gramont regimen, sFULV2). Vorinostat was given QD x 3 on an every-2-week cycle. sFULV2 started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hrs followed by 5-FU 400 mg/m2 bolus and 5-FU 2400 mg/m2 over 46 hrs. Results: 24 pts were enrolled: Male/Female: 11/13; ECOG 0/1: 6/18; Age: median 60 (range 42–77) yrs. 21 pts had colorectal cancer (CRC), 1 had gastric, 1 had esophageal, and 1 had anal cancer. Vorinostat dose-levels (DL) were 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1700 mg, and 2000 mg. Dose-limiting toxicities (DLT), consisting of fatigue and hand-and-foot syndrome (H&F), were seen in 2 of 3 pts at the 2000 mg DL. None of the 6 pts at the 1700 mg DL had a DLT. Cycle 1 grade 3/4 toxicities consisted of thrombocytopenia, GI bleeding, fatigue, and H&F in 2 pts at the 2000 mg DL and a non-DLT G3 diarrhea (lasted <24 hrs) in 1 pt at the 1700 mg DL. Grade 2 nausea, fatigue, and anorexia were common; especially at DL ≥ 1700 mg. Antitumor activity was noted in pts with CRC despite prior refractoriness to 5-FU and failure to oxaliplatin, irinotecan, and cetuximab in all pts. 12/21 CRC pts had a confirmed SD (11) or PR (1). CRC pts had a median PFS of 4 months, a ≥ 6 months PFS rate of 43%, and a ≥ 8 months PFS rate of 33%. Conclusions: The maximum tolerated dose (MTD) of vorinostat in combination with sFULV2 is 1700 mg PO QD x 3 every 2 weeks. This combination is associated with considerable activity in pts with 5-FU-refractory CRC and warrants further investigation. An expanded MTD cohort is accruing to investigate 5-FU-vorinostat PK interaction and intra-tumor TS down-regulation. (This work was supported by a grant from CTEP and the ACS.)

No significant financial relationships to disclose.
Vandetanib plus mFOLFOX6 in patients with advanced colorectal cancer (CRC): A randomized, double-blind, placebo-controlled phase II study
Authors: Yang T. S. , Oh D. Y. , Guimbaud R. , Szanto J. , Salek T. , Thurzo L. , Vieitez J. M. , Pover G. M. , Kim T. W.
Published: August 2020

4084

Background: Vandetanib is a once-daily oral agent that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Eligible patients with advanced CRC and who had previously progressed after an irinotecan- and fluoropyrimidine-containing regimen were randomized 1:1:1 to receive once-daily oral vandetanib (100 or 300 mg) + modified FOLFOX6 (mFOLFOX6) or placebo + mFOLFOX6; mFOLFOX6 was given as standard 14-day treatment cycles (oxaliplatin 85 mg/m2 2-hr and leucovorin 400 mg/m2 2-hr i.v. infusions, followed by 5- fluorouracil [5-FU] 400 mg/mg2 i.v. bolus and 5-FU 2400 mg/m2 46-hr i.v. infusion). The primary objective was to compare the number of patients with a progression event on or before a mandatory tumor assessment visit at data cut-off (∼4 months after last patient randomized). A progression event was defined as the earliest of objective and/or clinical disease progression, or death from any cause. Results: Between March and November 2007, 104 patients (aged 32–81 years) were randomized to receive study treatment ( Table ). At data cut-off on 8 March 2008, there was a greater % of progression events in the vandetanib 100 mg arm compared with placebo (72% [n=23] versus 65% [n=24]; HR=1.21, 2-sided 80% CI 0.82–1.80; 2-sided P=0.53), and also in the vandetanib 300 mg arm compared with placebo (77% [n=27] versus 65% [n=24]; HR=1.41, 2-sided 80% CI 0.96–2.07; 2-sided P=0.25). All except one patient in each group experienced an adverse event (AE) during the study with diarrhea, nausea, thrombocytopenia, and peripheral sensory neuropathy the most commonly reported AEs ( Table ). Neutropenia was the only CTC grade 4 AE to occur in >1 patient in any group (n=2, vandetanib 100 mg arm; n=0, vandetanib 300 mg arm; n=3, placebo arm). Conclusions: In this study of patients with advanced, previously treated CRC, there was no efficacy benefit for vandetanib (100 or 300 mg) + mFOLFOX6 versus placebo + mFOLFOX6.

[Table: see text]

[Table: see text]
Resectability and agreement between surgeons: Review of CT and MR scan of the CELIM study: (Multicenter randomized trial of cetuximab/FOLFOX versus cetuximab/FOLFIRI in unresectable liver metastases
Authors: Bechstein W. O. , Lang H. , Köhne C. , Parisi F. , Raab H. R. , Frilling A. , Konopke R. , Weitz J. , Stroszczynski C. , Folprecht G.
Published: August 2020

4091

Background: Liver resection of patients with colorectal cancer liver metastasis (mets) may provide curative therapy. The decision for resection is based on CT- or MRI scans and includes technical aspects (esp. remaining liver tissue) and prognostic factors (i.e. number of metastases). Methods: During two workshops, CT- or MRI scans at baseline (BL) and after 4 months treatment (follow-up, F-U) of CELIM-patients (pts) were presented to surgeons (surg.) who were blinded to each other, the time of investigation (BL or F-U) and clinical data. Scans were allocated to one of the following categories: (1) resection, (2) exploration, (3) borderline resectable (prior chemotherapy preferred) or (4) non-resectable If scans were allocated to category (3) or (4), the reason (technical or poor prognosis) was stated. For evaluation of resectability over time, pts were regarded as resectable according to presented imaging, if ≥ 50% of surg. voted for (1) or (2). Inter-observer variability was evaluated by a reduced model, too: operation (1+2), borderline, primary chemo therapy preferred (3) and non-resectable, chemotherapy (4). Critical disagreements were assumed if ≥1 surg. voted for (4) and ≥ 50% surg. for (1+2) or vice versa. Results: Seven surg. (≥ 5/workshop) participated at the review. A total of 180 scans were reviewed. Both, BL and F-U scans, were available for 75 pts (68% of study pts). During the review, 24 pts changed from ‘non-resectable‘ at BL to ‘resectable‘ at F-U, 5 pts from ‘resectable‘ to ‘non-resectable‘, 29 pts remained ‘non-resectable‘, and 17 pts ‘resectable‘ (19 pts more resectable at F-U; chi-square: p=.021). R0 resection was actually performed in 16/29 pts classified as ‘resectable‘ (55%) and 13/54 pts not classified as ‘resectable‘ (24%) according to presented BL- images. In the full model (6 possibilities), the agreement between surg. was 51.4 %, p<.001. In the clinically more important reduced model, the agreement was 63.5% (p<.001). Critical disagreements were observed in 18 cases (10%). Conclusions: Resectability according to scans increased significantly during the CELIM trial. Regarding the clinical approach, different surgeons had a high degree of agreement.

[Table: see text]
Postoperative liver function recovery after hepatic resection for colorectal metastases previously treated with bevacizumab
Authors: Adam R. , Wicherts D. A. , de Haas R. J. , Lévi F. , Paule B. , Azoulay D. , Castaing D.
Published: August 2020

4093

Background: The influence of bevacizumab on postoperative morbidity in patients with colorectal liver metastases (CLM) submitted to hepatectomy has been evaluated. However, in spite of a potential inhibition of liver regeneration, its impact on postoperative liver function recovery remains unknown. Methods: From July 2005 to December 2007, we evaluated 37 patients treated with bevacizumab prior to hepatectomy. Postoperative evolution of liver function variables was compared with that of 70 bevacizumab-naïve patients. Recorded parameters included prothrombin time, serum aspartate and alanine aminotransferase levels, and serum gamma-glutamyltransferase and total bilirubin levels. Results: Most patients of the bevacizumab group received 1 line of chemotherapy (62% vs 54% in the control group) (P=0.43). Bevacizumab was combined to 5-fluorouracil (5-FU), leucovorin (LV) and irinotecan or 5-FU, LV and oxaliplatin in the last preoperative line, in 57% and 30% of cases, respectively. Patients received a mean total number of 10.4+5.7 and 11.1+6.2 cycles of preoperative chemotherapy in the bevacizumab and control group (P=0.56). The median number of administered bevacizumab cycles was 6 (range: 3–25). Bevacizumab administration was stopped at a median of 7.9 weeks before surgery (range: 3.6–18.0). Major hepatectomies were performed in 41% and 36% of bevacizumab and control patients, respectively (P=0.62). Baseline liver function tests as well as postoperative liver function recovery were similar between patients treated with or without bevacizumab (Table). Postoperative morbidity occurred in 35% of bevacizumab patients and in 43% of control patients (P=0.44). Conclusions: Preoperative bevacizumab treatment has no impact on short-term liver function recovery after hepatic resection for CLM and has no deleterious effect on the incidence of postoperative morbidity.

[Table: see text]

No significant financial relationships to disclose.
An animal model for chemotherapy-associated steatohepatitis (CASH) and its prevention by the oral administration of fatty acid bile acid conjugate (FABAC)
Authors: Keizman D. , Maimon N. , Ish-Shalom M. , Buchbut D. , Inbar M. , Klein B. , Bernheim J. , Goldiner I. , Leikin- Frenkel A. , Shpigel S. , Konikoff F.
Published: August 2020

4098

Background: Preoperative chemotherapy (irinotecan and oxaliplatin), used in patients undergoing hepatic resection of colorectal liver metastases, is associated with the development of CASH. This hepatic injury increases the risk of perioperative morbidity and mortality. An animal model for CASH has not yet been described. Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules that were shown to prevent the formation of diet induced fatty liver. The present study was designed to establish an animal model of CASH and to use it to study the effect of FABAC on its occurrence. Methods: C57B1/6 mice were given different doses of intraperitoneally injected oxaliplatin and irinotecan. Once weekly administered oxaliplatin at a dose of 6mg/m2 for a total dose of 24mg/ m2, was best tolerated and most consistently associated with CASH in comparison to higher doses of oxaliplatin or different irinotecan regimens. Thus it was chosen as the induction model for CASH. Subsequently, 32 mice were divided into a control group (no treatment, n=6), oxaliplatin group (n=14), and a CASH prevention group (n=12) treated by oxaliplatin and C20-FABAC (arachidyl-amido-cholanoic acid) at a dose of 150 mg/kg/day administered by gavage. The animals were sacrificed after 28 days. Their livers were homogenized and analyzed for fat content (measured as mg lipid/g liver tissue). Results: There were no significant differences in animal or liver weights between the groups. Liver fat content, was significantly lower (P<0.0001) among the control (51.63 mg/g) and prevention (62.13 mg/g) groups versus the oxaliplatin group (95.35 mg/g). The difference between the control and prevention groups was not significant. To the best of our knowledge this is the first description of a model and a potential preventive treatment for CASH. Conclusions: C57B1/6 mice treated by intraperitoneal injection of weekly oxaliplatin at a dose of 6mg/m2 for a total of 24mg/m2, can be used as a model for CASH. Oral FABAC therapy reduces the development of chemotherapy associated steatohepatitis in animals treated with oxaliplatin.

No significant financial relationships to disclose.
Evaluation of the treatment of peritoneal carcinomatosis of colorectal cancer (CRC) with complete cytoreduction and hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) with oxaliplatin: A Belgian multicenter prospective phase II clinical study
Authors: Hompes D. , D’Hoore A. , Van Cutsem E. , Ceelen W. , Peeters M. , Van der Speeten K. , Bertrand C. , Kerger J. , Legendre H.
Published: August 2020

4101

Background: Up to 25% of patients with metastatic CRC present with peritoneal carcinomatosis (PC) as the only site of metastases. The concept of Complete Cytoreductive Surgery (CCRS) followed by Hyperthermia and Intraperitoneal Chemotherapy (HIPEC) was developed, aiming for locoregional disease control and long-term survival. Methods: This prospective multicentre registry included 48 patients (M/F ratio 17/31) with PC from CRC, who underwent CCRS and HIPEC with oxaliplatin(460mg/m2). In 72.9% of patients the primary tumor had been previously resected. Median PCI (peritoneal cancer index) was 11 [1–22], with a median of 6 [1–11] abdominal regions involved and a median lesion size score of 3 [1–3]. In 11 cases associated lymph nodes (63.6% mesenteric, 27.3% para-aortic) were resected. To obtain CCRS a median of 2 [2–6] organs needed to be resected, with anterior resection in 45.8%, total colectomy in 8.3% and small bowel resection in 12.5% of cases. A median of 1 [0–6] anastomosis was performed per patient, of which one third were low and 82.1% were performed after HIPEC. Eleven ileostomies and 5 colostomies were constructed. Results: Median operation time was 460min.[125–840], with a median blood loss of 475ml [2- 6000]. HIPEC posed few procedural problems. There was no postoperative mortality. Complication rate was 52.1%, with 18 intra- and 17 extra-abdominal complications. Anastomotic leakage occurred in 10.4% of patients, bleeding in 6.3% and prolonged ileus in 22.9%. Median hospital stay was 20 [5–65] days. Occurrence of intra-abdominal complications significantly affected hospital stay (p=0.0012), but no risk factors for occurrence of postoperative complications could be clearly identified. Median follow-up was 22.7 [3.2–55.7] months, with 91.7% 2-year overall survival. Progression-free survival at 2 years is 64.6%, with PC recurrence in 29.2% of patients and other metastatic disease in 25%. Multivariate analysis only retained the CEA-level as a significant prognostic factor (p=0.0065). Conclusions: CCRS followed by HIPEC for PC of colorectal origin is safe and has longer than expected PFS and OS.

No significant financial relationships to disclose.
Oral fluoropyrimidines versus 5-fluorouracil for colorectal cancer: Results of a systematic review and meta-analysis
Authors: Sasse A. D. , Sasse E. C. , dos Santos L. V. , Lima J. S. , Nascente C. M. , Saito H. P. , Tariki M. S. , Conceicao V. C. , Carvalho A. M. , Siqueira N. S.
Published: August 2020

4111

Background: Previous studies showed that continuous intravenous infusion (cIV) of 5-fluorouracil (5FU) is associated with best tumor response in comparison to bolus 5-FU and perhaps, a slight increase of overall survival. There are some non-inferiority trials comparing oral fluoropyrimidines with bolus or cIV of 5FU, but there is still no definitive evidence of equivalence. This systematic review evaluated the efficacy of oral fluoropyrimidines compared to bolus or cIV administration of 5FU in colorectal cancer. Methods: PubMed, EMBASE, CENTRAL and LILACS databases were searched. Eligible studies were randomized trials (RCTs) comparing chemotherapy regimens containing oral fluoropyrimidines (capecitabine, UFT or Tegafur) and 5FU (bolus or cIV) in patients with colorectal cancer. The primary outcome was overall survival (OS). Secondary outcomes included response rate (RR), progression-free survival (PFS) and disease-free-survival (DFS). Hazard Ratio (HR) and Odds Ratio (OR) with fixed effect model were used for meta- analysis and were expressed with 95% confidence intervals (CI). Results: We included results from 20 RCTs, with a total of 14,779 patients. Compared to cIV of 5FU, capecitabine resulted in lower RR (OR 0.82; 95% CI 0.72 to 0.95; p=0.006), shorter PFS (HR 1.09; 95% CI 1.01 to 1.17; p=0.02) and was associated with a non- significant reduction in OS (HR 1.05; 95%CI 0.97 to 1.14; p=0.23). Compared to bolus 5FU, capecitabine resulted in lower RR (OR 0.80; 95% CI 0.65 to 0.98; p=0.004), but similar OS and PFS. Compared to bolus 5FU, the use of other fluoropyrimidines resulted in similar RR, OS and PFS. Conclusions: Oral fluoropyrimidines are equivalent to bolus 5FU in terms of efficacy, but provides less benefit than cIV 5FU. Combination chemotherapy with cIV 5FU remains the first choice for patients with colorectal cancer.

[Table: see text]
Phase II study of capecitabine and oxaliplatin with concurrent radiation therapy (XELOX-XRT) for squamous cell carcinoma of the anal canal
Authors: Eng C. , Chang G. J. , Das P. , Rodriguez-Bigas M. , Skibber J. M. , Qiao W. , Rosner G. L. , Ukegbu L. T. , Wolff R. A. , Crane C. H.
Published: August 2020

4116

Background: Definitive therapy for squamous cell carcinoma (SCC) of the anal canal consists of external beam radiotherapy with concurrent 5-fluorouracil and mitomycin C or cisplatin. This regimen can be toxic but curative in 80–85% of cases with remaining patients requiring salvage surgical resection. The purpose of this study was to evaluate the tolerability and efficacy of XELOX-XRT as definitive treatment for anal cancer. Primary objectives were time to treatment failure and occurrence of treatment-related toxicity. Methods: Patients with histologically proven SCC of the anal canal, AJCC Stage II-IIIB (T2–4 or N+M0), ECOG PS 0–1, HIV-, and no prior therapy were eligible for XELOX-based chemoradiotherapy. Chemotherapy initially consisted of capecitabine (825 mg/m2) BID, M-F and weekly oxaliplatin (50 mg/m2) (Group 1) with subsequent modification to omission of chemotherapy during weeks 3 and 6 (Group 2). Radiation therapy was provided in the following manner: T1 (45 Gy in 25 fractions), T2 (55 Gy in 30 fractions), and T3–4 (59 Gy in 32 fractions). Intensity-modulated radiation therapy (IMRT) was allowed. Interim safety analysis was conducted 3 months after the 10th pt. Patients were followed in a multidisciplinary manner. Response was determined by CT/MRI, digital rectal examination, and proctoscopy. A biopsy was performed for clinical suspicion of residual or progressive disease. Results: Twenty patients were evaluable for toxicity; 17 for response. Five of 11 (45%) patients developed grade 3 treatment-related diarrhea (Group 1). Therefore, the chemotherapy schedule was modified and only 1 of 9 patients in Group 2 developed grade 3 diarrhea. Complete response rates were 90% in Group 1 and 100% in Group 2. One patient in Group 1 developed distant failure. After a median follow-up of 19 months, no patient has developed local recurrence or required salvage resection with colostomy for a colostomy-free rate of 100%. Conclusions: The combination of capecitabine, oxaliplatin, and radiation therapy (XELOX-XRT) is effective for locally advanced squamous cell carcinoma of the anal canal. This trial continues accrual and updated results will be provided.

[Table: see text]
Colorectal cancer stem cells: Characterization and functional analysis
Authors: Yeung T. , Wilding J. , Bodmer W.
Published: August 2020

4124

Background: Cancer stem cells are defined as cells within a tumour that are able to self-renew and differentiate into all cell lineages within that tumour. With our extensive panel of colorectal cell lines, our aims are: 1) To characterise and isolate cancer stem cells based on stem cell markers, morphological appearances and the ability to form multiple lineages; 2) To understand how cancer stem cells drive tumour growth and progression. Methods: 1) Fluorescent Activated Cell Sorting (FACS); 2) In vitro soft agar clonogenic and Matrigel differentiation assays; 3) In vivo tumourigenic NOD/SCID mice assay; 4) Confocal immunofluorescence imaging. Results: 1) A subpopulation of cells can differentiate into crypt-like megacolonies, retaining the ability to self-renew and differentiate. SW1222 cell line forms heterogeneous colonies when single cells are plated in Matrigel. Megacolonies can both self-renew and form terminally differentiated small colonies, whereas small colonies cannot form megacolonies. Megacolonies develop crypt-like structures and increase their expression of differentiation markers (CDX-1, CK-20) over time. Experiments are currently under way to confirm that cells from megacolonies are able to initiate tumours in NOD/SCID mice. Some cell lines retain the ability to differentiate into both neuroendocrine and epithelial lineages. 2) CD44+CD24+ enriches for the cancer stem cell population. Colorectal cancer cell lines HCT116, HT29, LS180, LS174T and SW1222 express both CD44 and CD24. The CD44+CD24+ subpopulation is the most clonogenic. In SW1222, CD44+CD24+ cells enrich for megacolonies and can reform all four CD44/CD24 subpopulations. 3) Hypoxia reduces differentiation, increases stem-like phenotype and enhances clonogenicity. Hypoxia increases the proportion of undifferentiated colorectal cancer cells when plated on Matrigel and increases clonogenicity. Conclusions: 1) Colorectal cancer cell lines contain subpopulations of cells that have the ability to self-renew, differentiate and drive tumour growth, and may be characterised by their cell surface markers and colony morphology. 2) CD44+CD24+ can be used as markers for colorectal cancer stem cells. 3) Hypoxia increases the stem-like phenotype of cancer cells, reduces differentiation and increases clonogenicity.

No significant financial relationships to disclose.
“Poker” schedule of weekly alternating 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIR-B/FOX) in advanced colorectal cancer: A phase II study
Authors: Santomaggio A. , Ricevuto E. , Cannita K. , Bruera G. , Tudini M. , Lanfiuti Baldi P. , Mancini M. , Porzio G. , Marchetti P. , Ficorella C.
Published: August 2020

4125

Background: Triplet combinations associating antimetabolites with irinotecan (CPT-11) and/or oxaliplatin (OHP) and/or bevacizumab (BEV) show increased activity in same phase III studies vs doublets, with objective responses (OR) between 40% and 60%. Thus we evaluated in a phase II study the addition of BEV to the triplet combination CPT-11/OHP/5-fluorouracil (5-FU) as first line chemotherapy in metastatic colorectal carcinoma (MCC). Methods: Main inclusion criteria: histologically diagnosis of colorectal cancer (CRC) with measurable disease; age 18–75 yrs; adequate bone marrow reserve and renal and hepatic function; no cardiac diseases; no uncontrolled hypertension; no thromboembolic diseases or coagulopathy, no preexisting bleeding diatheses. Treatment schedule: weekly 5-FU 12-h timed-flat-infusion (from 10:00 pm to 10:00 am) 900 mg/m2/d 1–2, 8–9, 15–16 and 22- 23; CPT-11 160 mg/m2 plus BEV 5 mg/kg days 1 and 15; OHP 80 mg/m2 days 8 and 22, every 4 weeks. A Simon two-stage optimal design was planned: power 80%, error probability α 5%, error probability β 20%, P0 50%, P1 70%, sample size 43 pts (I stage 8/15 OR; II stage 26/43 OR). Primary endpoint: OR. Secondary endpoints: time to progression (TTP), overall survival (OS), toxicity and quality of life. Results: Forty-eight pts were enrolled. Median number of cycles per patient was 5 (range 1–9). In the expected 43 pts assessable intent-to-treat (ITT), OR were 84% (α0.05, CI +12): 2 complete and 34 partial responses. In the overall 48 pts, 46 were assessable ITT: OR 80% (α0.05, CI +12), 2 complete and 35 partial responses, 4 stable disease and 5 progression. Median TTP was 12 months (2+-33+), median OS was 25 months (2+-34+), with a median follow-up of 12 months (2–34). Cumulative G3–4 toxicities by pts were: diarrhea 27%, mucositis 6%, hypertension 2%, hypertransaminasemy 2%, neutropenia 10%. No toxic deaths have occurred. Received-DI: CPT-11 84% of projected-DI, OHP 82%, 5-FU 85%, BEV 84%, per pt respectively. 17 pts (35%) had only liver metastasis and R0 resection was performed in 3 pts (18%). Conclusions: “Poker” combination with FIR-B/FOX schedule shows higher activity than triplet combinations. Thus it may be considered as the most active first line treatment of MCC.

No significant financial relationships to disclose.
A phase II study of the anti-IGFR antibody MK-0646 in combination with cetuximab and irinotecan in the treatment of chemorefractory metastatic colorectal cancer
Authors: Watkins D. J. , Tabernero J. , Schmoll H. J. , Trarbach T. , Ramos F. J. , Hsu K. , Gates M. , Clark J. , LeVan P. , Cunningham D.
Published: August 2020

4127

Background: Evidence of cross-talk between EGFR and IGFR signaling pathways provide a logical rationale for combining anti-EGFR and anti-IGFR strategies in the treatment of cancer. Prior to commencing a blinded randomised phase II study, an opened-labelled safety run-in was undertaken to assess the tolerability of a three-drug combination utilizing irinotecan (Ir), cetuximab (Cx) and two schedules of MK-0646 (Mk). Methods: Eligible patients (pts) had previously failed both Ir and oxaliplatin and had progressed on or within 3 months of their last therapy. Pts were required to have measurable disease and tissue samples available for tumour KRAS testing. Pts were randomised to receive either Mk 10mg/kg weekly (Arm A) or Mk 15mg/kg loading followed by 7.5mg/kg every alternate week (Arm B). All randomised pts also received Cx 400mg/m2 loading followed by 250mg/m2 weekly and Ir according to the same dose and schedule as they had previously received. Patients continued on treatment until disease progression with radiological response assessments undertaken every 6 weeks. Results: 10 pts were recruited to Arm A and 8 to Arm B. Pt characteristics: median age 60.5 years, male 67%, PS 0/1 33%/67%. Median number of prior chemotherapy regimens 3. The median number of cycles of Mk received in Arm A and B is 25 and 8 respectively. Reported grade III/IV toxicities in Arm A and Arm B were: neutropenia 30% and 0%, diarrhoea 30% and 25%, hypomagnesemia 0% and 25%. Hyperglycemia (≥ grade 2) was seen in 10% of Arm A and 25% in Arm B. Acneiform skin toxicity (≥ grade 2) was seen in 30% of Arm A and 62% of Arm B. The radiological response rate was 33% in Arm A and 14% in Arm B. The median time on study drug is 5.8 months in Arm A and 3.9 months in Arm B. 2 pts on Arm A and 1 in Arm B remain on study therapy. Tumour KRAS testing is in progress. Conclusions: The combination of MK-0646, cetuximab and irinotecan is tolerable with no concerning overlapping toxicities highlighted. PFS and KRAS data will be available for presentation. The efficacy of this three drug combination is under evaluation in an ongoing randomised phase II/III study.

[Table: see text]
Analysis of survival with modified docetaxel, cisplatin, fluorouracil (mDCF), and bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma: Results of a phase II clinical trial
Authors: Kelsen D. , Jhawer M. , Ilson D. , Tse A. , Randazzo J. , Robinson E. , Capanu M. , Shah M. A.
Published: August 2020

4512

Background: Metastatic GE cancer is an aggressive disease with poor patient (pt) outcomes. Despite response rates of 30–60% to combination chemotherapy, response duration is usually 4–6 mo and 24-mo survival is 5–10%. The addition of BEV to chemotherapy has improved survival in several solid tumors, and has demonstrated encouraging activity in GE cancer (Shah et al, JCO 2006). We report mature tolerability and efficacy results of mDCF+BEV in GE cancer, with an emphasis on prolonged pt survival. Methods: Previously untreated metastatic GE pts with adequate end organ function received BEV 10mg/kg, Docetaxel 40mg/m2, FU 400mg/m2, Leucovorin 400mg/m2 on day 1, FU 1000 mg/m2/day x 2 days IVCI, and Cisplatin 40mg/m2 on day 3. Treatment is repeated every 14 days without prophylactic growth factor support. The primary objective is to improve 6-month progression free survival (PFS) from 43% (historical DCF control) to 63% with the addition of BEV. Target accrual is 44 evaluable pts, with 10% type I & II error. Secondary objectives include tolerability, response rates (RECIST), median PFS, 12-mo survival, and overall survival (OS). Results: Pt enrollment has completed: median age 57(range 29–74), median KPS 80% (70–100), M:F 32:12, gastric/GEJ/esophagus 22:17:5. In 39 patients with measurable disease we observed 26 confirmed partial responses (67%, 95% CI 50%- 81%), and 12 (31%) stable disease. Six-month PFS is 79% (95% CI 68%-93%), the median PFS is 12 mo (95% CI: 8.8–16). At median follow up of 12.3 mo, median OS is 16.2 mo (95%CI 11.4-infinitiy). 12- and 18-mo OS is 63% (95%CI 44–77%) and 46% (95%CI 27–63%), respectively. Minimal chemotherapy related grade 3–4 adverse events were observed: fatigue (20%), dehydration (13%), mucositis (9%), nausea/vomiting (7%), febrile neutropenia (4%). BEV related adverse event was perforation (n=1) and bleeding (n=1). 31% developed grade 3–4 venous thromboembolism, of which 93% were asymptomatic. No grade 3–4 hypertension, proteinuria or arterial thrombosis was observed. Conclusions: mDCF+BEV appears tolerable and has notable long term pt outcomes: 6-mo PFS is 79% (surpassing our efficacy endpoint), median OS 16.2 mo, and 18-mo OS 46%.

No significant financial relationships to disclose.
A randomized controlled trial (RCT) comparing best supportive care (BSC), 5-FU plus folinic acid (FUFA) and, gemcitabine plus oxaliplatin (Gem-Ox) in management of unresectable gallbladder cancer (GBC)
Authors: Dwary A. D. , Sharma A. , Mohanti B. K. , Pal S. , Garg P. , Raina V. , Shukla N. K. , Deo S. V. , Thulkar S. , Sreenivas V.
Published: August 2020

4521

Background: GBC is common in females residing in the northern part of India. Surgery is the only curative treatment. Unfortunately most patients present in advance and unresectable stage (median survival 3–4 months). Chemotherapy regimens for GBC are not yet standardized. Studies are few and mostly retrospective with small sample size and usually combine heterogeneous malignancies. Adequately powered RCT are not available. This was rationale to undertake study. Methods: It was single center, open label, three armed RCT. Ethical clearance was taken. Planned sample size was 81 to have type I & type II error probabilities of 0.05 & 0.2 respectively. Primary end point was to compare OS in unresectable GBC between BSC vs. FUFA vs. Gem-Ox arms. Secondary end points were to compare PFS in three arms and toxicity analysis of chemotherapy arms. Inclusion criteria were: proven unresectable GBC, performance state ≤2, adequate bone marrow reserve and normal biochemical profile (bilirubin≤3 mg % & liver enzymes within 5 times of upper limit). Patients in BSC group received symptomatic treatment without anticancer therapy. In FUFA group, weekly bolus doses of 5-FU (425mg/m2) plus Folinic acid (20 mg/m2) were given for a maximum of 30 weeks. In Gem-Ox group patients received gemcitabine (900 mg/m2) plus oxaliplatin (80 mg/m2) days 1 and 8 q3 weekly till maximum of 6 cycles. Results: Eighty one patients were randomized (BSC=27, FUFA=28, Gem-Ox=26). Median OS in BSC, FUFA and gem- Ox arms was 4.5 (CI 0.2–8.8), 5.3 (CI 3–6.2) and 9.3 (CI 5–14) months respectively (p= 0.039)). Median PFS was 2.8 (CI 1.8–3.8), 3.5 (CI 3.2–3.8) and 8.5 (CI 5.7–11.3) months in BSC, FUFA and Gem-Ox arm respectively (p= 0.0001). Chemotherapy arms were generally well tolerated. There was no difference in grade 3/4 toxicities in FUFA and Gem-Ox arm except for deranged liver function test, which was more in Gem-Ox arm (p=0.04). There was no toxic death. Conclusions: Probably this is the first RCT confirming efficacy of chemotherapy (Gem-Ox) compared to BSC in improving OS and PFS in unresectable GBC. Both chemotherapy arms were well tolerated.

No significant financial relationships to disclose.
A randomized phase II trial of a drug eluting bead in the treatment of hepatocellular carcinoma by transcatheter arterial chemoembolization
Authors: Lencioni R. , Malagari K. , Vogl T. , Pilleul F. , Denys A. , Watkinson A. , Lammer J.
Published: August 2020

4523

Background: Transcatheter arterial chemoembolization (TACE) has been shown to offer a survival benefit for patients with intermediate-stage hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes the administration of a doxorubicin-in-oil emulsion followed by gelatine sponge particles. Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. Purpose of this randomized trial was to compare conventional TACE with DEB-TACE for the treatment of intermediate-stage HCC in patients with cirrhosis. Methods: Two hundred and twelve patients (185 males and 27 females; mean age, 67 years) with Child-Pugh A or B liver cirrhosis and large and/or multinodular, unresectable HCC were randomized to receive DEB-TACE (DC Bead; Biocompatibles, UK) uploaded with doxorubicin or conventional TACE with doxorubicin, lipiodol, and gelatin sponge particles. Randomization was stratified according to Child Pugh status (A or B), performance status (ECOG 0 or 1), bilobar disease (yes or no) and prior curative treatment (yes or no). Tumor response at 6 months was the primary study endpoint. An independent, blinded review of magnetic resonance imaging studies was conducted to assess tumor response according to amended RECIST criteria. Results: DEB-TACE with doxorubicin showed a higher rate of complete response, objective response and disease control compared with conventional TACE (27% vs 22%; 52% vs 44%; and 63% vs 52%, respectively; p>0.05). Patients with Child Pugh B, ECOG 1, bilobar disease and recurrence following curative treatment showed a significant increase in objective response (p=0.038) compared to the control. There was a marked reduction in serious liver toxicity in patients treated with DEB-TACE. The rate of doxorubicin related side effects was significantly lower (p=0.0001) in the DEB-TACE group compared with the conventional TACE group. Conclusions: DEB-TACE with doxorubicin is safe and effective in the treatment of intermediate-stage HCC and may offer benefit to patients with more advanced disease.

No significant financial relationships to disclose.
Drug eluting beads versus conventional TACE for unresectable hepatocellular carcinoma: Survival benefits and safety
Authors: Dhanasekaran R. , Kooby D. A. , Staley C. A. , Kauh J. S. , Kim H. S.
Published: August 2020

4524

Background: Conventional transarterial chemoembolization (TACE) has long been used as palliative transcatheter therapy for patients with unresectable hepatocellular carcinoma (HCC). Drug eluting beads (DEB) are a newer drug delivery system that can be loaded with doxorubicin. Though therapy with DEB is feasible, the survival advantage of this therapy over conventional TACE has not been established. Methods: Consecutive patients who received transcatheter therapy with Doxorubicin DEB or conventional TACE as sole therapy over a period of 1998 to 2008 were studied. Patients who underwent resection, transplantation, radioembolization or combination therapies have been excluded from the study. Statistical analysis was performed using Kaplan Meier Estimator with a log rank test, Chi-square and independent T-tests. Results: A total of 73 patients were included in the study, 47(64.4%) received therapy with DEB (group A) and 26(35.6%) underwent conventional TACE (group B). The demographic, tumor burden and liver reserve characteristics of patients in the two groups were statistically similar. Median survival from diagnosis of HCC in group A and B were 610 days(352–866) and 284 days(4–563) (p=0.03). Median survivals from the time of first transcatheter therapy in group A and B were 403 days(373–679) and 114 days (183–460)(p=0.01). The survival rates in group A and B at 6 months, 1yr and 2 yrs were 71%, 66%, 40% and 58%, 46%, 19%. On analysis of patients in Child Pugh class A and B, median survivals in group A and B were 390 days(298–491) and 114 days(41–187)(p=0.004). No difference in survival was found in Child Pugh class C. 6.4%(3/47) of patients treated with DEB and 7.7%(2/26) of patients treated with conventional TACE developed liver failure in the post procedure period. All patients who developed liver failure belonged to Child Pugh class C. No other major complications were reported in either group. Conclusions: In patients with unresectable HCC, transcatheter therapy with Doxorubicin eluting beads offers a survival advantage over conventional TACE. The safety profile of the two treatment modalities appears similar.

No significant financial relationships to disclose.
SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: A phase I/II study
Authors: Von Hoff D. D. , Ramanathan R. , Borad M. , Laheru D. , Smith L. , Wood T. , Korn R. , Desai N. , Iglesias J. , Hidalgo M.
Published: August 2020

4525

Background: Pancreatic cancer cells and surrounding stroma are known to overexpress SPARC (secreted protein acid rich in cysteine), which is associated with poor clinical outcomes. nab-P, an albumin-bound nanoparticle form of paclitaxel increased tumor accumulation of paclitaxel through binding of albumin to SPARC. This disease specific phase 1 study was designed to evaluate the safety and efficacy of G + nab-P and the correlation of response with tumor SPARC and serum CA19–9 levels. Methods: nab-P doses (100–150 mg/m2) + (G) (1000 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle to pts with metastatic pancreatic adenocarcinoma and with no prior chemotherapy for their metastatic disease. Level 3 SPARC staining by immunohistochemistry was considered positive. Results: 63 pts received treatment. The most common grade 3 and 4 adverse event that occurred in >20% of pts was neutropenia. Nine (18%) pts and 4 (8%) pts had a grade 3/4 event, respectively. Neuropathy was also observed. One combination-associated death due to sepsis occurred at the 150 mg/m2 nab-P level. Serial PET scans of 53 pts with outside adjudication to date showed 12 (23%) complete responses, 29 (55%) partial responses (PRs) and 4 (8%) stable disease (SD). By RECIST criteria, of the 49 pts evaluable to date, 1(2%) had CR, 12 (24%) had PR, and 20 (41%) had SD. The median survival was 9 months to date. SPARC data were available for 35 pts, of which 10 (29%) were SPARC+ and 25 (71%) were SPARC-. Of these, 27 pts had evaluable response data. Pts that were SPARC+ (8/27) were more likely to be responders (6/8, 75%) than pts who were SPARC- (5/19, 26%), P = 0.03, Fisher's exact test. Median progression-free survival (PFS) increased from 4.8 months for SPARC- pts (22 pts) to 6.2 months for SPARC+ pts (9 pts); however, these data are still immature. Of 45 pts with elevated CA19–9 at baseline, 42 (93%) had maximum decrease of >40% with a median maximum decrease of 92%. Conclusions: The combination of nab-P and G was generally well tolerated and had substantial enough antitumor activity in patients with pancreatic cancer to warrant a phase III clinical trial. SPARC+ status in these patients was associated with higher response rate and longer PFS.

[Table: see text]
Adjuvant gemcitabine alone versus gemcitabine-based chemoradiation after curative resection for pancreatic cancer: Updated results of a randomized EORTC/FFCD/GERCOR phase II study (40013–22012/9203)
Authors: Van Laethem J. L. , Mornex F. , Azria D. , van Tienhoven G. , Mauer M. , Praet M. , Budach V. , Hammel P. , Van Cutsem E. , Haustermans K.
Published: August 2020

4527

Background: The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is debated. This randomized phase II intergroup study demonstrated the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer (Proc ASCO 2008, 4514). Long term and survival data are now reported. Methods: Patients were randomized within 8 weeks after surgery to receive either 4 cycles of gemcitabine 1000 mg/m2 given over 30 minutes every 3 weeks (control arm) or gemcitabine 1000 mg/m2 for 2 cycles followed by weekly gemcitabine 300 mg/m2 with concurrent radiation of 50.4 Gy given in 28 fractions of 1.8 Gy (experimental arm). The co-primary endpoints were completion of treatment and tolerability. Secondary endpoints were late toxicity, DFS and OS. Results: Between 9/04 and 1/07, 90 patients were randomized by 29 centers (45:45). Treatment arms were balanced in terms of patient/tumour characteristics. Follow-up was equal for both arms with an overall median follow-up of 27.1 months. In the control arm, 5 patients were ineligible, including 2 not treated. In the experimental arm, CRT was delivered to 36 of 45 patients (80%). Treatment was completed per protocol by 86.7% and 73.3% (80% CI 63.1–81.9%) of randomized patients in the control and experimental arms, respectively. Grade 4 toxicity was 0% and 4.4%, respectively. In the CRT arm, 2 patients experienced grade 3 late toxicity (anorexia 1 and epigastric pain 1). In the CRT experimental arm, 33 DFS events were noted and 23 deaths versus 34 and 24, respectively, in the control arm. Median DFS was 12 months in the experimental arm vs. 11 months in the control arm (p=0.6). Median overall survival was 24 months both in the experimental arm and the control arm. Distant progression was similar in both arms while the rate of first local recurrence was lower in the chemoradiation arm (11 vs 24 %, p=0.16). Conclusions: Post-op modern gemcitabine-based CRT is feasible and well- tolerated after long-term follow-up, and a larger trial should assess its true benefit to that of standard gemcitabine alone.

[Table: see text]
Rash as a marker for the efficacy of gemcitabine plus erlotinib-based therapy in pancreatic cancer: Results from the AViTA Study
Authors: Verslype C. , Vervenne W. , Bennouna J. , Humblet Y. , Cosaert J. , Van Cutsem E.
Published: August 2020

4532

Background: The EGFR inhibitor, erlotinib (E), in combination with gemcitabine (G), provides a significant survival benefit in metastatic pancreatic cancer. Rash, a common toxicity with EGFR inhibitors, has been proposed as a potential marker of erlotinib efficacy in multiple tumor types. The recent phase III study of GE ± bevacizumab (B) (Vervenne et al. ASCO 2008) provides a further opportunity to consider this topic. Methods: Chemo-naïve patients (pts) with metastatic pancreatic adenocarcinoma and KPS of 60–100 were randomized to GE-placebo (GE-P) or GE-B; pts received B/P 5mg/kg q2w plus E (100mg/d) and G (1,000mg/m2) given weekly for 7 weeks during the first 8-weekly cycle, followed by weekly for 3 weeks during subsequent 4-weekly cycles. Results: 607 pts were recruited; the arms were well balanced with respect to baseline characteristics. The addition of B to GE produced a significant benefit in PFS (hazard ratio [HR] 0.73, p=0.0002), and a trend towards longer OS (HR 0.89, p = 0.2087; median 7.1 mo vs 6.0 mo for GE-P). GE-B was well tolerated with no new safety signals observed. The incidence of rash was higher in the GE-B arm (73% vs 62% in the GE-P arm). There was a clear trend towards longer OS with increased grade of rash (see table ); this trend was apparent in both arms of the study. There was no difference in OS between treatment groups for any rash grade. Conclusions: The observed relationship between higher grades of rash and longer median OS supports the findings of the phase III PA.3 study of G ± E (Moore et al. JCO 2007), in pts with advanced pancreatic cancer. Studies are under way to prospectively investigate the relationship between rash and efficacy with erlotinib-based regimens in pancreatic cancer.

[Table: see text]

[Table: see text]
Planned interim analysis of the intergroup FFCD-GERCOR-FNCLCC-AERO phase III study comparing two sequences of chemotherapy in locally advanced or metastatic gastric cancers
Authors: Guimbaud R. , Bouché O. , Rebischung C. , Bonnetain F. , Louvet C. , Viret F. , André T. , Samalin E. , Gorent J. , Dutel J. , Bedenne L.
Published: August 2020

4533

Background: There are several standard chemotherapies in locally advanced or metastatic gastric or cardia adenocarcinoma, including ECF. Methods: Patients (pts) with a gastric or cardiac adenocarcinoma, locally advanced or metastatic, not surgically curable, with a WHO PS ≤2 and evaluable or measurable lesions, were randomized (1:1) according to the following sequences: ECC (epirubicin 50 mg/m2 D1+ cisplatin 60 mg/m2 D1 + capecitabine 2000 mg/m2 D2 to D15, every 3 weeks) in 1st line, then FOLFIRI (IRI 180 mg/m2 D1, leucovorin 400 mg/m2 D1, bolus 5FU 400 mg/m2 D1 and continuous 5FU 2400 mg/m2 in 46h, every 2 weeks) in 2nd line (Arm A) vs the reverse sequence (Arm B) with a stratification for center, PS, adjuvant treatment, site, linitis and measurable disease. To show an improvement in median time to treatment failure for the 1st line (TTF: time between randomization and progression, or treatment discontinuation or recurrence or death) of 15 to 20 weeks for arm B (α bilateral 5%; β 20 %), 381 failures and 416 pts are required in 4-year period. An interim analysis is planned when at least 190 failures are observed (ITT). TTF is estimated according to the Kaplan Meier method and compared with a Log-rank test. Results: In arm A and B, 174 and 175 pts were included respectively, between 17/06/05 and 21/12/07. Pts characteristics are: PS 1: 51%, med. age 60 years, gastric 67%, M+ 88%, resected primary tumor 27% and linitis 23%. In arms A and B respectively, 141 and 147 pts received at least one dose in 1st line and 61 and 44 pts in 2nd line. Toxicities during the first line is more frequent in the ECC than in the FOLFIRI arm: grade 3/4 (88 vs 68% - p ≤0.0001) and grade 3/4 hemato toxicities (69 vs 36% - p ≤0.001). In 2nd line, toxicities frequency is not different in both arms. The median TTF in 1st line (n = 310 pts) is 4.7 months [3.8 - 5.7] for ECC and 5.2 months [4.4–6.0] for FOLFIRI (Log Rank p = 0. 78). Regarding the 252 failures observed (67% of the required events), the significance level to reject H0 is p = 0.012 (EAST V5). Conclusions: It is not possible yet to conclude to the superiority of FOLFIRI in 1st line; the final analysis after observation of 381 failures is required. Regarding toxicity, hemato-toxicity is more frequent with ECC in 1st line.

[Table: see text]