bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic relevance of genetic aberrations in gastrointestinal stromal tumors.
Authors: Mazurenko N. N. , Beliakov I. S. , Tsyganova I. V. , Bardina E. M. , Anurova O. A. , Gagarin I. M. , Skoromislova E. V. , Arhiri P. P. , Nikulin M. P. , Stilidi I. S.
Published: February 2017

49

Background: Gastrointestinal stromal tumours (GISTs) contain oncogenic KIT or PDGFRA tyrosine kinase (TK) mutations leading to disturbance of downstream signaling pathways that contribute to GIST pathogenesis. Additional genetic aberrations were found in GISTs, demonstrating the involvement of other genes important in tumor progression. The aim of the study was to evaluate the prognostic relevance of different TK mutations in GISTs and to analyze the additional genetic aberrations in GISTs according to mutational status.

Methods: 180 GIST patients were examined for KIT (9, 11, 13, 17 exons) and PDGFRA mutations (12, 14, 18 exons) by direct sequencing of DNA obtained from microdissected tumor sections. Tumor tissue DNA from 44 GISTs patients was screened for loss of heterozygosity (LOH) at 11 microsatellite loci on 1p, 9p, 14q, 15q and 22q arms.

Results: KIT and PDGFRA mutations were identified in 76.1% and 10% of GISTs, respectively. 13.9% GISTs had no mutations (wild type). Most of KIT mutations were located in exon 11 (65%) and exon 9 (9.4%). Prognostic significance of TK mutations was evaluated. There was a trend of better survival for patients with PDGFRA mutation then with KIT mutation or wild type GISTs. The higher overall survival prior to target therapy was shown for patients with duplication or point mutation in KIT exon 11 in comparison to exon 11 deletion. Analysis of LOH revealed allelic deletions in 85% of GISTs, more frequently at 14q arm. There was a different LOH pattern in subgroups of GISTs. GISTs with PDGFRA mutation and with KIT exon 11 point mutation had LOH at 14q, while GISTs with KIT exon 11 deletions revealed high LOH frequency also on 22q, 15q and 1p arms. LOH in wild type GISTs occurred on all chromosomes with low frequency. LOH on 9p was found exclusively in metastatic and recurrent GISTs. Specific gene loci of frequent LOH were identified on 9p, 15q and 22q that may be contributed to GIST progression.

Conclusions: Specific mutations are associated with GISTs prognosis. Tumors with point mutations and duplications in KIT exon 11 are associated with a better survival then GISTs with other KIT mutations. Specific pattern of allelic deletions was identified in subgroups of GISTs according to type of mutation and tumor progression.

No significant financial relationships to disclose.
Effect of catumaxomab treatment in patients with peritoneal carcinomatosis and malignant ascites due to gastrointestinal cancers on survival.
Authors: Ströhlein M. A. , Essing M. M. , Hennig M. , Seimetz D. , Ott M. G. , Heiss M. M.
Published: February 2017

490

Background: In 2009 the trifunctional antibody catumaxomab was approved for the intraperitoneal (i.p.) treatment of malignant ascites (MA) in EpCAM-positive carcinomas in Europe. Overall survival (OS) results for gastric cancer patients from the pivotal trial showed a significant treatment benefit of catumaxomab in this patient group. We present the results for the gastrointestinal (GI) cancer subgroup from the pivotal trial including long-term survivors.

Methods: A total of 86 patients with MA due to GI cancer (gastric, pancreatic, colon, esophagus, rectum carcinoma) were treated with paracentesis plus catumaxomab (59 patients) vs. paracentesis alone (control, 27 patients). The primary endpoint was puncture-free survival; main secondary endpoints were time to next puncture, overall survival and safety parameters. The endpoints were compared between the catumaxomab and the control group using the Kaplan-Meier method and log-rank test. Analyses were performed for the Full Analysis Set (FAS) and the Safety Set (patients who received at least 1 catumaxomab infusion; 95%).

Results: For puncture-free survival, a median of 35 days for catumaxomab vs. 14 days for control was observed (p<0.0001, HR: 0.340 with 95 % CI from 0.194 to 0.597, FAS). Time to next puncture resulted in a median of 118 days vs. 15 days (p<0.0001, HR: 0.161 with 95 % CI from 0.069 to 0.378, FAS). Although the study was not powered nor designed for OS, the difference between treatment and control arm was significant for the Safety Set (median: 61 vs. 44 days, p<0.05, HR: 0.553). ADRs were generally mild to moderate, limited to the treatment period and reversible.

Conclusions: I.p. catumaxomab is an EMA-approved treatment for patients suffering from malignant ascites. The positive efficacy results were demonstrated in an advanced stage patient population together with a predictable and manageable safety profile. Patients suffering from peritoneal carcinomatosis with malignant ascites due to GI cancers experience a significant survival benefit from i.p. treatment with catumaxomab.

[Table: see text]
Biological impact of skip metastasis in patients with gastrointestinal cancers undergoing sentinel lymph node mapping.
Authors: Saha S. , Mozayen M. , Sirop S. , Korant A. , Nalluri S. , Machek O. L. , Manyam M. , Ng P. L. , Nagpal S. , Wiese D.
Published: February 2017

499

Background: As in melanoma and breast cancers, sentinel lymph node (SLN) mapping has been successfully used in gastrointestinal (GI) cancers (Ca) for accurate nodal staging. However, due to variable incidence of skip metastasis between different parts of the GI tract, its usefulness has been questioned for the proper staging. Hence, we aimed to evaluate the rates of skip mets, its mechanism and its biological impact in GICa.

Methods: A search of English literature was performed incorporating MEDLINE and Cochrane library database using the following terms: skip metastasis, sentinel node, colorectal, gastric, and esophageal cancer. The following were excluded: comments, case reports, reviews, fewer than 40 patients in the study. The remaining were used for data extraction.

Results: Between 2000-2009, 27 studies including 3,589 patients (122 esophageal, 1,185 gastric, 2,113 colon, and 169 rectal cancers) were reviewed. The overall success rate of SLNM was 95% (96.6% in esophageal, 94% in gastric, 94.3% in colon, and 95.6% in rectal cancer). Nodal positivity (positive SLN and/or non-SLN) was 34% in esophageal, 36.6% in gastric, 48.1% in colon, and 41% in rectal cancers. Rates of skip mets were 18%, 14%, 20%, and 15% in esophageal, gastric, colon, and rectal cancers respectively. In patients with skip mets, T3/T4 disease was found in 65%, 44%, and 82.5% of patients with esophageal, gastric and colon cancers respectively. The average tumor size ranged between 3 cm in gastric to 4.4 cm in colon cancer. The most common primary site for skip mets in colon cancer was the right side (50%), and in LN basin 7, 8, 9 in gastric cancer. All node positive (true and false negative) patients were staged as stage III and were treated with adjuvant chemotherapy.

Conclusions: Skip mets are common in T3/T4 disease, and in larger tumors suggesting difficulty injecting the dye circumferentially. All node positive patients (true positive and skip mets) are treated with chemotherapy. Hence, skip mets has no real clinical impact on either the staging, treatment, or the outcome of the disease.

No significant financial relationships to disclose.
A double-blind, randomized placebo-controlled, phase II study of maintenance enzastaurin (ENZ) with 5-FU/leucovorin (LV) plus bevacizumab (BV) following first-line therapy for metastatic colorectal cancer (mCRC).
Authors: Wolff R. A. , Schepp W. , DiBartolomeo M. , Hossain A. , Stoffregen C. , Nicol S. , Heinemann V.
Published: February 2017

501

Background: Maintenance therapy is designed to maximize progression-free survival (PFS) and minimize toxicity in advanced CRC. ENZ is an oral serine/threonine kinase inhibitor that targets PKC-b and the AKT/PI3K pathway. Preclinical studies demonstrated synergistic antitumor effects when ENZ was combined with BV. In phase I studies, the combination was well tolerated. This phase II study assessed ENZ with 5-FU/LV plus BV as maintenance therapy for mCRC.

Methods: Patients had locally advanced or mCRC, and completed 6 cycles of first-line chemotherapy ≤4 wks prior to randomization. Arm A received a loading dose of ENZ 1,125 mg, followed by 500 mg/d subsequent doses. Arm B received placebo. Both groups received 5-FU/LV (LV 400 mg/m2 IV, 5-FU 400 mg/m2 bolus, 5-FU 2,400 mg/m2 IV) plus BV 5 mg/kg IV, every 2 wks. Patients were treated with 5-FU/LV plus BV plus either ENZ or placebo until disease progression or for 1 yr. Primary endpoint was PFS from randomization. Secondary endpoints were overall survival (OS) from randomization, and OS and PFS from start of first-line therapy. Analysis was done after 50 events (objective or clinical progression).

Results: 58 patients were randomized to Arm A (57 treated), 59 to Arm B (58 treated). 82 (70.1%) patients discontinued treatment (Arm A, 42 [72.4%]; Arm B, 40 [67.8%]), the majority due to disease progression. Median cycles were 9 in Arm A, 10 in Arm B. Median PFS in months was 5.8 in Arm A and 8.1 in Arm B (hazard ratio [HR]=1.35, 95% CI: 0.84, 2.16; protocol specified one-sided test, p=0.896). Median OS was not calculable due to high censoring (77.6% in Arm A and 91.5% in Arm B). Median PFS in months from start of first-line therapy was 8.9 in Arm A and 11.3 in Arm B (HR=1.39, 95% CI: 0.86, 2.23; one-sided, p=0.913). More patients developed thrombosis or embolism (TE), including pulmonary embolism, on Arm A (5 [8.8%] patients had grade 3 and 5 [8.8%] grade 4 TE) compared with Arm B (no grade 3 and 1 [1.7%] grade 4 TE).

Conclusions: ENZ did not demonstrate an advantage in PFS compared to BV-based therapy alone. Further development of maintenance therapy with ENZ is not recommended for mCRC.

[Table: see text]
A population-based study of metastatic colorectal cancer (mCRC) in people age 80 and older: Findings from the South Australian Clinical Registry (SACR) for mCRC.
Authors: Jain K. , Beeke C. , Price T. J. , Young G. P. , Roder D. , Padbury R. , Townsend A. R. , Richards A. , Karapetis C. S.
Published: February 2017

514

Background: Life expectancy is increasing and more patients (pts) with mCRC are presenting at an advanced age (>80). Optimal management approach for this group of pts is not well defined as they are under-represented in clinical trials.

Methods: The SACR for mCRC collects data on mCRC pts diagnosed after 1/2/2006. We examined cancer characteristics, treatments administered and outcomes for pts aged >80 yrs. Comparison was made with pts <80 yrs.

Results: Data from 1737 mCRC pts has been entered to date of which 522 (30%) pts were aged ≥ 80. Key patient characteristics and treatments are reported in the table. The majority had grade 2 tumours. Grade 3 differentiation was reported in lower proportion of pts ≥80 yrs than the younger group (18% v 26%, p < 0.001). Only 23.6% of pts >80 received chemotherapy (CT). Of these, 63% received single agent CT (mostly capecitabine) while 37% received combination CT as first line treatment. In contrast, 67% of pts <80 received CT, 73% of which received combination CT and 27% single agent (majority capecitabine) as their first line CT. Pts aged ≥ 80 had fewer liver resections and were also less likely to receive radiotherapy or monoclonal antibodies. Median survival was 7.1 mths for >80 yrs v 17.4 mths for <80 yrs, p < 0.001. Median survival for pts treated with chemotherapy was 19 mths for >80 and 21.7 mths for <80, p = 0.141. Pts without any treatment had a poor survival regardless of their age (median survival 2.9 mths >80 yrs v 2.4 mths <80 yrs).

Conclusions: Older pts (≥ 80 yrs) were less likely to receive intervention for their mCRC and had poorer survival. However, survival for selected elderly pts, who received CT, was similar to those <80, despite most receiving single agent therapy.

[Table: see text]

[Table: see text]
A randomized phase II study of modified OPTIMOX1 or FOLFOX in advanced colorectal cancer.
Authors: Mikami C.
Published: February 2017

519

Background: A combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) is a standard first-line regimen for advanced or unresectable colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity, but the OPTIMOX1 (stop and go) approach offers a reasonable strategy. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX4 or modified FOLFOX6 (+/− bevacizumab), a simplified leucovorin and fluorouracil regimen with normal-dose oxaliplatin.

Methods: Previously untreated patients were randomly assigned to either FOLFOX administered every 2 weeks until progression (arm FOL) or FOLFOX for six cycles, maintenance without oxaliplatin for six cycles, and continued every six cycles until progression (arm OPT).

Results: Sixty patients (arm FOL [n=35], arm OPT [n=33]) were enrolled. The median number of treatment cycles was 10 (range, 3-28) in arm FOL and 12.5 (range, 1-32) in arm OPT. Cumulative dose of oxaliplatin was 850 mg/m2 in arm FOL and 552.5 mg/m2 in arm OPT. Median progression-free survival was 8.5 months in patients allocated to arm FOL compared with 15 months in patients allocated to arm OPT. Response rates evaluated by RECIST criteria were 50% with arm FOL and 64% with arm OPT. National Cancer Institute Common Toxicity Criteria grade 3 toxicity was observed in 37.1% of the patients in arm FOL and 24.0% of patients in arm OPT. Grade 3 sensory neuropathy was observed in 22.8% of the patients in arm FOL and 6% of patients in arm OPT.

Conclusions: Our modified OPTIMOX1 regimen may be effective and safe treatment to prevent oxaliplatin-induced neuropathy in advanced or unresectable colorectal cancer patients.

No significant financial relationships to disclose.
Evaluation of predictive factors of response of preoperative chemoradiotherapy (CRT) for rectal cancer biopsy specimens collected one week after the start of therapy.
Authors: Suzuki T. , Sadahiro S. , Maeda Y. , Tanaka A. , Okada K. , Ogoshi K. , Kamijo A. , Murayama C.
Published: February 2017

521

Background: Preoperative CRT is the standard therapy for advanced rectal cancer. It has been reported that not only local recurrence but also distant metastasis are few in patients (pts) with remarkable histologic response. However, no definitive predictive factor has been established. The aim of this study was to determine whether biopsy collected before and one week after the start of CRT has significance as a predictive factor.

Methods: Subjects were 72 pts with cT3/T4NxM0 rectal cancer who underwent preoperative CRT (40 or 45 Gy in 20 or 25 frs. with oral UFT or S-1 based chemotherapy). Pathologic response was assessed based on tumor regression grade (TRG) and tumor reduction rate (TRR) was calculated from barium enema images. Biopsy specimens were evaluated by proliferative index (Ki67), apoptosis and its related p53/p21 immunological staining and H-E staining.

Results: For biopsy specimens collected before the start of CRT, a significant increase in TRR was observed in p21 positive pts (p = 0.04), but no factor related to the histological response. For biopsy specimens collected one week after the start of CRT, TRR were 50±13% for p21 positive pts and 40±14% for negative pts, 51±13% for apoptosis positive pts and 41±14% for negative pts, and 53±11% for pts with moderate effect recognized on H-E staining and 40±14% for pts with mild effects, respectively. The difference between positive and negative pts was significant (p<0.01, p<0.01, and p<0.01, respectively). The percentages of pts with moderate or higher histological effect (TRG 1 and 2) were significantly high in pts who were p21 positive, apoptosis positive, and had a moderate effect on H-E staining (p=0.01, p=0.04, and p<0.01, respectively). In other words, for biopsy specimens taken before the start of CRT, p21 was the only predictive factor, however, for biopsy specimens collected one week after the start of CRT, apoptosis and the effect recognized on H-E staining were also predictive factors in addition to p21.

Conclusions: In CRT for rectal cancer, biopsy samples collected one week after the start of therapy increases the number of reliable predictive factors of response.

No significant financial relationships to disclose.
Tolerance of full-dose sorafenib (S) combined with irinotecan (I; weekly, two on, one off) and cetuximab (C) in previously treated patients with advanced colorectal cancer (CRC).
Authors: Dasari A. , Rudek M. A. , Arcaroli J. , Powell R. W. , Carducci M. A. , Laheru D. , Wright J. J. , Hidalgo M. , Messersmith W. A. , Azad N. S.
Published: February 2017

522

Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways are qualified targets in CRC, and are both inhibited by S. Preclinical evidence suggests S may also overcome cetuximab resistance. We previously reported (2008 GI Symposium, abstr#435) excessive toxicity of this combination with I 120 mg/m2 days (d) 1,8,15,22 every 42 d; the study was amended with an alternative I dose/schedule and the phase I results are presented.

Methods: Patients (pts) with advanced, pretreated CRC irrespective of KRAS mutation status with ECOG PS 0-2 and good organ function were eligible. The original dose/schedule of I was combined with C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S PO daily with dose level (DL) 1 = 200mg QD, DL2=200 mg BID and DL 3=400 mg BID. 2/4 pts had DLTs: grade (g) 3 fatigue and febrile neutropenia. The dose/schedule were amended to I 100 mg/m2 d1, 8 of 21d cycles (c) without changing S or C. As with the original design, there was a C/S lead-in for 2 weeks in c1, thus c1 (DLT window) was 5 weeks (w).

Results: In the original design, 5 subjects were recruited; after the study amendment, 13 additional pts were recruited (3, 3 and 7 pts respectively at amended DL1, DL2 and DL3). Overall, median age was 56.5 yrs, M: F 12:6 and colon: rectal cancer 16:2. All patients are evaluable and 3 are still on treatment (10+ - 20+ w). At the amended I dose/schedule, there were no further DLTs. Any c g3 toxicities included constitutional (fatigue:2, dehydration:1), gastrointestinal (nausea:1, vomiting:2, diarrhea:1), metabolic (hypomagnesemia:2 including one with tetany; hypokalemia:3), elevated ALT:1 and neutropenia:1. G 4 toxicities included neutropenia:1, thrombocytopenia:1. Two pts (one KRAS MT) had partial response with one pt (KRAS WT) on treatment for >44 w. 10 pts had stable disease (5–20+ w). PK/PD analysis is ongoing.

Conclusions: The recommended phase II dose is I 100 mg/m2d1,8; C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S 400 mg PO BID. The regimen is tolerable in advanced, pretreated CRC. Due to the limited responses and current phase III studies with S in CRC, there are no plans to open the phase II portion at this time.

No significant financial relationships to disclose.
Racial disparities in colon cancer: Retrospective analysis of VACCR database.
Authors: Didwaniya N. , Gonsalves W. , Silberstein P. T. , Subbiah S.
Published: February 2017

528

Background: A racial/ethnic difference in colon cancer survival has been described in literature. However the reasons for this are unclear and access to health care is one of the factors that have been implicated. We plan to examine the clinicopathologic factors of Caucasians (CA) and African Americans (AA) in an equal to access health care system.

Methods: 21,992 patients from 1995 to 2009 were identified from the VA Central Cancer Registry database. Age, race, stage, histology, lymph node status, and type of treatment received data were collected.

Results: Out of 21,992 patients, 17,924 were CA and 4,068 were AA. 98.07% of CA and 97.83% of all AA were males. Pathological T stages were as follows: T1 = 15.58% vs. 16.13%, T2 = 18.81% vs. 17.56%, T3 = 55.48% vs. 56.03%, T4 = 10.13% vs. 10.28% for CA and AA respectively. Stage-specific incidence, histological grades, and lymph nodal involvement rates were similar in both groups. 77.16% of CA and 77.03% of all AA received chemotherapy. 82.07% of CA and 78.78% of all AA underwent surgery. Median overall survival in CA was 30.73 months and in AA it was 27 months (p < 0.0001). Stage-specific survival (in months) was significantly better for CA in early-stage disease (p < 0.0001) but is similar for both races in metastatic disease (see Table). Median survival in male and female sex irrespective of race was 29.867 months and 35.667 months respectively.

Conclusions: Overall survival is better in CA when compared to AA in an equal to access health care system. This survival difference was present only in early-stage disease while in metastatic disease the survival was uniformly poor. Incidence as per stage, lymph node status,and grade were not significantly different among AA and CA. Tumor biology and post-treatment surveillance are potential factors and this needs to be investigated further.

[Table: see text]

No significant financial relationships to disclose.
Coagulo-fibrinolytic activity as a predictor of efficacy in bevacizumab-combined chemotherapy in metastatic colorectal cancer patients.
Authors: Suenaga M. , Matsusaka S. , Watanabe T. , Takagi K. , Kuboki Y. , Ozaka M. , Shinozaki E. , Chin K. , Mizunuma N. , Hatake K.
Published: February 2017

533

Background: The combination of bevacizumab (BV) and chemotherapy in the first-line and second-line treatment of metastatic colorectal cancer (mCRC) has been shown to improve survival. Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. However, the relationship between coagulo-fibrinolytic activity factors and treatment efficacy remains to be clarified. The aim of this study was to determine potential coagulo-fibrinolytic activity markers impacting survival.

Methods: Among 119 consecutive patients included in the study, 85 received first-line FOLFOX4 plus BV 5 mg/kg and 34 received second-line FOLFIRI plus BV 5 mg/kg until progression of disease or unmanageable toxicity occurred. Coagulo-fibrinolytic activity factors, including D-dimer, thrombin antithrombin complex (TAT) and carbohydrate antigen 125 (CA125) encoded by the MUC16 mucin gene were evaluated as candidate predictors of outcome.

Results: In first-line treatment, overall response, median progression-free survival (PFS) and two-year survival rate were 61.9%, 518 days and 67.3%, respectively. In second-line treatment, overall response, median PFS and median overall survival (OS) were 23.5%, 248 days and 651 days, respectively. The outcomes of the univariate analysis were as follows: normal D-dimer and CA125 levels at baseline were associated with better PFS and OS in first-line treatment; normal TAT and CA125 levels at baseline were associated with better PFS and OS in second-line treatment. According to the results of the multivariate analysis, normal D-dimer level was associated with longer PFS in first-line treatment, and only CA125 level at baseline was an independent predictor of both PFS and OS in second-line treatment.

Conclusions: The results suggest that coagulo-fibrinolytic activity factors such as TAT, D-dimer or CA125 may be useful predictors of outcome in mCRC patients receiving BV in combination with chemotherapy.

No significant financial relationships to disclose.
Phase II study of preoperative helical tomotherapy with a simultaneous integrated boost for rectal cancer.
Authors: Engels B. , Tournel K. , Everaert H. , Sermeus A. , Storme G. , Verellen D. , De Ridder M.
Published: February 2017

537

Background: The addition of concomitant chemotherapy to preoperative radiotherapy is standard of care for patients with T3-4 rectal cancer. The combined treatment modality increases the complete response rate and local control, but has no impact on survival or the incidence of distant metastases. Besides, it is associated with considerable toxicity. As an alternative strategy, we explored prospectively preoperative helical tomotherapy with a simultaneous integrated boost (SIB).

Methods: 106 patients were treated with intensity-modulated and image-guided radiotherapy using the Tomotherapy Hi-Art II system. A dose of 46 Gy, in daily fractions of 2 Gy, was delivered to the mesorectum and draining lymph nodes, without concomitant chemotherapy. In patients with a circumferential resection margin (CRM) less than 2 mm on magnetic resonance imaging, a SIB was delivered to the tumor up to a total dose of 55.2 Gy. Acute and late side effects were scored using the NCI-CTC AE v. 3.0. Stage III patients received standard adjuvant chemotherapy.

Results: 100 patients (94%) presented with a T3-4 tumor, of which 52 patients entered the boost group (CRM < 2 mm). 54 patients entered the no-boost group. One patient in the no-boost group developed a radiohypersensitivity reaction, resulting in a complete tumor remission, a grade 3 acute and grade 5 late enteritis. No other grade 3+ acute toxicities occurred. With a median follow-up of 32 months (range, 6-58), grade 3+ late gastrointestinal and urinary toxicity was observed in 7 patients (6%) and 4 patients (4%), respectively. Until yet, 2 locoregional relapses were observed. The actuarial 3-year local control, progression-free survival, and overall survival were 97%, 74% and 83%, respectively.

Conclusions: Preoperative helical tomotherapy displays a favourable toxicity profile in patients with T3-4 rectal cancer. A SIB can be safely administered in patients with a narrow CRM and results in a promising local control.

No significant financial relationships to disclose.
Phase I dose escalation and pharmacokinetics study of intravenous aflibercept plus irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) in patients with metastatic colorectal cancer.
Authors: Yamazaki K. , Yoshino T. , Yamaguchi K. , Boku N. , Machida N. , Onozawa Y. , Asayama M. , Doi T. , Ohtsu A. , Aoyama T.
Published: February 2017

538

Background: Aflibercept (AF), a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor. This study assessed the safety, dose limiting toxicities (DLTs), recommended dose (RD), and the pharmacokinetics (PK) of AF in combination with FOLFIRI.

Methods: This was an open-label, sequential-cohort, dose-escalation study of intravenous AF administered every 2 weeks, in combination with FOLFIRI (fixed doses) in patients (pts) with metastatic colorectal cancer (MCRC). Two dose levels (DL) of AF (2 and 4 mg/kg) were set, and 3-6 pts were to be recruited in each DL. DLTs were to be evaluated in the first 2 cycles. RD was defined as the highest AF dose at which <33% of all evaluable pts experienced DLTs. After establishment of RD, 10 additional pts were treated at RD. PK of AF, irinotecan, SN38, and 5-FU were studied in cycle 1.

Results: 16 pts (3 at 2 mg/kg and 13 at 4 mg/kg) with MCRC were treated (M/F, 10/6; median age, 57.0 [47-69]; and ECOG PS 0/1, 9/7), and all had received prior chemotherapies. A total of 131 cycles of AF + FOLFIRI were administered at the two DLs of AF (2 and 4 mg/kg). No DLT was observed. The most common all-causality grade 3/4 adverse events were neutropenia (75.0 %) including one febrile neutropenia after DLT evaluation period and hypertension (25.0%). There was no major safety issue at the RD. Response rate and progression free survival at RD (N=13 pts) was 7.8% and 7.6 month, respectively.

Conclusions: RD was determined as 4 mg/kg in this first clinical study of AF in Japanese pts with MCRC. The combination of AF (4 mg/kg) and FOLFIRI was well tolerated in line with results of prior overseas studies. The PK results in Japanese patients showed similar tendency to those reported in patients from other regions of the world.

[Table: see text]
Single-institution experience comparing double-barreled wet colostomy to ileal conduit for urinary and fecal diversion.
Authors: Chokshi R. J. , Kuhrt M. P. , Arrese D. , Parks L. , Johnson M. , Martin E. W.
Published: February 2017

542

Background: Patients with advanced primary or recurrent colorectal cancers that undergo total pelvic exenteration for cure or palliation require proximal urinary and fecal diversion. The most commonly used diversion technique is use of an ileal conduit (IC) and end colostomy. At our institute, the double-barreled wet colostomy (DBWC) has been shown to be have similar outcomes and technically feasible.

Methods: Between 2004 and 2010, 37 patients underwent total pelvic exenteration for advanced primary or recurrent colorectal cancer. Two groups were identified based on the technique used for their urinary diversion, either by way of an IC (n = 4) or DBWC (n = 33). Demographics, periprocedural events, and outcomes were compared between the two groups.

Results: The two groups were similar in the terms of age, gender, and comorbidities. Thirty-three patients (89%) underwent a DBWC and four patients (11%) underwent an IC. All of these patients underwent a total pelvic exenteration for advanced primary (27%) or recurrent colorectal cancer (73%) either for cure or for palliation. Twenty patients underwent R0 resection (54%), and 17 patients had non-R0 resection (46%). Complications, length of stay, and operative times between both groups were similar. Median survival for both groups showed no statistical difference.

Conclusions: DBWC is a safe and feasible alternative to the traditional ileal conduit for urinary diversion. It provides a single stoma to care for, and an intact contralateral abdominal muscle to use as a vertical rectus abdominus musculocutaneous flap for reconstruction. This technique is easy to learn and is not associated with higher operative times, length of stay, morbidity, or mortality.

[Table: see text]

No significant financial relationships to disclose.
Preclinical antitumor activity and mechanisms of action of apricoxib, a clinical COX-2 inhibitor.
Authors: Burrows F.
Published: February 2017

543

Background: Apricoxib, a selective COX-2 inhibitor, is currently in phase II trials, but its anticancer mechanisms of action could be better defined. Apricoxib inhibits COX-2 enzymatic activity and suppresses production of PGE2 and VEGF at low nanomolar concentrations but also directly inhibits tumor cell proliferation and survival with 10-20μM potency. In this study we characterized the in vivo activity of apricoxib in xenograft models of lung, breast and colorectal carcinoma. Also, we examined the relationship between the PK, PD and antitumor activity and the effect of the drug on both tumor cell-autonomous functions and aspects of the tumor-host relationship in the HT29 model.

Methods: Human tumor xenografts were grown in nude mice and apricoxib was given daily PO. Drug levels were quantified by LC-MS and VEGF levels by ELISA. Vessel density, apoptosis, proliferation and EMT were assessed by immunohistochemistry.

Results: Apricoxib significantly retarded tumor growth in NSCLC models and also enhanced the efficacy of SOC drugs in breast and lung tumors. In the HT29 model, the drug was active at both doses tested. Drug concentrations in plasma and tumors peaked at 2-10 μM within an hour and decreased rapidly to submicromolar levels but concentrations persisted above the active concentration for inhibition of PGE2 production for >24h. This strongly indicates that apricoxib exerts its in vivo activity via blockade of COX-2-dependent PGE2 production. Plasma VEGF levels decreased to zero for 6h post-dose, but returned to baseline by 24h. CD31 and Endomucin staining revealed no drug effect on microvessel density, although the percentage of immature vessels was reduced, as determined by pericyte coverage/NG2 expression. Apoptosis was significantly increased by TUNEL in apricoxib-treated tumors. PCNA analysis revealed a decrease in proliferating cells. ECAD expression was significantly increased in treated animals, whereas ZEB1 expression was lower, suggesting that COX-2 activity also plays an important role in EMT.

Conclusions: Apricoxib possesses antitumor activity as a single agent and in combination. In the HT29 model, apricoxib inhibits tumor proliferation and survival, normalizes tumor vasculature and reverses EMT.

[Table: see text]
SUNCAP, a phase II study with sunitinib and capecitabine in patients with metastatic colorectal cancer (MCRC) refractory to previous treatment with 5FU/irinotecan/oxaliplatin.
Authors: Samson B. , Latreille J. , Nguyen N. T. , Sperlich C. , Berbiche D. , Tournigand C.
Published: February 2017

545

Background: Patients (pts) with MCRC refractory/resistant to Irinotecan and Oxaliplatin have a poor prognosis. Sunitinib is an oral TKI that selectively inhibits the VEGFR 1, 2, 3, PDGFR and FLT3, CSF-1R, RET. Phase II studies with single agent sunitinib in patients with MCRC did not demonstrate a meaningful ORR but showed acceptable safety profile and warranted further study.

Methods: We conducted a phase II escalating dose of sunitinib (S) and capecitabine (C) to assess the efficacy of this oral treatment given on a 2 wks every 3 wks schedule, (level 0, S: 37,5 mg, C: 2,000mg/m2, level +1, S: 50 mg, C: 2,000 mg/m2, level +2, S: 50 mg, C: 2,500 mg/m2 and level -1:S: 25 mg, C: 1,500 mg/m2. Treatment was initiated at level 0 and increased at level +1 and +2 at cycle 3 and 5 if no grade 2/3 toxicity was observed. Between 02.2009 and 06.2010, 15 pts previously exposed to oxaliplatin/irinotecan/bevazizumab were enrolled, all of them had progressive disease at the time of study entry. Primary objective was ORR. Treatment was given until PD or unacceptable toxicity.

Results: Pts characteristics were: sex: 12M/3F, median age: 65 years [41-75], primary tumors: colon: 13, rectum: 2, ECOG PS 0/1: 8/7, median nb of metastatic sites: 3, KRAS status: WT/MT/Unknown: 1/9/5. Escalating to level +1:53%, level +2: 7%. Median nb of cycles received/pt: 5. All pts were evaluable for toxicity (tox): SAEs: 40%, any tox. grade 1/2/3(%): 93/60/ 40. Neutropenia gr. 1/2/3(%): 13/13/7, thrombocytopenia gr.1/2/3(%): 13/20/7. Fatigue gr.1/2/3(%): 27/20/7. Nausea gr.1: 27%. Diarrhea gr.1: 13%. Hand foot syndrome gr. 1/2/3 (%): 13/13/27. Mucositis gr. 1/2/3(%): 7/20/7. Hypertension gr.2: 13%. Thyroïd gr.1: 27%. ORR (CR+PR): 0%, confirmed SD: 7/15: 47%, PD: 8/15: 53%. Median PFS: 137 days [95%CI: 112-162], median OS: 291 days [95%CI: 99-482].

Conclusions: In this heavily pretreated patients, sunitinib in combination with capecitabine appears feasible, with acceptable toxicity. 47% of patients had a confirmed stable disease. Although no objective response was observed, the high level of stable disease may suggest a role of this combination for maintenance therapy.

[Table: see text]
Preoperative chemoradiotherapy with capecitabine and oxaliplatin in patients with locally advanced rectal cancer.
Authors: Marrodan I. , Azkona E. , Carrera S. , Aresti U. , Calvo B. , Buque A. , Sancho A. , Ruiz de Lobera A. , Munoz Llarena A. , Lopez-Vivanco G.
Published: February 2017

548

Background: Locally advanced rectal carcinoma is associated with high rate of abdomino-perineal amputation. We analyzed a cohort of patients (pts) diagnosed of locally advanced rectal cancer, treated with neoadjuvant chemoradiotherapy (QT-RT) with capecitabine and oxaliplatin (XELOX) followed by four cycles of adjuvant XELOX after surgery.

Methods: Patients with locally advanced rectal cancer (T3-T4 and/or N+) were treated with oxaliplatin (50mg/m2 day 1, 8, 22 and 29) and capecitabine (1,650mg/m2 on days 1 to 14 and 22 to 35) combined with pelvic radiotherapy (180 cGy/day; 45Gy in 25 fractions). Surgery was scheduled 4 to 6 weeks after completion QT-RT. Four cycles of adjuvant XELOX were administered (capecitabine 2,000mg/m2 on days 1 to 14 and oxaliplatin 130mg/m2 on day 1) every 3 weeks. Main end points assessed were: rate of sphincter preservation, pathologic complete response (pCR) rate and the feasibility of postoperative chemotherapy.

Results: From March 2007 to April 2010, 98 pts with locally advanced rectal cancer were included. M/F: 66/32; ECOG 0/1: 19/79; median age: 64 (38-81); upper/mid/distal rectum: 13/50/35; clinical stage: cT3/N- 9, cT2-T3/N+ 72, cT4/N- 4, cT4/N+ 13. Full dose of preoperative QT-RT was administered in 93 pts (95%). Main toxicities were grade 1/2 neurotoxicity (56/4) and grade 2/3 diarrhea (23/10). After treatment 96 pts underwent surgery. Sphincter preservation, R0 resections and pCR were achieved in 57, 93 pts and 17 (18%) patients, respectively, and 65 pts (66%) received all 4 cycles of adjuvant XELOX. Grade 3/4 toxicities included diarrhea 3/0, vomiting 2/0, neurotoxicity 5/0, hand-foot syndrome 1/0, neutropenia 4/0 and thrombopenia 0/4. 3-year progression-free and overall survival were 66% and 72%, respectively. No toxic deaths were reported. Downstaging in T/N stage was achieved in 53/71 pts (55/74%) respectively.

Conclusions: Combination preoperative QT-RT with capecitabine and oxaliplatin is a well tolerated regimen and achieves encouraging rates of pCR, R0 resection, sphincter preservation and tumor downstaging in patients with locally advanced rectal cancer.

No significant financial relationships to disclose.
A phase Ib, open-label, dose-escalation study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.
Authors: Eskens F. , Oldenhuis C. N. , Bhargava P. , Loos W. , Esteves B. , van Doorn L. , Cotreau M. M. , Dhillon R. , Gietema J. A. , De Vries E.
Published: February 2017

549

Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors.

Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6.

Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level.

Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned.

[Table: see text]
Delays in adjuvant chemotherapy following AP resection for low rectal cancer: Audit results and implications for clinical practice.
Authors: Nimalasena S. S. , Gaya A. M.
Published: February 2017

562

Background: Abdominoperineal resection (APR) remains the surgical procedure of choice for low rectal cancer. Historically, it has been associated with high rates of postoperative haemorrhage, infection, and wound dehiscence. The perineal wound is particularly at risk, with rates of 16-41% reported. This may delay adjuvant chemotherapy and adversely affect survival.

Methods: Patients who underwent APR in our cancer network between March 2009 and June 2010 were identified. Records were reviewed with respect to complications and any impact on adjuvant chemotherapy.

Results: 28 patients underwent APR. The majority had Duke's C (68%) and Duke's B (14%) tumors. All received neoadjuvant chemoradiotherapy (CRT) to 45-54Gy with capecitabine 825 mg/m2 BD. Adjuvant chemotherapy (CAPOX, FOLFOX or capecitabine) was planned in 25/28 (89%) patients. 2 declined, and of the remaining 23, 12 patients (52%) could not receive chemotherapy (Table). Of patients who received adjuvant chemotherapy, the average delay in starting was 2 weeks. At the time of reporting, 25/28 (86%) patients are alive without disease recurrence. One patient who did not receive adjuvant chemotherapy due to wound dehiscence, has recurrent pelvic disease, and is receiving best supportive care. Two patients died of metastatic disease; one could not receive adjuvant chemotherapy due to wound infection.

Conclusions: Our audit has highlighted that a significant proportion of patients undergoing APR do not receive adjuvant chemotherapy on time due to wound complications. Often the time taken for wound healing exceeds 3 months, by which time the benefit of chemotherapy is negligible. Phase II studies of neoadjuvant chemotherapy prior to CRT for locally advanced rectal cancer have shown impressive progression-free and overall survival rates, with good compliance rates and favorable toxicity profiles. Further studies are needed. Patients with low rectal tumours who require APR, should be considered for a neoadjuvant chemotherapy approach.

[Table: see text]

No significant financial relationships to disclose.
Early prediction of pathological complete response (pCR) of rectal cancer after 1 week of preoperative radiochemotherapy (RCT) using positron emission computererized tomography (PET-CT) imaging.
Authors: Purim O. , Goldberg N. , Kundel Y. , Brenner R. , Efremov N. , Gordon N. , Morgenstern S. , Wasserberg N. , Brenner B.
Published: February 2017

572

Background: Preoperative radiochemotherapy (RCT) is the standard treatment of locally advanced rectal cancer (LARC), obtaining pathological complete response (pCR) in 15%-30% of cases. Post-RCT reduction of 18F-fluorodeoxyglucose (FDG) uptake within the tumor compared with the baseline, i.e. the tumor's metabolic response, correlates with pCR. However, an earlier prediction of pCR could enable tailored modifications of the treatment. We hence evaluated the correlation between the metabolic response after only one week of RCT for LARC and the actual pCR at the post-RCT surgery.

Methods: Patients (pts) were eligible for this prospective study if they had LARC, defined as T3-4NX or TxN+ tumors by pre-treatment PET-CT and endoscopic ultrasound. Pts received standard RCT regimen, consisting of 50.4Gy radiotherapy concurrently with a fluoropyrimidine-based chemotherapy, followed by surgery. Pts underwent baseline FDG-PET-CT imaging within 2 weeks prior to the initiation of RCT and a second one on day 8 of RCT. Maximum standardized uptake value (SUV-max) was measured in both scans and changes in FDG- uptake were recorded. Man-Whitney test was used to evaluate differences in the SUV-max between baseline and day 8 in pts obtaining pCR and those who did not.

Results: Twenty pts participated in the study. Half were males and the median age was 64 years. Ten pts had T3N0 tumors and 10 had T3N+ disease. Radical surgery was done in 19 pts and local excision in one. Considering the entire group, there was a borderline-significant difference between the metabolic response of pts with pCR and those without pCR (Chi-square = 3.429, p = 0.064). Yet, the changes in FGD-uptake were able to identify pts who achieved pCR and those who did not: only pts with a decrease of more than 33% in SUV-max had pCR while none of the pts who had less than 8.9% decrease in SUV-max had pCR.

Conclusions: A decrease in SUV-max between baseline-PET-CT scans and scans done after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned.

No significant financial relationships to disclose.
Patient (Pt)-reported symptoms of chemotherapy (chemo) and VEGFR/EGFR antibody therapies for the treatment of metastatic colorectal cancer (MCRC) in a U.S. community-based oncology practice network.
Authors: Feinberg B. A. , Gilmore A. , Lunacsek O. , Haislip S. , Yu E. , Yim Y. , Gilmore J. W.
Published: February 2017

575

Background: Targeted therapies for MCRC have increased treatment (Tx) options in multiple therapy lines. Symptoms associated with MCRC Tx have not been well studied from the Pt perspective. Objective: To characterize symptoms reported by MCRC Pts treated with chemotherapy and/or targeted drugs at a large US oncology network.

Methods: Pt reported symptom data were linked to electronic medical records and Pt charts from Georgia Cancer Specialists in Southeast US. MCRC Pts aged ≥18 years with ≥1 administration of chemo or targeted therapy between 1/2007-3/2009 were included. Pt reports captured 13 symptoms, onset, and severity. Due to small sample sizes, no statistical comparisons were conducted.

Results: 332 MCRC Pts were included (median age 62 years, 47% male, median weight 74 kg, 48% ECOG PS 0 or 1). Amongst Pts receiving 1L Tx (n=299), 78% received bevacizumab (BV) +/- chemo, 4% cetuximab (CX) +/- chemo, 15% chemo only, and 2% other. 162 Pts received 2L Tx: 49% BV +/- chemo, 17% chemo only, 28% CX +/- chemo, and 6% other. The 5 most common symptoms in 1L Tx for all severity ratings were 36% fatigue, 20% nausea, 17% weight (wt) loss, 15% diarrhea, and 9% constipation. The 5 most common symptoms in all 2L Tx groups were 44% fatigue, 27% nausea, 19% diarrhea, 16% wt loss, and 11% abdomen pain. 2L moderate, severe, or disabling symptoms reported in >10% Pts receiving BV +/- chemo, CX +/- chemo, and chemo only Tx are shown in the table.

Conclusions: The most commonly reported symptoms by 1L and 2L MCRC Pts were fatigue, nausea, diarrhea, and weight loss. Overall, a numerically higher % of 2L Pts treated with CX +/- chemo reported moderate, severe, and disabling symptoms than Pts receiving BV +/- chemo and chemo alone. Rash was not observed in the BV +/- chemo group. Further research of MCRC Pt reported symptoms in a larger sample size are warranted.

[Table: see text]

[Table: see text]