bluuebunny/crossref_metadata_2025 huggingface dataset:
Irinotecan-induced neutropenia and UGT1A1*28: Does dose matter?
Authors: Hoskins J. M. , Goldberg R. M. , McLeod H. L.
Published: March 2020

4023

Background: On July 7 2005, the Food and Drug Administration (FDA) of the U.S.A. and Pfizer Pharmaceuticals changed the package insert information for irinotecan to include a patient’s UGT1A1*28 genotype as a risk factor for severe neutropenia. This change resulted from the findings of four pharmacogenetic studies that identified a 2.5 to 17-fold risk of toxicity in homozygous UGT1A1*28 patients receiving irinotecan. Notably, a total number of 34 patients in the four studies were homozygous for the UGT1A1*28 allele. Subsequent studies on larger patient cohorts treated with other dosage regimens have failed to consistently replicate the UGT1A1*28 genotype-toxicity associations, thus confounding the development of dosing recommendations. This has contributed to confusion on how best to select a safe dose of irinotecan for a patient who is homozygous for UGT1A1*28. Methods: We reviewed the data presented in ten irinotecan pharmacogenetic studies (825 patients) and assessed the correlations between the incidence of irinotecan-induced hematological toxicities (grade III/IV) in UGT1A1*28/*28 patients, irinotecan dose, and overall toxicity. Results: We found that the incidence of grade III/IV hematological toxicities in UGT1A1*28/*28 patients was positively related to both irinotecan dose (Spearman Rank correlation rS=0.68; P=0.04; N=10 studies) and the overall incidence of toxicity of a regimen (rS=0.88; P=0.002; N=10 studies). The incidence of severe hematological toxicity amongst all patients was not related to irinotecan dose (rS=0.44; P=0.20, N=10 studies). Conclusions: Our results suggest that the risk of experiencing irinotecan-induced hematological toxicity for UGT1A1*28/*28 patients is a function of the dose of irinotecan administered. In the spirit of maximizing patient safety, we support the use of genotype-based dosing of irinotecan for high doses of irinotecan, but believe it may not be as useful for lower doses and suggest strategies for dosing patients with irinotecan.

[Table: see text]

No significant financial relationships to disclose.
18F-FDG PET changes management and improves prognostic stratification in patients with colorectal cancer: results of a prospective, multi-centre study
Authors: Scott A. M. , Gunawardana D. , Kelly B. , Stuckey J. , Byrne A. , Ranshaw J. , Fulham M.
Published: March 2020

4025

Background: The aims were to: 1) examine the impact of PET in changing management in patients with proven or suspected recurrence of colorectal cancer and, 2) assess the impact of management change on disease free survival. Methods: Symptomatic patients (Group A) with a residual structural lesion suspicious for recurrent tumour, or patients (Group B) with pulmonary or hepatic metastases, which were potentially resectable as determined by conventional imaging, underwent PET scans. Pre- and post-PET management plans were documented blinded to PET results. Patients were followed for 12 months to determine actual management and to assess clinical outcomes. Results: A total of 191 patients (118M:73F, mean age 66 yrs) were recruited. PET detected additional sites of disease in 48.4% of Group A and 43.9% of Group B patients. Importantly, a change in planned management was documented in 65.6% of Group A and 49.0% of Group B patients. Follow-up confirmed implementation of management plans in 96% of patients. Analysis of follow-up data to 12 months post- PET showed that in Group A progressive disease was identified in 60.5% of patients with additional lesions detected on PET compared with conventional imaging, and 36.2% patients with no additional lesions detected by PET (p=0.0364); in Group B progressive disease was identified in 65.9% of patients with additional lesions detected on PET and 39.2% patients with no additional lesions detected by PET (p=0.0198). Patient follow-up also showed that PET provided valuable prognostic information in patients stratified into curative/palliative intent groups. Conclusions: These data unequivocally demonstrate the significant impact of PET on management and outcomes in patients with suspected recurrent colorectal cancer.

No significant financial relationships to disclose.
Updated results of BICC-C study comparing first-line irinotecan/fluoropymidine combinations with or without celecoxib in mCRC: Updated efficacy data
Authors: Fuchs C. , Marshall J. , Mitchell E. , Wierzbicki R. , Ganju V. , Jeffery M. , Schultz J. , Richards D. A. , Soufi-Mahjoubi R. , Barrueco J.
Published: March 2020

4027

Background: This multicenter, randomized study assessed efficacy & safety for irinotecan/fluoropyrimidines combinations in previously untreated mCRC. Methods: Pts were randomized to: infusional FOLFIRI, modified bolus IFL (mIFL), or CapeIri; and concurrent celecoxib or placebo in a double-blind fashion. The protocol was amended in April 2004: bevacizumab (bev) was added to the FOLFIRI and mIFL arms, whereas CapeIri was discontinued. Period 1 (P1) and Period 2 (P2) designate subjects enrolled before or after the amendment. Initial efficacy & safety analyses were reported at ASCO ’06. We now report follow-up of 46 months for P1 and 31 months for P2. Results: 430 pts were treated in P1 and 117 pts in P2. Baseline characteristics and post-study treatment were balanced. P1 results: Median progression free survival (PFS) was 7.6 mos for FOLFIRI; 5.9 mos for mIFL (p=0.004); and 5.8 mos for CapeIri (p=0.015). Median overall survival (OS) was 23.1 mos for FOLFIRI; 17.6 mos for mIFL (p=0.087); and 18.9 mos for CapeIri (p=0.27). One-year survival rate favored FOLFIRI (75%) compared to either mIFL (65%) or CapeIri (66%). Overall Response Rate (ORR) was 47% in FOLFIRI, 43% in mIFL, 39% in CapeIri (not significantly different). P2 results: Median PFS was 11.2 mos for FOLFIRI+bev and 8.3 mos for mIFL+bev (p=0.28). Median OS was not reached for FOLFIRI+bev but was 19.2 mos for mIFL+bev (p=0.007). One-year survival rate favored FOLFIRI+bev (87%) when compared to mIFL+bev (61%). ORR was 58% for FOLFIRI+bev and 54% for mIFL+bev (p=0.73). Common grade = 3 AEs are listed below. Celecoxib did not impact safety or efficacy. Conclusions: First line FOLFIRI or FOLFIRI+bev were superior to their comparators and show favorable results in survival and tolerability in untreated mCRC. Median survival for FOLFIRI+bev has not been reached.

[Table: see text]

No significant financial relationships to disclose.
Final results of CONFIRM 2: A multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo
Authors: Kohne C. , Bajetta E. , Lin E. , Valle J. W. , Van Cutsem E. , Hecht J. R. , Moore M. , Germond C. J. , Meinhardt G. , Jacques C.
Published: March 2020

4033

Background: PTK/ZK, a novel, oral, anti-angiogenic compound that inhibits all VEGF receptors has been investigated in two multinational randomized phase 3 studies in 1st (CONFIRM 1) and 2nd line (CONFIRM 2) mCRC. Interim analyses (IA) have been presented at ASCO 2005 and 2006, respectively. Methods: In CONFIRM 2, 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically documented mCRC, pre-treatment for metastatic disease with irinotecan-/fluoropyrimidine- based therapy, measurable disease by RECIST, PS of 0–2 and adequate organ function. Pts were stratified based on PS (0 vs. 1–2) and baseline serum Lactate Dehydrogenase (LDH = vs. >1.5 × ULN). The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (LDH > 1.5 × ULN). Results: At the time of IA in July 2005, OS was 12.1 mo in the PTK/ZK and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, a marker for poor prognosis in mCRC, is predictive of the outcome in the PTK/ZK arm. When treated with PTK/ZK, high LDH pts showed a strong improvement in PFS (5.6 mo vs. 3.8 mo; HR: 0.63; p<0.001) and in OS (9.6 mo vs. 7.5 mo; HR: 0.78; p=0.10). Adverse events (AE) were similar to that of the CONFIRM 1 trial. Final analysis for OS, PFS and safety is planned for Feb. 2007 after 732 events (compared to 413 in the IA) and will be presented at the meeting. Conclusions: While the primary endpoint for OS was not met in the IA, PTK/ZK improves PFS significantly in the overall population, and shows strong activity (improved PFS and OS) in patients with high baseline serum LDH. Final results of the study will be presented at the meeting.

No significant financial relationships to disclose.
Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study
Authors: Bokemeyer C. , Bondarenko I. , Makhson A. , Hartmann J. T. , Aparicio J. , Zampino M. , Donea S. , Ludwig H. , Zubel A. , Koralewski P.
Published: March 2020

4035

Background: FOLFOX-4 is a standard first-line treatment for patients (pts) with mCRC. The IgG1 monoclonal antibody cetuximab has proven activity in combination with cytotoxic chemotherapy. Excellent response rates (RRs) have been reported with first-line cetuximab and FOLFOX-4. This randomized, controlled study was conducted to compare RRs of FOLFOX-4 + cetuximab vs FOLFOX-4. Methods: Pts with previously untreated epidermal growth factor receptor (EGFR)-expressing mCRC not resectable with curative intent were eligible. They were randomized 1:1, stratified by ECOG performance status (PS) (0–1 vs 2), to either Group A (cetuximab 400 mg/m2 initial dose then 250 mg/m2/week plus FOLFOX-4 every 2 weeks [oxaliplatin 85 mg/m2 day (d) 1; FA 200 mg/m2 d1, 2; 5-FU 400 mg/m2 bolus + 600 mg/m2 infusion over 22 h, d1, 2]) or Group B (FOLFOX-4 only). The primary objective was the best confirmed RR assessed by independent review; secondary objectives were progression- free survival (PFS), overall survival (OS), the R0 resection rate after metastatic surgery of curative intent and safety. Results: Between July 2005 and March 2006, 337 pts were randomized and treated in more than 70 centers in Europe. 181 (53.7%) pts were male; the median age of all pts was 61.0 years [24–82]; 305 (90.5%) pts had an ECOG PS of 0 or 1, and 32 (9.5%) of 2. The best overall confirmed RR was 45.6% in A and 35.7% in B. For pts with ECOG PS 0–1, RR was 49.0% in A and 36.8% in B (Odds Ratio 1.648, 95%CI [1.043- 2.604]). PFS and OS results are not yet available. The most common grade 3/4 adverse events were neutropenia (27.6% in A; 31.5% in B), diarrhea (7.1 and 6.0%), leucopenia (7.1 and 5.4%) and rash (9.4%, in A only). Conclusions: The addition of cetuximab increased the RR of FOLFOX-4 in first-line treatment of mCRC. Grade 3/4 adverse events, with the exception of skin rash, were not significantly more frequent in the cetuximab arm.

No significant financial relationships to disclose.
Treatment patterns and outcomes of patients with pT3N0 rectal cancer in a population-based setting
Authors: Johal B. S. , Phang P. , McGahan C. , Hay J. , Brown C. , Kennecke H.
Published: March 2020

4039

Background: Adjuvant radiation (R) and chemotherapy (C) is generally recommended for patients (pts) with pT3N0 rectal cancer. Patterns of adjuvant therapy and outcomes among pts with pT3N0 rectal cancer referred to the British Columbia Cancer Agency (BCCA) were determined. Methods: The BCCA Colorectal Cancer Outcomes Unit database was used to identify referred pts with pT3N0 rectal carcinoma diagnosed between 2000–2004. During this period, “short course” R (25Gy/5, surgery within 10 days) was recommended for resectable cT3 tumors followed by 6 months of C. If not treated pre-operatively (pre-op), guidelines specified post-op “long course” (45Gy/25) R and C. Three treatment groups were identified: Surgery alone (S), S and R (SR), and S, R and C (SRC). Eligible pts had complete surgical resection with or without Total Mesorectal Excision (TME). Pts treated with “downstaging” pre-op long course R, with S and C only (13 pts) or with R2 resection were excluded. Locoregional Recurrence (LR) and Distant Recurrence (DR) rates determined. Reasons for non-treatment were determined by chart review. Results: 303 pts were identified, with median follow-up of 33.5 months. Significant differences in age, tumor height, grade, and R therapy existed between groups ( Table I ). TME status, R status and Radial Margin positivity were similar. LR rates were 15% (S), 2% (SR) and 1.4% (SRC). DR rates were 11.7% (S), 7.9% (SR) and 8.5% (SRC). Median Overall Survival (OS) and Disease Free Survival (DFS) was not reached. Conclusions: Treatment of pT3N0 rectal cancer was variable and significant heterogeneity existed between groups receiving S, SR and SRC. Nevertheless, LR rates were very low in pts receiving R and substantially higher in pts who did not. DR rates were similar across groups, irrespective of C history. Reasons for not receiving R or C were primarily patient related (medical/post- operative considerations, patient refusal). Potential physician related factors (non-referral) accounted for 28% of lack of C treatment in the SR group.

[Table: see text]

No significant financial relationships to disclose.
Preoperative FU-based chemoradiation with or without weekly oxaliplatin in locally advanced rectal cancer: Preliminary safety findings of the STAR (Studio Terapia Adiuvante Retto)-01 randomized trial
Authors: Aschele C. , Pinto C. , Cordio S. , Rosati G. , Bonetti A. , Alabiso O. , Siena S. , Pucciarelli S. , Boni L. , Cionini L.
Published: March 2020

4040

Introduction: Oxaliplatin (OXA) significantly enhances the efficacy of 5-Fluorouracil (FU)-based chemotherapy (CT) in metastatic and radically resected, early stage colon cancer. Weekly OXA, at systemically active doses, can be added to preoperative FU-based pelvic chemoradiation (CRT) (Aschele, Ann Oncol 2005). Methods: An open-label, multicenter, randomized, phase III trial was launched to compare the efficacy (disease-free and overall survival) and activity (pathological response rate) of infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (Arm A) to that of the same regimen plus weekly OXA (60 mg/msq weekly x 6) (Arm B). TME surgery is scheduled 6–8 weeks after completing CRT. FU-based adjuvant CT (4 cycles) is planned in both arms. Eligible patients (pts) have resectable tumors located within 12 cm from the anal verge and radiological evidence of perirectal fat or regional nodes involvement. Results: 410 pts (median age 63 years; males/females: 66/34 %; cT3/cT4: 66/18 %; cN+: 56 %; median distance from the anal verge: 6 cm) were randomized between 11/2003 and 10/2006 at 40 Italian centers. Toxicity data from the first 250 randomized pts are reported in the table . CRT was completed by 89 % and 74 % of pts in arm A and B, respectively. The median cumulative dose of delivered radiotherapy was 50.4 Gy in both arms. 120 of 123 pts in arm A and 109 of 112 pts in arm B were operated with a median interval from the end of treatment to surgery of 7.3 and 7.4 weeks, respectively. Conclusions: This analysis provides the first comparative toxicity data showing that OXA, at systemically active doses, can be safely added to standard FU-based CRT with an increased frequency and severity of acute toxicity but without major unexpected adverse events and without affecting the ability to deliver full RT doses and to perform surgery.

[Table: see text]

No significant financial relationships to disclose.
Bevacizumab, a vascular endothelial growth factor (VEGF) specific antibody reduces interstitial fluid pressure (IFP) in human rectal cancer xenograft (HT29) by day 5: Is this evidence for rescheduling its timing relative to chemotherapy?
Authors: Dani M. , Vojnovic B. , Newman R. , Honess D. , Wilson I. , Mitchell I. , Glynne-Jones R.
Published: March 2020

4043

Background: Interstitial fluid pressure (IFP) of most solid tumours is increased relative to normal tissues; this is thought to be associated with the development of structurally and functionally abnormal blood and lymphatic vessels and interstitial fibrosis. Such interstitial hypertension creates a barrier for tumour transvascular transport, consequently compromising the delivery and efficacy of chemotherapy. We investigated the effect of Bevacizumab on IFP of a human rectal cancer xenograft. Methods: SCID mice bearing subcutaneous HT29 tumours of =8.5 mm diameter received a single dose of 10 mg/kg Bevacizumab intraperitoneally; controls received saline. Tumour IFP was measured in sedated mice (Hypnorm) on days 1, 3 and 5 post injection, using the wick-in-needle technique. Experiments were conducted under Home Office licence and approved by the local ethical committee. Results: Groups of 8 treated and control tumours were examined on days 1, 3 and 5 (n = 48). IFP was significantly lower (p<0.0001) on day 5 in treated than control tumours (mean ± SD 15.1 ± 4.7 cf 36.9 ± 5.6 mm Hg). No significant differences (p>0.05) between treated and control groups were seen on day 1 (31.8 ± 3.5 cf 30.6 ± 3.1 mm Hg) or day 3 (33.4 ± 5.5 cf 31.5 ± 3.2 mm Hg). No data were acquired on day 7 as the tumours ulcerated. Conclusions: Our data show that Bevacizumab causes a significant reduction of tumour IFP, but not until 5 days after treatment. Reduced IFP could augment uptake of cytotoxic drugs into tumour cells, hence timing of Bevacizumab relative to the first dose of chemotherapy could be of critical importance.

No significant financial relationships to disclose.
Delayed start of adjuvant 5-FU/leucovorin based chemotherapy in colon cancer is safe up to 12 weeks postoperatively
Authors: Carlsson G. , Albertsson P. , Gustavsson B.
Published: March 2020

4056

Background: Postoperatively adjuvant chemotherapy with 5-Fluorouracil modulated by leucovorin alone or in combination with Oxaliplatin significantly reduce the risk of recurrence and prolong the disease free survival (DFS) in patients with a radical resection for colonic carcinoma. In all reported studies the chemotherapy has started within 6–8 weeks after surgery. Due to complications following surgery it is not always possible to start adjuvant chemotherapy within this time frame. The aim of the present retrospective study was to investigate the effect on risk of recurrence and effect on DFS in patients treated in clinical routine practice in one single institution. Methods: Between 1992 and 2004, 234 patients (121 females, 113 males) with a median age of 66 years (range 25–84 years) received weekly bolus 5-FU/leucovorin postoperatively for 6 months. 211 (90.2%) had a Dukes′ C tumour and 23 (9.8%) high risk Dukes′ B tumour. The median time from surgery and start of adjuvant therapy was 71 days (range 30–190 days). Patients were divided in three groups, where chemotherapy started within 6 weeks, 8 weeks and 12 weeks after surgery and the frequency of recurrent disease and DFS were compared between these groups. Results: Medium follow-up was 35.6 months (range 2,7- 140.6 months). Five patients (21.7%) with Dukes′ B tumours and 76 patients (36.0%) with Dukes′ C tumours recurred during the follow-up period. There were no differences in the proportion of Dukes′ B and C tumours between the three groups. Recurrent disease was more frequent but no significant difference in patients that started within 6 weeks (52.6%) compared with patients that started within 8 weeks (45.5%) and 12 weeks (35.5%). In all three groups there was a tendency to better DFS in patients that started later than 6 or 8 weeks, but these differences were not significant. Conclusions: Starting adjuvant 5-Fluorouracil/leucovorin alone later than 6–8 weeks do not negatively effect the risk of recurrent disease or DFS.

No significant financial relationships to disclose.
Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI and monotherapy for mCRC: First BEATrial
Authors: Kretzschmar A. , Van Cutsem E. , Michael M. , Rivera F. , Berry S. , DiBartolomeo M. , Mazier M. , Lutiger B. , Cunningham D.
Published: March 2020

4072

Background: In a phase III pivotal trial in patients (pts) with metastatic colorectal cancer (mCRC), BEV (BEV, Avastin®) increased overall survival (OS) by 30% when added to first-line IFL chemotherapy (CT). Recently, a second trial reported a significant improvement in progression free survival (PFS) when BEV was added to FOLFOX/XELOX in a similar patient population. Although, First BEAT was opened to evaluate the safety profile of BEV in a broader pt population using a variety of CT regimens, efficacy endpoints were investigated. Methods: First BEAT enrolled 1,927 mCRC patients in 41 countries between June 2004 and February 2006. Eligible pts were treated with first-line CT (physician’s choice) in combination with BEV (5mg/kg q2w [5-FU-based CT] or 7.5mg/kg q3w [capecitabine [cap, Xeloda®]-based CT]) until disease progression. Secondary endpoints included OS, time to progression (TTP) and PFS. Disease progression was assessed by investigators. Results: By Nov 15th, 2006, 1,914/1,927 pts had data available for analysis (male 58%; median age 59 years, 33% =65 years; ECOG PS 0/1 65%/34%). Median follow-up was 15 months; 60-day mortality was 2.5%. Patients receiving 5-FU/cap CT appeared to have poorer prognosis with respect to age =65 years (41%), ECOG PS 0/1 (58%/42%) and 60-day mortality rate (6.6%), compared with those receiving doublet CT regimens. The most common first-line CT regimens used with BEV were FOLFOX (28%), FOLFIRI (26%), XELOX (18%) and 5-FU or cap CT (16%). Median PFS was 10.4 (95% CI: 10.1–10.9 months, based on 882 events), 10.5 (9.7 - 11.6) in FOLFOX, 10.3 (9.7 - 10.7) in XELOX, 11.1 (10.2–12.0) in FOLFIRI and 9.1 (8.1–10.3) in pts receiving 5-FU or cap CT, respectively. TTP was 10.8 (95% CI: 10.4–11.3 months, based on 805 events). Updated analyses will be presented. Conclusions: In this ongoing, large community-based study, the preliminary efficacy of first line BEV in mCRC pts receiving a variety of CT regimens appears consistent with that observed in large phase III randomised trials.

[Table: see text]
Metastatic colorectal cancer (mCRC) patterns of care: Implications for clinical trial design
Authors: Denlinger C. S. , Collins M. A. , Wong Y. , Litwin S. , Meropol N. J.
Published: March 2020

4079

Background: New approaches have expanded options for patients (pts) with mCRC. To characterize current practice paradigms that might bear on clinical trial design, we analyzed decision-making and treatment patterns in pts treated at a Comprehensive Cancer Center since the introduction of cetuximab (CET), and bevacizumab (BV). Methods: A retrospective review of all pts diagnosed with mCRC between 3/1/04 and 8/28/06 treated at Fox Chase Cancer Center. Results: 160 pts were treated, with 157 pts receiving at least one therapy regimen by 10 attending oncologists. There were 350 changes in therapy with 246 (70%) including continuation of at least one prior drug (92 BV, 111 fluoropyrimidines, 43 other). The most common reasons for treatment change were toxicity (33%), progressive disease (PD) (29%), treatment breaks (15%), and metastasectomy (11%) ( Table ). PD was a more common cause for treatment discontinuation in later phases of treatment (18% initial regimen vs. 36% subsequent regimens, p=0.0002). 24% of pts treated with oxaliplatin (OX) discontinued due to neuropathy. Hypersensitivity caused discontinuation in 5% of pts with OX and 7% of pts with CET. Resection of metastases was undertaken in 38% of pts. 43% of these pts received neoadjuvant therapy, and 56% received adjuvant therapy. 30% of pts have died, 29% remain on active treatment, 28% are on a treatment break, 3% are on hospice, and 11% are lost to follow-up. Conclusions: PD is no longer the primary reason for change of therapy in pts with mCRC. Metastasectomy is common and OX neuropathy is often treatment-limiting. These findings have important implications for endpoint selection and design of clinical trials in mCRC. Future clinical trials in mCRC must recognize treatment complexities and capture key components of decision-making that may result in prolonged survival. Furthermore, treatment breaks represent a potential window for the evaluation of new drugs.

[Table: see text]

No significant financial relationships to disclose.
A phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)
Authors: Fakih M. G. , Pendyala L. , Smith P. , Creaven P. , Toth K. , Zwiebel J. , Frankel S. , Litwin A. , Huffman L. , Egorin M.
Published: March 2020

4088

Background: At 5μM, vorinostat decreases thymidilate synthase (TS) expression by ∼ 40 fold, which translates into synergistic antitumor activity when added to 5-FU. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design with a planned expansion of the maximum tolerated dose (MTD) cohort to 10 patients (pts). Vorinostat (100mg, 200mg, 300mg, 400 mg dose levels) was given twice daily for 1 week followed by 1 week break. FOLFOX was administered at a fixed standard dose every 2 weeks on the 4th day of vorinostat. Tumor biopsies were obtained from liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 19 pts were treated on study (M/F: 12/7; median age: 58; ECOG 0/1: 6/13). All pts had failed prior FOLFOX therapy. Dose-limiting toxicities (DLT) were noted in 3 pts: 2/4 pts at dose level (DL)4 (vorinostat 400mg BID) consisting of grade (G) 3 fatigue, & diarrhea in 1 pt and G3 fatigue in the other; 1/8 pts at DL3 (MTD, vorinostat 300mg BID) consisting of G3 fatigue, anorexia, nausea, and dehydration. 8 pts have been treated at the MTD for a total of 38 cycles. “All Cycles” G3–4 toxicities at the MTD consisted of 2 pts with G3 neutropenia and 2 pts with G3 thrombocytopenia along with the above described DLT. Responses were evaluable in 17 pts: 0 Objective Response, 8 Stable Disease (4 confirmed). TS expression by IHC and by RT-PCR showed modest decreases in 2/6 patients after vorinostat treatment. Cmax of SAHA was < 2μM at all investigated DL, which could explain the lack of adequate TS down-regulation. Conclusions: vorinostat 300mg PO BID × 1 week every 2 weeks in combination with FOLFOX is the established recommended dose. The lack of significant TS down-regulation may be due to the suboptimal serum vorinostat concentrations. Alternate shorter vorinostat schedules may allow for further daily dose escalations and hence for better likelihood of TS down-regulation. This study was partly supported by CTEP, NCI.

No significant financial relationships to disclose.
Phase II study of infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer
Authors: Kopetz S. , Glover K. Y. , Eng C. , Wolff R. A. , Chang D. Z. , Adinin R. B. , Morris J. , Abbruzzese J. L. , Hoff P. M.
Published: March 2020

4089

Background: When compared to bolus 5-fluorouracil (F), leucovorin (L), and irinotecan (I) regimens such as IFL, the infusional F, L, I regimen (FOLFIRI) resulted in a improved toxicity profile with a response rate (RR) of 35% and median progression free survival (PFS) of 6.7 months. When combined with bevacizumab (B) as first-line treatment, IFL demonstrated improved activity with a RR of 45% and a median PFS of 10.6 months. Combining FOLFIRI and B may further improve the efficacy. Methods: We designed a single-arm, phase II trial of FOLFIRI+B with B (5mg/kg), I (180mg/m2), bolus of F (400mg/m2) and L (400mg/m2) with a 46-hour infusion of F (2400mg/m2) every 2 weeks. The primary endpoint was PFS. Chemotherapy naïve mCRC patients (pts) with a performance status of 0–2 received B alone on Day -14, starting FOLFIRI+B on Day 1. Proteomic and radiographic correlative studies were completed and will be reported separately. Results: N=41 pts, median age 56 y/o (range 26–78), M:F = 16:25, 5 pts with prior adjuvant therapy, were enrolled from 1/2005 to 1/2007. A total of 502 cycles have been administered (median = 12). The median PFS is 12.6 months. Response rate by intention-to-treat analysis was 62% (24 pts), with 33% stable disease (13 pts). Responses occurred after a median of 4 months of therapy. Fifteen pts remain on treatment; 26 pts are off study: 7 for progressive disease, 2 withdrew consent, 7 for toxicity and 2 for surgery unrelated to cancer. Eight pts were removed from the study for metastasectomies. Grade 3 or 4 toxicities included 17 occurrences of grade = 3 neutropenia, including 1 grade 4 febrile neutropenia, 4 grade 4 pulmonary emboli, 2 grade 3 hand-foot syndrome, and 1 grade 3 diarrhea. One pt included in the analysis developed a possible microperforation, manifested by peritonitis, after B alone and never received FOLFIRI. Conclusion: FOLFIRI+B is well-tolerated and efficacious, with an impressive PFS that compares favorably to historical controls. This regimen is an excellent choice as a first-line treatment for mCRC.

No significant financial relationships to disclose.
Vandetanib with mFOLFOX6 in advanced colorectal adenocarcinoma: An open-label, multicenter phase I study
Authors: Michael M. , Tebbutt N. , Gibbs P. , Smith R. , Godwood A. , Oliver S.
Published: March 2020

4095

Background: Vandetanib (ZD6474) is a once-daily oral anticancer agent that selectively inhibits VEGFR- dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation. The primary objective of this Phase I study was to establish the safety and tolerability of the vandetanib + mFOLFOX6 combination in patients with metastatic colorectal cancer (CRC). Secondary objectives included an assessment of pharmacokinetic (PK) interactions between vandetanib and mFOLFOX6, and preliminary evaluation of efficacy (RECIST). Methods: Patients with CRC who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) plus standard 14-day treatment cycles of mFOLFOX6 (oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 2-hr IV; 5-fluorouracil [5-FU] 400 mg/mg2 IV bolus and 5-FU 2400 mg/m2 46-hr IV). If <2 of 6 evaluable patients (ie, having completed 6 weeks of vandetanib treatment with associated mFOLFOX6 cycles) experienced a vandetanib-related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + mFOLFOX6. Results: Seventeen patients (12 male/5 female; 7 1st-line/10 2nd-line; mean age 61 years, range 48–75) received vandetanib 100 mg (n=9) or 300 mg (n=8) + mFOLFOX6; the median number of oxaliplatin cycles was 8. Two DLTs were reported: one patient receiving 100 mg vandetanib developed diarrhea (CTC grade 2), dehydration, electrolyte imbalance and QTc prolongation, and one patient receiving vandetanib 300 mg developed diarrhea (grade 3) that responded to dose reduction. Common adverse events (AEs), irrespective of grade, were diarrhea, nausea, lethargy (all n=11), neutropenia and peripheral neuropathy (both n=10); AEs =grade 3 reported in more than one patient were diarrhea (n=4, all grade 3) and neutropenia (n=5, grade 3; n=2, grade 4). There was no apparent PK interaction between vandetanib and oxaliplatin or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=3), stable disease =8 weeks (n=8), and progressive disease (n=3). Conclusions: In patients with advanced CRC, combining once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies

No significant financial relationships to disclose.
Phase II clinical study of combination therapy with irinotecan and S-1(IRIS) for inoperable recurrent advanced colorectal cancer (2nd report): For Hokkaido Gastrointestinal Cancer Study Group (HGCSG)
Authors: Komatsu Y. , Yuki S. , Iwanaga I. , Kudo M. , Tateyama M. , Amano T. , Sakata Y. , Asaka M.
Published: March 2020

4105

Background: We planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. We reported the interim reports of this study in colorectal cancer patients at ASCO 2006. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: Forty patients were enrolled in the present study. There were 23 men and 17 women. The median age was 62 years (range: 34 to 74 years). Two patients showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Three patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrhea drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Forty pts. are evaluable for efficacy: RR was 52.5% (CR 1, PR 20, SD 17, PD 2, 95% CI, 37–68%) and Disease Control Rate (CR+PR+SD) was seen in 96.0% of pts. PFS of this regimen is 311 days. MST is not reached. Conclusions: IRIS therapy achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. It seems that IRIS is a good treatment equal to FOLFIRI. Non-inferiority randomized phase III trial of IRIS vs. mFOLFOX6 (IFOX study) was planned, and it has been already started now. The latest data will be reported at the meeting.

No significant financial relationships to disclose.
Microarray analysis of formalin-fixed paraffin-embedded specimens shows distinct gene expression patterns in tumors containing the transforming growth factor beta receptor 6A polymorphism (TGFBR1*6A)
Authors: Omori A. , Stephens C. , Cooc J. , Danenberg P. V. , Danenberg K. , Lenz H. , Pasche B.
Published: March 2020

4111

Introduction: A frequent polymorphism of the type I transforming growth factor beta receptor (TGFBR1) is TGFBR1*6A (6A), which has a deletion of 3 CGC triplets coding for alanine within a 9-alanine (9A) repeat of TGFBR1 exon 1. 6A may act as a tumor susceptibility allele through switching TGF-beta growth inhibitory signals into growth stimulatory signals and also appears to be acquired in some cases by primary colon cancers and their liver metastases. Our aim in this study was to compare the gene expression profiles of colorectal tumors bearing the 6A and the more common 9A genotypes to discover pathways that might be differentially induced by the 6A polymorphism. Methods: 28 colorectal tumors with matched synchronous metastases and 23 non-metastatic colorectal tumors were analyzed for TGFBR1 exon 1 genotype by a PCR-based assay. Nine metastatic and 10 non-metastatic tumors were analyzed by gene expression microarrays. Following microdissection of paraffin-embedded specimens, RNA was isolated, amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Results: Among the 28 primary metastatic tumors, 19 were 9A (68%), 8 were 9A/6A heterozygotes (29%) and 1 was a 6A homozygote (3%). There was 100% genotype correspondence with the matched metastases. Among the 23 non-metastatic tumors, 18 were 9A (78%), 3 were heterozygotes (13%) and 2 were 6A/6A (9%). Microarray analysis showed 578 differentially expressed genes in the metastatic tumors and 467 in the non-metastatic tumors between the 6A and 9A genotypes (p<0.01). Significant pathway deregulation between 9A and 6A genotypes included estrogen receptor signaling and histidine metabolism in the non-metastatic tumors and B cell receptor, GM-CSF, SAPK/JNK and IL-4 signaling in the metastatic tumors. Conclusion: Microarray analysis shows differentially expressed genes in the 6A genotype compared to 9A, with different deregulated pathways in metastatic and non-metastatic tumors. This alludes to 6A-specific downstream signaling effects, which may contribute to tumor development and progression.

No significant financial relationships to disclose.
Evaluation of Spondin-1 as a predictive marker for palliative 5-FU-based chemotherapy in metastatic colorectal cancer
Authors: Brueckl W. M. , Wirtz R. M. , Croner R. S. , Boxberger F. , Papadopoulos T. , Kirchner T. , Hahn E. G. , Hohenberger W. , Wein A.
Published: March 2020

4112

Background: An individualized tumor tailored chemotherapy may improve survival of patients with metastatic colorectal carcinoma (CRC). Therefore, we analyzed gene expression profiles of liver metastases and primaries of patients with CRC before application of a palliative 5-Fluorouracil based chemotherapy (AIO regimen) due to find predictive markers. These potential markers had to: (1) be highly expressed in the primary (2) and in the metastases, (3) be applicable to qRT-PCR of formalin-fixed paraffin embedded (FFPE) sections, and (4) remain their predictive power in a test set cohort. Methods: The training set consisted of 30 specimen from primary CRC and metastatic liver, which were laser micro dissected, the RNA was amplified and hybridized to Affymetrix HG U-133A microarrays. Additionally, RNA was isolated from FFPE sections of the same tumors and a qRT-PCR was performed for specific gene expression analysis. After surgery of the primary tumor all patients were treated with the AIO regimen. The test set consisted of 61 metastatic CRC patients, who were treated with the AIO regimen and where FFPE sections were available. Markers who showed promising predictive power and fulfilled criteria 1–3 (cp. background) were tested in the validation cohort. Response to chemotherapy was verified by CT scans according to WHO criteria. Results: By using statistical tests we identified some markers showing promising predictive power. However, most of them did not fulfill the further criteria. Spondin-1 expressions were very predictive for response (CR, PR) with a sensitivity of 62.5% and a specifity of 87.5% in the training set. Additionally, Spondin-1 was highly expressed as well in the tumors as in the metastases of CRC. Furthermore, the Affymetrix expression values for Spondin-1 were highly comparable with the RT-PCR data using FFPE sections from the same specimen. In the FFPE test set Spondin-1 remained its predictive value with sensitivity and specifity rates of 53.3% and 70.0%, respectively. Conclusions: Spondin-1 is an attractive candidate for further evaluation of response in CRC tumors treated with a 5-FU based chemotherapy as it is predictive and robust in terms of use in FFPE material. Further research with additional predictive markers to increase accuracy is ongoing.

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Predictive value of EGFR mRNA levels assessed by quantitative RT-PCR in primary tumors of patients treated with cetuximab for metastatic colorectal cancer
Authors: Briasoulis E. C. , Papamichael D. , Tzachanis D. , Christodoulou C. , Samantas E. , Razis E. , Papakostas P. , Bakoyiannis C. , Wirtz R. M. , Kalogeras K. T.
Published: March 2020

4121

Background: The epidermal growth factor receptor (EGFR) protein is the nominal target of the monoclonal therapeutic antibody cetuximab. Yet, repeated failure of EGFR immunohistochemistry (IHC) in predicting treatment outcome has questioned its value in colorectal cancer (CRC). Therefore search for a valid molecular predictor of cetuximab efficacy is highly justified. Methods: 64 CRC patients were treated with standard chemotherapy plus cetuximab in the metastatic setting. RNA was isolated from fixed tumor tissue samples employing an experimental method based on magnetic beads from Siemens Medical Solutions Diagnostics, followed by kinetic one-step RT-PCR for EGFR, HER-2, HER-3, and HER-4 analysis. EGFR protein levels were also assessed by IHC in 62 of the patients, using the 31G7 clone of the mouse monoclonal antibody (Zymed). Slides scored 1+, 2+ and 3+ were considered EGFR protein positive. Results: After a median follow-up of 17 months, median survival was 15.1 months, while median time to disease progression (TTP) was 6.6 months. For the RT-PCR results an objective cut-off at the 2nd quartile (median) for the HER family was chosen. EGFR RNA levels above the median value, demonstrated predictive value in terms of a prolonged TTP (9.3 vs. 5.5 months, p=0.017). No difference was found in terms of survival (24.6 vs. 12.6 months, p=0.106). EGRF assessed by IHC and the rest of the HER family markers assessed by RT-PCR failed to predict TTP outcome or survival. Finally, no agreement was found between the IHC and RT-PCR methods when assessing EGFR. Conclusions: The results of this retrospective study show a predictive value of EGFR RNA levels assessed by RT-PCR on TTP, as opposed to EGFR protein levels. Prospective validation studies are needed to prove if this biomarker is the missing molecular predictor of response to cetuximab.

No significant financial relationships to disclose.
Vascular endothelial growth factor gene polymorphisms and risk of colorectal cancer
Authors: Cho Y. , Chae Y. , Kim J. , Shon S. , Moon J. , Jeon S. , Park J. , Lee I. , Lee I. , Choi G. , Jun S.
Published: March 2020

4123

Background: Angiogenesis is closely related to the development, growth, and metastasis of solid tumors, including colorectal cancer (CRC), and the vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor. Accordingly, the present study was conducted to evaluate the potential association between two VEGF polymorphisms (+405G > C, and 936C > T) and the risk of CRC. Methods: The VEGF genotypes were determined using fresh colorectal tumor tissue from 477 patients with CRC who underwent surgical resection and peripheral blood lymphocytes from 413 healthy controls based on a polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/DHPLC) assay. The incidence of genotypes and haplotypes of two VEGF polymorphisms was compared between the patients with CRC and the controls. Results: The distribution of genotypes and allele frequencies of the 936C > T polymorphism in the CRC group did not differ from those in the control group. However, compared with the combined GC and CC genotype, the GG genotype of +405G > C polymorphism was significantly associated with an increased risk of CRC [odds ratio (OR), 1.575; 95% confidence interval (CI), 1.178–2.104; P = 0.002]. In the haplotype analyses, haplotype +405G / 936C was also associated with a significantly increased risk of CRC (OR, 1.264; 95% CI, 1.043–1.531; P = 0.017), whereas haplotype +405C / 936C was associated with a decreased risk of CRC (OR, 0.818; 95% CI, 0.677–0.989; P = 0.038). None of the VEGF polymorphisms studied significantly influenced the clinical or pathologic features of CRC. Conclusions: These findings suggest that the VEGF +405G > C polymorphism may be associated with the risk of CRC in the Korean population.

No significant financial relationships to disclose.
Assessment of the MMRpredict model for prediction of DNA mismatch repair gene mutations (Lynch Syndrome)
Authors: Nigon S. K. , Lindor N. M.
Published: March 2020

4127

Background: The MMRpredict model, developed at the University of Edinburgh, is a web-based model developed to predict which patients diagnosed with colorectal cancer (CRC) under age 55 years have germline mutations in a DNA mismatch repair (MMR) gene [Barnetson et al., NEngJMed 2006;354:2751–63]. Stage 1 MMRpredict estimates the carrier probability for MMR mutations from clinical parameters (age of diagnosis of colorectal cancer, proximal vs distal site, family history, multiple primary CRCs). We evaluated the performance of Stage 1 of this model in a well characterized cohort of colorectal cancer patients. Methods: Cases with CRC were identified through the Minnesota Cancer Surveillance System (MCSS), a population based registry and Mayo Clinic Rochester, a clinical practice. All were consented participants in the Mayo Colon Cancer Family Registry. Of 342 cases tested for MMR mutations (MLH1, MSH2, MSH6), 45 had insufficient information on colon site and 62 were older than 55 and could not be used in the study. The remaining 235 included 110 females/125 males; 90 cases with proximal site/145 with distal site; 229/235 were self-identified as White. Results: We defined 5 probability risk groups based on output from the MMRpredict web model Stage 1: 1–10%, 11–25%, 26–50%, 51–75%, and 76–100%. In our study, the number of cases in each of these groups was 60, 45, 65, 34, and 31, respectively. The corresponding number of mutations in each group was 1 (1.7%), 4 (8.9%), 9 (13.8%), 3 (8.8%), and 11 (35.5%). Overall, 28/235 patients were found to have mutations (11.9%), compared to predicted range of 62–107 (26–45%). Conclusion: MMRpredict Stage 1 over-estimated the probability of detecting a MMR gene mutation in this study. This may reflect ascertainment issues or genetics of different populations.

No significant financial relationships to disclose.
Polymorphisms in estrogen receptor beta, interleukin-8, and interleukin-8 receptor associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5-fluorouracil/oxaliplatin
Authors: Ladner R. D. , Gordon M. A. , Zhang W. , Yang D. , Nagashima F. , Chang H. , Lurje G. , Borucka E. , Lenz H.
Published: March 2020

4130

Background: Many factors contribute to the progression of colorectal cancer and to chemoresistance. Two factors that have recently gained attention are angiogenesis and sex hormones. Interleukin-8 and its receptors play a critical role in angiogenesis, and polymorphisms in these genes have previously been reported to predict clinical outcome and resistance to therapy in a variety of cancer types. In addition, gender and the subsequent varied levels of sex hormones between males and females may also have an impact on colorectal cancer progression. Sex hormones such as estrogen exert their effects on the cell by binding to steroid receptors such as estrogen receptor beta (ER-β). It is known that ER-β is predominantly expressed in the colon, and that differential expression of this gene is predictive of clinical outcome. Therefore, functional polymorphisms within ER-β, IL-8, and the IL-8 receptors may prove to be molecular markers for predicting clinical outcome in colorectal cancer patients. Methods: 173 patients were enrolled in this phase II study. 152 patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. Polymorphisms in estrogen receptor beta, IL-8, and CXCR2 (IL-8 receptor) were tested by PCR. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. IL-8 T251A polymorphism was predictive of time to tumor progression (p=0.04, log-rank test). ER-β CA repeat polymorphism was predictive of tumor response as well as time to tumor progression (p=0.015, p=0.012, respectively). ER-β A730G SNP was also predictive of time to tumor progression (p=0.03). Polymorphism in CXCR2 was predictive of tumor response (p=0.034). Conclusions: Our results suggest that polymorphisms within IL-8, CXCR2, and ER-β may affect the progression of colorectal cancer and subsequent clinical outcome. These results highlight the importance of angiogenesis and hormone levels in colorectal cancer.

No significant financial relationships to disclose.