bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival following recurrence in patients with adjuvant colon cancer: Findings from the 20,800-patient ACCENT dataset
Authors: O’Connell M. J.
Published: March 2020

4009

Purpose: To examine 4 possible prognostic factors in patients (pts) with recurrent (rec) stage II and III colon cancer: time from randomization to rec (< 1 yr, 1–2 yrs 2–3 yrs 3–4 yrs, 4+ yrs), initial stage (II vs III), initial adjuvant treatment (adj rx) (5-FU based vs no rx control), and era pt entered onto study (1978–1985, 1986–1992, 1993–1999). Methods: The Adjuvant Colon Cancer Endpoints (ACCENT) dataset, including individual pt data from 18 trials and over 20,800 pts testing 5-FU based adj rx for pts with stage II and III colon cancer, was analyzed using univariate and multivariate Cox proportional hazards models, stratified by study. The QUASAR trial (Lancet, 2000) was excluded due to non protocol specified follow-up for rec. No data was available on rx subsequent to rec, or tumor characteristics at time of rec. Results: 5,713 of 17,381 (32.9%) of pts experienced rec. Median survival following rec was 13.4 months. Primary results from univariate models are shown in the table . Time from randomization to rec was highly prognostic of survival following rec (p<0.0001); this result was primarily driven by pts with initial stage III disease. Longer survival following rec was also seen in pts with initial stage II vs III disease (p<0.0001), with a 15% 6 year OS in initial stage II pts, pts entered more recently onto trials (p< 0.0001), and pts initially treated with surgery alone vs 5-FU adj rx (p=0.0005). All relationships were maintained in multivariate models. Conclusions: Time from initial rx and initial stage are important prognostic factors in pts with rec colon cancer. Survival following rec increased modestly from 1980–1995 possibly due to improvements in surgery, chemotherapy, supportive care, or unknown selection effects. Pts who rec following adj rx have poorer prognosis than those untreated, which may be a selection effect (only more aggressive tumors escape adj rx), or a sensitivity effect (those without adj rx retain sensitivity to 5-FU in the rec setting).

[Table: see text]

No significant financial relationships to disclose.
Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with metastatic colorectal cancer (MCRC)
Authors: Rothenberg M. L. , Navarro M. , Butts C. , Bang Y. , Cox J. V. , Goel R. , Gollins S. , Siu L. L. , Cunningham D.
Published: March 2020

4031

Background: Capecitabine is an oral fluoropyrimidine that has demonstrated similar efficacy to 5-FU/LV in the 1st-line treatment of MCRC. Most patients now receive multi-agent chemotherapy and FOLFOX4 has become a popular regimen in this setting. We conducted a phase III study comparing XELOX with FOLFOX4 in patients who had received prior treatment with irinotecan in combination with bolus and/or infusional 5-FU/LV for MCRC. The primary endpoint of the study was time-to-tumor progression (TTP). With 610 patients, this study had 80% power to detect non-inferiority of the XELOX vs. FOLFOX, defined by a progression hazard ratio (HR) of <1.3. Methods: Patients were treated with XELOX (oxaliplatin 130mg/m2 i.v., capecitabine 1,000mg/m2 bid oral x 14 days, q3w) or FOLFOX4 (as described previously). Results: The study recruited 627 patients (the intent-to-treat - ITT - group). Baseline characteristics were well balanced. The primary objective of the study was met with a progression HR of 0.97 for the XELOX group (95% CI, 0.83–1.14). Median TTP was 4.8 months for XELOX- and 4.7 months for FOLFOX4-treated patients. Overall survival was also similar between the groups with a death HR of 1.03 for the XELOX group (95% CI, 0.87–1.23). Median survival was 11.9 months for XELOX- and 12.6 months for FOLFOX4-treated patients. Grade 3/4 toxicities occurred in 60.1% of XELOX- and 72.4% of FOLFOX4-treated patients. The most common treatment-related grade 3/4 adverse events (XELOX vs. FOLFOX4) were: diarrhea (20 vs. 5%), neutropenia (5 vs. 35%), fatigue (5 vs. 8%), paresthesia (9 vs. 8%), nausea/vomiting (6 vs. 5%). The rate of grade 3 hand-foot syndrome was 3.5% with XELOX and 0.6% with FOLFOX4. The 60-day all cause mortality was 3.9% in XELOX- and 4.2% in FOLFOX4-treated patients. Conclusions: These results demonstrate that second-line treatment with XELOX is non-inferior to FOLFOX4 in terms of PFS. Results for overall survival and response rates were also similar between the two groups. The safety profile was similar to previous studies, with no unexpected toxicities. Study supported by Hoffmann-La Roche.

No significant financial relationships to disclose.
Phase I/II study of neoadjuvant bevacizumab with radiation therapy and 5-fluorouracil in patients with rectal cancer: initial results
Authors: Willett C. , Duda D. , Boucher Y. , di Tomaso E. , Clark J. , Blaszkowsky L. , Czito B. , Bendell J. , Jain R.
Published: March 2020

4041

Background: A phase I/II study of neoadjuvant bevacizumab with 5-fluorouracil and radiation therapy in patients with locally advanced rectal cancer was undertaken to determine whether inhibition of VEGF is safe and has clinical benefits by enhancing chemo- radiation therapy. Methods: 22 patients with endoscopic ultrasound or surface coil MRI staged T3/T4 non-metastatic rectal cancer were enrolled from 2001–2006. All patients completed 4 cycles of neoadjuvant therapy including: 1) bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 2) peripheral venous infusion 5-FU (225 mg/m2/24 hours) administration each treatment week of cycles 2 - 4; 3) external beam irradiation delivery (50.4 Gy in 28 fractions over 5.5 weeks); and 4) surgery 7 to 9 weeks after completion of all neoadjuvant therapy. Correlative studies were undertaken before and during the trial. We collected serial tumor biopsies, PET-FDG scans, and analyzed blood and urine for potential biomarkers. Results: Mean pre-therapy tumor size was 4.7 cm (2–9 cm). Post-treatment surgical specimens usually had well-demarcated shallow ulcerations with a mean diameter of 2.4 cm (0.7–6 cm). In response to the neoadjuvant regimen, all patients had significantly (p<0.01) decreased FDG-uptake by PET. Histologic examination showed no residual primary cancer in 5 patients (ypT0). Of 17 patients with residual disease, microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 in 3 patients, ypT2 in 4 patients, ypT3 in 10 patients). Downstaging was seen in 12/22 tumors. 8 patients had microscopic nodal metastases. Bevacizumab alone and combined treatment were both associated with increased plasma VEGF and PlGF levels in 18/18 patients (P<0.01 at all 4 timepoints compared to baseline). Viable CECs were decreased by VEGF blockade at day 3 (P<0.01 compared to baseline), and peak CEC levels during treatment was correlated with histologic tumor response (2.77 [1.18–3.18] for T3 patients, n=9 versus 1.14 [0.82–1.53] for T0-T2 patients, n=12; p=0.05). Conclusions: Addition of bevacizumab at a dose of 5 mg/kg to standard chemo-radiation is safe in patients with locally advanced rectal cancer. Bevacizumab is active and the combined regimen yields promising results.

[Table: see text]
Phase II study of preoperative chemoradiation (CRT) with cetuximab, irinotecan and capecitabine in patients with locally advanced resectable rectal cancer
Authors: Hong Y. S. , Kim D. Y. , Lee K. S. , Lim S. B. , Choi H. S. , Jeong S. Y. , Kim J. H. , Im S. A. , Kim T. W. , Jung K. H.
Published: March 2020

4045

Background: Preoperative CRT with irinotecan and capecitabine is effective and safe in rectal cancer. Cetuximab, an EGFR- targeted agent, is synergistic with chemotherapy and radiotherapy. We conducted this study to determine efficacy and safety of cetuximab, irinotecan, and capecitabine as a combined preoperative CRT in patients with locally advanced resectable rectal cancer. Methods: This is a non-randomized, open-label, multicenter phase II study with cetuximab 400mg/m2 on D-6 (1 week before radiation) followed by cetuximab 250mg/m2 and irinotecan 40mg/m2 once a week (D1, 8, 15, 22, & 29) and capecitabine 1650mg/m2/day for weekdays only during radiation. Radiotherapy was given to a total dose of 50.4 Gy/28 fractions starting on D1. Main eligibility criteria were histologically proven rectal adenocarcinoma; T3–4 lesions; age 18 - 75 years; ECOG PS 0 - 2; no prior chemotherapy or EGFR targeted therapy. Total mesorectal excision was planned to be performed 4–8 weeks after completion of CRT. Results: Between May 2006 and Dec 2006, 40 patients were enrolled; median age 56.5 years (34 - 72); M/F 32/8; PS 0–1/2 38/2; cT3/T4 36/4; cN0/N+ 8/32; median tumor location from anal verge 5.5cm (0 - 8.0); moderately-differentiated adenocarcinoma 29. At present, 21 patients completed preoperative CRT and were evaluable for toxicity. Grade 3/4 toxicities included leucopenia (2, 9.5%), neutropenia (1, 4.8%), anemia (1, 4.8%) and diarrhea (1, 4.8%). Grade 2 hypersensitivity reactions and skin rashes were observed in 2 (9.5%) and 9 patients (42.9%), respectively and no grade >1 hand-foot syndrome was observed. Of 10 patients who underwent surgery (all R0 resection) till now, 9 were treated with sphincter saving procedure. Pathologic T0 and N0 were observed in 3 and 7 patients, respectively. Pathologic complete responses were observed in 2 patients and another 2 patients had only minimal microscopic residual tumor. Conclusions: Preoperative CRT with cetuximab, irinotecan and capecitabine showed promising preliminary pathologic responses with mild toxicity profiles. Study enrollment has now been completed and further results of efficacy and safety will be presented.

No significant financial relationships to disclose.
A prospective randomized phase III trial of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with stage II colon cancer
Authors: Schippinger W. , Samonigg H. , Greil R. , Tschmelitsch J. , Steger G. , Jakesz R. , Gnant M. , Hofbauer F. , Rabl H. , Thaler J.
Published: March 2020

4052

Background: Whereas several studies showed adjuvant chemotherapy to improve survival of patients with stage III colon cancer, survival benefit from adjuvant treatment in patients with stage II disease is a matter of controversy. Methods: Patients with curatively resected stage II colon cancer (T3–4, N0, M0) according to UICC were randomized to either adjuvant chemotherapy with 5-FU/LV (100 mg/m2 LV + 450 mg/m2 5-FU weekly, w 1–6, in 8 w cycles x 7) or surveillance only. Primary endpoint was overall survival (OS) with 636 patients originally planned to demonstrate a difference in OS of 10% with 85% power and alfa =0.05 in a final analysis 7 years after study initiation. After accrual of 535 patients between 11/1993 and 6/2003, recruitment was stopped ahead of schedule for low accrual rates. Results: 505 patients were eligible and evaluable for analyses. After a median follow-up of 96 months, 56 (21.8%) patients have died in the 5-FU/LV arm and 58 (23.4%) in the surveillance arm. There was no statistically significant difference in OS between the two treatment arms (HR 1.137, 95% CI 0.787–1.641, p=0.4947, chi square), thus the primary endpoint of the study was not met. Disease relapse was documented in 35 (13.6%) patients of the chemotherapy arm and in 48 (19.4%) patients of the control arm. The relative risk for disease relapse was higher for patients in the surveillance arm compared to patients in the 5-FU/LV arm, however, this difference was statistically not significant (HR 1.506, 95% CI 0.974–2.328, p=0.0657, chi square). Subgroup analysis including in the chemotherapy arm only patients who received at least one cycle of 5-FU/LV (n=250), showed a statistically significantly lower risk for relapse in patients treated with 5- FU/LV (HR 1.559, 95% CI 1.001–2.429, p=0.0477, chi square). Conclusions: Results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, adjuvant chemotherapy did not significantly improve DFS and OS.

No significant financial relationships to disclose.
Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases
Authors: Miller G. , Biernacki P. , Kemeny N. , Gonen M. , Downey R. , Jarnagin W. R. , D’Angelica M. , Fong Y. , Blumgart L. H. , DeMatteo R. P.
Published: March 2020

4059

Background: Surgical resection of isolated hepatic or pulmonary colorectal metastases prolongs survival in selected patients. However, the benefits of resection and appropriate selection criteria in patients who develop both hepatic and pulmonary metastases are ill-defined. Methods: Data were prospectively collected from 131 patients with colorectal cancer who underwent resection of both hepatic and pulmonary metastases over a 20-year period. Median follow-up was 6.6 years from the time of resection of the primary tumor. Patient, treatment, and outcome variables were analyzed using log-rank, Cox regression, and Kaplan-Meier methods. Results: The site of first metastasis was the liver in 65% of patients, lung in 11%, and both simultaneously in 24%. Multiple hepatic metastases were present in 51% of patients and multiple pulmonary metastases were found in 48%. Hepatic lobectomy or trisegmentectomy was required in 61% of patients while most lung metastases (80%) were treated with wedge excisions. Median survival from resection of the primary disease, first site of metastasis, and second site of metastasis was 6.9, 5.0, and 3.3 years, respectively. After resection of disease at the second site of metastasis, the 1, 3, 5, and 10 year disease-specific survival rates were 91, 55, 31 and 19%, respectively. An analysis of prognostic factors revealed that survival was significantly longer when the disease-free interval between the development of the first and second sites of metastases exceeded one year, in patients with a single liver metastasis, and in patients younger than 55 years. Conclusions: Surgical resection of both hepatic and pulmonary colorectal metastases is associated with prolonged survival in selected patients. Patients with a longer disease free interval between metastases and those with single liver lesions had the best outcomes.

[Table: see text]

No significant financial relationships to disclose.
Hepatic resection following rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy
Authors: Aloia T. , Levi F. , Wicherts D. A. , Haas de R. J. , Paule B. , Bralet M. , Bouchahda M. , Azoulay D. , Castaing D. , Adam R.
Published: March 2020

4061

Background: The impact of cetuximab-containing chemotherapy on resectability of previously unresectable colorectal liver metastases (CLM) is unknown, especially in patients resistant to first-line chemotherapy. This study was performed to determine the cetuximab resectability rate, and to examine the outcomes of these heavily pretreated patients after hepatic resection. Methods: From February 2004 to April 2006, we evaluated 151 patients with unresectable CLM resistant to initial chemotherapy and subsequently treated with cetuximab-containing regimens. 133 patients (88%) were completely treated at our institution and 18 patients (12%) received systemic therapy elsewhere. Resectability rates, perioperative outcomes, survivals, and histopathological analysis of the tumoral and non- tumoral liver were assessed. Results: 27 patients were operated after a median of 6 cycles of cetuximab + irinotecan (20/27), oxaliplatin (4/27), or both (1/27). 18 of these patients (67%) had failed at least 2 lines of prior chemotherapy. 25 patients underwent hepatectomy, including 9 of 133 patients completely treated at our institution (resectability rate: 7%) and 16 of 18 referred patients. Postoperative mortality was 3.7% (1/27), with a complication rate of 50%. Complete tumor necrosis was observed in 2 patients (8%). Histopathological liver abnormalities were found in 9 patients (36%), without any specific lesion related to cetuximab. After a median follow-up of 16 months (range 6–39), all but one resected patients were alive, 10 of whom were disease-free. Conclusions: For CLM refractory to conventional chemotherapy, combination chemotherapy with cetuximab significantly increased resectability rates with no appreciable increase in operative mortality or liver injury. Longer follow-up is awaited to confirm the encouraging results of this new oncosurgical strategy.

No significant financial relationships to disclose.
Safety and quality of life (QoL) findings from a randomized phase III study of capecitabine (X) + oxaliplatin (O) (XELOX) vs. infusional 5-FU/LV + O (FOLFOX-6) in metastatic colorectal cancer (MCRC)
Authors: Hebbar M. , Bennouna J. , Boige V. , Ychou M. , Lledo G. , Adenis A. , Faroux R. , Rebischung C. , Douillard J. , Conroy T.
Published: March 2020

4099

Background: A recent phase III trial in first-line MCRC showed that XELOX is non-inferior to infusional 5-FU + oxaliplatin (FOLFOX-4) for progression-free survival (PFS) [Cassidy ESMO 2006]. Here we present safety and QoL findings from a study of XELOX vs. FOLFOX-6 in first-line MCRC. Methods: Between 16 May 03 and 31 Aug 04, 306 patients (pts) were randomized to receive either XELOX (156 pts: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (150 pts: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Primary objective: demonstrate non inferiority of XELOX in terms of best response rate (RECIST). Secondary objectives: evaluate QoL and pt satisfaction with care by EORTC QLQ-C30 and FACIT (chemotherapy convenience and satisfaction) questionnaires. Pts completed questionnaires at baseline, before cycles 3/4, 6/8 and at final visit in XELOX/FOLFOX-6 arms, respectively. Results: 245 pts (QLQ-C30) and 225 pts (satisfaction) were evaluable for QoL. The compliance rate was >70%. At baseline, QoL scores were not significantly different. QLQ-C30 functional and symptomatic scores were stable in both arms. According to FACIT, there was no difference between arms, although XELOX-treated pts wasted less hours of their free time than those on FOLFOX-6: 10±23 vs. 37±68 hours, respectively (p=0.007). XELOX was a more ‘comfortable’ treatment (p<0.001 vs. FOLFOX-6 at 2nd evaluation and p=0.009 at 3rd evaluation). Safety profile was acceptable in both arms. In the safety population (n=304), XELOX pts had more grade 3/4 hand-foot syndrome (3 vs. 1% p=0.215), thrombocytopenia (12 vs. 5% p=0.052) and diarrhea (12% vs. 7% p=0.1), but less grade 3/4 febrile neutropenia (0 vs. 6% p=0.001) and neuropathy (8 vs. 19% p=0.003) than those on FOLFOX-6. Treatment discontinuation for toxicity was 19% and 23% for XELOX and FOLFOX-6 arms, respectively. Conclusions: XELOX is comparable to FOLFOX-6 in terms of QoL with less time wasted receiving XELOX. XELOX is also non-inferior to FOLFOX-6 (primary endpoint met/presented at same meeting) with a similar safety profile in first-line MCRC.

No significant financial relationships to disclose.
Outcomes differences for African Americans and Caucasians treated with bevacizumab, FOLFOX4 or the combination in patients with metastatic colorectal cancer (MCRC): Results from the Eastern Cooperative Oncology Group Study E3200
Authors: Catalano P. J. , Mitchell E. P. , Giantonio B. J. , Meropol N. J. , Benson A. B.
Published: March 2020

4100

Background: The relationship between race and clinical outcomes with systemic chemotherapy in patients with metastatic colorectal cancer is uncertain. E3200 is a large, randomized, multicenter phase III trial that demonstrated a gain in overall survival (OS), progression free survival (PFS) and response (RR) for the addition of bevacizumab to FOLFOX4 in previously treated patients with MCRC. We analyzed outcomes for African Americans and Caucasian patients enrolled in E3200. Methods: Patients enrolled in E3200 were randomized to one of three treatments: FOLFOX4, bevacizumab, or the combination. OS, PFS, RR and cycles of chemotherapy were examined as a function of race in 779 patients. Demographic information including race was collected by data management personnel at study sites and reported at registration. Results: There were no differences noted for Caucasians and African Americans with regards to: disease extent, performance status, gender, prior therapy and age distribution (not shown). Outcomes by race are tabulated. Conclusion: These results suggest outcomes differences based on race in the treatment of patients with MCRC. Additional studies are required to elucidate the cause for the observed variation.

[Table: see text]

No significant financial relationships to disclose.
Tissue factor promoter polymorphism as a prognostic factor in patients with metastatic colon cancer
Authors: Yang D. , Schultheis A. M. , Lurje G. , Iqbal S. , Chang H. , Zhang W. , Groshen S. , Gordon M. , Nagashima F. , Lenz H.
Published: March 2020

4108

Background: Tissue Factor (TF), a transmembrane glycoprotein, initiates the physiologic coagulation cascade. Cumulative evidence implies that TF plays a key role in tumor angiogenesis. Elevated TF expression has been reported to be associated with poor survival in patients in solid tumor. We investigated whether a functional TF promoter polymorphism -603 A/G is a prognostic factor in patients with advanced colon cancer because the G allele had been linked to high constitutive TF gene expression in human monocytes in healthy volunteers. Methods: 318 patients with metastatic colon cancer treated at the USC/Norris Comprehensive Cancer Center or the LA County/USC Medical Center during 1992 through 2003 were included in this study. Genomic DNA was extracted from white blood cells of peripheral blood samples using the QiaAmp kit (Qiagen, Valencia, CA). The TF polymorphism was genotyped by PCR-RFLP-based approach. The association between the TF polymorphism and overall survival was examined using the log-rank and trend test. The association between TF polymorphism and baseline demographic characteristics was tested using the χ2 test or Fisher’s exact test when appropriate. Results: There were 141 females and 177 males, with a median age of 58 years (range 25–86). The cohort comprised 234 whites, 43 Asians, 15 Blacks, 24 Hispanics, and 2 Native Americans. The median survival was 13.7 months with a median follow-up of 2.3 years. Asians were less likely to bear the G allele compared to other racial groups (P < 0.001, Fisher’s exact test). Patients who carried 1 or 2 G alleles were at higher risk of poor survival compared to patients with no G alleles (A/A) (P = 0.038, trend test). The median overall survival was 14.7 vs. 11.9 months for patients with A/A vs. patients with G/G or A/G, respectively. Conclusions: This study suggests that TF may be a prognostic factor for patients with metastatic colon cancer. The finding should be validated with future prospective clinical studies.

No significant financial relationships to disclose.
Serum matrilysin (MMP7) levels are associated with progression, in curatively resected colorectal cancer (CRC) patients
Authors: Martinez-Fernandez A. , Pineda E. , Visa L. , Garcia-Albeniz X. , Auge J. , Nadal C. , Castells A. , Lacy A. , Maurel J.
Published: March 2020

4124

Background: Matrilysin (MMP7) has been shown to be over-expressed in CRC, specially in liver metastases. Additionally MMP7 over-expression in primary tumor, predict metastatic potential in early-stage disease (Gut 12:1751;2005). As the activated pro-domain, could be detected in serum by ELISA method, we search if it could also identify a subgroup of non-metastatic CRC patients with a higher risk of relapse. Methods: Serum MMP7 (S-MMP7) was measured by commercially available ELISA, in 92 healthy controls and 175 consecutive patients before undergoing laparoscopy-assisted or open curative resection for CRC, between July 2003 to December 2004. Clinic- pathologic variables were tested for their effect on disease-free survival (DFS) in univariate and multivariate Cox regression analysis. Results: S-MMP7 levels were significantly higher in CRC patients than in controls (p=0.02). Mean age in CRC patients was 71 years (range 31–90). Median nodal retrieval was 14 (range 0–47). The median S-MMP7 (4.9 ng/ml) was chosen for cut-off value. After a median follow- up of 26 months, the rate of DFS was 72%. Univariate analysis identified high S-MMP7 levels, CEA concentration, age, extent of primary tumor and lymph-node metastases as variables associated with DFS. Multivariate analysis identified lymph-node metastases (OR.1,88, p=0.046) and S-MMP7 (OR.1,103, p=0.039) as independent prognostics factors. Conclusions: With a short follow-up, S-MMP7 levels predict recurrence in curatively resected CRC. As a subset of these patients could be managed with secondary liver resection, S-MMP7 determination would be particularly warranted for more intensive surveillance strategies.

No significant financial relationships to disclose.
Vascular endothelial growth factor (VEGF) gene polymorphisms associated with prognosis for patients with colorectal cancer
Authors: Chae Y. , Kim J. , Sohn S. , Cho Y. , Moon J. , Jeon S. , Park J. , Lee I. , Choi G. , Jun S.
Published: March 2020

4125

Background: Vascular endothelial growth factor (VEGF) or its family may be considered to play an important role in lymphangiogenesis and lymphatic tumor spread, thereby affecting prognosis of colorectal cancer. Accordingly, the present study analyzed VEGF gene polymorphisms and their impact on the prognosis for patients with colorectal cancer. Patients and Methods: Four hundred and sixty-five consecutive patients with surgically treated colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tumor tissue and 3 VEGF (-2578C > A, -634G > C, and +936C > T) gene polymorphisms determined using a PCR/DHPLC (Polymerase chain reaction/Denaturing high-performance liquid chromatography) assay. Results: The median age of the patients was 64 years (range, 21–89), and 264 (56.7%) patients had colon cancer and 201 (48.2%) patients rectal cancer. Pathologic stages evaluable (n=464) after surgery were as follows: stage I (n=79, 17.0%), stage II (n=157, 33.8%), stage III (n=157, 33.8%), and stage IV (n=71, 15.3%). Multivariate survival analysis including stage, differentiation, and CEA level showed that survival for patients with the -634CC (overall survival [OS]: hazard ratio [HR]=0.175, P<0.001; progression-free survival [PFS]: HR=0.554, P=0.040) or GC genotype (OS: HR=0.158, P<0.001; PFS: HR=0.630, P=0.044) were better than for patients with the -634GG genotype, whereas the +936TT (OS: HR=65.959, P<0.001; PFS: HR=2.823, P=0.016) or CT genotype (OS: HR=16.116, P<0.001; PFS: HR=3.507, P<0.001) were associated with a worse survival compared to the CC genotype. In haplotype analysis, the -2578A/-634G/+936T haplotype exhibited a significantly worse survival when compared to the wild -2578C/-634G/+936C haplotype (OS: HR=4.670, P<0.001; PFS: HR=3.624, P<0.001). Conclusions: VEGF gene polymorphisms were found to be an independent prognostic marker for patients with colorectal cancer. Accordingly, the analysis of VEGF gene polymorphisms can help identify patient subgroups at high risk of a poor disease outcome.

No significant financial relationships to disclose.
EGFR, Cox-2, and EGF polymorphisms associated with progression-free survival of EGFR-expressing metastatic colorectal cancer patients treated with single-agent cetuximab (IMCL-0144)
Authors: Nagashima F. , Zhang W. , Gordon M. , Chang H. M. , Lurje G. , Borucka E. , Yang D. , Ladner R. , Rowinsky E. , Lenz H. J.
Published: March 2020

4129

Background: A phase II study of cetuximab (IMCL-0144) has shown response rate of 12 % in patients with EGFR expressing metastatic colorectal cancer (mCRC). Recently, we reported that polymorphisms in the EGFR pathway may be useful molecular markers to predict clinical outcome. In this larger study, we tested whether polymorphisms in genes involved in the EGFR and angiogenesis pathway will be associated with clinical outcome. Methods: We analyzed 136 tissue samples from 346 mCRC pts enrolled in the phase II study of cetuximab (IMCL-0144), 133 cases were informative. The response rate in these 133 pts was 10% with a median progression-free survival (PFS) of 1.3 months (95% CI, 1.2 to 1.5) and an overall survival time (OS) of 5.5 months (95% CI, 4.1 to 7.5). Gr3–4 toxicity was observed in 56%. Gene polymorphisms of EGFR, Cox-2, EGF, cyclin D1, fragment c γ receptor 2A (FCGR2A), FCGR3A, VEGF, IL-8 were assessed from gDNA extracted from tissue samples by using PCR-based RFLP technique. Univariate analysis (Fisher’s exact test for response; log-rank test for PFS and OS) was performed to examine associations between polymorphisms and clinical outcome. A classification and regression tree (CART) analysis was used to identify subgroups of patients who were more likely to benefit from cetuximab. Results: Pts with EGFR G497C GA, Cox-2 G-765C CC, EGF A61G GG genotype showed better PFS (p=0.02, 1.8mo. vs. 1.2mo.; p=0.03, 6.9mo. vs. 1.3mo.; p=0.04, 1.4mo. vs. 1.2mo.), respectively. We found trends in associations between Cox-2 and tumor response (p=0.09), between EGF and Gr3–4 toxixity (p=0.06). CART analyses indicated that germline polymorphisms in EGFR, EGF, Cox-2, Cyclin D1, IL-8, FCGR2A and FCGR3A genes could be used to identify patients who benefit most likely of cetuximab therapy. Conclusions: Our data suggest that the polymorphisms of EGFR, Cox-2, and EGF may be useful molecular markers to predict clinical outcome in mCRC pts treated with single-agent cetuximab. And prospective studies will need to be done to confirm these preliminary findings.

[Table: see text]
Infusion-related reactions (IRR) associated with cetuximab plus irinotecan treatment in patients with irinotecan-resistant metastatic colorectal cancer (mCRC): Findings from the MABEL study
Authors: Siena S. , Glynne-Jones R. , Thaler J. , Adenis A. , Preusser P. , Aguilar E. Aranda , Aapro M. , Loos A. , Esser R. , Wilke H.
Published: March 2020

4137

Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in mCRC patients (pts) who have failed prior irinotecan therapy. In previous studies with cetuximab, IRRs were observed in a small proportion of pts especially at the first infusion. Methods: MABEL investigated cetuximab plus irinotecan in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. A secondary objective of MABEL was to further study cetuximab-related adverse events. Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study. Data analyzed included prophylactic pre-medication, IRRs and medication for IRRs. Prophylactic medication given before the first cetuximab infusion was categorized as chlorphenamine antihistamines, antihistamines other than chlorphenamine, and any antihistamines plus corticosteroids. Results: Overall, 1147 pts were treated in this study: median age was 62 years [25–84], Karnofsky performance status was =70% and 64% pts were male. 1,122 patients were pre-treated with antihistamines. The frequency of IRRs was lower in pts who received antihistamines plus corticosteroids than in pts who received antihistamines alone (9.6% vs 25.6% any grade, 1% vs 4.7% grade 3/4 IRRs). The primary efficacy variable of MABEL was the 12-weeks progression-free survival (PFS) status. Efficacy results by pre-medication groups for PFS (see table ) and overall survival do not suggest differences related to prophylactic pre-medication. Conclusions: The data suggest that the type of pre-medication impacts on the occurrence of IRRs, and that the addition of corticosteroids to antihistamines reduces IRRs without altering antitumor efficacy in the analyzed pre-medication groups.

[Table: see text]

No significant financial relationships to disclose.
A prospective study to evaluate the role of gene expression profiles (GEP) in predicting clinical outcome of patients (pts) receiving preoperative chemotherapy for oesophagogastric (OG) cancer
Authors: Rao S. , Cunningham D. , Benson M. , Te Poele R. , Welsh L. , Starling N. , Norman A. , Saffery C. , Workman P. , Clarke P.
Published: March 2020

4501

Background: Whilst preoperative chemotherapy has demonstrated survival benefit for pts with potentially resectable OG cancer it is not possible to predict the benefit for an individual pt. This study was designed to prospectively correlate GEP with clinical outcome. Methods: Eligible pts were deemed to have resectable disease after staging CT, EUS, and laparoscopy as indicated & following discussion at the multidisciplinary team meeting. All pts received neoadjuvant platinum & fluoropyrimidine based chemotherapy & clinical data were entered prospectively onto a study specific database. GEP were produced from total RNA isolated from snap frozen pre treatment tumour biopsies obtained at baseline endoscopy. Labelled cDNA was hybridised versus a universal human reference using an in house c DNA array of 22,000 clones. Results: Of the pts with adequate follow up accrued between 2002–2005, 35 met the quality control measures for the arrays. Median age=66 yrs (47–83); male=32, female=3; tumour subsites: oesophagus=23, oesophago-gastric junction (OGJ)=12; adenocarcinoma=35; T stage: T 2=3, T3=30, T4=2; N stage: N0=12, N1=23; performance status 0=7, 1=28. Median follow up=938 days. Median overall survival (OS) = 570 days. Prognostic groups were designated according to the median OS (days) of the group: good > median and poor < median. Supervised hierarchical clustering of normalised data revealed significantly differentially expressed genes based on OS (p<0.01) with 2 distinct clusters: a poor outcome group: N= 17 (2yr OS 17.6%) [95% CI: 4.3–38.3], a good outcome group: N=18 (2 yr OS 55%) [95% CI: 30.5–74.8]. Of the differentially expressed genes, those involved in receptor tyrosine kinase signalling & cell growth were amongst the most significantly affected pathways. Conclusions: This novel technique using GEP in tumour biopsies has successfully identified groups of tumours with distinct gene expression profiles that correlate with survival. The approach warrants further validation in a larger cohort. It could facilitate the development of tailored treatment according to individual tumour biology in OG cancer.

No significant financial relationships to disclose.
Individual patient data-based meta-analysis assessing pre-operative chemotherapy in resectable oesophageal carcinoma
Authors: Thirion P. G. , Michiels S. , Le Maître A. , Tierney J.
Published: March 2020

4512

Background: Optimal management of operable localised oesophageal carcinoma remains to be determined. The debate is fuelled by some positive individual trials showing a benefit of preoperative chemotherapy (CT+S) or preoperative chemo-radiotherapy (CRT+S) over surgery alone (S). Our group has initiated an individual patient data-based meta-analysis to quantify the potential benefit of CT+S over S. Methods: The methodology used for trial identification and data analysis has been previously reported. The primary endpoint was overall survival (OS). The secondary endpoints were disease-free-survival (DFS) analyzed with a 6 months landmark method, tumour resectability (complete resection rate) and post-operative mortality. The logrank-test, stratified by trial, and hazard ratio (HR) were used for comparison. Subgroup analyses by age, sex, performance status, and histologic type were prospectively planned. Results: Twelve eligible randomized trials (2,284 patients) were identified. Individual patient data from 9 trials (2,102 patients) with a median follow-up of 5.3 years were available for the OS analysis. There was a statistically significant OS benefit in favour of CT+S (HR=0.87, 95% CI 0.79–0.95, p=0.003) translating into a 5-year absolute OS increase of 4% (from 16 to 20%). Based on 7 trials (1,849 patients), the HR for DFS was 0.82 (95% CI 0.74–0.91, p=0.001) in favour of CT+S, representing a 5-year absolute DFS benefit of 4% (from 6 to 10%). The complete resection rate across 8 trials (1,933 patients) was significantly greater in the CT+S arm (67%) compared to the S arm (62%) (OR=0.81, 95% CI 0.67–0.98, p=0.03). No difference was seen in postoperative death (6.7%). No interaction between treatment effect and patients characteristics was seen. Conclusions: Individual patient data-based meta-analysis represents the highest level of evidence and this study shows a small but significant overall and disease-free survival benefit in favour of preoperative chemotherapy over surgery alone. Unrestricted grants from LNCC and Sanofi-Aventis.

No significant financial relationships to disclose.
A randomized second line trial in patients with gemcitabine refractory advanced pancreatic cancer - CONKO 003
Authors: Riess H. , Pelzer U. , Stieler J. , Schwaner I. , Heil G. , Görner M. , Mölle M. , Hilbig A. , Dörken B. , Oettle H.
Published: March 2020

4517

Objective: For nearly ten years gemcitabine (G) was standard first line therapy for patients (pts) with advanced pancreatic cancer (APC). There is no consensus about second line therapy after disease progression while receiving G, but 5-FU-based regimens are considered. Results about randomized second line studies in APC are very rare. Our phase II study (ASCO 2002) showed activity of the OFF (oxaliplatin/folinic Acid (FA)/5-fluorouracil (FU) [24h] ) regimen in 23 pts. To examine the impact and the side effects of oxaliplatin we initiated a multicenter phase III study to compare OFF and FF in pts with G refractory APC. Methods: Pts with CT/ MRT confirmed failure with G in first line therapy, Karnofsky Performance Status (KPS) >60%, controlled pain, adequate hematological, renal and liver functions were eligible. Pts were stratified according to duration of first line therapy, KPS and tumor stage. We randomized pts to outpatient treatment with FF (FU 2g/m2 (24h)/ FA 200 mg/m2 (30min) on d1, d8, d15 and d22) or OFF (FF+Oxaliplatin 85mg/m2, d8, d22). In both arms the next cycle started on day 43. Pts were followed with regular staging every 3 months or at any signs of disease progression. Results: Until now we randomized 161 of 165 (planned) pts between 02/2004 and 01/2007. So we expect to present first results (side effects, progression free survival, overall survival) at the meeting.

No significant financial relationships to disclose.
Phase II study of docetaxel in combination with oxaliplatin in patients with metastatic or locally advanced esophagogastric cancer previously untreated with chemotherapy for advanced disease. Results of the CECOG-Study ESGAS.1.2.001
Authors: Hejna M. , Zacherl J. , Ba-Ssalamah A. , Püspök A. , Pluschnig U. , Brodowicz T. , Zielinski C. C. , Raderer M.
Published: March 2020

4527

Background: A phase II trial was performed to determine the antitumor efficacy and tolerance of combined docetaxel and oxaliplatin in previously untreated, advanced patients with gastroesophageal adenocarcinoma. Methods: Thirty-six patients with histologically confirmed advanced gastroesophageal adenocarcinoma were entered in this trial. Treatment consisted of 3-weekly courses of docetaxel 80 mg/m2 and oxaliplatin 100 mg/m2 both given on day 1. A 5-day course of human granulocyte colony stimulating factor (G-CSF) 5 μg/kg/day was given subcutaneously to prevent neutropenia; in addition, if haemoglobin was <12.0 mg/dl, erythropoietin 10,000 IU was administered subcutaneously 3 times per week. Primary objective was to evaluate the time to progression. Results: The confirmed overall response rate was 36%, including 3 complete responses (8.3%) and 10 partial responses (27.7%). Fifteen patients (41.7%) had stable disease and 8 (22.3%) progressed while on treatment. The median time to response was 2.5 months, the median time to progression was 5.3 (1- 33+) months and the median overall survival time was 9.8 (2.5–35+) months with 8 (22%) patients currently alive. Hematologic toxicity was common, though WHO grade 3/4 neutropenia occurred only in 6 (17%) patients and anaemia also in 6 (17%) patients, respectively. Nonhematologic adverse reactions were usually mild to moderate; grade 3 toxicities included emesis, diarrhoea and mucositis each in 1 patient (3%). Conclusion: Our data suggest that the combination of docetaxel and oxaliplatin with G-CSF and erythropoietin has a promising therapeutic index in patients with advanced gastroesophageal adenocarcinoma.

No significant financial relationships to disclose.
Definitive chemo-radiotherapy (CRT) with folfox 4 or 5FU-cisplatin as first line treatment for patients (pts) with inoperable esophageal cancer (IEC): Final results of a randomized phase II study
Authors: Conroy T. , Yataghene Y. , Etienne P. L. , Michel P. , Senellart H. , Raoul J. L. , Mineur L. , Rives M. , Mirabel X. , Adenis A.
Published: March 2020

4532

Background: The RTOG regimen of concurrent CRT with 5FU/CDDP represents the standard treatment of pts with IEC (Al- Sarraf JCO, 1997). As new combinations are required to improve survival, we launched a multicenter randomized phase II study to assess the feasibility and endoscopic complete response rate (ECRR) of combination CRT with Folfox 4 (arm A) or 5FU/CDDP (arm B) in pts with IEC. Methods: Radiotherapy (RT) was in both arms 50 Gy (2Gy/fraction) 5 days/ week for 5 weeks. In Arm A, pts received 6 biweekly cycles (cy): Oxaliplatin 85mg/m2 d1 and Leucovorin 200mg/m2 followed by 5-FU 400mg/m2 bolus and 600mg/m2 22h continuous infusion (C.I.) d1–2 ; the first 3 cy were delivered during RT, the 3 other after. Arm B: 4 cy were delivered: CDDP 75mg/m2 d1 followed by 5FU 1,000 mg/m2/d C.I. d1–4, the first two cy during RT and 2 other after RT. To be evaluable pts must have completed the concurrent CRT. Response evaluation (esophagoscopy + CT-scan) was done on week 15; ECRR was reviewed by an independent expert committee. Results: 97 pts (A/B= 53/44) were included and 95 treated: 19% adenocarcinoma, 81% squamous cell carcinoma; median age 59 [39–81] and PS 0–1: 98%. In arms A/B, 89/91% of pts completed the concurrent CRT and 75/70% the full treatment. Main NCI-CTC grade (G) 3–4 toxicities (% per pt) were in arms A/B: neutropenia 19/19, febrile neutropenia 12/5, neutropenic infection 2/7, esophagitis 8/14. Neurotoxicity: in arms A/B, 13%/ 2% of pts had G 2 and 46%/13% G 1 neuropathy, no G 3 neuropathy occurred. 47/40 pts (90%) were evaluable for response. In the ITT population, the ECRR was 44.7% and 30.0%, median TTP was 15.0 [9.9–18.9] / 9.5 [7.6- not reached (NR)] months (mos), median Event Free Survival was 11.6 [8.6–17.2]/ 7.8 [5.1–9.9] mos and the median overall survival was 22.7 [16.7-NR]/ 14.7 [9.2–17.2] mos, in arms A and B respectively. Conclusions: The new concurrent CRT with Folfox4 is a well tolerated and convenient combination with promising efficacy associated with very good survival results. Final data will be presented at the meeting. The study continues as a phase III trial.

No significant financial relationships to disclose.
E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/RT or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged adenocarcinoma of the esophagus
Authors: Kleinberg L. , Powell M. E. , Forastiere A. , Keller S. , Anne P. , Benson A. B.
Published: March 2020

4533

Background: E1201 included operable esophageal adenocarcinoma, staged II-IVa by EUS. Endpoints were pathologic complete response (pCR), toxicity, and tolerability of these two experimental regimens. pCR was used as a surrogate endpoint. As previously reported, the pCr rates indicated that these regimens did not meet criteria for further study based on a target of 45% against the null hypothesis of 25% for standard therapy. This report contains details of toxicity, tolerability of adjuvant chemotherapy, and prognostic value of EUS staging. Materials/Methods: 90 eligible pts enrolled. Arm A was Cisplatin (C) 30mg/m2 and Irinotecan (I) 50 mg/m2 on days (d) 1,8,22,29 of 45 Gy RT/5 weeks. Post-op therapy was C 30 mg/m2 and I 65 mg/m2 d 1, 8 q21 days x 3. Arm B therapy was C 30 mg/m2 and Paclitaxel (P) 50 mg/m2 1 hour infusion d 1,8,15, 22, 29 with RT. Postoperative therapy was C 75 mg/m2 and P 175 mg/m2 day 1 q21 days x 3. Results: Of all eligible patients, 83% (38/46) and 70% (31/44) had a complete resection with negative margins and 6/46 (15%) (95% CI = 5%, 26%) and 7/44 (16%) (95% CI = 7%, 30%) had pCR on arm A and B respectively. Confirmed EUS staging was available for 71 pts, Path CR rate was 3/19(16%) for stage T2- 3N0M0 and 7/52(14%) for stages T1–3N1M0 or T1–3N0- 1M1a. The incidence of ≥ grade 3 hematology toxicity, dysphagia, and diarrhea during neoadjuvant therapy were 20 (43%), 6 (13%), 4 (9%) for arm A (nTOX=47) and 18 (39%), 9 (20%), and 1 (23%) for arm B (nTOX=46). Zero, one, two and three cycles of adjuvant chemotherapy were received by 26%, 20 %, 5% and 49% of operated patients in arm A (n=41) and 36%, 14%, 3%, and 47% in arm B (n=36). Two of 77 (3%) operated patients died within 30 days of surgery. Conclusions: The low pCR rates suggest that neither regimen is likely to advance treatment of esophageal/GEJ adenoca over preoperative cisplatin/5-FU/RT and therefore do not warrent pursuing. EUS stage did not appear to influence response rate with these regimens. Moreover, these regimens are associated with significant toxicity and, as with other regimens, only a minority of patients were able to receive the planned adjuvant therapy. Survival follow-up continues.

No significant financial relationships to disclose.
FOXO3a predicts for survival and its phosphorylated form is downregulated following mTOR or MEK inhibitor therapy in Hepatocellular Carcinoma
Authors: Teo M. , Huynh H. T. , Hee S. W. , Phoon Y. P. , Quek R. , Wang P. , Toh H. C.
Published: March 2020

4538

Background: Hepatocellular carcinoma (HCC) is an aggressive cancer endemic in Asia with few effective treatments. We hypothesize that FOXO3a may be a potential prognostic marker in HCC and analyze the effects of targeted therapy acting on the PI3K/AKT pathway, of which FOXO3a is downstream. PI3K activates serine/threonine protein kinase AKT, causing FOXO3a phosphorylation and its nuclear translocation, promoting apoptosis. Tumor suppressor, promyelocytic leukemia (PML), inactivates nuclear phosphorylated AKT (pAKT). mTOR, also of the P13K/AKT pathway, is dysregulated in many cancers. PI3K is an effector of RAS, which controls downstream mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) pathway. AZD6244 is a selective inhibitor of MEK1/2. RAD001 (Everolimus) specifically inhibits mTOR. Avastin (bevacizumab) is an anti-angiogenic agent. These therapies have shown clinical efficacy in various cancers, including preliminary results with either RAD001 or avastin treatment in HCC. Method: We analyzed FOXO3a status in 91 stage I and II HCC patients using relative real-time PCR and immunoblotting analysis. Using a primary human HCC xenograft SCID mouse model, we examined tumor efficacy and molecular effects of AZD6244, RAD001 and Avastin treatment. Results: The median survival of the high FOXO3a-expressing group (2-fold increased expression vs normal, >2.0, n=16) was 27 months versus 95 months for the low expressing group (2-fold decreased expression vs normal, <0.5, n=58) (p=0.037). Pearson correlation analysis indicated a positive correlation between FOXO3a and PML (n=46, correlation=0.533, p<0.001). Immunoblotting results for 8 random HCC samples reveal increased levels of pFOXO3a (Ser253) in all tumor tissue compared to adjacent normal. Treatment of HCC xenograft mice with AZD6244 or RAD001 caused significant tumor shrinkage and reduced levels of pAKT (Ser308) and pFOXO3a (Ser318). Avastin had cytostatic effects and unchanged levels of pFOXO3a (Ser318). Conclusion: FOXO3a predicts for overall survival in HCC. A positive correlation is established between FOXO3a and PML. AZD6244 and RAD001 can induce tumor regression via the AKT-FOXO3a pathway in HCC xenografts.

No significant financial relationships to disclose.