bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant radiotherapy ± tegafur-uracil plus leucovorin in rectal adenocarcinoma: Final results of a French multicenter phase III study
Authors: Gamelin E. , Mineur L. , Chevelle C. , Cailleux P. , Martin L. , Bastit L. , Roullet B. , Hasbini A. , Savary J. , Cellier P.
Published: August 2020

4104

Background: Neoadjuvant chemoradiotherapy (CRT) with tegafur-uracil (UFT) plus leucovorin (LV) has shown promising results in patients with rectal adenocarcinoma (RAC). We therefore conducted a phase III trial to compare neoadjuvant CRT with UFT/LV versus radiotherapy (RT) alone. Methods: One hundred seventy seven pts with RAC stage T3 (T4 if anal extension) N<2, M0 were randomized to either RT alone (RT) (1.8 Gy/d, 45 G total) 5 days/w for 5 weeks or combined to CT (CRT) with daily UFT 300 mg/m2 plus leucovorin 75 mg for 5 weeks. TME surgery was performed 6–8 weeks after treatment. Adjuvant CT permitted at investigator discretion. Primary endpoint was pathological complete response rate (pCR), secondary endpoints included downstaging, QOL, sphincter preservation, recurrence rates, disease-free and overall survival. Results: Of 177 pts, 87 pts were allocated to RT and 90 to CRT. Compliance: RT dose intensity 98.8 % (n=86) in RT arm vs 95.6 % (n=86) in CRT arm with UFT mean dose 295.7 ± 19.8 mg/m2. 172 pts underwent surgery (97.2%), 5 pts were not resected (4 liver and 1 lung metastases plus 1 CVA). Both RT and CRT were well tolerated. No neutropenia and only 1 grade IV diarrhea in the CRT arm were observed. Treatment related death occurred in 4 patients, 3 in the RT arm and 1 in the CRT arm respectively. With a median follow-up at 22.3 mo, median OS is not yet reached. Conclusions: Neoadjuvant radiotherapy combined with UFT increases significantly the pCR rate with an acceptable toxicity. Further survival data will be presented. This is the first randomized study of neoadjuvant CRT highlighting the improvement of the pCR rate with UFT.

[Table: see text]

[Table: see text]
Effect of downstaging without complete pathologic response after neoadjuvant treatment on cancer outcomes for cIII and cII rectal cancers
Authors: Lobato L. F. , Stocchi L. , da Luz Moreira A. , Kalady M. , Dietz D. , Geisler D. , Lavery I. , Fazio V.
Published: August 2020

4108

Background: Neoadjuvant chemoradiation followed by surgery is standard of care for locally advanced rectal cancer. The impact of downstaging on prognosis when pathologic complete response (pCR) cannot be achieved remains unclear. The aim of this study was to evaluate whether downstaging impacts prognosis in patients with cII vs. cIII rectal cancer. Methods: We identified from our colorectal cancer database 233 patients with primary cII and cIII rectal cancer staged by CT and ERUS/MRI who received 5FU-based chemoradiation followed by R0 surgery after a median interval of 7 weeks during 1997–2007. Median radiotherapy dose was 5040 cGy. We excluded 58 patients with pCR and. Compared among the remaining 175 patients pathologic downstaging (cII to ypI, cIII to ypII or ypI) vs. No pathologic downstaging (c stage ≤ yp stage). Outcomes evaluated were 5-year overall survival, 3-year recurrence-free survival, overall recurrence, local recurrence and distant recurrence. Results: Median age was 58 years and median follow-up was 48 months. Patients with cII vs. cIII stage were statistically comparable regarding demographics, chemoradiation regimen, interval to surgery after neoadjuvant treatment, tumor distance from anal verge, operations performed and follow-up. The incidence of downstaging was increased in stage cIII vs. cII patients (68% vs. 21%, p <0.001). With the exception of local recurrence rates, downstaging resulted in significantly improved cancer outcomes for cIII but not cII ( Table ). Conclusions: Downstaging without pCR is a significant prognostic factor for patients with stage cIII rectal cancer. A larger sample size is required to confirm lack of downstaging benefits in stage cII.

[Table: see text]

No significant financial relationships to disclose.
Neoadjuvant chemoradiation therapy with capecitabine (X) plus cetuximab (C), and external beam radiotherapy (RT) in locally advanced rectal cancer (LARC): ABCSG trial R03
Authors: Eisterer W. M. , De Vries A. , Oefner D. , Greil R. , Rabl H. , Tschmelitsch J. , Schmid R. , Kapp K. , Zehentmayr F. , Thaler J.
Published: August 2020

4109

Background: Pre-operative chemoradiation is a standard treatment for LARC. X and C are synergistic with radiotherapy and active in colorectal neoplasms. This phase II multicenter trial was designed to assess the feasability and tolerability of a preoperative combination of X, C, plus RT in patients with LARC. Secondary endpoints were downstaging-rate and induction of complete pathological response (CPR). Only patients (pts.) with MRT-documented T3/T4-tumours were included. Methods: Pts. with potentially resectable cT4 or cT3 LARC (lower/mid rectum) were enrolled. Chemoradiotherapy consisted of X (825mg/sqm twice daily on RT-days weeks 1–4), C (400mg/sqm loading dose once per week, 200mg/sqm weekly x 4) and pelvic RT 3D conformation technique (1.8Gy/day, 45Gy total). Surgery was performed 28–42 days after completion of RT. Results: 31 pts. were enrolled, median age was 61 years (range 41 to 80), PS 0: 22 pts. (71%), PS 1: 8 pts. (26%), PS 2: 1 pt. (3%). 21 pts. (68%) presented with cT4, 10 pts. (32%) with cT3 tumors. 25 pts. (81%) had positive lymph nodes (LN) by imaging, 2 pts. were LN-negative, 4 pts. (13%) are not evaluable for N-stage. 28 pts (90%) are available for evaluation of toxicity and efficacy. Treatment with X and C plus RT was well tolerated, in only 4 pts. grade 3 toxicity was observed: acneiform skin rash 2 pts (7%), diarrhea 3 pts (11%), 1 pt. (4%) suffered from grade 4 diarrhea. Median dose intensity of X and C was >95% during the entire treatment period. Tumor downstaging was observed in 14 pts. (50%) total, 12/19 (63%) T4 tumours and 2/9 (22%) T3 tumors responded. While no patient achieved a CPR, in 14 pts. a lymph node clearing (ypN0) was observed. Conclusions: The combination of capecitabine and cetuximab plus radiotherapy is a well tolerated preoperative treatment regime for LARC (cT3/4). The main toxicity consisted of diarrhea. The combination is effective in the primary tumor as well as in the lymph nodes, both with possible impact on therapy outcome.

No significant financial relationships to disclose.
Meta-analysis of gender effect for first-line chronomodulated 5-fluorouracil-leucovorin-oxaliplatin (ChronoFLO) compared with FOLFOX or constant infusion (conventional delivery, CONV) against metastatic colorectal cancer (MCC) in three international controlled phase III randomized trials (RT)
Authors: Levi F. , Innominato P. , Poncet A. , Moreau T. , Iacobelli S. , Focan C. , Garufi C. , Bjarnason G. , Adam R. , Giacchetti S. ,   for the ARTBC Chronotherapy Group
Published: August 2020

4112

Background: Gender predicted for the most effective schedule in a RT of ChronoFLO vs CONV against MCC: overall survival (OS) was significantly increased in men on chronoFLO vs FOLFOX, whereas the reverse was found in women (Giacchetti, JCO 2006). Methods: To assess the relevance of gender for patient (pt) outcome, meta-analysis was performed on individual pt data (IPD) from 3 RT in 845 MCC pts treated with chronoFLO vs CONV (346 F, 499 M at 36 centers in 1990–2002)(Lévi, JNCI 1994; Lancet 1997). Data bases were merged and updated at 9 y after inclusion of the 1st pt. Main prognostic factors were comparable in each RT according to gender and treatment arm (median age: 61y; PS=0, 46% pts; liver M, 85% pts; liver involvement >25%, 41% pts; lung M, 37% pts; CEA>10, 56% pts). Results: No significant difference was found according to delivery schedule or gender in the whole population for Response Rate (RR), Progression-Free Survival (PFS) and OS. However, men on chronoFLO had highest RR, longest PFS and OS. PFS and OS were highest in women on CONV ( Table ). The rate of complete macroscopic resections of liver metastases (R0+R1) was 12.5% in men on chronoFLO vs 7.8–8.5% in men on CONV or in women on either schedule. A complete histologic response of liver metastases was documented in 2.1% of the men on chronoFLO vs 0–1.1% in the other groups. The relative risk of an earlier death in men vs women was 0.76 [95% CL, 0.91 to 0.94] on chronoFLO and 1.24 [0.99 to 1.56] on CONV. Conclusions: This IPD meta-analysis of 3 RT in MCC with a minimum follow up of 5 years confirms that men benefit from chronoFLO as compared to CONV delivery, with regard to long term outcome and medico-surgical strategy. ChronoFLO should be preferred to conventional oxaliplatin-5-FU-LV schedules in men with MCC. Support: ARTBC Internationale, P. Brousse Hospital, Villejuif, France.

[Table: see text]

No significant financial relationships to disclose.
Molecular biology from bench-to-bedside: Which colorectal cancer patients to refer for genetic counseling
Authors: Jensen L. H. , Dysager L. , Lindebjerg J. , Kølvraa S. , Byriel L. , Crüger D. G.
Published: August 2020

4113

Background: The single most common cause of hereditary colorectal cancer is the Lynch syndrome, which is associated with deficiency of the mismatch repair genes MLH1, MSH2, or MSH6. Most MLH1 negative tumors are sporadic in origin, and they can be identified if harbouring a BRAF V600E mutation or hypermethylation of the MLH1 promoter. If Lynch syndrome is detected in a patient and its family, screening can prevent death from new colorectal cancer. A family history should always be obtained, but in small families or patients with de-novo mutations and mutations with late or low penetrance, this is not sufficient. The aim of this study was to validate our previously suggested clinically applicable strategy based on molecular characteristics for identifying which patients to refer for genetic counselling. Methods: The strategy was validated in an unselected cohort of 287 colorectal cancer patients. All tumors was tested for MLH1, MSH2, and MSH6 with immunohistochemistry. DNA from MLH1 negative tumors was sequenced for BRAF mutations. If wild-type, MLH1 promoter was analyzed with methylation specific multiplex ligation-dependent probe amplification (MLPA). MLH1 negative tumors were considered sporadic if BRAF V600E mutation or MLH1 promoter hypermethylation was found. A follow up was done on patients with MSH2 or MSH6 negative tumors and MLH1 negative cases not shown to be sporadic. Results: Most tumors, 251 (88%), stained positive for all three proteins. Six (2%) had negative MSH2 and one (<1%) isolated loss of MSH6. MLH1 was negative in 29 cases (10%). DNA quality allowed BRAF analysis in 27 of these with 14 mutations and 13 wild-type. DNA quality allowed MLPA in four of the 13 BRAF wild-type, and all four were methylated. Subsequently, Lynch syndrome could not be ruled out in 18 patients. A follow-up at 8–10 years revealed four definite Lynch syndrome and four highly suspicious. Conclusions: An easy and clinically applicable step-wise approach with immunohistochemistry (100%), BRAF sequencing (10%), and methylation analysis (5%) identified several patients with hereditary cancer. The family history should be supplemented with a molecular screening for whom to send for genetic counselling.

No significant financial relationships to disclose.
Survival after surgery in patients with initially resectable metastasis receiving adjuvant/neoadjuvant FOLFOX therapy and in patients who had surgery after FOLFOX therapy
Authors: Perez-Staub N. , Chibaudel B. , Paye F. , Taieb J. , Gayet B. , Bourges O. , André T. , Tournigand C. , Louvet C. , de Gramont A.
Published: August 2020

4118

Background: Surgery of metastases can cure approximately 20% of metastatic colorectal cancer (MCRC). About 15% of MCRC pts are resectable at presentation. Among the other pts, 10 to 30% can benefit from a salvage surgery after response to chemotherapy, improving their prognostic. We report here the results in pts resectable at presentation and in pts who underwent surgery after chemotherapy in phase 2 and 3 studies. Methods: We retrospectively analysed 167 pts who underwent R0/R1 surgery, 46 pts at presentation in a phase 2 study testing a combination of FOLFOX followed by FOLFIRI (MIROX, Taieb JCO 2005), and 121 pts who underwent a salvage surgery after FOLFOX treatment in OPTIMOX1 (Tournigand, JCO 2006) and OPTIMOX2 (Maindrault-Goebel, ASCO 2007) after updating the survival. Results: Patients’ baseline characteristics were (MIROX/OPTIMOX %): median age 56/62 yrs, PS 0 50/73, metachronous metastasis 41/21, ≥ 2 met sites 11/18, liver met 78/88, lung met 11/19, other met 17/10, two-stage surgery 9/10, second surgery after relapse 39/22, R0 resection 91/ 85. 114 among 142 evaluable patients had a response to FOLFOX (80%). Median time from randomisation to surgery was 8 mths in the OPTIMOX group. In the MIROX group, 46% had surgery of metastases before chemotherapy. Median disease-free survival from R0/R1 surgery was 18.6 months in MIROX group vs 9.4 months in OPTIMOX group (p=0.006).Median overall survival was 104.8 months in MIROX group vs 42.6 months in OPTIMOX group (p=0.02). Furthermore, initially resectable remained the strongest prognostic factor in this series. Conclusions: MCRC pts initially resectable at presentation have a better prognosis than pts who underwent a salvage surgery after FOLFOX chemotherapy.

No significant financial relationships to disclose.
Phase II study to evaluate the efficacy of capecitabine combined with bevacizumab as first-line treatment in elderly patients with advanced or metastatic colorectal adenocarcinoma
Authors: Feliu J. , Safont M. , Salud A. , Losa F. , García-Girón C. , Bosch C. , Escudero P. , López R. , Madroñal C. , González-Barón M.
Published: August 2020

4119

Background: Colorectal adenocarcinoma is the most common cancer in subjects over 70 years old. New therapies have been developed but limited data about their activity are available in elderly population. Results obtained with capecitabine have shown an appropriate safety and efficacy profile in these patients. The aim of the present study is to evaluate the overall response rate in that patient's population who presents colorectal adenocarcinoma and are treated with the combination of capecitabine+BVZ. Methods: This is a multicentric, non-controlled, open label, phase II clinical trial. Capecitabine(1250mg/m2 bid, orally)+BVZ(7.5mg/kg, intravenously) treatment was administered in 3-week length cycles until disease progression. Capecitabine dose was reduced to 1000mg/m2 when the creatinine clearance was between 30 and 50ml/min. Results: A total of 59 patients were included (57.6%, male). Mean age was 76±4.1 years. ECOG status was 0–1 in 96.5 % of the patients. Activities of daily living: moderate to severe dependence and functional incapacity in 24.5% and 5.6% of the patients by Lawton and Barthel scales, respectively. Comorbidities: hypertension (61%), venous thrombosis (5.1%), cardiac disease (5.1%) and acute cerebrovascular accident history (3.4%). Metastases were detected in liver (84.7%), lung (45.8%), local/regional (18.6%) and other locations (5.1%). Mean number of cycles of capecitabine+BVZ was 6.8±6.1. Most frequent grade 3–4 toxicities observed were hand-foot-syndrome (18.6%), diarrhea (8.5%), deep venous thrombosis (6.8%), pain (5.1%) and mucositis (3.4%). Four patients died due to toxicity (mucositis, digestive hemorrhage, hematological toxicity and sepsis, respectively). Metastasis resection was performed in 10.2% of the patients. Treatment response was: 33.3% partial response and 59.0% stable disease. Median progression-free survival was 10.8 months. Conclusions: The combination capecitabine+BVZ in elderly patients appears to have a manageable safety profile and achieves promising results in terms of response rates and progression free-survival.

No significant financial relationships to disclose.
Use of tumor site as a prognosticator: Population-based analysis of rectosigmoid and rectum cancers
Authors: Raj K. P. , Ziogas A. , Barleben A. R. , Stamos M. J. , Zell J. A.
Published: August 2020

4123

Background: The study examines the prognostic significance of tumor location exclusively in rectosigmoid and rectal cancers. Although tumor location has traditionally been regarded as a prognostic determinant, data in support of this claim are lacking. We set out to determine this using data from a large population-based California Cancer Registry (CCR). Methods: A retrospective analysis of surgically treated cancer cases involving the rectum and rectosigmoid from 1994–2006 with a follow-up until January 2008 in CCR was conducted. Sub-site tumor location of the cancers involving the rectum was either defined as rectosigmoid or mid/distal rectum. Site-specific survival analyses were conducted by Kaplan-Meier method and hazard ratio calculated using Cox proportional hazard ratios (HR). Results: A total of 33,418 rectal cancer cases were identified, including 12,407 (37.1%) rectosigmoid cancers and 21,011 (62.9%) mid/distal rectum cancers. No significant differences by tumor location were noticed for age, gender, stage, histological type, grade or socioeconomic status. Fewer rectosigmoid cancers received radiation (81.9% vs. 62.3% p=<0.0001)) compared to mid/distal rectum cancers. After adjustment for treatment and relevant clinical factors, an improved rate of CRC-specific survival was noticed in non-metastatic rectosigmoid cancers when compared to cancers involving the mid/distal rectum. A significant decrease in mortality was observed in Stage-I [HR- 0.74(0.63–0.86)], Stage-II [HR-0.76(0.69–0.85)] and Stage-III [HR- 0.90 (0.83–0.98)] rectosigmoid cancers when compared to mid/distal rectum cancers. Number of lymph nodes examined (>12 vs. <12) was an independent prognostic factor for survival in Stage-II patients [HR-0.74 (0.63–0.87)]. Conclusions: Among locoregional cases, rectosigmoid cancers were found to have an improved CRC-specific survival compared to mid/distal rectum cancers, which was independent of other relevant clinical factors.

[Table: see text]

No significant financial relationships to disclose.
Impact of mucinous histology on prognosis for patients with radically resected stage Dukes B2 and C colon cancer: Preliminary results
Authors: Catalano V. , Loupakis F. , Bisonni R. , Torresi U. , Santini D. , Silva R. R. , Giustini L. , Falcone A. , D’Emidio S. , Rocchi M. , Graziano F.
Published: August 2020

4126

Background: Previous reports have suggested that mucinous colorectal adenocarcinomas have a poorer prognosis than nonmucinous colorectal adenocarcinomas. This retrospective analysis was conducted to explore whether mucinous carcinoma (MC) is associated with a worse prognosis than nonmucinous carcinoma (NMC) for patients with Dukes B2 and C radically resected colon cancer. Methods: We investigated 1,006 unselected patients who underwent curative surgery for sporadic colon cancer and followed up at six Oncology Department between 1998 and 2006. Univariate and multivariate analyses were performed to determine prognostic factors of survival. Results: MC accounted for 17.9% (n=180) of all colon carcinomas. Patient characteristics were as follows. MC: M/F 104/76; median age, 68 (range, 28–97); pT1/2/3/4, 1/4/153/22; Dukes B2/C 98/82; invasion 26 (14%); ≥12 examined lymph nodes, 115 (64%); adjuvant chemotherapy, 110 (61%). NMC: M/F 445/381; median age, 68 (range, 29–95); pT1/2/3/4, 9/51/715/51; Dukes B2/C 384/442; invasion 199 (24%); ≥12 examined lymph nodes, 499 (60%); adjuvant chemotherapy, 545 (66%). MC were more frequently located in the proximal colon (54.4% versus 34.6% for NMC; p<0.001). No difference between MC and NMC in disease-free survival (hazard ratio, HR 1.01; 95% CI, 0.76–1.36; p=0.92) and overall survival (HR 1.05; 95% CI, 0.74–1.49; p=0.78) was found. After stratification by stage of disease, MC and NMC had no statistically significant difference in 5-year disease-free survival (Dukes B2: 79.1% and 78.1%, respectively, p=0.86; Dukes C: 53.8% and 56.2%, respectively, p=0.58) and overall survival (Dukes B2: 84.2% and 85.5%, respectively, p=0.80; Dukes C: 68.0% and 67.3% p=0.52). Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage at diagnosis (p<0.0001), grading (p<0.0001), and number of lymph node examined (p=0.0002) in the specimen. Conclusions: In this preliminary analysis, patients with mucinous histology who underwent surgery with curative intent for stage Dukes B2 and C colon cancer had similar prognosis compared to NMC.

No significant financial relationships to disclose.
Prospective randomized study comparing fourth-week surgery versus eighth- week surgery after neoadjuvant concomitant radiotherapy and infusional 5-FU in T3–4/N0+ rectal cancer: Istanbul R-01 Study
Authors: Saglam S. , Bugra D. , Kaytan Saglam E. , Yamaner S. , Asoglu O. , Balik E. , Oral E. N. , Sakar B. , Kizir A. , Kapran Y. , Camlica H.
Published: August 2020

4131

Background: Prospective randomized study has been designed to compare the efficacy of fourth week surgery (4WS) versus eighth week surgery (8WS) after concomitant neoadjuvant chemoradiotherapy (NeoadjCTRT) on local recurrence and overall survival (OS) in cT3–4/N0+, mid and distal localized (intraperitoneal) rectal cancers. Pathological regression grades (PRG;Dworak) were evaluated after neoadjCTRT. Methods: During Jan 2002- Nov 2007; 170 pts were randomized to the study in Istanbul University Oncology Institute and Medical Faculty. All rectal cancer pts are T3–4/N0+; distal and mid rectum and received 45 Gy conventionally fractionated RT in 25 daily fractions of 1.8 Gy combined with 225 mg/m2/day continous infusion 5-FU. Preoperative staging was performed by endorectal USG and /or MRI and abdominal CT.4cycles FUFA is standard as adjuvant treatment after surgery. Results: 17 pts have been removed (M1, frozen pelvis, refuse surgery, disease progression). Clinical T3N+ was 60.8% before surgery. 76 pts were operated at 4WS and 77 pts at 8WS. Median follow-up was 30 (2–71) months. APR was 31.4%. LAR was 68.6%. Surgical margin positiveness (SMP) and <2mm were detected in 14 pts. R0 resection rate was 90.8%. Median harvested lymph node number were 13. PRG were PRG 0 (1.3%); PRGI in (24.2%); PRGII in (40.5%); PRGIII (17%); PRGIV in (17%). There is no statistical significance between 4WS vs 8WS on pathological regression scores. Local recurrence developed in 8 pts (PRGI:3pts; PRGII:4; PRGrIV:1). There is no statistical difference 4WS v 8WS on local recurrence (5 pts/3). Local recurrence rate was 8.4% in distal rectum (7 pts) and 1.2% in mid rectum (1pts) (p=0.023). SMP and <2mm was statistically significant in local recurrence (p=0.003). 5 years OS were similar in 4WS 75.2% and 8WS 73.9%. Distant metastasis is significant (liver, lung, bone) in distal rectal tumors (p=0,007). SMP or < 2mm is significantly poor in OS (p<0.0001). Conclusions: There is no difference 4WS vs 8WS on local recurrence, OS and PRGs. Important factors for local recurrence and (OS) are having distal rectal tumor and SMP and <2mm. Distal rectal tumors have prone to distant metastases.

No significant financial relationships to disclose.
The prognostic value of polymorphisms in the insulin-like growth factor receptor (IGFR) pathway in patients with locally advanced pancreatic cancer (LAPC)
Authors: Shroff R. T. , Javle M. M. , Dong X. , Kumar V. S. , Krishnan S. , Wolff R. A. , Abbruzzese J. L. , Li D.
Published: August 2020

4500

Background: The IGFR pathway is activated in pancreatic cancer and may result in aggressive disease course. The study of single nucleotide polymorphisms (SNPs) involved in this pathway may provide prognostic information and predict response to IGFR directed agents. We investigated IGFR pathway SNPs in patients with LAPC. Methods: We evaluated 39 SNPs from 7 candidate genes in the IGFR pathway (IGF1R, IGF2R, IGF1, IGF2, IRS1, IRS2, IGFBP3) in 105 LAPC patients. DNA extraction from whole blood was performed using the Qiagen Flexigene DNA and Promega Maxwell 16 kits. Genotyping was performed using the Sequenom method. Overall survival was measured from date of diagnosis to date of death or last follow-up. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare survival of patients according to genotype corrected for previously identified prognostic factors, including induction chemotherapy, CA 19–9, albumin, LDH, hemoglobin and Karnofsky performance status (KPS). Results: Median survival time (MST) was 15 months (95% CI 13.3–16.7). Induction chemotherapy, LDH, CA 19–9 level, hemoglobin, and KPS were not significantly associated with survival. Serum albumin and three SNPs of the IGF pathway (IGF1R IVS20–3431A>G, IRS1 G971R, and IGF2 *4352A>G) were significantly associated with prognosis ( Table ). Two of the three genotypes remained as significant predictors for survival in Cox regression analysis when adjusted for clinical factors. A significant combined genotype effect was observed wherein patients with all three deleterious alleles had significantly worse survival than those with only two or one (10 vs. 16.3 vs. 21.3 months, p< 0.0001). Conclusions: These data suggest that SNPs in the IGFR pathway genes may have prognostic value for LAPC patients. This information may identify population subgroups that could benefit from IGFR-targeted agents.

[Table: see text]

No significant financial relationships to disclose.
A randomized trial of gemcitabine (G) versus G plus cisplatin in chemotherapy-naive advanced pancreatic adenocarcinoma: The GIP-1 (Gruppo Italiano Pancreas— GOIM/GISCAD/GOIRC) study
Authors: Colucci G. , Labianca R. , Di Costanzo F. , Gebbia V. , Cartenì G. , Massidda B. , Frontini L. , Falconi M. , Gallo C. , Di Maio M.
Published: August 2020

4504

Background: Single-agent gemcitabine (G) remains standard treatment for advanced pancreatic adenocarcinoma (APC). The GIP-1 randomized phase III trial (clinicaltrials.gov ID NCT00813696 ) was performed to compare the combination of cisplatin (P) and G vs. G alone as 1st-line treatment. Methods: Patients (pts) with locally advanced and/or metastatic pancreatic adenocarcinoma, age 18–75, Karnofsky Performance Status (KPS) ≥50, were randomized to receive G (arm A) or G+P (arm B). In arm A, G was administered at 1000 mg/m2 weekly for 7 consecutive wks, and, after a 2-week rest, on day 1, 8, 15 every 4 wks. In Arm B, P 25 mg/m2 weekly (with the exception of day 22) was added to G, same dose used in Arm A (Colucci et al, Cancer 2002; 94:902–10). No maximum number of cycles was planned. Primary endpoint was overall survival (OS). Clinical benefit (CB), objective response rate (ORR), progression-free survival (PFS), toxicity and quality of life were secondary endpoints. To have 80% power of detecting a 0.74 Hazard Ratio (HR) of death (corresponding to increase in median OS from 4.8 to 6.5 months, with bilateral alpha=0.05, 400 pts were planned and 355 deaths were required for final analysis. Results: From April 2002 to April 2007, 400 pts were enrolled (A:199, B; 201) in 46 Italian Institutions. Median age was 63 yrs (range 35–75), 59% were males, 84% stage IV, 83% KPS≥80. After a median follow-up of 38.2 months and 357 deaths, median OS was 8.3 vs 7.2 months in arm A and B, respectively (HR 1.10, 95% CI 0.89–1.35, p=0.38). Median PFS was 3.9 vs 3.8 months in arm A and B, respectively (HR 0.97, 95% CI 0.80–1.19, p=0.80). ORR was 10.1% in arm A and 12.9% in B (p=0.37). CB response was experienced by 23.0% and 15.1% (Arm A vs B, p=0.057). Patients assigned to combination arm experienced more anaemia (all grades: 50% vs 39%, G3: 5% vs 1%), more neutropenia (all grades: 44% vs 36%, G3&4: 25% vs 14%) and more thrombocytopenia (all grades: 57% vs 29%, G3&4: 16% vs 5%). No relevant differences were seen in non-haematological toxicity. Conclusions: Weekly combination of P and G, compared to single-agent G as 1st-line treatment of APC, failed to demonstrate any improvement in OS, PFS, ORR and clinical benefit.

No significant financial relationships to disclose.
Prospective multicenter trial of sentinel node mapping for gastric cancer
Authors: Kitagawa Y. , Takeuchi H. , Takagi Y. , Natsugoe S. , Terashima M. , Murakami N. , Fujimura T. , Sakamoto J. , Aikou T. , Kitajima M.
Published: August 2020

4518

Background: The sentinel node (SN) concept has revolutionized the approach to the surgical staging of both melanoma and breast cancer, and these techniques can yield patient benefit by avoiding various complications due to unnecessary prophylactic regional lymph node dissection in cases with negative SN for cancer metastasis. Clinical application of SN mapping for early gastric cancer had been controversial for years. However, single institutional results of SN mapping for early gastric cancer are almost acceptable results in terms of detection rate and accuracy to determine lymph node status. We hypothesized that SN mapping plays a key role to obtain individual information and allows modification of the surgical procedure for early gastric cancer. Methods: The Japan Society of Sentinel Node Navigation Surgery (JSNNS) has conducted a prospective multicenter trial of SN mapping by a dual tracer method with radioactive colloid and blue dye. Between September 2004 and March 2008, 433 patients with early gastric cancer were accrued at 12 comprehensive hospitals. Patients were enrolled under JSNNS and each institutional review board-approved protocols. Eligibility criteria were that patients had clinically T1N0M0 or T2N0M0 single tumor with diameter of primary lesion less than 4cm without any previous treatments. Technetium-99m tin colloid and isosulfan blue were utilized as dual tracers for SN mapping. Results: SN mapping has been performed for 397 patients with early gastric cancer. Detection rate of hot and/or blue node using our procedure was 97.5% (387/397). The mean number of sentinel nodes per case was 5.6. Fifty-three of 57 cases with lymph node metastasis showed positive sentinel nodes. The sensitivity to detect metastasis based on SN status was therefore 93% in our experience. Accuracy of metastatic status based on SN was 99% (383/387). In two of the four SN false-negative cases, the tumor involved to pT2, and only one case showed the metastatic lymph node beyond the SN basin. Conclusions: Our results suggest that SN concept for clinically N0 early gastric cancer could be validated, and minimized gastrectomy with individualized selective and modified lymphadenectomy for early gastric cancer with negative SN should become feasible and clinically useful as less invasive surgical procedures.

No significant financial relationships to disclose.
A multicenter, randomized phase II trial of gemcitabine and oxaliplatin (GEMOX) alone or in combination with biweekly cetuximab in the first-line treatment of advanced biliary cancer: Interim analysis of the BINGO trial
Authors: Malka D. , Trarbach T. , Fartoux L. , Mendiboure J. , de la Fouchardière C. , Viret F. , Assenat E. , Boucher E. , Rosmorduc O. , Greten T.
Published: August 2020

4520

Background: There is no standard regimen for palliative chemotherapy of advanced biliary cancers. The GEMOX regimen is an option (BJC 2008). EGFR over-expression has been observed in advanced biliary cancers suggesting that the combination with anti-EGFR monoclonal antibodies may be appropriate. Methods: Patients with advanced biliary cancer, WHO performance status 0–1, and without prior palliative chemotherapy were eligible for this international, open-label, two-stage, randomized phase II trial. Patients received GEMOX (gemcitabine, 1000 mg/m2 [10 mg/m2/min] at day [D]1; oxaliplatin, 100 mg/m2 at D2) alone (arm A) or with cetuximab (500 mg/m2 at D1 or 2, arm B), every 2 weeks. Randomization was stratified according to tumor stage and location, center, and prior treatments. The primary endpoint was 4-month crude progression-free survival (PFS) rate (H0 hypothesis, < 40%; H1, ≥ 60%; planned sample size, 50 patients per arm). Secondary endpoints were response rate, PFS, overall survival, toxicity, early response assessment by PET, and blood/tumor EGFR signalling pathway member analyses. A data safety monitoring board-approved interim analysis was performed at the end of the first stage (18 patients per arm, minimal follow- up 4 months). Results: From October 2007 to October 2008, we enrolled 101 patients (median age, 62 yrs; male, 60%; metastatic, 86%; non-gallbladder, 76%). Among the 36 patients at the time of the interim analysis, the median number of treatment cycles was 6 and 8 in arms A and B, respectively. 76% (arm A) and 67% (arm B) had NCI-CTC grade 3–4 toxicity, mainly cytopenia (41%/39%), peripheral neuropathy (modified Levi's scale grade 2–3: 29%/33%), fatigue (6%/22%), gastrointestinal toxicity (12%/17%), and rash/hypersensitivity (0%/17%). The 4-month PFS rate was 44% (95% CI, 20–70) and 61% (95% CI, 36–83) in arms A and B, respectively. Conclusions: The GEMOX-cetuximab regimen seems well tolerated in patients with advanced biliary cancer. Adding cetuximab to GEMOX showed promising activity and therefore the trial was continued. Updated results on the whole population for primary and secondary endpoints will be available at the meeting.

[Table: see text]
Cationic liposomal paclitaxel in combination with gemcitabine in patients with advanced pancreatic cancer: A phase II trial
Authors: Loehr M. , Bodoky G. , Fölsch U. , Märten A. , Karrasch M. , Lilla C. , Meyer I. , Osinsky D. , Szanto J. , Lutz M.
Published: August 2020

4526

Background: EndoTAG-1 is a novel cationic liposomal formulation of paclitaxel being developed for the treatment of solid malignancies. It acts by targeting activated negatively charged endothelial cells of tumor blood vessels. We present safety and efficacy data of a randomized, controlled phase II trial in pancreatic cancer (PC). Methods: 200 patients with advanced PC were randomized to 1st line treatment with weekly gemcitabine (GEM: 1000 mg/m2) and twice weekly infusions of EndoTAG-1 (E) at 3 different dose levels (Elow: 11 mg/m2, Emed: 22 mg/m2, Ehigh: 44 mg/m2) or GEM monotherapy. Patients were treated for 7 weeks and followed up for overall survival (OS) for at least 1 year. After finishing study treatment, any anti-tumor therapy was allowed. A subgroup of patients had the option to receive repeated cycles of combination therapy in case of at least stable disease according to RECIST until disease progression. Results: Median OS was substantially higher in the GEM+Emed and GEM+ Ehigh groups than the GEM monotherapy group. Adjusted hazard ratios for OS were 0.72 (95% CI 0.46–1.13) and 0.67 (0.43–1.07). In patients receiving >1 treatment cycle, median OS was 11.5 months (GEM+Ehigh); in the GEM+Emed group 75% of patients were alive at 1 year. Treatment with EndoTAG-1 and gemcitabine was generally well tolerated. A trend for increasing adverse event frequency with EndoTAG-1 dose was observed for infusion-related reactions associated with chills and pyrexia, and thrombocytopenia. The overall frequency of serious adverse events in the GEM+E groups was low, the most frequent SAE being pyrexia in 4 (8%) patients in the GEM+Ehigh group. There was no indication for significant organ toxicity associated with EndoTAG-1, even in patients receiving multiple treatment cycles. Conclusions: This phase II trial indicates a considerable survival benefit for patients with advanced PC receiving EndoTAG-1 in combination with gemcitabine and a favourable safety profile warranting further development of EndoTAG-1 in this indication.

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Heritable interleukin-17F (IL17F) gene variation and overall survival (OS) in pancreatic cancer patients (pts): Results from a genome-wide association study (GWAS) in CALGB 80303
Authors: Innocenti F. , Owzar K. , Cox N. , Evans P. , Kubo M. , Hollis D. , Mushiroda T. , Kindler H. L. , Nakamura Y. , Ratain M. J.
Published: August 2020

4531

Background: CALGB 80303 was a randomized, phase III study in 602 advanced pancreatic cancer (PC) pts treated with gemcitabine plus either bevacizumab or placebo. No difference in OS was observed between the two arms (Kindler, ASCO 2007). As part of the study, we prospectively collected germline DNA for pharmacogenetic studies, originally focusing on the association of candidate genes with OS and toxicity. We subsequently amended the study to conduct a GWAS in order to identify other associations. Methods: Germline DNA was isolated from peripheral blood on 352 pts, and was typed for more than 550,000 SNPs using the Illumina550 platform. The associations between OS and SNPs were investigated using the log-rank test. A review of the clinical data and ancestry genomic analysis identified 294 pts who were clinically eligible and determined to be genetically European, and this subset was used for the primary analysis. Results: For the analysis of OS, pts in both arms were pooled, and two SNPs were associated with OS using genome-wide criteria (p≤10–7). This included an intergenic SNP on chromosome 15 (rs7174643), and a nonsynonymous SNP in the IL17F gene ( rs763780 ) with an allelic frequency of 3.9% (H161R, p<2.7x10–8). Median OS was significantly shorter for the H/R heterozygotes (3.1 months, 95% CI 2.3–4.3, n=23), as compared to the H/H homozygotes (6.8 months, 95% CI 5.8–7.3, n=271). This association remained highly significant when the analysis was stratified by extent of disease or previous radiotherapy. There was no evidence of an interaction with bevacizumab, suggesting that this SNP is prognostic rather than predictive. Conclusions: Heritable variation in IL17F may be a prognostic marker for PC. Wildtype (161H) IL17F is a pro-inflammatory, anti-angiogenic cytokine (Starnes, J Immunol 2001). The 161R mutant IL17F antagonizes wildtype IL17F (Kawaguchi, J Allergy Clin Immunol, 2006), potentially resulting in a pro-angiogenic effect. Replication studies in PC and other solid tumors are indicated.

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Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment in advanced gastric cancer: A nonrandomized multicenter AIO phase II study
Authors: Kanzler S. , Trarbach T. , Seufferlein T. , Kubicka S. , Lordick F. , Geissler M. , Daum S. , Galle P. R. , Moehler M. ,   German Arbeitsgemeinschaft Internistische Onkologie (AIO)
Published: August 2020

4534

Background: Cetuximab has demonstrated high efficacy in combination with irinotecan-based therapies in metastatic colorectal cancer and irinotecan/folinic acid/5-FU (IF) may be an effective alternative to cisplatin-based regimens in advanced gastric cancer. We therefore conducted a phase II AIO study to evaluate the tolerability and efficacy of cetuximab combined with IF as first-line treatment in patients with advanced gastric cancer. Methods: Patients (pts) were eligible with untreated adenocarcinoma of the stomach or oesophagogastric junction, with ECOG performance status (PS) < 2, measurable lesions and adequate organ functions. Pts received weekly cetuximab (first dose 400 mg/m2, subsequent doses 250 mg/m2) combined with chemotherapy consisting of irinotecan (80 mg/m2) plus 24 hours continuous infusion of sodium folinic acid (Na-FA: 200 mg/m2) and 5-FU (1500 mg/m2) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle. Treatment was continued until tumor progression and tumor assessments were performed every 2nd cycle. Results: Between Aug 2006 and Sep 2007, 49 pts were enrolled: 71% were males, median age was 63 years (range 33–77), median PS was 0 (65% pts), and 69% of pts and 31% of pts had gastric and oesophagogastric junction carcinomas, respectively. The median treatment time was 15.2 weeks (range 1.1–69.1). Grade 3/4 toxicities were diarrhoea (17% pts), skin reactions (13% pts), anorexia (9% pts), anaemia and fatigue (7%pts), allergic reactions, leucopoenia and neutropenia (4% pts each). Among 48 response-evaluable pts, the overall response rate (CR + PR) was 42% (CR 4%/PR 38%) and the tumour control rate was 73%. Median progression-free and overall survival times were 8.5 months (36.6 weeks; 95% CI 30.1; 48.1) and 16.6 months (71.1 weeks; 95% CI 50; 93.4), respectively. Conclusions: Cetuximab plus IF was well tolerated and encouraging survival data were observed. Cetuximab combined with chemotherapy in advanced or metastatic gastric cancer is under further investigation in an ongoing phase III trial.

No significant financial relationships to disclose.
Impact of dihydropyrimidine dehydrogenase status of biopsy specimens on efficacy of irinotecan plus cisplatin, S-1, or 5-FU as first-line treatment of advanced gastric cancer patients in JCOG9912
Authors: Yamada Y. , Yamamoto S. , Ohtsu A. , Suzuki Y. , Nasu J. , Yamaguchi K. , Denda T. , Tsuji A. , Hara Y. , Boku N. ,   Gastrointestinal Oncology Study Group/Japan Clinical Oncology Group
Published: August 2020

4535

Background: JCOG9912 (randomized phase III trial) showed a significant non-inferiority of S-1 to 5-FU (P<0.001); however, either S-1 or irinotecan plus cisplatin (IP) failed to show superiority to 5-FU (P=0.034 and 0.055, respectively) in overall survival. Excision repair cross-complementing group 1 (ERCC1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are reportedly related to outcome of advanced gastric cancer (AGC) patients (pts) treated with IP or 5-FU. Efficacy analyses are performed to evaluate the status of ERCC1, TS, DPD and 5 biomarkers related to anticancer drug sensitivity in first-line pts treated with IP, S-1, or 5-FU monotherapy under controlled conditions. Methods: Blocks from endoscopic biopsy specimens of primary lesions before chemotherapy were available from 365 of 704 pts in JCOG9912. Using laser-captured microdissection and real-time RT-PCR, we analyzed mRNA expression of ERCC1, TS, DPD in paraffin-embedded specimens. Expression levels of each gene were categorized into low and high values at each median. Results: The subjects with available tissue for analysis were representative of all randomized pts; 232 samples were assessable for TS, 168 for DPD, and 235 for ERCC1. There were no statistical differences in patient numbers between 3 arms. Pts with high TS showed worse progression-free survival (PFS) compared with those with low TS (hazard ratio (HR):1.26 [95%CI: 0.97–1.63]) in all pts; there was no difference in PFS between DPD and ERCC1 expression level. IP showed better PFS than S-1 in low DPD (HR: 0.57 [95%CI: 0.32–1.01]) but not in high DPD (HR: 1.24 [95%CI: 0.76–2.04]); there was no clear difference in PFS between pts treated with IP and S-1 regardless of TS and ERCC1 expression status. S-1 showed almost consistently better PFS than 5-FU regardless of mRNA expression status. Conclusions: This large analysis showed the prognostic value of TS status in AGC pts and the predictive value of DPD status for IP and S-1 as first-line treatment. Studies of DPD as a predictive marker for IP activity in AGC are warranted in future personalized phase III.

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Meta-analyses of randomized trials assessing the interest of postoperative adjuvant chemotherapy and prognostic factors in gastric cancer
Authors: Buyse M. E. , Pignon J. ,   GASTRIC
Published: August 2020

4539

Background: Despite potentially curative resection of stomach cancer, 50%-90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) compared surgery alone (S) to adjuvant chemotherapy (S+CT), but definitive evidence is lacking. Our group has initiated an individual patient data (IPD)-based meta-analysis of all RCTs in the adjuvant gastric setting to quantify the potential benefit of S+CT over S, to study the role of various prognostic factors and their potential interactions with treatments. Methods: All RCTs closed to accrual at the end of 2003 were eligible. Trials with radiotherapy, intraperitoneal chemotherapy, or immunotherapy were excluded. The primary endpoint was OS, the secondary endpoint DFS. Baselines variables included age, sex, tumour size (T) and stage, type of resection (D0, D1, D2 or more), performance status (PS) and geographic area. The Logrank test was stratified by trial and treatment arm. Interaction with treatment was explored with Cox model stratified on trial. No multivariate analysis was performed due to the numerous missing data. Results: Thirty-one eligible RCTs (6,613 patients) were identified. As of December 2008, IPD were available from 16 trials (3,710 patients) with a median follow-up exceeding 8 years. OS benefit was significantly in favour of CT (HR=0.83, 95% CI 0.76–0.91, p <0.0001) with absolute benefit of 6.3% at 5 years. Were associated with lower survival, older age (>66 vs <50) (HR=1.51, 95%CI= 1.31–1.73), PS2 (HR=1.71, 95%CI=1.35–2.15), higher UICC stage (HR=1.41 per unit 95%CI=1.35–1.46) and T>1 (HR=1.57 per unit, 95%CI=1.47–1.67). There was also a strong geographical influence on prognosis (HR=0.30, 95%CI 0.26–0.34 and HR=1.26, 95%CI 1.13–1.41, respectively in Asia and in the US as compared to Europe). Treatment interactions were not identified for all but the stage. Treatment effect appeared slightly stronger for patients with higher stages (HR for treatment effect from 0.88 in stage I to 0.66 in stage IV). Conclusions: Our interim results show a modest but significant OS benefit in favour of adjuvant CT and confirm the impact of tumour staging as well as age and PS on OS. Asian patients have a much better survival than other patients.

No significant financial relationships to disclose.
Hereditary diffuse gastric cancer (HDGC): Clinical characteristics of a prospective cohort of HDGC patients with and without CDH1 mutation and patients with sporadic GC
Authors: Shah M. A. , Pristyazhnyuk Y. , Jhawer M. , Coombes S. , Harlan M. , Randazzo J. , Perera R. J. , Pascarelli K. M. , Coit D. , Kelsen D. P.
Published: August 2020

4543

Background: HDGC is an autosomal dominant cancer syndrome associated with early onset diffuse GC. Germline mutations in E-cadherin(CDH1) cause the disease but are identified in only 20–30% of pts meeting clinical criteria. We began a prospective multicenter GC registry to capture epidemiologic and family history data matched with DNA and tissue to characterize phenotypic and risk factor profiles and their associations with HDGC and other non-HDGC hereditable GC. Herein, we report the clinical characteristics of HDGC, the subset of HDGC pts with CDH1 mutation, pts with sporadic GC, and non-cancer controls. Methods: All patients with GC are eligible for registry participation. HDGC criteria: diffuse GC(< age 45), diffuse GC(< age 50) with 1 relative with GC, diffuse GC(any age) with 2 or more relatives with GC, or a personal or family history of diffuse GC with lobular breast cancer or signet ring colon cancer. Non-HDGC high risk pts: diagnosed < age 50 or with a family history of GC(at least one 1st degree or two 2nd degree relatives with GC), but do not meet HDGC criteria. Sporadic GC: diagnosed > age 50, without family history. Participants complete a family history and epidemiology/ risk factor questionnaire, and provide blood and tissue for repository. Results: 465 participants have enrolled since Jan 2006. Questionnaires are available from 331 participants(69%), see table . CDH1 mutations have been identified in 10 families(16%) and prophylactic gastrectomies in CDH1 mutation carriers have been performed in 8 pts, each without major complications. Pt demographics and epidemiology were not notably different amongst all groups. Conclusions: Except for age and histology, the demographic breakdown and epidemiology of HDGC pts with and without CDH1 mutation is similar to other non HDGC high genetic risk pts and similar to pts with sporadic GC. The GC registry will expand to international sites. (Supported by the DeGregorio Family Foundation)

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No significant financial relationships to disclose.