bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer
Authors: Lambrechts D. , De Roock W. , Prenen H. , De Schutter J. , Jacobs B. , Biesmans B. , Claes B. , De Hertogh G. , Van Cutsem E. , Tejpar S.
Published: August 2020

4020

Background: KRAS mutations (MUT) negatively affect outcome after cetuximab (CTX) in metastatic colorectal cancer (mCRC). As only 40% of KRAS wild-type (WT) respond it is possible that other MUT, constitutively activating the Ras/Erk or PI3K/Akt pathways, are present in the non-responding KRAS WT. We analyzed the KRAS, BRAF, NRAS & PIK3CA MUT status in 276 chemorefractory CRC treated with CTX +- irinotecan and correlated the MUT status with outcome. Methods: KRAS codon 12,13, 61&146, BRAF V600E, NRAS codon 12&13, PIK3CA E542K, E545K, A, G, V (exon 9), H1047Y, R, L (exon 20), N345K, R88Q and Q546K MUT were evaluated on FFPE primary CRC using the Sequenom MALDI TOF MassArray system. A two- sided Fisher's exact test was used to evaluate the association between PIK3CA, KRAS, BRAF & NRAS MUT and objective response (OR). Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: 116/276 (42%) CRC had a KRAS MUT, 96% of which occurred in codon 12 or 13. KRAS WT was associated with OR (p<.0001), longer median PFS (p<.0001) and OS (p<.0001). 15/153 (9.8%) KRAS WT had a BRAF MUT. BRAF WT was associated with OR (p=.01), longer PFS (p<.0001) and OS (p=.007). 5/98 (5%) KRAS WT had an NRAS MUT and none of these showed OR. KRAS, BRAF and NRAS MUT were mutually exclusive. The combined KRAS/BRAF/NRAS WT state was associated with OR (p<.0001), longer PFS (p<.0001) and OS (p<.0001). 23/200 (12%) CRC carried a PIK3CA mutation: 5/39 (13%) of responders and 18/160 (11%) of non-responders (p=.781). Median PFS and OS were not associated with PIK3CA MUT state (p=.760 & p=.698) overall, nor in the KRAS/BRAF/NRAS WT subgroup (p=.946 & p=.509). 5/13 (38.5%) PIK3CA MUT KRAS/BRAF/NRAS WT CRC showed an OR. 13/107 (12%) of KRAS/BRAF/NRAS WT and 10/93 (11%) of KRAS/BRAF/NRAS MUT tumors harbored a PIK3CA MUT (p=.826). Conclusions: KRAS, BRAF & NRAS MUT are mutually exclusive and occur in at least 47% of CRC. Like KRAS WT, BRAF WT state of the primary is significantly associated with outcome in mCRC treated with CTX. The combined KRAS/BRAF/NRAS WT state is significantly associated with outcome. PIK3CA MUT occur independently of the KRAS/BRAF/NRAS MUT status. We cannot provide any evidence for a strong role of PIK3CA MUT as a marker in determining outcome to CTX.

[Table: see text]
Amphiregulin (AR) expression in the prediction of benefit from cetuximab plus irinotecan in KRAS wild-type metastatic colorectal cancer (mCRC) patients
Authors: Loupakis F. , Cremolini C. , Perrone G. , Stasi I. , Salvatore L. , Vincenzi B. , Ruzzo A. , Ronzoni M. , Bencardino K. , Falcone A.
Published: August 2020

4021

Background: AR is an endogenous ligand of Epidermal Growth Factor Receptor (EGFR), whose binding is prevented in the presence of cetuximab. Methods: We retrospectively assessed KRAS mutational status and AR expression at immunohistochemistry (IHC) in 86 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. AR-IHC was performed on tissue sections from paraffin-embedded primary tumors. Specimens were defined AR-low or AR-high according to a score (range 0–300) obtained multiplying intensity (0 to 3+) by percentage of stained cells (0–100%). According to the results of a ROC analysis, we identified a cut-off value of 18. The association between AR-IHC and treatment outcome in terms of response rate (RR), PFS, and OS was investigated in the subgroup of KRAS wild-type patients. Results: Eighty-six consecutive patients were included. M/F = 44/42, median age = 67 (41–78), median number of previous lines of chemotherapy = 2 (1–5). Among 51 (59%) KRAS wild-type patients, 12 PRs and 1 CR were observed, for an overall RR of 25% (13/51). AR-IHC was high, low or unconclusive in 27, 22 and 2 cases respectively. AR-low patients reported a significantly worse RR (2/22, 9%) compared with AR-high (10/27, 37%) (p = 0.024) and a trend toward shorter PFS (3.5 vs 5.3 months, HR 0.88 [95%CI: 0.46–1.60], p = 0.628) and OS (8.8 vs 15.1 months, HR 0.60 [95%CI: 0.30–1.10], p = 0.106). Conclusions: These results underline the potential role of endogenous ligands in influencing the activity of anti-EGFR monoclonal antibodies. Absent or low AR expression at IHC may be related to resistance to cetuximab plus irinotecan. Further data regarding the prognostic impact of AR expression are needed.

No significant financial relationships to disclose.
VEGF and VEGFR1 gene expression levels and tumor recurrence in adjuvant colon cancer
Authors: Ning Y. , Lurje G. , Danenberg K. , Cooc J. , Yang D. , Pohl A. , Zhang W. , Lenz H.
Published: August 2020

4040

Background: Tumor recurrence after curative resection is still a major problem in the management of adjuvant colon cancer, with recurrence rate approximately 30–40%. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. Our group previously showed that angiogenesis gene polymorphisms (VEGF and IL-8) may associated with tumor recurrence in adjuvant colon cancer (Lurje Ann Oncol, 2008). Here we tested the hypothesis whether gene expression levels of angiogenesis pathway (COX-2, EGFR, VEGF, VEGFR1, VEGFR2 and IL-8) could also predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Tissue samples from 140 adjuvant colon cancer patients (69 females and 71 males with a median age of 59 years; range=28–86) were available for gene expression assays. These tissue samples were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) and LAC+USC medical center between 1999 and 2006. Sixty-three patients had stage II and 77 had stage III colon cancer. The median follow-up was 5.4 years (range=2.0–16.8). 51 of 140 patients (36.4%) developed tumor recurrence with a 5-year probability of 0.28 ± 0.06 for stage II and 0.40 ± 0.06 for stage III colon cancer patients. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan). Results: We found VEGF and VEGFR1 gene expression levels independently significantly associated with time to tumor recurrence in adjuvant colon cancer patients. Patients with lower VEGF gene expression and lower VEGFR1 gene expression levels had significantly longer time to tumor recurrence compared to those with higher VEGF and higher VEGFR1 gene expression levels (p<0.05, log-rank test). Conclusions: VEGF and VEGFR1 gene expression levels may predict tumor recurrence risk in adjuvant colon cancer patients. Our exploratory data warrant future confirmatory trial.

[Table: see text]
Use of a prognostic pathway signature for colorectal cancer comprised of EGFR/COX2 and imatinib drug target activation to predict occult metastasis in M0 CRC
Authors: Pierobon M. , Silvestri A. , Calvert V. , Deng J. , Belluco C. , Nitti D. , Colombatti A. , Mammano E. , Liotta L. , Petricoin E.
Published: August 2020

4042

Background: Development of distant metastasis is the main cause of death among CRC patients. Approximately 30% of CRC patients initially staged M0-N0 die from tumor recurrence. Previously, we determined that members of EGFR/PDGFR/cAbl/cKit pathways were hyperactivated in hepatic synchronous CRC metastasis compared to primary tumor. In order to determine if this signature was a distinguished repertoire of the early stage primary tumor, we analyzed 58 CRC M0 at the moment of the diagnosis that upon 5 yr follow-up had differing disease progressions. Methods: All tissues were immediately snap frozen after surgery. Reverse phase protein microarray (RPMA) was performed using microdissected material to generate multiplexed pathway profiling. For each sample 75 different endpoints were analyzed. Results: Statistical comparison of the 75 endpoints in 8 M0 patients who progressed to M1 and 50 patients who remained M0 regardless of initial staging, revealed a number of signaling proteins whose activation/phosphorylation were elevated and subsumed in a linked pathway. Specifically COX2 and c-Kit/PDGFR/Notch were highly activated in the 8 patients with occult metastasis. A prognostic pathway signature comprised of 13 interlinked molecules was developed. Univariate, ROC and Kaplan-Meier analysis of this signature revealed a statistically significant prognostic signature with an AUC of 0.87 and a 95% confidence interval. Conclusions: A signaling portrait of 13 interlinked proteins provided a strong prognostic indicator for metastasis regardless of stage. This signature was comprised of the phosphorylation/activation of growth factor receptors, including the entire suite of Gleevec targets. A large number of these prognostic signature components were previously found activated in the metastatic lesions themselves which indicates a potential functional role of this linked protein network in metastatic progression and maintenance. If validated in larger study sets, clinical trials to test Gleevec therapy combined with Cox2 /EGFR inhibitors to prevent/delay development of distant metastasis in patients with M0 should be considered.

[Table: see text]
Nodal positivity between <12 and >12 lymph nodes harvested in colorectal cancer undergoing SLNM compared with conventional surgery
Authors: Wiese D. , Soni M. , Gayer A. , Korant A. , Sirop S. , Chakravaty B. , Arora S. , Iddings D. , Saha S.
Published: August 2020

4048

Background: Sentinel Lymph Node Mapping (SLNM) upstages significantly more patients (pts) than conventional surgery (Conv Sx) in Colon Cancer (CCa). According to current guidelines, the examination of 12 or more LNs are required to ensure accurate staging. Our study compares the rates of nodal positivity between differing numbers of total Lymph Nodes (LNs) harvested to see if the nodal positivity of <12 LN harvested by SLNM is equivalent to >12 LN obtained by Conv Sx. Methods: Of 951 pts with CCa, 545 pts underwent SLNM and standard oncological resection; 406 pts received Conv Sx without SLNM. The total number of LNs harvested for each pt as well as number of pts with metastatic LNs were recorded. Pts were grouped according to 2–11 LNs, 12–25 LNs and >25 LNs. Results: Of 951 pts, 81 pts in SLNM group and 6 in Conv Sx group were excluded due to benign disease. Average (avg) total nodes harvested in 2–11 node group for SLNM and Conv Sx was 7.9 vs 6.8 nodes respectively. Overall nodal positivity for SLNM pts and Conv Sx pts in the 2–11 node groups was 48% vs. 33% (p=.02). In the 12–25 node group, avg total number of LNs harvested was 17.23 and 16.32 respectively. In the 12–25 node group, 53% of pts in the SLNM arm had +ve nodes vs 44% (p=0.17) in the Conv Sx group. In pts with >25 nodes harvested avg nodal positivity was 33.78% vs 32.38% for SLNM and Conv Sx. Overall nodal positivity was 55% for SLNM vs 37% for Conv Sx group. When SLNM pts with 2–11 LN harvested were compared to Conv Sx pts with 12–25 LN harvested, nodal positivity was 48% vs 44% (p=0.55). Conclusions: Increased survival has been shown when >12 nodes are harvested in CCa. On avg SLNM identified a higher number of total nodes than conventional surgery. In addition, SLNM pts had higher nodal positivity with <12 LNs harvested compared to the nodal positivity of >12 nodes harvested in the Conv Sx group. A higher number of LN harvested coupled with a greater nodal positivity with less LNs make SLNM a more accurate way to stage CCa.

[Table: see text]

No significant financial relationships to disclose.
Evaultion of CD133, VEGF, or EGFR as predictive markers of distant recurrence after preoperative chemoradiotherapy in rectal cancer
Authors: Inoue Y. , Tanaka K. , Saigusa S. , Yokoe T. , Yasuda H. , Toiyama Y. , Miki C. , Yanagi H. , Kusunoki M.
Published: August 2020

4050

Background: CD133 has been postulated to be a colon cancer stem cells (CSCs) marker. Recent investigations suggest that CSCs might contribute to cancer recurrence and resistance to conventional therapies. This study aimed to evaluate the role of CD133 in residual cancer cells after chemoradiotherapy (CRT) for rectal cancer. Methods: Forty patients with rectal cancer underwent CRT followed by surgery. Total RNAs of rectal cancer cells before (n=30) and after (n=40) CRT were isolated. Residual cancer cells after CRT were collected from formalin-fixed paraffin-embedded (FFPE) specimens using microdissection. Intratumoral CD133, vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) were measured using real-time reverse transcription polymerase chain reaction. Immunohistochemical staining of CD133 after CRT was also investigated. Results: CD133 in residual cancer cells was higher than in stromal cells on post-CRT specimens (p<0.0001). CD133 was increased in post-CRT specimens (p=0.0184), while VEGF and EGFR were decreased during CRT (p<0.0001 and p=0.0002, respectively). There were positive correlations between CD133 and VEGF (p=0.0392) or EGFR (p<0.0001) in pre-CRT specimens. Any correlations were not found in post-CRT specimens. Patients who developed distant recurrence had a higher post-CRT CD133 compared with those patients without recurrence (p=0.0136). Elevated post-CRT CD133 was associated with poor disease free survival (p=0.0168). Immunohistochemically, cytoplasmic and apical/endoluminal membranous CD133 staining was observed in residual cancer cells after CRT. Conclusions: CD133 in residual cancer cells after CRT may indicate a treatment resistant phenotype in putative CSCs. Elevated CD133 but not VEGF or EGFR on FFPE specimens may be a predictive marker of distant recurrence and poor survival after preoperative CRT in rectal cancer.

No significant financial relationships to disclose.
Comorbidity and overall survival (OS) in cetuximab-treated patients with advanced colorectal cancer (ACRC)—Results from NCIC CTG CO.17: A phase III trial of cetuximab versus best supportive care (BSC)
Authors: Powell E. D. , Asmis T. , Jonker D. , Tu D. , Karapetis C. , Jeffery M. , O’Callaghan C.
Published: August 2020

4074

Background: The interplay between comorbidity, age and performance status (PS) as predictors of outcome in ACRC is not well described. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. Methods: Comorbidity was independently evaluated by 2 physicians using the Charlson Comorbidity Index (CCI), a previously validated measure of comorbidity based on the presence or absence of index medical conditions weighted according to their affect on mortality. CCI score was correlated with demographic data (age, gender), PS, site of primary, time from diagnosis to randomization, body mass index, hemoglobin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine clearance, K-ras status and OS. Results: 572 patients were included. 41% were ≥65 years and 25% had comorbidities at randomization. CCI score was 1 in 21% and ≥ 2 in 4%. In multivariate analysis (MVA) of all covariates, only older age (≥65 years) was associated with greater comorbidity (p=0.005). OS was different among 3 comorbidity groups (CCI score 0, 1, ≥ 2) in univariate analysis (median OS 4.9 vs 5.9 vs 4.8 months;, logrank p=0.04) but not in MVA. Conversely, lower PS remained associated with better OS in MVA (HR 1.96 for PS=2 vs. PS=0, p<0.0001). Age was not associated with OS (p=0.11). Other factors significantly associated with OS in MVA included time from diagnosis to randomization, LDH, ALP, hemoglobin, Kras status and cetuximab treatment. In the BSC arm, comorbidity was not associated with OS in MVA (HR 0.83 CCI 1 vs. CCI0, p=0.26 and HR 0.90 for CCI2 vs. CCI0, p=0.78) suggesting comorbidity is not prognostic in this setting. Patients with higher CCI score had a nonsignificant trend toward greater treatment effects. Patients ≥65 years had less gr≥3 vomiting (1.8 vs 7.9%, p=0.034) but more dyspnea (24.5 vs 11.2%, p=0.005). Patients with higher CCI scores had less vomiting (p=0.008) but more non-neutropenic infection (p=0.012). Conclusions: In this clinical trial, comorbidity and age were not independent predictors of survival, highlighting the difference between comorbidity and PS.

[Table: see text]
mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab (B) alone or with erlotinib (E) in first-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety analysis of DREAM study
Authors: Tournigand C. , Samson B. , Scheithauer W. , Louvet C. , Andre T. , Lledo G. , Latreille J. , Viret F. , Chibaudel B. , de Gramont A.
Published: August 2020

4077

Background: Anti-VEGF or EGFR inhibitors demonstrated clinical activity in combination with chemotherapy (CT) in mCRC. The DREAM trial compares, after an induction CT of 6 cy of FOLFOX-B or XELOX-B, a maintenance with B ± E. We report here a pre-planned safety analysis of induction (I) and maintenance (M) phase for the first 200 patients. Methods: Patients (pts) with untreated mCRC were randomly assigned to 2 arms (I): mFOLFOX+B (n=100), or mXELOX+B (n=100). mFOLFOX-B: LV 400 mg/m2, Oxaliplatin (ox) 100 mg/m2, B 5 mg/kg d1, 5FU ci 2.4g/m2 46h, q2w, mXELOX-B: Ox 100 mg/m2 d1, capecitabine 2.5 g/m2 d1–7, B 5mg/kg, q2w. To date, 117 pts with a disease control after 6 cy have had a 2nd randomisation (M): B alone (7.5 mg/kg q3w, n=56) or B+E 150 mg/d (n=61) until PD. Results: Pts characteristics were: sex: 124M/76F, median age: 62.4 years (26–80), primary tumors: colon 152, rectum 53, synchronous metastases: 150 pts, > 1 metastase site: 115, PS 0/1: 134/66, Alk. Ph.>UNL: 87 pts, and LDH>UNL: 88pts. For I, 92 pts in mFOLFOX-B and 93 in XELOX-B were evaluable for toxicity (tox). Tox (%) for mFOLFOX-B/XELOX-B were: any toxicity grade (gr) 3 or 4: 21/30; neutropenia gr 3 6/1, gr 4 0/2; febrile neutropenia gr 3 1/1, gr 4 0/1; thrombopenia gr 3 0/1, gr 4 0/2; anemia gr 2 8/15, gr 3 2/1; nausea gr 2 17/15, gr 3 4/6; vomiting gr 2 10/12, gr 3 2/5; mucositis gr 2 6/6, gr 3 0/4; diarrhea gr 2 8/12, gr 3 5/20, gr 4 0/1; neuropathy gr 2 23/17 gr 3 3/1; HFS gr 2 0/7, gr 3 0/2; hypertension gr 2 2/3, gr 3 1/0; proteinuria gr 2 1/5; SAEs 14/25. For M, 56 pts in B and 61 pts in B+E were evaluable. Tox (% B/B+E) were: neutropenia gr 2 0/3; thrombopenia gr 2 2/0; nausea gr 2 2/2, gr 3 2/0; vomiting gr 3 2/0; mucositis gr 2 2/3; diarrhea gr 2 0/6, gr 3 2/6; skin tox gr 1 9/31, gr 2 0/38, gr 3 0/16, gr 4 0/2; proteinuria gr 2 5/5; hypertension gr 1 9/15, gr 2 3/8, gr 3 3/0. Conclusions: This interim safety analysis demonstrated that induction with mFOLFOX-B or XELOX-B as well as maintenance with B or B + E appears to be well-tolerated, without unexpected side effects. The DREAM study is ongoing, with a prolonged induction phase of 6 months (3 mo with ox then 3 mo with fluoropyrimidines-B) before randomisation for maintenance therapy.

[Table: see text]
Phase I study of the IXO regimen, irinotecan (I), capecitabine (X), oxaliplatin (O), as first-line therapy for metastatic colorectal cancer: Final survival results
Authors: Maroun J. , Jonker D. , Cripps C. , Goel R. , Asmis T. , Marginean H. , Chiritescu G.
Published: August 2020

4082

Background: This study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and efficacy of the IXO regimen when used as first-line treatment for metastatic colorectal cancer (mCRC). Methods: Patients with ECOG PS 0–2, histologically proven, chemo-naïve, non-resectable mCRC were eligible. Phase I starting doses were as follows: I (180 mg/m2 i.v.) d1, X (850 mg/m2 bid orally) d2–15, O (85 mg/m2 i.v.) d1; q3w. Dose escalation (3+3 design) was based on toxicity observed at previous dose levels (DL) until DLT and the MTD were reached. Results: 39 pts (31 male/8 female, median age 58 years, ECOG PS 0–1 in 37, 95%) received a median of 11 cycles (range 1–34) at 8 DLs. 39 pts were evaluable for toxicity. The most common grade 3/4 hematological adverse events (AEs) were granulocytopenia (60%) and fever/febrile neutropenia (18%). The most common grade 3 non-hematological AEs were diarrhea (15%), vomiting (10%), fatigue (8%). No grade 3/4 neuropathy was reported. DLTs: 1 DLT was observed at each of the first 4 DLs, no DLTs at DL5 & 6, 1 at DL7 and 2 at DL8. MTD was reached at DL8. The recommended phase II dose (DL7) is as follows: I (160 mg/m2), X (950 mg/m2), O (100 mg/m2). Efficacy: 38 pts are evaluable for efficacy. The RR is 74% (95% CI 60–89), including 4 CRs, 25 PRs and 6 SDs. The disease control rate is 90% (95% CI 80–100). 10 (26%) pts had subsequent liver surgery with curative intent; 1 had lung resection. Median progression-free survival was 12.3 months (95% CI, 8–17). Overall median survival was 26.4 months (95% CI, 13–36). Conclusions: Diarrhea is the main DLT. Severe neutropenia was of short duration and manageable. The IXO regimen is well tolerated and highly effective as first-line treatment for mCRC. It appears to be particularly effective in downsizing of initially unresectable colorectal cancer liver metastases. A phase II study to confirm the efficacy/safety of IXO in combination with bevacizumab (Avastin) is ongoing. Supported by: Hoffmann La-Roche, Sanofi-Aventis, Pfizer Canada.

[Table: see text]
Transarterial chemoembolization (TACE) of liver metastases (LM) from colorectal carcinoma (CRC) adopting drug eluting beads preloaded with irinotecan (DEBIRI): Results of a phase II study on 82 patients
Authors: Aliberti C. , Benea G. , Tilli M. , Fiorentini G.
Published: August 2020

4092

Background: DC beads are new embolic microspheres capable to load IRI. The present phase II study investigated response and side effects after TACE adopting DEBIRI in 82 patients with LM from CRC not resectable and in progression after two lines of chemtherapy. Methods: A total of 185 TACE procedures were performed. A suspension of polyvinyl-alcohol beads (DC Bead) preloaded with Irinotecan ( 81 TACE procedures with 2ml of microspheres preloaded with 100mgr of Irinotecan and 104 with 4ml loaded with 200mgr of Irinotecan) was delivered selectively into hepatic arteries. All pts received a well defined prophylactic treatment against nausea and vomiting, infections, and upper quadrant right pain (UQRP).Tropisetron, hydration, antibiotics, morphine and intra-arterial lidocaine was delivered as reported in previous experiences ( ASCO GI abs 356,2007; IN VIVO. 21, 6, 2007). Follow-up studies were performed by contrast enhanced spiral multislice computed tomography (MsCT) 1 month after the procedures and every 3 months or when clinically required. Quality of life (QoL) was assessed by Edmonton SAS improvement scale before, after TACE and then monthly. Results: We obtained 100% technical success in TACEs performed, and no complications due to the procedure occurred. Patients developed a postembolization-syndrome with the following side effects : UQRP (G2), fever (G2), nausea (G2) and increased transaminases (G2–3) in 40%,80%,80%,70% respectively out of 185 procedures done. One pt presented acute pancreatitis. The median follow-up was 18.2 months. Within 1 month after treatment, CT scan showed significant ( 75–100%) reduction of metastatic contrast enhancement in all lesions treated. Therapeutic response (according to RECIST was observed in 78% of patients. After TACE. 75 out 82 pts (90%) declare a general improvement of QoL long lasting. Conclusions: We suggest that TACE with DEBIRI could be a palliative therapy for LM from CRC. Our promising experience need to be confirmed with further phase III studies. Mid and long-term results need to be carefully evaluated comparing them with systemic chemotherapy.

No significant financial relationships to disclose.
Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from digestive or primitive origin: A multi-institutional study of 1,290 patients
Authors: Glehen O. , Elias D. , Gilly F. N. , Boutitie F. , Bereder J. M. , Quenet F. , Sideris L. , Mansvelt B. , Lorimier G. ,   Association Française de Chirurgie
Published: August 2020

4102

Background: Peritoneal carcinomatosis (PC) from non-gynecologic malignancies has long been regarded a terminal disease with a short median survival. Over the past decade, new locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved and suggest improved survival. Methods: A retrospective multicentric study was performed in French speaking centers to evaluate the toxicity and the principal prognostic factors in order to identify the best indications. All patients had cytoreductive surgery and PIC (hyperthermic intraperitoneal chemotherapy (HIPEC) and or early postoperative intraperitoneal chemotherapy (EPIC)). Results: The study included 1290 patients from 25 institutions between February 1989 and December 2007. The principal etiologies of PC were colorectal adenocarcinoma (N=523), pseudomyxoma peritonei (N=301), gastric adenocarcinoma (N=159), peritoneal mesothelioma (N=88), and appendiceal adenocarcinoma (N=50). Mortality and morbidity rates were 4.1% and 33.8%, respectively. By multivariate analysis, age, extent of the PC, and the institution's experience had a significant influence on toxicity. The overall median survival was 34 months: 30 months for colorectal PC, not reached for pseudomyxoma peritonei, 9 months for gastric PC, 41 months for peritoneal mesothelioma, and 77 months for PC from appendiceal adenocarcinoma. Independent prognostic indicators by multivariate analysis were the institution's experience, etiology, completeness of cytoreductive surgery, extent of carcinomatosis, and lymph node involvement. Conclusions: The therapeutic approach combining cytoreductive surgery with PIC may achieve long-term survival in a selected group of patients with PC from non-gynecologic origin with acceptable mortality and morbidity. This treatment should be reserved to experienced institutions involved in the management of PC.

No significant financial relationships to disclose.
Impact of bevacizumab (bev) on overall survival (OS) in patients (pts) with metastatic colorectal cancer (MCRC): A population-based study
Authors: Renouf D. J. , Lim H. J. , Speers C. , Villa D. , Gill S. , Blanke C. D. , O’Reilly S. E. , Kennecke H.
Published: August 2020

4114

Background: As of 2003, irinotecan or oxaliplatin in combination with fluorouracil was standard treatment for MCRC in British Columbia (BC). The addition of bev to chemotherapy (CT) was approved in BC in 2006. We compared OS between referred pts diagnosed with MCRC in 2003/2004 (pre-bev era) and 2006 (bev era). Methods: All pts diagnosed with MCRC in 2003/04 and 2006, and referred to the BC Cancer Agency (BCCA) were included. The BCCA is a cancer network with centers throughout BC, ≈60% of MCRC pts in BC are referred to the BCCA. Systemic therapy (ST) is centrally funded and treatment data was obtained from the pharmacy database. The primary endpoint was OS of all pts within each cohort. Secondary endpoints were OS in pts treated with ST, and in those not treated. Kaplan Meier method was used for survival analysis. Subgroup analysis based on age was performed. Results: 1417 pts were included: 969 from 2003/04, and 448 from 2006. Median age at diagnosis of MCRC was 68y in 2003/04 and 69y in 2006. Median follow up time was 47.3 and 21.4 mos respectively. Between 2003/04 and 2006 the proportion of pts treated with ST for MCRC increased from 61.1% to 67.6% (p= 0.02). Proportion of pts who received irinotecan, oxaliplatin and fluorouracil did not change (24.7% to 23.7%, p=0.68). Proportion of pts who received bev increased (5.9% to 30.6%, p<0.001). Median OS significantly improved for the entire cohort (13.8 to 17.3 mos, p<0.001). Median OS for pts who received ST for MCRC improved (18.6 to 23.6 mos, p=0.001). Median OS for pts who did not receive ST did not change (6.1 to 5.9 mos, p=0.65). Of pts who received ST, the proportion who received bev increased in pts <70 (12.7% to 58%, p<0.001) and in pts ≥70 (3.6% to 22.7%, p<0.001). Median OS for pts <70 who received ST for MCRC improved (20.3 to 26.5 mos, p = 0.002). Median OS for pts ≥70 who received ST for MCRC improved (16.5 to 19.9 mos), but this was not significant (p=0.16). Conclusions: In this population based study, median OS for MCRC significantly increased between 2003/04 and 2006. The improvement in survival appears to be limited to pts treated with ST for metastatic disease. The main difference in ST has been the addition of bev. On a population basis, the addition of bev to CT is associated with a significant improvement in OS in MCRC.

No significant financial relationships to disclose.
A phase I study of pazopanib in combination with FOLFOX 6 or capeOx in subjects with colorectal cancer
Authors: Brady J. , Middleton M. , Midgley R. S. , Mallath M. K. , Corrie P. , Sirohi B. , Chau I. , Digumarti R. , Botbyl J. , Lager J. J.
Published: August 2020

4133

Background: Pazopanib (paz) is a tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGF-α, -β, and c-kit. Inhibition of angiogenic pathways in combination with chemotherapy has been shown to benefit patients (pts) with colorectal cancer (CRC). Methods: Pts with previously untreated advanced or metastatic CRC and adequate organ function were assigned to paz with FOLFOX6 (FO) or capeOx (CO) by their physician. Doses of paz were escalated with full strength chemotherapy, starting at 400mg daily. The optimally tolerated regimen (OTR) was the combination dose at which <1/6 pts experienced dose-limiting toxicity (DLT). Results: Fifty pts were enrolled in FO (paz 400 mg, n=6; 800, 15), CO (400, 12; 800, 9) and reduced capecitabine (rc) CO (800, 8) cohorts: median age = 55.5, M/F = 37/13. Pts have remained on therapy for a median of 3 (range 0–17) months. Three pts remain on study. Safety data is available on 41. The most common AEs are summarized in the table below. The OTR was exceeded with CO in combination with 800 mg and 400 mg of pazopanib, but was not exceeded with 800 mg pazopanib when capecitabine was reduced to 850 mg/m2 twice daily or with FO with 800 mg pazopanib. Efficacy and pharmacokinetic analyses are ongoing. Conclusions: The OTRs were achieved at 800 mg paz with full-dose FO, and at 800mg paz with rcCO.

[Table: see text]

[Table: see text]
Gemcitabine with or without cisplatin in patients (pts) with advanced or metastatic biliary tract cancer (ABC): Results of a multicenter, randomized phase III trial (the UK ABC-02 trial)
Authors: Valle J. W. , Wasan H. S. , Palmer D. D. , Cunningham D. , Anthoney D. A. , Maraveyas A. , Hughes S. K. , Roughton M. , Bridgewater J. A.
Published: August 2020

4503

Background: There is no established standard chemotherapy for pts with inoperable ABC. We previously reported an improvement in progression-free survival (PFS) in a randomised phase II trial of 86 pts (ABC-01) using gemcitabine/cisplatin (GemCis) vs. gemcitabine (Gem) (Valle ASCO-GI 2006, abstr. 98). This study was extended into ABC-02, a phase III trial, to recruit a further 314 pts with overall survival (OS) as the primary end-point. Methods: Consenting pts with histologically/cytologically-confirmed ABC, aged ≥18 years, ECOG performance status 0 - 2, and adequate haematological, hepatic and renal function were randomised to receive either Cis (25 mg/m2) followed by Gem (1000 mg/m2 D1, 8 q21d) for 8 cycles, or Gem alone (1000 mg/m2 on D1, 8, 15 q28d) for 6 cycles, stratified by extent of disease, site of primary tumour, ECOG score and centre. The trial had an 80% power to detect an OS hazard ratio of 0.73. Results: From May 2005 to October 2008, 324 pts were randomised to ABC- 02 from 34 UK centres. We report the pre-planned combined analysis of ABC-01 and ABC-02 based on 410 pts (GemCis=206/Gem=204). Patient characteristics: median age 64 yrs (range 23–85); male (47%); metastatic disease (75%), locally advanced (25%); gallbladder (36%), bile duct (59%), ampulla (5%); and ECOG 0–1 (87%), 2 (12%). With a median follow-up of 6.1 months and 263 deaths, the median OS was greater with GemCis than Gem, 11.7 vs. 8.2 months (log rank p=0.002), with hazard ratio 0.68 (95%-CI 0.53, 0.86). The median PFS was greater with GemCis than Gem, 8.5 vs. 6.5 months (log rank p=0.003), with hazard ratio 0.70 (95%-CI 0.56, 0.88).Toxicity was similar between the arms (by week 12, 57% had a grade 3/4 toxicity in each arm), though there was a slight excess of neutropenia using GemCis. Conclusions: This is the largest ever study in ABC and demonstrates a clear survival advantage for GemCis without added clinically significant toxicity, setting a new international standard of care.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: Randomized EORTC phase III trial #40954
Authors: Schuhmacher C. , Schlag P. , Lordick F. , Hohenberger W. , Heise J. , Haag C. , Gretschel S. , Mauer M. E. , Lutz M. , Siewert J. R.
Published: August 2020

4510

Background: Combined pre- and postoperative chemotherapy improves overall survival in operable gastric cancer, although postoperative treatment is not feasible in half of the patients. We conducted a randomized phase III trial with thorough attention to preoperative staging and to the extent of surgical resection to assess the value of neoadjuvant chemotherapy (CTx). Methods: Patients with locally advanced adenocarcinoma of the stomach and cardia were randomized between primary surgery or two 48-day cycles of weekly folinic acid 500 mg/m2/2h, 5-FU 2,000 mg/m2/24h plus biweekly cisplatin 50 mg/m2/1h followed by surgery. The study was designed to detect an improvement in median survival from 17 months with surgery to 24 months with CTx plus surgery (HR=0.708, power of 80%, type I error of 4% to allow for an interim analysis). It was planned to randomize 360 patients in order to observe the 262 deaths required for the final analysis. Results: From 7/99 to 2/04, 144 patients were randomized (72:72) with comparable baseline characteristics. Median follow-up is 4.4 years. Based on 67 deaths, overall survival between the two arms did not differ (HR=0.84; 95% CI: 0.52 to 1.35; p=0.466). Median survival exceeded 36 months in both arms. Due to low accrual, this trial was stopped early. The unexpected long median survival in the surgery arm would have made the primary objective difficult to reach anyway. Based on 77 events, difference in time to progression was borderline significant (HR=0.66; 95% CI, 0.42–1.03; p=0.065). Response rate to CTx was 35.2% (95% CI: 23.7%-45.7%). The R0-resection rate was 81.9 % after CTx as compared to 66.7% with surgery alone (P=0.036). There were no major differences in intra- or postoperative complications. Conclusions: This prematurely closed trial showed a significantly increased rate of R0 resections after CTx although it could not demonstrate a survival benefit. The outcome after a radical surgical procedure alone with extended lymphadenectomy was better than expected.

No significant financial relationships to disclose.
Updated results of randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG 9912)
Authors: Fuse N. , Fukuda H. , Yamada Y. , Sawaki A. , Koizumi W. , Suzuki Y. , Yamaguchi K. , Takiuchi H. , Ohtsu A. , Boku N. ,   Gastrointestinal Oncology Study Group/Japan Clinical Oncology Group
Published: August 2020

4514

Background: We reported the primary results of JCOG9912 in ASCO 2007. In the planning, this study with 230 patients (pts) per arm had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (HR=1.16) of S-1 at 6 months in overall survival (OS) and 0.05 study-wise 1-sided alpha. Primary analysis was conducted in Feb 2007, one year after the last patient accrual with 601 deaths (85%) of all randomized 704 pts. S-1 showed statistically significant non-inferiority to 5-FU (p<0.001), but after adjusting for multiplicity either S-1 or CP failed to show statistically significant superiority to 5-FU (CP, hazard ratio (HR)=0.85 (95% CI, 0.70–1.04), p=0.055 and S-1, HR=0.83 (0.68–1.01), p=0.034). Methods: The survival information of all surviving 103 pts at the primary analysis was updated in Apr 2008 when 660 pts (94%) were dead. An updated analysis and multivariate analyses with Cox proportional hazard model were conducted. The multivariate analysis model included arms, sex, age, tumor status (unresectable/recurrent), PS, the number of metastatic sites, target lesion (TL), macroscopic type, histological type and peritoneal dissemination. Results: The updated results are shown in Table . OS curves and HRs remained almost identical to the previous report. Multivariate analyses showed that number of metastatic sites (≥2), PS (≥1), presence of TL were associated with worse survival, and that the adjusted HRs of CP and S-1 were 0.79 (0.65–0.95, p=0.014) and 0.80 (0.66–0.96, p=0.017), respectively. There was no significant interaction among baseline factors and treatment arms. Conclusions: The updated results reconfirmed the primary conclusion that S-1 monotherapy can be a new standard regimen for advanced gastric cancer, and suggest that CP is still worthy for further clinical investigation.

[Table: see text]

[Table: see text]
Chemoradiation of resected gastric cancer: A 10-year follow-up of the phase III trial INT0116 (SWOG 9008)
Authors: Macdonald J. S. , Benedetti J. , Smalley S. , Haller D. , Hundahl S. , Jessup J. , Ajani J. , Gunderson L. , Goldman B. , Martenson J.
Published: August 2020

4515

Background: INT0116 (SWOG 9008) was a prospectively randomized phase III trial of postoperative adjuvant therapy utilizing 5-FU/leucovorin plus external beam radiation in 582 eligible cases of resected stage IB-IV(M0) stomach and gastroesophageal junction cancers. Initial results (NEJM 345: 725, 2001) showed both overall and disease free survivals improved by chemoradiation. Methods:We now report INT0116 results with >10years median follow-up. Exploratory subset outcomes are also reported. Results: INT0116 continues to show benefit for chemoradiation with hazard ratios (HR) for survival (HR=1.32, p=.004) and disease free survival (HR=1.51, p<.001) favoring chemoradiation. Subset analyses were performed for sex, race, T and N stage, D-level of surgical resection, tumor location (proximal or other), histology (intestinal or diffuse) and Maruyama index. Chemoradiation benefited all subsets with the exceptions of women and diffuse histology. In women the HR for therapy was 1.0(0.68–1.45). The HR for therapy in diffuse histology cases was 0.97(0.62–1.40). Interaction between these factors is suggested as women were significantly more likely to have diffuse histology than men (56% versus 33%). A multivariate analysis of sex and histology did not detect an effect of sex once histology was included. These data suggest that sex may not be an independent variable for lack of response to chemoradiation but that diffuse histology may be. Long term toxicities were examined. Thirty-five second tumors occurred in 31 cases. Twenty-two occurred in chemoradiation cases and 9 in surgery only cases. Second tumors represented a spectrum of types of neoplasms commonly occurring in this age group (median age 60 years). Excessive numbers of tumors known to be caused by radiation and/or chemotherapy were not noted. More tumors may have occurred in the treated patients since their death rates were less than surgery only cases. Conclusions: With >10 years median follow-up, survival remains improved in stage IB-IV (M0) gastric cancer cases treated with post-operative chemoradiaiton. All subsets benefit from this treatment with the exception of cases with diffuse histology. Women may be more likely to have diffuse histology gastric cancers. No increases in late toxic effects were noted.

No significant financial relationships to disclose.
Use of bone marrow micrometastasis to predict disease-free and overall survival in esophageal cancer: Evaluation of 304 cases
Authors: Vashist Y. K. , Effenberger K. E. , Bachmann K. , Pantel K. , Izbicki J. R. , Yekebas E. F.
Published: August 2020

4519

Background: The presence of bone marrow micrometastases (BMM) yields prognostic information for patients at higher risk for recurrence and death. Aim of the study was to evaluate the role of BMM in esophageal cancer (EC). Methods: 304 consecutive patients operated for EC and with BMM status were included into the prospective study. BMM were assessed by a pan-anti- cytokeratin monoclonal antibody, A45-B/B3. Associations between BMM status and clinicopathological parameters as well as disease-free (DFS) and overall survival (OS) were calculated with chi-square-, log-rank test and Cox multivariate analysis. Results: Out of 304 patients 109 (35.9%) were BMM positive (BMM+) and 195 (64.1%) negative (BMM-). Significant correlation was found between BMM and tumor size, nodal stage and recurrence (P=0.02, 0.002 and <0.0001). DFS and OS were significantly better in BMM- compared to BMM+ patients (median 44.2 and 31.6 vs. 10.4 and 12.4 months, P<0.0001). Sub-analyses revealed that nodal negative (N-) patients with BMM- had a significant better DFS and OS compared to N- and BMM+ patients (50.8 and 41.5 vs. 18.0 and 16.3 months, P<0.0001). Nodal positive patients (N+) with BMM- had a better DFS and OS compared to N+ and BMM+ patients (22.1 and 24.8 vs. 9.0 and 11.3 months, P<0.0001). In the Cox multivariate analysis BMM was the strongest predictor of DFS and OS with a hazard ratio of 3.1 and 2.9 (P<0.0001). Also tumor size and nodal stage were found to be significant predictors, whereas age and sex were not. All analyses were repeated after stratification of the study group to underlying tumor type (adenocarcinoma (AC) and squamous cell carcinoma (SCC)). Significant differences were found at all levels as reported for the entire study group above within the AC and SCC group as well. Conclusions: To our knowledge this is the largest study evaluating the role of BMM in EC. Survival sub-analyses stratified to nodal and bone marrow status revealed a significant role of BMM in EC. Presence of BMM proved to be the strongest predictor of DFS and OS in AC and SCC of the esophageus.

No significant financial relationships to disclose.
Outcome prediction based on single nucleotide polymorphisms (SNPs) in DNA repair paths in patients (pts) with esophageal adenocarcinoma (EAC) treated with preoperative (preop) cisplatin (C)-based chemoradiation (CRT): Results from the Eastern Cooperative Oncology Group (ECOG)
Authors: Yoon H. H. , Powell M. , Murphy K. , Montgomery E. A. , Hafez M. J. , Liu G. , Forastiere A. A. , Benson A. B. , Kleinberg L. R. , Gibson M. K. ,   for the ECOG E1201-T1 Study Group
Published: August 2020

4530

Background: EAC has eluded cure even with platin-based CRT. Stratifying pts by likelihood of success is one approach to improving outcomes. We assessed whether SNPs in DNA repair paths are associated with complete pathologic response (pCR) in EAC pts who received C-based CRT followed by surgery. Methods: Patients and specimens: Pretreatment biopsy or post-CRT resection samples were obtained from pts (EAC, stage II-IVa) treated on a randomized phase II trial, E1201 (n=86), of preop CRT (RT to 45 Gy). Arm A: Preop C 30 mg/m2 + irinotecan (I) 50 mg/m2 days (d) 1, 8, 22, 29 with RT. Post-op C 30 mg/m2 + I 65 mg/m2 d 1, 8 q21 days x 3. Arm B: Preop C 30 mg/m2 + paclitaxel (P) 50 mg/m2 d 1, 8, 15, 22, 29 with RT. Post-op C 75 mg/m2 + P 175 mg/m2 d 1 q21 days x 3. Clinical outcome - pCR: (A) 14% [95% CI 5.5%, 28.5%]; (B) 16% [95% CI 6.7%, 30.1%]. Median overall survival (OS): (A) 34.9 m (months) [90% CI 23.5, not reached]; (B) 20.9 m [90% CI 17.4, 46.7]. Experimental procedure: Normal tissue was microdissected from unstained sections of paraffin-embedded tissue. DNA was extracted (Qiagen). Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight (Sequenom) for all SNPs. Each SNP was dichotomized a priori into: (1) major homozygote vs (2) minor (heterozygote plus minor homozygote) allele groups. Data analysis was performed centrally, with lab investigators blinded to clinical data. Exact logistic regression was used to derive ORs for non-pCR, using the major homozygote as the reference (2-sided p values). Results: Germline DNA was available in 68 pts; 60 were eligible and began therapy ( Table ). Conclusions: In this homogenous, well-defined cohort, the XRCC1 Arg399Gln minor allele group was associated with lower pCR (p=0.06). Lab data on a panel of additional SNPs have been collected and are under analysis for presentation at the meeting.

[Table: see text]

[Table: see text]
A multicenter phase II study of induction CT with FOLFOX-4 and cetuximab followed by RT and cetuximab in locally advanced esophageal cancer (LAEC)
Authors: De Vita F. , Orditura M. , Innocente R. , Vecchione L. , Pinto C. , Chiarion Sileni V. , Martinelli E. , Ruol A. , Catalano G. , Ciardiello F.
Published: August 2020

4546

Background: Preoperative CRT improves the survival of pts with EC when compared with surgery alone. Epidermal growth factor receptor (EGFR) is overexpressed in 30–90% of EC and is associated with poor prognosis, providing the rationale for using the anti-EGFR monoclonal antibody cetuximab (C). The purpose of the study was to investigate the efficacy, toxicity and feasibility of C with FOLFOX- 4 regimen as induction CT followed by C and RT in pts with LAEC in a multicenter setting. Methods: Eligibility criteria: resectable, locally advanced (uT3 or uN1, T4 if deemed resectable) squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the esophagus; staged by EUS, CT and PET scan; age 18–70y; PS <2; normal organ functions.All pts received induction treatment with C at a starting dose of 400 mg/m2 and further weekly infusion at a maintenance dose of 250 mg/m2 and 4 cycles of FOLFOX-4 every two weeks. Post-induction EUS and CT scans were performed, while a PET scan was repeated early before second cycle of CT: pts without PD were given daily RT (180cGy fractions to 5040cGy) with concurrent weekly C. Post RT, EUS plus biopsies, CT scan and PET were performed. At wk 18, pts without PD had esophagectomy. Simons two stage design was used. Primary endpoint was histopathological response rate. Results: Up to December 2008, 40 pts, 30 men, were enrolled from 4 institutions; median age 59 y (35–70y); AC 12; SCC 28; stage II 15, stage III 25 pts. At this time 32/40 pts were evaluable. The most frequent grade 3/4 toxicity of chemoradiotherapy were skin (32%),neutropenia (29%) and esophagitis (9%); 10 pts had no resection (9 progressive disease,1 patient's refusal). Of 22 operated pts, 17 pts (77%) had RO-resection, 5 pts had palliative surgery.2 pts died due to complications after surgery (1 after > 30 days). The pathological response rate was 68 %, with a complete histopathological remission recorded in 6 pts (27%);17 pts (53%) are still alive without residual or recurrent disease. Conclusions: The current findings suggest the feasibility of incorporating cetuximab into a preoperative regimen for LAEC pts and an encouraging antineoplastic activity with 68% histopathological responders.

No significant financial relationships to disclose.