bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of bevacizumab in combination with cetuximab plus irinotecan in irinotecan-refractory colorectal cancer (CRC) patients who have progressed on a bevacizumab-containing regimen (The BOND 2.5 Study)
Authors: Segal N. H. , Reidy-Lagunes D. , Capanu M. , Kemeny N. , Chung K. , Kelsen D. , Hollywood E. , Goodman-Davis N. , Saltz L. B. 
Published: August 2020

4087 Background: We previously showed that adding bevacizumab (bev) to cetuximab (cetux) plus irinotecan (IRI) in bev-naïve, IRI-refractory CRC patients is feasible, and yielded a favorable response rate and time to tumor progression (TTP) compared with historical controls (Saltz: JCO, 2007). Since most CRC patients now receive a bev-containing regimen prior to cetux, we evaluated the addition of bev to cetux plus IRI (CBI) in patients with metastatic CRC who had previously progressed on chemo + bev. Methods: All patients were naïve to cetux. The importance of KRAS mutation was not appreciated when the trial was designed and this has not yet been evaluated. Patients received IRI at the same dose and schedule as last received prior to study, Cetux 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bev 5 mg/kg given every two weeks or 7.5 mg/kg given every three weeks. Results: 33 received treatment. Median age was 58 (range 29–85). Median number of prior regimens was 2 (range 1–2). Median performance status was ECOG 1 (range 0–1). Patients received a median of 2 cycles (range 1–15). Grade 3/4 Toxicities: Acneiform Rash 18%, hypomagnesemia 6%, hypophosphatemia 6%, Neutropenia 15%, Diarrhea 6%. One patient developed neutropenic fever and one patient had a hypersensitivity reaction to cetux. At a median follow up of 32 months (range 21–32 months) in 33 evaluable patients, we observed 3 (9%) partial responses and 11 (33%) patients with stable disease for > 4 months. Median TTP was 3.9 months (95% CI: 1.3 - 6.8). Median survival was 10.6 months (95% CI: 6.6 - 13.8). Conclusions: The toxicity profile was similar to what would have been expected from the individual agents alone. Recognizing the limitations of cross-study comparisons, the response rates and TTP seen with CBI in patients who have previously progressed on bev do not appear to be as encouraging as the 37% response rate and 7.3 months TTP seen in the BOND 2 trial of bev-naïve CRC patients. Ongoing randomized trials, including SWOG 0600, will be needed to definitively determine the contribution of continued use of bev after progression on a bev-containing regimen. Supported by Genentech. [Table: see text]
Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), administered as single agent in patients (pts) with colorectal cancer (CRC) refractory to standard regimens
Authors: Rimassa L. , Sobrero A. F. , Santoro A. , Andretta V. , Gregorc V. , Sclafani F. , Caprioni F. , Caligaris-Cappio F. , Lambiase A. , Bordignon C. 
Published: August 2020

4088 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed by tumor blood vessels. In preclinical models, NGR-hTNF showed antitumor activity both at low and at high doses. Methods: Pts with CRC resistant/refractory to standard treatments, including biological agents, were treated with low-dose NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary end-point with reassessment performed q6w. Results: From January to May 2007, 33 pts with radiologically- documented progressive disease after last therapy were evaluated over 111 cycles (range, 1–10). Pts characteristics were: median age: 65 years (range, 53 to 79); M/F 16/17; PS 0/1 26/7. Median number of prior regimens was 3 (range, 2 to 5). Eight pts (25%) were pre-treated with ≥4 lines and 22 (67%) with biological agents. Neither grade 3–4 treatment-related adverse events nor toxicity-related deaths were observed. Main grade 1–2 toxicities per patient were infusion-related chills (47%) and transient blood pressure increase (9%). One partial response (3%) lasting 5 months and 12 stable diseases (36%) were reported. Median PFS was 2.5 months (95% CI, 2.2–2.8). In a post-hoc analysis, no differences in PFS were detected according to baseline characteristics. With a median follow-up time of 18.4 months (95% CI, 18.3–18.5), 11 pts (33%) were still alive. Median overall survival (OS) was 13.1 months and the 2-year OS rate was 22%. In the subset of stable or responder pts, the median PFS and OS were 3.8 months and 15.4 months, respectively. The 6-month PFS rate in the prior-biological and biological-naïve cohorts was 5% and 20%, respectively, whereas 1-year OS rate was 41% and 72%, respectively. Conclusions: Based on the favorable toxicity profile and disease control in heavily pre-treated CRC patients, NGR-hTNF will be further developed in combination with standard chemotherapy. [Table: see text]
Prospective randomized study comparing hepatic intra-arterial injection of Yttrium-90 resin-microspheres (HAI-Y90) with protracted IV 5FU (5FU CI) versus 5FU CI alone for patients with liver-limited metastatic colorectal cancer (LMCRC) refractory to standard chemotherapy (CT)
Authors: Van Den Eynde M. , Hendlisz A. , Peeters M. , Defreyne L. , Maleux G. , Vannoote J. , Delatte P. , Paesmans M. , Van Laethem J. , Flamen P. 
Published: August 2020

4096 Background: Chemorefractory LMCRC has a poor prognosis. We hypothesized a significant improvement of the patient's outcome after internal radiotherapy of the hepatic metastases with HAI-Y90 given along with 5FU CI over 5FU CI alone. Methods: This prospective, multicentric, randomized trial compared arm A: 5FU CI (300 mg/m2 D1–14 q3weeks) with arm B: HAI-Y90 and 5FU CI (225 mg/m2 D1–14 followed by 300 mg/m2 D1–14 q3weeks) until disease progression. Eligibility criteria were: chemo-refractory (5FU, oxaliplatin, irinotecan) LMCRC, PS max 2, normal direct bilirubin, and no lung shunting. Primary endpoint was time to liver progression (TTLP). Secondary endpoints were time to progression (TTP), overall survival (OS) and safety. Cross-over (HAI-Y90 monotherapy) was permitted in arm A after disease progression. Analysis was by intention to treat. To detect an increase in median TTLP from 6 to 18 weeks, 35 local progressions were needed (alpha 5%, power 90%). Distribution of time to events variables was modelled through Cox regression (likelihood ratio tests). Results: Trial randomized 46 patients (pts) of whom 44 were eligible for analysis (23 in arm A and 21 in arm B). Pts’ characteristics in the 2 arms were well balanced. Local progression was documented in 41 pts. Median length of follow-up was 108 weeks. Results are summarized in the table . Treatment was well tolerated with few side effects reported, essentially grade 3 asthenia (5 pts; 22%) in arm A. Most pts (25/44) received further treatment after local progression, including 10 pts with cross-over to HAI-Y90 in arm A, which may explain to some degree the lack of difference in OS. Conclusions: HAI-Y90 with 5FU CI significantly improves TTLP and TTP over 5FU CI alone and is a valid salvage therapeutic option for chemo-refractory LMCRC. [Table: see text] No significant financial relationships to disclose.
Multicenter randomized phase II study of chemoradiation (CRT) followed by surgery (S) and chemotherapy (CT) versus induction CT followed by CRT and S in high-risk rectal cancer: GCR-3 final efficacy and safety results
Authors: Fernandez-Martos C. , Aparicio J. , Salud A. , Alonso V. , Massuti B. , Safont M. , Vera R. , Escudero P. , Maurel J. , Pericay C. 
Published: August 2020

4103 Background: In locally advanced RC the optimal therapeutic sequence remains an important clinical question. Induction CT prior to CRT and S may be associated with better efficacy and compliance. Methods: Eligible pts had medium or distal high risk RC defined by MRI and/or US: Tumors within 2mm of mesorectal fascia, distal T3 at/below levators, resectable T4 and T3N+. Pts, stratified by center, were randomized assigned to receive either Arm A : capecitabine (Cap) 825 mg/m2 BID 5 d/w, oxaliplatin (Ox) 50 mg/m2 IV weekly x 5 and concomitant RT: 50.4 Gy in 28 fractions. S was planned 5–6 w after CRT. Post-op four cycles of Cap 1,000 mg/m2 bid days 1 to 14; Ox 130 mg/m2 day 1 or Arm B: Induction CapOx followed by CRT and S. Two parallel, Simon 2-stage designs: α=0.05 β=0.1; 24 evaluable pts/arm 1st stage and 54 pts/arm for 2nd stage. Primary endpoint: pathological complete response (pCR). Secondary endpoints included toxicity and treatment compliance. Results: 108 Pts were randomly assigned (arm A/B, 52/56), and 103 were assessable (49/54) from 14 sites. Median age 62/60 years, Male 65/70%. During treatment period 6 pts died A/B: 2 vascular, 1 suicide/ 3 post-op. Pts with any grade ¾ toxicity during CRT were arm A/B: 29% (14/49) and 23% (12/53). Any grade ¾ toxicity during adjuvant/induction CT were 51% (19/37) and 17% (9/54); χ2,p= 0.0004. On an intent-to-treat basis the pCR for Arm A/B was achieved in seven (13.5%; 95% CI, 5.6%-25.8%) and eight (14.3%; 95% CI, 6.4%-26.2%). R0 resections were achieved in 92% (45/49) and 88% (48/54). 51% (25/49) and 93% (50/54) received all four cycles of adjuvant/induction CT (χ2;p<0.0001). Relative Median Dose intensity of adjuvant /induction CT was 0.74/0.96 (Wilcoxon; p<0.0001) for Cap and 0.75/1.0 (Wilcoxon; p<0.0001) for Ox. Conclusions: Induction CT prior to CRT has more favorable compliance and toxicity profiles. Furthermore, there is no compromise in pCR and R0 resection rates. Larger trials evaluating this strategy are justified. [Table: see text]
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.