bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI versus FOLFIRI in the G.O.N.O. randomized phase III study in metastatic colorectal cancer (MCRC)
Authors: Falcone A. , Andreuccetti M. , Brunetti I. , Ricci S. , Barbara C. , Evangelista W. , Passeri V. , Chiara S. , Allegrini G. , Masi G. 
Published: March 2020

4026 Background: As previously reported (ASCO 2006) the G.O.N.O. conduced a phase III study comparing FOLFIRI to FOLFOXIRI in 244 patients (pts) with not resectable MCRC. At a median follow-up of 18.4 months (mos) we reported significant improvements in response-rate (RR), R0 resection of metastases (mts), PFS and OS for FOLFOXIRI. Methods: Results have been updated (median follow-up of 36.2 mos) and 14 variables were tested as possible prognostic factors for response, R0 resection, PFS and OS. Results: At this updated analysis 225 (111 vs 114) pts have progressed and 180 (84 vs 96) have died. Results confirm the significant improvements for FOLFOXIRI in terms of confirmed RR (60% vs 34% p<0.001), R0 resection of residual mts (15% vs 6% p=0.033 and 36% vs 12% p=0.017 for pts with liver only mts), PFS (median 9.8 vs 6.9 mos p<0.001) and OS (median 23.6 vs 16.7 mos p=0.042) at the cost of a modest and acceptable increase in toxicity. In the logistic regression multivariate analysis treatment with FOLFOXIRI was the only independent predictive factor for response (HR:2.9, p<0.001) and for achieving an R0 surgical resection of mts (HR:3.1, p=0.018). The Cox’s multivariate analysis demonstrates that independent prognostic factors for improved time to progression were treatment with FOLFOXIRI (HR:0.64, p<0.001), and ECOG PS = 0 (HR:0.73, p=0.02) and for time to death were treatment with FOLFOXIRI (HR:0.74, p=0.04) and liver involvement <25% (HR:0.57, p=0.006). The benefits of FOLFOXIRI was consistent across all subgroups, including those with unfavorable prognosis such as pts with time from diagnosis to randomization <3 mos, multiple site of disease or liver involvement ≥ 25%. Conclusions: FOLFOXIRI confirms to be the first combination demonstrated to be superior to an infusional 5FU containing doublet as FOLFIRI in terms of RR, R0 resections, PFS and OS. FOLFOXIRI represents a new treatment option in MCRC and its use and study is of particular interest in a neoadjuvant strategy, in pts with few chances to achieve a three-drug exposure in a sequential strategy and in combination with targeted agents. Partially supported by Fondazione ARCO. No significant financial relationships to disclose.
Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/ NO16966, a randomized phase III trial in first-line metastatic colorectal cancer
Authors: Saltz L. , Clarke S. , Diaz-Rubio E. , Scheithauer W. , Figer A. , Wong R. , Koski S. , Lichinitser M. , Yang T. , Cassidy J. 
Published: March 2020

4028 Background: NO16966 is the first phase III trial to evaluate the combination of Bev with oxaliplatin-based chemotherapy (FOLFOX4 or the XELOX regimen) in the first-line setting. Methods: 1401 pts were randomized to receive FOLFOX4 (oxaliplatin, 5-FU, leucovorin as described previously) or XELOX (oxaliplatin 130mg/m2 iv, capecitabine 1000mg/m2 bid oral d1–14, q3w) plus Bev (5mg/kg q 2 weeks for FOLFOX, 7.5mg/kg q 3 weeks for XELOX) or Placebo in a 2x2 factorial design. Results: The addition of Bev to oxaliplatin-based chemotherapy demonstrated a significant benefit in terms of PFS in the primary analysis (HR 0.83; 97.5% CI 0.72- 0.95, p=0.0023). Prespecified analysis of PFS on treatment (defined as progressive disease or death within 28 days from the last dose of study treatment) and PFS analysis based on tumor assessments by an independent review committee (IRC) were consistent with the benefit observed in the primary analysis. PFS results are shown in Table 1 . 34% of patients have died and the median follow-up for survival at this time is 18.6 months. Mature overall survival data will be presented at the meeting. Conclusions: This large, international phase III trial demonstrates that the addition of Bev to oxaliplatin-based chemotherapy regimens significantly improves PFS. [Table: see text] [Table: see text]
Efficacy and safety findings from a randomized phase III study of capecitabine (X) + oxaliplatin (O) (XELOX) vs. infusional 5- FU/LV + O (FOLFOX-6) for metastatic colorectal cancer (MCRC)
Authors: Ducreux M. , Bennouna J. , Hebbar M. , Ychou M. , Lledo G. , Conroy T. , Adenis A. , Faroux R. , Rebischung C. , Douillard J. 
Published: March 2020

4029 Background: X has comparable efficacy, safety and convenience benefits over 5-FU/LV (Mayo clinic) in adjuvant colon cancer and first-line MCRC. A recent phase III trial in first line MCRC showed that XELOX is well tolerated and non inferior to FOLFOX-4 for progression-free survival (PFS) [Cassidy ESMO 2006]. Methods: We initiated a phase III trial to demonstrate non inferiority in terms of best response rates (RR, RECIST) of XELOX versus FOLFOX-6 as first-line therapy in patients (pts) with MCRC. Between 16 May 03 and 31 Aug 04, 306 patients (intention to treat), were randomized to receive either XELOX (n=156: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (n=150: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Efficacy results are presented in the per protocol population (PP) (n=284:144 pts XELOX; 140 pts FOLFOX-6). Results: Baseline characteristics were well balanced. Pts received a median of 8 and 11 cycles of XELOX (range 0–8) and FOLFOX-6 (range 0–12), respectively. Dose intensity (median) for oxaliplatin was 99.6% and 95.4% with XELOX and FOLFOX-6, respectively. Best RR (independent review, PP) was 42% and 46% with XELOX and FOLFOX-6, respectively. Difference between groups for RR was 4.7%; upper limit of 95% unilateral CI (14.4%) was below non-inferiority margin of 15%. RR by investigators (PP) was 46% for each arm. With a median follow up of 16.5 months (range 0.4–38.3), median PFS and overall survival (PP) were 9.3/19.9 vs. 9.7/18.4 months with XELOX and FOLFOX-6, respectively. In the safety population (n=304), XELOX pts had more grade 3/4 hand-foot syndrome (3 vs. 0%, p=0.21), thrombocytopenia (12 vs. 5% p=0.052), and diarrhea (12% vs. 7% p=0.1), but less grade 3/4 febrile neutropenia (0 vs. 6% p=0.001), neuropathy (8 vs. 19% p=0.003), than those on FOLFOX-6. Treatment discontinuation for toxicity was 19% and 23% in XELOX and FOLFOX-6 arms, respectively. Conclusions: The primary endpoint has been met: XELOX is non inferior to FOLFOX-6, with a good safety profile in first-line MCRC. No significant financial relationships to disclose.
Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Results from a large observational study (BRiTE)
Authors: Grothey A. , Sugrue M. , Hedrick E. , Purdie D. , Yi J. , Dong W. , Kozloff M. 
Published: March 2020

4036 Background: While BV prolongs OS when used with standard 1st- or 2nd-line chemotherapy (CT) in mCRC, no data exist on the effects of BBP. A previous report from BRiTE showed favorable median OS (27.1 mo, 95% CI 24.8-NE), with 1st line PFS (median 10.1 mo, 95% CI:9.7–10.4) comparable to historical mCRC trials, suggesting significant impact of post-progression survival on OS. This exploratory analysis evaluates the association of various pre- and post-treatment variables with OS in BRiTE. Methods: Pt population and methods have been described previously (Kozloff, ASCO 2006). All pts in BRiTE received BV as part of 1st-line therapy. The use of BBP and choice of CT were at investigator’s discretion. Kaplan-Meier methods were used to estimate PFS and OS. Cox’s proportional hazard model was used to assess the independent effects of pre- and post-treatment pt- related factors on OS, including age, ECOG PS, albumin, alkaline phosphatase, site of primary tumor, 1st-line CT regimen, 1st-line PFS, exposure to all 3 active CT agents, receipt of any 2nd-line CT, exposure to cetuximab, and BBP. Though there was variability observed in patterns of BBP, including continuous and discontinuous use, for the purpose of this analysis, BBP was defined as any exposure to BV after 1st progression (PD). Results: A total of 1,953 pts were treated in BRiTE. At median follow-up of 17.5 mo, there were 1,369 1st PD and 839 deaths. Among pts with 1st PD, 65.2% received any 2nd-line CT, 34.8% received cetuximab, and 53.8% received BBP. In a multivariate analysis, BBP and exposure to any 2nd-line CT were independently associated with increased OS (both p<0.0001). Age ≥65, PS ≥1, low albumin, elevated alkaline phosphatase, colon primary, and use of IFL were associated with inferior OS. Conclusions: BBP appears to be associated with longer OS in BRiTE. This finding supports the evaluation of BBP in prospective randomized clinical trials. Other factors that may have impacted this finding, including physician-related variables, will be investigated in future analyses. [Table: see text]
Association of skin toxicity (ST) severity with clinical outcomes and health-related quality of life (HRQoL) with panitunumab (Pmab)
Authors: Humblet Y. , Peeters M. , Siena S. , Hendlisz A. , Neyns B. , Sobrero A. , Wolf M. , Woolley M. , Amado R. , Van Cutsem E. 
Published: March 2020

4038 Background: STs are associated with epidermal growth factor receptor (EGFr) inhibition. Studies of anti-EGFr inhibitors have shown associations between the severity of ST per clinical toxicity grading and response rate, progression-free-survival (PFS) and overall survival (OS). However a correlation between these endpoints and ST severity as measured by ST patient reported outcomes (PRO) and the impact of ST on HRQoL is unknown. We evaluated the associations among PFS, OS and ST PRO, and the impact of ST on overall HRQoL for Pmab. Methods: In a phase 3 study of mCRC patients (pts) with disease progression after treatment (tx) with standard chemotherapy, pts were randomized to best supportive care (BSC) ± Pmab 6mg/kg Q2W. ST was measured using modified NCI-CTC v3.0 grading criteria and a modified Dermatology Life Quality Index (mDLQI). HRQoL (EQ-5D and EORTC QLQ-C30 Global QoL subscale) and CRC symptoms (NCCN/FACT CRC symptom index, FCSI) were also measured. Analyses of ST with PFS and OS were restricted to pts in the Pmab arm with ≥ grade (gr) 1 ST that were progression-free at least 28 days. These analyses were adjusted for randomization factors. Hazard ratios (HR) and correlation analyses were used to determine relationships between PFS and OS to ST, and ST to overall HRQoL. Results: Tx with Pmab (n=231) prolonged PFS vs BSC alone (n=232; p<.0001). The incidence of gr 2–4 ST was higher in the Pmab arm. OS was significantly prolonged in pts with more severe ST (gr 2–4 vs. gr 1; HR=0.67; p=0.0235). Lower mDLQI scores (worse ST) also predicted improved OS (Cox model, p<0.0001). Similar results were seen with PFS. Pearson correlation coefficients showed that the minimum post- baseline mDLQI score was inversely associated with post-baseline median HRQoL and CRC symptom scores, suggesting that Pmab pts with more severe ST have a higher (better) HRQoL (p=0.0006, 0.0148, 0.2487) and improved CRC symptom scores (p=0.0649). Conclusions: Pts with gr 2–4 ST appear to experience longer PFS and OS compared to those with gr 1 ST. Pts reporting the greatest bother from their ST also tend to report better overall HRQoL and reduced CRC symptoms. [Table: see text]
Cetuximab, capecitabine, and oxaliplatin (Cet-CapOx) with concurrent radiotherapy (RT) in advanced rectal cancer (RC): Results of a phase I/II trial
Authors: Arnold D. , Hipp M. , Liersch T. , Dellas K. , Koelbl O. , Hohenberger W. , Lordick F. , Sülberg H. , Sauer R. , Rödel C. 
Published: March 2020

4042 Background: CapOx given concurrently with neoadjuvant RT in rectal cancer is well tolerated and has achieved high rates of pathologic complete response (pCR) in phase II trials. Cetuximab is active in metastatic colorectal cancer. Synergy of cetuximab with RT resulted in improved survival (vs. RT alone) in head and neck cancer. This trial was to evaluate feasibility and efficacy of Cet-CapOx in RT of rectal cancer, with maximal tolerated dose as primary endpoint in phase I, and pCR as primary endpoint in phase II. Method: Patients (pts) had to have untreated, T3–4 and/or N+ disease per MRI or CT plus endoscopic ultrasound, M1 allowed, normal organ function. During conventionally fractionated RT (1.8 Gy for 28 days [d]), cetuximab was given in standard dose (400 mg/m2 on d - 7, then 6 weekly doses of 250 mg/m2, to d35). CapOx was administered as in the phase II trial of our group (Rödel et al, J Clin Oncol 2007), with oxaliplatin (50 mg/m2 d 1,8,22 and 29) plus capecitabine (d1–14 and d22–35) at 3 dose levels: 1,000, 1,300 and 1,650 mg/m2/day. Results: 60 pts were enrolled: Median age 62 [35–83] yrs., male 61%, T3/T4 83/17%, N+ 85%, M1 20%. 7/ 3/ 50 pts. were treated on levels 1/ 2/ 3: as only 1 pt. experienced DLT (diarrhea 4°) on level 1 and none on level 2, level 3 was chosen for phase II (n=50 pts.). Most common toxicity was CTC grade 3 diarrhea in 14% of pts. Full dose of all drugs and of RT was administered in >90% of cycles. No grade 4 toxicity occurred. 53/60 pts underwent resection after completed chemoradiation without increase of perioperative complications when compared to historic controls of CapOx-RT alone. Radiologic downstaging (17 pts. evaluated so far) was seen in 35% for T category and in 67% for N category. Pathologic complete response (45 pts. evaluable) was observed in 9% of pts, another 38% had “good regression” (>50% of tumor cells). Conclusion: CapOx can safely be combined with cetuximab without requiring dose reduction of chemo- or radiotherapy and leads to significant downstaging. However, the relatively low rate of pathologic responses underachieved the assumptions. [Table: see text]
Preoperative chemoradiotherapy with capecitabine and oxaliplatin in locally advanced rectal carcinoma: A phase II trial
Authors: Alonso V. , Lambea J. , Salud A. , Valencia J. , Mira M. , Polo S. , Escudero P. , Sierra E. , Monzon A. 
Published: March 2020

4044 Background: The aim of this phase II trial was to assess the impact of preoperative external radiation therapy combined with Capecitabine and Oxaliplatin on pathologic tumor response, sphincter preservation and tumor control in patients with locally advanced rectal carcinoma. Methods: Sixty-seven patients with locally advanced rectal carcinoma (T3/T4 or N+) received radiotherapy (50.4 Gy/28 fractions) and chemotherapy with Capecitabine 825 mg/m2/12 hours on days 1–5 + Oxaliplatin 50 mg/m2 on day 1 every week (weeks 1–6). Surgery with TME was performed 6–7 weeks after the end of the treatment. Adjuvant chemotherapy was administered after surgery according investigator‘s crtiteria. Results: Patients have been recruited between February 2005 and June 2006. 47 male/20 female. Median age 67 years (range 38–79). Performance status (ECOG) 0 in 45 patients. Clinical stage (determined by EUS+CT or RMI): cT2 3p/cT3 58p/cT4 6p/cN+ 47p. Tumor location (from anal verge): = 5 cm in 27p. Median CEA level 3,69 ng/ml (0,7–391). Surgery (performed in 65 patients) consisted of low anterior resection in 37p, abdominal perineal resection in 28p. Tumor downstaging was observed in 52p (78%), 50 (76,9%) had negative lymph nodes, including 13p with complete pathological response (19,4%) and ten with only microfoci of tumor remaining (14,9%). 80% of the patients received adjuvant chemotherapy. Main adverse effects (NCI-CTC): diarrhea G3/4 25%, sensitive peripheral neurotoxicity G1 60%, skin G2 9%, skin G3 3%, nausea/vomiting G2 7.5%, fatigue G2 50%, fatigue G3 4%, neutropenia G3/4 4%. Conclusions: Those results show that preoperative chemoradiotherapy with capecitabine and oxaliplatin is a well tolerated regimen for locally advanced operable rectal cancer leading to a high probability of tumor downstaging. No significant financial relationships to disclose.
Tumor microsatellite-instability status to predict benefit of adjuvant chemotherapy for stage III colon cancer
Authors: Chang G. J. , Lee K. Y. , Eng C. , Kattepogu K. M. , Richey S. , Skibber J. M. , Rodriguez-Bigas M. A. , Hamilton S. R. 
Published: March 2020

4046 Background: Microsatellite instability (MSI) is an alternative pathway to colon cancer pathogenesis and may be categorized by the degree of MSI exhibited as MSI-high (MSI-H), MSI-low (MSI-L) or microsatellite stable (MSS). The aim of this study was to determine the prognostic impact MSI status on survival in stage III colon cancer. Methods: A total of 197 patients who received curative resection of stage III colon cancer from 1991 through 2002 were identified. Records of these patients were retrospectively evaluated to determine chemotherapy (CTx) use and vital status. DNA extracted from paraffin embedded tumor specimens was amplified by polymerase chain reaction using a panel of 7 markers. MSI-H was defined as instability in >40% of markers and low as instability in >0% but <40% of markers. Overall survival based on MSI and CTx status was compared using Kaplan-Meier analysis and the log-rank test and Cox multiple regression to adjust for covariates. Results: Median follow-up was 5.4 years. There were 25 (13%) MSI-H, 38 (19%) MSI-L and 134 (68%) MSS patients. Median age was 56 years (MSI-H), 65 years (MSI-L) and 62 years (MSS). 5-fluorouracil adjuvant CTx was completed in 135 (69%), not completed in 36 (18%) and unknown in 26 (13%) patients. Tumors were left sided in 56% of the cohort, 72% among MSI-H, 60% among MSI-L, 51% among MSS. 5-year overall survival after adjuvant CTx ranged 71–82% and was not significantly different among the groups. Completion of CTx improved survival among MSS, HR 0.18 (95% confidence [CI] 0.07–0.42, p<0.0001), but not among MSI- H, HR 0.83 (95% CI 0.19–3.60, p=0.79), with an intermediate effect among MSI-L, HR 0.36 (95% CI 0.09–1.47, p=0.0562). The effect of completing adjuvant CTx persisted after adjustment for age, sex, stage (IIIA, B, C), and histology, RR 0.19 (95% CI 0.089–0.41, p<0.0001), RR 0.059 (95% CI 0.009–0.39, p=0.003), RR 0.26 (95% CI 0.01–13.3, p=0.31) for MSS, MSI-L, and MSI-H, respectively. Conclusions: 5-fluorouracil based adjuvant chemotherapy did not affect overall survival in patients with stage III colon cancer who are MSI-H due to a high baseline survival rate without adjuvant therapy. Adjuvant chemotherapy did improve survival in patients who are MSS and an intermediate effect was seen in paitents who are MSI-L. No significant financial relationships to disclose.
Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: A final report
Authors: Kim T. , Lee J. , Lee J. , Lee K. , Kang Y. , Yu C. , Kim J. , Ahn S. , Kim J. , Lee J. 
Published: March 2020

4050 Background: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. Methods: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m2/d and leucovorin 20 mg/m2/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. (J Clin Oncol 2002 20:1751- 8) Results: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 94 months for surviving patients, there was a trend for improved disease-free survival(DFS) in arm I compared with arm II, although it was not reached statistical significance (72% v. 63% at 7 years; P =.157). Especially, in patients who received abdominoperineal resection (APR), DFS was prolonged in arm I compared with arm II (66% v. 41% at 7 years; P=.033) Thirty six recurrences (26.7%) occurred in arm I and 49 (35.3%) in arm II (P =.151). Overall survival was not significantly different between arms I and II (71% v. 68% at 7 years; P =.855). Conclusions: With a long-term follow-up, this study failed to show a significant survival advantage for early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer. In patients with APR, significant improvement in DFS for arm I was observed. No significant financial relationships to disclose.
Safety results of a phase III randomized trial of adjuvant treatment with 5- fluorouracil and folinic acid with or without irinotecan, in Dukes B2 and C colon cancer
Authors: Papakostas P. , Kalofonos H. P. , Pentheroudakis G. , Timotheadou E. , Papadimitriou C. , Tsavdaridis D. , Economopoulos T. , Galani E. , Bafaloukos D. , Aravantinos G. 
Published: March 2020

4053 Background: The aim of our phase III study was to compare the effectiveness and the toxicity profile of 5-Fluorouracil (5- FU) + folinic acid (FA) + irinotecan (CPT-11) as adjuvant chemotherapy for resectable colon cancer (Dukes B2 and C) to that of 5-FU + FA which was considered the standard treatment. Since patients are still on follow-up regarding the primary endpoint, only safety results will be presented. Methods: Eligible patients received either 5-FU (450 mg/m2 bolus) + FA (200 mg/m2, 120 min infusion) + CPT- 11 (80 mg/m2, 90 min infusion) given 4 weeks on, two weeks off for a total of 6 treatment cycles (Arm A) or 5-FU (500 mg/m2 bolus) + FA (200 mg/m2, 120 min infusion) given 6 weeks on, two weeks off for a total of 4 treatment cycles (Arm B). Results: From January 1999 to September 2004, 910 patients (pts) were enrolled in this multi-center phase III trial. Safety data are available for 826 of the 910 pts, (415 in arm A and 411 in arm B). The total number of chemotherapy courses delivered was 8,906 (92%) in arm A and 8,775 (91%) in arm B, with median courses per patient 24 in both groups. Among patients who received treatment as randomized (403 in arm A and 398 in arm B), treatment was completed in 342 pts (82%) in arm A and in 341 pts (83%) in arm B. The number of patients who discontinued the treatment was 61 (15%) in arm A and 57 (14%) in arm B. Hospitalizations because of toxic effects happened in 37 pts (9%) in arm A and in 45 pts (11%) in arm B. Three deaths occurred in both arms. Use of G-CSF was more common in arm A (94 pts, 23%) than in arm B (38 pts, 9.5%) (p< 0.001). Significantly higher grade 3/4 neutropenia was observed in group A (11% in arm A and 3% in arm B, p< 0.001). Severe diarrhea was also frequently reported in both groups. Conclusions: These data show that both regimens have comparable and manageable toxicity profiles as adjuvant treatment in colon cancer. Severe neutropenia was more often seen in arm A. No significant financial relationships to disclose.