bluuebunny/crossref_metadata_2025 huggingface dataset:
Endpoints in adjuvant trials: A systematic review of the literature in colon cancer and proposed definitions for future trials
Authors: Buyse M. E. , Punt K. J. , Köhne C. H. , Hohenberger P. , Labianca R. , Schmoll H. J. , Pahlman L. , Sobrero A. F. , Douillard J. Y.
Published: March 2020

4018

Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors.

[Table: see text]

No significant financial relationships to disclose.
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.
Phase IV study of first-line bevacizumab plus irinotecan and infusional 5-FU/LV in patients with metastatic colorectal cancer: AVIRI
Authors: Sobrero A. F. , Young S. , Balcewicz M. , Chiarra S. , Perez Carrion R. , Mainwaring P. , Gapski J. , Clarke S. , Langer B. , Ackland S.
Published: March 2020

4068

Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF. In a phase III trial (AVF2107g), BEV significantly improved overall (OS) and progression-free survival (PFS) when combined with first-line irinotecan plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (IFL) in patients with metastatic colorectal cancer (mCRC). A multicentre, open-label trial is being conducted to evaluate the efficacy and safety of first-line BEV in combination with irinotecan and infusional 5-FU (FOLFIRI), a widely used first-line chemotherapy (CT) regimen. Methods: Patients had to have: mCRC; no surgery within 28 days; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function; no CNS metastases. CT consisted of a minimum of six cycles of irinotecan plus infusional 5-FU/LV according to the classical FOLFIRI regimen; variations like the simplified FOLFIRI and the weekly regimen were also allowed. BEV 5mg/kg was given on day 1 with CT and then every 2 weeks until disease progression. Tumour assessments were performed every 3 months during the first 12 months and every 4 months thereafter. Safety was assessed at the time of CT administration and every 4 weeks thereafter. The primary objective was PFS; secondary objectives included safety, overall response rate, time to response, duration of response and OS. Results: A total of 209 patients were enrolled at 31 centres worldwide, between April and November 2005. An interim analysis showed that the safety profile of BEV plus FOLFIRI appeared to be similar to that reported for Avastin plus IFL. The 44% overall response rate and 90% disease control rate are at least equivalent to that reported in comparable trials. Additionally, the 6 months PFS estimate of 82% was superior to that reported in AVF2107. Mature PFS data will be presented. Conclusions: AVIRI is the largest clinical trial, to date, to report data for BEV in combination with FOLFIRI in first-line patients with mCRC. The safety profile appears consistent with that observed in other BEV trials in mCRC, while the preliminary efficacy data suggest that this regimen is as active as the bolus regimen.

No significant financial relationships to disclose.
Safety and efficacy of first-line irinotecan/fluoropymidine combinations in mCRC patients >65 years compared with those ≤65: The BICC-C study
Authors: Barrueco J. , Marshall J. , Mitchell E. , Wierzbicki R. , Ganju V. , Jeffery M. , Schultz J. , Richards D. , Soufi-Mahjoubi R. , Fuchs C.
Published: March 2020

4076

Background: BICC-C was a multicenter, randomized study that assessed efficacy & safety of irinotecan/fluoropyrimidines combinations in previously untreated mCRC patients. This study showed that FOLFIRI or FOLFIRI+bev were superior to their comparators (Proc ASCO 2006). We conducted a secondary analysis of efficacy & safety among all patients >65 years compared with those =65. Methods: Pts were randomized to: infusional FOLFIRI, modified bolus IFL (mIFL), or CapeIri; and concurrent celecoxib or placebo in a double-blind fashion. The protocol was amended in April 2004 and bevacizumab (bev) was added to the FOLFIRI and mIFL arms whereas CapeIri was discontinued. Period 1 (P1) and Period 2 (P2) designate subjects enrolled before or after the amendment. Results: Of 430 pts enrolled in P1, 150 were age >65 (median 71; range, 66–87) and 280 were = 65 (median, 56; 20–65). Of 117 pts in P2, 75 were >65 (median, 73; 66–84) and 42 were = 65 (median, 54; 32–65). No significant differences in efficacy or safety were observed between the two age groups. Results for P1: median progression free survival (PFS) was 6.5 and 6.7 mos; and median overall survival (OS) was 18.8 and 19.2 for >65 and =65, respectively. For the FOLFIRI regimen specifically median PFS was 7.5 and 7.6 mos, and median OS was 20.1 and 24.3 mos for >65 and =65, respectively. Results for P2: median PFS was 10.3 and 10.6 mos; and median OS was 19.8 and 23 mos for >65 and =65, respectively. For the FOLFIRI+bev regimen specifically median PFS was 11.1 and 11.2 mos for >65 and =65 respectively, and median OS has not yet been reached for either subgroup at time of analysis. Common grade = 3 AEs are listed below. Conclusions: Efficacy and safety for first line irinotecan/fluoropyrimidine regimens and for FOLFIRI & FOLFIRI+bev, specifically, did not differ for older and younger mCRC patients.

[Table: see text]

[Table: see text]
Impact of irinotecan and oxaliplatin on overall survival in patients with metastatic colorectal cancer (MCRC): A population- based study
Authors: Lim H. J. , Fitzgerald C. , Gill S. , Melosky B. , Speers C. , Barnett J. , Kennecke H.
Published: March 2020

4077

Background: Over the past 10 years, chemotherapeutic options for MCRC has significantly expanded from 5-FU based therapy, to include irinotecan and oxaliplatin. The effect of the availability of these treatments on overall survival is evaluated among patients in 3 time cohorts referred to the British Columbia Cancer Agency (BCCA). Methods: Patients with newly diagnosed or relapsed metastatic colorectal cancer referred to the BCCA in 1995/96, 2000 and 2003/04 were included. In 1995/96, 5-FU was the only palliative chemotherapy agent available at BCCA and irinotecan and oxaliplatin were available in 2000 and 2003, respectively. A one year period was used for the irinotecan cohort to minimize overlap between groups. Overall survival estimates were generated using the Kaplan Meier method. Survival was calculated from time of diagnosis of distant metastatic disease to either death or last contact date. Results: Cohorts were generally similar, however, a significantly higher proportion of patients received chemotherapy in more recent eras ( Table 1 ). Only 25% of patients received both irinotecan and oxaliplatin in 2003/4 and only 10 % received biologic therapies. An improvement in median survival of 3.6 months was observed. The improvement in the treated subgroup was 4.2 months. Outcomes of patients untreated with chemotherapy were unchanged between cohorts. Conclusions: In this population based study, the proportion of patients with MCRC treated with chemotherapy significantly increased between 1995/6 and 2000/2003/4. Patients treated with chemotherapy experienced a 4.2 month increase in median survival in 2003/4 compared to 1995/6. Survival improvements were only significant in the time period when all three effective chemotherapies (5FU, irinotecan and oxaliplatin) were available. As bevacizumab was not available until 2006, its survival impact in this population is not yet known.

[Table: see text]

No significant financial relationships to disclose.
Targeted chemoradiation for metastatic colorectal cancer: A phase I trial of oral capecitabine combined with 131I- huA33
Authors: Herbertson R. A. , Tebbutt N. , Gill S. , Lee F. T. , Chappell B. , Cavicchiolo T. , Skrinos E. , Poon A. , Saunder T. , Scott A. M.
Published: March 2020

4078

Background: HuA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and >95% of human colon cancers, but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 weeks, but eliminated from normal colonocytes within days. This phase 1 study used radio-labeled huA33 in combination with capecitabine chemotherapy to target chemoradiation to metastatic colorectal cancer. Methods: The primary objective was safety and tolerability of the combination of capecitabine and 131I-huA33. Pharmacokinetics, biodistribution, immunogenicity, and tumor response were also assessed. Eligibility included measurable metastatic colorectal cancer, adequate hematological and biochemical function, and informed consent. An outpatient scout 131I-huA33 dose was followed by a single therapy infusion one week later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the12 week trial. Tumor targeting was assessed using gamma camera and single photon emission computerized tomography (SPECT) imaging. Results: 16 patients have enrolled with 2 currently on treatment, including one in the final dose cohort. Accrual will be completed by March 2007. The dose escalation protocol was amended following 2 dose limiting toxicities in the second cohort, but subsequent cohorts demonstrated good tolerability. Biodistribution analysis demonstrated excellent tumor targeting of the known tumor sites, expected transient bowel uptake, but no other normal tissue uptake. Maximal duration of stable disease is currently 3 years. Conclusions: 131I-huA33 achieves specific targeting of radiotherapy to sites of metastasis and can be safely combined with chemotherapy. This provides an opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients.

[Table: see text]

No significant financial relationships to disclose.
Cost-minimization analysis of a phase III study of capecitabine + oxaliplatin (XELOX) vs. infusional 5-FU/LV + oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer (MCRC) in the French setting
Authors: Perrocheau G. , Bennouna J. , Ducreux M. , Hebbar M. , Ychou M. , Lledo G. , Conroy T. , Adenis A. , Faroux R. , Douillard J.
Published: March 2020

4083

Background: A recent phase III trial in first-line MCRC showed that XELOX is well tolerated and non inferior to FOLFOX-4 in terms of progression-free survival (PFS) [Cassidy ESMO 2006]. We conducted a phase III trial of XELOX vs. FOLFOX-6 as first-line treatment for MCRC. Methods: 306 patients were randomized to receive either XELOX (n=156: capecitabine 1,000mg/m2 bid d1–14, oxaliplatin 130mg/m2 d1, q3w) or FOLFOX-6 (n=150: oxaliplatin 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400- 3,000mg/m2 46h infusion, q2w) for 6 months. Primary objective: demonstrate non-inferiority of XELOX (best response rate, RECIST). A cost minimization has been conducted from the French hospital perspective. The hospitalizations for chemotherapy (drug administration) were compiled and the direct hospital costs estimated using official tariffs of the national ‘PMSI’ database, directly derived from the Diagnosis Related Group (DRG). Results: The ITT population comprises 306 patients (156 on XELOX, 150 on FOLFOX-6). Baseline characteristics were well balanced. Patients received an average of 6.1±2.4 and 9.2±3.2 cycles of XELOX and FOLFOX-6, respectively. The number of hospitalizations was 6.5±2.6 and 9.5±4.1 for XELOX and FOLFOX-6, respectively. The costs of hospitalization for chemotherapy are available for 282 patients (142 in the XELOX arm and 140 in the FOLFOX-6 arm). The average cost of chemotherapy per cycle per patient was 608±446€ in the XELOX arm and 1,043±787€ in the FOLFOX-6 arm (p<0.001). Conclusions: As we have shown in the efficacy and safety abstracts also presented at this meeting, XELOX is non inferior to FOLFOX-6 in terms of best response rate with a comparable safety profile. In addition, XELOX appears to decrease hospital resource consumption compared with FOLFOX-6.

No significant financial relationships to disclose.
Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study
Authors: Sheikh H. , Valle J. W. , Palmer K. , Wilson G. , Sjursen A. , Craven O. , Swindell R. , Saunders M. P.
Published: March 2020

4084

Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS.

No significant financial relationships to disclose.
Phase I study of oral S-1 in combination with oxaliplatin (oxali) and bevacizumab (bev) in patients with advanced solid tumors
Authors: Zhang J. , Chung K. , Zergebel C. , Urrea P. , Quinones M. , Saltz L.
Published: March 2020

4091

Background: S-1 is a novel oral fluoropyrimidine (tegafur, CDHP and potassium oxonate) designed for enhanced DPD inhibition and reduced GI toxicity. Bev and oxali have demonstrated safety and synergistic anti-tumor activity with oral and IV fluoropyrimidines. The primary objective is to investigate the safety and maximum tolerated dose (MTD) of S-1 combined with bevacizumab and oxaliplatin in patients with advanced solid tumors. Secondary objective is to investigate the clinical pharmacokinetics (PK) of the components of S-1 (FT, CDHP, Oxo), 5-FU, a-fluoro-β-alanine, cyanuric acid, uracil, and oxali and to document any antitumor activity. Methods: ECOG 0/1 patients with advanced or metastatic solid tumors received oral S-1 starting at 20 mg/m2/dose BID x 14 days (classic 3+3 cohort dose escalation by 5mg/m2/dose until MTD), plus fixed doses of bev 7.5 mg/kg IV day 1, and Oxali 130 mg/m2 IV day 1 of every 3 week cycle, with discontinuation of oxali after 4 cycles. Reintroduction of oxali was allowed upon progression of disease. Toxicity, antitumor activity and PKs were assessed. The MTD was defined as the highest dose level at which < 33% of the patients experience a dose- limiting toxicity (DLT) during the first 2 cycles. Results: Of 22 evaluable patients, 3 patients were treated at 20mg/m2 S1 and 13 patients were treated at 25mg/m2 S1 without a DLT. At 30mg/m2, two patients experienced a DLT(Grade 3 diarrhea, Grade 4 mucositis). The MTD and recommended phase II dose of S-1 is 25mg/m2 in combination with oxali and bev. A median of 8 cycles of S-1 were initiated at the 25 mg/m2 dose level. Common MTD level toxicities included fatigue (62%), nausea (62%) and diarrhea (46%), with no grade 4 toxicities observed. Best responses (RECIST): stable disease(16 patients), partial response (2 patients), non-measurable disease (3 patients). The Day 8 AUC(0–8) of 5-FU at 20/25/30 mg/m2 dose level were 230±115 hr*ng/ml, 470±172 hr*ng/ml and 502±169 hr*ng/ml, respectively. Conclusions: The MTD combination of 25mg/m2 S-1, oxali and bev can be given safely. The study will be expanded to test S-1 one week on, one week off schedule in combination with oxali/bev every two weeks.

No significant financial relationships to disclose.
Phase II study of the A-ICOX regimen [bevacizumab (Bev), weekly intermittent capecitabine (Cap) and oxaliplatin (Ox)] for untreated advanced colorectal cancer (CRC)
Authors: Ramanathan R. K. , Rajasenan K. , Crandall T. , Balaban E. P. , Pinkerton R. A. , Kane P. , Potter D. M. , Dranko S. , Schmotzer A. , Lembersky B. C.
Published: March 2020

4092

Background: FOLFOX in combination with Bev is a standard regimen for treating advanced CRC. Cap on a d 1–14 schedule every 3 weeks is now being substituted for 5-flurouracil (CapOx); however optimal doses and schedules of Cap in combination with Ox and Bev needs continued evaluation. Intermittent weekly Cap (3,500 mg/m2, d 1–7) with Ox (85 mg/m2) every 2 weeks compared to the standard CapOx regimen in untreated advanced CRC has shown superior response and time-to-progression in Europe (Scheithauer W et al. J Clin Oncol. 21,1307; 2003). Methods: This phase II trial is designed to evaluate the A-ICOX regimen in US patients with CRC. The primary endpoint is to detect a 50% improvement in median progression free survival (PFS) from 8 to 12 months. With a sample of 40 patients, a 1-sided level 0.1 log-rank test has 81% power to detect this difference. Patients with advanced untreated CRC are eligible for study. Cap is administered at the dose of 2,500 mg/m2 in two divided doses on d 1–7 (n=11) and has been increased to 3000 mg/m2 dose (n=26), based on tolerability of the lower dose. The dose of Ox is 85 mg/m2 and Bev is 5 mg/kg. Cycles are repeated every 2 weeks. Results: Thirty-seven of 40 pts have been enrolled, with 30 evaluable for toxicity and response. Patient characteristics: Male (n=19); ECOG performance status 0 (n=18), 1 (n=12); median age 63 (range 38–80 years). Median cycles administered 4 (range 1–17). Partial responses were seen in 10 pts (33%), and metastasectomy was performed in 8 pts (27%). The PFS analysis is premature at this point. Gr 3/4 hematological toxicity occurred in only 2 pts (7 %). Other gr 3/4 adverse events have included: diarrhea (10 %), hand-foot syndrome (7 %), peripheral neuropathy (7%), nausea (7%) and vomiting (7 %). Conclusions: The first US experience of the A-ICOX regimen shows it to be very well tolerated, and Cap (3,000 mg/m2, d 1–7) in combination with Ox and Bev therapy can be safely administered. The incidence of subsequent metastasectomy, a marker of activity, is encouraging. A phase III trial of the A-ICOX regimen is now being conducted against standard Q-3 weekly CapOx/Bev. (Study supported by Genentech and Roche Pharmaceuticals)

[Table: see text]
The combination of capecitabine (C), irinotecan (I) and oxaliplatin (O) (XELOXIRI) as first line treatment of metastatic colorectal cancer (MCRC): Preliminary results of a pilot study by the Gruppo Oncologico Nord-Ovest (G.O.N.O.)
Authors: Masi G. , Bursi S. , Loupakis F. , Barletta M. , Baldi G. , Antonuzzo A. , Sonaglio C. , Pfanner E. , Petrini I. , Falcone A.
Published: March 2020

4096

Background: FOLFOXIRI demonstrated manageable toxicities and improved activity and efficacy compared to FOLFIRI in MCRC in a phase III trial by the G.O.N.O. group. Oral C has demonstrated similar efficacy to 5-FU and might substitute 5-FU in the FOLFOXIRI regimen. Methods: The G.O.N.O. started a pilot study to evaluate the combination of escalating doses of C with fixed doses of I, O (XELOXIRI) in metastatic and not resectable CRC patients (pts). The objectives of the study are the definition of the recommended dose (RD) of C in combination with I and O, safety and activity of the combination and analysis of plasma pharmacokinetics. The planned treatment in the first 3 patients was: I 165 mg/sqm over 1-h on day 1, O 85 mg/sqm over 2-h on day 1 and C 2,500 mg/sqm/die from day 1 to 7, repeated every 2 weeks. C dose was increased to 3,000 mg/sqm/die or decreased to 2,000 mg/sqm/die in subsequent groups of 3 to 6 pts on the basis of the observed dose limiting toxicities (DLT). Results: Up today 33 patients have been enrolled. Main patients characteristic are: sex (M/F) = 22/11, PS (0/1/2) = 28/4/1, age (median/range) = 65/42–76, sites of disease (single/multiple) = 18/15. The DLT was G3–4 diarrhea that was observed in 2 out 6 patients receiving C at 2500 mg/sqm, in 2 out 3 patients receiving C at 3,000 mg/sqm and in 1 out 6 patients receiving C at 2,000 mg/sqm. This last dose was defined the RD. Among the 23 patients treated at the RD main G3–4 toxicities were: diarrhea 17%, neutropenia 26%, thrombocytopenia 9%, neurotoxicity 4%. One toxic death for diarrhea and sepsis occurred. Up today 21 out of the 23 patients (2 patients too early) treated at the RD are assessable for response (ITT analysis) and 15 RP, 3 SD and 3 treatment failures have been observed with a response rate of 71% (95% CI: 48–89%). At a median follow-up of 10.3 months median PFS is 9.0+ months and median OS isn’t yet reached. Conclusions: XELOXIRI is a feasible regimen with diarrhea being the DLT. The recommended dose of C is 2,000 mg/sqm. At the RD toxicity is manageable and preliminary results in terms of activity are promising. Partially supported by Fondazione ARCO.

No significant financial relationships to disclose.