To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer.
This is a retrospective multicenter cohort, evaluating ...the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m
, irinotecan 90 mg/m
, 5-fluorouracil infusion 2400 mg/m
per 46 h; day 3: irinotecan 90 mg/m
) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept (
= 3), more than one prior treatment line in irinotecan-naïve patients (
= 3), and inadequate liver function (
= 3). In the "irinotecan-naïve" patients (
= 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the "pre-exposed irinotecan" patients (
= 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively.
Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.
High-throughput screening (HTS) hit 1 was previously identified as an inhibitor of the Akt/mTOR (Akt/mammalian target of rapamycin) signaling, which is a major target in oncology. The cytotoxicity of ...1 was determined on a panel of human cancer cells lines with an IC50 comprised between 30 and 140 μM. Subsequent structure–activity relationship (SAR) studies led us to the identification of compounds that displayed an enhanced cytotoxicity. We demonstrated also that these molecules directly bind to mTOR complex 1 (mTORC1) and inhibit its kinase activity.
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•23 benzofurane derivatives of an HTS hit were synthesized and examined for their cytotoxicity in cancer cells.•SARs for these analogs as anti-cancer agents were identified.•These compounds bind to mTOR complex 1 (mTORC1) and inhibit its kinase activity.
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•The first method to replace the 8b hydroxyl of flavaglines is described.•A cyclic sulfite intermediate is optimal to introduce an azide on flavaglines.•Acylamino or mesylamino ...derivatives are not cytotoxic.
Flavaglines represent a class of potent anticancer agents. Herein, we demonstrated that a classical strategy in pharmacomodulation, i.e. the isosteric replacement of an alcohol by an acylamino or a mesylamino moiety leads to inactive compounds. In addition, the development of a convenient method to introduce an azide on the cyclopentabbenzofuran skeleton of these compounds was achieved using a cyclic sulfite intermediate.
We evaluated the prognostic value of KRAS and primary tumor location (PTL) for overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) in metastatic colorectal ...cancer (mCRC).
Individual patient data from the DREAM phase III study were retrospectively analyzed. PTL was defined as right-sided or left-sided if tumor arising from the cecum to transverse colon or from the splenic flexure to the rectum, respectively. OS, PFS, and PPS were estimated using the Kaplan-Meier method and compared using log-rank test.
Among 700 patients included in the DREAM study, both PTL and KRAS were available for 536 (76.6%) patients. PTL showed stronger prognostic impact than KRAS status for OS (HRPTL, 1.62 vs. HRKRAS, 1.37), PFS (HRPTL, 1.27 vs. HRKRAS, 1.15) and PPS (HRPTL, 1.54 vs. HRKRAS, 1.33). Interaction between PTL and KRAS was significant (Pinteraction = .003). A negative impact of KRAS mutation was observed for OS and PPS, but not for PFS. Right-sided tumor was associated with poorer Eastern Cooperative Oncology Group performance status, anemia, and KRAS mutation, whereas left-sided KRAS wild-type tumor was associated with an increased lactate dehydrogenase. In patients with KRAS mutant mCRC, alkaline phosphatase was the main prognostic factor whatever the tumor site, whereas in those with KRAS wild-type tumors, prognostic factors varied according to PTL. The exposition to the anti-epidermal growth factor receptor (anti-EGFR) agents during and after study was similar in patients with left-sided and right-sided KRAS wild-type tumors.
Our findings suggest that a better prognosis of patients with mCRC with left-sided tumors is driven more strongly by PPS than by PFS when compared with patients with right-sided tumors, whatever the KRAS mutation status. This phenomenon was independent from the exposition to poststudy anti-EGFR monoclonal antibody.
This is the first report showing that the better prognosis of patients with mCRC with left-sided tumors is driven more strongly by post-progression survival than by progression-free survival when compared with right-sided tumors, whatever KRAS mutation status. This phenomenon was independent from the exposure to poststudy anti-EGFR monoclonal antibody.
Abstract Background First-line oxaliplatin-based therapy is the standard treatment of metastatic colorectal cancer (mCRC), but its dose-limiting toxicity is sensory neuropathy. The OPTIMisation of ...OXaliplatin (OPTIMOX) stop-and-go approach with oxaliplatin-free interval (OFI) offers a reasonable strategy. Influence of the first-line oxaliplatin-based treatment efficacy and the duration of OFI on tumour sensitivity to oxaliplatin reintroduction were investigated. Methods This was a pooled analysis of OPTIMOX1 and OPTIMOX2 studies, on 285 patients with previously untreated mCRC and FOLFOX reintroduction. An optimal OFI was estimated. Efficacy endpoints measured from reintroduction of FOLFOX included response rate (RR), progression-free survival (PFS) and overall survival (OS). Findings Two groups of OFI <6 and ⩾6 months, were defined. The RR following FOLFOX reintroduction were 14% and 22% in patients with an OFI <6 and ⩾6 months, respectively (overall RR 19%). The median PFS after FOLFOX reintroduction following OFI< 6 and ⩾6 months were 3.0 95% confidence intervals (CI): 2.7–3.7 and 5.5 months 95% CI: 4.8–6.5, respectively. The median OS following OFI <6 months was 8.8 months 95% CI: 7.5–10.5 and OFI ⩾6 was months 16.8 months 95% CI: 15.3–19.6. In the case of partial response (PR), median PFS and OS were 4.6 95% CI: 4.1–5.0 and 14 months 95% CI: 12.1–16.4, respectively, whereas in patients with initial stable disease (SD) 3.4 95% CI: 2.7–4.7 and 10.3 months 95% CI: 7.3–12.9, respectively. Interpretation A sensitive population of patients more likely to benefit from oxaliplatin reintroduction is defined by the efficacy of induction therapy followed by an OFI of at least 6 months between two periods of FOLFOX therapy. OFI of <6 months identifies a subgroup of partially-resistant patients who can still benefit from oxaliplatin reintroduction.
Abstract Background Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled ...trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. Methods Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006–2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1–9). Results For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. Conclusion The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.
Adding oxaliplatin to adjuvant 5-fluorouracil (5-FU) chemotherapy improves 3-year disease-free survival (DFS) after resection of stage III colon cancer. Several studies suggest that patients with ...tumors exhibiting defective mismatch repair (MMR) do not benefit from adjuvant 5-FU chemotherapy, but there are few data on 5-FU-oxaliplatin (FOLFOX) adjuvant chemotherapy in this setting. The aim of this study was to evaluate the prognostic value of MMR status for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy.
MMR status was determined by microsatellite instability testing or immunohistochemistry in 303 unselected patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy in 9 centers. Cox proportional hazards models were used to examine the association between MMR status and 3-year DFS.
The 3-year DFS rate was significantly higher in the 34 patients (11.2% of the study population) with defective MMR tumors (90.5%) than in patients with proficient MMR tumors (73.8%; log-rank test; HR = 2.16; 95% CI, 1.09-4.27; P = 0.027). In multivariate analysis, MMR status remained an independent significant prognostic factor for DFS (HR = 4.48; 95% CI, 1.34-14.99; P = 0.015).
MMR status is an independent prognostic biomarker for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy.
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