Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the ...main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up.
Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires.
Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76–1.36 andP = 0.3, HR = 0.87; 95% CI, 0.66–1.15, respectively. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51–1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3–4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms.
The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.
This open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.
Patients were ...randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary end point was progression-free survival (PFS).
In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years 95% confidence interval (CI), 2.0 to not reached with cetuximab and 2.0 years (95% CI, 1.5–2.8) with control hazard ratio (HR), 0.79; 95% CI, 0.58–1.07; P = 0.13. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2–4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52–1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31–0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64–1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.
Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.
NCT01107639
The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain.
One hundred and nineteen patients with LAPC, World ...Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m2/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m2/day, days 1–5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m2 weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m2 weekly, 3/4 weeks) was given in both arms until disease progression or toxicity.
Overall survival was shorter in the CHRT than in GEM arm median survival 8.6 (99% confidence interval 7.1–11.4) and 13 months (8.7–18.1), P = 0.03. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3–4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%).
This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.
Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of ...bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population.
Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator’s choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria.
About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75–91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT).
Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.
Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) ...with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.
Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan IRI: LV5FU2–irinotecan or simplified LV5FU2–irinotecan (FOLFIRI). The CLASSIC arm was defined as LV5FU2 or LV5FU2–irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).
From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2–irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75–92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66–1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67–1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75–1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55–0.92). More patients presented grade 3–4 toxicities in IRI (52.2% versus 76.3%).
In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.
NCT00303771.
Background
Patterns of disease recurrence in patients with oesophageal cancer following treatment with neoadjuvant chemoradiotherapy and surgery (nCRTS) or surgery alone are poorly reported. An ...understanding of patterns of disease recurrence is important for subsequent treatment planning.
Methods
An analysis was undertaken of patterns of disease recurrence from a phase III multicentre randomized trial (FFCD9901) comparing nCRTS with surgery alone in patients with stage I and II oesophageal cancer.
Results
Some 170 patients undergoing surgical resection were included in the study. R0 resection rates were similar in the two groups: 94 per cent following nCRTS versus 92 per cent after surgery alone (P = 0·749). After a median follow‐up of 94·2 months, recurrent disease was found in 39·4 per cent of the overall cohort (31 per cent after nCRTS versus 47 per cent following surgery alone; P = 0·030). Locoregional recurrence was diagnosed in 41 patients (17 versus 30 per cent respectively; P = 0·047) and distant metastatic recurrence in 47 (23 versus 31 per cent respectively; P = 0·244). Metastatic recurrence was more frequent in patients with adenocarcinoma than in those with squamous cell cancer (40 versus 23·1 per cent respectively; P = 0·032). ypT0 N0 category was associated with prolonged time to mixed locoregional and metastatic recurrence (P = 0·009), and time to locoregional (P = 0·044) and metastatic (P = 0·055) recurrence. In multivariable analysis, node‐positive disease predicted both locoregional (P = 0·001) and metastatic (P < 0·001) recurrence.
Conclusion
Locoregional disease control following nCRTS indicated a local field effect not related solely to completeness of resection. pN+ disease was strongly predictive of time to locoregional and metastatic disease recurrence.
Multimodal treatment reduces locoregional but not distant metastatic recurrence
Abstract Objective To assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC). Design Among the 294 patients with ...non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test. Results Among the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p = 0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval CI, 0.4–0.8; p = 0.0002) and OS (HR, 0.4; CI, 0.3–0.6; p < 0.0001). Both median PFS (5.1 4.6–5.6 versus 2.9 2.2–4.1 months; p = 0.001) and OS (16.3 13.7–19.2 versus 9.6 7.4–12.5; p < 0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary ( n = 43). Conclusion Resection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.
Background: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. Patients and methods: A total of 400 patients ...with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A—LV5FU2 leucovorin 200 mg/m2, 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m2 bolus, 600 mg/m2 22-h continuous infusion, days 1 and 2 or B—LV5FU2 + IRI (irinotecan 180 mg/m2 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). Results: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% 95% confidence interval (CI) 53% to 66% and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed hazard ratio (HR) = 1.12, 95% CI 0.85–1.47, P = 0.42 even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74–1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. Conclusion: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.
A recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal ...cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival.
A total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18).
Both groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil–cisplatin arm only (p = 0.047).
During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil–cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020).
Analyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil–cisplatin regimen as part of definitive CRT.
•A longitudinal analysis of the health-related quality of life (HRQOL) data of the PRODIGE 5 randomised trial is proposed.•The HRQOL longitudinal analysis was performed using a linear mixed model and time until definitive deterioration.•The prognostic ability of baseline HRQOL domains for progression-free survival and overall survival were tested.•Chemoradiotherapy significantly worsens fatigue, social and physical functions, with subsequent recovery from 24 weeks.•Multivariate analysis confirmed the prognostic value of stage at diagnosis and possibly the baseline QLQ-OES18 EAT score.
Summary
Background
A phase I dose‐escalation trial of transarterial chemoembolisation (TACE) with idarubicin‐loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC).
Aim
...To estimate the maximum‐tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life.
Methods
Patients received a single TACE session with injection of 2 mL drug‐eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose‐limiting toxicity (DLT) in 20% of patients.
Results
Twenty‐one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5‐, 10‐ and 15‐mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST, elevated γ‐glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months – not reached); the median overall survival was 24.5 months (95% CI 14.7 months – not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly.
Conclusions
Using drug‐eluting beads, the maximum‐tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559).
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