The FIRE-3 trial investigated combination chemotherapy plus either cetuximab or bevacizumab in patients with untreated metastatic colorectal cancer (mCRC) not scheduled for upfront surgery. We aimed ...to determine the number of patients who present with potentially resectable disease during systemic first-line therapy and to compare the findings with study reports concerning resections and outcome.
This evaluation of 448 patients was performed as central review blinded for treatment, other reviewers' evaluations and conducted interventions. Resectability was defined if at least 50% of the reviewers recommended surgical-based intervention. Overall survival was assessed by Kaplan–Meier method.
Resectability increased from 22% (97/448) at baseline before treatment to 53% (238/448) at best response (P < 0.001), compared with an actual secondary resection rate for metastases of 16% (72/448). At baseline (23% versus 20%) and best response (53% versus 53%), potential resectability of metastases in this molecular unselected population was similar in cetuximab-treated patients versus bevacizumab-treated patients and not limited to patients with one-organ disease. The actual resection rate of metastases was significantly associated with treatment setting (P = 0.02; university hospital versus hospital/practice). Overall survival was 51.3 months (95% confidence interval CI 35.9–66.7) in patients with resectable disease who received surgery, 30.8 months (95% CI 26.6–34.9) in patients with resectable disease without surgery and 18.6 months (95% CI 15.8–21.3) in patients with unresectable disease (P < 0.001).
Our findings illustrate the potential for conversion to resectability in mCRC, certain reluctance towards metastatic resections in clinical practice and the need for pre-planned and continuous evaluation for metastatic resection in high-volume centres.
NCT00433927.
•We report a central review for resectability of 448 patients with metastatic colorectal cancer receiving first-line therapy (FIRE-3 trial).•Twenty-two percent of the patients before systemic therapy and 53% of the patients at best response were considered candidates for resection.•Actual reported resectability was 16% in the evaluated cohort.•Actual resection rates were significantly associated with treatment context (university hospital versus other hospitals/practices).
Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.
Patients with previously untreated, ...metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.
Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.
Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.
Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for ...this conversion strategy needs further evaluation.
Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012.
Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 95% confidence interval (CI) 27.2–44.2 months arm A: 35.8 (95% CI 28.1–43.6), arm B: 29.0 (95% CI 16.0–41.9) months, HR 1.03 (95% CI 0.66–1.61), P = 0.9. The median PFS was 10.8 (95% CI 9.3–12.2) months arm A: 11.2 (95% CI 7.2–15.3), arm B: 10.5 (95% CI 8.9–12.2) months, HR 1.18 (95% CI 0.79–1.74), P = 0.4. Patients who underwent R0 resection (n = 36) achieved a better median OS 53.9 (95% CI 35.9–71.9) months than those who did not 21.9 (95% CI 17.1–26.7) months, P < 0.001. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8–14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%).
This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for ‘conversion’ treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional ‘line of therapy’ in those patients who are not cured.
NCT00153998, www.clinicaltrials.gov.
The treatment of patients with colorectal liver metastases has been changed with the improved surgical techniques and the increasingly effective systemic therapy. It represents therefore a model for ...the therapy in other situations with limited metastatic disease. Because the overall survival is associated with metastasectomy, the treatment of patients with liver metastases should be discussed in a team with experienced liver surgeons. Options to increase or to achieve resectability are especially "conversion" chemotherapy, but also i. e. portal vein embolization and two step resections.
Background:: Long-term survival is reported in patients with liver metastases of colorectal cancer. Recently, an increased number of reports on liver resection following neoadjuvant chemotherapy in ...patients with initially unresectable liver metastases has been published.
Methods:: We analysed all published or presented trials and retrospective studies that report the rate of objective response and the rate of resection of initially unresectable metastases to correlate objective response and the rate of resection of metastases.
Results:: In studies that enrolled patients with metastases confined to the liver, 24–54% of patients were resected following chemotherapy, compared to 1–26% of patients in trials that included non-selected patients with metastatic colorectal cancer. A strong correlation was found between response rates and the resection rate in studies with patients with isolated liver metastases (r=0.96, P=0.002). Likewise, in studies with non-selected patients, the resection rate of metastases also was associated with the objective response rate (r=0.74, P<0.001).
Conclusions:: Patient selection and efficacy of pre-operative chemotherapy are both strong predictors for resectability of liver metastases. Resectability is a novel endpoint focusing on the curative potential of treatment compared with classical endpoints of response or progression-free survival that are important if palliation is the aim. Therefore, patients with potentially resectable liver metastases should be investigated in special trials and interdisciplinary teams.
The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based ...therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC.
Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis.
Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% 95% confidence interval (CI) 17.2–34.4 for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2–30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89–9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62–9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74–1.36). The response rates were 49.1% (95% CI 39.7–58.6) and 45.9% (95% CI 36.4–55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%).
No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity.
NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.
Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we ...aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor.
Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator’s choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS).
Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T.
In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.
•Adjuvant platinum-based chemotherapy is accepted as standard of care in stage II and III (NSCLC) patients.•Several studies addressed the question of whether molecular tumor markers may serve as predictive biomarkers.•ITACA was planned to evaluate the predictive utility of ERCC1 and TS mRNA expression levels in completely resected NSCLC.•ITACA results indicate that adjuvant chemotherapy customization based on ERCC1 and TS mRNA levels did not improve efficacy.•In terms of safety, the pharmacogenomic-driven arm was associated with better efficacy/toxicity ratio.
The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.
We analyzed the pronostic impact of ...KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model.
KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35–2.04; P < 0.001 but not codon 13 (HR 1.23, 95% CI 0.85–1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51–2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00–2.56; P = 0.051).
KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.
This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based ...chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial.
We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3–4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60–70, and ≥70years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis.
A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P<0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50months, in patients aged <60years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P=0.013) and systemic recurrences (P=0.023), DFS (P=0.011), and even overall survival (OS; P=0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40–70years compared with elderly patients treated with oxaliplatin.
The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60years with advanced rectal cancer. Patients aged ≥70years had no benefit.
NCT00349076
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