Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates ...the association.
Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence.
Among 2630 patients with cancer recurrence (1491 men 56.7%, mean age, 58.5 19–85 years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio aHR, 0.82; 95% CI confidence interval, 0.69–0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58–1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73–2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67–4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence.
In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.
NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.
Clinicians managing colorectal cancer patients need to appreciate that more than 60% of their patients are >70 years of age, and that these proportions may increase further in the future. Many will ...have co-morbidity and frailty issues and in an era of rapidly expanding therapeutic options, this may present formidable challenges. We present the SIOG updated recommendations for managing such patients.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in Europe and worldwide, with the peak incidence in patients >70 years of age. However, as the treatment algorithms for the treatment of patients with CRC become ever more complex, it is clear that a significant percentage of older CRC patients (>70 years) are being less than optimally treated. This document provides a summary of an International Society of Geriatric Oncology (SIOG) task force meeting convened in Paris in 2013 to update the existing expert recommendations for the treatment of older (geriatric) CRC patients published in 2009 and includes overviews of the recent data on epidemiology, geriatric assessment as it relates to surgery and oncology, and the ability of older CRC patients to tolerate surgery, adjuvant chemotherapy, treatment of their metastatic disease including palliative chemotherapy with and without the use of the biologics, and finally the use of adjuvant and palliative radiotherapy in the treatment of older rectal cancer patients. An overview of each area was presented by one of the task force experts and comments invited from other task force members.
Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study ...comparing GemOx with Gem alone in advanced pancreatic cancer.
Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion).
Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem).
These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.
Highlights • Preclinical research identified c-MET as a promising target for head and neck cancer. • c-MET activation mediates important functions in both malignant and stromal cells. • Aberrant ...signalling includes mutations, amplifications, crosstalk, and overexpression. • Immunohistochemical c-MET overexpression may have prognostic and predictive value. • c-MET inhibition may overcome resistance to EGFR tyrosine kinase inhibitors
Indication for primary tumour resection (PTR) in asymptomatic metastatic colorectal cancer (mCRC) patients is unclear. Previous retrospective analyses suggest a survival benefit for patients who ...underwent PTR. The aim was to evaluate the prognostic value of PTR in patients with synchronous mCRC by analysis of recent large RCTs including systemic therapy with modern targeted agents.
Individual patient data (IPD) of 3423 patients enrolled into 8 randomised controlled trials (RCTs) with first-line systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analysed.
The number of patients with unresected synchronous mCRC, resected synchronous mCRC and metachronous mCRC was 710 (21%), 1705 (50%) and 1008 (29%), respectively. Adjusting for age, gender, performance status (PS) and prior chemotherapy, the unresected group had a significantly worse median overall survival (16.4 m) compared with the synchronous resected (22.2 m; hazard ratio HR 1.60, 95% CI 1.43–1.78) and metachronous (22.4 m; HR 1.81, 95% CI 1.58–2.07) groups. Similarly, median progression-free survival was significantly worse for the unresected group compared with the synchronous resected (HR 1.31, 95% CI 1.19–1.44) and metachronous (HR 1.47, 95% CI 1.30–1.66) groups. In a multivariate analysis, the observed associations remained significant.
This largest IPD analysis of mCRC trials to date demonstrates an improved survival in synchronous mCRC patients after PTR. These results may be subject to bias since reasons for (non)resection were not available. Until results of ongoing RCTs are available, both upfront PTR followed by systemic treatment and upfront systemic treatment are considered appropriate treatment strategies.
•Data of RCTs regarding primary tumour resection (PTR) in synchronous metastatic colorectal cancer (mCRC) are lacking.•All patients in this analysis of 8 large mCRC trials in the ARCAD database received modern systemic treatment including targeted agents.•Synchronous mCRC patients with upfront PTR have a significant improved survival of almost 6 months compared to unresected mCRC patients.•Results of ongoing RCTs are warranted to obtain a definitive conclusion about the survival benefit of PTR in synchronous mCRC.
KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of ...benefit.
Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HR
) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis.
5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HR
0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HR
0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HR
0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HR
1.04, 95% CI 0.86-1.26) (p
= 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (p
= 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (p
= 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (p
= 0.004).
The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.
Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over ...a 10-year period in patients with stage III colon cancer who received this regimen.
Individual patient data from the ACCENT database was used to compare the outcomes in older (1998–2003) and newer (2004–2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade.
A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence 3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj) = 0.83 (95% CI, 0.74–0.92), P = 0.0008, disease-free survival (DFS) 3-year rate, 74.7% versus 72.3%; HRadj = 0.88 (0.79–0.98), P = 0.024, survival after recurrence (SAR) median time, 27.0 versus 17.7 months; HRadj = 0.65 (0.57–0.74), P < 0.0001, and overall survival (OS) 5-year rate, 80.9% versus 75.7%; HRadj = 0.78 (0.69–0.88), P < 0.0001. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1–3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors.
Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints.
NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.
•Improved outcomes were observed in stage III colon cancer patients who received adjuvant FOLFOX/FLOX therapy after 2004.•Adherence to sufficient lymph nodes examination is continuously recommended for better treatment decision making.•Re-validation of three-year DFS as the surrogate endpoint of OS in adjuvant clinical trials is needed.•Re-evaluation of optimal follow-up of OS to confirm trial findings based on DFS endpoints is needed.
PEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or ...docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer.
Patients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m2, irinotecan 300 mg/m2 or docetaxel (Taxotere) 75 mg/m2 every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error β = 0.10, null hypothesis of ORR was 5%).
Forty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3–4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%).
The ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting.
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