Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular ...BRAF, PIK3CA, and PTEN.
Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment-biomarker interaction.
A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61).
In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size.
Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and ...examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables.
We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using χ(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided.
In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P < .001), delayed TTR (P < .001), and fewer distant recurrences (22% vs 12%; P < .001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P < .001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P = .006).
Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors.
Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients ...with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value.
We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups.
Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval CI, 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97).
Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone. (ClinicalTrials.gov number, NCT00079066.)
Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been ...demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive FFCD Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia ENG trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials.
After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil FU 400 mg/m(2) administered intravenously IV once daily plus dl-leucovorin 200 mg/m(2) FFCD x 5 days or FU 370 mg/m(2) plus l-leucovorin 100 mg/m(2) IV x 5 days ENG for six cycles at 28-day intervals) or to surgery alone (S arm).
A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis.
This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus-based regimen after complete resection of colorectal cancer metastases.
Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective ...agent in patients with resected pancreatic cancer.
To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer.
The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up.
Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months.
Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life.
Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval CI, 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 95% CI, 0.81-1.08). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.
Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer.
clinicaltrials.gov Identifier: NCT00058201.
The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of ...brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity.
Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS).
A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio HR, 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively.
Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
We present the full data release of the 12CO (3–2) High-Resolution Survey (COHRS), which has mapped the inner Galactic plane over the range of 9.°5 ≤ l ≤ 62.°3 and ∣b∣ ≤ 0.°5. COHRS has been carried ...out using the Heterodyne Array Receiver Program on the 15 m James Clerk Maxwell Telescope in Hawaii. The released data are smoothed to have a spatial resolution of 16.″6 and a velocity resolution of 0.635 km s−1, achieving a mean rms of ∼0.6 K on TA*. The COHRS data are useful for investigating detailed three-dimensional structures of individual molecular clouds and large-scale structures such as spiral arms in the Galactic plane. Furthermore, data from other available public surveys of different CO isotopologues and transitions with similar angular resolutions to this survey, such as FUGIN, SEDIGISM, and CHIMPS/CHIMPS2, allow studies of the physical properties of molecular clouds and comparison of their states. In this paper, we report further observations on the second release and improved data reduction since the original COHRS release. We discuss the characteristics of the COHRS data and present integrated-emission images and a position–velocity (PV) map of the region covered. The PV map shows a good match with spiral-arm traces from existing CO and H i surveys. We also obtain and compare integrated one-dimensional distributions of 12CO (1–0) and (3–2) and those of star-forming populations.
Although early intervention is increasingly advocated to prevent and relieve distress in patients with metastatic cancer, the risk factors for such symptoms and their trajectory are not well ...established. We therefore conducted a longitudinal study to determine the course and predictors of depressive symptoms.
Patients (N = 365) with metastatic gastrointestinal or lung cancer completed measures of physical distress, self-esteem, attachment security, spiritual well-being, social support, hopelessness, and depression at baseline; physical distress, social support, hopelessness, and depression were subsequently assessed at 2-month intervals.
Of the sample, 35% reported at least mild depressive symptoms, with 16% reporting moderate to severe depressive symptoms that persisted in at least one third of such individuals. Moderate to severe depressive symptoms were almost three times more common in the final 3 months of life than > or = 1 year before death. Predictors of depressive symptoms included younger age, antidepressant use at baseline, lower self-esteem and spiritual well-being, and greater attachment anxiety, hopelessness, physical burden of illness, and proximity to death. The combination of greater physical suffering and psychosocial vulnerability put individuals at greatest risk for depression.
Depressive symptoms in advanced cancer patients are relatively common and may arise as a final common pathway of distress in response to psychosocial vulnerabilities, physical suffering, and proximity to death. These findings support the need for an integrated approach to address emotional and physical distress in this population and to determine whether early intervention may prevent depression at the end of life.
Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of ...microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer.
Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers.
Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 95 percent confidence interval, 0.14 to 0.72; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 95 percent confidence interval, 0.62 to 1.86; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 95 percent confidence interval, 0.53 to 0.99; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability.
Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.
A prospective cohort study was conducted to evaluate toxicity, quality of life (QOL), and clinical outcomes in patients treated with intensity modulated radiation therapy (IMRT) and concurrent ...chemotherapy for anal and perianal cancer.
From June 2008 to November 2010, patients with anal or perianal cancer treated with IMRT were eligible. Radiation dose was 27 Gy in 15 fractions to 36 Gy in 20 fractions for elective targets and 45 Gy in 25 fractions to 63 Gy in 35 fractions for gross targets using standardized, institutional guidelines, with no planned treatment breaks. The chemotherapy regimen was 5-fluorouracil and mitomycin C. Toxicity was graded with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Correlations between dosimetric parameters and both physician-graded toxicities and patient-reported outcomes were evaluated by polyserial correlation.
Fifty-eight patients were enrolled. The median follow-up time was 34 months; the median age was 56 years; 52% of patients were female; and 19% were human immunodeficiency virus-positive. Stage I, II, III, and IV disease was found in 9%, 57%, 26%, and 9% of patients, respectively. Twenty-six patients (45%) required a treatment break because of acute toxicity, mainly dermatitis (23/26). Acute grade 3 + toxicities included skin 46%, hematologic 38%, gastrointestinal 9%, and genitourinary 0. The 2-year overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS), and cumulative locoregional failure (LRF) rates were 90%, 77%, 84%, and 16%, respectively. The global QOL/health status, skin, defecation, and pain scores were significantly worse at the end of treatment than at baseline, but they returned to baseline 3 months after treatment. Social functioning and appetite scores were significantly better at 12 months than at baseline. Multiple dose-volume parameters correlated moderately with diarrhea, skin, and hematologic toxicity scores.
IMRT reduces acute grade 3 + hematologic and gastrointestinal toxicities compared with reports from non-IMRT series, without compromising locoregional control. The reported QOL scores most relevant to acute toxicities returned to baseline by 3 months after treatment.
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