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1.  LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases--a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial 
BMC Cancer  2012;12:144.
Background
15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods/Design
This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 μg once weekly for 8 weeks, followed by s.c. L-BLP25 930 μg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion
The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion.
Trial Registration
EudraCT Number 2011-000218-20
doi:10.1186/1471-2407-12-144
PMCID: PMC3342924  PMID: 22494623
2.  Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value 
PLoS Medicine  2013;10(5):e1001453.
Background
Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.
Methods and Findings
Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype–like, normal-like, serrated CC phenotype–like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II–III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1–2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available.
Conclusions
We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cancer of the large bowel (colorectal cancer) is the third most common cancer in men and the second most common cancer in women worldwide. Despite recent advances in the screening, diagnosis, and treatment of colorectal cancer, an estimated 608,000 people die every year from this form of cancer—8% of all cancer deaths. The prognosis and treatment options for colorectal cancer depend on five pathological stages (0–IV), each of which has a different treatment option and five year survival rate, so it is important that the stage is correctly identified. Unfortunately, pathological staging fails to accurately predict recurrence (relapse) in patients undergoing surgery for localized colorectal cancer, which is a concern, as 10%–20% of patients with stage II and 30%–40% of those with stage III colorectal cancer develop recurrence.
Why Was This Study Done?
Previous studies have investigated whether there are any possible gene expression profiles (identified through microarray techniques) that can help predict prognosis of colorectal cancer, but so far, there have been no firm conclusions that can aid clinical practice. In this study, the researchers used genetic information from a French multicenter study to identify a standard, reproducible molecular classification based on gene expression analysis of colorectal cancer. The authors also assessed whether there were any associations between the identified molecular subtypes and clinical and pathological factors, common DNA alterations, and prognosis.
What Did the Researchers Do and Find?
The researchers used genetic information from a cohort of 750 patients with stage I to IV colorectal cancer who underwent surgery between 1987 and 2007 in seven centers in France. The researchers identified relevant clinical and pathological staging information for each patient from the medical records and calculated recurrence-free survival (the time from surgery to the first recurrence) for patients with stage II or III disease. In the genetic analysis, 566 tumor samples were suitable—443 were used in a discovery set, to create the classification, and the remainder were used in a validation set, to test the classification. The researchers also used information from eight public datasets to validate their findings.
Using these methods, the researchers classified the colon cancer samples into six molecular subtypes (based on gene expression data) and, on further analysis and validation, were able to distinguish the main biological characteristics and deregulated pathways associated with each subtype. Importantly, the researchers found that that these six subtypes were associated with distinct clinical and pathological characteristics, molecular alterations, specific gene expression signatures, and deregulated signaling pathways. In the prognostic analysis based on recurrence-free survival, the researchers found that patients whose tumors were classified in one of two clusters (C4 and C6) had poorer recurrence-free survival than the other patients.
What Do These Findings Mean?
These findings suggest that it is possible to classify colorectal cancer into six robust molecular subtypes that might help identify new prognostic subgroups and could provide a basis for developing robust prognostic genetic signatures for stage II and III colorectal cancer and for identifying specific markers for the different subtypes that might be targets for future drug development. However, as this study was retrospective and did not include some known predictors of colorectal cancer prognosis, such as tumor grade and number of nodes examined, the significance and robustness of the prognostic classification requires further confirmation with large prospective patient cohorts.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001453.
The American Cancer Society provides information about colorectal cancer and also about how colorectal cancer is staged
The US National Cancer Institute also provides information on colon and rectal cancer and colon cancer stages
doi:10.1371/journal.pmed.1001453
PMCID: PMC3660251  PMID: 23700391
3.  Evaluating Letrozole and Tamoxifen Alone and in Sequence for Postmenopausal Women with Steroid Hormone Receptor-Positive Breast Cancer: the BIG 1-98 Randomized Clinical Trial at 8.1 years Median Follow-Up 
The lancet oncology  2011;12(12):1101-1108.
Background
Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast cancer recurrence and death. Therefore, trials evaluating endocrine therapies for this patient population require extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8.1 years median follow-up.
Methods
BIG 1-98 is a randomized, phase III, double-blind trial of 8010 postmenopausal women with hormone receptor-positive early breast cancer that compares five years of tamoxifen or letrozole monotherapy or sequential treatment with two years of one of these agents followed by three years of the other. The primary efficacy endpoint is disease-free survival (DFS: events comprise invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without prior cancer event), and secondary endpoints are overall survival (OS), distant recurrence-free interval (DRFI) and breast cancer-free interval (BCFI). The monotherapy comparison includes patients randomized to tamoxifen × 5 years (n=2459) or letrozole × 5 years (n=2463). In 2005, after significant DFS benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of 619 patients in the tamoxifen arm. The comparison of sequential treatments to letrozole monotherapy includes patients enrolled in the four-arm option of the trial and randomized to letrozole × 5 years (n=1546), letrozole × 2 years followed by tamoxifen × 3 years (n=1540), or tamoxifen × 2 years followed by letrozole × 3 years (n=1548). All patients have completed study treatment; follow up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.gov NCT00004205.
Findings
At a median follow-up of 8.7 years from randomization (range 0–12.4), letrozole monotherapy is significantly better than tamoxifen, whether using IPCW or intention-to-treat (ITT) analysis [IPCW: DFS HR 0.82 (95% CI 0.74–0.92), OS HR 0.79 (0.69–0.900, DRFI HR 0.79 (0.68–0.92), BCFI HR 0.80 (0.70–0.92); ITT: DFS HR 0.86 (0.78–0.96), OS HR 0.87 (0.77–0.999), DRFI HR 0.86 (0.74–0.998), BCFI HR 0.86 (0.76–0.98)]. At a median follow-up of 8.0 years from randomization (range 0–11.2), there were no statistically significant differences in any of the four endpoints for either sequence compared with letrozole monotherapy. Eight-year ITT estimates [each with SE ≤ 1.1%] for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78.6%, 77.8%, 77.3% for DFS; 87.5%, 87.7%, 85.9% for OS; 89.9%, 88.7%, 88.1% for DRFI; and 86.1%, 85.3%, 84.3% for BCFI.
Interpretation
For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared to tamoxifen. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but may represent useful strategies considering individual patient’s risk of recurrence and treatment tolerability: more thromboembolic events, vaginal bleeding, hot flushes and night sweats with tamoxifen, while more vaginal dryness, bone fractures, osteoporosis, arthralgia/myalgia, and higher grade cardiac events with letrozole.
Funding
Novartis, United States National Cancer Institute, International Breast Cancer Study Group.
doi:10.1016/S1470-2045(11)70270-4
PMCID: PMC3235950  PMID: 22018631
aromatase inhibitor; letrozole; breast cancer; adjuvant therapy; endocrine therapy; tamoxifen
4.  Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer 
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of published literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based and Economic Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: An Evidence-Based and Ecopnomic Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis
Objective
To review and synthesize the available evidence regarding the laboratory performance, prognostic value, and predictive value of Oncotype-DX for the target population.
Clinical Need: Condition and Target Population
The target population of this review is women with newly diagnosed early stage (stage I–IIIa) invasive breast cancer that is estrogen-receptor (ER) positive and/or progesterone-receptor (PR) positive. Much of this review, however, is relevant for women with early stage (I and II) invasive breast cancer that is specifically ER positive, lymph node (LN) negative and human epidermal growth factor receptor 2 (HER-2/neu) negative. This refined population represents an estimated incident population of 3,315 new breast cancers in Ontario (according to 2007 data). Currently it is estimated that only 15% of these women will develop a distant metastasis at 10 years; however, a far great proportion currently receive adjuvant chemotherapy, suggesting that more women are being treated with chemotherapy than can benefit. There is therefore a need to develop better prognostic and predictive tools to improve the selection of women that may benefit from adjuvant chemotherapy.
Technology of Concern
The Oncotype-DX Breast Cancer Assay (Genomic Health, Redwood City, CA) quantifies gene expression for 21 genes in breast cancer tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early breast cancer that is newly diagnosed. The panel of 21 genes include genes associated with tumour proliferation and invasion, as well as other genes related to HER-2/neu expression, ER expression, and progesterone receptor (PR) expression.
Research Questions
What is the laboratory performance of Oncotype-DX?
How reliable is Oncotype-DX (i.e., how repeatable and reproducible is Oncotype-DX)?
How often does Oncotype-DX fail to give a useable result?
What is the prognostic value of Oncotype-DX?*
Is Oncotype-DX recurrence score associated with the risk of distant recurrence or death due to any cause in women with early breast cancer receiving tamoxifen?
What is the predictive value of Oncotype-DX?*
Does Oncoytpe-DX recurrence score predict significant benefit in terms of improvements in 10-year distant recurrence or death due to any cause for women receiving tamoxifen plus chemotherapy in comparison to women receiving tamoxifen alone?
How does Oncotype-DX compare to other known predictors of risk such as Adjuvant! Online?
How does Oncotype-DX impact patient quality of life and clinical/patient decision-making?
Research Methods
Literature Search
Search Strategy
A literature search was performed on March 19th, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st, 2006 to March 19th, 2010. A starting search date of January 1st, 2006 was because a comprehensive systematic review of Oncotype-DX was identified in preliminary literature searching. This systematic review, by Marchionni et al. (2008), included literature up to January 1st, 2007. All studies identified in the review by Marchionni et al. as well as those identified in updated literature searching were used to form the evidentiary base of this review. The quality of the overall body of evidence was identified as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Any observational trial, controlled clinical trial, randomized controlled trial (RCT), meta-analysis or systematic review that reported on the laboratory performance, prognostic value and/or predictive value of Oncotype-DX testing, or other outcome relevant to the Key Questions, specific to the target population was included.
Exclusion Criteria
Studies that did not report original data or original data analysis,
Studies published in a language other than English,
Studies reported only in abstract or as poster presentations (such publications were not sought nor included in this review since the MAS does not generally consider evidence that is not subject to peer review nor does the MAS consider evidence that lacks detailed description of methodology).
Outcomes of Interest
Outcomes of interest varied depending on the Key Question. For the Key Questions of prognostic and predictive value (Key Questions #2 and #3), the prospectively defined primary outcome was risk of 10-year distant recurrence. The prospectively defined secondary outcome was 10-year death due to any cause (i.e., overall survival). All additional outcomes such as risk of locoregional recurrence or disease-free survival (DFS) were not prospectively determined for this review but were reported as presented in included trials; these outcomes are referenced as tertiary outcomes in this review. Outcomes for other Key Questions (i.e., Key Questions #1, #4 and #5) were not prospectively defined due to the variability in endpoints relevant for these questions.
Summary of Findings
A total of 26 studies were included. Of these 26 studies, only five studies were relevant to the primary questions of this review (Key Questions #2 and #3). The following conclusions were drawn from the entire body of evidence:
There is a lack of external validation to support the reliability of Oncotype-DX; however, the current available evidence derived from internal industry validation studies suggests that Oncotype-DX is reliable (i.e., Oncotype-DX is repeatable and reproducible).
Current available evidence suggests a moderate failure rate of Oncotype-DX testing; however, the failure rate observed across clinical trials included in this review is likely inflated; the current Ontario experience suggests an acceptably lower rate of test failure.
In women with newly diagnosed early breast cancer (stage I–II) that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node negative:
There is low quality evidence that Oncotype-DX has prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole (the latter for postmenopausal women only),
There is very low quality evidence that Oncotype-DX can predict which women will benefit from adjuvant CMF/MF chemotherapy in women being treated with adjuvant tamoxifen.
In postmenopausal women with newly diagnosed early breast cancer that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node positive:
There is low quality evidence that Oncotype-DX has limited prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole,
There is very low quality evidence that Oncotype-DX has limited predictive value for predicting which women will benefit from adjuvant CAF chemotherapy in women who are being treated with adjuvant tamoxifen.
There are methodological and statistical limitations that affect both the generalizability of the current available evidence, as well as the magnitude and statistical strength of the observed effect sizes; in particular:
Of the major predictive trials, Oncotype-DX scores were only produced for a small subset of women (<40% of the original randomized population) potentially disabling the effects of treatment randomization and opening the possibility of selection bias;
Data is not specific to HER-2/neu-negative women;
There were limitations with multivariate statistical analyses.
Additional trials of observational design may provide further validation of the prognostic and predictive value of Oncotype-DX; however, it is unlikely that prospective or randomized data will become available in the near future due to ethical, time and resource considerations.
There is currently insufficient evidence investigating how Oncoytpe-DX compares to other known prognostic estimators of risk, such as Adjuvant! Online, and there is insufficient evidence investigating how Oncotype-DX would impact clinician/patient decision-making in a setting generalizable to Ontario.
PMCID: PMC3382301  PMID: 23074401
5.  Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data 
The Lancet Oncology  2013;14(7):619-626.
Summary
Background
The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels.
Methods
We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints.
Findings
In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2=0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2=0·95, 0·91–0·98 for modified vs standard radiotherapy).
Interpretation
We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted.
Funding
Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
doi:10.1016/S1470-2045(13)70158-X
PMCID: PMC3732017  PMID: 23680111
6.  Bifractionated CPT-11 with LV5FU2 infusion (FOLFIRI-3) in combination with bevacizumab: clinical outcomes in first-line metastatic colorectal cancers according to plasma angiopoietin-2 levels 
BMC Cancer  2013;13:611.
Background
Optimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients.
Methods
We conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline.
Results
Overall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002).
Conclusions
As front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2.
doi:10.1186/1471-2407-13-611
PMCID: PMC3877948  PMID: 24373251
Colorectal cancer; Bevacizumab; FOLFIRI3; Irinotecan; Angiopoietin-2
7.  KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer 
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based and Economic Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based and Economic Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis.
Objective
The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer (mCRC) with two anti-EGFR agents, cetuximab and panitumumab. Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing.
Clinical Need: Condition and Target Population
Metastatic colorectal cancer (mCRC) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis (TNM) system or stage D in the Duke’s classification system. Patients with advanced colorectal cancer (mCRC) either present with metastatic disease or develop it through disease progression.
KRAS (Kristen-RAS, a member of the rat sarcoma virus (ras) gene family of oncogenes) is frequently mutated in epithelial cancers such as colorectal cancer, with mutations occurring in mutational hotspots (codons 12 and 13) of the KRAS protein. Involved in EGFR-mediated signalling of cellular processes such as cell proliferation, resistance to apoptosis, enhanced cell motility and neoangiogenesis, a mutation in the KRAS gene is believed to be involved in cancer pathogenesis. Such a mutation is also hypothesized to be involved in resistance to targeted anti-EGFR (epidermal growth factor receptor with tyrosine kinase activity) treatments such as cetuximab and panitumumab, hence, the important in evaluating the evidence on the predictive value of KRAS testing in this context.
KRAS Mutation Testing in Advanced Colorectal Cancer
Both cetuximab and panitumumab are indicated by Health Canada in the treatment of patients with metastatic colorectal cancer whose tumours are WT for the KRAS gene. Cetuximab may be offered as monotherapy in patients intolerant to irinotecan-based chemotherapy or in patients who have failed both irinotecan and oxaliplatin-based regimens and who received a fluoropyrimidine. It can also be administered in combination with irinotecan in patients refractory to other irinotecan-based chemotherapy regimens. Panitumumab is only indicated as a single agent after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
In Ontario, patients with advanced colorectal cancer who are refractory to chemotherapy may be offered the targeted anti-EGFR treatments cetuximab or panitumumab. Eligibility for these treatments is based on the KRAS status of their tumour, derived from tissue collected from surgical or biopsy specimens. It is believed that KRAS status is not affected by treatments, therefore, for patients for whom surgical tissue is available for KRAS testing, additional biopsies prior to treatment with these targeted agents is not necessary. For patients that have not undergone surgery or for whom surgical tissue is not available, a biopsy of either the primary or metastatic site is required to determine their KRAS status. This is possible as status at the metastatic and primary tumour sites is considered to be similar.
Research Question
To determine if there is predictive value of KRAS testing in guiding treatment decisions with anti-EGFR targeted therapies in advanced colorectal cancer patients refractory to chemotherapy.
Research Methods
Literature Search
The Medical Advisory Secretariat followed its standard procedures and on May 18, 2010, searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database.
The subject headings and keywords searched included colorectal cancer, cetuximab, panitumumab, and KRAS testing. The search was further restricted to English-language articles published between January 1, 2009 and May 18, 2010 resulting in 1335 articles for review. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters. Studies published from January 1, 2005 to December 31, 2008 were identified in a health technology assessment conducted by the Agency for Healthcare Research and Quality (AHRQ), published in 2010. In total, 14 observational studies were identified for inclusion in this EBA: 4 for cetuximab monotherapy, 7 for the cetuximab-irinotecan combination therapy, and 3 to be included in the review for panitumumab monotherapy
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 2005 to May 2010, inclusive.
Randomized controlled trials (RCTs) or observational studies, including single arm treatment studies that include KRAS testing.
Studies with data on main outcomes of interest, overall and progression-free survival.
Studies of third line treatment with cetuximab or panitumumab in patients with advanced colorectal cancer refractory to chemotherapy.
For the cetuximab-irinotecan evaluation, studies in which at least 70% of patients in the study received this combination therapy.
Exclusion Criteria
Studies whose entire sample was included in subsequent publications which have been included in this EBA.
Studies in pediatric populations.
Case reports, comments, editorials, or letters.
Outcomes of Interest
Overall survival (OS), median
Progression-free-survival (PFS), median.
Response rates.
Adverse event rates.
Quality of life (QOL).
Summary of Findings of Systematic Review
Cetuximab or Panitumumab Monotherapy
Based on moderate GRADE observational evidence, there is improvement in PFS and OS favouring patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to those with the mutation.
Cetuximab-Irinotecan Combination Therapy
There is low GRADE evidence that testing for KRAS may optimize survival benefits in patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to those with the mutation.
However, cetuximab-irinotecan combination treatments based on KRAS status discount any effect of cetuximab in possibly reversing resistance to irinotecan in patients with the mutation, as observed effects were lower than for patients without the mutation. Clinical experts have raised concerns about the biological plausibility of this observation and this conclusion would, therefore, be regarded as hypothesis generating.
Economic Analysis
Cost-effectiveness and budget impact analyses were conducted incorporating estimates of effectiveness from this systematic review. Evaluation of relative cost-effectiveness, based on a decision-analytic cost-utility analysis, assessed testing for KRAS genetic mutations versus no testing in the context of treatment with cetuximab monotherapy, panitumumab monotherapy, cetuximab in combination with irinotecan, and best supportive care.
Of importance to note is that the cost-effectiveness analysis focused on the impact of testing for KRAS mutations compared to no testing in the context of different treatment options, and does not assess the cost-effectiveness of the drug treatments alone.
Conclusions
KRAS status is predictive of outcomes in cetuximab and panitumumab monotherapy, and in cetuximab-irinotecan combination therapy.
While KRAS testing is cost-effective for all strategies considered, it is not equally cost-effective for all treatment options.
PMCID: PMC3377508  PMID: 23074403
8.  Liver resection for colorectal cancer metastases 
Current Oncology  2013;20(3):e255-e265.
Questions
Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)?
What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy (“conversion”)?
What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy?
Perspectives
Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%–10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required.
Methodology
Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline.
Practice Guideline
These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent.
1(a). Patients with liver and lung metastases should be seen in consultation with a thoracic surgeon. Combined or staged metastasectomy is recommended when, taking into account anatomic and physiologic considerations, the assessment is that all pulmonary metastases can also be completely removed. Furthermore, liver resection may be indicated in patients who have had a prior lung resection, and vice versa.
1(b). Routine liver resection is not recommended in patients with portal nodal disease. This group includes patients with radiologically suspicious portal nodes or malignant portal nodes found preoperatively or intraoperatively. Liver plus nodal resection, together with perioperative systemic therapy, may be an option—after a full discussion with the patient—in cases with limited nodal involvement and with metastases that can be completely resected.
1(c). Routine liver resection is not recommended in patients with nonpulmonary ehms. Liver plus extrahepatic resection, together with perioperative systemic therapy, may be an option—after a full discussion with the patient—for metastases that can be completely resected.
2(a). Perioperative chemotherapy, either before and after resection, or after resection, is recommended in patients with resectable liver metastatic disease. This recommendation extends to patients with ehms that can be completely resected (R0). Risks and potential benefits of perioperative chemotherapy should be discussed for patients with resectable liver metastases. The data on whether patients with previous oxaliplatin-based chemotherapy or a short interval from completion of adjuvant therapy for primary crc might benefit from perioperative chemotherapy are limited.
2(b). Liver resection is recommended in patients with initially unresectable metastatic liver disease who have a sufficient downstaging response to conversion chemotherapy. If complete resection has been achieved, postoperative chemotherapy should be considered.
3. Surgical resection of all lesions, including lesions with rcr, is recommended when technically feasible and when adequate functional liver can be left as a remnant. When a lesion with rcr is present in a portion of the liver that cannot be resected, surgery may still be a reasonable therapeutic strategy if all other visible disease can be resected. Postoperative chemotherapy might be considered in those patients. Close follow-up of the lesion with rcr is warranted to allow localized treatment or further resection for an in situ recurrence.
doi:10.3747/co.20.1341
PMCID: PMC3671032  PMID: 23737695
Colorectal cancer metastases; liver resection; hepatic resection; chemotherapy; complete response; downstaging
9.  GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study 
BMC Cancer  2014;14:183.
Background
In Europe, gastric cancer remains diagnosed at advanced stage (serosal and/or lymph node involvement). Despite curative management combining perioperative systemic chemotherapy and gastrectomy with D1-D2 lymph node dissection, 5-year survival rates of T3 and/or N + patients remain under 30%. More than 50% of recurrences are peritoneal and/or locoregional. The use of adjuvant hyperthermic intraperitoneal chemotherapy that eliminates free cancer cells that can be released into peritoneal cavity during the gastrectomy and prevents peritoneal carcinomatosis recurrences, was extensively evaluated by several randomized trials conducted in Asia. Two meta-analysis reported that adjuvant hyperthermic intraperitoneal chemotherapy significantly reduces the peritoneal recurrences and significantly improves the overall survival. As it was previously done for the evaluation of the extension of lymph node dissection, it seems very important to validate on European or caucasian patients the results observed in trials performed in Asia.
Methods/design
GASTRICHIP is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of hyperthermic intraperitoneal chemotherapy with oxaliplatin on patients with gastric cancer involving the serosa and/or lymph node involvement and/or with positive cytology at peritoneal washing, treated with perioperative systemic chemotherapy and D1-D2 curative gastrectomy. Peroperatively, at the end of curative surgery, patients will be randomized after preoperatively written consent has been given for participation. Primary endpoint will be overall survival from the date of surgery to the date of death or to the end of follow-up (5 years). Secondary endpoint will be 3- and 5-year recurrence-free survival, site of recurrence, morbidity, and quality of life. An ancillary study will compare the incidence of positive peritoneal cytology pre- and post-gastrectomy in two arms of the study, and assess its impact on 5-year survival. The number of patients to be randomized was calculated to be 306.
Trial registration
EudraCT number: 2012-005748-12, ClinicalTrials.gov identifier: NCT01882933.
doi:10.1186/1471-2407-14-183
PMCID: PMC3995601  PMID: 24628950
Gastric adenocarcinoma; Hyperthermic intraperitoneal chemotherapy; Oxaliplatin; Peritoneal carcinomatosis
10.  Optimal schedule of adjuvant chemotherapy with S-1 for stage III colon cancer: study protocol for a randomized controlled trial 
Trials  2013;14:17.
Background
Although, in Western countries, oxaliplatin-based regimens have been established as a gold standard treatment for patients with stage III or high risk stage II colon cancer after curative resection, in Japan fluorouracil-based regimens have been widely accepted and recommended in the guidelines for adjuvant settings in patients with stage III colon cancer. S-1, an oral preparation evolved from uracil and tegafur, has equivalent efficacy to uracil and tegafur/leucovorin for treating patients with advanced colorectal cancer and might be a suitable regimen in an adjuvant setting. However, the completion rate of the standard six-week cycle of the S-1 regimen is poor and the establishment of an optimal treatment schedule is critical. Therefore, we will conduct a multicenter randomized phase II trial to compare six-week and three-week cycles to establish the optimal schedule of S-1 adjuvant therapy for patients with stage III colon cancer after curative resection.
Methods/Design
The study is an open-label, multicenter randomized phase II trial. The primary endpoint of this study is three-year disease-free survival rate. Secondary endpoints are the completion rate of the treatment, relative dose intensity, overall survival, disease-free survival, and incidence of adverse events. The sample size was 200, determined with a significance level of 0.20, power of 0.80, and non-inferiority margin of a 10% absolute difference in the primary endpoint.
Discussion
Although S-1 has not been approved yet as a standard treatment of colon cancer in an adjuvant setting, it is a promising option. Moreover, in Japan S-1 is a standard treatment for patients with stage II/III gastric cancer after curative resection and a promising option for patients with colorectal liver metastases in an adjuvant setting. However, a six-week cycle of treatment is not considered to be the best schedule, and some clinicians use a modified schedule, such as a three-week cycle to keep a sufficient dose intensity with few adverse events. Therefore, it will be useful to determine whether a three-week cycle has an equal or greater efficacy and tolerance to side-effects compared with the standard six-week cycle schedule, and thus may be the most suitable treatment schedule for S-1 treatment.
Trial registration
The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000006750.
doi:10.1186/1745-6215-14-17
PMCID: PMC3564899  PMID: 23320901
Colon cancer; Stage III; Adjuvant chemotherapy; S-1
11.  Adjuvant radiotherapy for stage I endometrial cancer 
Background
This is an updated version of the original Cochrane review published in Issue 2, 2007. The role of radiotherapy (both pelvic external beam radiotherapy (EBRT) and vaginal intracavity brachytherapy (VBT)) in stage I endometrial cancer following hysterectomy remains controversial.
Objectives
To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer.
Search methods
We searched The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Specialised Register to end-2005 for the original review, and extended the search to January 2012 for the update.
Selection criteria
We included randomised controlled trials (RCTs) that compared post-operative adjuvant radiotherapy (either EBRTor VBT, or both) versus no radiotherapy or VBT in women with stage I endometrial cancer.
Data collection and analysis
Two review authors independently assessed trials and extracted data to a specifically designed data collection form. The primary outcome was overall survival. Secondary outcomes were endometrial cancer-related deaths, locoregional recurrence and distant recurrence. Meta-analyses were performed using Cochrane Review Manager Software 5.1.
Main results
We included eight trials. Seven trials (3628 women) compared EBRT with no EBRT (or VBT), and one trial (645 women) compared VBTwith no additional treatment. We considered six of the eight trials to be of a high quality. Time-to-event data were not available for all trials and all outcomes.
EBRT (with or without VBT) compared with no EBRT (or VBT alone) for stage I endometrial carcinoma significantly reduced locoregional recurrence (time-to-event data: five trials, 2965 women; Hazard Ratio (HR) 0.36, 95% Confidence Interval (CI) 0.25 to 0.52; and dichotomous data: seven trials, 3628 women; Risk Ratio (RR) 0.33, 95% CI 0.23 to 0.47). This reduced risk of locoregional recurrence did not translate into improved overall survival (time-to-event data: five trials, 2,965 women; HR 0.99, 95% CI 0.82 to 1.20; and dichotomous data: seven trials, 3628 women; RR 0.98, 95% CI 0.83 to 1.15) or improved endometrial cancer-related survival (time-to-event data: five trials, 2965 women; HR 0.96, 95% CI 0.72 to 1.28; and dichotomous data: seven trials, 3628 women; RR 1.02, 95% CI 0.81 to 1.29) or improved distant recurrence rates (dichotomous data: seven trials, 3628 women; RR 1.04, 95% CI 0.80 to 1.35).
EBRT did not improve survival outcomes in either the intermediate-risk or high-risk subgroups, although high-risk data were limited, and a benefit of EBRT for high-risk women could not be excluded. One trial (PORTEC-2) compared EBRT with VBT in the high-intermediate risk group and reported that VBT was effective in ensuring vaginal control with a non-significant difference in loco-regional relapse rate compared to EBRT (5.1% versus 2.1%; HR 2.08, 95% CI 0.71 to 6.09; P = 0·17). In the subgroup of low-risk patients (IA/B and grade 1/2), EBRT increased the risk of endometrial carcinoma-related deaths (including treatment-related deaths) (two trials, 517 women; RR 2.64, 95% CI 1.05 to 6.66) but there was a lack of data on overall survival. We considered the evidence for the low-risk subgroup to be of a low quality.
EBRT was associated with significantly increased severe acute toxicity (two trials, 1328 patients, RR 4.68, 95% CI 1.35 to 16.16), increased severe late toxicity (six trials, 3501 women; RR 2.58, 95% CI 1.61 to 4.11) and significant reductions in quality of life scores and rectal and bladder function more than 10 years after randomisation (one trial, 351 women) compared with no EBRT.
One trial of VBT versus no additional treatment in women with low-risk lesions reported a non-significant reduction in locoregional recurrence in the VBT group compared with the no additional treatment group (RR 0.39, (95% CI 0.14 to 1.09). There were no significant differences in survival outcomes in this trial.
Authors’ conclusions
EBRT reduces the risk of locoregional recurrence but has no significant impact on cancer-related deaths or overall survival. It is associated with significant morbidity and a reduction in quality of life. There is no demonstrable survival advantage from adjuvant EBRT for high-risk stage I endometrial cancer, however, the meta-analyses of this subgroup were underpowered and also included high-intermediate risk women, therefore we cannot exclude a small benefit in the high-risk subgroup. EBRT may have an adverse effect on endometrial cancer survival when used to treat uncomplicated low-risk (IA/B grade 1/2) endometrial cancer. For the intermediate to high-intermediate risk group, VBT alone appears to be adequate in ensuring vaginal control compared to EBRT. Further research is needed to guide practice for lesions that are truly high risk. In addition, the definitions of risk should be standardised.
doi:10.1002/14651858.CD003916.pub4
PMCID: PMC4164955  PMID: 22513918
Endometrial Neoplasms [pathology; *radiotherapy; surgery]; Neoplasm Staging; Radiotherapy, Adjuvant [methods]; Randomized Controlled Trials as Topic; Survival Analysis; Female; Humans
12.  Adjuvant Chemotherapy Using the FOLFOX Regimen in Colon Cancer 
Purpose
Great progress has been made in the adjuvant treatment of colon cancer. The aim of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy using the FOLFOX regimen in patients with stage III and high-risk stage II colon cancer.
Methods
Eighty-two patients who underwent a potentially curative resection for stage III or high-risk stage II colon cancer were enrolled in this retrospective study. They received FOLFOX4 or modified FOLFOX6. The primary endpoint was disease-free survival.
Results
During the median follow-up of 37 months (range, 21 to 61 months), 14 patients experienced disease relapse. The disease-free survival rate at 3 years was 82.9%: 84.6% for stage II and 82.6% for stage III. At the time of the analysis, 8 patients were dead from recurrence. The probability of overall survival at 5 years was 74.5%: 90% for stage II and 74.6% for stage III. Grade 3 or 4 hematologic adverse events included neutropenia (40.2%), anemia (2.4%), and thrombocytopenia (1.2%). Gastrointestinal toxicities included grade 3 or 4 nausea (4.9%) and stomatitis (2.4%). Peripheral sensory neuropathy was observed in 81.7% of the patients during treatment. Of the 11 patients (13.4%) who had grade 3 peripheral sensory neuropathy during treatment, grade 3 symptoms were persistent in 3 patients with gait disturbance at the time of analysis. No treatment-related deaths were recorded.
Conclusion
Postoperative chemotherapy using the FOLFOX regimen, oxaliplatin in combination with 5-fluorouracil and leucovorin, is effective and tolerable in patients with stage III and high-risk stage II colon cancer.
doi:10.3393/jksc.2011.27.3.140
PMCID: PMC3145885  PMID: 21829769
Colonic neoplasms; Adjuvant chemotherapy; Oxaliplatin; FOLFOX protocol
13.  Predicting survival after pulmonary metastasectomy for colorectal cancer: previous liver metastases matter 
BMC Surgery  2010;10:17.
Background
Few patients with lung metastases from colorectal cancer (CRC) are candidates for surgical therapy with a curative intent, and it is currently impossible to identify those who may benefit the most from thoracotomy. The aim of this study was to determine the impact of various parameters on survival after pulmonary metastasectomy for CRC.
Methods
We performed a retrospective analysis of 40 consecutive patients (median age 63.5 [range 33-82] years) who underwent resection of pulmonary metastases from CRC in our institution from 1996 to 2009.
Results
Median follow-up was 33 (range 4-139) months. Twenty-four (60%) patients did not have previous liver metastases before undergoing lung surgery. Median disease-free interval between primary colorectal tumor and development of lung metastases was 32.5 months. 3- and 5-year overall survival after thoracotomy was 70.1% and 43.4%, respectively. In multivariate analysis, the following parameters were correlated with tumor recurrence after thoracotomy; a history of previous liver metastases (HR = 3.8, 95%CI 1.4-9.8); and lung surgery other than wedge resection (HR = 3.0, 95%CI 1.1-7.8). Prior resection of liver metastases was also correlated with an increased risk of death (HR = 5.1, 95% CI 1.1-24.8, p = 0.04). Median survival after thoracotomy was 87 (range 34-139) months in the group of patients without liver metastases versus 40 (range 28-51) months in patients who had undergone prior hepatectomy (p = 0.09).
Conclusion
The main parameter associated with poor outcome after lung resection of CRC metastases is a history of liver metastases.
doi:10.1186/1471-2482-10-17
PMCID: PMC2887792  PMID: 20525275
14.  Pathological serosa and node-based classification accurately predicts gastric cancer recurrence risk and outcome, and determines potential and limitation of a Japanese-style extensive surgery for Western patients: A prospective with quality control 10-year follow-up study 
British Journal of Cancer  2001;84(12):1602-1609.
UICC classification accurately predicts overall survival but not recurrence-risk. We report here data of overall and first site-specific recurrence following curative surgery useful for the development of recurrence-oriented preventive target therapies. Patients who underwent resection for gastric cancer were stratified according to curability of surgery [curative (R0) vs non-curative resection], extent of surgery [limited (D1) vs extended (D2) node dissection] and pathological nodal/serosal status. The intent-to-treat principle, log-rank test and Cox regression analysis were used for statistical analysis of time-to-event (recurrence, death) endpoints. Curative resection only produced a chance of cure whereas survival was very poor following non-curative resection (P < 0.0001). For D2 R0 subgroup of patients, a pathological serosa and a node state-based classification into three groups, proved to be of clinical implication. Risk of recurrence after a median follow-up of 92 months was low among patients with both serosa and node-negative cancer (first group; 11%), moderate among those with either serosa or node-positive cancer (second group; 53%) and very high among those with both serosa and node-positive cancer (third group; 83%). In multivariate analysis, the relative risks of recurrence and death from gastric cancer among patients in the second and third groups, as compared to those in the first, were 7.07 (95% CI, 2.36–21.17;P  = 0.0002) and 16.19 (95% CI, 5.76–45.54;P < 0.0001) respectively. First site-specific recurrence analysis revealed: low rate of loco-regional recurrence alone (12%), serosa state determinant factor of the site-recurrence (peritoneal for serosa-positive and haematogenous for serosa-negative cancers) and dramatic increase of all types of recurrence by the presence of nodal metastases. Our findings demonstrate that a pathological serosa- and node-based classification is very simple and predicts accurately site-specific recurrence-risks. Furthermore they reveal that risk of recurrence following curative D2 surgery alone is low for serosa- and node-negative cancers, but very high in serosa- and node-positive cancers suggesting the need for new therapeutic strategies in this subgroup of patients. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1720
PMCID: PMC2363675  PMID: 11401312
gastric cancer; extensive surgery; recurrence; survival; prognostic factors
15.  Study protocol of the SACURA trial: a randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer 
BMC Cancer  2012;12:281.
Background
Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy, but the usefulness of adjuvant chemotherapy for stage II colon cancer remains controversial. The major Western guidelines recommend adjuvant chemotherapy for “high-risk stage II” cancer, but this is not clearly defined and the efficacy has not been confirmed.
Methods/design
SACURA trial is a multicenter randomized phase III study which aims to evaluate the superiority of 1-year adjuvant treatment with UFT to observation without any adjuvant treatment after surgery for stage II colon cancer in a large population, and to identify “high-risk factors of recurrence/death” in stage II colon cancer and predictors of efficacy and adverse events of the chemotherapy. Patients aged between 20 and 80 years with curatively resected stage II colon cancer are randomly assigned to a observation group or UFT adjuvant therapy group (UFT at 500–600 mg/day as tegafur in 2 divided doses after meals for 5 days, followed by 2-day rest. This 1-week treatment cycle is repeated for 1 year). The patients are followed up for 5 years until recurrence or death. Treatment delivery and adverse events are entered into a web-based case report form system every 3 months. The target sample size is 2,000 patients. The primary endpoint is disease-free survival, and the secondary endpoints are overall survival, recurrence-free survival, and incidence and severity of adverse events. In an additional translational study, the mRNA expression of 5-FU-related enzymes, microsatellite instability and chromosomal instability, and histopathological factors including tumor budding are assessed to evaluate correlation with recurrences, survivals and adverse events.
Discussion
A total of 2,024 patients were enrolled from October 2006 to July 2010. The results of this study will provide important information that help to improve the therapeutic strategy for stage II colon cancer.
Trial registration
ClinicalTrials.gov NCT00392899.
doi:10.1186/1471-2407-12-281
PMCID: PMC3459783  PMID: 22769569
Colon cancer; Stage II; Adjuvant chemotherapy; UFT; Risk factor; Predictive factor; Prognostic factor; Surgery-alone; Randomized controlled trial; Japan
16.  Human Papillomavirus-16 Infection in Advanced Oral Cavity Cancer Patients Is Related to an Increased Risk of Distant Metastases and Poor Survival 
PLoS ONE  2012;7(7):e40767.
Background
Human papillomavirus (HPV) is an oncogenic virus causing oropharyngeal cancers and resulting in a favorable outcome after the treatment. The role of HPV in oral cavity squamous cell carcinoma (OSCC) remains ambiguous.
Objective
This study aimed to examine the effect of HPV infection on disease control among patients with OSCC following radical surgery with radiation-based adjuvant therapy.
Patients and Method
We prospectively followed 173 patients with advanced OSCC (96% were stage III/IV) who had undergone radical surgery and adjuvant therapy between 2004 and 2006. They were followed between surgery and death or up to 60 months. Surgical specimens were examined using a PCR-based HPV blot test. The primary endpoints were the risk of relapse and the time to relapse; the secondary endpoints were disease-free survival, disease-specific survival, and overall survival.
Results
The prevalence of HPV-positive OSCC was 22%; HPV-16 (9%) and HPV-18 (7%) were the genotypes most commonly encountered. Solitary HPV-16 infection was a poor predictor of 5-year distant metastases (hazard ratio, 3.4; 95% confidence interval, 1.4–8.0; P = 0.005), disease-free survival (P = 0.037), disease-specific survival (P = 0.006), and overall survival (P = 0.010), whereas HPV-18 infection had no impact on 5-year outcomes. The rate of 5-year distant metastases was significantly higher in the HPV-16 or level IV/V metastasis group compared with both the extracapsular spread or tumor depth ≥11-mm group and patients without risk factors (P<0.001).
Conclusions
HPV infections in advanced OSCC patients are not uncommon and clinically relevant. Compared with HPV-16-negative advanced OSCC patients, those with a single HPV-16 infection are at higher risk of distant metastases and poor survival despite undergoing radiation-based adjuvant therapy and require a more aggressive adjuvant treatment and a more thorough follow-up.
doi:10.1371/journal.pone.0040767
PMCID: PMC3395633  PMID: 22808258
17.  The influence of micrometastases on prognosis and survival in stage I-II colon cancer patients: the Enroute⊕ Study 
BMC Surgery  2011;11:11.
Background
The presence of lymph node metastases remains the most reliable prognostic predictor and the gold indicator for adjuvant treatment in colon cancer (CC). In spite of a potentially curative resection, 20 to 30% of CC patients testing negative for lymph node metastases (i.e. pN0) will subsequently develop locoregional and/or systemic metastases within 5 years. The presence of occult nodal isolated tumor cells (ITCs) and/or micrometastases (MMs) at the time of resection predisposes CC patients to high risk for disease recurrence. These pN0micro+ patients harbouring occult micrometastases may benefit from adjuvant treatment. The purpose of the present study is to delineate the subset of pN0 patients with micrometastases (pN0micro+) and evaluate the benefits from adjuvant chemotherapy in pN0micro+ CC patients.
Methods/design
EnRoute+ is an open label, multicenter, randomized controlled clinical trial. All CC patients (age above 18 years) without synchronous locoregional lymph node and/or systemic metastases (clinical stage I-II disease) and operated upon with curative intent are eligible for inclusion. All resected specimens of patients are subject to an ex vivo sentinel lymph node mapping procedure (SLNM) following curative resection. The investigation for micrometastases in pN0 patients is done by extended serial sectioning and immunohistochemistry for pan-cytokeratin in sentinel lymph nodes which are tumour negative upon standard pathological examination. Patients with ITC/MM-positive sentinel lymph nodes (pN0micro+) are randomized for adjuvant chemotherapy following the CAPOX treatment scheme or observation. The primary endpoint is 3-year disease free survival (DFS).
Discussion
The EnRoute+ study is designed to improve prognosis in high-risk stage I/II pN0 micro+ CC patients by reducing disease recurrence by adjuvant chemotherapy.
Trial Registration
ClinicalTrials.gov: NCT01097265
doi:10.1186/1471-2482-11-11
PMCID: PMC3123166  PMID: 21569373
18.  Sequential surgical resection of hepatic and pulmonary metastases from colorectal cancer 
Langenbeck's Archives of Surgery  2010;395(8):1129-1138.
Background
Resection of isolated hepatic or pulmonary metastases from colorectal cancer is widely accepted and associated with a 5-year survival rate of 25–40%. The value of aggressive surgical management in patients with both hepatic and pulmonary metastases still remains a controversial area.
Materials and methods
A retrospective review of 1,497 patients with colorectal carcinoma (CRC) was analysed. Of 73 patients identified with resection of CRC and, at some point in time, both liver and lung metastases, 17 patients underwent metastasectomy (resection group). The remaining 56 patients comprised the non-resection group. Primary tumour, hepatic and pulmonary metastases of all patients were surgically treated in our department of surgery, and the results are that of a single institution.
Results
The resection group had a 3-year survival of 77%, a 5-year survival of 55% and a 10-year survival of 18%; median survival was 98 months. The longest overall survival was 136 months; six patients are still alive. In the resection group, overall survival was significantly higher than in the non-resection group (p < 0.01). Independent from the chronology of metastasectomy, 5-year survival was 55% with respect to the primary resection, 28% with respect to the first metastasectomy and 14% with respect to the second metastasectomy. A disease-free interval (>18 months), stage III (UICC) and age (<70 years) were found to be significant prognostic factors for overall survival.
Conclusion
Our report strongly supports aggressive surgical therapy in patients with both hepatic and pulmonary metastases from CRC. Overall survival for surgically treated selected patients with both hepatic and pulmonary metastases from CRC is comparable to hepatic or pulmonary metastasectomy. Simultaneous metastases tend to have a poorer outcome than metachronous metastases.
doi:10.1007/s00423-010-0595-4
PMCID: PMC2974188  PMID: 20165954
Colorectal cancer; Lung metastases; Hepatic metastases; Metastasectomy
19.  Circulating tumor cells are associated with diffuse spread in stage IV colorectal cancer patients 
Cancer Biology & Therapy  2013;14(12):1174-1181.
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States when combining both genders. Circulating tumor cells (CTCs) are a prognostic marker for stage IV CRC patients. We hypothesized that CTC quantity varies among stage IV CRC populations.
Methods
Blood (7.5 ml) was prospectively collected from 90 stage IV CRC patients. EpCAM+ CTCs were analyzed with the FDA-approved CellSearch® system. CRC tumors were immunohistochemically stained for EpCAM expression. Imaging and clinicopathological data were collected. Statistical analysis was performed using correlation analysis, Kruskal–Wallis, Fisher exact, and log-rank test.
Results
CTCs were detectable in 36/90 (40%) patients. Diffuse CRC metastases were associated with the highest CTC prevalence (24/40 [60%]), in contrast to limited lung (2/19 [11%]) or liver (10/31 [32%]) metastases (P = 0.027). The overall mean CTC number was 2.0 (range 0–56.3). The mean CTC number in patients with diffuse metastases was significantly higher (3.7 [SEM ± 1.7, range 0–56.3]) than with limited lung metastases (0.1 [± 0.1; range 0–1]) or liver metastases (0.9 [± 0.3, range 0–7.0]) (P = 0.001). CRC tumors were consistently expressing EpCAM. CTC numbers did not correlate with serum CEA levels or other routine clinical parameters (P = N.S.). Patients with diffuse metastases had the poorest overall survival (P = 0.0042).
Conclusions
CRC patients with diffuse metastases have the highest number of CTCs, in contrast to limited metastases to the liver or lungs. Future studies should correlate CTCs with recurrence patterns in patients with resected CRC lung or liver metastases to investigate whether CTCs represent micrometastatic disease causing early relapses.
doi:10.4161/cbt.26884
PMCID: PMC3912041  PMID: 24153154
colorectal cancer; circulating tumor cells; metastasis
20.  A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment 
BMC Cancer  2010;10:545.
Background
About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.
Methods/design
The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life.
Conclusion
The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA.
Trial Registration
ClinicalTrials.gov Identifier NCT00394992
doi:10.1186/1471-2407-10-545
PMCID: PMC2958953  PMID: 20937118
21.  Results of emergency Hartmann's operation for obstructive or perforated left-sided colorectal cancer 
Background
Up to 15% of colorectal cancer (CRC) patients present with obstructive or perforated tumours, and require emergency surgery. The Hartmann's procedure (HP) provides the opportunity to achieve a potentially curative (R0) resection, while minimizing surgical trauma in poor-risk patients. The aim of this study was to assess the surgical (operative mortality), and oncological (long-term survival after curative resection) results of emergency HP for obstructive or perforated left-sided CRC.
Methods
A retrospective review of 50 patients who underwent emergency HP for perforated/obstructive CRC in our institution between 1995 and 2006.
Results
Median age of patients was 75 (range 22–95) years and the indications for HP were obstruction (32) and perforation (18 patients). Operative mortality and morbidity were 8% and 26% respectively. 35 patients (70%) were operated with a curative intent; in this group, overall 1-, 3- and 5-year survival rates were 80%, 54% and 40%. In univariate analysis, the presence of lymph node metastases was associated with poor 5-year survival (62% [Stage II] vs. 27% [Stage III], log-rank test, p = 0.02). Eleven patients (22%) had their operation reversed with a median delay of 225 (range 94–390) days. In this subgroup, two patients died from distant metastases, but there were no instances of loco-regional recurrence.
Conclusion
Hartmann's operation remains a good option to palliate symptoms in 30% of patients with left-sided CRC who are not candidates to a curative resection. For those who have a curative resection, the oncological outcome is acceptable, especially stage II patients, who appear to benefit the most from this surgical strategy.
doi:10.1186/1477-7819-6-90
PMCID: PMC2546403  PMID: 18721476
22.  Downregulation of miR-193a-5p correlates with lymph node metastasis and poor prognosis in colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(34):12241-12248.
AIM: To investigate the correlation of miR-193a-5p with lymph node metastasis and postoperative survival of colorectal cancer (CRC) patients.
METHODS: A total of 304 formalin-fixed, paraffin-embedded specimens (69 paired cancer and normal tissues, 55 primary tumors of stage III CRC and matched lymph nodes, and 56 primary tumors of stage II CRC) were included in this study. The relative expression levels of miR-193a-5p in the normal mucosa, primary cancer, and metastatic lymph node lesions were measured by quantitative real-time reverse transcriptase polymerase chain reaction. We evaluated the association of its expression with colorectal cancer lymph node metastasis, clinicopathological factors, and patient survival.
RESULTS: The relative expression level of miR-193a-5p was significantly lower in CRC tissues than in the normal mucosa (P = 0.0060). The expression levels of miR-193a-5p were lower in primary CRC tissues with lymph node metastases than in those without metastases (P = 0.0006), and decreased expression of miR-193a-5p correlated with advanced lymph node metastatic stage (P = 0.0007). Kaplan-Meier analysis showed that patients with low miR-193a-5p expression had decreased disease-free survival (DFS) (P = 0.0026) and poor overall survival (OS) (P = 0.0003). Interestingly, for the group of patients with lymph node metastases, miR-193a-5p expression was also related to survival. Patients with low miR-193a-5p expression had decreased DFS (P = 0.0262) and poor OS (P = 0.0230). Moreover, multivariate analysis indicated that downregulation of miR-193a-5p was an independent predictor of poor OS.
CONCLUSION: Downregulation of miR-193a-5p correlates with lymph node metastasis and poor survival of CRC. miR-193a-5p may be a useful biomarker for CRC diagnosis, metastasis and prognosis prediction.
doi:10.3748/wjg.v20.i34.12241
PMCID: PMC4161809  PMID: 25232258
miR-193a-5p; Colorectal cancer; Lymph node metastasis; Prognosis; Biomarker
23.  Outcomes Among Black Patients With Stage II and III Colon Cancer Receiving Chemotherapy: An Analysis of ACCENT Adjuvant Trials 
Background
Among patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials.
Methods
We assessed 14 611 patients (1218 black and 13 393 white) who received standardized adjuvant treatment in 12 randomized controlled clinical trials conducted in North America for resected stage II and stage III colon cancer between 1977 and 2002. Individual patient data on covariates and outcomes were extracted from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database. The endpoints examined in this meta-analysis were overall survival (time to death), recurrence-free survival (time to recurrence or death), and recurrence-free interval (time to recurrence). Cox models were stratified by study and controlled for sex, stage, age, and treatment to determine the effect of race. Kaplan–Meier estimates were adjusted for similar covariates to control for confounding. All statistical tests were two-sided.
Results
Black patients were younger than whites (median age, 58 vs 61 years, respectively; P < .001) and more likely to be female (55% vs 45%, respectively; P < .001). Overall survival was worse in black patients than whites (hazard ratio [HR] of death = 1.22, 95% confidence interval [CI] = 1.11 to 1.34, P < .001). Five-year overall survival rates for blacks and whites were 68.2% and 72.8%, respectively. When subsets defined by sex, stage, and age were analyzed, overall survival was consistently worse in black patients. Recurrence-free survival was worse in black patients than whites (HR of recurrence or death = 1.14, 95% CI = 1.04 to 1.24, P = .0045). Three-year recurrence-free survival rates in blacks and whites were 68.4% and 72.1%, respectively. In contrast, recurrence-free interval was similar in black and white patients (HR of recurrence = 1.08, 95% CI = 0.97 to 1.19, P = .15). Three-year recurrence-free interval rates in blacks and whites were 71.3% and 74.2%, respectively.
Conclusions
Black patients with resected stage II and stage III colon cancer who were treated with the same therapy as white patients experienced worse overall and recurrence-free survival, but similar recurrence-free interval, compared with white patients. The differences in survival may be mostly because of factors unrelated to the patients’ adjuvant colon cancer treatment.
doi:10.1093/jnci/djr310
PMCID: PMC3196480  PMID: 21997132
24.  Outcomes of rectal cancer with liver oligometastases 
Purpose
In patients with oligometastatic colorectal cancer to the liver, long term survival is possible and a multi-modality treatment approach may be considered. This is a report of a single institution experience of oligometastatic rectal cancer patients after treatment of the primary tumor and pelvic lymph nodes with extended course chemoradiation therapy.
Methods
Between 2004 and 2013, 26 oligometastatic rectal cancer patients with liver metastases were treated with extended course chemoradiation at our institution followed by total mesorectal excision (TME). Amongst these there were 17 men and 9 women. The mean age at the time of diagnosis was 59.8 years, with a range from 36 to 87 years of age. Eleven patients had metastases in other sites in addition to liver, and one patient in our cohort had lung metastasis with no liver metastasis. Kaplan-Meier method was used to generate overall survival (OS), progression free survival (PFS), distant metastases (DM) and local control (LC).
Results
OS rates were 95%, and 70% at 12 and 24 months respectively, with a mean survival time of 40.5 months. PFS rates were 91% and 36% at 12 and 24 months respectively, with a mean PFS time of 23.1 months. LC rates were 91% and 66% at 12 and 24 months respectively. DM rates were 0% and 61% at 12 and 24 months respectively. Finally, when censoring deaths, progression of liver metastases and distant progression, Kaplan-Meier analysis demonstrated five events of local failure.
Conclusions
This series demonstrated an OS of 70% at 24 months, with a mean survival of 40.5 months. Significantly, LC was only 66% despite the use of extended course chemoradiation and TME. This data suggests that many patients with oligometastatic rectal cancer will survive past 2 years, and that a substantial number will fail locally as well as distantly. Therefore, a multimodality approach is reasonable. Recent data suggests that a hypofractionated radiation regiment of 25 Gy in 5 Gy fractions allows an equivalent LC compared to extended course chemoradiation with 50.4 Gy in 1.8 Gy fractions. A short course of radiation may be more consistent with the goals of care of the oligometastatic rectal cancer patient who is at high risk of recurrence.
doi:10.3978/j.issn.2078-6891.2014.078
PMCID: PMC4226821  PMID: 25436119
Chemotherapy; radiation therapy; rectal cancer; oligometastases
25.  Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial 
The Lancet Oncology  2012;13(5):549-558.
Summary
Background
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
Methods
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
Findings
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90–1·06). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
Interpretation
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.
Funding
Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).
doi:10.1016/S1470-2045(12)70088-8
PMCID: PMC3398767  PMID: 22452894

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