Management Of Metastatic Colorectal Cancer Research Articles

Genetic polymorphisms associated with oxaliplatin-induced peripheral neurotoxicity in Japanese patients with colorectal cancer

Pharmacogenomic associations between severe oxaliplatininduced chronic peripheral neurotoxicity (OXCPN) (Grade 2 lasting for > 7 days or Grade 3) and 9 single nucleotide polymorphisms (SNPs) in 8 genes (TAC1, FOXC1, ITGA1, ACYP2, DLEU7, BTG4, CAMK2N1, and FARS2) were reported by the genomewide association study (GWAS) in Korean patients. The present study was designed to explore reliable predictors of OXCPN and thereby improve the management of metastatic colorectal cancer (CRC). We retrospectively investigated pharmacogenomic characteristics of OXCPN in 70 Japanese patients with CRC who received oxaliplatin-based chemotherapy and updated the results of our previous analysis of ERCC1 (C118T, rs11615 and C8092A, rs3212986) and GSTP1 (Ile105Val, rs1695) polymorphisms. Univariate analysis suggested potential associations of severe OXCPN with rs843748 in ACYP2 and rs17140129 in FARS2, as well as with the absence of diabetes mellitus (DM) (p = 0.056, 0.072, and 0.029, respectively). There was no association between severe OXCPN and any of the 7 other SNPs. Multiple logistic regression analysis showed that an increased risk of severe OXCPN was related to rs17140129 and the absence of DM (p = 0.034 and 0.030, respectively). On updated analysis, polymorphisms of ERCC1 (C118T, rs11615) and rs10486003 in TAC1 were associated with time to the onset of Grade 1 OXCPN (p = 0.024 and 0.049, respectively). Severe OXCPN is significantly related to rs17140129, found in the GWAS of Korean patients, in Japanese patients. Patients without DM are more likely to have OXCPN. The association between ERCC1 polymorphism and time to the onset of OXCPN was significant on updated analysis.

A case of the utilization of genomic information in the management of metastatic colorectal cancer.

444 Background: Anectodal success using genomic information to personalize and guide cancer therapy in rare tumours has been reported. This is a case report of the use of genomic information in the management of metastatic colorectal cancer. Methods: A 31 year old female presented with metastatic disease from the colon to the liver and retroperitoneal lymph nodes. She was treated with aspirin and 4 cycles of 5FU/Irinotecan/Bevacizumab before blood and liver biopsies were taken. Sections from the primary tissue embedded in paraffin were compared to metastatic disease in the liver and blood. Two platforms were used: a targeted deep sequencing of 46 genes via a cancer specific amplicon assay and whole genome sequencing and RNA sequencing followed by bioinformatics approaches were employed to identify genes with somatic variants, copy number variations, losses of heterozygosity, structural variation, and expression changes. Results: Genome sequencing followed by bioinformatics analysis detected ~100 somatic mutations, ~100 amplified genes with increased expression, and ~90 down-regulated genes with copy number loss in the metastasis. Other interesting observations included increased allelic frequencies in BRAF V600E, and SMAD4 R361C as well as high gene copy amplifications in VEGFA and MAGI from the primary to the metastasis, and lack of somatic mutation in KRAS. Conclusions: The upregulation of VEGF pathways from the primary compared to the metastasis suggests a significant shift in tumour biology likely as a result of the bevacizumab and COX-2 inhibition from aspirin; this may have implications when anti-VEGF therapy is withdrawn. The BRAF mutation and wild type KRAS status may suggest that combination of a BRAF inhibitor with EGFR inhibition is warranted. This information demonstrated the benefit of therapy on a genomic level and aided in determining possible future targets and modifications to conventional therapy.

BRAF, KRAS, and Phosphatidylinositol 3-Kinase in the Management of Metastatic Colorectal Cancer

Currently, the incorporation of monoclonal antibodies in metastatic colorectal cancer treatment is a reality. Mutated genes such as those encoding KRAS, BRAF, and phosphatidylinositol 3-kinase have been implicated in the lack of efficacy of epidermal growth factor receptor inhibitors. This review briefly describes each of these genes and their pathways, as well as their prevalence in colorectal cancer tumors. The main purpose of this article is to correlate KRAS, BRAF, and phosphatidylinositol 3-kinase individually in the management of metastatic colorectal cancer, their real influence as predictive and/or prognostic markers, and this correlation with treatment outcome. Lastly, it concisely points some of the possible resistance mechanisms for epidermal growth factor receptor inhibitors.

Metastatic colorectal cancer-prolonging overall survival with targeted therapies.

This review provides an updated overview of the management of metastatic colorectal cancer (CRC). With widespread application of personalized therapy based on specific patient and tumor characteristics, this will enable the oncologists to optimize overall survival while maintaining quality of life. The role of k-ras and braf testing in helping select systemic therapy that includes cetuximab or bevacizumab is clarified. Current management of metastatic CRC is based on careful attention to these finer points, explained in this article.

Granulomatous Lung Disease Requiring Mechanical Ventilation Induced by a Single Application of Oxaliplatin-Based Chemotherapy for Colorectal Cancer: A Case Report

Combined chemotherapeutic regimens in conjunction with oxaliplatin are considered safe and effective treatment options in the clinical management of metastatic colorectal cancer. A 62-year-old male patient with a metastatic rectal carcinoma developed a pulmonary reaction after the first application of the combined standard chemotherapy regimen (5-fluorouracil and sodium folinic acid as a 24 h infusion and oxaliplatin). Following the first dose of chemotherapy, the patient developed acute dyspnoea and fever. A computerised scan of the chest revealed bilateral pulmonary patchy consolidation. Despite high-dose empiric antibiotic and antimycotic treatment, no clinical improvement was seen. The patient's condition deteriorated, and he required invasive mechanical ventilation. Diagnostic thoracoscopic wedge resections were performed for further diagnosis. The histological workup revealed distinct granulomatous inflammation, but no microbial pathogens were to be found. Thereupon, a drug-induced reaction to chemotherapy was suspected and high-dose steroid treatment initiated. Subsequently, the patient's respiratory condition improved and he was extubated. The present case exemplifies the rare course of a bilateral pneumonia-like, drug-induced granulomatous reaction following a single application of oxaliplatin. In addition to the known side effects of oxaliplatin-containing combination chemotherapy, unexpected serious adverse events in the form of pulmonary toxicities should also be taken into account.

Novel Drugs Targeting the Epidermal Growth Factor Receptor and Its Downstream Pathways in the Treatment of Colorectal Cancer: A Systematic Review

Colorectal cancer is the second most common malignancy among men and women in the United States, and the 5-year survival rate remains poor despite recent advances in chemotherapy and targeted agents. The mainstay of therapy for advanced disease remains the cytotoxic chemotherapy including 5-FU, irinotecan, and oxaliplatin. The USFDA approval and introduction of targeted therapies, including cetuximab and panitumumab (monoclonal antibodies targeting the epidermal growth factor receptor (EGFR)) and bevacizumab (monoclonal antibody targeting the vascular epithelial growth factor (VEGF)), has improved the median survival of patients with metastatic colorectal cancer to around 24 months. Clearly, better and more efficacious drugs are needed, and target-specific agents remain the future of cancer treatment. On this front, rapid advances are being made, which are likely to change the future of the management of metastatic colorectal cancer. However, absence of specific biomarkers for the use of targeted agents, in the subset of population who will benefit from the treatment, remains a major drawback. In this paper, we review agents that are in phases 1 and 2 clinical development, specifically targeting the EGFR and its subsequent downstream pathways.

Cost-Minimization Analysis of the Treatment of Patients With Metastatic Colorectal Cancer in Greece

BackgroundIn 2008, colorectal cancer was the fourth most common cause of cancer-related death worldwide. Monotherapy with monoclonal antibodies directed against the epidermal growth factor receptor, such as cetuximab and panitumumab, has recently been introduced in the management of metastatic colorectal cancer (mCRC) patients. ObjectiveThe aim of this study was to conduct a cost-minimization analysis comparing panitumumab with cetuximab in the treatment of patients with epidermal growth factor receptor–expressing mCRC with nonmutated (wild-type) Kirsten rat sarcoma viral oncogene homolog in Greece. The perspective of analysis was that of payers (Social Security Sickness Fund) and the country's National Health Service (NHS). MethodsThe model was designed to contain probabilistic parameters to account for uncertainty and variation in these parameters. All resources consumed in local hospitals in the management of patients in each case were evaluated. Two analyses were performed: 1 evaluating cost per milligram and another evaluating cost per vial. ResultsFrom a payer perspective, the mean 20-week total cost per patient for panitumumab and cetuximab was: (1) per-milligram analysis: €16,349 and €18,242, respectively; and (2) per-vial analysis: €18,808 and €19,701. From the NHS perspective, the mean total costs per patient were slightly higher; however, the use of panitumumab was associated with a 17.7% and 12.4% cost reduction in per-milligram and per-vial analysis, respectively. The results of probabilistic models confirmed those of the deterministic analyses. ConclusionIn the Greek NHS and Social Security Sickness Fund setting, panitumumab monotherapy potentially constitutes a cost-saving option (versus cetuximab monotherapy) in the management of patients with mCRC and no mutation of Kirsten rat sarcoma viral oncogene homolog.

Lessons Learned from the Bevacizumab Experience

Bevacizumab is an important agent in the oncologic armamentarium, with activity in a broad spectrum of solid tumors. It has been approved in the management of metastatic colorectal cancer, non-small cell lung cancer, renal cancers, and recurrent glioblastoma multiforme. We reviewed the published literature and briefing documents of the US Food and Drug Administration that provided the data leading to approval or change in approval status. Bevacizumab initially received accelerated approval for the treatment of advanced breast cancer. However, lack of confirmatory data from additional clinical trials resulted in the loss of that indication. Both the expected and unexpected toxicities reported from clinical trials using bevacizumab have helped us to understand the drug's mechanism of action and to identify who are most likely to benefit from this important agent. The side effects of treatment may provide important information about drug mechanism and efficacy. Bevacizumab is clearly an important agent in oncology and is likely to become more significant once a clinical or pathological marker to predict its efficacy has been identified.

210P - Review of the Current Status of Kras Mutation Testing in France in 2011: The Flash-Kras Study

ABSTRACT Background KRAS testing is required before treatment initiation of cetuximab in the management of metastatic colorectal cancer (mCRC). The objective of the study was to examine the current situation in 2011 regarding KRAS testing in the initial management of mCRC. Methods This observational, retrospective, national study was carried out between March 28th and April 8th 2011. During this period 538 patients with mCRC were included across 160 french hospitals. The main objective was to assess the rate of KRAS testing in patients who had started first line (L1) treatment for mCRC. The secondary objectives were to describe the time taken and techniques used for KRAS testing, the possible reasons this test was not requested, to describe and analyse the clinical characteristics of the patients and the planned L1 treatments and those finally received. Results KRAS testing was carried out for 433 patients (81.1%) and not carried out for 101 patients (18.9%). The main reasons for not requesting the KRAS status were (several answers possible): anti-EGFR not prescribed (n = 58), candidate for surgery (n = 8), samples not useable (n = 5), age of the patient (n = 3), other (n = 24), data missing (n = 13). The genotyping results were available after a mean delay of 23.6 ± 28.2 days. The KRAS testing was requested by an oncologist (45.5%), a gastroenterologist (31%), a surgeon (11.2%), a pathologist (7.2%) or a multidisciplinary group (5.1%) approximately 15 days (-66.5;33.6) median (min; max) after the diagnosis of metastases, and 15 days (-66.9;3.7) median (min; max) before the start of L1 treatment. Result of KRAS status had not been received before the L1 treatment was chosen in 56.6% of the patients. For patients with wild-type KRAS status whose therapeutic management was modified after the result of KRAS testing (n = 108), this change was a prescription of an anti-EGFR in 77.8% of the cases. Conclusion The Flash-KRAS study is the first one to assess the current modalities of KRAS genotyping in France. It shows that in 2011 the KRAS test is an integral part of the management of patients with mCRC. Nonetheless, it shows disparities between regions in terms of time to obtain results, which need to be improved to be compatible with the therapeutic management. Disclosure M. Ducreux: Merck Serono. A. Lievre: Merck Serono. P. Artru: Merck Serono. M. Guiu: Merck Serono. J. Merlin: Merck Serono. J.C. Sabourin: Merck Serono. J. Viguier: Merck Serono. A. Seronde: Merck Serono. P. Laurent-Puig: Merck Serono. All other authors have declared no conflicts of interest.

Clinical Implications of Circulating Tumor Cells in Advanced Colorectal Cancer

It has previously been reported that circulating tumor cells (CTCs) can be a promising prognostic marker in the management of metastatic colorectal cancer (mCRC). CTCs are tumor-derived biomarkers circulating in the peripheral blood of patients, and are recognized as a valuable non-invasive alternative for detection of micro-metastases. Molecular and quantitative characterization of CTCs may also reveal potential novel therapeutic targets to further individualize cancer management. Additionally, CTC analysis combined with individual prognostic factors may enable prediction of therapy-specific response. This article discusses the significance of CTCs with particular focus on detection and clinical outcomes in mCRC.

MicroRNAs and response to anti-EGFR therapy in metastatic colorectal cancer.

e21002 Background: The discovery of KRAS gene as response predictive factor to anti-EGFR antibodies supposed a revolution in the pharmacological management of metastatic colorectal cancer (mCRC) patients (pts), since only KRAS native (WT) pts are possible responders (R) and susceptible to be treated with this targeted therapy. However, the appearance of non-responders (NR) among KRAS WT pts during the administration of anti-EGFR therapy has stimulated the research in additional predictive markers. Here, we explore the putative role of microRNA (miRNA) deregulation as predictive tool of response to anti-EGFR therapy in mCRC pts. Methods: Tissue samples of mCRC were obtained as formalin-fixed paraffin-embedded (FFPE) specimens from the archives of our institution, after obtaining informed consent of pts. Genomic DNA was extracted using Qiaamp DNA mini kit (Qiagen). For the mutational testing of KRAS gene, we use the TheraScreen KRAS PCR kit (DxS, Qiagen). miRNA-containing total RNA was extracted using Tripure (Roche). miRNA expression was analyzed by SYBR-green-based RT-qPCR in a LightCycler 480 (Roche) device using the Human Cancer RT2 miRNA PCR array (SABiosciences, Qiagen). First data analysis was performed with the application provided by supplier (SABiosciences, Qiagen). Bioinformatic analyses were performed in miRBase 18, TargetScanHuman 6.0 and TarBase 6.0 databases. Additional statistical analyses were performed on R 2.14 (R Foundation), SPSS 19 (IBM) and Prism (GraphPad). Results: We analyze 9 primary colon cancer and 3 non-matched normal adjacent (NAT) tissues. Tumor samples corresponded to 6 KRAS WT and 3 KRAS mutated pts. Among KRAS WT pts, 3 had shown response to anti-EGFR antibodies and 3 did not. Samples were analyzed in duplicate for the expression of 88 cancer-related miRNAs. We found 22 miRNAs significantly (p<0.01) upregulated (>4-fold) when comparing KRAS WT NR versus R pts. From these 22 miRNAs, we detected only 6 when we search in databases for experimentally tested or predicted miRNA interactions with KRAS. Conclusions: We found a miRNA signature which could be utilized as response predictive tool for anti-EGFR therapy in mCRC pts. Further analysis will be necessary to establish the performance of this signature.

Review of the current status of KRAS mutation testing in France in 2011: The Flash-KRAS study.

e14129 Background: KRAS testing is required before treatment initiation of cetuximab in the management of metastatic colorectal cancer (mCRC). The objective of the study was to examine the current situation in 2011 regarding KRAS testing in the initial management of mCRC. Methods: This observational, retrospective, national study was carried out between March 28th and April 8th 2011. During this period 538 patients with mCRC were included across 160 french hospitals. The main objective was to assess the rate of KRAS testing in patients who had started first line (L1) treatment for mCRC. The secondary objectives were to describe the time taken and techniques used for KRAS testing, the possible reasons this test was not requested, to describe and analyse the clinical characteristics of the patients and the planned L1 treatments and those finally received. Results: KRAS testing was carried out for 433 patients (81.1%) and not carried out for 101 patients (18.9%). The main reasons for not requesting the KRAS status were (several answers possible): anti-EGFR not prescribed (n=58), candidate for surgery (n=8), samples not useable (n=5), age of the patient (n=3), other (n=24), data missing (n=13). The genotyping results were available after a mean delay of 23.6 ± 28.2 days. The KRAS testing was requested by an oncologist (45.5%), a gastroenterologist (31%), a surgeon (11.2%), a pathologist (7.2%) or a multidisciplinary group (5.1%) approximately 15 days (-66.5;33.6) median (min ; max) after the diagnosis of metastases, and 15 days (-66.9;3.7) median (min ; max) before the start of L1 treatment. Result of KRAS status had not been received before the L1 treatment was chosen in 56.6% of the patients. For patients with wild-type KRAS status whose therapeutic management was modified after the result of KRAS testing (n=108), this change was a prescription of an anti-EGFR in 77.8% of the cases. Conclusions: The Flash-KRAS study is the first one to assess the current modalities of KRAS genotyping in France. It shows that in 2011 the KRAS test is an integral part of the management of patients with mCRC. Nonetheless, it shows disparities between regions in terms of time to obtain results, which need to be improved to be compatible with the therapeutic management.

Cetuximab in metastatic colorectal cancer

Management of metastatic colorectal cancer has evolved in the last 10 years, with the availability of targeted therapies resulting in improvement in quality of life and overall survival. Cetuximab is a chimeric monoclonal antibody that binds to the EGF receptor, and the net effects are inhibition of tumor growth, invasion, angiogenesis and metastasis. Cetuximab binding to the EGF receptor is also known to augment the effects of chemotherapy and radiotherapy. Only tumors expressing wild-type KRAS respond to cetuximab and improvements in progression-free survival and overall survival are seen, whereas patients with mutant KRAS are considered to be resistant. Cetuximab is currently available worldwide for use as monotherapy or in combination with chemotherapy in first-, second- or third-line settings in metastatic colorectal cancer patients with wild-type KRAS.

Use of KRAS codon 13 mutations to predict response to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma.

453 Background: The predictive role of KRAS mutation in therapeutic management of metastatic colorectal cancer has been much investigated. However, the association between KRAS mutations and rectal cancer response to neoadjuvant chemoradiation therapy (CRT) remains unclear. Our objectives were to determine the incidence of KRAS mutations in patients with rectal cancer and identify potential correlations with response to CRT. Methods: Patients with Stage II-III rectal cancer (n=148) from a multicenter prospective clinical trial were assessed. DNA was extracted from pretreatment tumor biopsies; and genotyping of KRAS was completed by PCR and direct sequencing. All patients underwent pre-operative CRT followed by surgery; and treatment response was evaluated by a pathologist. Surgical specimens without evidence of residual disease were deemed to have a pathologic complete response (pCR). Results: Overall, 60 of 148 (40.5%) patients had KRAS mutation. Breakdown of the different KRAS mutations revealed that 40 (66.7%) mutations occurred in codon 12, 12 (20.0%) in codon 13, 5 (8.3%) in codon 61, and 3 (5.0%) in other locations. When examining the relationship between KRAS and CRT response, we observed that detection of any KRAS mutation was associated with a decreased rate of pCR compared to wild-type KRAS (13.3% vs. 33.0%, respectively; p=0.007). More specifically, patients with KRAS codon 13 mutations did not respond to CRT compared to non-codon 13 mutations (p=0.037). In contrast, the detection of codon 12 or codon 61 mutations was not associated with response to CRT ( Table ). Conclusions: Patients with KRAS mutation have lower response rates to CRT compared to patients with wild-type KRAS. However, our results indicate that this association does not apply to all KRAS mutations, rather to KRAS codon 13 mutation alone. Thus, these data are the first to show that patients with KRAS codon 13 mutations may not derive pCR from neoadjuvant CRT. [Table: see text]

Comparative effectiveness of chemotherapy in elderly patients with metastatic colorectal cancer.

463 Background: The management of metastatic colorectal cancer (mCRC) has evolved considerably with advances in chemotherapeutic agents that have led to improved outcomes. Less is known about the benefits of newer agents in the real-world setting. The objective of this study was to evaluate treatment patterns and survival in older, demographically diverse mCRC patients. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 5931 stage IIIB, IIIC and IV CRC patients diagnosed between 1/1/ 2000 – 12/31/2007, who were >66 years, enrolled in Medicare Parts A and B, and received first-line treatment with 5FU/LV (n=2907), CAP (capecitabine; n=963), FOLFOX (n=1856) or CAPOX (CAP + oxaliplatin; n=205). Date of last follow-up was 12/31/2009. Statistical comparisons were made between 5FU/LV vs. CAP and FOLFOX vs. CAPOX. Cox regression with backward elimination estimated the relative risk of death, adjusting for demographic and clinical factors. Results: Compared to 5FU/LV, patients treated with CAP were older (>80 years) at diagnosis (36% vs. 22%; p<.0001) and more likely female (59% vs. 53%; p=.0025), while patients receiving CAPOX were older (>80 years: 12% vs 8%; p<0.05) compared to FOLFOX. The mean time to chemotherapy initiation after diagnosis was similar between CAP and 5FU/LV (76 vs. 71 days) and between FOLFOX and CAPOX (75 vs. 70 days). The mean duration of treatment was longer for 5FU/LV (144 days) vs. CAP (122 days; p<.0001) and comparable between CAPOX (144 days) and FOLFOX (150 days; p=0.2139). The incidence of adverse events (AE) within 180 days after initiation of treatment were higher in patients treated with 5FU/LV (37%) vs. CAP (9%); p<.0001 and in FOLFOX (58%) vs. CAPOX (44%); p<0.0001. In multivariate analysis there were no significant differences in risk of death between CAP and 5FU/LV, and between CAPOX and FOLFOX ( table ). Conclusions: Overall survival was comparable between CAP and 5FU/LV and between CAPOX and FOLFOX with fewer AEs associated with CAP and CAPOX. This provides real-world confirmation of clinical trial data. [Table: see text]

Development of a Research Agenda for the Management of Metastatic Colorectal Cancer: Proceedings from a Multidisciplinary Research Consensus Panel

Colorectal cancer (CRC), the second leading cause of cancer death in the United States, occurs in an estimated more than 145,000 patients annually, with almost 50,000 deaths each year. Metastatic liver disease is the cause of death in the majority of them (1,2). Liver-only metastases affect up to one half of patients with CRC (1,2), with approximately 15% (range, 8%–26%) presenting synchronously (3,4) and an additional 15% found metachronously during the next 5 years (3). Colorectal liver metastases (CLMs) are resectable in 20%–25% of patients only; some of the remaining 75%–80% may benefit from “downsizing” therapy, which can result in 10%–20% more patients becoming resectable. Overall survival rates in patients with either primarily or secondarily resectable CLMs can be as high as 58% at 5 years and 15% at 10 years (5,6). Current front-line treatments available to improve downsizing and resectability include systemic therapies (chemotherapy with or without bevacizumab or cetuximab) and pre-operative portal vein embolization (PVE). Other approaches include local ablation therapies, regional intraarterial therapies with embolization (transcatheter arterial chemoembolization, or radio-embolization by selective internal radiation therapy with Yttrium 90-loaded microspheres) or infusion (ie, hepatic arterial infusion [HAI] pump chemotherapy), and external beam radiation therapy (RT). The role of these liver-targeted therapies to promote conversion from unresectable to resectable liver disease remains an evaluation in progress. For the majority of patients with unresectable CRC liver metastases, standard of care is first- and second-line triplet chemotherapy, which is associated with a median survival of 18–24 months (7–10). Multiple single-institution retrospective reports suggest the potential for improvement in survival time by the addition of liver-directed therapies such as chemoembolization, HAI, or radioembolization. This has not been prospectively evaluated in controlled trials, but could potentially represent a major development in Interventional Oncology (IO). The Society of Interventional Radiology (SIR) Foundation has identified the management of metastatic CRC (mCRC) as an emerging inter-ventional radiologic research priority and convened a Research Consensus Panel (RCP) Meeting on October 3, 2011 to establish a prioritized research agenda. This article reports the proceedings from this meeting.

Therapeutic potential of surgery for metastatic colorectal cancer

Evidence of the clinical benefit of surgery or metastasectomy for metastatic colorectal cancer to disease sites including the liver, lung, peritoneum, and pelvis as a potentially curative option is now available in the literature. The oncologic outcome of this treatment strategy achieves 5-year survival ranging between 20% and 50%. These survival gains have not been previously observed in the management of metastatic colorectal cancer. Treatment of potential surgical candidates requires a combined modality approach with systemic therapies to achieve macroscopic tumor removal and microscopic targeting of tumor deposits to achieve disease control. In nonsurgical candidates, systemic therapy, radiation therapy, and interventional oncology procedures may potentially facilitate sufficient disease downstaging for surgery. The purpose of this article is to provide a comprehensive review of the therapeutic advances in the surgical management of metastatic colorectal cancer.

Directions for further improvements of treatment of metastatic colorectal cancer

It is clear that over the last 10 years, significant progress has been achieved with surgical management of metastatic colorectal cancer (mCRC). Today all mCRC patients should be evaluated by a mul...

Corrigendum: Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective

In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the “gold standard”—the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer.

Corrigendum: Progression-Free Survival in Advanced Ovarian Cancer: A Canadian Review and Expert Panel Perspective

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.