Strategies for the delay of surgery in the management of resectable hepatobiliary malignancies during the COVID-19 pandemic.

Objective: We aimed to review data about delaying strategies for the management of hepatobiliary cancers requiring surgery during the covid-19 pandemic. Background: Given the covid-19 pandemic, many jurisdictions, to spare resources, have limited access to operating rooms for elective surgical activity, including cancer, thus forcing deferral or cancellation of cancer surgeries. Surgery for hepatobiliary cancer is high-risk and particularly resource-intensive. Surgeons must critically appraise which patients will benefit most from surgery and which ones have other therapeutic options to delay surgery. Little guidance is currently available about potential delaying strategies for hepatobiliary cancers when surgery is not possible. Methods: An international multidisciplinary panel reviewed the available literature to summarize data relating to standard-of-care surgical management and possible mitigating strategies to be used as a bridge to surgery for colorectal liver metastases, hepatocellular carcinoma, gallbladder cancer, intrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma. Results: Outcomes of surgery during the covid-19 pandemic are reviewed. Resource requirements are summarized, including logistics and adverse effects profiles for hepatectomy and delaying strategies using systemic, percutaneous and radiation ablative, and liver embolic therapies. For each cancer type, the long-term oncologic outcomes of hepatectomy and the clinical tools that can be used to prognosticate for individual patients are detailed. Conclusions: There are a variety of delaying strategies to consider if availability of operating rooms decreases. This review summarizes available data to provide guidance about possible delaying strategies depending on patient, resource, institution, and systems factors. Multidisciplinary team discussions should be leveraged to consider patient- and tumour-specific information for each individual case.

Sequence of therapy and survival in patients with advanced pancreatic neuroendocrine tumours.

Background: Pancreatic neuroendocrine tumours (pnets) often present as advanced disease. The optimal sequence of therapy is unknown. Methods: Sequential patients with advanced pnets referred to BC Cancer between 2000 and 2013 who received 1 or more treatment modalities were reviewed, and treatment patterns, progression-free survival (pfs), and overall survival (os) were characterized. Systemic treatments included chemotherapy, small-molecule therapy, and peptide receptor radionuclide therapy. Results: In 66 cases of advanced pnets, median patient age was 61.2 years (25%-75% interquartile range: 50.8-66.2 years), and men constituted 47% of the group. First-line therapies were surgery (36%), chemotherapy (33%), and somatostatin analogues (32%). Compared with first-line systemic therapy, surgery in the first line was associated with increased pfs and os (20.6 months vs. 6.3 months and 100.3 months vs. 30.5 months respectively, p < 0.05). In 42 patients (64%) who received more than 1 line of therapy, no difference in os or pfs between second-line therapies was observed. Conclusions: Our results confirm the primary role of surgery for advanced pnets. New systemic treatments will further increase options.

A retrospective observational study to estimate the attrition of patients across lines of systemic treatment for metastatic colorectal cancer in Canada.

Background: Selection and sequencing of treatment regimens for individual patients with metastatic colorectal cancer (mcrc) is driven by maintaining reasonable quality of life and extending survival, as well as by access to and cost of therapies. The objectives of the present study were to describe, for patients with mcrc, attrition across lines of systemic therapy, patterns of therapy and their timing, and KRAS status. Methods: A retrospective chart review at 6 Canadian academic centres included sequential patients who were diagnosed with mcrc from 1 January 2009 onward and who initiated first-line systemic treatment for mcrc between 1 January and 31 December 2009. Death was included as a competing risk in the analysis. Results: The analysis included 200 patients who started first-line therapy. The proportions of patients who started second-, third-, and fourth-line systemic therapy were 70%, 30%, and 15% respectively. Chemotherapy plus bevacizumab was the most common first-line combination (66%). The most common first-line regimen was folfiri plus bevacizumab. KRAS testing was performed in 103 patients (52%), and 38 of 68 patients (56%, 19% overall) with confirmed KRAS wild-type tumours received an epidermal growth factor receptor inhibitor (egfri), which was more common in later lines. Most KRAS testing occurred after initiation of second-line therapy. Conclusions: In the modern treatment era, a high proportion of patients receive at least two lines of therapy for mcrc, but only 19% receive egfri therapy. Earlier KRAS testing and therapy with an egfri might allow a greater proportion of patients to access all 5 active treatment agents.

Prognostic effect of sidedness in early stage versus advanced colon cancer.

BACKGROUND AND AIMS: The prognostic effect of sidedness in colorectal cancer has been evaluated in numerous prospective and retrospective cohorts. Most of these have reported overall survival data; there is scant relapse-free survival data in early stage disease. This study aimed to determine the effect of tumor sidedness in survival in early stage and relapsed colon cancer. METHODS: Patients with stage I-III colorectal cancer were identified from the BC Cancer Agency Gastrointestinal Cancer Outcomes Unit. Survival analysis by stage and sidedness was compared with the log-rank test. Baseline characteristics were controlled by multivariate Cox-proportional hazard models. In relapsed patients, bevacizumab and EGFR inhibitor (EGFRI) treatments were included and tested for interaction. RESULTS: Among 5378 patients with stage I-III colon cancer, patients with right-sided stage II tumors experienced better relapse-free survival compared with those with left-sided tumors; right-sidedness was not prognostic for RFS in stage III disease. When survival was considered in patients who relapsed, right-sided tumors had inferior survival after relapse in both stage II and stage III tumors. At relapse, right-sided outcomes were inferior regardless of biologic therapy. An interaction test revealed a significant association between sidedness and survival with EGFRIs. CONCLUSIONS: In this large, population-based study, right-sided presentation has a significant prognostic impact: in early stage, right-sidedness is favorably prognostic among stage II tumors and not prognostic in stage III disease. After relapse, right- sidedness is associated with an inferior prognosis, regardless of initial stage of presentation. Colon tumor sidedness is independently prognostic and may be considered in treatment assignment for both early stage and advanced disease.

Patterns of practice with third-line anti-EGFR antibody for metastatic colorectal cancer.

BACKGROUND: Therapy with anti-epidermal growth factor receptor (egfr) monoclonal antibody improves outcomes for patients with metastatic colorectal cancer (mcrc) in the first-, second-, and third-line trial settings. In British Columbia, the use of egfr inhibitors (egfris) is confined to third-line therapy, which might lower the proportion of patients who receive this therapy. The objective of the present study was to describe egfri treatment patterns when those agents are limited to the third-line setting. The results will inform decisions about optimal use of egfri agents, including earlier in the course of therapy for metastatic disease. METHODS: All patients with newly diagnosed mcrc who were referred to BC Cancer Agency clinics in 2009 were included in the study. Prognostic and treatment information was prospectively collected; KRAS test results were determined by chart review. RESULTS: The study included 443 patients with a median age of 66 years. For the 321 patients who received systemic therapy, median survival was 22.3 months. Of the 117 patients who were treated with 5-fluorouracil, oxaliplatin, and irinotecan, and who were potentially eligible for egfri therapy, 90% (105 patients) were tested for KRAS status. Of the 60 patients with KRAS wild-type tumours, 82% (49 patients) received egfri therapy. CONCLUSIONS: When egfri therapy is limited to the third-line setting, only a small proportion of patients receive such therapy, with death and poor performance status preventing its use in the rest. Availability of egfri in earlier lines of therapy could increase the proportion of patients treated with all active systemic agents.

Consensus statement: the 16th Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Saskatoon, Saskatchewan; September 5-6, 2014.

The 16th annual Western Canadian Gastrointestinal Cancer Consensus Conference was held in Saskatoon, Saskatchewan, September 4-5, 2014. The Consensus Conference is an interactive, multidisciplinary event attended by health care professionals from across western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) involved in the care of gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.

Factors associated with delayed time to adjuvant chemotherapy in stage iii colon cancer.

BACKGROUND: Adjuvant chemotherapy started more than 56 days after colon cancer resection has been associated with lesser overall survival among patients with stage iii colon cancer. The objective of the present population-based study was to determine, in referred patients with resected stage iii colon cancer, factors associated with delayed time to adjuvant chemotherapy (ttac), defined as more than 56 days from the date of surgery. METHODS: Eligible patients had been diagnosed with stage iii colon cancer and had received at least 1 cycle of adjuvant chemotherapy at one of the four regional cancer treatment sites during 2008-2009. Prognostic and treatment information was prospectively collected through the BC Cancer Agency's GI Cancers Outcomes Unit, and Charlson comorbidity score was retrospectively determined by chart review. Chi-square and Wilcoxon rank-sum tests were used to measure associations between the timing of adjuvant chemotherapy and select prognostic and treatment variables. RESULTS: Median ttac from surgery for the 395 included patients was 58 days, with 54% of the patients receiving adjuvant chemotherapy beyond the recommended 56 days. On multivariate analysis, only treatment at the highest-volume site was independently associated with delayed ttac. Comorbidity index, age, performance status, T stage, tumour location, and oral chemotherapy (compared with intravenous) were not independently associated with delayed ttac. Delays were observed during each interval associated with the patient's transition from surgery to first cycle of adjuvant chemotherapy. CONCLUSIONS: More than half the patients failed to receive adjuvant chemotherapy within the recommended ttac of 56 days. Delayed ttac was associated with process-related delays rather than with patient- or disease-related factors. Efforts to improve timely referral, triage of consultations, and chemotherapy wait lists are required.

Panitumumab monotherapy compared with cetuximab and irinotecan combination therapy in patients with previously treated KRAS wild-type metastatic colorectal cancer.

BACKGROUND: The survival benefit for single-agent anti-epidermal growth factor receptor (egfr) therapy compared with combination therapy with irinotecan in KRAS wildtype (wt) metastatic colorectal cancer (mcrc) patients in the third-line treatment setting is not known. The objective of the present study was to describe the characteristics of, and to compare survival outcomes in, two cohorts of patients treated with either singleagent panitumumab or combination therapy with cetuximab and irinotecan. METHODS: The study enrolled patients with KRAS wt mcrc previously treated with both irinotecan and oxaliplatin who had received either panitumumab or combination cetuximab-irinotecan before April 1, 2011, at the BC Cancer Agency (bcca). Patients were excluded if they had received anti-egfr agents in earlier lines of therapy. Data were prospectively collected, except for performance status (ps), which was determined by chart review. Information about systemic therapy was extracted from the bcca Pharmacy Database. RESULTS: Of 178 eligible patients, 141 received panitumumab, and 37 received cetuximab-irinotecan. Compared with patients treated with cetuximab-irinotecan, panitumumab-treated patients were significantly older and more likely to have an Eastern Cooperative Oncology Group (ecog) ps of 2 or 3 (27.7% vs. 2.7%, p = 0.001). Other baseline prognostic variables and prior and subsequent therapies were similar. Median overall survival was 7.7 months for the panitumumab group and 8.3 months for the cetuximab-irinotecan group. Multivariate analysis demonstrated that survival outcomes were similar regardless of the therapy selected (hazard ratio: 1.28; p = 0.34). An ecog ps of 2 or 3 compared with 0 or 1 was the only significant prognostic factor in this treatment setting (hazard ratio: 3.37; p < 0.01). CONCLUSIONS: Single-agent panitumumab and cetuximab-irinotecan are both reasonable third-line treatment options, with similar outcomes, for patients with chemoresistant mcrc.

Tumor markers in metastatic breast cancer subtypes: frequency of elevation and correlation with outcome.

BACKGROUND: Little is known about the correlations between tumor markers (TMs), breast cancer subtypes, site(s) of metastasis and prognosis. METHODS: Women diagnosed with metastatic breast cancer were included. Breast cancer subtypes were defined as LuminalA, LuminalB, LuminalHer2, Her2, Basal and non-Basal triple negative (TN). Levels of elevation of TM values [cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA 125)] among the subtypes were analyzed. Site(s) of metastasis and outcomes were captured. RESULTS: Eight hundred and ten patients were included. Luminal subtypes were associated with an elevation in at least one TM: 90.8% of LuminalHer2+, 90% of LuminalB and 88.6% of LuminalA. TMs were less frequently elevated in Basal (74.1%) and non-Basal TN (71.4%) cases (P < 0.001). CA 15-3 was the most frequently elevated TM. The incidence of TM elevation did not differ between patients with solitary versus multiple metastatic sites. Breast cancer-specific survival (BCSS) was significantly worse for patients with elevated TMs (P = 0.001). CONCLUSIONS: TM elevation of CA 15-3, CEA and/or CA 125 was documented in the majority of patients with metastatic breast cancer with CA 15-3 occurring most commonly. Luminal subtypes expressed elevated TMs significantly more frequently compared with the non-Luminal groups. TM elevation was not different between the different sites of metastasis. Overall, elevated TMs predicted a worse BCSS.

Is breast-conserving therapy a safe option for patients with tumor multicentricity and multifocality?

BACKGROUND: We compared outcomes after breast-conserving therapy (BCT) and mastectomy in multicentric (MC)/multifocal (MF) versus unifocal breast cancer. PATIENTS AND METHODS: Women with stage I-II disease were classified as having unifocal or MC/MF disease. MC/MF and other prognostic factors were compared using binary logistic regression analysis. Univariate and multivariate analyses (MVAs) for relapse were carried out using cumulative incidence curves and Fine and Gray regression models. For the BCT group, matched analysis was added. RESULTS: Median follow-up was 7.9 years, 11 983 having BCT (unifocal: 11 683, MC/MF: 300) and 7771 having mastectomy (unifocal: 6884, MC/MF: 887). MC/MF patients treated with BCT were 50-69 years old, free of extensive ductal carcinoma in situ (DCIS), and had smaller tumors. The cumulative 10-year local recurrence rates among unifocal and MC/MF disease were 4.6% [95% confidence interval (CI) 4.1% to 5.0%] versus 5.5% (95% CI 2.6% to 9.9%) for the BCT group, P = 0.76 and 5.8% (95% CI 5.2% to 6.5%) versus 6.5% (95% CI 4.7% to 8.7%) for the mastectomy group, P = 0.77. MC/MF was not a significant factor for relapse or survival on MVA. In the matched analysis, relapse rates were similar in the unifocal and MC/MF groups, P = 0.60. CONCLUSION: BCT is a reasonable option in selected MC/MF cases, particularly those women aged 50-69 years old with small (<1 cm) MF tumors and without an extensive DCIS component.

Consensus recommendations for the use of anti-egfr therapies in metastatic colorectal cancer.

In January 2010, a panel of Canadian oncologists with particular expertise in colorectal cancer (crc) gathered to develop a consensus guideline on the use of therapies against the epidermal growth factor receptor (egfr) in the management of metastatic crc (mcrc). This paper uses a case-based approach to summarize the consensus recommendations developed during that meeting.These are the consensus recommendations:Testing for the KRAS status of the tumour should be performed as soon as an egfr inhibitor is being considered as an option for treatment.Anti-egfr therapies are not recommended for the treatment of patients with tumours showing mutated KRAS status.For a patient with wild-type KRAS and an Eastern Cooperative Oncology Group status of 0-2, whose mcrc has previously been treated with a fluoropyrimidine, irinotecan, and oxaliplatin, switching to an egfr inhibitor is a recommended strategy.Cetuximab, cetuximab plus irinotecan, and panitumumab are all options for third-line therapy in patients with wild-type KRAS, provided that tolerability is acceptable.

Consensus recommendations for the diagnosis and management of well-differentiated gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National Expert Group.

Well-differentiated neuroendocrine tumours (nets-previously called "carcinoid tumours") are relatively rare tumours originating from the diffuse neuroendocrine system; they are found most often in the bronchial or gastrointestinal systems. In Canada, gastroenterohepatic NETS represent less than 0.25% of oncology cases. Because of the relative rarity of these tumours, diagnostic and therapeutic approaches vary and are often based on individual physician experience. A number of European and North American groups have developed consensus guidelines for the diagnosis and management of well-differentiated gastroenterohepatic NETS, and in 2006, Canadian consensus guidelines were published by a Canadian expert group. The updated and expanded current Canadian guidelines are based on a consensus meeting held in Paris, France, in 2008 and are based on the most current literature.

Does HER2 status influence locoregional failure rates in breast cancer patients treated with mastectomy for pT1-2pN0 disease?

BACKGROUND: The impact of HER2 overexpression on the locoregional control of breast cancer is controversial. PATIENTS AND METHODS: Data on 906 women diagnosed with pT(1-2)pN(0) breast cancer from 1986 to 1992 with known HER2 status and treated with a modified radical mastectomy without adjuvant radiotherapy or adjuvant trastuzumab were analyzed with respect to local relapse-free survival (LRFS), regional relapse-free survival (RRFS) and distant relapse-free survival (DRFS). Log-rank statistics were used to compare 10-year Kaplan-Meier curves of LRFS, RRFS and DRFS in HER2+ and HER2- patients. RESULTS: Median follow-up was 12.8 years. HER2+ patients had a worse DRFS (P = 0.028) but there was no statistically significant difference in LRFS or RRFS between HER2+ and HER2- patients (P = 0.32 and 0.24 for LRFS and RRFS, respectively). Ten-year LRFS estimates among HER2+ patients was 91.3% and 86.9% for HER2- patients. Ten-year RRFS estimates for HER2+ and HER2- patients were 88.0% and 93.0%, respectively. CONCLUSION: HER2 overexpression was not associated with higher local or regional recurrence risk in subjects with pT(1-2)pN(0) breast cancer following mastectomy and nodal dissection after a median follow-up of >12 years.

Predictors of positive radial margin status in a population-based cohort of patients with rectal cancer.

BACKGROUND: Surgical margin status is an important predictor of risk of relapse among patients with rectal cancer. METHODS: Patients referred to the British Columbia Cancer Agency for consideration of adjuvant therapy for rectal adenocarcinoma were included. Predictors of margin positivity were determined from uni- and multivariate analysis. RESULTS: Among 340 patients, 83% had negative resection margins. In 268 patients with resectable tumours, a significantly higher rate of margin positivity was observed in low rectal tumours (32.2%) as compared with mid-rectal (3.9%) and high rectal (14.3%) tumours. Among 59 patients with locally advanced rectal cancer treated with preoperative radiation (with or without chemotherapy), 32% with low tumours had margin positivity. Of patients with T4 tumours, 50% (11/22) had a positive resection margin. CONCLUSIONS: In a population cohort, distal-third rectal location, locally advanced presentation, and T4 cancer represent subgroups for whom further improvement in therapy is required.

SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2'deoxycytidine to increase SPARC expression and improve therapy response.

Poor clinical outcomes in cancer can often be attributed to inadequate response to chemotherapy. Strategies to overcome either primary or acquired chemoresistance may ultimately impact on patients' survival favourably. We previously showed that lower levels of SPARC were associated with therapy-refractory colorectal cancers (CRC), and that upregulating its expression enhances chemo-sensitivity resulting in greater tumour regression in vivo. Here, we examined aberrant hypermethylation of the SPARC promoter as a potential mechanism for repressing SPARC in CRCs and whether restoration of its expression with a demethylating agent 5-Aza-2'deoxycytidine (5-Aza) could enhance chemosensitivity. Initially, the methylation status of the SPARC promoter from primary human CRCs were assessed following isolation of genomic DNA from laser capture microdissected specimens by direct DNA sequencing. MIP101, RKO, HCT 116, and HT-29 CRC cell lines were also used to evaluate the effect of 5-Aza on: SPARC promoter methylation, SPARC expression, the interaction between DNMT1 and the SPARC promoter (ChIP assay), cell viability, apoptosis, and cell proliferation. Our results revealed global hypermethylation of the SPARC promoter in CRCs, and identified specific CpG sites that were consistently methylated in CRCs but not in normal colon. We also demonstrate that SPARC repression in CRC cell lines could be reversed following exposure to 5-Aza, which resulted in increased SPARC expression, leading to a significant reduction in cell viability (by an additional 39% in RKO cells) and greater apoptosis (an additional 18% in RKO cells), when combined with 5-FU in vitro (in comparison to 5-FU alone). Our exciting findings suggest potential diagnostic markers of CRCs based on specific methylated CpG sites. Moreover, the results reveal the therapeutic utility of employing demethylating agents to improve response through augmentation of SPARC expression.

Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen.

BACKGROUND: Letrozole after 5 years of adjuvant tamoxifen results in a significant reduction in risk of recurrence from estrogen receptor (ER) positive breast cancer. An individualized estimate of the risk of relapse and death after 5 years of tamoxifen could improve decisions regarding extended hormonal therapy. METHODS: The British Columbia Breast Cancer Outcomes database was used to identify women aged 45 years or older at the time of diagnosis with early-stage (I-IIIA) breast cancer who received tamoxifen and were disease free 5 years after diagnosis. Ten-year breast cancer event rates and mortality were calculated as well as annualized hazard rates of recurrence. RESULTS: A total of 1086 women were identified with a median age of 64 years and follow-up of 10.5 years. The relative risk (RR) of death was 3.1 (P=0.003) and for recurrence was 1.7 (P=0.037) for N1 (one to three positive nodes) versus N0 (zero nodes positive) disease. N2 (four to nine nodes positive) had a RR of 5.8 (P<0.001) for death and 3.0 (P=0.002) for recurrence. Low tumor grade and high ER level subgroups had a more favorable prognosis. Annual breast cancer risk between years 6 and 10 was, respectively, 2.2%, 3.5% and 7.6% for N0, N1 and N2 disease and 2.6% and 4.5% for T1 and T2 breast cancer. CONCLUSION: T and N stages predicted late relapse and death from breast cancer in a population-based cohort of postmenopausal women. Risk estimates reported herein may be used to optimize decision making regarding adjuvant therapy after 5 years of tamoxifen.