Sulaiman Nanji

Chemotherapy-induced Liver Injury in Metastatic Colorectal Cancer: Semiquantitative Histologic Analysis of 334 Resected Liver Specimens Shows That Vascular Injury but not Steatohepatitis Is Associated With Preoperative Chemotherapy

The use of newer chemotherapeutic agents before resection of colorectal cancer liver metastases has been linked with parenchymal liver injury, in particular preoperative irinotecan and oxaliplatin with chemotherapy-associated steatohepatitis (CASH) and vascular parenchymal injury, respectively. We retrospectively assessed 334 cases from 2002 to 2007 and correlated pathologic findings with chemotherapy use and perioperative course. Features of fatty liver disease were graded according to established schemes, and several features of vascular injury, including sinusoidal dilation, nodular regenerative hyperplasia and parenchymal extinction lesions (PELs), were also scored semiquantitatively and a combined vascular injury (CVI) score was determined. Moderate and severe fatty injury was uncommon with steatohepatitis detected in 8 cases (2.4%), 7 of whom did not receive chemotherapy. Multivariate analysis showed steatosis greater than 33% and steatohepatitis were independently associated with Body Mass Index of 30 or more (P<0.001) but not chemotherapy. Vascular injuries were detected in 117 cases, were significantly associated with oxaliplatin, and the combined assessment of vascular features (a CVI score of 3 or more) was more strongly associated with oxaliplatin (P=0.0004) than any one feature in isolation. Perioperative outcome was not associated with parenchymal injury or preoperative chemotherapy. We conclude that although CASH is uncommon in this population vascular injury is frequently seen in resection specimens, but pathologic examination limited to sinusoidal dilation misses the majority of these. Semiquantitative measurement enables reproducible assessment of vascular injuries, allows comparison between studies, and may help inform future treatment decisions in patients with limited hepatic reserve.

Predictors of peri-opertative morbidity and liver dysfunction after hepatic resection in patients with chronic liver disease

BACKGROUND Hepatic resection in patients with chronic liver disease (CLD) is associated with a risk of post-operative liver failure and higher morbidity than patients without liver disease. There is no universal risk stratification scheme for CLD patients undergoing resection. OBJECTIVES The aim of the present study was to evaluate the association between routine pre-operative laboratory investigations, model for end-stage liver disease (MELD), indocyanine green retention at 15 min (ICG15) and post-operative outcomes in CLD patients undergoing liver resection. METHODS A retrospective review of patients undergoing resection for hepatocellular carcinoma (HCC) at the University Health Network was preformed. ICG15 results, pre- and post-operative laboratory results were obtained from clinical records. Adjusted odds ratios (AOR) were calculated for associations between pre-operative factors and post-operative outcomes using multivariate logistic regression adjusting for patient age and number of segments resected. RESULTS Between 2001 and 2005, 129 CLD patients underwent surgical resection for HCC. Procedures included 51 (40%) resections of ≤ 2 segments, 52 (40%) hemihepatectomies and 25 (19%) extended hepatic resections. Thirty- and 90-day post-operative mortality was 1.6% and 4.1%, respectively. Prolonged (>10 days) hospital length of stay (LOS) was independently associated with an ICG15 >15% {AOR [95% confidence interval (CI)]= 8.5 (1.4-51)} and an international normalized ratio (INR) > 1.2 [AOR (95% CI) = 5.0 (1.4-18.6)]. An ICG15 > 15% and MELD score were independent predictors of prolonged LOS. An ICG15 > 15% was also independently associated with MELD > 20 on post-operative day 3 [AOR (95% CI) = 24.3 (1.8-319)]. CONCLUSIONS Elevated ICG retention was independently associated with post-operative liver dysfunction and morbidity. The utility of ICG in combination with other biochemical measures to predict outcomes after hepatic resection in CLD patients requires further prospective study.

Management and Outcome of Colorectal Cancer Liver Metastases in Elderly Patients: A Population-Based Study

IMPORTANCE Surgical resection is standard treatment for patients with colorectal cancer (CRC) liver metastases (LM). Limited data describe practice and outcomes among elderly patients. OBJECTIVE To describe management and outcomes of surgical resection of CRC LM in elderly patients in routine practice. DESIGN, SETTING, AND PARTICIPANTS Population-based retrospective cohort study of routine clinical practices in the Canadian province of Ontario. All cases of CRC in Ontario who underwent resection of LM between January 1, 2002, and December 31, 2009, were identified using the population-based Ontario Cancer Registry and included in this study. Complete information about vital status in the Ontario Cancer Registry was available up to December 31, 2012; cause of death was available up to December 31, 2010. Final study analyses were performed March 13, 2015. Surgical resections of CRC LM were identified from hospital admission records. Pathology reports provided details regarding extent of disease and surgical procedure. Patients were classified into 3 age groups: younger than 65 years, 65 to 74 years, and 75 years or older. We describe volume of resected CRC LM as a ratio of incident cases per CRC LM resection. Use of perioperative chemotherapy was identified through linked electronic treatment and physician billing records. Preoperative and postoperative chemotherapy was defined as chemotherapy given within 16 weeks of surgery. MAIN OUTCOMES AND MEASURES Overall survival and cancer-specific survival measured from time of LM resection. RESULTS We identified 1310 patients: 710 (54%) younger than 65 years; 414 (32%) 65 to 74 years; and 186 (14%) 75 years or older. Case volumes of CRC LM resection varied substantially across age groups. For patients younger than 65 years, there was 1 resection per 26 incident cases; 65 to 74 years, 1 per 38; and 75 years or older, 1 per 101 (P<.001). Patients less than 65 years of age had a mean of 2.3 lesions; 65 to 74 years, 2.0; and 75 years or older, 1.6 (P<.001). For patients younger than 65 years, mean size of the largest lesion was 4.0 cm; patients 65 to 74 years, 4.4 cm; and 75 years or older, 4.5 cm (P=.04). The likelihood patients younger than 65 years were to undergo a major liver resection of more than 3 segments was 65%; 65 to 74 years, 65%; and 75 years or older, 42% (P=.04). The percentage of patients younger than 65 years who underwent perioperative chemotherapy was 71% (501 of 710); 65 to 74 years, 57% (237 of 414); and 75 years or older, 41% (77 of 186) (P<.001). The incidence of 90-day mortality for patients younger than 65 years was 2% (11 of 710); 65 to 74 years, 5% (20 of 414); and 75 years or older, 8% (14 of 186) (P<.001). Cancer-specific survival at 5 years for patients younger than 65 years of age was 49%; 65 to 74 years, 47%; and 75 years or older, 35% (P<.001). Overall survival for patients younger than 65 years was 49%; 65 to 74 years, 44%; and 75 years or older, 28% (P<.001). CONCLUSIONS AND RELEVANCE Resection of CRC LM is associated with greater risk of postoperative mortality among elderly patients despite less aggressive treatment. Although the long-term outcomes are inferior to younger patients, a substantial proportion of elderly patients will have long-term survival.

Association Between Prognosis and Tumor Laterality in Early-Stage Colon Cancer

Importance Recent data have suggested that disease biology and outcome of colon cancer may differ between right-sided and left-sided tumors. However, the literature on the prognostic value of tumor laterality is conflicting. Objective To explore differences in laterality based on disease characteristics and outcomes in a population-based cohort of early-stage colon cancer. Design, Setting, and Participants This investigation was a population-based retrospective cohort study of patients with early-stage colon cancer from the province of Ontario, Canada. Electronic records of treatment were linked to the Ontario Cancer Registry to identify all patients with colon cancer who underwent resection between January 1, 2002, and December 31, 2008. The date of the final analysis was October 20, 2016. The study population included a 25% random sample of all patients with resected stage I to III disease. Right-sided colon cancer was defined as any tumor arising in the cecum, ascending colon, hepatic flexure, or transverse colon. Left-sided colon cancer was defined as any tumor arising in the splenic flexure, descending colon, sigmoid colon, or rectosigmoid colon. Main Outcomes and Measures Overall survival (OS) and cancer-specific survival (CSS) measured from the time of resection. Results This study identified 6365 patients with early-stage colon cancer (48.7% [3098 of 6365] female). Their median age was 72 years, and 51.7% (3291 of 6365) had right-sided disease. Stage distribution was 18.3% (1163 of 6365) stage I, 38.4% (2446 of 6365) stage II, and 43.3% (2756 of 6365) stage III. Patients with right-sided colon cancer were more likely to be older (median age, 73 vs 70 years; P < .001) and female (54.4% [1790 of 3291] vs 42.6% [1308 of 3074], P < .001) and have greater comorbidity. Right-sided cancers were more likely to be T4 (19.2% [631 of 3291] vs 15.9% [490 of 3074], P < .001) and poorly differentiated (21.1% [695 of 3291] vs 9.6% [295 of 3074], P < .001) but less likely to be node positive (42.0% [1383 of 3291] vs 44.7% [1373 of 3074], P = .03) compared with left-sided disease. In adjusted analyses, there was no difference in long-term survival for right-sided compared with left-sided colon cancer: the hazard ratios were 1.00 (95% CI, 0.92-1.08) for OS and 1.00 (95% CI, 0.91-1.10) for CSS. These results were consistent when the survival analyses were restricted to stage III disease: the hazard ratios were 1.03 (95% CI, 0.93-1.14) for OS and 1.10 (95% CI, 0.97-1.24) for CSS. Conclusions and Relevance In this population-based cohort of early-stage resected colon cancer, disease laterality was not associated with long-term OS or CSS.

Surgical resection and peri-operative chemotherapy for colorectal cancer liver metastases: A population-based study

BACKGROUND Most literature describing surgery for colorectal cancer (CRC) liver metastases (LM) comes from high volume centres. Here, we report management and outcomes achieved in routine clinical practice. METHODS All cases of CRC in Ontario who underwent resection of LM in 1994-2009 were identified using the population-based Ontario Cancer Registry. Electronic treatment records identified chemotherapy delivery. Temporal trends are described for 3 periods: 1994-1999, 2000-2004, 2005-2009. We describe volume of resected CRCLM as a ratio of incident cases per CRCLM resection. Overall (OS) and cancer-specific survival (CSS) are measured from time of LM resection. RESULTS 2717 patients underwent resection of CRCLM. Between 1994 and 2009 there was a 78% increase in case volume; from one resection for every 48 incident cases to one resection for every 27 incident cases, p < 0.001. Use of peri-operative chemotherapy increased over study periods from 44% (306/700), to 52% (429/830), to 65% (777/1187, p < 0.001). Chemotherapy utilization rates varied across geographic regions (range 43%-69%, p < 0.001). Post-operative mortality rates at 30 and 90 days were 2.5% and 4.3% respectively. Five year OS during the study periods was 36% (95% CI 32-39%), 40% (95% CI 36-43%), and 46% (95% CI 43-49%) (p < 0.001); CSS was 38% (95% CI 35-42%), 42% (95% CI 38-45%), 49% (95% CI 44-53%) (p < 0.001). The temporal improvement in OS/CSS persisted on adjusted analyses. CONCLUSIONS Outcomes of patients with resected CRCLM in routine practice is comparable to those reported from high volume centres. Survival improved over the study period despite a greater proportion of patients with CRC undergoing liver resection.

Liver resection after chemotherapy and tumour downsizing in patients with initially unresectable colorectal cancer liver metastases

OBJECTIVES Among patients with initially unresectable colorectal cancer liver metastases (CLM), a subset are rendered resectable following the administration of systemic chemotherapy. This study reports the results achieved in liver resections performed at a single hepatobiliary referral centre after downsizing chemotherapy in patients with initially unresectable CLM. METHODS All liver resections for CLM performed over a 10-year period at the Toronto General Hospital were considered. Data on initially non-resectable patients who received systemic therapy and later underwent surgery were included for analysis. RESULTS Between January 2002 and July 2012, 754 liver resections for CLM were performed. A total of 24 patients were found to meet the study inclusion criteria. Bilobar CLM were present in 23 of these 24 patients. The median number of tumours was seven (range: 2-15) and median tumour size was 7.0 cm (range: 1.0-12.8 cm) before systemic therapy. All patients received oxaliplatin- or irinotecan-based chemotherapy. Fourteen patients received combined treatment with bevacizumab. Negative margin (R0) resection was accomplished in 21 of 24 patients. There was no perioperative mortality. Ten patients suffered perioperative morbidity. Eighteen patients suffered recurrence of disease within 9 months. Rates of disease-free survival at 1, 2 and 3 years were 47.6% [95% confidence interval (CI) 30.4-74.6%], 23.8% (95% CI 11.1-51.2%) and 19.0% (95% CI 7.9-46.0%), respectively. Overall survival at 1, 2 and 3 years was 91.5% (95% CI 80.8-100%), 65.3% (95% CI 48.5-88.0%) and 55.2% (95% CI 37.7-80.7%), respectively. CONCLUSIONS Liver resection in initially unresectable CLM can be performed with low rates of morbidity and mortality in patients who respond to systemic chemotherapy, although these patients do experience a high frequency of disease recurrence.

Increased incidence but improved median overall survival for biliary tract cancers diagnosed in Ontario from 1994 through 2012: A population-based study

To the authors’ knowledge, the incidence of biliary tract cancer (BTC) in Canada is unknown. In the current study, the authors sought to describe the epidemiology of BTC using a large population‐based cancer database from Ontario, Canada.

Is there a sex effect in colon cancer? Disease characteristics, management, and outcomes in routine clinical practice

INTRODUCTION The incidence of colon cancer varies by sex. Whether women and men show differences in extent of disease, treatment, and outcomes is not well described. We used a large population-based cohort to evaluate sex differences in colon cancer. METHODS Using the Ontario Cancer Registry, all cases of colon cancer treated with surgery in Ontario during 2002-2008 were identified. Electronic records of treatment identified use of surgery and adjuvant chemotherapy. Pathology reports for a random 25% sample of all cases were obtained, and disease characteristics, treatment, and outcomes in women and men were compared. A Cox proportional hazards model was used to identify factors associated with overall (os) and cancer-specific survival (css). RESULTS The study population included 7249 patients who underwent resection of colon cancer; 49% (n = 3556) were women. Stage of disease and histologic grade did not vary by sex. Compared with men, women were more likely to have right-sided disease (55% vs. 44%, p ≤ 0.001). Surgical procedure and lymph node yield did not differ by sex. Adjuvant chemotherapy was delivered to 18% of patients with stage ii and 64% of patients with stage iii disease; when adjusted for patient- and disease-related factors, use of adjuvant chemotherapy was similar for women and men [relative risk: 0.99; 95% confidence interval (ci): 0.94 to 1.03]. Adjusted analyses demonstrated that os [hazard ratio (hr): 0.80; 95% ci: 0.75 to 0.86] and css (hr: 0.82; 95% ci: 0.76 to 0.90) were superior for women compared with men. CONCLUSIONS Long-term survival after colon cancer is significantly better for women than for men, which is not explained by any substantial differences in extent of disease or treatment delivered.

Lymph node evaluation for colon cancer in routine clinical practice: a population-based study

BACKGROUND Guidelines recommend that 12 or more lymph nodes (lns) be evaluated during surgical resection of colon cancer. Here, we report ln yield and its association with survival in routine practice. METHODS Electronic records of treatment were linked to the population-based Ontario Cancer Registry to identify all patients with colon cancer treated during 2002-2008. The study population (n = 5508) included a 25% random sample of patients with stage ii or iii disease. Modified Poisson regression was used to identify factors associated with ln yield; Cox models were used to explore the association between ln yield and overall (os) and cancer-specific survival (css). RESULTS During 2002-2008, median ln yield increased to 17 from 11 nodes (p < 0.001), and the proportion of patients with 12 or more nodes evaluated increased to 86% from 45% (p < 0.001). Lymph node positivity did not change over time (to 53% from 54%, p = 0.357). Greater ln yield was associated with younger age (p < 0.001), less comorbidity (p = 0.004), higher socioeconomic status (p = 0.001), right-sided tumours (p < 0.001), and higher hospital volume (p < 0.001). In adjusted analyses, a ln yield of less than 12 nodes was associated with inferior os and css for stages ii and iii disease [stage ii os hazard ratio (hr): 1.36; 95% confidence interval (ci): 1.19 to 1.56; stage ii css hr: 1.52; 95% ci: 1.26 to 1.83; and stage iii os hr: 1.45; 95% ci: 1.30 to 1.61; stage iii css hr: 1.54; 95% ci: 1.36 to 1.75]. CONCLUSIONS Despite a temporal increase in ln yield, the proportion of cases with ln positivity has not changed. Lymph node yield is associated with survival in patients with stages ii and iii colon cancer. The association between ln yield and survival is unlikely to be a result of stage migration.

Population-based study to re-evaluate optimal lymph node yield in colonic cancer

It is well established that lymph node (LN) yield in colonic cancer resection has prognostic significance, although optimal numbers are not clear. Here, LN thresholds associated with both LN positivity and survival were evaluated in a single population‐based data set.