The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: a multicentered retrospective analysis.

BACKGROUND: Colorectal cancer remains the second leading cause of cancer death in North America. Fluorouracil and oxaliplatin based adjuvant chemotherapy for resected colon cancer (CC) reduces cancer recurrence, but also causes significant toxicity requiring dose reductions. The effect of dose intensity on survival outcomes is not fully understood and strengthening the evidence supports informed decision making between patients and oncologists. METHODS: Patients treated with adjuvant chemotherapy, between 2006 and 2011, for resected colon cancer at four Canadian academic cancer centers were retrospectively analyzed. All patients must have received oxaliplatin with either capecitabine (CAPOX) or 5-FU (FOLFOX). Dose intensity (DI) was calculated as total delivered dose of an individual chemotherapy agent divided by the cumulative intended dose of that agent. The influence of DI on overall survival was examined. RESULTS: Five hundred thirty-one patients with high-risk stage II or stage III resected CC were eligible and included in the analysis. FOLFOX was the most common regimen (69.6%) with 29.7% of patients receiving CAPOX and 0.7% receiving both therapies. Median follow-up was 36.7 months. The median DI for 5-FU and capecitabine was 100% and 100% with 13.6% and 9.8% of patients receiving ≤ 80% DI, respectively. The median DI of oxaliplatin was 70% with 56.8% of patients receiving ≤ 80% DI. A DI of > 80% for each chemotherapy component was associated with a significant improvement in overall survival compared to those with a DI of ≤ 80% (5-FU HR = 0.23, 95% CI = 0.08-0.65, p = 0.006; capecitabine HR = 0.56, 95% CI = 0.33-0.94, p = 0.026; oxaliplatin HR = 0.52, 95% CI = 0.33-0.82, p = 0.005). Patients with T2 and/or N2 disease with an oxaliplatin DI > 80% had a trend towards improved survival (HR = 0.62, 95% CI = 0.38-1.02, p = 0.06). CONCLUSIONS: In resected CC an adjuvant chemotherapy DI of > 80%, of each chemotherapy agent, is associated with improved overall survival.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

PURPOSE: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAFV600E, and mismatch repair status. RESULTS: Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High (P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION: Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.

Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update.

PURPOSE: To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer. METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS: Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Current Attitudes toward Unfunded Cancer Therapies among Canadian Medical Oncologists.

BACKGROUND: Despite successes in the development of innovative anticancer therapies, the fiscal and capacity restraints of the Canadian public healthcare system result in challenges with drug access. A meaningful proportion of systemic therapies ultimately do not receive public funding despite supporting clinical evidence. In this study, we assessed Canadian medical oncologists' current attitudes toward discussing publicly unfunded cancer treatments with patients and predictors of different practices. METHODS: A web-based survey consisting of multiple choice and case-based scenarios was distributed to medical oncologists identified through the Royal College of Physicians and Surgeons of Canada directory. RESULTS: A total of 116 responses were received. Almost all respondents reported discussing publicly unfunded treatments, including those who did so for Health Canada (HC) approved treatments (50%) and those who discussed off-label treatments (i.e., not HC approved) as guided by national guidelines (48%). Respondents in practice for over 15 years versus less than 5 years (OR 0.14, 95% CI 0.04-0.50, p = 0.002) and those who worked in a community practice versus comprehensive cancer center (OR 0.17, 95% CI 0.03-0.91, p = 0.04) were significantly less likely to discuss off-label treatment options with their patients. Almost half of respondents (47%) indicated that their institution did not permit the administration of unfunded treatments. CONCLUSIONS: There is variability in medical oncologists' practices when it comes to discussing unfunded therapies. Given the limitations within Canada's publicly funded healthcare system, physicians are faced with the challenge of navigating an increasingly complex balance between patient care and available resources. Engagement of relevant stakeholders and policy makers is crucial in the continued evaluation of Canada's drug funding process.

Association of Adiponectin and Vitamin D With Tumor Infiltrating Lymphocytes and Survival in Stage III Colon Cancer.

Background: Adipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided. Results: We found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index >30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P < .001), in men vs women (median = 8185 vs 11 567 ng/mL; P < .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P < .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (<30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS. Conclusions: Lower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.

Rationale and Design of the IROCAS Study: Multicenter, International, Randomized Phase 3 Trial Comparing Adjuvant Modified (m) FOLFIRINOX to mFOLFOX6 in Patients With High-Risk Stage III (pT4 and/or N2) Colon Cancer-A UNICANCER GI-PRODIGE Trial.

BACKGROUND: According to the IDEA trial, 6-month adjuvant chemotherapy should remain the treatment standard in stage III T4 or N2 colon cancer. The relatively poor survival in this high-risk subgroup-a 3-year disease-free survival (DFS) rate of 65%-and the potential synergistic efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan suggest that FOLFIRINOX may be a regimen of particular interest in this setting. PATIENTS AND METHODS: This multicenter international phase 3 trial (ClinicalTrials.gov NCT02967289) being conducted in 49 centers in France and Canada plans to randomize (1:1; minimization method) 640 patients aged 18 to 70 years with Eastern Cooperative Oncology Group performance status ≤ 1. Randomization occurs within 42 days (with treatment initiated within 56 days) after curative-intent R0 surgical resection of a pT4N1 or pT1-4N2 colon adenocarcinoma. Patients will be randomized to receive adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, and 5-FU 2.4 g/m2 over 46 hours) or modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU bolus 400 mg/m2, then 2.4 g/m2 over 46 hours) every 2 weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. A gain of 9% in 3-year DFS (primary end point) is expected (74% in the experimental arm vs. 65% in the control arm; α, 5% [2-sided log-rank test]; 1-ß, 80%). Secondary end points of this study include 2-year DFS, overall survival, and toxicity.

Survival Impact of CAPOX Versus FOLFOX in the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: Capecitabine and oxaliplatin (CAPOX) and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are both used in the adjuvant treatment of colon cancer, and while their efficacy is assumed to be similar, they have not been directly compared. We reviewed the toxicity profiles, relative dose intensity (RDI), and survival associated with these regimens across a multi-institutional cohort. PATIENTS AND METHODS: We identified 394 consecutively treated patients with stage III colon cancer who received an oxaliplatin-containing regimen. RDI was defined as the total dose received divided by the intended total dose if all cycles were received. RESULTS: FOLFOX was associated with increased mucositis (6.2% vs. 0.7%, P = .0069) and neutropenia (25.9% vs. 8.6%, P < .0001), while CAPOX was associated with increased dose-limiting toxicities (DLTs) (90.7% vs. 80.2%, P = .0055), diarrhea (31.8% vs. 9.0%, P < .0001), and hand-foot syndrome (19.9% vs. 2.1%, P < .0001). Higher median RDI of fluoropyrimidine (93.7% vs. 80.0%, P < .0001) and oxaliplatin (87.2% vs. 76.3%, P < .0001) was noted for patients receiving FOLFOX. Reducing the duration from 6 to 3 months would have prevented 28.7% of FOLFOX and 20.5% of CAPOX patients from ever experiencing a DLT (P = .0008). Overall survival did not differ by regimen (hazard ratio = 0.73; 95% confidence interval 0.45-1.22; P = .24). However, CAPOX was associated with improved disease-free survival (3-year disease-free survival 83.8% vs. 73.4%, P = .022), which remained significant in high-risk (T4 or N2) (P = .039) but not low-risk patients (P = .19). CONCLUSION: CAPOX may be associated with improved disease-free survival despite greater toxicities and lower RDI. Reducing adjuvant chemotherapy duration to 3 months would prevent 26% of patients from ever experiencing a DLT.

Utilization of capecitabine plus oxaliplatin and 5-fluorouracil/folinic acid plus oxaliplatin in the adjuvant treatment of stage IIB and stage III colon cancer: A multi-centre, retrospective, chart review study.

Purpose First, to assess drug utilization rates of capecitabine plus oxaliplatin (CAPOX) versus 5-fluorouracil plus oxaliplatin (mFOLFOX6) regimens in the treatment of stage IIB and stage III colon cancer. Second, to assess patient characteristics used to select CAPOX versus FOLFOX therapy, dose-limiting toxicities, dose intensities and treatment completion rates. Methods Patients with resected stage IIB or stage III colon cancer from five British Columbia Cancer Agency centres treated with CAPOX or mFOLFOX6 were selected for the analysis. Protocol utilization rates, patient characteristics and toxicities of the two regimens were collected and compared by descriptive statistics. Results A total of 306 patients were included over study period. mFOLFOX6 is the most commonly used regimen with 69% utilization rate. CAPOX patients were younger (57 years old vs. 62 years old, p < 0.01), but no other significant differences were found. CAPOX was associated with more dose-limiting toxicities compared to mFOLFOX6 (95% vs. 82%, p < 0.01). Fewer patients completed the intended 24-week course of CAPOX compared to mFOLFOX6 (67% vs. 82%, p < 0.01). Conclusion FOLFOX is the most commonly utilized adjuvant treatment option for stage IIB and stage III colon cancer in British Columbia, and is associated with better tolerability and higher treatment completion rates.

Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).

Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.

Reasons for Underuse of Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer.

BACKGROUND: Undertreatment has been frequently reported in the elderly cancer patient population. For this reason, we aimed to characterize adjuvant chemotherapy (AC) use among elderly patients (EPs) with stage III colon cancer (CC) and to identify potential reasons for undertreatment. PATIENTS AND METHODS: Patients diagnosed with stage III CC between 2008 and 2010 were included in this review. Multivariate Cox regression models were constructed to evaluate the associations between AC and cancer-specific, disease-free, and overall survival and to determine whether these were modified by age. RESULTS: We identified 810 patients: 423 (52%) men, 423 (52%) young patients (YPs), and 603 (74%) received AC. Compared with YPs, EPs were less likely to receive AC (57% vs. 91%; P < .01), particularly 5-fluorouracil and oxaliplatin (FOLFOX) (32% vs. 74%, P < .01). Frequent reasons for nontreatment included age, comorbidities, and perceived minimal benefit from AC. When AC was given, EPs had similar rates of treatment discontinuations (34% vs. 26%; P > .05) and dose reductions (63% vs. 61%; P > .05) as YPs. Reasons for treatment interruptions included side effects, progressive disease, and patient choice. Receipt of either FOLFOX or capecitabine was correlated with improved cancer-specific survival, disease-free survival, and overall survival compared with surgery alone; this effect was not modified by age. CONCLUSION: Elderly patients with stage III CC frequently received either no AC or capecitabine monotherapy because of advanced age and comorbidities. The effect of AC on survival was similar across age groups, with comparable side effects and rates of treatment modifications. AC should not be withheld because of advanced age alone.

Effect of Adjuvant FOLFOX Chemotherapy Duration on Outcomes of Patients With Stage III Colon Cancer.

BACKGROUND: Studies have demonstrated that patients with stage III colon cancer who receive adjuvant FOLFOX (5-fluorouracil and oxaliplatin) chemotherapy experience an improved disease-free (DFS) and overall survival (OS). However, the magnitude of benefit among patients who discontinue FOLFOX early is not well known. We sought to examine the rate of FOLFOX treatment completion, determine the factors associated with adherence, and explore the relationship between duration of FOLFOX treatment and survival. PATIENTS AND METHODS: We analyzed patients diagnosed with stage III colon cancer from 2006 to 2010 and initiated at least 1 cycle of adjuvant FOLFOX at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the clinical factors associated with treatment completion, which was defined as receipt of ≥ 10 cycles of FOLFOX. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between early FOLFOX discontinuation and DFS and OS. RESULTS: We identified 616 patients: median age of 62 years (range, 26-80), 321 (52%) men, 536 (87%) with T3/4 tumors, and 245 (40%) with N2 disease. Among them, 183 (30%) received < 10 and 433 (70%) received ≥ 10 cycles. Adjusting for covariates, female sex and the absence of obstruction or perforation were each associated with receiving ≥ 10 cycles of FOLFOX (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.12-2.32; P = .01 and OR, 1.82; 95% CI, 1.08-3.05; P = .02, respectively). In multivariate analyses, early discontinuation of FOLFOX did not affect DFS or OS (hazard ratio [HR], 1.16; 95% CI, 0.82-1.63; P = .40 and HR, 1.07; 95% CI, 0.70-1.61; P = .76, respectively). CONCLUSION: Early discontinuation of FOLFOX was not associated with differences in survival outcomes, lending support to clinical trials that are under way to evaluate the efficacy of shorter durations of therapy.

Effect of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer.

BACKGROUND: Less than 8 weeks has been recommended as the optimal time to initiate AC based on 2 meta-analyses that suggested worse survival with delayed AC. However, neither study included patients treated with an oxaliplatin-based chemotherapy. We aimed to investigate the effect of delay in initiating oxaliplatin-based chemotherapy on RFS and CSS for stage III colon cancer. PATIENTS AND METHODS: Records of patients who initiated oxaliplatin-based AC for stage III colon cancer between 2006 and 2011 at the British Columbia Cancer Agency were retrospectively reviewed. Cox proportional models were used to analyze the effect of time to AC (TTAC) on RFS and CSS. TTAC was categorized into ≤ 8 weeks (G1) and > 8 weeks (G2). RESULTS: Six hundred thirty-five patients were included (G1, n = 291; G2, n = 344). Median time from surgery to initiation of AC was 8.3 weeks. At a median follow-up of 57.9 months, 176 patients (27.7%) had disease recurrence and 118 (18.6%) had died. Five-year RFS was 70.9% (95% confidence interval [CI], 65.2-76.5) for G1 and 72.1% (95% CI, 67.2-77) for G2. Five-year CSS was 82% for G1 (95% CI, 87.09-76.91) and 82.8% for G2 (95% CI, 78.30-87.30). On multivariate analysis, delayed TTAC did not have prognostic significance on either RFS (hazard ratio [HR], 1.08; P = .609) or CSS (HR, 1.02; P = .893). CONCLUSION: In our population-based study, TTAC after stage III colon cancer resection did not have an effect on RFS or CSS. Contrary to most of the existing data, which are primarily based on 5-fluorouracil-based AC, delay of oxaliplatin-based AC beyond 8 weeks did not appear to be associated with inferior outcomes.

Neutropenia and relative dose intensity on adjuvant FOLFOX chemotherapy are not associated with survival for resected colon cancer.

PURPOSE: Adjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy for resected high-risk colon cancer is associated with a low risk of febrile neutropenia (FN). Neutropenia, however, is a common cause of dose modification or delay with unknown consequences on outcomes. We examined the effect of neutropenia-related and other dose-limiting toxicities and relative dose intensity of oxaliplatin and 5-FU, on relapse-free and overall survival in patients treated with FOLFOX chemotherapy for resected high-risk colon cancer. METHODS: A chart review was conducted on patients treated at the British Columbia Cancer Agency receiving ≥1 cycle of mFOLFOX6 chemotherapy for resected stage II or III colon cancer between January 1, 2006, and December 31, 2007. Relapse-free survival (RFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. RESULTS: One hundred fourteen patients (median age 59 years, 44 % male, 98 % stage III, median follow-up 5.2 years) were included. Ninety percent of the patients experienced any dose-limiting toxicity (DLT), while 58 % of the patients had a neutropenia-related DLT. There were no documented episodes of FN. Granulocyte colony-stimulating factor (GCSF) was used in 10 % of the patients. Median relative dose intensity (RDI) was 81 and 85 % for oxaliplatin and 5-FU, respectively. Oxaliplatin and 5-FU RDI were not associated with RFS or OS when analyzed as continuous variables or categorically. Grade II or grade III/IV neutropenia compared to no neutropenia was not associated with RFS or OS. CONCLUSIONS: DLTs affect the majority of patients on adjuvant FOLFOX for high-risk colon cancer, but RFS and OS do not appear to be affected by the associated lower RDI of oxaliplatin and 5-FU.

Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147.

BACKGROUND: Two arms with FOLFIRI, with or without cetuximab, were initially included in the randomized phase III intergroup clinical trial NCCTG (North Central Cancer Treatment Group) N0147. When other contemporary trials demonstrated no benefit to using irinotecan as adjuvant therapy, the FOLFIRI-containing arms were discontinued. We report the clinical outcomes for patients randomized to FOLFIRI with or without cetuximab. PATIENTS AND METHODS: After resection, patients were randomized to 12 biweekly cycles of FOLFIRI, with or without cetuximab. KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation status was retrospectively determined in a central lab. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity. RESULTS: One hundred and six patients received FOLFIRI and 40 received FOLFIRI plus cetuximab. Median follow-up was 5.95 years (range, 0.1-7.0 years). The addition of cetuximab showed a trend toward improved DFS (hazard ratio [HR], 0.53; 95% CI, 0.26-1.1; P = .09) and OS (HR, 0.45; 95% CI, 0.17-1.16; P = .10) in the overall group, regardless of KRAS status, and in patients with wild type KRAS. Grade ≥ 3 nonhematologic adverse effects were significantly increased in the cetuximab versus FOLFIRI-alone arm (68% vs. 46%; P = .02). Adjuvant FOLFIRI resulted in a 3-year DFS less than that expected for FOLFOX. CONCLUSION: In this small randomized subset of patients with resected stage III colon cancer, the addition of cetuximab to FOLFIRI was associated with a nonsignificant trend toward improved DFS and OS. Nevertheless, considering the limitations of this analysis, FOLFOX without the addition of a biologic agent remains the standard of care for adjuvant therapy in resected stage III colon cancer.

In a 'real-world', clinic-based community setting, sorafenib dose of 400 mg/day is as effective as standard dose of 800 mg/day in patients with advanced hepatocellular carcimona, with better tolerance and similar survival.

BACKGROUND: Sorafenib, an oral multityrosine kinase inhibitor, has been approved for treatment of unresectable hepatocellular carcinoma (HCC). British Columbia (BC) was the first province in Canada to provide drug coverage for sorafenib. OBJECTIVE: To review the BC experience with sorafenib to assess its effectiveness and tolerance in a 'real-world' clinical setting. METHODS: A retrospective clinic chart review identified 99 patients referred to the BC Cancer Agency from 2008 to 2010 with a diagnosis of HCC who qualified for treatment with sorafenib. RESULTS: Therapy with sorafenib was initiated and continued at a reduced dosage of 400 mg/day in 66 of 99 patients, with 22 patients requiring further dose reduction. Full- and reduced-dose group patients had similar baseline characteristics, except for a higher proportion of female patients (P=0.02) and individuals with alcoholic liver disease (P=0.04) in the full-dose group. The incidence of any grade of adverse effects was higher in the full-dose group (94% versus 77% in the reduced-dose group; P=0.04). Dose reduction rates were significantly higher in the full-dose group, occurring in 66% versus 24% of reduced-dose group patients (P=0.001). The overall survival rates were similar between the two groups: 7.8 months versus 7.1 months in full- versus reduced-dose groups (P=0.14), as were radiological progression rates and alpha-fetoprotein levels. CONCLUSIONS: In a review of 99 patients in a 'real-world' community setting, a sorafenib dose of 400 mg/day was better tolerated and had similar efficacy compared with a sorafenib dose of 800 mg/day with respect to survival and outcomes.

Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.

CONTEXT: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. OBJECTIVE: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. MAIN OUTCOME MEASURES: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. RESULTS: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. CONCLUSION: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00079274.

Real-world impact of availability of adjuvant therapy on outcomes in patients with resected pancreatic adenocarcinoma: a Canadian Cancer Agency experience.

BACKGROUND: Patients with resected pancreatic cancer (PC) have a poor prognosis. In 2004, European Study Group for Pancreatic Cancer 1 (ESPAC1) showed that the use of adjuvant therapy (AT) with 5-fluorouracil (5-FU) improves overall survival (OS). Subsequently, the British Columbia Cancer Agency (BCCA) introduced guidelines to offer AT as the standard of care for patients with resected PC. This study reviews the OS and disease-free survival (DFS) in a pre-AT era (2000 to 2004) to the AT era (2005 to 2008) at the BCCA. METHODS: Using pathology records, all PC resections at Vancouver General Hospital from 2000 to 2008 were identified. Patients referred to the BCCA and their treatment records were obtained from the Cancer Agency Information System and BCCA pharmacy database. Charts were reviewed to abstract patient and tumor characteristics, DFS, and OS. Outcomes were compared by log-rank comparison. RESULTS: In the pre-AT era, 53 resections were recorded, with 64% referred to the BCCA. Median age was 65 years; poorly differentiated 59% and margin positive 38%. About 24% of patients received AT: all 5-FU. In the AT era, 64 resections were recorded, with 86% referred. Median age was 65 years, poorly differentiated 34% and margin positive 34%. 69% of patients received AT: 61% 5FU and 39% gemcitabine. Major reasons for no AT: delayed referral or metastases at time of referral 45% and poor performance status 35%. Pre-AT DFS 13 months versus 15 months AT era (P=0.55). Pre-AT OS 19 months versus 18 months AT era (P=0.59). CONCLUSIONS: Since the guideline for AT, there was an increase in the proportion of patients referred and treated, however, over 30% still do not receive or complete AT. In this single-institution series, there was no difference in survival outcomes between the pre-AT and AT eras. Strategies to improve rate and timeliness of referral should be explored.

Prognostic web-based models for stage II and III colon cancer: A population and clinical trials-based validation of numeracy and adjuvant! online.

BACKGROUND: Numeracy and Adjuvant! are 2 web-based calculators that are used widely to estimate the prognosis and potential benefit of adjuvant 5-fluorouracil (5-FU)-based therapy for patients with stage II and III colon cancer. In this study, the authors compared the predicted survival estimates from these models with the actual observed estimates in independent datasets that were derived from a population cohort and from clinical trials. METHODS: The population cohort was derived from the British Columbia Colorectal Cancer Outcomes Unit database, which identified referred patients with stage II and III colon cancer from 1995 to 1996 and from 1999 to 2003. Patients who were enrolled in North Central Cancer Trials Group (NCCTG) trials NCCTG 94651 and NCCTG 914653 were included in the trials dataset. Patient and disease data were used to predict 5-year relapse-free and overall survival using both tools. RESULTS: In the population-based dataset (N = 2033), Adjuvant! offered more reliable predictions of prognosis for patients who underwent surgery alone, but it had reliability similar to that of Numeracy for predicting the prognosis for patients who received adjuvant 5-FU. Both models tended to overestimate survival for patients with stage II disease who received 5-FU. In the trials dataset of patients who underwent and received 5-FU (N = 1729), Numeracy and Adjuvant! demonstrated similar performance and improved correctness. CONCLUSIONS: This independent validation analysis demonstrated that both Numeracy and Adjuvant! had similar predictive performance and acceptable reliability for patients with stage III disease. Survival outcomes of patients with stage II colon cancer who received adjuvant 5-FU were slightly lower than estimated by either model.

Adjuvant chemotherapy for resected stage II and III colon cancer: comparison of two widely used prognostic calculators.

Two Web-based prognostic calculators (Adjuvant! and Numeracy) are widely used to individualize decisions regarding adjuvant therapy among patients with resected stage II and III colon cancer. However, these tools have not been directly compared. Hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were then applied to three postsurgical therapy choices: observation, 5-fluorouracil (5-FU), or FOLFOX (5-FU, leucovorin, and oxaliplatin chemotherapy) to obtain the predicted 5-year disease-free survival (DFS) and overall survival (OS). Wilcoxon signed rank tests were used to compare the numerical predictions between the Adjuvant! and Numeracy calculators for each combination. A total of 192 hypothetical patient scenarios were obtained. For these patients, DFS and OS predictions from Adjuvant! were statistically significantly different than Numeracy (P <.05), except for four of 144 categories. While the estimated benefit in DFS and OS for 5-FU compared to surgery obtained from Adjuvant! and Numeracy were similar, the benefit in DFS and OS for FOLFOX over 5-FU, obtained from the Adjuvant! tool was slightly lower than that estimated from Numeracy. Among patients with resected stage II and III colon cancer, the DFS and OS estimates obtained from Numeracy and Adjuvant!, regarding the benefit of 5-FU over surgery, are similar, but the benefits of FOLFOX over 5-FU differ. Validation studies are needed to clarify the discrepancy and to assess the accuracy of these tools for predicting actual patient outcomes.

Intraperitoneal treatment for peritoneal mucinous carcinomatosis of appendiceal origin after operative management: long-term follow-up of the Mayo Clinic experience.

OBJECTIVE: To determine prognostic factors and the impact of intraperitoneal (IP) treatment after surgical resection of peritoneal mucinous carcinomatosis (PMC) of appendiceal origin. SUMMARY OF BACKGROUND DATA: PMC is a rare, malignant, intra-abdominal neoplasm that produces large amounts of mucin. Patients typically present with diffuse peritoneal disease. After surgical treatment, multiple locoregional recurrences are common; recurrences outside the abdomen are infrequent. Treatment regimens include debulking, radiotherapy with IP radioisotopes, and chemotherapies (IP, systemic, or both). Because reported data are variable and heterogeneous, treatment evaluations are challenging. METHODS: We retrospectively reviewed 115 consecutive patients with PMC who underwent maximal surgical resection with or without postoperative therapy between 1985 and 2000 at Mayo Clinic Rochester. After maximal resection, 37 patients received IP 5-fluorouracil, 35 of whom also received IP chromic phosphate P 32. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival. RESULTS: All gross disease was removed in 61% of patients. With a median follow-up of 6.1 years, the median OS was 8.1 years. Median OS for patients receiving versus not receiving IP therapy was 23.5 years versus 7.5 years, respectively. The 5-, 10-, and 15-year OS for those receiving and not receiving IP therapy was 82%, 65%, and 52% versus 60%, 27%, and 15%, respectively. Adverse prognostic factors for OS identified by univariate analysis included partial mucin debulking, adenocarcinoma histology, systemic chemotherapy, diffuse IP disease at presentation, and no IP therapy. On multivariate analysis, diffuse IP disease at presentation and no IP therapy remained significant. A separate analysis was performed for the 70 patients who underwent gross total resection, 51% of whom received IP therapy. Adverse prognostic factors for OS included adenocarcinoma histology, systemic chemotherapy, and no IP therapy. CONCLUSIONS: This large, single-institution, retrospective series with long-term follow-up suggests that IP chromic phosphate P 32 and 5-fluorouracil after maximal surgical resection of PMC of appendiceal origin is associated with improved OS and disease-free survival.