The association between sociodemographic, clinical, and potentially preventive therapies with oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.

PURPOSE: The purpose of this retrospective cohort study was to evaluate whether several potentially preventive therapies reduced the rate of oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer patients and to assess the relationship of sociodemographic/clinical factors with OIPN diagnosis. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Eligible patients were diagnosed with colorectal cancer between 2007 and 2015, ≥ 66 years of age, and treated with oxaliplatin. Two definitions were used to denote diagnosis of OIPN based on diagnosis codes: OIPN 1 (specific definition, drug-induced polyneuropathy) and OIPN 2 (broader definition, additional codes for peripheral neuropathy). Cox regression was used to obtain hazard ratios (HR) with 95% confidence intervals (CI) for the relative rate of OIPN within 2 years of oxaliplatin initiation. RESULTS: There were 4792 subjects available for analysis. At 2 years, the unadjusted cumulative incidence of OIPN 1 was 13.1% and 27.1% for OIPN 2. For both outcomes, no therapies reduced the rate of OIPN diagnosis. The anticonvulsants gabapentin and oxcarbazepine/carbamazepine were associated with an increased rate of OIPN (both definitions) as were increasing cycles of oxaliplatin. Compared to younger patients, those 75-84 years of age experienced a 15% decreased rate of OIPN. For OIPN 2, prior peripheral neuropathy and moderate/severe liver disease were also associated with an increased hazard rate. For OIPN 1, state buy-in health insurance coverage was associated with a decreased hazard rate. CONCLUSION: Additional studies are needed to identify preventive therapeutics for OIPN in cancer patients treated with oxaliplatin.

Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

Modeling the Cost-Effectiveness of Adjuvant Chemotherapy for Stage III Colon Cancer in South African Public Hospitals.

PURPOSE: Cancer incidence is rising in low- and middle-income countries, where resource constraints often complicate therapeutic decisions. Here, we perform a cost-effectiveness analysis to identify the optimal adjuvant chemotherapy strategy for patients with stage III colon cancer treated in South African (ZA) public hospitals. METHODS: A decision-analytic Markov model was developed to compare lifetime costs and outcomes for patients with stage III colon cancer treated with six adjuvant chemotherapy regimens in ZA public hospitals: fluorouracil, leucovorin, and oxaliplatin for 3 and 6 months; capecitabine and oxaliplatin (CAPOX) for 3 and 6 months; capecitabine for 6 months; and fluorouracil/leucovorin for 6 months. Transition probabilities were derived from clinical trials to estimate risks of toxicity, disease recurrence, and survival. Societal costs and utilities were obtained from literature. The primary outcome was the incremental cost-effectiveness ratio in international dollars (I$) per disability-adjusted life-year (DALY) averted, compared with no therapy, at a willingness-to-pay (WTP) threshold of I$13,006.56. RESULTS: CAPOX for 3 months was cost-effective (I$5,381.17 and 5.74 DALYs averted) compared with no adjuvant chemotherapy. Fluorouracil, leucovorin, and oxaliplatin for 6 months was on the efficiency frontier with 5.91 DALYs averted but, with an incremental cost-effectiveness ratio of I$99,021.36/DALY averted, exceeded the WTP threshold. CONCLUSION: In ZA public hospitals, CAPOX for 3 months is the cost-effective adjuvant treatment for stage III colon cancer. The optimal strategy in other settings may change according to local WTP thresholds. Decision analytic tools can play a vital role in selecting cost-effective cancer therapeutics in resource-constrained settings.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Assessment of Duration and Effects of 3 vs 6 Months of Adjuvant Chemotherapy in High-Risk Stage II Colorectal Cancer: A Subgroup Analysis of the TOSCA Randomized Clinical Trial.

Importance: The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. Objective: To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. Design, Setting, and Participants: The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Interventions: Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. Main Outcome and Measures: A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. Results: Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89; P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, -6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. Conclusions and Relevance: In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT0064660.

Comparisons of Efficacy, Safety, and Cost of Chemotherapy Regimens FOLFOX4 and FOLFIRINOX in Rectal Cancer: A Randomized, Multicenter Study.

BACKGROUND The currently available chemotherapeutic regimens do not use a specifically designed drug delivery system. The objective of this study was to compare outcome measures, adverse effects, and cost of FOLFOX4 and FOLFIRINOX treatments in rectal cancer patients. MATERIAL AND METHODS We enrolled patients who, after surgery, did not undergo chemotherapy or radiotherapy (Control group); were administered 200 mg/m² folinic acid, 400 mg/m² fluorouracil, and 85 mg/m² oxaliplatin (FFO group); or were administered 400 mg/m² folinic acid, 400 mg/m² fluorouracil, 180 mg/m² irinotecan, and 85 mg/m2 oxaliplatin (FFIO group). We recorded tumor and nodal staging, carbohydrate antigen 19-9, serum carcinoembryonic antigen, total cost of treatment, disease recurrence, overall survival, and adverse effects. We used the 2-tailed paired t test following Turkey post hoc test for adverse effects, recurrence analysis, and cost of treatment at 95% of confidence level. RESULTS Surgery (p=0.00089), FOLFOX4 (p=0.000167), and FOLFIRINOX (p=0.00013) improved disease-free conditions. Only surgery failed to maintain carbohydrate antigen and carcinoembryonic antigen 19-9 levels. The cost of chemotherapeutic treatments was in the order of FFIO group > FFO group > Control group. Non-fatal treatment-emergent adverse effects were due to chemotherapeutic drugs. However, fatal chemotherapeutic treatment-emergent adverse effects were observed only in the FFIO group. Overall survival, irrespective of cancerous condition, was higher in the FFO group. CONCLUSIONS FOLFIRINOX had less total cancer recurrence than FOLFOX4. However, FOLFIRINOX had more fatal treatment-emergent adverse effects and excessive cost of treatment than FOLFOX4 regimen.

[Chemotherapy for colorectal cancer: Pragmatic assessment of prescription changes and relative dose intensity]. / Chimiothérapies dans le cancer colorectal : étude pragmatique des modifications de prescription et de dose intensité.

INTRODUCTION: Chemotherapy induced toxicities can generate changes in prescribing and relative dose intensity which have an impact on therapeutic efficacy. METHOD: This is a prospective observational study performed in hepato-gastroenterology department for 6 months. All patients treated for colorectal cancer and beginning a protocol with at least one parenteral drug have been included. RESULTS: Among the 48 patients enrolled, 85.4% of them had at least one prescription change, which concerned 30.3% of 238 cycles. Of the 766 analyzed prescription lines, 16.6% of them were postponed and/or 6.7% had modified dosage and/or 5.6% were stopped prematurely. Grades 2 to 4 adverse reactions were responsible for at least one change prescribing to 64.6% of patients and 17.6% of cycles. Toxicity induced prescription changes were mainly due to clinical toxicities (79.3%). The rate of patients with a relative dose intensity greater than 70% was 92.9% in adjuvant state, 66.7% and 62.5% in metastatic state first line and second and subsequent line. CONCLUSION: High-grade clinical toxicities are the main chemotherapy prescription change pattern in colorectal cancer. Knowledge of toxicities before the patient's arrival is expected to target patients for which the drug preparation can be anticipated and for which a cycle postponement, dose adjustment or discontinuation is necessary.

Comparison of treatment patterns, resource utilization, and cost of care in patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel plus gemcitabine or FOLFIRINOX.

BACKGROUND: We compared real-world treatment patterns, resource utilization, and cost of care for patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel + gemcitabine or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin). METHODS: This was a retrospective study of inpatient and hospital-based outpatient data in the United States. Primary endpoints included median time to treatment discontinuation (TTD) and total cost of care per patient per month. Secondary endpoints included supportive care costs and hospitalization rate and length. RESULTS: Overall, 345 patients were included (nab-paclitaxel + gemcitabine, n = 182; FOLFIRINOX, n = 163). Median TTD was significantly longer with nab-paclitaxel + gemcitabine vs FOLFIRINOX (4.3 vs 2.8 months; P = .0009). Mean acquisition cost was higher with nab-paclitaxel + gemcitabine ($10,643 vs $6549; P = .0043), but mean total cost of care was lower ($16,628 vs $19,936; P = .1740). Supportive care cost was significantly lower with nab-paclitaxel + gemcitabine ($1995 vs $6456; P < .0001). Hospitalization rate and length were both significantly lower with nab-paclitaxel + gemcitabine. CONCLUSIONS: Despite higher acquisition costs with nab-paclitaxel + gemcitabine, FOLFIRINOX-treated patients had higher total costs driven by supportive care. Toxicity-related costs and drug acquisition costs should be considered when evaluating total cost of care.

Chemotherapy-induced Sinusoidal Injury (CSI) score: a novel histologic assessment of chemotherapy-related hepatic sinusoidal injury in patients with colorectal liver metastasis.

BACKGROUND: Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI). METHODS: The expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores. RESULTS: Abnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02). CONCLUSIONS: The CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.

Bioequivalence of Branded and Generic Oxaliplatin: From Preclinical Assessment to Clinical Incidence of Hypersensitivity Reactions.

BACKGROUND: Generic anticancer drugs represent an opportunity in terms of cost savings but there are some concerns about their tolerability. The safety profiles of generic versus branded oxaliplatin formulations have never been studied in detail. PATIENTS AND METHODS: We tested in vitro concentrations, stability and efficacy of branded versus generic oxaliplatin formulations, then we retrospectively collected data about hypersensitivity reactions (HSR) of 427 colorectal cancer patients treated with oxaliplatin-based regimens. RESULTS: No significant difference in oxaliplatin concentration or time-dependent antiproliferative activity between branded and generic oxaliplatin was detected. The incidence of HSR was 12.1% (33/273 patients) in those treated with branded and 9.8% (15/154 patients) in those treated with generic oxaliplatin (p=0.46). The occurrence of grade III-IV HSRs and severe HSRs leading to oxaliplatin discontinuation were comparable. CONCLUSION: No difference between generic and branded formulations of oxaliplatin were demonstrated in preclinical nor in clinical settings. Generic oxaliplatin can be considered a safe alternative to branded formulation.

Assessment of Injection Site Reactions for Peripheral Intravenous Oxaliplatin Infusion and Potential Remedies.

We investigated the medical and nursing records of 19 patients with unresectable advanced recurrent colorectal cancers treated using oxaliplatin and capecitabine(CapeOX)with or without bevacizumab at the outpatient tumor center of Showa UniversityHospital between November 1, 2009 and November 30, 2011, to clarifydifferences in the incidence of injection site reactions according to the use or non-use of an intravenous infusion solution warming device. Vascular pain and other injection site reactions occurred in 13 patients(68.4%). Injection site reactions occurred in 33 of the total of 77 chemotherapytreatments (42.9%). No difference in incidence of injection site reactions was seen according to whether the intravenous infusion solution warmer was used. The most common time to onset of injection site reactions after commencing oxaliplatin administration was 60-90 min, and symptoms were seen to decrease when non-steroidal anti-inflammatorydrugs were coadministered. We intend to leverage these studyfindings to demonstrate the mechanism of onset for injection site reactions and to propose measures for handling adverse drug reactions.

Preoperative assessment of chemotherapeutic associated liver injury based on indocyanine green retention test.

BACKGROUND: The aim of the study was to assess the capacity of indocyanine green retention test at 15 min (ICGR15) to predict chemotherapeutic-associated liver injuries (CALI). METHODS: Patients undergoing liver resection for CLM that received preoperative oxaliplatin and/or irintecan-based chemotherapy within 3 months before surgery and scheduled first hepatectomy were considered. RESULTS: 166 out of 983 patients treated between 01/2001 and 04/2014 fulfilled the inclusion criteria. The median number of cycles of preoperative chemotherapy was 6.0 ± 4.87. Chemotherapy was mainly based on oxaliplatin in 123 (74.1%). Bevacizumab was associated in 51(31%) patients. A total of 102 (61.4%) patients had at least 1 CALI. Grade 2-3 steatosis occurred in 56 (33.7%) patients and steatohepatitis in19(11.5%). Sinusoidal obstructive syndrome (SOS) was presented in 93 (56%) patients. 23(13.8%) patients had nodular regeneration hyperplasia. At multivariate analysis the only predictive factor of ICGR≥10% was age≥65 years (p = 0.001). A median split (ICGR15 = 8%) was used to categorized ICGR15 value. Multivariate analysis showed that age≥ 65 [OR 2.530 (CI95% 1.28-4.97) p < 0.001], male sex [OR 2.614 (CI95% 1.31-5.20) p < 0.001], SOS [OR 1.954 (CI95% 1.00-3.81) p = 0.050] and administration of Bevacizumab [OR 2.201 (CI95% 1.07-4.50) p = 0.031] were predictive factors for ICGR≥8%. CONCLUSIONS: ICGR15 test can predict the diagnosis of SOS. High ICGR15 value is more common in elderly male patients and after bevacizumab administration.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials.

BACKGROUND: Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. METHODS: We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. RESULTS: A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. CONCLUSION: We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254.

BACKGROUND: Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. METHODS: We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 (NCT00003594), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. FINDINGS: In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p<0·0001). In trial NCCTG N9741 there was an increased incidence of early nausea for patients given irinotecan plus oxaliplatin (IROX) compared with those given 5-fluorouracil plus oxaliplatin (FOLFOX; cycle 1 mean grade nausea 1·1 [SD 1·0] vs 0·6 [0·7]; p<0·0001). Event charts showed earlier occurrences of higher grades of diarrhoea for patients given IROX compared with those given FOLFOX, and the AUC analysis shows a higher magnitude of diarrhoea consistently over time throughout the study in patients given IROX versus those given FOLFOX (mean AUC 4·2 [SD 5·2] vs 2·9 [4·2]; p<0·0001). INTERPRETATION: The ToxT analytical approach incorporates the dimension of time into adverse event assessment and offers a more comprehensive depiction of toxic effects than present methods. With new, continuously administered targeted agents, immunotherapy, and maintenance regimens, these improved longitudinal analyses are directly relevant to patients and are crucial in cancer clinical trials. FUNDING: National Cancer Institute of the National Institutes of Health and the Mayo Comprehensive Cancer Center.

Population-Based Cost-Minimization Analysis of CAPOX Versus Modified FOLFOX6 in the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: Evidence suggests that CAPOX (capecitabine and oxaliplatin) has efficacy similar to 5-fluorouracil and oxaliplatin (mFOLFOX6) in the adjuvant treatment of colon cancer. CAPOX is partly administered orally and associated with a 3-week rather than a 2-week treatment cycle. A population-based cost-minimization analysis was conducted from the health care payer and societal perspectives to evaluate the potential cost savings of replacing mFOLFOX6 with CAPOX. METHODS: We applied treatment and toxicity data from phase III trials of CAPOX and FOLFOX-based regimens to the adjuvant colon cancer population in British Columbia, Canada. In this cost-minimization analysis we compared the total costs associated with chemotherapy medications, drug administration and delivery, hospital and clinic visits, treatment-related toxicities, and central venous access devices. Costs to patients in terms of lost time and travel were also considered. It was assumed that patients would receive either 8 cycles of CAPOX or 12 cycles of mFOLFOX6. RESULTS: From the payer perspective, the use of CAPOX resulted in cost savings of $5339 CAD per patient compared with the use of mFOLFOX6. From a societal perspective, CAPOX was also associated with savings of $6080 CAD per patient. The greatest cost savings with CAPOX were attributed to fewer visits for chemotherapy treatment and decreased central venous access device usage. CAPOX was also associated with reduced loss of time and decreased travel for patients because of the requirement of fewer clinic visits. CONCLUSIONS: Replacement of mFOLFOX6 with CAPOX in the adjuvant treatment of colon cancer might be associated with potential cost savings from the payer and societal perspectives.

The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: a Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of aflibercept (Sanofi) to submit clinical and cost-effectiveness evidence for aflibercept in combination with irinotecan and fluorouracil-based therapy [irinotecan/5-fluorouracil/folinic acid (FOLFIRI)] for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA307 issued in March 2014. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The clinical effectiveness data were derived from one good-quality double-blind randomised controlled trial (RCT), the VELOUR trial, which compared aflibercept plus FOLFIRI with placebo plus FOLFIRI. This RCT found a small but statistically significant increase in overall survival (OS); the difference in median OS was 1.44 months (13.5 months in the aflibercept group and 12.06 months in the placebo group). There was also a statistically significant increase in progression-free survival (PFS) with aflibercept; the difference in median PFS was 2.23 months (6.9 months in the aflibercept group and 4.67 months in the placebo group). However, grade 3-4 adverse events were more frequent in the aflibercept group than the placebo group: 83.5% compared with 62.5%. Treatment-emergent adverse events led to permanent discontinuation of treatment in 26.8% of patients in the aflibercept group and 12.1% of patients in the placebo group. The manufacturer's submission included an estimation of mean OS benefit based on extrapolation of the data, which was considerably longer than the median OS benefit reported (4.7 vs. 1.44 months). The ERG considered this to be an over estimate. The base-case incremental cost-effectiveness ratio (ICER) for the overall population was reported by the manufacturer to be £36,294 per quality-adjusted life-year (QALY). After correcting the model programming and updating the model to include the ERG's preferred parameter estimates, the ICER from the ERG's alternative base case was £54,368 per QALY. The extrapolation of the OS curves was the key cost-effectiveness driver and a major source of uncertainty in the model. Additional scenarios related to the extrapolation of OS undertaken by the ERG resulted in ICERs between £62,894 and £92,089 per QALY. After consideration of the manufacturer's submission and the ERG's critique, and submissions from other stakeholders, the NICE Appraisal Committee concluded that aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost effective use of National Health Service resources for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended for the treatment of metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen in NICE guidance TA307.

A cost-effectiveness analysis of a chemoresponse assay for treatment of patients with recurrent epithelial ovarian cancer.

OBJECTIVE: Clinical validation of a chemoresponse assay was recently published, demonstrating a significant increase in overall survival in recurrent ovarian cancer patients treated with therapies to which their tumor was sensitive in the assay. The current study investigates the cost effectiveness of using the assay at the time of ovarian cancer recurrence from the payer's perspective. METHODS: Using a Markov state transition model, patient characteristics and survival data from the recent clinical study, the cumulative costs over the study horizon (71 months) for both the baseline (no assay) and intervention (assay consistent, hypothetical) cohorts were evaluated. RESULTS: The assay consistent cohort had an incremental cost effectiveness ratio (ICER) of $6206 per life year saved (LYS), as compared to the baseline cohort. Cost-effectiveness was further demonstrated in platinum-sensitive and platinum-resistant populations treated with assay-sensitive therapies, with ICERs of $2773 per LYS and $2736 per LYS, respectively. CONCLUSIONS: The use of a chemoresponse assay to inform treatment decisions in recurrent ovarian cancer patients has the potential to be cost-effective in both platinum-sensitive and platinum-resistant patients.

Efficacy and safety of single agent or combination adjuvant chemotherapy in elderly patients with colon cancer: a Canadian cancer institute experience.

BACKGROUND: The pattern of adjuvant chemotherapy (AC) use, toxicity profile, and survival benefit in elderly patients with colon cancer (CC) is unclear. We sought to (1) determine whether patients ≥ 65 years with stage III CC were offered single-agent or combination AC, (2) evaluate the reason for selecting single-agent versus combination AC, (3) evaluate the toxicity profile of single-agent and combination AC in the elderly, and (4) determine whether a survival benefit exists for elderly patients receiving combination AC. PATIENTS AND METHODS: A retrospective analysis of records of patients ≥ 65 years diagnosed with stage III CC from 2004 to 2010 was performed to identify baseline characteristics, AC protocols, toxicity, dose intensity, and survival. RESULTS: Two hundred sixty-eight patients ≥ 65 years were diagnosed and treated with AC from 2004 to 2010. Of these patients, 178 were treated with single-agent AC and 90 were treated with combination AC. The most common reasons for choosing single-agent AC were patient preference, comorbidities, and lack of drug coverage. For each year over 65 years, the odds of receiving combination over single-agent AC decreased by 22%. There were more dose delays, dose reductions, and early chemotherapy discontinuation in the combination AC group because of hematologic toxicity. The 5-year overall survival (OS) was 73% in patients who received single-agent AC compared with 84% in those who received combination AC. There was no difference in cancer-related deaths between the groups. CONCLUSION: In elderly patients treated with AC for stage III CC, single-agent AC is used more frequently than combination AC, based on age, comorbidities, and patient choice. Toxicity with combination AC in elderly patients is high. No survival benefit was seen with combination AC over single-agent AC.

Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016).

Oxaliplatin, a third-generation platinum compound incorporating oxalate and 1,2-diaminocyclohexane platinum, has been widely used in chemotherapy regimens for the treatment of metastatic colorectal cancer. Because of its wide spectrum of antitumor activity, oxaliplatin has been applied for the treatment of other carcinomas. However, the antitumor activity of single-agent oxaliplatin is insufficient. To increase its antitumor effects, polymeric micellar nanoparticles incorporating 1,2-diaminocyclohexane platinum (NC-4016) have been developed. The present study was designed to evaluate the efficacy of NC-4016 and its association with peripheral neuropathy, which is a primary dose-limiting factor in oxaliplatin therapy. The in vitro antitumor activity of NC-4016 was investigated using human carcinoma cell lines. To investigate the antitumor effects of NC-4016 in vivo, nude mice bearing the human carcinoma cell line KB were administered NC-4016 or oxaliplatin. The in vitro growth-inhibiting effect of NC-4016 was significantly weaker than that of oxaliplatin. However, the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in vivo. Moreover, we compared the severity of peripheral neuropathy induced by oxaliplatin and NC-4016 in a rat model. Oxaliplatin, NC-4016, or 5% glucose (control) were administered by a single tail vein injection. In the oxaliplatin-treated rats, neither mechanical nor heat allodynia was observed during the experimental period, whereas cold hyperalgesia/allodynia was observed from day 1 to 7. Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. The present study demonstrated that the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in a mouse model of human carcinoma cell line KB. In addition, NC-4016-treated rats did not develop acute cold hypersensitivity, which is frequently experienced by patients after oxaliplatin administration.