Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review.

BACKGROUND: Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. METHODS: Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA). RESULTS: Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. CONCLUSIONS: Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.

Medical Oncologists' Perspectives on How the Results of the IDEA Collaboration Impact the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy are noninferior to 6 months. Our study objectives were to characterize medical oncologists' perspectives toward the results of the IDEA collaboration and to evaluate how IDEA impacted prescribing patterns of adjuvant FOLFOX and CAPOX in colon cancer. MATERIALS AND METHODS: A list of questions developed by four medical oncologists regarding IDEA results were formulated and distributed online to gastrointestinal medical oncologists globally. Descriptive statistics and chi-square tests were used to summarize information. RESULTS: Of 174 responses, 145 were complete and analyzed. Responses were obtained globally from South America (53%); the U.S. and Canada (28%); Europe, Australia, and New Zealand (12%); and Asia (7%). Most clinicians (98%) were aware of the IDEA study. Prior to IDEA, clinicians preferred FOLFOX over CAPOX (81% vs. 19%). Subsequent to IDEA, 55% of clinicians preferred CAPOX over FOLFOX (odds ratio, 5.0; 95% confidence interval, 3.0-8.5; p < .01 compared with pre-IDEA). Two thirds (68%) of responders tailored duration of adjuvant therapy based on risk stratification. Most oncologists (76%) were more willing to discontinue oxaliplatin early if toxicities develop after the results of IDEA. Half of responders (50%) found that IDEA increased their confidence in decision making for adjuvant treatment; 36% were unchanged, and 15% indicated decreased confidence. Less than half (48%) were comfortable communicating the study results and the concept of a noninferiority trial with patients. CONCLUSION: IDEA appears to have shifted clinician preference from FOLFOX to CAPOX for adjuvant therapy, and most clinicians now use a risk-stratified approach in determining duration of adjuvant therapy. Patient education resources may facilitate better communication of IDEA results to patients. IMPLICATIONS FOR PRACTICE: This global survey illustrates that most gastrointestinal medical oncologists now use a risk-stratified approach for determining the duration of adjuvant chemotherapy for stage III colon cancer. Clinicians are five times more likely to choose CAPOX over FOLFOX after the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration results.

Cost-Effectiveness Analysis of Cytoreductive Surgery and HIPEC Compared With Systemic Chemotherapy in Isolated Peritoneal Carcinomatosis From Metastatic Colorectal Cancer.

BACKGROUND: Cost-effectiveness evaluations of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC) from metastatic colorectal cancer (mCRC) in the United States are lacking. METHODS: The authors developed a Markov model to evaluate the cost-effectiveness of CRS/HIPEC compared with systemic chemotherapy for isolated PC from mCRC from a societal perspective in the United States. The systemic treatment regimens consisted of FOLFOX, FOLFIRI, bevacizumab, cetuximab, and pantitumumab. The model inputs including costs, probabilities, survival, progression, and utilities were taken from the literature. The cycle length for the model was 2 weeks, and the time horizon was 7 years. A discount rate of 3% was applied. The model was tested for internal and external validation, and robustness was established with univariate sensitivity and probabilistic sensitivity analyses (PSA). The primary outcomes were total costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER). A willingness-to-pay (WTP) threshold of $100,000 per QALY was assumed. RESULTS: The ICER for treatment with CRS/HIPEC compared with systemic chemotherapy was $91,034 per QALY gained ($74,098 per LY gained). The univariate sensitivity analysis showed that the total costs for treatment with CRS/HIPEC had the largest effect on the calculated ICER. The CRS/HIPEC treatment was a cost-effective strategy during the majority of simulations in the PSA. The average ICER for 100,000 simulations in the PSA was $70,807 per QALY gained. The likelihood of CRS/HIPEC being a cost-effective strategy at the WTP threshold was 87%. CONCLUSIONS: The CRS/HIPEC procedure is a cost-effective treatment for isolated PC from mCRC in the United States.

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.