Syed Zafar

BACKGROUND: Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. METHODS: All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). RESULTS: A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1-14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60-84%). Median PFS and OS were 3.9 months (95% CI, 2.3-4.5) and 7.1 months (95% CI: 5.8-10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. CONCLUSION: The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. TRIAL REGISTRATION: This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

PURPOSE: Financial toxicity is a well-recognized adverse effect of cancer care, yet little is known about how women consider treatment costs when facing preference-sensitive decisions for breast cancer surgery or how surgical treatment choice affects financial harm. We sought to determine how financial costs and burden relate to decisions for breast cancer surgery. METHODS: Women (≥ 18 years old) with a history of breast cancer were recruited from the Army of Women and Sisters Network to complete an 88-item electronic survey. Descriptive statistics and regression analysis were used to evaluate the impact of costs on surgical decisions and financial harm after breast cancer surgery. RESULTS: A total of 607 women with stage 0 to III breast cancer were included. Most were white (90%), were insured privately (70%) or by Medicare (25%), were college educated (78%), and reported household incomes of more than $74,000 (56%). Forty-three percent underwent breast-conserving surgery, 25% underwent mastectomy, 32% underwent bilateral mastectomy, and 36% underwent breast reconstruction. Twenty-eight percent reported that costs of treatment influenced their surgical decisions, and at incomes of $45,000 per year, costs were prioritized over breast preservation or appearance. Overall, 35% reported financial burden as a result of their cancer treatment, and 78% never discussed costs with their cancer team. When compared with breast-conserving surgery, bilateral mastectomy with or without reconstruction was significantly associated with higher incurred debt, significant to catastrophic financial burden, treatment-related financial hardship, and altered employment. Among the highest incomes, 65% of women were fiscally unprepared, reporting higher-than-expected (26%) treatment costs. CONCLUSION: Cancer treatment costs influenced decisions for breast cancer surgery, and comparably effective surgical treatments differed significantly in their risk of patient-reported financial burden, debt, and impact on employment. Cost transparency may inform preference-sensitive surgical decisions and improve patient-centered care.

PURPOSE: This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer. METHODS: The first stage of this study was a standard "3 + 3" open-label dose-escalation scheme. Cohorts of 3-6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis. RESULTS: Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level - 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level - 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events. CONCLUSIONS: The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer.

Because of the rising costs of cancer care and ongoing challenges in ensuring access to quality care, there is an increasing need to prioritize spending and define the benefits of therapy in proportion to costs. The term "value" has gained favor as means to define the relative utility of a medical intervention in terms of benefits, risks, and financial costs, which in turn can help clinicians, patients, and policy makers prioritize "high-value" care. While numerous value concepts have been proposed, a comprehensive discussion of value initiatives along the care continuum is missing. In this Commentary, we propose a health system taxonomy of value initiatives in cancer care to discuss what the field needs to progress.