Cisplatin-Based versus Carboplatin-Based Chemotherapy for Extrapulmonary Neuroendocrine Carcinomas: A Real-World Study.

OBJECTIVE: This study aimed to assess the survival differences between cisplatin/etoposide versus carboplatin/etoposide chemotherapy regimens in the management of patients with extrapulmonary neuroendocrine carcinomas (NECs). METHODS: Administrative cancer care databases in the province of Alberta, Canada, were reviewed, and patients with extrapulmonary NECs (including those with small cell and large cell neuroendocrine carcinomas) who were treated with either cisplatin/etoposide or carboplatin/etoposide, 2004-2019, were reviewed. Kaplan-Meier survival estimates were used to compare the survival outcomes according to the type of platinum agent, and multivariable Cox regression analysis was used to assess the impact of the type of platinum agent on overall survival outcomes. RESULTS: A total of 263 eligible patients were included in this analysis. These include 176 patients who received cisplatin/etoposide and 87 patients who received carboplatin/etoposide. Using Kaplan-Meier survival estimates, patients treated with cisplatin had better overall survival compared to patients treated with carboplatin (p = 0.005). Multivariable Cox regression analysis suggested that the following factors were associated with worse overall survival: higher Charlson comorbidity index (HR: 1.17; 95% CI: 1.05-1.30), gastrointestinal primary site (HR: 1.55; 95% CI: 1.12-2.14), stage IV disease (HR: 1.75; 95% CI: 1.28-2.38), and use of carboplatin (HR: 1.40; 95% CI: 1.02-1.92). CONCLUSIONS: The current study suggested that cisplatin/etoposide might be associated with better overall survival compared to carboplatin/etoposide among patients with extrapulmonary NECs. It is unclear if this is related to differences in inherent responsiveness to the 2 platinum agents or due to differences in comorbidity burden between the 2 treatment groups.

Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study.

Importance: Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H). Objective: To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. Design, Setting, and Participants: A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. Interventions: We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. Main Outcomes and Measures: The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). Results: Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). Conclusions and Relevance: This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02870920.

Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III).

PURPOSE: To compare the efficacy of cediranib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKI]) with that of bevacizumab (anti-VEGF-A monoclonal antibody) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer] had an adaptive phase II/III design. Patients randomly assigned 1:1:1 received mFOLFOX6 [oxaliplatin 85 mg/m(2) and leucovorin 400 mg/m(2) intravenously followed by fluorouracil 400 mg/m(2) intravenously on day 1 and then continuous infusion of 2,400 mg/m(2) over the next 46 hours every 2 weeks] with cediranib (20 or 30 mg per day) or bevacizumab (5 mg/kg every 14 days). An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab (randomly assigned 1:1). The primary objective was to compare progression-free survival (PFS). RESULTS: In all, 1,422 patients received mFOLFOX6/cediranib 20 mg (n = 709) or mFOLFOX6/bevacizumab (n = 713). Primary analysis revealed no significant difference between arms for PFS (hazard ratio [HR], 1.10; 95% CI, 0.97 to 1.25; P = .119), overall survival (OS; HR, 0.95; 95% CI, 0.82 to 1.10; P = .541), or overall response rate (46.3% v 47.3%). Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab. The PFS upper 95% CI was outside the predefined noninferiority limit (HR < 1.2). Common adverse events with more than 5% incidence in the cediranib arm included diarrhea, neutropenia, and hypertension. Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients (median 10 v 12 cycles). Patient-reported outcomes (PROs) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients (P < .001). CONCLUSION: Cediranib activity, in terms of PFS and OS, was comparable to that of bevacizumab when added to mFOLFOX6; however, the predefined boundary for PFS noninferiority was not met. The cediranib safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab. Investigation of oral TKIs in CRC continues.

Final results of a phase II clinical trial of weekly docetaxel in combination with capecitabine in anthracycline-pretreated metastatic breast cancer.

The addition of capecitabine to docetaxel on a 3-week schedule resulted in superior response rate, increased time to progression (TTP), and improved overall survival in patients with anthracycline-pretreated metastatic breast cancer (MBC). Because the toxicity profile of weekly docetaxel differs from the standard 21-day docetaxel schedule, we performed a phase I/II trial to test the efficacy and safety of weekly docetaxel in combination with capecitabine given for 14 days every 21 days. The phase I study identified the doses of docetaxel (30 mg/m2 weekly) and capecitabine (900 mg/m2 twice daily on days 1-14 every 21 days) used in phase II. Twenty female patients with measurable or assessable MBC were enrolled. Eighteen patients had previously received anthracyclines; 2 had contraindications to anthracyclines. Patients remained on study for a maximum of eight 3-week cycles or until tumor progression or unacceptable toxicity occurred; response assessments were scheduled after cycle 2, 5, and 8. Seventeen patients were assessed after cycle 2; 3 subjects (18%) had a partial response (PR), 9 had stable disease (53%; SD), and 5 patients (29%) had progressive disease (PD). Ten patients were assessable after cycle 5. Two patients (20%) had a PR, 5 patients (50%) had SD, and 3 patients (30%) had PD. The most common grade 3 toxicities were nail loss (45%), asthenia (30%), and hand-foot syndrome (30%), and toxicities led to study discontinuation in 10 patients. The median time to treatment failure was 10 weeks and median TTP was 26 weeks. The median duration of response was 9 weeks and the median duration of SD was 16 weeks. The median overall survival was 82 weeks. This schedule of weekly docetaxel in combination with day 1-14 capecitabine has activity; however, toxicity discourages the use of this schedule in lieu of the standard docetaxel/capecitabine regimen.

Immunohistochemical variation of human equilibrative nucleoside transporter 1 protein in primary breast cancers.

Gemcitabine and capecitabine are nucleoside analogues used in chemotherapy strategies for the treatment of breast cancer. We previously demonstrated that deficiency in hENT1, the most abundant and widely distributed plasma membrane nucleoside transporter in human cells, confers high-level resistance to gemcitabine toxicity in vitro, whereas the relationship between hENT1 activity and capecitabine toxicity is unknown. To determine the relationship between capecitabine cytotoxicity and hENT1 abundance, cultured MDA-MB-435s human mammary carcinoma cells were exposed to graded concentrations of the capecitabine metabolites, 5'-deoxy-5-fluorouridine or 5-fluorouracil, in the presence and absence of nitrobenzylmercaptopurine ribonucleoside (NBMPR), a tight-binding inhibitor of hENT1. The presence of NBMPR reduced the cytotoxic effects of 5'-deoxy-5-fluorouridine, indicating that hENT1 also enabled cellular uptake of this capecitabine metabolite by breast cancer cells. We report here the development of an immunohistochemical method to assess the hENT1 abundance of malignant cells in solid tumors. Frozen sections of 33 primary breast cancers were stained with monoclonal antibodies raised against a synthetic peptide derived from the large intracellular loop of hENT1, and staining intensity was scored on a 0-4+ scale. hENT1 staining intensity varied markedly among breast samples (4 with score 0, 5 with score 1+, 7 with score 2+, 14 with score 3+, 3 with score 4+), suggesting that at least 9 of the tumors were hENT1 deficient. We conclude that because hENT1 deficiency has previously been associated with nucleoside drug resistance, immunohistochemical staining of hENT1 warrants further study as a predictive tool for guiding the appropriate use of gemcitabine and capecitabine in the treatment of breast cancer.