Clinical Outcomes Following Regionalization of Gastric Cancer Care in a US Integrated Health Care System.

PURPOSE: In 2016, Kaiser Permanente Northern California regionalized gastric cancer care, introducing a regional comprehensive multidisciplinary care team, standardizing staging and chemotherapy, and implementing laparoscopic gastrectomy and D2 lymphadenectomy for patients eligible for curative-intent surgery. This study evaluated the effect of regionalization on outcomes. METHODS: The retrospective cohort study included gastric cancer cases diagnosed from January 2010 to May 2018. Information was obtained from the electronic medical record, cancer registry, state vital statistics, and chart review. Overall survival was compared in patients with all stages of disease, stage I-III disease, and curative-intent gastrectomy patients using annual inception cohorts. For the latter, the surgical approach and surgical outcomes were also compared. RESULTS: Among 1,429 eligible patients with gastric cancer with all stages of disease, one third were treated after regionalization, 650 had stage I-III disease, and 394 underwent curative-intent surgery. Among surgical patients, neoadjuvant chemotherapy utilization increased from 35% to 66% (P < .0001), laparoscopic gastrectomy increased from 18% to 92% (P < .0001), and D2 lymphadenectomy increased from 2% to 80% (P < .0001). Dissection of ≥ 15 lymph nodes increased from 61% to 95% (P < .0001). Surgical complication rates did not appear to increase after regionalization. Length of hospitalization decreased from 7 to 3 days (P < .001). Overall survival at 2 years was as follows: all stages, 32.8% pre and 37.3% post (P = .20); stage I-III cases with or without surgery, 55.6% and 61.1%, respectively (P = .25); and among surgery patients, 72.7% and 85.5%, respectively (P < .03). CONCLUSION: Regionalization of gastric cancer care within an integrated system allowed comprehensive multidisciplinary care, conversion to laparoscopic gastrectomy and D2 lymphadenectomy, increased overall survival among surgery patients, and no increase in surgical complications.

Phase 1 study of alisertib (MLN8237) and weekly irinotecan in adults with advanced solid tumors.

PURPOSE: Aurora kinases are overexpressed or amplified in numerous malignancies. This study was designed to determine the safety and tolerability of the Aurora A kinase inhibitor alisertib (MLN8237) when combined with weekly irinotecan. METHODS: In this single-center phase 1 study, adult patients with refractory advanced solid tumors received 100 mg/m2 irinotecan intravenously on day 1 and 8 of a 21-day cycle. Alisertib at planned escalating dose levels of 20-60 mg was administered orally twice per day on days 1-3 and 8-10. Patients homozygous for UGT1A1*28 were excluded. The primary objective was the safety of alisertib when combined with irinotecan to determine the maximum tolerated dose (MTD). Secondary objectives included overall response rate by RECIST and pharmacokinetics in a planned expansion cohort of patients with colorectal cancer treated at the MTD. RESULTS: A total of 17 patients enrolled at three dose levels. Dose-limiting toxicities included diarrhea, dehydration, and neutropenia. The MTD of alisertib combined with weekly irinotecan was 20 mg twice per day on days 1-3 and 8-10. One fatal cardiac arrest at the highest dose level tested was deemed possibly related to drug treatment. One partial response in 11 efficacy evaluable patients (9%) occurred in a patient with small cell lung cancer. The study was terminated prior to the planned expansion in patients with colorectal cancer. CONCLUSION: In contrast to prior results in a pediatric population, adult patients did not tolerate alisertib combined with irinotecan at clinically meaningful doses due to hematologic and gastrointestinal toxicities. The study was registered with ClinicalTrials.gov under study number NCT01923337 on Aug 15, 2013.

A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors.

PURPOSE: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. METHODS: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120-360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. RESULTS: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy. CONCLUSIONS: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

Integrating Chemotherapy into the Management of Oligometastatic Colorectal Cancer: Evidence-Based Approach Using Clinical Trial Findings.

BACKGROUND: This study used case reports to review the role of systemic chemotherapy in oligometastatic colorectal cancer (CRC) and to suggest ways to integrate clinical research findings into the interdisciplinary management of this potentially curable subset of patients. METHODS: This educational review discusses the role of chemotherapy in the management of oligometastatic metastatic CRC. RESULTS: In initially resectable oligometastatic CRC, the goal of chemotherapy is to eradicate micrometastatic disease. Perioperative 5-fluorouracil and oxaliplatin together with surgical resection can result in 5-year survival rates as high as 57 %. With the development of increasingly successful chemotherapy regimens, attention is being paid to chemotherapy used to convert patients with initially unresectable metastasis to patients with a chance of surgical cure. The choice of chemotherapy regimen requires consideration of the goals for therapy and assessment of both tumor- and patient-specific factors. CONCLUSION: This report discusses the choice and timing of chemotherapy in patients with initially resectable and borderline resectable metastatic CRC. Coordinated multidisciplinary care of such patients can optimize survival outcomes and result in cure for patients with this otherwise lethal disease.

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors.

PURPOSE: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m(2) and up to 10 doses of docetaxel (75 mg/m(2)) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. RESULTS: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. CONCLUSIONS: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m(2).

Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results.

PURPOSE: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. METHODS: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m(2) as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. RESULTS: The median PFS was 2.07 months (95% CI; 1.87-5.50 months) and the ORR was 11%. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23%), lymphopenia (23%), and fatigue (13%). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. CONCLUSIONS: Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.

Low-lying rectal cancer with anal canal involvement: abdominoperineal or low anterior resection after neoadjuvant chemoradiotherapy.

BACKGROUND: Rectal cancer with anal involvement is typically treated with abdominoperineal resection (APR). However, patients treated with neoadjuvant chemoradiotherapy with good clinical response and tumor regression from the anus present a controversial management dilemma. This is a report of patients treated with low anterior resection (LAR) versus APR. METHODS: Patients with T2-3N0-2M0 (IIA-IIIC) rectal cancer with anal canal involvement were eligible. Anal canal involvement was determined by sigmoidoscopy/colonoscopy or endoscopic ultrasound. Patients were treated in the prone position with the three-field technique to 45-50.4 Gy at 1.8 Gy/fraction given concurrently with 5-fluorouracil. Patients then underwent APR/LAR via total mesorectal excision 4-6 weeks after chemoradiotherapy. LAR was performed in patients with good sphincter function at presentation, in those with sufficient tumor regression away from anal canal to permit LAR, and in those compliant with close follow-up. RESULTS: A total of 32 patients with rectal cancer with anal canal involvement were treated with neoadjuvant chemoradiotherapy. Local control was 85% and 89% for patients treated with APR and LAR, respectively. Overall survival was 76% and 86% in patients treated with APR and LAR, respectively. Pathologic complete response was seen in 24% of patients who underwent APR and 27% of patients who underwent LAR. CONCLUSION: Rectal cancers with anal involvement with good clinical response after neoadjuvant chemoradiotherapy are typically treated with APR. However, LAR may be a feasible alternative, particularly in those with excellent clinical response to neoadjuvant treatment with sufficient tumor regression away from the anal canal. In these patients close follow-up is necessary, and APR may be reserved as salvage when needed.