Clinical and molecular characterization of patients with cancer of unknown primary in the modern era.

BACKGROUND: On the basis of historical data, patients with cancer of unknown primary (CUP) are generally assumed to have a dismal prognosis with overall survival of less than 1 year. Treatment is typically cytotoxic chemotherapy guided by histologic features and the pattern of metastatic spread. The purpose of this study was to provide a clinical and pathologic description of patients with CUP in the modern era, to define the frequency of clinically actionable molecular alterations in this population, to determine how molecular testing can alter therapeutic decisions, and to investigate novel uses of next-generation sequencing in the evaluation and treatment of patients with CUP. PATIENTS AND METHODS: Under Institutional Review Board approval, we identified all CUP patients evaluated at our institution over a recent 2-year period. We documented demographic information, clinical outcomes, pathologic evaluations, next-generation sequencing of available tumor tissue, use of targeted therapies, and clinical trial enrollment. RESULTS: We identified 333 patients with a diagnosis of CUP evaluated at our institution from 1 January 2014 through 30 June 2016. Of these patients, 150 had targeted next-generation sequencing carried out on available tissue. Median overall survival in this cohort was 13 months. Forty-five of 150 (30%) patients had potentially targetable genomic alterations identified by tumor molecular profiling, and 15 of 150 (10%) received targeted therapies. Dominant mutation signatures were identified in 21 of 150 (14%), largely implicating exogenous mutagen exposures such as ultraviolet radiation and tobacco. CONCLUSIONS: Patients with CUP represent a heterogeneous population, harboring a variety of potentially targetable alterations. Next-generation sequencing may provide an opportunity for CUP patients to benefit from novel personalized therapies.

A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.

BACKGROUND: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. METHODS: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m(-2) and cisplatin 25 mg m(-2) on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand-foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m(-2), cisplatin 20 mg m(-2) and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57-77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. RESULTS: A total of 39 patients were accrued. The most common grade 3-4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34-66%). Median PFS and overall survival were 6.5 (95% CI: 3.5-8.3) and 14.4 months (95% CI: 11.6-19.2 months), respectively. No correlation was observed between pERK and outcomes. CONCLUSION: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

Tobacco use is associated with increased recurrence and death from gastric cancer.

BACKGROUND: Tobacco use increases the risk of developing gastric cancer. We examined the hypothesis that gastric cancer developing in patients with a history of tobacco use may be associated with increased risk of cancer-specific death after curative surgical resection. METHODS: From the Memorial Sloan-Kettering Cancer Center Gastric Cancer prospective surgical database, we collected baseline demographic data and tumor characteristics from all patients who had undergone curative resection for gastric cancer between 1995 and 2009 and who had not received pre- or postoperative chemo- or radiotherapy. A smoking history was defined as >100 cigarettes' lifetime use. The primary end point was gastric cancer disease-specific survival (DSS); secondary end points were 5-year disease-free survival (DFS) and overall survival (OS). Gastric cancer-specific hazard was modeled by Cox regression. RESULTS: A total of 699 eligible patients were identified with a median age of 70 years (range 25-96 years); 410 (59%) were current or previous smokers. Smoking was associated with gastroesophageal junction/cardia tumors and white non-Hispanic ethnicity. Multivariate analysis included the following variables: tumor stage, age, performance status, diabetes mellitus, gender, and tumor location. In this analysis, the hazard ratio for gastric cancer DSS in smokers was 1.43 (95% confidence interval 1.08-1.91, P=0.01). Smoking was also an independent significant risk factor for worse 5-year DFS (hazard ratio 1.46, P=0.007) and OS (hazard ratio 1.48, P=0.003). Among 516 patients for whom tobacco pack-year usage was available, both heavy (≥20 pack-years) and light (<20 pack-years) tobacco use was significantly associated with DSS, DFS, and OS. CONCLUSIONS: Smoking history appears to be an independent risk factor for death from gastric cancer in patients who have undergone curative surgical resection.

Risk factors for developing a new venous thromboembolism in ambulatory patients with non-hematologic malignancies and impact on survival for gastroesophageal malignancies.

BACKGROUND: Venous thromboembolism(VTE) is a significant, common comorbidity of cancer patients associated with increased mortality. We evaluated the incidence and risk factors for developing a new VTE in ambulatory cancer patients while they were receiving therapy for advanced cancer. We also examined the affect of developing a new VTE on survival for patients with gastroesophageal malignancies. METHODS: All patients with non-hematologic malignancies who were treated using investigator-initiated therapeutic protocols at Memorial Sloan Kettering Cancer Center (MSKCC) from 2003 through to 2005 were identified for this cohort study. The occurrence of VTE was prospectively recorded in an actively managed clinical research database. Baseline laboratory parameters, treatment details and tumor type were correlated with VTE risk and patient survival. RESULTS: 115 out of 2120 patients being treated for advanced malignancy developed a new VTE (12.8 VTEs/100 person-years). In multivariate analysis, a diagnosis of gastroesophageal cancer (hazard ratio (HR), 2.76 (1.41-5.38); P=0.003), pancreatic cancer (HR, 2.26 (1.06-4.80); P=0.05), use of white cell growth factors (HR 1.69(1.09-2.64); P=0.02) and irinotecan therapy (HR, 1.89 (1.29-3.59); P=0.05) were independently associated with VTE development. Hemoglobin >10 g dL(-1) (HR, 0.52 (0.3-0.91); P=0.02) and albumin ≥ 4 g dL(-1) (HR, 0.61 (0.39-0.94); P=0.024) were associated with reduced VTE risk. The unadjusted HR for death among ambulatory gastroesophageal cancer patients with VTE is 0.89 (0.61-1.3), P=0.53. After adjusting for confounding risk factors associated with survival, the HR for death associated with VTE is 0.78 (0.5-1.2), P=0.25. CONCLUSION: Upper gastrointestinal malignancies are independently associated with the development of a new VTE, implicating tumor biology in VTE development. Even after adjusting for prognostic factors, we were unable to demonstrate an adverse impact on survival due to the new development of VTE amongst patients with active gastroesophageal malignancy receiving therapy.

Pancreatic adenocarcinoma in a young patient population--12-year experience at Memorial Sloan Kettering Cancer Center.

BACKGROUND: There is a dearth of data in a younger population of patients with pancreatic ductal adenocarcinoma (PAC) regarding epidemiology, genetics, prognosis, and outcome. This report examines a large cohort of patients with PAC

Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer.

BACKGROUND: The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5-fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone (Dex) in the adjuvant setting after hepatic resection. METHODS: Thirty-five patients with resected liver metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU. RESULTS: The initial dose of HAI FUDR was fixed at 0.12 mg/kg x pump volume divided by pump flow rate plus Dex infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85 to 100 mg/m2 and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m2. The LV dose was fixed at 400 mg/m). Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4-year survival and progression-free survival were 88% and 50%, respectively. CONCLUSIONS: Adjuvant therapy after liver resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m2 and 5-FU by continuous infusion at 2000 g/m2 with LV at 400 mg/m2 is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).

BACKGROUND: The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. METHODS: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47). CONCLUSIONS: GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.

Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis.

BACKGROUND: Response rates to systemic chemotherapy are low after tumor progression on oxaliplatin regimens. Hepatic arterial infusion (HAI) therapy in patients with tumor progression is a viable alternative. PATIENTS AND METHODS: Thirty-nine heavily pre-treated patients (all receiving prior oxaliplatin) with unresectable colorectal hepatic metastases were treated with systemic CPT-11 and concurrent HAI floxuridine (FUDR) and dexamethasone (DEX). RESULTS: Partial responses were seen in 44% of patients. Median time to hepatic progression was 8.6 months, and median time to overall progression was 6.5 months. Median survival from time of initiation of HAI was 20.1 months [95% confidence interval (CI) 16.9-21.4] and from the initiation of treatment of metastatic disease, 32.01 months (95% CI 29.1-34.6). After a median follow-up of 19.1 months, seven patients (18%) proceeded to potentially curative surgery. Grade 3/4 toxic effects included neutropenia (13%), diarrhea (15%), intra-abdominal hemorrhage (2%), and bleeding duodenal ulcer (2%). Elevated liver function tests were seen, including bilirubin concentration >3 mg/dl (7%), alkaline phosphatase 2X baseline (20%), and aspartate aminotransferase >3X baseline (26%). CONCLUSIONS: HAI FUDR/DEX plus systemic CPT-11 achieves a response rate of 44% and a median overall survival of 20 months in heavily pre-treated patients with colorectal hepatic metastases all receiving previous oxaliplatin; 18% of patients proceeded to surgical resection or ablation.

Systemic chemotherapy does not increase the risk of gastrointestinal perforation.

BACKGROUND: Gastrointestinal perforation is a rare complication of gastric cancer. Although there is the perception of chemotherapy aggravating the perforation risk, the rate of perforation in patients with gastric cancer receiving chemotherapy is unknown. This study describes the incidence and clinical course of patients with gastric or gastroesophageal junction (GEJ) carcinoma who experience a perforation while receiving chemotherapy. PATIENTS AND METHODS: The records of patients with gastric or GEJ adenocarcinoma over a 6-year period who received chemotherapy for locally advanced or metastatic disease were reviewed. Extracted information included demographics, treatment received, and overall survival was calculated. RESULTS: 1032 patients at MSKCC received systemic cytotoxic chemotherapy for locally advanced or metastatic gastric or GEJ carcinoma; 11 patients experienced a perforation (1.1%, 95% CI 0.5-1.9%); 5/11 (45%) patients received further chemotherapy and had a median survival of 5.6 months. CONCLUSIONS: The rate of perforation in patients with advanced GEJ/gastric adenocarcinoma receiving chemotherapy is 1.1%, which is the same rate as in surgical series of patients presenting with perforation. Chemotherapy does not significantly add to the risk of gastrointestinal perforation.