Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer

BackgroundMethylnaltrexone (MNTX), a peripherally acting μ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data suggest that MOR activation can play a role in cancer progression and can be a target for anticancer therapy.Patients and methodsPooled data from advanced end-stage cancer patients with OIC, despite laxatives, treated in two randomized (phase III and IV), placebo-controlled trials with MNTX were analyzed for overall survival (OS) in an unplanned post hoc analysis. MNTX or placebo was given subcutaneously during the double-blinded phase, which was followed by the open-label phase, allowing MNTX treatment irrespective of initial randomization.ResultsIn two randomized, controlled trials, 229 cancer patients were randomized to MNTX (117, 51%) or placebo (112, 49%). Distribution of patients' characteristics and major tumor types did not significantly differ between arms. Treatment with MNTX compared with placebo [76 days, 95% confidence interval (CI) 43–109 versus 56 days, 95% CI 43–69; P = 0.033] and response (laxation) to treatment compared with no response (118 days, 95% CI 59–177 versus 55 days, 95% CI 40–70; P < 0.001) had a longer median OS, despite 56 (50%) of 112 patients ultimately crossing over from placebo to MNTX. Multivariable analysis demonstrated that response to therapy [hazard ratio (HR) 0.47, 95% CI 0.29–0.76; P = 0.002) and albumin ≥3.5 (HR 0.46, 95% CI 0.30–0.69; P < 0.001) were independent prognostic factors for increased OS. Of interest, there was no difference in OS between MNTX and placebo in 134 patients with advanced illness other than cancer treated in these randomized studies (P = 0.88).ConclusionThis unplanned post hoc analysis of two randomized trials demonstrates that treatment with MNTX and, even more so, response to MNTX are associated with increased OS, which supports the preclinical hypothesis that MOR can play a role in cancer progression. Targeting MOR with MNTX warrants further investigation in cancer therapy.Clinical trials numberNCT00401362, NCT00672477.     

Maintenance bevacizumab is associated with increased hemoglobin in patients with advanced, nonsquamous, non-small cell lung cancer

We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL (p =.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p =.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients.     

Combination chemotherapy in advanced lung cancer with increased survival.

Twenty-eight patients with lung cancer, 26 with extensive disease, were treated with the drugs Cytoxan (Cyt) and methotrexate (MTX). The schedule was based on cellular kinetics concepts. Initial therapy was with Cyt 1.1 g/m2 (intravenously) followed by MTX 20 mg/m2 orally, twice weekly, started 9 days later, when the tumor was considered to be most susceptible to an S-phase-specific drug. The course was repeated at three-week intervals. Based on dose response curves, Cyt and MTX dose modifications were individually adjusted to the whit blood cell counts and platelet counts over a 3-week period. Twenty of 28 patients (five of seven large cell, five of eight adenocarcinoma, 10 or 11 small cell, none of two epidermoid) responded with greater than or equal 50% tumor reduction. Ten patients had complete responses, seven of whom had small cell carcinoma. Two of the nonresponders were nonevaluable. Five patients were alive and the extimated median survival time of the patients is almost 1 year, which compares quite favorably to previous reports. On this schedule of therapy, very high doses of Cyt and MTX were maintained with less than 3% incidence per course of a WBC less than 1,500/mm3 or a platelet count less than 50,000/mm3.     

Hospital volume is associated with survival but not multimodality therapy in Medicare patients with advanced head and neck cancer

BACKGROUND:

Given the complexity of management of advanced head and neck squamous cell carcinoma (HNSCC), this study hypothesized that high hospital volume would be associated with receiving National Comprehensive Cancer Network (NCCN) guideline therapy and improved survival in patients with advanced HNSCC.

METHODS:

The Surveillance, Epidemiology, and End Results (SEER)‐Medicare database was used to identify patients with advanced HNSCC. Treatment modalities and survival were determined using Medicare data. Hospital volume was determined by the number of patients with HNSCC treated at each hospital.

RESULTS:

There were 1195 patients with advanced HNSCC who met inclusion criteria. In multivariable analyses, high hospital volume was not associated with receiving multimodality therapy per NCCN guidelines (odds ratio = 1.02, 95% confidence interval = 0.66‐1.60), but showed a nearly significant inverse association with survival in a model adjusted for National Cancer Institute–designated cancer center status, age, sex, race, socioeconomic status, marital status, comorbidity, year of diagnosis, tumor site, and tumor stage (hazard ratio = 0.85, 95% confidence interval = 0.69‐1.04).

CONCLUSIONS:

Medicare patients with advanced HNSCC treated at high‐volume hospitals were not more likely to receive NCCN guideline therapy, but had nearly statistically significant better survival, when compared with patients treated at low‐volume hospitals. These results suggest that features of high‐volume hospitals other than delivery of NCCN guideline therapy influence survival. Cancer 2013. © 2013 American Cancer Society.     

Prophylactic lymph node dissection in patients with advanced gastric cancer promotes increased survival time.

BACKGROUND. There is no consensus of opinion regarding the efficacy of lymph node dissection. METHODS. Data were analyzed from 452 patients with advanced gastric cancer who underwent curative resection in the Department of Surgery II, Kyushu University Hospital, between 1970 and 1985, with special reference to the lymph node metastasis. RESULTS. Metastatic lesions were evident in the dissected lymph nodes of 300 of 452 (66.4%) patients. Survival time for patients without lymph node metastasis was longer than for those with it (P less than 0.01). In patients without lymph node metastasis, the tumor was smaller, serosal invasion was less prominent, tumor growth was less infiltrating, and the tumor stage was, therefore, less advanced. Lymphatic involvement was found in 38.9% of the patients with no evidence of lymph node metastasis. CONCLUSIONS. Because the postoperative mortality rate is low in patients with lymph node dissection, the authors advocate prophylactic lymph node dissection to prevent a recurrence.     

CXCR4 expression on circulating pan-cytokeratin positive cells is associated with survival in patients with advanced non-small cell lung cancer

Background  

The CXC chemokine, CXCL12, and its receptor, CXCR4 promote metastases of a variety of solid tumors, including non-small cell lung cancer (NSCLC). The expression of CXCR4 on tumor cells may represent a critical biomarker for their propensity to metastasize. This study was performed to evaluate the hypothesis that co-expression of pan-cytokeratin and CXCR4 may be a prognostic marker for patients with advanced NSCLC.     

Obesity is associated with improved survival in patients with organ-confined clear-cell kidney cancer

Objectives  

Obesity increases the risk of developing renal cell carcinoma (RCC); however, it remains unclear whether obesity is associated with RCC aggressiveness and survival. We assessed whether different body mass index (BMI) levels at the time of surgery had an effect on long-term prognosis of RCC patients.     

Matrix metalloproteinase-9 is associated with disease-free survival and overall survival in patients with gastric cancer

Matrix metalloproteinase-9 is a member of the Matrix metalloproteinases (MMP) family, which is overexpressed in some solid tumor and thought to enhance the tumor invasion and metastasis ability. Our study is to investigate the association of MMP-9 expression with disease-free survival and overall survival of patients with gastric cancer. Clinical gastric cancer specimens and adjacent normal tissues from 286 patients who had not received neoadjuvant chemotherapy were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival and overall survival. High level of MMP-9 expression was detected in gastric cancer, significantly more than in adjacent normal epithelial cells. In gastric cancer, MMP-9 was significantly positively correlated with depth of invasion, lymph node metastasis and distant metastasis. However, no correlations between MMP-9 expression and patients' age, sex, tumor location or differentiation status were detected. The disease-free survival and overall survival were significantly shorter for patients with MMP-9 positive than those with MMP-9 negative tumors. Multivariate analysis identified MMP-9 was an independent prognostic factor for both disease-free survival and overall survival. Our findings provided convincing evidence for MMP-9 as an important role in human gastric cancer recurrence and prognosis. It might also serve as a novel target for both prognostic prediction and therapeutics.     

Overexpression of NUAK1 is associated with disease-free survival and overall survival in patients with gastric cancer

Transient receptor potential vanilloid 2 (TRPV2) was proved to play a crucial role in the tumor progression of various cancers. The association between the expression of TRPV2 and clinical outcome in cancer patients has not been studied yet. We aim to elucidate the role of TRPV2 in predicting prognosis of patients with esophageal squamous cell carcinoma (ESCC). Fresh frozen samples were collected immediately from 170 patients with ESCC after surgical resection from 2003 to 2008, including 45 pairs of tumor tissues and non-tumor tissues. TRPV2 expression was measured by quantitative real-time PCR. TRPV2 mRNA was over-expressed in ESCC tissues and cell lines. High expression of TRPV2 was observed more frequently in patients with advanced pT stage (P < 0.001), lymph node metastasis (P = 0.010) and advanced pathological stage (P = 0.001). Patients with high expression of TRPV2 (>44.40, n = 83) had worse 5-year disease-specific survival (40.0 vs 62.6 %, P < 0.001) and disease-free survival (38.4 vs 61.5 %, P < 0.001) than that with low expression (≤44.40, n = 87). Multivariate analysis found that the expression of TRPV2 mRNA (HR 2.19, 95 % CI 1.39–3.46, P = 0.031) and pN category (HR 2.13, 95 % CI 1.36–3.33, P = 0.001) were independent prognostic factors. Overexpression of TRPV2 mRNA was associated with poor prognosis and might serve as a novel prognostic biomarker for resected ESCC patients in early stage.     

Pancreatic polypeptide is increased in patients with advanced malignant disease

BACKGROUND: Augmented secretion of pancreatic polypeptide (PP) has been demonstrated in patients with severe systemic diseases or endocrine tumors. The aim of this study was to evaluate PP and autonomic neuropathy in patients with advanced malignant disease. MATERIALS AND METHODS: Basal PP assessments and five cardiovascular tests for autonomic function were used. Twenty patients, including 11 patients with lung cancer (69 yrs +/- 11, mean +/- SD) and 10 healthy age-matched controls, were studied. RESULTS: PP levels were significantly higher in the patients than in the controls (pmol/L 107.0 +/- 111.4 versus 28.2 +/- 13.4, p<0.05). In the parasympathetical tests, the patients showed significantly decreased heart rate response to the Valsalva manoeuvre (ratio 1.20 +/- 0.19 versus 1.46 +/- 0.23, p<0.005). Also, in the sympathetical tests, the blood pressure response to standing up was significantly decreased (mmHg -3.84 +/- 17.53 versus 10.80 +/- 8.89, p<0.05). The heart rate response to standing up and deep breathing as well as the blood pressure response to sustained handgrip, did not differ significantly between the groups. In spite of the apparent autonomic dysfunction among cancer patients with advanced malignant disease, PP levels were significantly higher in these patients when compared with healthy controls. CONCLUSION: PP levels were significantly higher in patients with advanced cancer than controls, regardless of autonomic dysfunction in the cancer patients. This finding supports the hypothesis that PP may, in some cancer patients, be a marker of advanced malignant disease.     

Improved survival is associated with treatment at high‐volume teaching facilities for patients with advanced stage laryngeal cancer

BACKGROUND:

Because of the multidisciplinary nature of treatment for advanced laryngeal cancer, the authors hypothesized that treatment at high‐volume teaching/research facilities is associated with improved survival.

METHODS:

After exclusions, 19,326 patients who were diagnosed with advanced laryngeal cancer (stage III and IV) between 1996 and 2002 and who received treatment (chemoradiotherapy [CRT], total laryngectomy [TL], or radiotherapy [RT]) were analyzed from the National Cancer Database (NCDB). Facilities were classified into 6 groups (low‐volume and high‐volume teaching/research facilities, low‐volume and high‐volume community cancer centers, and low‐volume and high‐volume community facilities). Multivariate proportional hazards regression modeling was used to determine 90‐day, 365‐day, and 4‐year hazard ratio (HR) estimates.

RESULTS:

Treatment included TL (37.6%), CRT (29.4%), and RT alone (33%). Overall, 36.2% of patients were treated at high‐volume teaching/research centers (average, 17.1 cases per year). Among all patients, 20% died within the first year. In multivariate models that were controlled for covariates, 90‐day, 365‐day, and 4 year HR estimates for death were lowest for high‐volume teaching/research centers.

CONCLUSIONS:

Receiving treatment at high‐volume teaching/research facilities was associated with improved survival. Undergoing total laryngectomy also was associated with improved survival. The current results suggested that the regionalization of care for patients with advanced‐stage laryngeal cancer has occurred, because most patients were treated either at high‐volume teaching/research facilities or at high‐volume community cancer centers. Future studies should investigate the factors associated with better survival at high‐volume teaching/research facilities, such as quality of care, processes of care, and referral patterns. Cancer 2010. © 2010 American Cancer Society.     

Preoperative multidisciplinary team assessment is associated with improved survival in patients with locally advanced colon cancer; a nationwide cohort study in 3157 patients

IntroductionMultidisciplinary team (MDT) assessment is associated with improved survival in locally advanced rectal cancer, but the effect of an MDT assessment on survival in locally advanced colon cancer has not been reported. The aim of this national population-based cohort study was to establish if preoperative MDT assessment affects prognosis in patients with primary locally advanced colon cancer.Material and methodsAll patients in Sweden with locally advanced colon cancer, without metastatic disease, who underwent an elective colon resection between 2010 and 2017 were identified through the Swedish Colorectal Cancer Registry (SCRCR), and the cohort was linked to national registers. Data on patient characteristics, preoperative staging, surgical procedures, recurrence and survival were collected from SCRCR. The association between MDT assessment and colon cancer-specific survival was evaluated using Kaplan-Meier survival curves and Cox proportional hazards models. The multivariable analysis was adjusted for sex, age, ASA grade, CCI, time period, pN, region and preoperative MDT.ResultsMDT assessment was performed in 2663 patients (84.4%) of 3157 eligible patients. The 3-year colon cancer-specific survival was higher following MDT, compared with no MDT assessment (80% versus 68%). MDT assessment was independently associated with reduced colon cancer-specific mortality (HR 0.70, 0.57–0.84 95% CI).ConclusionPreoperative MDT assessment is associated with an improved long-term survival in patients with locally advanced colon cancer and should be mandatory in patients with suspected locally advanced colon cancer.     

Neoadjuvant chemoradiation is associated with improved overall survival in older patients with esophageal cancer

Objectives

The aim of this study was to characterize outcomes associated with neoadjuvant chemoradiation prior to esophagectomy, compared to esophagectomy alone, in older patients with esophageal cancer.

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

Squamous cell carcinoma of the oesophagus (SCCO) is still a pathology of bad prognosis. Specific therapies are now developed against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, c-kit receptor (CD117), vascular endothelial growth factor (VEGF) and p53 protein. This study was aimed at assessing their expression in a large series of SCCO, as well as their potential therapeutic interest in this pathology. Immunohistochemical expression of these factors was assessed retrospectively in 107 cases of SCCO with primary surgery, as well as their relationships to recurrence, metastasis and overall survival on a long-term follow-up. Human epidermal growth factor receptor 2 and CD117 were expressed in less than 3% of the cases. Epidermal growth factor receptor and p53 were overexpressed in 68.2 and 66.4% of the cases, and VEGF in 38.3%. Epidermal growth factor receptor overexpression was significantly related to vascular invasion (P=0.023). Its diffuse positivity was significantly related in multivariate analysis to higher local recurrence (P=0.006) and lower overall survival (P=0.003), in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment. These results highlight the great potential prognostic and therapeutic interest of evaluating EGFR diffuse positivity in locally advanced SCCO.