James A. Posey

Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer.

The angiogenic response of a progressing malignancy is characterized by a shift in the balance of stimulatory and inhibiting factors of angiogenesis. Recognition of the regulated steps in tumor angiogenesis provides unique targets for developing anti-tumor therapy. Vitaxin is a humanized monoclonal antibody, which has specificity for the integrin alpha v beta 3 (vitronectin receptor). This antibody can impair the vascular response of endothelial cell growth factors in vitro and inhibit tumor cell mediated angiogenesis in pre-clinical animal models. Patients with metastatic cancer who failed standard therapy received intravenous doses of 10, 50 or 200 mg in cohorts of three patients. The unlabeled dose of Vitaxin was infused on days 0 and 21 of a treatment cycle. All patients received a pre-therapy imaging dose of 1 mg of Tc-99m Vitaxin with gamma camera imaging studies. There was no significant toxicity noted in these three dose levels. There were no objective anti-tumor responses. Three patients received two cycles of therapy and had stable disease at day 85 when taken off study. Radioimaging of tumor vasculature was unsuccessful although one patient with alpha v beta 3 positive melanoma had imaging of tumor sites. There was no immune response to Vitaxin in any patient. Patients receiving 10 mg doses of Vitaxin had poor plasma recovery of injected doses and brief circulation in plasma. Doses of 50 and 200 mg had plasma recovery that better approximated the predicted levels in plasma and circulation half-lives of approximately 7 days. This data suggests that an every three-week schedule of Vitaxin at doses of 200 mg (2.5-3.5 mg/kg) can maintain circulating levels of antibody with little or no toxicity. Future studies will be challenged to define anti-tumor activity in malignancy or appropriate surrogates of anti-tumor effect and explore escalating doses and alternate schedules of administration.

Phase I Trial of Weekly Tigatuzumab, an Agonistic Humanized Monoclonal Antibody Targeting Death Receptor 5 (DR5)

BACKGROUND TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8. METHODS A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly. RESULTS Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days. CONCLUSIONS Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.

Predictive Capacity of Three Comorbidity Indices in Estimating Mortality After Surgery for Colon Cancer

PURPOSE Although, for patients with cancer, comorbidity can affect the timing of cancer detection, treatment, and prognosis, there is little information relating to the question of whether the choice of comorbidity index affects the results of studies. Therefore, to compare the association of comorbidity with mortality after surgery for colon cancer, this study evaluated the Adult Comorbidity Evaluation-27 (ACE-27), the National Institute on Aging (NIA) and National Cancer Institute (NCI) Comorbidity Index, and the Charlson Comorbidity Index (CCI). PATIENTS AND METHODS The study population consisted of colon cancer patients (N = 496) who underwent surgery at the University of Alabama at Birmingham Hospital from 1981 to 2002. Hazard ratios (HRs) with 95% CIs were obtained using the method of Cox proportional hazards for the three comorbidity indices in predicting overall and colon cancer-specific mortality. The point estimates obtained for comorbidity and other risk factors across the three models were compared. RESULTS For each index, the highest comorbidity burden was significantly associated with poorer overall survival (ACE-27: HR = 1.63; 95% CI, 1.24 to 2.15; NIA/NCI: HR = 1.83; 95% CI, 1.29 to 2.61; CCI: HR = 1.46; 95% CI, 1.14 to 1.88) as well as colon cancer-specific survival. For the other risk factors, there was little variation in the point estimates across the three models. CONCLUSION The results obtained from these three indices were strikingly similar. For patients with severe comorbidity, all three indices were statistically significant in predicting shorter survival after surgery for colon cancer.

Effect of Comorbidity and Body Mass Index on the Survival of African-American and Caucasian Patients With Colon Cancer

There is a survival disparity between African Americans and Caucasians who have colon cancer. The objectives of the current study were to quantify the impact of comorbidity and body mass index (BMI) on survival and to assess whether these 2 variables account for the decreased survival among African Americans.

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Purpose: To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of ≤2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m2. The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m2. Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m2. Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 ± 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC0-∞) > 20 ng h/mL and 0 of 10 patients with an AUC0-∞ ≤ 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m2. The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m2). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.

Resectability of Pancreatic Adenocarcinoma in Patients with Locally Advanced Disease Downstaged by Preoperative Therapy: A Challenge for MDCT

OBJECTIVE The purpose of this study was to determine whether preoperative neoadjuvant therapy in patients with locally advanced pancreatic cancer affects the ability of multiphasic MDCT to predict successful surgical resection. MATERIALS AND METHODS From 2000 to 2006, there were 12 patients with prior neoadjuvant therapy successfully downstaged by CT and 31 age-matched pancreatic cancer patients without preoperative therapy who underwent pancreatic MDCT followed by attempted pancreaticoduodenectomy. Three readers blinded to surgical findings independently analyzed immediate preoperative MDCT scans of 43 patients comprising the retrospective data set in random order for vascular involvement (degree of contact and narrowing) and distant metastases. Individual reader sensitivity and specificity for resectability prediction were compared for study and control groups using the Fishers exact test. Interobserver agreement was assessed using the kappa statistic. RESULTS Seven (58%) of 12 neoadjuvant-treated adenocarcinomas and 10 (32%) of 31 control pancreatic carcinomas were resectable (p > 0.05). For resectable disease, sensitivities were 86%, 71%, and 14% for the neoadjuvant group and 90%, 90%, and 60% for the control group (p > 0.05). Specificities were 80%, 100%, and 100% for the neoadjuvant group and 57%, 43%, and 76% for the control group (reader 2 specificity difference, p = 0.04). The multi rater kappa value of resectability prediction for neoadjuvant patients was 0.28, and that for control subjects was 0.63 (p < 0.001). In the neoadjuvant group, the majority of individual reader errors were false-negative resectability interpretations resulting from overestimation of vascular involvement. Consideration of degrees of venous abutment did not improve estimation of resectability in patients with neoadjuvant therapy. CONCLUSION Sensitivity for prediction of resectability tends to be lower for patients with locally advanced pancreatic cancer that has been downstaged by neoadjuvant therapy, but this trend is not statistically significant. Interobserver variability for determination of resectability is statistically higher than for controls who did not receive preoperative therapy.

Bax expression is a candidate prognostic and predictive marker of colorectal cancer

OBJECTIVE Since the anti-tumor activity of 5-fluorouracil (5-FU) is due to induction of apoptosis, we assessed the value of expression of key apoptotic molecules (Bax, Bcl-2 and p53) in predicting the efficacy of 5-FU therapy for colorectal adenocarcinomas (CRCs). METHODS Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 patients matched for age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation who had undergone only surgery (without any pre- or post-surgery therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2, and p53. Also, these CRCs were evaluated for Bax mutations. The predictive capacity or prognostic value of these markers was assessed by estimating overall survival. RESULTS The majority of low Bax expressing CRCs have exhibited mutations at the G (8) tract. There was no significant difference in overall survival rates between the categories of surgery alone and 5-FU-treated patients. However, a better survival was observed for patients who received chemotherapy when their CRCs had low Bax/Bcl2 ratio (HR, 1.55; 95% CI: 1.46-31.00). Patients who received surgery alone and whose CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (95% CI: 1.78-15.94), when controlled for tumor stage and other confounders. Bcl-2 and nuclear p53 accumulation had no predictive value in either patient group. CONCLUSION These findings are the first to demonstrate that high Bax expression is a good prognosticator for patients who underwent surgery alone, and that patient with low Bax/Bcl-2 expression ratio benefit from 5-FU-based adjuvant therapies.

Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity.

Increased susceptibility to 5‐fluorouracil (5‐FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5‐FU. Life‐threatening 5‐FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early‐onset severe or life‐threatening 5‐FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5‐FU metabolites.

Evaluation of lymph node numbers for adequate staging of Stage II and III colon cancer

BackgroundAlthough evaluation of at least 12 lymph nodes (LNs) is recommended as the minimum number of nodes required for accurate staging of colon cancer patients, there is disagreement on what constitutes an adequate identification of such LNs.MethodsTo evaluate the minimum number of LNs for adequate staging of Stage II and III colon cancer, 490 patients were categorized into groups based on 1-6, 7-11, 12-19, and ≥ 20 LNs collected.ResultsFor patients with Stage II or III disease, examination of 12 LNs was not significantly associated with recurrence or mortality. For Stage II (HR = 0.33; 95% CI, 0.12-0.91), but not for Stage III patients (HR = 1.59; 95% CI, 0.54-4.64), examination of ≥20 LNs was associated with a reduced risk of recurrence within 2 years. However, examination of ≥20 LNs had a 55% (Stage II, HR = 0.45; 95% CI, 0.23-0.87) and a 31% (Stage III, HR = 0.69; 95% CI, 0.38-1.26) decreased risk of mortality, respectively. For each six additional LNs examined from Stage III patients, there was a 19% increased probability of finding a positive LN (parameter estimate = 0.18510, p < 0.0001). For Stage II and III colon cancers, there was improved survival and a decreased risk of recurrence with an increased number of LNs examined, regardless of the cutoff-points. Examination of ≥7 or ≥12 LNs had similar outcomes, but there were significant outcome benefits at the ≥20 cutoff-point only for Stage II patients. For Stage III patients, examination of 6 additional LNs detected one additional positive LN.ConclusionsThus, the 12 LN cut-off point cannot be supported as requisite in determining adequate staging of colon cancer based on current data. However, a minimum of 6 LNs should be examined for adequate staging of Stage II and III colon cancer patients.