Marwan Fakih

Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

Metastatic colorectal cancer: current state and future directions.

Substantial improvements have been made in the management of metastatic colorectal cancer over the last two decades. The overall survival of patients diagnosed with unresectable metastatic colorectal cancer has increased from approximately 1 year during the era of fluoropyrimidine monotherapy to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. More effective therapeutic combinations have increased the rate of curative-intent surgical resections, resulting in median survival in this subgroup that exceed 5 years. Here we review the landscape of systemic therapies for unresectable metastatic colorectal cancer during the current era of targeted therapies, review the effects of RAS and BRAF mutations on clinical decision making, and reflect on future directions for the treatment of metastatic colorectal cancer.

Selenium supplementation and colorectal adenomas: An analysis of the nutritional prevention of cancer trial

Selenium status has been inversely associated with colorectal cancers (CRC) and adenomas. This investigation evaluates the association between selenium supplementation and prevalent and incident colorectal adenomas and CRC detected during the Nutritional Prevention of Cancer trial follow‐up. Of the 1,312 randomized to 200 mcg of selenized yeast of matching placebo, 598 participants underwent endoscopic screening (flexible sigmoidoscopy or colonoscopy) for CRC sometime during the follow‐up period, which ended in February 1, 1996. There was no colorectal screening performed at baseline. Of those screened, 77% were male (with a mean age of 62.8 years), 42% were former and 25% were current smokers. Adenomas were classified as prevalent (identified at the first endoscopic examination postrandomization during the follow‐up period) or incident (identified at the second or subsequent examination). Ninety‐nine prevalent and 61 incident adenomas were ascertained. Logistic regression odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender and smoking status. For prevalent adenomas, there was a suggestive but nonsignificant decrease in risk associated with selenium treatment (OR = 0.67, 95% CI = 0.43–1.05). Subjects in the lowest tertile of baseline selenium (OR = 0.27, 95% CI = 0.09–0.77) and current smokers (OR = 0.27, 95% CI = 0.11–0.66) had significant reductions in risk. The OR for incident adenomas was 0.98 (95% CI = 0.57–1.68). In addition to being associated with a reduced risk of incident CRC, selenium supplementation was associated with a significantly reduced risk of prevalent adenomas, but only among subjects with either a low baseline selenium level or among current smokers.

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Purpose: In preclinical models, calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination. Experimental Design: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions. Results: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 μg/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 μg/wk calcitriol dose level. The relationship between calcitriol dose and peak serum calcitriol (Cmax) and systemic exposure (AUC) was linear. Mean (±SD) serum calcitriol Cmax at the MTD was 6.68 ± 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies. Conclusions: High doses of weekly i.v. calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 μg calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.

A Phase II Study of Gemcitabine and Capecitabine in Advanced Cholangiocarcinoma and Carcinoma of the Gallbladder: A Single-Institution Prospective Study

AimTo determine the clinical benefit response (CBR), time to tumor progression (TTP), overall survival, and effect on quality of life (QOL) of gemcitabine and capecitabine in patients with advanced biliary cancer.MethodsGemcitabine (1000 mg/m2 IV over 30 minutes on days 1 and 8) and capecitabine (650 mg/m2 orally twice daily for 14 days) were administered and repeated every 21 days. All patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Pancreatic Cancer Module (EORTC QLQ-C30-PAN 26) questionnaire on day 1 of each cycle. Cumulative QOL scores were calculated. The two-stage design required 17 patients to evaluate the confirmed response at nine weeks.ResultsTwelve patients with a median age of 54 years were enrolled. A median of eight cycles per patient were completed. With a median follow-up of 18.2 months, the CBR (two partial response and five stable disease) was 58% [95% confidence interval (CI) 28–85%]. Four out of seven patients with CBR had no decline in QOL with chemotherapy. The probability of survival at one year was 0.58. Median TTP and overall survival were 9.0 and 14.0 months, respectively. Nine patients had grade 3 or 4 toxicities. There were no treatment-related deaths.ConclusionsGemcitabine and capecitabine at this dose and schedule are well tolerated and effective and may offer clinical benefit and maintain QOL in patients with advanced biliary cancer. This regimen merits further investigation in the neoadjuvant setting.

Significance of Signet-Ring Cells in Patients with Colorectal Cancer

PurposeWe performed a retrospective study to determine the pattern of metastases and overall outcome of patients with tumors exhibiting a component of signet-ring cells comprising < 50 percent of the tumor mass.MethodsMedical records of 753 patients with primary colorectal cancer were retrospectively studied. Patients who had tumors with < 50 percent signet-ring cells were classified as having a component of signet-ring cells. The outcome of patients with a component of signet-ring cells was compared to all patients with mucinous adenocarcinoma (defined as adenocarcinomas with ≥ 50 percent mucin) to all patients with adenocarcinomas with a component of mucin (defined as adenocarcinomas with < 50 percent mucin) and to 100 randomly selected patients with adenocarcinomas lacking mucin or signet-ring cells.ResultsFive percent of patients had a component of signet-ring cells, 3 percent had mucinous adenocarcinoma, 9 percent had a component of mucinous adenocarcinoma, and 83 percent had adenocarcinoma lacking mucinous or signet components. Patients with a component of signet-ring cells and mucinous adenocarcinomas metastasized predominantly to the peritoneum/ovaries (75 and 56 percent of metastatic cases, respectively) and rarely to liver/lungs. The pattern of metastases of patients with adenocarcinoma without mucinous or signet components predominantly involved the liver/lungs and rarely the peritoneum/ovaries (12.5 percent). The pattern of metastases for patients with a component of mucinous adenocarcinoma was intermediate between mucinous adenocarcinoma and adenocarcinoma without mucin or signet-ring component. No differences in survival in Stage IV patients were seen among the four subgroups.ConclusionsPatients with a component of signet-ring cells cancers, similar to mucinous adenocarcinoma, have a predisposition to metastasize to the peritoneum/ovaries.

Effect of 25-Hydroxyvitamin D Status on Serological Response to Influenza Vaccine in Prostate Cancer Patients

Epidemiologic data suggest that there is an association between vitamin D deficiency and influenza infection. We conducted a prospective influenza vaccination study to determine the influence of vitamin D status on serological response to influenza vaccine in prostate cancer (CaP) patients.

Phase II Study of Weekly Intravenous Oxaliplatin Combined With Oral Daily Capecitabine and Radiotherapy With Biologic Correlates in Neoadjuvant Treatment of Rectal Adenocarcinoma

PURPOSE To evaluate the efficacy of a combination of capecitabine, oxaliplatin, and radiotherapy (RT) in the neoadjuvant treatment of Stage II and III rectal cancers. METHODS Capecitabine was given at 725 mg/m(2) orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given intravenously at 50 mg/m(2) once weekly five times starting the first day of RT. The radiation dose was 50.4 Gy in 28 fractions (1.8 Gy/fraction), five fractions weekly. Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and apoptosis. RESULTS A total of 25 patients were enrolled in this study; 6 patients (24%) had a complete pathologic response. T-downstaging occurred in 52% of patients, and N-downstaging occurred in 53%. Grade 3 diarrhea was the most common Grade 3-4 toxicity, occurring in 20% of patients. Only 2 patients experienced disease recurrence, with a median of 20 months of follow-up. Thymidylate synthase, thymidine phosphorylase, ERCC1, and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies, nor did they predict for T-downstaging or a complete pathologic response. CONCLUSION Capecitabine at 725 mg/m(2) orally twice daily, oxaliplatin 50 mg/m(2)/wk, and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls.

TRAIL Receptor Agonist Conatumumab With Modified FOLFOX6 Plus Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: A Randomized Phase 1b/2 Trial

In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5).

Adjuvant FOLFOX Chemotherapy and Splenomegaly in Patients with Stages II–III Colorectal Cancer

Background: The impact of adjuvant chemotherapy on hepatic function and portal hypertension in patients with stages II–III colon cancer has not been previously described. We conducted a retrospective study to assess the effects of adjuvant FOLFOX chemotherapy on the splenic index (SI) as a surrogate marker for portal hypertension. Methods: Stage II–IIIcolorectal cancer patients treated with adjuvant FOLFOX or fluorouracil/leucovorin (5-FU/LV) at Roswell Park Cancer Institute between2002 and 2006were identified. Computerizedtomography (CT) scans obtained prior to and at completion of chemotherapy, and every 6 months thereafter were reviewed. Splenic size was evaluated using the SI (SI = length × width × height of the spleen). Results: 40 patientswere identified in the FOLFOX group and 23 in the 5-FU/LV group. After 6 months of adjuvant chemotherapy, the mean increase in SI was 45.7 and 16.3% in the FOLFOX and 5-FU/LV groups, respectively (p = 0.0069). SI increased by >100% in 6 patients (15%) in the FOLFOX group versus none in the 5-FU/LV group (p = 0.16). The mean SI at completion of adjuvant chemotherapy was significantly higher in the FOLFOX group than in the 5-FU/LV group (p = 0.007). The mean SI decreased steadily over a period of 2 years after discontinuation of FOLFOX, suggesting potential reversibility of oxaliplatin-induced hepatic injury in this setting. Conclusions: Adjuvant FOLFOX significantly increases the SI in patients with resected colorectal cancer in comparison to adjuvant 5-FU/LV. The increase in SI may be a marker of oxaliplatin-induced hepatic injury and should be investigated further in prospective longitudinal studies of oxaliplatin-based adjuvant chemotherapy.