Basil F. El-Rayes

Neoadjuvant docetaxel and estramustine chemotherapy in high-risk/locallyadvanced prostate cancer.

OBJECTIVES To evaluate the efficacy and safety of neoadjuvant docetaxel and estramustine in patients with high-risk, newly diagnosed, prostate cancer. METHODS Eligible patients had prostate cancer with one or more of the following criteria: clinical Stage T2b or greater, prostate-specific antigen (PSA) of 15 ng/mL or greater, and/or Gleason score of 8 to 10. Chemotherapy consisted of docetaxel (70 mg/m(2)) on day 1 and estramustine (280 mg three times daily) on days 1 to 3 every 21 days for three to six courses. This was followed by local therapy, as deemed appropriate. RESULTS Twenty-one patients with a median age of 60 years, median PSA level of 16.1 ng/mL (range 2.4 to 175), and median baseline testosterone of 3.4 ng/mL were enrolled. Seven patients met one of the inclusion criteria, 10 met two, and 4 met three. The Gleason score was 8 or greater in 14 patients. A median of five cycles of chemotherapy was delivered. The most frequent high-grade toxicities were grade 3 (8 patients) and 4 (1 patient) neutropenia and deep venous thrombosis (grade 3 in 2 patients) before institution of low-dose warfarin. All patients responded as determined by protocol-defined criteria. Ten patients underwent radical prostatectomy, with negative surgical margins in 7 patients, and 11 received radiotherapy with negative preradiotherapy biopsies in 2. CONCLUSIONS Induction docetaxel and estramustine is well tolerated and feasible in patients with newly diagnosed, high-risk prostate cancer. This combination is active; however, its efficacy relative to hormonal therapy will require a controlled randomized trial.

Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line.

Abstract: Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-κB activity. In contrast, chemotherapeutic agents inadvertently induce NF-κB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-κB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 μmol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-κB EMSA were performed. The combination of 30 μmol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-κB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-κB–inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-κB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer.

Potentiation of the Effect of Erlotinib by Genistein in Pancreatic Cancer: The Role of Akt and Nuclear Factor-κB

The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-kappaB (NF-kappaB). The expression of EGFR, Akt, and NF-kappaB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-kappaB. Genistein significantly increased (P < 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-kappaB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-kappaB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-kappaB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein.

A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers.

BACKGROUND Bevacizumab has demonstrated antitumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. PATIENTS AND METHODS Previously untreated patients with locally advanced or metastatic disease and a performance status (PS) of 0-1 were eligible for this study. Patients received bevacizumab at 7.5 mg/kg, docetaxel at 70 mg/m(2), and oxaliplatin at 75 mg/m(2) administered on day 1 of a 21-day cycle. The primary end point of the study was progression-free survival (PFS). RESULTS A total of 38 eligible patients (median age 57 years, 45% gastric, 55% PS 0) were enrolled on to the study. Median PFS was 6.6 months [95% confidence interval (CI) 4.4-10.5] and median survival 11.1 months (95% CI 8.2-15.3). Complete responses were documented in 2 (5%) patients, partial responses in 14 (37%), and stable disease in 14 (37%). No treatment-related deaths were observed. The most commonly reported grade 3-4 toxicity was neutropenia (34%), and gastrointestinal perforation occurred in three patients (8%). CONCLUSION The combination of bevacizumab, docetaxel, and oxaliplatin has promising activity for further evaluation in randomized trials.

A Phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer

SummaryBackground. Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer.Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m2 over 100 minutes, cisplatin 35 mg/m2 I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days.Results. Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6–7.6 months). The probability of survival at 6 months was 46% (90% CI, 27–62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients.Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.

Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy

The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-κB (NF-κB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 μmol/L), celecoxib (1 and 10 μmol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-κB activation. Growth inhibition and apoptosis were significantly (P < 0.05) higher in BxPC-3, HPAC, and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib. However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 μmol/L) and celecoxib (10 μmol/L) compared with celecoxib- or erlotinib-treated cells. Celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-κB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) Celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-κB inactivation contributes to the potentiation of erlotinib by celecoxib. [Mol Cancer Ther 2005;4(12):1943–51]

Phase II Study of Gemcitabine, Cisplatin, and Infusional Fluorouracil in Advanced Pancreatic Cancer

PURPOSE This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m2 intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m2 IV on days 1 and 15; and FU 175 mg/m2/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria. RESULTS A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications. CONCLUSION The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.

Developments in the systemic therapy of pancreatic cancer.

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States of America. Progress in the treatment of this disease in the past several decades has been very modest. Several new agents with activity against pancreatic cancer have been identified. Of these, gemcitabine is the most promising agent when used in combination with other drugs. Pilot phase II studies combining gemcitabine with 5-flourouracil, irinotecan, docetaxel, or cisplatin show improved outcomes in objective response rates and survival that need to be confirmed in larger randomized studies. Advancement in the understanding of the molecular biology of neoplasia in recent years has helped identify several molecular targets for future new drug development in pancreatic cancer. Assessment of response to therapy of pancreatic cancer has been a difficult challenge. Functional imaging with techniques such as positron emission tomography (PET) may yield a more precise and timely objective evaluation of response to treatment.

Phase II trial of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site

The purposes of this study were to evaluate efficacy and toxicity of the combination of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site (CUP).

A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer

Objectives:The purpose of this study was to evaluate the safety and efficacy of preoperative capecitabine and radiation therapy (RT) in patients with locally advanced rectal cancer (LARC). Methods:Patients with adenocarcinoma of the rectum stage ≥T3 or ≥N1 were treated with capecitabine 1330 mg/m2 per day in 2 divided doses days 1 to 42 and 50.4 Gy of RT in 28 1.8-Gy fractions. Patients with metastatic disease were eligible provided that operative intervention on primary site was anticipated. Surgery resection occurred 4 to 6 weeks after completion of preoperative therapy. Results:Thirty eligible patients were enrolled at two institutions. Median age and performance status were 62 years and 90%, respectively. Twenty-eight patients (93%) completed combined modality therapy and 27 underwent resection, including 17 abdominal-perineal and 9 low anterior resections. Three of 27 (11%) had pathologic complete response (pCR) with an additional 7 (26%) having minimal residual disease. Two patients who were felt to require abdominal perineal resection prior to combined modality therapy (CMT) were able to have sphincter-sparing surgery. No patients had progression during CMT which precluded surgical resection. Treatment was well tolerated with ≥grade 3 toxicities limited to diarrhea (5 patients), hand-foot syndrome (1 patient), dermatitis (1 patient). Twenty-four patients are living, 18 with no evidence of disease. Conclusions:The combination of preoperative capecitabine and RT in patients with LARC has significant antitumor activity, efficacy, and a low toxicity profile.