Denice D. Tsao-Wei

Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia

PURPOSE Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of bevacizumab and metronomic oral cyclophosphamide in women with recurrent OC. PATIENTS AND METHODS Patients with measurable disease and prior treatment with a platinum-containing regimen were eligible. Up to two different regimens for recurrent disease were allowed. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and oral cyclophosphamide 50 mg/d. The primary end point was progression-free survival at 6 months. Plasma levels of VEGF, E-selectin, and thrombospondin-1 were obtained serially. RESULTS Seventy patients were enrolled. The probability of being alive and progression free at 6 months was 56% (+/- 6% SE). A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. The most common serious toxicities were hypertension, fatigue, and pain. Bevacizumab-related toxicities included four episodes of gastrointestinal perforation or fistula, two episodes each of CNS ischemia and pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound healing complication. There were three treatment-related deaths. Levels of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome. CONCLUSION The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.

Temozolomide for treatment-resistant recurrent meningioma.

A prospective Phase II study of temozolomide (TMZ) was conducted in 16 patients with refractory meningioma. All patients had previously been treated with surgery and involved-field radiotherapy; however, no patient had prior chemotherapy. TMZ was administered orally for 42 consecutive days every 10 weeks. Grade 3 or greater TMZ-related toxicity included anemia (25%), fatigue (18.7%), neutropenia (37.5%), seizures (6.3%), and thrombocytopenia (18.7%). No patient demonstrated a neuroradiographic complete or partial response. Time to tumor progression ranged from 2.5 to 5.0 months (median 5.0 months); survival ranged from 4 to 9 months (median 7.5 months).

Early Ductal Decompression Versus Conservative Management for Gallstone Pancreatitis With Ampullary Obstruction: A Prospective Randomized Clinical Trial

Objective:To compare the efficacy of endoscopic retrograde cholangiopancreatography ± endoscopic sphincterotomy (ERCP ± ES) versus traditional conservative management in early gallstone pancreatitis with persistent ampullary obstruction (GSP + AO). Summary Background Data:The effectiveness of early ERCP ± ES in this setting is controversial. Methods:Sixty-one consecutive patients with GSP + AO within 48 hours from the onset of symptoms were randomized to receive either conservative treatment and selective ERCP ± ES after 48 hours (control group, 31 patients) or initial conservative treatment and systematic ERCP ± ES within 48 hours if obstruction persisted 24 hours or longer (study group, 30 patients). Patient outcome was compared in relation to treatment groups and to duration of obstruction. Results:In the control group, 22 patients disobstructed spontaneously within 48 hours; 3 of the remaining 9 patients underwent ERCP ± ES and none had impacted stones. In the study group, 16 patients disobstructed spontaneously and 14 underwent ERCP within 48 hours from the onset of symptoms; impacted stones were found and extracted by ES in 79% (11 of 14) of these. Patients:There were no deaths in either group. Patients in the study group showed a shorter period of obstruction (P = 0.016) and a lower rate of immediate complications (P = 0.026) than controls. Patients with obstruction lasting ≤48 hours regardless of the treatment group had fewer immediate complications than those whose obstruction persisted longer (P < 0.001). Conclusions:This study shows that in patients with GSP + AO limiting the duration of obstruction to not longer than 48 hours by ERCP + ES decreased morbidity.

Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer

Abstract. Thymidylate synthase is a target enzyme for chemotherapeutic agents such as 5-fluorouracil and capecitabine, its oral prodrug. The human thymidylate synthase gene promoter is polymorphic, having either double or triple repeats of a 28-bp sequence. It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S). Capecitabine is converted to 5-fluorouracil by a sequential triple enzyme pathway, with the last step catalyzed by the tumor-associated angiogenic factor thymidine phosphorylase. We have recently shown that individuals with metastatic colorectal cancer treated with 5-fluorouracil have a higher response rate if they are homozygous for the genotype S/S as opposed to S/L or L/L. Our hypothesis is that individuals homozygous for the double repeat variant (S/S) should have a better response to capecitabine than their counterparts with S/L or L/L. In this retrospective pilot study we assessed the thymidylate synthase polymorphic status of 24 patients with metastatic colorectal cancer and determined their response to capecitabine. We found that 75% (3/4) of individuals with the S/S variant responded to capecitabine, compared to 8% (1/12) and 25% (2/8) of those with the S/L and L/L variants, respectively. Our data suggest that genotyping patients for the thymidylate synthase polymorphism would be useful in identifying patients who are more likely to respond to capecitabine treatment for advanced colorectal cancer.

Carditis : A manifestation of gastroesophageal reflux disease

This series consists of 141 patients in whom cardiac mucosa (CM) was present in biopsy samples from the gastroesophageal junctional region. Inflammation of CM, irrespective of its exact anatomic location, was defined as carditis and classified as acute or chronic based on the number of inflammatory cells present. In all cases, CM showed significant chronic inflammation. One hundred and eleven (79%) of the 141 patients with carditis showed no evidence of gastritis in biopsy samples from the gastric antrum and body. Helicobacter pylori was present in 20 of 141 (14%) patients; of these, 17 had evidence of a pangastritis, with 15 of these patients also showing H. pylori in CM. Patients with severe chronic inflammation in CM had a significantly higher acid exposure of the lower esophagus as quantitated by a 24-hour pH test than those with mild chronic inflammation in CM. Acute inflammation was uncommon in CM; it was present in only 26 of 141 (18.4%) patients. There was no significant difference in acid exposure of the lower esophagus between patients with and without acute inflammation in CM. The presence of acute inflammation in CM was significantly associated with distal gastritis and H. pylori infection. Men with carditis had quantitatively higher acid exposure of the lower esophagus than did women with this disorder. This difference was greatest in men with severe inflammation in CM who had no evidence of distal gastritis. These findings provide evidence that chronic inflammation in CM is strongly associated with acid reflux and that H. pylori is not a significant etiologic factor in carditis. They also show that in patients with CM in whom H. pylori gastritis develops, the infection frequently spreads to involve CM, resulting in acute inflammation with neutrophils that is superimposed on the chronic inflammation already present.

Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits breast cancer progression

We report the results of a multidisciplinary study on the inhibitory effect of a snake venom disintegrin, contortrostatin, a 13.5 kDa homodimeric protein isolated from Agkistrodon contortrix contortrix (southern copperhead) venom, on breast cancer progression. We demonstrate that contortrostatin binds to integrins and blocks the adhesion of human breast cancer cells (MDA-MB-435) to extracellular matrix (ECM) proteins including fibronectin and vitronectin, but it has no effect on adhesion of the cells to laminin and Matrigel. Contortrostatin also prevents invasion of MDA-MB-435 cells through an artificial Matrigel basement membrane. Daily local injection of contortrostatin (5 μg per mouse per day) into MDA-MB-435 tumor masses in an orthotopic xenograft nude mouse model inhibits growth of the tumor by 74% (p = 0.0164). More importantly, it reduces the number of pulmonary macro-metastasis of the breast cancer by 68% (p < 0.001), and micro-metastasis by 62.4% (p < 0.001). Contortrostatin is not cytotoxic to cancer cells, and does not inhibit proliferation of the breast cancer cells in vitro. However, contortrostatin inhibits angiogenesis induced by the breast cancer, as shown by immunohistochemical quantitation of the vascular endothelial cells in tumor tissue removed from the nude mice. We have identified αvβ3, an important integrin mediating cell motility and tumor invasion, as one of the binding sites of contortrostatin on MDA-MB-435 cells. We conclude that contortrostatin blocks αvβ3, and perhaps other integrins, and thus inhibits in vivo progression.

Treatment of patients with ovarian carcinoma with pegylated liposomal doxorubicin

Pegylated liposomal doxorubicin is a new formulation with activity against epithelial ovarian carcinoma (EOC). The authors sought to determine patient characteristics that may predict for response to this treatment and favorable time to failure as well as survival.

Update on impact of moderate dose of adjuvant radiation on urinary continence and sexual potency in prostate cancer patients treated with nerve-sparing prostatectomy

OBJECTIVES Adjuvant radiotherapy to the prostatic bed at moderate doses of 45 to 54 Gy achieves results comparable to higher doses. We studied the effect of moderate doses of postoperative radiation therapy on urinary continence and sexual potency in prostate cancer patients who had undergone nerve-sparing prostatectomy. METHODS Between November 1983 and December 1992, 255 prostate cancer patients were selected to undergo nerve-sparing prostatectomy. A total of 94 (37%) patients had received adjuvant postoperative radiotherapy, 45 to 54 Gy to the prostatic bed, based on microscopic positive margins, seminal vesicle involvement, and/or Gleason score. Subjective patient reports regarding the potency and urinary continence status were recorded during a semistructured telephone interview at 3 or more years after treatment. The findings in irradiated and nonirradiated patients were compared and correlated to those obtained from the same patients preoperatively and 1 year postoperatively. RESULTS At 3 or more years of follow-up no significant difference among irradiated and nonirradiated patients was detected. Most patients described optimal urinary continence and approximately one third had maintained potency after bilateral nerve-sparing prostatectomy. None of the patients who had undergone unilateral nerve-sparing surgery remained potent. Using a multivariable analysis, the significant predictors for maintaining potency were the status at 1 year postoperatively and bilateral versus unilateral nerve-sparing procedure. CONCLUSIONS Doses of adjuvant radiation therapy in the range used (45 to 54 Gy) did not affect the long-term pattern of maintenance of either function.

Phase I Study of Vincristine, Irinotecan, and 131I-Metaiodobenzylguanidine for Patients with Relapsed or Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan. Experimental Design: Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBG-avid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standard phase I organ function requirements. Irinotecan (20 mg/m2/dose IV) was given on days 0 to 4 and 7 to 11, with vincristine (1.5 mg/m2 IV) on days 0 and 7. MIBG was given on day 1 following a 3 + 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more. Results: Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9–26.8 years) received 1 (n = 17), 2 (n = 5), or 3 (n = 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Two of 6 patients at the 18 mCi/kg dose level had dose-limiting toxicity (DLT), including one with protocol-defined DLT with prolonged mild aspartate aminotransferase elevation. Eighteen mCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18 mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients. Conclusions: MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan. Clin Cancer Res; 18(9); 2679–86. ©2012 AACR.

Salvage Chemotherapy with Cyclophosphamide for Recurrent, Temozolomide-Refractory Glioblastoma Multiforme

The primary objective of the current prospective Phase II study of cyclophosphamide (CYC) in adult patients with recurrent, temozolomide‐refractory glioblastoma multiforme was to evaluate 6‐month progression‐free survival (PFS).