Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer.

BACKGROUND: A previous dose-escalation trial of the vascular disrupting agent combretastatin A4 phosphate (CA4P) given before carboplatin, paclitaxel, or both showed responses in 7 of 18 patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with ovarian cancer that had relapsed and who could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63 mg/m(2) minimum 18 h before paclitaxel 175 mg/m(2) and carboplatin AUC (area under the concentration curve) 5, repeated every 3 weeks. RESULTS: Five of the first 18 patients' disease responded, so the study was extended and closed after 44 patients were recruited. Grade ≥2 toxic effects were neutropenia in 75% and thrombocytopenia in 9% of patients (weekly blood counts), tumour pain, fatigue, and neuropathy, with one patient with rapidly reversible ataxia. Hypertension (23% of patients) was controlled by glyceryl trinitrate or prophylactic amlodipine. The response rate by RECIST was 13.5% and by Gynecologic Cancer InterGroup CA 125 criteria 34%. CONCLUSIONS: The addition of CA4P to paclitaxel and carboplatin is well tolerated and appears to produce a higher response rate in this patient population than if the chemotherapy was given without CA4P. A planned randomised trial will test this hypothesis.

A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer.

BACKGROUND: The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy. METHODS: Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin. RESULTS: Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma. CONCLUSION: The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

HLA association with response and toxicity in melanoma patients treated with interleukin 2-based immunotherapy.

Peripheral blood lymphocytes from 146 patients with metastatic melanoma undergoing interleukin 2 (IL-2)-based immunotherapy were characterized for HLA A, B, Cw, DR, DQw, and DRw specificities. Patients had been enrolled into sequential treatment protocols with either IL-2 alone (28) or in combination with tumor-infiltrating lymphocytes (TILs) (86), alpha-interferon (26), lymphokine-activated killer cells (16), radiation therapy (7), cyclophosphamide (3), tumor necrosis factor (1), and interleukin 4 (1) for a total of 168 courses of therapy. HLA phenotype was then correlated with response rate and toxicity to IL-2. We noted: (a) a significant difference in the frequency of A11 (20.5% versus 10.2%; P < 0.05) allele between melanoma patients and the North American Caucasian population; (b) a significantly higher frequency of A11 phenotype among responders (40.5%) than in the melanoma patient population (20.5%; P < 0.01), which was even more obvious among patients responding to TIL therapy (47.4% versus 22.1%; P < 0.05); within TIL patients, responders also had an increased frequency of A19 (42.1% versus 25.6%; P < 0.05); (c) a correlation between the number of TILs received and response rate (P < 0.005); and (d) an association between DR4 haplotype and decreased tolerance to IL-2 among the patients receiving TILs (P = 0.01). These results suggest that, in melanoma patients, some HLA Class I specificities may predict for a greater likelihood of response to IL-2-based therapy, while HLA Class II phenotype correlates with tolerance to the combination of TIL and IL-2 therapy.

Vascular access in the cancer patient.

Patients requiring frequent blood sampling and/or frequent intravenous fluid administration can be difficult to manage clinically once peripheral veins become exhausted. Not only can peripheral vascular access be difficult in these patients, but patients begin to dread the attempts at blood sampling and intravenous line placement more than the chemotherapy regimen.At Howard University Hospital, several different types of commercial vascular access devices have been employed that afford reliable and dependable use in cancer patients requiring chemotherapy and blood monitoring. With the increased use of these devices, one unpleasant aspect in the management of the cancer patient, that of repeated attempts at vascular access, can be eliminated.

Massive upper gastrointestinal bleeding in a patient with a duodenal diverticulum: a case report and review of the literature.

Diverticula of the duodenum occur in approximately 2% to 5% of individuals who have had upper gastrointestinal (GI) series; the majority of these patients are asymptomatic. These diverticula occasionally result in the obstruction of the biliary and pancreatic ducts, which leads to jaundice and pancreatitis. Other complications such as hemorrhage, perforation, sepsis, and death can occur. This article reports a case of upper GI bleeding in a patient who was found to have duodenal diverticula by upper GI series and endoscopy. Diverticulectomy was performed, and microscopic examination of the specimen showed dilated blood vessel suggestive of angiodysplasia.

Hemodynamic effects of the administration of tumor-infiltrating lymphocytes to cancer patients.

Tumor-infiltrating lymphocytes (TILs) can mediate tumor regression in selected patients with advanced cancer. To study some of the physiological changes associated with TIL administration, hemodynamic effects were measured while 2 x 10(10) to 20 x 10(10) TILs (mean 10 +/- 1 x 10(10)) were infused into 22 patients. In 10 patients, the first bag of TILs was administered without any interleukin-2 (IL-2) in the infusion bag; subsequent bags in the same patients and all bags in the next 12 patients contained IL-2 in low concentrations (300,000 IU). Two hours following infusion (as compared with baseline), patients developed tachycardia (110 +/- 3.3 vs. 76 +/- 3.5 beats/min; p < 0.001), increased cardiac index (4.9 +/- 0.2 vs. 3.2 +/- 0.13 L/min/m2; p < 0.001), decreased systemic vascular resistance (677 +/- 37 vs. 1185 +/- 63 dyn/s/cm5; p < 0.001), and increased pulmonary artery diastolic pressure (15.9 +/- 1.4 vs. 10.6 +/- 1.1 mm Hg; p = 0.002). No significant changes in systemic blood pressure were noted. Analysis of data obtained in the 10 patients after infusion of the first bag of TILs (4.5 +/- 0.4 x 10(10)) without IL-2 present in the infusate revealed similar, though less severe, changes. No significant correlation was noted between in vitro production of tumor necrosis factor-alpha, interferon-gamma, and granulocyte-macrophage colony-stimulating factor by TILs and hemodynamic effects when administered to patients. These results indicate that TIL infusion can cause hemodynamic changes similar to those previously reported in patients undergoing IL-2 therapy.