Avi B. Markowitz

Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma.

PURPOSE To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.

Phase II Trial of Weekly Paclitaxel in Patients With Previously Treated Advanced Urothelial Cancer

PURPOSE We evaluated the efficacy and toxicity of weekly paclitaxel in patients with previously treated advanced urothelial cancer. PATIENTS AND METHODS Patients with urothelial cancer who had received one prior systemic chemotherapy regimen for advanced disease and had evidence of disease progression were eligible for enrollment. Patients received paclitaxel 80 mg/m(2) by 1-hour intravenous infusion weekly. A cycle of therapy consisted of four weekly treatments. RESULTS The study enrolled 31 patients. Mean age was 66 years, and 45% of patients had three or more involved metastatic sites. Only 26% of patients had responded to prior chemotherapy. The median number of cycles delivered was three (range, one to eight) at a mean weekly paclitaxel dose of 79 mg/m(2). Three patients achieved a partial response (10%; 95% confidence interval, 0% to 20%). Median time to progression was 2.2 months, and median overall survival time was 7.2 months. Therapy was well tolerated with minimal hematologic toxicity. Grade 3 nonhematologic toxicities were also uncommon. CONCLUSION Although the overall response rate to weekly paclitaxel in patients with previously treated advanced urothelial cancer was modest, the chemotherapy-refractory nature of the study population should be considered.

Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer.

PURPOSE To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.

Phase II study of paclitaxel therapy for unresectable biliary tree carcinomas.

PURPOSE To evaluate the efficacy of paclitaxel administered to patients with unresectable adenocarcinomas of the gallbladder and biliary tree over 3 hours every 21 days. PATIENTS AND METHODS Fifteen patients with unresectable and/or metastatic carcinoma of the gallbladder and bile ducts received intravenous paclitaxel over 3 hours after premedication with dexamethasone, diphenhydramine, and cimetidine. Treatment was repeated every 21 days, and one complete course of therapy was comprised of two such 21-day treatment cycles. The initial dose of paclitaxel was 170 mg/m2, and this was elevated to 200 mg/m2 due to tolerance within the initial patient cohort. RESULTS All patients were assessable for both toxicity and response: 11 with bile duct cancer and four with gall-bladder carcinoma. Forty-three cycles of therapy were delivered during the trial (median, two), and one patient remains on treatment. No complete or partial responses were noted, although two patients achieved minor responses that lasted 2 and 2+ months, respectively. There were no deaths on this study, and all but one of the patients is still alive. The therapy was well tolerated, and hematologic and mucosal toxic effects were moderate and readily reversible, although significant neuromuscular adverse effects were noted. CONCLUSION These findings indicate that paclitaxel, administered on this schedule, is tolerable, but is unlikely to have activity in metastatic carcinomas of the biliary tree. It is unclear whether a different regimen of paclitaxel, or another taxane, may have activity in these neoplasms.

Surgery Following Response to Interfergn-α-Baseb Therapy for Residual Renal Cell Carcinoma

AbstractThe role of aggressive surgery for metastatic renal cancer in the era of biological therapy is not clear. Therefore, we reviewed 17 patients who, between February 1987 and August 1990, underwent surgical resection of residual masses following initial response to interferon-α-based therapy. Viable tumor persisted in 15 patients (88%), whereas only inflammatory response was detected in 2. Of the patients 11 (65%) remained disease-free at a median of 12 months postoperatively (range 5 to 29), with an overall median survival of 26 months (range 6 to 34) from treatment initiation. These data suggest that surgery may be of therapeutic benefit in select patients with renal cell carcinoma who do not meet traditional criteria for surgical resection. Prospective trials are being performed to determine whether there is a role for aggressive surgical resection of persistent disease in patients with advanced renal cell carcinoma who have previously responded to interferon-α-based therapy.

Clinical Manifestations of Vasculitis in Patients With Solid Tumors: A Case Report and Review of the Literature

Vasculitis is characterized by inflammatory changes and necrosis of blood vessels. Involvement of arteries and veins of diverse sizes throughout the body is possible and results in a multiplicity of clinical manifestations. Primary and secondary forms of vasculitis exist. Secondary vasculitis has been linked to several processes, including infections, drugs, and allergic, rheumatologic, and neoplastic disease. The majority of patients with malignant neoplasm-associated vasculitis who have been described had hematologic neoplasms. We report a patient with adenocarcinoma of the colon and vasculitis and review the 36 cases of vasculitis in patients with solid tumors documented in the world literature. The most common malignant neoplasms were non-small-cell lung cancer and prostate, breast, colon, and renal cancer. Cutaneous leukocytoclastic vasculitis and nerve and muscle microvasculitis were the most frequently observed vasculitic subtypes. Importantly, in 71% of the cases, manifestations of vasculitis appeared before or concurrent with the initial recognition or the relapse of the tumor. Management strategies that met with success in at least half the patients in whom they were used included corticosteroids, cyclophosphamide, and treatment of the underlying cancer. Prognosis may be primarily related to the ability to control the malignant neoplasm, as most of the patients who died did so because of tumor progression.

Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial

BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. FINDINGS Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54-78) in the chemoradiotherapy group and 61% (50-71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3-4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. FUNDING Amgen.

Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon alfa-2b in patients with advanced cancer.

PURPOSE Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. PATIENTS AND METHODS FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 x 10(6) U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. RESULTS The maximum-tolerated dose of rIFN-a was 10 x 10(6) U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Css; range, 0.77 +/- 0.35 mumol/L to 1.85 +/- 0.48 mumol/L), elimination half-life (t1/2; mean, 9.7 +/- 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 mumol/L x hours), total-body clearance (CI; range, 1,172 to 3,236 mL/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 mumol/L) was greater than that before rIFN-a administration (1.02 mumol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. CONCLUSION rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

Granulocyte-macrophage colony-stimulating factor as a cause of paraneoplastic leukaemoid reaction in advanced transitional cell carcinoma

Abstract. Increasing evidence suggests that paraneoplastic syndromes may be mediated by tumour‐related cytokine release, although the specific factor(s) involved remain poorly defined. Colony‐stimulating factors (CSF) and interleukins (IL) promote colony growth in semi‐solid media and, when administered in recombinant form, increase blood counts in patients. However, normal serum CSF levels in individuals with physiologic blood counts and the relationship between specific serum CSF levels and paraneoplastic leukaemoid reaction are not well established. In this study, we found that normal serum levels of granulocyte‐macrophage CSF (GM‐CSF), as measured by ELISA, were generally < 55 pg ml−1; IL‐3, < 30 pg ml−1; and granulocyte CSF (G‐CSF), < 50 pg ml−1. In contrast, high levels of GM‐CSF (132 pg ml−1), but not G‐CSF or IL‐3, were found in a patient with a transitional cell carcinoma of the renal pelvis and increased leukocytosis correlating with the tumour burden. The GM‐CSF was biologically active, as demonstrated by its ability to stimulate colony growth in vitro. Based on these results it appears that autonomous production of GM‐CSF is one possible pathophysiologic mechanism underlying leukaemoid reaction in cancer patients.

Novel tumor necrosis factor toxic effects. Pulmonary hemorrhage and severe hepatic dysfunction

Recombinant human tumor necrosis factor is an investigational antitumor agent currently undergoing clinical trials. Previous reports of pulmonary and hepatic toxicities include mild reversible decline in pulmonary diffusing capacity and mild elevation of bilirubin and transaminases. This report describes two novel toxicities in patients receiving their first intravenous dose of tumor necrosis factor: pulmonary hemorrhage and severe hepatic dysfunction. These patients received no other antitumor therapy for at least 4 weeks before tumor necrosis factor treatment and no additional antitumor therapy concomitant with tumor necrosis factor. An analysis of the possible pathogenesis is presented.