Brian J. Lewis

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial.

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.

Acquired immune dysfunction in homosexual men: immunologic profiles.

Homosexual men with Kaposi sarcoma, lymphadenopathy syndrome, opportunistic infection, and nonhomosexual traditional Kaposi sarcoma were evaluated for B cell, T cell, and complement immunity and compared to normal controls and homosexual controls. No significant immunologic abnormalities were found in the traditional Kaposi group. All homosexual groups, including the homosexual controls, had a significant decrease in the helper/suppressor cell ratio. Functional abnormalities of T-cell immunity were observed in the homosexual Kaposi sarcoma, lymphadenopathy syndrome, and opportunistic infection groups. Significant elevations of IgG, IgM, IgA, and IgE were found in the lymphadenopathy group, while only IgG and IgA were elevated in the Kaposi sarcoma group. C3, C4, and immune complexes were normal, while total hemolytic complement activity was increased in the Kaposi sarcoma and lymphadenopathy syndrome groups.

Toxicities and complications of implanted pump hepatic arterial and intravenous floxuridine infusion

Toxicities and complications were prospectively analyzed in patients with liver metastases receiving hepatic intra‐arterial (IA) and systemic intravenous (IV) floxuridine (FUDR) with the Infusaid (Intermedics‐Infusaid Corp., Norwood, MA) implantable pump. Among 55 patients treated with IA FUDR (0.3–0.1 mg/kg/day × 14, every 28 days), elevations in liver enzyme values, not attributable to disease progression, developed in 96% of patients. Serious biliary toxicity occurred in 31 patients (56%). In 16, biliary sclerosis was documented radiographically and was diagnosed clinically in 15 additional patients. Ten patients were hospitalized for biliary toxicity, including five who required cholecystectomy for acalculous cholecystitis. Because of the high reported incidence of serious gastroduodenal toxicity after IA FUDR infusion, our procedure for hepatic arterial cannulation was designed to eliminate misperfusion of the stomach and duodenum with drug; none of our patients experienced FUDR‐associated gastroduodenal ulceration or bleeding. Cyclic IV FUDR (0.05–0.15 mg/kg/day × 14, every 28 days) was administered to 31 participants of the Northern California Oncology Group trial (3L‐82‐1) of IV versus IA FUDR. Dose‐limiting toxicity was diarrhea. Serious toxicities were: protracted diarrhea (three), dermatitis (two), tear duct stenosis (two), and stomatitis (two). Three patients were hospitalized for toxicity. No hematologic or biliary toxicity occurred. The optimal route for treatment of hepatic metastases with continuous FUDR infusion has not yet been established. Systemic IV infusion has low morbidity, but preliminary response data need to be substantiated in controlled clinical trials before there can be widespread clinical application. High response rates for IA infusion have been previously documented. Morbidity due to acalculous cholecystitis and gastroduodenal ulceration can now be avoided. Despite significant progress in characterization of hepatobiliary toxicity, it remains dose‐limiting. Continuous IA FUDR infusion should remain under the aegis of dedicated treatment centers until standardized protocols with diminished toxicity are established.

Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver

Hepatic metastases of colorectal origin are resistant to radiation and immunotherapy. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients, and surgical resection is feasible in approximately 20% of patients who have a solitary or unilobar lesion. Infusion of cytotoxic agents into the hepatic artery, introduced 2 decades ago, is the most promising form of therapy for unresectable hepatic metastases. Fluorouracil, floxuridine, and mitomycin have been most commonly administered by hepatic arterial infusion. The recent development of a totally implantable pump has allowed prolonged ambulatory infusion of chemotherapeutic agents into the hepatic artery. We review the recent data on the pharmacology, therapeutic outcome, administration techniques, and complications of hepatic arterial chemotherapy. Future trials in this area should use uniform stratification variables and standardized criteria for evaluating response, time to progression, and survival.

The chemotherapy of Hodgkin's disease: past experiences and future directions.

From the standpoint of chemotherapy, the first progress in the treatment of Hodgkins disease was the identification of the activity of nitrogen mustard in the 1940s. The initial antitumor effect of the drug created a great excitement. However, when all patients later relapsed, there was subsequent dejection and skepticism about the utility of drug therapy. Fortunately, in the 1950s and 1960s, the development of other effective agents (vinca alkaloids, corticosteroids, and methylhydrazines) in conjunction with the elucidation of the principles of combination chemotherapy led to a marked increase in the antitumor response rate of patients with Hodgkins disease. The value of many of these drug combinations remains under study. Nonetheless, approximately 75% of all patients with advanced Hodgkins disease treated today with combination chemotherapy can achieve a complete remission. In addition, over half of these remain disease‐free long enough to be considered cured. The development of effective treatment, both local (radiotherapy) and systemic (MOPP chemotherapy), has given the clinical investigator the tools to complete, in the 1970s, the therapeutic experiments necessary to refine both the interrelationship between the treatments and their impact upon the natural history of Hodgkins disease.

LYMPHADENOPATHY: ENDPOINT OR PRODROME? UPDATE OF A 24‐MONTH PROSPECTIVE STUDY

This article presents preliminary 24-month findings from a prospective study initiated in San Francisco in 1981 with the following objectives: to refine the clinical definition of the lymphadenopathy syndrome; to compare these patients to patients with Category A acquired immunodeficiency syndrome (AIDS) with regard to epidemiologic, virologic, and immunologic variables; to follow a cohort of these patients to establish the natural history of the syndrome; and to evaluate screening variables for early transformation to more malignant manifestations of AIDS. It was hypothesized that the lymph node syndrome is prodromal AIDS, and that such patients are at risk of developing Kaposis sarcoma, lymphoma, Pneumocystis carinii pneumonia, and other opportunistic infections. 200 homosexual lymphadenopathy patients, with a mean age of 33 years, have been enrolled in the study. These men have had an average of 800 sexual partners, and have a history of past sexually transmitted diseases. The graph of the year of onset of adenopathy parallels the exponentially increasing number of new AIDS cases over the past 4 years. Systemic symptoms seen in these patients resemble those in patients with Kaposis sarcoma and P. carinii pneumonia. 1/3 of lymphadenopathy patients give a history of antecedent flu-like illness, often with fever, diarrhea, and upper respiratory symptoms lasting for 1 week, that occurred 1-2 months before the appearance of their nodes. Involvement of inguinal and axillary nodes has been observed in 100% of patients, while 80% have enlarged posterior cervical nodes. The average patient has 10 nodal groups involved. Immunologic testing reveals a reversal of the T-lymphocyte helper:suppressor ratio (mean of 0.7), and 2/3 of patients have both decreased absolute number and percentage of helper cells with increased suppressors. 198 of these patients have remained with persistent generalized lymphadenopathy without transformation to AIDS, yielding a 1% conversion rate. It is concluded that the lymphadenopathy syndrome is a distinct new syndrome most certainly AIDS-related. Further study will reveal whether it is truly prodromal or an alternate phenotypic response to a common inciting insult.