Gregory Sarna

The Treatment of Renal Cell Carcinoma with Human Leukocyte Alpha-Interferon

An extended phase II trial of human leukocyte (alpha) interferon was done in 48 patients with measurable metastatic renal cell carcinoma, 43 of whom were evaluable. Of these patients 1 (2.5 per cent) had a complete response that was maintained after 19 months, 6 (14 per cent) had a partial response and an additional 23 per cent had either a minimal response or stabilization of previously growing metastases for greater than 3 months. Toxicity caused termination of treatment in only 1 patient and generally was tolerable. Major toxicity consisted of fever (80 per cent), fatigue (80 per cent) and hematologic toxicity (42 per cent), which was severe in only 2 patients. Characteristics of patients responding to therapy were good performance status, previous nephrectomy and metastases limited to the lungs. The results achieved with human leukocyte interferon were superior to those achieved by immunotherapy or chemotherapy at this and other institutions, and further trials are warranted.

Comparative morbidity of axillary lymph node dissection and the sentinel lymph node technique: Implications for patients with breast cancer

Objective:To assess our long-term complications from complete axillary lymph node dissection (AXLND) in patients with breast cancer. Summary Background Data:Complete AXLND as part of the surgical therapy for breast cancer has come under increased scrutiny due the use of the sentinel lymph node (SLN) biopsy technique to assess the status of the axillary nodes. As the enthusiasm for the SLN technique has increased, our impression has been that the perceived complication rate from AXLND has increased dramatically while the negative aspects of the SLN technique have been underemphasized. Methods:Female patients seen in routine follow-up over a 1-year period were eligible for our retrospective study of the long-term complications from AXLND if they were a minimum of 1 year out from all primary therapy; ie, surgery, radiation, and/or chemotherapy. All patients had previously undergone either a modified radical mastectomy (MRM) or a segmental mastectomy with axillary dissection and postoperative radiation (SegAx/XRT). All patients had a Level I–III dissection. Objective measurements, including upper and lower arm circumferences and body mass index (BMI), were obtained, and a subjective evaluation from the patients was conducted. Results:Ninety-four patients were eligible for our study; 44 had undergone MRM, and 50 had undergone SegAx/XRT. The average number of nodes removed was 25.6 (standard deviation, 8). Thirty-three percent of the patients had positive nodal disease, 95% of the patients had an upper arm circumference within 2 cm of the unaffected side, and 93.3% had a lower arm circumference within 2 cm of the unaffected side. Subjectively, 90.4% of the patients had either no or minimal arm swelling, and 96.8% of the patients had “good” or “excellent” overall arm function. The most common long-term symptom was numbness involving the upper, inner aspect of the affected arm (25.5%). Conclusions:Our data indicate that a complete AXLND can be performed with minimal long-term morbidity. The lower the morbidity of AXLND, the less acceptable are the unique complications of the SLN technique.

High-dose combined-modality therapy and autologous bone marrow transplantation in resistant cancer

Fourteen patients with resistant cancers received high-dose chemotherapy and total body irradiation followed by rescue with autologous cryopreserved bone marrow cells. In seven patients, disease has remained in remission for periods up to two years. These data indicate that effectiveness of high-dose combined-modality therapy and bone marrow autotransplantation in patients with resistant cancer. The high incidence of non-marrow toxicity may be reduced by the use of this modality before patients have received extensive therapy.

Veno-occlusive disease of the liver after high-dose mitomycin C therapy and autologous bone marrow transplantation

Twenty‐nine patients with refractory malignancies underwent intensive therapy with mitomycin C (60, 75, or 90 mg/m2 IV) and autologous bone marrow transplantation. Six patients developed the clinical syndrome of hepatic veno‐occlusive disease (VOD) characterized by progressive abnormalities in liver function, abdominal pain, and ascites 15–70 days after mitomycin C therapy. Postmortem material was available in 16 patients, including four patients who had the clinical syndrome. VOD of the central and sublobular hepatic veins was noted in these four patients. VOD was discovered incidentally at autopsy in one of 12 patients without antemortem clinical evidence of disease. Two patients with abnormalities of liver function but without ascites or right upper quadrant pain had no evidence of VOD at autospy. Although not statistically significant, there was a greater incidence of VOD with increasing doses of mitomycin C. When bone marrow toxicity of mitomycin C was overcome by autologous bone marrow transplantation, the development of VOD appeared to be the limiting factor in dose escalation.

Clinical thermochemotherapy a controlled trial in advanced cancer patients

In vitro and in vivo animal studies and some clinical trials have shown apparent benefit from thermochemotherapy; however, this treatment modality has not been adequately tested in humans. This investigation evaluated response to and toxicity of secondary thermochemotherapy, using each patient as his own control. Patients with advanced cancer who had documented, disease progression while receiving chemotherapy alone were subsequently treated with the same drug, by the same dose and route, combined with localized hyperthermia. Thirty‐four patients whose diseases included metastatic colon carcinoma, melanoma, sarcoma and hepatoma in viscera (29) or surface tissues (5) were treated with combination thermochemotherapy for 1 hour daily for 5 days/month. Effective heating from 41 to 45°C minimum tumor temperature was possible in 17/19 (89%) tumors in which temperatures could be measured safely. The authors observed 5 (15%) tumor regressions for 1 to 5 months (median, 2 months), and 19 (56%) tumor stabilizations (growth arrest of previously progressive disease) for 1 to 9 months (median, 4 months). Subjective improvement in activity and/or pain control occurred in 6 (18%) patients and 20 (59%) had no progression of symptoms during treatment. Moreover, there was no detectable morbidity from localized hyperthermia, and no evidence of increased chemotherapy toxicity. While the mechanism(s) of response is poorly understood, the documented disease regressions and stabilizations of previously progressive disease in 24 (71%) patients during secondary combination thermochemotherapy indicates that the addition of hyperthermia may have useful anticancer activity. Expanded trials are warranted.

Immune Interventions in Disease

Three therapeutic areas of clinical immunology that have seen active development recently are immunopharmacology of immunosuppressive drugs; clinical use of the alpha-, beta-, and gamma-interferons and interleukin-2; and monoclonal antibody applications in marrow transplantation and antitumor therapy. Understanding of the immune regulatory systems and of the soluble factors that convey information between immune and related cells (for example, lymphokines and cytokines and their receptors) has improved substantially. New information about established immunosuppressive drugs and the introduction of new drugs are providing new opportunities for effective treatment of autoimmune diseases and improved effectiveness of organ transplantation. Clinical trials are evaluating the use of interleukin-2 in immunodeficiency disorders and neoplastic disease. Monoclonal antibodies, which have been successfully applied to diagnostic procedures, have been shown to be useful for therapeutic applications in marrow transplantation and antitumor treatment.

Pulmonary and systemic hemodynamic effects of cardiac glycosides

any physiological actions of digitalis glvcosides have been elucidated only recently although their effects in reversing congestive heart failure and slowing the heart rate have long been known.1-3 These drugs increase myocardial contractility and produce generalized vasoconstriction with consequent increase in systemic resistance. In some species, they also evoke constriction of the hepatic veins, with resultant splanchnic pooling. These actions are similar in normal subjects and those with congestive cardiac failure, but cardiac output varies with the way in which venous return is altered. In contrast to the extensive information on cardiac and systemic actions, little is known of the way in which digitalis glycosides affect the lung circulation.4-6 Because of the potential importance of digitalis-induced vasoconstriction on the pulmonary vasculature, this report concerns the effects of acetyl strophanthidin, strophanthidin (ouabain), and digoxin on the pulmonary as well as systemic circulation of the intact unanesthetized dog. In additional experiments, to eliminate the possible role of altered right or left heart dynamics, a preparation was devised in which a mechanical pump replaced the right heart and maintained pulmonary blood flow constant. Concurrently, left atria1 pressure was maintained at con-trol level after glycoside injection.

Oral vinzolidine as therapy for Kaposi's sarcoma and carcinomas of lung, breast, and colon/rectum.

SummaryVinzolidine, a semisynthetic vinca alkaloid, was studied as oral therapy in 30 patients with Kaposis sarcoma, non-small cell lung cancer, colorectal cancer, and breast cancer. Substantial variations in morbidity were observed among the patients, some patients receiving doses up to 45 mg/m2 without toxicity while others had severe hematologic toxicity at doses as low as 25 mg/m2. Nausea/vomiting and diarrhea also occurred. Responses were seen in two of 11 patients with Kaposis sarcoma but not in other patients. Unpredictable severe hematologic toxicity led to early closure of this study. The heterogeneity of patient tolerance may relate to variable oral drug biovailability, and it is conceivable that vinzolidine could be administered more safely by the IV route.

Amphotericin B plus combination chemotherapy for extensive non-small cell bronchogenic carcinoma

SummarySixteen patients with extensive non-small carcinoma of the lung were treated with methotrexate, vincristine, cyclophosphamide, and adriamycin. Cyclophosphamide and adriamycin were administered after pretreatment with amphotericin B. Amphotericin B-related toxicity was mild; cytotoxic chemotherapy-related toxicity was tolerable. The partial response rate was 12.5% and median survival was between 19 and 20 weeks. Response rate and survival were not superior to those of a similar drug combination lacking amphotericin B.

A comparative study of intravenous versus intralymphatic interleukin-2, with assessment of effects of interleukin-2 on both peripheral blood and thoracic-duct lymph

Recombinant human interleukin-2 (IL-2) was administered by the intravenous (i.v.) or intralymphatic (i.l.) route to 14 patients with advanced malignancy. IL-2 was given in doses of 600,000 IU/kg or 1,050,000 IU/kg daily x 5. Thoracic duct (TD) catheters were placed, and both TD lymphocytes (TDL) and peripheral blood lymphocytes (PBL) were studied. Five of eight patients at the 600,000 IU/kg dose experienced grade III toxicity as did five of six patients at the 1,050,000 IU/kg dose. Two episodes of grade IV toxicity were seen at the higher dose. The i.l. and i.v. routes had a similar toxicity profile excepting lymphangitis/pedal infection, seen only with i.l. administration. One partial response was seen in a patient with renal cell carcinoma. Lymphopenia was seen early in therapy, with lymphocytosis by day 6. Lymphoid yield of the TD catheter fell early in therapy, then increased over baseline by the end of treatment. Intralymphatic administration resulted in a prolonged serum t1/2 and lower serum levels than did i.v. administration, but resulted in higher TD levels. Antibodies against IL-2 were ubiquitous but had no clear effects. Lymphocyte trafficking studies suggested that IL-2 affected lymphocyte redistribution to liver, spleen, bone marrow, and lymph nodes. NK activity and phenotype and LAK activity increased in response to IL-2, with no advantage for TDL. Tumor necrosis factor-alpha and gamma-interferon levels increased sporadically with treatment. The i.l. route offered no advantage over the i.v. route, and TDL offered no advantage over PBL.