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Biomedical subjects

S S Agarwala

Publications and source records attributed to S S Agarwala.

At least 19 recordsLinked to original sources

Burden of illness associated with metastatic melanoma: an audit of 100 consecutive referral center cases.

BACKGROUND: Although long-term survival in patients with metastatic melanoma (MM) is infrequent, response to a variety of cytotoxic and immunotherapies occurs and survival varies based on the site of metastases. Because different patterns of care of MM are likely to vary substantially in their intensity and resource use, the authors audited care at a regional referral center. METHODS: The records of 100 consecutive new patients with MM who presented at the University of Pittsburgh Cancer Institute (UPCI) after January 1997 were audited. Demographics, disease sites, and treatment prior to presentation at UPCI as well as the diagnostic and therapeutic methods undertaken at UPCI were tracked monthly with regard to inpatient and outpatient activity. RESULTS: The median age of the patient cohort was 51 years was a median 2.2 years after the time of initial diagnosis. Eighty-two percent of the patients had died and only 8% had been lost to long-term follow-up. Eighty-seven percent of patients had been referred to UPCI and 28% had received some treatment prior to presenting at UPCI. The median survival was 9.0 months. The lung was the most common symptomatic site and 38% of patients developed central nervous system (CNS) metastases. Eighty-four percent of patients initially were treated on a research protocol 30% of whom were part of a Phase III study. Twenty-nine percent of the patients were never hospitalized. The most common reason for hospitalization was elective treatment with high-dose interleukin-2. Lifetime hospital days averaged only 7.3 days. Therapeutic actions (if ever given) by category type were surgery in 23% of patients, radiation therapy in 44%, immunotherapy in 75%, and chemotherapy in 51%. Using assigned values for the identified resources used, the approximate cost per patient averaged $59,400. CONCLUSIONS: The current audit of MM patients demonstrated that lung and CNS metastases dominate a broad variety of complications, that clinical trial participation was the norm, that hospitalizations occurred relatively infrequently, and that the direct health care costs of current treatment patterns are among the highest for all malignancies. Medical auditing of contemporary American cancer care provides meaningful insights into its patterns of care.

Adult↗

High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801.

PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12 weeks x 8). PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to > or = four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29). CONCLUSION: This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.

Adult↗

High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696.

PURPOSE: High-dose interferon alfa-2b (IFNalpha2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNalpha2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNalpha2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNalpha2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high-risk melanoma (AJCC stages IIB, III, and IV). RESULTS: The results demonstrate that IFNalpha2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNalpha2b and GMK is well tolerated in this patient population. CONCLUSION: Cox analysis of the results of the combination with IFNalpha2b show improvement in the relapse-free survival of patients with very high-risk melanoma (including those with resectable M1 disease).

Adult↗

Histamine dihydrochloride: inhibiting oxidants and synergising IL-2-mediated immune activation in the tumour microenvironment.

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro, inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC). Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia (AML), objective responses occur in a minority of patients and survival is not significantly extended, except for a minority of patients with MM using high-dose regimens which have not been widely adopted. In vitro findings suggest that the addition of histamine to IL-2 therapy might improve response rates and disease-free survival by protecting the cells of the immune system from oxidative stress and inducing natural endogenous immune cytotoxicity. An IL-2/histamine Phase III trial is in progress in a population of AML patients. A recently completed Phase III trial of IL-2 vs. IL-2/histamine in patients with MM demonstrated a trend towards a superior survival benefit from IL-2/histamine for all patients entered, and a statistically significant survival benefit for patients with hepatic metastases.

Animals↗

Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer.

Guanine ribonucleosides substituted at the 8 position of the guanine ring are a unique class of immunomodulators, the lead compound of which is 7-allyl-8-oxoguanosine (loxoribine). We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer. Twenty-four patients were treated in three dose tiers of 8 patients each, utilizing a unique statistical design, so that within each group, patients were randomized in blocks of 4 to receive loxoribine initially and then placebo 4 weeks later--a sequence that was reversed in the remaining 4 patients. In 23 courses of loxoribine and 20 courses of placebo, toxicity was mild and infrequent at all dose tiers (1 mg/kg, 5 mg/kg and 10 mg/kg. Both antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity were transiently depressed following loxoribine administration at all doses. Loxoribine is safe at doses up to 10 mg/kg in patients with advanced cancer, and produces modest immunologic effects. Further testing, particularly in conjunction with other immunologic agents, is warranted.

Adjuvants, Immunologic↗

Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma.

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier. Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite. These pharmacologic properties make it an ideal agent for treating central nervous system malignancies. In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure. In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile. More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazine-treated patients. Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients. TMZ may become an important part of treatment regimens for advanced metastatic melanoma.

Administration, Oral↗

A phase III randomized trial of dacarbazine and carboplatin with and without tamoxifen in the treatment of patients with metastatic melanoma.

BACKGROUND: Metastatic melanoma is a disease associated with a poor prognosis, and dacarbazine is still the reference agent. The authors conducted a randomized trial to test the benefit of adding tamoxifen to dacarbazine and carboplatin chemotherapy for previously untreated patients with metastatic melanoma. METHODS: Eligible patients with histologically confirmed, measurable metastatic melanoma were randomized to carboplatin 300 mg/m2 and dacarbazine 1 g/m2 administered intravenously on Day 1 with or without tamoxifen 20 mg/day administered orally throughout the treatment period (C + D +/- T). Chemotherapy was repeated in 28-day treatment cycles for a minimum of 2 cycles or until disease progression. The study was designed to be stopped after accrual of 28 patients per treatment arm based on 80% power to detect an improvement in response from 20% to 40% among patients treated with tamoxifen. RESULTS: A total of 56 patients were randomized; all were evaluable for response and survival. The 2 treatment groups were well balanced for various prognostic factors; 75% of patients had predominant visceral disease. Complete and partial responses combined were 10.7% in the C + D arm and 14.3% in the C + D + T arm (P=1.0). Median survival was 7 months for C + D and 4.6 months for C + D + T (the difference was not significant). The median time to disease progression was worse for the patients treated with tamoxifen (P=0.03). Toxicity was similar in the two groups, with no episodes of deep venous thrombosis. CONCLUSIONS: The addition of tamoxifen did not improve the response rate, time to progression, or survival compared with chemotherapy with dacarbazine and carboplatin in unselected patients with metastatic melanoma.

Antineoplastic Combined Chemotherapy Protocols↗

Adjuvant chemotherapy in head and neck cancer.

Chemotherapy for head and neck cancer in the adjuvant setting is still experimental at the present time. In general, chemotherapy, given as an adjuvant to surgery and radiation therapy, has not been effective in improving local control or overall survival. Many of the regimens tested would be considered suboptimal by today's standards, and the experimental patient population in these studies have been heterogenous without stringent application of "high-risk" features. Concurrent radiation and chemotherapy seems to be promising and is the focus of ongoing research efforts. The true role of this approach will have to await the completion and analysis of currently active trials, such as the intergroup high-risk adjuvant trial.

Antineoplastic Agents↗

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

Adult↗

A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies.

Temozolomide (TMZ) is an oral imidazotetrazinone that is spontaneously converted to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH. MTIC methylates DNA at the O6 position of guanine, although this lesion may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (AGAT). In this study, TMZ was combined with cisplatin (CDDP), because both agents have single-agent activity against melanoma and other tumor types. Additionally, CDDP has been shown to inactivate AGAT, and subtherapeutic concentrations of CDDP have been shown to increase the sensitivity of leukemic blasts to TMZ. This Phase I study sought to determine the toxicities, recommended dose, and pharmacological profile of the TMZ/CDDP combination. Patients were treated with oral TMZ daily for 5 consecutive days together with CDDP on day 1 (4 h after TMZ) every 4 weeks at the following TMZ (mg/m2/day)/CDDP (mg/m2) dose levels: 100/75, 150/75, 200/75, and 200/100. Plasma samples were obtained on days 1 and 2 to evaluate the pharmacokinetic parameters of TMZ alone and in combination with CDDP. Fifteen patients received a total of 44 courses of TMZ/CDDP. The principal toxicities of the regimen consisted of neutropenia, thrombocytopenia, nausea, and vomiting, which were intolerable in two of six new patients treated at the 200/100 mg/m2 dose level. Of five patients receiving 17 courses at the next lower dose level (200/75 mg/m2), none experienced dose-limiting toxicity. Antitumor activity was observed in patients with non-small cell lung cancer, squamous cell carcinoma of the tongue, and leiomyosarcoma of the uterus. Pharmacokinetic studies of TMZ revealed the following pertinent parameters (mean +/- SD): time to maximum plasma concentration (Tmax) = 1.1+/-0.6 h (day 1) and 1.7+/-0.9 h (day 2); elimination half-life (t1/2) = 1.74+/-0.22 h (day 1) and 2.35+/-0.70 h (day 2); and clearance (Cl(s)/F) = 115+/-27 ml/min/m2 (day 1) and 141+/-109 ml/min/m2 (day 2). TMZ drug exposure, described by the area under the plasma concentration-time curve (AUCinfinity) and the maximum plasma concentration (Cmax), was similar on days 1 and 2. On the basis of these results, the recommended doses for Phase II clinical trials are TMZ 200 mg/m2/day for 5 days with 75 mg/m2 CDDP on day 1, every 4 weeks. The addition of CDDP did not affect the tolerable dose of single-agent TMZ (200 mg/m2/day x 5 days), nor did it substantially alter the pharmacokinetic behavior of TMZ.

Adult↗

Adjuvant therapy of melanoma.

Patients with AJCC Stage IIB and III melanoma have a poor 5-year survival rate which has been the driving force behind attempts to find an effective adjuvant therapy for this stage of disease that would effectively reduce relapse and improve survival. Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum, and levamisole have not been successful in achieving this goal, nor have trials with chemotherapy in the adjuvant setting, including high-dose chemotherapy with autologous bone marrow transplantation. The recent Eastern Cooperative Oncology Group (ECOG) 1684 study showed significant improvement in relapse-free and overall survival with high doses of alpha interferon (IFNalpha) given for 1 year. Lower dosages of IFNalpha have to date been unsuccessful in impacting upon long-term survival. Recent data with vaccines have been encouraging, and the GM2-KLH vaccine is the focus of ongoing intergroup study comparing this treatment with IFNalpha in resected Stage IIB and III melanoma. The various regimens are reviewed in this article.

Antineoplastic Agents↗

Adjuvant interferon treatment for melanoma.

After decades of research, the adjuvant therapy of patients with melanoma has recently shown significant survival and relapse-free interval benefit for the intravenous and subcutaneous administration of maximally tolerable dosages of recombinant IFN alpha 2b in a trial conducted by the ECOG (E1684). Despite the toxicity of this therapy, retrospective analyses of its impact upon quality-of-life using Q-TWiST methods and cost-efficacy analyses all argue for the benefit and utility of this intervention, especially for node-positive patients with resectable melanoma at highest risk of relapse. A confirmatory trial has been completed and will mature in the spring of 1998. The impact of lower dosages of IFN, apparent transiently during and for a period of time following treatment has not been sustained with longer follow-up in a number of trials. Current approaches in Europe and North America focus upon refinement of dose and duration of treatment with IFN and their potential interactions with, and comparison with, active specific immunotherapy with vaccines. A recently emerging area of research is the patient with stage IIA melanoma and the potential role of an abbreviated high-dose regimen of IFN alpha in this patient subset.

Adjuvants, Pharmaceutic↗

Paraneoplastic syndromes.

The paraneoplastic syndromes are effects of cancer that occur at sites remote from the primary tumor and its metastases. Recognition of these disorders is important from both diagnostic and therapeutic viewpoints. The important paraneoplastic syndromes involving the endocrine, nervous, hematologic, and dermatologic systems are discussed in this article.

Humans↗

Interferons in melanoma.

The interferons are complex proteins that have been widely tested as therapy for neoplastic diseases. Interferon (IFN)-alpha has been the most extensively studied in melanoma. It produces responses in about 16% of metastatic melanomas, about one third of which are complete. It has been combined with chemotherapy and biologic therapy in an attempt to improve on this response rate, but despite encouraging reports from single-institution trials, firm evidence for improved efficacy is still forthcoming. Randomized trials of sequenced biochemotherapies should shed further light on this issue. The outlook in the adjuvant setting is much brighter with the recently reported positive results of the European Cooperative Oncology Group trial E1684 that showed improved overall and disease-free survival for high-risk patients treated with IFN-alpha. The lack of efficacy of lower dosages and different schedules of administration argues for the use of maximally tolerated doses. IFN-gamma has proved disappointing in cases of both metastatic and high risk for relapse melanoma, but has been effective in locoregional disease, particularly in combination with tumor necrosis factor-alpha and melphalan. Further research will need to focus on sequencing, improved methods of administration, and efforts to reduce toxicity.

Antineoplastic Agents↗

Potential uses of interferon alpha 2 as adjuvant therapy in cancer.

BACKGROUND: The purpose of this study was to provide an overview of the potential uses of adjuvant interferon (IFN) therapy for resected solid tumors at high risk for postsurgical relapse. METHODS: A MEDLINE search (1970-1994) of the English-language literature for original articles, reviews, and abstracts addressing IFN use in the adjuvant setting together with the authors' collective experience formed the basis for this review. RESULTS: The use of adjuvant IFN-alpha has been studied most extensively in conjunction with the treatment of melanoma. Fewer data are available on IFN-alpha use for the treatment of other solid tumors. In melanoma, there is evidence from Intergroup trials (Eastern Cooperative Oncology Group and World Health Organization) that IFN-alpha 2a given for 1-3 years prolongs the interval to relapse and may have a survival benefit. Trials of adjuvant IFN, with and without chemotherapy, are ongoing in the treatment of renal cell carcinoma and colorectal adenocarcinoma. Its value in the treatment of osteosarcoma and high-grade astrocytoma is unknown. CONCLUSIONS: The use of IFN in the adjuvant setting is an exciting area of medical and surgical oncology and has the potential to prolong the time to relapse and to increase survival of patients with melanoma. Its role in the adjuvant therapy of other solid tumors remains to be defined.

Antineoplastic Agents↗

Evaluation of the combination of vinblastine and quinidine in patients with metastatic renal cell carcinoma. A phase I study.

Quinidine is known to inhibit p-glycoprotein and enhance the activity of vinblastine against cultured renal carcinoma cells. We have combined quinidine and vinblastine in a Phase I trial in patients with metastatic renal cell carcinoma. Twenty-three patients were entered. Prior treatment included nephrectomy (15 patients), radiation (1 patient) and interferons (8 patients). Cohorts of patients were treated at one of three quinidine dose levels (100, 200, and 400 mg); one patient received 300 mg. Quinidine was given orally 4 times daily starting 3 days prior to the first dose of vinblastine of 5 mg/m2 intravenously given once a week. Hematologic parameters, EKG, and quinidine levels were monitored weekly. Mean quinidine levels in each dose tier were 1.58, 2.59, and 4.24 micrograms/ml, respectively. The dose-limiting toxicity was leukopenia, which necessitated dose interruptions in 16 patients. The mean nadir WBC count (x 10(9)/L) was 3.47, 2.3, and 1.73 in each dose tier, respectively. Corresponding values for the mean maximum decrease in WBC count from baseline were 3.85, 5.86, and 6.53, respectively. There was a trend for leukopenia to become more severe with increasing doses of quinidine. Other toxicities included mild nausea and vomiting in all patients, and hypotension and paralytic ileus in one patient each. No cardiac toxicity was observed. One patient had a complete remission and 4 patients had stable disease. We conclude that quinidine and vinblastine may be administered together safely in a clinical setting, with leukopenia being dose-limiting. Further studies are needed to determine any therapeutic advantage over vinblastine alone.

Adult↗