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Biomedical subjects

L E Flaherty

Publications and source records attributed to L E Flaherty.

33 records · Page 2Linked to original sources
PubMed1995

A phase III randomized, double-blind multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma.

BACKGROUND: In a Phase II trial, surgical adjuvant active specific immunotherapy using a live vaccinia virus-augmented allogeneic polyvalent melanoma cell lysate, vaccinia melanoma oncolysate (VMO), produced a significant disease free interval (DFI) in patients with International Union Against Cancer Stage II melanoma with positive lymph nodes. Therefore, a Phase III randomized prospective, double-blind, multiinstitutional, surgical adjuvant VMO trial was performed to determine the efficacy of VMO to increase the DFI and the overall survival in this group of patients with Stage II disease. METHODS: Two hundred and fifty patients with Stage II melanoma were divided into two postsurgical groups. One group received VMO (total protein equals 2 mg/ml) and the other received the placebo of live vaccinia vaccine virus (V) (10(5.4) TCID50/ml), an adjuvant component of the VMO. Patients initially received these biologics once a week for 13 weeks and then once every 2 weeks for an additional 39 weeks or until recurrence. All surviving patients have been followed for at least 30 months. RESULTS: Statistical analysis of survival data (n = 217) for this first interim analysis shows that there is no statistically significant (P = 0.99) increase in DFI of patients treated with VMO (n = 104) when compared with V (n = 113). The median DFI is 38.0 months for patients treated with VMO and 37.0 months for patients treated with V. At 2- and 4-year intervals, 70 and 38%, respectively, of patients treated with VMO vs. 66 and 36%, respectively, of patients treated with V were free of melanoma. The median overall survival is not available because the patients treated with VMO have not yet reached the 50% mark and the median overall survival is 45.0 months for patients treated with V. At 2- and 4-year intervals, 70 and 38%, respectively, of VMO-treated patients survived when compared with 66 and 36%, respectively, of patients treated with V. Although the overall survival of patients treated with VMO is not statistically significant (P = 0.88) at this point, there is an increasing trend in the overall survival of patients treated with VMO; a 10% increase at the 4-year time point. Moreover, in the subset analysis, VMO-treated male patients (n = 63) showed a 17% improvement in survival at 4-year time point when compared with male patients treated with V (n = 67) (P = 0.19) at the same time point and male patients (n = 20) between the ages of 44 and 57 having 1-5 positive lymph nodes showed a 37% difference in overall survival at the 4-year time point when compared with those patients treated with V (n = 18) (P = 0.13) at the same time point. CONCLUSION: In this first interim analysis, active specific immunotherapy with VMO vs. V showed no difference in the disease free interval or overall survival. Subset analyses likewise showed no significant differences in outcome but the data suggest a potential difference in immunoreactivity between male and female patients with melanoma that awaits further follow up and may merit further investigation.

Adult↗
PubMed1995

Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma. A Southwest Oncology Group study.

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27-81), with performance status 0-2 were treated with merbarone 1000 mg/m2/day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-responders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%-19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%0, malaise (23%), weakness (20%), alopecia (17%), diarrhea (17), anorexia (14%) transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5'nucleotidase increase (9%), and fever (9%). Hematologic toxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.

Adult↗
PubMed1995

A phase II trial of piroxantrone in disseminated malignant melanoma. A Southwest Oncology Group study.

Piroxantrone is one of the anthrapyrazoles developed in an effort to combine the broad antitumor activity of the anthracyclines with decreased myocardial toxicity. It has shown activity in metastatic melanoma during phase I trials. The Southwest Oncology Group (SWOG) conducted a phase II trial in disseminated malignant melanoma with piroxantrone administered at 150 mg/m2 intravenously over 1 h every 21 days, based upon the phase I experience. Forty-six eligible patients were registered to the trial and 44 were evaluable for response. Two partial responses, Wayne of 6 and 9 months duration were observed for an overall response rate of 5% (95% confidence interval 1%-15%). Thirty-six of 46 eligible patients have died with an estimated median survival of 5 months (95% confidence interval 3-8 months). Toxicities were tolerable with granulocytopenia being the predominant toxicity. Based upon the observed response rate, it is concluded that piroxantrone administered at this dose and schedule has detectable but minimal activity, and does not warrant further investigation in this disease.

Adult↗
PubMed1994

Oral etoposide in the treatment of hormone-refractory prostate cancer.

BACKGROUND: Hormone-refractory prostate cancer generally remains a chemotherapy-resistant tumor and therefore warrants the continued evaluation of promising agents. METHODS: Twenty-two eligible patients with hormone-refractory prostate cancer were treated with oral etoposide at a dosage of 50 mg/m2/day for 21 days in a 28-day cycle. Response was evaluated using standard solid tumor response criteria. RESULTS: There were two partial responses of 6 and 14 months' duration, respectively. Two patients had disease stabilization, one for 6 months and one for 12 months. Median survival was 31 weeks, with an overall 1-year survival of 30%. Reversible alopecia and myelosuppression were the primary toxicities noted. CONCLUSIONS: Single-agent oral etoposide has minimal activity in patients with hormone-refractory prostate cancer.

Adenocarcinoma↗
PubMed1994

Phase II trial of recombinant interleukin-1 beta in patients with metastatic renal cell carcinoma.

Interleukin-1 (IL-1) plays a central role in the immune system, partly by stimulating the production of interleukin-2 (IL-2) and other cytokines by lymphocytes. In preclinical studies, recombinant interleukin-1 (rIL-1 beta) has shown antitumor activity. We conducted a phase II trial to evaluate the efficacy of rIL-1 in metastatic renal cell carcinoma (RCC). rIL-1 beta was given at a dose of 50 ng/kg i.v. daily for 5 days on a 28-day schedule. Nineteen patients were registered; 16 completed two cycles and were evaluable for response. There were no complete or partial responses to treatment. Toxicity was generally mild and typically involved grades I and II fever, rigors, hypotension, and weight gain. Severe neurologic toxicity was seen in two patients, grade IV seizures were seen in one, and grade III somnolence was seen in another. Analysis of soluble IL-2 receptor (sIL-2r) levels revealed an increase from a mean pretreatment level of 4,567 pg/ml to a mean of 6,124 pg/ml posttreatment (p < 0.001). The mean pretreatment IL-6 level was 51 pg/ml, increased to 84 pg/ml posttreatment (p < 0.05). Patients with bulky disease had higher sIL-2r levels, and patients with tumor fevers had higher IL-6 and sIL-2r levels than patients without fever did. A neutrophilic leukocytosis and a mild thrombocytosis were observed in response to rIL-1 beta administration. We conclude that rIL-1 beta in this dose and schedule is inactive in metastatic RCC.

Adult↗
PubMed1994

Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate.

PURPOSE: Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy. PATIENTS AND METHODS: Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression. RESULTS: Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria. Of 24 patients with disease limited to bone, six (25%) demonstrated improvement and nine (38%) demonstrated stability in their bone scans. Five men (21%) demonstrated a decrease of at least 75% in pretreatment PSA levels and 14 (58%) demonstrated at least a 50% decrease; the median survival duration has not been reached in these patients. Pretreatment performance status is an important predictor of survival. CONCLUSION: We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer.

Adenocarcinoma↗
PubMed1993

A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma.

BACKGROUND: Based on prior experience with dacarbazine (DTIC) and an outpatient interleukin-2 (IL-2) regimen, the current study was conducted to improve the antitumor efficacy and assess the immunologic interactions between chemotherapy and IL-2. METHODS: Thirty-two patients were registered onto a treatment program, which included DTIC 750 mg/m2 with cisplatin 100 mg/m2, each by intravenous bolus on day 1. Recombinant IL-2 was administered on an outpatient basis intravenously by 15-30-minute infusion (24.0 x 10(6) IU/m2) daily on days 12-16 and 19-23 of a 28-day cycle for three cycles and then every 42 days for responding patients. RESULTS: There were responses in 13 of the 32 registered patients (41% response rate), including five complete and eight partial remissions. Responses in the liver, lung, spleen, lymph nodes, and soft tissue sites were noted. The median duration of response was 8.0 months (range, 3.0-20.0+ months), and the overall median survival duration was 10.2 months. Three patients (9%) are alive, free of disease, without any treatment at 32.0+, 36.0+, and 42.0+ months after initiation of treatment. Only minor nephrotoxicity was observed, and treatment delays were rare. CONCLUSIONS: Additional chemotherapeutic, hormonal, or biologic agents may be added to enhance efficacy further if they have toxicities that do not overlap.

Adolescent↗
PubMed1990

A phase I-II study of dacarbazine in combination with outpatient interleukin-2 in metastatic malignant melanoma.

Because of encouraging response rates published with recombinant interleukin-2 (rIL-2) alone in metastatic malignant melanoma (MMM), dacarbazine (DTIC) and rIL-2 were sequentially combined to evaluate efficacy, toxicity, pharmacokinetics, and immunologic interaction. Thirty-two patients aged 18 to 67 years have received 127 courses of treatment. The dose of DTIC was 1.0 g/m2 as a 24-hour infusion every 28 days on day 1. Recombinant interleukin-2 (2.0, 3.0, 4.0, or 5.0 x 10(6) Cetus units/m2) was administered as a 30-minute infusion on days 15 through 19 and 22 through 26 of each 28-day cycle. Seven of 32 patients (22%) who received therapy had a remission, one complete and six partial. The complete response was in a lung mass. Partial responses were seen in lymph nodes, liver, and lung. The median duration of response was 4.7 months. One patient is in persistent partial remission of the liver for greater than 2 years. One patient had residual mediastinal disease resected after partial response and remains without evidence of disease for 18+ months. This regimen was generally well tolerated, did not create overlapping toxicity, and produced encouraging responses in visceral sites. This provides a framework for future combinations of chemotherapy with rIL-2 alone or in combination with other biologic response modifiers in an outpatient setting.

Adolescent↗
PubMed1990

Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients.

In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I-II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-amino-imidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m2, 24-h i.v. infusion) was given on day 1 and rIL-2 (2-4 million Cetus units/m2, 30-min i.v. injection), on days 15-19 and 22-26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P = 0.02). After rIL-2, the total body clearance (ClT) was increased (P = 0.04), as was the volume of distribution at steady state (Vss; P = 0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P = 0.03). No significant difference was detected in the elimination phase of DTIC when half-lives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the alpha- and beta-phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with alpha- and beta-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.

Chromatography, High Pressure Liquid↗
PubMed1990

Scintigraphic findings in patients with shoulder pain caused by interleukin-2.

Interleukin-2 is receiving widespread interest as an immunotherapeutic agent in the treatment of certain cancers. Severe arthralgias recently have been reported as a significant side effect, and the cause of pain is unknown. Because interleukin-2 is an immune modulator, we reviewed the 99mTc-methylene diphosphonate scintigrams in nine patients who had developed shoulder arthralgias while receiving interleukin-2 for metastatic melanoma. In eight of the patients, the scintigrams showed diffuse increased uptake of radionuclide in the shoulders. Four patients had radiographs of their shoulders, all of which were normal. Bone scintigraphy in patients receiving interleukin-2 as immunotherapy for metastatic melanoma shows increased radionuclide activity in the shoulders. This process may relate to the role of interleukin-2 as a mediator in the inflammatory response.

Adult↗
PubMedDate not supplied

A phase II evaluation of all-trans-retinoic acid plus interferon alfa-2a in stage IV melanoma: a Southwest Oncology Group study.

BACKGROUND: Interferon alfa has modest but definite activity in the treatment of metastatic melanoma and is the only agent currently available for adjuvant therapy of high-risk resected disease. A variety of retinoic acid derivatives have been shown to be synergistic with interferon alfa in vitro and in vivo, with nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have clinical relevance for the treatment of advanced as well as localized disease. PURPOSE: To determine the efficacy and toxicity of a combination of interferon alfa-2a and all-trans-retinoic acid in patients with measurable metastatic melanoma, the South-west Oncology Group conducted a phase II clinical trial. PATIENTS AND METHODS: Fifty-seven patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered; five patients were unevaluable. Treatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m2 orally twice daily for 21 days followed by 7 days' rest) plus subcutaneously administered interferon alfa-2a (6 MU/m2 three times a week). RESULTS: Two complete and three partial responses were observed among 52 evaluable patients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or subcutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side effects. There was one case of grade III hyperlipidemia. CONCLUSION: The combination of recombinant human interferon alfa-2a with all-trans-retinoic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma in either the advanced disease or the adjuvant settings.

Adult↗