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Biomedical subjects

A C Buzaid

Publications and source records attributed to A C Buzaid.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phase II study of neoadjuvant concurrent biochemotherapy in melanoma patients with local-regional metastases.

Our results with concurrent biochemotherapy in patients with stage IV melanoma have been encouraging. Based on these data, we conducted a phase II study to determine the clinical and histological response rate to neoadjuvant concurrent biochemotherapy in patients with local-regional metastases of cutaneous melanoma (stage III). A total of 65 patients with biopsy-proven, measurable and potentially resectable local-regional disease (nodal, satellite/in-transit metastases and/or local recurrence) were treated with cisplatin 20 mg/m2 intravenously (i.v.) on days 1 to 4, vinblastine 1.5 mg/m2 i.v. on days 1 to 4, dacarbazine 800 mg/m2 i.v. on day 1 only, interleukin-2 9 MIU/m2 per day i.v. by 96 h continuous infusion on days 1 to 4, and interferon-alpha 2a 5 MU/m2 subcutaneously on days 1 to 5, repeated every 3 weeks. Patients underwent surgery after two to four courses of biochemotherapy. Those with tumour regression after two preoperative courses received two additional postoperative courses. Of the 64 patients assessable for clinical response, 28 (44%) had a partial response. Of the 62 patients whose response was assessed histologically, four (6.5%) had no evidence of viable tumour in the surgical specimen (pathological complete remission, pCR) and 27 (43.5%) had a partial response, giving an overall response rate of 50%. Tumour burden did not correlate with response, although patients who achieved a pCR had a significantly lower tumour burden (P = 0.02). Our phase II study indicates that neoadjuvant biochemotherapy is an active treatment for melanoma patients with local-regional metastases. However, it is unclear if biochemotherapy is more active than chemotherapy alone; phase III randomized trials are ongoing to answer this question in patients with stage IV disease.

Adolescent↗
PubMed1998

Prognostic factors for survival of patients treated systemically for disseminated melanoma.

PURPOSE: The current American Joint Commission on Cancer (AJCC) staging system distinguishes between soft tissue and visceral metastases in advanced (stage IV) melanoma. We sought to verify these staging criteria and to identify prognostic variables that could be used to evaluate the impact of systemic therapy on long-term survival during the prior decade. PATIENTS AND METHODS: We conducted a retrospective study of patients with advanced cutaneous melanoma enrolled in clinical trials between 1979 and 1989 at The University of Texas M.D. Anderson Cancer Center. Pretreatment age, sex, number of organs with metastases, serum levels of lactate dehydrogenase (LDH) and albumin, and period of enrollment were analyzed using a Cox proportional hazards model of survival. RESULTS: In univariate and multivariate analyses that involved 318 stage IV patients, normal serum levels of LDH and albumin, soft tissue and/or single visceral organ metastases (especially lung), female sex, and enrollment late in the decade were independent positive predictors for survival. In multivariate analyses, the current AJCC criteria did not significantly predict outcome. Systemic treatment response did not bias these results, and only 4% of patients had a complete response. Patients who lived more than 2 years (11%) had a mix of favorable prognostic characteristics and a high frequency of systemic or surgically induced complete response. CONCLUSION: This study supports the use of stratification parameters that reflect the favorable prognostic impact of soft tissue or single visceral organ metastases and normal serum levels of LDH and albumin at time of enrollment in advanced melanoma trials. Improved survival over the prior decade probably reflects advances in diagnostic and palliative interventions.

Adult↗
PubMed1998

Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma.

PURPOSE: To evaluate the antitumor activity and toxicity of concurrent biochemotherapy that uses cisplatin, vinblastine, and docarbazine (DTIC) (CVD) in combination with interferon alfa-2a (IFN-alpha) and interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS: Between October 1992 and October 1993, 53 patients with a documented diagnosis of metastatic melanoma with measurable lesions and an Eastern Oncology Cooperative Group (ECOG) performance status of 2 or less were enrolled onto this study. Patients were required to have no clinically significant cardiac dysfunction and to be free from symptomatic brain metastases. The treatment consisted of cisplatin 20 mg/m2 daily for 4 days; vinblastine 1.6 mg/m2 daily for 4 days; and DTIC 800 mg/m2 intravenously (i.v.) day 1 with IL-2 9 x 10(6) IU/m2 i.v. by continuous infusion daily for 4 days and IFN-alpha 5 x 10(6) U/m2 subcutaneously daily for 5 days, repeated at 21-day intervals. Response was assessed after two cycles and patients who responded were continued on treatment for a total of six cycles. RESULTS: Among 53 assessable patients, 11 patients (21%) achieved a complete response (CR) and 23 patients (43%) achieved a partial response (PR), for an overall objective response rate of 64%. The median time to disease progression for all patients was 5 months. The median survival of all patients entered onto the trial was 11.8 months. Among the 11 patients who achieved a CR, five patients (9%) have remained in continuous CR for 50+ to 61+ months. The toxicity of biochemotherapy consisted of severe myelosuppression, significant nausea and vomiting, and moderately severe hypotension that required inpatient hospital care for each 5-day cycle of treatment. There were no treatment-related deaths. CONCLUSION: Concurrent biochemotherapy for patients with advanced melanoma is capable of producing high CR and overall response rates and resulted in durable complete remissions in a small fraction of patients. Toxicity, although severe, was manageable in a routine inpatient hospital environment.

Adult↗
PubMed1998

Active immunotherapy with ultraviolet B-irradiated autologous whole melanoma cells plus DETOX in patients with metastatic melanoma.

Our objective was to determine the clinical activity, toxicity, and immunological effects of active immunotherapy using UVB-irradiated (UVR) autologous tumor (AT) cells plus adjuvant DETOX in metastatic melanoma patients. Eligibility included nonanergic patients fully recovered after resection of 5 or more grams of metastatic melanoma. Treatment consisted of intradermal injections of 10(7) UVR-AT plus 0.25 ml of DETOX every 2 weeks x 6, then monthly. Peripheral blood mononuclear cells (PBMCs) were harvested for cytotoxicity assays, and skin testing was performed for delayed-type hypersensitivity (DTH) determinations before the first, fourth, seventh, and subsequent treatments. Forty-two patients were treated, 18 in the adjuvant setting and 24 with measurable disease. Among the latter group, there were two durable responses in soft-tissue sites and in a bone metastasis. Treatment was well tolerated. Thirty-five patients were assessable for immunological parameters; 10 of these patients, including the 2 responders, demonstrated early induction of PBMC cytotoxicity against AT cells that persisted up to 10 months on treatment before falling to background levels. In five of seven patients, the fall-off heralded progressive disease. Late induction of a weak DTH reaction to AT cells was observed in eight patients. Active immunotherapy with UVR-AT + DETOX had modest but definite clinical activity in advanced melanoma. The induction of both PBMC cytotoxicity and DTH reactivity to AT cells supported a specific systemic immune effect of treatment, although the former more closely followed disease course in this study.

Adjuvants, Immunologic↗
PubMed1997

Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma.

PURPOSE: A phase II study was undertaken to determine the efficacy of tirapazamine (TPZ) combined with cisplatin (cDDP) in patients with metastatic melanoma. PATIENTS AND METHODS: Between June 1994 and November 1995, 48 patients with metastatic melanoma were treated with TPZ (260 mg/m2, administered intravenously over two hours) followed in one-hour by cDDP (75 mg/m2 over one hour) every 21 days. Sixteen patients had received prior chemotherapy, and 13 of these had failed to respond to prior cDDP. None of the patients had symptomatic brain metastasis. RESULTS: Nine patients had partial responses, with an overall response rate of 19% (95% confidence interval (95% CI) of 9%-33%). The median duration of response was six months. None of the responders had received prior chemotherapy. Responses were seen in 8 (33%, confidence interval of 16%-55%) of 24 patients with primary cutaneous melanoma who had received no prior chemotherapy and in the only patient with previously untreated conjunctival melanoma. There were no responders among the seven patients with choroidal melanoma and 16 patients with previously treated cutaneous melanoma. Two patients with partial responses were rendered free of gross disease surgically three months after completing eight courses of TPZ-cDDP; they remain free of tumor recurrence. Responses were seen in lymph nodes (27%), lung (26%), skin (20%), adrenal gland (20%), soft tissues (17%) and liver (17%). Common toxicities included muscle cramps, fatigue, gastrointestinal effects and peripheral neuropathy. Fatigue, nausea, vomiting, anorexia, and muscle cramps were grade 3 or 4 in less than 10% of the courses. Neutropenia and thrombocytopenia were rare. CONCLUSION: The TPZ-cDDP combination has definite activity against chemotherapy-naïve patients with cutaneous melanoma and warrant further studies in combination with other cytotoxic agents.

Adult↗
PubMed1997

Treatment of advanced pancreatic adenocarcinoma with 5-FU, leucovorin, interferon-alpha-2b, and cisplatin.

Previous laboratory and clinical studies support the ability of interferon (IFN) to enhance the antitumor properties of chemotherapy agents, including cisplatin and 5-fluorouracil (5-FU). A phase I-II clinical trial was initiated to treat several tumor types with IFN-alpha-2b, cisplatin, 5-FU, and leucovorin (LV), given daily for 5 days of a 28-day cycle. Because of preliminary results, this was continued as a phase II trial in 18 patients with metastatic adenocarcinoma of the pancreas. Each treatment day consisted of IFN 5 million u/m2 s.c. (maximum, 10 million U), CDDP 20 mg/m2 i.v. over 1 h, LV 20 mg/m2 i.v.p., and 5-FU 250-275 mg/m2 i.v.p. All patients had measurable disease with no prior chemotherapy for metastatic disease, and all had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Six of the 16 patients evaluable for response had partial responses (PRs) (37.5%) with a median response duration of 4 months, and all responding patients survived > or = 8 months. Median survival of all 18 treated patients was 5 months. Severe gastrointestinal toxicity (nausea, diarrhea, or requirement for i.v. hydration) was common. Grade 4 hematologic toxicity was seen in six patients. The response rate observed is promising and supports the concept that IFN may potentiate the effects of standard chemotherapy agents. However, the toxicities observed with this dosage schedule were considerable and further studies are needed to develop a less toxic regimen.

Adenocarcinoma↗
PubMed1997

A phase II study of interferon-alpha 2b with dacarbazine, carmustine, cisplatin and tamoxifen in metastatic melanoma.

A phase II trial was conducted to determine the efficacy and toxicity of the addition of interferon-alpha 2b (IFN-alpha) to the chemotherapy combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin and tamoxifen (DBCT), in patients with stage III or IV melanoma. Treatment consisted of DTIC 220 mg/m2 and cisplatin 25 mg/m2 intravenously on days 1-3, BCNU 100 mg/m2 IV on day 1 only, tamoxifen 20 mg orally twice daily and IFN-alpha 5 x 10(6) units/m2 subcutaneously on days 1-5. Cycles were repeated every 4 weeks. All patients received a loading dose of tamoxifen 100 mg orally twice daily for 5 days before the first course of therapy. Of the 24 patients treated, three (13%) achieved a complete response (CR) and six (25%) a partial response (PR), for an overall response rate of 38% (95% confidence interval, 17-58%). Two patients, one who achieved a clinical CR and one a PR, had pathologically confirmed complete responses. Severe myelosuppression occurred in 47% of cycles and constitutional symptoms were common. Overall, the addition of IFN-alpha to the DBCT regimen did not appear to enhance the response rate and may have increased toxicity.

Adolescent↗
PubMed1997

Selective and synergistic activity of L-S,R-buthionine sulfoximine on malignant melanoma is accompanied by decreased expression of glutathione-S-transferase.

L-buthionine-S,R-sulfoximine (BSO) selectivley inhibits glutathione (GSH) synthesis. Malignant melanoma may be uniquely dependent on GSH and its linked enzymes, glutathione S-transferase (GST) and GSH-peroxidase, for metabolism of reactive orthoquinones and peroxides produced during melanin synthesis. We compared the in vitro effects of BSO on melanoma cell lines and fresh melanoma specimens (n = 118) with breast and ovarian cell lines and solid tumors (n = 244). IC50 values (microM) for BSO on melanoma, breast and ovarian tumor specimens were 1.9, 8.6, and 29, respectively. The IC90 for melanoma was 25.5 microM, a level 20-fold lower than steady state levels achieved clinically. The sensitivity of individual specimens of melanoma correlated with their melanin content (r = 0.63). BSO synergistically enhanced BCNU activity against melanoma cell lines and human tumors. We followed GSH levels, GST enzyme activity, GST isoenzyme profiles and mRNA levels after BSO. BSO (50 microM) treatment for 48 hr resulted in a 95% decrease in ZAZ and M14 melanoma cell line GSH levels, and a 60% decrease in GST enzyme activity. GST-mu protein and mRNA levels were significantly reduced in both cell lines. GST-pi expression was unaffected. These data suggest that BSO action on melanoma may be related to GSH depletion, diminishing the capacity to scavenge toxic metabolites produced during melanin synthesis. We report here for the first time that BSO enhancement of alkylator action may be related in part to down regulation of GST. BSO may be a clinically useful adjunct in the treatment of malignant melanoma.

Antimetabolites, Antineoplastic↗
PubMed1997

Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system.

PURPOSE: To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system. METHODS: Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature. RESULTS: Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size. CONCLUSION: Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.

Humans↗
PubMed1997

Evaluation of tyrosinase mRNA as a tumor marker in the blood of melanoma patients.

PURPOSE: The value of tyrosinase messenger RNA (mRNA) detection in the peripheral blood by reverse-transcription polymerase chain reaction (RT-PCR) as a melanoma marker remains controversial. The purpose of this study was to compare the sensitivities of two different blood processing techniques for tyrosinase mRNA detection and evaluate its potential clinical value. METHODS: A total of 50 patients with progressive stage IV melanoma was studied. Two blood processing methods were used: RNA extraction from the whole blood and RNA extraction from density gradient-isolated peripheral-blood mononuclear cells (PBMC). The RNA samples were tested with a sensitive nested-primer RT-PCR assay. RT-PCR results were also correlated with serum lactate dehydrogenase (LDH), treatment status, and presence of visceral versus nonvisceral metastases. RESULTS: Thirteen (26%) of the density gradient and five (10%) of the whole blood processed samples were PCR positive (P = .011). Serum LDH levels were found to be significantly higher in PCR-positive PBMC-processed patients (P = .015). There was no significant difference in the detection rates between visceral versus nonvisceral metastases or between prior treatment versus no prior treatment. CONCLUSION: Using a density gradient method to process the blood samples resulted in a higher detection rate of tyrosinase mRNA than extracting the RNA from the whole blood. However, the relatively low sensitivity in patients with disseminated and progressive disease compared with other reports suggests that tyrosinase mRNA may be of limited value in the management of malignant melanoma.

Adult↗
PubMed1996

Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer.

Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine, could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-pg. P_pg expression was detected both in the patient who responded to vinblastine plus trifluoperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in the heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha.

BACKGROUND: Metastatic melanoma is commonly treated with chemotherapy and/or biological agents used separately. In this study we have investigated the efficacy of combined chemotherapy using cisplatin, vinblastine, DTIC (CVD) and biological therapy using interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) in patients with metastatic melanoma. PATIENTS AND METHODS: All patients had advanced, inoperable melanoma without prior treatment with chemotherapy or biotherapy, a performance status of ECOG 0-2 and no evidence of symptomatic brain metastases. The CVD regimen consisted of cisplatin 20 mg/m2/d x 4, vinblastine 1.6 mg/m2/d x 5 and DTIC 800 mg/m2 x 1, repeated at 21-day intervals. The biotherapy regimen included IL-2, 9 x 10(6) IU/ m2/d x 4 days and IFN-alpha 5 x 10(6) U/m2/d SC x 5 days. The CVD and biotherapy regimens were integrated initially, in an alternating manner at 6-week intervals and subsequently, in a sequential fashion where patients were randomized to receive either CVD immediately followed by biotherapy (CVD/Bio) or the reverse sequence (Bio/CVD). Patients were admitted to the hospital for IL-2 administration and for monitoring and treatment of IL-2 induced side effects. The phase II results of the integrated therapy (biochemotherapy) studies were retrospectively compared to our previously reported results with the CVD regimen used alone. RESULTS: The alternating biochemotherapy program was used in 40 patients and the sequential biochemotherapy was used in 62 patients. The alternating regimen produced 2 CRs and 11 PRs for an overall response rate of 33% among 39 evaluable patients. The sequential biochemotherapy produced 14 CRs and 23 PRs for an overall response rate of 60% (95% CI, 47% to 72%). The sequence of CVD/Bio resulted in a higher response rate (11 CRs + 11 PRs (69%)) compared to the Bio/CVD sequence (3 CRs + 12 PRs (50%)). Although the duration of PRs was short (median, 8 months), the median duration of CRs was 3+years and 10 of 16 CRs are currently disease free for periods of 3+ to 6+ years. The median survival of patients receiving sequential biochemotherapy was 13 months compared to 9 months for the CVD treated group (P = 0.04). Treatment with biochemotherapy was associated with severe toxicity including intense myelosuppression, infections, IL-2 induced constitutional toxicity and hypotension. However, the IL-2 induced toxicities were generally manageable on a regular ward, except for 15% of the patients who required transfer to an intensive care unit for treatment of complications associated with the treatment. CONCLUSIONS: The sequential combination of CVD with IL-2 + IFN-alpha appears to have produced an increase in the number of durable responses in patients with metastatic melanoma. The toxicity of this program, although severe, was manageable. The biochemotherapy regimen produced an apparent increase in the median survival compared to that observed with the CVD regimen. However, a prospective comparison of these two regimens will be required to confirm these observations.

Adult↗
PubMed1996

Interleukin-6 production and secretion in human melanoma cell lines: regulation by interleukin-1.

These investigations were designed to test the hypothesis that exogenous and/or endogenous interleukin-1 (IL-1) regulates interleukin-6 (IL-6) production in human melanoma cell lines. Ten cell lines were examined for IL-1 and IL-6 expression. Six of these 10 lines constitutively expressed detectable IL-6 mRNA by RT-PCR; three of these six cell lines also produced intracellular and secreted IL-6 as evidenced by positive reaction for IL-6 using immunohistochemistry staining and ELISA methods; three others produced only intracellular IL-6. Addition of exogenous IL-1 alpha was shown to have the following effects on IL-6 production: first, de novo induction of detectable IL-6 intracellular protein and secreted IL-6 in a cell line void of either; second, stimulation of IL-6 secretion in all three cell lines producing only intracellular IL-6 protein; and third, quantitative enhancement of IL-6 secretion in cell lines that constitutively secreted IL-6. Three of the 10 lines which secreted IL-6 also constitutively secreted IL-1 alpha. Experiments employing the IL-1 receptor antagonist confirmed an extracellular receptor-mediated role of IL-1 in regulation of IL-6 production in such cells. These results indicate that IL-1 can regulate IL-6 in human melanoma cells; however, heterogeneity in the constitutive expression as well as variability in response exists with respect to these two cytokines.

Cell Division↗
PubMed1995

Acute rhabdomyolysis after concurrent administration of interleukin-2, interferon-alfa, and chemotherapy for metastatic melanoma.

BACKGROUND: Acute rhabdomyolysis has been described to occur only rarely after systemic administration of cancer chemotherapy drugs, such as cytarabine and 5-azafluorene. A single case of rhabdomyolysis after treatment with alfa-interferon recently was reported, but to the authors' knowledge, there have been no published cases of clinically relevant rhabdomyolysis after systemic therapy with the other agents. METHODS: The case of a 28-year-old woman with metastatic melanoma and no known history of neuromuscular disorders who developed severe myalgia followed by acute, extensive rhabdomyolysis with multiorgan failure after concurrent administration of systemic biologic therapy and chemotherapy consisting of alfa-interferon, interleukin-2, cisplatin, vinblastine, and dacarbazine is described. RESULTS: The patient sustained considerable morbidity requiring hemodialysis and respiratory support but eventually recovered. Review of the literature revealed no reported cases of acute rhabdomyolysis after the systemic administration of these agents with the exception of alfa-interferon. CONCLUSION: Acute rhabdomyolysis should be considered when evaluating patients receiving similar biochemotherapy regimens, particularly for those regimens that are alfa-interferon-based and for patients who develop myalgia along with evidence of multiorgan failure.

Acute Disease↗