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V K Sondak

Publications and source records attributed to V K Sondak.

At least 19 recordsLinked to original sources
PubMed2001

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↗
PubMed2001

Gender and other survival predictors in patients with metastatic melanoma on Southwest Oncology Group trials.

BACKGROUND: Some studies have suggested that women with metastatic malignant melanoma have a better survival rate than men. However, little is known about the effect of gender on survival in combination with other clinical variables and treatment variables. Thus, an analysis of 813 eligible patients from 15 consecutive Southwest Oncology Group (SWOG) Phase II or III trials evaluating chemotherapy or chemoimmunotherapy for metastatic melanoma was performed. METHODS: A multivariate Cox regression model was used. RESULTS: Poor performance status (P < 0.001), more organ sites with metastases (OSM) (P < 0.001), liver involvement (P < 0.001), and nonliver visceral involvement (P = 0.01) were highly significant predictors of worse survival, whereas the disease free interval (P = 0.08) had borderline significance. After adjustment for all factors, there was no difference in overall survival between men and women (P = 0.19). Women had a longer disease free interval (P = 0.003) and fewer OSM (P = 0.004) at study registration than men. CONCLUSIONS: The current study found that performance status, OSM, and type of visceral involvement were independent predictors of survival in patients with metastic malignant melanoma and should be used as stratification factors in future Phase III trials. However, the current study also found that gender did not appear to be a significant independent predictor of survival for this stage of disease. A longer disease free interval from initial diagnosis and fewer OSMs may partly explain the improved outcome reported for women in selected trials. The study concluded that further investigation of the biologic differences at early stage diagnosis should be undertaken to determine whether women truly have a different pace of disease progression and a different metastatic pattern.

Adolescent↗
PubMed2001

Early stage (I, II, III) melanoma.

Metastatic melanoma beyond the regional nodes (American Joint Committee on Cancer stage IV) is a highly lethal disease. Few affected individuals survive beyond 5 years despite aggressive treatment. Clearly, effective adjuvant therapies to prevent the development of stage IV disease in at-risk patients are worthwhile and acceptable to patients, even if they are associated with significant toxicities. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adherence to the standards of care for the surgical management of melanoma patients with high-risk primary disease or regional disease will help optimize the benefit that can be derived from adjuvant therapy. Clinical trials remain critically important as we seek to improve the outcome for melanoma patients, but for high-risk melanoma patients outside the context of clinical trials, adjuvant therapy with high-dose interferon-alfa2b should be considered a standard treatment option.

Biopsy↗
PubMed2001

Application of molecular cytogenetic techniques in a case study of human cutaneous metastatic melanoma.

Consistent structural chromosome rearrangements have rarely been identified in adult solid tumors. The introduction of advanced molecular cytogenetic techniques has provided new ways of analyzing highly complex karyotypes commonly encountered in these malignancies. This study describes a detailed molecular cytogenetic analysis of a sporadic human cutaneous melanoma biopsy, M92-047, using a combination of G-banding, fluorescence in situ hybridization (FISH), chromosome microdissection, and comparative genomic hybridization (CGH). G-banding revealed that this tumor was composed primarily of closely related near-diploid and near-tetraploid cell subpopulations containing several clonal numerical and structural chromosome alterations. Fluorescence in situ hybridization using whole chromosome painting probes and chromosome arm painting probes, was employed to verify the rearranged chromosomes; dic(1;4), der(8)t(1;8), and der(15)t(6;15), whereas marker chromosomes dic(8;1;16), der(12)t(9;12), and der(17)t(13;17) were discerned by chromosome microdissection and subsequent reverse in situ hybridization (rev ish) analysis. Comparative genomic hybridization illustrated DNA copy number changes in good agreement with the karyotypic analysis. Although this line exhibits recurrent alterations representative of melanoma, two unique breakpoints--1p13 and 8p21--were identified in two different rearranged chromosomes, suggesting potentially important regions for further dissection by molecular genetic techniques. This report demonstrates the advantages of combining multiple techniques in order to obtain a detailed description of cytogenetic changes in melanoma.

Aged↗
PubMed2001

Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study.

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

Adult↗
PubMed2000

A modified p53 overcomes mdm2-mediated oncogenic transformation: a potential cancer therapeutic agent.

The antiproliferative activities of wild-type (wt) p53 are inhibited by mdm2 (murine double minute2) oncogene product. We tested growth suppression activity of p53 14/19, an engineered p53 variant, which does not bind mdm2 and is completely resistant to the inhibition by mdm2. p53 14/19, unlike wt p53, suppressed the growth of cancer cells that contain amplified mdm2 oncogene efficiently by direct DNA transfection or adenovirus-mediated gene transfer. In addition, p53 14/19 also inhibited the growth of several different cancer cell lines expressing low levels of mdm2 oncogene product as efficiently as wt p53. We further examined the antioncogenic potencies of p53 14/19 in the rat embryo fibroblast cotransformation assay. Addition of wt p53 failed to cause any significant decrease in ras plus mdm2 foci counts. In contrast, cotransfection of p53 14/19 with ras and mdm2 significantly reduced foci number. In similar experiments, cotransfection of wt p53 or 14/19 p53 resulted in significant inhibition of oncogenic transformation in rat embryo fibroblast mediated by an activated ras plus c-myc, adenovirus E1A, or human papillomavirus E7 oncogenes. Therefore, these results suggest that p53 14/19 modified tumor suppressor gene may be a promising therapeutic agent for human cancers that express abnormally high levels of mdm2 oncogene product.

Adenoviridae↗
PubMed2000

High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.

PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNalpha2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs). PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNalpha2b (HDI) for 1 year and low-dose IFNalpha2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months' median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P(2) =.05); for LDI versus Obs, it was 1.19 (P(2) =.17). By Cox analysis, the impact of HDI on RFS achieved significance (P(2) =.03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFNalpha-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFNalpha2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690. CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNalpha2b that is dose-dependent and significant for HDI by Cox multivariable analysis.

Aged↗
PubMed2000

CT of recurrent retroperitoneal sarcomas.

OBJECTIVE: We reviewed the medical records and CT scans of 33 patients with recurrent retroperitoneal sarcomas to determine the patterns of recurrent disease. MATERIALS AND METHODS: We reviewed the medical records and CT examinations obtained at the time the recurrence was diagnosed and tabulated data for all patients. Data for patients with high-grade malignancies were compared with those of patients with low-grade malignancies to determine whether there were differences in the interval between initial tumor resection and recurrence. We also compared CT appearances to determine patterns of recurrent disease. RESULTS: Twenty-five of 33 recurrences were detected within 2 years of initial surgery. Only 16 patients had symptoms, and when present, most symptoms were nonspecific. In 28 (85%) patients, recurrent tumor was in the abdomen at the time of diagnosis. In nine patients, the largest detectable abdominal tumor was less than 5 cm in diameter. Interval to recurrence was similar for patients with low- and high-grade tumors. Although the CT appearance was similar for both grades, distant metastases were identified only in patients with high-grade malignancies. CONCLUSION: Primary retroperitoneal malignancies frequently recur within 2 years of initial surgical resection. For asymptomatic patients, diagnosis is typically made during routine follow-up CT. Most patients have abdominal recurrences that may be small when first detected.

Adult↗
PubMed2000

Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study.

Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15-20% of baseline. The level III dose of TM (120 mg/ day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.

Adult↗
PubMed1999

Phase II trial of biochemotherapy with interferon alpha, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial.

The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.

Adolescent↗
PubMed1999

Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience.

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks. RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8(+) infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

Adult↗
PubMed1998

Preoperative idoxuridine and radiation for large soft tissue sarcomas: clinical results with five-year follow-up.

BACKGROUND: Local control remains an important issue in the management of large soft tissue sarcomas. Radiation is the main adjuvant to surgery for local therapy of sarcomas, but it requires relatively high doses, hitherto considered prohibitive in areas such as the retroperitoneum. We developed a preoperative treatment approach to large soft tissue sarcomas that would deliver a high total dose of radiation administered in conjunction with the halogenated pyrimidine radiosensitizer idoxuridine (IdUrd). METHODS: Thirty-seven patients with large sarcomas of the head and neck, mediastinum, retroperitoneum, or extremity received three or five cycles of sequential IdUrd infusion (1000-1600 mg/m2/d x 5 d) alternating weekly with twice daily radiation (125-150 cGy per dose) and were then evaluated for resection. The delivered preoperative radiation dose was up to 6250 to 7500 cGy. RESULTS: Five patients (14%) had a partial response to preoperative therapy, and 28 of 37 patients underwent successful resection. There were no intra- or postoperative deaths. Local control was achieved in 19 of 28 resected patients, but in only 1 of 6 patients who remained unresectable despite therapy. With a median follow-up of 5.8 years, 28% of patients are alive with no evidence of disease, 17% are alive with disease, and 53% have died of their disease. CONCLUSIONS: Using the dose and schedule we employed, resection of large soft tissue sarcomas was possible after high-dose radiation delivered in conjunction with IdUrd. Although local control was acceptable, the high rate of distant failure represents a limitation of any local approach to the treatment of large soft tissue sarcomas and suggests the need for integration of this approach with an effective systemic therapy.

Adolescent↗
PubMed1998

Advances in melanoma therapy.

This review discusses several advances in melanoma therapy that have recently occurred or are presently in a developmental stage. We discuss the history and present dogma regarding assessment of the regional lymph nodes and adjuvant therapy for melanoma. Of special interest is radiolymphatic sentinel node mapping of the lymph nodes and adjuvant interferon alfa-2b for thick primary lesions and stage III disease. We also discuss several evolving novel and innovative genetic immunotherapy approaches for patients with stage IV disease.

Chemotherapy, Adjuvant↗