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Biomedical subjects

Maurie Markman

Publications and source records attributed to Maurie Markman.

At least 19 recordsLinked to original sources
PubMed2003

Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial.

PURPOSE: To determine whether continuing paclitaxel for an extended time period in women with advanced ovarian cancer who had achieved a clinically defined complete response to a platinum/paclitaxel-based chemotherapy could prolong subsequent progression-free survival (PFS) and affect ultimate survival. PATIENTS AND METHODS: Patients were randomly assigned to either three or 12 cycles of single-agent paclitaxel administered every 28 days and were then followed up for progression-free and overall survival. RESULTS: As of September 6, 2001, 277 patients (262 assessable) had entered the trial, with a total of 54 PFS events having developed among 222 patients with follow-up data. With the exception of peripheral neuropathy, there were no major differences in toxicity between the regimens. The median PFS was 21 and 28 months in the three-cycle and 12-cycle paclitaxel arms, respectively. One-sided P values from an unadjusted log-rank test and an adjusted Cox model analysis (for stratification factors) were.0035 and.0023, respectively, both in favor of the 12-cycle arm. The Cox model-adjusted three-cycle versus the 12-cycle progression hazard ratio was estimated to be 2.31 (99% confidence interval, 1.08 to 4.94). With a protocol-specified early termination boundary of P =.005, these findings led the Southwest Oncology Group Data Safety Monitoring Committee to discontinue the trial. As of the date of study closure, there was no difference in overall survival between the treatment arms. CONCLUSION: Twelve cycles of single-agent paclitaxel administered to women with advanced ovarian cancer who attain a clinically defined complete response to initial platinum/paclitaxel-based chemotherapy significantly prolongs the duration of PFS.

Aged↗
PubMed2003

Role of intraperitoneal chemotherapy in the front-line setting.

During the last several decades, clinical investigators have confirmed the safety and pharmacokinetic advantage associated with the intraperitoneal delivery of a number of antineoplastic agents with known activity in ovarian cancer. Phase II experience has revealed that objective responses, including surgically documented complete remissions, can occur when regional drug delivery is used as second-line treatment of this malignancy. Three randomized trials have shown that when cisplatin-based intraperitoneal treatment is used in the front-line setting, it results in superior progression-free and overall survival compared with intravenous cisplatin. Despite these facts, an ultimate role for regional drug delivery as initial treatment of ovarian cancer will require additional trials to define how to optimize the use of this unique therapeutic strategy.

Antineoplastic Agents↗
PubMed2003

Combined intraperitoneal and intravenous chemotherapy for women with optimally debulked ovarian cancer: results from an intergroup phase II trial.

PURPOSE: The median survival time for women with optimally debulked adenocarcinoma of the ovary treated with intravenous (IV) chemotherapy is 41 to 52 months, and the 2-year survival rate is 65% to 70%. Recent studies evaluating intraperitoneal (IP) chemotherapy have reported a median survival time of 49 to 63 months and 2-year survival rates of 70% to 80%. This phase II trial was undertaken to evaluate the feasibility of and 2-year survival rate achieved by the combination of IP paclitaxel, IP cisplatin, and IV paclitaxel in women with optimally debulked, stage III ovarian cancer. PATIENTS AND METHODS: Treatment consisted of paclitaxel 135 mg/m(2) IV over 24 hours on days 1 to 2, cisplatin 100 mg/m(2) IP on day 2, and paclitaxel 60 mg/m(2) IP on day 8 administered every 21 days for six cycles. RESULTS: In 68 assessable women with optimal stage III ovarian cancer, the 2-year survival rate was 91%, and the median survival time was 51 months. The 2-year disease-free survival rate was 66%, and median disease-free survival time was 33 months. Ninety-six percent of all patients experienced at least one grade 3 to 4 adverse event during therapy, with the most common events being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Seventy-one percent of patients completed all six cycles of IV/IP therapy as planned. CONCLUSION: Combined IV and IP chemotherapy with cisplatin and paclitaxel is associated with a very promising 2-year survival rate in women with optimally debulked ovarian cancer. The ultimate impact of this approach on overall survival requires further evaluation in a randomized trial setting.

Adenocarcinoma↗
PubMed2003

Phase II trial of single agent carboplatin followed by dose-intense paclitaxel, followed by maintenance paclitaxel therapy in stage IV ovarian, fallopian tube, and peritoneal cancers: a Southwest Oncology Group trial.

OBJECTIVE: To improve the survival of women with stage IV epithelial ovarian cancer the Southwest Oncology Group conducted a phase II trial examining two novel treatment strategies: (a) modification of the chemotherapy regimen (carboplatin/paclitaxel) based on evidence of response during treatment and (b) "maintenance therapy," with the monthly administration of single agent paclitaxel (maximum 2 years). METHODS: Individuals with histologically documented stage IV ovarian, fallopian tube, or peritoneal cancers initially received a maximum of 3 courses of single agent carboplatin (AUC 6), with the decision to administer a subsequent course based on specific response criteria (i.e., declines in serum CA-125 or shrinkage of measurable mass lesions). This was followed by single agent paclitaxel (150 mg/m(2)), delivered every 2 weeks for a maximum of 6 courses, again based on evidence of continued response to the treatment program. Finally, in the absence of disease progression or unacceptable toxicity, patients received single agent paclitaxel (175 mg/m2) for a maximum of 24 monthly courses. The primary study end point was 2-year overall survival, which was to be compared to the survival of a previously published historical control population [stage IV ovarian cancer patients treated with a "standard" cisplatin/paclitaxel regimen (GOG 111; McGuire WP, N Eng E J Med 1996; 334:1)]. This analysis was employed to determine if this novel strategy was worthy of further clinical investigation in a controlled clinical trial. RESULTS: There were 53 patients entered this multicenter study, of whom 50 were evaluable for toxicity and 51 for survival. There were 2 treatment-related deaths. Grades 2 and 3 neutrotoxicity were observed in 18 and 4% of patients, respectively. There were no major treatment-related protocol violations. The overall 2-year survival was 48% (95% CI, 34-62%), compared to 60% for the historical control group. CONCLUSIONS: While this trial demonstrated the feasibility of delivering a treatment regimen requiring frequent alternations in therapy based on predetermined changes in objective parameters of response, further exploration of this specific management approach does not appear warranted in stage IV ovarian cancer, based on the survival outcome compared to a reasonably similar historical control population. As this trial demonstrates, the prospective determination of clinical end points in a phase II study (e.g., 2-year survival) that will lead to continued evaluation of a particular investigative strategy in a large-scale randomized trial can be an effective method to reduce the bias and uncertainty often associated with this complex decision process.

Adult↗
PubMed2003

Phase II trial of danazol in advanced, recurrent, or persistent endometrial cancer: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate the activity and toxicity of danazol in advanced, recurrent, or persistent endometrial carcinoma. METHODS: Eligible patients with advanced, recurrent, or persistent endometrial carcinoma not amenable to curative therapy were treated with danazol at a dose of 100 mg four times per day until disease progression or toxicity necessitated discontinuation. Eligibility criteria included the presence of measurable disease and no prior chemotherapy. Immunohistochemical analysis of metastatic tumor tissue for estrogen and progesterone receptors was required. RESULTS: Twenty-five patients were enrolled and 3 were excluded. Six patients had tumors staining positive for both estrogen and progesterone receptors. There were no responders among 22 eligible patients. Six patients (27%) demonstrated stable disease as their best response. The median progression-free survival and overall survival were 1.9 and 14.4 months, respectively. A median total dose of 21.7 (range: 1.4 to 67.2) of danazol was administered. Therapy was discontinued in 5 eligible patients due to toxicity. Four of these patients experienced hepatic toxicity. CONCLUSIONS: Danazol has minimal activity in advanced, recurrent, or persistent endometrial carcinoma.

Aged↗
PubMed2003

Relationship between a history of systemic allergic reactions and risk of subsequent carboplatin hypersensitivity.

OBJECTIVE: The establishment of clinical features identifying patients at a heightened risk for the development of carboplatin hypersensitivity may assist in the management of this important toxicity. Based on a previous report suggesting a history of "bee sting" allergy predicted for paclitaxel hypersensitivity, we attempted to determine if there was a relationship between a history of prior systemic allergic reactions and the subsequent development of carboplatin hypersensitivity. PATIENTS AND METHODS: The medical records of all women treated in the Gynecologic Cancer Program of the Cleveland Clinic from June 1995 to May 2002 who received >6 cycles of platinum-based chemotherapy were retrospectively reviewed for a history of prior systemic hypersensitivity (e.g., medications, environmental exposure). The incidence of "positive" allergic histories was then examined in relation to the subsequent risk of patients developing either a documented carboplatin hypersensitivity reaction or a "positive" carboplatin skin test. RESULTS: The analysis included 174 patients (91 undergoing "carboplatin skin testing") who received > 6 courses of carboplatin. Of 53 patients with no recorded history of systemic hypersensitivity treated prior to our routine use of carboplatin skin testing, 19% experienced an allergic reaction, in contrast to a 40% incidence of a documented carboplatin reaction in 30 patients with a recorded history of hypersensitivity to a medication or environmental exposure (P < 0.05). For the 55 patients with no history of systemic hypersensitivity who underwent carboplatin skin-testing, 27% had a positive test result, in comparison to a 36% positive test rate in women with a previous history of a systemic hypersensitivity reaction recorded in the medical record (P > 0.05). CONCLUSION: This analysis suggests that patients with a prior history of systemic hypersensitivity to medications or environmental exposures may be at a heightened risk for experiencing allergic reactions to carboplatin.

Anaphylaxis↗
PubMed2003

Optimizing primary chemotherapy in ovarian cancer.

Primary chemotherapy for advanced ovarian cancer includes the administration of a platinum agent (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). Most patients (60% to 80%) experience subjective and objective evidence of a favorable response, with prolonged disease-free and overall survival being noted in a substantial subset of this population. Future investigative efforts will focus on the incorporation of new and novel antineoplastic agents into standard treatment, with the important goals of improving biologic activity, enhancing overall quality of life, and extending survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Intraperitoneal antineoplastic drug delivery: rationale and results.

The use of intraperitoneal drug delivery in the treatment of malignant disease confined to the peritoneal cavity is based on the theoretical potential for increased exposure of the tumour to antineoplastic agents leading to improved cytotoxicity. Phase I studies have explored the safety and pharmacokinetic advantage of the regional administration of several drugs, including cisplatin (10 times higher than systemic delivery) and paclitaxel (1000 times higher). Phase II trials of second-line intraperitoneal chemotherapy of ovarian cancer, generally with cisplatin, have shown the potential for patients to achieve surgically-documented complete responses. Randomised trials of second-line regional therapy in patients with ovarian cancer have yet to be conducted, although non-randomised single institution experience has suggested the potential for long-term disease-free survival with this strategy. By contrast, several well-planned randomised trials of first-line intraperitoneal chemotherapy of small-volume residual advanced ovarian cancer after primary surgical cytoreduction have reported a survival advantage with regional drug delivery. Although a rationale can be proposed for intraperitoneal antineoplastic drug delivery in non-ovarian malignant disease involving the peritoneal cavity, current data do not support the use of this strategy outside the confines of well-designed clinical trials.

Antineoplastic Agents↗
PubMed2003

Management of toxicities associated with the administration of taxanes.

The taxanes (paclitaxel and docetaxel) are highly active cytotoxic antineoplastic agents. Common toxicities of the drugs include total alopecia, hypersensitivity reactions, bone marrow suppression (principally neutropenia), arthralgia, myalgias, and peripheral neuropathy. When administered as a 3-h infusion, paclitaxel appears to be associated with a lower risk of neutropenia and a greater risk of peripheral neuropathy, compared to either 24-h infusion paclitaxel or docetaxel (1-h infusion). Neither paclitaxel nor docetaxel is associated with a high risk for significant emesis. High cumulative doses of docetaxel have been shown to produce fluid retention (e.g., oedema, ascites, pleural effusions), while paclitaxel, when combined with doxorubicin, increases the risk of anthracycline-induced heart failure. Both paclitaxel and docetaxel have been administered at lower dose levels, on a weekly schedule, with acceptable toxicity profiles. In general, the side effects of the taxanes are manageable, and few patients discontinue treatment due to excessive toxicity.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Unfolding the pathophysiological role of bioactive lysophospholipids.

Lysophospholipids (LPLs), including glycerol- and sphingoid-based lipids, stimulate cell signaling and play important pathophysiological roles in humans and other animals. These LPLs include lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC). Analyses of LPLs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPLs in human diseases, but also their potential application as biomarkers and/or therapeutic targets. In recent years, the identification and/or characterization of the plasma membrane receptors for LPLs and enzymes regulating the metabolism of LPLs have greatly facilitated our understanding of their role and signaling properties. In vitro and in vivo functional and signaling studies have revealed the broad and potent biological effects of LPLs and the mechanisms of LPL actions in different cellular systems. Development of specific antagonists for each of the LPL receptors will provide powerful tools for dissecting signaling pathways mediated by receptor subtypes. More importantly, these antagonists may serve as therapeutics for relevant diseases. Genetic depletion of LPL receptors in mice has provided and will continue to provide critical information on the pathophysiological roles of LPL receptors. It is important to further evaluate the significance of targeting these bioactive LPL receptors, their downstream signaling molecules, and/or metabolic enzymes in the treatment of cancers and other diseases.

Animals↗