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Biomedical subjects

Maurie Markman

Publications and source records attributed to Maurie Markman.

At least 127 records · Page 7Linked to original sources
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

Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian cancer.

OBJECTIVE: There is a need to find agents with activity in platinum and taxane refractory ovarian cancer to be employed as second-line therapy in the malignancy. Limited clinical trial experience has suggested that gemcitabine possesses activity in this clinical setting. We wished to further define the level of activity of gemcitabine in women with well-characterized platinum/taxane refractory disease. METHODS: Patients with ovarian or fallopian tube cancer or primary carcinoma of the peritoneum, whose disease had either failed to respond to a platinum and taxane treatment, or had responded but the "treatment free interval (TFI)" was < or =3 months, or if the TFI was >3 months and they had been retreated with the agents and not responded (or experienced a TFI of <3 months), were eligible for treatment on this phase 2 single institution protocol. Gemcitabine was administered weekly (as a 1-h infusion) for 3 weeks, followed by 1-week break. RESULTS: A total of 51 patients were treated on this trial. The initial dose level (1250 mg/m(2)/week) resulted in excessive toxicity (fatigue, fever/chills, bone marrow suppression). The modified starting dose (1000 mg/m(2)/week) resulted in a more acceptable side effect profile. Eight patients (16%) with measurable disease (n = 4) or evaluable disease by CA-125 criteria (n = 4) achieved an objective response (median duration of response: 4 months; range 2-13 months). CONCLUSION: Single agent gemcitabine possesses modest, but definite, activity in patients with well-characterized platinum/taxane resistant ovarian cancer. It is reasonable to consider this drug for second-line (or later) treatment in this clinical setting.

Adult↗
PubMed2003

Gemcitabine-induced radiation recall dermatitis following whole pelvic radiation therapy.

OBJECTIVES: Radiation recall dermatitis secondary to gemcitabine use has been reported in isolated cases of patients treated for breast and lung cancers. There have been no reports of radiation recall dermatitis from gemcitabine after whole pelvic radiation therapy employed as a treatment of a gynecologic cancer. CASE: A 67-year-old woman was treated with whole pelvic radiation for palliation of lower extremity swelling and pain due to recurrent ovarian adenocarcinoma. Three months later, the patient was treated with gemcitabine for three courses. Therapy was discontinued secondary to severe cellulitis and edema of the skin of the anterior abdominal wall in the field of her prior radiation therapy. CONCLUSIONS: Radiation recall dermatitis secondary to gemcitabine should be considered in any patient with pelvic or lower abdominal skin abnormalities after pelvic radiation and subsequent gemcitabine therapy.

Adenocarcinoma↗
PubMed2003

Apoptotic pathways of epothilone BMS 310705.

OBJECTIVE: BMS 310705 is a novel water-soluble analog of epothilone B currently in phase I clinical evaluation in the treatment of malignancies such as ovarian, renal, bladder, and lung carcinoma. Using an early passage cell culture model derived from the ascites of a patient clinically refractory to platinum/paclitaxel therapy, we evaluated the pathway of caspase-mediated apoptosis. METHODS: Cells were treated for 1 h and subsequently evaluated for apoptosis, survival, and caspase activity. Apoptosis was determined by fluorescent microscopy. Caspase-3, -8, and -9 activities were determined by fluorometry using target tetrapeptide substrates. Mitochondrial release of cytochrome c was determined by immunoblot analysis. RESULTS: After treatment with BMS 310705, apoptosis was confirmed in >25% of cells at 24 h. Survival was significantly lower (P < 0.02) in cells treated with 0.05 micro M BMS 310705 vs paclitaxel. Analysis revealed an increase of caspase-9 and -3 activity; no caspase -8 activity was observed. Release of cytochrome c was detected at 12 h following treatment. SN-38 and topotecan failed to induce apoptosis. CONCLUSIONS: BMS 310705 induces significant apoptosis, decreases survival, and utilizes the mitochondrial-mediated pathway for apoptosis in this model.

Antineoplastic Agents↗
PubMed2003

Carboplatin plus paclitaxel combination chemotherapy: impact of sequence of drug administration on treatment-induced neutropenia.

OBJECTIVE: While the importance of the sequence of administration of cisplatin and paclitaxel on the degree of observed neutropenia has been documented, there is limited information available in the oncology literature to determine whether there exists sequence-dependent toxicity for the combination of carboplatin plus paclitaxel. METHODS: Patients with advanced gynecologic malignancies were randomized to receive either carboplatin (AUC 6), followed by paclitaxel (175 mg/m(2) over 3 h) (C-P), or the same doses of the agents delivered in the opposite sequence (P-C). The primary endpoint was the degree of neutropenia experienced during the initial treatment course. RESULTS: A total of 40 patients (median age: 63) entered this trial, of whom 27 had complete pretreatment and nadir counts available for course 1 and 24 for both course 1 and course 2. By random chance, patients initially receiving P-C began therapy with a higher baseline ANC than those treated with C-P. During course 1, the P-C population was noted to have a greater reduction, from baseline, in ANC (P = 0.02), but no difference in absolute nadir counts (ignoring the baseline value) (P = 0.64). There was no difference between P-C, followed by C-P, versus C-P, followed by P-C in the severity of neutropenia experienced during course 2 (P = 0.38). CONCLUSIONS: The sequence of carboplatin/paclitaxel administration does not exert a significant influence on the level of observed neutropenia. This finding leads to the suggestion that the sequence of drug delivery can be modified, as necessary, to satisfy unique requirements of individual patients and to establish the optimal drug delivery strategy of an innovative investigational treatment regimen.

Antineoplastic Combined Chemotherapy Protocols↗
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

Supportive care.

Explore the source record for details and available documents.

Anorexia↗
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

Toxicities of the platinum antineoplastic agents.

The platinum agents (cisplatin, carboplatin and oxaliplatin) are among the most useful anticancer agents available to oncologists. The drugs have the potential to produce both mild and more serious side effects. However, in general, the platinum agents can be delivered with acceptable toxicity, even when used in combination chemotherapy regimens. Furthermore, with appropriate dose modifications, the large majority of patients who may benefit from this class of cytotoxic pharmaceutical drugs will be able to complete a planned therapeutic programme.

Antineoplastic Agents↗
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↗
PubMed2003

Toxicity associated with carboplatin/paclitaxel/Irinotecan use in advanced ovarian cancer: preliminary analysis.

Despite the high objective response rate of advanced ovarian cancer to combination platinum/taxane-based chemotherapy, the majority of patients ultimately experience disease progression. Thus, there is a need to find new management strategies that can improve upon the results of existing therapies. We are currently conducting a phase II trial to explore the toxicity and potential efficacy of a three-drug program, which adds irinotecan (CPT-11, Camptosar) at 100 mg/m2 to carboplatin (Paraplatin) at an area under the concentration-time curve of 5 and paclitaxel at 150 mg/m2 over 3 hours. Treatment was initially given on an every-3-week schedule, but was subsequently changed to an every-4-week schedule due to excessive bone marrow toxicity. The study remains in progress, with 26 patients currently evaluable for toxicity, which has included grade 4 neutropenia (42% incidence), grade 4 thrombocytopenia (12%), and grade 3 emesis (12%), with one patient each experiencing grade 3 diarrhea, hepatic dysfunction, and insomnia. Data regarding response rates are immature. Our preliminary analysis reveals that the combination of carboplatin/paclitaxel/irinotecan can be administered to women with advanced ovarian cancer with significant, but overall acceptable, toxicity. Randomized trials will be required to define a possible role for this three-drug combination chemotherapy regimen in the standard management of advanced ovarian cancer.

Antineoplastic Agents↗
PubMed2003

Rationale for maintenance or consolidation therapy in ovarian cancer.

Despite the high objective response rare of advanced ovarian cancer to platinum-based chemotherapy, relapse is common and most patients ultimately experience disease progression. These data lead to the hypothesis that extending treatment beyond the standard 6 cycles may improve both progression-free and overall survival in a patient population demonstrated to have exhibited major inherent chemosensitivity to the primary chemotherapy program. A preliminary analysis of a randomized phase III trial conducted by the Southwest Oncology Group and the Gynecologic Oncology Group has revealed that 12 monthly cycles of single-agent paclitaxel delivered to patients with advanced ovarian cancer who have attained a clinically defined complete response to initial platinum/paclitaxel chemotherapy results in a highly statistically significant reduction in the risk of recurrence. This proof of principle study should lead to further investigation in defining an optimal maintenance or consolidation strategy for the treatment of women with advanced ovarian cancer.

Antineoplastic Agents↗