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Biomedical subjects

Maurie Markman

Publications and source records attributed to Maurie Markman.

At least 109 records · Page 6Linked to original sources

The research misconception.

Recently, several researchers and philosophers argued that clinical research trials are not therapy. Their position is based on foundational research ethics documents, such as the Belmont Report, on conceptual analysis, and on the general way clinical trials are conducted. After examining and rejecting these arguments, we claim that good research is consistent with good therapy; that often trials are good therapy; and that a blanket attack on clinical trials as non-therapeutic creates a research misconception. This misconception is potentially harmful because it could weaken trial recruitment, could adversely affect funding for trials, and could overturn needed moral safeguards on therapeutic trials. Our more careful and accurate analysis of the nature of clinical trials can avoid such problems.

Adult↗

Improving the toxicity profile of chemotherapy for advanced ovarian cancer: a potential role for CT-2103.

Significant progress has been made in the management of advanced ovarian cancer. Response rates to platinum-based chemotherapy are respectable; however, recurrence continues to be the rule rather than the exception. Chemotherapy is administered as initial treatment and for disease recurrence, often over a period of many years--thus ovarian cancer is considered a chronic disease by many oncologists. The importance of the taxanes in the treatment of ovarian cancer is well established. However, taxanes are associated with numerous toxicities, resulting in the need for alternative dosing strategies that produce fewer side effects, or the discovery of novel taxanes with equivalent anti-tumor activity, but a more favorable toxicity profile. Several taxanes are in development including CT-2103, a macromolecule consisting of paclitaxel conjugated to a biodegradable, water-soluble polymer of glutamic acid. Clinical data of CT-2103 as a single agent and in combination have demonstrated activity in previously treated ovarian cancer patients, both in platinum-sensitive and platinum-resistant disease. CT-2103 appears to be potentially associated with a more favorable toxicity profile relative to paclitaxel, and enhanced solubility allows for a 10-minute infusion. Ongoing trials employing this agent will focus on extending survival, optimizing quality of life, and defining a possible role for CT-2103 in the standard management of advanced ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗

Expanded experience with an intradermal skin test to predict for the presence or absence of carboplatin hypersensitivity.

PURPOSE: Carboplatin-associated hypersensitivity is increasingly recognized as a potentially serious toxicity when this agent is administered for more than six total cycles. PATIENTS AND METHODS: Our group has used a predictive skin test in women with gynecologic cancers who have previously received more than six cumulative cycles of platinum-based chemotherapy. Thirty minutes before all subsequent carboplatin courses, a 0.02-mL aliquot from the solution prepared for treatment is injected intradermally. A positive test is considered to be a > or = 5-mm wheal, with a surrounding flare. RESULTS: From October 1998 through March 2003, 126 patients received a total of 717 carboplatin skin tests (median per patient, four tests; range, one to 54 tests). Of the 668 negative tests (93% of the total performed), 10 were associated with evidence of carboplatin hypersensitivity (1.5% false-negative rate; 95% CI, 0.6% to 2.4%), none of which were severe (eg, dyspnea, hypotension, cardiac/respiratory compromise). Of the 41 positive tests, the decision was made to not deliver the drug to 32 patients, although seven women ultimately underwent a future attempt at re-treatment with a platinum agent using a desensitization program. In seven episodes where patients received the carboplatin despite the finding of a positive test, six were associated with the development of symptoms of anaphylaxis (none severe). CONCLUSION: A negative carboplatin skin test seems to predict with reasonable reliability for the absence of a severe hypersensitivity reaction with the subsequent drug infusion. The implications of a positive test remain less certain, but limited experience with continued treatment suggests this approach must be undertaken with considerable caution.

Adult↗

Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity reactions.

PURPOSE: Carboplatin hypersensitivity is an increasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged approach to re-treating patients with a high risk for this potentially serious side effect could permit the safe delivery of this class of cytotoxic drugs. METHODS: Five patients with gynecologic malignancies who had either experienced a documented carboplatin hypersensitivity reaction ( n =4) or had a "positive" carboplatin skin test ( n =1), received a multi-drug oral regimen administered over several days which was designed to block known mediators of anaphylaxis. Four of these individuals subsequently underwent treatment with either cisplatin or carboplatin employing a "dose escalation" desensitization schema. RESULTS: Four patients underwent successful treatment with either cisplatin or carboplatin (3, 4, 5, 6+ total additional courses) without any further evidence of hypersensitivity. CONCLUSION: In this preliminary report of a limited patient population, we have demonstrated the ability to safely deliver a platinum agent to individuals with either documented carboplatin hypersensitivity, or a high risk for this potentially serious toxicity of carboplatin. Further exploration of this novel management strategy in a larger group of patients is indicated.

Antineoplastic Agents↗

Phase 2 trial of pegylated liposomal doxorubicin in advanced endometrial cancer.

PURPOSE: To evaluate the efficacy and toxicity of pegylated liposomal doxorubicin in patients with advanced endometrial cancer. METHODS: Pegylated liposomal doxorubicin was administered at a dose of 40 mg/m2, and repeated on an every 28-day schedule. RESULTS: A total of 19 patients were enrolled in this phase 2 trial. Fourteen patients had received prior chemotherapy (carboplatin/paclitaxel-9; cisplatin/paclitaxel-3; single agent paclitaxel-2), seven prior radiation therapy, and three prior hormonal therapy. No patients had previously received doxorubicin. Two patients (11%) developed grade 1 hand-foot syndrome following treatment with pegylated liposomal doxorubicin. There were no episodes of cardiac dysfunction (>10% reduction in baseline ejection fraction). Three patients required hospitalization for nausea, vomiting, anemia, and dehydration. Only 2 (11%) patients required dose reduction. Four of 19 patients (21%; 95% CI: 3-39%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy (duration of responses: 2 months, 3 months, 4 months, 6+ months). CONCLUSION: The pegylated liposomal doxorubicin regimen employed in this trial exhibited an acceptable toxicity profile (cardiac dysfunction, hand-foot syndrome). Definite, although modest, antineoplastic activity in a patient population with recurrent or advanced endometrial cancer was documented.

Aged↗

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↗

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↗

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↗

Consolidation/maintenance chemotherapy for ovarian cancer.

A recently reported randomized trial has demonstrated that administration of single-agent paclitaxel to women with advanced ovarian cancer who attain a clinically defined complete response to platinum/paclitaxel-based chemotherapy can substantially improve progression-free survival. Whether this strategy will improve overall survival in this clinical setting remains uncertain.

Antineoplastic Agents↗

Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum.

OBJECTIVE: Previously reported data have suggested the lack of complete cross-resistance between docetaxel and paclitaxel in ovarian cancer. We wished to evaluate the biological and clinical activity of docetaxel in a patient population with well-characterized platinum and paclitaxel-refractory ovarian cancer. METHODS: In this single-institution phase 2 trial, 30 women with advanced ovarian cancer whose disease had either failed to respond to primary platinum-paclitaxel chemotherapy or where the cancer had progressed within 3 months of their last treatment with both a platinum agent and paclitaxel were treated with single agent docetaxel (75 mg/m(2) q 3 weeks). Due to a prior history of excessive chemotherapy-induced neutropenia, 3 patients initiated treatment at a dose of 60 mg/m(2). RESULTS: The median number of courses of docetaxel delivered on this protocol was 3 (range 1-7), with 7 patients requiring dose reductions due to treatment-related side effects. The most common toxicities included grade 4 neutropenia, neutropenic fever, and grade >/=2 fatigue experienced by 9 (30%), 2 (7%), 5 (17%) patients, respectively. Three patients (10%) achieved both an objective response (by CA-125 criteria) and symptomatic improvement (e.g., decrease in pain and ascites). The durations of responses were 3, 4, and 6 months. CONCLUSION: Single-agent docetaxel has modest, but definite activity in patients with well-characterized platinum and paclitaxel-resistant ovarian cancer. Use of this drug should be considered a rational management approach in appropriately selected patients in this clinical setting.

Adult↗