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Biomedical subjects

M Markman

Publications and source records attributed to M Markman.

At least 19 recordsLinked to original sources
PubMed1992

Impact of laparotomy finding of significant intraabdominal adhesions on the surgically defined complete response rate to subsequent salvage intraperitoneal chemotherapy.

One possible explanation for the failure of the high concentrations of cytotoxic agents achieved following intraperitoneal (i.p.) drug delivery to produce a favorable response in patients with ovarian cancer is the inability of the drug-containing fluid to be adequately distributed throughout the peritoneal cavity, usually because of intraabdominal adhesion formation. To evaluate the influence of the severity of adhesions, observed at the time of laparotomy performed immediately preceding the initiation of i.p. therapy, on the ability to achieve a surgically defined complete response (S-CR), we retrospectively reviewed the operative reports of 70 patients with small-volume residual ovarian cancer treated on one of three phase-2 salvage i.p. trials at the Memorial Sloan-Kettering Cancer Center. The S-CR rate in the 36 patients with limited adhesion formation observed upon entering the peritoneal cavity was 28%, compared to 35% in the 34 patients with extensive adhesions (P greater than 0.05). In 33 patients treated with a phase-2 cisplatin-based i.p. program, who had previously responded to systemic platinum, 47% (8/17) and 44% (7/16) of those with limited and extensive adhesions, respectively, achieved a S-CR (P greater than 0.05). We conclude that the presence of extensive adhesions observed within the peritoneal cavity at the time of a laparotomy performed immediately prior to the initiation of i.p. therapy does not have a negative impact on the potential to achieve an S-CR, assuming it is technically feasible to lyse all significant adhesions prior to the completion of the operative procedure.

Abdomen↗
PubMed1992

Phase 2 trial of chronic low-dose oral etoposide as salvage therapy of platinum-refractory ovarian cancer.

Eighteen previously treated patients with advanced ovarian cancer were entered into a phase 2 trial of chronic low-dose oral etoposide (50 mg/day for 20 days, repeated every 28 days) to determine the activity of this therapeutic strategy in organoplatinum-refractory disease. The treatment program was generally well tolerated, with mild neutropenia the most common side-effect encountered. One patient (6%; 95% confidence interval = 0-17%) achieved a partial response, which lasted for 11 months. Three additional patients (17%), who failed to meet the criteria of a partial response, demonstrated objective evidence of antineoplastic activity. Chronic low-dose oral etoposide administration is associated with definite, although modest, activity in platinum-refractory ovarian cancer.

Carboplatin↗
PubMed1992

Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma.

In an effort to examine the potential clinical utility of intraperitoneal (i.p.) therapy in the management of patients with malignant peritoneal mesothelioma, 19 individuals with this disease were treated with a cisplatin-based i.p. treatment regimen. All but 1 patient also received i.p. mitomycin. The treatment was generally well tolerated, although a maximum of only four or five courses of cisplatin (100 mg/m2 every 28 days) and mitomycin (5-10 mg/treatment given 7 days after each i.p. cisplatin administration) could be administered, the treatment principally being stopped because of disease progression or catheter failure. Of 15 patients with malignant ascites, 7 (47%) experienced control of fluid reaccumulation ranging from 2 months to 73+ months (median 8 months). While the median survival for the 19 patients was only 9 months, 4 (21%) patients survived for more than 3 years from the initiation of therapy, and 2 patients are currently alive and clinically disease-free more than 5 years from the start of the i.p. treatment program. We conclude that a subset of patients with peritoneal mesothelioma, principally those with small-volume residual disease following surgical tumor debulking, can benefit from a cisplatin-based i.p. treatment strategy with control of ascites and prolonged disease-free survival.

Adult↗
PubMed1992

Association between pretreatment CA-125 levels and surgically documented complete responses in patients with ovarian cancer treated with second-line intraperitoneal therapy.

Approximately 20%-40% of patients with small-volume residual ovarian cancer, following systemically administered platinum-based chemotherapy, will respond to a second-line intraperitoneal treatment regimen. In an effort to improve the selection criteria for patients being considered for this regional therapeutic approach, we retrospectively evaluated the influence of pretreatment CA-125 levels on the ability of a group of 70 patients with small-volume residual ovarian cancer (no tumor mass greater than 1 cm in diameter) to achieve a surgically defined complete response (S-CR) following treatment on one of three phase-2 intraperitoneal chemotherapy trials conducted at the Memorial Sloan-Kettering Cancer Center. Overall, 18/46 (39%) patients with normal pretreatment CA-125 levels (less than or equal to units/ml) achieved a S-CR, compared to only 4/24 patients (17%) with an elevated pretreatment value (chi 2 = 3.7, P greater than 0.5). Despite the lower S-CR rate in patients with elevated CA-125 levels, the duration of response and survival were similar in the two patient populations achieving a S-CR. Thus, we conclude that an elevated pretreatment CA-125 level in a patient with small-volume residual ovarian cancer should not be used by itself to disqualify an individual from consideration for a second-line intraperitoneal treatment regimen, although the finding suggests a reduced likelihood of achieving a S-CR with this therapeutic approach.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Salvage intraperitoneal therapy of small-volume residual ovarian cancer: impact of pretreatment finding of peritoneal carcinomatosis on the surgical complete response rate.

Second-line intraperitoneal (i.p.) therapy has been demonstrated to result in surgically defined complete responses (S-CR) in 25%-40% of patients with small-volume residual ovarian cancer (microscopic disease or largest tumor mass less than 1 cm in diameter). To evaluate the influence of the surgical finding of diffuse peritoneal carcinomatosis on the S-CR rate to salvage i.p. therapy in this patient population, we retrospectively reviewed the operative reports of 70 patients with small-volume residual ovarian cancer treated on one of three phase-2 second-line i.p. trials at the Memorial Sloan-Kettering Cancer Center. Of the 11 patients with diffuse carcinomatosis, none achieved a S-CR compared to a S-CR rate of 37% (22/59) in patients without this surgical finding (chi 2 = 6.0; P less than 0.025). However, of the 7 patients with diffuse carcinomatosis treated on a cisplatin-based i.p. program, the only 2 who had previously responded to systemic platinum also experienced a response (partial) to the i.p. cisplatin regimen. In conclusion, while the surgical finding of diffuse peritoneal carcinomatosis indicates a poor prognosis in patients with small-volume residual ovarian cancer for response to i.p. chemotherapy, patients in this clinical setting with prior evidence of platinum sensitivity may experience some benefit from an i.p. cisplatin-based treatment strategy.

Cisplatin↗
PubMed1992

Phase 2 trial of intraperitoneal carboplatin and etoposide as salvage treatment of advanced epithelial ovarian cancer.

To evaluate the efficacy of intraperitoneal (IP) carboplatin-based therapy as salvage treatment of ovarian cancer, 46 patients with persistent or recurrent ovarian cancer following initial systemic chemotherapy were treated with a regimen of carboplatin (200-300 mg/m2) and etoposide (100 mg/m2) administered on a monthly schedule. A maximum of six courses of therapy was delivered, followed by a response laparotomy. The treatment program was well tolerated, except for bone marrow suppression, with one-quarter of patients developing platelet count depressions to < or = 50,000/mm3, and one-third experiencing hemoglobin levels of < or = 8 g/dl during treatment. Twelve (38%) of 32 patients evaluable for efficacy of the treatment program achieved a surgically documented response, including 8 (25%) complete responses. Of 25 patients whose largest tumor mass at the initiation of therapy measured < or = 0.5 cm, 11 (44%) responded, including 8 (32%) complete responses. We conclude that the IP administration of carboplatin can result in surgically documented responses when used in the salvage setting in patients with advanced ovarian cancer. The relative efficacy of carboplatin versus cisplatin when administered by the IP route to patients with ovarian cancer previously treated with platinum-based systemic therapy remains to be defined.

Adult↗
PubMed1992

Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma.

Five versus ten cycles of cyclophosphamide, doxorubicin, and cisplatin (CAP) were compared in advanced ovarian carcinoma by a prospective randomized study of 78 patients, 41 receiving 5 cycles (CAP5) and 37 receiving 10 cycles (CAP10) of chemotherapy. Patients were stratified by histologic grade and size of residual disease. Cyclophosphamide, 600 mg/m2, doxorubicin, 40 mg/m2, and cisplatin, 100 mg/m2, were administered every 4 weeks for 5 or 10 cycles. Second-look laparotomy was performed to evaluate response and plan further therapy. CAP5 patients found a second-look laparotomy to have partially responded to chemotherapy were treated with 5 additional cycles of CAP. CAP10 was more toxic than CAP5 with respect to myelosuppression, hospital admissions for nadir fever, median elevation of creatinine, and degree of peripheral neuropathy. Median follow-up is 64 months. CAP5 and CAP10 were equivalent in surgically documented complete responses (34 versus 35%) and survival (P = 0.41). Twelve partial responders to CAP5 received additional CAP chemotherapy; one complete response resulted. We conclude that CAP5 is preferable to CAP10 in treatment of advanced ovarian cancer as it is equally effective and less toxic.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Characteristics of patients with small-volume residual ovarian cancer unresponsive to cisplatin-based ip chemotherapy: lessons learned from a Gynecologic Oncology Group phase II trial of ip cisplatin and recombinant alpha-interferon.

The Gynecologic Oncology Group conducted a phase II trial of intraperitoneal (ip) cisplatin plus recombinant human alpha-interferon in patients with small-volume persistent/recurrent ovarian cancer. This study was based on the known single agent activity of the drugs administered by the ip route and experimental evidence of cytotoxic synergy between the agents. In 18 evaluable patients, only 1 partial response was observed (5.5% response rate). In an effort to explain these disappointing findings, patients were retrospectively divided into two groups; those with favorable disease (documented response to systemic platinum and absence of surgical findings of diffuse carcinomatosis at laparotomy prior to initiation of ip therapy) or unfavorable disease (no evidence of response to systemic platinum and/or laparotomy findings of diffuse carcinomatosis before ip treatment). The favorable patient population would be predicted to have a far greater chance of responding to local therapy, but only 3 of the evaluable patients fell into this category. In the 15 unfavorable patients, only 1 partial response was observed (7% response rate). We conclude that patients who have failed to demonstrate a response to systemic cisplatin or carboplatin or who have diffuse carcinomatosis at second-look laparotomy are poor candidates for second-line ip cisplatin-based therapy, even if they are considered to have small-volume residual disease (each individual tumor nodules less than 0.5-1 cm). Such patients should be considered for alternative therapeutic strategies.

Adult↗
PubMed1992

Systemic therapy for gynecologic cancer.

Over the past year, a number of important papers have appeared in the medical literature dealing with the chemotherapeutic management of gynecologic cancers. Among these papers, several studies have again demonstrated the superiority of platinum-based chemotherapy regimens for ovarian cancer compared with non-platinum-containing regimens, and have confirmed the equivalence of carboplatin to cisplatin in advanced disease. A number of trials have reported activity for intraperitoneal chemotherapy regimens in patients with small-volume residual disease. In endometrial cancer, combination cisplatin-based chemotherapy programs have been reported to achieve an overall 40% to 50% objective response rate. Although induction chemotherapy has been advocated in the management of advanced localized cervical cancer, this conclusion has yet to be supported by the results of randomized trials. The etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine regimen has been demonstrated to be highly effective in patients with high-risk gestational trophoblastic tumors. Finally, a recent report has demonstrated that it is possible to perform conservative surgery in patients with germ cell tumors to preserve fertility without compromising therapeutic efficacy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease.

PURPOSE: There is a critical need to find new antineoplastic drugs that are active in platinum-refractory ovarian cancer. We conducted a phase II trial of single-agent ifosfamide with mesna uroprotection in patients with ovarian cancer previously treated with an organoplatinum compound to assess its activity in this clinical setting. PATIENTS AND METHODS: Ifosfamide (1.0 or 1.2 g/m2/d for 5 days, delivered on a monthly schedule) was administered to the 57 patients entered onto this trial. Dose reductions were permitted for unacceptable toxicities. RESULTS: Toxicity included severe bone marrow suppression (WBC count less than 1,000/microL and/or platelet count less than 50,000/microL), renal dysfunction (serum creatinine level greater than 2.0 mg/dL), and reversible CNS dysfunction (disorientation, hallucinations, somnolence, and agitation), which occurred in 20%, 14%, and 12% of patients, respectively. Of 41 patients with strictly defined platinum-refractory ovarian cancer, five (12%) demonstrated a partial (four) or complete (one) response to this treatment program. CONCLUSION: Single-agent ifosfamide has modest but unequivocal activity in platinum-resistant ovarian cancer. Further studies of this drug used as a front-line agent along with an organoplatinum compound or as part of a dose-intensification program with bone marrow, peripheral stem cell, or colony-stimulating factor support are indicated. In addition, single-agent ifosfamide is a reasonable standard second-line treatment strategy in appropriately selected patients with platinum-refractory ovarian cancer.

Acute Kidney Injury↗
PubMed1992

Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies.

PURPOSE: Intrapleural cisplatin-based chemotherapy has been used in the treatment of patients with malignant pleural mesothelioma and malignant pleural effusions, but the pharmacokinetics of this form of chemotherapy have not been previously evaluated. We performed pharmacokinetic studies on 12 patients who received both intrapleural cisplatin and mitomycin immediately following pleurectomy/decortication for malignant pleural mesothelioma. PATIENTS AND METHODS: Simultaneous pleural fluid and plasma samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, and 24 hours after administration of the intrapleural chemotherapy (cisplatin 100 mg/m2 and mitomycin 8 mg/m2), and after cisplatin (total and free) and mitomycin levels were measured. The mean peak levels, the areas under the concentration-time curve (AUC) and the drug half-lives (t1/2s) in plasma and pleural fluid were compared using the paired t test. Differences were considered significant if P less than or equal to .05. RESULTS: Systemic absorption was rapid, with peak plasma levels being reached within 1 hour of administration of the intrapleural chemotherapy. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly attained during systemic administration of these drugs at similar doses. However, the mean peak cisplatin and mitomycin levels, and their mean AUCs, were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage (on a logarithmic scale) for pleural to plasma AUCs for both cisplatin and mitomycin. The mean t1/2s for cisplatin and mitomycin were significantly longer in the plasma than in the pleural fluid. CONCLUSIONS: The pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. Our findings show that intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage, but also produces significant and sustained drug plasma levels.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Impact on survival of surgically defined favorable responses to salvage intraperitoneal chemotherapy in small-volume residual ovarian cancer.

PURPOSE: To evaluate the impact on survival of the attainment of surgically defined favorable responses (S-R) to salvage intraperitoneal (IP) chemotherapy after initial systemic cytotoxic drug delivery. PATIENTS AND METHODS: We examined the survival of patients who were treated on one of three phase II IP trials that were conducted at the Memorial Sloan-Kettering Cancer Center. A total of 58 patients whose largest residual tumor masses measured less than or equal to 0.5 cm in maximum diameter at the initiation of this salvage therapy were assessable for response, 28 of whom (48%) demonstrated a S-R, which included 19 (33%) who achieved a surgically defined complete response (S-CR). RESULTS: With a median follow-up of 43+ months (range, 33+ to 58+ months) from the initiation of IP therapy, 12 of 19 (63%) have recurred. The median duration of S-CR for the 10 patients with microscopic residual disease was 32 months compared with 15 months for the nine patients with macroscopic residual disease (largest tumor mass less than or equal to 0.5 cm; P greater than .1). For patients with microscopic residual disease who experienced a S-CR (n = 10) after salvage IP therapy, the median overall survival from the initiation of therapy has not been reached, but will exceed 4 years compared with a 25-month median survival for the nonresponding patients (n = 13; P = .004). The median survival for the 18 patients with small-volume macroscopic disease who responded to therapy was 40 months compared with 19 months for the nonresponders (P = .009). CONCLUSION: Although the results of this evaluation are encouraging and suggest that the attainment of a S-R, particularly a S-CR, after IP chemotherapy may result in a clinically meaningful favorable impact on survival, a randomized controlled trial will be required to address definitively this important issue.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study.

PURPOSE: To evaluate the safety and pharmacology of the intraperitoneal (IP) administration of the antineoplastic agent taxol. PATIENTS AND METHODS: Twenty-five pretreated patients who were entered onto a phase I clinical trial; 24 had advanced ovarian cancer. Patients were treated with taxol administered IP in 2 L of normal saline every 3 to 4 weeks. The starting dose was 25 mg/m2. There were no intrapatient dose escalations. RESULTS: The dose-limiting toxicity was the development of severe abdominal pain at taxol doses more than 175 mg/m2. Moderate leukopenia (WBC count less than 2,000/mm3) was observed at IP doses of greater than or equal to 175 mg/m2. The exposure of the peritoneal cavity (peak levels and area under the time-versus-concentration curve [AUC]) to taxol after IP delivery exceeded that of the plasma by approximately 1,000-fold. However, concentrations of the agent previously shown to produce cytotoxicity in experimental systems were demonstrated in the systemic compartment after regional delivery, which was considered important. Significant concentrations of taxol persisted within the peritoneal cavity for more than 24 to 48 hours after a single IP installation. Several antitumor responses, which included control of platinum-refractory ascites, were documented. CONCLUSION: Taxol can be delivered by the IP route with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure.

Alkaloids↗
PubMed1992

Mixed mesodermal tumor of the ovary: analysis of prognostic factors in 31 cases.

OBJECTIVE: To determine significant prognostic factors in patients with mixed mesodermal tumors of the ovary. METHODS: Thirty-one cases of mixed mesodermal tumor of the ovary treated at Memorial Sloan-Kettering Cancer Center between 1977-1990 were reviewed retrospectively. The mean patient age was 61 years. Distribution by stage was as follows: I, seven (23%); II, one (3%); III, 15 (48%); and IV, eight (26%). The median follow-up for survivors was 62 months. Following primary surgery, chemotherapy included cisplatin (four), doxorubicin (seven), or both (ten); six patients received various other treatments. RESULTS: The median survival for the entire group was 10.6 months. In 19 cases (61%), heterologous sarcomatous elements were present in the primary tumor, whereas 12 (39%) contained homologous elements only. There was a trend toward improved survival in patients whose primary tumors had only homologous stromal elements (P = .06). The overall survival was significantly better for the eight patients with early-stage (I, II) disease than for the 23 patients with advanced-stage (III, IV) disease (P = .01). The size of residual disease after cytoreductive surgery was not a significant prognostic factor. There was no difference in survival between the ten women whose metastatic disease contained only epithelial elements and the 16 whose metastases contained mesenchymal elements as well (P = .23). CONCLUSIONS: This study confirms previous observations that mixed mesodermal tumors of the ovary are a highly malignant group of tumors that respond poorly to chemotherapy. In addition, we demonstrated that prognosis is independent of the presence or absence of sarcomatous elements in the metastases.

Aged↗