Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population.
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Carboplatin↗
Biomedical subjects
M Markman
Publications and source records attributed to M Markman.
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↗
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↗
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↗
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↗
Ethical difficulties with randomized clinical trials involving cancer patients: examples from the field of gynecologic oncology.
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Antineoplastic Combined Chemotherapy Protocols↗
Pharmacokinetic study of intraperitoneal streptozotocin.
Streptozotocin, a nitrosourea, has limited antitumour activity. However, in concentrations and exposures higher than those achieved after intravenous dosing, streptozotocin has been reported to sensitize various cell lines in vitro to other nitrosoureas or alkylating agents. We hypothesized that the intraperitoneal administration of streptozotocin would achieve concentrations and exposures in the peritoneal cavity sufficient for this sensitization to take place. The pharmacokinetics of streptozotocin in the peritoneal cavity and in plasma were determined in patients who received 1 g of streptozotocin via the intraperitoneal route. Fifteen courses were administered to 12 patients. The mean total area under the concentration versus time curves (AUC) was 183 +/- 31 (SE) mM min in the peritoneal cavity (5 courses) and 5.3 +/- 1.1 (SE) mM min in plasma (6 courses). The mean peritoneal to plasma AUC ratio was 64 +/- 23 (5 courses). The mean peak streptozotocin concentrations in the peritoneal cavity (5 courses) and plasma (6 courses) were 1.9 +/- 0.4 mM and 0.03 +/- 0.01 mM, respectively. No significant toxicity was observed on any course. We conclude that intraperitoneal administration of streptozotocin is feasible, and that drug concentrations and exposures are in an appropriate range in the peritoneal cavity to cause sensitization to other nitrosoureas.
Adult↗
Exploring the use of chronic low-dose oral etoposide in ovarian cancer: is there a role for this "new drug" in the management of platinum-refractory disease?
Despite showing high objective response rates (70% to 80%) to cisplatin- or carboplatin-based chemotherapy, most patients with ovarian cancer ultimately die of complications of their disease. Etoposide, given either as a single agent or in combination with the organoplatinum compounds, has produced disappointingly low response rates in the salvage setting. Based on recent data that suggest chronic administration of oral etoposide is superior to single daily dosing every 3 to 4 weeks, and the failure of previous trials to evaluate etoposide's activity in cisplatin-resistant malignancies, we have begun a phase II trial of chronic, low-dose oral etoposide in patients with clinically defined, platinum-resistant ovarian cancer. Thus far, 11 patients have been entered into the study. Neutropenia, the most prevalent toxicity, has precluded several patients from receiving the full 20-day course of 50 mg/d. No responses to treatment have been observed in nine evaluable patients. The study continues to accrue patients. The final results of this study and other trials should help determine the efficacy of chronic low-dose oral etoposide administration in patients with ovarian cancer.
Administration, Oral↗
High-performance liquid chromatographic method for the simultaneous measurement of floxuridine and fluorouracil in human body fluids.
A method for the simultaneous measurement of floxuridine (5-fluorodeoxyuridine) and fluorouracil in human plasma and peritoneal fluid has been developed. This method utilizes high-performance liquid chromatographic analysis with a Zorbax RX column (25 cm x 4.6 mm I.D.) plus a guard cartridge of the same material. The sensitivity limits for this assay are 0.25 mumol/l in a 20-microliters sample. The detection limit at a signal-to-noise ratio of 3 is 2.5 nmol/l. This procedure has been used to quantitatively measure concentration versus time profiles of floxuridine and fluorouracil in plasma and peritoneal fluid of human patients after receiving intraperitoneal administration of floxuridine.
Ascitic Fluid↗
A phase II trial of PALA + dipyridamole in patients with advanced soft-tissue sarcoma.
A total of 21 patients with advanced soft tissue sarcoma enrolled in a phase II trial of 3.5 g/m2 N-phosphonacetyl-L-aspartate (PALA) given intravenously every 3 weeks plus 50 mg/m2 dipyridamole (Persantine) given orally every 6 h. Dipyridamole administration was initiated 1 week before the first dose of PALA. Peak and trough plasma concentrations of dipyridamole were measured before and after the first dose of PALA in 14 patients. In all, 19 patients were evaluable for therapeutic response. One subject experienced partial regression of a pulmonary metastasis; no other major response was observed. Diarrhea was the most prominent toxicity; in one patient it was life-threatening and was associated with a severe rash. On the day preceding PALA administration, the median peak plasma concentration of dipyridamole was 2,208 ng/ml and the median trough value was 904 ng/ml. Similar values were obtained on the day of PALA administration. Although the levels achieved were similar to those required to modulate the activity of PALA in preclinical systems, the therapeutic results obtained in the present study were not superior to those reported for PALA alone in previously treated patients with soft-tissue sarcoma.
Adult↗
Phase-1 trial of high-dose intravenous cisplatin with simultaneous intravenous sodium thiosulfate.
Previous pharmacological and clinical data have suggested that it is possible to increase significantly the dose of "active" cisplatin delivered systemically by the simultaneous administration of intravenous sodium thiosulfate. In order to define more critically the toxicity and potential efficacy of this therapeutic approach, 36 patients with a variety of solid tumors and limited pretreatment were entered into a phase-1 trial of high-dose intravenous cisplatin plus sodium thiosulfate. The maximally tolerated dose of cisplatin was found to be 200 mg/m2, excessive renal toxicity being observed at a dose of 225 mg/m2 (6/14 courses associated with serum creatinine rise to greater than 2.0 mg-%). Following several courses of high-dose cisplatin, peripheral neuropathy becomes the limiting toxicity (9/15 patients receiving at least three courses of cisplatin at greater than or equal to 150 mg/m2 experienced at least grade-1 neuropathy). Significant ototoxicity developed after only one or two treatment courses, but with continued treatment hearing loss appeared to stabilize in the moderately severe range in most patients. Major responses (PR/CR) were observed in 7/27 evaluable patients. We conclude that cisplatin can be administered at a dose at 200 mg/m2 as a 2-h infusion (with simultaneous sodium thiosulfate) with significant but acceptable toxicities and without evidence of loss of anti-neoplastic activity (secondary to the presence of thiosulfate). However, owing to the development of neurotoxicity most patients will be unable to receive more than three courses of this high-dose treatment regimen.
Adult↗
Phase II trial of high-dose cisplatin with sodium thiosulfate nephroprotection in patients with advanced carcinoma of the uterine cervix previously untreated with chemotherapy.
Cisplatin is one of the most active single agents in the treatment of advanced cancer of the cervix. The concurrent administration of the nephroprotective agent, sodium thiosulfate, has enabled exploitation of the therapeutic potential of cisplatin. To explore the role of cisplatin dose intensity in the treatment of patients with cancer of the uterine cervix, patients with persistent/recurrent measurable disease were treated with cisplatin at 200 mg/m2 as a 2-hr infusion with sodium thiosulfate given at 3.3 g/m2 1 hr prior to cisplatin and 6.6 g/m2 during the cisplatin infusion. Treatment was repeated monthly. Due to the known cumulative toxicity of cisplatin, treatment beyond two cycles (400 mg/m2) was given only to those patients who had at least demonstrated a PR. Audiologic evaluation was done prior to each cycle of treatment. Eleven patients were entered with a median age of 43 years (range, 25-57), a median KPS of 80% (range, 60-90%), and nine epidermoid and two adenocarcinoma, and all patients had received previous pelvic irradiation. Twenty-eight cycles of treatment were given: 1, five cycles; 3, three cycles; 7, two cycles. No greater than or equal to 3+ hematologic, neurologic, or renal toxicity was demonstrated. Ototoxicity was demonstrated in the mild to moderate hearing loss range (3000-8000 Hz). The greatest threshold shift occurred after the first course of cisplatin. There were three PRs with a maximum duration of 4 months. Due to the significant toxicities encountered, the low response rate, and the limited duration of responses, this trial was closed early to accrual.
Adult↗
Intraperitoneal chemotherapy: analysis of complications with an implanted subcutaneous port and catheter system.
To determine the morbidity associated with delivery of intraperitoneal chemotherapy via subcutaneous semipermanent infusion catheters, we analyzed the data on 227 patients treated from April 1985 through December 1989. A total of 249 catheters were inserted and used to administer chemotherapy in these patients. There were 40 (17.6%) complications associated with the use of 230 original catheters, with 20 patients experiencing catheter inflow obstruction and 20 developing catheter-related infections; the latter group included 8 patients with bowel perforations. Although there was a trend toward an increase in catheter-related infections in association with large bowel surgery and appendectomies, sample size limited statistical analysis. There were 7 (36.8%) complications associated with the use of 19 replacement catheters. This rate was significantly increased (P = 0.03) when compared with the complication rate of original catheters. This system functions well and has an acceptable level of morbidity for delivery of intraperitoneal chemotherapy in gynecologic cancer patients.
Catheterization↗
Late effects of cisplatin-based chemotherapy on renal function in patients with ovarian carcinoma.
While the acute toxicity of cisplatin on renal function is well described, the long-term effects have received little attention in the medical literature. In an effort to examine this important issue, we evaluated the renal function of a group of 60 women with ovarian cancer who received a second-line cisplatin-based chemotherapy program at the Memorial Sloan-Kettering Cancer Center longer than 6 months following the completion of their initial cisplatin-based chemotherapeutic regimen. These patients had not received any cisplatin for a median of 19 months (range, 6-57 months) prior to beginning the second-line program. Only 4 patients (7%) had a serum creatinine value greater than 1.3 mg/dl (upper limit of normal in our laboratory) at the time of initiation of the second-line program. In each case, the serum creatinine was less than or equal to 1.6 mg/dl. An additional 6 patients (10%) had a greater than 50% increase in serum creatinine above the initial baseline value prior to any treatment, but were still within the normal range. Following second-line cisplatin therapy, only 1 of the 60 patients (2%) experienced a serum creatinine rise to greater than 2.0 mg/dl. We conclude that a limited number of patients with ovarian cancer who are long-term survivors following cisplatin-based chemotherapy exhibit evidence of a mild persistent compromise of renal function and, in general, second-line cisplatin can be administered to previously treated patients without the development of serious renal dysfunction.
Adult↗
Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy.
Prior studies of the risk of recurrence following negative second-look laparotomy have included patients treated with a variety of chemotherapeutic regimens, including nonplatinum regimens. We have examined the long-term outcome and risk factors for recurrence among a homogeneous group of platinum-treated patients. During the years 1978-1987, 91 patients at Memorial Sloan-Kettering Cancer Center had a negative second-look laparotomy following platinum-based chemotherapy for epithelial ovarian cancer. The mean age at diagnosis was 57 years, with a range of 30 to 79. Distribution by stage was as follows: I, 10; II, 18; III, 57; IV, 6. The mean number of cycles of platinum prior to second-look surgery was 6.3. The mean number of biopsies taken at negative second-look laparotomy was 12. Lymph node biopsies were done in 47/91 (52%) of patients. Median follow-up from the date of second-look laparotomy was 54.6 months among survivors. Forty of ninety-one patients (44%) have had recurrence, almost 40% of which were outside the peritoneal cavity. The mean interval from negative second-look laparotomy to recurrence was 24 months (range, 2-70 months). By multivariate analysis the risk of recurrence was significantly related to stage (P = 0.017), histologic grade (P = 0.041), and the amount of tumor remaining after the first operation for ovarian cancer (P = 0.015). Recurrence by stage was as follows: stage I, 1/10 (10%); stage II, 5/18 (28%); stage III, 31/57 (54%); stage IV, 3/6 (50%). Recurrence by grade was as follows: grade 1, 4/18 (22%); grade 2, 11/28 (39%); grade 3, 25/45 (56%). There was no relationship between the risk of recurrence and the number of cycles of platinum, the number of biopsies performed at second-look, or the number of months from primary surgery to second-look. Patients having negative second-look laparotomy following platinum-based chemotherapy for advanced epithelial ovarian cancer have a substantial risk of recurrence, particularly within the first 3 years. Such patients should be offered participation in clinical trials of consolidation therapy directed against both intraperitoneal and extraperitoneal disease.
Adult↗
Cisplatin-based combination chemotherapy in carcinoma of the fallopian tube.
Forty-three cases of primary tubal adenocarcinoma were treated at Memorial Sloan-Kettering Cancer Center between 1979 and 1989. Thirty-eight patients who received cisplatin-based combination chemotherapy following primary surgery were reviewed. The mean patient age was 59 years, with 86% postmenopausal. Distribution by stage was as follows: I, 3 (7%); II, 4 (11%); III, 27 (71%); and IV, 4 (11%). Median follow-up from the time of diagnosis was 62 months (range, 5-132). Overall survival for all 38 patients by Kaplan-Meier analysis was 51% at 5 years. Excluding stage I, patients with no residual disease following surgery had a significantly higher 5-year survival (83%) than those left with gross residual disease (28%). Twenty-six patients underwent a second-look procedure. Of the 21 patients with advanced (stages III, IV) disease undergoing reexploration, 11 (52%) had a negative second-look and 10 (48%) were positive. Ten of the eleven patients with a negative second-look remain clinically free of disease with a median follow-up of 49 months. One patient with stage III disease had recurred after 47 months. Carcinoma of the fallopian tube appears to respond favorably to cisplatin-based multiagent chemotherapy. Patients with advanced-stage disease who achieve a negative second-look appear to have an improved possibility of remaining disease-free over similar-stage patients with ovarian cancer.
Adult↗
Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: influence of a prior response to intravenous cisplatin.
Phase II trials of second-line intraperitoneal (IP) cisplatin-based therapy in patients with ovarian cancer have demonstrated the ability of this approach to produce objective antitumor responses, including surgically defined complete responses (CRs), in individuals with persistent small-volume disease after front-line cisplatin-based intravenous (IV) treatment. To examine the influence of a prior response to systemic cisplatin on the activity of second-line IP cisplatin, we retrospectively analyzed two phase II trials of cisplatin-based IP therapy in persistent/recurrent ovarian cancer conducted at our institution. Of the 89 assessable patients on the two trials, 52 (58%) had previously responded to IV cisplatin. The overall response and CR rates to second-line IP cisplatin-based therapy in this previously responding population were 56% and 33%, respectively, compared with overall response and CR rates in the 37 nonresponders to IV cisplatin of 11% and 3%, respectively (P less than .001; chi 2, 1 df). In the 36 patients responding to systemic cisplatin and whose largest tumor mass measured less than 1 cm at IP cisplatin initiation, a 42% CR rate was observed, compared with a 7% CR rate in the 14 patients with the same bulk of disease who had previously failed to respond to systemic cisplatin (P less than .025). We conclude that a prior response to systemic cisplatin strongly influences the antineoplastic activity of second-line IP cisplatin in ovarian cancer.
Antineoplastic Combined Chemotherapy Protocols↗