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Biomedical subjects

M Markman

Publications and source records attributed to M Markman.

At least 253 records · Page 14Linked to original sources
PubMed1991

Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma.

Preclinical evaluation has suggested impressive concentration-dependent cytotoxic synergy between cisplatin and cytarabine in ovarian carcinoma. To further evaluate the clinical relevance of these observations, 39 patients with refractory or recurrent ovarian carcinoma were entered onto a phase II trial of intraperitoneal (IP) cisplatin (100 to 105 mg/m2 per course) plus cytarabine (600 to 900 mg per course). Treatment was administered over 2 or 3 days for a maximum of five monthly courses, followed by surgical reevaluation in patients without clinical evidence of disease. The 3-day regimen was discontinued secondary to the development of severe thrombocytopenia (five of 12 courses platelets decreased to less than 50,000/mm3). Additional toxicities included abdominal pain (moderate to severe at some time during therapy in 46% of patients), fever without evidence of infection (44%), and bacterial peritonitis (10%). Three patients declined surgical reassessment. Fourteen of 36 (39%; 95% confidence interval [CI], 23% to 55%) assessable patients demonstrated surgically defined responses, including 12 of 23 (52%; 95% CI, 32% to 72%) patients with tumor nodules less than 1 cm in diameter and only two of 13 (15%; 95% CI, 0% to 34%) patients with any lesion greater than 1 cm. There were seven (30%; 95% CI, 11% to 49%) surgically defined complete responses (CRs) in patients with less than 1 cm disease and none in patients with larger tumor nodules. IP cisplatin/cytarabine results in a high surgically defined response rate in patients with minimal residual ovarian carcinoma, but activity is low in patients with bulky intraabdominal disease.

Adult↗
PubMed1991

Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin.

In an effort to critically define the incidence and clinical characteristics of secondary responses to cisplatin-based therapy in patients with ovarian cancer previously treated with a cisplatin-based program, a retrospective review was undertaken of patients at the Memorial Sloan-Kettering Cancer Center who received greater than or equal to two cisplatin/carboplatin-based programs. Eighty-two patients were identified who met the entry criteria of having had a cisplatin-free interval (CFI) of more than 4 months between the completion of their first regimen and the institution of a second cisplatin/carboplatin program. Of the 72 assessable patients (10 had no measurable disease, and a laparotomy was not performed to assess response), 31 (43%) responded, including 10 surgically defined complete responses (S-CRs). The overall response rates (and S-CR rate), based on duration of CFI, were 5 to 12 months, 27% (5%); 13 to 24 months, 33% (11%); and more than 24 months, 59% (22%). Twenty-nine patients (35%) received noncisplatin/carboplatin-containing treatments between the cisplatin programs. Patients without any treatment for more than 24 months from the completion of their initial therapy experienced a 77% (17 of 22) response rate and a 32% (seven of 22) S-CR rate. In conclusion, secondary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.

Adult↗
PubMed1991

Phase II trial of weekly or biweekly intraperitoneal mitoxantrone in epithelial ovarian cancer.

Previous experimental and clinical evaluation has suggested that ovarian cancer is sensitive to the cytotoxic effects of mitoxantrone at concentrations achievable within the peritoneal cavity after intraperitoneal (IP) administration. Unfortunately, the use of the drug delivered IP at high doses (20 mg/m2 in 2 L normal saline [NS]) on a monthly schedule is compromised by severe local effects secondary to the irritant properties of the drug. To reduce toxicity and take advantage of minimal systemic drug exposure following IP administration, we treated 28 patients with a lower drug concentration of mitoxantrone (10 mg/m2 in 2 L NS), but on a weekly or every other week schedule (total, 12 courses). Compared with the monthly program, this regimen caused less pain, allowed for a higher cumulative dose of mitoxantrone to be delivered, and resulted in less serious treatment-related morbidity. Four of 13 assessable patients (31%) whose largest tumor was less than or equal to 1 cm in diameter demonstrated a surgically defined response. All responding patients had failed previously or exhibited a minimal response to cisplatin. Despite the improved toxicity profile of this regimen, the overall response rate was similar to the monthly program, probably secondary to inadequate IP drug distribution in many patients. Future investigative efforts using IP mitoxantrone as therapy for ovarian cancer might focus on developing methods to improve drug delivery to all sites of tumor within the peritoneal cavity (eg, intraoperative therapy, increased treatment volumes, and antiinflammatory agents to reduce adhesion formation).

Adult↗
PubMed1991

Supportive care.

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed1990

Aggressive chemosurgical debulking in patients with advanced ovarian cancer.

From July 1986 to June 1989, 43 evaluable patients with advanced ovarian cancer were treated on protocol with initial cytoreductive surgery, two courses of high-intensity intravenous Cytoxan (1000 mg/m2) and cisplatin (120-200 mg/m2) chemotherapy, and repeat debulking laparotomy in an effort to maximize response to a subsequent four cycles of intraperitoneal platinum-based chemotherapy. Two patients were stage IIIA, 2 stage IIIB, 28 stage IIIC, and 11 stage IV. Five tumors were grade 1, 9 grade 2, and 29 grade 3. Thirty-eight (88%) patients had bulky tumor (5-25 cm) found at first laparotomy; 25 of these had greater than 1-cm residual after initial debulking. Following two cycles of intensive intravenous chemotherapy 18 of these 25 had greater than 1-cm disease found at second laparotomy; 12 of 18 underwent secondary cytoreduction to less than 1 cm. Thus, 30 of these 38 (79%) patients entered the intraperitoneal phase of the protocol with less than 1-cm disease. Four patients had 2- to 5-cm tumor at initial laparotomy; two of four were debulked to less than 1-cm residual. All four were found to have less than 1-cm disease at second laparotomy. This combination regimen was well tolerated. There was one treatment-related death. In sum, 42 of 43 patients had tumor greater than 2 cm at staging laparotomy and 38 (88%) had large, bulky disease (5-25 cm); 34 of 43 (79%) entered the intraperitoneal phase of the protocol with optimal (less than 1-cm) disease. Aggressive chemosurgical cytoreduction in patients with bulky advanced ovarian cancer can leave a large proportion of patients with minimal residual disease and maximize their chances of responding to subsequent intraperitoneal chemotherapy.

Cisplatin↗
PubMed1990

Expression of P-glycoprotein in epithelial ovarian cancer: evaluation as a marker of multidrug resistance.

The multidrug-resistance gene, MDR1, encodes a plasma membrane glycoprotein termed P-glycoprotein that mediates active cellular efflux of certain chemotherapeutic agents. P-Glycoprotein expression was evaluated in 98 frozen tumor specimens from 57 patients with epithelial ovarian cancer by the indirect immunoperoxidase technique with monoclonal antibodies C219 and JSB-1 used for detection. Tumor specimens were further characterized antigenically with a panel of monoclonal antibodies representing a variety of epithelial cell antigens. Included were 57 specimens from 33 previously untreated patients; 11 specimens were also available from eight patients in this group after chemotherapy. An additional 30 specimens were studied from 24 other patients after chemotherapy. In only four of the 57 patients with ovarian cancer (7%) did one or more of the specimens express P-glycoprotein. Two of these patients had tumors that were considered clinically drug resistant. No increase in P-glycoprotein expression was noted after exposure to chemotherapy, including the eight individuals for whom specimens were available both before and after treatment. Although drug resistance is a major problem in treatment of ovarian cancer, resistance to the drugs most active against these tumors probably occurs through a mechanism other than expression of the MDR1 gene product.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Phase II trial of intraperitoneal mitoxantrone in the management of refractory ovarian cancer.

To define both the toxicity and efficacy of intraperitoneal mitoxantrone in the treatment of refractory ovarian carcinoma, 31 patients were entered onto a phase II trial of this agent delivered in a 2 L treatment volume on a monthly basis. Due to excessive local pain at the initial dose level (30 mg/m2), the amount of drug delivered with each treatment course was reduced to 20 mg/m2. Despite this reduction, 74% of patients required narcotic analgesia during treatment. In addition, there were four episodes of bowel obstruction (one requiring surgical intervention) during therapy, and two patients developed bowel obstruction and intraabdominal abscesses following the completion of treatment. Six of 18 evaluable patients (33%) whose largest tumor diameter was less than or equal to 1 cm at protocol initiation experienced surgically documented responses, compared with one of 11 patients (9%) whose largest tumor was greater than 1 cm in diameter. If the two patients exhibiting what we called a mixed response to treatment are included, seven of 21 patients previously treated with intraperitoneal cisplatin responded to this treatment program, including four patients who had failed to respond to intraperitoneal cisplatin. No responding patient has demonstrated clinical evidence of relapse with a median follow-up of 7 months (range, 3+ to 13+ months) from response laparotomy. Intraperitoneal mitoxantrone is an active treatment program in patients with small-volume refractory ovarian carcinoma, but local toxicity can be severe. Due to the toxicity encountered with this specific program, its use cannot be recommended for standard clinical practice. However, in view of the activity observed in refractory ovarian carcinoma, including responses in patients who had previously failed intraperitoneal cisplatin, it is important to continue to explore alternative therapeutic regimens using intraperitoneal mitoxantrone to reduce local toxicity while maintaining or improving efficacy.

Carcinoma↗
PubMed1990

Supportive care.

Explore the source record for details and available documents.

Antibiotics, Antineoplastic↗
PubMed1990

Clinical use of differentiating agents in cancer therapy.

Conceptually, the use of cytodifferentiation agents to suppress oncogenicity may prove most effective in long-term continuous treatment of patients whose tumors display some inherent expression of differentiated characteristics. This is the case in many pre-malignant lesions. The difficulty in evaluating the therapeutic role for HMBA, the retinoids, and cytosine arabinoside is oftentimes in separating in vivo cytotoxic from cytodifferentiation effects. Only with further studies will it be determined whether these and other cytodifferentiation agents are therapeutically useful and whether they can provide additional understanding of the processes of cellular transformation and differentiation with which they interact.

Acetamides↗
PubMed1989

Synergistic activity of tumor necrosis factor and interferon in a nude mouse model of human ovarian cancer.

In vitro and in vivo studies suggest a synergistic inhibition of tumor growth by the combination of certain interferons and tumor necrosis factors. We have examined the activity of two of these agents in an animal model of human ovarian cancer. The human ovarian cancer cell line SK-OV3 was grown subcutaneously in immunodeficient mice. Mean relative tumor volume was determined weekly by external tumor measurements and a standard formula. Animals were treated by intraperitoneal injection with (1) recombinant human tumor necrosis factor alpha (rHTNF) 5 or 10 micrograms/day; (2) recombinant murine interferon gamma (rMIFN) 5 x 10(4) units per day; or (3) a combination of rHTNF 5 micrograms/day and rMIFN 5 x 10(4) units/day. Simultaneous control groups were run for all experiments. Administration of rHTNF alone in either dose had no effect on rate of tumor growth. Administration of rMIFN at a dose of 5 x 10(4) units/day produced a marginal decrease in rate of tumor growth. Animals receiving both rHTNF 5 micrograms/day and rMIFN 5 x 10(4) units daily showed marked inhibition of tumor growth, with the mean relative tumor volume after 4 weeks of treatment measuring 0.75 +/- 0.91 in the treatment group and 11.06 +/- 2.96 in the control group. rHTNF and rMIFN demonstrate a synergistic inhibition of tumor growth in this animal model of human ovarian cancer.

Animals↗
PubMed1989

Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma.

The value of secondary cytoreductive surgery at the time of second-look laparotomy in patients with epithelial ovarian carcinoma is not established. Sixty-seven patients with residual carcinoma found at the time of second-look laparotomy performed at Memorial Sloan-Kettering Cancer Center between December 1, 1978, and May 30, 1986, were evaluated for survival relative to the success of secondary cytoreductive surgery. At second-look laparotomy, 17 patients had microscopic disease, 28 patients had disease less than 2 cm and 22 patients had disease greater than 2 cm. After secondary cytoreductive surgery 33 patients had microscopic disease, 26 patients had disease less than 2 cm, and 7 patients had disease greater than 2 cm (1 unknown). Five-year survival by Kaplan-Meier calculation was 62% for patients found to have microscopic disease at second-look laparotomy and 51% for patients whose disease was rendered microscopic by secondary cytoreductive surgery (P = 0.55). Patients left with gross disease (either less than or greater than 2 cm) had 5-year survivals of less than 10% (P = 0.013 compared with microscopic residual). Secondary cytoreductive surgery at the time of second-look laparotomy in patients with epithelial ovarian carcinoma may result in improved survival of patients who are reduced to microscopic residual disease.

Adult↗
PubMed1989

Long-term access to the peritoneal cavity in ovarian cancer patients.

One hundred thirty-six totally implanted peritoneal catheter systems were placed in 130 patients. No complications occurred at catheter placement. A total of 629 courses of intraperitoneal therapy were administered. The average catheter has remained in place for 4.5 months (range 1-19 months). Seven catheters (5.1%) were removed for infection. An additional 7 catheters were removed because of blockage, for a total removal rate due to complications of 10.2%. Catheters were not used for drainage of the peritoneal cavity. The totally implanted peritoneal catheter system provides a reliable means for long-term access to the peritoneal cavity in patients with ovarian cancer.

Antineoplastic Agents↗
PubMed1989

Biochemical modulation of cisplatin toxicity.

The biochemical modulation of cisplatin toxicity has contributed substantially to the safe and effective administration of cisplatin in the clinic. In most cases, however, the demonstration of clinical efficacy has preceded the understanding of mechanisms by which these agents provide protection to normal tissues. A number of protocols are now available to ameliorate cisplatin-induced nephrotoxicity; these approaches have been so successful that renal toxicity is rarely of clinical significance today. However, the dramatic escalation in cisplatin dose engendered by the use of modulators has resulted in new dose-limiting toxicities involving the nervous system and the bone marrow. Although preliminary data suggests that certain modulators may reduce these toxicities, extensive clinical trials will be necessary to substantiate the beneficial effects in the clinic. Further clinical studies will also be necessary to determine the optimum scheduling for the newer agents and to provide convincing evidence of efficacy in man. Finally, modulator combinations (i.e. DDTC and hypertonic saline) have the potential to provide the broadest coverage of normal tissue protection and appear to merit more extensive clinical investigation. Cisplatin has demonstrated remarkable clinical efficacy at currently tolerated doses; further advances in the biochemical modulation of cisplatin toxicity should provide significant therapeutic gains for this important drug in the future.

Animals↗