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Biomedical subjects

M Markman

Publications and source records attributed to M Markman.

At least 307 records · Page 17Linked to original sources
PubMed1986

Plasma uridine changes in cancer patients treated with the combination of dipyridamole and N-phosphonacetyl-L-aspartate.

Dipyridamole (DP) and N-phosphonacetyl-L-aspartate (PALA) act synergistically in vitro against many cell lines and in vivo against human ovarian carcinoma xenografts. We have conducted a phase I clinical trial of DP p.o. (50 mg/m2, every 6 h) in combination with PALA (starting at 500 mg/m2 i.v. with 300-mg dose escalations). Sixty-five patients were entered into this study, and we have established the maximum tolerated dose of PALA to be 4.5 g/m2 when combined with DP, which is approximately 80% of the previously reported maximum tolerated dose for PALA alone. The observed toxicities of DP plus PALA were mild and were similar to those reported for PALA alone. Bone marrow toxicities were not evident at any PALA dose. Ten patients with a mean pretreatment plasma uridine concentration of 3.49 +/- 1.28 (SD) microM had their plasma uridine reduced to 2.29 +/- 0.70 microM 9 h after DP p.o. A peak plasma DP concentration of 1.86 +/- 0.99 microM was achieved approximately 2 h after p.o. dosing. Nine patients who had a reduced plasma uridine concentration of 2.46 +/- 0.61 microM after 1 week of DP had their plasma uridine further reduced by PALA to 0.87 +/- 0.23 microM 7 h post-PALA. Daily plasma uridine measurements in two patients during their DP treatment confirmed the previously described pattern for Day 1, but the data suggest a slight recovery (15%) in plasma uridine by Day 2. Daily sampling in two other patients after a single PALA dose of 4.2 g/m2 showed that their plasma uridine declined 5 h after the PALA dose and remained depressed for 6 days in one patient and 11 days in the other. These results suggest that DP worked in synergy with PALA to lower circulating uridine in cancer patients. The mechanism for the ability of DP to reduce plasma uridine is not known, but there is evidence that DP can inhibit cellular efflux of uridine as well as its uptake. DP may reduce plasma nucleoside pools in addition to blocking nucleoside salvage and therefore have general applicability in other chemotherapy regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Complications of extensive adhesion formation after intraperitoneal chemotherapy.

The results of modeling studies have suggested and clinical investigations have confirmed a major pharmacokinetic advantage for exposure of the peritoneal cavity to certain chemotherapeutic agents compared with exposure of the systemic circulation when these drugs are delivered through the intraperitoneal route. Objective antitumor responses and significant palliation of symptoms have been demonstrated. One major concern with the use of intraperitoneal therapy is the risk of inducing peritoneal sclerosis and extensive adhesion formation. At the University of California at San Diego (UCSD) Cancer Center, 115 patients with advanced intra-abdominal malignant conditions have been treated with several intraperitoneal chemotherapy programs. To date, with a total of 1,103 patient-months of follow-up study, seven episodes of small intestinal obstruction have developed of which two were definitely and five possibly related to chemotherapy induced adhesion formation. The development of methods to prevent or decrease peritoneal sclerosis will allow for greater application of this innovative therapeutic approach.

Adult↗
PubMed1985

High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity.

Recent published reports have suggested that cisplatin administered in high doses or in certain combination chemotherapy can cause serious neurotoxicity in a large percentage of patients treated. In several high-dose cisplatin-based intracavitary chemotherapy trials with the simultaneous intravenous administration of sodium thiosulfate, the incidence of clinically relevant neurotoxicity has been extremely low. In addition, several patients with serious preexisting cisplatin-induced neurologic dysfunction were treated without worsening of their clinical condition. It is suggested that thiosulfate might have been responsible for the low incidence of neurotoxicity in this patient population. Further experimental and clinical investigation of the potential of this agent to protect against cisplatin-induced neuropathy appears warranted.

Adolescent↗
PubMed1985

Intraperitoneal chemotherapy for advanced ovarian cancer.

Treatment of patients with advanced ovarian cancer who have failure of first-line chemotherapy is rarely effective. Preliminary pharmacokinetic and phase II clinical studies established the feasibility of delivering relatively high concentrations of cisplatin intraperitoneally via a semipermanent catheter, while using intravenous sodium thiosulfate as a neutralizing agent to decrease the nephrotoxicity of cisplatin. Sixty patients with advanced ovarian cancer, all of whom had failure of first-line chemotherapy (including cisplatin in 56 of 60), were treated with high-dose intraperitoneal cisplatin in combination with doxorubicin and/or cytarabine. Of the 46 patients evaluable for response, 19 (42%) showed an objective response, most often (12/19) disappearance of malignant ascites. No serious drug-associated morbidity was observed aside from three cases of intestinal obstruction which may have been due in part to drug-induced adhesions. It is felt that prospective studies to compare the efficacy of intraperitoneal chemotherapy with other forms of "salvage" therapy, as well as its use as initial chemotherapy for advanced ovarian cancer, need to be done.

Altretamine↗
PubMed1985

Cisplatin and cytarabine administered intrapleurally as treatment of malignant pleural effusions.

Eight patients with histologically-documented malignant pleural effusions received a total of ten courses of intrapleurally administered chemotherapy with cisplatin (100 mg/m2) and cytarabine (10(-2) M). Sodium thiosulfate was simultaneously administered intravenously to protect against cisplatin-induced nephrotoxicity. There was no local toxicity observed and the only significant systemic toxicity (bone marrow depression) developed in a patient with poor marrow reserve prior to the initiation of therapy. Six of seven evaluable patients exhibited major reductions (greater than 75%) in the size of their effusions lasting for 2 to 10 plus months (median: 4 months). We conclude that the intrapleural administration of this chemotherapy regimen results in objective and subjective improvement in patients with malignant pleural effusions with minimal local and systemic toxicity (except for cisplatin-induced emesis) and does not require chest tube drainage or prolonged hospitalization.

Adult↗
PubMed1985

Infectious peritonitis in patients receiving intraperitoneal chemotherapy.

A total of 32 episodes of infectious peritonitis developed in 90 patients receiving intraperitoneal chemotherapy. Staphylococcus epidermidis was the organism most commonly cultured, accounting for 65 percent of isolates. Result of initial gram stain was positive in 35 percent of cases. The development of fever and abdominal pain as well as rising peripheral and peritoneal fluid white blood cell counts was helpful in the making of a diagnosis of infectious peritonitis. Seventy-five percent of patients were cured with antibiotic therapy alone whereas one quarter also required removal of the semi-permanent catheter. Patients treated with intraperitoneal chemotherapy delivered by dialysis exchange over several days exhibited significantly more episodes of infection than patients treated by a single-drug instillation each month. Although the development of bacterial peritonitis remains a problem during intracavitary chemotherapy, the use of subcutaneous ports and meticulous sterile technique during catheter manipulation will hopefully decrease the risk of occurrence of this potentially avoidable complication.

Anti-Bacterial Agents↗
PubMed1985

Nephrotoxicity of high-dose intracavitary cisplatin with intravenous thiosulfate protection.

Sodium thiosulfate has been shown experimentally to protect against cisplatin-induced renal insufficiency by inactivating the nephrotoxic as well as cytotoxic properties of the agent. However, significant plasma levels of 'active' cisplatin have been demonstrated following high-dose intracavitary cisplatin administration with simultaneous intravenous thiosulfate delivery. At the UCSD Cancer Center 131 patients have been treated with a total of 485 courses (median per patient, 3; range 1-18) of intrapleural or intraperitoneal cisplatin with intravenous thiosulfate protection. Seventy-six patients (58%) had previously been treated with intravenous cisplatin. A total of 14 courses (2.9%) of intracavitary therapy were complicated by a serum creatinine rise to greater than 1.5 mg% which, in all but three cases, returned to the normal range within 1 month following treatment. All but one patient demonstrating clinical evidence of nephrotoxicity had been heavily pretreated with cisplatin. We conclude that thiosulfate can protect against clinically significant cisplatin-induced nephrotoxicity by cisplatin delivered in high doses via the intracavitary route.

Acute Kidney Injury↗
PubMed1985

Intracavitary chemotherapy.

Pharmacokinetic modeling has suggested, and clinical investigations have confirmed, that intracavitary drug administration can result in a much greater drug exposure for the cavity into which the agent is instilled compared to the plasma. Both the safety and the efficacy of several agents administered individually or in combination have now been demonstrated. Several malignancies, in particular ovarian carcinoma and malignant mesothelioma, which remain confined to body cavities for much of their natural history, might be most rationally treated by the intracavitary treatment approach. Early clinical trials have demonstrated significant activity of intracavitary chemotherapy in both of these malignancies. Optimal drugs and dosages as well as appropriate scheduling for the various tumors involving body cavities remain to be defined. Whether or not combination intracavitary chemotherapy will significantly improve survival of patients with malignant disease confined to body cavities must await carefully controlled clinical trials comparing this treatment approach to standard systemically administered chemotherapy.

Absorption↗
PubMed1985

Anti-peptide antibodies detect oncogene-related proteins in urine.

Antisera to a number of synthetic peptides predicted from nucleic acid sequences of oncogenes have been used to screen 483 urine samples of cancer patients, pregnant women, and normal controls for the presence of immunologically related proteins. Increased levels of oncogene-related proteins are found during neoplasia and pregnancy. The differential detection of these oncogene-related proteins indicates that panels of monoclonal antibodies may provide a convenient noninvasive means of detecting, classifying, and staging a wide variety of malignancies and may be useful in following fetal development during pregnancy.

Antibodies, Monoclonal↗
PubMed1985

Daily intraperitoneal administration of cytarabine in a patient with peritoneal mesothelioma.

A 58 year old male with advanced peritoneal malignant mesothelioma was treated with the daily (5 days/week) intraperitoneal administration of cytarabine in a large treatment volume (1-2 liters) for 7 weeks. While a clinical benefit was not observed, there was no systemic toxicity (except for mild emesis) during or following the intraperitoneal treatment program. Long-term exposure of slow growing solid tumors in the peritoneal cavity to a cell-cycle phase-specific agent with limited systemic exposure and toxicity is an innovative and potentially important means of rationally utilizing this class of anti-neoplastic drugs.

Cisplatin↗
PubMed1985

Maintenance of peritoneal catheter function by the intraperitoneal administration of 32% dextran 70.

Thirty-two percent dextran 70 was administered to 53 patients receiving intraperitoneal (i.p.) chemotherapy in an attempt to better maintain catheter function. One hundred milliliters of 32% dextran 70 was administered i.p. at the time of catheter placement and at the completion of each course of chemotherapy (every 3 to 4 weeks). Analysis of the functional survival of the dextran treated catheters and 20 historical controls was performed. The cumulative probabilities of catheters maintaining bi-directional function in the dextran treated and control groups were 0.75 and 0.50 respectively. This difference was statistically significant at p = 0.051 by two-tailed Wilcoxon analysis. The difference between survival of dextran treated and control catheters increased if patients who received intraperitoneal doxorubicin were factored out (p = 0.035 by two-tailed Wilcoxon analysis). Plasma and peritoneal dextran levels were measured on 9 courses in 8 patients. Dextran was detectable in the peritoneal cavity up to 7 days after administration. The "apparent half-life" of dextran 70 in the peritoneal cavity was 36 hours. Plasma dextran concentrations increased for 2 days following i.p. administration and then decreased with an apparent half-life of 36 hours. One patient experienced chills and another had an anaphylactoid reaction following administration of the dextran. This study suggests that i.p. administration of 32% dextran 70 may be an effective means of minimizing peritoneal catheter failures.

Adult↗
PubMed1985

Intrapericardial instillation of cisplatin in a patient with a large malignant effusion.

Cisplatin (10 mg in 50 ml normal saline) was administered daily for five days directly into the pericardial cavity of a patient with metastatic nonsmall cell lung cancer and a malignant pericardial effusion. No systemic or local side effects were observed. A dramatic decrease in reaccumulation of pericardial fluid was noted which persisted until the patient's death four months later. On the basis of this experience, further investigation of the intrapericardial administration of cisplatin as treatment to control malignant pericardial effusions appears warranted.

Adenocarcinoma↗
PubMed1985

The intraoperative intraperitoneal administration of cisplatin: a case report.

A 63-year-old female with endometrial carcinoma who had received prior extensive systemic chemotherapy and pelvic radiotherapy was administered intraoperative cisplatin (100 mg/m2) by the i.p. route. The method and timing of chemotherapy administration were chosen to optimize delivery of the antineoplastic agent to tumor remaining following debulking surgery. There was no evidence of excessive or unexpected local or systemic toxicity. The intraoperative i.p. instillation of chemotherapeutic agents has the theoretical potential of improving to a limited degree the problem of insuring adequate drug distribution over i.p. chemotherapy.

Cisplatin↗
PubMed1985

High-dose cisplatin with sodium thiosulfate protection.

Nephrotoxicity frequently limits the dose of cisplatin to less than 120 mg/m2 per injection. Sodium thiosulfate is a neutralizing agent for cisplatin that protects against renal damage. To determine whether injection of thiosulfate would permit larger doses of cisplatin to be administered, a fixed 9.9-g/m2 dose of thiosulfate was given intravenously over three hours concurrently with escalating doses of cisplatin. Cisplatin was administered over the last two hours of the thiosulfate infusion. Using this technique, it was possible to escalate the cisplatin dose to 225 mg/m2 before dose-limiting toxicities were encountered. Comparison of cisplatin pharmacokinetics in patients treated with 202.5 mg/m2 plus thiosulfate to those in patients treated with 100 mg/m2 without thiosulfate indicated that there were no changes in the elimination rate constant, volume of distribution, or total body clearance of cisplatin. The total drug exposure for the plasma was approximately twofold at the higher cisplatin dose. This study demonstrates that concurrent administration of thiosulfate permits at least a twofold increase in dose and total exposure to cisplatin.

Adolescent↗
PubMed1985

Intraperitoneal chemotherapy with high-dose cisplatin and cytosine arabinoside for refractory ovarian carcinoma and other malignancies principally involving the peritoneal cavity.

Sixty-two patients with refractory ovarian carcinoma or other malignancies principally confined to the peritoneal cavity were treated with an intraperitoneal combination chemotherapy regimen consisting of cisplatin (100 mg/m2 or 200 mg/m2) and cytosine arabinoside (4 X 10(-3) mol/L or 10(-2) mol/L). Sodium thiosulfate was simultaneously administered intravenously (IV) to protect against cisplatin-induced nephrotoxicity. Sixteen of 52 evaluable patients demonstrated evidence of a clinical response including 14 (36%) of 39 with refractory ovarian carcinoma. Systemic toxicity was not severe except for cisplatin-induced emesis and a single episode of major renal insufficiency. Dose-limiting toxicity was bone marrow suppression with cytosine arabinoside administered at 10(-2) mol/L. We conclude that combination intraperitoneal therapy with high-dose cisplatin and cytosine arbinoside can be safely administered with objective tumor responses observed in patients with ovarian carcinoma refractory to front-line chemotherapy and in occassional individuals with other malignancies principally confined to the peritoneal cavity.

Adult↗
PubMed1985

Intensive alternating chemotherapy regimen in small cell carcinoma of the lung.

Fifty-five patients with small cell carcinoma of the lung (SCCL) were treated with alternating courses of CAV (cyclophosphamide, doxorubicin, and vincristine) and VHM (etoposide, hexamethylmelamine, and methotrexate) at 21-day intervals. One regimen contained high-dose cyclophosphamide (2400 mg/m2 iv), while the second contained an increased dose of etoposide (250 mg/m2 iv on Days 1-3). Patients achieving a complete response (CR) received a minimum of six cycles of therapy or two cycles beyond the achievement of CR. These patients as well as those with partial response with disease limited to the lung then received radiotherapy to the lung primary (5100 rads in 300-rad fractions) as well as prophylactic cranial radiotherapy (3000 rads in 300-rad fractions). All therapy was subsequently stopped until relapse. There were no deaths during the aplastic periods induced by the intensive chemotherapy. CR was achieved in 57% of the patients and partial response was achieved in 38%. The actuarial median survival for the 27 patients with extensive disease was 13.5 months and for the 28 patients with limited disease was 13 months. Survival at this point appears comparable to less intensive regimens in which maintenance therapy was given. We conclude that prolonged intensive induction chemotherapy in SCCL is well-tolerated. Studies are needed to examine in a randomized trial the role of alternating combinations and maintenance therapy in SCCL.

Actuarial Analysis↗