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Biomedical subjects

K M Pisters

Publications and source records attributed to K M Pisters.

At least 37 records · Page 2Linked to original sources

Induction paclitaxel/carboplatin in early stage non-small cell lung cancer. Bimodality Lung Oncology Team.

In this feasibility study, a 3-hour infusion of 225 mg/m2 paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was combined with carboplatin dosed to an area under the concentration-time curve of 6 to treat patients with stage T2N0, T1-2N1, or T3N0-1 (excluding superior sulcus tumors) non-small cell lung cancer. Nineteen of a planned 80 patients have been enrolled. To assure that patients meet the study's criteria for inclusion, rigorous physical and laboratory investigations are performed before, during, and after the preoperative chemotherapy and again before the postsurgical chemotherapy. Treatment includes two cycles of preoperative chemotherapy, followed within 3 to 6 weeks with thoracotomy. Up to three cycles of postoperative chemotherapy are planned, commencing 3 to 8 weeks after surgery, as tolerated. To date, 14 patients have completed induction chemotherapy, nine of whom have undergone surgical resection. Three patients have completed postoperative chemotherapy. The study treatment has been well tolerated with no unexpected toxicities. Very preliminary results suggest that perioperative paclitaxel/carboplatin appears to be a feasible and tolerable regimen in patients with early stage non-small cell lung cancer and warrants further investigation. More mature results may provide the basis for an intergroup randomized trial comparing this regimen with surgery alone for patients with early stage disease.

Adult↗

Paclitaxel/carboplatin chemotherapy as primary treatment of brain metastases in non-small cell lung cancer: a preliminary report.

Chemotherapy has been rarely considered an important treatment modality for brain metastases. Based on the hypothesis that the lack of efficacy of chemotherapy, rather than the blood-brain barrier itself, may be the major hindrance to the successful chemotherapeutic treatment of brain metastases, we started a trial in which a selected group of non-small cell lung cancer patients with brain metastases received primary treatment with systemic chemotherapy. The treatment consisted of three courses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 225 mg/m2 given intravenously over 3 hours and carboplatin dosed to an area under the concentration-time curve of 6, with close monitoring of the lesion by computed tomography or magnetic resonance imaging of the brain after each chemotherapy course. Any radiographic or clinical evidence of progression in the brain during treatment or no improvement in the brain after three cycles of chemotherapy mandated whole brain irradiation (30 Gy in 10 fractions). Responding patients received three additional courses of chemotherapy; whole brain irradiation was given after completion of all six chemotherapy cycles. To date, five patients have been enrolled, and one has achieved partial remission both in the brain and at the extracranial site. Other patients did not achieve major objective responses either in the brain or at the extracranial sites. These preliminary results, which are consistent with the study hypothesis, support the feasibility of our approach. We therefore continue to accrue patients for this study.

Adult↗

Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

Aged↗

High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer.

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.

Administration, Oral↗

Oral combination antiemetics in patients with small cell lung cancer receiving cisplatin or cyclophosphamide plus doxorubicin.

BACKGROUND: Intravenous antiemetic combinations containing a 5-HT3 receptor antagonist (like metoclopramide, ondansetron, or granisetron) with dexamethasone have become the standard therapy for the treatment of acute chemotherapy-induced vomiting. Intravenous antiemetics, however, can be more costly and take more time to prepare and deliver, and therefore are not preferred for home, outpatient, or office use. The objective of this study was to determine the antiemetic activity and safety of the oral combination antiemetic regimen of metoclopramide, dexamethasone, and diphenhydramine in patients with small cell lung cancer receiving standard outpatient chemotherapy programs. METHODS: Fifty-two patients receiving initial cisplatin (60 mg/m2) or cyclophosphamide (600-1500 mg/m2) plus doxorubicin (30-45 mg/m2) received an oral regimen of metoclopramide (3 mg/kg x 2 then 2 mg/kg x 2 or 4 doses), dexamethasone (20 mg) and diphenhydramine (50 mg x 2 or 3 doses) (oral MDD), beginning 30 minutes before chemotherapy. RESULTS: Vomiting was prevented in 15 of 21 (76%) patients (95% confidence interval [CI], 53%-92%) receiving cisplatin and 21 of 31 (71%) individuals (95% CI, 52%-86%) given cyclophosphamide plus doxorubicin. Adverse effects were mild and transient and included sedation, loose stools, akathisia, and hiccoughs. CONCLUSIONS: The oral MDD antiemetic regimen prevented acute emesis in 73% of the patients entered and was well tolerated in this population of patients with small cell lung cancer.

Administration, Oral↗

Phase II trial of a 75-mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer.

BACKGROUND: A prior Phase II study of a 100-mg/m2 dose of docetaxel conducted at the Memorial Sloan-Kettering Cancer Center (New York, NY) demonstrated a 38% response rate with grade 3 or 4 neutropenia in 76% of the patients and a grade 2 or greater rash or infusion-related reaction in 41% and 34% of the patients, respectively. The current Phase II study sought to determine the activity of a 75-mg/m2 dose of docetaxel to establish whether this lower dose, combined with prednisone, ameliorates toxicity. METHODS: Twenty untreated patients with advanced non-small cell lung cancer (NSCLC) received a 1-hour 75-mg/m2 dose of docetaxel every 21 days. Fifty milligrams of prednisone were administered twice the day before chemotherapy and once each of the next 3 days. Patients' disease-related symptoms were assessed prospectively using the Lung Cancer Symptom Scale (LCSS). RESULTS: All patients were assessable for response and toxicity. Five patients had a major objective response (25%; 95% confidence interval, 11-50%). The median duration of response was 9.1 months. The projected 1-year survival was 71%. Grade 3 or 4 neutropenia occurred in 70% of the patients. Grade 2 or greater rash and infusion-related reactions decreased to 25% each. Analysis of the LCSS measurements found that six of nine component symptoms improved on Day 22, and all improved when baseline measurements were compared with the best value for each patient during the study. CONCLUSIONS: Docetaxel administered at a dose of 75 mg/m2 every 21 days shows significant antitumor activity in untreated patients with NSCLC: Neutropenia is comparable with that observed at a 100-mg/m2 dose. The number of infusional reactions and rash decreased when docetaxel at this dose was administered with prednisone. Based on response rates observed in trials using a 100-mg/m2 dose with similar degrees of neutropenia, a 100-mg/m2 dose with steroid pretreatment is recommended future trials.

Adult↗

Effectiveness and toxicity of preoperative therapy in stage IIIA non-small cell lung cancer including the Memorial Sloan-Kettering experience with induction MVP in patients with bulky mediastinal lymph node metastases (Clinical N2).

The use of preoperative chemotherapy with mitomycin, vinblastine and cisplatin (MVP) has led to improved complete resection rates and survival in Stage IIIA non-small cell lung cancer with bulky, ipsilateral, mediastinal lymph node metastases (Clinical N2 disease). The addition of preoperative irradiation has also been explored with results not substantially different from preoperative cisplatin-based chemotherapy alone. While preoperative chemotherapy has been shown to be feasible, the toxicity of both the chemotherapy and the subsequent resection is of concern with an overall treatment-related mortality of nearly 8%. The careful selection of patients, swift management of neutropenia, and meticulous perioperative pulmonary care has the potential to reduce the mortality from multimodality therapy. Having shown survival benefit in multiple single-institution and randomized trials, induction chemotherapy followed by surgery or irradiation is now the treatment of choice for patients with Stage IIIA non-small cell lung cancer with mediastinal lymph node metastases.

Antineoplastic Combined Chemotherapy Protocols↗

Ifosfamide plus high-dose cisplatin in patients with non-small cell lung cancer previously treated with chemotherapy.

This study determined the maximum tolerated dose (MTD) of ifosfamide that could be given with high-dose cisplatin to non-small cell lung cancer (NSCLC) patients previously treated with non-platin-containing chemotherapy and to assess the efficacy of this combination. Twenty-three patients with inoperable NSCLC treated with one prior chemotherapy regimen received continuous infusion ifosfamide 1.2 g/m2 per day with MESNA for 5 days every 35 days and cisplatin 120 mg/m2. After one patient who received cisplatin as a single dose developed grade 4 nephrotoxicity and myelosuppression, cisplatin was given in four divided doses (30 mg/m2 per day) and the ifosfamide dose was lowered to 1.0 g/m2 per day, infused over 4 days. Dose-limiting grades 3 and 4 leukopenia was seen in 43%. A major objective response rate of 9% was observed. The 1-year survival was 30%, with a median survival of 6.4 months. The MTD of ifosfamide administered with cisplatin (30 mg/m2 per day for 4 consecutive days) to this population of patients is 1.0 g/m2 daily for 4 days. This combination produced limited anticancer activity and significant toxicity. Excessive toxicity was observed when cisplatin was given as a single dose with ifosfamide, and this schedule should not be used.

Antineoplastic Combined Chemotherapy Protocols↗

New chemotherapeutic agents for non-small cell lung cancer.

The identification of new chemotherapeutic agents for the treatment of non-small cell lung cancer should proceed in a structured, logical fashion. Agents should be evaluated on the basis of multiple objective and subjective end points. A 15% or greater major objective response rate, demonstrated in multiple single-agent phase II trials, is considered the lower limit for an agent to be deemed clinically active in this disease. A number of drugs previously have been identified in this category, including cisplatin, ifosfamide, mitomycin, paclitaxel, and the vinca alkaloids vinblastine and vindesine. Most of these conventional agents have been explored alone, in a variety of doses and schedules, and in combination. In the last several years clinical development has produced new agents, including chloroquinoxaline sulfonamide, docetaxel, edatrexate, gemcitabine, irinotecan, topotecan, and vinorelbine, which hold promise for more successful treatment of this lethal disease.

Aminopterin↗

The addition of ondansetron to the combination of metoclopramide, dexamethasone, and lorazepam did not improve vomiting prevention in patients receiving high-dose cisplatin.

BACKGROUND: Serotonin has been shown to be an important mediator of chemotherapy-induced vomiting. Ondansetron is a potent and highly specific antagonist of the 5-HT3 serotonin receptor. The objective of the current trial was to determine if the addition of ondansetron to the combination of metoclopramide, dexamethasone, and lorazepam (MDL) could improve the control of vomiting in patients receiving high-dose cisplatin. The three-drug MDL antiemetic regimen has been shown to prevent vomiting in 67% of patients receiving high-dose cisplatin. METHODS: Thirty-two patients receiving initial cisplatin (greater than or equal to 100 mg/m2) were given intravenous lorazepam, 1.5 mg/m2 (maximum dose, 3 mg), one dose 45 minutes before cisplatin; metoclopramide, 3 mg/kg 40 minutes before and 90 minutes after cisplatin; ondansetron, 0.3 mg/kg 25 minutes before and 3.5 hours after cisplatin; and dexamethasone, 20 mg, one dose 10 minutes before cisplatin. Patients were followed for 24 hours after cisplatin administration. RESULTS: Vomiting was prevented in 67% of patients (95% confidence interval, 47-83%). Adverse effects were mild and transient and included sedation, headache, serum aspartate transaminase, and alanine transaminase elevations, akathisia, and hiccups. CONCLUSIONS: Vomiting was prevented in two thirds of patients treated with MDL plus ondansetron, a result similar to that observed in earlier trials of MDL alone. The lack of improvement in emetic control by the addition of ondansetron suggests that vomiting mediated through 5-HT3 receptors is already effectively blocked. Emesis that occurs despite pretreatment with MDL is likely mediated by other mechanisms.

Adult↗

Randomized trial comparing postoperative chemotherapy with vindesine and cisplatin plus thoracic irradiation with irradiation alone in stage III (N2) non-small cell lung cancer.

This prospective randomized trial was performed to determine whether postoperative chemotherapy with vindesine and cisplatin could lengthen time to progression and overall survival in stage III (T1-3N2M0) non-small cell lung cancer (NSCLC) patients. Seventy-two patients were entered; 36 were randomized to receive chemotherapy. Patients were stratified by extent of resection (complete vs. incomplete) and histology (squamous vs. nonsquamous). All had surgery and mediastinal irradiation 6-7 weeks post-thoracotomy. Incompletely resected patients had intraoperative 125I and/or 192Ir implantation. Vindesine (3 mg/m2) weekly x 5, then every 2 weeks x 8, and cisplatin (120 mg/m2) days 1, 29, 71, 113 were planned for those randomized to chemotherapy. No difference in time to progression (median 9.2 months for radiation + chemotherapy vs. 9.0 months for radiation, P = 0.35) or overall survival (16.3 months for radiation + chemotherapy vs. 19.1 months for radiation, P = 0.42) was found. Postoperative vindesine and cisplatin did not prolong time to progression or survival in this population of stage III NSCLC.

Adult↗

Delayed emesis following anticancer chemotherapy.

As the control of acute chemotherapy-induced emesis has improved, delayed emesis (occurring 24 h or more after treatment) has become the most bothersome vomiting problem. Delayed vomiting occurs after treatment with many anticancer drugs, but has been most often studied following cisplatin or combinations of cyclophosphamide and anthracyclines. The mechanism of this phenomenon is unknown. Empirical trials of antiemetic agents effective in controlling acute emesis identified the combination of metoclopramide and dexamethasone as useful in lessening delayed emesis after displatin in a randomized, placebo-controlled study. The specific serotonin receptor (5-HT3) antagonist ondansetron yielded results equivalent to the prior placebo results in a phase II trial using identical methodology in similar patients given cisplatin. Following anthracycline and cyclophosphamide combination chemotherapy, the delayed vomiting prevention observed with dexamethasone alone exceeds that of ondansetron. These observations suggest that delayed emesis is primarily mediated by neurotransmitters other than serotonin. Since delayed emesis occurs more frequently in patients who experience nausea and vomiting on the day they receive chemotherapy, tested combination antiemetic regimens, employing a 5-HT3 antagonist (either granisetron, metoclopramide, ondansetron or tropisetron), dexamethasone, and a benzodiazepine (lorazepam and alprazolam) should be routinely employed. This approach provides the best protection for acute and delayed emesis. Further research, looking beyond the specific 5-HT3 antagonists, provides the best strategy to improve the control of delayed symptoms.

Antibiotics, Antineoplastic↗

Randomized phase II trial comparing two versus three doses of ondansetron when used in combination with dexamethasone in patients receiving cisplatin > or = 100 mg/m2.

Ondansetron controls cisplatin-induced emesis when given in three 0.15 mg/kg doses, and preliminary data suggest that control may be maintained when fewer doses are employed. Prior trials have further shown improved antiemetic effects and fewer adverse effects of cisplatin treatment when neurotransmitter receptor blockers are combined with dexamethasone. This trial was undertaken to determine the effectiveness of the combination of dexamethasone and ondansetron and to see if equivalent results could be obtained with only two doses of ondansetron. There were 44 patients receiving initial cisplatin at a dose > or = 100 mg/m2, each given dexamethasone 20 mg and randomized to receive either two or three 0.15 mg/kg doses of ondansetron. Vomiting prevention was identical (35%) whether two or three doses were given. No new adverse effects were noted and cisplatin-induced diarrhea, usually seen in up to 60% of patients given this dose of cisplatin, was noted in only 5%. Although this trial did not demonstrate enhanced antiemetic effects with the combination, other investigators have done so and all agree that the regimen is safe and reduces adverse effects. Further exploration and use of the combination of ondansetron and dexamethasone, and studies testing fewer doses of ondansetron in this regimen are warranted.

Adult↗

Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer.

PURPOSE: This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Docetaxel was administered to 29 patients with unresectable stage III and IV NSCLC at a dose of 100 mg/m2 intravenously (IV) over 1 hour every 21 days. No premedication was given to the first 16 patients. Premedication with diphenhydramine was instituted for the remainder. No patient had previously received chemotherapy. Seven patients had undergone prior radiation therapy. RESULTS: All patients were assessable for response and toxicity. Eleven of 29 patients (38%) had a major objective response (95% confidence interval, 21% to 58%). The median duration of response was 5.3 months. Febrile neutropenia occurred in 41% of patients and in 11% of 134 courses of docetaxel. Nonhematologic toxicities included infusion-related hypersensitivity reactions, fluid retention, rash, alopecia, and sensory neuropathy. Premedication with diphenhydramine did not decrease the incidence of infusion-related hypersensitivity reactions. CONCLUSION: At this dose and schedule, docetaxel demonstrates significant antitumor activity in patients with advanced NSCLC. Further investigations of this agent in NSCLC are indicated.

Adult↗

Enhancing the effectiveness of the specific serotonin antagonists. Combination antiemetic therapy with dexamethasone.

Combinations of drugs have become standard therapy for the prevention of vomiting caused by anticancer drugs like cisplatin. Recently, a new class of antiemetic agents, the potent and specific 5-HT3 receptor antagonists such as ondansetron, granisetron, and tropisetron, have been shown to be more effective and better tolerated than metoclopramide. This report describes the rationale for combination antiemetic therapy, details the testing of metoclopramide-based regimens as a model for combination therapy development, reviews completed trials of ondansetron plus dexamethasone, and offers strategies to further alleviate vomiting during anticancer chemotherapy. The reported trials testing metoclopramide-based combinations were reviewed and that experience was applied to the ongoing studies of ondansetron when used with dexamethasone and other agents. Combinations of metoclopramide, dexamethasone, and lorazepam prevented acute emesis caused by high-dose cisplatin in 63% of patients, lessened side effects, and were convenient enough to administer to outpatients. Completed trials of ondansetron and dexamethasone demonstrated improved vomiting control over ondansetron alone while using less cumbersome schedules. Attempts to improve ondansetron-based antiemetic regimens by developing optimal drug doses and schedules and adding adjuvant and different classes of antiemetic agents are now in clinical testing. Based on previous experience and current results, combinations of a specific serotonin agonist and dexamethasone are the best treatment for prevention of vomiting induced by chemotherapy. Future clinical research should aim to refine antiemetic regimens and improve emetic control through the use of new antiemetic and adjuvant agents.

Antiemetics↗

Dose-ranging antiemetic evaluation of the serotonin antagonist RG 12915 in patients receiving anticancer chemotherapy.

BACKGROUND: RG 12915 is a potent, selective 5-HT3 receptor antagonist with a biologic half-life of 11-20 hours. RG 12915 prevents cisplatin-induced emesis in ferrets at doses of 0.03 mg/kg. Animal toxicology studies permitted safe testing in humans at doses of up to 2.0 mg/kg. This dose-ranging trial of intravenous RG 12915 was performed to determine the optimal dosage and adverse effects and to observe for antiemetic effects in patients receiving anticancer chemotherapy. METHODS: Twenty-six patients receiving chemotherapy likely to cause vomiting received a single intravenous dose of RG 12915 at a rate of 3 ml/minute beginning 60 minutes before chemotherapy. Four dose levels were explored: 0.25, 0.50, 1.0, and 2.0 mg/kg. RESULTS: No dose-limiting toxicities were observed. All adverse effects were mild and transient and included discomfort at the infusion site, hyperglycemia, headache, serum aspartate transaminase (AST) and alanine transaminase (ALT) elevations, and sedation. Antiemetic efficacy was seen in patients receiving cisplatin at doses of greater than or equal to 100 mg/m2. CONCLUSION: RG 12915 can be administered safely at the dose levels explored. Single intravenous doses of RG 12915 prevented or lessened emesis caused by chemotherapy, including cisplatin given at doses of greater than or equal to 100 mg/m2. RG 12915 warrants further testing. Of the doses tested, the 2.0 mg/kg dose is the most appropriate for further exploration.

Adolescent↗

Dose-ranging antiemetic evaluation of the serotonin antagonist tropisetron in patients receiving anti-cancer chemotherapy.

BACKGROUND: Tropisetron (ICS 205-930) antagonizes the serotonin type 3 receptor and has antiemetic activity in animals given cisplatin. Its mean serum half-life in 11.1 hours. METHODS: In this dose-ranging trial, 22 patients undergoing anti-cancer chemotherapy received 24 courses of a single intravenous infusion of tropisetron beginning 30 minutes before chemotherapy. Four dose levels were explored (range, 12-48 mg/m2). RESULTS: Toxicities were mild and included headache, transient elevations of serum alanine transaminase and/or aspartate transaminase levels, and sedation. No akathisia or acute dystonic reactions were observed. Thirty-six percent of patients had no emesis, and 58% had two or fewer emetic episodes. Ten patients received high-dose cisplatin (dose, > or = 100 mg/m2) as initial chemotherapy. Of these, 30% had no emesis, and 60% had two or fewer episodes. CONCLUSIONS: Tropisetron can be administered safely in the doses tested with no dose-limiting toxicities. The encouraging antiemetic efficacy, mild toxicities, lack of extrapyramidal effects, and convenience of a single 15-minute infusion regimen make this drug appropriate for study in additional trials.

Adult↗

Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients.

From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗