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Biomedical subjects

R F Ozols

Publications and source records attributed to R F Ozols.

At least 19 recordsLinked to original sources
PubMed1996

Identification of zinc finger mRNAs using domain-specific differential display.

An oligonucleotide primer specific for a conserved amino acid region of the Cys2/His2 zinc finger proteins was used in conjunction with mRNA differential display to amplify related mRNAs from a human ovarian cancer cell line. Six of the 12 cDNAs analyzed from the differential display polyacrylamide gel exhibited zinc finger homology at the nucleotide and predicted amino acid sequence level. None of these cDNA fragments, however, shared complete homology with genes encoding any known zinc finger proteins. All 6 cDNA fragments with zinc finger homology had a poly-A tail and 3 of these fragments contained a putative polyadenylation signal. Northern blot analysis was performed using radiolabeled probes prepared from the 12 cDNA fragments. Two of the 6 cDNA fragments with zinc finger homology hybridized to 3.6- and 6.0-kb mRNAs. In addition, 2 of the fragments which did not contain significant homology to zinc finger or any other known sequences hybridized to 4.1- and 5.8-kb mRNAs. These results suggest that domain-specific differential display may be a useful approach for the identification of novel gene family members as well as for the analysis of changes in gene expression of family members between related cell lines or tissue samples.

Amino Acid Sequence↗
PubMed1996

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.

Adult↗
PubMed1996

Successful parenteral desensitization to paclitaxel.

BACKGROUND: Paclitaxel, a member of a new class of antineoplastic agents called the taxanes, has been associated with anaphylactoid reactions. OBJECTIVE: We report a case of successful parental desensitization to paclitaxel. METHODS: Desensitization was performed with serial 10-fold dilutions (up to 1:100,000) of paclitaxel in sufficient volume to administer successive doses of 1, 2, 4, and 8 ml. Basophil histamine release tests were performed with paclitaxel alone, vehicle alone, and paclitaxel and vehicle combined to determine which agent was responsible for the anaphylactoid reactions. RESULTS: After parental desensitization was performed, the patient was able to tolerate infusion of paclitaxel without complications or need for antihistamines or steroids. Basophil histamine release occurred only with paclitaxel and not with the vehicle. CONCLUSIONS: Successful parenteral desensitization to paclitaxel can be achieved; it is paclitaxel, and not its vehicle, that is most likely responsible for anaphylactoid reactions in patients undergoing treatment.

Adult↗
PubMed1996

Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.

PURPOSE AND METHODS: Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. RESULTS: The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively. CONCLUSION: A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.

Adult↗
PubMed1996

Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Adult↗
PubMed1995

Time-dependent pharmacodynamic models in cancer chemotherapy: population pharmacodynamic model for glutathione depletion following modulation by buthionine sulfoximine (BSO) in a Phase I trial of melphalan and BSO.

The development of time-dependent pharmacodynamic models in cancer chemotherapy has been extremely limited. A population approach was used to develop such a model to describe the effect of buthionine sulfoximine (BSO), via its active S-isomer (S-BSO), on glutathione (GSH) depletion in peripheral mononuclear cells. The Phase I trial utilized escalating doses of BSO, from 5 to 17 gm/m2, as a multiple infusion regimen. The population model consisted of a linear 2-compartment pharmacokinetic model coupled to an indirect response model. The indirect response model consisted of a GSH compartment with input and output rate processes that are modulated as a function of S-BSO and GSH concentrations. The model predicted the observed gradual depletion of GSH, a nadir at approximately 30 h after the last dose of BSO, and a return to baseline GSH levels. On the basis of an IC50 estimate of about 1.6 microM for inhibition of gamma-glutamylcysteine synthetase, the target enzyme of BSO, the population model predicted near identical GSH concentration time profiles over the dose range studied. Time-dependent pharmacodynamic models are seen as a powerful means to design dosing regimens and to provide a mathematical platform for mechanistic based models.

Adult↗
PubMed1995

Evidence for altered regulation of gamma-glutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines.

We have shown previously that tumor cell resistance to cisplatin is associated with elevated intracellular levels of glutathione, which is accomplished at least in part by increased expression of the heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCS). To investigate the mechanism by which gamma-GCS expression is elevated, we have examined four related human ovarian cancer cell lines with increasing cisplatin resistance. Relative amounts of steady-state gamma-GCS mRNA in CP70, C30, and C200 were 4.8, 6.0, and 10.6, respectively, compared to the parental A2780 cell line, and a proportional increase in the transcriptional rate but not RNA stability was demonstrated. In contrast, no increase in mRNA for the gamma-GCS light subunit was found. To determine the mechanism of upregulation of this mRNA, we have cloned the promoter of the gene that encodes the heavy subunit of gamma-GCS. This region contains AP-1, NF-kappa B, XRE, AP-2, EpRE, CAAT, and TATA box elements upstream of the transcription initiation site and two MREs between this site and the start codon for the protein. Using gel mobility shift assays, we have found nuclear extract binding activity to the AP-1 response element to be closely associated with the level of gamma-GCS gene expression. A supershift assay showed that the AP-1 DNA-binding complexes are predominantly formed by dimers of JUN family members. Consistent with this finding, the expression of c-JUN was found to be elevated in the resistant cells. In contrast to AP-1 binding, AP-2 and NF-kappa B binding were inversely related to resistance. Furthermore, we have examined a partial revertant of the C200-resistant cells, which shows lower glutathione levels, and found decreased gamma-GCS expression associated with decreased AP-1 binding activity.

Antineoplastic Agents↗
PubMed1995

Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2.

We have examined 41 forms of ovarian cancer for genetic alterations on chromosome 9 using a combination of five RFLP DNA probes and 15 simple tandem repeat polymorphisms. Genetic imbalance (i.e., loss of heterozygosity, microsatellite instability, amplification) for 1 or more informative markers on chromosome 9 was observed in 66% (27 of 41) of our tumor panel. Genetic imbalance was observed on 9q in 59% (24 of 41) of tumors informative for at least one locus. In contrast, only 13% (5 of 40) of informative tumors demonstrated a genetic alteration involving 9p. Furthermore, allelic loss on 9q was more common in late stage tumors (63%, 17 of 27) and poorly differentiated tumors (75%, 15 of 20) as compared to benign and early stage tumors (30%, 3 of 10). Evaluation of 15 tumors showing limited regions of genetic imbalance has identified 2 candidate tumor suppressor regions on 9q and 1 on 9p. Interestingly, the regions defined to 9p21-p24, 9q31, and 9q32-q34 all overlap with several known disease loci. In this aspect, the potential role of the CDKN2 gene at 9p21-p22 in ovarian carcinogenesis was assessed in an extended panel of ovarian tumors, 11 human ovarian carcinoma cell lines, and 1 cervical tumor cell line. With the use of comparative multiplex PCR, homozygous deletions were detected in 16 of 115 (14%) fresh tumors and 3 of 12 cancer cell lines. For those tumors demonstrating allelic loss for markers on 9p no somatic mutations were observed in the retained allele of CDKN2, as determined by single-strand conformation polymorphism analysis, but a mutation was observed in an additional cell line. Furthermore, CDKN2 mRNA levels were similar in the 9 cancer cell lines that retain CDKN2, as compared to normal human ovarian surface epithelial cell lines. Overall, our results suggest the potential involvement of a gene or genes on chromosome 9q and de-emphasize a significant role for the CDKN2 gene on 9p in the initiation and progression of ovarian cancer.

Adenocarcinoma, Mucinous↗
PubMed1995

Phase I study of phosphonacetyl-L-aspartate, 5-fluorouracil, and leucovorin in patients with advanced cancer.

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer.

Exogenous leucovorin is a source of reduced folate which enhances the inhibition of thymidylate synthase that results from 5-fluorouracil (5-FU) administration. Extracellular reduced folate concentrations of 1 microM have been reported to yield maximal enzyme inhibition in several cell lines treated with 5-FU in vitro. Clinical studies indicate that low doses of leucovorin have equivalent efficacy to higher doses in successfully modulating 5-FU in the treatment of colorectal cancer. Based on pharmacokinetics at higher doses, steady-state total plasma reduced folate concentrations of 1 microM would be expected from the administration of leucovorin 50 mg/m2 by 24 h infusion. This dose was admixed with 5-FU 2300 mg/m2 and administered by 24 h-infusion weekly to 38 patients with advanced colorectal cancer, of whom 32 are evaluable for response. Disease sites included liver (33 patients), lung (12 patients), and bone (4 patients). Toxicity was mild to moderate, except for grade 3 diarrhea in 5 patients, and chest pain in 2 patients. Among the 32 evaluable patients, there were 14 partial remissions for a total response rate of 44% (95% confidence interval 27-61%). The median duration of response was seven (range 1 to 20+) months, and median duration of survival 16 months. These results support the use of low doses of leucovorin to modulate weekly infusional 5-FU in colorectal cancer, and provide a basis for the integration of this regimen with other modulators of 5-FU.

Adult↗
PubMed1995

Phase II study of topotecan in metastatic hormone-refractory prostate cancer.

Systemic chemotherapy with currently available agents has not improved survival for patients with hormone refractory prostate cancer (HRPC), consequently, the evaluation of new agents is warranted. Topotecan is a specific inhibitor of topoisomerase I with broad antitumor activity in preclinical studies. The purpose of this phase II trial was to determine the objective response rate of topotecan administered as a 30 minute infusion for five consecutive days in men with metastatic HRPC. Thirty-four evaluable patients were treated with topotecan 1.1-1.5 mg/m2 as a 30 minute infusion daily for five days, repeated every three weeks until disease progression or unacceptable toxicity. Response was assessed with a combination of standard solid tumor response criteria and the serum prostate specific antigen (PSA) for patients with bidimensionally measurable disease, and by serial measurements of the PSA in patients with bone only (evaluable) disease. One of 13 patients (7.6%) with measurable soft tissue disease had a PR in nodal sites. Of 21 patients with only osseous metastases, 1 (4.7%) had improvement in bone scan. Six of the 34 evaluable patients (17.6%) had the serum PSA decrease by > or = 50% and 2 (5.8%) had PSA decreases of > or = 75%. Toxicity was chiefly hematologic with 66% of patients experiencing Grade 3 or 4 granulocytopenia. Thirty-nine percent of cycles required a delay to allow for hematologic recovery and ten patients required red cell transfusions. Non-hematologic toxicity, mainly nausea and alopecia, was mild. Topotecan administered at this dose and schedule has limited activity in patients with HRPC. Further trials of topo I inhibition in HRPC should utilize alternative schedules of topotecan (e.g., prolonged infusion) or other camptothecin analogs with more potent topo I inhibitory activity.

Aged↗
PubMed1995

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis.

PURPOSE: To determine the activity and toxicity of combination paclitaxel (24 hours) and carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligibility required measurable disease (stage IV or stage IIIB with malignant pleural effusion), Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, absolute neutrophil count > or = 2,000/microL, platelet count > or = 100,000/microL serum creatinine concentration < or = 1.5 mg/dL, and bilirubin level < or = 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m2/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m2 per cycle to a maximum of 215 mg/m2. Treatment was repeated at 3-week intervals for six cycles. RESULTS: From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. Two hundred sixty-eight cycles were administered; 32 patients (59%) completed all six cycles. Twenty-five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 granulocytopenia occurred in 57% of patients after the first cycle, but decreased to 35% during the second cycle after introduction of G-CSF and consistently remained < or = 22% during subsequent cycles. Seven episodes of neutropenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia occurred in 47% and 33% of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 215 mg/m2 in > or = 70% of patients who received three or more cycles. At an AUC of 7.5, the median first-cycle carboplatin dose was 424 mg/m2 (range, 273 to 709 mg/m2). The objective response rate was 62%, with five (9%) complete responses and 28 (53%) partial responses. The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The 1-year survival rate is 54%. CONCLUSION: The paclitaxel-carboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.

Adult↗
PubMed1995

USA update on paclitaxel in ovarian cancer.

In the United States, the role of paclitaxel in the treatment of advanced ovarian cancer has expanded markedly in the last 2 years. The drug was initially approved by the Food and Drug Administration for refractory ovarian cancer. However, on the basis of a large prospective randomized trial by the Gynaecologic Oncology Group, paclitaxel together with a platinum compound has now become accepted as a standard form of chemotherapy for previously untreated patients with ovarian cancer. There still remain many unanswered questions as how to best utilize paclitaxel together with platinum compounds. Clinical trials are currently in progress evaluating the dose intensity of paclitaxel, the effect of schedule of administration, and the relative efficacy and toxicity of paclitaxel plus carboplatin vs. paclitaxel plus cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Current status of chemotherapy for ovarian cancer.

Standard treatment for patients with advanced ovarian cancer has been cytoreductive surgery followed by combination chemotherapy. Until recently, platinum-based chemotherapy was considered optimal and patients were treated with regimens built around either cisplatin or carboplatin. Recently, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to be a highly active agent in refractory ovarian cancer patients. Subsequently, the Gynecologic Oncology Group performed a prospective randomized trial of paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide in suboptimal stage III and IV ovarian cancer patients. Based on higher response rates, longer time to progression, and marked improvement in median survival (37.5 months compared with 24.4 months), the Gynecologic Oncology Group currently considers paclitaxel plus cisplatin to be the new standard regimen for patients with advanced disease. More recently, paclitaxel plus carboplatin also has been evaluated in previously untreated patients. Using area under the curve dosing for carboplatin, it was demonstrated that this agent could be combined with paclitaxel (175 mg/m2 in a 3-hour infusion) with acceptable toxicity. All current Gynecologic Oncology Group protocols for untreated patients with ovarian cancer use a paclitaxel-based regimen. These clinical trials are evaluating the relative efficacy of carboplatin plus paclitaxel versus cisplatin plus paclitaxel as well as differences in dose and schedule and number of cycles of treatment. Investigational studies are continuing with high-dose chemotherapy that requires hematologic support as well as with intraperitoneal therapy (cisplatin or paclitaxel).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Carboplatin and paclitaxel in ovarian cancer.

A phase I trial of carboplatin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) therapy for untreated patients with advanced ovarian cancer has been completed, demonstrating that these drugs can be combined in full doses with acceptable toxicity. This combination has now gone forward to be evaluated in prospective randomized trials. The Gynecologic Oncology Group will be doing a randomized trial comparing therapy with cisplatin plus paclitaxel versus carboplatin plus paclitaxel in patients with optimal stage III ovarian cancer. Patients with limited-stage disease but with poor prognostic features will be randomly assigned to receive either three or six cycles of carboplatin plus paclitaxel. Carboplatin will be dosed using the Calvert formula at an area under the plasma concentration versus time curve of 7.5 and paclitaxel will be administered at a dose of 175 mg/m2 by 3-hour continuous infusion. Cycles are planned to be administered every 21 days without granulocyte-colony stimulating factor.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Paclitaxel by 24- or 1-hour infusion n combination with carboplatin in advanced non-small cell lung cancer: the Fox Chase Cancer Center experience.

A phase II trial of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin included 54 chemotherapy-naive patients with advanced non-small cell lung cancer. Eligibility mandated Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate hematologic, renal, and hepatic function. Paclitaxel 135 mg/m2 over 24 hours preceded carboplatin dosed to an area under the concentration-time curve of 7.5. Six planned courses were given every 3 weeks. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, and paclitaxel increased 40 mg/m2/cycle (maximum, 215 mg/m2) in patients with absolute neutrophil and platelet nadirs exceeding 500/microL and 50,000/microL, respectively. Grade 3 or 4 neutropenia, observed in 54% of patients during cycle 1, declined to 35% during cycle 2 and to 22% or less during cycles 3 through 6. Neuropathy, myalgias/arthralgias, and thrombocytopenia were mild but cumulative. In 53 evaluable patients, the objective response rate was 62%, with 9% complete remissions and a median response duration of 6 months (range, 1 to 19+ months). At median potential follow-up of 16 months, 9% of patients remain progression free (52+ to 80+ weeks). Median survival is 12.5 months; 1-year survival is 54%. Paclitaxel/carboplatin is highly active in advanced non-small cell lung cancer; granulocyte colony-stimulating factor abrogates neutropenia as the dose-limiting toxicity, but has no effect on the cumulative incidence of thrombocytopenia or treatment delays. One-hour paclitaxel infusion is minimally myelosuppressive, logistically easier, and less costly. A follow-up study combined paclitaxel (175 mg/m2) over 1 hour followed by carboplatin (area under the concentration-time curve, 7.5). In the absence of grade 4 myelosuppression, paclitaxel was increased 35 mg/m2/cycle (maximum, 280 mg/m2). Granulocyte colony-stimulating factor was implemented only after neutropenic fever or grade 4 neutropenia. Of 17 patients entered, 13 are evaluable for toxicity and seven for response. Four patients have sustained a partial response, two a minor response, and one stable disease. The incidence of grade 3 or 4 neutropenia, thrombocytopenia, and anemia in cycle 1 was 38%, 16%, and 0%, respectively, and 72%, 28%, and 28%, respectively, during cycle 2. Major nonhematologic toxicities include myalgias and arthralgias (54%) and fatigue and neuropathy (78%), the latter cumulative and progressive over successive cycles. Preliminary data suggest comparable activity for the 1- and 24 hour paclitaxel infusions in combination with carboplatin. The more severe neuropathy of the 1-hour paclitaxel/carboplatin combination may be related to the paclitaxel dosing schema (175 mg/m2 to as high as 280 mg/m2).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗