Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

BACKGROUND: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. METHODS: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. RESULTS: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. CONCLUSION: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

A phase I trial of carboxyamido-triazole and paclitaxel for relapsed solid tumors: potential efficacy of the combination and demonstration of pharmacokinetic interaction.

PURPOSE: Preclinical and clinical investigation of the combination of the antiangiogenesis/anti-invasion agent carboxyamido-triazole (CAI) administered with the cytotoxic agent paclitaxel (PAX). EXPERIMENTAL DESIGN: Colony-forming assays were used to test the activity of CAI plus PAX on A2780 human ovarian cancer. The sequence of CAI followed by PAX (CAI>Pax) was modeled in nude mice to test for potential additive toxicity. The Phase I clinical dose escalation schema tested p.o. administered CAI in PEG-400 (50-100 mg/m(2)) or micronized CAI (250 mg/m(2)) for 8 days followed by a 3-h infusion of PAX (110-250 mg/m(2)) every 21 days. Patients were assessed for toxicity, pharmacokinetics of CAI and PAX, and disease outcome. RESULTS: In preclinical studies, CAI>Pax was additive in A2780 human ovarian cancer cell lines when CAI (1 or 5 microM) preceded subtherapeutic doses of PAX. CAI did not reverse PAX resistance and collateral resistance to CAI was documented in PAX-resistant cells. CAI>PAX administration had no overt additive toxicity in nude mice. Thirty-nine patients were treated on a dose-escalation Phase I trial using daily oral CAI for 8 days followed by the PAX infusion. Pharmacokinetic analysis revealed that PAX caused an acute increase in circulating CAI concentrations in a dose-dependent fashion. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Three partial responses and two minor responses were observed. CONCLUSIONS: The sequential combination of CAI and PAX is well tolerated, and the activity observed suggests that further study of the combination is warranted.

Synchronous inflammatory breast cancer and advanced ovarian carcinoma: a case with prolonged disease-free survival.

Despite the known association of these malignancies, the incidence of a synchronous presentation of breast and ovarian cancer is low, and the current literature does not address an approach to this clinical problem directly. We report a greater than 2.5 year disease-free survival in a patient treated for synchronous stage IIIB inflammatory breast cancer and stage IIIC epithelial ovarian cancer. The prolonged disease-free survival in our case may provide some guidance in this unusual clinical situation.

Future directions with taxane therapy.

The potential biochemical and genetic mechanisms by which a cell might experience a decreased sensitivity to taxanes and other drugs of this class are discussed in the first part of this article. The use of taxanes in the current gynecologic-oncologic clinical setting is reviewed with special consideration given to the pharmacokinetics of taxane in relation to dose intensity and length of administration.

Dose intensive combination platinum and cyclophosphamide in the treatment of patients with advanced untreated epithelial ovarian cancer.

BACKGROUND: The authors combined cisplatin and carboplatin together with cyclophosphamide to maximize platinum dose intensity in patients with advanced epithelial ovarian cancer (AOC). METHODS: The authors treated 26 consecutive, newly diagnosed patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III/IV AOC with carboplatin, 600 mg/m2, on Day 1; cyclophosphamide, 250 mg/m2, on Day 1; and cisplatin, 100 mg/m2, on Day 8 every 4 weeks with or without pretreatment with amifostine (range, 740-1140 mg/m2). Platinum dose intensity was estimated using a 4:1 conversion for equipotent doses of cisplatin and carboplatin for expression as cisplatin dose equivalents (CDE). RESULTS: The mean administered CDE was 49.4 mg/m2/week, which was 79% of the planned dose. Hematologic toxicity was severe, with FIGO Grade 3-4 anemia in 81% of patients, Grade 3-4 neutropenia in 92% of patients, and Grade 4 thrombocytopenia in 96% of patients. Eleven patients (42%) were admitted to the hospital for febrile neutropenia and there was 1 toxic death. Sensory neuropathy > or = Grade 2 occurred in 10 patients (38%), ototoxicity > or = Grade 2 occurred in 18 patients (69%), and 6 patients (23%) required long term hearing aids. Elevations in serum creatinine > or = Grade 2 occurred in 7 patients (27%) and > or = Grade 2 hypomagnesemia was noted in 23 patients (88%). Other Grade 3 toxicities were nausea (42%), emesis (38%), fatigue (15%), mucositis (4%), and respiratory toxicities (4%). Twenty-two of 26 patients (85%) had a clinical response (19 with a complete response [CR] and 3 with a partial response). Pathologic CR was demonstrated in 10 of 26 patients (38%) and residual microscopic disease in 4 of 26 patients (15%) for a total pathologic response rate of 53%. The median progression free survival was 13.5 months and the median overall survival was 37.2 months at a median potential follow-up of 79.3 months. Three of 26 patients remained free of disease at 66, 71, and 103 months, respectively. CONCLUSIONS: Although dose intensive combination platinum treatment combined with cyclophosphamide in patients with AOC is active, it also is associated with substantial toxicity.

Pharmacokinetics of elemental platinum (ultrafiltrate and total) after a thirty minute intravenous infusion of ormaplatin.

Preclinical data suggest that ormaplatin (tetrachloro-(dl-trans)-1, 2-diamminocyclohexaneplatinum) has substantial activity in cisplatin-resistant tumor models and may be less nephrotoxic than cisplatin. Based on these data we initiated a phase I clinical trial in patients with refractory metastatic cancer. This report characterizes the pharmacokinetic profile of both the total plasma concentrations of elemental platinum and the unbound ultrafiltrate concentrations of elemental platinum, following a 30 min intravenous infusion of ormaplatin. Platinum concentrations were determined by AAS, and pharmacokinetic parameters for both the total plasma concentration and the ultrafiltrate concentration of elemental platinum were determined using both compartmental and noncompartmental methods. Twenty-eight patients (14 males and 14 females; median age, 58) received ormaplatin. There was a linear relationship between Cmax and dose (r2 = 0.945) and AUC and dose (r2 = 0.976). Ormaplatin is more accurately described by a two-compartment model than by a one-compartment model. The distribution half-life (t1/2 alpha) was 0.3 h and the terminal half-life (t1/2 beta) was 39.1 h. The volume of the central compartment (V) was 68.6 L and the volume of distribution at steady state (Vdss) was 183 L. Like total plasma platinum, unbound platinum is also best characterized by a two-compartment model. The elimination of free platinum is also biphasic with a distribution half-life (t1/2 alpha) of 0.3 h and a terminal half-life (t1/2 beta) of 19.3 h. The mean volume of the central compartment (V) was 200.5 L, and the mean volume of distribution at steady state (Vdss) was 560.5 L. Clinical development of ormaplatin has been terminated due to increased frequency of neurological complications noted over other platinum agents; however, the pharmacokinetics are, in general, similar to those of other clinically used platinum compounds.

Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations.

PURPOSE: Cytostatic agents targeted against angiogenesis and tumor cell invasive potential form a new class of investigational drugs. Orally administered carboxyamidotriazole (CAI) (NSC609974) is both antiangiogenic and antimetastatic. An encapsulated micronized powder formulation has been developed to optimize CAI administration. A phase I dose escalation trial with pharmacokinetic analysis has been performed. PATIENTS AND METHODS: Twenty-one patients with refractory solid tumors and good end organ function and performance status were enrolled onto the study. Patients received a test dose followed 1 week later by daily administration of CAI in the encapsulated micronized formulation at doses of 100 to 350 mg/m2. Patients remained on CAI until disease progression or dose-limiting toxicity. Plasma samples were taken to characterize the pharmacokinetic parameters of this formulation of CAI. RESULTS: All patients were assessable for toxicity and 18 were assessable for pharmacokinetics and response analysis. Grade 1 and 2 gastrointestinal side effects were observed in up to 50% of patients. Dose-limiting toxicity was observed in both patients treated at 350 mg/m2/d, consisting of reversible grade 2 to 3 cerebellar ataxia (n = 1) and confusion (n = 1). One minor response (MR) was observed in a patient with renal cell carcinoma and another nine patients had disease stabilization (MR + SD = 47%). Pharmacokinetic analysis demonstrated reduced bioavailability (58% reduction) compared with the PEG-400 liquid formulation previously reported. CONCLUSION: The better toxicity profile of encapsulated micronized CAI with similar frequency of disease stabilization and ease of administration compared with the liquid or gelatin capsule, suggests that the micronized formulation is a preferable formulation for subsequent studies. A dose of 300 mg/m2/d is proposed for phase II investigations.

A phase I/II study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy of poor-prognosis advanced-stage epithelial ovarian cancer.

Epithelial ovarian cancer patients with bulky residual tumor have a poor response to therapy and limited survival. We investigated the addition of dose-intense paclitaxel to cisplatin and cyclophosphamide for patients with FIGO III/IV epithelial ovarian cancer. Paclitaxel dose was intensified from 135 to 250 mg/m2 and administered in combination with cisplatin at > or = 75 mg/m2 and cyclophosphamide at 750 mg/m2. Thirty-one of 36 patients (86%) and 25 (70%) had > or = 2 and > or = 3 cm residual disease after surgery, respectively. One-third had stage IV disease, and 80% had grade 3 tumors. The maximally tolerated doses (MTD) were paclitaxel at 250 mg/m2, cisplatin at 75 mg/m2, and cyclophosphamide at 750 mg/m2 on a 21-day cycle with G-CSF, 10 micrograms/kg/day. Administered dose intensity at the MTD was > or = 86%. Reversible grade 3 peripheral neuropathy occurred in 28% of patients and fever during neutropenia in 2/352 cycles (0.5%). The pathologic response rate is 36% with an additional 25% having minimal microscopic disease. Median progression-free and overall survivals for patients receiving paclitaxel at 250 mg/m2 at a median potential follow-up of 22 months have not been reached for the cohort nor for the > or = 3-cm subgroup. This regimen should be evaluated in a prospective, randomized clinical trial.

Borderline ovarian tumors.

Borderline tumor of the ovary (BOT) is an epithelial tumor with a low rate of growth and a low potential to invade or metastasize. This tumor often is associated with a significantly better prognosis than epithelial ovarian cancer. Most tumors are either serous or mucinous in histology and present as early stage lesions. However, stage III lesions with peritoneal implants are not uncommon. Patients with early stage lesions have an excellent prognosis. Patients with higher stage lesions have a worse prognosis. Long-term follow-up of patients with BOT is required since the tumor can recur up to 20 years after the initial diagnosis. Recently, investigators have begun to identify subsets of patients with a worse prognosis, such as patients with aneuploid tumors. Treatment for early stage lesions is surgical and conservative surgery can be accomplished successfully in younger patients who desire to maintain fertility. Treatment for later stage lesions has been approached in a variety of ways. All approaches initially begin with maximal cytoreductive surgery. Studies suggest that early stage disease should be managed with surgery alone. Conflicting results on the usefulness of adjuvant therapy for patients with later stage disease have been obtained. At this time, the usefulness of adjuvant therapy for advanced disease remains undetermined. Further understanding of the basis of the disease and analysis of specific higher risk subsets might identify patients in whom adjuvant therapy could be tested in the setting of controlled clinical trials.

A phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of the ovary.

We have conducted a disease specific phase I study of paclitaxel and cyclophosphamide in recurrent adenocarcinoma of the ovary. This was done to take advantage of the cellular and molecular synergism between paclitaxel and DNA-damaging agents, with the hope of avoiding paclitaxel-cisplatin toxicities. Paclitaxel was given as a 24-hr CIVI, after which cyclophosphamide was given as a 60-min infusion. Cycles of therapy were repeated every 3 weeks; and granulocyte colony-simulating factor (G-CSF) was given in a "flexible" dosing fashion. Starting doses were 170 mg/m2 paclitaxel and 750 mg/m2 cyclophosphamide. Dose-limiting toxicity (DLT) was seen at the doses of 250 mg/m2 paclitaxel and 1250 mg/m2 cyclophosphamide. DLT was cumulative thrombocytopenia. There were six nonhematologic grade 3 or 4 toxicities experienced in the study. Eleven of 20 evaluable patients (55%) have achieved an objective response (4 CCR;7 PR). Three of four CCRs were confirmed by negative findings at peritoneoscopy. The median number of prior therapies was 2 (range 1-4) and 17 individuals had platinum-refractory disease. We conclude that paclitaxel followed by cyclophosphamide is an active combination in recurrent ovarian cancer and that further study is needed to determine if this combination is truly better than paclitaxel alone.

Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers.

Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-excitable calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. Inhibition of calcium influx and calcium-dependent events is a potential common mechanism underlying these effects of CAI. The cytostatic and antiangiogenic properties of CAI led to its development for clinical investigation. In a Phase I clinical trial open to patients with refractory solid tumors, 49 patients received p.o. administered CAI daily or every other day. Two oral formulations, PEG-400 CAI solution and a gelatin capsule containing CAI in PEG-400, were tested. All administered dosages of CAI yielded plasma concentration at or above the range demonstrated to be effective in inhibiting signaling and cancer progression in vitro and in preclinical models (1 microgram/ml, 2.3 microM). Toxicity of p.o. administered CAI most commonly consisted of dose-related grade 1-2 nausea, vomiting, and occasional anorexia. CAI administration at bedtime ameliorated gastrointestinal complaints in many patients; others required addition of simple antiemetic regimens, usually consisting of metoclopropamide or prochlorperazine. Gastrointestinal complaints were the cause for compliance-limiting toxicity at 175 mg/m2/day of the liquid formulation and 125 mg/m2/day of the gelatin capsule formation. Reversible and rare sensory axonal neuropathy (grade 3, 1 patient) and neutropenia (grade 4, 1 patient) were dose-limiting toxicities observed at the 330 mg/m2 every-other-day liquid CAI dose level. No evidence of cumulative end organ damage or central nervous system injury was observed. Disease stabilization and improvement in performance status was observed. Disease stabilization and improvement in performance status was observed in 49% of evaluable patients who had disease progression before CAI. Disease stabilization and associated improvement in performance status was seen in patients with renal cell carcinoma (7 months), pancreaticobiliary carcinomas (3, 5, and 5 months), melanoma (7 months), ovarian cancer (7 months), and non-small cell lung cancer (3 months). The recommended Phase II doses from this trial are 150 mg/m2/day in the liquid formation and 100 mg/m2/day in the gelatin capsule formation.

Paclitaxel dose intensity.

Paclitaxel is effective in the treatment of cancer of the ovary and cancer of the breast, as well as other malignancies. We have analyzed available phase II data in these two diseases, to assess the possibility that paclitaxel dose intensity may be important in the induction of disease response. When analyzed by the methods developed by Hrynuik and Levin, available data suggest that the relationship between objective disease response and paclitaxel dose intensity in recurrent cancer of the ovary is strongly statistically significant with a two-sided p value of 0.022. Available data suggest that the relationship in breast cancer is even stronger, with a two-sided p value of 0.004. In both diseases, optimal results have been observed at the dose schedule of 250 mg/m2/21 days, given as a 24 hour IV infusion. We have also performed an analysis comparing the only two prospective randomized studies that examined the potential role of dose intensity for this drug in cancer of the ovary. At 135 mg/m2/21 days, the objective response rate was 13.2%; and at 250 mg/m2/21 days, the objective response rate was 35.9%. The response rate seen at the intermediate dose of 175 were intermediate to 135 and 250; and linear regression analysis shows a correlation coefficient for these data of 0.946. Since flexible cytokine support may be essential in maintaining paclitaxel dose intensity, we have also discussed this approach as well as the paclitaxel dosing strategy that is associated with optimal clinical results in recurrent cancer of the ovary.

Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer: molecular rationale and early clinical results.

The three most active types of agents in the treatment of cancer of the ovary are platinum compounds (cisplatin or carboplatin), bifunctional alkylating agents (cyclophosphamide, melphalan, etc), and the recently developed natural product paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). In an effort to improve long-term disease-free survival in patients with advanced disease, we have developed a three-drug regimen consisting of cisplatin, paclitaxel, and cyclophosphamide. Granulocyte-colony stimulating factor is given as bone marrow support using a flexible dosing approach. The molecular basis for this approach is founded in the positive molecular interactions between cisplatin and bifunctional alkylating agents and between paclitaxel and DNA-damaging agents. Cisplatin and cyclophosphamide damage DNA by two very different mechanisms; the respective importance of DNA strand "kinking" versus DNA strand "cross-linking" may explain the positive cell kill interaction between these two drugs. Paclitaxel appears to markedly slow the repair of DNA lesions caused by DNA-damaging agents, which may include radiation-induced lesions, cisplatin adducts, and cyclophosphamide cross-links. Clinical data to date from several different groups strongly suggest that these molecular interactions translate into positive clinical benefit in human ovarian cancer. Preliminary data from our clinical trial show that these three agents are well tolerated in the doses administered and that this combination shows exceptional promise as a possible therapeutic advance in this disease.

Cutaneous manifestations of Taxol therapy.

Taxol is a novel chemotherapeutic agent that has produced substantial responses in early clinical studies [1]. Taxol has excellent activity in a number of malignancies based on recently completed clinical trials, including a 30% response rate in platinum-refractory ovarian cancer patients [2-5]. We are currently conducting trials of dose-intense taxol with granulocyte colony stimulating factor (G-CSF) support in relapsed or refractory ovarian cancer patients. Such dose intensification produces a major response rate in 50% of patients with this disease [6]. Taxol was supplied in 5 ml ampules (6 mg/ml) in polyethoxylated castor oil (Cremophor EL) 50% and dehydrated alcohol and the dose was diluted in either 0.9% sodium chloride or 5% dextrose at concentrations of 0.6 to 1.2 mg/ml. We have noted 3 patients with previously unreported cutaneous manifestations which we believe are taxol related and also report our overall complication rate with the administration of taxol by peripheral intravenous lines.

Flexible granulocyte colony-stimulating factor dosing in ovarian cancer patients who receive dose-intense taxol therapy.

As has been reported with other chemotherapeutic agents, evidence is emerging to suggest that increased taxol dose intensity is associated with improved therapeutic efficacy. Granulocyte colony-stimulating factor (G-CSF) effectively protects the bone marrow from taxol-induced neutropenia and allows for higher taxol dose administration. This report addresses the optimal use of G-CSF as a supportive agent for dose-intense taxol therapy. Forty-seven patients were evaluated. Each ovarian cancer patient received taxol with G-CSF support, with starting doses of 250 mg/m2 per 21 days and 10 micrograms/kg/d, respectively. Five patients were treated with the same dose of G-CSF for multiple cycles. Forty-two patients were given "flexible" G-CSF dosing. Instead of reducing taxol dose after a cycle of therapy complicated by febrile neutropenia (F+N+), the G-CSF dose was increased. Only after a second episode of F+N+ was the taxol dose reduced. The initial 5 patients who developed F+N+ after taxol (250 mg/m2) and G-CSF (10 micrograms/kg/d) were retreated at the same doses of both drugs; subsequently, 4 of 5 patients had another episode of F+N+. With flexible G-CSF dosing, taxol dose intensity could be maintained at the target level in 34 of 42 patients (81% of the cohort). Sixteen of these patients (38% of the cohort) would have required taxol dose reductions for F+N+ if flexible G-CSF dosing had not been used. By increasing the G-CSF dose when indicated, patients at high risk for recurrence of F+N+, because they had already experienced one episode, appeared to have a lower risk of developing a recurrent episode. These data suggest that flexible G-CSF dosing may have merit and may allow the administration of more dose-intense taxol. A prospective, randomized, controlled clinical trial of flexible G-CSF dosing versus fixed-dose G-CSF appears warranted.

Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer.

BACKGROUND: Paclitaxel (Taxol), a diterpene plant product that promotes tubulin polymerization, has documented activity against a number of solid tumors, including ovarian cancer and breast cancer. PURPOSE: Our purpose was to conduct a phase II clinical trial investigating the response of patients with advanced recurrent ovarian carcinoma to high-dose paclitaxel combined with granulocyte colony-stimulating factor (G-CSF). METHODS: A prospective phase II clinical trial of patients with advanced-stage, recurrent ovarian cancer was undertaken. Patients received 250 mg/m2 paclitaxel every 21 days; cycles were given on a rigid schedule; delays were permitted only for extreme circumstances. G-CSF at a dose of 10 micrograms/kg per day was given to ameliorate myelo-suppression. If a patient showed fever and neutropenia, G-CSF dosage was increased to 20 micrograms/kg per day so that paclitaxel dose intensity could be maintained. Patients were assessed for response every two cycles, and those with complete radiographic resolution of disease underwent peritoneoscopy. RESULTS: Forty-four patients were assessable for response. Twenty-one had a reduction in tumor volume greater than 50%, yielding an objective response rate of 48% (21 of 44 patients; 95% confidence interval, 32%-63%). Six (14%) of the 44 patients had complete radiographic resolution of disease; two of the six also had negative biopsy specimens and washings at peritoneoscopy. Age, number of prior regimens, and clinical platinum resistance did not influence response rate or ability to maintain dose intensity. Dose intensity was maintained at the targeted level for up to 14 consecutive cycles of therapy. CONCLUSIONS: We observed a 48% response rate with dose-intense paclitaxel for patients with advanced-stage, platinum-resistant, recurrent ovarian cancer. The response rate is higher than previously reported for paclitaxel at a lower dose in similar cohorts of patients treated without G-CSF. Comparison of phase II studies of paclitaxel suggests a dose-response relationship. Therapy with dose-intense paclitaxel and G-CSF should be considered for patients with advanced, platinum-refractory ovarian cancer.

Incapacitating autonomic neuropathy precipitated by taxol.

Taxol is one of the more significant advances in cancer chemotherapy in the last 10-15 years with a 30-50% response rate in both breast and ovarian cancers. The toxicity profile of taxol is still evolving as changes in the dosing and scheduling of the drug are instituted. We herein present the first evidence of taxol-induced quantifiable, objective autonomic neuropathy in two patients, one with and one without diabetes. The patients did not have symptoms of autonomic dysfunction prior to taxol therapy. Both developed severe orthostatic hypotension following completion of 24-hr infusional taxol at 170-250 mg/m2 and both improved markedly on fludrocortisone. Other possible etiologies of orthostatic hypotension were ruled out. Noninvasive autonomic tests performed on the first patient included tilt test, Valsalva ratio, heart rate variation with respiration, and change in diastolic blood pressure with hand grip; all were markedly abnormal. Noninvasive autonomic tests should be considered as part of the evaluation of patients on taxol who develop generalized weakness and orthostasis.

Taxol dose intensification and its clinical implications.

Taxol is the most exciting new anticancer agent developed in the past two decades. Of great interest is its level of activity in ovarian cancer, as well as substantial activity in breast cancer, nonsmall-cell lung cancer, melanoma, and other malignancies. Recent studies suggest that when taxol is administered in a fashion to increase milligram dosage per unit time (mg/m2/week), the response rate in patients with ovarian cancer is markedly increased. This article reviews studies that suggest taxol dose intensity is important in the treatment of patients with ovarian cancer.

The absence of cumulative bone marrow toxicity in patients with recurrent adenocarcinoma of the ovary receiving dose-intense taxol and granulocyte colony stimulating factor.

Forty-eight patients with recurrent adenocarcinoma of the ovary were treated with taxol and granulocyte colony stimulating factor (G-CSF), with a target taxol dose intensity of 250 mg/m2 every 3 weeks (83.3 mg/m2/week). We have assessed the patterns of granulocyte and platelet toxicity seen in this cohort. Individual patients received up to nine cycles of therapy. Criteria for entry onto protocol included good end organ function, good performance status and the absence of substantial co-morbid disease. Mean taxol dose intensity was 79.0 mg/m2/week for the whole cohort and did not diminish with increased duration of therapy. Granulocytopenia and thrombocytopenia were well controlled, with the average duration of platelet and neutropenic nadirs being less than 1 day for all cycles. There was no evidence of cumulative toxicity for granulocytes nor platelets, for up to eight cycles of therapy. We conclude that taxol, when given with G-CSF support, can be safely administered in a dose-intense fashion for multiple cycles of therapy, without cumulative bone marrow toxicity.