Corticosteroid Premedication Research Articles

Efficacy of Pegfilgrastim and Darbepoetin Alfa As Hematopoietic Support for Dose-Dense Every-2-Week Adjuvant Breast Cancer Chemotherapy

Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established. Women with stage I to III breast cancer received dose-dense AC --> paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 microg SQ every 2 weeks for hemoglobin < or = 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion. Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC --> paclitaxel in Cancer and Leukemia Group B 9741. Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC --> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.

Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer

ABI-007, the first biologically interactive albumin-bound paclitaxel in a nanameter particle, free of solvents, was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with standard paclitaxel. Patients were randomly assigned to 3-week cycles of either ABI-007 260 mg/m(2) intravenously without premedication (n = 229) or standard paclitaxel 175 mg/m(2) intravenously with premedication (n = 225). ABI-007 demonstrated significantly higher response rates compared with standard paclitaxel (33% v 19%, respectively; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 weeks, respectively; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% v 22%, respectively; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm (10% v 2%, respectively; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. ABI-007 demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.

Weekly docetaxel, estramustine phosphate and low-dose dexamethasone in Japanese men with hormone refractory prostate cancer

4789 Background: Recently, docetaxel have shown promising clinical results in patients with hormone-refractory prostate cancer (HRPC). However, their optimal treatment schedule has not been established. The current study determined the efficacy and toxicity of weekly docetaxel, estramustine phosphate (EMP), and low-dose dexamethasone in men with HRPC. Methods: Eligible patients had castrate testosterone levels and evidence of progressive HRPC after hormone therapy. Prior chemotherapy was allowed; including prior EMP. Patients with progressive HRPC received 25mg/m docetaxel weekly for 3 weeks, followed by a 1-week treatment rest. Patients were treated with EMP 560 mg/day and dexamethasone 1 mg PO daily. All patients did not receive commonly corticosteroid premedication. Results: Data on the first 22 patients are available. The median age was 71 (54–83), median PS 0 (0–1), and median PSA at study entry 205 ng/ml (16–1400). Bone metastases were present in 19/22 pts (86%); Patients received an average of 6.0 cycles of therapy. 16/22 (72.7%) had 50% PSA reduction; 11/22 (50%) had 75% PSA reduction, and 6 patients (27.2%) had normalization of PSA. Maximum response occurred after 3.5 cycles. Grade 3–4 toxicities were uncommon. Only 3 patients (11.7%) experienced Grade 3 anemia. No patients had leucopenia and neutropenic fever. Other toxicities were all < Grade 2. Conclusions: A combination of low dose of weekly docetaxel, daily estramustine plus low dose of oral dexamethasone has demonstrated promising efficacy and tolerability in HRPC patients with a history of extensive prior treatment. No significant financial relationships to disclose.

The role of growth factor support following neutropenic events in early stage breast cancer (BC) patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC): A sub-analysis of BCIRG 001

677 Background: TAC significantly improves disease-free and overall survival over FAC (HR 0.70, 0.68, respectively) and is emerging as one of the most active adjuvant treatments in patients (pts) with node positive early stage (BC) (Martin, SABCS 2003 #43). TAC is generally well tolerated but is associated with a higher incidence of febrile neutropenia (FN) vs FAC. ASCO clinical practice guidelines recommend secondary prophylaxis with G-CSF after FN in a prior cycle to maintain dose intensity. Methods: Pts with node-positive BC were randomized to TAC (75/50/500 mg/m2 q3wk x 6) or FAC (500/50/500 mg/m2 q3wk x 6). Corticosteroid premedication and prophylactic ciprofloxacin were given with TAC, but not with FAC. In case of FN (≥ gr 2 fever with gr 4 neutropenia), pts were treated with G-CSF for all subsequent cycles. This retrospective sub-group analysis compares the incidence of FN for cycles treated without and with G-CSF. Results: 1491 patients were accrued with 1480 evaluable for safety (TAC 744, FAC 736). A similar number of cycles were delivered in both arms (TAC 4010; FAC 4007). FN: TAC 183 pts (24.7% pts, 5.4% cycles), FAC 18 pts (2.5% pts, 0.5% cycles) with at least half the FN occurring in the first cycle (TAC: 97/183 pts; FAC 9/18 pts). G-CSF was administered to 250 TAC pts and 93 FAC pts. Among these, G-CSF was used as secondary prophylaxis for 87% (TAC) and 44% (FAC) of pts. The rate of FN (per cycle) without vs with G-CSF (+G) among all pts was: TAC 187/3114 (6.0%) vs TAC+G 28/896 (3.1%); FAC 19/3704 (0.5%) vs FAC+G 1/303 (0.3%). There were no septic deaths during treatment with either TAC or FAC, regardless of the use of GCSF. Conclusions: Among pts treated with TAC, the use of G-CSF decreased the incidence of neutropenic complications, although it remained higher than for pts treated with FAC. For pts experiencing a neutropenic event with TAC, secondary prophylaxis with G-CSF is appropriate. The impact of G-CSF on other clinical safety parameters will also be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis

The role of growth factor support following neutropenic events in early stage breast cancer (BC) patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC): A sub-analysis of BCIRG 001

677 Background: TAC significantly improves disease-free and overall survival over FAC (HR 0.70, 0.68, respectively) and is emerging as one of the most active adjuvant treatments in patients (pts) with node positive early stage (BC) (Martin, SABCS 2003 #43). TAC is generally well tolerated but is associated with a higher incidence of febrile neutropenia (FN) vs FAC. ASCO clinical practice guidelines recommend secondary prophylaxis with G-CSF after FN in a prior cycle to maintain dose intensity. Methods: Pts with node-positive BC were randomized to TAC (75/50/500 mg/m2 q3wk x 6) or FAC (500/50/500 mg/m2 q3wk x 6). Corticosteroid premedication and prophylactic ciprofloxacin were given with TAC, but not with FAC. In case of FN (≥ gr 2 fever with gr 4 neutropenia), pts were treated with G-CSF for all subsequent cycles. This retrospective sub-group analysis compares the incidence of FN for cycles treated without and with G-CSF. Results: 1491 patients were accrued with 1480 evaluable for safety (TAC 744, FAC 736...

Factors Predicting Docetaxel-Related Toxicity: Experience at a Single Institution

We studied factors predicting docetaxel-related toxicity in 113 unselected patients with metastatic cancer treated under routine daily practice. Docetaxel was administered in either a weekly, bi-weekly or tri-weekly schedule. All patients received prophylactic dexamethasone. Twenty-six patients were aged 70 or more, and 28 (24.8%) had an ECOG performance status (PS) score ≥2. Primary tumors were mainly in breast, lung, and stomach (58, 25, and 14 patients, respectively). Most patients had metastases at two or more sites and were heavily pretreated. NCI-CTC graded toxicities were mild. Grade 3/4 leucopenia and neutropenia occurred in 19.4% and 10.6% of patients, respectively, with febrile neutropenia in 2 patients. Severe nonhematologic toxicities were rare, except for asthenia (8 patients). Complete alopecia occurred in 26.6% of patients. A proportional-odds regression analysis demonstrated that the tri-weekly schedule and older age represented independent risk factors for all-grade leucopenia, whereas a poor PS for anemia. Primary tumor in breast, tri-weekly schedule, an abbreviated and low dose of corticosteroids premedication, and high duration and cumulative dose of docetaxel were factors predicting asthenia. Risk factors for alopecia and vomiting were tri-weekly schedule and high docetaxel cumulative dose, respectively. In conclusion, in daily clinical practice docetaxel toxicity may be correlated with factors related to patient, disease, and treatment characteristics. Taking into account these variables could be a first step toward individualizing treatment.

Weekly Low-Dose Docetaxel in Advanced Hormone-Resistant Prostate Cancer Patients Previously Exposed to Chemotherapy

Objective: The aim of this study was to evaluate the activity and tolerability of docetaxel in patients with hormone-resistant prostate cancer previously exposed to chemotherapy. Methods: We enrolled 27 patients with hormone-resistant prostatic cancer that had progressed during first-line chemotherapy. The primary end-point was palliative response defined as a 2-point reduction in the 6-point present pain intensity scale, and an improvement in Karnofsky performance status of one 10-point category. The treatment consisted of weekly docetaxel 25 mg/m² body surface area administered by means of a 1-hour intravenous infusion with corticosteroid premedication. Results: The primary criterion of palliative response was met in 13 patients (48%) after eight treatment cycles; its median duration was 6 months (range 1–8). Mean global quality of life improved in 8 and 10 patients after respectively four and eight treatment cycles. After a median follow-up of 8 months, 21 patients had died: the median survival was 9+ months (range 2–18). Weekly docetaxel was very well tolerated: grade 3 neutropenia occurred in 1 patient and grade 3 anemia in 2. Conclusions: Weekly low-dose docetaxel is an effective and well-tolerated treatment for patients with hormone-resistant prostate cancer previously exposed to chemotherapy.

Weekly low-dose docetaxel in advanced non-small cell lung cancer previously treated with two chemotherapy regimens

Background: The role of salvage chemotherapy in advanced non-small cell lung cancer (NSCLC) is still controversial, but the recent development of a number of active antineoplastic agents has created new possibilities for disease management. The aim of this study was to evaluate the activity and safety of weekly docetaxel treatment in patients with advanced NSCLC previously treated with two chemotherapy regimens. Patients and Methods: The study involved 26 patients with histologically documented stage IIIB, IV or recurrent metastatic NSCLC previously treated with two non-taxane based-chemotherapy regimens. They all received docetaxel 25 mg/m 2/week administered as a 1-h infusion in an outpatient setting with corticosteroid premedication. Results: Fourteen of the 26 patients (54%) had distant metastases and 12 (46%) chest-localised disease. Six patients (23%; confidence interval: 9.8–44.1%) showed a partial response, 8 (31%) stable disease, and 12 (46%) progressive disease. The median time to progression was 4 months (range 2–8), and the median survival was 7+ months (range 3–13+). There were no statistically significant differences between the global quality of life scores recorded at baseline and those recorded after subsequent cycles. The treatment was very well tolerated. Conclusion: The results of this study suggest that weekly low-dose docetaxel is effective, well tolerated and maintains a relatively good quality of life in patients with advanced NSCLC previously exposed to two chemotherapy regimens.

Radiation Recall Dermatitis in a Patient Treated with Dacarbazine

Radiation recall describes an inflammatory reaction at a previously irradiated site associated with the use of chemotherapeutic agents. Dacarbazine, a tetrazine cytotoxic drug, has not been noted to cause this phenomenon. We report the case history of a 44-year-old female patient who developed a recall dermatitis due to dacarbazine in a site previously irradiated for the treatment of malignant melanoma. The skin erythema responded quickly to oral corticosteroid treatment. Further cycles of dacarbazine were facilitated with oral corticosteroid premedication. We conclude that dacarbazine should be considered as a potential cause of radiation recall dermatitis and that this can be managed and prevented with oral corticosteroids.

Phase I dose-finding and pharmacokinetic study of docetaxel and vinorelbine as first-line chemotherapy for metastatic breast cancer

Anthracycline-containing regimens are widely used in advanced breast cancer. However, there is a need for new, non-anthracycline regimens that are active in patients for whom anthracyclines are contraindicated. The aim of this study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs) and recommended doses of docetaxel and vinorelbine as first-line chemotherapy in patients with metastatic breast cancer. The pharmacokinetics of both drugs was also evaluated. Thirty-four women with first-line metastatic breast cancer were treated with docetaxel, 60-100 mg/m2 (day 1), and vinorelbine, 20-22.5 mg/m2 (days 1 and 5), repeated every three weeks and administered on an outpatient basis. Two MTDs were determined: MTD1 was defined at the dose level using docetaxel 75 mg/m2, and vinorelbine 22.5 mg/m2 DLT being a grade 3 stomatitis that was more related to the dose of vinorelbine than that of docetaxel. Therefore, the study continued with a fixed dose of vinorelbine, 20 mg/m2, and docetaxel 85-100 mg/m2. MTD2 was defined at the dose level combining docetaxel, 100 mg/m2, and vinorelbine, 20 mg/m2; DLTs were grade 3 stomatitis and severe asthenia. Fluid retention was observed in 41% of patients but was never severe or a reason for patient discontinuation. In comparison with historical experience, Daflon 500 did not seem to increase the efficacy of the three-day corticosteroid premedication by further reducing the incidence or severity of fluid retention. No significant neurotoxicity was observed and no patient discontinued the study due to this site effect. Activity was observed at all dose levels and at all metastatic sites, with an overall response rate of 71% (95% CI: 52.0%-85.8%). The median time to progression was 31.4 weeks (95% CI: 12-48 weeks) and median survival was 15.6 months (95% CI: 2.6-26.6 months). The pharmacokinetics of docetaxel and vinorelbine were not modified between day 1 and day 3 when the two drugs were combined with the day 1 administration schedule used in this study. The recommended doses for phase II studies are docetaxel, 75 mg/m2 (day 1), plus vinorelbine, 20 mg/m2 (days 1 and 5), repeated every three weeks. At these doses, the combination was found to be active and well tolerated.

A phase II trial of docetaxel in platinum pre-treated patients with advanced epithelial ovarian cancer: A Japanese Cooperative Study

BackgroundThis phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in Japanese patients with advanced ovarian cancer. Patients and methodsDocetaxel was administered at a dose of 70 mg/m2 intravenously to patients with platinum pretreated advanced ovarian cancer. Treatment was repeated every three weeks. No routine corticosteroid premedication was given. ResultsNinety patients with advanced ovarian cancer were entered and sixty were assessable for response. The overall response rate was 28% in the assessable patients (95% confidence interval (95% CI): 17.5%–41.4%). CA125 responses were seen in 8 (24%) of 34 assessable patients for CA125 criteria. The 36 platinum-refractory patients had a response rate of 25% compared with 33% in the platinum-sensitive patients. The predominant toxicity was neutropenia, with 86% of the patients experiencing grade 3 or 4. Hypersensitivity reactions occurred in 37% of the patients and were not life threatening. Edema was mild and infrequent. ConclusionDocetaxel at 70 mg/m2 demonstrated effectiveness as a treatment of both platinum-sensitive and platinum-refractory ovarian cancer patients, with a low incidence of severe hypersensitivity reactions and edema.

Phase II study of docetaxel in the treatment of patients with advanced non-small cell lung cancer in routine daily practice

The purpose of this study was to evaluate the efficacy and safety of docetaxel as first- and second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) under routine clinical conditions. Two hundred and three patients with advanced NSCLC received docetaxel 100 mg/m 2 (1-h intravenous infusion) every 3 weeks, with oral corticosteroid pre-medication, of whom 173 were eligible. Median age was 60 (29–78) years and median Karnofsky performance status was 80% (60–100). A total of 77% of patients had metastatic disease, 33% had bone metastases and 18% had liver metastases. The treatment was second-line or more for 72 patients (35%). Overall response rates in the eligible population were 19.7% [95% CI, 12.5–23.0] for both treatments, 22.6% for first-line treatment and 13.8% for second-line treatment. Median survival was 8.3 months and 1-year survival was 35% for the overall population (8.7 months and 38%, respectively, for patients receiving first-line treatment and 7.2 months and 27%, respectively, for patients receiving second-line treatment). Neutropenia, grade 3 and 4, occurred in 57% of the cycles and 5% of patients experienced febrile neutropenia. Alopecia (62% of patients), neuro-sensory symptoms (32%), asthenia (28%), diarrhea (22%), nausea (22%) and nail disorders (20%) were the most common non-hematological adverse effects. A total of 33% of patients suffered fluid retention, despite the use of corticosteroid pre-medication, but this was only severe in 1.5% of patients. It was possible to confirm the efficacy of docetaxel as a single agent for first- and second-line chemotherapy in a large patient population treated in a community setting.

Docetaxel in the community setting: An analysis of 377 breast cancer patients treated with docetaxel (Taxotere®) in the UK

Given as first- or second-line chemotherapy docetaxel appears to have great potential in advanced breast cancer. Three hundred and seventy-seven locally advanced or metastatic breast cancer patients received docetaxel (Taxotere) as part of a named patient programme under the care of 108 oncologists from 61 cancer units across the UK. The recommended starting dose was 100 mg/m2, but patients at higher risk of toxicity started at 75 mg/m2. All patients received corticosteroid premedication. The modal number of prior chemotherapy regimens was 2 (range 1-7). 342 patients (91%) had at least one prior anthracycline-based regimen. Response was graded according to the managing clinician's best judgement without formal criteria. The overall response rate (ORR) was 46% among the 331 evaluable patients. 46% among the 299 patients who were anthracycline resistant and 35% among the 82 patients who were anthracycline refractory (progressive disease being the best response obtained to the most recent anthracycline containing regimen). One hundred and ninety-three patients started at the full dose of 100 mg/m2 with an ORR of 55% and 129 started at 75 mg m2 with an ORR of 33%. In October 1997, some two years after the programme had started, 26 of 377 patients were still alive, although no complete remissions have lasted to this date. Kaplan-Meier survival analysis yielded a median survival of 194 days (95% CI: 178-218 days). Haematological parameters were checked before each course of docetaxel and additionally as clinically indicated. The safety data confirmed that docetaxel has a manageable, predictable side effect profile; 29 of 377 (7.7%) patients were hospitalised as a result of neutropenic sepsis. The results of this named patient programme over a two year timespan confirm that docetaxel is an effective chemotherapy option in patients with locally advanced and/or metastatic breast cancer, including an 'anthracycline refractory' population.

Efficacy and safety of docetaxel in clinical trials.

The efficacy and safety of docetaxel in clinical trials in patients with a variety of malignancies are reviewed. The overall response rate for docetaxel as a first-line treatment for metastatic breast cancer is 59%. Docetaxel in combination with doxorubicin or vinorelbine has proved particularly effective in the first-line treatment of metastatic breast cancer. Docetaxel is also one of the most active single agents in the treatment of non-small-cell lung cancer (NSCLC), producing an overall response rate of 27% when used as a first-line agent. Docetaxel plus cisplatin was more effective against NSCLC than either drug used alone, yielding response rates of 33-48%. Docetaxel has shown activity against a variety of other tumors, including ovarian cancer (response rate in second-line therapy, 34%), head-and-neck cancer (response rate in first-line therapy, 35%), and soft-tissue sarcoma (response rate in first-line therapy, 32%). The main toxic effect is grade 3-4 neutropenia, which occurs in 57% of treatment cycles but is brief and manageable. The dosage of docetaxel should be reduced from 100 mg/m2 to 75 mg/m2 if patients have neutropenia lasting more than one week, febrile neutropenia, or impaired liver function. Other adverse effects include severe fluid retention and asthenia. Some adverse effects can be avoided by administering corticosteroid premedication. Docetaxel has shown efficacy against a wide range of cancers in clinical trials and has a manageable adverse-effect profile.

A multicentre phase II study of the efficacy and safety of docetaxel as first-line treatment of advanced breast cancer: Report of the Clinical Screening Group of the EORTC

Two previous phase II trials of docetaxels as first line chemotherapy of advanced breast cancer have been conducted by the Clinical Screening Group of the EORTC. In these 2 studies, docetaxel 100 mg/m2 and 75 mg/m2 were administered without routine premedication and produced overall response rates of 68% and 52% respectively. Fluid retention was the most problematic adverse event in these 2 studies in which premedication was not routinely administered. This study investigated the efficacy and safety profile of docetaxel with a 1-day prophylactic premedication. Docetaxel 100 mg/m2 was administered intravenously over 1 hour, every 3 weeks, to 37 women (aged 29-65 years) with advanced breast cancer. A 1-day regimen of intravenous antihistamine and oral corticosteroids was given with each dose. Full doses of docetaxel were administered in 179 of 200 cycles (89.5%), giving a median relative dose intensity of 0.98. Tumour regression was achieved in 25 patients (7.66%) after a median of 7 weeks, and 2 patients (5.4%) had a complete response. Response rates were 67.9% in patients with visceral metastases, 76.9% in liver metastases and 83.3% in patients with > 2 organs involved. The median time to progression was 31 weeks (range 1-36+). After a median follow-up time of 6.9 months (range 4.6-9.4), 31 patients (83.7%) were still alive. The most common adverse events (AE) were neutropenia (97%), alopecia (97%, grade 1-2), fluid retention (89%, mainly mild to moderate) and neurosensory disorders (81%, mainly mild to moderate). Only 5 patients experienced febrile neutropenia requiring hospitalisation and/or antibiotic therapy. Sixteen patients discontinued treatment because of fluid retention; nevertheless, 13 of these achieved an objective antitumour response and none had any significant deterioration in performance status. AEs were generally reversible and easily managed, and there were no deaths attributable to docetaxel-related AEs. Docetaxel produces very effective tumour response with acceptable tolerability when used as first-line chemotherapy in patients with advanced breast cancer. The 1-day premedication regimen used in this study was less effective in reducing the incidence and severity or delaying the onset of fluid retention than the currently recommended 5-day corticosteroid premedication. The optimum premedication regimen remains to be defined.

Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.

Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.

Docetaxel in stage III and IV non-small cell lung cancer

Phase II studies have been conducted to evaluate the efficacy and tolerability of docetaxel in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Docetaxel was administered to patients with stage III and IV NSCLC at a dose of 100 mg/m2 intravenously over 1 h every 3 weeks. Patients included in these four phase II studies had received either no prior chemotherapy (n = 114) or treatment with cisplatin- or carboplatin-containing regimens (n = 57). Major objective response rates were reported in 33-38% of previously untreated evaluable patients and in 21-27% of previously treated evaluable patients. Neutropenia was the most common adverse event. Non-haematological adverse events included hypersensitivity reactions, skin rash, alopecia and fluid retention. Docetaxel demonstrates significant antitumour activity in patients with advanced NSCLC. Further investigations of this agent with corticosteroid premedication, colony-stimulating factors and other agents active in NSCLC are indicated.

Docetaxel.

We reviewed the preclinical and clinical profiles of the antineoplastic taxoid docetaxel (Taxotere, Rhône-Poulenc Rorer, Collegeville, PA). From the literature and manufacturer's data, we detail docetaxel's activity, tolerability, and pharmacokinetics in preclinical and phase I studies and its activity and side effects in phase II trials in various neoplasms. Docetaxel promotes the assembly of and stabilizes microtubules, preventing their depolymerization. In phase I studies in patients with solid tumors refractory to standard chemotherapy, docetaxel's major dose-limiting toxicity (DLT) was dose- but not schedule-dependent neutropenia; another major side effect was schedule-dependent grade 3 mucositis. Other, generally less severe effects included hypersensitivity reactions (HSRs), neurotoxicities, cutaneous reactions, alopecia, and asthenia. Responses were observed in breast, bronchial, and ovarian carcinomas. The recommended dose for phase II studies was 100 mg/m2 as a 1-hour intravenous (i.v.) infusion every 3 weeks. Preliminary phase II results confirmed docetaxel's activity against breast, non-small-cell and small-cell lung, ovarian, head and neck, and gastric cancers; melanoma; and soft tissue sarcomas. Neutropenia again was the principal dose-limiting side effect. Nonhematologic effects, usually grade 1 or 2, including HSRs, were common. HSRs were manageable with premedication. Corticosteroid premedication partially alleviated fluid retention seen after repeated docetaxel courses. Studies are evaluating docetaxel in various combination regimens in advanced breast cancer, non-small-cell lung cancer, and other solid tumors. Multicenter and single-institution studies have demonstrated docetaxel's consistent significant activity in various cancers. Phase III and combination therapy trials are ongoing. Work is in progress to understand and prevent/resolve some of this drug's side effects.

Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer.

This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with platinum-refractory ovarian cancer. Twenty-five patients with platinum-refractory advanced ovarian cancer were treated. Twenty of the patients had failed to respond to platinum-based front-line chemotherapy and five had failed to respond to platinum-based therapy repeated at relapse. One patient had received prior pelvic radiation therapy. Patients were required to have bidimensionally measurable disease. Docetaxel was administered at a dose of 100 mg/m2 intravenously (i.v.) over 1 hour every 21 days. Twenty patients received no corticosteroid premedication and five received premedication with corticosteroids and antihistamines. Eight of 23 assessable patients (35%) had a partial response (PR; 95% confidence interval, 16% to 57%). The median response duration was 5 months. Hospitalization for toxicity, predominantly neutropenic fever, occurred in 12 patients (48%) and 16% of courses. Anemia was common in the study population. Nonhematologic toxicities included alopecia, rash, fluid retention, diarrhea, peripheral neuropathy, and hypersensitivity reactions. Docetaxel demonstrates significant activity in patients with platinum-refractory advanced ovarian cancer. Routine premedication is recommended. Further investigations of this agent in ovarian cancer, including combinations with other active agents, appear indicated.

Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease.

We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation. Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media. Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration. Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.