Economic and policy implications of adopting paclitaxel as first-line therapy for advanced ovarian cancer: an Ontario perspective

PURPOSE: To determine the potential economic and policy implications that result from incorporating paclitaxel into first-line therapy for stage 3 and 4 ovarian cancer patients in the province of Ontario, Canada. METHODS: A cost-effectiveness analysis was conducted to compare cisplatin/cyclophosphamide (CC), a standard therapy, with cisplatin/paclitaxel (CT). Based on survival curves from a clinical trial, mean costs and survival were calculated. Sensitivity analyses were conducted based on altering the duration of paclitaxel infusion, discount rates, and efficacy of paclitaxel. RESULTS: The mean survival duration is prolonged from 2.06 years with the standard therapy to 2.44 years with the paclitaxel combination. The paclitaxel therapy is more expensive, with a mean cost of $17,469 (Canadian) per patient treated with CT compared with $5,228 per patient with CC. The incremental cost-effectiveness ratio is $32,213 per year gained. Sensitivity analyses show that the conclusions remain unchanged. The use of CT as first-line treatment for advanced ovarian cancer patients in Ontario requires an additional $9 million per year over and above the present costs to treat this patient population. CONCLUSION: Although paclitaxel-based therapy prolongs survival, it comes at an increased cost. It may not be possible to fund paclitaxel treatment using resources presently allocated to first-line chemotherapy for advanced ovarian cancer. The policy implications for absorbing the cost of paclitaxel in the context of a publicly funded health care system are discussed.     

Treatments for newly diagnosed advanced ovarian cancer: analysis of survival data and cost-effectiveness evaluation

The main therapeutic options currently available for patients with newly diagnosed advanced ovarian cancer include: (i) cisplatin-based chemotherapy at conventional doses without paclitaxel, (ii) paclitaxel+cisplatin at conventional doses and (iii) high-dose chemotherapy with autologous hematopoietic rescue. After conducting a literature search to identify large-scale clinical trials based on these three therapeutic modalities, we carried out an analysis of the survival data and evaluated the cost-effectiveness ratio where appropriate. Cost data were obtained from published information. Effectiveness was estimated by determining the values of mean lifetime survival (MLS). Our analysis included a total of 15 clinical trials. The values of MLS were 3.05 years per patient for cisplatin-based chemotherapy at conventional doses without paclitaxel (1931 patients), 2.95 years per patient for chemotherapy with paclitaxel+cisplatin at conventional doses (184 patients) and 5.76 years per patient for high-dose chemotherapy with autologous hematopoietic rescue (53 patients). As compared with cisplatin-based chemotherapy without paclitaxel, high-dose treatments with hematopoietic rescue yielded a significantly better survival. Using cisplatin-based chemotherapy as a reference term, the incremental cost-effectiveness ratio for high-dose treatments was $25641 per life year gained (discounted dollars per discounted life year gained). Sensitivity testing suggested that the ratio remained below $50000 under most circumstances. We conclude that in the treatment of patients with advanced ovarian cancer, high-dose chemotherapy with hematopoietic rescue seems to be more effective and more cost-effective than standard treatments with cisplatin-based regimens at conventional doses.     

Structural modeling of the pro-ocytocin-neurophysin precursor

This article reviews the information currently available on the pharmacoeconomic profile of taxanes in ovarian cancer. Because paclitaxel is the only taxene approved for this clinical indication, our overview is almost entirely focused on the cost-effectiveness profile of this drug. In advanced ovarian cancer, first-line regimens based on paclitaxel have been reported to be more effective than standard therapy based on cyclophosphamide + cisplatin. The improved survival with paclitaxel and the increased cost induced by this drug have prompted a series of pharmacoeconomic analyses, the results of which are summarized and discussed. Three studies, published between 1996 and 1997, calculated the cost per life-year gained using paclitaxel + cisplatin as opposed to cyclophosphamide + cisplatin. The estimates of survival gain and increased expenditure using paclitaxel were very similar; consequently, the results produced by these three analyses were homogeneous with values of cost per life-year gained around $20000. Because this value is below the conventional limit of $50000, the pharmacoeconomic results on paclitaxel suggest a favorable cost-effectiveness profile. Docetaxel is another taxane proposed for the treatment of advanced ovarian cancer; however, the drug has not yet been approved for this clinical indication and so a pharmacoeconomic assessment on this agent is still premature.     

Cost-utility model comparing docetaxel and paclitaxel in advanced breast cancer patients

Relevant data from direct comparisons in clinical trials are not available for economic evaluations of docetaxel and paclitaxel in the management of metastatic breast cancer. A modified Markov model is used to estimate the incremental cost in US$ per quality-adjusted life-year (QALY) for docetaxel versus paclitaxel in managing metastatic breast cancer patients in the US. The model incorporates the latest available clinical trial data (response rates of 47.8% for docetaxel and 25% for paclitaxel, chemotherapy-specific toxicities, time to progression, and 1-year survival) from studies against other comparators. Medical care resources were estimated by US oncologists and costed using US data sources. Utility scores were obtained from 29 US oncology nurses. The base case and subsequent sensitivity analyses show that docetaxel management of advanced breast cancer is more costly per patient but yields higher health benefits than paclitaxel therapy. The cost per QALY gained by docetaxel is $8615, and ranges between $3943 and $9416 in sensitivity analyses. These results confirm those of an earlier model using preliminary data and compare favorably with other cost-utility results in this patient group.     

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. PATIENTS AND METHODS: Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. RESULTS: Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. CONCLUSION: The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.     

Exercise testing and prognosis in adult cystic fibrosis

PURPOSE: The objective of our study was to determine the maximum tolerable doses (MTDs) of both paclitaxel and cisplatin when given in a weekly schedule alone or simultaneously with G-CSF in advanced solid neoplasms. PATIENTS AND METHODS: Patients with advanced cancer either chemotherapy-naive or resistant to standard treatments received paclitaxel in a three-hour infusion followed by cisplatin, with or without the addition of r-HuG-CSF (5 micrograms/kg s.c. days three to five). The starting doses of CDDP and paclitaxel were 25 mg/m2/week and 45 mg/m2/week, respectively. During the first six courses the dosages of the two drugs were alternately escalated by 20% (CDDP = 5 mg/m2/week, and paclitaxel 10 mg/m2/week) at each step until the appearance of dose-limiting toxicity (DLT) in one-third or more of the patients enrolled in that cohort. RESULTS: Fifty-five patients with cancer (16 lung, 16 breast, 11 ovarian, 7 head and neck, 1 renal, 1 esophageal, 1 cervical, 1 soft-tissue sarcoma, and 1 of unknown primary), 25 of whom were pretreated, were entered into the study. A total of 439 weekly courses were delivered. In chemotherapy-na?ve patients, the MTDs of cisplatin and paclitaxel were 30 mg/m2/week and 65 mg/m2/week, respectively, in the absence of G-CSF support, which increased to 40 mg/m2/week and 85 mg/m2/week, respectively, when G-CSF was given. There were no toxic deaths in this study. Neutropenia was the main dose-limiting toxicity (100/439 courses), but was seldom severe. Neurotoxicity was quite frequent (18 of 55 patients for the total of 88 courses) but never dose-limiting. It was more frequent and clinically relevant in cisplatin-pretreated patients. Overall 18 patients (eight ovarian, five breast, three lung, and two head and neck) achieved objective responses. CONCLUSIONS: The cisplatin-paclitaxel weekly administration seems a safe, practical and effective therapeutical approach in patients with advanced solid neoplasms. Large phase II trials are warranted to accurately define the efficacy of this schedule in cisplatin-paclitaxel sensitive tumors.     

Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM)

Lonidamine (LND) is a unique antineoplastic drug derived from indazole-3-carboxylic acid which inhibits oxygen consumption and aerobic glycolysis, interfering with energy metabolism of neoplastic cells. LND has been experimentally shown to potentiate the cytotoxic effects of epirubicin (EPI) in human breast cancer cell lines, cisplatin activity in both platinum-sensitive and -resistant human ovarian carcinoma cell lines, and EPI antineoplastic activity in some recent phase III trials carried out in advanced breast cancer. A multicenter phase II trial was carried out with the combination of cisplatin 60 mg/m2, EPI 100 mg/m2 and LND 450 mg/day p.o. in three refracted doses/day starting 2 days before cisplatin and EPI (day -2 and -1), stopping 2 days after chemotherapy (day 0, +1 and +2). Thirty patients with metastatic breast cancer were enrolled into the study. Twenty-nine patients were evaluable for objective response. The overall response rate accordingly to an intent-to-treat analysis was 73% (95% CL 54-88%). Four patients achieved complete response (13%; 95% CL 4-31%) with a median duration of 9.5 months (range 4-16) and 18 patients had partial response (60%; 95% CL 41-77%) with a median duration of 9.8 months. Stable disease was obtained in five cases (17%) and progressive disease was recorded in three patients. One patient died of progressive cancer before restaging. The overall median survival of the whole series of patients was 14+ months. The most frequent toxicities were represented by gastrointestinal and hematological side effects. The combination of cisplatin + EPI plus oral LND is active against metastatic breast carcinoma. The antineoplastic activity of the cisplatin + EPI + LND regimen is as high as that reported for more aggressive regimens such as the fluorouracil + doxorubicin + cyclophosphamide combinations without an increase in toxic effects.     

Gemcitabine: a cytidine analogue active against solid tumors

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of gemcitabine are reviewed. Gemcitabine is a deoxycytidine-analogue antimetabolite with activity against some solid tumors. Gemcitabine is phosphorylated intracellularly to difluorodeoxycytidine triphosphate, which terminates DNA-chain elongation and competitively inhibits DNA polymerase and ribonucleotide reductase. After i.v. administration, gemcitabine is rapidly distributed into total body water. The drug is deaminated in the plasma to inactive difluorodeoxyuridine; both gemcitabine and difluorodeoxyuridine are primarily renally eliminated. In clinical studies, gemcitabine reduced pain and improved function in patients with advanced pancreatic cancer. Gemcitabine has shown some activity against non-small-cell lung cancer, particularly when combined with cisplatin or ifosfamide. The agent has also shown modest activity against advanced ovarian and breast cancer. Adverse effects include dose-limiting myelosuppression, flu-like symptoms, nausea, vomiting, and rash. Gemcitabine has FDA-approved labeling for use in the treatment of locally advanced and metastatic pancreatic cancer. The recommended dosage for this indication is 1000 mg/m2 (as the hydrochloride salt) i.v. given over 30 minutes weekly for seven weeks, followed after one week of rest by 1000 mg/ m2 i.v. given over 30 minutes weekly for three weeks every four weeks. Gemcitabine palliates symptoms in patients with advanced or metastatic pancreatic cancer. More study is needed to determine gemcitabine's role in the treatment of non-small-cell lung cancer, ovarian cancer, and breast cancer.     

The taxoids. Comparative clinical pharmacology and therapeutic potential

Paclitaxel and docetaxel are 2 compounds from the new taxoid class of anti-cancer agents. Both drugs are very similar in preclinical activity, mechanism of action and spectrum of clinical activity. Some subtle differences in the intracellular retention of docetaxel may account for its lack of schedule-related myelosuppression and greater potency, and may be relevant to the skin toxicity and oedema which it produces. Early data suggest that there may be differing behaviour of anthracycline/taxoid combinations with respect to cardiotoxicity. Paclitaxel has been studied in several first-line combination therapy trials in ovarian cancer. Here, paclitaxel in combination with a platinum compound seems to have proven itself as a standard regimen. It is uncertain if docetaxel will be evaluated in this context. An abundance of clinical data is available for both analogues in the advanced, metastatic setting of breast cancer. Both also have been compared as single agents with doxorubicin with the results suggesting paclitaxel in a 3-hour infusion is inferior to the anthracycline (in terms of response rate), and those of docetaxel suggesting it is superior to the same dose of doxorubicin. This indirect comparison favours the activity of docetaxel; however, it is clear that in the dose/schedules studied, the taxoid compounds are not equitoxic. Either agent by itself, in the treatment of metastatic breast cancer, remains appropriate; however, lack of cumulative toxicity may make paclitaxel more attractive in some situations where prolonged administration is foreseen. Lung cancer trials have also confirmed the activity of both agents, although docetaxel appears to have slightly more promising activity in previously treated patients than paclitaxel. Paclitaxel in combination with cisplatin has been evaluated in randomised trials as first-line treatment of non-small-cell lung cancer (NSCLC). The results of these trials taken together suggest that this combination has an impact on survival similar to other new regimens now considered 'standard' in the front-line setting in this disease. Unfortunately, despite all the phase II data generated in numerous tumour types, little else can be said about the role of either taxoid in the 'standard' management of malignant disease. It will be some years yet before taxoid-based combinations have been evaluated sufficiently in randomised trials such that the impact of this novel class can be adequately assessed in terms of survival and cure rates.     

Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.     

Distributed clinical neurophysiology

We have performed a clinical phase I trial of a combination treatment with paclitaxel given as 3-hour infusion and cisplatin to determine the maximum tolerated dose and the dose-limiting toxicity in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Treatment was repeated every 21 days. Doses administered ranged from 135 mg/m2 paclitaxel/75 mg/m2 cisplatin to 250 mg/m2 paclitaxel/100 mg/m2 cisplatin. Twenty-four patients have been entered into this study. The maximum tolerated dose was determined to be 225-250 mg/m2 paclitaxel/100 mg/m2 cisplatin. The dose-limiting toxicity of this regimen was myelosuppression (granulocytopenia). Neurosensory and neuromotor toxicity was moderate. However, analyses of threshold electrotonus studies indicated subclinical neurotoxicity in most patients. One patient receiving 200 mg/m2 paclitaxel/100 mg/m2 cisplatin developed grade 3 motor-neurotoxicity. Orthostatic hypotension was observed in 8 patients receiving doses of 200 mg/m2 paclitaxel/100 mg/m2 cisplatin or higher. Objective responses were observed at paclitaxel 175 mg/m2/ cisplatin 100 mg/m2 (n = 5; complete response in 1 patient), paclitaxel 200 mg/ m2/cisplatin 100 mg/m2 (n = 3; partial response in 3 patients) and at paclitaxel 225 mg/m2/cisplatin 100 mg/m2 (n = 8; partial response in 1 patient). Eleven additional patients had stable disease. We conclude that paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer and that orthostatic hypotension may be a potentially significant clinical toxicity.     

Knowledge and attitudes among California dental care providers regarding child abuse and neglect

Combination chemotherapy with paclitaxel plus a platinum compound (carboplatin or cisplatin) is the current regimen of choice for the treatment of advanced epithelial ovarian cancer. The two most widely used combinations are paclitaxel (135 mg/m2, 24-hour infusion) plus cisplatin (75 mg/m2) or paclitaxel (175 mg/m2, 3-hour infusion) plus carboplating dosed to an area under curve of 7.5. Randomized trials are in progress comparing these two regimens. Numerous other clinical issues remain regarding how to maximize the effectiveness of this therapy, including dose and schedule, duration of treatment, route of administration, and incorporation of other agents with novel mechanisms of cytotoxicity. New agents currently undergoing evolution as part of novel induction regimens have been shown to have significant activity in recurrent ovarian cancer and include topotecan, gemcitabine, oral etoposide, and encapsulated doxorubicin.     

Families of repeated DNA in the oomycete Phytophthora infestans and their distribution within the genus

Paclitaxel (Taxol) is a new class of anti-tumor agents which act by promoting the assembly and inhibiting the disassembly of microtubules. Single-agent studies have shown its significant activity for advanced cancers in various organs including ovary, lung, breast, and head and neck. Combination therapies with other anticancer agents have been extensively investigated in these cancers. Paclitaxel combined with cisplatin is now considered to be the standard treatment for advanced ovarian cancer. In other cancers, promising results have been obtained in several studies of paclitaxel-based chemotherapy. Major toxicities of paclitaxel-monotherapy are hypersensitivity reaction, neutropenia, and peripheral neuropathy. Combination of other cytotoxic agents sometimes leads to severer toxicities such as neurotoxicity with cisplatin and cardiotoxicity with anthracycline. Although further evaluation is needed, paclitaxel will be a main agent in the treatment of advanced solid tumors.     

Chemotherapy immediately following autologous stem-cell transplantation in patients with advanced breast cancer

Most patients relapse after high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT) for metastatic breast cancer. Further chemotherapy immediately after hematopoietic recovery from ASCT is not given for fear of irreversibly damaging the newly engrafted stem cells. In a pilot chemoprotection trial, autologous CD34+ cells from patients with metastatic breast cancer were exposed to a replication-incompetent retroviral vector carrying MDR-1 cDNA and then reinfused after HDCT. Immediately on recovery, patients received multiple courses of escalating dose paclitaxel. All of the 10 patients tolerated reinfusion of modified cells without any toxicity and had myeloid engraftment within 12 days (range, 11-14). The bone marrow cells of three patients contained vector MDR-1-positive cells only at the time of the first course of posttransplant paclitaxel, indicating that the MDR-1 vector-modified cells had only short-term engrafting potential. A total of 83 courses of paclitaxel were administered starting at a median of 30 (range, 21-32) days from ASCT. The median dose of paclitaxel was 225 mg/m2 and the median interval between paclitaxel cycles of therapy was 21 (range, 20-41) days. Five of the six CR patients were able to receive all of the 12 courses of paclitaxel. Three patients who had achieved less than a complete response to the HDCT (2 patients) and partial response (1 patient) were converted to complete clinical responses during the 12 cycles of paclitaxel. No delayed toxicity or bone marrow failure was noted in these patients with a median follow-up of 2 years from ASCT. This is the first study of chemotherapy immediately after transplantation with autologous CD34+ cells. These data indicate that paclitaxel can be safely administered immediately after ASCT without any delayed toxicities. Paclitaxel given immediately after ASCT can further improve the response to pretransplant chemotherapy in patients with advanced breast cancer.     

Chemotherapy for advanced non-small cell lung cancer: past, present, and future

Until recently, chemotherapeutic intervention in advanced and metastatic non-small cell lung cancer (NSCLC) has been viewed with a certain degree of nihilism. Although meta-analysis of randomized clinical studies from the 1970s and 1980s comparing cisplatin-based chemotherapy to best supportive care in metastatic NSCLC showed improvement in survival, it was modest at best. A number of novel agents have been developed with significant activity against NSCLC in the past 5 to 6 years and are being incorporated into the therapy of this disease. These agents include paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. Clearly there has been improvement in response rates, and in some cases the responses have been durable with an increase in the number of 1- and 2-year survivors. The next generation of studies has evaluated combinations of these novel agents with either cisplatin or carboplatin for patients with NSCLC and the results have been provocative, with 1-year survival rates as high as 54%. A randomized phase III study of the Eastern Cooperative Oncology Group has shown the superiority of paclitaxel-cisplatin regimens over etoposide-cisplatin for patients with advanced and metastatic NSCLC. The vinorelbine-cisplatin regimen has also proven to have significant, albeit modest benefit in survival when compared with cisplatin alone. These combination regimens have now become the reference regimens in ongoing randomized studies. There is continued interest in developing new agents, or selective approaches that effect novel targets with the hope of showing improved therapeutic activity. Some of these approaches include gene therapy, monoclonal antibodies, and introduction of antisense oligodeoxynucleotides. With better understanding of the molecular and cellular biology of lung cancer, the hope for the future is to combine the mechanistic approaches with new drug development to define an effective, optimal, and definitive regimen for NSCLC.     

Australian multicentre phase II trial of paclitaxel in women with metastatic breast cancer and prior chemotherapy

OBJECTIVE: To determine the efficacy and safety of paclitaxel given as a three-hour infusion in patients with metastatic breast cancer which had progressed despite hormonal therapy and/or chemotherapy. DESIGN AND SETTING: Multicentre phase it trial undertaken in five major centres or hospitals in Sydney, Melbourne and Adelaide. PATIENTS AND METHODS: 50 patients with clinically or radiologically measurable or evaluable metastatic breast cancer recruited between March and July 1993. All had received prior chemotherapy, with subsequent disease progression. INTERVENTION: Paclitaxel (Anzatax, Faulding) was given at a dose of 175 mg/m2 intravenously over three hours every three weeks for up to nine courses. MAIN OUTCOME MEASURES: Response rate (partial or complete); duration of progression-free survival; duration of survival; and adverse reactions. RESULTS: Patients had a median age of 51 years; 62% had received at least two prior drug regimens for metastatic breast cancer and 48% had anthracycline-resistant tumours. A median of six paclitaxel courses was given per patient. Overall response rate was 18% (95% confidence interval [95% CI], 9%-31%), with complete responses in four patients (8%). In patients with anthracycline-resistant tumours, response rate was 25% (95% CI, 10%-47%). Response was not influenced by extent of prior treatment. Estimated median progression-free survival was 4.1 months (95% CI, 3.2-6.0 months) and estimated median survival was 6.3 months (95% CI, 6.2-10.3 months). Treatment was well tolerated, with neutropenia the major toxic effect. CONCLUSIONS: Paclitaxel (three-hour infusion) has significant activity in heavily pretreated patients with metastatic breast cancer, including anthracycline-resistant tumours.     

A guinea pig''s view on prostate cancer screening trials

Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.     

A possible association between paternal longevity and major depression among elderly men

Platinum-based chemotherapy is the standard treatment for advanced ovarian cancer, with response rates of 40-60%. In patients who fail platinum treatment, paclitaxel has resulted in response rates of 10-48%. Docetaxel has partial non-cross-resistance with and is twice as potent in vitro as paclitaxel in inhibiting microtubule disaggregation. The combination of docetaxel and cyclophosphamide is synergistic in pre-clinical studies and clinically active in breast cancer. We present the case of a patient with platinum and paclitaxel refractory ovarian cancer who achieved a remission with docetaxel and cyclophosphamide.     

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.     

Translocation (11;14)(q13;q32) and overexpression of cyclin D1 protein in a CD23-positive low-grade B-cell neoplasm

BACKGROUND: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin-paclitaxel. DESIGN: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients. PATIENTS AND METHODS: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m2 followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg x ml-1 x min. RESULTS: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%-54%). Response rates for platinum-refractory patients and those with early (> or = 3 and < 12 months) and late (> 12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy. CONCLUSION: This combined paclitaxel-carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy.