Comparison of 2-Weekly and 3-Weekly Dosing of Docetaxel in Metastatic Prostate Cancer

IntroductionDocetaxel 75 mg/m² every 3 weeks is the standard schedule for metastatic prostate cancer (mPC). Alternative dosing of 50 mg/m² every 2 weeks may be an option for frail patients. Our aim is to define which factors influence the choice of schedule and to compare the outcomes of both schedules in daily clinical practice.Patients and MethodsWe retrospectively included patients with mPC treated with docetaxel in our institution. We compared data from patients treated with 3-weekly, 75 mg/m² docetaxel or 2-weekly, 50 mg/m² docetaxel, including basal characteristics, predefined prognostic factors, treatment received, toxicity and survival data.ResultsWe included 200 patients, 86% of whom presented castration resistant mPC. A total of 158 patients (79%) were treated with 3-weekly scheme. Compared with these patients, patients treated with 2-weekly scheme were significantly older, had higher Eastern Cooperative Oncology Group performance status (ECOG PS) and Charlson Comorbidity Index, presented more visceral metastases and needed opioid treatment more frequently. Patients treated with 2-weekly scheme presented shorter median overall survival; however, these differences were not shown after multivariate analysis with significant prognostic factors. Patients treated with 2-weekly scheme had more treatment delays and suspensions, but less clinically impairing toxicities such as febrile neutropenia, neuropathy and diarrhea; toxic deaths were 5 in the 3-weekly group while none in the 2-weekly group.ConclusionCompared to docetaxel 75 mg/m² every 3 weeks, dosing of 50 mg/m² every 2 weeks may be an alternative for older, frailer and more comorbid patients. Two-weekly dosing may be used more frequently in selected patients.     

Concurrent twice-a-week docetaxel and radiotherapy: a dose escalation trial with immunological toxicity evaluation

Purpose: In vitro studies show that docetaxel (Taxotere) is potent radiosensitizer. In a previous study we observed a 27% complete response rate after radiotherapy and weekly docetaxel for non–small-cell lung cancer. In this dose escalation study we investigated the feasibility of a twice-a-week docetaxel regimen together with conventionally fractionated radiotherapy for brain, chest, and pelvic tumors.Methods and Materials: Nine patients with stage IIIb lung cancer, 9 with stage IVa pelvic tumors, and 9 with brain glioblastoma were recruited. The starting dose was 15 mg/m² (twice a week) and was escalated by 4 mg/m² increments every 3 patients with chest, pelvic, and brain tumors.Results: The maximum tolerated dose of docetaxel was 15 mg/m² (twice a week) for chest and pelvic cancer patients. The dose-limiting toxicity (DLT) was asthenia and mucosal toxicity (esophagitis or diarrhea in chest and pelvic tumors, respectively). Patients with glioblastomas received 23 mg/m² (twice a week) without toxicity. Complete response of the chest disease was observed in 3/9 (33%) patients and partial response in 4/9 (44%). Three patients with glioblastoma had a partial response. In pelvic malignancies a high complete response rate was observed (4/9; 45%). Severe monocytopenia and lymphocytopenia were observed during the fourth week of treatment. IgG and IgA immunoglobulins were also reduced. This coincided with the onset of asthenia and severe mucosal toxicity. Asthenia was absent in patients treated for brain tumors, and lymphocyte toxicity was less pronounced.Conclusions: Docetaxel radiochemotherapy is a promising therapeutic approach for locally advanced cancer. The recommended dose of docetaxel for chest and pelvic cancer patients is 15 mg/m² twice a week. Patients with brain tumors can be safely treated with higher doses of docetaxel (23 mg/m² twice a week) without toxicity. The severe immunologic toxicity observed suggests that granulocyte–macrophage colony-stimulating factor (GM-CSF) and immunoglobulin administration may be important in the efficacy and tolerance of taxane-based radiochemotherapy. Randomized trials are required to assess whether the efficacy of docetaxel radiochemotherapy depends on the frequency of docetaxel administration during radiation treatment.     

Weekly docetaxel in minimally pretreated cancer patients: A dose-escalation study focused on feasibility and cumulative toxicity of long-term administration

Background: Docetaxel is an agent with impressive clinical activity but a rather poor profile of toxicity when given every three weeks. Therefore, optimisation of its clinical use is highly warranted. This is a dose-escalation study of weekly docetaxel particularly focused on the feasibility of long-term administration and characterisation of cumulative toxicity.Patients and methods: Twenty-six patients (11 female/15 male, median age 56, range 23–73) were treated over the range of 25–50 mg/m²/week. Dose-limiting toxicity for this schedule was defined as any grade >2 antiproliferative toxic effect resulting in a >2-week delay for re-administration of the drug, or any grade >2 organ-specific toxicity. Patients were monitored clinically and electrophysiologically for neurotoxicity. No prolonged corticosteroid co-medication or prophylactic haematopoietic growth factors were given.Results: A median/mean number of 8.5/8.7 consecutive weekly courses were given per patient. The maximum tolerated dose that prevented on-schedule administration of the drug was 50 mg/m². The main cumulative toxicities were a mild fluid retention and dacryorrhea which became evident as the number of treatment courses increased. Grade 2 alopecia and fatigue were observed only at 45 mg/m² and higher. Activity was seen at all of the dose levels studied.Conclusions: Long-term weekly administration of docetaxel is feasible at doses up to 45 mg/m²/week with acceptable toxicity. Further clinical evaluation is justified at this schedule and 40 mg/m²/week of docetaxel is proposed for phase II studies as an active dose with minimal toxicity.     

Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study

Purpose:The objective of this study was to determine thedocetaxel MTD when combined with gemcitabine or vinorelbine in advanced breastcancer patients who had received previous anthracycline-based chemotherapy foradvanced disease. Patients and methods:Advanced breast cancer patients aged between18 and 70 with ECOG PS 0–2 who had not responded to, or had relapsedafter, first-line anthracycline-based chemotherapy, were randomized to receiveeither gemcitabine 1000 mg/m² or vinorelbine 25 mg/m²in combination with escalating doses of docetaxel (starting from 30mg/m²), all on days 1 and 8 every three weeks. Escalation wasstopped if >33% of patients treated at a given dose level showed DLTat the first cycle. Results:A total of 34 patients with locally advanced (8) ormetastatic disease (26) were treated, for a total of 94 cycles delivered.Nineteen patients received docetaxel in combination with gemcitabine and 15with vinorelbine. All patients had been pretreated with anthracyclines, and24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of40/m² proved to be safe when combined on days 1 and 8 withgemcitabine, while a dose of 35 mg/m² was tolerated in combinationwith vinorelbine. Overall, nine episodes of DLT, all of them neutropenia,occurred at the first cycle. Considering all 94 cyles, grades 3 or 4neutropenia and thrombocytopenia occurred in 15 (44%), and 7(20%) patients. Non-hematologic toxicity was mild, except for threecases of grade 2 peripheral neuropathy. All patients were assessed forresponse on an 'intent-to-treat' basis. Overall, five partial responses wererecorded (docetaxel + gemcitabine = 3 and docetaxel + vinorelbine = 2), fora 15% (95% CI: 5%–31%) overall responserate. Only 1 of 24 (4%) patients who had received weekly dose-densepaclitaxel responded to treatment. Conclusions:The weekly docetaxel administration in combinationwith either gemcitabine or vinorelbine is a well-tolerated treatment forheavily pretreated advanced breast cancer patients. This approach, althoughsometimes capable of achieving a major response, does not seem advisable inadvanced breast cancer patients refractory to both anthracyclines andpaclitaxel.     

Docetaxel as rescue medication in anthracycline- and ifosfamide-resistant locally advanced or metastatic soft tissue sarcoma: Results of a phase II trial

Background:Metastatic soft tissue sarcoma not amenable tocurative surgery has a dismal prognosis. Aggressive treatment withanthracyclines and ifosfamide represents the current therapeuticmainstay in these patients, most of whom succumb to relapses. Thus, theefficacy of subsequent therapeutic approaches has to be weighed againsttoxicity caused by palliative treatment. Patients and methods:Patients with locally advanced ormetastatic soft tissue sarcoma refractory to treatment withanthracyclines and ifosfamide were enrolled into the present phase IIstudy. Patients were assigned to receive docetaxel at 100mg/m² every three weeks. In case of severe toxicity, patientswere switched to a weekly schedule of docetaxel (40mg/m²). Results:A total of 106 cycles (80% at the scheduled100 mg/m² dose level) were administered in 27 patients.Partial response was observed in 4 (15%) patients and 4(15%) patients experienced disease stabilization. Medianprogression free survival and overall survival were 2.4 (range:0.9–23.9) and 7.7 (range: 1.0–44.3) months,respectively. Upon renewed progression, three patients initiallyresponsive to treatment with docetaxel were successfully reinduced bytreatment with docetaxel. The safety profile of docetaxel was tolerableand the administration mostly manageable on an outpatient basis. Conclusions:Our results suggest that docetaxel representsan efficacious and tolerable treatment in a minority of patientsrefractory to standard treatment. There is a need for betteridentification of patients most likely to benefit from salvage treatmentwith docetaxel.     

Phase I/II dose escalation study of docetaxel and carboplatin combination supported with amifostine and GM-CSF in patients with incomplete response following docetaxel chemo-radiotherapy: additional chemotherapy enhances regression of residual cancer

Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in the context of a dose escalation phase I study. Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following docetaxel radio-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine and GM-CSF. The starting dose of docetaxel was 40 mg/m² every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m², while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m²) was administered i.v. before carboplatin and GM-CSF (480μg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were given and response was assessed 2 weeks after the end of chemotherapy. None out of four patients treated in the 6th dose level cohort (50mg/m² of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2–4 hematologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg edema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4–12% of patients. Out of four patients treated in a 7th cohort (docetaxel 60mg/m² and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m²) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF. Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients treated with taxanes.     

Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma

We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m², the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m²/day on days 1–4, vincristine 0.4 mg/m²/day on days 1–4, doxorubicin 10 mg/m²/day on days 1–4, cyclophosphamide 750 mg/m²/day on day 6, and prednisolone 60 mg/m²/day on days 1–6). Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies.Key Words: Bortezomib, Multiple myeloma, Peripheral neuropathy, Dorsal column degeneration     

A phase I-II study of gemcitabine and docetaxel in advanced pancreatic cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Background: Gemcitabine and docetaxel have been claimed to be active single agents in advanced pancreatic cancer. We determined the maximum tolerable dose of docetaxel combined with a weekly fixed dose of gemcitabine and assessed the activity of this combination in advanced pancreatic cancer.Patients and methods: Phase I. Patients were treated with gemcitabine on days 1 and 8, every three weeks, at a fixed dose of 1,000 mg/m²; docetaxel was given at escalating doses starting from 70 mg/m² on day 8. Phase II. In accord with the optimal two-stage phase II study design, 18 patients were treated with gemcitabine (1000 mg/m²) and the maximum tolerable dose of docetaxel (70 mg/m²).Results: Phase I. Dose-limiting toxicities occurred at the second dose level of docetaxel (80 mg/m²), with all three patients developing grades 3 or 4 neutropenia. Consequently, the dose tested in the phase II study was 70 mg/m². Phase II. In the 18 patients enrolled in the study, we registered only one partial response. The time to progression was 3 months, and the median treatment survival was 5.4 months. Grade 3–4 toxicities consisted of neutropenia (three episodes) and thrombocytopenia (two episodes). Furthermore, 10 patients complained of grade 3 fatigue.Conclusions: The addition of docetaxel to gemcitabine does not appear to be useful in advanced pancreatic cancer, since gemcitabine alone achieves similar results.     

Docetaxel Therapy for Advanced Hepatocellular Carcinoma Developed in Healthy Liver: Report of Three Cases

Abstract

Systemic chemotherapy is generally ineffective in patients with advanced hepatocellular carcinoma (HCC). This could be partly explained by the frequent underlying cirrhosis, which induces serious toxicity requiring dose attenuation or drug discontinuation. We present observations of three patients with HCC developed in healthy liver and treated with docetaxel (100 mg/m² every 3 weeks in one patient; 30 mg/m² weekly, three times every 4 weeks in two patients). An objective partial response with long-term survival was obtained in all cases without severe toxicity. These results suggest that chemotherapy, and especially docetaxel, could be safe and effective in patients with HCC developed in healthy liver, and should be assessed in specific trials.     

Weekly docetaxel for patients with platinum/paclitaxel/irinotecan-resistant relapsed ovarian cancer: a phase I study

Background This study was designed to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RD) of weekly docetaxel treatment in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.Methods Patients were enrolled on the basis of inclusion and exclusion criteria. Docetaxel was administered intravenously over a 60-min period on days 1, 8, and 15. Four dosage levels, 30, 35, 40, and 45mg/m², were employed, and the dosage was escalated from level 1 to level 4. DLT criteria were established, and the DLT was used as the criterion for deciding the MTD and RD.Results Twelve patients were enrolled. No grade 3/4 hematological toxicities were manifested at any dosage level. Grade 3/4 nonhematologic toxicities were manifested at level 4, consisting of fatigue/asthenia in 2 patients and neuropathy/sensory toxicity in 1 patient. Level 4 (45mg/m²) was thus judged to be the MTD, and the RD was concluded to be one level lower, i.e., level 3 (40mg/m²).Conclusions It was concluded that the RD for weekly docetaxel therapy is 40mg/m² per week in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.     

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

Background and purpose:Anthracycline-containing regimens arewidely used in advanced breast cancer. However, there is a need for new,non-anthracycline regimens that are active in patients for whom anthracyclinesare contraindicated. The aim of this study was to determine the maximumtolerated dose (MTD), the dose-limiting toxicities (DLTs) and recommendeddoses of docetaxel and vinorelbine as first-line chemotherapy in patients withmetastatic breast cancer. The pharmacokinetics of both drugs was alsoevaluated. Patients and methods:Thirty-four women with first-line metastaticbreast cancer were treated with docetaxel, 60–100 mg/m² (day1), and vinorelbine, 20–22.5 mg/m² (days 1 and 5), repeatedevery three weeks and administered on an outpatient basis. Results:Two MTDs were determined: MTD1 was defined at the doselevel using docetaxel 75 mg/m², and vinorelbine 22.5mg/m²; DLT being a grade 3 stomatitis that was more related to thedose of vinorelbine than that of docetaxel. Therefore, the study continuedwith a fixed dose of vinorelbine, 20 mg/m², and docetaxel85–100 mg/m². MTD2 was defined at the dose level combiningdocetaxel, 100 mg/m², and vinorelbine, 20 mg/m²; DLTswere grade 3 stomatitis and severe asthenia. Fluid retention was observed in41% of patients but was never severe or a reason for patientdiscontinuation. In comparison with historical experience, Daflon 500® didnot seem to increase the efficacy of the three-day corticosteroidpremedication by further reducing the incidence or severity of fluidretention. No significant neurotoxicity was observed and no patientdiscontinued the study due to this site effect. Activity was observed at alldose levels and at all metastatic sites, with an overall response rate of71% (95% CI: 52.0%–85.8%). The median timeto progression was 31.4 weeks (95% CI: 12–48 weeks) and mediansurvival was 15.6 months (95% CI: 2.6–26.6 months). Thepharmacokinetics of docetaxel and vinorelbine were not modified between day1 and day 3 when the two drugs were combined with the day 1 administrationschedule used in this study. Conclusion:The recommended doses for phase II studies aredocetaxel, 75 mg/m² (day 1), plus vinorelbine, 20 mg/m²(days 1 and 5), repeated every three weeks. At these doses, the combinationwas found to be active and well tolerated.     

Pharmacokinetics,dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose

Docetaxel (Taxotere^®) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m² every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m² every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to α1‐acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m². The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m², compared to the US/European patients treated with 75–100 mg/m² dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m² is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy.     

Randomized phase II study of nab‐paclitaxel as first‐line chemotherapy in patients with HER2‐negative metastatic breast cancer

Weekly administration of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open‐label phase II study to compare the efficacy and safety of weekly nab‐paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2‐negative MBC. The primary endpoint was progression‐free survival (PFS). Patients were randomized to receive nab‐paclitaxel (150 mg/m² nab‐paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m² docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab‐paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab‐paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab‐paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab‐paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab‐paclitaxel 150 mg/m² did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab‐paclitaxel and docetaxel.     

Epiphora (Excessive tearing) and other ocular manifestations related to weekly docetaxel

Purpose Epiphora due to canalicular stenosis is, a recently described side effect of weekly docetaxel. We prospectively evaluated the incidence of this complication and other ocular manifestations in patients treated at our medical center. Patients and methods Twenty-one consecutive patients (breast cancer: 14; metastatic non-small cell lung cancer: 6; metastatic nasopharyngeal carcinoma: 1) (female/male: 14/7; age range; 34–78 yr) were treated with weekly docetaxel (35 mg/m²/wk iv for 6 wk, cycles repeated every 49 d). A standard questionnaire regarding epiphora was completed before each dose of docetaxel Patients who complained of excessive tearing underwent a thorough ophthalmologic evaluation before receiving the next dose. Results Epiphora due to stenosis of the lacrimal puncti, and canaliculi developed in seven (33%) patients following a cumulative dose of 208–645 mg/m² (median: 400 mg/m²). Two patients developed complete canalicular stenosis requiring surgery. Epiphora was accompanied by madarosis and ectodermalization of the palpebral and bulbar conjunctiva, complete in five patients. Treatment was discontinued due to epiphora in two (10%) patients. After a median follow-up of 11 mo, four patients still had epiphora. Conclusion Epiphora due to canalicular stenosis is a frequent complication of weekly docetaxel and might be dose limiting. Irreversible damage requiring, surgical intervention may develop despite close monitoring.     

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy followed by adjuvant doxorubicin and cyclophosphamide therapy in stage II and III breast cancer patients: results of a phase II study

Introduction The purpose of this phase II study was to evaluate the efficacy and safety of neoadjuvant docetaxel/gemcitabine treatment in a biweekly regimen. Materials and methods Patients with stage II/III breast cancer were treated with docetaxel (65 mg/m²) followed by gemcitabine (2500 mg/m²) every 2 weeks for 6 cycles. Patients with a clinical response or stable disease underwent mastectomy or breast-conserving surgery plus axillary dissection. After surgery, patients received 4 cycles of standard doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 21 days. Results Thirty-five patients were included in the trial. The overall response rate was 71.4% (95% CI: 53.7–85.4), with 8 complete and 17 partial responses. Breast conservation was possible in 59% of the patients. Toxicity was manageable. Conclusions We consider biweekly docetaxel and gemcitabine could be an active and tolerable regimen option in the neoadjuvant setting sequentially with standard adjuvant doxorubicin-cyclophosphamide in patients with stage II or III breast cancer.     

Phase I trial of weekly docetaxel with a 4-weekly cisplatin administration in patients with advanced gastric carcinoma

The docetaxel-cisplatin combination is active against several tumors including gastric cancer but it is followed by severe myelosuppression. Recent experience with weekly taxanes has demonstrated a mild myelotoxicity with high dose intensity. We investigated in a phase I study a weekly schedule of docetaxel on days 1, 8 and 15 and cisplatin on day 1 every 4 weeks in 19 patients with advanced gastric cancer with no prior chemotherapy. Cohorts of patients were treated with escalating doses of docetaxel (starting dose 30 mg/m² per week and increments of 10 mg/m² per week) and cisplatin (starting dose 70 mg/m² and increments of 5 mg/m²). Febrile neutropenia was the only dose-limiting event occurring in four (20%) patients; the dose-limiting toxicity was reached at dose level three (docetaxel 40 mg/m² per week and cisplatin 75 mg/m²). The maximum-tolerated dose was 40 mg/m² per week for docetaxel and 70 mg/m² every 4 weeks for cisplatin. Grade 3/4 neutropenia occurred in six patients (30%); early death occurred in one patient with septic shock because of neutropenia and another with acute coronary ischemia. Two (11%) complete and two (11%) partial responses were documented (ORR 22%; 95% CI 3–39%), with a median response duration of 5 months and median time to progression of 7 months. In conclusion, the combination of weekly docetaxel plus cisplatin is feasible with moderate toxicity and merits further investigation in phase II studies in advanced gastric cancer.Presented as an abstract at the 15th International Congress on Anti-Cancer Treatment, Paris, 9–12 February 2004.     

Phase I study of the novel taxane CT-2103 in patients with advanced solid tumors

Background CT-2103 (Cell Therapeutics, Seattle, Wash.) is a water-soluble macromolecular conjugate of paclitaxel to a polyglutamate backbone, designed to enhance tumor permeability and to improve intratumoral delivery of paclitaxel. Preclinical studies indicate that CT-2103 has substantial antitumor efficacy in xenograft tumor models.Methods We performed a phase I trial in patients with advanced solid tumors to determine the maximum tolerated doses (MTD) of CT-2103 when administered as short intravenous infusion every 3 weeks.Results Seven patients received a total of 16 cycles (range 1–3) of CT-2103 at doses of 235 and 270 mg/m². Two of five patients treated at 235 mg/m² and one of two patients treated at 270 mg/m² experienced grade 3/4 neutropenia. Four patients experienced a marked increase in PTT within 30 min of the start of infusion. Neuropathy was more severe than expected. Two patients developed grade 3 neuropathy that prompted a 50% dose reduction of CT-2103 and persisted for 8 months in one, and over a year in the other. Three patients experienced grade 1 or 2 neuropathy. Neurotoxicity was cumulative and prevented patients from receiving prolonged administration of CT-2103.Conclusions The unexpectedly high rate of cumulative toxicity observed in our study needs to be taken into consideration in future trials of CT-2103. Prior taxane use may not be a predictor of severe neurotoxicity.     

Doxorubicin and cyclophosphamide followed by weekly docetaxel as neoadjuvant treatment of early breast cancer: analysis of biological markers in a GEICAM phase II study

Introduction  To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer. Patients and methods  Patients received 60 mg/m² of A and 600 mg/m² of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m² and with a 2-week resting period. Results  Sixty-three women were included. On an intentionto-treat basis, clinical response rate was 90% (95% CI: 83–98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated. Conclusion  Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.     

Second-line chemotherapy for non-small cell lung cancer

Several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer. The TAX 317 trial found that patients treated with docetaxel (Taxotere^®) 75 mg/m² had significantly longer survival than those treated with best supportive care alone. In addition, symptom control was better for patients who received chemotherapy. The TAX 320 trial found that treatment with docetaxel 75or 100 mg/m²resulted in significantly higher response rates than treatment with vinorelbine (Navelbine^®) or ifosfamide (Mitoxana^®), and the 1-year survival rate was also significantly better for patients treated with docetaxel 75 mg/m². A large randomized trial compared pemetrexed (LY-231514 or Alimta^®) 500 mg/m² with docetaxel 75 mg/m². Response and survival rates were similar in the two treatment arms, however, the toxicity profile of pemetrexed was superior to that of docetaxel with significantly less Grade 3/4 neutropenia and febrile neutropenia. Fewer patients in the pemetrexed arm required hospitalization. Topotecan (Hycamtin^®) 2.3 mg/m²/day orally for 5 days has been compared with docetaxel 75 mg/m²in a large 800-patient study. The results of this trial are awaited. Gemcitabine (Gemzar^®) and irinotecan (Campto^®) have been evaluated both as single agents and in combination with each other and study results do not suggest that either of these drugs is superior to docetaxel or pemetrexed. The vinca alkaloid vinorelbine has proved to be inferior to docetaxel in a randomized trial. The epidermal growth factor receptor inhibitors gefitinib (ZD1839, Iressa^®) and erlotinib (CP-358774, OSI 774, Tarceva^®) have been evaluated in Phase II trials in the second- and third-line setting. Both drugs have demonstrated interesting response rates ranging from 10 to almost 20%. The results of placebo-controlled randomized trials of this family of drugs are awaited. In summary, several studies have now found a definite role for the second-line treatment of patients with non-small cell lung cancer.     

A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

Background

Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.

Methods

LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m² IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.

Results

Twenty-four patients were treated for 1–30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m². Two out of two patients experienced grade 4 neutropenia at the 132 mg/m² dose level. When an additional three patients were treated at the expanded 110 mg/m² dose level, two experienced grade 4 neutropenia. The 85 mg/m² dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m² with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %.

Conclusion

LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m² without G-CSF or 110 mg/m² with G-CSF.