A randomized phase 2 trial comparing 3‐hour versus 96‐hour infusion schedules of paclitaxel for the treatment of metastatic breast cancer

BACKGROUND:

This study was performed to compare efficacy and toxicity profiles of paclitaxel using 3‐hour versus 96‐hour infusion schedules.

METHODS:

Patients with metastatic breast cancer (MBC) were randomly assigned to receive paclitaxel starting at a dose of 250 mg/m² intravenously (iv) over 3 hours every 21 days or paclitaxel starting at a dose of 140 mg/m² iv over 96 hours every 21 days. Stratification variables included number of prior chemotherapy regimens and previous response to anthracyclines. Response was assessed every 2 cycles using bidimensional measurements. Patients were allowed to cross over at disease progression or therapy intolerance.

RESULTS:

A total of 214 patients received therapy (107 patients per arm). Response rates were similar: 23.4% in the 3‐hour arm and 29.9% in the 96‐hour arm (P = .28). The median duration of response (8.9 months vs 5.7 months; P = .75) and progression‐free survival (5.0 months vs 3.8 months; P = .17) slightly favored the 96‐hour arm. Overall survival was slightly longer in the 3‐hour arm (14.2 months vs 12.7 months; P = .57). One patient who crossed over to the 96‐hour arm (N = 18) developed a partial response; no response was noted with crossover to the 3‐hour arm (N = 10). Myalgia/arthralgia and neuropathy were more frequent in the 3‐hour arm, whereas mucositis, neutropenic fever/infection, and diarrhea were more common in the 96‐hour arm.

CONCLUSIONS:

Paclitaxel given by 3‐hour or 96‐hour infusion was active in MBC. The 96‐hour paclitaxel regimen did not significantly improve response or time to disease progression, was more cumbersome to administer, and was associated with greater myelosuppression (but less neuropathy and myalgia) compared with the 3‐hour schedule. Cancer 2010. © 2010 American Cancer Society.     

A phase 2 clinical trial of nab‐paclitaxel in previously treated and chemotherapy‐naive patients with metastatic melanoma

BACKGROUND:

nab‐Paclitaxel (ABI‐007, Abraxane), a 130‐nM, albumin‐bound (nab) particle form of Cremophor‐free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab‐paclitaxel were evaluated in previously treated and chemotherapy‐naive patients with metastatic melanoma (MM).

METHODS:

Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab‐Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m² (in previously treated patients) or 150 mg/m² (in chemotherapy‐naive patients).

RESULTS:

Thirty‐seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy‐naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy‐naive cohorts, respectively. The median progression‐free survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy‐naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy‐naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy‐naive patients were treated without dose reduction. Eight (22%) chemotherapy‐naive patients discontinued therapy because of toxicities. Drug‐related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue.

CONCLUSIONS:

nab‐Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy‐naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab‐Paclitaxel therapy of MM should be investigated further in controlled clinical trials. Cancer 2010. © 2010 American Cancer Society.     

Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus‐associated Kaposi sarcoma

BACKGROUND:

Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)‐associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined.

METHODS:

Patients with advanced HIV‐associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m² intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m² iv every 3 weeks. The KS Functional Assessment of HIV (FAHI) quality of life instrument was used before and after every other treatment cycle.

RESULTS:

The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the paclitaxel arm and 37 in the PLD arm; 73% of patients received highly active antiretroviral therapy (HAART) and 32% had an undetectable viral load (<400 copies/mL). Treatment was associated with significant improvements in pain (P = .024) and swelling (P < .001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the paclitaxel and PLD arms revealed comparable response rates (56% vs 46%; P = .49), median progression‐free survival (17.5 months vs 12.2 months; P = .66), and 2‐year survival rates (79% vs 78%; P = .75), but somewhat more grade 3 to 5 toxicity for paclitaxel (84% vs 66%; P = .077).

CONCLUSIONS:

Treatment with either paclitaxel or PLD appears to produce significant improvements in pain and swelling in patients with advanced, symptomatic, HIV‐associated KS treated in the HAART era. Cancer 2010. © 2010 American Cancer Society.     

Bilateral facial nerve palsy secondary to the administration of high-dose paclitaxel

Bilateral facial nerve palsy is an uncommon occurrence. We describe a case of bilateral facial nerve palsy secondary to a single cycle of high-dose paclitaxel therapy (825 mg/m²), in a woman with breast cancer. Prior to her high-dose therapy, she had a residual grade 2 peripheral neuropathy following treatment with ten cycles of standard-dose paclitaxel (total dose 3200 mg). The features of the peripheral neuropathy due to standard-dose paclitaxel, which can be both motor and sensory, are well described. Cumulative paclitaxel dose is considered a risk factor for development of the neuropathy. Although facial nerve palsy secondary to paclitaxel is not previously reported, other cranial nerve toxicity has been described. Consistent with reports of the reversibility of paclitaxel-induced peripheral neuropathy, the facial nerve palsies in our patient resolved over 23 months. Ongoing studies of high-dose paclitaxel warrant close attention to its cumulative neurotoxic effects, particularly in patients previously treated with neurotoxic chemotherapy.     

Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer

BACKGROUND:

Patients with extensive stage small cell lung cancer (SCLC) who develop disease progression with standard cisplatin‐based therapy are reported to have a poor overall prognosis. Irinotecan and paclitaxel are active as single agents and exhibit preclinical synergy in SCLC cell lines. A phase 2 study was conducted to evaluate this combination in patients with recurrent or refractory SCLC.

METHODS:

Patients with SCLC who progressed with 1 prior chemotherapy regimen and had measurable disease present; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; and adequate bone marrow, hepatic, and renal function were included in the study. Paclitaxel (at a dose of 75 mg/m²) and irinotecan (at a dose of 50 mg/m²) were administered intravenously on Days 1 and 8 of each 3‐week treatment cycle. Therapy was continued until disease progression or unacceptable toxicity. The target response rate of interest was ≥30%.

RESULTS:

A total of 55 patients were enrolled, 51 of whom received at least 1 dose of therapy. The majority of the patients had an ECOG PS of 0 or 1 (96%). A median of 3 cycles of treatment was administered, and 15 patients received ≥6 cycles. Seventeen patients experienced toxicity of grade 3 or higher (neutropenia in 8 patients and fatigue in 5 patients). The overall response rate was 21%. The median survival was 25.4 weeks, and the 1‐year survival rate was 22%.

CONCLUSIONS:

The regimen of irinotecan and paclitaxel was found to be tolerated well in patients with recurrent or refractory SCLC. Although modest anticancer activity was noted, the efficacy failed to meet the primary endpoint of interest. Cancer 2010. © 2010 American Cancer Society.     

Ten‐year follow‐up of a phase 2 study of dose‐intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor‐prognosis,advanced‐stage epithelial ovarian cancer

BACKGROUND:

The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced‐stage epithelial ovarian cancer (EOC) who were receiving dose‐intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule.

METHODS:

Patients with stage III/IV EOC received cyclophosphamide 750 mg/m², followed by a 24‐hour infusion of paclitaxel 250 mg/m² and cisplatin 75 mg/m² on Day 2. Filgrastim began on Day 3 at 10 μg/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel.

RESULTS:

Sixty‐two patients were enrolled. Thirty‐two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent‐to‐treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow‐up of 11.4 years, the median progression‐free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel.

CONCLUSIONS:

The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose‐dense or dose‐intense paclitaxel regimens in women with newly diagnosed, advanced‐stage EOC. Cancer 2010. © 2010 American Cancer Society.     

Long‐term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer

BACKGROUND:

Testicular cancer is curable in the majority of men, and persisting treatment toxicity is a concern. The authors report a cross‐sectional study of the long‐term effects of chemotherapy (C) on neurologic function and development of Raynaud phenomenon.

METHODS:

Seven hundred thirty‐nine patients who were treated between 1982 and 1992 gave consent to enter the study. Patients were classified according to the receipt of C (n = 384) or no C (n = 355). Patients completed a general health questionnaire and a quality‐of‐life form (the European Organization for Research and Treatment of Cancer Quality‐of‐Life C30 questionnaire with testicular module). Symptom scores of 3 or 4 were considered clinically significant. Patients were assessed in the clinic, and clinical history was used to diagnose Raynaud phenomenon (RP) and tinnitus. Examinations included peripheral nerve function testing for light touch and vibration sense. Five hundred seventy‐seven patients underwent audiometry.

RESULTS:

On physician assessment, peripheral neuropathy and RP were more common after C (21.7% vs 9.1% [P<.001] and 20.3% vs 1.7% [P<.001], respectively). Similar results were obtained for symptom scores (12.5% vs 5.5% [P = .002] and 9.7% vs 3.7% [P<.001], respectively). On multivariate analysis, for peripheral neuropathy, the significant predictors were cisplatin dose, carboplatin dose, and age. For RP, the significant predictor was bleomycin. Significant differences in hearing thresholds were noted at 8000 hertz only and, on multivariate analysis, were related to age, cisplatin dose, and vincristine dose. Auditory symptom scores did not differ between groups.

CONCLUSIONS:

With long‐term follow‐up, peripheral neuropathy and RP remained detectable in approximately 20% of patients and caused significant symptoms in 10% of patients. Detectable effects on high frequency remained but caused little symptomatic problem. These effects persisted and were related to the cumulative chemotherapy dose. Cancer 2010. © 2010 American Cancer Society.     

Amelioration of Experimental Cisplatin and Paclitaxel Neuropathy with Glutamate

A major toxic effect of the chemotherapeutic agents paclitaxel and cisplatin is peripheral neuropathy. We report the use of a rat model of cytotoxic neuropathy to evaluate the role of glutamate as a possible neuroprotectant for these two drugs. Neuropathy was manifest as gait disturbance in 100% of paclitaxel treated animals after 2 weeks and 100% of cisplatin treated animals after 8 weeks. Significant elevations of mean tail-flick threshold, a measure of sensory impairment, were observed in animals treated with both cytotoxics. Impaired rota-rod performance was observed in both light and dark with paclitaxel, indicating motor neuropathy. There was a trend towards impairment in the dark for cisplatin, suggesting proprioceptive loss. In cytotoxic treated animals supplemented with oral sodium glutamate (approx. 500mg/kg/day in drinking water) from 24h before chemotherapy, there was a significant delay in time to onset of gait disturbance allowing significantly higher mean doses to be tolerated. Mean tail-flick and rota-rod scores were unchanged from baseline for both drugs. Glutamate therefore protected against both sensory and motor neuropathy. Similar doses of glutamate did not impair the cytotoxic efficacy of paclitaxel or cisplatin against a transplantable rat mammary adenocarcinoma grown subcutaneously in rats. Our findings suggest that glutamate warrants clinical trial as a neuroprotectant in patients receiving paclitaxel or cisplatin.     

A study of paclitaxel,carboplatin, and bortezomib in the treatment of metastatic malignant melanoma

BACKGROUND:

Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3‐drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma).

METHODS:

A 2‐stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3‐agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m² intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m²; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21‐day cycle. The primary endpoint of this trial was tumor response rate (TRR).

RESULTS:

Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1‐7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade ≥3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression‐free survival was 3.2 months, and the median overall survival was 7.0 months.

CONCLUSIONS:

Due to insufficient clinical efficacy, this trial did not proceed to second‐stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity. Cancer 2010. © 2010 American Cancer Society.     

Clinical and electrophysiological features of peripheral neuropathy induced by administration of cisplatin plus paclitaxel-based chemotherapy

The current prospective study sought to trace the incidence and severity of cisplatin plus paclitaxel (DDP+P)-induced neuropathy and to determine its clinical and electrophysiological pattern. Furthermore, it was attempted to describe its evolution by following up the course of peripheral neuropathy (PN) during chemotherapy as well as 3 months after its discontinuation. Thirteen adult patients scheduled to be treated with six courses of cumulative DDP+P-based regimens for a non-myeloid malignancy participated in this study. These patients were clinically and electrophysiologically monitored at baseline, during chemotherapy and 3 months after its discontinuation. The severity of PN was summarized by means of a modified PN score. Evidence of PN was disclosed in nine of the 13 patients (69.2%). The mean PN score for patients that manifested some grade of PN was 17.3 +/- 6.1 (range 9-28). All longitudinal comparisons concerning the motor conduction velocities (MCV) variables failed to reach significance. By contrast, comparisons of the mean changes at baseline and each of the follow-up studies revealed a significant decrease in all sensory action potentials examined. The follow-up evaluation performed 3 months after the discontinuation of chemotherapy showed that the DDP+P-induced neuropathy persists and progresses over time. Our results indicate that the majority of patients treated with a DDP+P-based regimen at full dose intensities would manifest an axonal, predominately sensory PN, of mild to moderate severity, which would persist for several months after the discontinuation of chemotherapy.     

Peripheral Neuropathy Due to Biweekly Paclitaxel,Epirubicin and Cisplatin in Patients with Advanced Ovarian Cancer

We assessed the peripheral neuropathic changes induced by biweekly combination chemotherapy including paclitaxel 100–165mg/m² (in a 3-h infusion), epirubicin 75mg/m² and cisplatin 50mg/m² (TEC) in patients with advanced ovarian cancer.Neurologic evaluation, including a standardized questionnaire, bed-side neurological examination, and quantitative determination of vibratory perception thresholds (VPT) and grip strength took place before therapy, after 3 and 6 cycles, and thereafter whenever possible. During chemotherapy all patients received granulocyte colony-stimulating factor from days 2 to 12. Pretreated patients received amifostine two times, before epirubicin and before cisplatin administration.Neuropathic symptoms developed in 11/13 non-pretreated patients and in 7/9 chemotherapy-pretreated patients. Neuropathic signs developed in all patients. Neuropathic symptoms and signs were predominantly sensory in character. VPT changes developed primarily in the feet. According to National Cancer Institute of Canada Common Toxicity Criteria, grade 3 peripheral neuropathy after 6 cycles developed in 1/6 and 2/4 non-pretreated patients who received TEC containing paclitaxel 150 and 165mg/m², respectively.We conclude that peripheral neuropathy is dose-limiting in chemonaïve patients treated with biweekly TEC combination chemotherapy, at paclitaxel dose level 165mg/m² in a 3-h intravenous administration.     

Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel

Toxic peripheral neuropathy is still a significant limiting factor for chemotherapy with paclitaxel (PAC), although glutamate and its closely related amino acid glutamine were claimed to ameliorate PAC neurotoxicity. This pilot trial aimed to evaluate the role of glutamate supplementation for preventing PAC-induced peripheral neuropathy in a randomized, placebo-controlled, double-blinded clinical and electro-diagnostic study. Forty-three ovarian cancer patients were available for analysis following six cycles of the same PAC-containing regimen: 23 had been supplemented by glutamate all along the treatment period, at a daily dose of three times 500 mg (group G), and 20 had received a placebo (group P). Patients were evaluated by neurological examinations, questionnaires and sensory–motor nerve conduction studies. There was no significant difference in the frequency of signs or symptoms between the two groups although neurotoxicity symptoms presented mostly with lower scores of severity in group G. However, this difference reached statistical significance only with regard to reported pain sensation ( P  = 0.011). Also the frequency of abnormal electro-diagnostic findings showed similarity between the two groups (G: 7/23 = 30.4%; P: 6/20 = 30%). This pilot study leads to the conclusion that glutamate supplementation at the chosen regimen fails to protect against peripheral neurotoxicity of PAC.     

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-na?ve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-na?ve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.     

Comparison of weekly versus every 3 weeks paclitaxel in the treatment of advanced solid tumors: a meta-analysis

Background

Paclitaxel is commonly given as a 3-h infusion every 3 weeks for a variety of malignancies. Several randomized clinical trials comparing weekly paclitaxel with Q3-week (Q3W) have produced mixed results in terms of efficacy and toxicity creating controversy about the ideal dose and schedule.

Methods

A literature search using PubMed, Cochrane Library, and Proceedings of the American Society of Clinical oncology from 1995 to 2011 was performed. We included all published and registered RTCs for advanced solid tumors which compared weekly paclitaxel with Q3W. Primary dependent variables – grade 3, 4 neutropenia rates and grade 3 sensory neuropathy rates – were analyzed for all cancer types. Secondary dependent variables – hazard ratios for survival and response rates – were analyzed for each cancer type. Moderators of cancer types, ethnicity, and paclitaxel dose ratio were analyzed for primary dependent variables.

Results

Ten trials were included. The summary effects of the meta-analysis revealed less grade 3, 4 neutropenia (odds ratio: 0.49, p = 0.0023) and a trend towards less grade 3 sensory neuropathy (odds ratio: 0.54, p = 0.092) with weekly paclitaxel compared with Q3W. Moderator analysis by meta-regression revealed that paclitaxel dose ratios have a significantly positive correlation with rates of G3/4 neutropenia and sensory neuropathy. In the five NSCLC (non small cell lung cancer) trials, the summary effect revealed a better response rate with weekly paclitaxel (odds ratio: 1.24, p = 0.042).

Conclusion

Weekly paclitaxel has a favorable toxicity profile compared to the current standard of Q3W paclitaxel.     

Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma

BACKGROUND:

Patients with urothelial carcinoma are not always amenable to cisplatin‐based chemotherapy. The authors previously reported that they achieved a 60% response rate in patients who failed on cisplatin‐based combination chemotherapy (methotrexate, vinblastine, doxorubicin, and cisplatin) by using a convenient outpatient regimen of gemcitabine (G) and paclitaxel (P) every 2 weeks. A multicenter trial was initiated in 5 Italian centers to evaluate this regimen as first‐line chemotherapy.

METHODS:

From January 2003 to April 2005, 54 patients who had histologically proven, measurable disease (according to Response Evaluation Criteria in Solid Tumors) with a World Health Organization (WHO) performance status (PS) from 0 to 2, metastatic or inoperable urothelial carcinoma, no prior systemic cytotoxic or biologic treatment, a creatinine clearance ≥40 mL per minute, and bilirubin <20 μmol/L received G at a dose of 2500 mg/m² in 30 minutes and P at a dose of 150 mg/m² in 3 hours every 2 weeks. Granulocyte–colony‐stimulating factor (G‐CSF) was given for 5 to 7 days for neutropenia toxicity of grade ≥3 (grading determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 guidelines). From 6 to 12 courses were planned. All patients received at least 1 cycle of therapy and were included in all analyses.

RESULTS:

The median patient age was 67 years (range 34‐78 years), and the median WHO PS was 1 (range, 0‐2). Metastases occurred in the lung in 17 patients (31%), in lymph nodes in 26 patients (54%), in the bladder in 20 patients (37%), in bone in 8 patients (15%), and in the liver in 8 patients (15%). Fifty‐nine percent of patients had >1 site of disease, and 13% of patients had ≥3 sites of disease. In total, 343 cycles were administered. Five patients achieved a complete response, and 15 patients achieved a partial response; thus, the overall response rate was 37% in an intent‐to‐treat analysis. Hematologic toxicity was predominant but manageable. G‐CSF was used in only 6% of cycles. The median survival was 13.2 months, and the median time to disease progression was 5.8 months.

CONCLUSIONS:

In a multicenter study, G and P was found to be a well–tolerated outpatient regimen. This regimen demonstrated promise and may be considered in patients who are unable to receive cisplatin. Cancer 2009. © 2009 American Cancer Society.     

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

PURPOSE: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity. EXPERIMENTAL DESIGN: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. RESULTS: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. CONCLUSIONS: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. Clin Cancer Res; 18(18); 5099-109. ?2012 AACR.     

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

Background:

This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel.

Methods:

A total of 22 patients received paclitaxel (135–175 mg m⁻²) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90–240 mg) daily.

Results:

One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m⁻². A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months.

Conclusion:

The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions.     

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas

BACKGROUND:

Data regarding the role of anthracyclines and taxanes as first‐line treatments of metastatic angiosarcoma are limited.

METHODS:

Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed.

RESULTS:

Seventy‐five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single‐agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression‐free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9‐6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4‐10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS.

CONCLUSIONS:

First‐line single‐agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS. Cancer 2011. © 2011 American Cancer Society.     

A phase 2 study of epothilone B analog BMS‐247550 (NSC 710428) in patients with relapsed aggressive non‐Hodgkin lymphomas

BACKGROUND:

The management of relapsed aggressive lymphomas remains problematic. Ixabepilone (BMS‐247550, epothilone B analog), a potent inhibitor of tubulin disassembly, has promising preclinical and early‐phase clinical activity in drug‐resistant malignancies.

METHODS:

This multicenter phase 2 clinical trial tested the activity and safety of ixabepilone in relapsed/refractory aggressive lymphoma patients with either chemosensitive (at least a partial response [PR] to most recent chemotherapy) or chemoresistant (less than PR to most recent chemotherapy) disease at 20 mg/m² given intravenously weekly on days 1, 8, and 15 of a 28‐day cycle.

RESULTS:

Fifty‐one enrolled patients with a median age of 66 years received at least 1 dose of ixabepilone. Diffuse large B‐cell lymphoma (n = 25; 49%), mantle cell lymphoma (n = 16; 31%), and transformed follicular lymphoma (n = 5; 10%) were the most frequent histologies. Patients were heavily pretreated, with more than one‐quarter having received 4 or more prior therapies. The overall response rate was 27% (14 of 51 patients) with 12% (6 patients) experiencing complete responses and 16% (8 patients) with PRs. All responses were in patients with chemosensitive disease. The median time to response was 2 cycles with a median duration of response of 9.7 months.

CONCLUSIONS:

Ixabepilone was well‐tolerated, with neutropenia, peripheral sensory neuropathy, fatigue, and nausea as the major toxicities. Ixabepilone has modest single‐agent activity in patients with recurrent chemosensitive aggressive lymphomas. Cancer 2013. © 2013 American Cancer Society.     

Subclinical pretreatment sensory deficits appear to predict the development of pain and numbness in patients with multiple myeloma undergoing chemotherapy

Purpose

Chemotherapy-induced peripheral neuropathy is a major complication in the treatment for cancer, including multiple myeloma (MM). Patients may develop painful and non-painful (e.g., numbness) neuropathy symptoms that impair function and often persist after therapy is terminated. This study tested the hypothesis that baseline subclinical neuropathy, as assessed by sensory thresholds, is related to the development of neuropathy symptoms (e.g., pain and numbness) in patients with MM undergoing treatment with chemotherapy.

Methods

Patients (n = 56) who had undergone two or fewer cycles of induction therapy and who had no evident neuropathy were assessed using quantitative sensory tests to determine multiple-modality sensory thresholds. Patient-reported pain and numbness were assessed through induction therapy (16 weeks) via the MD Anderson Symptom Inventory. A subset of participants (n = 15) continued reporting on their symptoms for an additional 16 weeks (“maintenance phase”).

Results

Patients with sharpness detection deficits at baseline (n = 11, 20 % of sample) reported less severe pain and numbness during induction therapy and less numbness during maintenance therapy (P < 0.05). During the maintenance phase, patients with warmth detection deficits (n = 5, 38 % of sample) reported more severe pain and numbness, and those with skin temperature deficits (n = 7, 47 % of maintenance sample) reported more severe pain (P < 0.05). These deficits were related to patient reported difficulty walking, a common symptom of peripheral neuropathy.

Conclusion

Our results suggest that baseline subclinical sensory deficits may be related to a patient’s risk for developing chemotherapy-induced peripheral neuropathy.