Dose-dense doxorubicin and cyclophosphamide followed by dose-dense albumin-bound paclitaxel plus bevacizumab is safe as adjuvant therapy in patients with early stage breast cancer

Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by cremophor-formulated paclitaxel (cf-P) was efficacious in metastatic breast cancer (BC). Albumin-bound paclitaxel (ab-P) was safe and more effective than cf-P, and the addition of bevacizumab to cf-P improved efficacy. This study compared the safety of dose-dense ab-P vs cf-P plus bevacizumab following dose-dense adjuvant AC for early-stage BC. Patients and Methods: Women with operable, histologically confirmed BC were randomized to 4 cycles of dose-dense A 60 mg/m² plus C 600 mg/m² IV with SC pegfilgrastim, followed by 4 cycles of either dose-dense IV ab-P 260 mg/m² or cf-P 175 mg/m². Bevacizumab was given during and following chemotherapy. 97 and 96% of patients completed 4 cycles of AC therapy, while 84 and 85% of patients completed 4 cycles of taxane therapy in the ab-P and cf-P arms, respectively (N = 197). Baseline patient characteristics were similar. The most common grade ≥3 taxane-related adverse events (AEs) were fatigue and neutropenia. Dose reductions were similar between the treatment arms. During AC therapy, the majority of dose reductions were due to febrile neutropenia; during taxane therapy, the majority of cases were due to neuropathy. No taxane-related dose interruption occurred in the ab-P arm, while 3 occurred in the cf-P arm due to hypersensitivity reactions. The mean cumulative paclitaxel dose was 950.5 and 660.8 mg/m² in the ab-P and cf-P arms, respectively. A 44% higher paclitaxel dose was delivered in the ab-P compared with the cf-P arm (P < 0.0001), while achieving a similar safety profile. ab-P plus bevacizumab following AC therapy without prophylactic premedications was tolerable in early-stage BC patients.     

A pilot study of adjuvant nanoparticle albumin-bound (<Emphasis Type="Italic">nab</Emphasis>) paclitaxel and cyclophosphamide,with trastuzumab in HER2-positive patients,in the treatment of early-stage breast cancer

nab-Paclitaxel has shown favorable efficacy and toxicity profiles compared to other taxanes in the treatment of metastatic breast cancer. In this pilot trial, we evaluated a nab-paclitaxel-containing adjuvant regimen in patients with early stage breast cancer. Patients with node-positive or high-risk node-negative early-stage breast cancer were eligible following completion of standard primary therapy. All the patients received four cycles, at 21-day intervals, of nab-paclitaxel (100 mg/m² IV days 1, 8, and 15) and cyclophosphamide (600 mg/m² IV day 1). HER2-positive patients also received trastuzumab 8 mg/kg IV on cycle 1 day 1, followed by 6 mg/kg every 21 days for a total of 52 weeks. The purpose of this trial was to evaluate feasibility and toxicity of this nab-paclitaxel-containing adjuvant regimen. 62 patients were treated between 2/08 and 11/08. The majority of the patients (87%) were HER2-negative. This adjuvant regimen was well tolerated, and full doses of all agents were administered in >90% of cycles. Grade 3/4 neutropenia occurred in 53% of the patients; however, only one episode of febrile neutropenia occurred in a total of 249 cycles administered. Other grade 3/4 adverse events occurred in less than 5% of patients. After short follow-up, all the patients remain alive and disease-free. The combination of nab-paclitaxel and cyclophosphamide, with or without trastuzumab, is feasible and well tolerated in patients with early stage breast cancer. Further investigation of the role of nab-paclitaxel in adjuvant breast cancer therapy is indicated, but definitive evaluation will require randomized phase III trials.     

<Emphasis Type="Italic">nab</Emphasis>-Paclitaxel weekly or every 3 weeks compared to standard docetaxel as first-line therapy in patients with metastatic breast cancer: an economic analysis of a prospective randomized trial

Docetaxel is an effective therapy for metastatic breast cancer (MBC) and considered a first-line standard of care in many jurisdictions. However, it may be associated with dose-limiting toxicity often requiring dose reductions, delays and in some cases prophylactic hematopoietic growth factors. A nanoparticle albumin-bound (nab) formulation of paclitaxel was developed to overcome the safety drawbacks of solvent-based taxanes and to improve efficacy. A randomized phase II trial comparing nab-paclitaxel 100 or 150 mg/m² weekly 3 out of 4 weeks and nab-paclitaxel 300 mg/m² every-3-week (q3w) to docetaxel 100 mg/m² q3w reported improved progression-free survival (PFS) and reduced toxicity with the former regimens. From resource use captured during the trial, an economic analysis from the perspective of the United Kingdom (UK) National Health Service was conducted. Resource use data contained within the trial database were converted to UK costs. These consisted of costs for chemotherapy, drug delivery, monitoring, supportive care drugs and hospitalization due to toxicity. Univariate and multivariate regression analyses were then conducted to compare the total cost of therapy in patients randomized to each of the four regimens. Growth factor use, hospitalization due to side effects and toxicity-induced protocol discontinuations were higher in the docetaxel group. When all of the cost components were combined for the entire population (N = 300), patients in the nab-paclitaxel 100 mg/m² weekly and 300 mg/m² q3w groups had comparable average costs to the docetaxel arm (￡15,396 vs. ￡15,809 vs. ￡12,923; P = NS). The nab-paclitaxel 150 mg/m² weekly arm had significantly higher overall costs of ￡27,222 per patient but had a significant improvement in PFS compared to docetaxel. Relative to docetaxel, the incremental costs per progression-free year gained with nab-paclitaxel 100, 150 mg/m² weekly and 300 mg/m² q3w were ￡5,600, ￡31,800 and ￡9,900, respectively. Given its improved safety profile, potentially enhanced efficacy and comparable economic impact, nab-paclitaxel (weekly or q3w) can be considered a reasonable alternative to docetaxel as first-line chemotherapy for MBC.     

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.     

Motor dominant neuropathy induced by adjuvant therapy with adriamycin and cyclophosphamide followed by dose-dense paclitaxel in a breast cancer patient

A 38-year-old woman underwent mastectomy and axillary lymph node dissection for invasive ductal carcinoma with multiple lymph node involvement. The patient received adriamycin 60 mg/m² and cyclophosphamide 600 mg/m² followed by weekly paclitaxel 80 mg/m² (without interruption) as adjuvant treatment. After receiving ten courses of paclitaxel, the patient developed motor neuropathy, with difficulty in ascending stairs and rising from a chair. A nerve conduction study demonstrated impairment of bilateral peroneal nerve function, although the sural sensory nerves were intact. After 2 weeks of withholding paclitaxel treatment, the motor neuropathy was alleviated and the scheduled doses were completed. A pharmacokinetic study of paclitaxel showed the possibility of elimination delay at the last infusion. We suggest that a dose-dense schedule of paclitaxel may be a significant risk factor for this kind of motor neuropathy.     

Feasibility and toxicity of dose-dense adjuvant chemotherapy in older women with breast cancer

Introduction The objective of this study was to examine the feasibility and toxicity of adjuvant dose-dense chemotherapy in older women with breast cancer. Methods A search of the Memorial Sloan-Kettering Cancer Center (MSKCC) breast cancer database was performed to identify all patients age 60 and older who underwent an initial consultation with a breast medical oncologist between October 1, 2002 and June 28, 2005. Inclusion criteria were: (1) age ≥ 60, (2) follow-up care obtained at MSKCC, (3) intent to treat with adjuvant dose-dense AC-T (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles followed by paclitaxel 175 mg/m² every 2 weeks for 4 cycles, with white blood cell growth factor support). Results One hundred sixty-two patients (mean age 66, range 60–76) with breast cancer, stages I (n = 5), II (n = 111), and III (n = 46) according to the sixth edition of the AJCC staging system, were included in this analysis. Forty-one percent (n = 67) experienced a grade 3 or 4 toxicity, 9% a grade 3 infection (n = 14), 6% grade 3 fatigue (n = 9), 5% neutropenic fever (n = 8), and 4% thromboembolic events (n = 7). Twenty-two percent (n = 36) did not complete the planned 8 cycles of treatment. There was no statistically significant association between age and either toxicity or treatment discontinuation. In multivariate analysis including age, pretreatment hemoglobin, and comorbidity, the presence of comorbidity (Charlson score ≥ 1) and a lower baseline hemoglobin score were associated with an increased risk of any grade 3 or 4 toxicity. Conclusions We found that the risk of toxicity depended more on comorbid medical conditions and baseline hemoglobin value than age in this cohort of older adults receiving dose-dense adjuvant chemotherapy.     

Prolonged dose-dense epirubicin and cyclophosphamide followed by paclitaxel in breast cancer is feasible

PurposeWe conducted a pilot study of dose-dense epirubicin/cyclophosphamide (EC) × 6 → paclitaxel (P) × 6 with pegfilgrastim. A previous dose-dense trial of FEC (5-fluorouracil [5-FU]/EC) × 6 with filgrastim → by weekly paclitaxel alternating with docetaxel × 18 was not feasible because of pneumonitis (with dose-dense FEC) and pericardial/pleural effusion (taxane phase). Dose-dense EC (without the 5-FU) is not associated with pneumonitis, and dose-dense paclitaxel (alone) is feasible. Primary objective was feasibility.Patients and MethodsPatients with resectable breast cancer were enrolled, regardless of surgery status, tumor size, or nodal status. Treatment regimen consisted of every-2-week EC (100/600 mg/m²) × 6 → by 2-weekly P (175 mg/m²) × 6 with pegfilgrastim 6 mg on day 2.ResultsBetween November 2004 and May 2005, 38 patients were enrolled. The median age was 47 years (range, 30-72 years); 33 of 38 (87%) were treated in the adjuvant setting and 27 of 33 (81%) had involved nodes (range, 1-46); 5 of 38 (13%) were treated pre-operatively; 33 of 38 (87%) completed all chemotherapy as planned; the remaining patients (13%) had treatment modifications for toxicity. Febrile neutropenia occurred in 6 of 38 patients (16 %) and only during EC. There were 12 hospitalizations in 9 of 38 patients (24%) enrolled.ConclusionDose-dense every-2-week EC × 6 → P × 6 with pegfilgrastim is feasible based on our prospective definition.     

A phase II feasibility trial of dose-dense docetaxel followed by doxorubicin/cyclophosphamide as adjuvant or neoadjuvant treatment for women with node-positive or high-risk node-negative breast cancer

PURPOSE: Dose-dense adjuvant chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel has improved results compared with standard dosing at 3-week intervals. Because docetaxel might be more active than paclitaxel in the treatment of metastatic breast cancer, we explored the feasibility of substituting docetaxel for paclitaxel in dose-dense adjuvant therapy. PATIENTS AND METHODS: Seventy-six patients with node-positive breast cancer received treatment with 4 cycles of docetaxel followed by 4 cycles of AC administered with pegfilgrastim at 2-week intervals. When treatment proved difficult for the first 33 patients, 2 additional cohorts were treated: first, with a reduction of pegfilgrastim and dexamethasone prophylaxis doses (cohort 2) and then with a reduction of docetaxel from 100 mg/m2 to 75 mg/m2 (cohort 3). RESULTS: Treatment with dose-dense docetaxel at 100 mg/m2 resulted in unacceptable toxicity (24% of patients required hospitalization) and compromised subsequent dosing of AC as a result of neutropenia on the day of scheduled treatment. Only 21 patients (40%) who received docetaxel 100 mg/m2 were able to receive all 8 doses at full dose and on schedule. Reduction of docetaxel to 75 mg/m2 allowed 74% of patients to receive all 8 doses as scheduled. Delivery of AC as scheduled occurred in 82% of patients who received docetaxel 75 mg/m2 versus 40% when docetaxel 100 mg/m2 was administered. CONCLUSION: Full-dose docetaxel is difficult to administer as part of this dose-dense treatment regimen. Docetaxel 75 mg/m2 can be administered with improved subsequent delivery of 4 courses of dose-dense AC. Until comparative clinical studies are available, docetaxel should not be substituted for paclitaxel in dose-dense adjuvant chemotherapy for patients with high-risk breast cancer.     

Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III–IVB head and neck squamous cell carcinoma (HNSCC)

BackgroundThere is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes.Patients and methodsThis was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m²), given with standard weekly cetuximab (450 mg/m² loading dose followed by 250 mg/m² weekly) and concurrent IMRT (total dose, 70 Gy).ResultsTwenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46–84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m²) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m²), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69–97).ConclusionThe recommended phase II dose for nab-paclitaxel is 60 mg/m² weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone.Clinicaltrials.gov IDNCT00736619.     

A phase I study of S-1 in combination with <Emphasis Type="Italic">nab</Emphasis>-paclitaxel in patients with unresectable or recurrent gastric cancer

Background

In Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study.

Methods

The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m² twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m² on day 1 or 8.

Results

Among the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m² twice daily plus nab-paclitaxel 220 mg/m² on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m² twice daily plus nab-paclitaxel 260 mg/m² on day 1). The most common grade 3–4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone.

Conclusions

Based on the present results, the RD was determined as level 3a (S-1 80 mg/m² twice daily plus nab-paclitaxel 260 mg/m² on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.

     

Phase I study of weekly nab‐paclitaxel combined with S‐1 in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer

We conducted a phase I study of a weekly nab‐paclitaxel and S‐1 combination therapy in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S‐1 dose (65 or 80 mg/m²) and nab‐paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose‐limiting toxicity was observed in one patient at Level 3 (100 mg/m² nab‐paclitaxel on days 1, 8, and 15 with 80 mg/m² S‐1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3–4 treatment‐related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression‐free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long‐term administration of this combination therapy.     

nab‐Paclitaxel in Combination With Weekly Carboplatin With Concurrent Radiotherapy in Stage III Non‐Small Cell Lung Cancer

Lessons Learned

• The concomitant use of weekly nab-paclitaxel and carboplatin with concurrent radiotherapy was demonstrated to be a safe therapeutic approach in this phase I trial of 10 evaluable patients with stage III NSCLC.
• Despite the lack of systemic glucocorticoids, there were no reported infusion reactions or cases of peripheral neuropathy in this trial, both of which are known to occur with the use of paclitaxel.

Background.

Unresectable stage III non-small cell lung cancer (NSCLC) has a 5-year survival rate of 20%, and concurrent chemoradiotherapy results in significant toxicity with the use of current chemotherapeutic agents. nab-Paclitaxel was approved by the U.S. Food and Drug Administration in October 2012 for use along with carboplatin in advanced NSCLC. This study was undertaken to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of weekly nab-paclitaxel given in combination with carboplatin and concurrent radiotherapy in patients with unresectable stage III NSCLC.

Methods.

Escalating doses of once-weekly nab-paclitaxel were given along with once-weekly carboplatin area under the plasma concentration time curve (AUC) of 2 and concurrent radiotherapy 66 Gy in 33 fractions, followed by 2 cycles of carboplatin and nab-paclitaxel consolidation chemotherapy.

Results.

Eleven patients were enrolled and received treatment per protocol, with 10 evaluable for efficacy and toxicity. At dose level 1 (nab-paclitaxel 60 mg/m²), 2 DLTs were observed: esophagitis and radiation dermatitis. Six patients were enrolled at dose level 0 (nab-paclitaxel 40 mg/m²) with no DLTs. Nine of 10 evaluable patients had a partial response.

Conclusion.

Concurrent chemoradiotherapy with nab-paclitaxel 40 mg/m² and carboplatin AUC 2 is a safe and well-tolerated therapeutic regimen in patients with stage III NSCLC. A separate phase I/II study to evaluate the efficacy of this regimen is under way.     

Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy.

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

Phase II Trial of Nab-Paclitaxel Compared With Docetaxel as First-Line Chemotherapy in Patients With Metastatic Breast Cancer: Final Analysis of Overall Survival

BackgroundA randomized phase II study in first-line MBC demonstrated superior efficacy and safety of weekly nab-paclitaxel compared with docetaxel. Final survival analyses and updated safety results are reported.Patients and MethodsThree hundred two patients with no previous chemotherapy for MBC were randomized to receive nab-paclitaxel 300 mg/m² q3w, nab-paclitaxel 100 mg/m² or 150 mg/m² the first 3 of 4 weeks (qw 3/4), or docetaxel 100 mg/m² q3w. The trial was powered for analyses of antitumor activity and safety.ResultsTreatment with nab-paclitaxel 150 mg/m² qw 3/4 resulted in a median overall survival (OS) of 33.8 months compared with 22.2, 27.7, and 26.6 months for nab-paclitaxel 100 mg/m² qw 3/4, nab-paclitaxel 300 mg/m² q3w, and docetaxel, respectively (overall P = .047). Patients receiving 150 mg/m² nab-paclitaxel had prolonged median OS compared with those in the 100 mg/m² nab-paclitaxel arm (hazard ratio, 0.575; P = .008). A trend toward a longer OS was noted in the 150 mg/m² nab-paclitaxel arm versus docetaxel arm (hazard ratio, 0.688). Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms compared with docetaxel.ConclusionsConsistent with previously published efficacy results, these data suggest that 150 mg/m² qw 3/4 may represent the most clinically efficacious nab-paclitaxel dosing regimen for patients with no previous chemotherapy for MBC. A phase III trial confirming these results would be necessary and prudent before widespread adoption of the 150 mg/m² dose in clinical practice.     

Reduction in Circulating Tumor Cell Count following Therapy with nab?-Paclitaxel plus Carboplatin in a Patient with Leptomeningeal Carcinomatosis from Breast Cancer

This case study reports on a 56-year-old woman with breast adenocarcinoma and leptomeningeal metastases. After initial chemotherapy with a dose-dense regimen of doxorubicin/cyclophosphamide followed by 3 cycles of docetaxel (100 mg/m²), a lumpectomy was performed that revealed invasive ductal carcinoma with lymph node involvement. Because of the extent of the disease, she underwent a mastectomy. Two months after the completion of initial chemotherapy, leptomeningeal metastases were detected on December 13, 2006. After completion of whole-brain radiation therapy, she received systemic chemotherapy with a novel albumin-bound 130-nm formulation of paclitaxel (nab®-paclitaxel) at 100 mg/m² combined with carboplatin AUC = 6, both given weekly. Clinical response was prompt, with a reduction in the circulating tumor cell (CTC) count from 63 before treatment to 2 after the first treatment cycle. While undergoing treatment with nab-paclitaxel plus carboplatin, she reported an improvement in neurologic symptoms, including a decrease in headaches, improved cognition and balance, and an overall improved quality of life. Before the third treatment cycle, she had a CTC count of 2. Without treatment, the median survival of patients diagnosed with leptomeningeal metastases is 4–6 weeks. However, this patient survived for 4 months after the diagnosis of leptomeningeal carcinomatosis. Treatment was discontinued because of complications of urosepsis, and the patient died on April 7, 2007. Our case shows that additional treatment with weekly nab-paclitaxel combined with carboplatin (AUC6) can prolong life for some patients with leptomeningeal carcinomatosis from breast cancer.Key words: Abraxane®, Chemotherapy, Circulating tumor cell count, Metastases, nab®-Paclitaxel, Taxanes     

nab-Paclitaxel dose and schedule in breast cancer

nab-Paclitaxel is approved for the treatment of metastatic breast cancer on an every-3-week schedule based on positive findings from a pivotal phase III trial in which nab-paclitaxel 260 mg/m² every 3 weeks was superior to solvent-based paclitaxel 175 mg/m² every 3 weeks for the primary endpoint of overall response rate (33 % vs 19 %; P = 0.001). Subsequently, a number of trials have examined different schedules, doses, and combinations in efforts to optimize nab-paclitaxel-based therapy for metastatic and early-stage breast cancer. The goal of this review is to evaluate the clinical experiences to date with nab-paclitaxel as a single agent or in combination with targeted agents in different treatment settings - with a focus on the feasibility of administration, adverse event profile, and standard efficacy endpoints, such as overall survival, progression-free survival, overall response rate, and pathologic complete response rate. In general, weekly dosing during the first 3 of 4 weeks appears to achieve the best clinical benefit in both the metastatic and early-stage settings. Furthermore, the data suggest that high doses of nab-paclitaxel, such as 150 mg/m² during first 3 of 4 weeks or 260 mg/m² every 2 weeks, may be more feasible and appropriate for treatment of early-stage disease compared with metastatic disease. Intense regimens of nab-paclitaxel may not be the best treatment approach for unselected patients with metastatic breast cancer, but may suit a subset of patients for whom immediate disease control is required. The growing number of nab-paclitaxel trials in breast cancer will lead to greater refinements in tailoring therapy to patients based on their individual disease and patient characteristics.     

Phase I/II study of albumin-bound nab-paclitaxel plus gemcitabine administered to Chinese patients with advanced pancreatic cancer

Purpose

The primary objective of this study was to evaluate the dose-limiting toxicities (DLTs) and identify the maximum-tolerated dose (MTD) and recommended dose of nab-paclitaxel plus gemcitabine as a first-line treatment in Chinese patients with advanced pancreatic ductal adenocarcinoma (PDA).

Methods

Patients with previously untreated advanced PDA were treated with nab-paclitaxel followed by gemcitabine (1,000 mg/m²) administered intravenously for 30 min on days 1 and 8 and repeated every 21 days.

Results

Patients received nab-paclitaxel at the following dose levels: 80 mg/m² (n = 3), 100 mg/m² (n = 6), and 120 mg/m² (n = 12). The DLTs evaluated were elevated alanine aminotransferase and febrile neutropenia. However, there had no two out of three to six patients experienced DLTs, the MTD was not met. A total of 93 cycles were administered. The most common grade 3/4 toxicities were neutropenia (9.52 %), thrombocytopenia (4.76 %), and sensory neuropathy (4.76 %). For 12 patients receiving 120 mg/m², the overall response rate and disease control rate were 41.67 and 83.33 %, respectively, and the median progression-free survival and overall survival were 5.23 and 12.17 months, respectively.

Conclusions

Treatment with albumin-bound nab-paclitaxel (120 mg/m²) plus gemcitabine has a favorable safety profile with an encouraging antitumor effect in Chinese patients.     

A phase I toxicity and feasibility trial of sequential dose-dense induction chemotherapy with doxorubicin,paclitaxel, and 5-fluorouracil followed by high dose consolidation for high-risk primary breast cancer

Purpose. We studied sequential dose-dense doxorubicin, paclitaxel, and 5-fluorouracil (A-T-F) before high dose chemotherapy (HDC) with autologous peripheral blood stem cell support (PBSCT). Our aims were to determine the maximum tolerated dose (MTD) of 5-FU in the dose-dense regimen and to determine the impact of dose-dense chemotherapy on HDC/PBSCT. Methods. Patients with Stage IIIB or Stage II or IIIA breast cancer with 4 involved ipsilateral lymph nodes were treated with nine cycles of chemotherapy at 14-day intervals. The regimen was doxorubicin at 80 mg/m² × 3, followed by paclitaxel at 140 mg/m² over 96 h × 3, then 5-FU at doses of 1285, 1470, or 1655 mg/m² by continuous intravenous infusion over 72 h × 3. Patients then underwent a G-CSF-stimulated peripheral blood stem cell (PBSC) apheresis prior to receiving HDC with autologous PBSCT. Results. We identified 1285 mg/m² as the MTD of 5-FU in this regimen. 5-FU-related DLTs included hand-foot syndrome, mucositis, and facial edema with somnolence. Unexpectedly, 3/19 treated patients developed congestive heart failure that prevented planned HDC. Compared to standard dose doxorubicin-containing adjuvant therapy, the dose-dense regimen also decreased CD34+ PBSC yields by about 40% (p = 0.049), requiring that 50% of patients have a supplemental bone marrow harvest. There was no difference in time to neutrophil, platelet, and red blood cell recovery after HDC. Conclusions. This regimen resulted in an unacceptably high rate of cardiac toxicity and is not recommended for further testing. It may be feasible to use a different schedule of 5-FU-containing dose-dense chemotherapy, particularly for the induction therapy of high-risk primary breast cancer prior to novel targeted therapies.     

nab-Paclitaxel for first-line treatment of patients with metastatic breast cancer and poor prognostic factors: a retrospective analysis

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated clinical benefit in metastatic breast cancer (MBC) in a randomized phase III trial versus paclitaxel (CA012; N = 454) and in a randomized phase II trial versus docetaxel (CA024; N = 300). This retrospective analysis examines whether patients with poor prognostic factors demonstrate similar outcomes to the intent-to-treat (ITT) populations in these trials. This retrospective analysis evaluated the efficacy and safety of previously untreated patients with MBC with the following poor prognostic factors: visceral dominant metastases and short disease-free interval (DFI; ≤2 years). In CA012 (n = 186 first-line patients), nab-paclitaxel demonstrated a significantly higher overall response rate (ORR) versus paclitaxel in patients with visceral dominant metastases (42 vs. 23 %; P = 0.022), whereas the higher ORR for nab-paclitaxel in patients with a short DFI (43 vs. 33 %; P = NS) was not statistically significant. In CA024, a significantly higher ORR for nab-paclitaxel 150 mg/m² versus docetaxel was observed in patients with visceral dominant metastases (76 vs. 37 %; P < 0.001). No significant differences in ORR were observed in patients with a short DFI. Although progression-free survival (PFS) and overall survival showed trends similar to ORR, statistical significance was only achieved for comparisons of PFS in patients with visceral dominant metastases in CA024 (13.1 months for nab-paclitaxel 150 mg/m² vs. 7.8 months for docetaxel [P = 0.019] and 7.5 months for nab-paclitaxel 100 mg/m² [P = 0.010]). Safety results were similar to previous reports of the ITT populations. nab-Paclitaxel demonstrated similar efficacy in patients with poor prognostic factors as in the ITT populations of these two trials. In each trial, ORR was significantly higher for nab-paclitaxel versus the comparator taxane among patients with visceral dominant metastases.     

nab-paclitaxel for the management of patients with advanced non-small-cell lung cancer

The 130 nm albumin-bound form of paclitaxel, nab-paclitaxel (Abraxane^®), was recently approved by the US FDA for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy. In a Phase III registrational trial, nab-paclitaxel plus carboplatin demonstrated a significantly improved overall response rate, the primary endpoint, and a trend toward improved survival compared with solvent-based paclitaxel plus carboplatin in patients with advanced NSCLC. Significantly less neutropenia, neuropathy, arthralgia, and myalgia were observed with the nab-paclitaxel regimen, but the solvent-based paclitaxel regimen produced less thrombocytopenia and anemia. The clinical experience with nab-paclitaxel to date and the role of this newly approved therapy in the management of NSCLC will be summarized in this article.