|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2007.12.6557 on October 29 2007 © 2007 American Society of Clinical Oncology. Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment
From the M.D. Anderson Cancer Center, Houston, TX; Instituto Nacional de Enfermedades Neoplasicas; Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; St Luke's Medical Center; Veterans Memorial Medical Center, Quezon City, Philippines; Yonsei Cancer Center, Seoul, Republic of Korea; Centro de Oncologia Rosario, Sante Fe; Hospital de Oncologia ‘Maria Curie,’ Buenos Aires, Argentina; Medical University of Gdansk, Gdansk, Poland; C.H.U. Jean Minjoz, Besançon; Centre Rene Gauducheau, Nantes; Institut Claudius Regaud, Toulouse, France; Bristol-Myers Squibb, Research and Development, Wallingford, CT; Cancer Hospital –Chinese Academy of Medical Sciences, Beijing, China; and Weill Medical College of Cornell University, New York, NY Address reprint requests to Eva S. Thomas, MD, 280 West MacArthur Blvd, Oakland, CA 94611; e-mail: eva.s.thomas{at}kp.org
Purpose Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer. Patients and Methods Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m2 intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m2 orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m2 on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.
Results Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [ Conclusion Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.
Breast cancer is the most prevalent malignancy in women and metastatic breast cancer is a leading cause of mortality, accounting for more than 400,000 deaths annually worldwide.1 Even though anthracyclines and taxanes are the most active agents in breast cancer, treatment failure occurs in a substantial number of patients and median survival for metastatic breast cancer remains 2 to 3 years.2-4 Resistance to antineoplastic agents, and in particular anthracyclines and taxanes, is a limiting factor in breast cancer therapy, either after metastatic or adjuvant treatment.3,5 With increasing use of anthracyclines and taxanes for early breast cancer, fewer effective options are available for patients with metastatic disease.3,4 Capecitabine is commonly used for the treatment of anthracycline- and/or taxane-pretreated metastatic breast cancer; however, objective response rates in phase II studies are only 20% to 28%.6,7 Therefore, there is an unmet need for new treatments of hormone- and chemotherapy-resistant, locally advanced, and metastatic breast cancer. The epothilones are a new class of antineoplastic agents that stabilize microtubule dynamics leading to apoptotic cell death. They were developed to overcome tumor resistance mechanisms. Ixabepilone (BMS-247550; Bristol-Myers Squibb, New York, NY), a semisynthetic analog of epothilone B, is the first agent in this class and has been specifically designed to provide enhanced antitumor activity relative to other antineoplastic agents. In preclinical models, ixabepilone demonstrated low susceptibility to mechanisms that confer tumor resistance, such as overexpression of efflux transporters (eg, P-glycoprotein and multidrug-resistance protein-1) and class III isoform of beta-tubulin.8,9 In phase II studies, single-agent ixabepilone showed clinical activity in metastatic breast cancer, with objective response rates ranging from 12% (in heavily pretreated patients, with disease refractory to anthracyclines, taxanes, and capecitabine) to 42% (in patients with metastatic disease after adjuvant anthracycline-based chemotherapy).10-13 Furthermore, preclinical data demonstrated synergy between ixabepilone and capecitabine.14 A phase I/II study identified the recommended dose for additional development and showed promising clinical activity of this combination in anthracycline- and taxane-pretreated metastatic breast cancer.15 We conducted a randomized, open-label, phase III study to compare ixabepilone plus capecitabine versus capecitabine alone in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.
Patients Women  18 years of age with measurable locally advanced or metastatic breast cancer pretreated with or resistant to anthracyclines and resistant to taxanes were eligible. Anthracycline and taxane resistance was defined as tumor progression during treatment or within 3 months of last dose in the metastatic setting, or recurrence within 6 months in the neoadjuvant or adjuvant setting (patients not resistant to anthracyclines were also eligible if they received a minimum cumulative anthracycline dose of doxorubicin 240 mg/m2 or epirubicin 360 mg/m2). The definition of taxane resistance was revised after 377 patients were enrolled to align entry criteria with clinical practice, to include recurrence within 4 months of the last dose in the metastatic setting or within 12 months in the adjuvant setting. Patients were allowed to receive up to three prior chemotherapy regimens in any setting, with sequential neoadjuvant/adjuvant treatment counting as one regimen. Karnofsky performance score of 70 to 100 and life expectancy 12 weeks were required.
Key exclusion criteria included brain metastases; motor or sensory neuropathy grade
Study Design Patients received ixabepilone 40 mg/m2 as a 3-hour intravenous infusion on day 1 of a 21-day cycle (diluent/vehicle for constitution: polyethoxylated castor oil and dehydrated ethanol, US Pharmacopeia, as a 50/50 vol/vol solution), plus oral capecitabine 2,000 mg/m2 administered in two divided doses each day on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m2 in two divided doses each day on days 1 through 14 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Histamine H1 and H2 receptor antagonists were administered to patients receiving ixabepilone before infusion to prevent hypersensitivity reactions. Crossover from capecitabine alone to combination therapy was not permitted.
Doses were reduced or discontinued based on tolerability. Events necessitating ixabepilone dose reduction (from 40 to 32 to 25 mg/m2) included grade 3 neuropathy lasting less than 7 days, grade 2 neuropathy lasting All randomly assigned patients were assessable for efficacy. Patients were assessed for tumor response every 6 weeks from random assignment until disease progression. Radiologic assessments and photographs of skin lesions were evaluated by independent radiology review (IRR), which was blinded to treatment assignment and investigator, using Response Evaluation Criteria in Solid Tumors. Selection of target lesions by IRR and tumor assessments were done independently of investigator evaluations. Patients who discontinued treatment for reasons other than progression were assessed every 6 weeks up to 24 weeks from random assignment and every 3 months thereafter. The primary end point was an intent-to-treat analysis of progression-free survival, defined as the time from random assignment to progressive disease or death as a result of any cause. Progressive disease, defined according to Response Evaluation Criteria in Solid Tumors, was determined from tumor assessment by IRR. Secondary end points included tumor response rate, time to response, duration of overall response (also assessed by IRR), overall survival, safety measures, and patient symptoms. All patients who received study drug were evaluated for safety. Adverse events and laboratory abnormalities were assessed according to CTCAE. Patient symptoms were measured at baseline and before each treatment cycle using the Functional Assessment of Cancer Therapy–Breast Symptom Index 8.
Statistical Analysis Additional secondary (subset) analyses of progression-free survival were performed for the randomly assigned population based on potential prognostic factors.
Patient Population Seven hundred fifty-two patients were enrolled and randomly assigned between September 2003 and January 2006 at 160 study sites in 22 countries. Of these, 737 patients were treated (369 with ixabepilone plus capecitabine and 368 with capecitabine alone).
Baseline demographics and clinical characteristics across treatment groups were well matched (Table 1). Fifteen percent of patients were human epidermal growth factor receptor (HER-2) positive. The majority of patients (65%) had
Treatment Exposure Patients receiving ixabepilone plus capecitabine received a median of five treatment cycles (range, one to 37 cycles), whereas patients in the capecitabine group received a median of four cycles (range, one to 33 cycles). In the combination group, 51% and 45% of patients required dose reduction of ixabepilone and capecitabine, respectively. In the capecitabine group, 37% of patients received a reduced dose.
The majority of patients received
Efficacy
Sensitivity analyses of potential confounding factors (including missing data/loss to follow-up, subsequent therapy before progression, and stratification factors at baseline) confirmed the robustness of the primary end point. Predefined subset analyses indicated that benefit was maintained consistently across subgroups (Fig 2). Benefit was evident irrespective of performance status, estrogen receptor, and HER-2 status. Low numbers preclude interpretation for individuals of African American/black race (n = 22), whereas patients with liver dysfunction (grade 2 liver function tests) should not be administered this combination based on safety findings described in Adverse Events. Interestingly, the improvement in progression-free survival for patients with normal or mild hepatic impairment was prolonged to 2.0 months (6.2 v 4.2 months; HR, 0.73).
Objective response rate. Ixabepilone plus capecitabine was also superior to capecitabine in terms of IRR objective response rate (35% v 14%; odds ratio, 3.2; P < .0001; Table 2). Investigator-assessed response rates were consistent (42% [95% CI, 37% to 47%] v 23% [95% CI, 18% to 27%], respectively).
IRR-assessed response rates of 33% (95% CI, 26% to 42%) and 14% (95% CI, 8% to 20%) were evident in an exploratory analysis of patients with intrinsic resistance to taxanes (ie, progressive disease as best response to prior taxane usage; Table 1). Median response duration was 6.4 months (95% CI, 5.6 to 7.1) for ixabepilone plus capecitabine and 5.6 months (95% CI, 4.2 to 7.5) for capecitabine. Time to response was similar for the two treatment groups: 11.7 and 12.0 weeks, respectively. An analysis of overall survival, a secondary end point of the study, is planned after 631 patients have died. Symptom assessment. Impact of treatment on symptoms measured by Functional Assessment of Cancer Therapy–Breast Symptom Index 8 revealed a statistically significant difference in favor of capecitabine; however, it is noteworthy that there was no clinically meaningful deterioration associated with the combination therapy.16 These results should be interpreted with caution because approximately 75% of data from both treatment arms were missing.
Adverse Events
Thirty-three (9%) patients receiving combination therapy and 39 (11%) from the capecitabine group died within 30 days of last dose (all causes). Among 42 patients with liver dysfunction at baseline (grade 2 liver function tests: AST or ALT 2.5x ULN or bilirubin 1.5x ULN), five of 16 (31%) patients receiving combination therapy died compared with five of 26 (19%) from the capecitabine group. These deaths were all related to neutropenia for the combination group and were due to progressive disease for the capecitabine group. Among patients with baseline grade 0/1 liver function tests, neutropenia-related deaths occurred in seven patients (seven of 353 patients; 1.9%) receiving combination therapy and three patients (three of 342 patients; 0.9%) treated with capecitabine. Peripheral neuropathy was common, primarily sensory, grade 1/2, cumulative, and generally reversible. Peripheral sensory neuropathy occurred in 65% of patients receiving ixabepilone plus capecitabine. Grade 3 sensory neuropathy occurred in 20% of patients and grade 4 sensory neuropathy occurred in 1% of patients. Discontinuation of one or both study drugs due to peripheral neuropathy occurred in 21% of patients receiving combination therapy after a median of six cycles. Events were managed in most cases with dose reduction. Patients with persistent grade 2/3 peripheral neuropathy received a median of three additional cycles (range, one to 16 cycles) after dose reduction. Median time from onset to improvement of grade 3/4 peripheral neuropathy (by one CTCAE grade) was 4.1 weeks, and median time to resolution to baseline or grade 1 was 6.0 weeks (Fig 3).
Myelosuppression was common in patients treated with ixabepilone plus capecitabine and consisted primarily of leukopenia and neutropenia, with a 5% incidence of febrile neutropenia (Table 3). Growth factor support, most frequently filgrastim, was administered to 20% of patients receiving combination therapy and to 3% of patients in the capecitabine group. Anemia and thrombocytopenia were generally grade 1/2 in both treatment groups. Study drug toxicity led to treatment discontinuation (both study drugs) for 18% of patients receiving combination therapy and for 7% of patients in the capecitabine group.
This phase III randomized study compared treatment with ixabepilone plus capecitabine v capecitabine alone in patients with locally advanced or metastatic breast cancer resistant to anthracyclines and taxanes. Ixabepilone plus capecitabine was associated with a 25% reduction in the estimated risk of disease progression compared with capecitabine alone. The objective response rate was also increased 2.4-fold. The median duration of response was 6.4 months for combination therapy and 5.6 months for the capecitabine group. Assessment of the primary end point of progression-free survival and several secondary end points was determined by independent review under blinded conditions.
This study is the first to our knowledge to demonstrate superior progression-free survival and objective response after the addition of a second agent to capecitabine in patients resistant to anthracyclines and taxanes, irrespective of HER-2 expression. The magnitude of this benefit in progression-free survival is comparable with that observed after first-line chemotherapy in taxane-naïve patients and is therefore clinically meaningful.17,18 Consistent clinical benefit in favor of combination therapy was maintained across subgroups, including patients with visceral metastases, more than two sites of metastatic disease, age Results from the capecitabine arm of this study are consistent with those reported from other recent phase III trials in metastatic breast cancer in which capecitabine was the comparator.20,21
Neuropathy, an event commonly associated with other tubulin-targeting agents, was also observed with ixabepilone. Neuropathy was primarily sensory, cumulative, and reversible (effectively managed by dose reduction or delay enabling a sufficient number of cycles to be administered to attain the observed levels of efficacy). Median time to onset of grade 3/4 peripheral neuropathy was four cycles. Grade 3/4 neuropathy improved by The incidence of adverse events commonly associated with capecitabine, such as hand-foot syndrome, was not exacerbated by the addition of ixabepilone. Leukopenia and neutropenia were more frequent with combination therapy, as was the incidence of neutropenia-related death. In the majority of cases, hematologic toxicity was managed by dose reduction; although growth factor support was permitted, routine use of growth factors is not recommended. A higher rate of neutropenia-related deaths was detected in patients with liver dysfunction through diligent safety monitoring, and eligibility criteria were amended rapidly to exclude these patients; once such patients were excluded, the incidence of death as a result of toxicity was reduced to 2%, with a rate similar to that of single-agent docetaxel. Dose reduction was common for patients receiving combination therapy; rates were comparable with those reported for docetaxel plus capecitabine.17 An exploratory analysis evaluating the impact of dose reduction on progression-free survival indicated no detrimental effect for patients who received a reduced dose. This study demonstrates that ixabepilone in combination with capecitabine possesses superior clinical efficacy to capecitabine alone in metastatic breast cancer that has progressed after multiple prior treatments, including anthracyclines and taxanes. Results provide support for the use of ixabepilone plus capecitabine in patients with metastatic disease pretreated or resistant to anthracyclines and resistant to taxanes, a population with limited effective treatment options. These findings warrant evaluation of the role of ixabepilone in earlier settings of breast cancer.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Judith V. Klimovsky, Bristol-Myers Squibb (C); Ronald A. Peck, Bristol-Myers Squibb (C); Pralay Mukhopadhyay, Bristol-Myers Squibb (C) Consultant or Advisory Role: Valorie F. Chan, Bristol-Myers Squibb (C), AstraZeneca (C) Stock Ownership: Judith V. Klimovsky, Bristol-Myers Squibb; Ronald A. Peck, Bristol-Myers Squibb; Pralay Mukhopadhyay, Bristol-Myers Squibb Honoraria: Linda T. Vahdat, Speaker San Antonio Breast Cancer Symposium, Advocacy Program Research Funding: Eva S. Thomas, Bristol-Myers Squibb Oncology; Linda T. Vahdat, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None
Conception and design: Eva S. Thomas, Judith V. Klimovsky, Ronald A. Peck, Linda T. Vahdat, Henri H. Roché Financial support: Judith V. Klimovsky, Ronald A. Peck Administrative support: Judith V. Klimovsky, Ronald A. Peck Provision of study materials or patients: Eva S. Thomas, Rubi K. Li, Hyun-Cheol Chung, Valorie F. Chan, Jacek Jassem, Fernando Hurtado de Mendoza, Binghe Xu, Guillermo L. Lerzo, Linda T. Vahdat, Henri H. Roché Collection and assembly of data: Eva S. Thomas, Judith V. Klimovsky, Fernando Hurtado de Mendoza, Ronald A. Peck Data analysis and interpretation: Eva S. Thomas, Henry L. Gomez, Judith V. Klimovsky, Ronald A. Peck, Pralay Mukhopadhyay, Linda T. Vahdat, Henri H. Roché Manuscript writing: Eva S. Thomas, Henry L. Gomez, Jacek Jassem, Xavier B. Pivot, Linda T. Vahdat Final approval of manuscript: Eva S. Thomas, Henry L. Gomez, Rubi K. Li, Hyun-Cheol Chung, Luis E. Fein, Valorie F. Chan, Jacek Jassem, Xavier B. Pivot, Judith V. Klimovsky, Fernando Hurtado de Mendoza, Binghe Xu, Mario Campone, Guillermo L. Lerzo, Ronald A. Peck, Pralay Mukhopadhyay, Linda T. Vahdat, Henri H. Roché
In addition to the authors, the following principal investigators participated in this study: Argentina: C.A. Bas, E. Batagelj, C.R. Blajman, R.H. Bordenave, B. Bosch, A. Castagnari, F. Coppola, N.A. Giacomi, G. Jarchum, S.L. Jovtis, J. Lacava, J.L. Martinez, I. Martinez Lazzarini, F. Rao, A. Tomadoni; Belgium: F. Bouttens, C. Focan, G. Jerusalem, P. Neven, J.B. Vermorken; Brazil: S.J. de Azevedo, C.A. Beato, A. Del Giglio, O. Feher, H.C. Freitas, S. Lago, R. Marques, A.M. Morelle, A. Murad, C.T. Oliveira, J.L. Pedrini, N.G. Skare; Canada: J. Chang, Y. Pesant, J.-A. Roy, T.N. Shenkier, M.E. Trudeau, L. Yelle; China: J. Feng, Z. Guan, Z. Jiang, S. Jiao, W. Liu, S. Qin, J. Ren, Z. Shen, Y. Wang; France: S. Abadie-Lacourtoisie, E. Achille, E. Brain, P. Chollet, J.-M. Ferrero, J.-P. Guastalla, A.-C. Hardy-Bessard, A. Lortholary, L. Mauriac, J.-F. Morere, M. Rotarski, D. Serin; Germany: W. Abendhardt, P. Fashing, P. Klare, F. Overkamp, M.J. Schaefers, A. Scharl, H. Tesch; Greece: D. Mouratidou, D. Skarlos, G. Stathopoulos; Hungary: M. Dank, E. Kover, L. Landherr, I. Lang, T. Pinter, J. Szanto; Italy: M. Aglietta, D. Amadori, E. Maiello, G. Marini; Korea: J.Y. Cho, S.-A. Im, Y.-H. Im, C.-S. Kim, S.B. Kim; Malaysia: A.Z. Bustam, S. Govindaraju; Mexico: J.A. De La Cruz-Vergas, E. Gamez-Ugalde, R.L. Quintana, T.R. Suarez Sahui; Philippines: A.H. Villalon; Poland: K. Drosik; Spain: J.M. Baselga, E. Ciruelos, R. Colomer, M. Margeli, J.I. Mayordomo, M. Munoz, A. Ruiz; Sweden: J. Bergh, Z. Einbeigi; Taiwan: P.-M. Chen, C.-J. Tai, W.-C. Su; Thailand: W. Arpornwirat, V. Ratanatharathorn, V. Srimuninnimit, N. Voravud; United Kingdom: R. Coleman, N. Davidson, S. Johnston, A.L. Jones, R.W. Laing, C. Price, M.W. Verrill, A.M. Wardley; United States of America: J. Abraham, R.J. Belt, A.M. Brufsky, S. Burdette-Radoux, S.G. Diab, L. Fehrenbacher, J.K. Giguere, R.O. Giudice, R.H. Greenberg, W. Hanna, V.L. Hansen, G.A.G. Houston, L.F. Hutchins, A.M. Keller, R.O. Kerr, R. Lambert-Falls, L.R. Laufman, M.C. Liu, A.P. Lyss, R.A. Michaelson, R.L. Moroose, E.A. Perez, M.C. Perry, H.S. Rugo, F.M. Senecal, T.D. Shuster, R.D. Siegel, P.T. Silberstein, K. Tkaczuk, D. Toppmeyer, D.A. Yardley.
published online ahead of print at www.jco.org on October 29, 2007. Supported by Bristol-Myers Squibb. Interim efficacy and safety analyses were supervised by an independent data-monitoring committee. The authors vouch for the completeness and accuracy of results presented. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 3, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24:2137-2150, 2006 2. Hortobagyi GN: Treatment of breast cancer. N Engl J Med 339:974-984, 1998 3. Valero V, Hortobagyi GN: Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer? J Clin Oncol 21:959-962, 2003 4. Bernard-Marty C, Cardoso F, Piccart MJ: Facts and controversies in systemic treatment of metastatic breast cancer. Oncologist 9:617-632, 2004 5. Longley DB, Johnston PG: Molecular mechanisms of drug resistance. J Pathol 205:275-292, 2005[CrossRef][Medline] 6. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999 7. Fumoleau P, Largillier R, Clippe C, et al: Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 40:536-542, 2004[CrossRef][Medline] 8. Lee FYF, Camuso A, Castenada S, et al: Preclinical studies of ixabepilone (BMS-247550) demonstrate optimal antitumor activity against both chemotherapy-sensitive and -resistant tumor types. Proc Am Assoc Cancer Res 47:119, 2006 (abstr 503) 9. Wartmann M, Altmann KH: The biology and medicinal chemistry of epothilones. Curr Med Chem Anticancer Agents 2:123-148, 2002[CrossRef][Medline] 10. Perez EA, Lerzo G, Pivot X, et al: Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 25:3407-3414, 2007 11. Thomas E, Tabernero J, Fornier M, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25:3399-3406, 2007 12. Low JA, Wedam SB, Lee JJ, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726-2734, 2005 13. Roché H, Yelle L, Peck R: Efficacy results of a phase II study of ixabepilone in patients with metastatic breast cancer previously treated with an anthracycline. Presented at the International Union Against Cancer World Cancer Congress, Washington, DC, July 8-12, 2006 (abstr 96-3). http://2006.confex.com/uicc/uicc/techprogram/P8062.HTM 14. Lee FY, Camuso A, Castenada C, et al: Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts. J Clin Oncol 24:597s, 2006 (suppl; abstr 12017) 15. Bunnell CA, Klimovsky J, Thomas E: Final efficacy results of a phase I/II trial of ixabepilone in combination with capecitabine in patients with metastatic breast cancer (MBC) previously treated with a taxane and an anthracycline. J Clin Oncol 24:568s, 2006 (suppl; abstr 10511) 16. Yost KJ, Yount SE, Eton DT, et al: Validation of the Functional Assessment of Cancer Therapy–Breast Symptom Index (FBSI). Breast Cancer Res Treat 90:295-298, 2005[CrossRef][Medline] 17. O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002 18. Albain KS, Nag S, Calderillo-Ruiz G, et al: Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival. J Clin Oncol 22:5s, 2004 (suppl; abstr 510) 19. Haffty BG, Yang Q, Reiss M, et al: Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24:5652-5657, 2006 20. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 21. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 22. Lee JJ, Swain SM: Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol 24:1633-1642, 2006 23. O'Shaughnessy J, Blum J, Sandbach J, et al: Weekly nanoparticle albumin paclitaxel (Abraxane) results in long-term disease control in patients with taxane-refractory metastatic breast cancer. 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 1070) 24. Seidman AD, Berry D, Cirrincione C, et al: CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized to T in HER2 normal MBC. J Clin Oncol 22:6s, 2004 (suppl; abstr 512) 25. Pignata S, De Placido S, Biamonte R, et al: Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian Cancer (MITO-4) retrospective study. BMC Cancer 6:5, 2006. http://www.biomedcentral.com/1471-2407/6/5[CrossRef][Medline] Submitted May 30, 2007; accepted August 21, 2007.
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
= .05) to detect a hazard ratio (HR) of 0.77 (assuming median progression-free survival of 3 months for capecitabine). The final 
