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Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2321-2327 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.128 Capecitabine Plus Paclitaxel As Front-Line Combination Therapy for Metastatic Breast Cancer: A Multicenter Phase II StudyFrom the Northwestern University, Chicago, IL; SW Oncology Associates, Lafayette, LA; Mid Dakota Clinic, Bismark, ND; Roche Laboratories Inc, Nutley, NJ; University of Cincinnati Medical Center, Cincinnati, OH; and Duke University Medical Center, Durham, NC Address reprint requests to William J. Gradishar, MD, Northwestern University, 676 N St. Clair, Suite 850, Chicago, IL, 60611; e-mail: w-gradishar{at}northwestern.edu
PURPOSE: The goal of this multicenter, open-label phase II study was the clinical evaluation of combination therapy with the oral fluoropyrimidine capecitabine and the taxane paclitaxel in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-seven patients with MBC received oral capecitabine at 1,650 mg/m2/d (825 mg/m2 twice daily) on days 1 through 14, and intravenous infusion of paclitaxel at 175 mg/m2 on day 1 of each 21-day treatment cycle. Treatment continued until disease progression, intolerable toxicity, or patient's decision to discontinue. Patients (35 to 76 years old) had a median Karnofsky performance status of 90%. Forty-four patients (94%) received study treatment as first-line therapy for metastatic disease. RESULTS: Objective responses occurred in 24 (51%) patients; seven (15%) complete responses and 17 (36%) partial responses. Stable disease lasting 180 days or more was observed in nine (19%); the clinical response rate was 70%. Median duration of response was 12.6 months, median time to disease progression was 10.6 months, and median overall survival time was 29.9 months. The most common treatment-related adverse events, regardless of severity, were alopecia, hand-foot syndrome, nausea, and fatigue. Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only grade 3 or 4 treatment-related adverse events that occurred in more than 10% of patients. CONCLUSION: The combination of capecitabine plus paclitaxel is a highly active and generally well-tolerated regimen for first-line treatment of MBC.
Despite advances in our understanding of the biology of breast cancer, once metastasis occurs, the vast majority of patients succumb to the disease. While new treatment strategies are under intense investigation, cytotoxic chemotherapy remains a crucial component of the therapeutic armamentarium. Capecitabine (Xeloda, Hoffmann-La Roche Inc, Nutley, NJ), a tumor-targeted oral fluoropyrimidine, was first approved in 1998 for the treatment of patients with breast cancer refractory to paclitaxel and anthracyclines.1,2 When used as monotherapy for women with metastatic breast cancer (MBC) that has recurred after previous chemotherapy, capecitabine induces response rates in the range of 20% to 36%, and median survival of greater than 1 year.3-6 Recently, the combination of capecitabine and the taxane docetaxel has been found to be even more effective than either agent used alone. Capecitabine plus docetaxel significantly increased survival compared with docetaxel alone (14.5 v 11.5 months) in patients with metastatic disease recurring after anthracycline therapy.7 The enhanced clinical efficacy of the combination of capecitabine and a taxane was predictable, given the mechanisms of action of the drugs and the results of preclinical studies. Capecitabine is an orally available fluoropyrimidine carbamate prodrug, which is converted to fluorouracil (FU) by a three-step enzymatic sequence. The final, rate-limiting step producing the active drug is catalyzed by thymidine phosphorylase (dThdPase). This enzyme is present in multiple normal tissues but is found at higher levels in tumors, resulting in preferential intratumor generation of cytotoxic drug.8,9 Several therapeutic agents, including the taxanes docetaxel and paclitaxel, have been shown to increase intratumoral dThdPase levels even further.10,11 Taxane-induced upregulation of dThdPase, either direct or via upregulation of tumor necrosis factor-alpha, could therefore augment the generation of active FU at the tumor site.12 Capecitabine, in turn, may enhance the antitumor effects of taxanes by inhibiting expression of bcl-2, a key antiapoptotic mediator. Preclinical studies using breast tumor samples revealed that tissues from p53-negative patients treated for 5 days with 5'-deoxy-5-fluorouridine (5'-dFUr), the immediate precursor to FU, had half the level of bcl-2 expression than that measured in untreated patients' tissue.13 Even greater suppression of bcl-2 expression, up to 20-fold, was observed in MX-1 and MAXF401 tumor xenografts after treatment with capecitabine.14 The existence of these reciprocally enhancing mechanisms may underlie the antitumor synergy between capecitabine and taxanes observed in preclinical tumor xenograft models. Taxanes plus FU, in the same models, show only an additive effect.11 In addition, because of the different mechanism of action of capecitabine and taxanes, no cross-resistance has been detected in tumor lines resistant to taxane or FU. Finally, the toxicity profile of capecitabine only partially overlaps that of the taxanes. The clinical evaluation of capecitabine in combination with taxanes is thus based on a sound molecular rationale and synergy documented in preclinical models. The efficacy of capecitabine/taxane combination therapy in MBC has been demonstrated recently in a large, international phase III study that compared capecitabine plus docetaxel with docetaxel monotherapy in patients with metastatic disease after failure of anthracycline-containing chemotherapy.7 The combination therapy demonstrated superior efficacy as measured by response rate, time to disease progression, and, most importantly, overall survival. Only one third of the patients in this trial received capecitabine/docetaxel as first-line therapy for metastatic disease. In the majority of patients, the combination therapy was second-line or third-line therapy. To further evaluate the efficacy of capecitabine in combination with taxanes, this phase II study examined the combination of capecitabine plus paclitaxel, at doses previously defined in a phase I study,15 in a patient population primarily receiving the treatment as first-line therapy for metastatic disease.
The primary objectives of the study were to evaluate the response rate and the safety of a capecitabine and paclitaxel combination regimen for first-line or second-line therapy in women with metastatic breast carcinoma. Secondary objectives included evaluation of the survival status and the overall efficacy profile (time to progression, time to response, and duration of response).
Patient Population Patients were ineligible if they had relapsed after taxane therapy less than 12 months before study entry, had more than one prior chemotherapeutic regimen for metastatic disease, or had any prior fluoropyrimidine therapy unless given in an adjuvant setting 12 months earlier. Patients were also excluded if they had a life expectancy of less than 3 months, treatment for other carcinomas within the last 5 years (except nonmelanoma skin cancer and treated in situ cervical cancer) prior unanticipated severe reaction to fluoropyrimidine therapy or known sensitivity to FU, an organ allograft, clinically significant cardiac disease, evidence of CNS metastases, history of uncontrolled seizures, CNS disorders or psychiatric disability, known existing coagulopathy and/or requiring concomitant coumarin-based anticoagulants, previous chemotherapy or radiotherapy less than 4 weeks before the start of study treatment, or unresolved related toxicities from such therapy. Patients were required to have near normal hematologic values (neutrophils > 1.5x 109/L; platelet count >100x 109/L) and renal function (serum creatinine < 1.5x upper limit of normal [ULN]; serum bilirubin < 1.5x ULN; ALT or AST < 2.5x ULN or < 5x ULN in the case of liver metastases, or alkaline phosphatase < 2.5x ULN or < 5x ULN in the case of liver metastases or < 10x ULN in the case of bone disease).
Study Treatment The duration of treatment depended on the individual response and tolerance. Patients with clearly documented progressive disease discontinued study treatment. Patients responding (complete or partial), or whose disease was stable, were treated until progression of disease, intolerable toxicity, or patient withdrawal from the study.
Dose Modifications
No dose adjustments were made for paclitaxel. Patients developing neutropenic fever received standard supportive care; granulocyte colony-stimulating factor was not used prophylactically. Study medication was delayed until the absolute neutrophil count was
Study Assessments At each study visit, hematology and blood chemistry measurements were taken and a general physical examination, including vital signs and physical measurements (such as weight and KPS), was performed. Additional radiographic imaging was performed as clinically indicated. Duration of treatment was based on tumor response. Adverse events were recorded throughout the study. Objective tumor responses were assessed by CT scan at 6, 12, and 18 weeks of treatment, and every 9 weeks thereafter until disease progression. Patients without a postbaseline tumor measurement were considered nonresponders. The best overall response achieved, using the standard WHO criteria of tumor response, was reported for each patient. A complete response (CR) required disappearance of all clinically detectable disease and a partial response (PR) required at least a 50% decrease in total size of the lesions (sum of the products of the two greatest perpendicular diameters of all measurable lesions), with no appearance of new lesions or progression of any lesion. Both CR and PR had to be confirmed by two observations not less than 4 weeks apart. Stable disease (SD) was defined as less than 50% decrease or a 25% increase in the size of one or more measurable lesions. Progressive disease was defined as a 25% or more increase in the sum of perpendicular diameters of one or more measurable lesions with individual minimal area greater than 2 cm2 or the appearance of new lesions. For malignant lesions with individual minimal areas of 2 cm2 or less, an increase in size of any individual lesion of at least 1 cm2 in area was required. Adverse events and medical care (eg, concomitant medications or medical procedures) were recorded throughout the study. The National Cancer Institute of Canada Common Toxicity Criteria were used to grade the adverse events; hand-foot syndrome was graded 1 to 3, as defined in previous capecitabine clinical studies.3,16
Statistical Analysis An exact 90% CI was calculated for the overall objective response rate using the Clopper-Pearson formula.18 The lower limit of 90% CI was used for the one-sided hypothesis test at a significance level of 5%. All eligible patients who received at least one dose of both study chemotherapy agents were included in the intent-to-treat analysis of efficacy and in the safety population. The Kaplan-Meier product-limit method was applied on survival, time to disease progression, time to objective response, and duration of overall response for responders to estimate survival function and median time to event.19 Safety parameters (adverse events, laboratory tests, and vital signs) were summarized.
Patient Demographics From May 1999 to December 2000, 48 women were enrolled in the study at 20 centers in the United States. Forty-seven patients were assessable for safety and response. One patient experienced a severe hypersensitivity reaction to paclitaxel and withdrew from the study before receiving capecitabine. Patient characteristics are summarized in Table 1. The patients ranged in age from 35 to 76 years (median, 54 years) and weighed 54 to 136 kilograms (median, 72.2 kg). The median KPS was 90% and the median time between initial diagnosis and enrollment was 52.4 months (range, 0.8 to 180.5 months). The estrogen-receptor and/or progesterone-receptor status of disease was positive in 49% and 47% of the patients, respectively, and unknown in 38% of patients. The most common sites of metastases were lung, bone, lymph nodes, and liver.
Prior cancer treatments are summarized in Table 2. The majority of patients had prior adjuvant or neoadjuvant chemotherapy regimens (68% anthracycline-containing, 49% FU-containing, and 9% taxane-containing regimens). Eleven patients (23%) were chemotherapy-naïve at study entry. All but three patients (94%; 44 of 47 patients) received study therapy as first-line treatment for metastatic disease. One patient had received doxorubicin-vinorelbine, one patient had received paclitaxel, and one had received paclitaxel-carboplatin for metastatic disease before study therapy. Prior treatment with paclitaxel in these two patients was completed more than 12 months before study entry.
Response to Treatment Objective tumor responses were observed in 24 of the assessable patients (51%; 90% CI, 38.2% to 63.8%); seven patients (15%) achieved a CR, and 17 patients (36%) achieved a PR. Stable disease (SD) was observed in an additional 14 patients (30%), of these, nine had SD lasting for more than 6 months (Table 3). The overall clinical benefit (CR + PR + SD  180 days) was 70%. The median time to response for the 24 responders was 3.9 months (95% CI, 2.6 to 17.0 months). The majority of the responders (17 patients; 70.8%) had multiple metastatic sites, predominately in lung, liver, and lymph nodes. All of the seven complete responders and 16 of the 17 partial responders received study therapy as first-line treatment.
The median duration of response was 12.6 months (95% CI, 10.3 to 17.2 months). The Kaplan-Meier estimate of median time to disease progression was 10.6 months (95% CI, 6.7 to 15.2; Fig 1). Median survival time for the total study population was 29.9 months (Fig 2).
Dose Modification A total of 424 cycles of capecitabine and paclitaxel were administered to the 47 treated patients. The median number of cycles was seven (range, one to 42 cycles), for an average of 123.3 days (range, 1 to 578 days). The average daily dose of capecitabine was 2,546 mg/d (range, 1,171 to 4,100 mg/d). On average, 78% of the planned daily dose of capecitabine was delivered. Dose reductions were required for 19 patients (40%) at some time during their therapy, ranging from cycle 1 to cycle 11 (Table 4). The protocol did not allow for dose adjustments of paclitaxel and no dose modifications were made.
Safety The most frequent treatment-related adverse events regardless of severity were alopecia, hand-foot syndrome, nausea, and fatigue. A total of 53 grade 3 or 4 treatment-related adverse events occurred in 27 of the patients (57%). The treatment-related adverse events that occurred in greater than 5% of patients are presented in Table 5. Of the 27 grade 3 or 4 adverse events occurring in more than 5% of patients, only two were grade 4 (one neutropenia and one fatigue). Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only grade 3 or 4 treatment-related adverse events that occurred in more than 10% of patients. Ten of the 48 enrolled patients (21%) discontinued participation in the study due to an adverse event, the latter included hand-foot syndrome, paresthesia, peripheral neuropathy, or hypersensitivity reaction (Table 6). One patient withdrew from the study after a hypersensitivity reaction during the first paclitaxel infusion, and received no capecitabine. Grade 3 or 4 laboratory abnormalities occurred in 32 patients (68%), with more than 10% of the patients experiencing grade 3 or 4 lymphopenia (23%) or hyperglycemia (28%).
Eleven patients (23%) experienced serious adverse events; of these, three serious adverse events were considered by the investigators to be unrelated to study treatment, and eight events (17%), including pulmonary embolism, peroneal nerve palsy, peripheral neuropathy, pyrexia, neutropenic fever, pleural effusion, dyspnea and cellulitis, were considered probably, possibly, or remotely related to study treatment.
This phase II study supports the concept that the complementary mechanisms of action and non-overlapping major toxicities of capecitabine and taxanes create a highly effective and well-tolerated combination chemotherapy regimen for MBC. Both capecitabine and taxanes are effective when used as monotherapy, and preclinical studies in tumor xenograft models demonstrate synergistic antitumor activity when the drugs are used in combination. This study evaluated a combination of capecitabine (825 mg/m2 twice daily on days 1 to 14 every 3 weeks) and paclitaxel (175 mg/m2 as a 3-hour infusion on day 1 every 3 weeks) in patients with metastatic breast cancer. This combination had been shown previously to present an acceptable toxicity profile without clinically relevant pharmacokinetic interactions.12 In the current study, the great majority of patients (94%) received the combination as first-line therapy for their metastatic disease. The combination therapy proved to have significant antitumor activity based on an overall objective response rate of 51%, a duration of response greater than 12 months, and clinical benefit rate of 70%. Most importantly, median survival was 29.9 months and median time to disease progression was 10.6 months. The toxicities associated with the combination of capecitabine plus paclitaxel were predictable and those of clinical importance were readily manageable. Alopecia and neutropenia, known side effects of paclitaxel, and hand-foot syndrome, a known side effect of capecitabine, were the only treatment-related adverse events that occurred at grade 3 or 4 intensity in more than 10% of the patients. The high clinical activity of capecitabine plus paclitaxel documented in this phase II study is consistent with that reported from the recent large international phase III trial of capecitabine combined with docetaxel, compared with docetaxel alone, in anthracycline-pretreated patients.7 The capecitabine plus docetaxel combination therapy resulted in an objective response rate of 42% versus 30% for docetaxel monotherapy (P = .006), median time to disease progression of 6.1 months versus 4.2 months, and an overall survival of 14.5 months versus 11.5 months (P = .0126), respectively. Currently, this is the only study demonstrating a survival advantage for combination chemotherapy over single-agent taxane therapy, with a manageable side effect profile. Of note, the patient population in the phase III trial was heavily pretreated, with 67% receiving study treatment as the second-line or third-line therapy of their metastatic disease. The combination therapy reduced the risk of death by 23% and the early separation of the survival curves in this study suggested that treatment prevented early deaths even in patients with poor prognosis. The dose of capecitabine used in this phase II study (825 mg/m2 twice daily) was significantly lower than that administered to patients in the international phase III study, in which patients received 1,250 mg/m2 of capecitabine twice daily. The lower dose is associated with lower frequency and severity of gastrointestinal toxicity. Only 4% of patients in this study experienced grade 3 diarrhea, as opposed to 14% of patients receiving capecitabine 1,250 mg/m2 twice daily, and diarrhea of all grades was reduced to nearly half the frequency of that observed with a higher dose (38% v 64%). No patient experienced grade 3 stomatitis in this study, while 17% of patients in the international study did. Treatment interruption or individual dose adjustment of capecitabine was generally effective in managing the adverse events, and there were no treatment-related deaths. In agreement with other current studies,2 the use of a lower dose of capecitabine (825 mg/m2 twice daily as opposed to 1,250 mg/m2 twice daily) produced good clinical benefit plus a reduction in clinically significant toxicity. An area of controversy that relates to the treatment of metastatic breast cancer is whether patients are better served by receiving sequential single-agent chemotherapy versus combination chemotherapy. Although some combination regimens are associated with higher response rates compared with single agents, few combination chemotherapy regimens have been associated with an improvement in survival. For an individual patient, optimizing the chances of obtaining a tumor response may be critical, particularly if the disease is progressing rapidly and/or there is significant visceral disease. For these patients, even in the absence of a survival advantage, combination chemotherapy may be an optimal treatment choice. The survival advantage that was observed in the trial comparing single-agent docetaxel with the combination of docetaxel and capecitabine7 may have been replicated by using the two drugs in sequence. The trial designs of the international study and this phase II study did not allow for an examination of this issue. Ultimately, the decision to use single agents or combination chemotherapy is based on an analysis of patient and disease characteristics. In summary, capecitabine, using an intermittent (2 weeks on, 1 week off) regimen of 825 mg/m2 twice daily in combination with paclitaxel at 175 mg/m2 at the beginning of each treatment cycle, provides an important first-line treatment option for metastatic breast cancer. This regimen combines efficacy, notably increased survival, with convenience and cost-effectiveness.20 Reducing the capecitabine dose from 1,250 to 825 mg/m2 twice daily has a beneficial effect on the toxicity profile, particularly for gastrointestinal events, without any apparent decrease in efficacy. Capecitabine, alone or in combination with docetaxel, is currently the standard of care for patients with MBC. This study supports the use of capecitabine in combination with taxanes as a drug class and also as a first-line treatment for metastatic breast cancer. This trial and other recent clinical studies also suggest that capecitabine will be effective in combination with other conventional and novel anticancer agents that have a complementary mechanism of action, both in breast cancer and other solid tumors.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Todd Hill, Roche Laboratories, Inc. Acted as a consultant within the last 2 years: Elyse E. Lower, Aventis, Genentech, Novartis, AstraZeneca. Received more than $2,000 a year from a company for either of the last 2 years: Todd Hill, Roche Laboratories, Inc; Yin-Miao Chen, Roche Laboratories, Inc; Dvorit Samid, Roche Laboratories, Inc; Elyse E. Lower, Aventis, Genentech, Novartis, AstraZeneca.
This study was supported by Roche Laboratories Inc. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, 2001, San Antonio Breast Cancer Symposium, 2002 and the European Cancer Conference, Copenhagen, Denmark, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Kaklamani VG, Gradishar WJ: Role of capecitabine (Xeloda) in breast cancer. Expert Rev Anticancer Ther 3:137-144, 2003[CrossRef][Medline] 2. O'Shaughnessy JA: The evolving role of capecitabine in breast cancer. Clin Breast Cancer 4:S20-25, 2003 (suppl 1)
3. 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 4. Blum JL, Dieras V, LoRusso PM, et al: Multicenter, phase II study of oral capecitabine in taxane-pretreated metastatic breast cancer. Cancer 92:1759-1768, 2001[CrossRef][Medline]
5. O'Shaughnessy JA, Blum J, Moiseyenko V, et al: Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247-1254, 2001 6. Talbot DC, Moiseyenko V, Van Belle S, et al: Randomized, Phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 86:1367-1372, 2002[CrossRef][Medline]
7. 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 8. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274-1281, 1998 9. Schuller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine in tumor following oral administration in colorectal cancer patients. Cancer Chemother Pharmacol 45:291-297, 2000[CrossRef][Medline] 10. Kano Y, Akutsu M, Tsunoda S, et al: Schedule-dependent interaction between paclitaxel and 5-fluorouracil in human carcinoma cell lines in vitro. Br J Cancer 74:704-710, 1996[Medline] 11. Ishitsuka H: Capecitabine: preclinical pharmacology studies. Invest New Drugs 18:343-354, 2000[CrossRef][Medline]
12. Fujimoto K, Tanaka K, Tominaga T: Schedule dependency of antitumor activity in combination therapy with capecitabine/5'-deoxy-5-fluorouridine and docetaxel in breast cancer models. Clin Cancer Res 7:1079-1086, 2001
13. Suzuki K, Kazui T, Yoshida M, et al: Drug-induced apoptosis and p53, bcl-2 and BAX expression in breast cancer tissues in vivo and fibroblast cells in vitro. Jpn J Clin Oncol 29:323-331, 1999 14. Fujimoto-Ouchi K, Yasuno H, Tanaka Y, et al: Schedule dependency of antitumor activity in combination therapy with capecitabine (Xeloda) and docetaxel in breast cancer models. Proc Am Assoc Cancer Res 42:463, 2001 (abstr)
15. Villalona-Calero MA, Weiss GR, Burris HA, et al: Phase I and pharmacokinetic study of the oral fluoropyrmidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies. J Clin Oncol 17:1915-1925, 1999
16. Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: Results of a randomized phase II study. J Clin Oncol 18:1337-1345, 2000 17. Brown BW, Herson J: STPLAN: An interactive study planning package. The American Statistician 35:164, 1981
18. Clopper CJ, Pearson ES: The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26:404, 1934 19. Slud E, Byar DP, Green SB: A comparison of reflected versus test-based confidence intervals for the median survival time, based on the censored data. Biometrics 40:587-600, 1984[CrossRef][Medline]
20. Verma S, Ilerich AL: Population-based pharmacoeconomic model for adopting capecitabine/docetaxel combination treatment for anthracycline-pretreated metastatic breast cancer. Oncologist 8:232-240, 2003 Submitted December 18, 2003; accepted March 22, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
