Article Tools
Breast Cancer
Article Tools
Phase II Trial of Capecitabine and Weekly Paclitaxel As First-Line Therapy for Metastatic Breast Cancer
Abstract
The taxanes and capecitabine have synergistic antitumor activity in preclinical models. This trial was designed to determine the efficacy and tolerability of weekly paclitaxel plus capecitabine as first-line treatment for metastatic breast cancer (MBC).
Participants had histologically proven breast cancer, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group. Exclusion criteria included prior taxane therapy or any prior capecitabine or infusional fluorouracil. Participants received capecitabine 825 mg/m2/dose orally bid (1,650 mg/m2/d) for days 1 to 14. Paclitaxel 80 mg/m2 was administered intravenously weekly on days 1 and 8. Cycles were repeated every 3 weeks. Responders (complete or partial) or those with stable disease were treated until progression of disease or intolerable toxicity.
Fifty-five women were enrolled; 94% received study therapy as first-line treatment for MBC. In the intent-to-treat population, objective responses (partial) were achieved in 30 patients (55%; 95% CI, 40% to 69%), and six additional patients had stable disease for 6 months or longer (clinical benefit rate of 65%). The median duration of response was 10 months (range, 2.5 to 18.7 months). Dose modifications and reductions were common, particularly for capecitabine, leading to a delivered dose-intensity of 75% for capecitabine and 91% for paclitaxel. The most frequent grade 3 to 4 treatment-related adverse events were hand-foot skin reaction (n = 10); neutropenia (n = 7); fatigue (n = 4); and leukopenia, diarrhea, and pain (n = 3 each).
Current goals of therapy for metastatic breast cancer (MBC) are to prolong survival, prolong disease control, and to provide better palliation for patients. To this end, combination therapy with agents with synergistic activity in preclinical models would be predicted to be highly active in patients. This study was developed to evaluate the efficacy and safety of combination therapy with weekly paclitaxel and capecitabine in women with MBC.
Capecitabine is an oral fluoropyrimidine that preferentially delivers fluorouracil (FU) to the tumor. Approved in 1998 as treatment for MBC refractory to paclitaxel and anthracyclines, capecitabine induces objective response rates (RR) of 20% to 36%, and median survival of more than 1 year.1-6 Capecitabine in combination with docetaxel has greater efficacy than single-agent docetaxel; the combination increased survival significantly compared with single-agent docetaxel (14.5 v 11.5 months) in patients with MBC who experienced disease progression after anthracycline therapy.7 The most common treatment-related adverse events (TRAEs), with capecitabine 1,250 mg/m2 bid and docetaxel 75 mg/m2 were alopecia, hand-foot skin reaction (HFS), nausea, and fatigue. Neutropenia (15%) and HFS (11%) were the only grade 3 or 4 TRAEs that occurred in more than 10% of patients. In this trial the tolerable delivered dose of capecitabine for most patients was 950 mg/m2 bid for 14 days.
Paclitaxel is an active agent in the treatment of MBC and is more effective when administered weekly compared with a schedule of once every 3 weeks.8-10 A randomized trial in women with MBC (Cancer and Leukemia Group B trial 9840) demonstrated significantly higher RR (40% v 28%; P = .0017) and a longer time to progression (TTP; 9 v 5 months; P = .0008) with the weekly administration of paclitaxel (80 to 100 mg/m2) compared with paclitaxel 175 mg/m2 on a schedule of once every 3 weeks among women receiving first- or second-line treatment.10 However, in this trial, weekly paclitaxel caused more grade 3 sensory and motor neuropathy compared with the regimen administered once every 3 weeks (23% and 8% v 12% and 4%, respectively). Weekly paclitaxel also improves pathologic complete response (CR) in operable breast cancer when compared with paclitaxel administered on an every 3 week schedule, with a pathologic CR rate of 28.2% compared with 15.7% when administered before chemotherapy with FU, doxorubicin, and cyclophosphamide.11
There is a theoretical advantage to using paclitaxel on a weekly schedule in conjunction with capecitabine based on the duration of the upregulation of thymidine phosphorylase (dThPase) by paclitaxel in model systems. The metabolism of capecitabine to the active agent, FU, provides insight into the rationale for combining capecitabine with taxanes in this phase II study. Breast cancers express more dThPase, the final enzymatic step in the metabolism of capecitabine to FU, than normal breast tissue.12 A number of chemotherapy agents increase the levels of dTHPase in tumor tissue.13 The rationale for combining paclitaxel with capecitabine is based on the upregulation of dTHPase, which has been demonstrated in a model of athymic mice bearing capecitabine-resistant human colon cancer xenografts. Treatment with paclitaxel led to a 7.9-fold increase in intratumoral dThPase. An increase in dThPase activity occurred 4 days after treatment with paclitaxel and persisted for 10 days.13 These data led to the current concept for this clinical trial, using paclitaxel on days 1 and 8 during a 14-day exposure to capecitabine in patients with MBC. Moreover, these agents have nonoverlapping toxicities and therefore can be combined with reasonable tolerability. It was anticipated that by allowing a week off from weekly paclitaxel therapy, the frequency of sensory neuropathy could be reduced.
In a phase I study in patients with various solid tumors, dose-limiting toxicities (diarrhea, HFS, and mucositis) occurred at capecitabine 2,000 mg/m2/d and paclitaxel 60 mg/m2/wk.14 The study was closed due to poor accrual; however, a subsequent phase I trial,15 in women with MBC, determined that the combination of paclitaxel administered at 175 mg/m2 every 3 weeks in conjunction with capecitabine at 1,650 mg/m2 divided bid for 14 days was the maximum-tolerated dose. Despite extensive prior therapy, substantial responses were seen in nine of 16 women (56%) with measurable disease, including two women who experienced a CR. Responses were durable, with the median duration of response of 8.0 months (range, 2.5 to 22.5 months) and the median TTP and survival were 9.3 months (range, 4 to 24 months) and 18.5 months (range, 11.5 to 30 months), respectively. Pharmacokinetic analysis showed no major interaction between these two agents when administered together. The most common nonhematologic toxicities were HFS and diarrhea.15
Uhlmann et al16 conducted a phase I study among Swiss women with MBC using weekly paclitaxel 80 mg/m2 on days 1, 8, and 15, with capecitabine administered orally on days 1 to 14 of a 21-day schedule, with four dose levels of capecitabine. The optimal dose of capecitabine was determined to be 1,000 mg/m2 bid based on cumulative toxicity (primarily skin toxicity) requiring dose modification. The RR was 40% (six of 15 assessable patients), with stable disease (SD) for at least 9 weeks in another seven patients. The median TTP was 6.3 months, and the median survival was 16.7 months.
O'Shaughnessy et al7 demonstrated in a large, international, multicenter, randomized phase III trial that capecitabine in combination with docetaxel produced significantly better results with regard to RR (42% v 30%), TTP (6.1 v 4.2 months), and overall survival (OS; 14.5 v 11.5 months). Although the combination was associated with significant toxicities (particularly stomatitis, diarrhea, and HFS), dose modification(s) ameliorated the adverse effects without influencing efficacy.7 It has been demonstrated that dose modification of capecitabine, when administered as a single agent for MBC, does not reduce efficacy.2
Given the high degree of efficacy of the docetaxel/capecitabine combination, but the significant toxicity observed with 1,250 mg/m2 bid capecitabine schedule, as well as the promising efficacy and safety observed with weekly paclitaxel/capecitabine in the phase I study by Uhlmann et al,16 we undertook this multicenter phase II study to determine the efficacy and safety of weekly paclitaxel plus capecitabine in MBC patients.
This phase II, open-label, multicenter study was conducted through the US Oncology network and the University of North Carolina Lineberger Comprehensive Cancer Center (Chapel Hill, NC). The protocol was approved by the institutional review boards of both institutions. All patients provided written informed consent. The study was conducted in compliance with Good Clinical Practice guidelines (sixth International Conference on Harmonisation and the Declaration of Helsinki).
Patients with histologically or cytologically confirmed breast cancer and evidence of measurable metastatic disease using Response Evaluation Criteria in Solid Tumors 17 were eligible for study. Patients had an Eastern Cooperative Oncology Group performance status 0 to 2; normal renal, hepatic, and hematologic function on prestudy evaluation.
Patients were ineligible if they had any prior taxane therapy, had prior therapy with oral capecitabine or infusional FU, had received more than one prior treatment regimen for MBC, had HER-2–overexpressing tumors (positive by fluorescent in situ hybridization or 3+ by immunohistochemistry) and had not received trastuzumab, or had ongoing peripheral neuropathy more than grade 1.
Patients received oral capecitabine (Xeloda; Roche, Nutley, NJ) 825 mg/m2 bid for 14 days, followed by 1 week off; 500-mg tablets were used in this study and the dose of capecitabine was rounded to the nearest 500 mg. Paclitaxel 80 mg/m2 was administered intravenously weekly (days 1 and 8) followed by 1 week off. Cycles were repeated every 21 days. Participants whose disease responded (CR or partial response [PR]), or those with SD, were treated until disease progression or intolerable toxicity.
Tumor lesions were measured using Response Evaluation Criteria in Solid Tumors17 at baseline and at the end of every other chemotherapy cycle. For patients who remained on treatment for ≥ 13 cycles, these assessments were done every third chemotherapy cycle. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria and coded using Coding Symbols for Thesaurus of Adverse Reaction Terms.
The primary objective of this study was to determine the objective RR (CR + PR) produced by weekly paclitaxel and oral capecitabine in taxane-naïve MBC patients. Secondary objectives included estimation of TTP, estimation of the proportion of patients who had stable or responding disease at 6 months after treatment initiation, and determination of safety of this regimen. Assuming Ho (the null hypothesis) P ≤ .3 and Ha (the alternative hypothesis) P > .5 with a significance level of .05 and 90% power, using a one-sample binomial exact method (StPlan version 4.2; University of Texas M.D. Anderson Cancer Center, Houston, TX), a total of 55 patients were needed to detect a 50% RR.
The Kaplan-Meier method18 was used to determine progression-free survival (PFS) and OS. Survival was measured from the date of first dose until death as a result of any cause, or to the date of last contact for surviving subjects. PFS was calculated from date of first dose to the date of progressive disease or death as a result of any cause. Patients who started a new treatment were censored for progression as of the date of the start of new treatment. Surviving patients who were progression free were censored at the last date of contact.
Responses were calculated as percentages of all patients in the intent-to-treat population and the 95% CI was calculated for the overall RR. Participants who received at least one dose of study drug were included in the toxicity analysis and the highest grade of toxicity was reported. The statistical analyses were run using SAS version 8.0 (SAS Institute Inc, Cary, NC).
Between February and December 2003, 55 women enrolled onto the study at 35 sites in the US Oncology Research network and at the University of North Carolina, and comprised the intent-to-treat population. Fifty-four patients were assessable for response and 55 were assessable for safety. Patient characteristics at baseline are summarized in Table 1. The age range was from 27 to 82 years (median, 58 years). Most patients had an Eastern Cooperative Oncology Group performance status of 0 to 1. The tumor estrogen receptor status was positive in 67% of women and progesterone receptor status was positive in 49%. Lung or liver metastases were present in 27 patients (49%) and 36 patients (65%), respectively. Among the 55 women treated in this study, 35 had received prior chemotherapy (32 patients only in the adjuvant setting); 25 patients (45%) had received an anthracycline, and nine patients (16%) had received prior bolus FU. No patient had received prior taxane treatment. Twenty (36%) of the women were chemotherapy naïve. Of the 55 patients, 94% received paclitaxel/capecitabine as first-line treatment for metastatic disease and three patients (6%) were treated with second-line paclitaxel/capecitabine (Table 1). Few patients were treated with second-line paclitaxel/capecitabine on this study given the common clinical practice of using taxanes in the first-line treatment of MBC and the requirement for the patients to be taxane naïve.
Objective PRs were observed in 30 of the 55 patients in the intent-to-treat population (55%; 95% CI, 40% to 69%). No patient had a CR. Thirteen additional women (24%) had SD, and six had SD for ≥ 6 months, for a clinical benefit (CR + PR + SD, ≥ 6 months) of 65% (Table 2). The median TTP based on Kaplan-Meier estimate was 10.1 months (range, 1 to 20.7 months; 95% CI, 7.4 to 10.7 months). The median duration of response was 10 months (range, 2.5 to 18.7 months). Fourteen of 54 assessable patients (26%) had duration of response more than 1 year (11 PR and three SD). Median survival for 55 women was 17 months.
A total of 473 cycles of paclitaxel and capecitabine were administered to the 55 women. The median number of cycles received was seven (range, one to 27). Dose modifications and/or discontinuation of therapy were necessary in 37 women (67%); 27 patients required dose reductions (13 patients [24%] in the paclitaxel dose and 27 patients [49%] in the capecitabine dose); therapy was discontinued in 14 patients (25%), all attributed to capecitabine (four patients had dose modifications before discontinuation). The dose modifications occurred mainly between cycles 2 and 9, primarily due to HFS, mucositis, and weight loss. Delivered dose-intensity, defined as actual dose/planned dose, was 75% for capecitabine and 91% for paclitaxel.
The most frequent grade 3 or 4 TRAEs were HFS (n = 10, grade 3) and neutropenia (n = 3, grade 3; n = 4, grade 4). All other grade 3 or 4 TRAEs occurred in ≤ three women (nausea, diarrhea, vomiting, pain, and sensory neuropathy). Two patients developed febrile neutropenia. All TRAEs are summarized in Table 3. Fourteen women discontinued study treatment due to toxicities, which are summarized in Table 4.
This is the first clinical trial of weekly paclitaxel and capecitabine in women with MBC. This combination demonstrated a high degree of antitumor activity and was tolerable over multiple cycles of therapy, although dose modifications and reductions (particularly of capecitabine) were common, predominantly with longer duration of treatment. Paclitaxel dosing on a weekly schedule, in conjunction with capecitabine, takes full advantage of the duration of the upregulation of dThPase by paclitaxel in model systems.
Gradishar et al19 conducted a phase II study of capecitabine and paclitaxel administered once every 3 weeks to evaluate further this promising paclitaxel/capecitabine combination. Capecitabine (825 mg/m2 bid days 1 through 14) and paclitaxel (175 mg/m2 day 1 of each 3-week cycle) were administered to 47 patients with MBC. Objective responses were seen in 24 women (51%; 90% CI, 38.2% to 63.8%), with seven CRs (15%). Nine women (19%) had SD for ≥ 180 days for a clinical benefit rate of 70%. Grade 3 or 4 TRAEs included neutropenia (15%) and HFS (11%); stomatitis and diarrhea occurred in less than 5% of patients. The median TTP was 10.6 months and the median OS was 29.9 months.
Other trials have used capecitabine at doses of 1,650 mg/m2/d.15,19 In this trial, 49% of patients required a capecitabine dose reduction at some point during their therapy; however, because the rates of grade 3 to 4 diarrhea and stomatitis were low and the incidence of grade 3 HFS (18%) was comparable to that in other studies with this dose of capecitabine, we recommend 1,650 mg/m2/d of capecitabine in combination with weekly paclitaxel as the starting dose, with dose modification used as needed.
In the current, multicenter trial of taxane-naïve women with MBC, treatment with combined capecitabine 825 mg/m2 bid days 1 to 14 and paclitaxel 80 mg/m2 on days 1 and 8 of each 3-week cycle resulted in an overall response rate of 55% (95% CI, 40% to 69%) and disease stabilization in 24% (95% CI, 11% to 36%). These results are comparable to other previously published phase II studies of the combination (CR + PR, 40% to 52%; SD, 19% to 47%; Table 5). Median TTP was 10.1 months, median duration of response was 10 months, and median survival was 17 months, which are comparable with the results from other phase II trials.
The incidence of grade 3 to 4 stomatitis or diarrhea in the current study was similar to what had been reported previously with capecitabine combined with paclitaxel administered once every 3 weeks,19,20 although neutropenia was 2% to 3% less frequent than that reported by Batista et al20 and Gradishar et al,19 respectively, and HFS was 7% more common than what was observed in either of these studies. Both stomatitis and diarrhea were somewhat less frequent than observed by Torrecillas21 in the capecitabine + paclitaxel arm (the regimen that was most similar to the current study). Dose reductions of capecitabine occurred in nearly half of the study participants, most commonly for HFS, which led to a delivered dose-intensity of 75% for capecitabine. The dose modification rate for capecitabine, in our study, was somewhat greater than that reported by Gradishar et al19 among women treated with paclitaxel once every 3 weeks and capecitabine (40%),19 although the delivered dose-intensity of capecitabine was comparable (78%).19 Differences in the rates of dose modification among these trials could possibly be accounted for by differences in the age of the participants, given that age and renal function affect the toxicities of capecitabine. The median age in this study (57.7 years) was older than in the trial by Gradishar et al19 (53.6 years), and nearly a third of the patients in this study were older than 65 years.
This trial supports the concept of using paclitaxel weekly on days 1 and 8 in conjunction with capecitabine administered for 14 days in patients with MBC. This is a highly active regimen, which has an acceptable safety profile. Our efficacy and safety results are comparable but not clearly superior to other studies using capecitabine plus paclitaxel at 175 mg/m2 administered once every 3 weeks.15,19-21 However, it is possible that by reducing the dose-intensity of paclitaxel by omitting a dose on day 15, that RRs were not superior to what has been reported for the schedule of paclitaxel dosing once every 3 weeks with comparable dosing of capecitabine.19-21 However, by omitting continuous weekly paclitaxel, neurotoxicity was minimized, with a grade 3 to 4 sensory neuropathy rate of 4%, which compares favorably with the sensory neuropathy rates seen in trials with paclitaxel administered alone on a weekly schedule (9% to 24%).8-10
Currently, a large randomized trial (01062) conducted through the US Oncology network is testing the impact of adding capecitabine to docetaxel after doxorubicin and cyclophosphamide chemotherapy in the adjuvant setting. The design of this trial was based on the results of a large phase III trial comparing docetaxel alone to the combination of docetaxel and capecitabine, which showed a survival advantage for the combination arm.7 A controversy in adjuvant breast cancer therapy has been whether the choice or schedule of the taxane influences disease-free survival or OS. Sparano et al22 recently reported the first results of E1199, which failed to show a difference in disease-free survival in early-stage breast cancer patients treated with either paclitaxel or docetaxel given weekly or once every 3 weeks after doxorubicin and cyclophosphamide. However, there were significant differences in toxicities, which favored paclitaxel. If capecitabine combined with either docetaxel or paclitaxel provides equal efficacy, as suggested by the randomized phase II study by Torrecillas et al,21 then the choice of taxane may be determined by the safety profile, which appears to favor combined paclitaxel and capecitabine. In addition, the option of sequential therapy is addressed by the trial by Torrecillas et al,21 which showed that although the RR of capecitabine followed by a taxane was less than the combination of either capecitabine plus docetaxel or capecitabine plus paclitaxel, and the toxicity was comparable, PFS and OS were similar. Because there is no clear superiority of combination therapy from this trial, the choice of sequential or combination therapy should be made based on patient characteristics.
In summary, the combination of capecitabine using a 2 weeks on, 1 week off schedule, in combination with paclitaxel administered on day 1 and 8 of a 21-day cycle, is a highly active and safe regimen for the treatment of MBC. This regimen of capecitabine and paclitaxel provides an important option for patients in addition to the regimen of docetaxel and capecitabine for MBC.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. 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.
| Authors | Employment | Leadership | Consultant | Stock | Honoraria | Research Funds | Testimony | Other |
|---|---|---|---|---|---|---|---|---|
| Joanne L. Blum | Roche (A) | |||||||
| Joyce A. O'Shaughnessy | Roche (A) |
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C) ≥ $100,000 (N/R) Not Required
Conception and design: Joanne L. Blum, E. Claire Dees, Lina Asmar, Joyce A. O'Shaughnessy
Provision of study materials or patients: Joanne L. Blum, E. Claire Dees, Aparna Chacko, Lisa Doane, Sukumar Ethirajan, Judith Hopkins, Richard McMahon, Suzan Merten, Angel Negron, Marcus Neubauer, Joyce A. O'Shaughnessy
Collection and assembly of data: Des Ilegbodu, Lina Asmar
Data analysis and interpretation: Joanne L. Blum, Des Ilegbodu, Kristi A. Boehm, Lina Asmar, Joyce A. O'Shaughnessy
Manuscript writing: Joanne L. Blum, Kristi A. Boehm, Lina Asmar, Joyce A. O'Shaughnessy
Final approval of manuscript: Joanne L. Blum, E. Claire Dees, Aparna Chacko, Lisa Doane, Sukumar Ethirajan, Judith Hopkins, Richard McMahon, Suzan Merten, Angel Negron, Marcus Neubauer, Des Ilegbodu, Kristi A. Boehm, Lina Asmar, Joyce A. O'Shaughnessy
|
| Characteristic | No. of Patients | % | |
|---|---|---|---|
| Total enrolled | 55 | ||
| Age, years | |||
| Median | 57.7 | ||
| Range | 26.6-81.9 | ||
| ≤ 49 | 13 | 24 | |
| 50-64 | 25 | 45 | |
| ≥ 65 | 17 | 31 | |
| Race/ethnicity | |||
| White | 46 | 84 | |
| Black | 8 | 14 | |
| Hispanic | 1 | 2 | |
| ER status | |||
| Positive | 37 | 67 | |
| Negative | 17 | 31 | |
| Unknown | 1 | 2 | |
| PR status | |||
| Positive | 27 | 49 | |
| Negative | 26 | 47 | |
| Unknown | 2 | 4 | |
| HER-2/neu status | |||
| 0 | 20 | 36 | |
| 1+ | 6 | 11 | |
| 2+ | 5 | 9 | |
| 3+ | 2 | 4 | |
| Not available | 22 | 40 | |
| Metastatic sites | |||
| Visceral | 31 | 56 | |
| Hepatic | 36 | 65 | |
| Lung | 27 | 49 | |
| Soft tissue | 21 | 38 | |
| Bone | 23 | 42 | |
| Other | 3 | 5 | |
| No. of metastatic sites | |||
| 1 | 16 | 29 | |
| 2 | 19 | 35 | |
| ≥ 3 | 20 | 36 | |
| Prior therapy | |||
| Prior adjuvant chemotherapy | 32 | 58 | |
| Anthracycline containing | 25 | 45 | |
| Methotrexate containing | 12 | 22 | |
| FU containing | 9 | 16 | |
| Taxane containing | 0 | ||
| Prior chemotherapy for metastatic disease | 3 | 6 | |
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; FU, fluorouracil.
|
| Outcome | No. of Patients | % |
|---|---|---|
| Total enrolled | 55 | |
| Total treated | 55 | |
| Assessable patients | 54 | |
| Overall response | 30 | 55 |
| 95% CI | 40 to 69 | |
| Best response | ||
| PR | 30 | 55 |
| SD ≥ 6 months | 6 | 11 |
| SD < 6 months | 7 | 13 |
| PD | 11 | 20 |
| NA (completed < 1 cycle) | 1 | 1 |
| Clinical benefit* | 36 | 65 |
| 95% CI | 52 to 78 | |
| Metastatic sites of PR or SD ≥ 6 months† | ||
| Liver | 24 | 44 |
| Bone | 14 | 26 |
| Lung (visceral) | 18 | 33 |
| Lung (pleural effusion) | 1 | 2 |
| Lymph nodes | 12 | 22 |
| Skin | 1 | 2 |
| Abdominal carcinomatosis | 1 | 2 |
Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease; NA, not assessable.
*Clinical benefit = PR + SD ≥ 6 months.
†Patients may have had more than one site of metastasis; each was counted separately.
|
| Body System and Adverse Event | Grades 1-2 | Grades 3-4 | ||||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | |||
| Hypersensitivity reaction | 1 | 2 | 1 | 2 | ||
| Anemia | 21 | 38 | 1 | 2 | ||
| Leukopenia | 11 | 20 | 3 | 5 | ||
| Neutropenia | 13 | 24 | 7 | 13 | ||
| Edema | 12 | 22 | 1 | 2 | ||
| Thromboembolic event | 1 | 2 | 1 | 2 | ||
| Fatigue | 32 | 58 | 4 | 7 | ||
| Alopecia | 32 | 58 | NA* | |||
| Hand-foot skin reaction | 17 | 31 | 10 | 18 | ||
| Stomatitis | 26 | 47 | 1 | 2 | ||
| Diarrhea | 24 | 44 | 3 | 5 | ||
| Nausea | 20 | 36 | 3 | 5 | ||
| Vomiting | 12 | 22 | 2 | 4 | ||
| Febrile neutropenia | 0 | 2 | 4 | |||
| Sensory neuropathy | 32 | 58 | 2 | 4 | ||
| Pain | 23 | 42 | 3 | 5 | ||
Abbreviation: NA, not applicable.
*Alopecia is only graded as 1 or 2.
|
| Adverse Event (COSTART term) | Total No. of Patients* |
|---|---|
| Hand-foot skin reaction | 4 |
| Diarrhea | 3 |
| Neuropathy | 2 |
| Edema (grade 3) | 1 |
| Vomiting (grade 3) | 1 |
| Dehydration | 1 |
| Dizziness (grade 3) | 1 |
| Embolism | 1 |
| Fatigue | 1 |
| Tachycardia (grade 3) | 1 |
NOTE. Fourteen patients discontinued the study treatment because of toxicity.
Abbreviation: COSTART, Coding Symbols for Thesaurus of Adverse Reaction Terms.
*Some patients had more than one adverse event responsible for discontinuation.
|
| Reference | Regimen | Patients | Responses | G3-4 TRAEs* | Other |
|---|---|---|---|---|---|
| Batista et al20 | CAPE 1,000 mg/m2 bid days 1-14 and PAC 175 mg/m2 day 1 of each 3-week cycle | N = 73; pretreated with anthracycline | CR = 11%; PR = 41%; SD = 29%; ORR = 52% | Neutropenia 16%, stomatitis NR (mucositis 3%), HFS 11%, and diarrhea 3% | Median DOR = 10.6 months; median TTP = 8.1 months; median survival = 16.5 months |
| Gradishar et al19 | CAPE 825 mg/m2 bid (1,650 mg/m2 total) days 1-14 and PAC 175 mg/m2 day 1 of each 3-week cycle | N = 47; 94% were untreated previously | CR = 15%; PR = 36%; SD = 19%; ORR = 51%; CBR = 70% | Neutropenia 15%, stomatitis NR, HFS 11%, and diarrhea NR | Median DOR = 12.6 months; median TTP = 10.6 months; median survival = 16.5 months |
| Torrecillas et al21 | CAPE + PAC: CAPE 825 mg/m2 bid days 1-14 plus PAC 175 mg/m2 day 1; all cycles were 21 days | N = 73 | ORR = 73% | Toxicities were similar between the three groups; neutropenia 0%, stomatitis 8%, HFS 19%, and diarrhea 11% | PFS = 9.2 months; OS = 29.0 months |
| CAPE + DOC: CAPE 825 mg/m2 bid days 1-14 plus DOC 75 mg/m2 day 1 | N = 71 | ORR = 76% | Neutropenia 1%, stomatitis 10%, HFS 28%, and diarrhea 13% | PFS = 10.1 months; OS = 45.1 months | |
| CAPE→taxane: CAPE 1,250 mg/m2 bid days 1-14 until progression, at which time single-agent PAC 175 mg/m2 or DOC 100 mg/m2 day 1 was administered | N = 62 | ORR = 58% | Neutropenia 3%, stomatitis 11%, HFS 29%, and diarrhea 14.5% | PFS = 8.6 months; OS = 32.0 months | |
| Uhlmann et al16 | Phase I; 80 mg/m2 weekly; and 5 dose levels of CAPE (800, 1,000, 1,500, 2,000, and 2,500 mg/m2) and PAC 80 mg/m2 days 1 and 8 of each 3-week cycle | N = 16; metastatic breast cancer | CR = 13%; PR = 27%; SD = 47%; ORR = 40%; CBR = 87% | Febrile neutropenia 7%, stomatitis NR, HFS 31%, and diarrhea NR | Median DOR NR; median TTP = 6.3 months; median survival = 16.7 months |
| Blum et al (current study for comparison) | CAPE 825 mg/m2 bid (1,650 mg/m2 total) days 1-14 and PAC (80 mg/m2 days 1 and 8 of each 3-week cycle | N = 55; taxane naïve | CR = 0%; PR = 55%; SD = 24%; ORR = 55%; CBR = 65% | Neutropenia 13%, stomatitis 2%, HFS 18%, and diarrhea 5% | Median DOR = 10.1 months; median TTP = 10.1 months; median survival = 17 months |
Abbreviations: CAPE, capecitabine; PAC, paclitaxel; TRAE, treatment-related adverse event; CR, complete response; PR, partial response; SD, stable disease; ORR, overall response rate; NR, not reported; HFS, hand-foot skin reaction; DOR, duration of response; TTP, time to progression; CBR, clinical benefit rate; DOC, docetaxel.
*Only grades 3-4 neutropenia, stomatitis, HFS reaction, and diarrhea are mentioned here for comparative purposes.
published online ahead of print at www.jco.org on August 21, 2006.
Supported by Roche Laboratories, Nutley, NJ.
Presented in part in poster format at the 2004 San Antonio Breast Cancer Symposium, San Antonio, TX, December 10, 2004.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
We thank the patients who participated in this clinical trial, the US Oncology physicians, the site coordinators, project manager Maria Crockett, and data reviewer Tamara Young.
| 1. | Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17::485,1999-493, Link, Google Scholar |
| 2. | Blum JL: The role of capecitabine, an oral, enzymatically activated fluoropyrimidine, in the treatment of metastatic breast cancer. Oncologist 6::56,2001-64, Crossref, Medline, Google Scholar |
| 3. | 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::1247,2001-1254, Crossref, Medline, Google Scholar |
| 4. | 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::1367,2002-1372, Crossref, Medline, Google Scholar |
| 5. | Kaklamani VG, Gradishar WJ: Role of capecitabine (Xeloda) in breast cancer. Expert Rev Anticancer Ther 3::137,2003-144, Crossref, Medline, Google Scholar |
| 6. | O'Shaughnessy JA: The evolving role of capecitabine in breast cancer. Clin Breast Cancer 4::S20,2003-S25, (suppl 1) Google Scholar |
| 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::2912,2002-2923, Link, Google Scholar |
| 8. | Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16::3353,1998-3361, Link, Google Scholar |
| 9. | Perez EA, Vogel CL, Irwin DH, et al: Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19::4216,2001-4223, Link, Google Scholar |
| 10. | 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 for T in HER2 normal MBC. J Clin Oncol 22::6s,2004, (abstr 512) Crossref, Google Scholar |
| 11. | Green MJ, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23::5983,2005-5992, Link, Google Scholar |
| 12. | 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::1274,1998-1281, Crossref, Medline, Google Scholar |
| 13. | Sawada N, Ishikawa T, Fukase Y, et al: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4::1013,1998-1019, Medline, Google Scholar |
| 14. | Elza-Brown K, Dees EC, Wolff AC, et al: A phase I study of capecitabine and weekly paclitaxel in advanced solid tumors. Proc Am Soc Clin Oncol 237a,2000, (abstr 921J) Medline, Google Scholar |
| 15. | Villalona-Calero MA, Blum JL, Jones SE, et al: A phase I and pharmacologic study of capecitabine and paclitaxel in breast cancer patients. Ann Oncol 12::605,2001-614, Crossref, Medline, Google Scholar |
| 16. | Uhlmann C, Ballabeni P, Rijken N, et al: Capecitabine with weekly paclitaxel for advanced breast cancer: A phase I dose-finding trial. Oncology 67::117,2004-122, Crossref, Medline, Google Scholar |
| 17. | Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92::205,2000-216, Crossref, Medline, Google Scholar |
| 18. | Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53::457,1958-481, Crossref, Google Scholar |
| 19. | Gradishar WJ, Meza LA, Amin B, et al: Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: A multicenter phase II study. J Clin Oncol 22::2321,2004-2327, Link, Google Scholar |
| 20. | Batista N, Perez-Manga G, Constenla M, et al: Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Br J Cancer 90::1740,2004-1746, Crossref, Medline, Google Scholar |
| 21. | Torrecillas L, Soto C, Cervantes G, et al: Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from the Mexican Oncology Study Group. Breast Cancer Res Treat 88::S200,2004, (abstr 5048) Google Scholar |
| 22. | Sparano JA, Wang M, Martino S, et al: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel administered every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer: Results of North American Breast Cancer Intergroup Trial E1199. Breast Cancer Res Treat , 2005 (abstr 48) www.abstracts2view.com/sabcs05/view.php?nu=SABCS05L_2020 Google Scholar |
