Safety and Efficacy of Two Different Doses of Capecitabine in the Treatment of Advanced Breast Cancer in Older Women
Publication: Journal of Clinical Oncology
Abstract
Purpose
To evaluate the safety and efficacy of capecitabine in older women with advanced breast cancer.
Patients and Methods
Seventy-three eligible patients (median age, 73 years; range, 65 to 89 years) were enrolled. The first 30 patients received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 21 days. Due to the occurrence of two toxic deaths, capecitabine 1,000 mg/m2 twice daily was given to the subsequent 43 patients.
Results
All patients were assessable for safety and efficacy. A total of 351 treatment cycles were administered (median, six per patient; range, one to eight cycles). Dose reductions due to toxicities were required in 30% of patients in the standard-dose group, but capecitabine was given without a dose reduction to 95% of patients in the low-dose group. Capecitabine demonstrated a favorable safety profile. The overall incidence of grade 3/4 toxicities was low: the most common events reported in ≤ 10% of the patients were fatigue, diarrhea, dyspnea, and nausea. In the standard-dose group, the response rate was 36.7% (95% CI, 19.9% to 56.1%). An additional seven patients had disease stabilization at ≥ 24 weeks. In the low-dose group, the response rate was 34.9% (95% CI, 21% to 50.9%). An additional 15 patients had prolonged stabilization. The median time to disease progression was 4 months in either group.
Conclusion
This study shows that capecitabine is safe and effective in the elderly breast cancer patient. Based on the overall results, the capecitabine dose of 1,000 mg/m2 twice daily merits consideration as “standard” for older patients who do not have severely impaired renal function.
Introduction
Age is a major risk factor for breast carcinoma: women 65 years and older have higher incidence and mortality rates compared with younger women.1 Despite recent advances in breast cancer therapy, physicians have been reluctant to enroll older women onto clinical trials, and there is a paucity of data for defining treatment strategies specific to this age group.2 Poor prognostic factors are generally less common in breast cancer in the elderly, with most of the tumors indolent and hormone-responsive.3 However, many patients will ultimately develop metastatic disease. Palliative chemotherapy is the treatment of choice for hormone receptor–negative tumors, progressive disease refractory to endocrine therapy, or life-threatening metastases, but the relatively poorer health status, on average, of older patients compared with younger patients can have a substantial impact on the clinical management. For fear of excessive toxicity from chemotherapy and other reasons, elderly patients are often offered suboptimal treatments for advanced disease.4 It is, therefore, especially important to incorporate the safety profile of the various cytotoxic agents when selecting the appropriate chemotherapy for an older patient. Furthermore, in the majority of older women with advanced disease refractory to endocrine manipulations, single-agent chemotherapy can be a reasonable therapeutic approach.5 Accordingly, recent studies support the use of sequential single-agent therapy because this strategy is generally less toxic and yields survival rates similar to those achieved with combination regimens.6-8 The ideal cytotoxic agent would reduce tumor burden and associated symptoms, with minimal toxicity. In addition, orally administered agents may represent a very attractive alternative to intravenous chemotherapy in older patients who have often received several previous lines of oral endocrine therapy sometimes for years.
Capecitabine (Xeloda; Hoffmann-La Roche Inc, Nutley, NJ) is a new, orally administered precursor of 5′-deoxy-5-fluorouridine (5′-DFUR) that is preferentially transformed into its active catabolite owing to a higher intratumoral expression of the activating enzyme thymidine phosphorylase.9 Phase II studies of capecitabine at 1,250 mg/m2 twice daily for 14 days every 21 days established a role for this agent in anthracycline- and taxane-pretreated metastatic breast cancer.10,11 In all clinical trials, capecitabine monotherapy has been well tolerated: the main and reversible adverse effects associated with the drug are palmar-plantar erythrodysaesthesia (PPE), diarrhea, and nausea.11 The favorable safety profile of capecitabine and the ability to readily manage drug-related toxicities by immediate treatment interruption and, if necessary, dose reduction to each patient’s tolerable dose, suggest that this agent might play a major role in the management of breast cancer in the elderly.
In 1999, a phase II study was initiated at the National Cancer Institute of Milan to assess the clinical tolerability and efficacy of capecitabine in older women with advanced breast cancer. When this study was started, available clinical data indicated a starting dose of 1,250 mg/m2 twice daily for 14 days followed by 7 days of rest, repeated every 3 weeks. After occurrence of two toxic deaths, we decided to continue the study but reduce the starting dose for subsequent patients to 1,000 mg/m2 twice daily. At that time, it was not already known that a lower dose of capecitabine is actually recommended for patients with moderate renal impairment at baseline, and a contraindication exists for patients with severely impaired creatinine clearance at baseline.12 Since renal function declines with age, further support is lent to our decision to amend the study protocol to investigate the safety of capecitabine in a sequential cohort of older patients, using a lower starting dose of the agent.
Patients and Methods
Study Design
This open-label, sequential phase II study was designed to investigate capecitabine in patients aged 65 years and older with metastatic breast cancer that was progressing at the time of study entry. The primary objective was to assess the safety profile of capecitabine. The secondary objective was to determine the efficacy in terms of response rate and time to disease progression (TTP).
The trial was conducted in full agreement with the principles of the Declaration of Helsinki and International Committee on Harmonization guidelines for good clinical practice. The trial protocol was approved before commencement by the local ethical review board. Written informed consent was obtained from each patient before the start of the study.
The first 30 patients received oral capecitabine at the standard starting dose of 1,250 mg/m2 twice-daily after breakfast and dinner, for 14 days, followed by a 7-day rest period. This 3-week treatment course was repeated at least once more. Due to lethal toxicities that occurred in this cohort of patients, the starting dose for the subsequent 43 patients was amended to 1,000 mg/m2 twice daily for 2 weeks, every 21 days (low-dose cohort). Patients responding or with stable disease (SD) at the end of the first 6 weeks were eligible to receive further treatment for up to 18 weeks (six cycles) or longer at the investigator’s discretion. Patients experiencing unacceptable toxicity were withdrawn from the study at any time.
Eligibility Criteria
All patients had a confirmed diagnosis of breast carcinoma with advanced disease that had previously been untreated, or treated with no more than two endocrine treatments and/or one cytotoxic regimen. Any previous cytotoxic therapy containing fluorouracil (FU) was permitted providing that treatment had been completed at least 1 year before study enrollment. Other eligibility criteria included measurable or assessable disease in at least one site that was outside a previously irradiated area, an Eastern Cooperative Oncology Group performance status of 0 to 2, and a life expectancy of at least 3 months. A minimum interval of 3 weeks between the last treatment and study enrollment was mandatory. Patients with clinically significant cardiac disease, including angina pectoris, history of congestive heart failure, or history of previous myocardial infarction within 12 months of study entry, were excluded, as were patients with other clinically significant disorders. Also excluded were patients who had experienced a prior severe and unexpected reaction to fluoropyrimidine therapy or who had known hypersensitivity to FU. Cutoff values for laboratory quantities were as follows: neutrophils ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 9.0 g/dL, serum bilirubin ≤ 1.5 × the upper limit of normal (ULN), AST and/or ALT ≤ 1.5 × ULN, alkaline phosphatase ≤ 2.5 × ULN (unless bone metastases were present in the absence of any liver disorders), and creatinine less than 1.6 mg/dL. Creatinine clearance was retrospectively estimated using the Cockroft and Gault equation: creatinine clearance (mL/min) = ([140 − age] × weight [kg] × 0.85)/(72 × serum creatinine [mg/dL]).13 Renal function was classified as normal (calculated creatinine clearance > 80 mL/min), mildly impaired (51 to 80 mL/min), moderately impaired (30 to 50 mL/min), or severely impaired (< 30 mL/min).12
Safety and Response Assessment
Pretreatment evaluation included a history and physical examination, hematology and blood chemistry, ECG, urinalysis, and tumor evaluation using standard radiologic methods. All laboratory tests were evaluated within 7 days before treatment start. During the treatment period, hematology and toxicity evaluations were performed every 3 weeks, whereas blood chemistry and tumor evaluation were carried out after every second cycle. All adverse events considered to be possibly, probably, or definitely related to study treatment were graded 1 to 4 according to National Cancer Institute of Canada Common Toxicity Criteria. PPE was graded 1 to 3 as defined in previous trials of capecitabine.10 In patients experiencing grade 2 or more severe toxicities, the standard capecitabine dose modification scheme, described in detail by Blum et al, was applied.10 Once the dose had been reduced due to toxicity, it was not to be increased at a later time.
Tumor responses were evaluated based on standard WHO criteria and had to be confirmed a minimum of 4 weeks after response was first observed. For patients achieving a tumor regression, duration of response was measured as time from first documentation of complete response (CR) or partial response (PR), to first observation of disease progression or death due to any cause. TTP was the interval from treatment start to the date of documented progressive disease (PD) or death due to any cause. Survival data were collected every 2 months after patients went off study.
Treatment compliance was assessed by counting unused medication that was returned at each clinic visit. Patients taking less than 80% of the anticipated dose of capecitabine were warned about their compliance, and those who stopped treatment for more than 1 week were withdrawn from the study for noncompliance (unless the treatment interruption was because of toxicity).
Statistical Considerations
The original sample size was based on the primary end point of the occurrence of grade 3 or 4 toxicity of any type. A classic two-stage design was utilized to permit early study termination.14 This approach is based on testing the null hypothesis that the probability of patients being free from severe toxicity is less than a predefined level against the alternative hypothesis that the probability is at least some desirable target level. In this study, these two probabilities were set to 60% and 75%, corresponding to a 15% difference. Assuming a 10% type 1 error rate and 90% power, a sample size of 71 patients was calculated. The trial had to be stopped if at least 13 of the first 34 enrolled patients experienced grade 3 or 4 toxicity. Otherwise, 37 additional patients had to be accrued, and the drug safety was considered as unsatisfactory in this indication if at least 24 of 71 patients experienced grade 3 or 4 toxicity. Results were reported with 95% CIs. Safety was evaluated in all patients who received at least one dose of capecitabine and had at least one further documented visit. Efficacy analysis was performed on the intention-to-treat (ITT) population, which included all patients who received at least one course of study treatment. However, patients who received less than 50% of the anticipated treatment during the first 6 weeks were excluded from the standard population. Within- and between-group comparisons were done by means of Fisher’s exact tests, using a 5% two-sided significance level.
Results
Patient Characteristics
Between May 1999 and February 2003, a total of 73 women received at least one course of capecitabine in two sequential dose cohorts. The median age was 73 years (range, 65 to 89 years), and the demographic characteristics of the study population are presented in Table 1. Baseline disease characteristics were not significantly different between the two cohorts, except for more hormone receptor–negative tumors in the first cohort (40%, P = .03). Seventy percent of patients treated with the standard dose had received no prior systemic treatments for advanced disease, compared with 49% in the low-dose group (P = .09). Nine patients in each cohort had prior exposure to cytotoxic chemotherapy (two patients receiving the low-dose capecitabine were pretreated with both adjuvant and palliative chemotherapy). In the standard-dose cohort, seven patients (23%) received prior FU-containing regimens; of these, six patients received the therapy as adjuvant treatment. In the low-dose cohort, eight patients (19%) received prior FU therapy; of these, five patients received the therapy as adjuvant treatment.
Safety
All 73 patients who received at least one dose of capecitabine were evaluated for toxicity. A total of 351 cycles were administered: 138 cycles in the standard-dose group and 213 in the low-dose group. The median number of cycles per patient was six (range, one to eight cycles) in either group. In the standard-starting-dose cohort, the mean delivered dose intensity was 757 mg/m2/wk (planned, 833 mg/m2/wk), which corresponds to 91% of the planned dose intensity. In the low-starting-dose cohort, the mean delivered dose intensity was 655 mg/m2/wk (planned, 667 mg/m2/wk), which corresponds to 98% of the planned dose intensity. It was not necessary to omit any of the planned doses in this study, but 30% of patients in the standard-dose cohort required a dose reduction (18% of drug administrations). The capecitabine dose was reduced to 75% of the starting dose in eight patients (27%), whereas the dose was reduced to 50% of the starting dose in three patients (10%, two of whom previously had had a dose reduction to 75% of the starting dose). The adverse events leading to dose reduction were fatigue (two patients), nausea (two patients), PPE (two patients), diarrhea (one patient), dyspnea (one patient), and stomatitis (one patient). Only two patients (5%) in the low-starting-dose cohort required a dose reduction (3% of drug administrations). The adverse events leading to dose reduction were neutropenia in one patient who had a dose reduction to 50% of the starting dose, and fatigue in one patient who had a dose reduction to 75% of the starting dose. Overall, dose modifications were required after a median of three cycles (range, one to four cycles). Two patients (7%) who received the standard dose of capecitabine discontinued treatment due to grade 3 diarrhea and early deterioration of general condition (considered related to study drug), respectively. In addition, two patients (7%) had a lethal toxicity. Grade 4 diarrhea occurred after three cycles of therapy in an 80-year-old woman with lymph node, pleural, and bone metastases. Despite therapeutic measures, the patient died due to severe dehydration. A 75-year-old woman with pulmonary metastases died soon after the first cycle of therapy due to grade 4 diarrhea, with severe dehydration. In the low-starting-dose cohort, three patients (7%) discontinued due to acute myocardial infarction, heart failure, or grade 4 diarrhea, respectively. In addition, there was one death that occurred in a 78-year-old woman with pleural and bone metastases. After the first cycle of capecitabine, the patient was hospitalized for grade 2 diarrhea, febrile neutropenia, and grade 3 dyspnea. Despite therapeutic measures, the patient died of heart failure, possibly related to study drug.
Table 2 lists the most common adverse events observed during the study. The majority of events were mild to moderate in intensity in both cohorts. There were no significant differences in the incidence of each type of toxicity between the two cohorts, but a trend toward an increased frequency of fatigue (all grades) was evident in the low-dose group (P = .06). Fatigue occurred in 46.5% of patients receiving the low dose, but was the reason for dose reduction in only one patient compared with two patients in the standard-dose group. Fatigue could not be related to anemia, and the distinction between cancer-related and treatment-related fatigue was difficult to determine in many of these elderly patients. The overall incidence of grade 3 or 4 treatment-related adverse events was low: the most frequently reported events were fatigue (10%), diarrhea (7%), dyspnea (5%), and nausea (5%). The numbers of patients experiencing severe toxicities were always less than the target levels predefined according to the statistical plan. Only two grade 4 adverse events were observed in the standard-dose group, consisting of two cases of diarrhea, whereas one case of grade 4 diarrhea was reported in the low-dose group. The incidence of severe toxicity was also analyzed according to age category. Grade 3 or 4 toxicity occurred in 17 (32%) of 53 women older than 70 years treated with capecitabine, compared with two (10%) of 20 patients aged 65 to 70 years (P = .05). Seven older patients receiving the standard dose experienced severe adverse events as compared with one younger patient (P = .67); 10 patients older than 70 years who were treated with the low dose had severe toxicities compared with one younger patient (P = .07).
The safety profile of capecitabine, according to baseline renal function estimated using the Cockroft and Gault equation, is reported in Table 3. All of the enrolled patients had renal impairment (defined as calculated creatinine clearance ≤ 80 mL/min) at baseline, but there were no patients with severely impaired renal function (creatinine clearance < 30 mL/min), in accordance with the study inclusion criteria. Median creatinine clearance values were 44.6 mL/min (range, 31.4 to 80.0 mL/min) and 53.5 mL/min (range, 33.0 to 80.5 mL/min) in the standard- and low-dose groups, respectively. Seventy percent of patients who received capecitabine 1,250 mg/m2 twice daily had moderate renal impairment (creatinine clearance, 30 to 50 mL/min), and the remaining 30% had mild renal impairment (creatinine clearance, 51 to 80 mL/min). In the standard-dose group, five women with moderate renal impairment experienced grade 3 or 4 adverse events compared with three women with mildly impaired renal function (not significant); six patients with moderate renal impairment required a dose reduction, compared with three patients with mildly impaired renal function (not significant). The majority of patients (63%) who received the low dose of capecitabine had mild renal impairment at baseline. In this dose cohort, no significant differences were evident in the frequency of both severe toxicities and dose reductions according to baseline renal function.
In the study population, except for nausea and stomatitis, which showed an increased frequency in patients with moderate renal impairment compared with those with mild renal impairment (P = .05 and P = .02, respectively), the occurrence of toxicity was not significantly different by creatinine clearance (Table 3). The response rate to capecitabine in the subgroup of patients with moderate renal impairment was similar to that achieved in patients with mildly impaired renal function (40.5% v 30.5%; P = .46), indicating that the efficacy of capecitabine was not compromised in women with moderate renal impairment.
Efficacy
All 73 enrolled patients had measurable disease at study entry and were assessable for efficacy according to the ITT analysis (Table 4). In the standard-dose cohort, 11 of 30 patients achieved tumor regression, for an overall response rate of 36.7% (95% CI, 19.9% to 56.1%). Responses were observed in several sites, including liver, lung, pleura, lymph nodes, and soft tissues, with a median duration of objective response of 4.3 months (range, 3.4 to 5.8 months). An additional seven patients (23%) had SD that lasted for at least 6 months. The overall benefit rate (CR + PR + SD ≥ 24 weeks) was 60.0% (95% CI, 40.6% to 77.4%), with a median duration of benefit of 8.0 months (range, 4.0 to 21.0 months). The median TTP was 3.9 months, and the median survival was 10 months.
In the low-dose cohort, the overall response rate was 34.9% (95% CI, 21.0% to 50.9%). An additional 15 patients (35%) achieved prolonged SD (clinical benefit rate, 69.8%; 95% CI, 53.9% to 82.8%). Sites of response included lung, liver, lymph nodes, skin nodules, bone, and breast, with a median duration of objective response of 4.3 months (range, 1.9 to 6.0 months) and a median duration of clinical benefit of 9.0 months (range, 3.0 to 23.0 months). The median TTP was 4.1 months, and the median survival was 16 months.
Patients who had received previous chemotherapy (n = 18) showed a response rate of 28% (95% CI, 9.7% to 53.5%), whereas patients without cytotoxic pretreatment (n = 55) exhibited a response rate of 38% (95% CI, 25.4% to 52.3%). According to prior therapy with FU, responses were seen in two of seven (29%) patients treated with the standard dose, whereas no responses were observed in eight pretreated patients receiving the low dose (P = .68).
Discussion
To the best of our knowledge, this is the first report specifically dealing with the use of capecitabine in a elderly population with breast cancer. When we started the study, available clinical data indicated a capecitabine dose of 2,500 mg/m2/d, as appropriate. Due to the occurrence of lethal toxicities, a lower starting dose (2,000 mg/m2/d) was considered more appropriate for older women included in the study. It is also worthy to point out that when the protocol was amended, there were no available data on the relationship between capecitabine’s safety and patient renal function.12
A total of 73 older women were treated with capecitabine in two sequential cohorts. The incidence of severe toxicities was low, and adverse events were predictable based on the mechanism of action of the agent. In the present study and in other clinical trials using capecitabine monotherapy, the most common adverse events included diarrhea, PPE, fatigue, nausea, and vomiting that were generally mild to moderate in intensity.15 Overall, the tolerability profile seemed more satisfactory in the low-dose group, for which a higher dose intensity could be delivered. When analyzing the safety data, it should also be considered that the vast majority of patients (77%) enrolled onto the study were ≥ 70 years of age. We found a relationship between older age and increased incidence of severe toxicities from capecitabine. Accordingly, special attention should be given to diarrhea, which, if not quickly treated, can easily be fatal in patients older than 70 years. It is known that many physiologic changes occur during aging that could potentially affect the pharmacokinetic and pharmacodynamic disposition of antineoplastic agents as well as the increased vulnerability of normal tissues to these drugs.16 Also, the incidence of age-related changes start increasing sharply between the ages of 70 and 75 years.17 In light of this as well as the recent literature data, we feel that it was worthwhile to retrospectively assess any relationships between surrogates of renal clearance and capecitabine safety in the study population.12,18 Systemic capecitabine clearance has been associated with renal function, and decreased renal clearance is observed in the older population as a group, with serum creatinine by itself a poor indicator of renal function.19 Therefore, the creatinine clearance rate at baseline for each patient was calculated according to the Cockroft and Gault equation.13 The study did not include patients with a wide range of calculated creatinine clearance, as eligibility was limited to women with serum creatinine less than 1.6 mg/dL, but, as predicted, all enrolled patients had some degree of renal function impairment based on this parameter. Within the range of renal function observed here, no firm conclusion concerning the impact of renal dysfunction on capecitabine safety was possible. However, it is worthy to point out the limitations due to the fact that the study was not designed to explore the incidence of drug-related toxicity in older patients who may have had preclinical renal impairment at baseline. The results from the retrospective analysis in a large number of patients with colorectal cancer recently reported by Cassidy et al showed that the safety profile of capecitabine in the subpopulation of patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline was quantitatively different from that seen in patients with normal renal function.12 Therefore, it was concluded that the decreased tolerability of capecitabine in older patients was caused primarily by an age-related decline in renal function, as evident from creatinine clearance calculated according to the Cockroft and Gault equation, whereas serum creatinine was still within normal limits. Accordingly, a reduction of the starting dose to 75% of the standard dose (approximately 2,000 mg/m2/d) in patients with moderate renal impairment was recommended.12 According to the dosing guidelines, the majority of patients (70%) included in the standard-dose group would receive a 25% reduction in the starting dose of capecitabine. Despite 63% of patients in the low-dose group receiving the starting dose of 2,500 mg/m2 per day, similar rates of tumor response were observed in both dose groups. Although the trial was not powered to demonstrate a statistical difference in clinical end points between the two doses of capecitabine, some evidence should be considered. The reduced dose should result in systemic exposure to 5′-DFUR, the most important metabolite of capecitabine, comparable to that of the standard dose in patients with normal renal function.18 Also, it has been reported that the efficacy of capecitabine was maintained in patients requiring dose modification for adverse events.12 Finally, the evidence might be consistent with the higher dose intensity that was delivered in the low-dose cohort as a whole.
The present study confirms that capecitabine is an effective treatment for breast cancer. It is worthy to note that 70% of patients who received the standard dose of capecitabine were previously untreated for advanced disease, and 40% of cases had hormone receptor–negative tumors. Overall, efficacy of the two starting doses was similar to that reported in a previous trial, in which first-line monotherapy with capecitabine at the dose of 2,500 mg/m2/d resulted in an objective response rate of 30% in 61 women aged 55 years and older.20
This study has shown in a large series that oral capecitabine is well tolerated and effective in older women with advanced breast cancer. Older patients may frequently exhibit diminished capacity to eliminate drugs, resulting in unusual sensitivity to standard dosing regimens. In light of this, the overall results of the study suggest that although the dose groups are small and nonrandomized, the capecitabine dose of 1,000 mg/m2 twice daily merits consideration as “standard” for women aged 70 years and older who are candidates to cytotoxic therapy for metastatic breast cancer and do not have severely impaired renal function.
Authors' Disclosures of Potential Conflicts of Interest
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. Honoraria: Emilio Bajetta, Janssen-Cilag. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
| Characteristic | Standard-Dose Cohort (n = 30) | Low-Dose Cohort (n = 43) | ||||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | |||
| Age, years | ||||||
| 65-69 | 6 | 20 | 11 | 26 | ||
| 70-79 | 19 | 63 | 31 | 72 | ||
| ≥ 80 | 5 | 17 | 1 | 2 | ||
| ECOG PS | ||||||
| 0 | 18 | 60 | 23 | 54 | ||
| 1 | 12 | 40 | 19 | 44 | ||
| 2 | 0 | 0 | 1 | 2 | ||
| Tumor receptor status | ||||||
| ER+ and/or PgR+ | 16 | 53 | 35 | 81 | ||
| ER− and PgR− | 12 | 40 | 6 | 14 | ||
| Unknown | 2 | 7 | 2 | 5 | ||
| Involved sites | ||||||
| Bone | 8 | 27 | 19 | 44 | ||
| Lung | 11 | 37 | 11 | 26 | ||
| Liver | 12 | 40 | 17 | 39 | ||
| Soft tissue | 14 | 47 | 25 | 58 | ||
| Other | 7 | 23 | 10 | 23 | ||
| No. of involved sites | ||||||
| 1 | 14 | 47 | 16 | 37 | ||
| 2 | 10 | 33 | 17 | 40 | ||
| ≥ 3 | 6 | 20 | 10 | 23 | ||
| Prior systemic therapies | ||||||
| Adjuvant tamoxifen | 9 | 30 | 21 | 49 | ||
| Neo-/adjuvant chemotherapy | 7 | 23 | 8 | 19 | ||
| First-line endocrine therapy | 7 | 23 | 14 | 33 | ||
| Second-line endocrine therapy | 2 | 7 | 8 | 19 | ||
| First-line chemotherapy | 2 | 7 | 3 | 7 | ||
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PgR, progesterone receptor.
| Event* | Standard-Dose Cohort (n = 30) | Low-Dose Cohort (n = 43) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Grade 1-2 | Grade 3-4 | Grade 1-2 | Grade 3-4 | |||||||||||
| No. of Patients | % | No. of Patients | % | No. of Patients | % | No. of Patients | % | |||||||
| Anemia | 1 | 3 | 0 | 0 | 1 | 2 | 0 | 0 | ||||||
| Diarrhea | 5 | 17 | 4 | 13 | 7 | 16 | 1 | 2 | ||||||
| Dyspnea | 3 | 10 | 2 | 10 | 1 | 2 | 2 | 5 | ||||||
| Fatigue | 4 | 13 | 2 | 7 | 15 | 35 | 5 | 12 | ||||||
| Nausea | 11 | 37 | 2 | 7 | 12 | 28 | 2 | 5 | ||||||
| Neutropenia | 2 | 7 | 0 | 0 | 4 | 9 | 1 | 2 | ||||||
| Pain | 5 | 17 | 0 | 0 | 3 | 7 | 1 | 2 | ||||||
| PPE | 14 | 47 | 0 | 0 | 15 | 35 | 1 | 2 | ||||||
| Stomatitis | 5 | 17 | 0 | 0 | 7 | 16 | 0 | 0 | ||||||
| Thrombocytopenia | 1 | 3 | 0 | 0 | 2 | 5 | 0 | 0 | ||||||
| Vomiting | 3 | 10 | 1 | 3 | 7 | 16 | 0 | 0 | ||||||
Abbreviation: PPE, palmar-plantar erythrodysaesthesia.
*
Toxicity graded according to National Cancer Institute of Canada Common Toxicity Criteria.
| Capecitabine Standard Dose at Creatinine Clearance Rate (mL/min) | Capecitabine Low Dose at Creatinine Clearance Rate (mL/min) | |||||
|---|---|---|---|---|---|---|
| 30-50 | 51-80 | 30-50 | 51-80 | |||
| No. of patients assessable | 21 | 9 | 16 | 27 | ||
| Age, years | ||||||
| Median | 74 | 72 | 72 | 72 | ||
| Range | 66-89 | 65-78 | 66-83 | 65-78 | ||
| Median duration of treatment, weeks | 18 | 18 | 15 | 18 | ||
| Incidence of grade 3 or 4 adverse events, % | 24 | 33 | 31 | 22 | ||
| Incidence of dose reductions, % | 29 | 33 | 6 | 4 | ||
| Incidence of toxic deaths, % | 5 | 11 | 6 | 0 | ||
| No. of patients with selected adverse events | ||||||
| Diarrhea (all grades) | 5 | 4 | 3 | 5 | ||
| Fatigue (all grades) | 5 | 1 | 7 | 13 | ||
| Nausea (all grades) | 10 | 3 | 8 | 6 | ||
| PPE (all grades) | 11 | 3 | 6 | 10 | ||
| Stomatitis (all grades) | 5 | 0 | 5 | 2 | ||
| Vomiting (all grades) | 4 | 0 | 3 | 4 | ||
| No. of patients achieving tumor response | 8 | 3 | 7 | 8 | ||
NOTE. Clearance calculated according to the Cockroft and Gault equation.
Abbreviation: PPE, palmar-plantar erythrodysaesthesia.
| Response Category* | Standard-Dose Cohort (n = 30) | Low-Dose Cohort (n = 43) | ||||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | |||
| Complete response | 1 | 3 | 1 | 2 | ||
| Partial response | 10 | 33 | 14 | 32 | ||
| Response rate | 11 | 36.7 | 15 | 34.9 | ||
| Stable disease | 10 | 33 | 20 | 46 | ||
| Progressive disease | 9 | 30 | 8 | 19 | ||
*
WHO criteria.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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© 2005 by American Society of Clinical Oncology.
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Published in print: April 01, 2005
Published online: September 21, 2016
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Safety and Efficacy of Two Different Doses of Capecitabine in the Treatment of Advanced Breast Cancer in Older Women. JCO 23, 2155-2161(2005).
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Journal of Clinical Oncology 2005 23:10, 2155-2161
Journal of Clinical Oncology 2005 23:10, 2155-2161
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