Annals of Oncology Advance Access originally published online on May 12, 2005
Annals of Oncology 2005 16(8):1289-1296; doi:10.1093/annonc/mdi253
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© 2005 European Society for Medical Oncology
Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature
1 Department of Breast Medical Oncology and 2 Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
* Correspondence to: Dr B. Hennessy, Faculty of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77 030, USA. Tel: +1-713-792-2740; Fax: +1-713-792-3708; Email: bhennessy{at}mdanderson.org
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Abstract |
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Background: Capecitabine is active against anthracycline- and taxane-pretreated metastatic breast cancer. Post-marketing use of capecitabine at the FDA-approved dose (2500 mg/m2/day) leads to unacceptable toxicity in many patients. Dose reductions anecdotally improve tolerability without compromising efficacy. This retrospective analysis was designed to verify these anecdotal reports.
Patients and methods: We retrospectively reviewed the records of 141 consecutive patients with metastatic breast cancer identified from pharmacy records as receiving capecitabine outside of a clinical trial between May 1998 and February 1999. Responses were defined as clinical improvement (ID), stabilization of disease (SD) for 6 weeks or longer, or progression (PD). Patients were grouped according to the starting dose level of capecitabine: A=2500±5% (dose range 2385–2560) mg/m2/day; B=2250±5% (range 2130–2350) mg/m2/day; C 
2000+5% (range 1000–2100) mg/m2/day. We also reviewed the safety profile of capecitabine at these doses and performed a safety review of capecitabine in phase II and III metastatic breast and colorectal cancer trials.
Results: Clinical data were available for 113 patients (105 for response, 106 for toxicity). The median age was 52.5 years and the mean number of prior metastatic chemotherapy regimens was 2 (range 0–7). The mean capecitabine starting dose was 2220 mg/m2/day and the median number of cycles administered was 4 (range 1–19). The mean tolerated dose was 2040 mg/m2/day (range 960–2670). Grade 3/4 toxic effects at dose levels A, B and C, respectively, included palmar–plantar erythrodysesthesia (33%, 63%, 20%), diarrhea (13%, 12%, 3%), stomatitis (8%, 0%, 3%), and nausea/vomiting (4%, 6%, 5%). Forty per cent of all patients required capecitabine dose reductions; fewer patients treated with 2000 mg/m2/day required dose modification (28%). Five per cent of the patients required discontinuation of capecitabine owing to toxicity. Patients started at the lowest doses of capecitabine did not have poorer response rates or shorter time to progression.
Conclusions: This retrospective analysis supports a starting dose of 2000 mg/m2/day because of its superior therapeutic index; however, patients may still have toxic effects and individualization of dosing is necessary. A phase III, multicenter, randomized study to establish the safety and efficacy of different doses of capecitabine is urgently needed.
Key words: capecitabine, toxicity, breast cancer
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Capecitabine is an orally administered third-generation fluoropyrimidine carbamate. It is a prodrug that is converted by three enzymatic reactions to 5-fluorouracil (FU) [1
]. The rate-limiting step is the final reaction, catalyzed by thymidine phosphorylase. Most tumors, including breast and colorectal cancers, have levels of this enzyme that exceed the levels in normal tissue from which the neoplasm arises [2, 3]. Thus, capecitabine has relatively selective cytotoxicity for tumor tissue. It has potential as a monotherapy in many tumor types and also in combination with other agents with different mechanisms of action and little overlap in toxic effects [4].
Single-agent capecitabine has considerable activity against breast cancer that is refractory to anthracyclines and taxanes, yielding response rates of 15%–29%, stable disease in 31%–46%, and median overall survival duration of 10.1–15.2 months in phase II studies [5–8]. No phase III randomized trials have compared single-agent capecitabine and other options in second- or third-line treatment of metastatic breast cancer, although cross-trial comparisons certainly suggest that capecitabine is one of the most active agents in this setting [9, 10]. The combination of capecitabine and docetaxel was shown to produce more favorable objective response rate, time to progression and, more importantly, median overall survival duration in anthracycline-pretreated patients with advanced breast cancer compared with docetaxel alone in a recently published phase III trial [11]. Capecitabine is approved by the US Food and Drug Administration (FDA) as a single agent for treatment of metastatic breast cancer resistant to anthracycline- and taxane-containing regimens and in combination with docetaxel for treatment of anthracycline-pretreated breast cancer. Moreover, small phase II randomized trials of capecitabine in patients whose breast cancer relapsed after high-dose therapy, of capecitabine versus paclitaxel in anthracycline-refractory metastatic breast cancer, and of capecitabine versus CMF (cyclophosphamide, methotrexate and 5-FU) as first-line treatment in metastatic breast cancer patients older than 55 years, all have shown encouraging activity for the fluoropyrimidine [12–15]. Capecitabine is currently being evaluated in combination with other cytotoxic agents in the first-line treatment of metastatic breast cancer, as primary or neoadjuvant therapy in patients with operable breast cancer, as adjuvant treatment, and as single-agent therapy in women older than 65 years [15, 16].
The capecitabine package insert recommends a starting capecitabine dose of 1250 mg/m2 twice daily for 14 days every 3 weeks. The main side-effects associated with capecitabine are palmar–plantar erythrodysesthesia (PPE, hand–foot syndrome), diarrhea and stomatitis. Hand–foot syndrome occurs in 18%–64% of patients in trials of capecitabine at this dose, with grade 3/4 changes occurring in 8%–24% [5–8, 11, 14, 15, 17–21]. Diarrhea occurs in 28%–63% of patients treated at 2500 mg/m2 per day, and grade 3/4 diarrhea in 5%–19%. Overall, capecitabine dose interruptions and reductions are necessary in approximately one-third of patients, and drug discontinuation has been required in as many as 17% of patients in clinical trials (range 7%–17%) [15]. Despite this, both the FDA and the package insert recommend this dose. Retrospective analysis has demonstrated that dose adjustment does not appear to have a negative impact on efficacy [6, 11].
In view of the frequent toxicity associated with 2500 mg/m2/day of capecitabine and the apparent preservation of efficacy at lower doses, we performed a retrospective study to determine whether a lower starting dose of capecitabine does indeed improve tolerability without compromising efficacy. In addition, we reviewed the major trials of capecitabine in breast cancer to determine the frequencies of toxic effects and consequent dose modification and the impact of dose reduction on therapeutic efficacy where this information is provided. We also reviewed the safety profile of capecitabine as described in the peer-reviewed literature.
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Patients and methods |
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This retrospective analysis was designed to evaluate the post-marketing safety of capecitabine in a consecutive series of heavily pretreated patients with metastatic breast cancer, to examine the safety profile and efficacy of capecitabine in the same population, and to determine the optimal dose of capecitabine in these patients. We performed a retrospective medical record review of patients identified from The University of Texas M. D. Anderson Cancer Center pharmacy database who were dispensed capecitabine for metastatic breast cancer between May 1998 and February 1999 and were monitored until 9 September 1999. We evaluated each patient record to determine the initial dose of capecitabine prescribed, the toxic effects experienced by the patient and their grade, any dose reduction in the drug, the clinical benefit rate, and changes in laboratory parameters during treatment.
Safety profile
Toxic effects were graded according to the National Cancer Institute (NCI, version 2.0) common toxicity criteria. Table 1 shows the grading scales for PPE, diarrhea and stomatitis. Treatment doses were initially chosen and/or reduced and treatment discontinued at the discretion of the attending physician.
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Response evaluation
Disease response was classified into three categories. Improvement of disease (ID) was defined as documented clinical improvement or benefit lasting for 6 weeks or longer. Stabilization of disease (SD) was defined as no change in disease determined by clinical evaluation lasting 6 weeks or longer. Disease progression (PD) was defined as any documented clinical evidence of progression within 6 weeks of initiation of therapy. Due to the retrospective nature of the data, these relevant end points were chosen to reflect everyday clinical practice and the treatment decisions made outside of the context of clinical trials. Time to progression (TTP) was also calculated based on the time the patient was started on capecitabine until evidence of progression warranting discontinuation of the capecitabine therapy.
Initial dose levels
Patients were retrospectively subdivided into three groups depending on their starting dose of capecitabine. Each group was then analyzed for the frequency of drug toxicity, dose reduction and response rate. These groups were determined based on the approved starting dose and the most commonly utilized doses in our patient population. The most common dose reduction was at 20% compared with the approved dose. However, many patients also fell close to the 10% level. Therefore, dose level A was a starting dose of 2500±5% (actual dose range 2385–2560) mg/m2/day. Dose level B was a starting dose of 2250±5% (range 2130–2350) mg/m2/day. Dose level C was a starting dose of <2000+5% (range 1000–2100) mg/m2/day.
Literature review
The literature review was performed by searching the Pubmed and Medline databases, using ‘capecitabine’, ‘breast’, ‘colorectal’, ‘cancer’ and ‘clinical trial’ as keywords to identify all published clinical trials of capecitabine in breast and colorectal cancer.
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Results |
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Patient characteristics
One hundred and forty-one patients given capecitabine for metastatic breast cancer between May 1998 and February 1999, and monitored until 9 September 1999, were identified from the M. D. Anderson Cancer Center pharmacy database, and their charts were reviewed. Of these, 113 patients were evaluable for response or tolerability (105 for response and 106 for tolerability). Twenty-eight patients were not evaluable. Several patients did not return to our institution for follow-up (16 patients) or did not have enough information in their medical record to determine efficacy or toxicity related to capecitabine (five patients). Four patients never received a dose of capecitabine. One patient died during the first cycle of capecitabine due to progressive disease. One patient was excluded from analyses due to participation in a protocol dictating the dose of capecitabine. One patient received a much higher than recommended dose of capecitabine and was therefore excluded from analyses.
Table 2 summarizes the patient characteristics. All but one of the patients were women and the majority were Caucasian (76%). Seventy-one per cent had visceral metastases and 16% had HER2/neu-positive tumors. Forty-five per cent of tumors were estrogen receptor positive. Fifty-seven per cent of the patients had received two or more prior chemotherapy regimens: 89% had been pretreated with both an anthracycline and taxane, and 86% had previously been given a fluoropyrimidine.
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When comparing the dosing groups, patients in group C were younger than in groups A or B. Dosing group C was more heavily pretreated when evaluating patients who had had three or more prior therapies for metastasis and fewer tumors were HER2-positive in dosing group B compared with A and C.
Dosing and administration
The mean starting dose of capecitabine was 2220 mg/m2/day. In all cases, treatment was administered in cycles of 14 consecutive days repeated at 3-week intervals; the median number of cycles administered was 4 (range 1–19). Forty per cent of all patients required a dose reduction for toxicity. There were fewer dose reductions among patients treated with capecitabine 2000 mg/m2/day (28%) than among patients started on 2500 mg/m2/day (41%). Sixty-three per cent of patients started on 2250 mg/m2/day required a dose reduction for toxicity. The mean tolerated dose of capecitabine was 2040 mg/m2/day, approximately 20% lower than the dose recommended in the package insert.
Response
Responses are summarized in Table 3. The ID rates were 18%, 20% and 24% for patients treated at capecitabine starting dose levels A, B and C, respectively. The SD rates were 35%, 47% and 37%, respectively. The median times to progression were 11.9 months, 19.9 months and 15.1 weeks in the three groups, respectively. It is apparent that the highest dose, 2500 mg/m2/day, yielded no greater benefit in response rate or time to progression than the other two dose levels used.
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Adverse events
Table 4 shows the frequencies of adverse events related to capecitabine in the study. PPE was the most common, as expected. For all grades of PPE, the frequency was 74% overall, and there was little difference in frequency among the three groups. Grade 3/4 PPE was seen in 33% of patients overall; it occurred in fewer patients starting at 2000 mg/m2/day than in those starting at 2500 mg/m2/day (20% versus 33%, respectively). Grade 3/4 diarrhea developed in 10% overall; it occurred less frequently in patients treated initially with the lowest doses of capecitabine (3% versus 13% in those treated with 2500 mg/m2/day). Grade 3/4 stomatitis was relatively infrequent (5% of all patients). However, stomatitis (all grades) occurred somewhat more often in patients given 2500 mg/m2/day than in those given 2000 mg/m2/day (45% versus 31%, respectively). Other common toxic effects included hyperbilirubinemia (21% overall). Overall, the most common toxic effects occurred less commonly in patients who started at the lowest capecitabine doses. As shown in Table 4, grade 3/4 changes in hematologic parameters occurred infrequently in these patients given single-agent capecitabine. Six per cent of all patients were hospitalized at some point as a result of toxicity. Table 5 shows the frequency of deaths during the study period (3% overall), as well as the percentage of patients who discontinued capecitabine because of toxicity (5% overall). It should be noted that only one death, from pneumonia, was possibly attributable to capecitabine toxicity.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Capecitabine is certainly an effective drug in the treatment of metastatic breast cancer [5
–17]. It has single-agent activity in patients with progressive disease after prior therapy and also considerable activity in combination with other cytotoxic agents. The package insert recommends starting capecitabine at 2500 mg/m2/day in two divided doses in breast and colon cancer. Capecitabine has a well-established toxicity profile. The most common toxic effects are PPE, diarrhea, stomatitis, nausea and vomiting. It is regarded as well tolerated, and this is a significant advantage in a drug that seems to selectively accumulate in tumor cells by nature of its mechanism of action. The oral route of administration is also advantageous. Its tolerability is particularly important in patients with metastatic breast cancer, the majority of whom are not cured with current treatments, and in whom palliation is the most important goal of therapy. We and others noticed in practice, however, that toxic effects are frequent at the 2500 mg/m2/day starting dose level, that many patients cannot tolerate that dose, and that most of these patients tolerate the drug after an appropriate dose reduction [22]. We sought to determine, by formal review, whether this is indeed the case. The frequency and severity of adverse events were greater in our population (using the 2500 mg/m2/day dose) than in those previously reported. The patients in our study were treated off protocol. They represent an unselected group of patients with metastatic breast cancer at our institution. They experienced frequent PPE and diarrhea with single-agent capecitabine; significantly, 33% of these patients experienced grade 3/4 hand–foot syndrome. PPE was somewhat less common in patients treated with 2000 mg/m2/day, as were stomatitis and grade 3/4 diarrhea. The mean tolerated dose was 2040 mg/m2/day, and lower doses of capecitabine did not compromise treatment efficacy in our retrospective analysis. Fewer patients who started at 2000 mg/m2/day than at higher doses of capecitabine required dose reduction.
Table 6 summarizes toxicity data from a number of trials of single-agent capecitabine in breast cancer and two pivotal trials in colon cancer [5–8, 14, 15, 18–21]. Capecitabine was started at 2500 mg/m2/day in all of these studies. The most common adverse effects were PPE and diarrhea. PPE (all grades) developed in 36%–62% of all patients and grade 3/4 PPE in 8%–22%. Diarrhea complicated treatment in 28%–58% of patients and was of grade 3/4 severity in 7%–19%. Stomatitis was seen in 9%–34%, with grade 3/4 stomatitis in 0%–12%. Grade 3/4 nausea and neutropenia were relatively uncommon in patients treated with capecitabine alone, occurring in 1%–10% and 1%–14% of patients, respectively. In most of the larger studies, grade 3/4 neutropenia developed in only 1%–3% of patients. Infection or neutropenic fever developed in 0.2%–11% of patients treated in these trials. The most common toxic effects occurred somewhat more frequently in our patients than in the patients in these trials, particularly hand–foot syndrome and stomatitis, while nausea and neutropenia occurred at about the same rates as in other studies. In these published studies the adverse effects associated with capecitabine therapy led to a dose reduction in 22%–54% of patients [5–8, 14, 15, 18]. In most cases, PPE and/or diarrhea were the dose-limiting toxic effects. Adverse events necessitated capecitabine discontinuation in as many as 17% of treated patients. These findings are similar to those in the patients in our study.
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Table 6 does not include data from a pivotal trial comparing the combination of capecitabine and docetaxel to docetaxel alone in anthracycline-pretreated patients [11
]. In that trial, the starting dose of capecitabine was 2500 mg/m2/day. Of patients treated on the combination arm, 64% had PPE (grade 3/4 in 24%), 63% had diarrhea (grade 3/4 in 14%), and 66% developed stomatitis (grade 3/4 in 17%). It is apparent that capecitabine was mostly responsible for PPE and also contributed to diarrhea in these patients (the incidences in the docetaxel only group were <10% and 45%, respectively). However, only 20% of patients actually had data collected regarding toxicity. Reduction of capecitabine dose was required in 4% of patients, and the doses of both drugs were modified in 51% of patients in the combination arm. Treatment discontinuation was necessary in 26% of the patients who received the combination. Twenty-eight per cent of patients in the combination arm were hospitalized at some point during the trial, but the investigators pointed out that most hospitalizations were due to neutropenic fever and that gastrointestinal and cutaneous adverse events rarely warranted hospitalization.
Capecitabine is activated preferentially in tumor cells by thymidine phosphorylase. It is known that certain chemotherapeutic drugs, such as taxanes and cyclophosphamide, as well as radiotherapy, upregulate this enzyme [23–25]. These agents have synergistic cytotoxicity with capecitabine, while 5-FU does not. Fluoropyrimidines are inactivated by another enzyme known as dihydropyrimidine dehydrogenase. In preclinical models, the efficacy of capecitabine is optimized in tumors with a high ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase [26]. Agents that increase this ratio (such as those mentioned) potentiate the cytotoxicity of capecitabine. This has already been borne out in the trial of capecitabine and docetaxel versus docetaxel alone in anthracycline-pretreated breast cancer [11]. Such preclinical data are very useful in devising appropriate drug combinations for study in clinical trials. It is logical that capecitabine is better dosed at well-tolerated levels in trials of combination therapy in which drug synergism should offset the need to maximize the capecitabine dose. It should be noted, furthermore, that the capecitabine dose must be reduced by 25% in patients with moderate renal impairment (calculated creatinine clearance 30–50 ml/min), poor performance status, extensive prior therapy (including high-dose chemotherapy with hematopoietic stem cell rescue), or comorbid medical conditions at baseline [18, 27]. In patients with creatinine clearance less than 30 ml/min, capecitabine is contraindicated.
Table 7 shows our recommended dose modifications for cases of capecitabine toxicity. It is apparent that the toxic effects associated with capecitabine therapy at 2500 mg/m2/day cause morbidity in a relatively high proportion of patients, necessitating frequent dose reduction. This is consistent with our experience. Since the most important goal of the treatment of metastatic breast cancer is symptom palliation, therapy associated with considerable morbidity defeats the purpose. Reduction of the capecitabine dose has been shown to improve drug tolerability in most cases [5–7, 11, 14, 15, 18–21]. Moreover, retrospective analysis of many of the capecitabine trials referenced here has found that dose reduction for adverse events related to capecitabine did not have an impact on efficacy of the drug [5, 6, 11, 14, 15, 18–20, 27]. This is supported by our data. In our experience, the mean tolerated dose of capecitabine is 2040 mg/m2/day. Thus, it seems appropriate to use the drug at a lower starting dose, perhaps 2000 mg/m2/day in two divided doses. If the patient tolerates this dose well, the dose can then be progressively increased in increments of 10%. O'Shaughnessy et al. [22], in another retrospective study, also found an improved therapeutic index for lower doses of capecitabine.
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However, our analysis does have some limitations. It is retrospective and based on a relatively small number of patients. Our three groups, stratified by dose level, are uneven in size and, prognostically, not comparable. The capecitabine dose used was not chosen randomly. Therefore, modest differences in efficacy might be overlooked. As such, a prospective dose-assessment trial for capecitabine is essential, and this was, in fact, a condition for FDA approval of the drug.
In summary, this retrospective review clearly shows that adverse events occur more frequently in patients receiving the recommended dose of capecitabine (2500 mg/m2/day) than previously reported in clinical trials. The mean tolerated dose of capecitabine is approximately 20% lower than the approved dose. A lower starting dose improves tolerability without compromising efficacy. We suggest an initial dose of 2000 mg/m2/day, but confirmation of our results in a prospective trial is required. We recommend an initial capecitabine dose of 1500–1750 mg/m2/day in those with moderate renal impairment, poor performance status or comorbid conditions. Finally, individualization of dosing is imperative.
Received for publication November 1, 2004. Revision received April 11, 2005. Accepted for publication April 12, 2005.
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References |
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