Evolution of Capecitabine Dosing in Breast Cancer

Review

Evolution of Capecitabine Dosing in Breast Cancer Michael Naughton Abstract In the United States, poor patient tolerability of the standard capecitabine dosing regimen (1250 mg/m2 twice daily on days 1-14 administered every 21 days) limits the established benefit of the agent. The observation that patient tolerability improves and efficacy is maintained with lower doses led to the investigation of various doses and schedules in patients with metastatic breast cancer. Capecitabine monotherapy in daily doses of 1000-2560 mg/m2 or in combination with a taxane in daily doses of 825-1250 mg/m2 has confirmed that tolerability improves and efficacy is maintained with lower-than-standard doses. Similar results have been observed with various dosing schedules, including continuous administration and 28-day, 7-day, and 7-days-on/7-days-off cycles. These findings suggest that capecitabine administered in a variety of doses and schedules might be a viable alternative to anthracyclinecontaining regimens as first- or second-line treatment in patients with metastatic breast cancer. Clinical Breast Cancer, Vol. 10, No. 2, 130-135, 2010; DOI: 10.3816/CBC.2010.n.017 Keywords: Docetaxel, Metastatic breast cancer, Tolerability

Introduction Breast cancer remains a major cause of death in women in the United States, accounting for an estimated 40,480 deaths in 2008.1 There is good news, however: the mortality rate for breast cancer declined from 32 to 24 per 100,000 persons between 1991 and 2004,1 and 5-year survival has increased significantly (P < .05), rising from 75% in 1975-1977 to 89% in 1996-2003.1 Several factors have contributed to these improved outcomes, among them early tumor detection and more effective therapies including the use of targeted treatments. Despite these gains, survival of patients with distant metastases remains poor, with 5-year survival rates of 27%. Thus, there is still a need for improved treatment.

Early Phase II Studies of Capecitabine in Metastatic Breast Cancer Capecitabine was approved by the US Food and Drug Administration in April 1998 as monotherapy for patients with metastatic breast cancer (MBC) resistant to paclitaxel and an anthracycline-containing regimen. Capecitabine was also approved for patients with MBC resistant to paclitaxel and for whom further anthracycline therapy is contraindicated. The dose of capecitabine approved for these indications, 1250 mg/m2 twice daily on days



Washington University School of Medicine, St. Louis, MO



Submitted: Jul 8, 2009; Revised: Dec 7, 2009; Accepted: Dec 17, 2009; Epub: Mar 5, 2010



Address for correspondence: Michael Naughton, MD, Washington University School of Medicine, Alvin J. Siteman Cancer Center, West County, 10 Barnes West Drive, Ste 100, St. Louis, MO 63141 Fax: 314-996-8277; e-mail: [email protected]



1-14 administered every 21 days, was based on 2 single-arm phase II studies.2 The first study involved 162 patients with MBC who were resistant to or whose disease had progressed on paclitaxel; 91% had received an anthracycline and 82% 5-fluorouracil (5-FU).2 Of the 135 patients with measurable disease, 27 (20%) had a complete or partial response, and 54 (40%) had stable disease. The median time to disease progression was 93 days. Responses were evenly distributed between patients with few or multiple organ sites with metastatic involvement. The most common treatment-related grade 3 or 4 adverse events (AEs) were diarrhea (14%) and hand-foot syndrome (10%). Similar results were observed in a subsequent study involving a similar patient population.3 The same capecitabine dosing regimen, 1250 mg/m2 twice daily on days 1-14 administered every 21 days, is also approved for use in combination with docetaxel in anthracycline-treated MBC. The regimen is based on a study involving 511 anthracycline-treated patients with MBC.4 Compared with docetaxel alone, the addition of capecitabine to docetaxel significantly increased the median time to disease progression (4.2 months vs. 6.1 months; P = .0001). Similarly, median survival was 11.5 months with single-agent docetaxel and 14.5 months with the combination (P = .0126). It has been observed that US patients tolerate standard dosing less well than do non-US populations. A multivariate analysis of 3 phase III clinical trials observed decreased tolerability of capecitabine in patients in the United States compared with patients in other countries.5 Two of the trials compared capecitabine with bolus 5-FU/leucovorin in metastatic colorectal cancer, and the third trial compared the combination of capecitabine and oxaliplatin with bolus 5-FU/leucovorin as adjuvant treatment for colon cancer.

This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.

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In patients with metastatic colorectal cancer, more grade 3/4 AEs (relative risk [RR], 1.77), dose reductions (RR, 1.72) and discontinuations (RR, 1.83) occurred in US than in non-US patients. Similarly, in the adjuvant colon cancer trial, more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were observed in US than in non-US patients. Overall, East Asian patients have the lowest risk and US patients the highest risk for grade 3/4 AEs, especially gastrointestinal events (nausea, vomiting, stomatitis) and neutropenia. The reason for this is not clear, although various factors might be involved.5 Ethnic factors such as genetic polymorphisms can result in significant pharmacokinetic variability, as has been observed with other medications, including some anticonvulsants, antidepressants, antihyperglycemics, and antihypertensives.6-9 However, limited data suggest no clinically important pharmacokinetic differences between White and Japanese patients.10 Other factors relating to the clinical trial methodology and reporting bias also might contribute to the observed differences in risk. These factors include differences in baseline characteristics (eg, age, gender, body-mass index, body surface area, creatinine clearance, and performance status) as well as dietary habits and cultural differences.

Initial Experience With Capecitabine Dose Reduction Trials involving early dose reduction suggested that tolerability was improved without compromising efficacy. One retrospective review analyzed the results of 4 phase II trials of capecitabine at the standard dose.11 The trials involved 321 patients with advanced cancer or MBC. The overall response rate was 21.8%. Compared with those whose dose was not reduced, the 131 patients whose capecitabine dose was reduced experienced no difference in the response rate or several other outcome measures. Among the patients who responded before rather than after the dose was reduced, there was little difference in the duration of response (201 days vs. 263 days), time to treatment failure (213 days vs. 263 days), or survival time (331 days vs. 393 days). Similar findings were observed in a more recent retrospective review of a phase III trial involving capecitabine and docetaxel. Patients received either capecitabine 1250 mg/m2 twice daily for 14 days plus docetaxel 75 mg/m2 on day 1 every 3 weeks or docetaxel 100 mg/m2 on day 1 every 3 weeks.12 Nearly two thirds (65%) of patients treated with the combination of capecitabine and docetaxel required a dose reduction, compared with 35% of those treated with docetaxel alone. Patients whose dose was reduced experienced fewer cycles with grade 3/4 AEs—17%, compared with 34% in those who were treated with full-dose therapy. The time to progression (median, 6.8 months vs. 6.2 months), time to death (median, 15 months vs. 14.6 months), and overall survival (OS; median, 16.3 months vs. 13.1 months) were similar for those whose dose of capecitabine plus docetaxel was reduced from cycle 2 onwards compared with those who received at least 4 cycles of full-dose capecitabine plus docetaxel.12 In summary, capecitabine is effective alone and in combination with docetaxel for the treatment of patients with MBC. However, in the United States, the standard dose of 1250 mg/m2 twice daily on days 1-14 given every 21 days often cannot be administered because of toxicity. Retrospective data suggest that a reduced dose achieves results comparable to those achieved with the standard dose.

Capecitabine Dosing Regimens in Metastatic Breast Cancer Two general approaches to modifying the dosing regimen of capecitabine in MBC have been taken: (1) reduction of the initial dose, and (2) different dosing schedules. Because reducing the initial dose of capecitabine appears to improve tolerability without compromising efficacy, several retrospective and prospective studies have investigated this approach.

Reducing the Initial Dose of Capecitabine The initial dose of capecitabine monotherapy has ranged from 1000 to 2560 mg/m2/day. This daily dose is generally administered in 2 divided doses for 14 days, then 7 days off. Trials have demonstrated a trend for an increase in the median number of cycles, and a decrease in the percentage of patients requiring dose reduction, as the dose of capecitabine decreased (Table 1).13-18 At the same time, the frequency of grade 3/4 AEs also generally decreased as the dose of capecitabine decreased. For example, at doses of capecitabine ranging from 2130 to 2560 mg/m2/day13 versus 2000 mg/m2/day,15-18 diarrhea occurred in 12%-13% versus ≤ 6%, respectively. Similarly, hand-foot syndrome occurred in 33%-63% versus ≤ 14%, respectively. There was, however, no clear trend between dose and response. In fact, 1 study that evaluated 3 dose levels of capecitabine found that there was no greater benefit in response rate or time to progression with the highest dose (2500 mg/m2/day) compared with the medium dose (2250 mg/m2/day) and low dose (< 1000 mg/m2/day).13 Capecitabine has been used over a range of reduced initial doses (825-1250 mg/m2 administered twice daily for 14 days, then 7 days off ) in combination with a taxane (Table 1).19-22 As first-line therapy in patients with MBC, capecitabine-containing regimens demonstrated efficacy similar to a combination of a taxane plus epirubicin.19-21 The response rate (complete plus partial) was 52%-53% for capecitabine plus taxane and 51% for epirubicin plus taxane.19,21 Similarly, the combination of capecitabine plus taxane was found to result in a median progression-free survival (PFS) of 12 months, compared with 9-11 months for epirubicin plus taxane.20,21 These differences were not statistically significant.19-21 Patient tolerability of the capecitabine plus taxane regimen was similar to the combination of a taxane plus epirubicin.19-21 As second-line sequential therapy in combination with a taxane, both PFS and OS were similar to combination therapy with a taxane.22 Patient tolerability was comparable with sequential versus combination therapy. These results demonstrate that using lower-than-standard initial doses of capecitabine is a viable alternative to anthracycline-containing regimens in the first- or second-line treatment of patients with MBC.

Different Dosing Schedules Another approach to modifying the dosing regimen of capecitabine in patients with MBC has been to use a dosing schedule other than the standard 3-week cycle. A preclinical study utilizing 2 human mammary xenograft models tested 4 dosing schedules of capecitabine administered for 6 weeks: (1) 14 days on, 7 days off; (2) 5 days on, 2 days off; (3) 2 days on, 5 days off, and (4) 7 days on, 7 days off.23

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Capecitabine Dosing in Breast Cancer Table 1A Studies Utilizing a Reduced Initial Dose of Capecitabine Study

Dosing Regimen

Previous Treatment

Outcomesa

Monotherapy mg/m2/d

Hennessy et al (2005)13

• Capecitabine 2385-2560 × 14 days every 3 weeks (dose reduction in 41%; n = 51) • Capecitabine 2130-2350 mg/m2/d × 14 days every 3 weeks (dose reduction in 63%; n = 17) • Capecitabine 1000-2100 mg/m2/d × 14 days every 3 weeks (dose reduction in 28%; n = 45)

Stockler et al (2007)14

• N = 325 • Capecitabine 2000 mg/m2/d × 14 days every 3 weeks • Capecitabine 1300 mg/m2/d × 21 days every 3 weeks • Cyclophosphamide 100 mg/m2/d × 14 days + methotrexate 40 mg/m2 days 1 and 8 + 5-fluorouracil (FU) 600 mg/m2 days 1 and 8 every 4 weeks

Bajetta et al

Anthracycline + taxane (89%) Fluoropyrimidine (86%)

Number of cycles (median): 4 ID: 18% vs. 20% vs. 24% SD: 35% vs. 47% vs. 37% TTP (median): 2.8 vs. 4.6 vs. 3.5 months HFS: 33% vs. 63% vs. 20% Diarrhea: 13% vs. 12% vs. 3%

None

OS (median): 22 vs. 18 months (P = .02) PFS (median): 7 vs. 7 months (P = .2) Response rate: 21% vs. 18% (P = .8) Capecitabine groups combined vs. cyclophosphamide + methotrexate + 5-FU

(2005)15

• Capecitabine 1000 mg/m2 BID × 14 days every 3 weeks (dose reduction in 5%; n = 30) • Capecitabine 1250 mg/m2 BID × 14 days every 3 weeks (dose reduction in 30%; n = 43)

Chemotherapy: 51% vs. 30%

Number of cycles (median): 6 CR: 2% vs. 3% PR: 32% vs. 33% TTP (median): 4.1 vs. 3.9 months Survival (median): 16 vs. 10 months Diarrhea: 2% vs. 13% Dyspnea: 5% vs. 10% Fatigue: 12% vs.7% Nausea: 5% vs. 7%

(2005)16

Capecitabine 1000 mg/m2 BID × 14 days every 3 weeks (n = 57)

Anthracycline (81%) Taxane (40%) 5-FU (23%) Hormone (12%)

Number of cycles (median): 4 CR: 2%; PR: 26%; TTP: 6 months Survival (median): 9 months; 1 year, 37%; 2 years, 20%; Nausea: 8%; Diarrhea: 4%

weeks (dose reduction in 37%; n = 63)

Anthracycline (52%) Taxane (22%)

Number of cycles (median): 5 CR + PR + SD: 56% TTP (median): 3.5 months OS (median): 12.5 months HFS: 14%; Diarrhea: 6%; Fatigue: 5%

Capecitabine 1000 mg/m2 BID × 14 days every 3 weeks (n = 69)

Chemotherapy (75%) Hormone (45%) Radiation (49%)

Number of cycles (median): 7.6 PR: 17%; SD: 52% TTP (median): 5 months; HFS: 9%; Fatigue: 4%

El-Helw et al

Yap et al (2007)17

Sezgin et al (2007)18

Capecitabine 1000 mg/m2 BID × 14 days every 3

aAdverse

events are grade 3/4 unless otherwise noted. Abbreviations: CR = complete response; HFS = hand-foot syndrome; ID = improved disease; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease; TTP = time to disease progression

The respective dose levels corresponded to 6 weeks’ total doses of 22.6, 15.1, 10.1, and 6.8 g/kg. While the schedules utilizing higher daily doses resulted in more toxicity, efficacy (as measured by tumor growth inhibition) was favorable in every schedule at the appropriate dose level. For example, in the MX-1 xenograft model, tumor growth inhibition was 49%, 54%, 65%, and 53% for the respective schedules at a toxic dose level of 15.1 g/kg. In the MAXF401 xenograft model at a toxic dose of 10.1 g/kg, tumor growth inhibition was 23%, 34%, 45%, and 38% for the respective schedules.

Continuous Administration The results of the Yanagisawa study have led to further testing in the clinical setting using other dosing schedules of capecitabine. The first of these used continuous administration of capecitabine with no drug-free period. This approach was based on the rationale that capecitabine is an S-phase–specific drug but with a short elimination half-life.24 Another rationale is that it may be easier for patients to remember to take the dose of capecitabine compared with a 14/7 schedule.

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In patients with advanced breast cancer, those treated with continuous administration of capecitabine at a daily dose of 1300 mg/m2/day achieved results—in terms of OS, median PFS, and response rate—similar to those achieved by patients treated with a comparable regimen of capecitabine (ie, 2000 mg/m2/day on days 1-14 every 21 days; P > .4 for each outcome).14 Another study found a lower incidence of AEs in patients with MBC treated with the continuous administration of capecitabine. Patients previously treated with anthracyclines and/or taxanes were randomized to capecitabine 800 mg/m2 twice daily every day or the standard regimen of 1250 mg/m2 twice daily on days 1-14 every 21 days. Preliminary data indicated that a median of 3 cycles was administered in both groups, with a median dose intensity of 93% and 73%, respectively.25 Grade 3/4 toxicities were hand-foot syndrome (29% vs. 71%), diarrhea (0 vs. 43%), stomatitis (14% vs. 29%), asthenia (0 vs. 14%), and febrile neutropenia (0 vs. 14%). Two patients in the standard regimen group discontinued treatment because of toxicity. The limited data from these two studies suggest that the continu-

Michael Naughton Table 1B Studies Utilizing a Reduced Initial Dose of Capecitabine Study

Dosing Regimen

Previous Treatment

Outcomesa

Combination Therapy • Docetaxel 75 day 1 + capecitabine 950 mg/m2 BID days 1-14 every 3 weeks • Docetaxel 75 mg/m2 day 1 + epirubicin 75 mg/m2 day 1 every 3 weeks

Anthracycline: 27% vs. 37%

CR: 8% vs. 11% PR: 45% vs. 40% Overall response: 52.9% vs. 51.5% (P = .8) TTP (median): 10.5 vs. 10.4 months (P = .9) Neutropenia: 46% vs. 57% (P = .07) Febrile neutropenia: 8% vs. 11% (P = .4) HFS: 3.6% vs. 0 (P = .02)

• Docetaxel 75 mg/m2 day 1 + capecitabine 1000 mg/m2 BID days 1-14 every 3 weeks (n = 136) • Docetaxel 75 mg/m2 day 1 + epirubicin 75 mg/m2 day 1 every 3 weeks (n = 136)

Anthracycline in majority

PFS (median): 12 vs. 9 months (P = .08) OS (median): 28 vs. 28 months (P = .92) HFS (grade 3): 17% vs. 0%

Anthracycline: 19% vs. 20%

Number of cycles (median): 6 CR: 7% vs. 8% PR: 45% vs. 43% SD: 35% vs. 37% PFS (median): 12.0 vs. 11.1 months (P = NS) OS (median): 25.6 vs. 24 months (P = NS) Neutropenia: 38% vs. 52% Leukopenia: 12% vs. 41% Diarrhea: 5% vs. ≤ 1% HFS (grade 3): 12% vs. 0

Anthracycline: 27% vs. 32% vs. 25%

PFS (median): 6.3 vs. 6.5 vs. 8.5 months (P = NS) OS (median): 31.5 vs. 33.1 vs. 28.6 months (P = NS) HFS: 19% vs. 8% vs. 13% Mucositis: 6% vs. 3% vs. 4%

mg/m2

Mavroudis et al (2008)19

Luporsi et al

(2008)20

Lük et al (2007)21

Soto et al (2006)22

• Capecitabine 1000 mg/m2 BID days 1-14 + paclitaxel 175 mg/m2 day 1 every 3 weeks (n = 170) • Paclitaxel 175 mg/m2 day 1 + epirubicin 60 mg/m2 day 1 every 3 weeks (n = 170)

• Capecitabine 1250 mg/m2 BID days 1-14 followed after progression by docetaxel 100 mg/m2 or paclitaxel 175 mg/m2 day 1 every 3 weeks (n = 91) • Capecitabine 825 mg/m2 BID days 1-14 + paclitaxel 175 mg/m2 day 1 every 3 weeks (n = 95) • Capecitabine 825 mg/m2 BID days 1-14 + D 75 mg/m2 day 1 every 3 weeks (n = 91)

aAdverse

events are grade 3/4 unless otherwise noted. Abbreviations: CR = complete response; D = docetaxel; HFS = hand-foot syndrome; ID = improved disease; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease; TTP = time to disease progression

ous administration of capecitabine is as effective but more tolerable than the standard 14/7 dosing schedule.

28-Day Cycle Another schedule, commonly used in Japan, involves administering capecitabine daily for 21 days every 28 days. Using this schedule, 4 trials administered capecitabine monotherapy at a daily dose of 1657 mg/m2.26-31 The overall response rate (complete plus partial) ranged from approximately 10%-44%, and the median time to disease progression from 2.8 to 5.2 months. Most patients had received previous treatment with an anthracycline and/or taxane.26,27 A fifth study used a capecitabine dose 25% lower (625 mg/m2 twice daily for 14 days on days 8 through 21 followed by 1 week off ), with cycles repeated every 28 days.31 Patients also received docetaxel 36 mg/m2 weekly for 3 weeks. The response rate was 51% with a median time to disease progression of 6 months. The overall response rate was 73% in chemotherapy-naive patients, compared with 40% in pretreated patients. In these 5 studies, patient tolerability of capecitabine was good. Grade 3/4 hand-foot syndrome occurred in 6%-18% and hyperbilirubinemia in as many as 10% of patients.26,27,31 It can be concluded that this 28-day cycle of lower-dose capecitabine monotherapy offers good efficacy and patient tolerability.

7-Day Cycle Another dosing strategy is to administer capecitabine on days 1 through 5 every 7 days. Favorable results using this 7-day cycle of capecitabine have been observed in patients with gastric32 or rectal33,34 cancer. The 7-day cycle has several potential benefits.35 First, it avoids the 7-day drug-free interval of the standard 21-day cycle and exploits the pharmacokinetic profile of capecitabine, which mimics continuous infusion of 5-FU. In fact, a crossover pharmacokinetic analysis has shown capecitabine 1000 mg/m2 twice daily for 3 cycles administered either 5 times per week or as the standard 21-day cycle to be bioequivalent.36 Another advantage of the 7-day cycle is that it takes advantage of the increased uptake of capecitabine in tumor tissue relative to adjacent tissue or plasma, as shown in human colon cancer xenograft models.37 The 5-fluorouracil area-under-the-curve was approximately 25 times higher in tumor tissue following capecitabine administration compared with 5-FU administration. Furthermore, capecitabine administration yielded 5-FU levels > 100 times higher in tumors than in plasma and > 20 times higher than in muscle. Using this 7-day cycle, a phase I trial administered capecitabine twice daily on weekdays (1331 mg/m2/day, escalating to 2510 mg/ m2/day) for a median of 12 weeks (range, 2-52 weeks).38 Of 8 breast cancer patients treated with ≥ 2000 mg/m2 of capecitabine

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daily, 3 achieved a partial response and 7 some clinical benefit. The median time to progression was 7 months. Capecitabine was well tolerated, with most treatment-related AEs grade 1 or 2. Although a small sample size, these results suggest that the 7-day weekday on/weekend off dosing regimen may be clinically beneficial, with improved patient tolerability.

7-on/7-off schedule of capecitabine appears to be clinically effective and well tolerated. The Society of Latin American and Caribbean Medical Oncology (SLACOM) in conjunction with investigators at Memorial Sloan-Kettering Cancer Center is planning a randomized phase III trial to test the capecitabine 14/7 schedule against the 7/7 schedule. This could be the definitive schedule study.43

7-On/7-Off Cycle

Conclusion

Finally, the 7-days-on/7-days-off schedule, with capecitabine administered on days 1 through 7 every 14 days, increasingly appears to be a viable alternative to raising the standard schedule. The 7-on/7-off cycle is based on a mathematical model to optimize efficacy and minimize toxicity. Increasing the dose rate has the theoretical benefit of minimizing the regrowth of cancer cells between chemotherapy cycles.39 In fact, the maximum impact of treatment (ratio of growth rates [perturbed/control]) has been shown to be greatest from 8.3 to 10.1 days in a xenograft model using different dose levels at 4 dose schedules of capecitabine.40 Based upon this xenograft model and early clinical evidence, several investigations have been conducted using the 7-on/7-off schedule of capecitabine. Preclinical data in mice showed that the maximum tolerated dose of capecitabine was 700 mg/kg using the 7-on/7-off schedule, compared with 400 mg/kg as historically observed with the standard 21-day 14-on/7-off cycle.41 Survival also was greater with the 7-on/7-off schedule. A phase I study of 21 patients with MBC used flat-dose capecitabine administered using the 7-on/7-off schedule. A 3-patients-per-cohort dose-escalation schedule was begun with capecitabine 1500 mg twice daily. Using a predefined algorithm, dose levels were increased by 500 mg following 28 days of monitoring until the maximum tolerated dose was achieved.42 The maximum tolerated dose was defined as the highest dose for which the incidence of dose-limiting toxicity was < 33%. Dose-limiting toxicity was defined as grade 3/4 nonhematologic toxicity or grade 3/4 hematologic toxicity lasting > 2 weeks despite growth factor support.42 The maximum tolerated dose of capecitabine administered on the 7-on/7-off schedule was 2000 mg twice daily. There were no grade 4/5 AEs. Grade 2/3 AEs were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%).42 These results confirm preclinical evidence demonstrating the 7-on/7-off schedule of capecitabine to be well tolerated. One additional 7-on/7-off phase II study has been undertaken based on the results of the phase I study and the modest improvement observed for the time to disease progression with the addition of bevacizumab to conventionally dosed capecitabine.43 Patients with previously treated MBC (n = 27) were given capecitabine 2000 mg twice daily 7-days-on/7-days-off in combination with bevacizumab 10 mg/kg every 2 weeks. After a median of six 4-week treatment cycles, 23 patients were evaluable for response. Partial response was observed in 7 (confirmed in 5) patients, stable disease for > 6 months in 6, stable disease for < 6 months in 7, and progressive disease in 3 patients. The most common grade 2/3 treatmentrelated toxicities were hand-foot syndrome (9/6), diarrhea (1/0), hypertension (1/2), and proteinuria (0/0). One case of grade 4 pulmonary embolism requiring discontinuation of bevacizumab occurred. This phase II study provides further evidence that a

Extensive clinical investigation has established that the standard 3-week cycle of capecitabine prolongs the time to disease progression with similar or prolonged OS in patients with MBC. However, tolerability of the approved dose has been poor in patients in the United States because of an increased risk of fluoropyrimidine toxicity. For this reason and based on retrospective analyses demonstrating similar benefits of reduced-dose capecitabine compared with the standard 3-week cycle, reduced capecitabine doses and alternative schedules have been sought to improve tolerability and enable longer treatment duration without compromising efficacy. Confirmation of these retrospective analyses in prospective clinical trials demonstrating the superior survival benefit of reduced-dose capecitabine compared with the combination of cyclophosphamide, methotrexate, and 5-FU as well as anthracycline-based therapy provides reassurance that a lower dose is highly effective. While the frequency of grade 3/4 AEs also generally decreased as the initial dose of capecitabine decreased, 1 trial found no clear trend between dose and response.13 Investigation of reduced-dose capecitabine continues. One randomized trial comparing the standard dose of capecitabine plus docetaxel, versus reduced-dose capecitabine plus docetaxel, has completed recruitment and should determine whether tolerability can be improved while maintaining the considerable efficacy of the combination. Preclinical and early clinical investigation of alternative dosing schedules, such as continuous administration, 28-day cycle, 7-day cycle, and 7-on/7-off, also has demonstrated good efficacy and tolerability. The efficacy and tolerability of the 7-on/7-off schedule under evaluation in the United States is promising, especially because it potentially simplifies administration when combined with agents administered every 14 or 28 days. While the results of trials involving reduced doses and alternative schedules of capecitabine alone and in combination with other agents in the treatment of MBC have been encouraging, the optimal approach to managing capecitabine toxicity, ie, dose reduction or schedule modification, is not clear. Consequently, the need for ongoing investigation is clear. In addition, other strategies to further improve the tolerability of capecitabine beyond lowering the dose or modifying the schedule while maintaining efficacy are warranted. For example, because some patients tolerate capecitabine more poorly than other patients, it would be helpful to be able to identify patients at high risk of capecitabine-related toxicity (eg, dihydropyrimidine dehydrogenase deficiency).44 Such investigation, looking at gene polymorphisms,45 for example, is under way. In summary, it appears that capecitabine offers flexibility in dosing while maintaining efficacy and acceptable patient tolerability. Because it is possible that different dosing regimens are appropriate in different populations, treatment can be optimized by tailoring the dose and schedule to each individual.

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Michael Naughton Acknowledgments Editorial assistance was provided by Insight Medical Communications Inc., which was financially supported by Roche Pharmaceuticals. Roche Pharmaceuticals did not participate in the preparation or writing of the manuscript, nor did they provide financial support to the author for the purpose of writing this manuscript.

Disclosures The author reports no relevant conflicts of interest.

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