New Directions With Capecitabine Combinations in Advanced Breast Cancer

ABSTRACT: Capecitabine (Xeloda) offers a unique mode of action. The drug is currentlybeing combined with other active agents in the treatment of advanced breastcancer. The recent demonstration of improved disease-free and overall survivalwith the capecitabine/docetaxel (Taxotere) combination, for example, hasencouraged investigation of additional capecitabine/taxane regimens andschedules. A unique aspect of the metabolic activation of capecitabine is theability of several anticancer drugs to upregulate the critical activating enzymethymidine phosphorylase. These preclinical findings have led to clinical trialsof several active agents in combination with capecitabine demonstrating highresponse rates in early results. In combination studies, capecitabine has beenassociated with very manageable toxicity. The combination of docetaxel/epirubicin(Ellence)/capecitabine (TEX) has shown particular promise in advanced disease,and should be evaluated in earlier disease. TEX is currently in phase III trialsof advanced disease. In preclinical studies, the combination of capecitabinewith inhibitors of HER2/neu (or the epidermal growth factor pathway) appears tohold significant promise both in breast cancer treatment and in treatment ofother tumors expressing these receptors. Continued evaluation of capecitabinecombinations will help to define the roles of this valuable agent, the only oralfluoropyrimidine for treatment of breast cancer available in the United States.[ONCOLOGY 16(Suppl 12):23-28, 2002]

Until recently, the managementof breast cancer with chemotherapeutic agents has led to modest benefits.[1] Hence, there is an urgent needto introduce new active agents into the management of this disease. Thedemonstration of a superior tumor response rate, time to disease progression,and overall survival with the combination of capecitabine (Xeloda) and docetaxel(Taxotere) compared with single-agent docetaxel in anthracycline-pretreatedpatients indicates the important role of capecitabine in the treatment ofadvanced breast cancer.[2]

The use of this agent in combination therapy in breast cancer patients,however, has only begun to be explored, as the agent has a unique mode of actionand can be combined safely with a variety of agents.[3] Potential forimprovement in the therapeutic index of treatment with capecitabine-containingcombinations is suggested by (1) activity of other treatments (eg, taxanes,cyclophosphamide [Cytoxan, Neosar], irinotecan [Camptosar], and vinorelbine [Navelbine],as well as radiation therapy) in increasing tumor levels of thymidinephosphorylase, the activating enzyme for capecitabine; (2) early-phase studiesshowing activity of combinations with a variety of different agents; and (3)preclinical data indicating potential for synergistic effects with a number ofcombinations.[4]

Combinations With Taxanes

In North America, cyclophosphamide/doxorubicin combinations at fullconventional dosages have been the basis of breast adjuvant treatment.[5-7]Based upon the enhanced response rates of phase III trials in the neoadjuvantsetting (National Surgical Adjuvant Breast and Bowel Project trial B-27) and inthe adjuvant setting (the Aberdeen trial), cyclophosphamide/doxorubicin followedby docetaxel may offer a new standard approach in the management ofearly-disease patients.[8-10] As capecitabine/taxane combinations demonstrate ahigher response rate and better survival than docetaxel alone in metastaticdisease, the combination is being advanced into treatment of earlier disease.The current US Oncology Adjuvant Trial (XEL242) addresses the question ofwhether or not the use of capecitabine/docetaxel following classicalcyclophosphamide/doxorubicin (Adriamycin) (AC) offers any benefit oversingle-agent docetaxel following AC. Additional similar studies are indevelopment.

Weekly Taxanes

Weekly taxanes may offer a therapeutic advantage over traditionalevery-3-week schedules of administration and are being actively studied.[11]Because of the ease of administration of taxanes on a weekly schedule and thepossibility of repetitively up-regulating thymidine phosphorylase, additionalstudies are exploring the feasibility of weekly taxane treatment in combinationwith capecitabine.

Preliminary findings using this approach in 19 anthracycline-pretreatedpatients with metastatic breast cancer demonstrated activity with acceptabletoxicity in an ongoing phase I/II study.[12] The recommended dose was identifiedas intermittent oral capecitabine at 900 mg/m² twice daily on a 14-day scheduleevery 3 weeks plus weekly docetaxel at 30 mg/m². There was a low incidence ofsevere myelosuppression, with only one grade 4 event (neutropenia) beingobserved; the most common grade 3 toxicity was palmar-plantar erythrodysesthesia(in 3 of 19 patients). Objective tumor response was observed in two patients,with seven patients demonstrating stable disease.[12]

Meza et al have reported findings in a phase II study of paclitaxel at 175 mg/m² every 3 weeks, plus capecitabine at 825 mg/m² twice daily on days 1 to 14, as first- or second-line treatment of metastatic breast cancer.[13] The patients had a median age of 52 years (range: 35-76 years) and a median Karnofsky performance status of 90. Among 47 evaluable patients, 34 patients received this therapy as first-line treatment, and 13 patients as second-line treatment. Of these patients, 13% (five patients with first-line treatment, and one with second-line treatment) achieved a complete response; 30% of patients achieved a partial response; and 38% had stable disease. Because of the small number of patients, there is some variation in the partial responses in patients receiving first- or second-line treatment (Figure 1). Overall, median time to disease progression was 44 weeks.[13]

Additional investigations, from which data are not yet available, includestudy of a capecitabine/docetaxel/trastuzumab (Herceptin) combination and study of sequential epirubicin (Ellence)/docetaxel/capecitabine inthe neoadjuvant setting.

Combinations With Other Agents

Further strategies for optimizing capecitabine activity include substitutingother agents that upregulate thymidine phosphorylase for docetaxel or combiningcapecitabine with alkylating agents, other standard agents, or biologics (eg,interferon, trastuzumab). Vinorelbine is an attractive agent to combine withcapecitabine, as the drug has a good toxicity profile and significanttherapeutic activity.[14]

Capecitabine/Vinorelbine Combination

Several investigators have reported on the use of the capecitabine/vinorelbinecombination. In a phase I study, 40 pretreated patients with advanced ormetastatic breast cancer received 21-day cycles of capecitabine at 500 to 1,250mg/m² twice daily on days 1 to 14 combined with IV vinorelbine at 12.5 to 22.5mg/m² on days 1 to 3.[15] The maximum tolerated dose of the combination has notyet been defined; preliminary reports indicate that minimal toxicity wasobserved. Among 33 evaluable patients treated at all dose levels, the objectiveresponse rate was 48%.[15]

A Swiss phase I/II study enrolled 36 patients, all of whom were 65 years ofage or older, and 61% of whom had visceral metastases. As first-line treatment,the group received capecitabine at 800 to 1,250 mg/m² twice daily on days 1 to14, and vinorelbine at 20 mg/m² IV on days 1 and 8, every 3 weeks.[16]Dose-limiting toxicities were neutropenia, stomatitis, diarrhea, and thrombosis.The maximum tolerated dose of capecitabine was 1,250 mg/m² in patients withoutbone involvement and 1,000 mg/m² in those with bone involvement. Tumor responseswere observed at all dose levels.[16]

In a small Korean phase II study, 24 patients with prior anthracycline andtaxane exposure, median age of 45 years, and a median of four prior chemotherapycycles received capecitabine at 1,250 mg/m² twice daily on days 1 to 14, incombination with vinorelbine at 25 mg/m² IV on days 1 and 8, every 3 weeks. Thereported overall response rate was 53%.[17]

Capecitabine/Idarubicin/Cyclophosphamide Oral Combination

Part of the attractiveness of capecitabine is its ability to be given in oraldoses,[18] which allows flexibility in treatment. Capecitabine has beenevaluated as part of an oral combination chemotherapy regimen with idarubicin (Idamycin)and cyclophosphamide. Treatment included capecitabine at 1,000 mg/m² twice dailyon days 1 to 14, oral idarubicin at 10 mg/m² on days 1, 3, and 5, and oralcyclophosphamide at 100 mg/m² on days 1 to 14, every 3 weeks. A total of 20patients described as heavily pretreated, with a median age of 52 years, andvisceral dominant disease were enrolled in the phase II trial. [19]

Objective response was observed in 15% of patients, with 40% having stabledisease. Toxicities consisted of grade 3 or 4 diarrhea in 10% of patients, grade3 vomiting in 10%, and grade 3 or 4 hand-foot syndrome in 15%. One patient hadgrade 3 neutropenia. The investigators concluded that the combination was activeand should be investigated in earlier-stage disease.[19]

Capecitabine/EGFR Inhibitors Combination

Another potential approach to enhance the efficacy of capecitabine is tointerfere with members of the epithelial growth factor receptor (EGFR)superfamily. HER2/neu, the second member of this superfamily, has been shown tobe a therapeutic target.[20] Inhibition of this receptor is associated withadditive or synergistic antitumor effects when combined with conventionalchemotherapeutic agents for breast cancers over-expressing this receptor.[21]Additional members of this class of receptors can be inhibited by smallmolecules directed at the receptor’s tyrosine kinase activity.[22]

We, therefore, have been interested in studying the combination of EGFR inhibitors with capecitabine metabolites in tissue culture as a preclinical model for future human studies.[23] Using human breast cancer cell lines in tissue culture and a median effects model,[24] which allows determination of drug combination effects for cytotoxic synergy, additive effects, or antagonism, we have found that the combination of capecitabine and an EGFR tyrosine kinase inhibitor (AG-1478)[25] has profound synergy.[23] AG-1478 inhibits all four EGFR receptor subgroups in cells although it was originally believed to be a specific inhibitor of EGFR-1 based upon cell-free assays. The drug exhibits striking synergy with 5'-deoxy-5-fluorouridine (the cytotoxic metabolite of capecitabine) in the MCF₇/ADR (Adriamycin [doxorubicin]-resistant) breast cancer cell line (Figure 2). This cell line expresses both the HER2/neu (EGFR-2) receptor and the EGFR-1 receptor.

Similar activity of the combination has been observed in the BT474 breast cancer cell line, which expresses HER2/neu but not EGFR-1.[23] In animal studies using BT474 breast cancer xenografts, the combination of capecitabine and trastuzumab, which inhibits HER2/neu receptors, produced additive if not synergistic effects (Figure 3).[32] Such findings suggest that combinations of capecitabine and EGFR inhibitors may have broad applicability in breast cancer, may be of value in other tumors that overexpress receptors of this class, and should be evaluated in clinical studies.

Additional trials currently are assessing combinations of capecitabine withcyclophosphamide/doxorubicin, cyclophosphamide/epirubicin, docetaxel/carboplatin(Paraplatin), and interferon-alfa (Roferon, Intron) in advanced breast cancerpatients. No data are yet available for these combinations.

A PotentialCapecitabine/Irinotecan Combination

Irinotecan recently has been shown to have activity in metastatic breastcancer refractory to either an anthracycline or a taxane.[27] In a randomizedphase II study, 102 patients with prior anthracycline or taxane exposure and amaximum of two prior chemotherapy courses in the metastatic setting receivedirinotecan at 100 mg/m² weekly for 4 weeks, or at 240 mg/m² every 3 weeks, in6-week cycles.[27] Preliminary data from this trial indicates an objectiveresponse rate of 29% when both treatment arms are combined.

Capecitabine as a single agent also has demonstrated antitumor activity inpatients refractory to anthracyclines and taxanes.[3] Further rationale forcombining irinotecan with capecitabine is provided in part from xenograftstudies of human A253 and FaDu head and neck tumors in nude mice. Theinvestigators noted synergistic anticancer effects when irinotecan is givenfirst, followed by a 24-hour delay before the start of capecitabinetreatment.[28] These studies also demonstrated that doses lower than the maximumtolerated doses still produced maximal antitumor effects with cures beingobserved with the combination but not with single-agent treatment.[28]

To evaluate the effects of this potentially useful combination in refractorybreast cancer, we have initiated a phase I trial of capecitabine/irinotecan inpatients with metastatic or inoperable solid tumors.[29] The trial was basedupon the animal xenograft data in that irinotecan is administered first, andthen, after a 24-hour delay, the capecitabine is initiated. Irinotecan is givenas a rapid intravenous injection once every 2 weeks, as this schedule is lesslikely to cause gastrointestinal toxicity than a weekly schedule. Thecapecitabine is administered daily for only 1 week with a washout phase of 7days to allow any hyperbilirubinemia (seen in 18% of patients treated with thisagent)[4] to resolve before the next irinotecan injection.

Patients receive irinotecan at 100 mg/m² IV on days 1 and 15, and oralcapecitabine at 500 to 1,250 mg/m² twice daily on days 2 to 8 and 16 to 22,every 28 days. For the first 16 patients enrolled, the mean age is 61 years; 13had prior chemotherapy (with an average of two prior chemotherapy courses) and 4had prior radiation therapy. Suggested phase I dosing has yet to be determined,but it is expected that the maximum tolerated dose will be at or above thestatic irinotecan dose.

The major toxicities to date have been leukopenia at day 8 and manageablegastrointestinal adverse events. Activity of the combination has been observedat all dose levels.[29] We believe that this combination needs furtherevaluation in breast cancer and gastrointestinal malignancies.

Docetaxel/Epirubicin/Capecitabine Combination

The potential benefits of a docetaxel/epirubicin/capecitabine combination are suggested by the preclinical synergy demonstrated with docetaxel/epirubicin in MCF7 breast cancer cell lines using the median effects model (Figure 4).[30,33] A phase II trial of this triplet in patients with locally advanced or metastatic breast cancer has been reported in abstract form.[31] Patients were aged 18 to 70 years, with Eastern Cooperative Oncology Group performance status 0 to 2, and no prior treatment for metastatic disease. Exclusion criteria included prior docetaxel treatment; anthracycline treatment within the prior 6 months; prior doxorubicin > 240 mg/m², epirubicin > 480 mg/m², or mitoxantrone > 70 mg/m²; cardiac disease; or history of grade 2 or greater neuropathy. Patients received oral capecitabine at 1,000 mg/m² twice daily on days 1 to 14, docetaxel at 75 mg/m² IV on day 1, and epirubicin at 75 mg/m² IV on day 1, every 21 days. Among the 67 patients entered, the median age was 53 years and median performance status was 0; 51% had locally advanced cancer and 30% had received prior chemotherapy, with 16% having received prior anthracycline treatment.

In the total group, 65 patients were evaluable for toxicity and 50 patients for response. The major response rate was 81% in locally advanced patients and 71% in metastatic disease patients. Further divisions of the responses are shown in Figure 5.[31]

Neutropenia (grades 3/4) was the predominant toxicity, occurring in 46% ofpatients. Of the 65 patients, 15% had febrile neutropenia. Asthenia was seen insix patients, mucositis in three, hand-foot syndrome in two, nausea and vomitingin six, and diarrhea in two. As this combination demonstrates significantactivity in both locally advanced and metastatic disease, the triplet iscurrently in phase III trials and also needs to be evaluated in treatment ofearlier disease.

Conclusions

The most mature study in advanced breast cancer demonstrated that thecapecitabine/docetaxel combination has shown a significant advantage in tumorresponse and in disease-free and overall survival in anthracycline-pretreatedpatients. Based upon preclinical studies, numerous rational combinations ofcapecitabine with other active agents in breast cancer are in development. Manyof these combinations have already shown early promise, while other regimensremain in early feasibility trials. Of the combinations tested to date, toxicityhas generally been very manageable. In some cases, particularly the docetaxel/epirubicin/capecitabinecombination, there is evidence to suggest that capecitabine combinations shouldbe evaluated in earlier-disease settings.

Capecitabine, as a single agent and in combination with docetaxel, hasrecently been introduced into breast adjuvant trials. Additional preclinicalstudies, both in tissue culture and in xenograft model systems, suggest that inhuman trials the combination of capecitabine and EGFR inhibitors, includingHER2/neu inhibitors, may offer enhanced therapeutic efficacy in both EGFR orHER2/neu-positive breast tumors and in other tumors over-expressing thesereceptors.

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