Capecitabine in the Treatment of Advanced Breast Cancer

This supplement to ONCOLOGY includes a collection of papers focusing on the clinical development and use of capecitabine (Xeloda), a novel agent with significant activity in patients suffering from metastatic breast cancer. It is now clear that this agent, which is delivered orally, has utility in such patients and can be considered for use in most patients with metastases that are resistant to hormonal treatments and have been previously treated with an anthracycline and a taxane.

Single-Agent Capecitabine

In terms of efficacy, single-agent capecitabine has beenassociated with response proportions similar to those seen with a variety offirst- and second-line drugs, and it has a unique but manageable toxicityprofile.[1,2] Only head-to-head randomized trials can definitively compareresponse proportions, duration of benefit, and survival (the latter beingarguably the most critical end point), but lacking these, it is reasonable toconclude that most of the agents we routinely use have activity levels in asimilar range.[3-10] At the same time, it is possible to compare some toxicitieseven lacking phase III data. For example, alopecia and significantmyelosuppression are rare with capecitabine, but hand-foot syndrome (palmar-plantarerythema) and diarrhea can be dose-limiting. These toxicities can be anticipatedand managed but require awareness and reactivity on the part of the clinician sothat capecitabine can be applied to advantage in the palliative treatment ofpatients with incurable disease.

The articles in this supplement highlight several interestingfacets of this drug’s role. First, the oral availability and flexible dosingmake it an attractive option for patients who clearly prefer nonparenteraltreatments. Second, the specific dose level initially studied and leading to theapproval and availability of capecitabine may be too high for many patients, anddosing below this level is probably safe and appropriate. Retrospective analysessuggest that dose reductions of up to 50% compared to the approved dose may notcompromise efficacy and do reduce toxicity.[11] Of course, only a properlydesigned prospective randomized trial can definitively address this possibility,but while waiting for such a study clinicians can draw a measure of comfort fromthese observations as they grapple with this issue on a daily basis. Third,there may be specific, biochemically advantageous combinations deserving study.The articles in this supplement address these issues and help us begin to planfurther studies.

Single-Agent vs Combination Therapy

In my article on single-agent vs combination therapy in advancedbreast cancer, I discuss available data on the use of active chemotherapy agentssuggesting that sequential single-agent therapy is associated with outcomessimilar to those achieved with concurrent combination therapy. Capecitabine hasbeen proven to be convenient and effective in advanced breast cancer and hasbeen shown to be safe in combination use. Whether its optimal use is insingle-agent or concurrent combination therapy, however, remains to bedetermined.

Despite the appropriate popularity of single agents in routineclinical practice, the potential for improved outcomes using rationally designedcombinations should not be dismissed casually. As but one example, the additionof the humanized monoclonal antibody to HER2 (trastuzumab [Herceptin]) tochemotherapy does improve outcomes compared to sequential application of theantibody after the failure of chemotherapy.[12] Hence, it is certainly possiblethat specific combinations might be advantageous even though there may be nogeneralized advantage when considering all combinations. Daniel Budman’sarticle reviews the preclinical rationale for several specific capecitabinecombinations, the optimization of dose required with each individual regimen,and the preliminary clinical data where available. Certainly the activity ofdocetaxel (Taxotere) given with capecitabine, capitalizing on the induction ofthymidine phosphorylase by docetaxel, provides strong support for furtherexploration of this and other potentially useful combinations. At the same timewe should remain exceedingly cautious about empirically utilizing these novelcombinations before they are broadly tested and reported.

Capecitabine/Docetaxel and Other Combinations

On the issue of one specific combination regimen, Joyce O’Shaughnessy’sarticle reviews the results of the randomized trial comparing capecitabine withdocetaxel vs docetaxel alone.[13] For patients with metastatic breast cancer therole that combination treatment should play in general remains uncertain.Multiple trials have failed to demonstrate a significant long-term advantage formodern combinations as compared to the most active single agents,notwithstanding the generally higher initial response rates seen in the formercase.[14-16] The docetaxel/capecitabine combination seems to defy thishistorical precedent by showing not only an increased response proportion butalso lengthened time to progression and survival. At the same time, we must atleast keep in mind the lack of sequential application of capecitabine followingsingle-agent docetaxel in all but a small minority of patients. Because of thisdesign, we can say for sure that this trial demonstrates the efficacy ofcapecitabine, but we can be less certain that the specific combination issuperior or that it should be broadly utilized. On the other hand, as discussedby Robert Livingston, this activity is highly motivating in terms of possibleadjuvant therapy regimens where the time on treatment may be a significantissue. As he describes, there are several trials planned that will attempt toincorporate capecitabine in the adjuvant setting. Other combinations may also bevery appropriate as adjuvant or neoadjuvant treatment and should be studied.

It is already apparent that capecitabine has changed ourapproach to patients with hormone-refractory metastatic breast cancer. It is oneof only a few orally available active chemotherapy agents for breast cancer, ithas a linear, manageable, and generally nonoverlapping toxicity profile, andthere is preclinical rationale for exploring a variety of other combinations. Aswe move forward in a variety of settings it will be important to support ongoingclinical trials to optimize the benefit our patients can receive from thisagent.

References:

1. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase IIstudy of capecitabine in paclitaxel-refractory metastatic breast cancer. J ClinOncol 17:485, 1999.

2. Budman DR: Capecitabine. Invest New Drugs 18:355-363, 2000.

3. Perez EA, Vogel CL, Irwin DH, et al: Multicenter phase IItrial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol19:4216-4223, 2001.

4. Jassem JT, Pienkowski A, Pluzanska S, et al: Doxorubicin andpaclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-linetherapy for women with metastatic breast cancer: Final results of a randomizedphase III multicenter trial. J Clin Oncol 19:1707-1715, 2001.

5. Paridaens R, Biganzoli L, Bruning P, et al: Paclitaxel versusdoxorubicin as first-line single-agent chemotherapy for metastatic breastcancer: A European Organization for Research and Treatment of Cancer RandomizedStudy with cross-over. J Clin Oncol 18:724, 2000.

6. Group TFES: Epirubicin-based chemotherapy in metastaticbreast cancer patients: role of dose-intensity and duration of treatment. J ClinOncol 18:3115-3124, 2000.

7. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospectiverandomized trial of docetaxel versus mitomycin plus vinblastine in patients withmetastatic breast cancer progressing despite previous anthracycline-containingchemotherapy. J Clin Oncol 17:1413, 1999.

8. Smith RE, Brown AM, Mamounas EP, et al: Randomized trial of3-hour versus 24-hour infusion of high-dose paclitaxel in patients withmetastatic or locally advanced breast cancer: National Surgical Adjuvant Breastand Bowel Project Protocol B-26. J Clin Oncol 17:3403-3411, 1999.

9. Vici P, Colucci G, Gebbia V, et al: First-line treatment withepirubicin and vinorelbine in metastatic breast cancer. J Clin Oncol20:2689-2694, 2002.

10. Zelek L, Cottu P, Tubiana-Hulin M, et al: Phase II study ofoxaliplatin and fluorouracil in taxane- and anthracycline-pretreated breastcancer patients. J Clin Oncol 20:2551-2558, 2002.

11. O’Shaughnessy J, Blum J: A retrospective evaluation of theimpact of dose reduction in patients treated with Xeloda (capecitabine)(abstract 400). Proc Am Soc Clin Oncol 2000.

12. Slamon D, Leyland-Jones B, Shak S: Use of chemotherapy plusa monoclonal antibody against HER2 for metastatic breast cancer thatoverexpresses HER2. N Engl J Med 344:783-792, 2001.

13. O’Shaughnessy J, Miles D, Vukelja S, et al: Superiorsurvival with capecitabine plus docetaxel combination therapy in anthracycline-pretreatedpatients with advanced breast cancer: Phase III trial results. J Clin Oncol20:2812-2823, 2002.

14. Heidemann E, Stoeger H, Souchon R, et al: Balance of time toprogression, quality of life, and overall survival: more gain from treatmentwith mitoxantrone (N) than with the combination of fluorouracil, epirubicin,cyclophosphamide (FEC). Results of a multicenter randomized trial (abstract284). Proc Am Soc Clin Oncol 19: 2000.

15. Joensuu H, Holli K, Heikkinen M, et al: Combinationchemotherapy versus single-agent therapy as first- and second-line treatment inmetastatic breast cancer: a prospective randomized trial. J Clin Oncol16:3720-3730, 1998.

16. Sledge G, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs paclitaxel vs doxorubicin + paclitaxel as first-line therapy for metastatic breast cancer: an intergroup trial. Proc Am Soc Clin Oncol 16:1a, 1997.