Capecitabine in the Treatment of Advanced Breast Cancer
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.
In terms of efficacy, single-agent capecitabine has been associated with response proportions similar to those seen with a variety of first- and second-line drugs, and it has a unique but manageable toxicity profile.[1,2] Only head-to-head randomized trials can definitively compare response proportions, duration of benefit, and survival (the latter being arguably the most critical end point), but lacking these, it is reasonable to conclude that most of the agents we routinely use have activity levels in a similar range.[3-10] At the same time, it is possible to compare some toxicities even lacking phase III data. For example, alopecia and significant myelosuppression are rare with capecitabine, but hand-foot syndrome (palmar-plantar erythema) and diarrhea can be dose-limiting. These toxicities can be anticipated and managed but require awareness and reactivity on the part of the clinician so that capecitabine can be applied to advantage in the palliative treatment of patients with incurable disease.
The articles in this supplement highlight several interesting facets of this drug’s role. First, the oral availability and flexible dosing make it an attractive option for patients who clearly prefer nonparenteral treatments. Second, the specific dose level initially studied and leading to the approval and availability of capecitabine may be too high for many patients, and dosing below this level is probably safe and appropriate. Retrospective analyses suggest that dose reductions of up to 50% compared to the approved dose may not compromise efficacy and do reduce toxicity. Of course, only a properly designed prospective randomized trial can definitively address this possibility, but while waiting for such a study clinicians can draw a measure of comfort from these 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 plan further studies.
Single-Agent vs Combination Therapy
In my article on single-agent vs combination therapy in advanced breast cancer, I discuss available data on the use of active chemotherapy agents suggesting that sequential single-agent therapy is associated with outcomes similar to those achieved with concurrent combination therapy. Capecitabine has been proven to be convenient and effective in advanced breast cancer and has been shown to be safe in combination use. Whether its optimal use is in single-agent or concurrent combination therapy, however, remains to be determined.
Despite the appropriate popularity of single agents in routine clinical practice, the potential for improved outcomes using rationally designed combinations should not be dismissed casually. As but one example, the addition of the humanized monoclonal antibody to HER2 (trastuzumab [Herceptin]) to chemotherapy does improve outcomes compared to sequential application of the antibody after the failure of chemotherapy. Hence, it is certainly possible that specific combinations might be advantageous even though there may be no generalized advantage when considering all combinations. Daniel Budman’s article reviews the preclinical rationale for several specific capecitabine combinations, the optimization of dose required with each individual regimen, and the preliminary clinical data where available. Certainly the activity of docetaxel (Taxotere) given with capecitabine, capitalizing on the induction of thymidine phosphorylase by docetaxel, provides strong support for further exploration of this and other potentially useful combinations. At the same time we should remain exceedingly cautious about empirically utilizing these novel combinations before they are broadly tested and reported.
Capecitabine/Docetaxel and Other Combinations
On the issue of one specific combination regimen, Joyce O’Shaughnessy’s article reviews the results of the randomized trial comparing capecitabine with docetaxel vs docetaxel alone. For patients with metastatic breast cancer the role that combination treatment should play in general remains uncertain. Multiple trials have failed to demonstrate a significant long-term advantage for modern combinations as compared to the most active single agents, notwithstanding the generally higher initial response rates seen in the former case.[14-16] The docetaxel/capecitabine combination seems to defy this historical precedent by showing not only an increased response proportion but also lengthened time to progression and survival. At the same time, we must at least keep in mind the lack of sequential application of capecitabine following single-agent docetaxel in all but a small minority of patients. Because of this design, we can say for sure that this trial demonstrates the efficacy of capecitabine, but we can be less certain that the specific combination is superior or that it should be broadly utilized. On the other hand, as discussed by Robert Livingston, this activity is highly motivating in terms of possible adjuvant therapy regimens where the time on treatment may be a significant issue. As he describes, there are several trials planned that will attempt to incorporate capecitabine in the adjuvant setting. Other combinations may also be very appropriate as adjuvant or neoadjuvant treatment and should be studied.
It is already apparent that capecitabine has changed our approach to patients with hormone-refractory metastatic breast cancer. It is one of only a few orally available active chemotherapy agents for breast cancer, it has a linear, manageable, and generally nonoverlapping toxicity profile, and there is preclinical rationale for exploring a variety of other combinations. As we move forward in a variety of settings it will be important to support ongoing clinical trials to optimize the benefit our patients can receive from this agent.
1. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 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 II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 19:4216-4223, 2001.
4. Jassem JT, Pienkowski A, Pluzanska S, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001.
5. Paridaens R, Biganzoli L, Bruning P, et al: Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: A European Organization for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol 18:724, 2000.
6. Group TFES: Epirubicin-based chemotherapy in metastatic breast cancer patients: role of dose-intensity and duration of treatment. J Clin Oncol 18:3115-3124, 2000.
7. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 17:1413, 1999.
8. Smith RE, Brown AM, Mamounas EP, et al: Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 17:3403-3411, 1999.
9. Vici P, Colucci G, Gebbia V, et al: First-line treatment with epirubicin and vinorelbine in metastatic breast cancer. J Clin Oncol 20:2689-2694, 2002.
10. Zelek L, Cottu P, Tubiana-Hulin M, et al: Phase II study of oxaliplatin and fluorouracil in taxane- and anthracycline-pretreated breast cancer patients. J Clin Oncol 20:2551-2558, 2002.
11. O’Shaughnessy J, Blum J: A retrospective evaluation of the impact 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 plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.
13. O’Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002.
14. Heidemann E, Stoeger H, Souchon R, et al: Balance of time to progression, quality of life, and overall survival: more gain from treatment with mitoxantrone (N) than with the combination of fluorouracil, epirubicin, cyclophosphamide (FEC). Results of a multicenter randomized trial (abstract 284). Proc Am Soc Clin Oncol 19: 2000.
15. Joensuu H, Holli K, Heikkinen M, et al: Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial. J Clin Oncol 16:3720-3730, 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.