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
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
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
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
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
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
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. 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.