What is the optimal first-line chemotherapy for women with metastases, including the role of combination regimens such as docetaxel-capecitabine?

OVERVIEW: Systemic treatment for metastatic breast cancer is not curative, and the primary goal of therapy is the maintenance and improvement in quality of life. In recent years, there has been a shift in medical oncology practice toward the use of less intensive chemotherapy in the metastatic setting, including the use of sequential single agents rather than combinations. The background of this trend is the lack of evidence that combination regimens improve survival. However, in December 2000, O’Shaughnessey et al. reported an improvement in the response rate and survival for women treated with the combination of capecitabine and docetaxel compared to docetaxel alone. A strong scientific rationale for this combination exists; namely, docetaxel upregulates thymidine phosphorylase, the enzyme that activates capecitabine to 5-fluorouracil. In addition to prompting researchers to look at this combination in the adjuvant and neoadjuvant setting, physicians in practice are utilizing this regimen, particularly in women with rapidly progressing metastases.

What first-line therapy would you recommend for the following patients with ER-negative, HER2-negative metastatic breast cancer?

		DOCETAXEL	DOCETAXEL/ CAPECITABINE	PACLITAXEL	VINORELBINE	OTHER/NONE*
	Asymptomatic 43-year-old woman with bone metastases who received adjuvant AC	35%	20%	10%	5%	30%
	Asymptomatic 63-year-old woman with bone metastases who received adjuvant AC	35%	10%	20%	10%	25%
	Asymptomatic 43-year-old woman with bone metastases who received adjuvant AC -T	15%	20%	5%	30%	30%
	Asymptomatic 63-year-old woman with bone metastases who received adjuvant AC -T	30%	-	5%	20%	45%
	Very ill 43-year-old woman with liver and lung metastases who received adjuvant AC -T	5%	25%	-	20%	-
	Very ill 63-year-old woman with liver and lung metastases who received adjuvant AC -T	20%	25%	-	15%	-
* The majority of therapies in this group included in “other” category were combinations of 2-4 chemotherapy agents, however, no combination accounted for more than 5% of those surveyed.

In which order would you utilize the following single-agent chemotherapy for the treatment of a woman with metastatic breast cancer with no prior adjuvant chemotherapy with no prior adjuvant chemotherapy?

A 55-year-old woman with asymptomatic lung metastases has been started on capecitabine, 2000 mg/M 2 in two divided doses (2 weeks on, then one week off). After 3 cycles, she has had no changes in the lesions, and no side effects. What would you generally do?

A 55-year-old woman with asymptomatic lung mets

CONTINUE THERAPY INCREASE DOSE TO 2500 MG/M 2 STOP CAPECITABINE/ CHANGE THERAPY CONTINUE CAPECITABINE/ ADD OTHER AGENT 35% 25% 20% 20%

RANDOMIZED TRIAL OF DOCETAXEL-CAPECITABINE VERSUS DOCETAXEL BACKGROUND

There were several reasons to combine docetaxel with capecitabine. First, they are both very active agents in treating metastatic breast cancer. Second, they have largely non-overlapping toxicities, and thirdly and very importantly, the two agents exhibit a rare example of biochemical synergism. Docetaxel quite profoundly upregulates the expression of thymidine phosphorylase, the pivotal and last enzyme in the metabolism of capecitabine to 5-FU at the tumor site. Thymidine phosphorylase is overexpressed in a majority of human breast cancers as well as a number of other cancers. When you put docetaxel and capecitabine together, there is clear synergistic tumor cell killing. So this trial was attempting to see whether this could translate into anything of real importance in women with metastatic breast cancer.

—Joyce O’Shaughnessy, MD

CLINICAL IMPLICATIONS

The docetaxel-capecitabine study is intriguing, and there’s certainly a biologic rationale for why that combination might be useful. In terms of toxicity, the combination would be a lot more tolerable with capecitabine dosed at 2,000 mg/m2 , and I think you could do that without decreasing the efficacy. A few more side effects — if survival really is prolonged — is something a lot of my patients would be willing to live with. It’s difficult to know how to use the data from this study in my practice, because the trial didn’t have a traditional crossover.

The best data we have on combination chemotherapy in metastatic disease is ECOG 1193, which randomized patients into one of three arms — doxorubicin alone, paclitaxel alone or the combination. The two single-agent arms crossed over to the other single agent at the time of progression. The combination resulted in a slightly higher response rate and a slightly longer time to progression but no difference in quality of life and overall survival.

—Kathy Miller, MD

DOCETAXEL-CAPECITABINE STUDY

In the docetaxel-capecitabine trial, concurrent use of docetaxel and capecitabine was better than single-agent docetaxel, and this surprised some people. The trial has been criticized, because not every patient who received docetaxel went on to receive second-line capecitabine. For the purist, trying to answer the question of sequential versus concurrent therapy, this trial doesn’t give us the exact answer. However, it is dramatic that there was a survival advantage in this trial. We have to take that very seriously.

—Edith A Perez, MD

CAPECITABINE: A RATIONALLY DERIVED AGENT

Capecitabine is a very intriguing, novel, chemically synthesized drug. The basis of its synthesis goes back to the 1980s, when various researchers described a technique called retrometabolic engineering. Capecitabine is a pro-drug, which undergoes enzymatic activation and can concentrate fluoropyrimidines in the tumor three to tenfold, resulting in potentially higher efficacy and selectivity due to this very clever engineering. The objective is to keep a very high concentration of the active drug — 5-FU — in the tumor and hopefully lessen host toxicity, thereby increasing its therapeutic index. Combined with other drugs such as taxanes, which upregulate thymidine phosphorylase — the enzymatic step to convert capecitabine into its active form — you can get curative potential. Using 5-FU under the same conditions, you do not.

—Daniel R Budman, MD

DOCETAXEL-CAPECITABINE STUDY: QUALITY OF LIFE

There is evolving evidence from a large randomized Phase III trial of over 500 patients that patients failing anthracycline therapy can maintain quality of life and increase disease-free and overall survival with the combination of docetaxel and capecitabine. In fact, the response and survival curves now show more benefit than when the data was initially presented. This is a standard of care that we have to look at carefully.

Quality of life is a critical issue in treating advanced disease. If we prolong duration of response without a reasonable quality of life, we are kidding ourselves. The docetaxel-capecitabine study was one of the few clinical trials where quality of life was a major endpoint. A rigorous quality-of-life measurement was used before and during the study, showing that patients receiving combination docetaxel-capecitabine actually had a better quality of life than patients receiving full-dose docetaxel alone. Although this may seem paradoxical, my interpretation is that if a patient has a response — and for example, her fungating tumor is gone — she can get out of bed, walk around and go to work, then obviously, there’s a quality of life benefit.

—Daniel R Budman, MD

LACK OF CROSSOVER IN THE DOCETAXEL-CAPECITABINE STUDY

In the docetaxel-capecitabine study, only 17% of the patients randomized to docetaxel crossed over to capecitabine after progression. However, a crossover in this trial would have been very difficult to accomplish. These were a tough group of patients. They had failed anthracyclines either in the adjuvant setting or in the metastatic setting, and, two-thirds of them had failed it in the metastatic setting. They had all received alkylating agents.

Three-quarters had already received fluoropyrimidines — so they already had failed 5-FU to a great degree.

The take-home message from the study is that if you have a higher response rate, a better quality of life, and a longer duration of survival with the combination, you probably can't do as well with a sequential regimen, because you're going to have a higher tumor burden. You're going to have more morbidity. We know that if you can reduce tumor burden, then you usually have better performance and better quality of life. A higher response rate with longer survival is obviously an advantage.

—Daniel R Budman, MD

ENZYMATIC CONVERSION OF CAPECITABINE TO 5-FLUOROURACIL

PHASE III TRIAL OF DOCETAXEL-CAPECITABINE (XT) COMBINATION THERAPY VS DOCETAXEL MONOTHERAPY (T) IN METASTATIC BREAST CANCER

X = capecitabine T = docetaxel

XT VERSUS T: BASELINE CHARACTERISTICS

Age (median=52-years-old) , performance status, hormone - receptor status and sites of metastases were equivalent between groups Two - thirds of patients had > 3 metastatic sites Prior chemotherpies : 100% had anthra cyclines , 90% had alkylating agents, 75% had 5-FU and about 10% had paclitaxel No difference in percentage of patients being treated first-line and about two - thirds received XT or T as second- or third-line treatment XT VERSUS T: DOSE REDUCTIONS AND QUALITY OF LIFE Dose reductions to 75% of initial dose were observed in two - thirds of patients in the XT arm for either capecitabine or docetaxel and in about one - third of docetaxel only patients Quality of life — assessed by EORTC QLQ-C30 global health status — showed a trend favoring XT compared to T

Derived from Vukelja S et al. Breast Cancer Res Treat 2001; Abstract 352.

EFFICACY OF XT VS T IN METASTATIC BREAST CANCER

Capecitabine/ Docetaxel Docetaxel Statistical Significance Time to progression 6.1 months [5.4-6.5] 4.2 months [3.4-4.5] log rank p=0.0001 CR + PR 42 [35.5-47.9]% 30 [24.2-35.7]% p = 0.006 Stable disease 38 [31.7-43.9]% 44 [38.0-50.5]%   Median survival 14.5 months [12.3-16.3] 11.5 months [9.8-12.7] log rank p=0.0126

Derived from Vukelja et al. 2001 San Antonio Breast Cancer Symposium. Abstract 352.

XT VERSUS T: POST-STUDY TREATMENT

Approximately two - thirds of patients received chemotherapy after XT or T. 17% of patients in the docetaxel only arm subsequently received capecitabine. Derived from Miles et al. Breast Cancer Res Treat 2001; Abstract 442 ; Vu kelja S et al. Breast Cancer Res Treat 2001; Abstract 352.

Classic Trial of Combination versus Sequential Chemotherapy

ECOG 1193: PHASE II/III RANDOMIZED TRIAL OF DOX VS TAX VS DOX/TAX/G-CSF IN PATIENTS WITH METASTATIC BREAST CANCER. NO PROTOCOL LINK

Each regimen was given q 3 weeks. At the time of progression , patients on ARM 1 were crossed over to ARM 2 and patients on ARM 2 were crossed over to ARM 1. Responses were seen in 20% of patients crossing from doxorubicin to paclitaxel and 14% of patients crossing from paclitaxel to doxorubicin. No differences were seen in global QOL between the 3 groups.

Sledge GW Jr et al. Phase III trial of do xorubicin versus paclitaxel versus doxorubicin plus paclitaxel as first-line therapy for meta-static breast cancer: An Intergroup trial. Proc ASCO 1997; Abstract 2.

NCI-V95-0680: PHASE III RANDOMIZED STUDY OF DOCETAXEL VERSUS PACLITAXEL IN WOMEN WITH METASTATIC OR LOCALLY ADVANCED, INOPERABLE ADENOCARCINOMA OF THE BREAST OPEN PROTOCOL

PROTOCOL IDS: 400 patients

STUDY CONTACT Peter Marcus Ravdin, Chair Ph: 210-567-4777 Aventis Pharmaceuticals, Inc.

THERADEX-B00-1370: PHASE III RANDOMIZED STUDY OF PACLITAXEL WITH OR WITHOUT CARBOPLATIN AS FIRST-LINE CHEMOTHERAPY IN ELDERLY WOMEN WITH METASTATIC BREAST CANCER OPEN PROTOCOL

PROJECTED ACCRUAL: 220 patients

Treatment continues every 4 weeks in the absence of disease progression or unacceptable toxicity

STUDY CONTACT: Edith A. Perez, Chair Ph: 507-284-5369 Theradex

LILLY-B9E-MC-JHQG: PHASE III RANDOMIZED STUDY OF PACLITAXEL WITH OR WITHOUT GEMCITABINE IN WOMEN WITH UNRESECTABLE, LOCALLY RECURRENT, OR METASTATIC BREAST CANCER OPEN PROTOCOL

PROJECTED ACCRUAL: Unspecified

Treatment continues every 21 days in the absence of disease progression

STUDY CONTACT: Furhan Yunus, Chair Ph: 901-725-1785 Eli Lilly and Company

E-2100: PHASE III RANDOMIZED STUDY OF PACLITAXEL WITH OR WITHOUT BEVACIZUMAB IN PATIENTS WITH LOCALLY RECURRENT OR METASTATIC BREAST CANCER APPROVED, NOT ACTIVE PROTOCOL

PROJECTED ACCRUAL: 316-650 patients will be accrued within 31 months

B = bevacizumab Treatment repeats every 4 weeks for 18 courses in the absence of disease progression or unacceptable toxicity

STUDY CONTACT: Kathy Miller, Chair Ph: 317-278-0426 Eastern Cooperative Oncology Group

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