What is the optimal adjuvant chemotherapy for invasive breast cancer?

OVERVIEW: The International Breast Cancer Overview clearly demonstrates that adjuvant chemotherapy has a significant impact on disease-free and overall survival, particularly in premenopausal women. A key current issue in ongoing trials in optimizing treatment is defining the role of adjuvant taxanes, including selection of patients, choice of paclitaxel versus docetaxel and optimal scheduling. Recent phase III randomized trial data demonstrating a survival benefit to capecitabine/docetaxel in metastatic disease has led to new trials looking at this combination in the adjuvant setting. The NIH Consensus statement noted the small but statistically significant advantage conferred by anthracycline-containing regimens, but concluded that the optimal anthracycline-containing regimen has not been identified. Current data on taxanes was considered inconclusive. The statement further noted that chemotherapy is generally offered to women with tumors over one centimeter, but in women with node-negative tumors under one centimeter, treatment should be individualized, as subsets of these patients have an excellent prognosis.

What adjuvant chemotherapy, if any, would you recommend for the following women with ER-positive, HER2-negative breast cancer?

NIH STATEMENT

...Available data indicate that adjuvant chemotherapy regimens that include an anthracycline result in a small but statistically significant improvement in survival compared to nonanthracycline-containing programs.

...Randomized trials have demonstrated threshold dose effects for two of the most active chemotherapeutic agents, doxorubicin (A) and cyclophosphamide (C). These two drugs are frequently administered together (AC) and appear to result in a comparable survival outcome, whether given preoperatively or postoperatively. However, AC has not been compared to cyclophosphamide/doxorubicin/5-fluorouracil (CAF) or cyclophosphamide/epirubicin/5-fluorouracil (CEF).

On the basis of available data, it is accepted practice to offer cytotoxic chemotherapy to most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node-negative and node-positive). For women with node-negative cancers less than 1 cm in diameter, the decision to consider chemotherapy should be individualized.

Taxanes (docetaxel, paclitaxel) have recently been demonstrated to be among the most active agents in the treatment of metastatic breast cancer. As a result, several studies have explored the clinical utility of adding these drugs to standard doxorubicin/cyclophosphamide treatment programs in the adjuvant treatment of node-positive, localized breast cancer.

Although a number of such trials have completed accrual and others remain in progress, currently available data are inconclusive and do not permit definitive recommendations regarding the impact of taxanes on either relapse-free or overall survival. There is no evidence to support the use of taxanes in node-negative breast cancer outside the setting of a clinical trial.

—NIH Consensus Conference 2000
Final Statement. Full-Text

ADJUVANT TAXANES

The addition of four cycles of paclitaxel after the completion of a standard course of CA substantially improves disease-free and overall survival of patients with early breast cancer. In light of more recent smaller but nonconfounded studies that demonstrated an advantage from adding four cycles of single agent taxane to four cycles of a doxorubicin-containing regimen, it is highly unlikely that all of the benefit for patients on the paclitaxel arm of this study is due simply to the longer duration of treatment in that arm of the trial.

—I Craig Henderson, MD et al.
NIH Consensus Conference 2000. Abstract

It is necessary to wait for future results of ongoing trials before pronouncing judgment on the value of taxanes in the adjuvant setting. It is also necessary to better define the population most likely to benefit from therapies of longer duration, intensification and multiple regimens. It no longer is reasonable to judge all breast cancer patients as having equal probability of benefit from a given therapy. That was a paradigm that worked well when adjuvant chemotherapy for breast cancer was in its infancy and little was known about the molecular heterogeneity of breast cancer. It is now of critical importance to design trials with the aid of molecular tumor profiles with potential predictive value to prospectively identify the subgroup most likely to benefit from the addition to therapy of taxanes and other new drugs.

—Martine J Piccart, MD, PhD et al.
NIH Consensus Conference 2000. Abstract

Both the NIH and St Gallen Consensus Conferences expressed a lack of enthusiasm for endorsing the addition of the taxanes as routine in node-positive patients, because the data were not mature enough. One of the more alarming issues about increasing the duration of chemotherapy is the potential for long-term cognitive problems, and we all see the patient who clearly is a different person mentally after chemotherapy. Certainly there are many possible causes for this — above and beyond cognitive deficits induced by chemotherapy — including the psychological effects of a cancer diagnosis such as stress and depression. It would be very nice to have some strong data on cognition, because that could be a real problem for a one- or two-percent survival tradeoff.

—Monica Morrow, MD

ADJUVANT THERAPY FOR LOW-RISK PATIENTS

Sometimes we neglect using some fairly well-established, reproducible prognostic factors. The SEER data and the American College of Surgeons’ National Cancer Database cannot reliably identify a subset of node-negative patients with tumors under a centimeter with a long-term survival of less than 90%.

There are also very good data showing that patients with histologic grade one tumors that are 1.1 to 2 centimeters have a survival that’s greater than 90%. Patients with grade one tumors are over-whelmingly ER-positive, so endocrine therapy is certainly a reasonable choice. The added absolute benefit of chemotherapy in this subset is extremely small, and sometimes that is not conveyed to women in a way that they can understand.

Another group is the special histologic subtypes, most notably tubular carcinoma but also mucinous carcinoma. Even a two to three centimeter tubular cancer has an outstanding prognosis, and, again, these are all receptor-positive. If physicians look at old consensus guidelines and just go in lock-step with the greater-than-1-centimeter number, they might potentially overtreat some patients by using chemotherapy.

—Monica Morrow, MD

CHOICE OF ANTHRACYCLINE REGIMEN

The 1995 overview established that anthracycline-containing regimens added benefit, but the choice of a specific regimen is also an issue. My reading of the literature is that we were too hasty in adopting four cycles of AC as a standard, and it was based more on convenience than true superiority over the previous standard, which was CMF. In fact, there are no convincing data that AC times four is superior to CMF.

On the other hand, if you look at the overview of randomized trials — with and without anthracyclines — there is superiority in favor of the anthracyclines. Most of that comes from three-drug regimens. You can interpret that as either the contribution of 5-fluorouracil — which is usually the third drug — or the contribution of duration of therapy.

Most of the three-drug combinations have been administered for six cycles, as opposed to the AC or EC regimens, which were given mostly for four cycles. In the adjuvant setting, one should try to use what has — at least on the basis of controlled trials — given the best results. In this case, I think we have compromised instead of going for the best.

I do not have incontrovertible proof that my hypothesis is completely correct, but I think there is more evidence on this side than on the other. If you read the original NSABP B-15 paper that compared AC to CMF, it is clear that the reason for recommending the adoption of AC is simply one of convenience.

I have stated this in public, including at the NIH Consensus Development Conference, although I was unsuccessful in making this sufficiently clear to the panel to sway their opinion. The Canadians are pursuing a clinical trial that will go to the heart of this matter by comparing FEC versus EC/paclitaxel versus AC/paclitaxel.

—Gabriel Hortobagyi, MD

PROPOSED INTERGROUP ADJUVANT STUDY COMPARING INTERMITTENT VERSUS CONTINUOUS AC FOLLOWED BY CAPECITABINE-DOCETAXEL VERSUS DOCETAXEL ALONE

The Intergroup is considering doing a Phase III randomized trial in the adjuvant setting for hormone receptor-negative, node-positive and high-risk node-negative breast cancer patients. The design is going to be a comparison of two different ways of giving AC followed by a comparison of docetaxel alone to the combination of docetaxel and capecitabine.

The initial randomization is based on observations from my group in Seattle that so-called continuous chemotherapy may be more effective than standard intermittent chemotherapy. The initial randomization is between a regimen of continuous AC plus G-CSF versus six cycles of AC.

The second randomization is based on the Phase III randomized trial that was done by O’Shaughnessy and her colleagues, comparing docetaxel at 100 milligrams per meter squared to the combination of docetaxel at a lower dose and capecitabine in patients with anthracycline-refractory stage IV disease.

That trial continues to show a statistically significant higher response rate for the combination, but more importantly a statistically significant longer time to progression and improvement in survival for patients receiving the two-drug combination as opposed to docetaxel alone. This is a very unusual finding in metastatic disease. In fact, the only other Stage IV trial that I can bring immediately to mind, that shows that kind of an advantage for chemotherapy is the combination of paclitaxel and trastuzumab versus paclitaxel alone in HER2-positive patients.

It seems very logical that if you have a drug combination that shows a survival advantage in Stage IV disease, it ought to show the same advantage in spades in the adjuvant setting, where you have a lower tumor burden. So, the purpose of the second randomization is to determine whether the combination of docetaxel and capecitabine does give us a superior result to the use of docetaxel alone in the adjuvant setting.

—Robert B. Livingston, MD

FUTURE TRIALS LOOKING AT DOCETAXEL-CAPECITABINE

In the adjuvant setting, we’d like to look at a comparison of AC versus docetaxel-capecitabine in node-negative or ER/PR-positive, node-positive breast cancer. Another research issue is that as the role of the taxanes is better defined in the adjuvant setting — particularly in patients with ER-negative tumors — the obvious thought is to add capecitabine in with the taxane to see if you can save more lives. And I would guess you probably could, if you can define the subset of women who will benefit from taxanes in the adjuvant setting.

—Joyce O’Shaughnessy, MD

CAPECITABINE-DOCETAXEL: IMPLICATIONS FOR THE ADJUVANT SETTING

The capecitabine-docetaxel study points towards the adjuvant situation where we are already using a lot of taxanes. With the right dose, adding capecitabine may not add very much toxicity and may give more of an anti-tumor effect. The metastatic setting has always been the testing ground for adjuvant regimens. And at least now, we have a solid scientific lead to potentially plug into adjuvant treatment.

—Stephen Jones, MD

MOVING CAPECITABINE/DOCETAXEL FROM THE METASTATIC TO THE ADJUVANT SETTING

One of the great advantages of studying combination therapy in the metastatic setting is that it allows us to identify regimens that we can take into the adjuvant setting, where evidence suggests that combination therapy is better than monotherapy. The Oxford overview analysis of single agent versus combination showed a clear improvement with combinations. We should develop studies in the adjuvant setting that take advantage of active and well tolerated combinations in the metastatic setting — I think docetaxel and capecitabine is a very good example.

—Debu Tripathy, MD

E-1199: PHASE III STUDY OF DOXORUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL OR DOCETAXEL IN WOMEN WITH NODE-POSITIVE OR HIGH-RISK NODE-NEGATIVE STAGE II OR IIIA BREAST CANCER OPEN PROTOCOL

PROJECTED ACCRUAL: A total of 5,000 patients will be accrued within 1.27 years.

ER- and/or PR-positive patients receive tamoxifen x 5 years after completion of chemotherapy

STUDY CONTACTS Joseph A Sparano, Chair, Ph: 718-904-2555 Eastern Cooperative Oncology Group Edith A Perez, Chair, Ph: 507-284-5369 North Central Cancer Treatment Group Silvana Martino, Chair, Ph: 310-998-3961 Southwest Oncology Group Vicky Eileen Jones, Chair, Ph: 858-657-8710 Cancer and Leukemia Group B

CLB-9344; INT-0148: PHASE III RANDOMIZED STUDY OF ADJUVANT CA (CYCLOPHOSPHAMIDE/ DOXORUBICIN) COMPARING STANDARD VS INTERMEDIATE VS HIGH-DOSE DOXORUBICIN WITH VS WITHOUT SUBSEQUENT PACLITAXEL IN WOMEN WITH NODE-POSITIVE BREAST CANCER CLOSED PROTOCOL

Tamoxifen given to ER/PR+ patients Henderson, IC et al. Adjuvant chemotheraphy: Taxanes — the “pro” position. NIH Conference on Early Breast Cancer, 2000. Abstract

NSABP B-28: PHASE III RANDOMIZED STUDY OF PACLITAXEL VS NO FURTHER CHEMOTHERAPY FOLLOWING DOXORUBICIN/ CYCLOPHOSPHAMIDE FOR RESECTED NODE-POSITIVE BREAST CANCER CLOSED PROTOCOL

Tamoxifen given for patients >= 50 and patients < 50 who are ER+ or PR+ Mamounas EP. Evaluating the use of paclitaxel following do xorubicin/ cyclophosphamide in patients with breast cancer and positive axillary nodes. NIH Consensus Conference on Early Breast Cancer, 2000. Abstract

NSABP B-30;CTSU: PHASE III RANDOMIZED STUDY OF ADJUVANT DOXORUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY DOCETAXEL VERSUS DOXORUBICIN AND DOCETAXEL VERSUS DOXORUBICIN, DOCETAXEL AND CYCLOPHOSPHAMIDE IN WOMEN WITH BREAST CANCER AND POSITIVE AXILLARY LYMPH NODES OPEN PROTOCOL

PROJECTED ACCRUAL: A total of 4,000 patients will be accrued within 3 years.

T= Docetaxel A= Doxorubicin C= Cyclophosphamide Tamoxifen given for 5 yrs to all ER+ or PR+ patients. Tamoxifen given to ER- or PR- patients and receptor unknown patients > 50 yrs old at physician’s discretion.

STUDY CONTACT Sandra M Swain, Chair, Ph: 301-435-9039 National Surgical Adjuvant Breast and Bowel Project

ADJUVANT FAC: LONG-TERM FOLLOW-UP OF FOUR MD ANDERSON TRIALS (1974-1986) 1107 PATIENTS: STAGE II OR III

10 year survival 1-3 positive nodes 72% 4-10 positive nodes 55% > 10 positive nodes 36% Estimated reduction in mortality compared to historical controls All 50% Age < 50 57% Age >= 50 44% Buzdar AU et al. Impact of FAC-adjuvant therapy on mortality of early breast cancer: Long-term results of the MD Anderson Cancer Center Studies, in Salmon SE (ed): Adjuvant Therapy of Cancer VIII, pp. 93-100. Philadelphia, Lippincott Williams & Wilkins, 1997.

NSABP B-15: PHASE III RANDOMIZED COMPARISON OF ADJUVANT CHEMOTHERAPY WITH AC (ADR/CTX) VS AC PLUS REINDUCTION WITH PARENTERAL CMF (INTR AVENOUS CTX/MTX/5-FU) VS CONVENTIONAL CMF IN PATIENTS WITH TOTALLY RESECTED BREAST CANCER WITH POSITIVE NODES CLOSED PROTOCOL

Fisher B et al. Two months of doxorubicin-cyclophosphomide with and without interval reinduction therapy compared with six months of cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from NSABP B-15. J Clin Oncol 1990;8:1483-1496. Abstract

NATIONAL CANCER INSTITUTE OF CANADA MA.21 TRIAL: PHASE III RANDOMIZED STUDY OF ADJUVANT CYCLOPHOSPHAMIDE, EPIRUBICIN AND FLUOROURACIL VERSUS CYCLOPHOSPHAMIDE, EPIRUBICIN, FILGRASTIM (G-CSF) AND EPOETIN ALFA FOLLOWED BY PACLITAXEL VERSUS CYCLOPHOSPHAMIDE AND DOXORUBICIN FOLLOWED BY PACLITAXEL IN PREMENOPAUSAL OR EARLY POSTMENOPAUSAL WOMEN WITH PREVIOUSLY RESECTED NODE-POSITIVE OR HIGH-RISK NODE-NEGATIVE STAGE I-IIIA BREAST CANCER OPEN PROTOCOL

T=paclitaxel STUDY CONTACT: Margot J Burnell, Chair, Ph: 506-648-6884 NCIC-Clinical Trials Group

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