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Section 8
Adjuvant Taxanes: Surgical Oncology Perspective

John Bryant, the NSABP’s chief statistician, has shown that the results of the Intergroup and NSABP trials are really in the same ballpark. The 95 percent confidence limits overlap, although the Intergroup study is positive and ours is not. We should look at this as having been a 30-year experiment with many different facets. It’s been difficult to demonstrate an important difference between two active drug regimens. The advantages of adding Taxol compared to AC alone are likely to be minor. But the disadvantages in terms of side effects and cost are not minor, and there is an economic issue to all of this. In the United States — where it isn’t clear who controls the cost of giving a drug like Taxol — no insurance company is going to say, "Don’t give it." In a country like Canada — where I practice — the decision is more likely to be made on a consensual basis by oncologists at a societal level. The structure of medicine in the United States pays too much attention to cost at the level of the individual person. The structure of medicine in Canada has a preoccupation with cost at a consensual level. It’s different, and there are trade-offs.

—Richard Margolese, MD

Both the NIH and St Gallen Consensus Conferences expressed a lack of enthusiasm for endorsing the addition of the taxanes as a routine in node-positive patients, because the data were not mature enough to make that decision at this time. One of the more alarming things about increasing the duration of chemotherapy is the issue of 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 with stress and depression. But 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

NSABP B-28: Phase III Randomized Study of Paclitaxel vs No Further Chemotherapy Following Doxorubicin/Cyclophosphamide for Resected Node-positive Breast Cancer (closed to accrual) Protocol 

Eligibility  Operable breast cancer node+

ARM 1 AC x 4
ARM 2 AC x 4 Taxol x 4

Tamoxifen given for patients > 50 and patients < 50 who are ER+ or PR+ 

Mamounas EP. Evaluating the use of paclitaxel following doxorubicin/cyclophos-phamide in patients with breast cancer and positive axillary nodes. NIH Consensus Conference on Early Breast Cancer, 2000. Abstract

NSABP B-28 TRIAL RESULTS (3RD INTERIM ANALYSIS)

Mamounas EP. NIH Consensus Conference on Early Breast Cancer, 2000. Abstract

CALGB-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 to accrual) Protocol 

Eligibility  Operable breast cancer, node+

ARM 1 AC (60 mg/M2)  x 4
paclitaxel x 4
No further treatment
ARM 2 AC (75 mg/M2)  x 4
paclitaxel x 4
No further treatment
ARM 3 AC (90 mg/M2)  x 4
paclitaxel x 4
No further treatment

Tamoxifen was offered to all patients with ER+ or PR+ tumors.

COMPARISON OF TWO KEY STUDIES

“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.

“The decision to use any form of adjuvant chemotherapy should be taken thoughtfully in a patient with a receptor-positive tumor scheduled to receive adjuvant tamoxifen. However, the evidence from this trial is not now sufficient to determine which chemotherapy regimen should be selected for these patients because this was an unplanned subset analysis, and the large trend towards a greater effect in receptor-negative patients was not statistically significant. When patients receive breast radiotherapy in addition to chemotherapy, it is reasonable to wait until completion of six months of CA plus paclitaxel before starting the radiotherapy.”

–Henderson 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.”

–Piccart et al. NIH Consensus Conference 2000. Abstract

NSABP B-30: 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 Nodes Protocol

Eligibility  Operable breast cancer, node+

ARM 1 AC x 4 T x 4
ARM 2 AT x 4
ARM 3 ATC x 4

T= Docetaxel

Tamoxifen given for 5 yrs to all ER+ or PR+ patients and to ER- or PR- patients > 50 yrs old at physician’s direction

2000 NIH Consensus Development Conference on Early Breast Cancer, Final Statement Full Text

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.

SELECT PUBLICATIONS

Balducci L & Beghe C. Pharmacology of chemotherapy in the older cancer patient. Cancer Control 1999;6(5). Full-Text

Brezden CB et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000;18:2695-701. Abstract

Gianni L et al. Adjuvant and neoadjuvant treatment of breast cancer. Semin Oncol 2001; 28(1):13-29. Abstract

Henderson, IC. Adjuvant chemotherapy: Taxanes — the "pro" position. NIH Consensus Conference on Early Breast Cancer, 2000. Abstract

Hutcheon AW et al. Primary chemotherapy in the treatment of breast cancer; Significantly enhanced clinical and pathological response with docetaxel. Proc. ASCO 2000;19. Abstract 317

Kaderman R. 2000 NIH Consensus Conference on Adjuvant Therapy of Breast Cancer. Poster, 2001 Miami Breast Cancer Conference. Full-Text

Lister-Sharp D et al. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer. Health Technol Assess 2000;4:1-113. Full-Text

Michaud LB et al. Risks and benefits of taxanes in breast and ovarian cancer. Drug Saf 2000;23:401-28. Abstract

Nabholtz JM et al. Chemotherapy of breast cancer: Are the taxanes going to change the natural history of breast cancer? Expert Opin Pharmacother 2000;1:187-206. Abstract

Piccart MJ. Taxanes in the adjuvant setting: Why not yet? NIH Consensus Conference on Early Breast Cancer 2000. Abstract

Schagen SB et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999;85(3):640-50. Abstract

Sledge GW et al. Phase III trial of doxorubicin 9A vs paclitaxel (T) vs doxorubicin + paclitaxel (A+T) as first-line therapy for metastatic breast cancer (MBC): An Intergroup trial. Proc. ASCO 1997;16. Abstract

Thomas E, Buzdar A, Theriault et al. Role of paclitaxel in adjuvant therapy of operable breast cancer: Preliminary results of prospective randomized clinical trial. Proc. ASCO 2000;19:74a. Abstract
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Editor’s Note

Sentinel Node Dissection:
Implications to Medical Oncology

Postmastectomy Radiation
Therapy

Ductal Carcinoma In Situ

ER/PR Results and Endocrine
Therapy

Adjuvant Therapy for Low-risk
Invasive Tumors

ATAC Trial: Arimidex vs
Tamoxifen vs Combination

Bisphosphonates in Primary
Breast Cancer 

Adjuvant Taxanes: Surgical
Oncology Perspective

Proposed IBIS 2 Prevention Trial:
Arimidex vs Tamoxifen vs Placebo

Predictions of Future Trends
in Breast Cancer Research

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