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Neoadjuvant Chemotherapy for Breast Cancer

In 1996, 184,300 women will be diagnosed with breast cancer and 44,000 women will die from breast cancer. Despite improvement in treatment options, the age adjusted cancer death rate has shown no improvement from 1930 through 1992.¹ Innovative treatments for breast cancer should therefore actively be sought.

The concept of preoperative chemotherapy has several advantages. These include a reduction in tumor size allowing for more breast-preserving procedures, an in vivo chemosensitivity assay and early treatment of micro-metastatic disease. Potential pitfalls include delay of local therapy and added toxicity.

Neoadjuvant chemotherapy was used initially in poor-prognosis patients (locally advanced and inflammatory breast cancer). Clinical response rates varying from 70 percent to 90 percent have been reported with a number of induction chemotherapies.^2,3 Additionally, therapy using preoperative chemotherapy, surgery and radiation has demonstrated an improvement in local control and disease free survival.^2,3

This data spurred the development of the NSABP B-18 trial. This trial compared in operable breast cancer, preoperative vs. postoperative administration of four cycles of AC [cyclophosphamide and Adriamycin (doxorubicin)] in 1,523 patients. The results show a 36 percent clinical CR and a 44 percent clinical PR. Patients who received preoperative chemotherapy also were more likely to undergo breast conservation than patients who received postoperative chemotherapy (68 percent vs. 60 percent; p=0.003). Additionally, there was evidence that preoperative chemotherapy resulted in axillary node downstaging Ñ 40 percent of patients with preoperative chemotherapy were pathologically node positive as compared to 58 percent of patients who received chemotherapy postoperatively. A significant correlation existed between tumor response and pathologic nodal status. In patients with a clinical CR to preoperative chemotherapy, 26 percent were node positive; in patients with a clinical PR, 47 percent were node positive; in patients with stable disease, 50 percent were node positive; and in patients with progressive disease, 67 percent were node positive.⁴ The hope is that this response in the primary tumor will translate to an improved survival rate.

These studies demonstrate that preoperative chemotherapy can improve the ability to offer breast-conserving surgery. Additionally, local control rates have not been compromised by the delay of local therapy. Finally, there has been no increase in surgical morbidity noted in patients undergoing neoadjuvant chemotherapy.

Another goal of preoperative chemotherapy is the ability to assess the response of an individual tumor to a chosen chemotherapy. Patients who respond to treatment tend to have a better disease-free and overall survival rate. Patients who fail to respond to initial chemotherapy should be considered for other investigational therapy, such as noncross resistant chemotherapy or high dose chemotherapy.

Preoperative chemotherapy also may favor eradication of micro-metastatic tumor clones. The Goldie-Coldman hypothesis states that with time the tumor cell population increases, as do the number of drug-resistant phenotypes. A delay in chemotherapy until after surgery could allow the development of drug resistance. To support this, animal models have shown a benefit in terms of both tumor kinetics and survival when chemotherapy is given preoperatively.⁵ Other animal studies have demonstrated an increase in the growth rate of metastatic foci once the primary tumor was removed.⁵

There continues to be ample reason to evaluate the worth of preoperative chemotherapy in patients with breast cancer. It has been proposed that new chemotherapeutic agents may improve responses of both the primary tumor and micro-metastases over the results seen with the AC regimen. Taxotere (docetaxel) is currently being investigated in such a role. Taxotere is an antimicrotubule agent that disrupts the normal equilibrium of the tubulin-microtuble system ultimately resulting in cell death. Taxotere in metastatic breast cancer demonstrates response rates of 54 percent to 87 percent.^6,7 Taxotere also has been shown to be noncross resistant to Adriamycin, with response rates of 56 percent in anthracycline resistant disease.⁸

The NSABP has designed a randomized clinical trial (B-27) to determine the effect of preoperative or postoperative Taxotere given after four cycles of preoperative AC vs. four cycles of preoperative AC alone. All patients will receive Tamoxifen therapy for five years beginning Day 1. The primary aim of this trial is to demonstrate a difference in survival. Secondary endpoints include evaluating differences in disease-free survival, clinical and pathological local tumor responses to preoperative chemotherapy, and the effect of preoperative chemotherapy on the rate of breast conservation. The nationwide accrual goal is 1,606 women.

Eligibility

• Invasive breast adenocarcinoma by FNA cytology or Core or Tru-cut biopsy.
• T1C-3N0M0 (>1 cm) or T1-3N1M0 (NO ulceration, erythema, infiltration of the skin, peau d'orange or ipsilateral fixed lymph nodes).
• Interval of < 63 days from diagnosis.
• Life expectancy > 10 years.
• No active cardiac disease
• No prior malignancies (except skin, CIS cervix and LCIS treated by surgery alone) or nonbreast cancer > 10 years.
• Pre-study: History, physical examination and bone scan prior to randomization, chest X-ray, CBC with diff, chem profile in the past three months; bilateral mammogram, gynecological examination and EKG in the past year.

It also is anticipated that Ellis Fischel Cancer Center will have available a pilot study evaluating preoperative Taxotere and Adriamycin combined with surgery and radiation for the high-risk woman with locally advanced or inflammatory breast cancer in late summer 1996.

For questions regarding these studies or to refer a patient for consideration of preoperative chemotherapy, please contact Dr. Vicki Dorr at 1 (800) 595-6559, Ext. 7462, or in Columbia (573) 882-7462; or the Ellis Fischel Clinical Trials Office at (573) 882-7440.

References

1. Parker SL, et al. Ca Cancer J Clin 1996:46:5-27.

2. Perez CA, et al. Cancer 1994;74S:453-65.

3. Perez CA, et al. Cancer 1994;74S:466-76.

4. Fisher B, et al. Proc Am Soc Clin Oncol 1994,13:A57.

5. Harris L, et al. Sem Oncol 1996;1S2,31-42.

6. Erazo-Valle A, et al. Proc Am Soc Clin Oncol 1995;14:A244.

7. Hudis CA, et al. J Clin Oncol 1996;14:58-65.

8. Ravdin P, et al. Proc Am Soc Clin Oncol 1995;14:A77.