MANAGEMENT OF LOCALLY ADVANCED BREAST CANCER

Even though awareness about breast cancer is improving at all levels, yet majority of our patients present in advanced stages. Locally advanced breast cancer (LABC) generally refers to primary tumour more than 5cm. (T3), or tumour fixed to chest wall / skin ulceration, satellite nodule or Peau d’orange (T4) or ipsilateral axillary nodes fixed to each other, deeper structures or skin (N2) or internal mammary nodes (N3). This refers to stages IIIa & IIIb and T3N0 from IIb of UICC TNM 1997. The patients in this group not just have large volume of disease locoregionally but also have high incidence of micrometastasis. Fortunately with better understanding of disease and teamwork amongst surgical, medical and radiation oncologists the results in this set of patients have improved remarkably, the accepted 5 year survival rate is over 60%. We will discuss the management under following headings:

1. Staging work up.

2. Treatment sequencing.

3. Systemic treatment.

4. Surgical options.

5. Radiotherapy.

Staging work up:

LABC patients have to be investigated for metastatic disease with the help of bone scan, X-ray chest, imaging for liver (ultrasound /CT scan) besides a bilateral mammogram, haemogram, liver function and renal function tests. Any abnormality in bone scan or raised serum alkaline phosphatase needs to be further evaluated through appropriate imaging investigations. Core needle biopsy is essential to evaluate the histopathological features, study the hormone receptor (estrogen and progesterone) and c-erbB-2 status before starting systemic treatment.

Treatment sequencing:

Till 1940s the 5-year survival rates in LABC were around 15%. In ‘operable’ cases surgery was performed and the rest were subjected to radiotherapy. It was soon realised that with the combination of radiotherapy and surgery the locoregional control was superior. However distant failure was still a major problem. Initially, oophorectomy proved to be of little survival advantage when compared with the remaining population. Similarly addition of single agent chemotherapy after surgery and radiotherapy was reported to offer superior local control and survival figures.

Induction or neoadjuvant chemotherapy was tried to convert unresectable tumors into resectable ones. Besides having several of these tumours under control it was also realised that there was an opportunity to have an in vitro study of tumour sensitivity to a particular set of drugs. In a prospective study at Guy’s hospital, patients were assigned either chemotherapy followed by radiotherapy or radiotherapy followed by chemotherapy as initial treatment for LABC and then subjected to maintenance chemotherapy. Survival in both the arms was similar. However when this was compared with those who had radiotherapy alone there was a definite survival advantage. This confirmed the superiority of combination treatment. Later reports from MD Anderson cancer centre, National Tumour Institute, Milan etc. confirmed the superior results from neoadjuvant chemotherapy in LABC.

In 1975, NCI, Milan began a trial of LABC in which after 3 cycles of chemotherapy patients were randomised to radiotherapy or surgery and on completion of this 6 more courses of chemotherapy were administered⁶. The best local control was achieved when surgery was interposed between chemotherapy: 82.3% vs 63.9% in the other arm. Five-year disease free survival rate was also superior: 25% vs. 4.9%.

In 1974, a multimodal treatment protocol was initiated at MDAnderson Cancer Centre, when all three modalities were put to use. After three cycles of chemotherapy response was classified as, complete response, major response, minor response, non-response resectable and non-response unresectable. Complete responders and unresectable tumours were subjected to radiotherapy and then 6-12 courses of chemotherapy. Remaining were operated (modified radical mastectomy) upon and then chemotherapy and lastly radiotherapy was delivered.

Systemic treatment:

The turn around in treatment of LABC came only after systemic treatment was integrated in its management. The related issues are, which drugs, when and how long to be used?

Several single agents have been used effectively in treatment of LABC. Adjuvant Cyclophosphamide, methotrexate and 5FU (CMF) for a period of 12 months was the first universally accepted polychemotherapy regime which was standard care in breast cancer for a long time. Through randomised studies it was proven that 6 cycles of CMF were as effective as 12. Now anthracycline based chemotherapy is recommended for all LABC patients because of their superiority over CMF. Six or more cycles of Cyclophosphamide, Adriamycin and 5FU (CAF) are recommended both as neoadjuvant or adjuvant (keeping the cumulative dose of adriamycin within permissible limits). Four courses of AC (adriamycin, cyclophosphamide) with a higher dose of Adriamycin delivered in shorter span of time have proven to be of similar efficacy as 6 cycles. Today CMF is used in LABC only for c-erb-B2 negative patients, with known cardiac problems (where adriamycin toxicity may be difficult to tolerate). It may also be used as adjuvant treatment after the patient is treated with 4 cycles of AC in neoadjuvant setting and the pathology report has documented CR in a c-erb-B2 negative tumour³. The literature on use of Taxanes is limited, however, it is suggestive of certain aspects. c-erb-B2 positive tumours have poor prognosis and are more likely to respond to taxanes. It is suggested that tumours with more than 10 positive nodes or higher proliferation rates may be treated by taxanes.

Several other agents viz. Vincristine, phenylalanine, vindesine, prednisolone etc. have also been used in combination in different trials or as second / third line in clinical practice.

All patients other than those with estrogen and progesterone negative status have to be treated with Tamoxifen for a period of 5 years. Patients with strongly positive c-erb-B2 are less likely to benefit from hormonal treatment, but it is yet to be fully established. After first line treatment has failed, second line drugs e.g. Femara are used.

Surgical options:

Issues relevant to surgery are when it should be done and what is the acceptable surgery? Today, in all T4 and N2 disease anterior chemotherapy is the standard treatment, however, T3 N0 or N1 disease is a grey area where surgery may be the first line and adjuvant treatment is planned based on the histopathological report. Those who advocate surgery first in these patients say that it gives more precise information about tumour characteristics, nodal status etc. and chemotherapy would be more effective after surgical debulking. This issue has not been resolved in a randomised study and it is unlikely that this will be addressed either. In retrospective studies the results in both these strategies (surgery first or chemotherapy first) are quite similar. In LABC, surgery may be considered first only if the axillary node is less than 2.5cm, and, the primary tumour can be operated with satisfactory surgical margins without the need for a tissue flap to cover the defect. If the patient desires to have breast conservation surgery and the tumour size is a limiting factor then neoadjuvant chemotherapy must be employed. Whenever in doubt in a clinical situation about one’s ability to deliver optimum surgery it is better to deliver chemotherapy first.

Surgery in LABC after neoadjuvant chemotherapy or as primary treatment in select patients may be modified radical mastectomy, breast conserving surgery or radical mastectomy. Requirement for radical mastectomy is rare. Before an individual is considered for breast conserving surgery the evaluation is done clinically, with a mammogram and ultrasound of the breast.

Following criteria should be met:

a. Residual tumour less than 5 cm. (initially Bonadonna et al considered only those patients where the residual tumour was less than 3cm.)

b. Resolution of skin oedema.

c. Absence of microcalcification.

d. No known evidence of multicentricity.

e. Patients desire for breast conservation.

MD Anderson cancer centre experience with majority of patients qualifying for breast conservation treatment after neoadjuvant chemotherapy has been repeated at NCI, Milan, Institute Curie, France, Thomas Jefferson University etc. and today breast conservation surgery is a part of standard care for these patients.

Is there an option of avoiding surgery if there is a complete clinical response after neoadjuvant chemotherapy?

In 1975 at NCI, Milan after neoadjuvant chemotherapy patients were randomised for radiotherapy or surgery and results were significantly inferior in the radiotherapy group. In the Bonadonna series of 157 patients, after neoadjuvant chemotherapy complete responses were seen in 27 patients of whom only nine were pathological CRs. Similarly, MD Anderson experience of clinical CRs was 17%. In both these studies the survival outcome in this subset of patients was far superior compared to the remaining group. We know that pathological CR is less than 50% in the group with clinical CR and it may be tempting to consider only radiotherapy after cCR. However today replacement of surgery by radiotherapy in the group with complete clinical response is only permissible in trial setting.

Radiotherapy:

Radiotherapy is an integral component in the management of LABC. It helps in achieving superior locoregional control and also survival along with surgery. Radiotherapy is recommended at the end of post-operative chemotherapy. Radiation is recommended for remaining breast or chest wall with tangential fields upto 50Gys and a boost of 15 Gys. to the scar or tumour bed. Axilla is treated after axillary dissection only if it is N2 disease. Internal mammary chain is treated with radiation if the tumour is in medial quadrant or there are more than 4 positive axillary nodes. Whenever axilla or internal mammary chain is treated with radiation, supraclavicular fossa is always included in the field of radiation.

Results of treatment of LABC have improved significantly in the last few decades mainly because of teamwork amongst medical, surgical and radiation oncologists. It is also a good example of how well designed trials to answer specific questions have increased our pace to find the solution to it.