Management of Early Breast Cancer

Key : Mast : Modified mastectomy; BCS : Breast Conservative Surgery; RT : Radiotherapy

The largest of the BCS trial of NSABP B–06 was recently updated with 15 years of follow-up. Equivalence of the treatments is confirmed but the interesting finding is that though local recurrence was high in those who had conservative surgery without radiation therapy, the overall survival in all the three arms of Total mastectomy, segmental mastectomy and segmental mastectomy with radiotherapy was the same. Many of the local recurrences in the arm with segmental mastectomy alone occurred many years later, which means that most of these represent residual foci of tumor not detected on pathologic margin analysis. Therefore these represent residual tumor cells unknowingly left in place for several years during which time they grew to clinical proportions and were at a later date discovered as a local recurrence. Despite this long stay of viable tumor cells in the breast, the distant disease failure rate and overall survival rate do not differ in the three groups. Thus it is clear that overall the patients who undergo lumpectomy alone don’t do worse than those who undergo mastectomy although lumpectomy carries a high rate of local recurrence. However today lumpectomy done without radiation to the remaining breast is an abandoned treatment.

The importance of this finding is that distant disease is not a function of local surgical method and that BCS is probably more feasible than most surgeons believe. Today even patients with large tumors and central tumors should also be considered for breast conservative surgery.

Indications for mastectomy

Today there are very few patients with early breast cancer who qualify for mastectomy. Though earlier European trials included tumors of 2.5 cm or less but latest NSABP trials have included tumors up to 5 cm . European trials initially did wide quadrentectomies for smaller tumours. These resulted in fewer local recurrences, but inferior cosmetic appearance without any benefit in overall survival. Today the NSABP definition of a free margin is simply one that does not cut across microscopic tumor. Even tumors that are close to or involves the nipple and areola complex can be resected together with over lying skin, areola and nipple just as they were peripheral. The cosmetic appearance of the left over breast will not be as desirable but far preferable to the cosmetic result of a mastectomy.

Hence in summary, most stage I or Stage II breast cancer should be considered for treatment with BCS. Only if the margins are extensively involved after surgical revision, if there is multifocal disease or extensive microcalcification of DCIS a modified radical mastectomy should be done. Other contraindications for BCS are :

Absolute Contra indications:

· First or second trimester of pregnancy

· Two or more tumors in separate quadrants of breast

· Diffuse malignant microcalcification

· History of prior therapeutic radiation to the breast region.

Relative contra indications:

· Large tumor / breast ratio

· History of connective tissue disorder

· Large breast size

· Tumor location beneath the breast

In the USA > 50 % of patient for early breast cancer get mastectomy. Physician’s bias also account for a large number of unnecessary mastectomies. Surgeons should impart with knowledge, educate and inform the patient about three options :

· Mastectomy alone

· Mastectomy with immediate reconstruction

· Breast Conservative Surgery with radiation to the breast

Hence today, better understanding of biology of the breast cancer, detection of smaller tumors over time, increasing use of systemic therapy, patient’s awareness and participation has changed the approach to local treatment of breast cancer. Patient should know the risks, complications and procedures involved. Patient should actively participate in the decision making.

Guidelines for Breast Conservative Surgery (BCS)

Major goal of BCS is to have cosmetically acceptable breast with resection of tumor and reasonable amount of normal breast tissue around it so as to get negative microscopic margins. This depends on optimal technique. NSABP surgeons published a guideline for BCS and these guidelines are :

Incision and Flaps

Incision should generally be placed directly over the tumor even for a mammographically detected lesion. Knowledge of a benign or malignant nature of lump influences the placement of incision. For this as far as possible pre-operative diagnosis is a useful adjunct. Circumareolar incisions shouldn’t be used. Incisions should be curvilinear or transverse both in the upper and lower quadrants. There is no need to remove the skin except for superficial tumors. Two separate incisions may be made for tumors in the upper and outer quadrant. Subcutaneous fat should be preserved. Haemostasis should be adequate to avoid distortion and follow up evaluation. Best cosmetic results are obtained by not putting in a drain. Incision should preferably be closed by a subcuticular stitch.

Preoperative Needle Biopsies and Localization

Calcifications and other subclinical architectural deformities are removed with the aid of preoperative radiograph localization. If a preoperative needle core biopsy is not possible it is better to manage these abnormalities as if they were carcinomas. If after wide local excision, the margins are negative there will be no need for a second procedure and if margins are positive, the proper markings and handling of the specimen by the pathologist will enable the surgeon to revise the excised area with little sacrifice of further tissue.

Today’s BCS is not the domain of surgeons but it is a collaborative effort between Surgeons, Radiologists, Pathologists, Radiation Oncologists, Reconstructive surgeons and Medical Oncologists.

Radiation therapy

As stated earlier, BCS involves wide lumpectomy followed by ERT. Radiotherapy with linear accelerator is considered ideal with limited radiation to lung volume. Whole breast dose is in the range of 45-50 Gy given at 1.8- 2 Gy / day. Boost dose of 15 Gy (Approx.) to tumor area in patients with close or positive margins is desirable.

Preoperative Chemotherapy

Preoperative or primary chemotherapy is an experimental approach for stages I and II. Many clinical trials of primary chemotherapy have been reported but none has shown a reliable advantage in survival. It does reduce the size of the primary tumor so that BCS is possible but in the NSABP trial of B-18, where preoperatively Adriamyecin and Cyclophosphamide was given to one arm, no difference in the distant disease free or overall survival was noticed. Preoperative chemotherapy showed complete response remission in 36% of the patients and pathological remission in 10%. Smaller tumors were more likely to have complete and pathological remission while larger tumors though downstaged had higher local recurrence rates besides resection of larger volumes of tissues. Though protocol B-18 confirmed that the preoperative chemotherapy would shrink the tumor to make BCS possible more frequently and that lymph node involvement was downstaged no difference was demonstrated in disease free survival or overall survival.

Local recurrence

Though local recurrence doesn’t jeopardize the chances of long-term survival, it is a psychologically disturbing factor for the patient besides having to have another surgery. For this it is important to recognize the factors responsible for local recurrence.

Initially EIC (Extensive Intraductal Component) coupled with poor nuclear grade was considered an important factor for prediction of local recurrence. Subsequently it was found that younger age is more likely to have EIC and is by itself a prediction for increased risk of local recurrence. Further reports indicated that patients with EIC had larger load of subclinical tumor burden and basically EIC is a predictor for positive margins. Abner et al⁽²⁰⁾ showed that even with histological negative margins, patients with extensive EIC have low rates of local recurrence. Hence it is obvious that negative margins are desirable especially in the presence of an EIC. If an extensive EIC is present and margins are positive, these can be revised and or recommended for mastectomy.

Some studies have found that Lymphatic Vessel Invasion. (LVI) is also a poor prognostic factor with regard to local recurrence and over all survival.

Infiltrating Lobular Carcinoma are not only infiltrative but also discontinuous and hence a wide excision with clearly negative microscopic margins is preferred. Definition of negative margin is absence of cancer cells within 1mm of inked margin and positive margin means presence of tumor at inked margins.

Pathological examination should include measurement of dimensions of intact gross specimen and inking of the surface (margins) of the specimen. While grossing measure the size of the tumor and the closest margin distance. Tissue should be taken for ER and PR. Microscopic description should include proximity, presence and extent of tumor cells at inked margins and identification of the margins involved.

Summary of Breast Conservative Surgery (BCS)

The 1992 NIH Consensus Development Conference reported that “Breast Conservation Treatment is an appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy and axillary dissection while preserving the breast”.

Very large tumors with grave signs should be treated by primary chemotherapy because these are essentially not stage I or II disease but stage III.

Surgeons should balance the cosmetic factors with techniques required for good local control. The primary concern should be adequate removal of the primary tumor with histologically negative margins.

Adjuvant Systemic Therapy

Most data indicate that adjuvant CT and or hormonal therapy in stages I and II diminish local recurrence rates compared to those not receiving adjuvant treatment. But that long term survivals and distant metastasis is not affected whether women had BCS or mastectomy.

Skin Sparing Mastectomy (SSM)

In SSM, no extra skin except for nipple areola complex with all the underlying breast and axillary contents including any biopsy scar is removed. Immediate reconstruction is done by transabdominal Myocutaneous Flap or expandable implant. In this SSM cosmetic results are better and local recurrence notes are same as that in Mastectomy.

Indications for Post op Radiation therapy

Post operative Radiation refers to the irradiation of chest wall and / or draining lymph nodes regions used as an adjuvant treatment following definitive mastectomy.

Before we consider post operative radiation therapy it is important to know that incidence of locoregional recurrence after mastectomy in node positive patients ranges from 10% - 25% whereas in node negative patients the local recurrence is seen only in the about 5%.^(22-23) Once a local recurrence is present, besides being psychologically distressing only 50% of these can be effectively controlled. Apart from the above consideration, the other theoretically explanation is that in those who recur the microscopic residual disease after mastectomy besides being the only site of persistent cancer can also be the source of distant metastasis.

Though post operative radiotherapy decreases the risk of local recurrence by about two thirds ⁽²⁴⁾, the Survival benefit improvements to still need to be evaluated by randomized trials.

Based on many randomized trials of premenopausal and postmenopausal women with or without nodal involvement and treated with or without ERT, it is concluded that ERT is not indicated in patients with uninvolved axillary nodes except when there is a clear evidence of positive margins specially at the depth. In patients with involved axillary nodes specially when more than 4 nodes are involved, ERT will greatly reduce the incidence of local recurrence and may improve overall survival in premenopausal patients. Patients with 10 or more positive nodes treated with high dose chemotherapy routinely receive post operative ERT following completion of chemotherapy. This is to reduce a high early local failure rate when patients were not irradiated.

Management of Axilla in early breast cancer

Axillary dissection of lymph nodes has three benefits :

· Local control of tumor in the axilla

· Prognostic significance

· potential survival benefit

NSABP B-04 trial in 1970 conclusively proved that axillary dissection had limited impact on survival.⁽²⁵⁾ In this trial patients with clinically negative axillary nodes were randomized to radiation mastectomy, total mastectomy with observation of the axillary nodes and a delayed dissection if positive axillary nodes appeared or total mastectomy with RT to the regional lymphatics. No statistically significant difference in the 10 year survival rate was found among the three groups, despite the fact that about 40% of the patients undergoing axillary dissection had positive nodes and similar number presumably had positive nodes in the observation arm only.

Based on this recognition that axillary dissection was principally a prognostic rather than therapeutic procedure a number of studies were undertaken to determine the extent of axillary surgery needed to determine whether nodes were positive. Many of the studies examined likelihood of skip metastasis i.e. involvement of level III nodes in the absence of involvement of level I or II and involvement of level II nodes in the absence of involvement of level I.⁽²⁶⁾ The conclusion from these studies is that removal of both level I and II is required as it is effective in providing local control in the axilla and provides enough nodes for prognosis. ⁽²⁷⁾

5 years probability of an axillary recurrence is about 20% in patients with no nodes examined and about 10% when one or two negative nodes are removed. It is thus recommended that more than ten nodes be removed to avoid misclassification and to avoid local recurrence. This normally would involve level I and II axillary nodal clearance.

Axillary nodal clearance at level I and II, also called ‘partial axillary lymph node dissection’ (ALND), involves removal of axillary nodes superior to the level of the axillary vein, lateral to the latisimus dorsi muscle and medially to the medial border of the pectoralis minor muscle. Long thoracic nerve, which supplies serratus anterior should be saved. Thoracodorsal nerve with its vein and artery should also be preserved if possible.

Major complications of injury or thrombosis of axillary vein for ALND are few. Minor complications of seroma formation, shoulder dysfunction, loss of sensation in the underarm and upper arm, and edema of the arm and breast are common.

Recent developments have led to the change in philosophy of axillary dissection under some special circumstances. This has happened due to detection of smaller lesions, mammographically detected lesions and routine use of post operative adjuvant chemotherapy even in node negative patients. Breast cancer with low risk of axillary involvement could be spared the axillary dissection. Tumors with microinvasive cancers, tubular cancers and DCIS have axillary metastasis in less than 5%. At present DCIS, DCIS with microinvasive element and pure tubular cancers less than 1 cm can be spared the axillary dissection.

Sentinel lymphnode biopsy (SLNB)

Sentinal node technique has the potential to allow the axillary dissection to be carried out in those with positive nodes and leave the ones with negative nodes. Sentinel node is the first lymph node to receive lymphatic drainage from a tumor. Several studies have shown that SLNB reliably predicts the status of axillary nodes. In the future axillary dissection might be avoided in patients who have no metastatic involvement of the sentinel node. First however the efficacy and false negative incidence of SLNB must be tested in the setting of randomized prospective trials before ALND is abandoned as the standard of care.

Radiotherapy to the axilla

A total dose 30 to 70 Gy is generally used. The mean dose is usually 50 Gy. Most fractionation schemes employ daily doses of 1.8 – 2 Gy over six weeks. Axillary RT is generally considered a treatment option only for the patient with clinically impalpable nodes. NSABP B-04 and Institute Curie trials have compared Radical Mastectomy, Mastectomy with RT to axilla/chest, and Mastectomy alone. At 10 years there was no significant difference between the groups that did and did not receive RT with respect to overall survival or local recurrence in the axilla. This study suggested that ALND and RT are equally effective treatment options in clinically node negative patients. The trial also suggested that delayed treatment of the axilla does not adversely affect breast cancer survival. These trials assert that “Axillary lymph node metastasis are an expression of bad prognosis rather than a determinant of overall survival”. The biggest disadvantage of treating the axilla with ERT is that the prognostic significance of axillary nodes is lost forever.

35 to 40% of patients with clinically detected invasive breast cancer proved to be node positive following ALND. Although the extent of ALND seems to have no effect on breast cancer mortality, it does influence the risk of axillary relapse. The greater the extent of ALND, the less the risk of axillary relapse. Following a level I and II dissection the risk of recurrence is reduced to 1-2 % while for level I ALND the risk of recurrence is more than 10%.

Summary

In summary treatment of axilla with either ALND or radiotherapy remains an integral part of the management of patients with invasive breast cancer. The issue of survival benefit of axillary treatment remains controversial. Axillary node dissection is an effective staging procedure and is essential for local control of disease in the axilla.

With breast cancer awareness, routine mammography and early detection of cases, less and less number of patients are node positive and hence many undergo unnecessary nodal dissection and the associated morbidity. Hence SLNB may eventually prove to be a preferred alternative to routine ALND. It must first be demonstrated that SLNB (without completion ALND) doesn’t adversely affect out come.

Patients with DCIS, DCIS with microinvasion and pure tubular carcinomas less than 1 cm in size need not have axillary dissection. All other patients require level I and II axillary dissection to prognosticate, to design adjuvant chemotherapy and to change the type of chemotherapy and to enter into high dose and newer chemotherapy trials.