Minimally invasive, maximal outcomes in breast surgery

Abstract

The contemporary treatment of breast cancer has evolved in response to numerous randomised control trials which have aided in the development of guidelines for effective treatment. Breast cancer surgery has progressed thanks in part to the advances made in chemotherapy, radiation therapy and early detection. As these advances continue the field of surgery needs to progress in tandem to maximise survival outcomes but to also minimise morbidity.

Introduction

The aim of oncological surgery is to effectively remove cancerous tissue with minimal injury to the surrounding normal tissue and maintain normal function. Historically the surgical management of breast cancer had been managed primarily by radical mastectomy, but this has since been superseded by treatment through breast conserving therapy.1, 2, 3, 4, 5 Breast conserving therapy (BCT) consists of the wide local excision of the tumour with negative margins followed by irradiation to the breast. This shift in the treatment of breast cancer was based on a number of randomised control trials which showed the equivocal survival and recurrence rates in patients treated either by mastectomy or BCT.

These trials provided excellent evidence that appropriate surgical management of breast cancer could be accomplished by removal of tumour alone provided negative margins were attained. This ushered in a new thinking in breast cancer treatment and helped pave the way towards a paradigm shift in the approach to breast cancer. This was a shift away from performing larger for all types of breast cancer and towards targeting breast cancer in a more direct manner, tailored to the disease of each patient and to the patient themselves. A number of factors have aided in the improved outcomes and quality of life observed today for so many women diagnosed with cancer. The advances seen in breast cancer, like the disease itself, are multifactorial and range from earlier detection in women, the pharmacological agents available and the role surgery plays in breast cancer.

The strides made in detection and treatments of breast cancer have translated into better outcomes for patients, nevertheless the cornerstone to treatment still remains surgery. However, the advancements made through numerous trials and studies have necessitated a change in how surgery is implemented and carried out. Various aspects of cancer biology and physiology have now been elucidated and targeted, which has triggered a change in how breast cancer is viewed.⁶ As a result the model of which the surgical management of breast cancer has been established should also change. This review aims to discuss some of the landmark changes which have occurred in the field of cancer treatment, and outlines where the surgical management of breast cancer is directed.

The benefits of pharmacological cytotoxic agents have been part of the accepted treatment of breast cancer for a number of decades, and optimisation of treatment have been validated through numerous clinical trials.⁷ The evolution of systemic chemotherapy has progressed from single agents to combination therapy and has incorporated the use of adjuvant targeting of specific receptors to treatment regimens.⁸ Current chemotherapy regimens consist mainly of anthracyclines either in combination with taxane treatment or administered separately⁹ and normally consists of six cycles of each regime or for six months.⁹ Recent clinical trials have shown some efficacy in using platinum based salts, bevacizumab, and PARP inhibitors for patients with triple negative breast cancer (TNBC) and carriers of BRCA mutations.10, 11 As far back as the 1998 the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed the benefit of adjuvant Oestrogen Receptor (ER) targeting through tamoxifen, which improved the ten year survival and recurrence rates of women with ER-positive or unknown ER-status tumours.¹² One of the greatest improvement in breast cancer treatment came through the targeting of HER2-positive breast cancers with the monoclonal antibody Trastuzumab. So great was the success of Trastuzumab on overall survival and prevention of disease recurrence that the trial had to be stopped early, and as a consequence the optimum duration of HER2 targeted therapy is unclear.¹³

More recently the use of the OncotypeDX recurrence score has allowed for the prediction of recurrence in patients with lymph-node negative, ER-positive tumours who have received Tamoxifen treatment.¹⁴ OncotypeDX has allowed clinicians to better make decisions on the treatment regimens designed for patients based on the genetic composition of the patients' tumours. This has allowed for the choice of better targeted therapy and to avoid unnecessary procedures and therapy such as chest wall or regional radiotherapy.¹⁴ Furthermore the OncotypeDX recurrence score was also able to predict if either WLE/Lumpectomy with whole breast irradiation or mastectomy would benefit the patient by reduction of local recurrence rates.¹⁵

Neoadjuvant systemic therapy (NST) describes chemotherapy that is administered to the patient before primary surgical excision of the tumour has taken place.¹⁶ The reasons for administering NST is to downstage tumour burden and facilitate surgery and improve breast conserving therapy rates.¹⁷ Putative advantages which have not shown proven benefits of NST are improved survival¹⁸ and that it allows for monitoring response to specific chemotherapy regimens that will be administered postoperatively.¹⁹ Patients with the greatest response to NST include patients with TNBC, high-grade oestrogen receptor positive, and HER2-positive breast cancers, while those with the lowest response to NST are patients with (a) tumours less than 2 cm, (b) those that are low grade ER-positive and (c) invasive lobular cancers.9, 20, 21 Patients who are appropriate candidates for chemotherapy can be considered for NST. However, not all patients will be deemed to benefit from NST; ironically those tumours which appear biologically less aggressive are the least likely to respond favourably.²²

Breast cancer screening programmes with mammography have provided a cost effective means to identifying breast lesions, which has translated into improved outcomes through the identification of early breast cancer.²³ Pre-clinical diagnosis of breast cancers translates into earlier intervention for tumours at earlier stages. This means tumours receiving treatment are smaller in size.²⁴ By identifying and treating breast cancer at an early stage the quality of life for many women has been improved.²⁵ Although mammography has always played a pivotal role in the early detection of breast cancer, it carries a sensitivity of only 79% in the screen detected population, a rate which decreases particularly in the denser breast tissue.26, 27 Traditional film mammography has now been superseded by digital mammography. The benefits of digital mammography, including a wide dynamic range and digital enhancement are now well recognised.²⁸ Advancements in computer technology and the introduction of digital imaging detectors have aided and improved the effectiveness of mammographic detected tumours.29, 30

As with so many aspects of breast cancer, the advancements in radiation therapy have improved the delivery of treatment to patients, the cosmetic outcomes post therapy and helped reduce the cost of administering therapy. In the NSABP B-06 trial the standard fractionation of the radiation given was 50 Gy of radiation over 35 days to be administered to the breast with no external-beam nor interstitial radiation given as a boost (Fisher et al., 2002). Ongoing trials are currently assessing the efficacy of using larger fractions of radiation in shorter intervals with lower total doses known as Hypofractionation. The Ontario Clinical Oncology Group developed a regime which delivered an accelerated course of 42.5 Gy in 16 fractions given over 22 days looking at the overall survival and recurrence rates in the hypofractionated group and the standard 50 Gy treatment.³¹ The Ontario Clinical Group Trialists did not observe any significant difference in overall survival or local recurrence over 12 years of follow-up. Various regimes are also being followed, specifically in the U.K. with the Standardization of Breast Radiotherapy (START) A³²and START B trials³³ which have shown similar results to the Ontario Clinical Oncology Group. Again these trials highlight the current trend in breast cancer treatment to minimise the amount of treatment while still obtaining the optimal results.

As with surgery of the breast, the surgical management of the axilla for treatment of breast cancer has changed which echos the impact that adjuvant treatment therapies have had on the treatment of breast cancer. The challenge of how to manage the axilla of patients with breast cancer is highlighted by the number of shifting views which has dictated how axillary surgery has been carried out in the past number of years.

Radical axillary lymph node dissection (ALND) along with radical breast excision was the standard of care for many years. It was the prevailing belief that in order to achieve adequate locoregional control and for the purposes of staging the disease, axillary dissection had to be performed. The increased risk of morbidity was deemed necessary to prevent lymphatic spread, improve recurrence rates and improve the overall survival. Axillary lymph node dissection involves the removal of the majority of lymph nodes posterior and distal to the pectoralis minor. Due to the proximity of these nodes to numerous neurovascular structures and due to the removal/disruption of the lymphatic system, ALND carried an increased risk of pain and range of motion discomfort, as well as secondary lymphoedema of the ipsilateral limb.

The NSABP B-04 clinical trial was initiated in 1971 and was one of the first published datasets to show that in patients with no clinically palpable nodes in the axilla, there was no survival benefit for patients who underwent radical mastectomy with ALND versus mastectomy with axillary irradiation or for those who had a mastectomy and had ALND delayed only until axillary lymph nodes were clinically involved detected.

Currently, sentinel lymph node biopsy (SLNB) has superseded the role of ALND, in early stage breast cancer. SLNB is a minimally invasive procedure which utilises a combination of modalities to locate the primary draining lymph node of the breast.³⁴ Using radioactive Tc99m or blue dye or a combination of the two, the surgeon is able to identify and remove the sentinel node or nodes. If the sentinel node is found to be negative then no further axillary surgery is required and patients could be staged accordingly. Where the sentinel node was found to be positive clinical guidelines had suggested that patients undergo completion ALND. The evidence for this practice has recently changed.

In 1999 the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial was commenced. This trial recruited women who were diagnosed with early breast cancer (T1 and T2 tumours), with clinically no palpable lymphadenopathy. Patients then underwent SLNB at the time of surgery, and those with positive sentinel lymph nodes (i.e.; those with pathological confirmed metastasis to the node) were then randomised into two groups: 1) subsequent ALND or 2) no further axillary treatment. Patients also underwent chemotherapy and tangential whole breast irradiation, which includes part of the axilla. The results of the Z0011 trail revealed that there was no survival or recurrence detriment associated with patients where no further surgical axillary treatment in sentinel node positive disease. The five year overall survival and five year disease free survival rates were was 91.8% and 82.2% with ALND compared with 92.5% and 83.9% with SLND alone.³⁵ As expected there was significantly higher rates of complications and morbidities in the ALND group compared with the SLNB alone group.35, 36 The Z0011 trial was encouraging for early stage breast cancer, though the scope of this study did not include patients with palpable node disease, Stage III breast cancer, patients treated by mastectomy, patients receiving partial breast irradiation/neoadjuvant chemotherapy, greater than three nodes exhibiting metastatic disease, or macroscopic extra-nodal extension.

Since this trial was commenced radical improvements in the chemotherapeutic regimes have been developed, HER2 targeted adjuvant treatment was not routinely used. Patients now receiving chemo-endocrine therapy are having their cancers targeted in much more specific ways. This is highlighted when comparing the NSABP B-04 and ACOSOG Z0011 trials five year survival data which shows the mastectomy only group in B-04 had a 60% survival rate with approximately 40% of these patients being node positive, compared to 90% five year survival rates observed in node positive patients in the Z0011 trial.¹⁵

By definition the goal of breast conserving surgery is to conserve breast tissue. Therefore the best margin in breast conserving surgery is one where the tumour has been removed and the residual tissue left behind can be best controlled with radiation therapy.37, 38 Clear guidelines and recommendations outline which patients are eligible for breast conserving therapy.39, 40 What has not been determined is the optimal tumour free surgical margin which should be obtained. Much debate has surrounded what should be considered a negative margin though, the implications of which have a direct impact on which patients should have further surgical treatment, i.e. those that will require a re-excision of margins. There appears to be no consensus margin that a majority of surgeons and radiation oncologist could come to when asked what the most appropriate surgical margin width should be. Larger margins should imply less likelihood of leaving cancerous tissue behind and thus decrease the likelihood of requiring further surgical re-excision.41, 42 Smaller margins should maintain a less invasive approach that is mindful of the aesthetics of a woman's breast that will remain after surgery and the reconstructive options that are available for women. The consequence of smaller margins though is the fear of leaving behind residual disease.

The NSABP B-06 trial began recruiting women from 1976 to 1984 with invasive breast cancers 4 cm or less, with positive or negative lymph nodes into three treatment cohorts: total mastectomy, wide local excision/lumpectomy, or wide local excision/lumpectomy with irradiation.⁴³ In 1975 the five year relative survival for breast cancer in the U.S. was 75.2%, as of 2006 the five year survival stands at 90.6%.⁴⁴ Recent ASTRO and ASCO guidelines now advise that the most minimal approach of “no tumour cells on the ink” is appropriate for invasive disease.45, 46 The vast improvement in survival rates cannot be due to greater surgical intervention, as the trend towards breast conserving surgery grows.