Adjuvant Radiation Therapy After Breast Conserving Surgery

OUTCOMES:
- Survival: Between 1961 and 1989, multiple international randomized clinical trials were performed to directly compare breast-conserving therapy (BCT) with mastectomy
- These trials consistently demonstrated similar overall and breast disease-specific survival (DSS) between the two approaches
- Since then, BCT has been considered at least equivalent to mastectomy in survival outcomes
Since 2013, a growing number of studies, both in the United States and internationally:
- Have associated BCT with better survival than mastectomy, regardless of age, stage, tumor characteristics, and cancer phenotypes
- As examples:
  - One cohort study of over 110,000 Californian women with stage I or II breast cancer:
    - Associated BCT with better overall survival (OS) than mastectomy without radiation (adjusted hazard ratio [HR] 0.81, 95% CI 0.80-0.83)
    - The DSS benefit was more pronounced among women age ≥ 50 with hormone receptor-positive disease (HR 0.86, 95% CI 0.82-0.91):
      - But was seen in all subgroups analyzed regardless of age, hormone receptor status, and cancer phenotypes
  - In a population-based study from the Netherlands that included over 170,000 patients, BCT conferred a survival advantage over mastectomy (HR 0.87, 95% CI 0.81-0.93) following correction for stage, age, and adjuvant therapies
- However, all of these were observational studies, which could be confounded by selection bias
- Thus, BCT is still considered “at least” equivalent:
  - Rather than superior to, mastectomy in survival outcomes
- Both approaches are acceptable options that should be selected based upon multidisciplinary clinician input and patient preference
The biologic plausibility of a more limited procedure (BCS) being superior to a more radical surgery (mastectomy):
- Can potentially be explained by the impact of adjuvant radiotherapy (RT) and the fact that mastectomy may not remove all breast tissue (thus leaving behind microscopic cancer foci)
- Indeed, we know that the success of BCT is contingent upon moderate-dose RT in eliminating subclinical foci of disease in the ipsilateral breast
- Adjuvant RT has been shown to substantially reduce the risk of in-breast recurrences
- Additionally, the isolated axillary recurrence rate after BCT:
  - Has been shown to be lower than that after mastectomy without radiation:
    - 1.1% versus 3.5% in a prospective nonrandomized study with 13 year follow-up
  - In that study, both overall survival (79.5% versus 64.3%) and disease-free survival (90.5% versus 84%) were better after BCT than after mastectomy:
    - Although the ipsilateral breast or chest wall recurrence-free survival rates were not statistically different (90.5% BCT versus 95% mastectomy; p = 0.428)
  - Thus, the survival benefit of BCT should at least be partially attributed to the protective effect of radiation
  - The tangential radiation fields originating from whole breast irradiation may help reduce recurrence by controlling minimal residual disease in the lower axilla
Local recurrence:
- Local control is important to overall survival:
  - Because local failure is a risk factor for distant metastasis
- Rough estimates indicate that:
  - One patient may die from breast cancer for every four local recurrences
- A higher locoregional recurrence rate for BCT:
  - Was reported in some of the early trials comparing BCT with mastectomy
- In randomized studies using variable surgical and radiation techniques:
  - Long-term recurrence rates in the treated breast following BCT range from:
    - 5% to 22%, compared with 4% to 14% with mastectomy
    - In those days, the risk of local recurrence after BCT was estimated to be around 1% per year, or 10% at 10 years:
      - However, the higher local recurrence rate did not appear to negatively impact survival
    - Since then, better imaging, more attention to margins, and more effective and longer durations of systemic therapy have reduced local recurrence rate after BCT to just:
      - 2% at 10 years:
        Thus, the local recurrence rate after contemporary treatment with BCT is no longer considered higher than that after mastectomy
- The local recurrence rate following BCT increases with:
  - Young age
  - Positive surgical margins
  - Node positivity
  - Estrogen receptor negativity
  - Absence of radiation therapy
- It is important to realize that these factors are not contraindications to BCT:
  - But their presence may influence the choice of treatment
Cosmetic outcome:
- In addition to local recurrence, another major goal of BCT is the preservation of a cosmetically acceptable breast
- With modern treatment techniques, an acceptable cosmetic outcome can be achieved in almost all patients without compromising local tumor control
- Many surgical factors will play a role in the ultimate cosmetic appearance of the breast:
  - These include the size and placement of the incision, management of the lumpectomy cavity, and the extent of axillary dissection if necessary
  - The surgeon has control over several of these issues, and careful attention to detail will improve the aesthetic results
  - The amount of resected breast tissue is the major determinant of appearance following BCS
  - Oncoplastic surgical techniques allow resection of a breast cancer with wide surgical margins while preserving the shape and appearance of the breast:
    - Patients with either:
      - A large tumor relative to their breast size or a central tumor are candidates for oncoplastic resections
    - Long-term outcomes of oncoplastic surgery are comparable or superior to those of standard breast conservation surgery
- Adjuvant radiotherapy can also influence cosmetic outcomes by:
  - Causing skin fibrosis:
    - The primary approach to prevention of radiation-induced fibrosis is through the use of appropriate radiation therapy doses and techniques that minimize the radiation exposure for normal tissue
    - For patients with established radiation-induced fibrosis, treatment is primarily symptomatic and includes:
      - A combination of pentoxifylline and tocopherol (vitamin E)
- Although treatment-related changes in the breast stabilize at approximately three years:
  - Other factors that affect the untreated breast, such as change in size because of weight gain or the normal ptosis seen with aging:
    - Continue to affect breast symmetry
- Such less-than-ideal cosmetic results can be remedied by reconstruction of the ipsilateral or contralateral breast