Radiotherapy in breast cancer is a success story that continues to be told. The intent has always been to achieve more while doing less. With surgery setting the scene for more conservative techniques, the quest has been on to see how much is too much when it comes to radiotherapy treatment.

It is well established that breast conservation followed by radiation to the remaining breast tissue is the standard of care based on the meta-analysis by the Early Breast Cancer Trialist’s Collaborative Group which conclusively established the benefit of radiation therapy post breast conservation surgery in terms of halving the local recurrence rate and reducing the deaths due to breast cancer by about a sixth. [1]

The so-called conventional fractionation is being challenged and revolutionised into something simpler and with shorter duration, given that it requires patients to undergo treatment for up to seven weeks causing many deserving women to choose mastectomy over breast conservation due to the inconvenience of commuting long distances for a long period of time for radiation.

The surgical methods in carcinoma breast have evolved from removing everything up to the chest wall to sparing the nipple and skin, defying surgical scars yet making sure the remaining breast tissue is just free of the ‘lump’. It is interesting to see what impact this has on radiotherapy.

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Does doing less of surgery mean that you have to do more of radiation?

With better understanding of the nature of the disease and how radiotherapy behaves in the remaining breast tissue, radiation oncologists around the world have been willing to experiment with the volume of breast treated and its fractionation.

The rationale behind treating the whole breast with radiation post breast conservation surgery has been that the surgery removes most of the macroscopic disease with some margin, while leaving behind most of the microscopic disease, up to 40% sometimes up to 4 cm from the resection cavity.

Early recurrence patterns post breast conserving surgery (BCS) and radiation therapy (RT) suggested that 60-70% of recurrences were at the primary site. [2] This strengthened the case in favour of RT boost to tumour bed and also emphasised the importance of clinical examination and imaging of the local area. Recurrences elsewhere in the breast were seen in 31% of patients and tended to occur much later. The role of boost is more significant in younger patients with extensive intraductal component, estrogen receptor (ER) negative status and margin positivity.

The expected side effects with RT are fibrosis, telangiectasia, compromised cosmetic outcomes, cardiac and lung effects and lymphedema. The prolonged period over which conventional fractionation is given also makes many women take a step back in favour of mastectomy or forgo the treatment altogether post BCS putting them at a high risk of local recurrence.

To overcome these difficult choices, radiation oncologists investigated the possibility of reducing the RT time by restructuring the schedule and fractionation. Another game changer in the modern era has been the advent of conformal techniques using precise imaging and delivery, further cementing the doses delivered and enabling reduction of normal tissue side effects.

Hypofractionated radiation therapy for early breast cancer

Encouraged by this, there were many more trials which tested hypofractionation in breast cancer. These did not show any difference with acute toxicity, local recurrence and survival. [3]

While in practice it is advised to follow conventional fractionation if the women are large breasted, to avoid oedema and fibrosis. With modern radiotherapy techniques such as Volumetric modulated arc therapy (VMAT) and Intensity-modulated radiotherapy (IMRT), it may be possible to reduce these effects even more and enable RT delivery with greater homogeneity. The optimal fractionation is somewhat undecided. It is suggested that a prescription of 40Gy/15fr if a boost is planned and 42.6Gy/16fr if a boost is not planned would be a reasonable dose.

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The IMPORT low trial

This trial has showed that PBI with reduced dose radiotherapy is non-inferior to WBI in a select group of patients namely age >50 years, margins negative by 2 mm, Tis or T1 stage, < 30mm, DCIS with margin negative by >2.5 mm, ER positive, Her-2 neu negative. PBI can be used either with EBRT or interstitial brachytherapy as per GEC-ESTRO guidelines to deliver RT at 40Gy/15fr.

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ELIOT and TARGIT trials

Intraoperative radiation therapy is a type of APBI where the radiation is given at the time of surgery using probes after the removal of the primary. The ELIOT and TARGIT trials have investigated the use of intraoperative electrons to treat the tumour bed as opposed to conventional radiation therapy. In Professor Tobias’s own words ‘TARGIT provides an immediacy and precision unachievable with other methods’. For the patients, it takes an extra thirty minutes in the OT and sometimes another extra admission day to complete two treatments in one go. However, concerns have been raised since an updated report of TARGIT revealed a significantly higher 5 year recurrence rate in the APBI arm. The design of the trial has also met with criticism across literature for the statistical design and short follow up data initially.

These questions have been partially answered by NSAPB B-39/RTOG 0413 trial which has shown that APBI is not equivalent to AWBI in terms of ipsilateral breast tumour recurrence, although close. The eligible population for this treatment in early breast cancer include patients 50 years or older, tumour size <30 mm, luminal A subtype, grade 1-2 tumour, margin >2 mm.

The COCHRANE meta-analysis has concluded that for the selected cases, although the overall survival is similar in APBI and AWBI, ipsilateral breast tumour recurrence and regional lymph nodal recurrence were worse with APBI as were the late effects and cosmesis.

With these advancements, the importance of marking the resection cavity with metallic clips couldn’t be emphasised enough in early breast cancer.

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Regional Nodal Irradiation (RNI) in early breast cancer

The regional lymphnodes considered for irradiation in breast cancer are the three levels of axillary nodes, supraclavicular nodes and internal mammary nodes. It is seen that in most cases of whole breast irradiation, level 1 and 2 are inadvertently treated. Level three is recommended to be treated if there is incomplete dissection, more than 50% of nodes dissected are positive and if there is extracapsular spread.

Sentinel lymph node biopsy has replaced conventional axillary lymph node dissection as the standard of care. In patients who have 1-2 lymph nodes positive for malignancy, the bone of contention was between further completion axillary dissection or radiotherapy to the remaining lymph nodes. The AMAROS trial addressed this and concluded that the two treatments are equivalent with respect to locoregional recurrence and radiotherapy was superior with regards to the lymphedema.

The MA.20, EORTC 22922/10925, DBCG-IMN and the French trials have addressed the role of supraclavicular node and internal mammary node irradiation in early breast cancer. These trials collectively revealed that RNI contributed to overall survival suggesting the importance of targeting microscopic disease.

MA.20 trial

RNI was added to WBI post BCS. A majority of the patients were either node negative or had 1-3 positive lymph nodes. WBI+RNI was superior to WBI alone with regards to locoregional recurrence (96.8% vs 94.5%), distant disease free survival (92.4% vs 87%) and overall survival (92.3% vs 90.7%) with a slight increase in pneumonitis and lymphedema.

EORTC 22922/10925

Stage I-III breast cancer patients with involved axillary nodes and medial quadrant tumour were given WBI+RNI or WBI alone. Fifteen year follow up shows that there is a significant reduction in breast cancer mortality and recurrence with RNI, however doesn’t translate into improved overall survival. LRR occurred in 1.8% vs 3.1%, breast cancer mortality was 15.8% vs 19.7% (p= 0.005).

DBCG-IMN study

The basic premise of this study was that the benefit, if at all, from irradiating IMN is offset by radiation induced heart disease due to inclusion of significant cardia in the IMN field. The study looked at irradiating IMN only in right sided breast tumours vs no IMN irradiation in left sided tumours of early stage node positive breast cancer. IMNI was associated with increase in overall survival of 3.7% at the end of 8 years of treatment. Breast cancer mortality decreased by 2.5% at two years. Medial and central tumour location with 1-3 involved nodes and 4 or more axillary lymph nodal burden were most benefitted from IMNI.

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There is lack of data of long term side effects with hypofractionation. With molecular subtyping of breast cancer having a major role in decision making, there is a need to tailor radiation treatment with regards to the CTV margins, adequacy of surgery and doses of RT. Patient anatomy such as very large breasts and very small breasts pose a challenge to hypofractionation. With partial breast irradiation lacking long term data as well, it should be administered to a highly selective group of patients and based on GEC ESTRO/ IMPORT LOW guidelines.

Breast cancer is being detected early and in younger people, thanks to genetic testing and screening mammograms. This has led to a large number of young cancer survivors. The upcoming trends focus on these survivors to improve on QOL, preserve fertility and possible enjoy a normal sexual life. It is a joint, multidisciplinary responsibility to make this possible by giving the patient what they deserve- a normal life.

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This article is part of a early breast cancer management series. To read the other articles, click below.

Early breast cancer (EBC)- Personalise approach using predictive and prognostic factors: Dr. Vishwanath S

Surgical options to consider for early breast cancer: Dr. Anil Kamath

Imaging modalities for Stage 0 and Stage 1 breast cancer: Dr. Govindarajan MJ

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Click to see references

[1] Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.

[2] Early breast cancer: predictors of breast cancer recurrence for patients treated with conservative surgery and radiation therapy

[3] Hypofractionated whole breast radiotherapy in breast conservation for early-stage breast cancer: a systematic review and metaanalysis of randomised trials.

The author, Dr. Bindu Venugopal is a Radiation Oncologist from Bengaluru.