Low-Dose Bath with Volumetric Modulated arc Therapy in Breast Cancer: “Much ado about Nothing?”

At the XXV AIRO National Congress held in Rimini, Italy, on November 7-10, 2015, the radiobiological and radioprotection aspects of low doses during radiotherapy (RT) with emerging technologies were discussed in several settings including the irradiation of breast cancer (BC).

For several decades, in BC irradiation, 3-dimensional conformal RT (3D-CRT) has been the accepted standard of care. To date, the usefulness of intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT) remains to be defined (1–2–3–4–5). Whereas IMRT overcomes unfavorable situations in selected patients (pectus excavatum, bilateral breast cancer) (6), its routine use has not been established.

Recently, there has been increasing interest in minimizing cardiac exposure in patients with left-sided BC, as such exposure may be related to long-term events (7). Darby and colleagues pointed out that RT to the heart increases the risk of ischemic disease by 7.4% per Gray, in the absence of a specific threshold (7). Their study reported on BC patients treated from 1958 with old RT; additionally, the radiation exposure dose to the heart was roughly estimated, without any consideration of patient anatomy. Nevertheless, a cardiotoxic risk of 4% per each Gray added to the mean heart dose was highlighted in a study by Mège et al (8).

Evans et al (9) considered of special interest the dose and changes to the main coronary arteries such as the left anterior descending (LAD) artery, which can be included in tangential beams. The authors concluded that particular attention should be paid to treatment planning in order to avoid cardiac structures and exclude the LAD artery wherever possible (9). Moreover, there was a higher prevalence of test abnormalities in those patients receiving left-sided radiation (59%) compared with those receiving radiation to the right side (8%) (10).

IMRT and VMAT are potentially able to better reduce high doses to the heart (11), lung and contralateral breast than 3D-CRT (12). Other approaches for decreasing heart exposure are active breath control, prone position, and partial breast irradiation. These techniques have demonstrated dosimetric advantages (13), but their benefit has not been carefully assessed in clinical practice.

IMRT and VMAT have been criticized for their hypothetical carcinogenetic role in the low-dose radiation exposure of surrounding healthy tissues (14), especially in the young. Several other potentially implicated factors include patient age, gene expression profile, individual habits, dose, volume, and organ at risk receiving RT. Young age appears the most relevant factor. This hypothesis derived from the atomic bomb survivors’ Life Span Study and the Childhood Cancer Survivors Study, reporting a probability of second cancer development of 7.9% at 30 years from the primary cancer, which diminishes by about 17% per decade (15–16–17–18–19–20).

The German Commission on Radiological Protection introduced the concept of stochastic risk volume (SRV), defined as the volume of normal tissue at risk of radiation-induced cancer after RT. Moreover, the mortality risk attributable to radiation-induced secondary tumors was estimated at 1%-2% after 10 years (21, 22).

Although the American Society for Radiation Oncology (ASTRO) recommends to not routinely use IMRT to deliver whole-breast RT, no clear evidence is yet available, especially in the adjuvant setting of BC treatment (6).

It is important to note that other confounding factors may affect the second cancer risk: BC patients are commonly eligible for long-term hormonal therapy and chemotherapy; such treatment is well recognized to increase the development of iatrogenic cancer. Nevertheless, the omission of these drugs has never been discussed.

Thus, in the modern era characterized by more conformed RT (IMRT, VMAT, helical tomotherapy, etc.), use of a plethora of molecular and genetic profiles is strongly advocated to predict the individual risk of carcinogenesis by robust predictive models. Until these data are available, the risk of second cancer after RT is to be balanced against the individual clinical benefit of the modern technique in reducing toxicity. Hence, the issue of low-dose bath with intensity-modulated techniques in BC still remains “much ado about nothing.”