Hypofractionation should be the standard of care for breast cancer radiotherapy

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Hypofractionation should be the standard of care for breast cancer radiotherapy

*Corresponding author: Dr Sanjiv Sharma, Department of Radiation Oncology, Manipal Hospital, Bangalore 560011 India; Email: sanjiv01sharma@yahoo.co.in

Clinical adoption of hypofractionation for breast cancer radiotherapy has been sub-optimal, despite sound rationale and robust level I evidence.  Radiobiological modelling, primarily spearheaded by the development of Linear Quadratic model, has shown that the biological effect of radiation is a function of total dose and fraction size, and that the inherent radiation sensitivity or α ⁄ β ratio of the tissue in question will modify the effect of fraction size. This model suggests that if the α ⁄ β ratio of the tumor is same or less than that of relevant normal tissue, then a larger dose per fraction with a modest decrease in total dose may be equally or potentially more effective than the conventionally fractionated radiotherapy.

Clinical advantages of hypofractionation are convenience, improved access to care, less cost to patient as well as the health care system and reduced resource utilization along with less skin toxicity due to lower total doses. Robust evidence has been generated for hypofractionation by four large wells conducted clinical trials[1-6], summarized here in Tables 1 & 2.

Table 1: Treatment results of four randomized trials

Table 2: Patient characteristics of four randomized trials

Hypofractionation conclusively was shown to be equivalent to conventional fractionation regarding various parameters of efficacy, cosmesis and toxicity. All treatment effects were independent of any of the patient, tumor or treatment related factors, like age, breast size, type of surgery, axillary nodal status, tumour grade, adjuvant chemotherapy use, tumour bed boost, and lymphatic radiotherapy. The trials conclusively showed that the fears of serious toxicity viz. ischaemic heart disease, rib fracture, brachial plexopathy, symptomatic lung fibrosis and damage to the normal breast tissues causing poor cosmesis, to be misplaced, and these should no longer be barriers to the wide spread adoption of this important clinical advance of the last decade. Additional reassurance is provided by the radiobiological modelling which suggests that hypofractionation tends to be less damaging to normal tissues like heart, lungs, normal breast tissue and brachial plexus, even under extreme assumptions about their fractionation sensitivity [7].

There is concern about applicability of these results to the patient’s groups that were either excluded or were poorly represented in these trials, viz. age < 50 years, ductal carcinoma in situ, locally advanced tumors, post neoadjuvant chemotherapy or targeted agents like Transtutumab, after mastectomy, immediate breast reconstruction, and regional lymph node radiotherapy. From a radiobiological point of view, it is unlikely that HFRT in these patients would result in substantially different outcomes, as borne out contemporary prospective data and recent ASTRO guidelines [8].

The most favourable observations were reported for the START B regimen. 40 Gy administered in 15 fractions of 2.67 Gy within 3 weeks resulted in significantly less acute and late toxicity and was associated with a significantly reduced distant metastasis rate and improved overall survival. This schedule has been widely adopted all over the world and represents the current standard of care. Boost can be added as clinically indicated.

The evidence generated by the trials detailed above has subsequently been incorporated by American Society for Radiation Oncology (ASTRO), National Institute for Health and Care Excellence (NICE), as well as many other societies in their national treatment guidelines [8-11].

UK investigators have gone one step further, with focus on 5-fraction schedules (FAST trial testing 5 fractions over 5 weeks and FAST FORWARD trial testing 5 fractions over one week), to test the limits of hypofractionation. These studies should help to determine the potential useful limits of hypofractionation for whole-breast irradiation. Future research will also need to focus on determining if all molecular subtypes of breast cancer are equally well controlled with hypofractionation.

Financial Disclosure

          The authors have no financial relationships relevant to this article to disclose.

Potential Conflicts of Interest

The authors have no conflicts of interest relevant to this article to disclose.

REFERENCES

  1. Whelan TJ, Pignol JP, Levine MN, et al.: Long-term results of hypo fractionated radiation therapy for breast cancer. N Engl J Med 2010; 362: 513–520.
  2. Yarnold J, Ashton A, Bliss J, et al.: Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol 2005; 75: 9–17.
  3. Owen JR, Ashton A, Bliss JM, et al.: Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 2006; 7: 467–471.
  4. Haviland JS, Owen JR, Dewar JA, et al.: The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 2013; 14: 1086–1094.
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  7. Appelt AL, Vogelius IR, Bentzen SM. Modern hypofractionation schedules for tangential whole breast irradiation decrease the fraction size-corrected dose to the heart. Clin Oncol (R Coll Radiol) 2013; 25: 147–52.
  8. Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast : Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Pract Radiat Oncol 2018; 81: 59–68.
  9. National Institute for Health and Clinical Excellence. NICE clinical guideline 80: early and locally advanced breast cancer: diagnosis and treatment. 2009.
  10. Sedlmayer F, Sautter-Bihl ML, Budach W, et al.: DEGRO practical guidelines: radiotherapy of breast cancer I: radiotherapy following breast conserving therapy for invasive breast cancer. Strahlenther Onkol 2013; 189: 825–833.
  11. Senkus E, Kyriakides S, Penault-Llorca F, et al.: Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(suppl 6):7–23.

 

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