332Views & Citations
Life expectancy is growing and breast cancer prevalence increases with age. In many cases, the diagnosis is late and they are undertreated based on chronological age. Radiation therapy (RT) is one of the main treatments as adjuvant treatment whenever possible and as definitive if not. Extreme hypo fractionation could be a good treatment schedule compared to daily conventional fractionation, in older women with comorbidities, social problems and who live far from the treatment center. The purpose of this article is to review extreme hypo fractionated schedules in elderly patients published in literature, in terms of loco regional recurrence and side effects. Loco regional recurrences were less of 16% in all series. The number of acute side grade 3 and grade 4 effects was less than 15%. The range of fibrosis as the most significant late side effect was between 15.1% and 39.2%. Extreme hypo fractionated RT seems to be a safe treatment without significant side effects.
Keywords: Aged, Breast neoplasms, Extreme hypo fractionation, Hypo fractionation, Radiotherapy
Life expectancy is growing and breast cancer prevalence increases with age, being the most commonly diagnosed form of cancer and the leading cause of cancer death in women . Although the diagnosis is increasing in older women, in many cases is late and they are undertreated based on chronological age . RT is one of the main treatments and it is absolutely necessary as adjuvant treatment after lumpectomy or after mastectomy when there is node disease, to improve local control, regional control and overall survival [3,4].
The conventional treatment schedule of RT is 50 Grays (Gy), delivered in 25 fractions, 5 days a week during 5 weeks, with or without a subsequent boost. Currently, a moderate hypo fractionated treatment delivered in 15-16 fractions, has been associated with equivalent long-term results than conventional schedule , although for the American Society for Radiation Oncology, there is not enough evidence when regional radiation is indicated . Breast cancer would benefit from higher doses per fraction, because its α/β ratio ranges from 3 to 5 Gy, as suggested START A and B studies [5,7]. Shortened treatments can improve the quality of life of elderly patients, who have more problems to receive the best treatment. The purpose of this minireview is to review the results of once-weekly hypo fractionated schedules in elderly patients published in literature, in terms of loco regional recurrence (LRR) and acute and late toxicity.
Currently, there are available data showing that a moderate hypo fractionated RT, delivered in 15-16 fractions during 3 weeks for early stage breast cancer is equivalent than conventional treatment (5 weeks) [5,7,8]. There is a tendency to undertreat elderly women due to different reasons like comorbidities, lack of social support, difficulties to attend the treatment or distance to the treatment center. Extreme hypo fractionation allows shortening treatments and lower spending . The α/β ratio of breast cancer ranges from 3 to 5 Gy, suggested by UK START trials, which implies that breast cancer would benefit from high doses per fraction.
Among published studies, the most important is the UK FAST trial, being the only phase III in the literature. This study compares conventional doses with two equivalent hypo fractionated schedules of 5.7 Gy and 6 Gy, delivered in 5 weekly fractions, in early breast cancer after lumpectomy. It was not the primary endpoint, but at 3 years, local control was 99.67%, only two patients developed local recurrence. Hypo fractionation was well tolerated with the vast majority of acute dermatitis grade 1 or less. Cosmetic changes were very similar between arms and a little bit greater in the group that received 6 Gy per fraction than in the group of 5.7 Gy (17.3% Vs 11.1% respectively) . There are six retrospective studies in the literature. Studies published by Rostom et al.  and Sanz et al.  included patients with all stages, with or without axillary lymph nodes. Patients were treated with lumpectomy, mastectomy and no surgery. The treatment schedules were 39 Gy in 6 weekly fractions of 6.5 Gy including axillary nodes, and some patients received an electron boost to residual tumour with a 3 fraction schedule of 3.2 Gy applied on alternate days in the Rostom et al. and in the Sanz et al. [10,11] firstly 6.25 Gy given in 6 weekly fractions and later 5 Gy schedule given in 6 weekly fractions, with or without a boost of one or two fractions. Nodes were irradiated in 15% patients. LRR was not correctly reported by Rostom et al.  while Sanz et al.  got at 5 years a local control of 96.5%. Most acute dermatitis was G1-2 in both studies. Late fibrosis and telangiectasia appeared in a few patients and in most of patient’s cosmetic was good or excellent. Hyperpigmentation, edema or mastitis were described [11,12].
Two retrospective studies included patients who were not underwent surgery, with all stages. The selected schedule for both studies was a total dose of 32.5 Gy in 5 weekly fractions of 6.5 Gy to the involved breast, followed by one to three weekly fractions as a boost. In both studies, the most selected dose for the treatment of axillary nodes when needed was 27.5 Gy in 5 weekly fractions of 5.5 Gy. Most of patients received hormone therapy. Maher et al. presented 16% developed LRR at 3 years and Courdi et al. 15% LRR at 5 years.
Most acute dermatitis was developed as G1-2. Fibrosis was developed in 39% in the group of Maher and 37.1% in Courdi et al [13,14].
Another two retrospective studies included patients who underwent lumpectomy. Kirova et al.  analyzed a group of 50 patients, with stages T1-2 N0-1. Rovea et al.  analyzed 291 patients with all stages, although the vast majority was T1 mic, T1 and T2, N0-2. The selected dose in both studies was 32.5 Gy in 5 weekly fractions of 6.5 Gy. After FAST trial, Rovea et al.  began to use a schedule of 30 Gy in 5 fractions of 6 Gy. Nodes were not irradiated in any. The results at 5 years were a cancer specific survival of 95% in both. Acute dermatitis was developed as grade 2 or less in most. Fibrosis, telangiectasia, hyperpigmentation and edema were described as late effects [15,16].
The prospective randomized trial published by Baillet et al.  and the prospective single-arm study published by Ortholan et al. included patients treated by lumpectomy, mastectomy or nothing. Both have included patients of all stages. Treatment schedule chosen by Baillet et al.  was to deliver 23 Gy in 4 fractions of 5 Gy for the first two sessions and another two fractions of 6.5 Gy, administered in 17 days. Forty-five patient treated with lumpectomy, received an additionally brachytherapy boost of 20 Gy. The treatment schedule chosen by Ortholan was a total of 32.5 Gy delivered in 5 weekly fractions of 6.5 Gy each one, followed by a boost of 1 or 2 more fractions in some patients or administered with brachytherapy in 4 patients. Node irradiation was not reported by Baillet et al.  and was administered in a 32% by Ortholan et al. At 5 years, LRR was 7% in the Baillet study and 2.3% in the Ortholan study. Acude side effects were less than G2. Fibrosis was the most common late effect. Telangiectasia, brachial lymphoedema and chronic pain were described [17,18].
There are two prospective single arm published studies that included patients after conserving surgery. The schedule selected by both studies was 30 Gy in 5 fractions of 6 Gy. In the Martin et al.  study it was delivered twice a week over 15 days. Nodes were negative. On the other hand, Dragun et al. administered it once a week followed by a boost of 1 more fraction of 5.7 or 6 Gy, 8.1 Gy given in 3 fractions or 10 Gy given in 5 fractions. Nodes could be positive or negative, but irradiation was not performed. At 3 years, LRR was 0% and 1.3% in Martin and Dragun studies respectively [19,20]. Acute dermatitis was mild in most of patients with an acute skin reaction greater than G2 in 22.8% reported by Dragun et al. Cellulitis was reported as late effect [19,20].
Globally a total of 87.1 % of lesions were treated with adjuvant RT and 12.9 % as definitive RT, both of them with or without a boost. Only 8.9 % of patients received a boost, 73.3% of patients did not receive a boost and in other 17.7% it was not specified. Summary of results are given in Table 1.
The most reported acute side effect was dermatitis, most of them moderate or mild. Acute dermatitis grade 3 decreases with hypo fractionation because a response to lower total dose which reduces late side effects [21-25]. The most collected late side effect was fibrosis followed by hyperpigmentation, telangiectasia, edema or local pain. Several factors such as the age, smoking, post-surgical cosmesis, chemotherapy, breast volume, total radiation therapy dose, technique, fractionation and boost radiation, can influence late effects and these side effects can have a significant physical and psychological impact on patients [26,27].
The studies reviewed collect data similar to historically standard schemes [5,7,8,28]. Results have shown a good loco regional control rates with a small number of LRR and an acceptable chronic toxicity despite being increased. It is necessary to emphasize that the vast majority of patients were older, most of them with an early stage and therefore a better prognosis and most of them received hormone therapy influencing loco regional control. The worst results in terms of loco regional control are observed in the groups that have not undergone surgery, and followed by patient groups that have not received a boost.
Extreme hypo fractionation in breast cancer in older women is a well-tolerated and safe treatment, without significant side effects. Surgery is preferable if possible and it is advisable to administer a boost. The delivered of weekly high doses per fraction, could be a good option especially for elderly patients with favorable early stage cancer, in advanced stages who are unfit to receive large daily treatments, or even in patients unfit for surgery despite increasing the risk of recurrence.
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, et al. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality for 36 cancers in 185 countries. CA Cancer J Clin 68: 394-424.
2. Bastiannet E. Liefers GJ, de Craen AJ, Kuppen PJ, van de Water W, et al. (2010) Breast cancer in elderly compared to younger patients in the Netherland: stage at diagnosis, treatment and survival in 127,805 unselected patients. Breast Cancer Res Treat 124: 801-807.
3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, Correa C, Taylor C, et al. (2011) 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. Lancet 378: 1707-1716.
4. Early Breast Cancer Trialists’ Collaborative Group, McGale P, Taylor C, Correa C, Cutter D, et al. (2014) Effect of radiotherapy after mastectomy and axillary g surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383: 2127-2135.
5. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, et al. (2008) The UK Standardisation of Breast Radiotherapy (START) Trial A of a radiotherapy hypo fractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 9: 331-341.
6. Smith BD, Bentzen SM, Correa CR, Hahn CA, Hardenbergh PH, et al. (2011) Fractionation for whole breast irradiation: an American Society for Radiation oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys 81: 59-68.
7. Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, et al. (2013) The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypo fractionation for treatment of early breast cancer: 10-year follow-up results of two randomized controlled trials. Lancet Oncol 14: 1086-1094.
8. Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, et al. (2010) Long-term results of hypo fractionated radiation therapy for breast cancer. N Engl J Med 362: 513-520.
9. Bekelman JE, Sylwestrzak G, Barron J, Liu J, Epstein AJ, et al. (2014) Uptake and costs of hypo fractionated vs. conventional whole breast irradiation after breast conserving surgery in the United States, 2008-2013. JAMA 312: 2542-2550.
10. FAST Trialists group, Agrawal RK, Alhasso A, Barrett-Lee PJ, Bliss JM, et al. (2011) First results of the randomized UK FAST Trial of radiotherapy hypofarctionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol 100: 93-100.
11. Rostom AY, Pradhan DG, White WF (1987) Once weekly irradiation in breast cancer. Int J Radiat Oncol Biol Phys 13: 551-555.
12. Sanz J, Zhao M, Rodríguez N, Granado R, Foro P, et al. (2018) Once-weekly hypofractionated radiotherapy for breast cancer in elderly patients: Efficacy and tolerance in 486 patients. Biomed Res Int 2018: 8321871.
13. Maher M, Campana F, Mosseri V, Dreyfus H, Vilcoq JR, et al. (1995) Breast cancer in elderly women: A retrospective analysis of combined treatment with tamoxifen and once-weekly irradiation. Int J Radiat Oncol Biol Phys 31: 783-789.
14. Courdi A, ortholan C, Hannoun-Lévi JM, Ferrero JM, Largillier R, et al. (2006) Long term results of hypo fractionated radiotherapy and hormonal without surgery for breast cancer in elderly patients. Radiother Oncol 79: 156-161.
15. Rovea P, Fozza A, Franco P, De Colle C, Cannizzaro A, et al. (2015) Once-weekly hypofractionated whole-breast radiotherapy after breast-conserving surgery in older patients: A potential alternative treatment schedule to daily 3-week hypo fractionation. Clin Breast Cancer 15: 270-276.
16. Kirova YM, Campana F, Savignoni A, Laki F, Muresan M, et al. (2009) Breast-conserving treatment in the elderly: long-term results of adjuvant hypo fractionated and normofractionated radiotherapy. Int J Radiat oncol Biol Phys 75: 76-81.
17. Baillet F, Housset M, Maylin C, Boisserie G, Bettahar R, et al. (1990) The use of a specific hypo fractionated radiation therapy regimen versus classical fractionation in the treatment of breast cancer: A randomized study of 230 patients. Int J Radiat Oncol Biol Phys 19: 1131-1133.
18. Ortholan C, Hannoun-Lévi JM, Ferrero JM, Largillier R, Courdi A (2005) Long-term results of adjuvant hypo fractionated radiotherapy for breast cancer in elderly patients. Int J Radiat Oncol Biol Phys 61: 154-162.
19. Martin S, Mannino M, Rostom A, Tait D, Donovan E, et al. (2008) Acude toxicity and 2-year adverse effects of 30 Gy in five fractions over 15 days to whole breast after local excision of early breast cancer. Clin Oncol (R Coll Radiol) 20: 502-505.
20. Dragun AE, Ajkav NJ, Riley EC, Roberts TL, Pan J, et al. (2017) First results of a phase 2 trial of once-weekly hypofractionated breast irradiation (WHBI) for early-stage breast cancer. Int J Radiat oncol Phys 98: 595-602.
21. Jones B, Dale RG, Deehan C, Hopkins KI, Morgan DA (2001) The role of biologically effective dose (BED) in clinical oncology. Clin Oncol (R Coll Radiol) 13: 71-81.
22. Yarnold J, Bentzen SM, Coles C, Haviland J (2011) Hypofractionated whole-breast radiotherapy for women with early breast cancer: Myths and realities. Int J Radiat oncol Biol Phys 79: 1-9.
23. Tutt A, Yarnold J (2006) Radiobiology of breast cancer. Clin Oncol (R Coll Radiol) 18: 166-178.
24. Qi XS, White J, Li XA (2011) Is α/β for breast cancer really low? Radiother Oncol 100: 282-288.
25. Dorr W, Hendry JH (2001) Consequential late effects in normal tissues. Radiother Oncol 61: 223-231.
26. Al-Ghazal SK, Fallowfield L, Blamey RW (1999) Does cosmetic outcome from treatment of primary breast cancer influence psychosocial morbidity? Eur J Surg Oncol 25: 571-573.
27. Mukesh M, Harris E, Jena R, Evans P, Coles C (2012) Relationship between irradiated breast volume and late normal tissue complications: A systematic review. Radiother Oncol 104: 1-10.
28. Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, et al. (2006) Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: Long-term results of a randomized trial. Lancet Oncol 7: 467-471.
- International Journal of AIDS (ISSN: 2644-3023)
- Journal of Immunology Research and Therapy (ISSN:2472-727X)
- Journal of Renal Transplantation Science (ISSN:2640-0847)
- Journal of Cardiology and Diagnostics Research (ISSN:2639-4634)
- Dermatology Clinics and Research (ISSN:2380-5609)
- Journal of Clinical Trials and Research (ISSN:2637-7373)
- Journal of Cell Signaling & Damage-Associated Molecular Patterns