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Modern breast cancer radiotherapy: comparisons

Here are some scientific papers comparing modern radiotherapy techniques:
Targeted radiotherapy for early breast cancer

Jayant S Vaidya, Max Bulsara, Frederik Wenz, Jeffrey S Tobias, David Joseph, Michael Baum

The Lancet: Vol 291, No 10115, p 26-27, 6 Jan 2018

"IMPORT LOW requires 3 weeks daily commute for radiotherapy, with its adverse physical, social, and environmental effects. This study reports significant benefit in only two of th patient-reported quality of life domains and, contrasting with TARGIT-A and GEC-ESTRO, no reduction in clinician-assessed radiotherapy toxicity. Although using existing machines, the greater complexity of methods used in this study could substantially increase the demand on radiotherapy departments and costs to the taxpayer; medical and departmental charges for intensity-modulated radiation therapy can be much higher. TARGIT-IORT is much more convenient for patients, less toxic, and incurs a lower overall cost to health systems such as the NHS. Patients clearly recognise these benefits, which enable a rapid return to normal life, and more than 20 000 people have chosen TARGIT-IORT in over 300 centres worldwide."

Risk-adapted TARGIT-IORT during lumpectomy for breast cancer - as effective as whole breast radiotherapy with lower non-breast cancer mortality. 
Including comments about Fast-Forward 5-day high-dose compressed radiotherapy regimen

"In the Fast-Forward trial[1], a substantial proportion of patients report moderate/marked toxicity. For example, 25% of patients receiving the 5-day regimen complained of a ‘harder or firmer breast’. This is consistent with their clinician-assessments of moderate to marked induration (firmness) of the breast outside the tumour area (incidence ratio of 19.1 (95%CI 2.57, 141.9) , p less than 0.0001 Supplemental Table A2 from reference[1]). This may be a 19-fold increase in only a small incidence by comparison with the control arm (1 vs 20 patients), but it is hardly an insignificant result. It means that a substantial portion of the breast was reportedly 19 times more likely to have moderate or marked induration compared with the control arm. We would like to remind those less familiar with radiotherapy toxicity that firmness and hardness of the breast are likely to be irreversible. We therefore find it surprising that with this high level of patient-reported toxicity, the authors claim that this intense and compressed regimen, although effective, is also “as safe in terms of normal tissue effects”. Furthermore, this regimen still irradiates the whole breast with its well-known hazards. No reduction in mortality was observed in the trial, and Fast-Forward still requires 7 to 15 hospital visits, including the consultation, planning, daily radiotherapy, and boost, when indicated. In addition, these patients face the inevitable delays between referral for radiotherapy, further referral for radiotherapy planning and an additional interval before the treatment itself actually starts. We are concerned that only this regimen (or no radiotherapy at all) might be offered to patients during the lengthy COVID-19 pandemic. In contrast, partial breast irradiation reduces non-breast cancer mortality and overall mortality[2, 3], and when given intraoperatively as TARGIT-IORT, the many additional advantages include lower toxicity[4], better quality of life[5, 6], and the avoidance of multiple hospital visits for post-operative radiotherapy[7]. There is even lower toxicity in the group receiving TARGIT-IORT alone, for all toxicities (pain, hyperpigmentation, lymphedema of the arm, ulceration, retraction, breast oedema, telangiectasis and fibrosis). Our group have previously confirmed that patients receiving TARGIT-IORT alone are at half the risk of developing higher grade toxicity (HR 0.46; p=0.010)[4]. Furthermore, patients who receive supplemental EBRT are not at a higher risk of developing this type of toxicity, with long-term results up to 12 years[8]. Fast Forward paper states that “5-year visit forms were available for 3681 (96%) patients of 3833 still in follow-up (not died, withdrawn, or lost).” This could not have been strictly true because at this point in follow up, the number ‘at risk’ on the Kaplan-Meier plot of overall survival at the 5-year mark (adding all 3 treatment groups together) was down to just 3213 patients, with 657 patients censored. These 657 censored patients would of course have been seen on or before the 5th anniversary of their day of randomisation. Therefore, unless 468 (3682 minus 3213) of the 657 patients were genuinely seen at the 5th anniversary of their day of randomisation, the completeness of follow up at 5 years would actually be lower than the 96% that they have claimed. If all these patients were seen before the 5th anniversary then the figure would be actually 3213/3833 which is 83.8%, rather than the 96% that they have led the readers to believe. References 1. Murray Brunt, A., et al., Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet, 2020. 395(10237): p. 1613-1626. 2. Vaidya, J.S., et al., Reduced Mortality With Partial-Breast Irradiation for Early Breast Cancer: A Meta-Analysis of Randomized Trials. Int J Radiat Oncol Biol Phys, 2016. 96(2): p. 259-265. 3. Vaidya, J.S., et al., Targeted radiotherapy for early breast cancer. Lancet, 2018. 391(10115): p. 26-27. 4. Sperk, E., et al., Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A. Breast Cancer Res Treat, 2012. 135(1): p. 253-60. 5. Corica, T., et al., Cosmesis and Breast-Related Quality of Life Outcomes After Intraoperative Radiation Therapy for Early Breast Cancer: A Substudy of the TARGIT-A Trial. Int J Radiat Oncol Biol Phys, 2016. 96(1): p. 55-64. 6. Welzel, G., et al., Health-related quality of life after breast-conserving surgery and intraoperative radiotherapy for breast cancer using low-kilovoltage X-rays. Annals of surgical oncology, 2010. 17 Suppl 3: p. 359-67. 7. Coombs, N.J., et al., Environmental and social benefits of the targeted intraoperative radiotherapy for breast cancer: data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT. BMJ Open, 2016. 6(5): p. e010703. 8. Pez, M., et al., Long-term outcome after intraoperative radiotherapy as a boost in breast cancer. Strahlenther Onkol, 2020. 196(4): p. 349-355.

Intraoperative radiation therapy for breast cancer: a patient's view (about GEC-ESTRO trial of brachytherapy)

The Lancet  VOLUME 387, ISSUE 10031, P1904-1905, MAY 07, 2016

"I am among the 500 or so women in the UK who are lucky enough to have received intraoperative radiation therapy, which was pioneered in London, UK. During my breast cancer treatment in July, 2012, a single long burst of radiation was delivered precisely into the tumour bed while the wound was open after lumpectomy. The next morning I was discharged from hospital. I was at my desk 2 days later and have continued in excellent health since then. Hence, I was dismayed to find that, in their Comment (Jan 16, p 201), Coles and Yarnold make no mention of intraoperative radiation therapy as a treatment option. Intraoperative radiation therapy is available in the UK and is being considered by the National Institute for Health and Care Excellence. Effective, fast, and easy for patients, it spares the skin and critical organs from the effects of radiation exposure. An estimated 20 000 patients have received this treatment in 250 centres in North America, Europe, the Middle East, and Asia. It has been incorporated into the Austrlian health-care system. It is much cheaper than external beam radiation therapy and less arduous to undergo than brachytherapy. In their Comment, Coles and Yarnold completely ignore this widely accepted treatment, which is both straightforward and gentle for the patient, and the demand for which is increasing. The fact that competent clinicians fail to acknowledge a treatment that is highly regarded by the informed consumer is, at the very least, ungenerous. Patients deserve better. I declare no competing interests."

Breast cancer radiation therapy (about Fast Forward trial)

The Lancet Vol 396, No 10262, p 1558-1559, 14 Nov 2020

"The FAST-Forward trial1 has an unusual design because Adrian Brunt and colleagues used a single non-inferiority margin and assumed that it applied to both 26 Gy and 27 Gy groups. Such an assumption questions the need for both of these groups. Prescribed doses were reduced from 40 Gy in 15 fractions to 26 Gy and 27 Gy in five fractions, without a clear explanation for these choices. Standard tissue modelling for late normal tissue effects2 predicts isoeffective doses close to 27 Gy, and a reduction to 26 Gy was made, perhaps for incomplete repair considerations.3 However, reduction to 25 Gy might have been preferable. Regarding late normal tissue effects, clinician, patient, and photographic assessments showed a trend towards higher effects with both 26 Gy and 27 Gy; however, significance was only reached with 27 Gy. The 10-year results on late normal tissue effects are likely to increase in significance as late effects continue to accrue. Cardiac toxicity has known latency, with effects starting a few years after exposure and lasting for 20 years.4 Patients should be advised of high toxicity, rather than be assured that 26 Gy in five fractions over 1 week is safe and a new standard of care. FAST-Forward appears to be particularly suited to current conditions during the COVID-19 pandemic. However, intraoperative radiotherapy5 is more suitable than hypofractionated radiotherapy because it is delivered during surgery, requires only a single fraction, and because partial breast irradiation reduces non-breast cancer and overall mortality.6 It is surprising that intraoperative radiotherapy was not considered at the trial design stage nor included in the discussion as a viable option for patients, despite being recommended by several international guidelines. We declare no competing interests.

Intraoperative radiotherapy for breast cancer: powerful evidence to change practice

Nature Reviews Clinical Oncology volume 18, pages187–188. Jan 2021

The effectiveness of PBI approaches such as TARGIT-IORT has been repeatedly demonstrated (Supplementary information), yet the authors do not mention this important concept. Instead, they promote[1 ] the intensive ‘Fast-Forward’ whole-breast-radiotherapy approach, which we argue represents overtreatment for the majority of patients and comes with well-known hazards: the most important adverse effects of an increased irradiated volume and the associated scattered irradiation are the substantially increased risks of cardiovascular[4,5] and cancer-related mortality[4,6], which are avoided by PBI techniques[7] such as TARGIT-IORT[2,8]. Conversely, as expected with WBRT techniques, there is no mortality benefit with Fast-Forward. Fast-Forward also entails inevitable post-operative delay plus 7–15 hospital visits (for consultation and planning followed by daily WBRT with or without boost). References 1 Sasieni, P. D. & Sawyer, E. J. Intraoperative radiotherapy for early breast cancer — insufficient evidence to change practice. Nat. Rev. Clin. Oncol. 17, 723–724 (2020). 2. Vaidya, J. S. et al. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial. BMJ 370, m2836 (2020). 3. Coombs, N. J. et al. Environmental and social benefits of the targeted intraoperative radiotherapy for breast cancer: data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT. BMJ Open 6, e010703 (2016). 4. Taylor, C. et al. Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J. Clin. Oncol. 35, 1641–1649 (2017). 5. Darby, S. C. et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N. Engl. J. Med. 368, 987–998 (2013). 6. Grantzau, T. & Overgaard, J. Risk of second nonbreast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients. Radiother. Oncol. 114, 56–65 (2015). 7. Vaidya, J. S. et al. Reduced mortality with partial-breast irradiation for early breast cancer: a meta-analysis of randomized trials. Int. J. Radiat. Oncol. Biol. Phys. 96, 259–265 (2016). 8. Aziz, M. H. et al. Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low-energy x-rays? Radiat. Oncol. 6, 174 (2011).

Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: an innovative patient-centred  treatment  

British Journal of Cancer  volume 124, pages1469–1474, Feb 2021

Principles of Cancer Treatment by Radiotherapy 

Surgery (Oxford) 15 Jan 2024 

TARGIT-IORT has many clear benefits in terms of survival and quality of life, as well as its environmental and social advantages.1-3 Patient preference studies have found that patients overwhelmingly prefer TARGIT-IORT.9,10 Moreover, regardless of the doctor’s or any professional body’s preference, offering all options to patients is now a mandatory require- ment for doctors in the UK, both professionally11 and legally.12 TARGIT-IORT is sometimes perceived as disruptive to concepts, pathways, and reimbursement systems of tradi- tional radiation therapy (Fig. 1). The distinguished chief edi- tor of this very journal, who served for 10 years from 2012, and has also been president and chair of the American Soci- ety for Radiation Oncology, previously shrewdly observed that, “fractionated radiation therapy for breast cancer com- prises a substantial proportion of the practice of the average contemporary radiation oncologist. Depending on your per- spective, intraoperative radiation therapy is thus either a very serious threat or a quantum leap forward.”13 However, this perceived threat could be turned into a win-win scenario: one team in Bangalore, India, has suc- cessfully used TARGIT-IORT within a model of equal pay- ment to the whole team irrespective of the choice of radiation therapy (listen to the UCL Minds podcast, “Where research transforms cancer treatment,” specifically at the 32-minute mark14). The American Society for Radia- tion Oncology has now announced its intention to intro- duce value-based payments,15 so we can reasonably expect that it will now promote using risk-adapted TARGIT- IORT during lumpectomy for breast cancer, which pro- vides the greatest value for money in improving the lives of patients with breast cancer.16 TARGIT-A research has been called one of the 5 major breakthroughs by the National Institute of Health Research, alongside the Oxford COVID vaccine work.17 The random- ized data from the TARGIT-A trial have led to global adop- tion, and TARGIT-IORT is included in many international guidelines.18 By early 2020, 45,000 patients have been treated in 260 centers (including >80 in the United States) in 36 countries, with an estimated 20 million miles of patient travel saved, together with a dramatic reduction of the carbon footprint of repeated radiation therapy attendan- ces, plus, of course, 2000 deaths prevented.19

The TARGIT-A randomized trial: TARGIT-IORT versus whole breast radiation therapy: Long-term local control and survival: Author reply 

Int J Radiat Oncol Biol Phys 2023; Vol 115 (1) 

Comparison between PBI techniques.jpg
Comparison of partial breast irradiation techniques.png
BJC paper on partial breast irradiation and TARGIT-IORT for breast cancer Feb 2021.png
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