A Randomised Controlled Trial to Evaluate both the Role and the Optimal Fractionation of Radiotherapy in the Conservative Management of Early Breast Cancer

doi:10.1016/j.clon.2012.08.003

Clinical Oncology

Volume 24, Issue 10, December 2012, Pages 697-706

https://doi.org/10.1016/j.clon.2012.08.003 Get rights and content

Abstract

Aims

Postoperative radiotherapy is routinely used in early breast cancer employing either 50 Gy in 25 daily fractions (long course) or 40 Gy in 15 daily fractions (short course). The role of radiotherapy and shorter fractionation regimens require validation.

Materials and methods

Patients with clinical stage I and II disease were randomised to receive immediate radiotherapy or delayed salvage treatment (no radiotherapy). Patients receiving radiotherapy were further randomised between long (50 Gy in 25 daily fractions) or short (40 Gy in 15 daily fractions) regimens. The primary outcome measure was time to first locoregional relapse. Reported results are at a median follow-up of 16.9 years (interquartile range 15.4–18.8).

Results

In total, 707 women were recruited between 1985 and 1992: median age 59 years (range 28–80), 68% postmenopausal, median tumour size 2.0 cm (range 0.12–8.0); 271 patients have relapsed: 110 radiotherapy, 161 no radiotherapy. The site of first relapse was locoregional158 (64%) and distant 87 (36%). There was an estimated 24% reduction in the risk of any competing event (local relapse, distant relapse or death) with radiotherapy (hazard ratio = 0.76; 95% confidence interval 0.65, 0.88). The benefit of radiotherapy treatment for all competing event types was statistically significant ( $X_{Wald}^{2}$ = 36.04, P < 0.001). Immediate radiotherapy reduced the risk of locoregional relapse by 62% (hazard ratio = 0.38; 95% confidence interval 0.27, 0.53), consistent across prognostic subgroups. No differences were seen between either radiotherapy fractionation schedules.

Conclusions

This study confirmed better locoregional control for patients with early breast cancer receiving radiotherapy. A radiotherapy schedule of 40 Gy in 15 daily fractions is an efficient and effective regimen that is at least as good as the international conventional regimen of 50 Gy in 25 daily fractions.

Introduction

Postoperative radiotherapy is routinely used in the conservative management of early breast cancer. However, it may benefit only a minority of patients [1], [2]. With the introduction of adjuvant therapy in the 1970s there was an emerging view that systemic treatment was the most important therapy for improving breast cancer survival. It was also anticipated that local control would improve as a result of these approaches and the role of radiotherapy needed to be redefined in light of this hypothesis. The PRIME-II trial is an ongoing large multicentre randomised controlled trial to assess the role of radical breast irradiation in older ‘low risk’ women undergoing breast conservation and adjuvant endocrine therapy recruiting sufficient patient numbers to have adequate power to detect small differences in local recurrence rates.

In 1985, the West Midlands Oncology Breast Cancer Group UK investigated the value of postoperative radiotherapy against surgery alone for local control and survival in patients with early clinical stage I and II disease. The conventionally adopted postoperative radiotherapy schedule was 50 Gy in 25 daily fractions. Shorter regimens (hypofractionated) had been reported with similar satisfactory results [3], [4]. Although the radiotherapy community had been suspicious that fraction sizes greater than 2.0 Gy might produce unacceptable late normal tissue toxicity [5], many centres had adopted a shorter treatment schedule of 2.67 Gy daily fractions. The primary objective of this trial was to compare patients receiving routine postoperative radiotherapy with patients receiving surgery alone with respect to locoregional relapse. All patients received tamoxifen (20 mg once daily) for a minimum of 2 years. Secondary objectives were to investigate the effect of routine postoperative radiotherapy on survival and to investigate the effect of radiotherapy fractionation upon local cancer control.

Section snippets

Study Population and Follow-up

Patients with early clinical stage I and II breast cancer were recruited across the West Midlands, and were randomised to immediate postoperative radiotherapy or follow-up only. Those receiving radiotherapy were further randomised between long- and short-course radiotherapy fractionation. Women were eligible if they had histologically proven adenocarcinoma of the breast that had been completely surgically removed resulting in a cosmetically satisfactory breast; clinical tumour measurement had

Results

In total, 707 women were recruited between August 1985 and December 1992 by 24 consultants in 14 hospitals across the West Midlands: 358 were randomised to receive radiotherapy and 349 were randomised to receive no radiotherapy (Figure 1). Patients had a median age of 59 (range 28–80) years, 68% were postmenopausal, 75%had infiltrating ductal carcinoma, 55%had grade 2 tumours with a median pathological tumour size of 2.0 (range 0.12–8.0) cm. Characteristics were balanced across the two

Discussion

Radiotherapy has now become an essential component of breast-conserving therapy because of the need to control residual disease after surgery [8]. Our study reports results with a long median follow-up of 16.9 years (interquartile range 15.4–18.8) and showed immediate radiotherapy reduced the risk of locoregional relapse by 62% (hazard ratio = 0.38; 95% confidence interval 0.27, 0.53) consistent across all prognostic subgroups and reduced the risk of competing events (relapse or death) overall

Acknowledgements

The authors are grateful to the clinicians who made up the West Midlands Oncology Breast Cancer Group and entered patients into the trial:

Dudley Road Hospital, Birmingham: Mr M.J.R. Lee, Mr M. Obeid, Mr P. Stonelake; General Hospital Birmingham: Mr G.D. Oates, Professor J. Alexander Williams; Queen Elizabeth/Selly Oak Hospitals Birmingham: Dr R. Beaney, Dr G. Blackledge, Professor J. Buckels, Mr J. Court, Mr R. Downing, Mr J. Fielding, Dr A. Goodman, Dr T. Latief, Mr J.M. Morrison, Dr T.

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Women's Preferences for Hypofractionated Radiation Therapy for Treatment of Early-Stage Breast Cancer: A Discrete Choice Experiment
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The primary treatment recommended for early-stage breast cancer is breast conserving surgery followed by external beam radiation therapy of the whole breast. Previously, radiation therapy for early-stage breast cancer was given using more fractions over longer durations. Guidelines support treatments with fewer fractions over a shorter time (hypofractionated radiation therapy). This study aimed to understand women's preferences for different features of treatments for early-stage breast cancer.
A discrete choice experiment with 12 choice tasks was conducted, describing the treatments by extent of surgery, duration of radiation treatment, need to relocate for treatment, local side effects, changes in breast appearance, costs, and difficulty with daily activities during and after treatment. Participants were women with breast cancer and from the general population. Mixed logit analyses were conducted and trade-offs between attributes estimated.
Four hundred twenty respondents completed the discrete choice experiment. The relative importance of attributes varied by respondent characteristics; the most influential attribute for younger women was type of surgery (breast conserving surgery). Type of surgery did not influence older women's preferences. Shorter treatment duration, avoiding relocation, fewer local side effects, and less difficulty with daily activities all positively influenced treatment preference. Younger women were willing to accept 32 to 40 days of radiation treatment before a treatment that included mastectomy was potentially acceptable.
Attributes of treatment such as duration, need for relocation, side effects, and effects on normal daily activities during and after treatment significantly influenced women's preference for treatment, including surgery. Our findings have the potential for real impact for patients and services including supporting one-on-one clinical discussions, supporting program and patient resource development, and informing service funding, organization, and delivery.
The Choosing Wisely Oncology Canada Cancer List: An Update
2023, Journal of Cancer Policy
Choosing Wisely (CW) Canada is a national campaign to identify unnecessary or harmful services that are frequently used in Canada. The original CW Oncology Canada Cancer list was developed in 2014. A CW Oncology Canada working group was established to review new evidence and guidelines and to update the current CW Oncology Canada Cancer List.
Between January and March 2022, we conducted a survey of members of the Canadian Association of Medical Oncology (CAMO), Canadian Association of Radiation Oncology (CARO) and the Canadian Society of Surgical Oncology (CSSO). We took the feedback from the survey, including potential new recommendations as well as those that were thought to be no longer relevant and up to date, and conducted a literature review with the assistance of the Canadian Agency for Drugs and Technology in Health (CADTH). The final updated list of recommendations was made by the CW Oncology Canada working group based on a consensus process.
We reviewed two potential recommendations to add and two potential recommendations to remove from the existing CW Oncology Canada Cancer List. The recommendation “Do not prescribe whole brain radiation over stereotactic radiosurgery for patient with limited brain metastases (≤4 lesions)” was supported by several evidence-based guidelines with the strength of recommendations ranging from strong to moderate and the quality of evidence ranging from level 1 to level 3. After reviewing the evidence, the working group felt that the other potential recommendation to add and the two potential recommendations to remove did not have sufficient strength and quality of evidence at this time to be added or removed from the list.
The updated Choosing Wisely Oncology Canada Cancer List consists of 11 items that oncologists should question in the treatment of patients with cancer. This list can be used to design specific interventions to reduce low value care.
Hypofractionation: The standard for external beam breast irradiation
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This overview provides the historical perspective of external beam breast hypofractionation over the last 50 years. It highlights the serious harm suffered by patients with breast cancer in the 1970's and 1980's because of new hypofractionation regimens based on a theoretical radiobiology model being adopted into clinical practice to solve a resource issue without testing within clinical trials and without the essential radiotherapy quality assurance.
It then describes the high-quality clinical trials comparing 3-week with 5-week standard of care regimens that were initiated based on a strong scientific rationale for hypofractionation in breast cancer. Today, there are still challenges with universal implementation of the results of these moderate hypofractionation studies, but there is now a substantial body of evidence to support 3-week breast radiotherapy with several large randomised trials still to report.
The limit of breast hypofractionation is then explored and randomised trials investigating 1-week radiotherapy are described. This approach is now standard of care in many countries for whole or partial breast radiotherapy and chest wall radiotherapy without immediate reconstruction. It also has the advantage of reducing burden of treatment for patients and providing cost-effective care.
Further research is needed to establish the safety and efficacy of 1-week breast locoregional radiotherapy and following immediate breast reconstruction. In addition, clinical studies are required to determine how a tumour bed boost for patients with breast cancer at higher risk of relapse can be incorporated simultaneously into a 1-week radiotherapy schedule. As such, the breast hypofractionation story is still unfolding.
Optimal radiotherapy after breast-conserving surgery for early breast cancer: A network meta-analysis of 23,418 patients
2022, Cancer/Radiotherapie
Citation Excerpt :
Except for the natural defect blinding, all studies were considered as high quality and low risk of bias. Although there were some differences in patient selection criteria, adjuvant therapy regimens and the RT technique included in the trial, local control rates were similar in the CF-WBI group, suggesting that it may be a way to control differences in selection [3,12–15,31–35]. The node-split method was used to assess inconsistency between direct and indirect evidence.
In order to explore whether partial breast irradiation can replace hypofractionated whole breast irradiation and whether the former two are superior to conventional fractionated whole breast irradiation, we conducted a network meta-analysis based on the data from the latest randomized controlled trials to evaluate the efficacy of these radiotherapy modalities.
Data from eligible studies were analyzed to determine the published events for ipsilateral breast tumor recurrence, distant metastasis, total deaths, and non-breast cancer-related deaths. In the case of low or high heterogeneity, the fixed-effect or random-effect model was used for statistical analysis respectively. NMA was performed by using the node-splitting model for two-category data among three radiotherapies based on a Bayesian method.
A total of 23,418 patients were included in 16 studies. For ipsilateral breast tumor recurrence, both pairwise (OR=1.9; CI95%: 1.2 -2.8; p<0.05) and indirect (OR=1.7; CI95%: 1.2 -2.4; p<0.05) comparison of three radiotherapies by network meta-analysis showed that conventional fractionated whole breast irradiation was significantly better than partial breast irradiation. Indirect comparison of three radiotherapies by network meta-analysis showed that hypofractionated whole breast irradiation was significantly better than partial breast irradiation (OR=1.6; CI95%: 1.0 -2.5; p<0.05). Network and paired meta-analyses found no significant differences in other endpoints among the three radiotherapies.
Overall, this network meta-analysis showed that partial breast irradiation was related to the increase of ipsilateral breast tumor recurrence compared with hypofractionated or conventional fractionated whole breast irradiation in patients with early-stage breast cancer.
Afin d’examiner si l’irradiation partielle du sein peut remplacer l’irradiation complète du sein hypofractionnée et si les deux premières sont supérieures à l’irradiation classique fractionnée du sein, nous avons mené une méta-analyse en réseau basée sur les données des derniers essais contrôlés randomisés pour évaluer l’efficacité de ces modalités de radiothérapie.
Les données des études admissibles ont été analysées afin de déterminer les événements publiés concernant la récidive des tumeurs mammaires homolatérales, les métastases à distance, le nombre total de décès et les décès non liés au cancer du sein. Dans le cas d’une hétérogénéité faible ou élevée, le modèle à effet fixe ou à effet aléatoIre a été utilisé respectivement pour l’analyse statistique. La méta-analyse en réseau a été réalisée en utilisant le modèle node-splitting pour des données à deux catégories parmi trois radiothérapies basées sur une méthode bayésienne.
Un total de 23 418 patientes a été inclus dans 16 études. Pour les tumeurs mammaires homolatérales, la comparaison par paires (odds ratio [OR]: 1,9; intervalle de confiance à 95% [IC95%]: 1,2-2,8; p < 0,05) et indirecte (OR: 1,7; IC95%: 1.2-2,4; p < 0,05) des trois radiothérapies par la méta-analyse en réseau a montré que l’irradiation classique fractionnée du sein était significativement meilleure que l’irradiation partielle du sein. La comparaison indirecte des trois radiothérapies effectuée par la méta-analyse en réseau a montré que l’irradiation complète du sein hypofractionnée était significativement meilleure que l’irradiation partielle du sein (OR: 1,6; IC95%: 1,0-2,5; p < 0,05). Le réseau et les méta-analyses appariées n’ont révélé aucune différence significative dans les autres paramètres des trois radiothérapies.
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Citation Excerpt :
After five years, there was also a higher incidence of cases of pulmonary fibrosis for the hypofractionated group as observed in the first scenario of the sensitivity analysis. However, we cannot be definitive in relation to the influence of the boost for pulmonary fibrosis, since the dose reinforcement was performed in different schemes and not in the entire population, and additionally a small part of the patients made use of chemotherapy [16,21–24]. Some outcomes presented high heterogeneity (I2 ≥ 50%).
To evaluate the efficacy and safety of hypofractionated radiotherapy in women with early stage breast cancer after breast conservative surgery.
We performed a search for randomized controlled trials (RCTs) that compare conventional fractioning and hypofractioned radiotherapy. The studied outcomes were local and loco-regional recurrence, disease-free survival, mortality, cardiac ischemia, rib fracture and pulmonary fibrosis up to 5 years and 5 years after treatment. Shrinkage of the breast, breast tightening, telangiectasia, breast edema, shoulder stiffness and arm edema were evaluated within 10 years. Cosmesis and acute skin radiation toxicity were evaluated.
Ten publications of six RCTs were included. No statistical difference in local and loco-regional recurrence, disease-free survival, mortality, cardiac ischemia, ribs fracture and pulmonary fibrosis, shrinkage of the breast, breast tightening, shoulder stiffness, arm edema and cosmesis was found. However, there was a significant difference in favor of hypofractionated for breast edema (RR 0.68, 95% CI 0.53 to 0.88, p = 0.003, 4675 patients), telangiectasia (RR 0.41, 95% CI 0.19 a 0.87, p = 0.02, 5167 patients), and acute skin radiation toxicity (RR 0.34, 95% CI 0.19 to 0.61, p = 0.0003, 347 patients).
There is no difference between conventional fractionation and hypofractionated in terms of efficacy when we evaluate local recurrence, loco-regional recurrence, distance recurrence, disease-free survival and mortality. There is also no difference concerning safety when we assess the occurrence of fibrosis, ischemia and ribs fractures. Hypofractionated showed better results in relation to breast edema, telangiectasia, and acute skin radiation toxicity.
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2015, Clinical Radiation Oncology

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Original ArticleA Randomised Controlled Trial to Evaluate both the Role and the Optimal Fractionation of Radiotherapy in the Conservative Management of Early Breast Cancer

Abstract

Aims

Materials and methods

Results

Conclusions

Introduction

Section snippets

Study Population and Follow-up

Results

Discussion

Acknowledgements

Lancet

Radiother Oncol

Clin Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Eur J Surg Oncol

Eur J Cancer

Int J Radiat Oncol Biol Phys

Clin Oncol

Lancet Oncol

Am J Surg

The BASO II trial of adjuvant radiotherapy versus none and tamoxifen versus none in small, node negative, grade I tumours [abstract 413]

Eur J Cancer

Clinical study of recurrence rate and survival time of patients with carcinoma of the breast treated by biopsy excision without any other therapy

J R Soc Med

Limited surgery with or without radiotherapy for early breast carcinoma

J Can Assoc Radiol

Original Article
A Randomised Controlled Trial to Evaluate both the Role and the Optimal Fractionation of Radiotherapy in the Conservative Management of Early Breast Cancer