Hypofractionation for Breast Cancer: Lessons Learned From Our Neighbors to the North and Across the Pond

Figure 1: Biologic Rationale of Hypofractionated Radiation

Table 1: Randomized Trials Evaluating Hypofractionated vs Conventional Whole-Breast Irradiation — Efficacy Outcomes

Table 2: Randomized Trials Evaluating Hypofractionated vs Conventional Whole-Breast Irradiation — Toxicity Outcomes

Figure 2: Symptomatic Reported Adverse Late Effects From the 10-Year Update of the START Trials: Median Follow-up Was 9.3 Years in the START A Trial and 9.9 Years in the START B Trial

Table 3: Randomized Trials Evaluating Hypofractionated vs Conventional Whole Breast Irradiation — Patient Subgroup Clinicopathologic and Treatment Characteristics

Figure 3: Hypofractionated Whole-Breast Radiation Dose Distribution

Table 4: Criteria for Treatment With Hypofractionated Breast Radiation, Based on ASTRO 2011 Consensus Guidelines and Update of the START Trials

Figure 4: Costs of Breast Cancer Radiation Treatment Options

Table 5: Ongoing Randomized Trials Evaluating Treatment With Hypofractionated vs Conventional Whole Breast Irradiation

Adjuvant whole breast irradiation was established within the standard of care for breast-conserving therapy in the early 1980s, following the results of major randomized trials comparing mastectomy vs breast-conserving surgery and radiation. Since that time, techniques and treatment strategies have evolved, but one major thread that carries forward is the need to balance cost, efficacy, complications, and convenience. Fortunately, data from randomized trials conducted in Canada and Great Britain provide a solid framework for the consideration of hypofractionated radiation in the treatment of breast cancer. In this review we discuss the rationale and underlying radiobiologic concepts for hypofractionation, and review the clinical trials and American Society for Radiation Oncology (ASTRO) guidelines supporting this approach. We also review the practical considerations for treatment planning, including dosimetric criteria and how to approach treatment of the node-positive patient. In the current era of healthcare reform and cost awareness, thoughtful utilization of hypofractionation may offer considerable savings to individual patients and the healthcare system-without compromising clinical outcomes or quality of life.

Introduction

Adjuvant radiotherapy following breast conservation surgery has been in use since the 1920s.[1] National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B06 demonstrated a significant local control benefit to the addition of radiotherapy over breast-conservation surgery alone (14.3% vs 39.2%; P < .001).[2] The traditional radiation protocol established in this era involved whole breast irradiation (WBI) to total doses of 45–50 Gy, administered in 1.8–2.0 Gy daily fractions over a 5- to 6-week period, with or without the addition of a 10–16 Gy boost to the tumor bed. Recent large randomized trials conducted in the United Kingdom and Canada have shown shorter hypofractionated regimens to have equal efficacy and toxicity, as well as noninferiority, compared with standard radiation treatment.[3-9] Based on these results, the American Society for Radiation Oncology (ASTRO) advises, “Don’t initiate whole breast radiotherapy as a part of breast-conservation therapy in women age ≥ 50 with early-stage invasive breast cancer without considering shorter treatment schedules.”[10] This article reviews the biological rationale, eligibility criteria, economic impact, and lingering controversies concerning hypofractionated radiotherapy for breast-conserving therapy.

Biological Rationale of Hypofractionation

In the early history of radiation therapy, it was recognized that a large dose of radiation given as a single fraction caused significant toxicity in normal tissue, with poor tumor control. Giving multiple, smaller doses of radiation over longer overall treatment times both reduced skin toxicity and improved tumor control. As proof of concept, Regaud’s experiments using the testis of rabbits and rams as a model showed that only through the use of multiple, smaller radiation doses could animals be rendered sterile without causing severe injury to the scrotum. Regaud reasoned that the continuous proliferation of sperm precursors mimicked the behavior of malignant tumors, and that the scrotal skin could serve as representative normal tissue at risk for radiation injury.[11] Thereafter, administration of radiation in smaller, multiple fractions became the new standard.

The linear quadratic model describes normal tissue and tumor sensitivity to changes in fractionation pattern, and compares different treatment regimens in terms of isoeffectiveness.[12,13] This model was first used by radiation biologists to measure the inherent radiosensitivity of cells in culture. The surviving fraction of cells as a function of radiation dose is described as having both linear (α) and quadratic (β) components, as shown here: S = e^{–(αD + βD²)} (Figure 1A).

S represents the fraction of cells surviving a dose D, α is the linear rate of cell kill, and β is the quadratic rate of cell kill. The radiation dose at which the linear and quadratic contributions to cell kill are equal is called the α/β ratio. The “curviness” of survival curves, particularly in the low-dose region, is critical to fractionation response because with each subsequent dose fraction, this low-dose region of the curve is recapitulated (Figure 1B), with the net effect of magnifying small differences in the initial slopes (ie, α component) of survival curves.

The linear-quadratic survival expression was adapted for use in modeling the dose response of normal tissue, and tumor responses to changing dose per fraction using clinically relevant endpoints (eg, tumor control, or the loss of structural integrity of a surrounding normal tissue).[14] Ambitious multifraction experiments with laboratory rodents (and some human data) established that late-responding normal tissues such as lung, spinal cord, and kidney have low α/β ratios, that is, a more curved dose-response relationship (Figure 1C), and therefore, a greater sensitivity to changing dose per fraction.[15] Early-responding normal tissues (eg, skin, gut mucosa, bone marrow) and most tumors, however, are characterized by high α/β ratios, a less curved dose-response relationship (Figure 1C), and accordingly, less sensitivity to changes in dose per fraction. This difference in response between normal tissues and tumors to changes in fractionation can be exploited clinically to increase the therapeutic ratio. There is clinical evidence that breast tumors may have an intermediate α/β ratio, lower than most other tumors and early-responding normal tissues, albeit not as low as most late-responding normal tissues.[16] As such, the therapeutic benefit of using smaller doses per fraction would be lost, and hypofractionation might therefore be indicated, provided the total dose is reduced in order to compensate for the higher late toxicity of the larger dose per fraction.

Hypofractionated vs Conventional RT: Prospective Trials

Several prospective nonrandomized and retrospective series in the 1990s reported excellent rates of local control, good cosmetic outcomes, and no concerning morbidities after use of a hypofractionated schedule for whole-breast radiotherapy.[17-20] Hypofractionated whole-breast irradiation (HF-WBI) has now been compared with conventional fractionation whole-breast irradiation (CF-WBI) in four randomized trials (Table 1).[3-9] A Cochrane meta-analysis in 2010, which did not include the 10-year results from the update of the UK Standardisation of Breast Radiotherapy (START) trials,[9] concluded that HF-WBI is unlikely to be detrimental when applied to a carefully selected group of women. Characteristics of the 7,095 participants in the studies included women with smaller tumors (89.8% < 3 cm), pathologically negative lymph nodes (79%), and small- to medium-sized breasts (87%), treated with breast-conserving surgery with negative pathologic margins. Local recurrence (risk ratio 0.97; P = .78) and 5-year survival (relative risk 0.89; P = .16) after HF-WBI were not significantly different when compared with outcomes from CF-WBI.[21]

The first reported randomized trial was performed by the Ontario Clinical Oncology Group (OCOG) in Canada.[3] The trial involved 1,234 women with lymph node–negative, margin-negative invasive breast cancer treated with breast-conserving surgery and level I and II axillary lymph node dissection. Baseline characteristics were balanced between treatment arms, including use of adjuvant tamoxifen (41%) or chemotherapy (11%), and enrollment was limited to patients with small to moderately sized breasts. In a median follow-up of 12 years, the shortened course of radiation did not compromise local tumor control. The 10-year risk of local invasive recurrence was 6.2% among patients treated with HF-WBI, compared with 6.7% of patients who received CF-WBI.[4] There were no observed differences in terms of overall survival, breast cancer mortality, or death due to other causes such as cardiac events, with a trend toward fewer local recurrences in the HF-WBI arm.

Similar noninferior efficacy was demonstrated in a randomized trial from the United Kingdom at the Royal Marsden Hospital and Gloucester Oncology Center (RMH/GOC).[6] The nonaccelerated HF-WBI schedules included either a total dose of 42.9 Gy or 39 Gy, in 13 equal fractions. Unlike in the Canadian trial, all treatments were delivered over a period of 5 weeks, to minimize potential confounding effects from changing the total length of treatment time. The 10-year local recurrence rate was lowest at 9.6% for the 42.9-Gy HF-WBI arm (P = .027), compared with 12.1% for the 50-Gy CF-WBI arm and 14.8% for the 39-Gy HF-WBI arm. START A and B, the successor trials to START, provided additional support for the safety and effectiveness of HF-WBI.[7-9] In the START A trial, both hypofractionated schedules were delivered over 5 weeks, similar to the prior UK RMH/GOC study, but the dose was reduced from 42.9 Gy to 41.6 Gy in the HF-WBI arm. In contrast, the hypofractionated schedule was accelerated in the START B trial, as in the Canadian trial, with delivery of 40 Gy in 15 fractions over 3 weeks. Locoregional recurrence rates at 5 and 10 years for the HF-WBI arms were reported in the ranges of 2.2%–5.2% and 4.3%–8.8%, respectively. These are similar to the 5- and 10-year locoregional recurrence rates of 3.3%–3.6% and 5.5%–7.4%, respectively, in the CF-WBI arms. Overall, 10-year rates of distant relapse, any breast cancer–related event or all-cause mortality were not significantly different between treatment regimens in START A. However, in the START B trial, there was a small but significant improvement in the rates of distant relapse, disease-free survival, and overall survival for the 40-Gy HF-WBI arm compared with patients in the 50-Gy CF-WBI treatment arm.[9]

Based on earlier experience with hypofractionated radiation treatment,[22] there was concern that this approach might result in unacceptably higher rates of acute and late toxicities. However, the four randomized studies have demonstrated that HF-WBI can be delivered without excess toxicity, compared with CF-WBI (Table 2 and Figure 2).[3-9]

Controversies Related to Hypofractionated Radiation Treatment of the Breast

Despite the excellent local control and cosmetic results of the above-described studies, there is still debate regarding use of hypofractionation in patients who were either excluded or under-represented in those investigations (Table 3). A panel of experts from ASTRO convened in 2010 to develop consensus recommendations for the appropriate use of HF-WBI. After a systematic review of the evidence from the literature, the task force defined a patient population in which hypofractionation is an appropriate treatment option. Suitable candidates include women > 50 years of age treated with breast-conserving surgery but not adjuvant chemotherapy, with node-negative breast cancer and tumors < 5 cm. The panel preferred the Canadian HF-WBI regimen in 16 fractions to a total dose of 42.5 Gy. Homogeneous doses should be achieved, with no inhomogeneity greater than ± 7% advised, and treatment fields should completely avoid the heart. There was no agreement on use of a boost to treat the tumor bed, or whether to use HF-WBI for patient groups underrepresented in the trials.[23] Given that the update of the START trials was published after the ASTRO guidelines were released, it may be worth revisiting the application of HF-WBI to controversial cases, including patients < 50 years of age; women with high-grade tumors, ductal carcinoma in situ (DCIS), or positive nodes requiring regional nodal irradiation; or patients with large breasts who would not have met the dosimetric requirements of the four major studies.

Age < 50 years

Women younger than 50 years of age have a higher risk of local failure compared with older patients. The meta-analysis by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) demonstrated that women < 50 years of age had a 20% to 35% risk of local recurrence at 10 years with breast-conserving surgery and radiation, despite realizing the largest absolute benefit from the addition of radiation.[24] Of the four major trials, only the Canadian study stratified by age and compared the two groups based on a preplanned analysis. No significant difference was detected in ipsilateral breast tumor recurrence between groups treated with HF-WBI vs CF-WBI for patients either older or younger than 50 years.[4] The Canadian study did not implement a boost to the tumor bed, which has been shown to improve local control, especially in younger women.[25] Despite the lack of a boost, the rates of recurrence at 5 years for women younger than 50 years of age were 4% and 7% after HF-WBI and CF-WBI, respectively.[3] However, because there were few patients under 50 years of age, the 2011 ASTRO Consensus Guidelines on breast hypofractionation did not recommend the use of hypofractionated regimens for patients younger than age 50.[23] The 10-year update of the START trials, which included 1,389 women younger than 50 and was published subsequent to the ASTRO guidelines, demonstrated that patients younger than 50 did not have an increased risk of breast cancer events with hypofractionated regimens. In fact, there was a trend toward benefit from the hypofractionated regimens in younger patients.[9] Thus, the more recent data from the START trial update would support consideration of hypofractionated breast irradiation for women under 50 years of age.

High-grade tumors

The reason for concern over hypofractionation in patients with high-grade tumors is similar to that regarding its use in younger women. Patients with high-grade tumors have a higher risk of local failure after radiation (28.6% in the EBCTCG meta-analysis).[24] Tumors that are more aggressive may require higher total doses to cure, with little benefit from using higher doses per fraction. A post-hoc analysis performed in the Canadian study demonstrated that among the 233 patients with grade 3 tumors, the rate of local failure in the HF-WBI arm was higher at 15.6%, compared with a local failure rate of 4.7% in the CF-WBI arm (hazard ratio [HR] = 3.08; P = .01).[4] As this finding is a possible statistical fluke, the consensus guidelines did not recommend against hypofractionation for grade 3 patients.[23] More recently, the START trials’ 10-year update also analyzed recurrence rates in 1,272 grade 3 patients, and the investigators found no difference in cancer events between standard and hypofractionated regimens.[9] One possible explanation for the difference in local failure is that the boost radiation was omitted in the Canadian trial but not in the START trial. The EORTC boost study demonstrated a preferential benefit to addition of a radiation boost to the tumor bed for patients with high-grade tumors.[26] Thus, use of a lumpectomy boost should be strongly considered for patients with high-grade tumors treated with hypofractionated breast irradiation.

DCIS

No prospective level 1 evidence exists to support use of hypofractionation for the treatment of DCIS, but multiple retrospective studies have demonstrated favorable local control when compared with historical controls.[27-29] The study at Princess Margaret Hospital in Canada performed a matched-pair analysis of patients treated with CF-WBI or HF-WBI.[29] At about 4 years of follow-up, there was no difference in the actuarial ipsilateral breast recurrence rate between the two groups (with 7% recurrence in the HF-WBI group vs 6% in the CF-WBI group).[29]

The biological rationale for treatment of DCIS with HF-WBI is sound, given that if early-stage invasive cancers have a low α/β ratio, it is very unlikely that less-aggressive noninvasive tumors such as DCIS will have a higher α/β ratio, requiring a higher total dose. Thus, HF-WBI for DCIS is unlikely to lead to worse tumor control compared with CF-WBI. In summary, although there is no level 1 evidence and the retrospective evidence comes from studies with short follow-up periods, it may be reasonable to consider hypofractionated regimens for DCIS.

Node-positive patients requiring regional nodal irradiation

The majority of patients treated with HF-WBI in the four randomized trials had node-negative, early-stage breast cancers. Thus, there is limited experience regarding safety and efficacy of HF-WBI in the treatment of node-positive patients who receive lymph node irradiation. There were no patients who had positive lymph nodes or received lymph node irradiation in the Canadian trial.[4] A minority of approximately 21%, 14%, and 7% of patients received regional nodal irradiation (RNI) in the RMH/GOC, START A, and START B trials,[8] respectively (Table 3). Development of radiation-induced brachial plexopathy (RIBP) is of particular concern in patients who have received hypofractionated treatment to the supraclavicular lymph nodes.[30-34] In a series of 449 women, 6% of patients developed RIBP from hypofractionated treatment to 45 Gy in 15 fractions of 3 Gy, compared with only 1% of patients receiving conventionally fractionated treatment to 54 Gy in 30 fractions of 1.8 Gy.[30] The Canadian trial, which had the longest median follow-up (12 years), reported no patients in either arm with brachial plexopathy.[4] Only 1 of 750 patients (0.1%) in the HF-WBI arm of 41.6 Gy in the START A trial developed brachial plexopathy at a median follow-up of 9.3 years, and there was no increase in potential symptoms of RNI, such as shoulder stiffness or arm edema, after HF-WBI in both START trials.[9] It is reassuring to see no higher rates of brachial plexus damage from HF-WBI across the four randomized trials, especially given that median time to development of symptoms has been as short as 10.5 months in a large series of 1,624 women with early-stage breast cancer treated with conservative surgery and adjuvant radiation.[35] However, longer follow-up is crucial to assess the true risk of RIBP from hypofractionated radiation regimens, since symptom onset has been reported as late as 19 years after treatment, with continued progression of neuropathic symptoms at 30 years after receipt of radiotherapy.[32]

Dosimetric constraints imposed by large breast size and the heart

Unfavorable patient anatomy, including large breast size or large chest wall separation, is associated with greater dose heterogeneity, thus the daily and total doses for HF-WBI are even higher at these “hot spots.”[36] Acute toxicities such as radiation dermatitis,[37-40] and late effects such as fibrosis and severe changes in breast appearance, have been associated with radiation dose inhomogeneity due to larger breast size.[41,42] It was this concern about increased toxicity of both conventional and hypofractionated radiation in women with large breasts that limited the eligibility criteria in the Canadian trial to patients with a maximum chest wall separation of ≤ 25 cm along the central axis.[3,4]

While there was no exclusion of patients with unfavorable anatomy in the START studies, women with presumed separations > 25 cm were underrepresented, as patients with large breasts were only 14.3% and 17.2% of the total population in START A and START B, respectively. Optimization of the dose homogeneity in the central axis was performed using higher energies to ensure that the maximum dose to the breast was no greater than 105% and no less than 95%. When the dose inhomogeneity was limited to within 5% along the central axis, subgroup meta-analysis of 4,672 patients from the START trials at almost 10-year median follow-up demonstrated that breast size was not a predictor of poor cosmetic outcomes and worse late normal-tissue effects after HF-WBI when compared with CF-WBI.[9]

Thus, given the dosimetric and anatomic constraints of the randomized studies, ASTRO guidelines recommend that dose inhomogeneity be limited to ± 7% of the prescribed dose along the central axis when using two-dimensional planning for HF-WBI.[23] It is important to note that while the four randomized trials used primarily two-dimensional treatment planning with optimization of dose homogeneity along the central axis, no requirements were recorded for homogeneity of the dose distribution away from the central axis.

Applicability of the dosimetric constraints today can be challenged by the technical advances in radiation treatment planning and delivery in recent years that were not tested in the randomized trials of HF-WBI. Today, three-dimensional CT-based treatment planning can be used to optimize delivery of WBI to the entire target volume, not just the central axis plane. The use of forward or inverse planned intensity-modulated radiation therapy (IMRT) and prone positioning can provide more uniform coverage of the target while minimizing the radiation dose to normal organs. These techniques can be used to safely treat patients with “unfavorable” anatomy who would have been excluded or underrepresented in the hypofractionated randomized trials. For example, the addition of multiple field-in-field segments to forward-planned three-dimensional conformal radiation therapy (3D-CRT) with tangential beams, sometimes referred to as “simple” IMRT, can be used to deliver a more homogeneous radiation dose and thus reduce “hot spots” within the treatment field (Figure 3). This treatment technique was evaluated separately by the groups in Canada and at Cambridge University.[39,43] The Canadian randomized study of 358 patients confirmed significantly less moist desquamation in the breast with forward-planned 3D-CRT employing several field-in-fields compared with traditionally planned radiation treatment with wedges (from 48% to 31%; P = .002).[39] The Cambridge Breast IMRT trial confirmed that improvement in dose homogeneity decreased late breast tissue toxicity in women of all breast sizes. Inhomogeneous standard tangential radiation treatment plans, defined as ≥ 2 cm³ volume receiving greater than 107% of the prescribed dose of 40 Gy in 15 fractions, were identified in 815 of 1,145 patients, who were then randomized to receive radiation or undergo replanning with simple IMRT. At 5 years, there was no difference in locoregional tumor control or overall survival. However, photographic and clinical assessment of breast toxicity demonstrated superior overall cosmesis and fewer skin telangiectasias for patients who had improved dose homogeneity with the “simple” IMRT/field-in-field technique.[43]

Thus, it is possible to adhere to ASTRO’s fifth Choosing Wisely goal, “Don’t routinely use intensity-modulated radiation therapy (IMRT) to deliver whole-breast radiotherapy as part of breast conservation therapy”,[10] when treating with HF-WBI, as modern 3D CT–guided treatment planning with field-in-field techniques allows for optimizing the dose homogeneity within the target volume and minimizing “hot spots” to normal tissue, achieving equivalent cosmetic outcomes compared with CF-WBI.

In addition to optimizing dosimetric constraints to the target volume, newer treatment techniques, such as prone positioning, and breathing-adaptive therapies, such as deep-inspiratory breath hold (DIBH), can allow for sparing of radiation dose to organs at risk for the development of late toxicities. For example, ASTRO guidelines recommend exclusion of the heart from the primary radiation fields due to concern that exposure of the heart to larger fraction sizes may lead to an increase in the risk of late cardiac events.[23]

Given the importance of avoiding cardiac toxicity from radiation, newer treatment techniques can be utilized to minimize the dose of radiation to the heart when treating patients with HF-WBI or CF-WBI. Prone positioning is useful for minimizing acute skin toxicities in patients with large, pendulous breasts[44] and reducing the radiation dose to the heart.[45,46] Breathing-adaptive therapies with gating of treatment to the deep inspiratory phase of the respiratory cycle allow for maximum separation of the heart and lungs from the target volume, thus delivering radiation during a breath hold to minimize long-term toxicity.[47,48] In summary, while the randomized trials evaluating HF-WBI had dosimetric constraints, newer techniques of delivering radiation allow for excellent coverage of the primary target volume while minimizing “hot spots” and radiation dose to critical organs, thus expanding the potential population of women who are candidates for HF-WBI.

Economic Considerations

Up to 30% of women in North America do not receive WBI after breast-conserving surgery. The lack of utilization of radiation after breast-conserving surgery has been attributed to age-related morbidity, travel distance to radiotherapy centers, personal inconvenience of daily treatments for several weeks, and economic costs, both to the patient and the healthcare system.[49-54] Several studies have confirmed that HF-WBI is associated with lower healthcare costs compared with conventional fractionation schedules (Figure 4).[55-57] Shorter treatment-duration times with hypofractionation schedules reduced costs by an estimated 24% to 30% in analyses from Australia and Belgium, respectively.[58,59] In addition to cost savings to the healthcare system, adopting HF-WBI allows for potential treatment of an increased number of patients by reducing the number of treatment visits and patients’ time on waiting lists for radiotherapy.[60]

Guidelines for Breast Hypofractionated Radiation Treatments

When the American Board of Internal Medicine (ABIM) Foundation enlisted professional societies to identify five specific treatments as part of the national Choosing Wisely campaign, breast radiation treatment options were targeted in two of the recommendations.[10] With the release of more mature results from the START trials, evidence supports progression beyond the 2011 ASTRO consensus guidelines to recommend hypofractionated radiation as the first treatment consideration for an expanded group of patients (Table 4). In summary, given equivalent cancer control, side effects, and cosmetic outcomes, hypofractionated WBI delivered with 3D conformal techniques is the most appropriate treatment choice in carefully selected patients.

Future Directions and Conclusions

Ongoing clinical trials are investigating several unanswered questions regarding HF-WBI (Table 5). Two randomized studies-by the Trans-Tasman Oncology Group (TROG) from Australia[61] and the Radiation Therapy Oncology Group (RTOG study 10-05)[62] are currently accruing patients with DCIS to assess the efficacy of hypofractionated radiation compared with conventionally fractionated breast treatment. The optimal hypofractionated treatment schedule was investigated in the now-closed British multicenter FAST trial, with preliminary results suggesting increased moderate to marked breast changes in patients who received 30 Gy in 5 fractions over 5 weeks compared with a standard radiation dose of 50 Gy in 25 fractions over 5 weeks.[63] Another British multicenter trial, the IMPORT HIGH, is evaluating the benefit of an integrated vs sequential tumor bed boost with hypofractionated treatment,[64] as is RTOG 10-05.[62] The Chinese Academy of Medical Sciences is evaluating the effectiveness and safety of hypofractionated radiation to the chest wall and regional supraclavicular nodes in breast cancer patients who were treated with mastectomy.[65] Finally, the French multicenter SHARE study (Standard or Hypofractionated Radiotherapy vs Accelerated Partial Breast Irradiation [APBI] for Breast Cancer) is evaluating CF-WBI, HF-WBI, and APBI in patients with small (< 2 cm) tumors.[66] Thus, ongoing randomized trials will further define the reasonable indications and limits of hypofractionated radiation for the treatment of breast cancer.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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