Minimizing toxicity in breast irradiation

KEYWORDS:

• Breast cancer
• radiation
• toxicity
• partial breast irradiation
• IMRT

Breast cancer represents the most common non-cutaneous malignancy amongst women in the United States with over 250,000 new cases per year [1]. With improved long-term outcomes, the number of breast cancer survivors continues to grow and as such so does data on the long-term toxicities associated with breast cancer treatment [2]. Radiation therapy represents an essential component in the management of ductal carcinoma in situ (DCIS), early stage, and locally advanced breast cancers; however, radiation can be associated with acute and chronic toxicities. The most common acute toxicities of radiation therapy include fatigue and skin reaction (erythema and desquamation) with chronic toxicities including skin changes, impaired cosmesis, lymphedema, and cardiac toxicity. At this time, innovations in radiation therapy paradigms and techniques are evaluating ways to reduce toxicity and improve quality of life while maintaining clinical outcomes.

Traditionally, radiation therapy following breast conserving surgery consisted of standard fractionation whole breast irradiation (WBI) delivered over 5–7 weeks [3,4]. However, alternatives now exist that offer the potential for reduced toxicity. One such approach is accelerated partial breast irradiation (APBI), in which the lumpectomy cavity plus a margin is treated rather than the whole breast. At this time, multiple randomized trials have been performed evaluating APBI, with no difference in clinical outcomes noted as compared to WBI. APBI can be delivered via interstitial brachytherapy, applicator brachytherapy, or external beam techniques. With respect to toxicity, data from a randomized Hungarian trial has demonstrated no difference in local control (5.1% WBI vs. 5.9% APBI) and improved cosmetic outcomes with partial breast (63% excellent/good WBI vs. 81% APBI) as compared to standard WBI, while the Group Europeen de Curietherapie and the European Society for Radiotherapy and Oncology randomized trial evaluated interstitial brachytherapy and found no difference in the rates of local recurrence (0.9% WBI vs. 1.4% APBI) and a trend for reduced late grade 2 to 3 skin toxicity (5.7% WBI vs. 3.2% APBI) with APBI as compared to WBI [5,6]. Similarly, review of the literature has demonstrated excellent cosmetic outcomes with applicator brachytherapy as compared to traditional techniques [7]. External-beam APBI was originally performed using three-dimensional conformal radiotherapy (3D-CRT) (34 Gy/10 fractions, twice daily) with concerns raised regarding toxicity and cosmetic outcomes [8,9]; however, advances in the technique have shown promise for improved outcomes. Data from the University of Florence randomized trial demonstrated improved acute (p = 0.0001) and chronic (p = 0.004) toxicities as well as cosmetic outcomes (p = 0.045) using an external-beam APBI technique (30 Gy/5 fractions, every other day) compared to WBI while incorporating intensity-modulated radiation therapy (IMRT) and a treatment schedule that delivered radiation every other day for the APBI arm [10]. Additionally, recently published data from the Intensity Modulated and Partial Organ Radiotherapy Low trial demonstrated no difference in the rates of recurrence at 5 years between APBI (40 Gy/15 fractions, once daily) and hypofractionated WBI with or without a simultaneous integrated boost (SIB) (0.5% APBI vs. 1.1% WBI vs. 0.2% WBI with SIB) with reduced rates of patient-reported moderate/marked breast appearance changes [11]. With improved innovations being developed including multi-lumen and strut applicators, it is expected that toxicity rates will continue to decline with APBI.

Traditionally, WBI was delivered using two-dimensional treatment planning with 3D-CRT replacing two-dimensional techniques over the past few decades. However, these techniques are associated with skin toxicities (erythema, desquamation, and breast pain), particularly in larger breasted women; rates of acute grade 2 or greater dermatitis can be 15–35% for all cases and higher with large breast volumes [12–15]. Rates of breast pain have been documented at 23–26% with WBI with cosmesis rated as excellent to good in 80–95% of cases [12–15]. An alternative technique is IMRT that allows for reduction of hot spots in the breast and therefore the potential for reduced acute and chronic skin toxicities. This has been seen in randomized studies as well as in institutional series, offering clinicians a technique with the potential to reduce acute and chronic skin toxicities and improve cosmesis with both standard and hypofractionated WBI; alternatively traditional 3D-CRT can be utilized with a field-in-field approach to limit hot spots [13–15]. An additional toxicity concern is radiation-induced cardiac disease with recent data suggesting increased cardiac events using older radiotherapy techniques [16]. However, multiple techniques are now available to reduce dose to the heart, particularly for left-sided breast cancers. The most well-studied technique is active breathing control (ABC) where the patient takes a moderately deep inspiratory breath hold, allowing for separation of the chest wall and heart [17]. Clinical and dosimetric data have demonstrated not only the feasibility of the technique but also its ability to reduce dose to heart [17,18]. Alternative cardiac-sparing techniques exist including IMRT, prone positioning, as well as techniques limiting the target volume such as APBI [19,20]. Clinicians can use the cardiac-sparing technique that fits best with their patient and tumor characteristics; for example, a large-breasted patient may benefit from IMRT or prone positioning to reduce skin and cardiac toxicity. Older patients unable to tolerate ABC may also be able to use IMRT or prone positioning, or in appropriately selected cases, APBI would be an alternative.

An alternative approach to minimizing toxicity is identifying patients who may not require radiation therapy. Older studies evaluating this approach demonstrated unacceptably high rates of local recurrence with a meta-analysis demonstrating a detriment in breast cancer mortality when omitting radiation following breast-conserving surgery [21,22]. More recently, studies have evaluated omitting radiation therapy using clinical and pathologic features to identify low-risk patients. Cancer and Leukemia Group B (CALGB) 9343 evaluated patients 70 years or older with T1N0 tumors that were estrogen receptor positive and randomized patients to tamoxifen with or without radiation therapy. With 10-year follow-up, omission of radiation therapy was associated with higher rates of local recurrence (10% vs. 2%), with no difference in survival noted [23]. Similarly, the Post-operative Radiotherapy In Minimum-risk Elderly - Phase II (PRIME II) trial evaluated the omission of radiation therapy in a low-risk cohort and found an increased risk of local recurrence at 5 years [24]. Studies evaluating this approach in patients with DCIS have also demonstrated increased rates of local recurrence without survival decrement; however, the Eastern Cooperative Oncology Group (ECOG) trial has continued to see increased rates of local failures without plateau with long-term follow-up [25,26]. As data to date have failed to identify a ‘low-risk’ cohort based on clinical and pathologic features that does not benefit from adjuvant radiation with respect to local control, studies have moved to using tumor genetics. Solin et al. evaluated this approach using samples from the ECOG DCIS study and found that recurrence score could stratify patients by local recurrence risk with similar results seen in a population-based validation study [27,28]. However, concerns exist regarding the rate of local recurrence in the low-risk cohort of patients identified by this test, and further, data have demonstrated that current testing is not cost-effective [29]. Moving forward, tests that utilize tumor genetics must be able to (1) identify a low-risk cohort with an appropriately low risk of local recurrence and (2) provide value as if all patients require testing, the cost of the testing may be prohibitive. Recent data from Liu et al. have suggested that such an approach may be based on breast cancer subtyping [30].

Breast cancer radiation therapy continues to evolve, providing clinicians with alternatives to traditional WBI that offer the ability to reduce toxicity and improve quality-of-life outcomes. These alternatives, which include changes to target volumes, techniques, and the use of tumor genetics, continue to evolve and will offer physicians the chance to provide their patients individualized treatment recommendations that account not only for their disease stage but also patient and tumor factors that impact outcomes. With respect to treatment algorithms to reduce breast toxicity, clinicians should (1) evaluate whether patients require radiation therapy (using CALGB and PRIME II criteria) and moving forward potentially tumor genetics, (2) if patients require radiation evaluate if they are candidates for hypofractionated WBI or APBI based on consensus guidelines or trial inclusion criteria, and (3) in patient requiring WBI, consider techniques such as IMRT (e.g. in large-breast patients) or cardiac-sparing procedures (left-sided cases) to minimize the potential for toxicity.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article was not funded.