This prospective, multicenter trial assessed the quality of life for 400 women with clinical or pathologic stage 0 to III breast cancer who had immediate implant reconstruction and planned for post-mastectomy radiation therapy to follow. Patients received conventional fractionation (5000 cGy in 25 fractions) vs hypofractionation (4256 cGy in 16 fractions). There was no significant difference noted in quality of life at 6 months follow-up between groups. However, hypofractionation was associated with fewer bothersome treatment-related adverse effects and higher physical well-being scores for those younger than 45 years of age at 6 months. Chest wall toxicity was not significantly different. This study adds to the growing experience with hypofractionation in patients with immediate implant reconstruction undergoing post mastectomy radiation therapy.

Reference (Pub-Med Link):Wong JS, Uno H, Tramontano AC, et al. Hypofractionated vs conventionally fractionated postmastectomy radiation after implant-based reconstruction: A randomized clinical trial. JAMA Oncol 2024;10:1370-1378. https://doi.org/10.1001/jamaoncol.2024.2652

Key Institution: Dana-Farber Cancer Institute, Multi-institutional

Keywords: Breast Cancer

This was a prospective registry study from the Netherlands. Between 2011 and 2015, patients with clinical T1-2N1 breast cancer treated with neoadjuvant chemotherapy and surgery across 17 centers were enrolled. Lymph node metastasis had to be confirmed histologically, and patients with 4 or more clinically suspicious nodes were not eligible. The study guidelines assigned patients to one of three risk groups based on their nodal response to chemo. Low-risk patients were ypN0, and they received whole breast radiation after lumpectomy but no chest wall or regional nodal irradiation (RNI) regardless of axillary surgery technique. Intermediate-risk patients had 1-3 residual positive nodes, and they received breast and chest wall radiation with radiation to the low axilla (levels I and II) only if no ALND was performed. High-risk patients had 4 or more residual positive nodes, and they received radiation to all of the above plus medial axilla/supraclavicular fossa. Only 6% received internal mammary radiation, though. Of 838 patients, 35% were low risk, 44% were intermediate risk, and 21% were high risk. Overall, 64% of patients actually received radiation according to the study guidelines. Guideline concordant radiation was most frequent in the high-risk group (86%) and least in the intermediate risk group (56%). So what was the source of variation? In the low-risk group, 37% of patients received more extensive RT than recommended. In the intermediate risk group, 17% received less than recommended RT while 29% received more than recommended. In the high-risk group, 14% received less than recommended RT. At 5 years, locoregional-only recurrence was rare (2.2%) and there was no difference in recurrence among risk groups. Any locoregional recurrence occurred in ~5% when counted along with distant recurrences. When looking only at patients treated per the study guidelines, locoregional recurrence remained low at 2.3% for low risk, 1% for intermediate risk, and 1.4% for high risk. In summary, this study showed that Response-adapted adjuvant radiation for lymph node positive (1-3) breast cancer treated with neoadjuvant chemotherapy results in a ~2% risk of locoregional recurrence at 5 years across risk groups.

Reference (Pub-Med Link): de Wild, S. R., de Munck, L., Simons, et al. (2022). De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study. Lancet Oncology, 23(9), 1201–1210. https://doi.org/10.1016/S1470-2045(22)00482-X

Key Institution: Netherlands
Keywords: Breast

Both the practice of tumor bed boost and moderately hypofractionated whole breast irradiation (WBI) has been accepted in the medical community for women with invasive breast cancer thanks to large, randomized trials. For the treatment of DCIS, however, such strength and level of evidence has not existed until BIG3-07/TROG 07.01.

This study enrolled 1608 women with non-low-risk DCIS across 136 participating centers in 11 countries. Eligible patients were age >18, unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1mm of clear radiation resection margins. “Non-low risk” DCIS was defined by having at least one clinical or pathological marker for increased risk of local recurrence: younger age (<50 y), symptomatic presentation, palpable tumor, microscopic tumor size measuring 15mm+, multifocal disease, intermediate or high nuclear grade, central necrosis, comedo-histology, or a radial surgical margin of less than 10 mm.

Patients were assigned to one of four groups (1:1:1:1) of no tumor bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after the treating center prespecified conventional or hypofractionated WBI. Conventional WBI was 50 Gy in 25 fractions, and hypofractionated WBI was 42.5 Gy in 16 fractions. The boost dose was 16 Gy in 8 fractions, delivered after WBI.

Tumor bed boost after postoperative WBI significantly reduced local recurrence (92.7% -> 97.1%, HR 0.47, p<0.001) with an increase in grade 2 or higher toxicity in breast pain (10% -> 14%, p=0.003) and induration (6% -> 14%, p<0.001). The effect of tumor bed boost was consistent across all patient subgroups. Moderately hypofractionated WBI was as safe and effective (5y FFLR 94.9% vs 94.9%)  as conventional fractionation in DCIS.

This is the only randomized phase 3 trial that examines the effects of both a tumor bed boost and WBI dose fractionation in patients with non-low-risk DCIS. This supports the adoption of moderately hypofractionated WBI with tumor bed boost in non-low-risk DCIS to improve the balance of local control, toxicity, and socioeconomic burdens of treatment. The international scale of this study supports generalizability of the findings. The 16-fraction schedule used in this study may not be the clinical limit of whole breast hypofractionation in DCIS, as use of 5-fraction regimens have been adopted for invasive breast following demonstrating of non-inferiority to 15-fraction regimens in regards to tumor control and normal tissue effects.

Reference (Pub-Med Link): Chua, B. H., Link, E. K., Kunkler, I. H., et al. (2022). Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study. Lancet (London, England), 400(10350), 431–440. https://doi.org/10.1016/S0140-6736(22)01246-6

Key Institution: Multi-Center, international

Keywords: breast

Women with early-stage breast cancer and large breast size (bra band ≥ 40 in and/or ≥ D cup) have been shown to have increased risk of toxic effects related to adjuvant breast radiotherapy. In this multicenter, phase 3, single-blind randomized clinical trial of 378 patients treated with adjuvant breast radiotherapy, 182 (51.0%) were treated in the supine position and 175 (49%) were treated in the prone position. Initially, patients were treated with conventional fractionation (50 Gy in 25 fractions), though the protocol was amended at 3 years to allow hypofractionation (42.5 Gy in 16 fractions). Authors found that treatment in the prone position was statistically significantly associated with lower rates of moist desquamation (26.9%), compared with treatment in the standard supine position (39.6%). They also showed increased toxic effects associated with use of a radiotherapy boost and conventional fractionation.

(Open Access)

Reference (Pub-Med Link): Vesprini, D., Davidson, M., Bosnic, S. et al. (2022). Effect of Supine vs Prone Breast Radiotherapy on Acute Toxic Effects of the Skin  Among Women With Large Breast Size: A Randomized Clinical Trial. JAMA Oncology, 8(7), 994–1000. https://doi.org/10.1001/jamaoncol.2022.1479

Key Institution: Sunnybrook Health Sciences Centre, Toronto, Canada
Keywords: Breast

Based on the CALGB 9343 study, patients age ≥ 70 with pT1N0 ER/PR + HER2- breast cancer treated with lumpectomy and endocrine therapy have been considered candidates for omission of radiotherapy. This NCDB retrospective analysis of 11,891 patients was conducted to determine whether recurrence score (RS) test (Oncotype Dx) is predictive of who may benefit from radiation following breast conservation therapy. Patients were stratified based on their RS where: low risk=1-10, intermediate risk=11-25, high risk=26-99. The study found an overall survival benefit with the use of radiotherapy in patients with RS≥ 11, but not in patients with RS< 11. Among older women with hormone receptor positive breast cancer and high and intermediate scores, there was a survival benefit with the addition of radiation. The authors recommend assessment of RS in this older subset of patients and adjuvant radiation should be considered when RS ≥ 11. Future prospective studies should evaluate the use of RS to determine benefit of radiation.

Reference (Pub-Med Link): Chevli, N., Haque, W., Tran, K. T., et al. (2022). 21-Gene recurrence score predictive for prognostic benefit of radiotherapy in patients age ≥ 70 with T1N0 ER/PR + HER2- breast cancer treated with breast conserving surgery and endocrine therapy. Radiotherapy and Oncology, 174, 37–43. https://doi.org/10.1016/j.radonc.2022.06.013

Key Institution: USA (NCDB analysis)
Keywords: Cancer Biology, Breast

Long-term (five-year) follow-up of TARGIT-A, a prospective phase III randomized trial of 1153 patients ≥ age 45 with invasive ductal carcinoma of the breast no larger than 3.5cm status post breast-conservation surgery randomized to delayed intraoperative radiation therapy (IORT) delivered as second operative procedure via reopening of lumpectomy site vs external beam radiation therapy (EBRT). Primary outcome: Noninferiority margin of 2.5% local recurrence (LR) rate at 5 years. 581 patients were randomized to IORT, 572 to EBRT. Delayed IORT was not non-inferior to EBRT. The 5-year LR rate was 3.96% for IORT vs 1.05% for EBRT (statistically significant). At long-term follow-up at median 9 years, the following measures were not statistically significantly different between groups: LR-free survival, mastectomy-free survival, distant disease-free survival, overall survival. Conclusion: patients treated with delayed IORT after lumpectomy had a higher rate of local recurrence compared to patients treated with EBRT, though no difference in mastectomy-free survival, distant disease-free survival, or overall survival.  

(Open Access)

Reference (PubMed Link): Vaidya JS, Bulsara M, Saunders C, et al. Effect of delayed targeted intraoperative radiotherapy vs whole-breast radiotherapy on local recurrence and survival: Long-term results from the targit-a randomized clinical trial in early breast cancer. JAMA Oncol 2020;6:e200249.

Key Institution: Multi-Institution (TARGIT-A trial)
Keywords: Breast cancer, intraoperative radiotherapy, whole breast irradiation

This trial was a randomized phase 3 non-inferiority trial which compared standard hypofractionated (40 Gy in 15 fx) to two ultra-hypofractionated regimens (26 Gy and 27 Gy in 5 weekly fx). Over 4000 patients were included and were T1-T3, N0-2, M0, any hormone and HER2 status allowed, after both breast conserving surgery and mastectomy.  No nodal coverage was allowed but 10 Gy or 16 Gy boost was allowed in 2 Gy fractions (25% received boost across all arms). Ipsilateral breast recurrence at5 years was found to be noninferior in both 26 and 27 Gy groups, and clinician as well as patient and photographic assessments of breast cosmesis were noninferior in the26 Gy group. There was also no difference in distant relapse or mortality between arms at 5 years. Of note very low risk patients (aged ≥65 years, pT1, grade 1 or 2, estrogen receptor [ER] positive, HER2 negative, pN0, M0) were excluded part way through the trial to increase the event rate. Overall, this trial showed very favorable results for the 26 Gy in 5 fx group with a moderate follow up in a favorable group of patients

(Open Access)

Reference (PubMed Link): 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.

Key Institution: Multi-Institutional
Keywords: Hypofractionated, breast cancer

This paper reports on a randomized controlled trial of women >40 years old with DCIS or N0 breast cancer treated with lumpectomy and randomized to external beam APBI (38.5Gy/10fx BID) or whole breast RT (WBI)(45.4/16fx or 50Gy/25fx). Primary outcomes were ipsilateral breast tumor recurrence (IBTR). 2135 women enrolled with median follow-up of 8.6 years. 8-year cumulative rates of IBTR were 3.0% with APBI and 2.8% with WBI, not significantly different. Acute >grade 2 toxicity occurred in 28% in APBI and 45% in WBI (p<0.0001). Late >grade 2 toxicity was 32% in APBI and 13% in WBI (p<0.0001). Adverse cosmesis was more common after APBI at 3 years (absolute difference 11.3%), 5 years (16.5%) and 7 years (17.7%). Overall, APBI had non-inferior IBTR compared to WBI. Although there was less acute toxicity with APBI, there was increased late toxicity as well as adverse cosmesis (potentially related to the BID fractionation schedule). 

Reference (PubMed Link): Whelan TJ, Julian JA, Berrang TS, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (rapid): A randomised controlled trial. Lancet 2019;394:2165-2172.

Key Institution: Multi-Institution (Canada, Australia, NZ)
Keywords: Breast cancer, APBI, whole breast irradiation

Breast-conserving surgery (lumpectomy) is a surgical oncologic resection where a localized, early stage, breast cancer is removed with a limited amount of surrounding tissue. This technique requires the supplementation of post-operative whole-breast radiation to reduce the risk of local recurrence. This was previously established to be equivalent to a modified radical mastectomy from a recurrence standpoint but spares the extensive morbidity and aesthetic changes associated with the surgery. Recently, efforts have been made to reduce both the quantity of normal breast exposed to radiation as well as the duration of the course in the adjuvant setting. Now resulting are the outcomes from a phase III randomized trial comparing whole-breast irradiation (WBI) to accelerated partial breast irradiation (APBI). Eligible patients were adult women with early stage (up to 3 positive lymph nodes) breast cancer who underwent lumpectomy with negative surgical margins. WBI was delivered to 50 Gy in 25 daily fractions with a supplemental tumor bed boost as decided by the treating clinicians. APBI was administered with either external-beam radiation to 38.5 Gy in 10 fractions over 5 treatment days or with brachytherapy to 34 Gy. Randomization stratification occurred according to stage, menopausal and hormone-receptor status as well as intention to receive chemotherapy. The primary outcome of in-breast tumor recurrence was analyzed in the intention-to-treat population. With a total of 4216 women enrolled across both arms, it was found that APBI did not meet the statistical criteria for equivalence to WBI with respect to the primary outcome of local recurrence. However, the weight of the clinical relevance of this result is controversial given it constituted an absolute difference of less than 1% in the 10-year cumulative incidence of local recurrence between the groups. Therefore, although strictly speaking APBI has a statistically significant increase in local recurrence, the value of this increase is minimal (< 1%) and may clinically permit its use in some women as an acceptable and more convenient regimen with similar toxicity profile per this trial. 

Reference (PubMed Link): Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: A randomised, phase 3, equivalence trial. Lancet 2019;394:2155-2164.

Key Institution: NRG Oncology
Keywords: accelerated partial breast irradiation (APBI), whole-breast RT, early-stage breast cancer, breast conserving surgery 

This multicenter, single-arm, prospective phase 2 trial assessed the effectiveness and safety of partial breast reirradiation after a second lumpectomy, to determine if it is an acceptable alternative to mastectomy. A total of 65 patients with ipsilateral recurrence after a second lumpectomy were enrolled, with the treatment of 3-dimentional conformal external beam partial breast reirradiation. Median follow-up was 5.5 years. The radiation dose was 1.5 Gy twice daily for 30 fractions. 58 patients were evaluable for the study, and 4 patients had breast cancer recurrence with 5-year cumulative incidence of 5%. Both distant-metastasis-free survival and overall survival rates were 95%. 4 patients (7%) had grade 3 toxicity and none had grade 4 toxicity. This study concluded that second breast conservation is an effective alternative to mastectomy.   

Reference (PubMed Link): Arthur DW, Winter KA, Kuerer HM, et al. Effectiveness of breast-conserving surgery and 3-dimensional conformal partial breast reirradiation for recurrence of breast cancer in the ipsilateral breast: The nrg oncology/rtog 1014 phase 2 clinical trial. JAMA Oncol 2019.

Key Institution:  Multi-Institutional (USA)
Keywords: Partial breast reirradiation, breast cancer, recurrence, second lumpectomy 

This study addressed an important question of the efficacy of hypofractionated radiotherapy in postmastectomy patients. 820 patients with primary T3-4 disease or at least 4 positive axillary LNs were randomized to receive 50 Gy in 25 fractions over 5 weeks or 43.5 Gy in 15 fractions over 3 weeks. The primary endpoint was 5-year locoregional recurrence, and 5% margin was used to establish non-inferiority design. The median follow-up was 58.5 months. The 5-year cumulative incidence of locoregional recurrence was 8.3% (hypofractionation) vs 8.1% (conventional fractionation), with p < 0.0001 for non-inferiority. Patients receiving hypofractionated radiotherapy had higher chance of grade 3 acute skin toxicity (8%) than those receiving conventional radiotherapy. This study concluded that postmastectomy hypofractionated radiotherapy was non-inferior to conventional fractionated radiotherapy with similar toxicity profile.

Reference (PubMed Link): Wang SL, Fang H, Song YW, et al. Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: A randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2019;20:352-360.

Key Institution: Chinese Academy of Medical Sciences and Peking Union Medical College
Keywords: Postmastectomy radiotherapy, hypofractionation, high-risk breast cancer, locoregional recurrence 

Regional nodal irradiation (RNI) is often recommended for patients following surgery for breast cancer who have risk factors for regional relapse. RNI often includes the internal mammary nodes (IMNs). However, treating the IMNs with radiotherapy increases the dose to the heart and lungs and may increase the long-term risk of toxicity. Proton beam radiation therapy may be able to spare cardiopulmonary radiation exposure although previously there had been no prospective studies showing a benefit.

In the present study, 70 patients completed proton beam radiation including RNI coverage between 2011 and 2016. 91% of these patients had left-sided breast cancers and 94% had stage II or stage III disease. 99% received chemotherapy. On assessment of radiation delivery, the authors found that the median dose to the chest wall/breast was 49.7 Gy and 48.8 Gy to the IMNs. For the 62 surviving patients, the 5-year rates for locoregional relapse and overall survival were 1.5% and 91%, respectively. Only one patient developed grade 2 radiation pneumonitis and no patients developed grade 3 or higher pneumonitis. No grade 4 or higher toxicities occurred. There was no evidence of changes in echocardiograms or cardiac biomarkers.

In conclusion, proton beam radiation therapy for breast cancer including RNI coverage was associated with low toxicity and comparable survival outcomes compared to what would be expected in terms of historical data.

Randomized studies are needed to directly compare protons vs photons, but these are encouraging preliminary findings.

Reference (PubMed Link): Jimenez RB, Hickey S, DePauw N, et al. Phase ii study of proton beam radiation therapy for patients with breast cancer requiring regional nodal irradiation. J Clin Oncol 2019;37:2778-2785.

Key Institution: Massachusetts General Hospital
Keywords: Proton therapy, breast cancer, regional nodal irradiation

The purpose of this study was to determine if 40 Gy in 10 daily fractions is a tolerable dose schema for accelerated partial breast irradiation (APBI) as compared to more traditional twice-daily regimens that have produced mixed cosmetic results in trials. 

There were 106 patients enrolled in the study. Median age was 62 years. All patient received lumpectomy for in-situ or early invasive disease. A 3-D conformal RT technique was used. 

Median follow-up was 58 months. Regarding recurrence outcomes, there were in total 3 recurrences: 2 local, 1 distant. Regarding cosmesis, 15% experienced grade 2 or greater skin toxicity with only two cases of grade 3 skin toxicity. The planning target volume (PTV) and breast volume receiving 20 Gy (V20) were found to be predictors of skin toxicity. The authors suggest that limiting breast V20 to less than 45% may limit skin toxicity, as 62% of patients who developed skin complications had a breast V20 greater than 50%. 

Given these results, 40 Gy in 10 daily fractions may be an appropriate APBI regimen in patients with early stage breast cancer. PTV and V20 may also be accurate predictors of skin toxicity and may be useful constraints in guiding treatment planning. More follow-up will be needed to determine the toxicity profile and safety of this regimen in the long-term. 

Reference (PubMed Link): Braunstein LZ, Thor M, Flynn J, et al. Daily fractionation of external beam accelerated partial breast irradiation to 40 gy is well tolerated and locally effective. Int J Radiat Oncol Biol Phys 2019;104:859-866.

Key Institution: Memorial Sloan Kettering Cancer Center
Keywords: Accelerated Partial Breast Irradiation, APBI, Skin Toxicity, Breast Cancer 

This randomized study was conducted in 537 patients from 22 surgical practices, randomly assigned online to the iCanDecide interactive and tailored Web site (intervention) or the iCanDecide static Web site (control). The aim was to determine the effect of iCanDecide, an interactive and tailored breast cancer treatment decision tool, on the rate of high-quality patient decisions—both informed and values concordant—regarding locoregional breast cancer treatment and on patient appraisal of decision making. The tailored and interactive iCanDecide Web site, which focused on knowledge building and values clarification, positively affected high-quality decisions largely by improving knowledge compared with static online information.

Harnessing available technology to improve oncology outcomes is a largely untapped avenue for clinical research and/or commercial enterprise. Decision making tools such as iCanDecide will become increasingly common in the next decade in a nationwide and global effort to bring quality control to diverse clinical settings. Experiences such as this study will serve to advance this aspect of oncology care. 

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Journal & Date: JCO, 2018
Key Institution: Multicenter
Keywords: Clinical decision making, breast cancer, oncologic surgery, technology, patient decision making, patient centered care