Sunday, September 24, 2023
The role of radiation therapy (RT) in optimizing locoregional control and survival in women with breast cancer has been established by numerous randomized trials and large meta-analyses.[1] For patients with node-negative breast cancer who undergo breast conserving surgery (BCS), RT to the whole breast is standard adjuvant local treatment. Whereas the benefits of RT are clear, optimal RT fractionation and scheduling remain controversial. Similarly, for patients with node-positive disease, particularly those with 1 to 3 positive nodes, the role of adjuvant RT to the regional nodes is also actively debated.
To improve the therapeutic ratio of RT in the modern era of conformal treatment planning, efforts are underway to evaluate novel techniques to improve precision in targeting tissues at risk while minimizing normal tissue exposure. Studies aimed at translating RT innovations into improved clinical outcomes were among the highlights of the 30th Annual San Antonio Breast Cancer Symposium (SABCS). In addition, long-term outcome data from prospective trials and from large population-based series were presented to address current controversies and to advance our knowledge of the role of RT in contemporary breast cancer management.
BCS followed by RT to the whole breast has been clearly demonstrated in randomized trials to provide local control and survival comparable to mastectomy.[1] Despite this evidence, in an analysis of Surveillance, Epidemiology, and End Results (SEER) registry data of 175,224 women diagnosed with invasive breast cancer between 1992 and 2003, Virnig and colleagues[2] reported the concerning observation that, although the use of BCS has increased in recent years, approximately 20% to 30% of women treated with BCS failed to receive adjuvant RT. Multivariate analysis showed that the trend in inadequate local treatment was not limited to favorable risk subgroups but also affected younger women aged 18 to 54 years as well as women with estrogen receptor-negative tumors. The reasons for this observed lack of RT use were unclear but may well be multifactorial, including the cost and inconvenience associated with traditional RT courses protracted over 5 to 6 weeks.
Long-term results of a randomized trial evaluating shorter RT scheduling, reported at SABCS 2007 by Whelan and colleagues on behalf of the Ontario Cooperative Oncology Group,[3] have the potential to change practice and increase access to RT among patients with early-stage breast cancer. Compared with standard RT schedules using 2 Gy fractions daily over 5 to 6 weeks, accelerated hypofractionated regimens deliver larger RT fraction sizes and fewer fractions over shorter durations of approximately 3 weeks, with potential radiobiological advantages, improved convenience, and reduced cost.
In this trial, 1234 patients with node-negative breast cancer treated by BCS with clear margins were randomized to receive whole breast RT with 42.5 Gy in 16 fractions (n = 622) or 50 Gy in 25 fractions (n = 612). At a median follow-up time of 12 years, local recurrence, disease-free survival, and overall survival rates were similar for the 2 treatment groups. Concerns regarding long-term normal tissue toxicities were also addressed with the updated analysis, which demonstrated equivalent cosmesis and late RT-related skin and soft tissue effects for the 2 groups.
Long-term effects of using RT fraction sizes larger than 2 Gy are also being prospectively evaluated in 2 Standardisation of Breast Radiotherapy (START) trials in the United Kingdom.[4] In START Trial A, 1129 women with early-stage breast cancer treated with BCS or mastectomy were randomized to 39 Gy or 41.6 Gy, each in 13 fractions, vs a control regimen of 50 Gy in 25 fractions. In START Trial B, 1079 women were randomized to 40 Gy in 15 fractions vs the same control regimen.
By 5 years after randomization, body image concerns were found to have diminished , with no differences between the regimens in both trials. However, patient-reported breast symptoms, breast tissue effects, and changes in skin appearance were more favorable in the 39 Gy and 40 Gy hypofractionated regimens.
Adoption of short RT regimens has previously been limited by clinicians' reservations about the potential for increased late morbidity, particularly in areas of dose inhomogeneity. The results of the Ontario and UK trials demonstrating equivalent or favorable normal tissue effects provide evidence supporting hypofractionated RT as a viable option for women with early-stage breast cancer. In addition, modern planning techniques to improve dose homogeneity, including 3-dimensional intensity-modulated radiation therapy using multiple segmented beams to achieve uniform dose distributions,[5,6] should be evaluated in the context of shorter treatment regimens to further minimize RT morbidity and promote acceptability.
In women with early breast cancer treated with BCS, approximately 70% to 80% of local recurrences occur at or near the primary tumor bed.[7,8] This observation has led to the hypothesis that, compared with standard whole breast RT, equivalent local control, reduced normal tissue toxicities, and improved convenience might be seen with RT that targets only the postsurgical tumor bed with a margin of adjacent breast tissue using accelerated schedules over shorter durations.
Currently available partial breast (PB) RT modalities include interstitial brachytherapy, balloon catheter systems, computed tomography-based conformal external beam techniques, and intraoperative electron beam therapy. In all of these modalities, PBRT is delivered over a short time, varying between a single intraoperative treatment to 10 fractions delivered twice a day over 5 to 7 treatment days.
At SABCS 2007, Rabinovitch and colleagues[9] reported toxicity and cosmesis outcomes from Radiation Therapy Oncology Group (RTOG) 95-17, the only completed phase 1/2 cooperative group trial evaluating multicatheter brachytherapy as sole adjuvant RT for patients with T1-2 invasive breast cancer. This trial enrolled 100 women with nonlobular breast cancer ≤ 3 cm who had 0 to 3 positive nodes. They were treated with BCS with clear margins, followed by either high dose rate or low dose rate brachytherapy. At a median follow-up time of 7.6 years, 8% of the high dose rate group and 21% of the low dose rate group had experienced grade 3 toxicity, including infection, wound dehiscence, skin thickening, fibrosis, pain, and telangiectasia, at some time after treatment. Good to excellent cosmesis was reported in the majority of patients at 3 years after treatment.
Streeter and colleagues[10] reported updated results from the only completed multi-institutional phase 2 trial of PBRT using a balloon catheter for patients with ductal carcinoma in situ. In this trial, 100 patients age ≥ 45 with unicentric ductal carcinoma in situ ≤ 5 cm, negative margins after BCS, and no residual microcalcifications on postoperative mammography underwent PBRT with 34 Gy in 10 fractions, twice daily, over 5 days. Four noninvasive local recurrences were identified, occurring 8 to 32 months after treatment. Good to excellent cosmesis was reported in 95% of subjects.
These 2 multi-institutional phase 1/2 trials corroborate single-institution reports demonstrating feasibility and safety of PBRT and support the progression to multi-institutional phase 3 randomized trials comparing PBRT with standard whole breast RT in patients with early breast cancer.
Waiting to start adjuvant RT after surgery is an issue of concern for patients and clinicians, but the effect of delay between surgery and RT on local control and survival has not been well elucidated.
Investigators from the Edinburgh Cancer Centre[11] reported on 1811 women treated with RT after BCS, 306 of whom received chemotherapy. Among patients not receiving chemotherapy, no significant trend between longer BCS-to-RT intervals and local recurrence or overall survival was observed. Among patients receiving chemotherapy, patients waiting > 24 weeks had poorer outcomes vs those waiting < 24 weeks, but this likely reflected the higher risk features of their disease.
In a related presentation, investigators from British Columbia[12] analyzed a larger cohort of 6428 women with T1-2 disease and 0 to 3 positive nodes who were treated with BCS and RT with no chemotherapy. A substantial number of these patients (n = 1451) waited > 12 weeks between BCS and RT. Outcomes were analyzed by 4-week intervals, with the > 4 to 8 week group selected as the reference group.
Kaplan-Meier analysis showed lower 10-year local control and breast cancer-specific survival with BCS to RT intervals > 20 weeks. These adverse outcomes persisted when unequal distributions of prognostic factors were accounted for by multivariate Cox modeling. Case-matched analyses further confirmed reduced local control (P = .001) and breast cancer-specific survival (P = .009) with BCS to RT intervals > 20 weeks. These data demonstrate that RT is effective even months after BCS and support the advice to patients to allow time for surgical healing and for considering treatment options; however, patients not receiving chemotherapy should start RT within 20 weeks after BCS.
There is consensus that advanced tumor stage or extensive nodal burden indicates high-risk disease warranting recommendations for adjuvant locoregional RT,[13,14] but the role of locoregional RT after mastectomy or BCS in patients with intermediate-risk disease, particularly in those with T1-2 breast cancer with 1 to 3 positive nodes, is more controversial. Because optimal locoregional control can favorably influence survival, the use of clinical and pathologic factors to identify high-risk subsets of patients with 1 to 3 positive nodes who might benefit from adjuvant therapy continues to receive research focus. At SABCS 2007, several groups reported data on locoregional RT use and associated outcomes in patients with 1 to 3 positive nodes.
Yau and colleagues[15] reviewed locoregional recurrence patterns associated with their institution's policy in 838 patients treated with mastectomy. In this series, high-risk disease was defined as tumors ≥ 4 cm with 1 to 3 positives nodes, any tumor with > 3 positive nodes, or positive surgical margins; "intermediate-risk" disease was defined as tumors < 4 cm with 1 to 3 positive nodes, or node-negative tumors with at least one risk factor, ie, large tumors ≥ 4 cm, lymphovascular invasion, or margins ≤ 2 mm. Patients with node-negative tumors without these factors were considered low risk and did not receive adjuvant RT.
At a median follow-up time of 5.5 years, the low-risk group treated without RT experienced significantly higher locoregional recurrence vs the intermediate-risk group treated with RT. In the low-risk subgroup, age < 50 and grade 3 histology were significant prognostic indicators for higher locoregional recurrence. This study adds to the growing literature suggesting that not all patients with node-negative breast cancer have low locoregional recurrence risks and highlights the need for additional research to identify high-risk subsets that can benefit from adjuvant treatment.
Finally, investigators from the Cambridge Breast Unit at Addenbrookes Hospital in the United Kingdom[16] reported on an audit of a prognostic index developed at their institution in 1999 to select high-risk patients for postmastectomy RT. The Cambridge Postmastectomy Radiotherapy Index (Table) assigned arbitrary scores to individual prognostic factors such as number of positive nodes, lymphovascular invasion, tumor size, pectoral muscle invasion, excision margins, and histologic grade.
| Score | 3 | 2 | 1 |
|---|---|---|---|
| Number of Positive Nodes or LVI | > 4 positive nodes | 1-3 positive nodes | LVI |
| Tumor Size | > 5 cm/T4 | 3-5 cm | 2-2.9 cm |
| Excision Margins | Pectoral muscle involvement or deep margin < 1 mm | -- | -- |
| Tumor Grade | -- | -- | Grade 3 |
LVI = lymphovascular invasion
The index was prospectively applied to 433 patients treated with mastectomy. Scores were summed and subjects with total scores ≥ 3 were offered postmastectomy RT. The 5-year actuarial locoregional recurrence rates were 9% for the high-risk group, and 4% each for the intermediate- and low-risk groups. Only 5 (1.4%) patients, 4 of whom were in the low-risk group not receiving RT, experienced isolated local recurrences.
This audit suggests that the Cambridge index might be a useful tool to select patients for postmastectomy RT. However, the index could likely be refined by incorporating other readily available clinical factors, such as young age and estrogen receptor-negative status, that were demonstrated in other series to be significant indicators of locoregional recurrence risk.[15,17] Validation testing of the index using independent datasets should also be performed to establish external validity prior to widespread clinical use.
The association between optimal locoregional control and survival is critical and continues to provide the impetus to better define selection criteria for adjuvant RT and to individualize treatment decisions. Modern conformal planning techniques have created opportunities to enhance the therapeutic ratio of RT by improving dose homogeneity to target tissues and limiting normal tissue exposure. Continued interdisciplinary clinical and translational research capitalizing on RT innovations will undoubtedly advance the common goal of achieving cure and improving quality of life for patients with breast cancer.
