Reducing Intensity of Treatment
Highly Accelerated Irradiation in 5 Fractions (HAI-5): Feasibility in Elderly Women With Early or Locally Advanced Breast Cancer

https://doi.org/10.1016/j.ijrobp.2017.01.229Get rights and content

Purpose

To investigate, in a prospective phase 1 to 2 trial, the safety and feasibility of delivering external beam radiation therapy in 5 fractions to the breast or thoracic wall, including boost and/or lymph nodes if needed, to women aged ≥65 years with breast cancer.

Methods and Materials

Ninety-five patients aged ≥65 years, referred for adjuvant radiation therapy, were treated in 5 fractions over 12 days with a total dose of 28.5 Gy/5.7 Gy to the breast or thoracic wall and, if indicated, 27 Gy/5.4 Gy to the lymph node regions and 32.5 Gy/6.5 Gy to 34.5 Gy/6.9 Gy to the tumor bed. The primary endpoint was clinically relevant dermatitis (grade ≥2).

Results

Mean follow-up time was 5.6 months, and mean age was 73.6 years. Clinically relevant dermatitis was observed in 11.6% of patients and only occurred in breast irradiation with boost (17.5% grade 2-3 vs 0% in the no-boost group). Although doses were high, treatment delivery with intensity modulated radiation therapy was swift, except for complex treatments, including lymph nodes for which single-arc volumetric modulated arc therapy was needed to reduce beam-on time.

Conclusion

Accelerated radiation therapy in 5 fractions was technically feasible and resulted in low acute toxicity. Clinically relevant erythema was only observed in patients receiving a boost, but still at an acceptable rate. Although the follow-up is still short, the results on acute toxicity after accelerated radiation therapy were encouraging. A 5-fraction schedule is well tolerated in the elderly and may lower the threshold for radiation therapy in this population.

Introduction

Breast cancer is the most frequent cancer type worldwide: with an incidence of 1,677,000 cases annually, it represents 11.9% of all cancers diagnosed (1). Along with an evidence-based indication for radiation therapy of 87%, it is the cancer type with the highest radiation therapy needs globally. Radiation therapy plays an important role in local control but also improves survival 2, 3, 4. Whereas optimal access to radiation therapy is a precondition to obtaining these clinical benefits, substantial gaps in radiation therapy access exist, not only in low- and middle-income countries where lack of resources may be the dominating factor, but even in regions with a higher welfare, such as Europe, Canada, and Australia 5, 6, 7, 8. In these countries, other barriers may determine the observed underutilization, of which age is a well-recognized one (9). Hence, where advanced age is associated with lower stage and more favorable prognostic outcomes, survival is paradoxically worse compared with younger cohorts, because many patients go undertreated owing to factors such as comorbidity, physician bias, cost, and psychosocial issues 10, 11, 12.

In 2007, the International Society of Geriatric Oncology published guidelines recommending that patients aged >70 years be treated according to standard guidelines, with exceptions for cases with significant comorbidity or low functional status (13). However, radiation therapy, chemotherapy, and hormonal therapy continue to be offered less frequently to patients of advancing age, resulting in higher mortality for early-stage breast cancer 14, 15.

Although increase of comorbidity and frailty is a gradual process, no uniform age threshold can be found for the decline in adherence to treatment guidelines, suggesting a psychological trigger rather than purely physiologic considerations (12). The most negative effect on overall survival and disease-specific survival is observed for radiation therapy 16, 17, especially in hormone receptor–negative breast cancer, where omission of radiation therapy results in higher numbers of deaths from breast cancer than from cardiovascular disease, even in those aged >80 years (18).

Living far from radiation facilities or having insufficient insurance coverage are established obstacles to receiving radiation therapy 19, 20, 21. Yet even in countries with adequate social security and wide availability of radiation therapy facilities, uptake decreases with age (9). Although radiation therapy treatment for breast cancer has moved toward hypofractionation as the new gold standard, older patients still remain reluctant to undergo radiation therapy.

For elderly patients with very early stage breast cancer, single-fraction intraoperative techniques may lower the threshold of access to radiation therapy 22, 23, or radiation therapy can even be omitted 24, 25. This is not the case in locally advanced stages or when poor prognostic characteristics are present 25, 26 and whole-breast irradiation (WBI) or thoracic wall irradiation (TWI) along with lymph node irradiation (LNI) are indicated. In these cases accelerated delivery in 5 fractions may overcome resistance to adequate locoregional treatment, provided it does not come at the cost of higher toxicity in this frail subset of the population. External beam radiation therapy for WBI in 5 fractions has been tested in several studies, yet little remains known about acceleration for TWI, or in case lymph nodes should be included or a boost added 27, 28, 29, 30, 31.

In preparation for a randomized, controlled trial comparing 5 versus 15 fractions over 10 or 15 days, a phase 1 to 2 study was performed, including all breast cancer stages in women aged ≥65 years.

This article reports on the feasibility of accelerated radiation therapy to the breast, thoracic wall, and lymph nodes and on the first clinical results, more specifically on acute toxicity.

Section snippets

Patient selection

All female patients age ≥65 years, referred for adjuvant radiation therapy after breast cancer surgery—breast-conserving or mastectomy—were offered the study protocol and included after signing the informed consent form, approved by the ethics committee of our institution. The exclusion criteria were the need for bilateral breast irradiation or re-irradiation, or the need for boost after mastectomy.

Image acquisition

Patients were simulated on a large-bore Toshiba Aquillion CT scanner (Toshiba Medical Systems,

Patient characteristics

Ninety-five patients were included in this analysis. Characteristics of patients, tumor, and treatment are described in Table 1. Mean age was 73.6 years, with 65% of patients aged >70 years. Two patients had not reached 65 years at the time of inclusion. The mean follow-up time was 5.6 months.

Forty-five percent of patients were diagnosed with early (stage I) breast cancer, 35% with stage II, and 20% with stage III or locally advanced. Poor prognostic subtyping was found in 45% of patients, with

Discussion

Undertreatment in the older population impacts local control and disease-free survival, especially in the intermediate- and high-risk groups 16, 18. Acceleration to 5 fractions in less than 2 weeks may possibly overcome resistance to adjuvant radiation therapy. However, the feasibility and safety of accelerated treatment need validation before applying these schedules beyond clinical trials. Because many patients present with advanced tumor stages, this trial was conceived to test acceleration

Acknowledgments

The authors thank Annick Van Greveling and Giselle Post, study nurses, for motivating breast cancer patients to participate in this and other ongoing studies; and David Vose and Pauline Page Jones for textual revision of the manuscript.

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    This research was supported by a grant (Klinisch Onderzoeks Fonds) from Ghent University Hospital. Study nurses were funded by Think Pink.

    Conflict of interest: W.D.N. reports grants from Think Pink and from Kom op tegen kanker, during the conduct of the study. L.V. reports grants from Susan G. Komen and from Kom op tegen kanker, outside the submitted work.

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