1. Hypofractionated Radiation Therapy for Early Stage Breast Cancer Patrick J. Gagnon, M.D. Resident, PGY-4 Radiation Medicine, OHSU Providence Hospital Breast Conference November 5, 2008

2. Outline  Hypofractionation  Benefits  Radiobiology  Disadvantages  Breast Conservation  Current Standard-of-Care  Hypofractionated Radiation  Whelan Data – JNCI (2002)  Whelan Update – ASTRO (2008)

3. Hypofractionation - Defined  Larger doses of radiation per treatment fraction delivering a full course of treatment over a shorter period of time compared to conventional fractionation  Typical fraction sizes: 1.8 – 2.0 Gy per day  Hypofractionation: 2.25 - >20 Gy per day  SBRT (lung, liver), pre-op rectal, glottic larynx

4. Hypofractionation - Benefits  Reduced cost (fewer fractions, increased throughput)  Increased convenience (1-3 weeks vs 6-7)  Decreased patient travel and lodging  Increased treatment compliance and acceptance of therapy  Improved access to care  Radiobiology

5. Hypofractionation - Radiobiology  Increased dose per fraction, increased tumor kill  Relative dose to late- responding tissues is higher than to early- responding tissues (mucosa, tumor) raising concerns about late- tissue toxicity

6. Hypofractionation - Disadvantages  Late normal tissue toxicity  Cosmesis  Loco-regional control  Biologically equivalent dose may actually be less than compared to standard fractionation

7. Breast Applications  Standard BCT includes lumpectomy with negative margins followed by whole breast radiation therapy  Radiation doses typically 45-50 Gy +/- lumpectomy cavity boost to ~61 Gy  Fraction sizes 1.8 – 2.0 Gy, often 33 fractions delivered over 6.5 weeks  Excellent local control and cosmesis

8. Long-term Results of a Randomized Trial of Accelerated Hypofractionated Whole Breast Irradiation Following Breast Conserving Surgery in Women with Node-Negative Breast Cancer  Whelan et. al., Canada  Plenary session, 50 th annual ASTRO Meeting, Boston  Initial data published in JNCI in 2002  10 year follow-up data presented at ASTRO

9. Randomized Trial of Breast Irradiation Schedules After Lumpectomy for Women With Lymph Node- Negative Breast Cancer  Results initially reported with median follow- up of 69 months (JNCI 2002;94:1143-50)  1234 patients, T1-2 N0 disease, lumpectomy with negative margins, 2 arm randomization  622 received 42.5 Gy in 16 fractions and 612 received 50 Gy in 25 fractions  Primary endpoint local recurrence  Secondary endpoints were distant recurrence, cosmesis, and late radiation toxicity

10. Randomized Trial of Breast Irradiation Schedules After Lumpectomy for Women With Lymph Node- Negative Breast Cancer

11. Local in-breast recurrence data from original study with 5 year follow-up

12. Long-term Results of a Randomized Trial of Accelerated Hypofractionated Whole Breast Irradiation Following Breast Conserving Surgery in Women with Node-Negative Breast Cancer  Median follow-up now 144 months  Local Recurrence at 10 years  6.2% (hypofrac)  6.7% (standard frac)  Cosmesis at 10 years (EORTC Rating System)  70% excellent (hypofrac)  71% excellent (standard frac)  Late mod-severe skin/sub-Q toxicity at 10 years  6% skin & 8% sub-Q (hypofrac)  3% skin & 4% sub-Q (standard frac)

13. Long-term Results of a Randomized Trial of Accelerated Hypofractionated Whole Breast Irradiation Following Breast Conserving Surgery in Women with Node-Negative Breast Cancer  Conclusions  Accelerated hypofractionated whole breast irradiation provides excellent long-term local control and limited late morbidity  Benefits of convenience and cost  Questions over late normal tissue toxicity remain  Standard arm does not match typical U.S. whole breast regimen (higher whole breast dose, no boost)  Cosmesis based on physician assessment rather than patient assessment  Is this the new “standard-of-care” or do we rely on our mature data and extensive clinical experience with conventionally fractionated whole breast radiation?

14. Acknowledgements  Thank you to Dr. Cha and the entire Providence Radiation Oncology Department  Providence Breast Conference  Dr. Charles Thomas, OHSU Radiation Medicine  Dr. Carol Marquez, OHSU Radiation Medicine  Dr. John Holland, OHSU Radiation Medicine