UVA Explores Same-Day Brachytherapy With Surgery for Early Breast Cancer

OncologyLive, Vol. 18/No. 09, Volume 18, Issue 09

The University of Virginia Cancer Center has developed a new method for delivering radiation therapy along with less invasive surgery in a more precise and personalized manner.

Shayna L. Showalter, MD

Assistant Professor, Surgery

Division of Surgical Oncology

University of Virginia Cancer Center

Charlottesville, VA

Although treatment for early-stage breast cancer offers excellent survival outcomes and low rates of disease recurrence, there is a need for improved radiation therapy strategies that would encourage more patients to pursue optimal, evidence-based choices. The University of Virginia (UVA) Cancer Center has developed a new method for delivering radiation therapy along with less invasive surgery in a more precise and personalized manner. Because more than half of the women diagnosed with breast cancer annually in the United States have early-stage disease, the potential impact of the UVA Cancer Center research is widespread.

Surgical treatment options for early-stage breast cancer include mastectomy or breast-conserving therapy (BCT), which involves a lumpectomy followed by radiation therapy, typically in the form of whole-breast irradiation (WBI). Large randomized clinical trials have established that mastectomy and BCT with WBI are appropriate treatment options for early- stage breast cancer, with equivalent survival outcomes.1-7 In 1990, the National Institutes of Health issued a consensus statement that supported the use of BCT and WBI as the preferred management for patients with invasive breast cancer.8 This report was followed by widespread adoption of BCT with WBI. BCT without WBI is associated with an unacceptably higher recurrence rate and a potential increase in mortality.1,9-11

However, despite the potential advantages of BCT, many eligible women opt instead to undergo mastectomy because of the long- and short-term adverse events (AEs) associated with WBI and the burden of treatment, which involves traveling to a radiation facility for daily treatments for 3 to 6 weeks.12 In addition, 20% of women who are treated with BCT never receive radiation as part of their treatment.13 Multiple factors contribute to the lower than expected use of BCT and the associated underutilization of adjuvant radiation, including cost, specific tumor characteristics, patient social and demographic factors, physician/patient bias, distance from the radiation facility, and lack of social support.12-15

Accelerated Partial Breast Irradiation

Intraoperative Radiation Therapy

Besides being time consuming and inconvenient for patients, WBI has other potential downsides, such as deleterious effects on adjacent tissues including the heart, lungs, ribs, contralateral breast, adjacent normal breast, and skin.16-18 Recent data on the use of WBI have demonstrated that it is associated with a dose-dependent increase in long-term incidence of ischemic heart disease.19 Theoretically, a safer and more convenient approach to adjuvant radiation therapy could allow more patients to choose BCT, decrease the number of patients treated with BCT who never receive adjuvant radiation, and reduce the complications associated with radiation therapy after BCT.We know that a majority of breast tumor recurrences, after treatment with BCT and WBI, occur in the same area of the breast as the original cancer.20-22 Accelerated partial-breast irradiation (APBI) is a modern alternative to WBI that makes BCT a realistic and palatable option for more women because it involves treating a limited and targeted volume of breast tissue in a much shorter course than traditional WBI and with less radiation to the heart. APBI has been studied in several large clinical trials with more than 10 years of follow-up and it is believed to be safe and effective in the local control of early-stage breast cancer.23-25Intraoperative radiation therapy (IORT) is a form of APBI that involves the delivery of a single fraction of radiation at the time of BCT. Primarily due to patient demand, IORT is becoming increasingly popular in the community because it offers maximal patient convenience and results in fewer skin and cardiac AEs when compared with WBI. Limitations to conventional breast IORT (CB-IORT) include lack of imaging for treatment planning and poor dosimetry.26 CB-IORT is performed in a standard operating room without a computed tomography (CT) scanner. The delivered doses result in a nonadjustable sphere or ellipsoid, with high doses to the applicator surface (20 Gy) and low doses to at-risk tissue 1 cm from the applicator (5-7 Gy).

Precision Breast IORT

Image 1. Integrated Brachytherapy Suite at UVA

Results from the TARGIT-A trial revealed 5-year breast cancer recurrence rates of 3.3% after CB-IORT, compared with 1.3% after WBI. The observed difference in recurrence rates satisfied the TARGIT-A trial’s prespecified statistical definition of equivalence for CB-IORT and WBI,27,28 but elicited apprehension among physicians. Despite strong patient interest and rapid adoption of CB-IORT in the United States,29 concerns regarding the efficacy of IORT have limited utilization and stimulated acrimonious debate among experts.30-32UVA Cancer Center has a unique, integrated brachytherapy suite with in-room CT imaging, shielding for high-dose rate (HDR) delivery, and an operating room table with full anesthesia capability (Image 1). The multidisciplinary breast team at the center developed Precision Breast IORT (PB-IORT), a novel form of IORT that leverages CT imaging to confirm applicator positioning, 3-D treatment planning, and an HDR brachytherapy iridium-192 source, to safely and accurately deliver a radiation therapy dose that is roughly twice the dose of CB-IORT methods. A phase I trial was conducted that established the safety and feasibility of PB-IORT.33 A multicenter phase II trial designed to establish the long-term efficacy of PB-IORT is accruing patients at UVA Cancer Center and at Thomas Jefferson University in Philadelphia, Pennsylvania.

The surgeon then returns to the brachytherapy suite, removes the catheter, and closes the incision in the breast. The patient is awakened and is able to return home the same day. In this fashion, patients with early-stage breast cancer are able to have their cancer removed and their customized HDR brachytherapy delivered all in one day.

In summary, the potential benefits of PB-IORT include (Image 2):

  1. Enhanced target volume coverage. The CT scan is used in computerized treatment planning to sculpt the radiation dose so that it encompasses the at-risk area.
  2. Normal tissue sparing. The customized radiation treatment plan carves the radiation dose away from the heart, skin, and ribs, leading to decreased toxicity to the heart and other organs.
  3. The ability to safely deliver a higher dose (12.5 Gy vs 5-7 Gy) to the lumpectomy bed. HDR brachytherapy is a superior technique for delivering the radiation dose, so we can deliver a higher prescription dose while maintaining the same maximum dose to breast tissue.

Image 2. Advantages of Precision Breast IORT

References

  1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233-1241.
  2. Blichert-Toft M, Brincker H, Andersen JA, et al. A Danish randomized trial comparing breast-preserving therapy with mastectomy in mammary carcinoma. Preliminary results. Acta Oncol. 1988;27(6A):671-677.
  3. Lichter AS, Lippman ME, Danforth DN Jr, et al. Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol. 1992;10(6):976-983.
  4. Sarrazin D, Lê MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol. 1989;14(3):177-184.
  5. van Dongen JA, Bartelink H, Fentiman IS, et al. Factors influencing local relapse and survival and results of salvage treatment after breast-conserving therapy in operable breast cancer: EORTC trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer. Eur J Cancer. 1992;28A(4-5):801-805.
  6. Veronesi U, Saccozzi R, Del Vecchio M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med. 1981;305(1):6-11.
  7. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312(11):665-673.
  8. Consensus conference. Treatment of early stage breast cancer. National Institutes of Health. Conn Med. 1991;55(2):101-107.
  9. Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol. 2001;12(7):997-1003.
  10. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087-2106.
  11. Darby S, McGale P, Correa C, et al; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707-1716. doi: 10.1016/S0140-6736(11)61629-2.
  12. Schroen AT, Brenin DR, Kelly MD, Knaus WA, Slingluff CL Jr. Impact of patient distance to radiation therapy on mastectomy use in early-stage breast cancer patients. J Clin Oncol. 2005;23(28):7074-7080.
  13. Showalter SL, Grover S, Sharma S, Lin L, Czerniecki BJ. Factors influencing surgical and adjuvant therapy in stage I breast cancer: a SEER 18 database analysis. Ann Surg Oncol. 2013;20(4):1287-1294. doi: 10.1245/s10434-012-2693-8.
  14. Jacobs LK, Kelley KA, Rosson GD, Detrani ME, Chang DC. Disparities in urban and rural mastectomy populations: the effects of patient- and county-level factors on likelihood of receipt of mastectomy. Ann Surg Oncol. 2008;15(10):2644-2652. doi: 10.1245/s10434-008-0053-5.
  15. Cox JA, Swanson TA. Current modalities of accelerated partial breast irradiation. Nat Rev Clin Oncol. 2013;10(6):344-356. doi: 10.1038/nrclinonc.2013.65.
  16. Kahán Z, Csenki M, Varga Z, et al. The risk of early and late lung sequelae after conformal radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys. 2007;68(3):673-681.
  17. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-565.
  18. Schaapveld M, Visser O, Louwman WJ, et al. The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: a population based study in the Netherlands. Breast Cancer Res Treat. 2008;110(1):189-197.
  19. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998. doi: 10.1056/NEJMoa1209825.
  20. Smith TE, Lee D, Turner BC, Carter D, Haffty BG. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys. 2000;48(5):1281-1289.
  21. Huang E, Buchholz TA, Meric F, et al. Classifying local disease recurrences after breast conservation therapy based on location and histology: new primary tumors have more favorable outcomes than true local disease recurrences. Cancer. 2002;95(10):2059-2067.
  22. Fowble B, Solin LJ, Schultz DJ, Rubenstein J, Goodman RL. Breast recurrence following conservative surgery and radiation: patterns of failure, prognosis, and pathologic findings from mastectomy specimens with implications for treatment. Int J Radiat Oncol Biol Phys. 1990;19(4):833-842.
  23. Shah C, Vicini F, Wazer DE, Arthur D, Patel RR. The American Brachytherapy Society consensus statement for accelerated partial breast irradiation. Brachytherapy. 2013;12(4):267-277. doi: 10.1016/j.brachy.2013.02.001.
  24. Mannino M, Yarnold J. Accelerated partial breast irradiation trials: diversity in rationale and design. Radiother Oncol. 2009;91(1):16-22. doi: 10.1016/j.radonc.2008.12.011.
  25. Offersen BV, Overgaard M, Kroman N, Overgaard J. Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review. Radiother Oncol. 2009;90(1):1-13. doi: 10.1016/j.radonc.2008.08.005.
  26. Khan AJ, Arthur DW, Vicini FA. On the road to intraoperative radiotherapy: more 'proceed with caution' signs. Oncology (Williston Park). 2013;27(2):113-114, 122.
  27. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91-102. doi: 10.1016/S0140-6736(10)60837-9.
  28. Vaidya JS, Wenz F, Bulsara M, et al; TARGIT trialists' group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603-613. doi: 10.1016/S0140-6736(13)61950-9.
  29. Peres J. Intraoperative radiotherapy makes uncertain headway in the U.S. J Natl Cancer Inst. 2012;104(12):895-897. doi: 10.1093/jnci/djs294.
  30. Vaidya JS, Bulsara M, Wenz F, et al; TARGIT trialists' group. Pride, prejudice, or science: attitudes towards the results of the TARGIT-A trial of targeted intraoperative radiation therapy for breast cancer. Int J Radiat Oncol Biol Phys. 2015;92(3):491-497. doi: 10.1016/j.ijrobp.2015.03.022.
  31. Zietman A. Letters regarding the TARGIT-A trial: the editor's introduction. Int J Radiat Oncol Biol Phys. 2015;92(5):951-952. doi: 10.1016/j.ijrobp.2015.05.048.
  32. Hepel J, Wazer DE. A flawed study should not define a new standard of care. Int J Radiat Oncol Biol Phys. 2015;91(2):255-257. doi: 10.1016/j.ijrobp.2014.09.019.
  33. Jones R, Libby B, Showalter SL, et al. Dosimetric comparison of Ir high-dose-rate brachytherapy vs. 50 kV x-rays as techniques for breast intraoperative radiation therapy: Conceptual development of image-guided intraoperative brachytherapy using a multilumen balloon applicator and in-room CT imaging. Brachytherapy. 2014;13(5):502-507. doi: 10.1016/j.brachy.2014.04.005.

When a patient is treated with PB-IORT at UVA Cancer Center, the BCT is performed in the brachytherapy suite. The surgeon then places a multilumen brachytherapy catheter into the lumpectomy bed. Next, without moving the patient, a CT image is obtained. This image facilitates confirmation of balloon placement and allows for any necessary adjustments to maximize the conformity of the breast tissue and the balloon. The physicist and radiation oncologist use the CT images to customize the radiation treatment plan. The 3-D treatment planning and multilumen catheter facilitate sculpting the dose away from normal tissues and allow for concentration of the dose in the specific area of the breast from which the tumor was removed. After the plan is made, the catheter is connected to the HDR brachytherapy source and the radiation treatment is delivered.