by Dr. C.H. Weaver M.D. Me 12/2021
Treatment for early stage breast cancer (ESBC) includes surgery, radiation, and/or systemic therapy with chemotherapy, immunotherapy or precision cancer medicines. The specific type and sequence of treatment for each person is individualized and is based on the stage of the cancer and its genomic profile.
Radiation therapy uses high energy x-rays to kill cancer cells that remain in the breast or surrounding lymph nodes after surgery and cause breast cancer to relapse locally in the breast, surrounding chest wall, or axilla. Radiation therapy is almost always utilized as part of the overall breast-conserving strategy because radiation decreases the risk of local cancer recurrence and improves survival.
Standard local treatment for ESBC involves either a mastectomy or a lumpectomy. A mastectomy involves removal of the entire breast, whereas a lumpectomy involves removal of the cancer and some surrounding tissue. Because a lumpectomy alone is associated with a higher rate of cancer recurrence than mastectomy, patients who elect to have a lumpectomy are also treated with radiation therapy. The combination of lumpectomy and radiation is referred to as breast-conserving therapy (BCT). Breast-conserving therapy and mastectomy decrease the risk of a local cancer recurrence and produce similar rates of long-term survival.1,2
Standard radiation therapy is typically delivered to the whole breast from a machine outside the body (external beam radiation therapy) on a daily basis for 5-7 weeks. Radiation may also be delivered “internally” using radioactive substances placed in needles, seeds, or thin tubes directly into or near the cancer; this method often requires less time. Doctors are evaluating other methods to deliver radiation over shorter time intervals to reduce the inconvenience of treatment and its side effects.2-6
Ductal Carcinoma In Situ (DCIS)
Patients with DCIS treated with mastectomy do not need treatment with radiation therapy. Radiation therapy after a lumpectomy however decreases the risk of cancer recurrence. In one clinical study, 818 women with DCIS and negative surgical margins were treated with breast radiation or no further therapy after a lumpectomy. Eight years following treatment, the recurrence of invasive cancer was 3.9% for patients treated with radiation therapy and 13.4% for patients not treated with radiation therapy.
Radiation and Breast Conserving Surgery for ESBC
Patients with node-negative ESBC treated with breast-conserving surgery utilizing a lumpectomy are currently recommended to receive additional treatment with radiation therapy to reduce the risk of local cancer recurrence and to prolong survival. Most individuals with node negative early stage breast cancer benefit from radiation therapy although it may not be necessary for women older than 70 with estrogen receptor positive disease. For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is greater than 20% even in women with node negative disease.6,7
The European Organization for Research and Treatment of Cancer conducted a clinical trial evaluating 5,318 women diagnosed with Stage I or II breast cancer who had undergone a lumpectomy followed by the standard dose of radiation. Approximately half of the patients were given an additional small dose of radiation (16 Gy) to the area where the cancer had been located, while the other half received no additional treatment. Data indicated that the additional dose of radiation to the site of the removed cancer reduced the overall rate of a local recurrence by nearly 50%. Women 40 years old and younger exhibited the largest benefit, with local recurrences occurring in only 10.2% of patients receiving additional radiation, compared to 19.5% of those receiving standard treatment. Overall survival rates and the development of distant metastases were similar whether women received an additional boost of radiation or standard therapy. Side effects including cosmetic results and fibrosis (formation of scar tissue) were not affected by the additional radiation.
Regional nodal irradiation is routinely given post-mastectomy to patients with involved lymph nodes; however, its role in patients with stage I-II ESBC who have breast-conserving surgery and whole-breast irradiation is less clear. A randomized trial of 1,832 women showed that administering regional nodal irradiation after breast-conserving surgery and whole-breast irradiation reduces the risk of recurrence but does not improve overall survival.8,9
Radiation Following Mastectomy for ESBC
Postoperative chest wall and regional lymph node radiation therapy has traditionally been given to selected patients considered at high risk for local regional failure after mastectomy because it decreases the risk of local regional recurrence.14
The results of two clinical studies evaluating treatment with mastectomy followed by chemotherapy with or without radiation in premenopausal women with Stage II-III breast cancer were reported in the New England Journal of Medicine. In both studies, women treated with radiation following mastectomy and chemotherapy lived longer and were less likely to develop a recurrence of cancer. Radiation therapy decreased the risk of dying from cancer by approximately 33%. The probability of surviving 10 years from treatment was increased from 54% to 64% and 45% to 54% in the two studies, respectively. No significant long-term side effects of radiation therapy were reported. Current evidence increasingly supports the use of radiation following surgery and chemotherapy in women with Stage II or III breast cancer. Certain groups of women known to be at high risk of local breast cancer recurrence should strongly consider radiation therapy. These include:
- Cancer greater than 5 centimeters in greatest dimension
- 4 or more involved axillary lymph nodes
- Cancer involving the margin of resection
- Grossly evident extra capsular nodal extension.
What is the Optimal Sequence of Radiation in Early Stage Breast Cancer?
The timing or sequence of radiation therapy may be important. A large clinical study has addressed the question of whether radiation therapy should be given before or after chemotherapy following breast-conserving surgery. Following breast-conserving surgery, half the patients were treated with chemotherapy followed by radiation and half were treated with radiation followed by chemotherapy. The patients treated with chemotherapy followed by radiation were more likely to be alive 5 years from treatment when compared with patients treated with radiation followed by chemotherapy. Patients treated with chemotherapy survived longer because they were less likely to experience systemic (metastatic) recurrence of their cancer. Patients treated with radiation first, however, were less likely to experience a local recurrence of their cancer.
It is much easier to treat local recurrence of cancer than systemic recurrence of cancer and this may explain why patients treated with chemotherapy followed by radiation had improved survival compared to patients treated with radiation followed by chemotherapy. An additional explanation is that delivering radiation therapy before chemotherapy treatment of systemic disease may adversely affect the doctor’s ability to deliver the chemotherapy treatment. Although the sequence of treatments is undergoing continued evaluation, the current data suggest that standard treatment of breast cancer outside the context of a clinical study should include definitive surgery first, followed by systemic chemotherapy and lastly, radiation. Hormone therapy can begin during or following radiation therapy. One notable exception to this sequence is patients with locally advanced breast cancer. In these patients, administration of chemotherapy prior to surgery (neoadjuvant) may allow for greater breast conservation.
Other studies have confirmed that delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome.16-19
Side Effects of Radiation
Side effects from external radiation therapy may include a swelling or heaviness in the breast, sunburn-like changes in the skin, and fatigue. Changes to the breast and skin usually go away in 6-12 months; however, in some women the breast may become smaller or firmer following radiation therapy. The size of the breast and the woman’s desire for breast reconstructive surgery are important considerations that should be addressed prior to receiving radiation treatment. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.4
Late effects of radiation are uncommon and can be minimized with current radiation delivery techniques but may include the following.
Heart Toxicity: Controversy existed as to whether radiation therapy to the left chest wall or was associated with increased cardiac mortality for many years. Women treated with radiation therapy before 1980 experienced an increased cardiac death rate after 10 to 15 years, compared with women with non-radiated or right-side-only radiated breast cancer. This was probably caused by the radiation of the heart.20-26
More precise radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying heart and cardiac mortality decreased accordingly.23,24 An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.25,26
Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. In patients who receive axillary lymph node dissection radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy.27-29
Stage IV or Recurrent Breast Cancer
Radiation therapy also plays an important role in women with Stage IV or recurrent breast cancer. Chemotherapy and hormonal treatment are the mainstay for women who have Stage IV breast cancer at the time of diagnosis. Local control of breast cancer eradication has less impact on a patient’s outcome because the major cause of treatment failure is systemic cancer recurrence. Therefore, radiation therapy to the involved breast has not typically been recommended for women receiving systemic chemo-hormonal therapy for metastatic breast cancer.
More recent aggressive chemotherapy treatment of Stage IV breast cancer has been reported to produce long-term survival without cancer recurrence in 15-20% of women. Since these women are not experiencing a systemic cancer recurrence, prevention of cancer recurrence in the breast or lymph nodes is of greater importance. The results of a clinical study in which women with Stage IV breast cancer achieving a complete remission to chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant and local radiation to the breast was recently reported and raises the question of whether radiation may be beneficial in women with Stage IV breast cancer in complete remission.
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In this study, the patients in complete remission treated with radiation therapy had a lower relapse rate and were more likely to be alive without evidence of cancer recurrence than women not treated with radiation therapy. The chance of relapse was 36% in patients not treated with radiation, compared to 19% in patients treated with radiation. Thirty-one percent of patients treated with radiation were alive without evidence of cancer recurrence at 4 years following treatment, compared to 21% of patients who were not treated with radiation. Patients treated with radiation were also more likely to live longer, with 30% alive 4 years following treatment, compared to only 16% of patients not treated with radiation.
While this clinical study was not designed to evaluate the role of radiation therapy in patients achieving a complete remission to chemotherapy, consolidative treatment with radiation therapy after chemotherapy-induced clinical remissions in women with Stage IV breast cancer appears to reduce the risk of cancer recurrence and may improve a patient’s chance of overall survival. Future clinical studies will need to be designed to evaluate the role of radiation in patients with Stage IV breast cancer in a more formal manner.
Radiation for Palliation: Radiation therapy also plays an important role in providing symptomatic relief from advanced breast cancer. Patients developing metastatic cancer to the bone, skin, selected lymph nodes, and other sites can achieve a complete remission when treated with radiation to the site of cancer recurrence. Radiation can relieve symptoms from cancer and prevent fractures of bones when used early.
Shorter-Course Radiation Therapy:
The current approach to radiation therapy involves several consecutive weeks of daily treatment. For many women, particularly those who have to travel long distances to reach a radiation therapy facility, this can interfere greatly with work and other activities of daily life doctors are evaluating ways to deliver radiation over shorter periods of time.
Accelerated Partial Breast Irradiation: (APBI) is radiation delivered at a more concentrated and higher dose over a shorter period of time, (typically over a one-week period). APBI can be delivered using intensity modulated radiation (IMRT) which delivers fractionated radiation, meaning that the total dose of radiation is delivered in many small daily, or twice daily, doses or internally using brachytherapy.
Single dose targeted intra-operative radiotherapy (TARGIT-IORT)
Researchers designed a clinical study to determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast EBRT for the treatment of early-stage breast cancer.
The study evaluated 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1 who were eligible for breast conservation treatment in 32 centers in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.
Prior to surgical lumpectomy patients were randomly assigned to receive either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).
- EBRT consisted of a standard daily whole breast radiotherapy administered over 3-6 weeks
- TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic as the only radiotherapy. TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).
The risk of a local breast cancer recurrence at five years from treatment was 2.11% for TARGIT-IORT compared with 0.95% for EBRT suggesting that TARGIT-IORT was non-inferior to EBRT. In the first five years, 13 additional local recurrences were reported with TARGIT-IORT (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) compared with EBRT. With long term follow-up no statistically significant difference was found for local recurrence-free survival, mastectomy-free survival, distant disease-free survival, or overall survival.
For patients with early breast cancer a risk adapted immediate single dose TARGIT-IORT during lumpectomy appears to be an effective alternative to EBRT, with comparable long term cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.33
Breast brachytherapy is an alternative to traditional external beam radiation therapy and another way to deliver APBI for women who choose breast-conserving surgery. Because of the relatively short duration of the treatment course, breast brachytherapy is an attractive option for women who choose lumpectomy over mastectomy, but do not wish to undergo six weeks of external beam radiation therapy. Women should discuss with their doctor, however, whether this is an appropriate approach for them.2-4
With breast brachytherapy, a site-specific, prescribed dose of radiation is administered during a five-day course of therapy. The procedure involves inserting a deflated balloon into the cavity where the cancer was removed. An applicator shaft, or catheter, connects the balloon to the outside of the breast. The balloon is filled with saline, and both the balloon and the catheter remain in place during the time the woman is undergoing treatment. During the treatment, a radioactive “seed” is inserted into the catheter within the balloon in an exact dose, minimizing radiation exposure to the rest of the breast, skin, ribs, lungs, and heart. No source of radiation remains in the patient’s body between treatments or after the final procedure. The catheter and balloon are removed after the final procedure. Some but not all trials have reported worse cosmetic results with APBI, and patients should discuss and understand whether this has been an issue at their treating institution.
Hypofractionated radiation therapy. Hypofractionation involves fewer radiation treatments with a higher dose of radiation at each treatment. Hypofractionated radiation therapy was compared to conventional radiation therapy in two clinical trials conducted in the U.K. Women treated with hypofractionated radiation therapy received a total radiation dose of 39 to 41.6 Gy administered over 13 to 15 visits. Women treated with conventional radiation therapy received a total radiation dose of 50 Gy administered over 25 visits. Risk of cancer recurrence was low with both approaches, and there was a suggestion that hypofractionation may result in better breast appearance. The long-term effects of hypofractionation remain unknown, however.30
Radiation “boost” therapy: Standard radiation therapy following a lumpectomy consists of a limited dose of radiation (50 Gy) to the entire affected breast. While this treatment leads to long-term outcomes similar to those from mastectomy, women under age 50 experience higher rates of local recurrences following this treatment regimen compared to their elder counterparts. Researchers have theorized that an additional boost of radiation aimed only at the area from which the cancer was removed would reduce the rates of local recurrences, especially in younger patients.
To evaluate the benefits and side effects of boost radiation, researchers affiliated with the European Organization for Research and Treatment of Cancer (EORTC) conducted a study among 5,318 women with early breast cancer.25 After breast-conserving surgery, all patients received 50 Gy of radiation to the entire breast. Half the patients also received a 16 Gy radiation boost to the area of the cancer. The remaining patients received no further radiation therapy.
- Ten-year survival was 82% in both study groups (the group that received boost radiation and the group that did not receive boost radiation).
- The ten-year risk of cancer recurrence within the breast was 6.2% in patients who received boost radiation and 10.2% in patients who did not receive boost radiation.
- Young women (those under the age of 40) experienced the greatest reduction in recurrence risk following boost radiation.
- Severe fibrosis occurred in 4.4% of patients treated with boost radiation, compared with only 1.6% of patients who did not receive boost radiation.
The researchers concluded that the addition of boost radiation reduced the risk of cancer recurrence within the breast, particularly in younger patients, but did not improve 10-year survival. (30-32)
Research Suggests Radiation may not Benefit Women with HR-positive, HER2-negative ESBC
A research study, presented at the Dec 2021 San Antonio Breast Cancer suggests that a novel 16-gene radiation therapy signature may identify women who don’t benefit from radiation therapy. The Princess Margaret Trial randomized patients ages 50 or older to radiotherapy and tamoxifen or tamoxifen alone after breast conserving surgery. The results suggest that the 16-gene radiation therapy signature may be used to identify patients with a low risk of locoregional recurrence who will not experience significant benefit from adjuvant radiotherapy. The 16-gene radiation therapy signature was developed by PFS Genomics.34
- Poggi MM, Danforth DN, Sciuto LC, et al. Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. Cancer 2003;98(4): 697-702.
- Edge SB, Niland JC, Bookman MA, et al. Emergence of sentinel node biopsy in breast cancer as standard-of care in academic comprehensive cancer centers. Journal of the National Cancer Institute2003;95:1514-1521.
- Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. The New England Journal of Medicine 2003;349:546-553.
- Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. Int J Radiat Oncol Biol Phys 21 (2): 339-46, 1991.
- Clarke M, Collins R, Darby S, et al.: 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 366 (9503): 2087-106, 2005.
- Eifel P, Axelson JA, Costa J, et al.: National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93 (13): 979-89, 2001.
- Darby S, McGale P, Correa C, et al.: 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 378 (9804): 1707-16, 2011.
- Romestaing P, Lehingue Y, Carrie C, et al.: Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 15 (3): 963-8, 1997.
- Whelan TJ, Olivotto IA, Parulekar WR, et al.: Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med 373 (4): 307-16, 2015.
- Poortmans PM, Collette S, Kirkove C, et al.: Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med 373 (4): 317-27, 2015.
- Budach W, Bölke E, Kammers K, et al.: Adjuvant radiation therapy of regional lymph nodes in breast cancer - a meta-analysis of randomized trials- an update. Radiat Oncol 10: 258, 2015.
- Ragaz J, Jackson SM, Le N, et al.: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337 (14): 956-62, 1997.
- Overgaard M, Hansen PS, Overgaard J, et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337 (14): 949-55, 1997.
- Fowble B, Gray R, Gilchrist K, et al.: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6 (7): 1107-17, 1988.
- Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 355 (9217): 1757-70, 2000.
- Recht A, Come SE, Henderson IC, et al.: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334 (21): 1356-61, 1996.
- Fisher B, Brown AM, Dimitrov NV, et al.: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8 (9): 1483-96, 1990.
- Wallgren A, Bernier J, Gelber RD, et al.: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35 (4): 649-59, 1996.
- Hickey BE, Francis DP, Lehman M: Sequencing of chemotherapy and radiotherapy for early breast cancer. Cochrane Database Syst Rev 4: CD005212, 2013.
- Paszat LF, Mackillop WJ, Groome PA, et al.: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 16 (8): 2625-31, 1998.
- Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61 (6): 866-8, 1990.
- Darby SC, McGale P, Taylor CW, et al.: 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 6 (8): 557-65, 2005.
- Højris I, Overgaard M, Christensen JJ, et al.: Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 354 (9188): 1425-30, 1999.
- Nixon AJ, Manola J, Gelman R, et al.: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16 (4): 1374-9, 1998.
- Giordano SH, Kuo YF, Freeman JL, et al.: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97 (6): 419-24, 2005.
- Harris EE, Correa C, Hwang WT, et al.: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24 (25): 4100-6, 2006.
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- Bartelink H, Horiot J, Poortmans P, et al. Impact of radiation dose on local control, fibrosis and survival after breast conserving treatment: 10-year results of the EORTC trial 22881-10882. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. Oral presentation December 14, 2006. Abstract #10.
- Dewar JA, Haviland JS, Agrawal RK et al. Hypofractionation for early breast cancer: First results of the UK standardization of breast radiotherapy (START) trials. Proceedings of the 43rd Annual Meeting of the American Society of Clinical Oncology. Chicago, IL. June 1-5, 2007. Abstract #LBA518.
- Kalinsky, K. et al., Oral Presentation: [GS2-07]. San Antonio Breast Cancer Symposium; December 2021.