Radiation Therapy for Early Stage Node Negative Breast Cancer

Cancer Connect

by Dr. C.H. Weaver M.D. updated 2/2020

Standard local treatment for early-stage breast cancer 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 typically treated with radiation therapy. The combination of lumpectomy and radiation is referred to as breast-conserving therapy. Breast-conserving therapy and mastectomy decrease the risk of a local cancer recurrence and produce similar rates of long-term survival. (1,2)

Radiation therapy is often delivered to the whole breast from a machine outside the body (external beam radiation therapy). This treatment is commonly delivered on a daily basis for 5-7 weeks. Doctors are increasingly using other methods to deliver radiation over shorter time intervals to reduce the inconvenience of treatment and its side effects.(2-6)

Why is radiation used to treat node negative breast cancer?

  • To allow for breast conserving surgery, to reduce the risk of local cancer recurrence and to prolong survival.

Who should receive radiation therapy?

  • 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.

How is radiation therapy delivered?

  • Radiation therapy uses high-energy X-rays or other types of radiation to kill the cancerous cells within the breast tissue. Radiation may be delivered through external radiation, which uses a machine to deliver the rays from outside the body or internal radiation therapy, which utilizes radioactive substances placed in needles, seeds, or thin tubes directly into or near the cancer; this method often requires less time.

What is Accelerated Partial Breast Irradiation?

  • 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.
  • Balloon brachytherapy is an alternative way to deliver APBI. With this approach, a small balloon is inserted into the lumpectomy cavity (the space created when the tumor is removed). A catheter attached to the balloon is used to deliver radioactive “seeds” to the site. This approach limits exposure of healthy tissue to radiation and can shorten treatment time to a week or less by delivering high doses of radiation. Because this approach requires many fewer weeks of treatment than conventional external beam radiation therapy, it may be a much more convenient. (2,3) Additionally, because partial breast irradiation is more targeted, there is less exposure to vital organs like the lungs and the heart.(4)
  • 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.

How soon after surgery should radiation start?

  • Some but no all research suggests radiation should begin within 6 weeks of surgery.

Explore the Clinical Trial Results Evaluating Radiation in ESBC

Radiation Reduces Mortality at 15 Years in Early Breast Cancer

Researchers affiliated with the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) evaluated breast-conserving therapy with or without radiation therapy to mastectomy with or without radiation therapy in a large analyses and found that radiation resulted in a significant difference in local regional recurrences and 15-year mortality.

  • Radiation in patients treated with breast-conserving therapy reduced local regional recurrences by 19%.
  • 15-year mortality from breast cancer was reduced from nearly 36% to 30% in patients treated with radiation therapy following breast-conserving therapy compared to those not treated with radiation therapy.
  • 15-year mortality from breast cancer was reduced from 60% to 54% in patients who received radiation therapy following a mastectomy compared to those treated with a mastectomy alone.

The researchers concluded that a reduction in the risk of local regional recurrences with the use of radiation therapy significantly reduces the long-term risk of death caused by early breast cancer.

Radiation therapy is associated with side effects such as fatigue, skin burns, and cosmetic changes. Additionally, patients often need to take time off from work in order to attend radiation treatment sessions. Therefore, clinical studies have been performed to evaluate shorter radiation treatment schedules with the goal of maintaining the highest survival benefit for patients.

Shorter Course APBI Radiation Therapy

The most recent research suggests shorter course APBI to the breast results in equivalent outcomes among patients with node negative breast cancer who have undergone breast conserving surgery compared to the standard longer course and higher dose.(2,3,10)

Accelerated partial breast irradiation after surgery is as effective as whole breast irradiation for preventing recurrence among patients with early stage node negative breast cancer, according to 10-year follow-up results from the APBI IMRT Florence clinical trial presented at the 2019 San Antonio Breast Cancer Symposium.

The Florence clinical trial included 520 women aged older than 40 years with stage I or stage II breast cancer. Half of the women were treated with accelerated partial breast irradiation, which consisted of a total 30 Gray of radiation to the tumor bed in five daily fractions. The other half of women received whole breast irradiation, which consisted of a total of 50 Gray administered in 25 daily fractions to the whole breast, plus a 10-Gray boost to the tumor bed in five daily fractions.

Initial analysis performed after 5 years of follow-up showed no significant differences in cancer recurrences and now with median follow-up of 10 years there is no difference in local recurrence rate or overall survival. Ten-year cumulative risk of local regional recurrence was 3.9% with accelerated partial breast irradiation and 3% with whole breast irradiation. Overall 97% of women treated survived 10 from initiation of treatment.

The findings support previous studies demonstrating that shorter course less invasive partial breast irradiation is an acceptable alternative to whole breast irradiation.

A second clinical trial called RAPID compared external beam APBI over one week to whole breast radiation delivered over three to five weeks between 2006 and 2011 in 33 cancer centers across Canada, Australia and New Zealand. The 2,135 patients were women aged 40 or older with ductal carcinoma or node-negative breast cancer which had been treated by breast conserving surgery.

At eight years, the risk of cancer recurrence in the breast was very low and similar for the two groups. For patients treated with APBI the risk was three per cent and for patients treated with whole breast radiation the risk was 2.8 per cent.

Although less early toxicity within three months of treatment was observed with APBI, the twice-daily regimen was likely associated with higher late toxic effects and worse cosmetic outcomes. This included increased small blood vessels visible on the skin, and thickening of breast tissue related to radiation. About 13 per cent of patients who had whole breast radiation had moderate toxicity, compared to 32 per cent for those who had APBI.(12)

UCLA scientists also evaluated APBI with interstitial multi-catheter brachytherapy and found that women diagnosed with breast cancer and treated with a shorter one-week regimen of partial breast radiation after the surgical lumpectomy, saw no increase in cancer recurrence or difference in cosmetic outcomes compared to women who received radiation of the entire breast for a period of up to six weeks after surgery.

The study followed over 1000 women who received partial breast irradiation after surgery, with an average follow-up of about seven years.

Being able to reduce the amount of time it takes for a woman to complete a course of radiation will open the door to this modality to women who previously opted for mastectomies due to inability to get to a radiation facility. Many women do not live close to a treatment center, but they might now consider spending a week away from home compared with more than a month. This also allows patients to get back to work and to their family. Larger studies may be needed to confirm these findings, and cosmetic outcomes and effects of exposure to higher daily dosing of radiation on other organs also need to be examined.

Breast Brachytherapy Linked with More Complications and Higher Mastectomy Rate

Although not found in the UCLA study, results from an early study of women treated with balloon brachytherapy using the MammoSite® Radiation Therapy System were published for 43 breast cancer patients who have been followed for a median of four years after treatment with MammoSite. There were no cancer recurrences among these women, and a majority had a good cosmetic outcome.

According to one study however the use of brachytherapy may result in more post-operative complications than conventional external beam radiation therapy, and may also increase the likelihood that a woman will later require a mastectomy.

Researchers at the MD Anderson Cancer Center conducted an analysis of Medicare claims data between 2000 and 2007. All of the women included in the analysis had been treated with breast-conserving surgery followed by either breast brachytherapy or whole-breast external beam radiation therapy.

  • Use of brachytherapy increased over time. In 2000, less than 1% of the women had been treated with brachytherapy. By 2007, 13% of women were being treated with brachytherapy.
  • Postoperative complications were more common in the brachytherapy group. Infectious complications, for example, developed in 16% of women treated with brachytherapy and 10% of women treated with external beam radiation therapy.
  • By five years after treatment, 4% of women treated with brachytherapy had required additional treatment with a mastectomy, compared with 2.2% of women who had received external beam radiation therapy. The researchers note that the higher rate of mastectomy in the brachytherapy group could be due to breast cancer recurrence or breast complications.

These results raise the possibility that breast brachytherapy may be less effective and more apt to cause breast complications than whole-breast external beam radiation therapy. This was not a randomized trial, however, and the results should not be viewed as definitive. Ongoing trials of breast brachytherapy will provide more conclusive information about the risks and benefits of this approach.(5)

Boost Radiation for Early Breast Cancer Improves Local Control but Not Survival

Breast-conserving surgery is generally followed by radiation therapy. In addition to receiving radiation therapy to the entire breast, women with early breast cancer often receive an additional boost of radiation to the area of the cancer with the goal of reducing the risk of recurrence. Boost radiation among women with stage I or stage II breast cancer reduces the risk of cancer recurrence within the breast but does not affect 10-year survival.(6)

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 stage breast cancer.

After breast-conserving surgery, all patients received radiation to the entire breast and half the patients also received a 16 Gy radiation "boost" to the area of the cancer.

  • The boost did not improve long term survival; ten-year survival was 82% for those that received boost radiation and those group that did not.
  • 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.

Doses a Delay in Radiation Increases Risk of Breast Cancer Recurrence?

Some but not all research suggests that for women who choose to undergo breast-conserving surgery for treatment of early stage breast cancer, a longer interval between surgery and the start of radiation therapy may increases the risk of local cancer recurrence.

Among women who undergo breast-conserving therapy, prompt treatment with radiation therapy after surgery may result in better outcomes than delayed radiation therapy. To explore this issue, researchers evaluated information from a large U.S. database that links cancer registry data with Medicare claims data. Information was available for more than 18,000 women over the age of 65 who had undergone breast-conserving therapy for Stage 0-II breast cancer and did not receive chemotherapy.

The average time from surgery to start of radiation therapy was 34 days and 30% of women started radiation therapy more than six weeks after surgery.

Longer intervals between surgery and the start of radiation therapy were linked with an increased risk of local cancer recurrence. For example, women who started radiation therapy more than six weeks after surgery were 19% more likely to experience local cancer recurrence than women who had a shorter interval between surgery and radiation.

Women were more likely to have a longer interval between surgery and the start of radiation therapy if they had positive lymph nodes, other health conditions, a history of low income, or were of Hispanic ethnicity or non-White race. Longer intervals were also more common in regions of the United States that had higher rates of breast-conserving therapy, suggesting that busy treatment facilities may have longer wait times.

These results suggest that starting radiation therapy as soon as possible after lumpectomy may reduce the risk of local cancer recurrence.

According to research published in the International Journal of Radiation Oncology, Biology and Physics, radiation therapy delayed for up to 16 weeks following surgery may not affect outcomes in patients with node-negative breast cancer.

Researchers from Canada conducted a study to determine whether delayed radiation therapy affects outcomes of women with node-negative breast cancer. This study included 568 patients who underwent surgery and radiation therapy without systemic chemotherapy therapy between 1985 and 1992.

The following time intervals of delayed radiation therapy were analyzed: 0-8 weeks following surgery; greater than 8 to 12 weeks following surgery; greater than 12 to 16 weeks following surgery; and greater than 16 weeks following surgery. The median follow-up was over 11 years.

  • There were no significant differences in terms of local cancer recurrences between the groups of patients treated with radiation at different time intervals following surgery.
  • There were no significant differences in terms of cancer-free survival between the groups of patients.

The researchers concluded that radiation therapy delivered up to 16 weeks following surgery appears to provide similar outcomes to radiation therapy delivered immediately following surgery among patients with node-negative breast cancer.(7)

These results from these studies suggest that starting radiation therapy as soon as possible after lumpectomy may reduce the risk of local cancer recurrence.(8)

Is Radiation Necessary for All Patients with Node Negative Disease?

Researchers are evaluating whether eliminating radiation in several groups of women is ongoing but inconclusive at this time. For example doctors are trying to determine if women over 70 years who have hormone receptor-positive, HER2-positive disease or those with luminal A breast cancer can avoid radiation altogether.

Some Older Women with Early-Stage Breast Cancer May Be Receiving Radiation That Is Unlikely to Add Benefit

Up to two-thirds of older women with early-stage breast cancer may be receiving radiation therapy that may not provide additional benefit. These findings were recently released online by the journal Cancer.

Findings suggest that women over age 70 who have stage I estrogen-receptor positive breast cancer may not benefit from the addition of radiation therapy, these older patients might do just as well with lumpectomy and additional therapy with tamoxifen alone, rather than both tamoxifen and radiotherapy.

Researchers evaluated data from the Surveillance, Epidemiology, and End Results (SEER) registry in over 40,000 women age 70 or older who underwent lumpectomy for early-stage breast cancer between 2000 and 2009 and found that radiation in addition to lumpectomy didn’t contribute to better outcomes for older women with early-stage breast cancer.

Many older women continue to receive radiation therapy that may not improve their outcomes over treatment with surgery and tamoxifen alone. Women should discuss the role of radiation with their treating physician and make sure the understand the most current research supporting or refuting its use.

Risk of Heart Disease from Breast Cancer Radiation

Although radiation exposure from breast cancer treatment is associated with a small risk of subsequent heart disease, the risk is lower than it was 20 years ago, according to the results of a study published in JAMA Internal Medicine. (9)

Radiation is used after surgery to kill any remaining cancer cells and this decreases the risk of local recurrence and improves survival. Like any treatment however, radiation carries risks—including an increased risk of heart disease when radiation is used on the left breast, which is closer to the heart.

Because long-term breast cancer survival rates have improved dramatically in recent decades, researchers continue to look for ways to minimize long-term treatment-related complications. Researchers conducted an analysis to evaluate the risk of developing heart disease as a result of radiation treatment to the left breast—and found that the risk varies depending on the underlying risk of heart disease.

They report that the average risk of developing heart disease as a result of radiation exposure for breast cancer treatment is less than one percent. The risk increases for woman who already have a high underlying risk of developing heart disease—in these cases, the risk may be as high as 1 in 30. In contrast, women who already have a very low underlying risk of heart disease may face odds as low as 1 in 3000, which is a tiny risk.

The researchers note that the risk of developing radiation-induced heart disease is small enough that women should not skip radiation treatment as a result of this risk.

Women who have a high underlying risk of heart disease can reduce their risk of radiation-induced heart disease in the same way that anyone might reduce their risk—through healthy diet, exercise, and avoidance of tobacco. Researchers continue to investigate changes to radiation treatment that might reduce the risk of heart disease for high-risk patients in the future.

MammoSite® for Early-stage Breast Cancer Treatment

MammoSite is a radiation delivery system that delivers partial breast irradiation over a period of five to seven days. Each day a specific dose of radiation is placed within the implanted tube for a short period of time. The radioactive material is removed each day, allowing patient to return to normal activities.

In this study, researchers evaluated three years of data regarding treatment efficacy, cosmetic results, and side effects associated with the use of MammoSite. A total of 1,440 women diagnosed with early-stage breast cancer who were undergoing breast conserving therapy, rather than mastectomy, were evaluated. Each received partial breast irradiation using the MammoSite delivery system.

Of the 1,440 women, 1,255 had invasive breast cancer with an average tumor size of 10mm; 194 women had ductal carcinoma in situ (DCIS), an early form of breast cancer that develops in the lining of the milk ducts of the breast. The overall period of follow-up was 30 months.

  • 23 women (1.6%) developed a breast tumor in the opposite breast. This occurrence was slightly higher among the women who had invasive breast cancer compared with those who had DCIS (1.11% versus 59%).
  • Six of the women (0.4%) were found to have cancer that had spread to a nearby lymph node.
  • Cosmetically, the women’s breasts were in good to excellent shape following treatment and follow up at 12 and 48 months.
  • The most common side effect was breast seroma, which occurred in 23.9% of women. (A breast seroma is gathering of serous fluid in the empty space left by the tubes placed for the delivery of radiation.) These seromas were mild in most cases, producing symptoms in only 10% of the women who developed them.

The researchers concluded that MammoSite is an effective treatment option for women with some forms of early breast cancer. Results and side effects were found to be similar to other forms of partial breast irradiation techniques with similar follow up. Patients are encouraged to speak to their physician regarding their treatment options. (11)

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​References:

  1. 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; 366:2087-2106.
  2. Oncology Times, Vol 22, No 6, pp 43-44, 2000
  3. American Society for Therapeutic Radiology and Oncology (ASTRO) Press Release. New One Week Radiation Treatment for Breast Cancer Patients Offers Promising Results. October 17, 2005.
  4. Source: UCLA newsroom.
  5. Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. Presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. December 6-10, 2011. Abstract S2-
  6. 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.
  7. Vujovic O, Yu E, Cherian A, et al. Eleven-Year Follow-Up Results in the Delay of Breast Irradiation After Conservative Breast Surgery in Node-Negative Breast Cancer Patients. International Journal of Radiation Oncology, Biology and Physics. 2006;64: 760-764.
  8. Punglia RS, Saito AM, Neville BA, Earle CC, Weeks JC. Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis. British Medical Journal [early online publication]. March 2, 2010.
  9. Brenner DJ, Shuryak I, Jozsef G, et al. Risk and risk reduction of major coronary events associated with contemporary breast radiotherapy. JAMA Internal Medicine. Published early online October 28, 2013. doi:10.1001/jamainternmed.2013.11790
  10. Meattini I, et al. Abstract GS4-06. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
  11. Vicini, F., Beitsch, P., Quiet, C., et al. Three year analysis of treatment efficacy, cosmesis, and toxicity by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial in patients treated with accelerated partial breast irradiation. Cancer. 2008. 112(4): 758-766.
  12. [External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19%2932515-2/fulltext)
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