A new approach to breast cancer radiation therapy

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Radiation therapy is an integral part of treating breast cancer with more than half of all patients with breast cancer receiving radiation therapy at some point during treatment. 

Stanford Cancer Institute member Frederick M. Dirbas, MD,  the John and Ann Doerr Faculty Scholar of Breast Surgery, and member of the Stanford Cancer Institute’s Radiation Biology Program, spoke about the intersection of surgery and current radiation therapy treatment for breast cancer and the promise of more efficient radiation therapy with fewer side effects.

Surgery and radiation therapy for breast cancer

Breast cancer patients can choose to have a mastectomy, in which the whole breast is removed, but more than 60% choose a lumpectomy where only the tumor and a small amount of surrounding normal tissue are removed. Radiation therapy is commonly used after a lumpectomy to eradicate any residual cancer cells in the vicinity of the original tumor. Radiation therapy reduces the rate of an in-breast cancer recurrence from approximately 35% to 10% or less. Meta-analyses with thousands of patients suggest that women who have lumpectomy and radiation therapy may even have a slightly higher survival rate than mastectomy alone. The roughly six-week course of post-lumpectomy, whole breast radiotherapy has gradually been reduced through successful clinical trials to three-week courses, and even more recently one-week courses in properly selected patients.  

In properly selected patients, radiation therapy can be in a more focused way to the affected portion of the breast using partial breast radiation therapy. This delivers less radiation to the whole breast and better protects the surrounding normal breast tissue. Dirbas notes that Stanford was an early adopter of partial breast irradiation and helped pioneer this technique. Intraoperative radiotherapy, a form of partial breast irradiation, is also used in select cases. With intraoperative radiotherapy a single dose of radiation is given in the operating room at the time of the lumpectomy and avoids the need for postoperative radiation.

With decades of experience with whole breast and partial breast irradiation, Dirbas says that surgeons and radiation oncologists are increasingly exploring the potential of repeat lumpectomies followed by radiation therapy for patients who experience a local recurrence in the breast. “In the past, the immediate recommendation was mastectomy. Now, there’s increasing interest, under the right circumstances, in offering repeat lumpectomy and breast radiotherapy so that the patient can still retain their breast. Efforts to develop standards in this area are progressing in the U.S. and Europe.”

Lymph node removal is also used as part of breast cancer treatment. Since removal of lymph nodes can lead to lymphedema, usually manifested as a swelling of the arm that can affect mobility and function, the technique of sentinel node biopsy now allows sampling of a few lymph nodes without committing a removal of one to two dozen nodes. Sentinel node biopsy has a 4 to 7% risk of lymphedema, while that number rises to over 30% in patients who have the traditional axillary node dissection. Unless circumstances dictate benefit from removing many lymph nodes, most patients are now managed with sentinel node biopsy alone or sentinel node biopsy combined with radiation therapy to lymph nodes.

“The ongoing goal in breast cancer is to minimize treatment through less invasive surgical procedures for the breast and lymph nodes, decreasing the scope of surgery and radiotherapy, and using radiotherapy in lieu of surgery when there is limited lymph node involvement.”

Other uses of breast cancer radiation therapy include decreasing the size of large, inoperable tumors to make surgical excision feasible, killing remaining cancer cells after a mastectomy for locally advanced tumors to suppress chest wall recurrence, treating chest wall recurrences that happen after mastectomy, and controlling metastatic breast cancer that has spread to other areas of the body such as the brain and bones.

The benefits of improving radiation therapy for breast cancer

There are both qualitative and quantitative reasons for improving radiation therapy for breast cancer. 

While many breast cancer patients tolerate radiation therapy well, side effects can include fatigue, headaches, tissue fibrosis, frozen shoulder, depression, anxiety, and painful, dry skin. Dirbas says that sometimes newly diagnosed patients will request a mastectomy even when they are candidates for a lumpectomy because they’ve heard of the possible side effects of radiotherapy. 

Given the frequent use of radiotherapy across the spectrum of patients with a breast cancer diagnosis, the number of individuals affected is quite large. It is projected that there will be over 4 million breast cancer survivors alive and treated with radiation therapy in 2030. Radiation therapy with fewer side effects would benefit many.

FLASH radiation therapy

A novel approach that builds on progress in other areas of breast surgery and radiation therapy resides in a novel approach to how radiation therapy is delivered. Conventional radiation therapy is given in units measured in gray, delivered at a dose-rate of 0.3 to 0.4 gray per second. The new approach, ultra-high dose rate radiotherapy, also known as FLASH-RT, or simply FLASH, is delivered at over 40 gray/second, which is about 100 times faster. With conventional dose rate radiotherapy, a typical radiation treatment would last a few minutes, while with FLASH the dose is delivered in under one second.

An even more appealing aspect of FLASH is that it appears to have the same tumor-killing effect as conventional radiation therapy while sparing normal tissue, which has been confirmed in several animal studies and with early follow up. A few trials in humans are underway. The application of FLASH for a variety of cancers is currently being studied, including by a team led by Stanford Cancer Institute member Billy Loo, MD, PhD. Dirbas cites a study by Loo and colleagues using a mouse model that showed FLASH only led to depigmentation of skin in the treated areas while conventional radiation therapy caused skin ulcers.

The promise of FLASH to improve breast cancer treatment

In his SCI 2021 Innovation Awards-funded pilot study, Dirbas confirmed in a mouse model that FLASH is as effective at killing breast cancer tumors as conventional radiation therapy. His group has received additional funding from the California Breast Cancer Research Program to see if FLASH has the same effect on human breast cancer tumors grown in mice. The study will also assess long-term differences in toxicity between FLASH and conventional radiation therapy to organs at risk for toxic side effects, such as the lung, during breast cancer treatment.

Dirbas says there’s been little attention to the application of FLASH to breast cancer. He attributes this to a greater focus on other tumors which often have a worse prognosis than breast cancer. suspects this is likely because greater effort has been directed in improving radiotherapy for other cancers, such as those of the pancreas and ovary, as delivering radiotherapy to the abdomen and pelvis has even more severe consequences than radiotherapy of the breast. However, by decreasing side effects and making radiation therapy treatment more tolerable, more patients with breast cancer may opt for a lumpectomy and radiation therapy rather than a mastectomy and those treated could have improved quality of life. Fewer side effects could also help patients who struggle with the decision to have a lumpectomy or mastectomy. For those who fear radiation therapy, fewer side effects could help patients avoid

FLASH could also simplify the administration of radiation therapy for the breast. Conventional radiation therapy is sometimes synchronized with the patient’s breathing so radiation is delivered at a point in the respiratory cycle where the heart is not in the radiation field. This requires the radiation beam to be turned on and off during radiation delivery. As the entire dose can be administered in under a second, FLASH may help radiation oncologists better protect the surrounding normal tissue while making the treatment more comfortable for patients.

Uncovering the biology behind radiation therapy

In the past, it was thought that radiation therapy worked solely by causing double-strand DNA breaks to kill cancer cells, but now it’s realized that the pathways of the DNA-damage response are complex and impact the immune system. While the full nature of the interaction between radiation therapy and the immune system remains unexplained, there is renewed interest in radiation therapy alone or in combination with drugs that augment the immune system, triggering elimination of cancer cells far away from the treated region. 

Understanding more fully how radiation therapy affects the immune system and more clearly identifying the molecular pathways activated by radiotherapy may help identify ways to favorably augment the anti-cancer effect of radiotherapy while also reducing long-term radiation therapy complications, like fibrosis, that result from pathways radiation therapy activates. Stanford Cancer Institute member Lingyin Li, PhD, developed new molecules that interact with some of these pathways and is collaborating with Dirbas to determine if these new agents can augment the benefit of radiation therapy and the immune system while seeking ways to block activation of pathways that damage normal tissue. Dr. Dirbas is also collaborating with Dr. Aaron Newman, PhD, another member of the Stanford Cancer Institute, to apply a new technology, spatial transcriptomics, to better understand the radiobiology of breast cancer.

“One of the unique things about breast cancer care and surgical oncology is that you really have to have more than a passing knowledge of what your colleagues are doing in their respective disciplines to do your job as best as possible. On so many levels, we’re trying to understand what causes breast cancer, and until we get to that point, we will continue to seek better ways of treating it, making treatment safer, and helping patients live longer. As we dive into these treatment-related radiation biology questions, I often wonder what else we can discover along the way.”

October 2024