Managing Long-Term Toxicity From Pelvic Radiation Therapy
A Conversation With Sarah E. Hoffe, MD
Advances over the past 3 decades in improvements in cancer prevention and screening strategies and more effective diagnostics and therapies in cancer care have led to unprecedented declines in death rates from all cancers, including prostate, gynecologic, and colorectal/anal cancers. The fastest decline so far was from 2017 to 2018, when the 1-year drop in cancer deaths fell to 2.4%.1 The steady progress in cancer advances has translated to nearly 17 million cancer survivors in the United States. By 2030, it is estimated that the number of survivors will increase to more than 22 million.2
Sarah E. Hoffe, MD
However, despite the advances in more effective treatments that are allowing more individuals to live long lives after a cancer diagnosis, some survivors, especially those who had pelvic cancers, will experience late effects from their treatment and a reduced quality of life. According to a presentation by Sarah E. Hoffe, MD, Section Head of GI Radiation Oncology at Moffitt Cancer Center, at the 2021 ASCO Annual Meeting,3 although radiation treatment techniques from conventional external-beam radiation therapy and three-dimensional conformal radiation therapy to current intensity-modulated radiation therapy have significantly improved, sparing damage to normal tissues, the late effects of pelvic radiation remain a persistent clinical management challenge.
“As we think about survivorship, it becomes more important to individualize plans, factoring in each patient’s baseline risk factors and other treatments that can have overlapping toxicities,” said Dr. Hoffe during her presentation. “At our center, we are starting to integrate the concept of “onco-wellness,” really focusing a lot on optimizing lifestyle medicine for patients at higher risk. At present, a variety of care models exist at different institutions without uniform consensus on the best time to transition patients treated for pelvic cancers. So, this remains an area of ongoing and very active investigation to optimize survivorship.”
Toxicities from radiotherapy can affect any tissue in the irradiated pelvis from the bone, blood vessels, gastrointestinal system, and genitourinary system to the gynecologic system. These adverse effects can result in a plethora of health issues, including bone fractures, accelerated peripheral vascular disease, proctitis, incontinence, fistula, urethral or ureteral stricture, erectile and bladder dysfunction, infertility, vaginal stenosis, and ovarian failure, Moreover, these side effects may occur 3 months to decades after treatment has been completed.
In an interview with The ASCO Post, Dr. Hoffe discussed the importance of taking a holistic approach to survivors of pelvic cancers to reduce their risk of long-term effects from radiation-induced toxicities, how to assess patients for late effects of treatment, and how to manage the care of these survivors.
Developing Onco-Wellness Survivorship Care Plans
Please talk about the concept of “onco-wellness” and what it entails in survivorship care plans.
We coined the term “onco-wellness” at my center because we take a holistic approach to protect patients from the side effects of their cancer and treatment to keep them well over the long term. To me, onco-wellness is an expanded focus of survivorship care that is introduced at the conclusion of active treatment for pelvic cancer. It includes a personalized care plan for the long-term and late effects of treatment; nutrition, physical activity, and rehabilitation recommendations; prevention strategies for secondary malignancies; and psychosocial needs. It has been a paradigm shift in how we think about the care of these patients over the past 20 years. Fortunately, as our treatments have gotten better and we are seeing more patients do well longer, many of us are now focusing on the fact that it’s not enough to cure patients. We must think about every aspect of their health in survivorship and be proactive in ensuring they have the best long-term health outcome.
We know that the risk for pelvic radiation toxicity includes several factors, such as the type, size, and location of the tumor, because certain tumors may require a larger field or dose of radiation. Patients with diabetes mellitus, inflammatory bowel disease, concurrent chemotherapy, prior abdominal surgery, collagen vascular disease, lower body mass index, and those who smoke are also at an increased risk for developing late radiation toxicities.
It is imperative that we educate our patients about these risk factors, so if they experience a problem, they know to come see us for treatment. For example, the most common issue for women is radiation-induced vaginal stenosis, which can be alleviated by using vaginal dilators. However, so many women come into my practice who were treated at other institutions and were never told about vaginal dilators. So, job number one is to be proactive in warding off potential problems for our patients.
In my practice, I routinely talk with my female patients at the time of their treatment consultation about the potential for vaginal stenosis following radiotherapy and counsel them to talk with their nurse practitioner about how to use a vaginal dilator. And every time I see those patients, I ask them if they are using the dilator and about any problems they may be having.
Studies evaluating the effect of vaginal dilators have shown that 82% of compliant patients could achieve their pretreatment vaginal size within 1 year. Remedies for the problem should also include hormone replacement therapy, if appropriate, and vaginal lubricants.
We have to think about every aspect of their health in survivorship and be proactive in ensuring they have the best long-term health outcome.— Sarah E. Hoffe, MD
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Assessing Long-Term Risk for Radiation-Induced Toxicity
How can patients with pelvic cancers be assessed for their long-term risk for radiation-induced toxicity, including its impact on fertility and childbearing, incontinence, erectile dysfunction and low testosterone, and secondary cancers? How can oncologists reduce their patients’ risk factors, for example, using advanced radiation planning techniques to prevent or reduce treatment side effects?
As we think about cancer survivorship, it becomes more important to individualize care plans, factoring in patients’ baseline risk factors and their potential treatment-related toxicities. Over the past decade, radiotherapy equipment and techniques have evolved to include approaches for dose escalation and normal tissue sparing. For example, in the treatment of anal cancer, intensity-modulated radiotherapy has become standard of care, because it delivers a more homogeneous dose distribution with sharper falloff doses at target boundaries, sparing adjacent normal tissue and reducing acute toxicity. However, we do not know if the technique decreases the risk of late toxicity. We think it does, and studies are ongoing, but we do not have all the answers yet.
The causes of late effects from pelvic radiation include the inducement of radical production and oxidative stress, which leads to damage to the vasculature within the irradiated field. Ultimately, it causes radiation fibrosis syndrome characterized by three phases: chronic inflammation mediated by endothelial cells; patchy fibrosis with high-density myofibroblasts; and fibroatrophic phase and loss of parenchymal cells. This syndrome can lead to myriad long-term effects, including infertility and erectile dysfunction.
For some patients of childbearing age, it may be possible to move the ovaries outside the pelvic radiation field and maintain their function. However, even if we can protect the ovaries, the irradiated uterus will not be able to function well enough to carry a fetus to full term.
Additional innovations also appear to decrease long-term radiation-induced toxicity. For instance, a rectal spacer may help to spare the anterior rectal wall from higher doses of radiation, proton therapy, and image-guided radiotherapy; with this technique, an image is taken daily and overlaid with the planning imaging. However, we need more predictive research in late effects to obtain definitive answers.
There are some patients, and we don’t know who they are yet, who have a higher risk of developing a secondary cancer after pelvic radiation; fortunately, the incidence is low. For example, the incidence of a secondary cancer is less than 5% in patients treated for prostate cancer. In addition, we may be able to prevent more secondary cancers in high-risk patients by using recent innovations, such as the rectal spacer, but we need clinical trial data to know whether they would be efficacious in these patients.
Mitigating the Late Effects of Radiotherapy
What are the risk factors for bone pain and fracture and for peripheral arterial disease following pelvic radiation? How are these conditions managed?
Currently, there are no large clinical trial data and only limited guidelines on the management of late radiation-induced toxicities. Peripheral vascular disease is another complication that can develop following radiotherapy, and it most commonly affects superficial and femoral arteries. Patients may present with pain and numbness in an extremity secondary to accelerated atherogenesis.
Patients who smoke and have high cholesterol levels are at high risk for late peripheral vascular disease and should be counseled on the benefits of quitting smoking before starting radiation therapy. If the disease progresses, patients may need angioplasty or peripheral vascular surgery to manage the condition.
Jamie H. Von Roenn, MD, FASCO
Similarly, pelvic radiotherapy may cause tiny fissures in the bones, weakening them and causing pain, which is indicative of a fracture. The most common fractures are sacral insufficiency fractures or a potential femoral fracture.
Older women who have osteoporosis, kidney or vascular disease, or have been on long-term steroids are especially vulnerable for bone pain and fractures following radiation therapy. I counsel these patients on remedies to reduce their risk, including increasing their intake of vitamin D and calcium, engaging in weight-bearing exercises, and taking bisphosphonates to reduce bone fractures.
The good news is that advanced radiation techniques have already decreased acute toxicities in the treatment of gastrointestinal, gynecologic, and genitourinary cancers, and we are hopeful they will decrease late toxicities as well.
As I mentioned previously, survivorship care should be individualized to take into account personal risk factors, as well as the effects from multimodality therapies. The combination of ongoing prospective clinical trials evaluating better treatment efficacy, prevention strategies such as those for vaginal stenosis, and upfront patient counseling should help mitigate some of the late effects from pelvic radiation therapy.
DISCLOSURE: Dr. Hoffe reported no conflicts of interest.
1. American Cancer Society: Facts & Figures 2021 Reports Another Record-Breaking 1-Year Drop in Cancer Deaths. Available at www.cancer.org/latest-news/facts-and-figures-2021.html. Accessed February 7, 2022.
2. American Cancer Society: Cancer Treatment & Survivorship Facts & Figures 2019–2021. Available at www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-treatment-and-survivorship-facts-and-figures/cancer-treatment-and-survivorship-facts-and-figures-2019-2021.pdf. Accessed on February 7, 2022.