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Making Waves: Improving Radiation in Gynecologic Oncology

Jane Fitch and Sharica Lewis are two women living in different parts of the country, born 20 years apart, who share a common memory. They both endured the grueling experience of radiation therapy as treatment for their cervical cancer — and today count themselves among the 1.3 million survivors of gynecologic cancer in the United States. Radiation therapy — also known as radiotherapy, irradiation and X-ray therapy — uses highenergy particles or waves to kill cancer cells. The energy from X-rays, gamma rays, electrons or protons damages cells by making small breaks in their DNA. This damage prevents the cells from dividing, and they eventually die after days or weeks of treatment. While radiation therapy selectively affects rapidly growing cancer cells, normal cells and tissue can also be damaged. This method is often used to treat gynecologic cancers including malignancies of the cervix, uterus, vulva and vagina.
Fitch, a 57-year-old resident of Charlotte, North Carolina, first started to worry when she noticed persistent and severe vaginal bleeding in May 2011. She thought it might be related to menopause, but on the fourth day, she fell unconscious in her bathroom. After waking up in the intensive care unit, a surgeon broke the news: Fitch had stage 2b cervical cancer, and her tumor was the size of a grapefruit. Similarly, Lewis’ diagnosis came after a bout of intense vaginal bleeding. In February 2015, the 37-year-old native of Cleveland, Texas visited her gynecologist, who performed a biopsy and discovered stage 1b cervical cancer. “From that point, I mentally prepared myself for what I was about to go through,” says Lewis. “I went to my doctors at MD Anderson Cancer Center, and they began to discuss my treatment plan and what was going to happen with me. For gynecologic cancers, radiation therapy is administered as a primary treatment, after surgery or to treat a recurrence; it can be given either in conjunction with chemotherapy (called chemoradiation) or alone. Two methods of delivery exist: external beam radiation therapy (EBRT), which uses a machine outside the body to send radiation toward the cancer, and brachytherapy, which uses a radioactive substance placed directly into or near the cancer. In some cases, both methods are used — usually EBRT first, followed by brachytherapy
Lewis and Fitch had treatment plans that included both types of radiotherapy and the chemotherapy drug cisplatin. After primary treatment consisting of six weeks of chemoradiation and two sessions of vaginal brachytherapy, Lewis was found to have no evidence of disease in September 2015. Fitch had radiation following a dilation and curettage (D and C) procedure to remove tissue from inside her uterus. Because of her more advanced stage of cancer, she went through 36 EBRT sessions, six rounds of cisplatin and almost a week of cervical brachytherapy. Then, she underwent a hysterectomy. “My (brachytherapy) doctor and main oncologist said they never saw a tumor shrink so quickly,” Fitch says. “It was really a blessing, and now I’m five years cancer-free.” THE INS AND OUTS OF EBRT EBRT, one of two main methods of radiation therapy used in women with gynecologic cancers, aims powerful X-rays at the cancer from outside the body, similar to the procedure of getting a regular imaging X-ray but at a much stronger dose. Once the patient is positioned in the right place, each treatment lasts only a few minutes. When radiation is the primary treatment for cervical cancer, it’s given in sessions five days a week for five to seven weeks,often combined with a low dose of the chemotherapy drug cisplatin. For endometrial cancer, sessions are five days a week lasting four to six weeks. The X-rays are emitted from a machine called a linear accelerator.

Three-dimensional conformal radiation therapy (3-D CRT) is a type of EBRT that uses medical imaging techniques such as computed tomography (CT) to see the size, shape and location of the tumor and surrounding organs. With this information, the radiation oncologist can use software to visualize the treatment area in three dimensions and specifically shape the radiation beams’ direction and intensity.
A more advanced type of 3-D CRT, called intensity modulated radiation therapy (IMRT), takes the tailoring of radiation delivery a step further by modifying the intensity within each beam and using computer-controlled collimators within linear accelerators. With IMRT, a single radiation beam is broken up into many “beamlets” that may then be adjusted individually. It allows for more precise adjustment of radiation to the tumor itself while limiting the amount given to nearby healthy tissue. “We used to do 2-D radiation, and then we moved to 3D-CRT, where we can see the tumor, bladder and rectum with a CT scan to do a better job shaping our fields,” says Jonathan Strauss, M.D., MBA, an assistant professor of radiation oncology at Northwestern University’s Feinberg School of Medicine. “Now there’s IMRT, a new form of radiation delivery that builds on 3D-CRT. You’re still using a CT scan for planning, but IMRT delivers the beam in more complex ways with the hope that it carves out the tumor area better and reduces toxicity further.
However, the evidence that IMRT improves outcomes over 3-D CRT for gynecologic cancers has yet to be published. Two phase 3 trials evaluating post-operative IMRT in patients with cervical or endometrial cancer are currently ongoing, one of which presented early results at the American Society for Radiation Oncology (ASTRO) 2016 Annual Meeting. The multicenter, randomized TIME-C study included 278 women with cervical or endometrial cancer and found that patients who had pelvic IMRT experienced less acute gastrointestinal (GI) toxicity than those who had conventional four-field radiation therapy. The other trial, PARCER, had its interim findings presented at the previous year’s ASTRO Annual Meeting. Postoperative IMRT was associated with a 14 percent reduction in moderate to severe bowel side effects in comparison with 3-D CRT, but the difference failed to reach statistical significance.

EXPLORING BRACHYTHERAPY

The second method of delivery is brachytherapy, or internal radiation therapy, which is sometimes used after EBRT in the treatment of vaginal, cervical and uterine cancers.Brachytherapy puts a source of radiation in or near the cancer to reduce exposure to surrounding tissues. After hysterectomy for endometrial cancer, a cylindrical applicator is placed in the vagina. For the definitive treatment of cervical cancer, an applicator is placed into and against the cervix. In each of these situations, a radioactive source is then fed through the applicator, stopping for precise periods of time along different dwell positions to optimally distribute the radiation dose. Low-dose rate (LDR) brachytherapy occurs over the course of a few days, but the patient must remain immobile throughout this time in a hospital bed while the device stays in place. On the other hand, high-dose rate (HDR) brachytherapy uses a higher dose of radiation for less than an hour per session. For endometrial cancer, HDR brachytherapy is given weekly or even daily for at least three sessions. A recent study by Strauss and his colleagues found better survival in women with stage 1 endometrioid adenocarcinoma of the uterus who had vaginal brachytherapy, as compared with patients who received no form of radiotherapy.
The data suggested that vaginal brachytherapy appeared to be more valuable than we had thought in stage 1 endometrial cancer,” he says. “What was also clear from the data is that, nationally, we did not have particularly good compliance with the current guidelines,” meaning that many women in this population were not being treated with any radiotherapy at all.

While vaginal brachytherapy is recommended for women with higher-risk stage 1a or any stage 1b disease, the study noted that 88 percent of those in stage 1a and 52 percent of stage 1b did not receive radiation therapy. Strauss points to issues of availability, given that brachytherapy isn’t found as often outside of large medical centers.

In other advances, more cancer centers are using magnetic resonance imaging (MRI) for treatment planning in brachytherapy. Ordinarily, the physician would use two-dimensional imaging to best cover the target area and minimize dose to any organs in the vicinity. In the past decade, several studies have found that the clinical outcome of patients with cervical cancer who receive MRI-guided brachytherapy will be improved compared with those who receive traditional 2-D planning. “With MRI-guided brachytherapy, we get a clearer 3-D view of patient and tumor anatomy, so we can better define tumors and decrease patient toxicity,” says Omar Ragab, M.D., assistant professor of clinical radiation oncology at Keck Medicine of the University of Southern California. Radiation therapy can also be used as a palliative treatment for those patients with advanced disease, as an effective way to stop bleeding and alleviate pain. Although radiotherapy is most often used in the curative setting, there are instances when the highest quality of life for the patient takes precedence over destroying her cancer. “Palliative radiation is a very strong tool that we have for all disease subsites,” says Ragab. “In gynecologic malignancies, we tend to use it for very painful lesions like in a bone or for patients that have bleeding from a tumor.SIDE EFFECTS

Despite the many recent advances in radiation therapy, it can still harm surrounding normal tissue and lead to many unwanted side effects. For instance, both Fitch and Lewis felt extremely tired and nauseated, and lost their appetites during treatment. Side effects of EBRT include fatigue, upset stomach, diarrhea, nausea/vomiting, vaginal pain, menstrual changes and low blood counts. Brachytherapy can have many of the same side effects as EBRT, such as fatigue, diarrhea, nausea, irritation of the bladder and low blood counts, but also may cause irritation of the vagina and vulva. Also, when chemotherapy is given with radiation, side effects like low blood counts, fatigue and nausea tend to be worse.

To improve quality of life, stratifying patients based on risk factors is one way to dole out only that treatment which is necessary, explains Dattatreyudu Nori, professor and executive vice chairman of the Radiation Oncology Department at The New York-Presbyterian Hospital/Weill Cornell Medical College. Instead of placing every woman on the same regimen, some studies show that giving radiation alone without chemotherapy may be adequate for certain low-risk patients.
The knowledge in radiation oncology for gynecologic cancer is continuously refined in terms of when to apply radiation, especially in endometrial cancer,” he says. “We have many randomized trials showing exactly which patients will benefit from radiation, so it’s not only the technological advances that help.”

In cervical cancer, Strauss notices a similar trend toward identifying an individual patient’s response to radiotherapy throughout treatment. For example, serial MRI could track and identify the subset of women whose disease responds more slowly. These patients could be likely to recur and might benefit from having a hysterectomy after radiation.

For some patients, such individualized treatment could help lessen short-term and long-term side effects. Long-term side effects of pelvic radiation can include vaginal stenosis or dryness, weakened bones and lymphedema (swelling) in the legs. Fitch is currently on disability due to problems with her bladder and colon, and Lewis suffers from occasional urinary incontinence due to her brachytherapy. Nevertheless, both women remain active in cervical cancer outreach and promote prevention through education about early vaccination, Pap testing and human papillomavirus (HPV) testing when recommended. Today, Fitch leads her local chapter of the National Cervical Cancer Coalition (NCCC) and works as a holistic health practitioner. Similarly, Lewis started an NCCC chapter in her town to get the word out about cervical cancer and how to prevent it. Perhaps the most important method is to make sure that preteens get vaccinated against HPV; although this could prevent most cases of the disease, the vaccine series is vastly underused. “I don’t want anybody to have to go through what I went through, because it was brutal, and there were times I didn’t think I would make it,” says Fitch. “But I always knew that, right off the bat, if I made it through this, my goal was to help someone else and let them know that there is hope.