Lower-dose radiotherapy for anal cancer could reduce adverse events, maintain efficacy

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Sebag-Montefiore reports no relevant financial disclosures.

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Treatment for anal cancer has advanced significantly over the years, but the standard radiotherapy regimen used regardless of tumor size has led to various immediate and long-term adverse events.

“We’ve made big improvements in the treatment of the disease, from a standard of radical surgery to showing that chemotherapy and radiotherapy combined is a very effective treatment,” David Sebag-Montefiore, MD, MBBS, an academic clinical oncologist at University of Leeds, told Healio. “As far as radiotherapy is concerned, though, we were currently giving the same dose of radiation to every patient with anal cancer, whether it was a very small tumor or a very large one. It was a one-size-fits-all approach.”

Sebag-Montefiore and his colleagues at University of Leeds, working with sites across the U.K., have embarked on a study called PLATO, which consists of three clinical trials (ACT3, ACT4 and ACT5) aimed at optimizing radiotherapy for patients with anal cancer. The ACT4 trial is assessing the potential of reducing the dose and duration of radiotherapy in patients with early-stage cancers up to 4 cm in size.

Sebag-Montefiore spoke with Healio about the inspiration for this study, the findings to date and the potential implications of the research on treatment of anal cancer.

Healio: What prompted you to conduct this study?

Sebag-Montefiore: I have been researching anal cancer for quite a long time — about 20 years. I am aware that in small studies, lower doses of radiotherapy had been used in small tumors. So, as part of the PLATO research platform, we designed three trials for the spectrum of anal cancer, from the very tiniest tumors to the largest, looking at tumors that were up to 4 cm in size. We wanted to test whether a lower dose would produce the same high level of success, but with fewer short-term and long-term adverse events.

Healio: What are some of the short- and long-term adverse events of radiotherapy in this patient population?

Sebag-Montefiore: The adverse events can be divided into those that occur during or shortly after the treatment is finished, and those that are longer-term. Most relate to the area of the body that is being treated. One of the most common is an inflammation of the cutaneous area around the genitals, during or shortly after radiotherapy is finished. That can be quite significant; it can be associated with urinary frequency and pain, and can also cause diarrhea. During radiotherapy there can also be a reduction in blood count due to the chemotherapy and radiotherapy combined. Those adverse events tend to improve after treatment concludes.

However, some adverse events may remain in the long term. The most significant long-term adverse events tend to be control over bowel function and impact on sexual function in both men and women. The genital structures are very close to the anal canal and the tumor itself. So, when we do research, it’s quite common to find that sexual function is impaired in the long term, and some patients are no longer sexually active due to the adverse events of treatment.

One thing to note is that as radiotherapy has become more sophisticated over the last 10 to 15 years, those adverse events have lessened. In some patients, however, they remain a significant problem.

Healio: How did you conduct your study?

Sebag-Montefiore: We took the view that if we were going to tackle this problem, we would test the standard dose of radiotherapy, which is given in 28 treatments, Monday to Friday. That’s a 5-and-a-half-week schedule. Patients are randomly assigned to receive either the standard dose of chemotherapy or the same amount every day but with a 4-and-a-half-week course of treatment given Monday to Friday. Chemotherapy was given at the same time as radiotherapy. So, on the first day, there is an injection of a drug called mitomycin C. On the days of radiotherapy, patients were taking capecitabine as chemotherapy tablets morning and evening for 5-and-a-half weeks, Monday to Friday. Those patients who received the shorter course took those tablets for 4-and-a-half weeks.

We entered 163 patients into the study, with two-thirds receiving the lower dose and one-third receiving the standard dose. We are looking at both the short-term results of the treatment and the longer-term results.

Healio: What did you find?

Sebag-Montefiore: What we have reported so far is on the short-term — up to 6 months — in terms of treatment success and adverse events. We need to wait a little bit longer to report the longer-term results.

When we looked at the two groups of patients, whether they were treated with the standard dose or the lower dose, the rate of complete disappearance of the tumor at 6 months was the same — around 90%. We also found that there was slightly less sexual dysfunction in the patients receiving the lower dose vs. those receiving the standard dose. At this stage, these results are very encouraging. We still need to wait for the 3-year follow-up results, but we are encouraged by these initial findings.

Healio: What do you think will be the potential implications of these findings?

Sebag-Montefiore: Ultimately, I think this trial will potentially be very influential if the lower-dose treatment arm performs as well as the standard dose in terms of eradicating the cancer, and also if the long-term adverse events are decreased. Given the fact that this would be the only clinical trial result in this rare disease to date, it is likely that the results will have a significant influence on whether a lower dose of radiotherapy is used in routine practice. At the moment, we don’t have high-level evidence, and the longer-term results of this study are, therefore, very important in determining whether patients might be safely treated with a lower dose in the future.

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For more information:

David Sebag-Montefiore, MD, MBBS, can be reached at University of Leeds St. James’s Institute of Oncology, Level 4 Bexley Wing, Beckett Street Leeds, LS9 7TF, U.K.; email: [email protected]; Twitter: @MontefioreD.