Our patients need us to be much more intelligent about the side effects of cancer treatment. Side effects are not inevitable, and they are not untreatable.— Jervoise Andreyev, MA, PhD
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Chemotherapy- and radiotherapy-induced gastrointestinal (GI) toxicities have risen alongside improved survival rates for many cancers, according to Jervoise Andreyev, MA, PhD, Consultant Gastroenterologist in GI Consequences of Cancer Treatment at the Royal Marsden Hospital in London.
“For every cancer, there has been some improvement,” said Dr. Andreyev at the 2016 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology
(MASCC/ISOO) International Symposium on Supportive Care in Cancer in Adelaide, Australia.1 “There’s still a lot to do, but some cancers are essentially curable. This is something worthy of celebration; however, this success story also has a price.”
Scope of the Problem
After pelvic irradiation, 90% of patients will experience a permanent change in bowel habits. Half these patients report that their bowel dysfunction affects their quality of life, and up to one-third label their symptoms moderate or severe, he reported.
Modern randomized controlled trials for GI cancer have shown rates of grade 3–4 toxicity to be 5% to 50%. According to Dr. Andreyev, of 75,000 persons treated with fluorouracil each year in the United Kingdom, 11,000 develop grade 3 toxicity and up to 4,000 of them die from diarrhea or associated neutropenic sepsis. “That’s quite an epidemic of deaths that nobody really talks about,” Dr. Andreyev commented.
Gastrointestinal toxicity also affects persons with other malignancies. Today, 85% of patients with rectal cancer will survive at least 1 year, and one in three who undergo surgery alone will develop chronic fecal incontinence. The addition of radiotherapy increases this proportion to half of all patients. Similarly, late toxicity after gynecologic cancer treatment is common, with grade 1–2 reported in 40% of patients and grade 3–4 in 10%.2 A study in patients with prostate cancer concluded that modern techniques do not completely abolish treatment-related symptoms.3
“Not one study tells us what to do or how to manage fecal incontinence,” he said. “It’s a recurrent theme that some aspects of cancer care are simply unimportant, and perhaps nobody is interested in thinking it’s their job to manage quality of life.”
Four Principles of Clinical Management
Dr. Andreyev acknowledged that oncology providers may not feel competent in managing GI problems; however, the first principle of clinical management is to identify the patient’s symptoms.
To help oncology providers in this area, Dr. Andreyev and his colleagues published a practice guidance on the management of acute and chronic GI problems arising as a result of cancer treatment,4 which has been endorsed by all GI professional organizations in the United Kingdom. Simply put, the guidelines suggest asking patients three questions. “If they answer ‘yes’ to any of these questions, that mandates a referral to a gastroenterologist,” he said.
The questions are: “Do you awaken from sleep to defecate?” “Do you have troublesome urgency of defecation and/or fecal leakage/soiling/incontinence?” “Do you have any GI symptoms preventing you from living a full life?”
“Incontinence is easy to deal with up to a point,” he added. “But urgency, that fear of incontinence, is absolutely devastating for patients and makes them frightened to leave the home.”
While symptoms can be an unreliable measure of the underlying GI problem, they can be an indication of the physiologic changes that may have occurred as a result of treatment. The second principle is to understand the underlying problem.
“Ten liters of fluid goes into the bowel every day, and hopefully, very little comes out,” he said. “But if you insult it, lots of things can happen.” Any insult in the upper GI tract can cause symptoms such as carbohydrate, fat, bile acid, or vitamin malabsorption, bacterial overgrowth, or visceral neuropathy, whereas an insult to the lower GI tract could cause altered microbiota, motility, and sphincter control.
“If patients have lactose intolerance, they should stop drinking milk, but if they have bile acid malabsorption, stopping them from drinking milk won’t help in the slightest,” he said. “What you need to do is treat the bile acid malabsorption properly.”
For example, lenalidomide (Revlimid), which is often given long-term in the treatment of multiple myeloma, will produce chronic diarrhea in 5% of patients, due to a specific defect that renders them highly sensitive to fat in their diet. “But that’s very easy for me to treat, and in our unit, not one patient has had to stop lenalidomide treatment because of diarrhea,” he said.
The third principle of clinical management is to be very systematic. Dr. Andreyev and his colleagues developed an algorithm that offers a list of tests and a sequence of treatments for 27 different GI symptoms. “Using this physiologic algorithmic approach, the management of people with these symptoms becomes straightforward,” he said. “If you identify the symptoms very carefully and arrange the appropriate tests to identify which physiology has gone wrong, it gives you simple treatment options.”
The fourth principle is to start to try and modify the underlying disease process. For example, after radiotherapy, over time there is progressive fibrosis of the GI tract and hence loss of function secondary to damage to the blood supply by the raiotherapy. Restoring the blood supply and tackling the fibrosis are likely to be possible.
Does It Work?
Dr. Andreyev has found that his patients’ “top 10 symptoms” generally are improved by the time they are discharged from his clinic, but to confirm these anecdotal reports, he and his colleagues conducted a trial to test their algorithm’s efficacy and cost-effectiveness.5 “The algorithm worked absolutely brilliantly compared to giving the patients a self-help booklet,” he said. For 94% of patients, nurses were found to utilize the algorithm as well as the physicians, and the approach was also found to be cost-effective.
“The important take-home message is, we can change things,” he emphasized. “Radiation-induced injury is a dynamic process, so you should be able to interfere.” He went on to stress the importance of manipulating the “consequential effect”—ie, the concept that an acute, severe response will be accompanied by worse chronic toxicity, independent of the radiotherapy dose. “Studies in animals for over 60 years have shown that if you change bile secretion and pancreatic secretion in the gut, there is much less toxicity, so we can manipulate this effect to stop the burden of long-term disease,” he explained.
“Our patients need us to be much more intelligent about the side effects of cancer treatment,” he said. “Side effects are not inevitable, and they are not untreatable.” ■
Disclosure: Dr. Andreyev reported no potential conflicts of interest.
1. Andreyev J: Chemo- and radiotherapy-induced gastrointestinal toxicity. 2016 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium on Supportive Care in Cancer. Plenary 2. Presented June 24, 2016.
2. Vale CL, Tierney JF, Davidson SE, et al: Substantial improvement in UK cervical cancer survival with chemoradiotherapy: Results of a royal college of radiologists’ audit. Clin Oncol (R Coll Radiol) 22:590-601, 2010.
3. Gulliford SL, Foo K, Morgan RC, et al: Dose-volume constraints to reduce rectal side effects from prostate radiotherapy: Evidence from MRC RT01 Trial ISRCTN 47772397. Int J Radiat Oncol Biol Phys 76:747-754, 2010.
5. Muls AC, Lalji A, Marshall C, et al: The holistic management of consequences of cancer treatment by a gastrointestinal and nutrition team: A financially viable approach to an enormous problem? Clin Med (Lond) 6:240-246, 2016.