Gastrointestinal Problems after Pelvic Radiotherapy: the Past, the Present and the Future

doi:10.1016/j.clon.2007.08.011

Clinical Oncology

Volume 19, Issue 10, December 2007, Pages 790-799

https://doi.org/10.1016/j.clon.2007.08.011 Get rights and content

Abstract

Up to 300 000 patients per year undergo pelvic radiotherapy worldwide. Nine out of 10 will develop a permanent change in their bowel habit as a result. Five out of 10 of all patients will say that this change in their bowel habit affects quality of life and two to three out of 10 will say that this effect on quality of life is moderate or severe. Between one in 10 and one in 20 patients will develop very serious complications within the first 10 years after treatment. This number will increase to two out of 10 by 20 years from the end of treatment. Although research carried out into the basic molecular, cytokine and physiological changes underlying radiation-induced bowel symptoms and the optimal treatment that should be provided to symptomatic patients is scant, it does seem probable that a significant proportion of these patients can be cured or improved by specialist gastroenterological intervention. However, most patients never get referred to a specialist gastroenterologist and research into late radiation bowel damage has not been considered a priority. With the advent of more effective cancer therapies leading to greater numbers of affected long-term survivors, much more emphasis is urgently required to provide better information to patients at the start and after treatment, developing techniques that might reduce the frequency of significant bowel toxicity and researching better ways of measuring and treating late-onset side-effects.

Section snippets

Background

In the UK, about 12 000 patients undergo pelvic radiotherapy annually. It is not known how many patients have this treatment worldwide, but extrapolation from the UK figures suggests that it may be 150 000 people in the Western world, although some estimates put it as high as 300 000. In the USA alone, there are 2.5 million survivors of cancer therapy who have received pelvic radiotherapy as part of their treatment [1]. The number of long-term survivors has tripled over the last three decades

How Difficult can it be to Measure Late Radiation-induced Bowel Dysfunction?

Prospective population studies in patients who have received pelvic radiotherapy have not been undertaken, so the natural history of radiation-induced bowel toxicity is not clear. However, there are a number of other reasons why the prevalence of late toxicity is uncertain.

Many patients are discharged from follow-up with their oncologist after 5 years and if they develop complications related to their radiotherapy treatment after that period, they may be treated elsewhere and their oncologist

Studies Examining Bowel Function that Affects Quality of Life

It is also difficult to define exactly when symptoms start to affect quality of life and why some people seek help for specific gastrointestinal symptoms when others do not. The most important question, however, despite the difficulty in interpreting the published data, is whether pelvic radiotherapy really does cause significant problems in large numbers of patients.

Life-threatening Bowel Problems after Pelvic Radiotherapy

Pelvic radiotherapy can induce some problems that cannot be ignored. These include transfusion-dependent bleeding, fistula formation, bowel obstruction and secondary malignancy. Again, because of the lack of population studies, the data predicting the incidence of these issues are very incomplete. It has been suggested, and intuitively seems probable, that because of the nature of radiation injury, the incidence of such severe problems increases with time [33]. Estimates of the significance of

What Chronic Gastrointestinal Symptoms Are Induced by Pelvic Radiotherapy and Why do They Happen?

The range of symptoms that patients describe is shown in Table 2. Some of these could be considered normal, but are perhaps reported because of a heightened awareness of potential health issues. The nomenclature used for radiation-induced injury suggests that toxicity arises from discrete lesions. Patients are often described as having either radiation proctitis, enteritis or colitis on the basis of the symptoms they have. However, several studies have suggested that symptoms alone are a poor

The Medical Management of the Symptomatic Patient

Looking at the range of symptoms and causes of loose stools listed in Table 2, Table 3, together with the increasing evidence that symptoms potentially arise from a number of different abnormalities affecting bowel function, it becomes clear that most patients require detailed investigation to make the initial diagnoses, so that effective treatments can be tried. The evidence base for the effective treatment of radiation-induced symptoms is very weak [16], but this does not necessarily mean

The Future

The development of gastrointestinal dysfunction after therapeutic pelvic radiotherapy depends on a complex pathological process. There is an initial acute inflammatory reaction that often starts to improve before the end of the radiotherapy treatment. Some time later, ischaemic changes develop and these probably induce fibrosis. The molecular and cytokine changes that underlie the whole process have hardly been investigated in humans. Animal models may have little in common with what is

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Cited by (172)

Interventions for Managing Late Gastrointestinal Symptoms Following Pelvic Radiotherapy: a Systematic Review and Meta-analysis
2024, Clinical Oncology
Pelvic radiotherapy can induce gastrointestinal injury and symptoms, which can affect quality of life. We assessed interventions for managing these symptoms.
A review of randomised controlled trials published between January 1990 and June 2023 from databases including MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, ISRCTN and grey literature sources was conducted. Meta-analyses were carried out using the DerSimonian and Laird random effects model to produce overall treatment differences with 95% confidence intervals.
Twenty-eight studies (2392 participants) of varying methodological quality were included. 4% formalin was superior to sucralfate for improving gastrointestinal symptom score (standardised mean difference [SMD] –1.07, 95% confidence interval –1.48 to –0.65). Argon plasma coagulation (APC) was inferior to sucralfate (SMD 1.22, 95% confidence interval 0.84 to 1.59). Counselling positively influenced symptom score (SMD –0.53, 95% confidence interval –0.76 to –0.29), whereas hyperbaric oxygen therapy showed conflicting results. Sucralfate combined with APC increased endoscopic markers of moderate–severe bleeding versus APC alone (risk ratio 2.26, 95% confidence interval 1.12 to 4.55). No definite conclusions on pain, incontinence, diarrhoea, tenesmus or quality of life interventions were confirmed.
Small study sizes, methodological quality and heterogeneity limit support of any individual intervention. APC and 4% formalin seem to be promising interventions, with further larger randomised controlled trials now warranted.
Racecadotril Versus Loperamide in Acute Radiation Enteritis: A Randomized, Double-Masked, Phase 3, Noninferiority Trial
2024, International Journal of Radiation Oncology Biology Physics
There is currently no gold standard for the management of acute radiation enteritis. We compared the efficacy and safety of Racecadotril, an anti-hypersecretory drug, versus Loperamide, an anti-motility agent, in acute radiation enteritis.
We conducted a randomized, double-masked, non-inferiority trial at a single research institute. Patients receiving curative radiation for pelvic malignancies, who developed grade 2 or 3 diarrhea (as per Common Terminology Criteria for Adverse Events, v 4.0) were included in the study. Patients in the intervention arm received Racecadotril and placebo. Patients in the control arm received Loperamide and placebo. The primary outcome was the resolution of diarrhea, 48 hours after the start of treatment.
162 patients were randomized between 2019 and 2022. On intention-to-treat analysis, 68/81 patients, 84%, (95% CI, 74.1%-91.2%) in the Racecadotril arm and 70/81, 86.4%, (95% CI, 77.0%-93.0%) in the Loperamide arm improved from grade 2 or 3 diarrhea to grade 1 or 0, (P= .66, χ² test). The difference in proportion was 2.4% (95% CI: –8.5% to 13.4%). Since the upper boundary of the 95% CI crossed our non-inferiority margin of 10% (13.4%) we could not prove the non-inferiority of Racecadotril over Loperamide. Rebound constipation was more in the Loperamide arm compared to Racecadotril (17.3% vs 6.2%; P = .028)
The non-inferiority of Racecadotril to Loperamide in acute radiation enteritis could not be demonstrated. However, Racecadotril can be the preferred drug of choice in acute radiation enteritis because Racecadotril does not affect bowel motility, achieved a high clinical success rate similar to that of Loperamide, and was associated with lesser side effects.
The ambivalence of radiotherapy: Re-framing effects and their temporalities in treatment for gynaecological cancer
2023, Social Science and Medicine
Within the biomedical paradigm, treatment effects are typically split into primary and secondary effects with temporality playing a key role in this separation. Yet, this kind of ordering of effects with some effects understood as happening on the ‘side’, secondary and temporary, does not fit with how they are experienced by many patients who undergo treatment for cancer. Drawing on empirical data from a research project that gathered narratives of women's experiences of radiotherapy for gynaecological cancer, we observe radiotherapeutic effects that are experienced as ambivalent and temporally diverse and as overlapping demands that the women endure and manage. We propose Derrida's concept of pharmakon as a relevant and useful analytic for understanding radiotherapy treatment, thus bringing into focus the ambivalent effects of radiotherapy - it is both therapeutic and toxic. Pharmakon, we argue, offers a way of disrupting the logics that govern current practices of therapeutic radiotherapy, and provides a way to re-negotiate the ordering and temporal understandings and practices of therapeutic efficacy, outcome and accountability of radiotherapy treatment - away from a temporal fragmentation of treatment effects and patients' bodily experiences to a focus on how best to support the whole patient in living with the ambivalent, temporally diverse and overlapping effects and demands of treatment.
Chemotherapy-induced ileitis associated or not with colitis in digestive oncology patients: An AGEO multicentre study
2023, Digestive and Liver Disease
The characteristics and management of ileitis induced by chemotherapy in cancer patients are poorly described in the literature.
This retrospective multicentre study enroled patients hospitalized in a digestive oncology unit for a symptomatic chemotherapy-induced ileitis.
Forty-three patients were included, with a regimen based on fluoropyrimidine and/or irinotecan in 95% of cases. Five patients were excluded due to the diagnosis of infectious ileitis (Clostridium difficile in 3 patients, Campylobacter jejuni in 1 patient and cytomegalovirus in 1 patient). The most frequently described symptoms were diarrhoea (77% including 54% of grade 3–4 diarrhoea), abdominal pain (58%), fever (51%) and vomiting (56%). An ileo-colonoscopy was performed in 35% of patients and did not show any specific results or severity criteria. The ileitis was complicated by bowel perforation and/or obstruction in 3 patients. Disease progression was favourable in 1–2 weeks in the vast majority of cases, on symptomatic treatment, allowing resumption of the chemotherapy regimen involved in 67% of patients.
Chemotherapy-induced ileitis is a rare complication that most often involves fluoropyri-midine- and/or irinotecan-based regimens. In most cases, endoscopic examinations were not contributory and do not seem useful in the event of non-severe symptomatology which most often develops favourably on symptomatic therapy, allowing resumption of the chemotherapy involved.
Low-grade intestinal inflammation two decades after pelvic radiotherapy
2023, eBioMedicine
Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.
We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection.
942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration.
Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors.
This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow’s foundation (MA and VP).
Sexual dysfunction in female patients with anal cancer treated with curative intent: A systematic review of the literature
2023, Radiotherapy and Oncology
Patients with anal squamous cell carcinoma (SCC) are treated with sphincter-preserving radiation therapy and concurrent chemotherapy, achieving excellent oncologic outcomes. Patients, however, may experience treatment-related morbidity including sexual dysfunction. The objective of this systematic review was to review the literature on sexual dysfunction in female patients treated for anal cancer and to identify knowledge gaps.
This systematic review was registered in PROSPERO prior to initiation. Databases searched included MEDLINE, Embase, PubMed, Cochrane, and Google Scholar. There were no restrictions on the study time period. Studies were limited to English. All study designs were included except review articles, letters to the editor, and case reports with less than ten patients.
In total, 1801 studies were retrieved and 19 met the inclusion criteria, including: 13 cross-sectional surveys, 3 prospective studies, 1 longitudinal intervention study, 1 retrospective chart review, 1 case control study. Sexual function was assessed using the female sexual functioning index (FSFI), EORTC-QLQ-CR30 and -CR38; response rates were low (<50 % in most studies). Sexual dysfunction was reported by up to 85 % of women; the most common symptoms being dyspareunia (17–65 %), vaginal dryness (22–88 %), and loss of libido (38–95 %). Gastrointestinal issues, such as bowel problems, and body image concerns additionally affected sexual function and quality of life.
Sexual dysfunction is a common issue affecting most female patients treated for anal cancer and there is a paucity of evidence on the management of this important survivorship issue. There is additionally a lack of ethnic, economic, and educational diversity and there are no studies addressing the unique needs of LGBTQ individuals - future studies should make a concerted effort to include a diverse patient population.

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OverviewGastrointestinal Problems after Pelvic Radiotherapy: the Past, the Present and the Future

Abstract

Section snippets

Background

How Difficult can it be to Measure Late Radiation-induced Bowel Dysfunction?

Studies Examining Bowel Function that Affects Quality of Life

Life-threatening Bowel Problems after Pelvic Radiotherapy

What Chronic Gastrointestinal Symptoms Are Induced by Pelvic Radiotherapy and Why do They Happen?

The Medical Management of the Symptomatic Patient

The Future

Int J Radiol Biol Phys

Clin Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Radiother Oncol

Urology

Int J Radiat Oncol Biol Phys

Clin Oncol (R Coll Radiol)

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Gastroenterol

Am J Gastroenterol

Gastrointest Endosc

Radiother Oncol

Int J Radiat Oncol Biol Phys

Am J Med

Gastroenterol

Gastroenterol

Clin Radiol

Gastroenterol

Gastroenterol

Int J Radiat Oncol Biol Phys

Clin Oncol

Clin Radiol

Bowel injury: current and evolving management strategies

Semin Radiat Oncol

Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology

Nat Rev Cancer

The gastrointestinal complications of pelvic radiotherapy: are they of any importance?

Gut

How patients manage gastrointestinal symptoms after pelvic radiotherapy

Aliment Pharmacol Ther

The inflammatory bowel disease questionnaire and the Vaizey incontinence questionnaire are useful to identify gastrointestinal toxicity after pelvic radiotherapy

Br J Cancer

The long-term effect of adjuvant post-operative chemoradiotherapy for rectal carcinoma on bowel function

Ann Surg

Overview
Gastrointestinal Problems after Pelvic Radiotherapy: the Past, the Present and the Future