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Christopher Wallis: Hello and thank you for joining us for this UroToday journal club discussion.

Today we're talking about a really important and impactful review paper entitled "Mechanisms Mitigation and Management of Urinary Toxicity from Prostate Radiotherapy." In this presentation, we'll focus on aspect related to male anatomy in subacute as well as acute and late toxicities.

I'm Chris Wallis, an Assistant Professor in the division of Urology at the University of Toronto. Joining me today is Zach Klaassen, an Assistant Professor in the division of Urology at the Medical College of Georgia.

You can see here the citation from this recent publication in Lancet Oncology, led by Dr. Martin. Radiotherapy, as most well know, is a widely utilized treatment approach in oncology, with a broad utilization for pelvic cancers including anorectal disease, cervical, male genital urinary cancers, including prostate and bladder. As a result of both earlier detection and better treatment approaches, we see improving survival for many patients diagnosed with localized cancers. As a result, there's an increasing importance in longterm survivorship and reducing treatment related morbidity.

For patients who are receiving pelvic radiotherapy, toxicity affecting urinary function is particularly important due to both its high prevalence and difficult management. In the context of pelvic radiation its used for prostate cancer is both longstanding and relatively prevalent. As a result, this has facilitated an understanding of the mechanisms and mitigation of radiation-related toxicity on the bladder.

In terms of urinary toxicity after pelvic radiation, historical studies have estimated that moderate to severe urinary toxicity may occur in up to 80% of patients who receive pelvic radiation. There are variations in this estimate that may derive from different methods of assessment, as well as different treatment approaches.

In the past few years, and we'll highlight some of these data, more recent studies have used standardized patient-reported outcome measures to capture the patient burden of urinary toxicity. Historically, when we considered principles of treatment delivery, there was an implied trade-off between treatment intensification leading to increased cure rates, however, also increased toxicity. We can see historical examples, including dose escalation. We saw that in the ASCENDE-RT trial in which the addition of a brachytherapy boost, which improved disease control through treatment intensification, was associated with increased toxicity. We also see this in the adjuvant radiotherapy setting following a surgery.

However, as we move forward, I think, and the authors well point out that we can take a bit more nuanced approach, that when we use emerging treatment approaches with risk-adapted strategies, we can really optimize both tumor control and urinary function. This includes an assessment of baseline function, consideration of the correct treatment paradigm, so that can be early salvage versus adjuvant radiation after surgery, particular radiotherapy techniques, as well as concurrent treatments that may help to provide supportive care and reduce the burden of toxicity on our patients.

When we consider urinary toxicity from radiotherapy, it's important to consider the anatomy affected. The male lower urinary tract is the relevant anatomy here for patients receiving prostate radiation. Lower urinary tract includes the bladder, prostate, and urethra.
When we treat the prostate with radiotherapy, a radiation dose to all of these organs is inevitable. Bladder, itself, functions as a distensible muscular storage reservoir with a number of layers. The first we'll discuss is the detrusor muscle, which is continuous with the internal urethral sphincter and is important for continence mechanisms.

Lining the bladder is the urothelium, and this runs continuously from the upper tract through the bladder and into the urethra. It has a critical function to prevent the entry of pathogens. During acute radiation toxicity, inflammation and thinning of the urothelium may occur. This may increase permeability, leading to both symptomatic cystitis or urethritis.

Deep to the urothelium lies the lamina propria. This is a connective tissue layer containing vascular lymphatic channels. In the short term or acute phase, there doesn't typically tend to be radiation induced toxicity here, but over the longer durations, ischemic effects of radiation within the lamina propria are considered a potential mechanism for chronic irritative symptoms that may arise after radiation.

Also relevant is the prostate. Obviously, this is the target of our radiation for prostate cancer. The prostate gland system, both fibromuscular stroma as well as glandular cells, and it encompasses the prostatic urethra running from the bladder neck downwards.

In the acute phase, radiation may actually cause swelling of the prostate, leading to obstructive symptoms in much the way that BPH does. However, in a more chronic phase, radiation tends to induce prosthetic fibrosis, leading to overall volume reduction, and so we don't see those long-term obstructive symptoms. The urethra carries urine from the bladder through to the urethral meatus. The posterior urethra begins in the bladder neck and includes both the prosthetic and membraneous components.
Importantly, the muscles surrounding the urethra, the internal and external sphincters, are critical for continence.

I'm now going to hand it over to Zach to walk us through issues related to both acute and subacute toxicity of radiotherapy.

Zachary Klaassen: Thanks so much, Chris.

Looking at acute and subacute GU toxicity, this is measuring urinary toxicity, which can be difficult because of its objectivity. So if we look at several ways to measure toxicity, this could be physician grading, which is subjective and under-reported, or it could be patient-reported such as EPIC-26, which is more complex to administer, but better captured. You can see here on the right, this is the first five questions from the EPIC-26 questionnaire.

There are numerous mechanisms for acute and subacute GU toxicity from prostate radiotherapy, including effects on the bladder, urethra, and prosthetic tissues. So this is just several ways that these toxicities may be captured. Looking a little bit further at acute and subacute toxicity, this is irritative GU toxicity. This affects about 50% of patients and symptoms frequently include frequency, dysuria, spasms, and urgency.

In conventional radiotherapy fractionation dose escalation is not associated with increased acute irritated GU toxicity. The urothelial degeneration typically limits the effective toxicity to roughly four to six weeks of symptoms. This typically arises secondary to urethritis or cystitis, and underlying mechanisms include direct urothelial damage, delayed fibrotic and vascular ischemic effects on the sphincters and detrusor muscle, acidity of the urine, which may be exacerbated for men with inflamed mucosa. So treatments for acute and subacute irritated GU toxicity include alkalization of the urine, anticholinergic medications, and also ruling out superimposed urinary tract infections.

The second component of acute and subacute toxicities of obstructive symptoms. This may occur due to intraprostatic hypertrophy, secondary to prostate stromal inflammation. This is typically treated and also successfully treated with alpha-blockers. This is typically worse in patients who have baseline obstructive symptoms and in patients that are receiving concurrent ADT. ADT over the long term may also lead to improvement in symptoms by shrinking the prostate over time.

Next, we're going to focus on several important topics related to late urinary toxicity, and these symptoms may occur for decades after radiotherapy and are frequently intractable. Thus, because of their intractability, the focuses on preventing these symptoms. When present, treatment often is quite difficult and requires collaboration between radiation oncologists and urologists.

The first component of late urinary toxicity is chronic urinary urgency, and this is often under-reported as most tools that look at these symptoms focus on obstructive symptoms of hematuria. However, focus studies show that lingering clinical effects can occur, such as chronic urinary urgency, and this is particularly common after brachytherapy. This may manifest as a reduced warning in the need to urinate and may be reversible during necrotic tissue or prostatitis. Typically, management focuses on addressing lifestyle factors, such as avoiding bladder irritants, including caffeine and alcohol, pelvic floor physical therapy, as well as antimuscarinic pharmacotherapy and Beta3 agonist pharmacotherapy, such as Myrbetriq.

The second component of urinary toxicity is incontinence. This is broken down into several components. This may be multifactorial, often requires urological intervention.

The first component is urgent incontinence, which may be present due to underlying bladder overactivity or cystitis or other causes.
Stressor incontinence is also common. This is due to a sub-functional sphincter which is overwhelmed by abdominal pressure, but is more common after radical prostatectomy rather than radiotherapy. Important to note is that ADT may cause sarcopenia of the pelvic floor muscles which contribute to incontinence, as well as intercurrent weight gain, which may also contribute to incontinence, especially stress incontinence. Management for stress incontinence is pelvic floor physiotherapy as well as several other surgical interventions which are available, including pelvic slings and artificial urinary sphincters.

Radiation-induced malignancy is among the most severe of the late toxicity and external beam radiotherapy has been estimated to be associated with a 0.1 to 3.8% increase in radiation-induced malignancy in several large meta analyses. This is clearly more common in younger patients as they have more of a lead time and further follow-up after the treatment. Affected sites which may result in malignancy include the colon and rectum, the urothelium, such as the bladder, as well as sarcomas. As tumors caused by radiotherapy may also occur in the absence of radiotherapy, it's important not to attribute symptoms to telangiectasia, but to initiate an appropriate workup. This often involves urologist such as a hematuria workup, which includes cystoscopy, imaging, and cytology.

Urologic evaluation for radiotherapy often identifies telangiectasia, which is mistakenly often called radiation cystitis, and this is incorrect because this is not an inflammatory process. This is caused by radiotherapy inducing capillary endothelial cell death, which leads to obliterative effects similar to endarteritis. In the GI setting, this is termed radiotherapy-associated vascular ectasia.
Given capillary fragility to telangiectasia is associated with increased risk of bleeding and this may also be exacerbated by superimposed urinary tract infections and trauma. Grade 3 or worse bleeding is more common on patients on anticoagulation, which has been estimated to be 15.5% for those on anticoagulants versus 3.6% for those that are not on treatment. Management for telangiectasia includes reassurance, judicious use of electrocautery, and in cases of severe and often refractory telangiectasia, patients may also receive alum, formalin, or hyperbaric oxygen which may improve symptoms.

Urethral strictures and bladder neck fibrosis may also occur after external beam radiation therapy, but are more common in the post-radical prostatectomy radiation or brachytherapy setting. For most post-RP patients, the longer duration between surgery and radiotherapy is associated with a lower risk of bladder neck fibrosis or urethral strictures.

Interestingly, in the ASCENDE-RT trial, this showed higher risk of strictures in patients receiving brachytherapy-boost radiotherapy, at 18.4% versus 5.2%, which had not received the brachytherapy boost. In terms of management of urethral strictures and bladder neck fibrosis, this includes intermittent self-dilatation, direct vision internal urethrotomies in severe cases, and also in the most severe case and then often refractory cases, the patient may need a urethroplasty.

In conclusion, all parts of the male lower urinary tract may be affected by pelvic radiotherapy. Acute and subacute GU toxicity includes irritative systems, which affects up to 50% of patients receiving pelvic radiotherapy and is often treated with anticholinergics. This also includes obstructive symptoms which occur secondary to intraprostatic hypertrophy and is often treated with alpha blockers, such as tamsulosin or Flomax. Finally, late GU toxicity may occur decades after radiotherapy and includes urgency incontinence, radiation-induced malignancy, telangiectasia, and urethral strictures.

Thank you very much for your attention. We hope we enjoyed this Uro Today journal club discussion.