A management Guide for Non Urologists to help improve patient management and outcomes.
Professor Kilian Walsh FRCSIUrol
Consultant Urological Surgeon
University College Hospital Galway
Mr Richard Walsh
Final Med University College Dublin
Radiotherapy is a well recognised and necessary treatment modality when considering a multidisciplinary approach to the management of urological cancers as both primary treatment and also as an adjunct in the palliative setting.
The increased utilisation of active surveillance for low grade low volume prostate cancer and novel therapies for bladder cancer may have resulted in a decrease in the prevalence of radiotherapy primary treatment sessions however radiotherapy continue’s to be an essential aspect in the treatment for prostate and bladder cancer. And as an adjunct in testicular cancer.
Similar to any intervention for cancer, Radiotherapy treatment can have side effects. Due to the anatomy of the pelvis and lower abdomen the treatment of urinary tract malignancy sees radiotherapy related complications not only related to the urinary tract but also the gastro-intestinal tract. These complications may include radiation cystitis, ureteric stricture,, urethral stricture, urinary fistula and secondary malignancies. The prevalence of these side effects can often be underestimated as they may develop as a late complication and may not be observed in the follow-up period or present as an emergency. A difficulty for treatment strategies can be that patients are likely to be older and have increased comorbidities. These side effects can impact on the patient’s quality of life and prove both difficult and costly to manage.
In this article we will discuss the management of these complications in an attempt to improve understanding of how they are optimally treated so as to improve the outcomes for patients whom are unfortunate enough to suffer a radiotherapy related complication.
This is the most recognised and prevalent urological side effect of radiation therapy occurring in 5-10% of those receiving pelvic irradiation, most commonly presenting in patients whom have undergone treatment for prostate and bladder cancer. One study found that it accounted for over 51.2% of radiotherapy side-effect related urological admissions.
Acute radiation cystitis is common and usually self limiting, occurring sometimes shortly after radiation exposure. Impairment of the urothelium leads to damage to deeper tissues due to contact with urine and spread of inflammation. A self limiting course of acute radiation cystitis may last for up to 3 months and is characterised by severe lower urinary tract symptoms such as dysuria, frequency and urgency. In a case of chronic radiation cystitis visible haematuria is the major presenting symptom and may vary in severity from mild to life threatening-hypovolemic shock. It will be associated with lower urinary tract symptoms such as dysuria, frequency, urgency and nocturia as well as formation of large blood clots which may increase the risk of urinary retention.
Due to the non-specific presentation of radiation cystitis in its presentation other causes of haematuria must be investigated and excluded when these patients present as an emergency. These include urinary tract infections, coagulopathies and secondary malignancy.
Acute radiation cystitis is usually a self limiting condition which may be managed conservatively and the mainstay of treatment involves management of symptoms. Anticholinergic medications such as tolteridine and solifenacin can be utilised in these cases to help reduce frequency, urgency and other lower urinary tract symptoms. Patients should be reviewed regularly.
Stabilisation, Irrigation and clot removal
Management of chronic radiation cystitis with visible haematuria is more complicated. In the acute setting if severe visible haematuria leading to hypovolemic shock is present, intravenous fluid resuscitation and blood transfusion must be considered. Once the patient has been stabilised a 22 or 24 french transurethral Silicone urinary catheter should be inserted into the bladder to commence a bladder washout followed by irrigation with saline and regular bladder washouts with an irrigating syringe should be continued until the urine is clear. This is considered first line therapy. There are other therapies available to treat continued bleeding.
If the bleeding does not settle a bladder washout with an Elik Evacuator under general anaesthetic or spinal block may be required.
Intravesical therapies using formalin and alum can be helpful once in contact with the damaged urothelium and may reduce ongoing bleeding.
Response rates with these agents typically range from 60-90% however there can be side effects with these medications which patients must be made aware of,. Alum has a more favourable side effect profile so may be used initially. Formalin is only recommended in cases of intractable hemorrhagic cystitis as it can cause severe bladder wall fibrosis leading possibly to the requirement of a urinary diversion if the fibrosis is very severe.
Systemic therapies are a more appealing option for treatment as they do not require hospitalisation however there is limited evidence to support their use. Therapies that have been used in treatment include WF10 which reduces inflammation, induces natural immunity and stimulates cellular defence mechanisms however it only rarely reverses the haematuria.
Hyperbaric oxygen (HBOT) therapy involves a special pressurised treatment chamber which delivers 100% oxygen at a higher pressure than is present in the atmosphere. This stimulates neo-angiogenesis facilitating reepithelialization healing. Complete resolution of haematuria has been found in 34-96% of patients following HBOT therapy. This usually involves 20-40 sessions so is seen as costly and resources are limited. HBOT can be construed an alternative to surgery if other more conservative measures fail
Ablation of damaged submucosal vasculature using laser therapy or diathermy is associated with a complete response in 75%-97% of cases. This is performed in the operating Theatre via a cystoscope with either a rollerball diathermy or Holmium or Green Light Laser.
In intractable cases Interventional radiology can perform embolisation of the iliac arteries, this has been shown to reduce haematuria with an efficacy of up to 100%. Gluteal pain is a recognised complication of this procedure. Bilateral Percutaneous nephrostomy for urinary drainage, cutaneous ureterostomy and ileal conduit formation are all considered if the Haematuria is persistent despite all the previous measures.. A transverse colon conduit is preferable over an ileal conduit if there is a concern that the small bowel has been irradiated, urinary diversion with or without cystectomy is considered a definitive treatment however it will carry a high morbidity and mortality and is a last resort
Fistulae may prove the most difficult to treat of the urological side effects of radiotherapy (Mundy AR). A fistula is defined as an abnormal connection between two body parts, such as an organ or blood vessel and another structure. The most common fistulae to form as a result of radiotherapy include vesicovaginal, rectovaginal and rectovesical. Fistulae which occur due to radiation tend to be large and multiple. The neck of the bladder receives the highest dose of radiation during external beam radiotherapy for prostate cancer and therefore is the most common site for a fistula should it occur. The pathophysiology of their formation is related to hypoxia and necrosis of the tissue with radiation. Subsequent weakness and fragility of tissues allows for abnormal connections to develop.
The presentation of a fistula is dependent on its location. A fistula between the urinary tract and GI tract will lead to symptoms such as recurrent urinary tract infections (and associated lower urinary tract symptoms), pneumaturia and faeces in the urine. A vesicovaginal fistula will lead to leakage of urine from the vagina.
Imaging of the fistula with CT scanning and contrast to determine size, location and surrounding tissue viability is a mainstay of diagnosis and planning for surgery. Cystoscopy and direct visualisation is the preferred method for this. A cystogram using methylene blue dye can also be used.
Management of a urinary fistula secondary to radiotherapy is complex. Surgery is considered the mainstay of curative treatment however due to previous irradiation of surrounding tissues healing can often be impaired after surgery. This means that ,unfortunately, failure of treatment and relapses are more common than in non-irradiated tissues. The most important aspect of surgical management is to provide diversion of urine away from the site of the fistula so that it will not recur.
The principles of fistula repair are to excise the fistulous tract, close the opening from each organ and lay a flap or graft between the two repaired edges so that they heal independently.
Initial management for a rectourethral fistula involves intestinal and urinary diversion to reduce the risk of major infection and sepsis. Further management depends on factors such as the size of the fistula and the comorbidities of the patient. Transperineal access to the fistula is the most common technique with transanal and trans-sphincteric approaches being considered a flap utilising the gracilis muscle can be used to protect the repair
In these cases either a transvaginal, transabdominal or combined approach can be used to repair the fistula. Omental, peritoneal or labial flaps are often used to cover the repair. Urinary drainage for 10 days via a supra-pubic catheter is required and a cystogram will confirm the integrity of the repair.
Strictures of the ureters tend to occur as a late complication of radiation exposure and more commonly than urethral strictures. Symptoms for this depend on the degree of stenosis, they can present with hydronephrosis on imaging, symptomatic loin pain or recurrent upper urinary tract infections.
For diagnosis urea and creatinine may show impaired renal function, physical examination, x-ray imaging, ultrasound, CT scan, MRI scan and diagnostic ureteroscopy.
Initial management is to ensure passage of urine this may be done through a percutaneous nephrostomy or ureteral stent.
Minimally invasive techniques include balloon dilatation and stent placement are preferred as an alternative to open surgery.
The surgical methods of choice involve reconstruction of the ureter with a buccal graft, Trans Uretero-ureterostomy, Boari flap for lower third ureteric strictures or if necessary a urinary diversion and stoma if the ureteric tissue is considered too unhealthy for reconstruction.
A urethral stricture can lead to voiding dysfunction and subsequently upper urinary tract damage. High total radiation dose is the most common risk factor for development of a urethral stricture with necrosis and hypoxia. Presentation includes irritative and obstructive symptoms with reduced urinary flow and possibly urinary retention.
Endoscopic treatment such as urethral dilatation and direct internal urethrotomy are minimally invasive but are associated with a significant risk of recurrence however for patients who are unsuitable for major reconstructive surgery this method is suitable.
Urethroplasty is the mainstay of surgical treatment. This involves removal of the stricture and primary anastomosis. In the case of a longer stenosis a substitution urethroplasty using a graft (buccal most commonly). Urinary incontinence is a significant risk of this procedure.
Radiation induced secondary malignancies are a rare late side effect of radiation therapy Epidemiological studies show a higher rate of bladder cancer in patients receiving radiation for prostate cancer compared with patients who underwent surgery or watchful waiting. These bladder cancers are commonly high grade and muscle invasive when diagnosed. Therefore it is important to be vigilant of the risk of bladder cancer in patients who have received radiation for prostate cancer and if they have a life expectancy of over 20 years the possibility of secondary malignancy needs to be included in their management discussion and a cystoscopy is indicated in the presence of any haematuria.
Radiotherapy is an important and effective modality in the treatment of urological malignancies. The side effects associated with radiotherapy can be significant and often underestimated. The side effects may present many years after radiotherapy treatment is administered and can affect quality of life outcomes for cancer survivor patients. Management can be complex however with an understanding of the appropriate strategies and with adequate resources they can be treated effectively in high quality urology centres with appropriate support.
Mundy AR, Andrich DE.
BJU Int. 2012 Aug;110(3):304-25. doi: 10.1111/j.1464-410X.2011.10864.x. Epub 2012 Feb 17.
Ma JL, Hennessey DB, Newell BP, Bolton DM, Lawrentschuk N.
BJU Int. 2018 May;121 Suppl 3:28-32. doi: 10.1111/bju.14145. Epub 2018 Feb 27.
Read more clinical features here
Read more of our latest news here