Radiation Cystitis And Hyperbaric Management


Article Author:
Nicholas Horan


Article Editor:
Jeffrey Cooper


Editors In Chief:
Heather Murphy-Lavoie
Jeffrey Cooper


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
1/28/2019 4:34:45 PM

Introduction

Radiation Cystitis is a term used to describe the side effect of inflammation and subsequent destruction to the normal anatomy of the urinary bladder at the cellular level after the use of radiation in the treatment of multiple cancer types, including, most commonly, pelvic cancers. Radiation therapy can be used for primary bladder cancer as well as for tumors in many organs surrounding the bladder, such as the colon, rectum, ovaries, uterus, and prostate. When the primary tumor is not located in the bladder, this leads to unintentional radiation exposure to the healthy bladder tissue. 

Damage from the treatment can either be acute (less than six months from radiation therapy completion) or delayed (more than six months after treatment) and can have varying levels of irritation and functional impairment to the bladder mucosa. If on the mild end of the spectrum, symptoms may include increased frequency, urgency, and possibly some dysuria. Infection should be ruled out with a urinalysis which may show microscopic hematuria. These symptoms can resolve over time. 

On the other end of the spectrum, patient's may experience symptoms such as urinary incontinence, gross hematuria, and progression of damage to the extent of fistula formation or necrotic bladder tissue. The treatment varies on the degree of symptoms. Overall, radiation cystitis can be detrimental to a patient's wellbeing after already having gone through a great deal in regards to cancer treatment. Providers are becoming more aware of the drastic effects a dysfunctional bladder can have on overall quality of life, but more investigation needs to be performed to best tailor radiation therapy while avoiding side effects such as this one. 

Etiology

Radiation is useful for cancer treatment due to its ability to interfere with DNA synthesis and stop rapidly dividing cancer cells from completing mitosis. It also has this same effect on healthy, normally dividing cells surrounding the tumor. Another effect is decreasing blood supply to the irradiated area by causing edema and fibrosis of the vessels (obliterative endarteritis) which can, in turn, lead to necrosis of tissue reliant on those vessels. [1]

Epidemiology

Variation in the incidence of radiation cystitis exists in the current literature. In general, the incidence of delayed radiation effects is estimated at 5% to 10%, and severe hematuria occurs 5% to 8% of the time. Differences in tumor type, the extent of cancer, type of radiation used, and total amount of radiation used create a wide range within the literature.

The average duration from completion of radiation therapy to the onset of symptoms is approximately 31.8 months. It develops more commonly in males than females (2.8:1).

Pathophysiology

It is held that the energy from the radiation affects three different components of the bladder: (1) It affects the urothelium by disrupting tight junctions, increasing elements of the cytoplasm, affecting DNA replication, and causing cellular edema. Once the mucosal cells die and shed, urine can then irritate submucosal cells. (2) It affects bladder vasculature by causing edema and perivascular fibrosis. (3) Finally, radiation affects the detrusor muscle by causing vascular ischemia, increasing fibroblasts and collagen deposition, and causing smooth muscle edema.

History and Physical

Acute complaints after completing radiation therapy may include frequency, urgency, dysuria, and hematuria (microscopic or macroscopic). Chronic effects can occur months to years later and are caused by fibrosis. In addition to the symptoms already mentioned, chronic effects can include urinary incontinence from detrusor dysfunction, hydronephrosis, mucosal ulceration, and fistula formation.

Evaluation

The level of severity of symptoms is graded by Radiation Therapy Oncology Group (RTOG) as follows:

  • Grade 1 - any evidence of epithelial damage or atrophy, telangiectasia, microscopic hematuria
  • Grade 2 - any moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria, intermittent urinary incontinence
  • Grade 3 - any severe frequency or urgency, severe telangiectasia, persistent incontinence, reduced bladder capacity < 150 mL, frequent hematuria
  • Grade 4 - any necrosis, fistula, hemorrhagic cystitis, reduced bladder capacity < 100 mL, refractory incontinence requiring either catheter or surgical intervention [2]

Workup focuses on ruling out more common etiologies of urinary symptoms. Urinalysis with urine culture and cytology should always be ordered initially to rule out bacterial infection and cancer. If the patient presents with a history of hematuria, a complete blood count (CBC) should be ordered to assess hemoglobin, white blood cell, and platelet counts. Additionally, if the patient has gross hematuria, it is important to assess volume status as well as order prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels. It is also important to assess renal function. A chemistry panel should be ordered to examine electrolyte levels, BUN levels, and creatinine.

Additionally, to further assess the extent of the damage, cystoscopy and renal ultrasound can be utilized. Cystoscopy may show white mucosa with telangiectasia.[3]

Treatment / Management

Treatment of radiation cystitis varies depending on the severity of symptoms. For grade 1 and grade 2 types, symptomatic relief is typically all that is necessary. If frequency and urgency are the predominant symptoms, anticholinergic medications can be used for relief. Additionally, bladder irrigation is usually considered the first-line treatment in all grades of the disease and can be used to remove clots if hematuria is present.[4] Fulguration with alum or silver nitrate may be used inside the bladder as well. [5]

Hyperbaric Oxygen Therapy (HBOT) is another form of noninvasive treatment that has become more prevalent in recent years. This therapy not only targets symptom relief but also has the capability of stopping the progression of the pathologic process. HBOT stimulates angiogenesis, which reestablishes blood flow to areas in danger of necrosis, and helps maintain bladder functionality. Studies have shown a complete response rate ranging from 27% to 100% of patients studied, with most showing more than 75% of patients with a complete response.[3][6]

One study showed that, even with milder symptoms,  patients treated within six months of hematuria onset had  96% complete or partial symptomatic resolution whereas those treated after six months had but a 66% response rate. This is supportive of (albeit not definitive for) the early use of hyperbaric oxygen therapy. [7]

More invasive measures may be necessary if late-stage complications occur or if the radiation cystitis is resistant to more conservative methods. Such situations include persistent hematuria, fistulas, severe detrusor contraction, or hydronephrosis. Failure of more conservative measures leading to cystectomy is associated with a high risk of complications and mortality. Severe complications in almost half (42%) and 90-day mortality is reported to be 16%.


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Radiation Cystitis And Hyperbaric Management - Questions

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Which of the following is NOT currently a proposed mechanism of injury to the bladder in radiation cystitis?



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A 76 year old male with a history of rectal cancer cured with chemotherapy and radiation therapy 15 years ago presents to his primary care physician for one week of increased urinary frequency and states he noticed a minor amount of blood while urinating this morning. He states he was feeling well until this started one week ago and has not noticed any other symptoms. Physical exam is unremarkable. What is the first step in the evaluation of this patient?



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A 76 year old patient with a history of rectal cancer cured with chemotherapy and radiation therapy 15 years ago presents to his primary care physician for one week of increased urinary frequency and states he noticed a minor amount of blood while urinating this morning. He states he was feeling well until this started one week ago and has not noticed any other symptoms. Physical exam is unremarkable. UA, culture, and cytology are performed and rule out infection and bladder cancer. UA is negative for RBCs currently. Cystoscopy shows moderate generalized telangiectasia without petechiae, erythema, and no blood clots. CBC shows a normal WBC count and normal hemoglobin level. Bladder capacity remains within normal limits. It is determined this patient likely has Grade 2 radiation cystitis. Which of the following is the best choice for initial treatment?



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An 84-year-old male is brought into the ER by his wife due to severe hematuria for the last 2 days. Beginning 4 days before that, he had been experiencing increased frequency, dysuria, and fatigue as well. He has a history of prostate cancer diagnosed 5 years ago and was given radiation therapy as part of his treatment plan. He otherwise has been healthy. What grade radiation cystitis does this patient have? Vital signs: BP 96/64, HR 110, RR 20, T 37 degrees C UA showed many RBCs but no signs of infection and cytology was not indicative of bladder cancer. CBC showed a hemoglobin of 9.0 g/dL. Chemistry panel and coagulation studies were within normal limits. Cystoscopy is performed and shows active bleeding and the presence of blood clots. There is generalized telangiectasia with petechiae present. No strictures, fistulas, or large areas of necrosis are noted. Irrigation and clot evacuation are performed during cystoscopic evaluation. Additionally, bladder function studies were performed and bladder capacity was found to be 130 mL (normal is 400-600 mL).



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An 84-year-old male is brought in due to severe hematuria for the last 2 days. Beginning 4 days before that, he had been experiencing increased frequency, dysuria, and fatigue as well. He has a history of prostate cancer diagnosed 5 years ago and was given radiation therapy. He has otherwise been healthy. Vital signs: BP 96/64, HR 110, RR 20, T 37 degrees C. He is given a 1 L bolus of normal saline. UA showed many RBCs but no signs of infection and cytology was not indicative of bladder cancer. CBC showed a hemoglobin of 9.0 g/dL. Chemistry panel and coagulation studies were within normal limits. Cystoscopy is performed and shows active bleeding and the presence of blood clots. There is generalized telangiectasia with petechiae present. No strictures, fistulas, or large areas of necrosis are noted. Irrigation and clot evacuation are performed during cystoscopic evaluation. Additionally, bladder function studies were performed and bladder capacity was found to be 130 ml (normal is 400-600 ml). Since bladder irrigation and clot evacuation have been performed, the bleeding has subsided. What is the best next step in the management of this patient's radiation cystitis?



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Radiation Cystitis And Hyperbaric Management - References

References

A Narrative Review on the Pathophysiology and Management for Radiation Cystitis., Browne C,Davis NF,Mac Craith E,Lennon GM,Mulvin DW,Quinlan DM,Mc Vey GP,Galvin DJ,, Advances in urology, 2015     [PubMed]
Outcomes of Radiation Injuries Using Hyperbaric Oxygen Therapy: An Observational Cohort Study., Niezgoda JA,Serena TE,Carter MJ,, Advances in skin & wound care, 2016 Jan     [PubMed]
Continuous bladder irrigation in the monoplace hyperbaric chamber: Two case reports., Cooper JS,Allinson P,Winn D,Keim L,Sippel J,Shalberg P,Fowler K,, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 2015 Sep-Oct     [PubMed]
Radiation Induced Cystitis and Proctitis - Prediction, Assessment and Management., Mallick S,Madan R,Julka PK,Rath GK,, Asian Pacific journal of cancer prevention : APJCP, 2015     [PubMed]
A Practical Approach to the Management of Radiation-Induced Hemorrhagic Cystitis., Liem X,Saad F,Delouya G,, Drugs, 2015 Sep     [PubMed]
Hyperbaric oxygen therapy for refractory radiation-induced hemorrhagic cystitis., Ribeiro de Oliveira TM,Carmelo Romão AJ,Gamito Guerreiro FM,Matos Lopes TM,, International journal of urology : official journal of the Japanese Urological Association, 2015 Oct     [PubMed]
Early hyperbaric oxygen therapy improves outcome for radiation-induced hemorrhagic cystitis., Chong KT,Hampson NB,Corman JM,, Urology, 2005 Apr     [PubMed]

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