Radiation Cystitis

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Radiation cystitis is a complication of radiation therapy to pelvic tumors. The urinary bladder can be irradiated intentionally for the treatment of bladder cancer or incidentally for the treatment of other pelvic malignancies. Manifestations of radiation cystitis can range from minor, temporary, irritative voiding symptoms and painless, microscopic hematuria to more severe complications, such as gross hematuria; contracted, nonfunctional bladder; persistent incontinence; fistula formation; necrosis; and death (see the image below). (See Presentation.)

Tumors of the pelvic organs (ie, prostate, bladder, colon, rectum) are common in men, constituting 35% of expected new cancer diagnoses for 2017. [1] In women, cancer of the colon and rectum, bladder, and genital tract (uterus, ovary, and vagina/vulva) are expected to make up 17% of new cancer diagnoses in 2017. [1] Radiation therapy is an important management tool for the treatment of these malignancies, creating significant potential for the development of radiation injury to the bladder.

Radiation morbidity is due to incidental treatment of healthy organs. Efforts to reduce the complications of radiation have led to improvements in delivery mechanisms of radiation to the target organ. Wide-field treatment was the standard of care, but it is associated with high morbidity. Cobalt therapy, because of its low energy, requires high doses to deliver adequate radiation to the tumor. Unfortunately, this results in higher doses to healthy structures near the target and, thus, high complication rates. (See Etiology and Pathophysiology.)

Newer techniques and energy sources focus therapy on the target, minimizing collateral radiation to healthy structures. These include conformal beam therapy and computed tomography (CT) or ultrasonography-guided brachytherapy. [2] Sources providing higher energies produce better tissue penetration, resulting in smaller doses to surrounding normal tissues. The use of more beams allows a lower dose per beam, thus reducing the maximum dose to normal structures beyond the target tissues.

Radiation therapy can be used as primary, adjuvant, or palliative treatment and often complements medical or surgical therapy for malignancies. Ideally, only the tumor receives radiation, excluding nontarget organs. Conformal beam therapy and brachytherapy attempt to do this. However, incidental irradiation of nearby tissues is unavoidable, either because of the invasion of surrounding organs by tumors or because of the proximity of cancers to neighboring pelvic structures.

Acute radiation cystitis is usually self-limiting and is generally managed with conservative symptomatic therapy or observation. Late radiation cystitis, which can develop months to years after radiation therapy, presents principally as hematuria, which ranges from mild to life-threatening. [3] A variety of intravesical agents has been used for these patients. Hypebaric oxygen therapy has shown success in severe or refractory cases. [4] See Treatment and Medication.

For patient education information, see the Cancer Center, as well as Bladder Cancer and Blood in the Urine.

Therapeutic radiation may be delivered via various external sources. It may be applied directly to the tumor, such as in interstitial or intracavitary therapy (brachytherapy), or it can be delivered by external beam therapy. Radiation therapy works through the transfer of energy from ionizing radiation to molecules within tumor cells and related tissues. Radiation interacts with intracellular water and produces free radicals that interfere with DNA synthesis, resulting in cell death. Cells that divide rapidly are most susceptible to radiation injury. Peak sensitivity to radiation is at the M and G2 phases of the cell reproductive cycle.

Radiation may also directly cause rapid cell death from mitotic arrest, point mutations in deoxyribonucleic acid (DNA), and cell membrane damage. Concomitant use of chemotherapeutic agents may work synergistically to increase the risk of developing bladder injury from radiation. Radiation can also cause vascular changes. Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to the irradiated tissue. Collagen deposition may also cause severe scarring and further blood-vessel obliteration, resulting in tissue hypoxia and necrosis. The fibrotic barriers left behind can also impair revascularization.

These events lead to mucosal ischemia and epithelial damage. In the bladder, this in turn may cause further submucosal fibrosis as the subepithelial tissues become exposed to the caustic effects of urine. Ulcer formation, radiation neuritis, and postradiation fibrosis may cause the clinical findings of pain and discomfort.

Pathologic findings in radiated bladders include early and late findings. Early findings are defined as those occurring within 12 months after treatment, whereas late findings occur more than 12 months after treatment.

Early findings include submucosal inflammation and fibrosis, perineural inflammation, surface ulceration, and epithelial atypia (eg, nuclear pleomorphism, hyperchromatism, granular cytoplasm); epithelial atypia may also be a late finding.

Late findings include changes that are mainly fibrovascular and demonstrated by luminal occlusion, vascular ectasia, and necrosis of vessel walls. Cells with epithelial damage show cytoplasmic vacuolization and epithelial proliferation. Physiologically, these changes may produce clinical symptoms resulting from (1) ischemia and fibrosis leading to loss of bladder muscle fibers and thus to dysfunctional voiding and (2) denervation supersensitivity from ischemia causing abnormal neural stimulation of the bladder.

The rate of long-term complications depends on the following 3 major factors:

Volume and area of bladder affected – If affected, the trigone is more symptomatic than is the dome of the bladder

Dose rate (< 0.8Gy/h decreases risk of cystitis) and daily fraction size (doses >2Gy/fraction increase risk)

Total dose – Toxicity increases when the total dose received exceeds 60Gy to the bladder; conformal beam therapy allows higher doses to the target tissue while maintaining lower total dose delivered to the bladder

The reported frequency of radiation cystitis varies because of difficulties in data collection (usually performed by questionnaire), differences in dosimetry and field size used, and the fact that various tumors are treated with different fields and include varying amounts of bladder exposure.

The overall frequency of radiation cystitis 1 year after treatment of bladder cancer is 9-21%; the reported mean is 14.2%. [5] For 3- to 4-box, small-field therapy (66 Gy), the frequency, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring, is as follows:

Grades 1 and 2: 24-64%

Grades 3 and 4: 2-9%

For conformal beam therapy (70-78 Gy), the frequency is as follows:

Grades 1 and 2: 65%

Grades 3 and 4: 9%

The overall frequency of radiation cystitis 1 year after treatment of cervical cancer is 3-6.7%; the reported mean is 4.9%. [6]

The frequency associated with combination 4-field external beam therapy (70-80 Gy) and cesium implants is as follows:

Grade 1: 1-3%

Grade 2: 1-2%

Grade 3: 2-5%

The overall frequency of radiation cystitis 1 year after treatment of bladder cancer is 2-47%; the reported mean is 17.8%.

The frequency associated with 3- to 6-beam, small-field therapy (32-57.5 Gy) is as follows:

Grades 1 and 2: 19-49%

Grades 3 and 4: 33-48%

Intensity-modulated radiotherapy (IMRT) has been shown to deliver higher doses to the target area while minimizing complications. IMRT is increasingly used for the treatment of prostate cancer; doses of 81 Gy have been delivered. The complication rate with IMRT is lower than that with 3-dimensional (3D) conformal beam therapy, although not all studies show a significant difference.

The frequency of toxicity with IMRT versus the frequency with 3D conformal radiotherapy is as follows.

Grade 2: IMRT, 17-36%; 3D conformal radiotherapy, 42-60%

Grade 3: IMRT, 0.3-0.5%; 3D conformal radiotherapy, 1-2%

After treatment for prostate cancer, rectal complications are much lower with conformal beam therapy than with 4-box, small-field therapy (19% vs 32%, grade 2 toxicity); however, the incidence of bladder complications is unchanged, probably because of the proximity of the bladder neck and unavoidable exposure to the urethra.

IMRT has also demonstrated a significant improvement in rectal complications compared with 3D conformal radiation therapy. Fewer grade 2 bladder complications occur with IMRT, but the rates of grade 3 complications are similar. GI symptoms can be further reduced by using fiducial marker–based position verification in patients with prostate cancer. [7]

A multicenter, phase II study conducted by Kim et al found that in patients with rectal cancer, preoperative chemoradiation with cetuximab, irinotecan, and capecitabine was active and well tolerated. [8]

After treatment for bladder cancer, acute symptoms (ie, those observed during treatment and lasting <1y) are usually self-limiting and occur in 50-80% of patients, regardless of tumor type.

Acute symptoms of radiation injury to the bladder are self-limiting and generally respond to symptomatic therapy, such as anticholinergic medications and analgesics. Severe complications of radiation injuries are difficult to manage because they tend to be chronic or recurrent and are occasionally refractory to therapy. Proper interpretation of treatment outcome is limited by few follow-up studies and the small number of patients reported in these studies.

The available follow-up studies performed with various treatment regimens demonstrate that although all have some effectiveness, no single modality is superior. They also show the recurrent nature of radiation complications of the bladder. Complications of radiation cystitis include hemorrhagic cystitis (3%-5%), vesical fistula (2%), and bladder neck contracture (3%-5%). Neoplasia and contracted bladder can also occur but are rare.

Cancer Facts & Figures 2017. American Cancer Society. Available at http://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed: January 23, 2017.

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Nicolas A Muruve, MD, FACS, FRCSC Associate Staff, Department of Urology, Cleveland Clinic Florida

Nicolas A Muruve, MD, FACS, FRCSC is a member of the following medical societies: American College of Surgeons, Society of Urologic Oncology, Canadian Urological Association, American Society of Transplant Surgeons, American Urological Association, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Edward David Kim, MD, FACS Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Sexual Medicine Society of North America, Tennessee Medical Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Endo, Avadel.

Michael Grasso III, MD Director of Endourology, Lenox Hill Hospital; Professor and Vice Chairman, Department of Urology, New York Medical College

Michael Grasso III, MD is a member of the following medical societies: American Medical Association, American Urological Association, Endourological Society, Medical Society of the State of New York, National Kidney Foundation, Société Internationale d’Urologie (International Society of Urology), and Society of Laparoendoscopic Surgeons

Disclosure: Karl Storz Endoscopy Consulting fee Consulting; Boston Scientific Consulting fee Consulting; Cook Urologic Consulting fee Consulting

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center

Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology

Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership

Radiation Cystitis

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