Management of Acute and Chronic Complications of Radiation Therapy for Pelvic Malignancy: An Overview*
Learning Objective: At the conclusion of this continuing medical education activity, the participant will identify different modalities to deliver pelvic radiation, appreciate acute and chronic toxicities of radiation therapy, and consider prevention and management options.
Divya Ajay, MD, MPH
Disclosures: Nothing to disclose
Fellow, Urinary Tract and Pelvic Reconstruction
Department of Urology
Chad Tang, MD
Disclosures: Nothing to disclose
Department of Radiation Oncology
Brian Chapin, MD
Disclosures: Nothing to disclose
Department of Urology
O. Lenaine Westney, MD
Disclosures: Boston Scientific: Consultant
Department of Urology
The University of Texas MD Anderson Cancer Center
*This AUA Update addresses the Core Curriculum topics of Oncology – Adult and Uroradiology, and the American Board of Urology Module: Oncology, Urinary Diversion and Adrenal.
Key Words: radiation injuries, pelvic neoplasms, radiotherapy, cystitis, proctitis
The American Cancer Society estimated that 516,410 new pelvic organ cancer cases would be diagnosed in 2018 including genital, prostate, bladder and colorectal malignancies,1 representing 30% of all newly diagnosed cancers. Radiation therapy has many applications in the primary, neoadjuvant, adjuvant and salvage setting for the treatment of pelvic malignancies. Randomized controlled trials have demonstrated improvement in overall and cancer specific survival for patients treated with RT, especially those with locally advanced disease. RT has been administered to 37% of prostate, 22% uterine, 44% cervical, 14% colon,40% rectal and 4% bladder cancer cases.2 Theclose proximity of organs in the pelvis makes them particularly vulnerable to radiation-induced injuries. With significant variation based on setting, dose and grade, a wide range of RT related adverse events is reported.
Ongoing strides in cancer treatment have prolonged the lifespan of patients with pelvic malignancies. Early detection, advancements in treatment techniques and systematic therapy have led to a decline in death rates for the 4 most common cancer types, which are colorectal, prostate, lung and breast, translating into 2.3 million fewer cancer deaths from 1991 to 2015.1 Subsequently, an increasing number of cancer survivors are living with quality of life altering side effects of RT. This subset of patients with progressive and permanent tissue damage is challenging to treat for the urologist. We describe contemporary RT modalities, acute and chronic toxicities of this therapy, treatment options and ongoing efforts in the prevention of injuries.
Types of delivery. The 2 primary forms of radiation delivery are external beam radiation therapy and brachytherapy. Both forms play an integral role in radiation delivery for pelvic malignancies.
As the name implies, the defining feature of EBRT is that radiation is created external to the patient and delivered to treat the internal tumors. Dose is invariably deposited between the site of radiation entry to the tumor, and between the tumor and site of exit. Thus, organs and critical structures that lay in the beam’s path can receive significant doses of radiation. With the advent of modern radiation techniques, including intensity modulated radiation therapy and stereotactic body radiation therapy, “entry” and “exit” dose in critical structures is minimized. For proton therapy the physical properties of the proton particle allow the radiation beam to stop at the tumor, thus producing minimal to no “exit” dose.
EBRT results in radiation energy absorbed upon beam entry and exit, thus it is difficult to treat with high doses of EBRT. The ready access and anatomic confines of the pelvis furnish unique opportunities to treat by placing radiation emitting sources in close proximity to the tumor. This form of radiation, known as brachytherapy, is delivered via either high dose rate or low dose rate. Given the physical properties of brachytherapy, dose fall is exponentially faster, thus allowing for significantly higher doses and minimal dose to surrounding structures (fig. 1).
For example, for the definitive treatment of prostate cancer, low dose rate is used to achieve doses in order of 115-145 Gy to the entire prostate. Significant portions (40% to 70%) of the prostate receiving 150% to 200% of this dose result in doses in excess of 230 to 290 Gy to many parts of the organ. In contrast, definitive prostate cancer is treated with EBRT to only 70 to 80 Gy. Thus anatomically accessible cancers, including penile and low/intermediate risk prostate cancers, can be treated with brachytherapy alone, while other cancers, including cervix, uterine, vaginal and high risk prostate cancer, are treated with combination EBRT and a brachytherapy boost, with EBRT covering larger areas of regional disease and brachytherapy allowing for significant dose escalation to the primary disease.
Grading. Radiation-induced toxicity is graded using published scales. The RTOG (Radiation Therapy Oncology Group/EORTC (European Organization for Research and Treatment of Cancer) system3 and LENT-SOMA4 were published in 1995. The National Cancer Institute developed CTCAE (Common Terminology Criteria for Adverse Events) scales in 2003.5 The current version 5 of the CTCAE has been adopted as the preferred platform for toxicity reporting in clinical trials. The RTOG is widely used for clinical documentation outside of the trial setting (Appendix 1).
ORGAN BASED ACUTE TREATMENT TOXICITIES
Bladder. For several decades primary RT was being used as bladder sparing monotherapy for muscle invasive bladder cancer in patients unfit for radical extirpative surgery. While radical cystectomy remains the standard of care for muscle invasive bladder cancer, combined modality therapy (maximal transurethral resection of bladder tumor, RT and radiosensitizing chemotherapy) has evolved in the last 20 years and proven to be oncologically superior to RT alone.6 Planned radiation for the bladder is typically between the mid sacroiliac region to the upper limit of the common iliac artery bifurcation with an initial dose of 40 Gy with further boosts to the whole bladder to 54 Gy and locoregional pelvic lymph nodes to 64 to 66 Gy.7
For patients receiving RT alone, the prospective trials BCON and BC2001 revealed grade 3 to 5 genitourinary toxicity in 32% and 21%, and grade 3 to 5 gastrointestinal toxicity in 5% and 2.7% of patients at a median follow-up of 36 and 69 months, respectively.8 Based on long-term survey data of bladder cancer survivors previously treated with RT alone, Fokdal et al reported urinary frequency in 42%, urinary incontinence in 22% and moderate to severe GI toxicities in 29%.9 Brachytherapy is rarely used for bladder cancer and is associated with high rates of adverse events up to 22%.
Prostate. Prostate cancer is the leading site of new cancer in men with an estimated 164,690 men diagnosed in 2018.1 EBRT and brachytherapy are used in the management of localized and locally advanced prostate cancer. RT has been shown to have comparable survival outcomes in select patients with intermediate or high risk localized prostate cancer.10
For patients receiving primary RT for localized prostate cancer, the IMRT technique of EBRT is believed to be more effective than the standard 3D-conformal RT for target coverage, dose homogeneity and reducing toxicity to normal organs. The median incidence of grade 2 to 5 GU toxicity was 18% (range 0% to 43%) for the IMRT cohorts in all studies and 21% (1% to 45%) for 3D-conformal RT.11 The median incidence of grade 2 to 5 GI toxicity was 6% (range 0% to 24%) for the IMRT cohorts and 15% (9% to 37%) for 3D-conformal RT. The most common acute GU adverse events in the IMRT cohort were dysuria (50%), straining (57%) and incontinence (37%). Tenesmus (49%) was the most common GI toxicity. Fatigue was reported in up to 55% of patients receiving primary RT.
In patients with high risk features, post-prostatectomy adjuvant RT has been shown to improve biochemical progression-free survival, distant metastasis-free survival and overall survival.12 Salvage RT is used after biochemical recurrence and improves prostate cancer specific mortality.13 Patients who receive adjuvant radiation have a 1.6-fold increased risk of post-prostatectomy urinary incontinence, and salvage RT is associated with lower GI and GU toxicities.14
Of patients receiving adjuvant RT 47% reported tenderness and fecal urgency, 5.3% grade 3 diarrhea, 3.2% proctitis, and rectal bleeding at 6 weeks.14 Urinary frequency was reported by 51% of patients and 6% to 8% experienced urinary incontinence.12 The risk of acute grade 3 to 5 urinary toxicities is significantly worse (18.1% versus 6.9%) with newer techniques like hypofractionation which attempt to deliver the same dose of radiation in a short interval of a higher daily dose.15
Brachytherapy is used to treat low risk and favorable intermediate risk disease as monotherapy or as a boost with EBRT and androgen deprivation therapy for unfavorable intermediate or high risk disease.16 Patients receiving monotherapy brachytherapy are reported to have grade 2 to 5 GU and GI toxicities of dysuria (8% to 9%), frequency (27%), retention (7% to 13%), gross hematuria (0% to 1%), diarrhea (2%) and tenesmus (1%). These rates are significantly higher in patients who received brachytherapy in combination with EBRT at 25% for dysuria, 38% frequency, 6% retention, 1% gross hematuria, 21% diarrhea and 21% tenesmus.17
Endometrial. Endometrial is the most commonly diagnosed gynecological cancer primarily affecting postmenopausal women between ages 60 and 80 years.1 Surgery is the cornerstone of treatment for non-metastatic disease. Postoperative RT is added for intermediate or high risk patients with brachytherapy alone as the standard of care.18 Brachytherapy can be delivered to the intact uterus preoperatively or curatively. Doses of 45 to 50 Gy are typically used.
GU complications after postoperative radiation for endometrial cancer are less common compared to cervical cancer, which may be secondary to the use of a single radiation modality and moderate dose. In patients receiving adjuvant RT 65% reported acute low grade toxicities leading to treatment interruptions in 8.8%.19 In the Gynecologic Oncology Group study of postoperative RT for endometrial cancer high grade GU toxicity was reported in 2% to 5% of patients and acute diarrhea occurred in 30%.20
Cervical. Cervical cancer affects young women, translating into a large number of cancer survivors. Surgical excision is the standard of care for early tumor stages (IB-IIA). However, patients with more advanced disease receive primary pelvic EBRT with brachytherapy (80 to 85 Gy) with or without chemotherapy.21 High grade acute GU and GI toxicities are reported at 6% to 10% and 24% to 26%, respectively, for patients receiving primary RT.22 These numbers are lower at approximately 2% to 8% GU and 8% to 9% GI toxicities for patients receiving adjuvant RT.
Anal and rectal. Surgical excision is first line therapy for anal carcinoma but local RT with chemotherapy is administered if inadequate margins are achieved and for locally advanced or metastatic cancers. For rectal cancer, preoperative chemoradiation (45 to 50 Gy) has led to significant improvements in disease specific survival. Acute grade 3 to 4 GU toxicities occurred in 1% to 2% of patients receiving preoperative chemoradiation therapy.23 These patients experienced 5% hematological, 20% gastrointestinal and 2% dermatological grade 3 to 4 adverse effects.
FIRST LINE THERAPIES OF SPECIFIC ACUTE TOXICITIES
Acute phase radiation toxicities are treated primarily by radiation oncologists using algorithms obtained from multispecialty consultation. Most acute radiation toxicities present during the middle of the radiation course, worsen through the radiation course and improve 1 to 3 months after radiation is complete. Appendix 2 includes common protocols followed by radiotherapists for acute GI and GU toxicities during treatment.
Diagnosis and management of genitourinary chronic toxicities. Radiation Cystitis: Radiation-induced cystitis occurs secondary to progressive obliterating endarteritis due to fibrosis of the vascular intima of the submucosal arterioles and capillaries, resulting in tissue hypoxia (fig. 2).24 Neovascularization may sometimes cause intractable gross hematuria, urgency, frequency and urinary incontinence, leading to significant morbidity and mortality. Incidence varies but is between 3% and 9% in survivors of bladder, prostate and cervical cancer with a mean latency period of 35 months.6 Radiation cystitis is a diagnosis of exclusion and thus, infectious (viral and bacterial), coagulopathy and malignant causes must be ruled out.
Limited published high quality data guide our management of radiation cystitis, and most current management is based on expert opinion corroborated by small case series. The first steps are stabilizing the patient, resuscitation, hyper-hydration and diuresis. Use of a large bore catheter and intermittent or continuous bladder irrigation with the goal of evacuating clot from the bladder is the next step. If formed clot is unable to be evacuated, cystoscopy, clot evacuation and fulguration of bleeding points from the bladder are required. Oral or parenteral agents, including conjugated estrogen, WF10 and pentosan polysulfate, can be administered.25 If the hematuria remains intractable, intravesicular agents are the next steps (Appendix 3).
Hyperbaric oxygen therapy was first described in 1985 for the treatment of radiation cystitis.26 One hundred percent oxygen is delivered to the patient at 2 to 3 atmospheres of pressure in a special chamber in 30 to 40 sessions of 90 minutes each. The proposed mechanism of action is an increase in local tissue oxygen tension, decreased edema, increased neovascularization and improved wound healing.27 Case series have indicated success rates between 80% and 90%, although most patients have recurrent symptoms with extended follow-up and a 5-year complete response rate of about 27%. Contraindications include claustrophobia, chronic obstructive pulmonary disease, seizures etc, and potential complications include barotrauma and oxygen toxicity.
Hemorrhagic cystitis refractory to these treatments requiring persistent transfusions may be treated with bladder embolization. Selective embolization of the anterior branch of the internal iliac bilaterally has been successful (~90%) in small series.28 The posterior branch should be avoided since it occludes the superior gluteal artery causing significant gluteal pain. Supravesical diversion using percutaneous nephrostomy tube with or without ureteral occlusion or urinary diversion is a more aggressive option. The intention is to divert the urokinase in urine away from the bladder facilitating hemostasis. However, leaving the bladder intact increases the risk of pyocystis (67%), hemorrhage (23%) and severe pain (13%). In such situations performing a concurrent vesicovaginostomy in survivors of cervical cancer or simple cystectomy has been shown to have better outcomes.29
Lower Urinary Tract Symptoms and Voiding Dysfunction: RT induces an inflammatory response mediated by reactive oxygen species and causes voiding dysfunction. Urodynamics is the gold standard for the study of voiding dysfunction. Short-term urodynamics at 1 to 2 and 5 to 6 months performed on a small cohort of women who underwent RT for cervical cancer demonstrated significant reductions in peak urinary flow, volume at first desire to void, cystometric capacity and bladder compliance.30 Similar results were reported in a study of survivors of cervical cancer 5 to 11 years after RT, including a reduction in volume of first bladder sensation and cystometric capacity, an increase in filling detrusor pressures and uninhibited contractions.31 In another study of a small cohort evaluated 3 and 18 months after radiation for prostate cancer a decrease in the volume of first bladder sensation and cystometric capacity was noted with no change in compliance.32 If behavioral modifications and medications fail, intravesical botulinum toxin may help increase bladder capacity.33 Further along the algorithm in the management of RT induced voiding dysfunction are bladder augmentation and urinary diversion. Long-term obstructive voiding symptoms may be managed with self-catheterization.
Transurethral resection of the prostate is associated with significant risk of incontinence and should be avoided for at least 1 to 2 years after radiation.34 Two techniques for the treatment of post-prostatectomy urinary incontinence include a transobturator sling and artificial urinary sphincter. Patients treated with adjuvant RT are at increased risk for urethral erosion, infection and failure of both techniques.35, 36
Vesicular Fistula: After prostate RT, fistulas from the bladder or urethra may develop anteriorly to the pubic symphysis or posteriorly to the rectum. They can track down the obturator canal, along the fascial planes of the adductor muscle and fistulize to the thigh. Fistulas have been reported in 0.3% to 3% of patients after brachytherapy and 0% to 0.6% of men after EBRT for prostate cancer.37 Risk factors for rectourethral or rectovesicular fistulas include a history of rectal stricture, urethral stricture, rectal biopsy, rectal argon beam therapy or transurethral prostate resection after radiation.
Urinary and fecal diversion is the mainstay of treatment, which in some cases is followed by delayed transperineal fistula repair with gracilis muscle flap interposition.38 Patients who have undergone prior bladder neck procedures presenting with chronic pelvic pain, difficulty walking, recurrent urinary tract infections and fatigue should be investigated for anterior fistulas and osteomyelitis of the pubic symphysis. These patients do not generally respond to conservative management with antibiotics and often require surgical debridement. It is imperative to assess bladder capacity and compliance to determine if a bladder sparing approach can be attempted.39
Female patients with bladder involvement of gynecological or anorectal cancers at the time of diagnosis are at increased risk for fistula to the bladder (fig. 3). All fistulas should be biopsied to rule out the presence of malignancy. Small vesicovaginal fistulas may be managed with simple fulguration and catheter drainage. Vesicovaginal fistulas associated with radiation often require surgical repair with muscle interposition, Martius or omental flaps and occasionally even urinary diversions.
Urethral Stricture/Bladder Neck Contracture: Periurethral fibrosis, atrophy and subsequent tissue contraction contribute to the pathophysiology of urethral strictures with a reported median latency period of 26.6 months (range 7.8 to 44 months) after RT (fig. 4).40 A meta-analysis of the prevalence of radiation induced urethral stricture revealed a pooled estimate prevalence of 1.5% (95% CI 0.9–2) after EBRT, 1.9% (95% CI 1.3–2.4) after brachytherapy, and 4.9% (95% CI 3.8–6) after EBRT and brachytherapy.41 The most common location is within the bulbomembranous urethra. Prior transurethral resection of the prostate significantly increases the risk of a stricture, likely due to devascularization.
Patients can present with a variety of obstructive lower urinary tract symptoms, hematuria or recurrent UTIs. A combination of cystoscopy, retrograde urethrogram, voiding cystogram and urethral ultrasound can help reveal the anatomy of the stricture. All radiated bladders must undergo functional testing before any reconstructive procedure to ensure adequate capacity and compliance. Patient reported quality of life measures and baseline sexual function should be documented. Endoscopic management may be attempted but the failure rate is as high as 50%.42 The majority of radiation induced urethral strictures are short bulbar strictures for which excision and primary repair have high success rates of 70% to 95%.43 For longer strictures, genital fasciocutaneous or buccal mucosal flaps have been used with 70% to 80% success at a median follow-up of 21 to 50 months.44 In a small cohort of patients with posterior urethral strictures isolated to the prostatic or membranous urethra intraperitoneal robotic reconstruction was successful without perineal mobilization of the urethra, hence sparing the bulbar arteries.45
Ureteral Strictures and Fistulas: Surgical ureteral stricture repair was recorded in 10.3% of women who underwent RT for cervical cancer based on records from an administrative database in Ontario, Canada.46 The first step in addressing ureteral strictures is to rule out recurrent cancer. Imaging with CT or MRI is recommended. Strictures can be managed endoscopically with dilation and stent placement, although more often than not ureteral reimplantation or ileal ureteral substitution is necessary. Ureteroiliac artery fistulas may present as a medical emergency and are treated with ureteral stent or ligation in conjunction with angioembolization.47
Fertility: Recent data have shown an increase in young adults diagnosed with colorectal cancer leading to a change in screening guidelines.48 Radiation to the testis affects germ cells and Leydig cells, subsequently impacting spermatogenesis and testosterone production, respectively. Radiation doses as low as 0.15 Gy led to a decrease in semen volume, and 0.3 to 0.5 Gy can cause temporary oligospermia requiring 9 to 18 months of recovery.49 Doses of 24 to 25 Gy cause direct germinal epithelium to be ablated and Leydig cell dysfunction.
Fertility is also a concern for cervical cancer survivors. Premenopausal women who undergo RT are at an increased risk of premature ovarian failure, menopause and infertility due to ovarian radiosensitivity. Doses as low as 1.7 to 2.6 Gy have been associated with temporary amenorrhea or sterility.50
Because of gonadal radiosensitivity, young men and women desiring fertility should be referred to reproductive endocrinology to explore options including sperm banking, ovarian transposition, ovarian autotransplant to upper limb or oocyte/embryo cryopreservation. Radiation protection devices such as testicular shielding should be used in young men to protect fertility and testosterone production.
Erectile Dysfunction: A meta-analysis of observational data revealed a pooled estimate of SHIM (Sexual Health Inventory for Men) confirmed an erectile dysfunction score <10 to 17 after RT in 34% of men (95% CI 0.29–0.39) at 1 year and 57% (95% CI 0.53–0.61) at 5.5 years.51 The etiology is multifactorial and includes radiation induced nerve damage, corporal fibrosis and cavernous artery insufficiency. Potential risk factors are preexisting diabetes, large radiation field size and penile doses >52.5 Gy with 70 Gy or more to the penile bulb. The use of phosphodiesterase type 5 inhibitors can be effective in the treatment of radiation induced erectile dysfunction. Other treatment options include the vacuum erection device, intracavernosal injection therapy, alprostadil urethral suppositories and inflatable penile prosthesis.
Diagnosis and management of gastrointestinal chronic toxicities. Enteritis: The small bowel is at risk for long-term morbidity when the dose of radiation exceeds 40 to 45 Gy. Strategies to prevent GI toxicity include multiple RT fields to avoid significant dose inhomogeneity, use of a belly board with the patient prone, and treatment with the bladder full to displace small bowel and rectum empty.52 Chronic radiation enteritis can result in malabsorption of vitamin B12, folic acid and bile salts, which should be monitored and managed with a multidisciplinary team of experts including gastroenterology, nutrition and a dedicated nursing staff.
Late complications of RT include small bowel obstruction, large bowel stricture or severe enteritis. Patients who have had prior abdominal or pelvic surgery and receive >50 Gy of radiation to the pelvis are at increased risk for small bowel obstruction. Extensive dense bowel adhesions can be managed conservatively, although surgical management may be required. Operative management often leads to bowel resection with an incidence of short bowel syndrome in 10% to 19% of patients who have undergone surgery for RT induced bowel injury.53
Proctitis: Radiation injury to the rectum is called radiation proctitis. Endoscopic findings with radiation proctitis include rectal pallor, telangiectasia, strictures and fistulas. Acute treatment is supportive including butyrate enemas, antidiarrheal agents and hydration. In a randomized controlled trial probiot- ics reduced the incidence of grade 2 to 4 diarrhea. In patients with chronic rectal bleeding endoscopic management with argon plasma coagulation, formalin application or hyperbaric oxygen may be effective.54 However, argon laser coagulation should be used sparingly as it can exacerbate bowel injury.
Other late complications. Radiation Dermatitis: Radiation dermatitis begins with generalized dryness and itching, followed by erythema and hyperpigmentation which may be asymptomatic or mildly painful. Patients with high body mass index, smoking history, vascular disease or poor nutrition are at increased risk. Retrospective data have shown that acute epithelial toxicity after RT for prostate cancer is associated with long-term freedom from biochemical recurrence, proposing a possible link between normal tissue and tumor radiosensitivity.55 Late effects include folliculitis, hyperpigmentation, subcutaneous fibrosis and telangiectasia. Hyperbaric therapy should be considered for grade IV toxicity such as ulceration and necrosis. Secondary malignancy should be ruled out with skin ulceration.
Lower Extremity Lymphedema: Lower extremity lymphedema develops in approximately 7% of patients with gynecological cancers treated with adjuvant radiation therapy.56 The majority of these cases improve or resolve within 18 months. Lower extremity lymphedema is treated with compression stockings or complex decongestion therapy with an occupational therapist. Refractory cases may require surgical intervention such as lymphaticovenous anastomoses.
Vaginal Stenosis: RT for pelvic cancers, especially brachytherapy, is a well recognized cause of vaginal stenosis or fibrosis occurring in up to two-thirds of patients.57 Vaginal stenosis is defined as abnormal shortening or narrowing of the vagina. Between 38% and 80% of patients with cervical cancer report vaginal stenosis and fibrosis.
Patients present with dyspareunia, post-coital bleeding, sexual dysfunction or low abdominal pain often within the first year after treatment. Doses >45 Gy EBRT, tumor extension into the vagina and postmenopausal status have been associated with increased risk .57 Regular intercourse or the use of vaginal dilators can stretch the vaginal mucosa and break down adhesions to maintain vaginal patency. Dilation should be initiated 4 weeks after RT at least 2 to 3 times per week and continued for 9 to 12 months. Topical estrogen, benzydamine or α-tocopherol may help prevent vaginal complications.
Radiation Induced Peripheral Neuropathies: Radiation induced peripheral neuropathies are rare but chronic, progressive and often irreversible. Pudendal nerve entrapment is uncommon and can present with chronic perineal sharp, burning pain. A nerve block can be diagnostic as well as therapeutic when supported by MRI, CT and pudendal nerve motor latency test. Case reports have described the use of a dorsal spinal cord stimulator for treatment.58
Bone Damage (fractures, avascular necrosis): Pelvic insufficiency fractures are stress fractures resulting from application of physiological stress to weakened bone. Observational studies have described PIFs in patients after irradiation for gynecological, anal, prostate and rectal cancers. In patients with prostate cancer RT alone was associated with a 76% increased risk of PIFs, and radiation in conjunction with androgen deprivation therapy further increased the risk to 146%.59 The fractures occurred a median of 6 to 20 months after RT, and patients presented with pelvic and back pain, and immobility. Older age, lower body weight, high radiation doses, curative treatment intent for gynecological cancer and female gender for rectal cancer were associated with a high risk of insufficiency fractures.60 Of note, most of these observational studies did not calculate a baseline bone mineral density prior to RT, hence we cannot establish a causal effect with certainty.
PIFs may be associated with severe hemorrhage requiring angioembolization. Most are treated non-surgically as they are difficult to treat surgically due to increased risk of infection and malfunction after RT. Potential pharmacological interventions to prevent PIFs are based on standard treatments for optimizing bone health, and include calcium and vitamin D, bisphosphonates, estrogen receptor modulators, denosumab, calcitonin, strontium etc. They may be required for at least 24 months after RT covering the interval when patients are at highest risk. Of note, bisphosphonates and denosumab may lower calcium levels, and cause ulceration and breakdown of the jaw.
Pelvic RT related interruption of blood supply to the hip is called avascular necrosis and is another well recognized complication of pelvic RT. The risk of avascular necrosis after pelvic radiation is 0.5%.61
SECONDARY MALIGNANCIES ASSOCIATED WITH RT
One of the worst consequences of radiation exposure is radiation induced tumorigenesis. A modified version of Cahan’s criteria, first described in 1948, is used to define radiation induced malignancies.62 These criteria are a) the tumor must have arisen in an irradiated field; b) a sufficient latent period, preferably longer than 4 years, must have lapsed between the initial irradiation and the alleged induced malignancy; c) the treated tumor and alleged induced tumor must have been biopsied, and each tumor must be of different histology; and d) the tissue in which the alleged induced tumor arose must have been normal (ie metabolically and genetically normal) prior to the radiation exposure. While the mechanism of action is under study, we know that high doses of ionizing radiation generate oxygen derived free radicals, which in turn induce DNA damage and causes apoptosis. Radiation can induce genomic instability in cells which enhances the rate at which mutations and other genetic changes arise in the descendants of the irradiated cells after many cycles of replication, increasing risk of malignant transformation.
Observational cohort studies have shown that survivors of cervical and endometrial cancers are at increased risk for second primary malignancies of the colon, rectum, bladder and genital sites.63 Compared to survivors of prostate cancer who only underwent surgery, those who received RT with surgery were at increased risk for bladder and colorectal cancers.64 In addition to radiation dosage, other factors such as host genotype influences may contribute to increased risk and repeated imaging may contribute to early detection.65 When the index of suspicion is high, urologists, in collaboration with primary care physicians, should participate in a screening program for early detection of secondary primary malignancies in cancer survivors.
FUTURE PROMISING IDEAS FOR PREVENTION AND TREATMENT
Radiation techniques. Constant improvement in radiation delivery, treatment algorithms, machines and organ motion tracking may usher in an era of reduced pelvic organ toxicity. A recent example is volumetric modulated arc therapy (VMAT), which is a type of IMRT that can reduce treatment time per fraction by using a rotational technique. This technique allows for greater control in dose-shaping through modulation of gantry speed, dose rate and collimator angle. Compared to fixed IMRT, VMAT has been shown to deliver lower doses to the bladder, rectum and femoral heads.66
New methods are being developed to track target organs with the goal to reduce uncertainty during treatment and thus reduce treated tissue volumes. Historically, fiducial marker placement, x-ray images and cone beam CT have been used for alignment. More recently, radio frequency transponders implanted in the prostate for real-time tracking during treatment is a newer technique that allows for better targeting, hence preventing under dosing of the tumor and minimizing dose to the other organs at risk.67 MRI-linac allows for on the spot plan adjustment.
Advanced particle therapy may also reduce toxicity. Intensity modulated proton therapy, carbon, helium and iron are being developed which may have a dosimetric advantage and added potential for increased biological effectiveness in hypoxic tumors, which could enhance overall therapeutic effectiveness.68
Radiogenomics. The goal of radiogenomics is to identify genomic markers that are predictive of the development of adverse effects resulting from RT. For instance, a validated pre-radiation biomarker assessment tool to determine future risk of enteritis is not available yet. However, recent genome-wide association studies have analyzed single nucleotide polymorphisms and identified a region of chromosome 11q14.3 that is associated with GI toxicity and increased rectal bleeding in prostate cancer.69 Acute radiation induced nocturia has been associated with variant alleles of the TGFβ1 gene.70 Findings like this could eventually lead to a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified or alternative treatments offered.
Spacers. Missohou evaluated the use of a silicon tissue expander prosthesis placed surgically in the pelvis followed by a subcutaneous injection before radiation in 29 children, which resulted in a 64% decreased bowel dose >40 Gy.71 Prostate-rectum hydrogel spacers used to displace the rectum away from the prostate to minimize rectal radiation injury during RT for prostate cancer have resulted in a 78% reduction in radiation dose delivered to the rectum. The 3-year incidence of grade ≥2 toxicity was significantly less with a rectal spacer (5.7% vs 0%) with minimal procedure related adverse events.72, 73
Complications of RT for pelvic cancers occur acutely and emerge for many years after treatment. While most complications can be managed conservatively, some patients experience grade 3 to 4 complications that are refractory to medical management. Careful monitoring and education of cancer survivors by a multidisciplinary care team are necessary before and after RT, and pre-therapy selection of appropriate patients is critical. Newer RT modalities and diagnostic genomic testing may help reduce the number of patients suffering from RT adverse effects in the future.
|Grade||CTCAE (version 5.0)||RTOG Acute||RTOG Chronic|
|0||No change||No change||No change|
|1||Asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated||Slight epithelial atrophy, mild telangiectasia (microscopic hematuria)|
|2||Moderate, local or non-invasive intervention indicated, limiting instrumental activities of daily living||Urination or nocturia less frequent than every hour, dysuria, urgency, bladder spasm requiring local anesthetic||Moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria|
|3||Severe or medically significant but not immediately life threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care and activities of daily living||Frequency with urgency and nocturia hourly or more, dysuria, pelvic pain or bladder spasm requiring regular frequent narcotic, gross hematuria with or without clot passage||Severe frequency and dysuria, severe generalized telangiectasia (often with petechiae), frequent hematuria, reduction in bladder capacity (<150 cc)|
|4||Life threatening consequences, urgent intervention indicated||Hematuria requiring transfusion, acute bladder obstruction not secondary to clot passage, ulceration or necrosis||Necrosis, contracted bladder capacity (<1000 cc), severe hemorrhagic cystitis|
|5||Death||Death||Death from uncontrolled Hematuria|
|Obstructive symptoms: patients presenting with urinary obstruction, hesitancy, decreased flow and incomplete emptying||Tamsulosin 0.4 mg daily with maximum dose 0.8 mg daily, main side effects are orthostatic hypotension and retrograde ejaculation, alternative treatment option is terazosin 1 mg daily (can be titrated up to 10 mg daily)|
|Urgency/frequency: patients presenting with increased urgency, frequency >once every 2 hours, urge urinary incontinence, penile pain, nocturia||First line: behavioral modifications including avoiding bladder irritants and timed voiding may be used Second line: medication including anticholinergics oxybutynin 5-15 mg XL daily and hyoscyamine 0.2 mg sublingual Q6H PRN; beta-3 agonists like mirabegron 25-50 mg daily may be started after discussing all relevant side effects|
|Cystitis: presenting with urgency/frequency with dysuria or hematuria||First line: urinalysis + urine culture to rule out urinary tract infection, treat if positive; if negative, ibuprofen (400 mg 2 tablets BID PRN, avoid if kidney disease present) and cranberry pills Second line: phenazopyridine hydrochloride 100-200 mg TID after meals as short course after educating patients that it turns urine orange and must be avoided if chronic kidney disease present|
|Diarrhea||Rule out other causes of diarrhea especially if presentation is early (eg Clostridium difficile) First line: diet modification (low residue, lower fiber, low dairy), managing hydration status Second line: Imodium titrating to a max of 8 pills/day Third line: alternating diphenoxylate hydrochloride and atropine sulfate 2 pills and loperamide 2 pills every 3 hours, rarely patients need intravenous hydration or nutritional support|
|Proctitis: rectal pain or bleeding||Rule out cancer recurrence|
First line: cortisone suppository
Second line: steroid enemas, butyrate enemas, sucralfate enema
|Nausea||First line: ondansetron hydrochloride 8 mg q8h PRN or used prophylactically prior to therapy|
Second line: prochlorperazine 10 mg q6H PRN
Third line: aprepitant
Fourth line: lorazepam, diphenhydramine 25 mg and haloperidol 1.5 mg 1 capsule q6H
|Vaginal stenosis/fibrosis: presenting with pain, sexual dysfunction, diminished vaginal length||Vaginal dilators or intercourse 2-3 times/week starting 2-3 weeks after completing RT to mitigate vaginal stenosis|
|Dermatitis||Grade 1-2: water soluble skin moisturizers such as Eucerin®, petroleum based emollients such as Aquaphor®, steroid creams, lidocaine jelly, non-stick dressing or silver sulfadiazine cream; daily sitz baths, sodium bicarbonate or epsom salts; daily fluconazole or topical antifungal creams for fungal superinfections in skin folds; acute or delayed cellulitis, specifically erysipelas, can occur in about 9% of patients and can be treated with cephalexin for 10-14 days|
|Agent||Mechanism of Action||Procedure||% Success||Complications|
|1% Alum in sterile water 74||Aluminum ammonium/ phosphate sulfate causes protein precipitation, vasoconstriction and decreased capillary permeability||50 Gm alum is dissolved in 5 L sterile water and used to irrigate the bladder at 250-300 cc/hour||Transit 50-100||Suprapubic pain, bladder spasms, transient low grade pyrexia, aluminum toxicity (neurological) especially in patients with renal failure|
|Aminocaproic acid75||Competitive inhibitor of plasminogen (urokinase), decreases fibrinolysis||Continue bladder irrigation with 200 mg/L normal saline for 24 hours after hematuria resolves *Bladder must be clot-free prior to administration or it will form hard clots that are difficult to eradicate||90||May increase risk of systemic thrombotic events|
|Silver nitrate76||Increased cyclic adenosine monophosphate levels with reduction in edema and inflammatory response, vasoconstriction and platelet aggregation||Intravesical instillation of prostaglandin F2-alpha 1 mg in 100 ml normal saline on days 1 and 2, and 0.5 mg in 50 ml of normal saline on days 3-4.||50-60||Severe bladder spams and mild fever|
|Prostaglandin (F2-alpha carboprost tromethamine)77||Increased cyclic adenos- ine monophosphate levels with reduction in edema and inflammatory response, vasoconstriction and platelet aggregation||Intravesical instillation of prostaglandin F2-alpha 1 mg in 100 ml normal saline on days 1 and 2, and 0.5 mg in 50 ml of normal saline on days 3-4.||50-60||Severe bladder spams and mild fever|
|Formalin (solution of formaldehyde)78||Induces cellular protein precipitation and capillary occlusion||Under general/spinal anesthesia start with 1% formalin, can titrate up to 10%; irrigate under gravity up to 300 cc in bladder, 10-15 mins contact time; irrigate with catheter on light traction to prevent urethral exposure; protect skin with Vaseline gauze; pack vagina *Ensure no vesicoureteral reflux||80-90||Fibrosis, ureteral strictures|
|Placental extract79||Growth factors and angiogenic factors||First trimester trophoblast tissue collected from aborted fetuses, processed and instilled via catheter for 30 mins 3 times weekly for 1 month, then weekly for 2 months||100||None|
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