Pelvic Radiation and Normal Tissue Toxicity

Pelvic Radiation and Normal Tissue Toxicity Sarah Nicholas, MD,* Linda Chen, MD,* Amanda Choflet, DNP, RN,* Amanda Fader, MD,† Zachary Guss, MD, MSc,* Sarah Hazell, MD,* Daniel Y. Song, MD,* Phuoc T. Tran, MD, PhD,* and Akila N. Viswanathan, MD, MPH* Radiation is a component of treatment for many pelvic malignancies, most often originating in the gynecologic, gastrointestinal, and genitourinary systems. Therefore, the management of acute and long-term side effects is an important part of practice as a radiation oncologist, and limiting morbidity is a primary goal. Toxicities vary and are dependent on treatment techniques. Advances in radiation delivery, imaging, and knowledge of underlying biologic determinants of radiation-induced normal tissue toxicity can guide treatment of acute and long-term side effects from pelvic radiation. Semin Radiat Oncol 27:358-369 C 2017 Elsevier Inc. All rights reserved.

Introduction

R

adiation treatment techniques for pelvic malignancy vary including whole pelvis, low pelvis, organ-only, 3D conformal radiation therapy (3D-CRT), intensity-modulated RT (IMRT), or brachytherapy. Selection of these specific techniques may be based on disease factors, the choice to use concurrent systemic therapy, and a variety of patient factors including comorbidities and performance status. Several grading schemes exist for RT toxicity, including the toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer1 and the Common Terminology Criteria for Adverse Events,2 which are useful when following patients in clinic and comparing outcomes. The Table lists the common acute and chronic side effects along with treatment options.

Gastrointestinal Toxicity Acute Toxicity Acute small bowel toxicity typically manifests as diarrhea, cramping, abdominal pain, or bloating and may be mitigated *Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD. †Division of Gynecologic Oncology, Johns Hopkins School of Medicine, Baltimore, MD. Conflict of Interest: none. Address reprint requests to Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, 401 N Broadway, Suite 1440, Baltimore, MD 21231. E-mail: [email protected], anv@ jhu.edu

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with acute and aggressive management during therapy, including both dietary changes and medication management. If diarrhea is not managed acutely, symptoms may last for several months after treatment. These changes are due to a variety of factors including bacterial overgrowth, nutrient malabsorption, changes in motility, or induced lactose intolerance.3 With prostate cancer, in which dose-escalated IMRT, and recently stereotactic body RT (SBRT), is used, rates of acute grade Z2 gastrointestinal (GI) toxicity range from 3%-20%.4,5 In RTOG 0126, which compared high-dose 3D-CRT and IMRT, there was reduction in dosage to normal tissues with IMRT, which corresponded to a decrease in acute Zgrade 2 GI toxicity and a trend to decreased chronic toxicity; however, this was not significantly different with regard to patient-reported bowel toxicity.6,7 Acute toxicity in clinical trials investigating SBRT for prostate cancer ranges from 10%-31% and 0%-7% for grade 1 and 2 GI toxicity, respectively.8,9 A randomized clinical trial (NRG 12-03) reported in an abstract the acute quality-of-life (QOL) outcomes for IMRT vs 3D conformal radiation for postoperative endometrial and cervical cancer; 278 patients were enrolled, and a statistically significant decrease in the number of serious events of diarrhea, fecal incontinence, and number of women requiring 4 or more antidiarrheal medications at week 5 was noted, though this difference did not last after treatment completed.10-12

Chronic Toxicity Preventing acute GI morbidity is critical to minimize the risk of late toxicities. Chronic or late toxicities can occur months or years after the radiation treatment and may include intermittent diarrhea, dysmotility, food intolerance, nutrient

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Table Toxicity and Treatment Toxicity

Treatment

Gastrointestinal Enteritis

Acute Diarrhea: antidiarrheals, hydration, and high- or low-fiber diet. If refractory, regular IV fluids, test for C. difficile Chronic Diarrhea: fiber, probitiotics, and avoidance of lactose Leakage: biofeedback, pelvic floor exercises Malabsorption: nutrition support, cholestyramine for bile salt deficiency, or low fat diet Proctitis Acute: topical hydrocortisone, steroid, or sucralfate enemas Chronic: argon laser, hyperbaric oxygen, vitamin A, and metronidazole Hemorrhoids Pain management; topical application of lidocaine and petroleum mixture Fistula or stricture Surgical evaluation Obstruction Bowel rest, may require surgery if refractory

Genitourinary

Cystitis Fistula Stricture

Acute: hydration, antibiotics, NSAIDs, and anticholingeric agents Chronic: hyperbaric oxygen and intravesical endoscopic procedure Surgical repair Stent placement

Sexual

Mucosal injury Stenosis Menopause Infertility Erectile Dysfunction

Hydrogen peroxide douche, hyperbaric oxygen, metronidazole, and oral or topical antifungal Vaginal dilator, benzydamine, and surgery Hormone replacement, serotonin reuptake inhibitors Fertility counseling before treatment Phosphodiesterase inhibitors, vacuum erection devices, injections with prostaglandins, and penile implants

Dermatologic

Dermatitis Desquamation Telangiectasia Fibrosis Ulceration

Antihistamines, colloidal oatmeal, and aloe Sitz bath, hyaluronic acid or calendula cream; hydrogel, silver sulfadiazine Laser therapy Massage, physical therapy Wound care, debridement, and biopsy for nonhealing lesions to rule out secondary malignancy

Hematologic

Anemia Consider transfusion if Hgb o 10 g/dL Neutropenia Infection precautions for ANC o 500 Thrombocytopenia Consider holding radiation for o 40,000/ μL

Bone

Osteopenia Fracture Necrosis

Vitamin D, calcium, exercise, bisphosphonates, SERMs, and estrogen Pain management, rest Surgery

NSAIDs, nonsteroidal anti-inflammatory drugs.

malabsorption,13 or fecal incontinence.14 Severe late small bowel toxicities such as fistula, obstruction, and hemorrhage are rare.15 In the colon, delayed radiation injury primarily affects water absorption, resulting in dehydration or constipation, which has a more favorable prognosis.13 Radiation proctitis, both acute and chronic, presents with diarrhea, tenesmus, or blood in the stool. Other late toxicities can include incontinence, anal discharge, or clustering and frequency of bowel movements.16 Dosimetric studies show a decrease in radiation dose to organs at risk (OAR) such as small bowel and rectum when comparing conventional 3D conformal plans to IMRT17,18 that have translated to less side effects. Chronic rectal toxicity is correlated to the volume of rectum receiving 70 Gy or more (V70), and should be kept as low as possible19. If this volume is o20%, men with prostate cancer have a 4 year freedom from late grade 2 toxicity of 93%.20 For gynecologic patients, rates of

chronic toxicity range from 6%-11% for IMRT, compared to 34%-50% for non-IMRT pelvic fields.21,22 A single-center prospective trial looking at locally advanced cervical cancer showed a decrease in acute and chronic GI toxicity when using IMRT instead of 3D conformal whole-pelvis radiation.23 Rates of chronic grade Z2 rectal toxicity appear consistently lower with SBRT, ranging from 5%-21% with SBRT vs 13%37% with 3D-CRT.4,5 Late grade 3 rectal toxicity ranges from 0%-3% with IMRT comparted to 3%-8% with non-IMRT.24-27 A recent pooling of QOL data from randomized control trials using SBRT for prostate cancer with a median follow-up of 3 years demonstrated declines in patient-reported bowel scores during treatment that returned to baseline 6 months posttreatment.28 Adaptive radiotherapy for both photons and protons may decrease dose to OAR such as bladder, bowel, and rectum.29,30 Image-guidance is another technique that reduces the dose to

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360 OARs and GI toxicity.31,32 A recently published study evaluating feasibility and dosimetric outcomes for image-guided adaptive proton therapy compared to photon-based imageguided radiation for 13 patients with cervical cancer showed a reduction in the mean dose to bowel and rectum (P o 0.001).29 Other technologies such as hydrogel spacers are employed at some institutions to decrease dose and toxicity by placing a physical spacer to protect OAR in both gynecologic33 and prostate cancer. In 1 multicenter study that enrolled 52 patients, the injection of this spacer between the rectum and the prostate resulted in a decreased V70 in 95.7% of patients.34 Another Phase III trial shows that the V70 can be reduced to a mean of 3.3% with spacer placement.35

Management Patients receiving extended-field treatment are often instructed to use antinausea and antacid medications prophylactically. Similarly, prophylactically preventing diarrhea is imperative. Dietary modifications, fiber supplements, or probiotics can all be used, but have limited evidence to support their use.36,37 Antidiarrheal agents should be prescribed at the first sign of loose stools, taken upon awakening, and 30 minutes before each meal daily rather than after watery stools. Despite initial success in smaller single-center studies,38,39 a multicenter trial investigating the use of sulfasalazine, an antiinflammatory agent to prevent acute diarrhea, was negative, and the authors caution that it may cause an unexpected increase in side effects.40 The use of amifostine has also been investigated though initial results were not verified in a larger study.41,42 Patients with refractory enteritis should be monitored for hydration status and malabsorption, especially of vitamin B12 and bile salt. Late radiation proctitis should be evaluated by endoscopy to rule out other causes such as infection or secondary malignancy; however, biopsy is not necessary for diagnosis and should be avoided due to an increased risk of ulcer formation due to poor wound healing.43 Oral agents such as metronidazole or vitamin A show efficacy in small randomized trials as well as sucralfate enemas.43 Hyperbaric oxygen treatment (HBOT),44 as well as laser coagulation, has been shown to be effective with limited complications;45 however, there have been recent conflicting randomized data on the effectiveness of HBOT for radiation-induced bowel dysfunction.46

those receiving no additional treatment.50 In PORTEC 2, high levels of bowel symptoms and decreased QOL were observed in those patients receiving postoperative external beam radiation treatment compared to vaginal brachytherapy.51 Genetic markers to predict acute and late normal tissue toxicity are still under investigation. Single nucleotide polymorphisms in plasminogen activator inhibitor type 1 and protease activated receptor 1, which are important in intestinal regulations and are mediators of radiation normal tissue injury, were found to be associated with acute GI toxicity in a population of patients with rectal cancer treated with radiation.52 Complementary DNA array analysis on tissue samples from patients with radiation enteritis reveal increased expression of genes encoding for enzymes involved in recruitment of immune cells, fibrinogen deposition, and extracellular matrix remodeling.53,54 These single nucleotide polymorphisms and the genes that they affect are potential targets to treat the longterm effects of radiation-induced injury in future clinical studies.

Genitourinary Toxicity Acute Toxicity Following external beam radiation to the pelvis, short-term, low-grade urinary symptoms, including dysuria, urinary frequency, nocturia, and hesitancy, are relatively common. About half of men treated with definitive external beam radiation therapy (EBRT) for prostate cancer will experience low-grade genitourinary (GU) toxicity.55-57 The incidence can vary, but similar percentages of women treated with pelvic radiation for gynecologic malignancies experience acute urinary symptoms. In the ProtecT trial, men treated with definitive RT for their prostate cancer had an increase in nocturia from 19% at baseline to 59% at 6 months after treatment. Similarly, daytime urinary frequency increased from 32% at baseline to 55% at 6 months after treatment; however, there was significant recovery back to baseline after 12 months.58 Acute urinary retention is a rare complication following brachytherapy for prostate cancer. In 1 series, 3% of men treated with brachytherapy required catheterization due to urinary retention.59 Independent predictive factors for urinary obstruction included preimplant prostate volume and International Prostate Symptom Score score for which patients are typically screened.

Special Considerations

Chronic Toxicity

Individuals with cancer concomitant with comorbidities such as diabetes, atherosclerosis, or inflammatory bowel disease are at increased risk of acute and late toxicity from radiation. Additionally, radiation-induced rectal bleeding may be exacerbated by anticoagulants. There is an increased frequency of side effects in patients with a history of abdominal surgery or receiving radiation in the adjuvant setting.47-49 Quality-of-life (QOL) data from the PORTEC-1 showed increased bowel symptoms as far out as 15 years from treatment, compared to

In a review of 2 RTOG trials using definitive irradiation for the treatment of prostate cancer, 7.7% of patients had grade 3 or higher urinary complications and 0.5% had complications that would require a major intervention such as laparotomy, cystectomy, or prolonged hospitalization.60 In this review, urethral stricture accounted for over half of the grade 3 GU toxicities. In an analysis of a number of potential risk factors, only total dose (470 Gy) was predictive for an increase in urinary toxicity. Long-term bladder dysfunction is a common

Pelvic radiation problem following RT for cervical carcinoma. In 1 analysis, 26% of women reported severe symptoms, including urgency, frequency, and incontinence 5-11 years after radiotherapy for cervical carcinoma.61 Ureteral stricture or fibrosis is a less common long-term complication, reported to occur in 1%-3% of patients treated with brachytherapy for gynecologic malignancies.62 In men with prostate cancer, the rate of strictures varies based on the treatment type with radical prostatectomy associated with the highest rate of stricture (8.4%), followed by brachytherapy plus EBRT (5.2%).63 The most common treatment for urethral stricture is outpatient management with dilation. Hemorrhagic cystitis can be a morbid and potentially lifethreatening complication of pelvic irradiation. The interval between treatment and onset of hemorrhagic cystitis can vary between months and years, but it is estimated that in historic series with 3D conformal treatment, up to 9% of patients receiving full dose pelvic RT will develop hematuria and up to 5%, particularly those treated with dose escalation, will develop severe hemorrhagic cystitis.64 In a series of 1784 patients with carcinoma of the cervix treated with both intracavitary and external beam radiotherapy, the incidence of hemorrhagic cystitis was reported as 6.5%.65 Although the mean onset of cystitis was 35 months following completion of RT, there were patients who developed radiation cystitis after a latent period of up to 20 years. Therefore, radiation-induced cystitis should be suspected at any time following the completion of RT. Vesicovaginal and ureterovaginal fistulas are a rare complication resulting from focal high-dose radiation injury. Fistula risk is heavily influenced by direct tumor invasion of GU structures before treatment. In a review of women diagnosed with stage IVA cervical cancer, 48% developed a fistula at a median time of 2.9 months from cancer diagnosis.66 In this analysis, fistula formation was significantly increased among smokers as compared to nonsmokers.

Management For acute symptoms, a workup is indicated that include urinalysis and urine culture to exclude other causes of urinary symptoms, conservative management of low-grade GU symptoms that include symptomatic management with a trial of nonsteroidal anti-inflammatory drugs, anticholinergic agents such as oxybutynin, or analgesics such as phenazopyridine. Symptoms are generally self-limited, and drugs can be discontinued as symptoms improve. Treatment for hemorrhagic cystitis is conservative and includes hydration, blood transfusions, and bladder irrigation with clot evacuation. In refractory, severe cases, embolization may be considered. Infection and primary bladder malignancy must also be evaluated. Other aggressive management options include intravesical or systemic agents, HBOT, and intravesical endoscopic procedures. Cystectomy and urinary diversion is a treatment option after exhausting all other conservative measures. It is unlikely that fistulas or strictures may be repaired surgically, which can be challenging due to the poor vascularity and wound healing following radiation.

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Special Considerations Aside from primary site of treatment, there are a number of other treatment-related factors that can influence potential GU toxicity, including total radiation dose, treatment volume, treatment modality (EBRT vs brachytherapy), and treatment technique (3D-CRT, IMRT, and image guidance). In a prospective study measuring QOL in men with prostate cancer, men treated with brachytherapy had increased irritation and obstructive urinary symptoms with longer time to resolution compared to men treated with external beam radiation.67 There are also other patient-related factors influencing radiation-related toxicity. As with GI bleeding, the use of anticoagulants can increase the incidence and severity of postradiation hematuria. Obesity and heavy smoking have also been documented as risk factors for bladder complications following RT for cervical cancer.68 Some recent studies suggest that ethnicity may be a factor in assessing toxicity due to the differential genotype distributions in patient populations. A recent study showed that Latin-American patients had higher rates of grade Z2 GI and GU toxicity when compared with European patients.69

Cutaneous Toxicity Acute Toxicity and Management Early skin reactions for conventionally fractionated pelvic RT typically arise in the first 2-3 weeks following initiation of RT. For dry desquamation, use of an unscented water-based moisturizing cream is recommended.70 Patients may find sitz baths helpful. Products containing hyaluronic acid or calendula cream may be particularly helpful, whereas compounds containing lanolin, alcohol, or metal salts are discouraged. A small percentage of patients may experience contact dermatitis due to calendula, which should prompt withdrawal of the offending agent and use of a different moisturizer.71,72 For pruritus refractory to moisturizers alone, antihistamines and aloe vera may be helpful but do not hydrate the skin. Skin products containing colloidal oatmeal can also relieve itching. Moist desquamation may be managed with soft silicone foam dressings applied to the affected area.73 Some apply hydrogel dressings although the data are mixed.74,75 In cases with high risk for or suspected bacterial superinfection, silver sulfadiazine can be applied twice daily but should be removed at least 4 hours before RT to avoid bolus effect, whereas nystatin cream is recommended for candida infections. Oral antibiotics may be required in significant cases. Oral analgesics can help address pain. Grade 3 or greater skin toxicities warrant assessment for a potential treatment break before proceeding with further RT.

Chronic Toxicity and Management Dry skin can be alleviated with moisturizers as described in the preceding section. Radiation-induced telangiectasia is often not bothersome to a patient, but laser intervention can be used to improve cosmesis.76 Radiation fibrosis remains difficult to manage despite a wide variety of interventions that are

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362 available. More conservatively, a patient can opt for a trial of physical therapy or massage.77 Pentoxifylline and vitamin E have been used, often with marginal or negative results for both prevention and therapy.78-80 If pentoxifylline and vitamin E is to be used, kinetic analysis suggests a prolonged course of therapy.81 HBOT has also been used, but the studies have not demonstrated clear benefit to this therapy for fibrosis.82,83 Quercetin, a flavonoid in plants, has shown promise in preclinical analysis.84 Ulcerations should be managed with wound care including dressings with or without ointment, debridement as needed, with biopsy considered for chronic ulcers to rule out radiation-induced skin cancer.85 Irradiated skin also harbors an increased risk of developing skin cancer.86,87

Special Considerations Radiation-induced skin toxicities comprise a diverse spectrum of injuries that are highly variable in incidence, temporality, and severity which vary according to numerous factors including anatomical site and technique.88-90 In general, primary sites close to or involving the skin surface require dose delivery to the skin, and therefore have a higher risk of toxicity than deeper structures. Within the context of gynecologic RT, reported skin reaction incidence ranges from fewer than half of patients in endometrial cancer to nearly all patients with vulvar cancer.91-93 Similarly, a man receiving external beam radiation for penile cancer will require more dose to the skin than a man receiving RT for prostate cancer. Bulky inguinal lymphadenopathy also increases the need for dose to the skin, particularly if bolus is required. Although many of these cases are mild or moderate, serious injury may result in radiation treatment breaks or disability. Predisposing factors for the development of radiationinduced skin toxicities can be conceptualized into therapeutic and patient-specific categories. With respect to the former, the use of lower megavoltage photon beam energy, proton therapy, field size, and the use of tangential fields can increase the risk of skin toxicity.94,95 The use of IMRT may reduce the risk of grade 3 or greater skin toxicities relative to 3D techniques for photon irradiation in the pelvis.88,96 In anal cancer, for example, RTOG 0529 demonstrated that IMRT with dose painting for anal cancer resulted in a 23% rate of grade 3 or greater acute skin toxicity, compared to 49% in the mitomycin-C arm of RTOG 98-11.97,98 Bolus, by design, increases dose to the skin. Dose, fractionation, concurrent radiosensitizing systemic therapy, and reirradiation are also important considerations.99 Comorbidities also influence the likelihood and severity of radiation skin reactions. Immunocompromised patients may have a higher risk of developing mucosal injury during RT. HIV-seropositivity has been associated with increased toxicity from RT, although the data are mixed for cutaneous toxicity in the context of RT for cervical cancer, and some studies did not correlate CD4 count with outcomes.100-102 Vascular compromise, including tobacco use and diabetes, may also increase the risk of skin toxicity, as well as comorbidities that are known to harbor increased risk of radiotoxicity in general such as

collagen vascular disease, specifically scleroderma. Obesity can also increase skin toxicity due to increased apposition of skin in the groin and pannus. The location of the primary, as well as coverage of involved or elective lymph nodes, often requires delivery of high radiation dose to the skin. Skincare practices from the treatment of other anatomical sites such as breast and head and neck are often applied for pelvic radiation. Prospective studies are limited, and those that have been reported are often underpowered. Much of the management of radiation-induced skin reactions, therefore, is based on institutional practice.

Sexual Toxicity Sexual and reproductive toxicities following pelvic radiation for gynecologic malignancies and genitourinary malignancies are an important consideration given the involvement and close proximity to critical reproductive structures. In particular, vaginal stenosis and premature ovarian failure in women, and erectile dysfunction and testicular infertility in men are associated with significant morbidity. These treatment-related morbidities affect sexual function, reproduction, and QOL in cancer survivors.103,104

Acute Toxicity: Gynecologic Radiation-induced vaginal complications from acute mucosal injury occur while on treatment. Mucosal injury is commonly observed clinically on treatment as mucosal discoloration due to sensitivity of basal progenitor cells within the epithelium.13,105,106 Low-grade vaginal mucositis is generally asymptomatic and well tolerated, however, higher-grade toxicity such as ulcerations, vaginal necrosis, and rectovaginal fistulas can also occur in a minority of patients. Risk factors for vaginal radiation injury include involvement of the radiosensitive distal vaginal mucosa, high cumulative surface doses or reirradiation, circumferential irradiation, and increased dose rate.107,108 During concurrent chemoradiation, vaginal mucosal changes may predispose patients to concomitant infections and early initiation of an antiyeast regimen (ie, Diflucan) or antibiotic coverage may decrease pruritus, pain, and reddening.

Chronic Toxicity: Gynecologic Late effects include vaginal dryness, dyspareunia, and vaginal stenosis. Vaginal stenosis is the narrowing or shortening of the vagina due to circumferential fibrosis, and affect 20%-88% of gynecologic patients who undergo radiation,109-112 although rates as low as 2.5% posttreatment vaginal stenosis have been reported with high dose rate intravaginal RT combined with surgery and external beam radiation.113 Higher rates of vaginal shortening are seen in patients age 450, concomitant chemotherapy, higher vaginal radiation doses, and lack of vaginal dilator use compliance.110,111,114-116 Clinically, patients may experience dyspareunia or bleeding with intercourse and occurs most commonly within the first year of radiation but

Pelvic radiation has been reported to range between 26 days and 5.5 years after definitive radiation.110,116,117 Premenopausal women who undergo radiotherapy are at significant risk for premature ovarian failure, menopause, and infertility due to ovarian radiosensitivity. Premature ovarian failure is defined as cessation of menstruation before age 40, and doses as low as 1.7-2.5 Gy have been associated with significant but temporary amenorrhea or sterility without recommencement of ovulation for several years.13 Moreover, in premenopausal patients, ovarian doses of 6 Gy have been associated with premature menopause.106 Modeling of radiation doses, which account for ovarian follicular decline with age, estimates that the dose in which 50% of patients would develop immediate ovarian failure is 18.9 Gy at birth, 16.9 Gy at age 10, 14.9 Gy at age 20, and 12.1 Gy at age 30.118 Additionally, premature menopause because of radiationrelated ovarian failure leads to hormonal changes, hot flashes, mood changes, and vaginal dryness. Moreover, pelvic radiation is correlated with miscarriage, preterm labor, low-birth weight, and placenta accreta.119 These outcomes are thought to be due to arteriolar damage and reduced fetoplacental blood flow as well as fibrosis that limit uterine distention after pelvic radiation.120

Management Treatments options for vaginal mucosal injury causing necrosis include hydrogen peroxide douching with 1:10 saline and HBOT.47 Oral metronidazole or antifungals can also be used to treat infections, which can occur on treatment due to alterations in the vaginal pH. Surgical debridement or highintensity pulse-lavage can be used on superficial necrotic tissue. To prevent late sexual dysfunction, education is provided regarding regular vaginal dilator use to promote vaginal patency, benzydamine, evaluation by a sexual function clinic, and surgical reconstruction.47,121,122 The symptoms of menopause can be managed with serotonin reuptake inhibitors, and systemic or vaginal hormone replacement therapy.47 Because of ovarian radiosensitivity, young premenopausal women desiring future fertility should be referred to a reproductive endocrinologist before undergoing pelvic radiotherapy. Options such as ovarian transposition or ovarian stimulation and oocyte or embryo cryopreservation may be considered in select women.

Acute Toxicity: Men Testicular radiation affects both germ cells and spermatogenesis as well as Leydig cells and testosterone production. Transient oligospermia can occur with 100-500 cGy requiring 9-18 months for recovery of surviving stem cells, and permanent azoospermia can occur with doses 0.75-3 Gy.123 Leydig cells are more radiosensitive than testicular germ cells, and while Leydig cell dysfunction leads to decreased testosterone dysfunction, this is associated with doses 420 Gy.124

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Chronic Toxicity: Men Following radiation, vascular changes leading to cavernous artery insufficiency are primarily implicated in male erectile dysfunction.125,126 Although predominantly vascular, neurogenic dysfunction due to dose to neurovascular structures have also been implicated.127 Following RT, diminished sexual function affects a significant proportion of patients ranging from 50%-75% of male patients who undergo external beam or prostate brachytherapy or both.128 Potential risk factors include large radiation field size, penile doses 452.5 Gy, and 70 Gy or more to the penile bulb, but there remains considerable controversy regarding the exact critical structures and tolerances that are responsible for radiationinduced impotence.129

Management Phosphodiesterase inhibitors such as sildenafil and tadalafil have been shown to effectively increase sexual function, though they may be associated with headaches, flushing, and dyspepsia.130,131 The RTOG performed a double-blinded crossover trial randomizing patients receiving radiation and androgen deprivation therapy to sildenafil or placebo therapy for 12 weeks, and then crossed over. Only a minority of patients saw a positive benefit; however, a response to treatment was seen in those receiving sildenafil.132 For patients with erectile dysfunction refractory to phosphodiesterase inhibitors, other treatment options include vacuum erection devices, intracavernosal injections with prostaglandins, and penile implants. Low testosterone levels can result in decreased libido and osteoporosis, and clinicians can consider careful bone density monitoring in these patients.133 Owing to the low dose that can cause azoospermia, patients who are interested in preserving fertility are encouraged to sperm bank before treatment, and testicular shielding can be used during treatment to lower testicular dose. Avoiding conception for 12 months after radiation can also be considered to allow generation of new spermatogonia and avoid fertilization with sperm that have radiation-induced defects.13

Hematologic Toxicity Acute Toxicity Recent data show that concurrent chemoradiation for solid malignancies (glioma, pancreas, and lung cancer) can lead to lymphopenia and is associated with decreased survival.134 With standard pelvic fields, large areas of the bone marrow are exposed to radiation. This causes a decrease in hematopoietic stem cells, which has the potential to cause increase toxicity, especially when given in conjunction with chemotherapy. Concurrent cisplatin is indicated for cervical cancer and some high-risk endometrial cancer, 5FU and MMC are used for anal cancer, and capecitabine is used concurrently for rectal cancer. Extended-field radiation to treat para-aortic or common iliac nodes in this setting causes high rates of acute hematologic toxicity in gynecologic patients.135 Patients with advanced cervical cancer are still at risk for local failure, and investigation

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364 of intensified treatment with gemcitabine and cisplatin increased grade 3-4 neutropenia and thrombocytopenia.136,137 Many studies show a decrease in bone marrow dose and hematologic toxicity with IMRT instead of 3D radiation.138141 A recent multicenter, single arm, phase II study by Mell et al142 reported a decrease in Z grade 3 neutropenia in patients with cervical cancer treated with bone marrow– sparing IMRT, from 27.1%-08.6%. In a small prospective series of gynecology patients, Brixey et al showed a decrease in Zgrade 2 WBC toxicity in patients receiving wholepelvis radiation than those receiving intensity-modulated WPRT. RTOG 0418 was a phase II clinical trial investigating IMRT for patients with postoperative cervical and endometrial cancer.138 They found correlation between the volume of bone marrow receiving 40 Gy or more (V40) to correlate with higher rates of grade 2 or greater hematologic toxicity.138 In patients with rectal cancer receiving concurrent IMRT and capecitabine, the lumbosacral spine V40 also correlated with grade Z2 hematologic toxicity.143 A similar retrospective study in anal cancer found an increase in grade 3 hematologic toxicity in patients with a lumbosacral bone marrow V40 4 41%.144 Advancements in imaging techniques may provide avenues to avoid active bone marrow and decrease hematologic toxicity. Both [18F] fluorothymidine positron emission tomography imaging and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (CT) identifies active bone marrow and can limit dose to these bone marrow regions.145,146 This is still being investigated, but a study of 45 patients with anal cancer revealed that irradiation of both high and low fluorodeoxyglucose uptake regions is associated with hematologic toxicity.147 This may be due to the sensitivity of these stem cells to radiation even at low doses, or due to the combined effect of chemotherapy.

Chronic Toxicity Chronic iron deficiency anemia may occur secondary to bleeding from bowel toxicity as described earlier.

Monitoring and Management of Hematologic Toxicity Patients undergoing treatment with concurrent chemotherapy are monitored with weekly blood counts. Radiation treatments are held when neutrophil counts decrease to 500/μL or platelets decrease to less than 40,000/μL.47 Chemotherapy is typically held when the absolute neutrophil count is less than 1500/μL or platelets decrease to less than 100,000/μL. Hemoglobin levels ideally should be maintained at more than 10 mg/dL especially in patients with cervical cancer.47

Bone Toxicity Acute Toxicity Radiation therapy does not normally cause acute injury to bone. Radiation doses increase bone toxicity in a

dose-dependent fashion and prevent healing particularly at 450 Gy.148,149

Chronic Toxicity Radiation changes to the bone occur owing to decreased osteoblast proliferation and decreased blood flow to bone from fibrosis of blood vessels.13 Bone resorption from osteoclast activity continues without opposition from osteoblasts, resulting in a decrease in bone matrix formation. These physiologic changes, together with other patient factors such as osteoporosis, kidney disease, vascular disease, or long-term use of steroids or bisphosphonates, can lead to pathologic fractures or osteoradionecrosis. There are a number of case reports regarding avascular femoral head necrosis from radiation, which is an uncommon but serious complication.150 Pelvic insufficiency fractures may be observed following radiation, due to the weightbearing nature of the sacroiliac joints. Fracture locations commonly include the pubic symphysis, pubic rami, and sacrum,151 and patients present primarily with pain.152 For patients treated for anal, cervical cancer, and rectal cancer, rates are reported to be 14%,153 between 8%20%,153-155 and 7%-11%,153,156 respectively. In patients with prostate cancer, 1 small retrospective series in patients who were mostly treated with 3D conformal RT showed an incidence of 6.8% at 5 years following whole-pelvic radiation157, but this has not otherwise been commonly reported after prostate RT. Radiation necrosis and osteomyelitis are also possible complications and have been reported as case reports.150,158 Diagnosis is typically made by CT scan, which will show sclerotic areas or fracture lines, and can exclude soft tissue mass and bone destruction which may suggest malignancy.159 In some cases, magnetic resonance is necessary and can detect abnormal marrow changes and will show the fracture, which is associated with edema, as low intensity on T1weighted images and high signal intensity on T2 and shortTI inversion recovery series.151,160 Bone scintigraphy is sensitive to detecting insufficiency fractures and show increased uptake along with the characteristic “H” sign.152,159

Management Osteoporosis prevention is important in these patients, and treatment focus includes maintaining bone mineral density with the use of calcium, vitamin D, and weightbearing exercises.161 Bisphosphonates, selective estrogen receptor modulators, estrogen, and calcitonin are pharmacologic agents used to prevent fractures.161 For fractures, it is important to rule out metastatic disease; however, biopsy should be used cautiously, because they are low yield, and the histopathology of healing bone resembles malignancy.162 Most patients can be treated conservatively with nonnarcotic pain medication and rest.152 CT-guided sacroplasty can be used for treatment, similar to vertebroplasty used for compression fractures.163 Combinations of pentoxyfylline, alone or in combination with other therapies, can be safe and effective for fractures or osteoradionecrosis164,165 but require further investigation.

Pelvic radiation

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