Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies

INTRODUCTION — Radiation therapy (RT) represents an important therapeutic component in the management of many gynecologic malignancies. Based upon evidence-based treatment guidelines, RT is indicated in up to 60 percent of cervical cancer patients, 45 percent of endometrial cancer patients, 35 percent of vulvar cancer patients, 100 percent of vaginal cancer patients, and 5 percent of patients with ovarian cancer [1,2].

In this topic, the spectrum of both acute and late side effects associated with RT, specifically as it relates to the treatment of gynecologic malignancies, will be reviewed. An understanding of potential side effects is important for patient management and survivorship issues. An overview of the general principles, modalities, and techniques of RT is found elsewhere. A more detailed discussion of the indications for RT for specific cancer sites and stages can be found in topic reviews for each cancer site. (See "Radiation therapy techniques in cancer treatment".)

OVERVIEW — RT for gynecologic cancers can be employed as primary (definitive) treatment, following surgery (adjuvant), or before surgery (neoadjuvant) in order to reduce the risk of recurrence. For some tumors, RT often is administered with concurrent chemotherapy (chemoradiation) and may incorporate brachytherapy. The normal tissues of the cervix and corpus of the uterus can tolerate high doses of radiation and can recover remarkably well from radiation injury. However, the surrounding normal tissues are more susceptible to radiation injury.

The incidence and severity of RT side effects depend upon the site, volume of tissue exposed, and treatment schedule, including total dose, dose per fraction, and type of radiation. Modifying factors such as previous surgery, concomitant chemotherapy, and comorbid illness also are influential. At least one large report indicates that smoking history is a strong predictor for both bowel and bladder complications from treatment [3].

Some patients may be at higher risk for RT-related toxicity. These include patients with:

●Active collagen vascular disease, which is a well-known relative contraindication to radiotherapy [4].

●Inflammatory bowel disease (IBD) – Patients with IBD may be at an increased risk of acute and late bowel complications [5], although the data appear to be conflicting, especially when trying to tease out the effects related to RT from those that might be related to the natural history of IBD [6,7].

●Vascular disorders – Retrospective data suggest that diabetes and hypertension may increase the risk for late toxicity, presumably related to microvascular disease. This includes reports of a greater preponderance of significant bowel complications following definitive radiation for cervix cancer [8,9], although the presence of these conditions was not associated with a greater risk for acute toxicity in at least one report that included women with endometrial cancer [10].

TIMING OF RT-RELATED TOXICITIES — Radiation therapy (RT) can be associated with side effects that can occur at any time during treatment or even years later. For purposes of this topic review, we will adopt the following definitions of these toxicities:

●Acute toxicities refer to those with onset during or shortly after the course of treatment.

●Subacute toxicities are those that initially manifest 4 to 12 weeks after RT has been completed. Most commonly, subacute effects represent prolonged recovery from more significant acute toxicity. Though effects are commonly observed during this period, there are very few distinct radiation injuries that are subacute in onset, such as pneumonitis or myositis.

●Late toxicities are those occurring after three months. These often reflect the spectrum of radiation tissue changes that can be lasting and irreversible.

GENITOURINARY SYSTEM TOXICITIES — The impact of RT on the genitourinary (GU) system depends on the dose of RT and the tissue impacted. However, defining dose-response relationships for acute complication risk to the urinary bladder has proven elusive, as volumes are constantly in a state of change [11]. The bladder typically tolerates common adjuvant doses of radiation better than bowel (45 to 50 Gy). For this reason, when administering whole-pelvic radiation, it is common to request that patients come to daily treatment with a full bladder in order to displace bowel from the pelvis. It is important to distinguish complications related to whole-bladder doses versus focal injury from higher radiation doses to partial bladder volumes, more commonly seen when incorporating brachytherapy (BT) as a component of treatment. When BT is employed as a means of dose escalation for definitive, nonoperative management of primary gynecologic malignancies, the risk of GU morbidity is higher, and spectrum of risk is different.

Acute radiation cystitis — Acute RT-related cystitis can be a common complication with conventionally dosed pelvic RT, although the incidence is highly variable. It can be associated with irritative voiding symptoms (dysuria, frequency, urgency, and nocturia) and bladder spasms. It is due to RT-induced bladder inflammation and edema, which can compromise urothelial integrity. The use of intensity-modulated RT has been shown to reduce patient-reported GU toxicity with adjuvant pelvic treatment following hysterectomy for cervical and endometrial cancer [12,13].

When they occur during RT, the symptoms typically resolve in one to two weeks after completing therapy. It is important, however, that other etiologies, such as a superimposed urinary tract infection, be ruled out.

Treatment depends upon the nature of symptoms, and conservative management is often appropriate. The effectiveness of medical therapy during the acute period is largely anecdotal. Since acute bladder effects are most commonly grade 1 or 2 and transient, there are minimal data on the comparative effectiveness of medical treatment. Some commonly employed strategies we utilize include:

●Non-steroidal anti-inflammatory drugs for patients who complain of irritative voiding symptoms

●Anticholinergics and/or antispasmodics (eg, oxybutynin or hyoscyamine) for cystitis or bladder spasm

●Cranberry juice or phenazopyridine for dysuria. Generally use of phenazopyridine is limited to two to three weeks when acute cystitis symptoms are at their worst.

Late signs and symptoms — Late GU toxicities generally arise as a result of RT-induced epithelial and microvascular changes, which can lead to changes in bladder physiology. These changes are often permanent and are largely mediated by fibrosis via collagen deposition within the epithelium and muscularis, resulting in diminished bladder capacity and loss of tissue compliance. Though the pathophysiology differs, late bladder effects can result in a similar spectrum of lower urinary tract symptoms to that seen in the acute phase, such as urgency and frequency. This is often attributed to bladder overactivity or contraction. With significant contraction, bladder dysfunction can result in urge incontinence.

At expected doses of external-beam RT employed for gynecologic cancers (40 to 50 Gy), the likelihood of serious lasting side effects is low [14]. Five-year follow-up of the Post-Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial randomizing 46 Gy adjuvant pelvic radiation and observation in patients with endometrial cancer observed no serious (grade 3 or 4) late GU toxicity in the radiotherapy arm [15]. There was a 5 percent absolute increase in reported grade 1 or 2 GU late effects attributed to radiotherapy [15]. Long-term quality of life analyses indicate that measurable differences persist at 15 years with regards to urinary function, specifically rates of urinary urgency, incontinence, and limitations in daily activities due to bladder symptoms [16].

Higher total doses of radiation can be associated with focal injury and lead to a risk of hematuria or ulceration. Persistent non-healing can result in stone formation. Contracture can produce pain syndromes. Ureteral stricture is uncommon without tumor involvement at presentation. Urethrovaginal and vesicovaginal fistula are also seen on occasion from focal, high-dose radiation injury. Fistula risk is also heavily influenced by direct tumor invasion of GU structures before therapy. In the definitive management of cervix cancer, where the incorporation of BT is considered standard of care, the probability of late grade 3 or 4 GU toxicity is <3 percent [17]. Modern series that incorporate three-dimensional treatment planning information into BT suggest that the risk for these late side effects correlates best with the maximum dose received by 2 cc of normal bladder (D2cc). The complication probability for a total equivalent dose of 101 Gy is approximately 10 percent, with newer analyses recommending a bladder dose D2cc constraint of 80 to 85 Gy in the absence of bladder involvement by tumor [18-20].

The timing of onset is typically one to three years after treatment, though much longer latencies have been described, particularly with the higher total doses of radiation associated with cervix cancer treatment [21]. Mild effects can be difficult to distinguish from the effects of aging or prior pelvic surgery. Obesity appears to increase the likelihood of serious complications [3]. In patients with a history of pelvic radiation, hemorrhagic cystitis can develop years down the road. Refractory cases are frequently complicated by the ongoing need for anticoagulation for comorbid illness. The preferred management is not well defined. Conservative management is preferred, as intervention can precipitate high-grade toxicity. Sodium pentosan polysulfate has been used for radiation-related hematuria with resolution of symptoms [22]. Cautery, intravesicular formalin, and argon plasma coagulation have also been described. High rates of symptomatic improvement have also been reported for hyperbaric oxygen when used to treat symptomatic late radiation cystitis [23,24].

GASTROINTESTINAL — Gastrointestinal (GI) toxicity is the most common source of both acute and late side effects from pelvic radiation, and the most likely to result in a measurable decline across multiple quality of life domains such as limitation of daily activities and impaired social function [25]. Both small and large intestines are susceptible to RT-related toxicity in the management of gynecologic cancers. The high proliferative rate of small bowel epithelium makes it more vulnerable to the acute effects of radiation than most other tissues. Following hysterectomy, much of the bowel comes to rest deeper in the pelvis, often accompanied by adhesions. The rectum is a common site for late injury, particularly when dose escalation is a component of management.

Acute radiation injury — The small bowel is very sensitive to the early effects of RT, and when it is contained within the RT field, radiation injury can present acutely as nausea and vomiting. This can be followed by the onset of diarrhea and abdominal cramping two to three weeks into a course of RT. This latency is believed to be due to accumulated damage and loss of normal crypt epithelium. Symptoms develop as a result of insufficient replacement of villus epithelium despite compensatory proliferation, resulting in inflammation and a compromised mucosal barrier [26]. In general, the symptoms of bowel wall mucosal injury can include cramping, diarrhea, anorexia, malaise, rectal discomfort, and tenesmus. The risk for bowel toxicity is a function of both total dose and volume irradiated. Based on findings from the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) project, it appears that limiting the volume of small bowel receiving >45 Gy correlates with a reduction in the risk of acute grade >3 GI toxicity. However, whether these dose-volume constraints will translate to reduced late toxicity has not yet been established [27]. At least one trial suggests that the degree of acute toxicity does predict for the development of late effects.

Acute radiation injury of the large bowel can be difficult to distinguish from changes attributed to the small bowel, as both can result in loose stool and cramping. Injury to the small bowel commonly leads to high-volume, watery diarrhea. Acute effects on large bowel can produce fecal urgency, clustered bowel movements, and tenesmus. Bowel obstruction, ileus, and GI bleeding are not characteristic of acute enteropathy, but can be seen as late toxicity.

For a standard adjuvant course of radiation (45 to 50 Gy) using conventional 3D conformal techniques, approximately 50 percent of patients will experience changes in bowel function in the acute setting. The likelihood for acute grade 3 GI side effects is around 3 percent [28,29]. The rate of grade >3 GI effects increases to approximately 20 percent in the definitive management of cervix cancer with combination cisplatin and dose escalation via brachytherapy (BT) [17]. This includes a 10 percent risk for grade 3 nausea and vomiting, which is uncommon with radiation alone.

In the era of combined chemoradiation, the largest difference in potential treatment toxicities compared with radiation alone is gastrointestinal. The concurrent use of cisplatin with pelvic radiation more than doubles the risk for grade ≥3 acute GI side effects [30].

Incorporating newer treatment techniques, such as intensity-modulated RT (IMRT), can minimize the amount of radiation received by normal bowel. Multiple single-arm studies pointed to a reduction in the probability of GI side effects with intensity-modulated pelvic radiation, which has been confirmed in randomized phase III trials [12,13,31-34]. When compared with standard four-field radiation, IMRT reduces patient-reported GI toxicity, reduces the need for anti-diarrheal medication, and improves quality of life in the acute setting [12,13].

The treatment of acute radiation injury is largely symptomatic:

●Proctitis and rectal discomfort often respond to small enemas with hydrocortisone or cod liver oil, anti-inflammatory suppositories, and a low-residue diet with no grease, spices, or insoluble fiber. Two small prospective studies demonstrate a benefit for topical sodium butyrate enemas in the treatment of acute radiation proctitis [35,36]. Butyrate is a short chain fatty acid, the preferred nutritional source for the colonic epithelium.

For the prevention of radiation proctitis, the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO) recommend probiotics, based on clinical trial results in colorectal cancer patients and those with pelvic malignancies [37]. Although the MASCC/ISOO also recommended intravenous amifostine for the prevention of radiation proctitis [38], supporting evidence comes largely from small studies in patients receiving radiotherapy for rectal cancer, without evidence of benefit in patients with other pelvic malignancies [39].

●Ondansetron has been shown to reduce radiotherapy-induced nausea and vomiting [40]. At least one randomized trial supports its superiority to the combination of chlorpromazine and dexamethasone [41]. The addition of dexamethasone to ondansetron appears to improve nausea control [42].

●Antidiarrheal medications are used symptomatically for enteritis and are safe in the acute setting. There are minimal data by which to refine treatment decisions. We typically initiate loperamide as a first measure. When symptoms are refractory, diphenoxylate-atropine and tincture of opium can be effective. A randomized trial shows that octreotide is more effective at controlling acute radiation-induced diarrhea than diphenoxylate-atropine [43]. With loperamide-refractory diarrhea, a smaller pilot study showed that subcutaneous octreotide led to complete resolution for 80 percent of patients, with a mean time to response of 2.7 days [44]. The MASCC/ISOO also recommends oral sulfasalazine to prevent radiation-induced enteropathy [38].

●Many agents have been tested for the prevention of acute effects. These include octreotide, sucralfate, mesalazine, and glutamine, but each has failed to show a reduction in GI toxicity.

●For patients with cervical or endometrial cancer undergoing RT and who are selenium-deficient (whole-blood selenium concentration <84 microg/L), a phase III trial showed that selenium repletion may be associated with reduced rates of grade 2 or higher diarrhea [45]. However, independent confirmation and validation of these results is needed before this approach can be considered standard.

●The use of probiotics has been studied as a preventive strategy for radiation enteritis. A meta-analysis of six randomized controlled trials demonstrated a lower incidence of radiation-induced diarrhea compared with placebo; however, there was no statistically significant difference in the antidiarrheal medication use or Bristol scale on stool form [46].

Late GI toxicity — Although normal small bowel motion is believed to reduce the risk of delayed toxicity, the small bowel is still at risk for late side effects. While the acute gastrointestinal (GI) symptoms of radiation typically resolve within two to four weeks after the completion of treatment, they can become more chronic issues. In most cases, there is a latency of six months to several years until late bowel complications are observed. The pathophysiology of chronic enteropathy is complex and can be related to radiation changes involving multiple tissues and cellular functions. Mucosal atrophy and loss of mucin-producing goblet cells can lead to chronic diarrhea and malabsorption. Fibrosis of the intestinal wall can lead to dysmotility (chronic) and risk for obstruction (acute presentation).

A small, randomized trial has shown a reduction in grade >2 late GI side effects with IMRT (13.6 versus 50 percent) in the treatment of locally advanced cervical cancer [47]. Another randomized controlled trial in the postoperative setting for cervical cancer demonstrated a reduction in late grade 2 or greater bowel toxicity with IMRT, with the greatest benefit seen in patients also receiving chemotherapy [34].

The symptoms of late GI toxicity include:

●Chronic diarrhea – When present symptoms may be best managed by a multidisciplinary team to include gastroenterology. Ongoing antidiarrheal medications are often necessary.  

●Malabsorption – This can be related to RT involving the distal ileum. For example, vitamin B12 deficiency after irradiation for cervical cancer occurs in 12 to 20 percent. This usually develops over a period of several years and commonly requires replacement [48-50]. Cholestyramine may be helpful when bile salt malabsorption is present.

●Recurrent bouts of ileus or obstruction. This is best managed conservatively when possible, but commonly requires surgery with resection and anastomosis. Prolonged chronic radiation enteritis can lead to malnutrition, and as such, perioperative nutritional therapy may be an important intervention.

●Proliferative mucosal telangiectasias or ulcerations – The development of mucosal telangiectasias and/or ulcerations is related to vascular sclerosis and is most commonly observed in the rectosigmoid colon (radiation-induced proctopathy). The signs can include painless hematochezia, tenesmus, or pain. In addition, characteristic changes of mucosal pallor and proliferative telangiectasias often are seen on the anterior rectal wall on endoscopic evaluation in asymptomatic patients. When present, the median time to onset is 14 months and symptoms typically appear within three years [51]. Most commonly, this late GI toxicity is seen in dose escalation and overall is an uncommon late effect, with a reported incidence of less than 10 percent in a trial performed by the Radiation Therapy Oncology Group (RTOG 90-01) [52]. Recent experience suggests that image-guided BT has the potential to further reduce its incidence [53]. Results from the prospective EMBRACE study of magnetic resonance imaging-guided adaptive BT reported that a rectal D_2cm3 <65 Gy was associated with one-half the risk of proctitis compared with a D_2cm3 ≥65 Gy [54]. For patients with such symptoms, a colonoscopy is required to exclude malignancy or other pathology.

●For patients with rectal proctopathy, conservative management is often appropriate. Avoiding constipation may limit episodes of bleeding. Medical therapy includes sucralfate enemas [38], an aluminum hydroxide complex that binds and protects injured mucosa [55,56]. Guidelines from the MASCC and ISOO suggest that hyperbaric oxygen may be helpful in the management of radiation proctitis [38], although data are mixed [57,58]. In our experience, hyperbaric oxygen may reduce bleeding in refractory cases of late radiation proctitis. Additionally, in refractory cases, endoscopic intervention can control bleeding with a high likelihood of durable response [59,60]. One study indicates that topical formalin is as effective as argon plasma coagulation at controlling bleeding [60]. Unlike acute proctitis, topical butyrate does not reduce symptoms of chronic proctitis [61]. Surgical management is reserved for intractable cases, such as transfusion-dependent bleeding, refractory pain, and fistula, although it is rarely indicated.

VAGINA — Vaginal toxicity is common for women undergoing treatment for cervical and uterine cancer, in which pelvic RT and/or brachytherapy (BT) is often administered. This can lead to sexual dysfunction and interfere with quality of life. As with each organ system reviewed in this topic, the highest incidence rates for vaginal toxicity are seen in the definitive management of locally advanced cervix cancer, where over half of women report sexual dysfunction [62]. Significant vaginal toxicity is much less likely with standard adjuvant therapy. One large institutional series reported no grade >2 vaginal toxicity with high-dose rate BT alone to the vaginal cuff in the treatment of endometrial cancer [63]. Similarly, vaginal toxicity was 1 percent, none severe, in a randomized trial assessing pelvic radiation versus observation [64]. In long-term follow-up of this trial, there was no difference in sexual quality of life metrics at 15 years observed in a post-menopausal population [16]. Common toxicities are discussed below.

Acute vaginal mucositis — Acutely, women can experience vaginal mucositis during or following pelvic RT, although the incidence is not well documented because large prospective trials have not consistently reported rates of vaginal toxicity. The pathogenesis is similar to RT-induced changes observed at other mucosal surfaces. Clinically, vaginal changes range from erythema to superficial ulceration, which may be associated with exudative changes, serous discharge, and a predisposition to infection.

We approach vaginal mucositis with a multi-tiered approach consisting of vulvar cleansing with mild soap or Sitz bathes to remove topical irritants, such as urine. Vaginal douches (eg, diluted hydrogen peroxide and water or the local anesthetic and anti-inflammatory agent, benzydamine) and local vaginal estrogen can improve symptoms. One systematic review consisting of both randomized trials and observational studies suggested that douches were effective therapeutic aides [65]. At this time, benzydamine is available only outside of the United States.

Vaginal ulceration or necrosis — Full thickness vaginal ulceration and necrosis are uncommon signs after RT, but when present, are often seen in women requiring interstitial BT for vaginal cancers [66]. Necrosis results from loss of progenitor cells in the mucosal basal layer, leading to delayed healing that can extend beyond three months. It has been observed that the proximal vagina has a greater radiation tolerance. The majority of serious complications, such as necrosis, occur in the distal vagina.  

Initial management is conservative. Douches, such as dilute hydrogen peroxide, should be used for cleansing. Patients should be monitored for signs of acute infection. Common strategies for persistent non-healing include pentoxifylline or hyperbaric oxygen, both of which are supported by small observational studies that show high rates of resolution of necrosis [67-69]. However, well-conducted prospective trials are needed in this area.

Vaginal stenosis — Stenosis is the most common late vaginal side effect, and it can be seen following pelvic radiation and/or BT. As a result of the subsequent shortening of vaginal length, pain with penetration (or vaginismus) is a frequent complaint, which is likely as a result of circumferential narrowing of the vaginal vault or the development of adhesions with the vagina. This can also interfere with the need for ongoing surveillance pelvic exams. At its most extreme, the vault can become obliterated due to agglutination of the vaginal walls.

Due to significant heterogeneity between patient populations, methods, endpoints, and older RT techniques, it is difficult to define the incidence of this complication. Perhaps the biggest risk of vaginal stenosis is the combined treatment of pelvic RT plus BT. A publication from the EMBRACE study investigators suggests planning goals for pelvic external-beam RT and image-guided BT to reduce the risk for vaginal stenosis [70]. Patient-reported outcomes suggest that sexual dysfunction as a consequence of vaginal morbidity is underreported [71]. When not contraindicated, an older randomized study shows that topical estrogen (one to three times weekly) applied in the first six months following radiation reduces dyspareunia and improves vaginal caliber [72]. When observed, this typically begins three to six months after therapy. This is often accompanied by mucosal pallor and telangiectasia on pelvic exam.

The primary treatment for stenosis is the application of vaginal dilators, which are available in grades of both length and width. However, while many guidelines support their use as both prevention and treatment for post-radiation vaginal stenosis, additional data on their efficacy are needed [73]. Two case series and a comparative study using historical controls suggest that dilation might be associated with a longer vaginal length [74,75], but at least two small randomized trials from one institution showed no improvement in sexual scores or global sexual health in women who were encouraged to practice dilation [76]. In addition, topical mitomycin may have a role, although the data are mostly evaluating it to prevent stenosis [77,78].

Fistulas — Rectovaginal and vesicovaginal fistulas are a rare, but a very serious potential complication of treatment. They are seen almost exclusively following the need for high-dose radiation to control gross disease involving the vagina or when tumor has invaded adjacent organs, such as bladder or rectosigmoid. The need for interstitial BT may increase this risk compared with intracavitary BT. Risk factors for fistula development include tumor invasion of the bladder or rectum and the development of necrosis following treatment [79]. When possible, persistent non-healing should be managed conservatively, as biopsy and surgical management can precipitate fistula development. As with vaginal necrosis, hyperbaric oxygen and pentoxifylline can be used.

OVARIES — Radiation to the ovaries may lead to infertility or premature menopause. In general, the ovaries are very sensitive to even low total doses of radiation and small fraction sizes, with oocytes being more sensitive than granulosa or thecal cells. At doses required for the management of adult malignancies, premature ovarian failure (POF) is the expected result when the ovaries remain within the radiation field. Sensitivity is age-dependent and observed to increase with advancing age. The dose predicted to result in POF immediately following treatment is 16.5 Gy at 20 years old and 14.3 Gy at 30 years old [80]. With lower-dose exposures (most commonly seen in pediatric malignancies), total-body irradiation, or internal scatter from an adjacent radiation field, estrogen levels can recover between 6 and 18 months. However, early menopause is still likely to occur. The dose necessary to eliminate 50 percent of remaining oocytes has been determined to be between 2 and 4 Gy [81].

In premenopausal women <40 years old, laparoscopic ovarian transposition may be employed before a course of pelvic radiation. Understanding of the indicated radiation field by the surgeon is necessary to enhance the probability of preservation, as it is desirable for the transposed ovary to be at least 3 cm from the radiation field border. Often, clips are used to allow the radiation oncologist to identify the ovaries' new location. High rates of preservation (80 to 88 percent) have been reported, with an improved likelihood of success when both ovaries are transposed [82,83].

It is important that transposition only be considered in patients considered at low risk for spread to the ovary. Metastases occurring within a transposed ovary have been described in the management of cervical cancer, with greater risk for adenocarcinomas than squamous cell carcinomas [84].

Hormone replacement therapy (for patients who do not undergo ovarian transposition) is discussed elsewhere. (See "Management of early-stage cervical cancer", section on 'Hormone replacement therapy for menopausal symptoms'.)

BONE AND BONE MARROW — Radiation does not typically result in acute injury to healthy bone. The side effects of radiation on mature bone are related to metabolic changes that can lead to skeletal consequences after a latency of several years. Pelvic radiation can increase the risk for pelvic or sacral insufficiency fractures [85-87]. Endothelial damage and intimal fibrosis can lead to reduced blood flow to healthy bone. Osteoblast proliferation is affected by radiation. This results in diminished synthesis of bone matrix, leading to unbalanced resorptive processes. The result can be the development of focal osteopenia in the radiation field that can be more vulnerable to fracture, particularly at weight-bearing sites.

Pelvic insufficiency fractures (PIF) are most commonly seen near the sacroiliac joints. The use of modern magnetic resonance imaging (MRI) has led to an increase in the discovery of clinically occult, asymptomatic fractures. The observed risk factors for the development of PIF include older age, preexisting osteopenia, diabetes mellitus, corticosteroid use, low body weight, and radiation dose >50 Gy [88-90].

More conformal techniques appear to reduce the risk. A systematic review and meta-analysis identified the five-year actuarial incidence of PIF at 15 percent following pelvic radiation, of which 59 percent were symptomatic. In studies using modern radiotherapy, such as intensity-modulated RT, the incidence was lower, at 4.8 percent [90].

Most acute grade 4 complications during chemoradiation are hematologic [91]. Hematopoietic cells are sensitive to low doses of radiation. It is estimated that up to 25 percent of bone marrow reserves are located in the bones of the pelvis. Intensity-modulated RT can be used to minimize the dose of radiation to pelvic marrow. Several studies suggest that this lowers the risk for hematologic complications and may improve the likelihood of completing all intended doses of chemotherapy [92-94].

Radiation-induced lumbosacral plexopathy has been described as a rare consequence of pelvic radiation when incorporating brachytherapy for dose escalation [95]. When observed, the risk is associated with doses that are non-standard and avoidable with modern techniques (>70 Gy). At standard adjuvant doses, this risk is negligible.

SKIN — Acute skin reactions range from erythema and soreness to moist desquamation, and on rare occasion, ulceration. High-energy photons (10 to 18 Mv) and multi-field arrangements are typically used with pelvic RT. Both of these factors have a skin-sparing effect on the distribution of radiation dose. As a result, any observed radiation dermatitis for treatment of gynecologic malignancies is typically mild.

The major exception is vulvar cancer, where grade 3 skin reactions are common, or any situation in which the inguinal nodes are included for treatment. The advent of intensity-modulated RT for vulvar cancer has improved the ability to minimize skin doses outside of the target volume, such as the perianal region.

Skin erythema or dry desquamation can be treated with skin hygiene, water-based creams, or ointments such as lanolin. Topical anesthetics can help manage discomfort. Moist desquamation can be managed with Silvadene cream until healing is complete. Dermatitis typically resolves gradually in one to three weeks. The late spectrum of potential soft tissue effects includes persistent hyperpigmentation, telangiectasia, and fibrosis. In addition, radiation-induced fibrosis may respond to oral pentoxifylline and alpha-tocopherol (vitamin E) [96].

SUMMARY

●Radiation therapy (RT) represents an important therapeutic component in the management of many gynecologic malignancies. Therefore, an understanding of potential side effects is important for patient management and survivorship issues. (See 'Introduction' above.)

●Some patients with a gynecologic cancer may be at higher risk for RT-related toxicity. These include patients with active collagen vascular disease, inflammatory bowel disease (IBD), and vascular disorders (including diabetes and hypertension). (See 'Overview' above.)

●RT can be associated with side effects that can occur at any time during treatment or even years later. (See 'Timing of RT-related toxicities' above.)

•Acute toxicities refer to those with onset during or shortly after the course of treatment.

•Subacute toxicities are those that initially manifest 4 to 12 weeks after RT has been completed.

•Late toxicities are those occurring after three months.

●Acute RT-related cystitis can be a common complication with conventionally dosed pelvic RT, although the incidence is highly variable. It can be associated with irritative voiding symptoms (dysuria, frequency, urgency, and nocturia) and bladder spasms. It is due to RT-induced bladder inflammation and edema, which can compromise urothelial integrity. When they occur during RT, the symptoms typically resolve in one to two weeks after completing therapy. (See 'Acute radiation cystitis' above.)

●Late GU toxicities generally arise as a result of RT-induced epithelial and microvascular changes, which can lead to changes in bladder physiology. These can result in a similar spectrum of lower urinary tract symptoms to that seen in the acute phase, such as urgency and frequency, which is often attributed to bladder overactivity or contraction. With significant contraction, bladder dysfunction can result in urge incontinence. However, at expected doses of external-beam RT employed for gynecologic cancers (40 to 50 Gy), the likelihood of serious lasting side effects is low. (See 'Late signs and symptoms' above.)

●The small bowel is very sensitive to the early effects of RT, and when it is contained within the RT field, radiation injury can present acutely as nausea, vomiting, and diarrhea. However, the treatment of acute radiation injury is largely symptomatic. Probiotics during radiation may be useful as a preventative strategy. (See 'Acute radiation injury' above.)

●The symptoms of late GI toxicity include chronic diarrhea, malabsorption, recurrent bouts of ileus or obstruction, and the development of mucosal telangiectasias or ulcerations. Advances in radiation techniques, including use of intensity-modulated RT and image-guided brachytherapy (BT), have resulted in a reduction in the incidence and severity of late GI toxicity. (See 'Late GI toxicity' above.)

●Vaginal toxicity is common for women undergoing treatment for cervical and uterine cancer, in which cases, either pelvic RT or vaginal BT is often administered. This can lead to sexual dysfunction and interfere with quality of life. (See 'Vagina' above.)

●Radiation to the ovaries may lead to infertility or premature menopause. The dose necessary to eliminate 50 percent of remaining oocytes has been determined to be between 2 and 4 Gy [81]. Due to these risks, for women who are premenopausal and aged <40 years old, laparoscopic ovarian transposition is often employed before a course of pelvic radiation. (See 'Ovaries' above.)

●Acute skin reactions range from erythema and soreness to moist desquamation, and on rare occasion, ulceration. High-energy photons (10 to 18 Mv) and multi-field arrangements are typically used with pelvic radiotherapy. Both of these factors have a skin-sparing effect on the distribution of radiation dose. As a result, any observed radiation dermatitis for treatment of gynecologic malignancies is typically mild. The major exception is vulvar cancer, where grade 3 skin reactions are common, or any situation in which the inguinal nodes are included for treatment. (See 'Skin' above.)