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Keywords:

  • radiation;
  • morbidity;
  • toxicity;
  • gynecologic cancer

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICTS OF INTEREST DISCLOSURES
  6. REFERENCES

Radiation therapy is a critical treatment modality in the management of patients with gynecologic tumors. New highly conformal external-beam and brachytherapy techniques have led to important reductions in recurrence and patient morbidity and mortality. However, patients who receive pelvic radiation for gynecologic malignancies may experience a unique constellation of toxicity because of the anatomic locations, combination with concurrent chemotherapy and/or surgery, as well as potential surgical interventions. Although side effects are often categorized into acute versus late toxicities, several late toxicities represent continuation and evolution of the same pathologic process. Comorbidities and radiation dose can significantly increase the risk of morbidity. Current understanding of the incidence of various morbidities in patients treated with current radiation techniques for gynecologic malignancies, the impact of chemotherapy and surgery, treatment options for those effects, and future areas of research are highlighted. Cancer 2014;120:3870–3883. © 2014 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICTS OF INTEREST DISCLOSURES
  6. REFERENCES

Approximately 94,890 women will be diagnosed with gynecologic cancer in the United States in 2014.[1] Although multimodality therapy may be curative, morbidity because of treatment presents a significant concern to patients, health care providers, and society. In this article, we highlight novel techniques for treating radiation-related morbidities as well as the role of surgical and medical management.

Gastrointestinal Complications of Pelvic Radiation

Incidence of gastrointestinal complications

One prospective trial demonstrated that approximately 30% of postoperative patients with endometrial cancer who received radiation therapy (RT) experienced acute diarrhea, which persisted in approximately 10% of patients up to 5 years after treatment.[2] Late toxicities are less common, and significant gastrointestinal (GI) symptoms (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥3) range from 3% to 8% of patients who receive postoperative treatment to the pelvis[3, 4] and up to 20% of patients with locally advanced and unresectable tumors who require external-beam RT (EBRT) with both dose escalation and brachytherapy.[5] Most recently, the use of image-guided and high-dose-rate (HDR) brachytherapy has significantly reduced overall long-term complication rates from 22.7% to 2.6%.[6, 7]

A validated preradiation biomarker-assessment tool to determine the risk of future enteritis is not available. Recent genome-wide association studies (GWAS) have analyzed single-nucleotide polymorphisms (SNPs) and identified those that may be associated with GI toxicity, including 1 region of chromosome 11q14.3 associated with rectal bleeding in prostate cancer.[8] Others have analyzed serum and fecal markers in an attempt to intervene early with treatment but have reported no conclusive findings.

Diagnosis of GI complications

For common symptoms like acute diarrhea, mucus, tenesmus, pain, or hemorrhoids controlled with medication, radiologic or invasive diagnostic tests such as endoscopy are not recommended (see Table 1). If symptoms progress, a computed tomography (CT) scan may be obtained; radiographically, the small bowel within the irradiated pelvis can become thickened, which can easily be appreciated on CT scans (Fig. 1). All patients who present with persistent, symptomatic rectal bleeding should be evaluated by flexible sigmoidoscopy or colonoscopy to rule out disease recurrence or an occult primary tumor. For patients with chronic radiation proctitis, endoscopic findings can include rectal pallor, telangiectasias (which are friable and prone to bleeding especially if the patient is on anti-coagulants), and possibly strictures, fistulae, or regions of ulceration (Fig. 2). Biopsies also should be avoided unless a new malignant process is suspected. Interventions such as argon-laser coagulation should be used judiciously to avoid exacerbation of bowel injury (see Table 2).

Table 1. Acute Toxicities of Pelvic Radiation
ToxicitySymptomsDiagnosisTreatment
  1. Abbreviations; ANC, absolute neutrophil count; C. diff, Clostridium difficile; CT, computed tomography; DTO, diluted tincture of opium; GI, gastrointestinal; GU, genitourinary; IV, intravenous; UTI, urinary tract infection.

GI (0-6 mo)   
EnteritisDiarrhea, tenesmus, mucusIf severe, CT; consider C. diff testingEarly changes (frequent loose stools, not watery): encourage oral fluids, psyllium, low fiber diet; for diarrhea (<4 episodes/d), imodium, check electrolytes, consider IV fluids; for diarrhea (4-8 episodes/d), lomotil, 1-2 × weekly IV fluids; for diarrhea (refractory), DTO drops, regular IV fluids, consider hospitalization
ProctitisRectal bleedingSigmoidoscopy or anoscopyTopical hydrocortisone/pramozine; steroid enemas, butyrate enemas, sucralfate enemas
Hemorrhoids Physical examination with visual inspectionAquaphor/lidocaine topically (mixed 1:1); oral pain regimen if severe
GU (0-6 mo)   
CystitisDysuria, frequency, urgencyAssess for UTIAntibiotics if infectious source; pyridium/ibuprofen if non-infectious; consider anticholinergic agents for obstructive symptoms
Hematologic   
Anemia Hematocrit <30 mg/dLConsider transfusion of packed erythrocytes
Neutropenia ANC <500/μLInfection risk precautions
Thrombocytopenia Platelets <40 mg/μLConsider holding radiation; transfuse platelets if count <10 × 103/μL
Dermatologic (0-6 mo)   
DermatitisPruritis, tenderness Moisturizing creams, Sitz bath, Domeboro soaks, antibiotics, antifungal agents
DesquamationPain, wound drainage Nonadherent hydrogel (Xeroform), or silver nylon dressing pads
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Figure 1. Acute radiation enteritis manifests as diffuse thickening, hyperemia, and hyper-enhancement (red arrows) of the small bowel wall in the pelvis on computerized tomography imaging.

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Figure 2. (Left) Rectal proctitis and (Right) ulceration are shown (courtesy of Dr. John Saltzman).

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Table 2. Late Toxicities of Pelvic Radiation
ToxicitySymptomsDiagnosisTreatment
  1. Abbreviations: CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; EGD, esophagogastroduodenoscopy; ER, estrogen receptor; GI, gastrointestinal; GU, genitourinary; MRI, magnetic resonance imaging.

GI (>6 mo)   
EnteritisUrgency, fecal leakage, diarrhea; malabsorptionCT with or without EGD/colonoscopy; malabsorption: fecal fat, breath testDiarrhea: psyllium, probiotics, low fiber diet; fecal leakage: physical therapy for perineal strengthening; malabsorption: vitamin B12, cholestyramine, parenteral nutrition, gastroenterology evaluation
ProctitisRectal bleeding, tenesmus, painBleeding, sigmoidoscopySulcrafate enema, steroids enema, argon laser coagulation, hyperbaric oxygen
FistulaMalodorous discharge, fecal incontinence Surgical evaluation for resection vs. colostomy
StricturePain, constipation, thin-caliber stools Surgical evaluation for resection, lysis of adhesions vs. colostomy
ObstructionNausea, pain, persistent ileus, adhesions Bowel rest; refractory: surgical evaluation for resection vs. colostomy
GU   
FistulaDischarge, incontinence, urethral edemaCystoscopy, biopsy to evaluate for recurrent diseaseSurgical repair, ileal conduit
ContractureFrequency, painUrodynamicsCystectomy with ileal conduit or bladder augmentation in severe cases
CystitisBleedingCystoscopyHyperbaric oxygen
StricturesPain, hesitancyRetrograde urethrogramSurgical dilation (urethral); stent placement (ureteral), urethroplasty or ureteroplasty
Gynecologic   
Vaginal stenosisBleeding with dilator use, and/or pain with intercoursePhysical examination with assessment of narrowing/lengthVaginal dilator; evaluation by sexual function clinic
MenopauseHot flashes Oral contraceptive, serotonin reuptake inhibitors, natural products
 Vaginal dryness Vaginal estrogen (caution in using for patients with ER-positive adenocarcinoma)
Dermatologic   
Telangiectasia  -------
Fibrosis  -------
UlcerationPainBiopsy to exclude recurrent diseaseHyperbaric oxygen
NecrosisSevere pain, infection, odorousBiopsy to exclude recurrent diseaseHydrogen peroxide douching, metronidazole, hyperbaric oxygen
Bone (>3 mo)   
Osteopenia DEXABisphosphonates; vitamin D and calcium
Insufficiency fracturePain, inability to ambulateX-ray, CT, PET, MRIPain management, weight-bear as tolerated, physical therapy as recommended by orthopedics
Avascular necrosisPain, disabilityX-ray, bone scan, CT, MRISurgical repair (total hip replacement)
Patient-related and treatment-related factors associated with GI toxicity

Prior abdominal or pelvic surgery has been associated with an increased risk of developing small bowel obstructions in patients who receive >50 Gray (Gy) of RT to the pelvis and can lead to adhesions, which limit intestinal displacement. In addition, patients with coexisting comorbidities, including prior pelvic inflammatory disease, vascular disease because of diabetes or arteriosclerosis, collagen vascular disease, a smoking history, or inflammatory bowel disease, may be at greater risk for developing acute and long-term radiation side effects.[5]

Improvements in radiation technique to reduce GI complications

Effective strategies to minimize or prevent GI toxicity include multiple RT fields to avoid significant dose inhomogeneity, the use of a “belly board” with the patient in the prone position, and treatment with the patient's bladder full to optimize physical displacement of the small bowel. Treatment planning with intensity-modulated RT (IMRT) optimization may further decrease the risk of GI toxicity. IMRT is a highly conformal, advanced type of radiation that uses multiple beams to conform to the tumor and minimize surrounding normal-tissue dose; it requires complex treatment planning, which entails significantly more time than 3-dimensional (3D) conformal RT (3D-CRT) radiation planning. Adaptive IMRT (image-guided radiation, IGRT) with adjustments during treatment may further reduce dose to normal tissues. Figure 3 depicts a 3D-CRT “belly board” 4-field plan compared with an IMRT plan. A recently published randomized study evaluated the toxicity and clinical outcomes of 44 patients with locally advanced cervical cancer who received either whole-pelvis RT or IMRT at a dose of 50.4 Gy in 28 fractions administered with concurrent cisplatin 40 mg/m2 followed by HDR intracavitary RT. Compared with 3D-CRT, IMRT was associated with significantly fewer grade ≥2 acute GI toxicities (63.6% vs 31.8%; P = .034) and grade ≥3 acute GI toxicities (27.3% vs 4.5%; P = .47). In addition, IMRT was associated with less chronic GI toxicity (50% vs 13.6%; P = .011). Dosimetric comparison between the 2 groups demonstrated significantly less dose to the rectum and small bowel, which likely accounted for these important clinical differences.[9]

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Figure 3. (A) Sagittal and (B) axial views of 3-dimensional conformal plans are compared with (C) an intensity-modulated radiotherapy plan for postoperative endometrial cancer. These images demonstrate bowel sparing with the intensity-modulated radiotherapy plan.

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Figure 4. MR axial and sagittal (top) and CT (bottom) brachytherapy images for cervical cancer showing the optimized maximal dose to the tumor while minimizing the dose to the bladder, rectum, and sigmoid.

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Figure 5. This image shows cystitis as observed during cystoscopy (courtesy of Dr. Graeme Steele).

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Total prescribed RT dose; daily fraction size; treatment duration; and volume of small bowel, large bowel, and rectum within the RT field all have been associated with the risk of GI toxicity. Brachytherapy, that is, internal radiation administered after the completion of external radiation for patients with locally advanced cervical cancer, is required for curative management. New techniques involving the use of 3D imaging with either CT or magnetic resonance imaging (MRI) (Fig. 4) allow for the placement of dose away from critical surrounding normal tissues in patients who receive HDR brachytherapy (Fig. 4). A CT and MR contouring-atlas was recently published.[10, 11] It is noteworthy that studies have demonstrated a significant reduction in toxicity when using these techniques.[6, 7, 12]

Treatment of Common GI Toxicities
Acute radiation enteritis

The management of acute radiation enteritis is mainly supportive. Patients who develop diarrhea may be treated with fiber products (psyllium) and probiotics, although the published studies to date have yielded mixed results.[13-17] Frequent use of antidiarrheal agents, such as loperamide or diphenoxylate and atropine, starting with 1 tablet a day before the development of diarrhea and increasing as needed, may be indicated. Fluid status and electrolytes also should be monitored carefully, because intravenous hydration may also be required if patients are unable to adequately maintain fluid intake. Aggressive management during treatment is important to reduce the risk of chronic enteropathy. Sucralfate has been tested in randomized trials and has demonstrated no benefit for either acute or late symptom prevention when administered either immediately after RT[18-21] or after argon plasma coagulation.[22]

Chronic radiation enteritis

Chronic radiation enteritis is optimally managed by a multidisciplinary team, including a radiation oncologist, gastroenterologist, medical oncologist, surgeon, nutritionist, and dedicated nursing staff. Patients who develop malabsorption should be referred to a gastroenterologist, and vitamin B12 levels should be monitored and supplemented if necessary. Cholestyramine may be useful in treating bile salt malabsorption. For patients who develop chronic diarrhea, antidiarrheal agents like loperamide may be helpful. Surgical resection may be required in up to 30% of patients because of persistent ileus, intestinal fistulization, or adhesions.[23]

After radiation, fibrosis and progressive obliterative vasculitis may occur, resulting in the need for surgical intervention. Extensive, dense interloop and pelvic bowel adhesions may present as a small bowel obstruction, large bowel stricture, or severe enteritis. Although preventive and nonsurgical management techniques are preferred, patients who are refractory to these interventions require operative management. The goals of operative management of irradiated bowel are manifold. These include operating early, minimizing dissection of adhesions to avoid bowel injury, resecting rather than bypassing bowel to preserve as much functional bowel as possible and avoid blind loop syndrome, and creating an anastomosis with unirradiated or healthy-appearing irradiated bowel. If there is concern regarding the vitality of an anastomosis, then there should be a low threshold for proximal diversion. In addition, if sufficient omentum is available, then creating an omental J-flap to cover a denuded pelvis may prevent additional adhesions and future obstructions. Because malnutrition is often an important component of chronic radiation enteritis, perioperative nutritional support with parenteral nutrition leads to improved outcomes.[24]

Acute radiation proctitis

Numerous anti-inflammatory agents,[21, 25] intestinal protectants,[26] intestinal antimotility agents,[27] and probiotics[28] have been studied as preventative strategies; however, to date, none of these agents have demonstrated the ability to definitively mitigate radiation toxicity. The treatment of acute radiation proctitis is mainly supportive and includes antidiarrheals and intravenous hydration as needed. Several studies have also suggested a potential benefit with short-chain fatty acid butyrate enemas, which may aid in accelerating the healing process of acute radiation damage.[29, 30]

Late radiation proctitis

If rectal bleeding does not cause symptoms, then treatment is not always necessary, because most cases will resolve spontaneously. For patients with severe bleeding, antiplatelet or anticoagulation therapy should be discontinued if possible. Stool softeners may aid in minimizing damage to friable rectal tissue with the passage of stool. Treatment with a 4-week course of metronidazole also has been effective, possibly because of the treatment of anaerobic bacteria, which may contribute to hypoxia or immunomodulatory effects.[31] For severe rectal bleeding that is refractory to medical management, patients may be referred for consideration of endoscopic therapy with argon-plasma coagulation. In cases of chronic rectal bleeding, hyperbaric oxygen has been effective in reducing chronic pelvic radiation toxicity that was refractory to all other therapy. Hyperbaric oxygen is generally safe and well tolerated, but the limited number of available treatment facilities, prolonged treatments, and expensive treatment costs may be prohibitive.

Genitourinary Complications of Pelvic Radiation

Pelvic radiation for gynecologic malignancy may result in both upper and lower tract genitourinary (GU) complications, which are dose-dependent and related to RT modality. Low-grade (grade 1-2) acute GU toxicity is relatively common during EBRT, with an incidence of 17% to 40% in the definitive treatment of cervical cancer with concurrent chemoradiotherapy.[5] The incidence of low-grade GU toxicity was similar at 43% in the Gynecologic Oncology Group (GOG) GOG-99 study of postoperative RT for endometrial cancer.[3] Severe urinary tract toxicity is relatively rare during treatment (range, 2%-5%). The Postoperative Radiation Therapy in Endometrial Cancer (PORTEC-2) trial demonstrated that urinary frequency was more common after vaginal brachytherapy than EBRT for endometrial cancer (an increase of 6% vs. 1% over baseline).[2]

Patient-related and treatment-related risk factors for GU toxicity

Treatment-related factors that influence the risk of GU toxicity include cumulative radiation dose, treatment volume, radiation modality (EBRT, brachytherapy, or both), and prior pelvic surgery.[32] The use of anticoagulation also may lead to higher rates of post-treatment bleeding. In patients who undergo radical hysterectomy, adjuvant radiation may cause higher rates of bladder dysfunction, hydroureteronephrosis, stress incontinence, and radiation cystitis.[33] Tobacco use has also been associated with fistula formation in patients with stage IVA cervical cancer and bladder involvement at diagnosis.[34] The use of concurrent chemotherapy reportedly does not increase the risk of late GU complications in patients with cervical cancer.[5]

Treatment of common GU toxicities

Patients with dysuria, urgency, or frequency should have a urinalysis and urine culture to assess for infection. After infection has been excluded, treatment options for dysuria include ibuprofen or phenazopyridine (Pyridium). Urinary urgency is effectively managed with anticholinergics like oxybutynin (Ditropan). Other agents, such as tolderodine (Detrol) and trospium (Sanctura), have similar efficacy but lower rates of confusion, dry eyes, dry mouth, and constipation compared with oxybutynin. If oral agents fail, then cystoscopic injection of botulinum toxin A into the detrusor muscle reportedly is effective.[35] Injections typically give 6 to 9 months of relief and may be repeated.

Late GU effects

Several large institutional series reported grade 1 and 2 late bladder complications in 28% to 45% of patients after definitive RT for cervical cancer, whereas severe bladder dysfunction was relatively uncommon.[5] Parkin et al noted a 26% incidence of severe urgency, frequency, and incontinence after RT for cervical cancer. Urodynamics performed before and after treatment revealed no differences in postvoid residual or maximum flow rate, although there were decreases in maximum bladder capacity and bladder compliance.[36, 37] In a series of 141 patients with cervical cancer who received MR-guided brachytherapy, the rate of grade 1 and 2 late complications was 16%, and the rate of grade 3 and 4 late complications requiring cystectomy was 1.4%.[7] In that study, the estimated dose to the 2-cc bladder volume that resulted in a 10% risk of grade 2, 3, and 4 complications was 101 Gy.

In contrast, GU complications after postoperative RT for endometrial cancer are less common, probably related to the use of a single radiation modality (EBRT or brachytherapy) and a relatively moderate delivered dose. Low-grade toxicity (grade 1-2) has been reported in 11% to 16% of patients in prospective trials, whereas grade 3 and 4 toxicity is rare.[3, 38] In patients with medically inoperable endometrial cancer who receive HDR brachytherapy, the reported major complications rate is 6%.[39, 40]

The reported rates of major urologic complications (grades 3-4) after RT for cervical cancer range from 1.3% to 14.5% at 3 years and most commonly include ureteral stricture and hemorrhagic cystitis (Fig. 5). Hemorrhagic cystitis may be treated with laser fulguration of ectatic vessels, intravesical alum or formalin, or hyperbaric oxygen.[41, 48]

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Figure 6. Lower vaginal necrosis is shown (courtesy of Dr. Beth Erickson).

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Ureteral strictures have been noted in 5% of patients after preoperative RT and in 2.5% of patients after definitive RT alone for cervical cancer.[5] Strictures of the ureter may be managed by endoscopic procedures, such as dilation or stent placement, but they often require ureteral reimplantation or ileal ureteral substitution. The classical teaching is that a ureteral stricture represents recurrent cancer until proven otherwise; imaging with CT or MRI is recommended. Patients who have bladder involvement at diagnosis are at risk of developing a vesicovaginal fistula after definitive RT.[34] Moore and colleagues reported that the diagnosis of vesicovaginal fistula followed the diagnosis of stage IVA cervical cancer by 2.9 months.[34] Fistulae should first undergo biopsy to rule out recurrence of malignancy. Small vesicovaginal fistulae may be managed with simple fulguration and catheter drainage, but they may require open surgical repair and, occasionally, urinary diversion. Ureteroarterial fistulae are rarely encountered and have a 10% acute mortality rate.[42] They should be treated with endovascular stent placement or, if this fails, open surgical repair.

Sexual Function After Pelvic Radiation

The most common gynecologic complications of pelvic radiation are ovarian failure in premenopausal patients and vaginal stenosis (VS) in any female patient who receives vaginal radiation. VS is defined as narrowing or shortening of the vaginal canal that may interfere with physical examination or sexual function. The incidence ranges from 20% to 88% of patients.[43, 45-47, 49] Other series have demonstrated that patients who undergo surgery and receive HDR vaginal brachytherapy alone have an incidence of VS from as low as 2.5%,[49] with the lowest rates reported in those who receive low-dose-per-fraction regimens,[50] to as high as 54% with tandem/ovoid treatments. Vaginal telangiectasia and pallor of the vaginal mucosa may be observed on follow-up examination. Sexual dysfunction can occur in about half of women who receive treatment for gynecologic malignancies with radiation.[51] Uterine distension is limited because of fibrosis after pelvic radiation. Consequently, the delivery of a full-term infant is not feasible after the uterus is treated with the pelvic radiation dose required for primary gynecologic malignancies.[52]

Time course of sexual dysfunction

Patients who receive radiation to the pelvis for locally advanced cervical cancer will have their ovaries irradiated and, thus, will undergo menopause, typically within the first 6 months after treatment.[53] Temporally, VS is most likely to occur within the first year of treatment but has been observed in as short a time as 26 days and as far out as 5.5 years from definitive therapy.[43, 44] The distal vaginal mucosa has less radiation tolerance than the mucosa in the upper region, and vaginal shortening may begin during the course of RT.[54] One randomized trial demonstrated higher rates of VS with higher vaginal brachytherapy doses.[55] In terms of quality of life,[56] a systematic review concluded that survivors of gynecologic cancer experience a broad range of sexual concerns after diagnosis and treatment.[57] In a study of patients with cervical cancer, compared with 6-year to 10-year survivors, those who were 2 to 5 years out from diagnosis had more sexual worry and body-image concerns. Notably, women who received radiation and also underwent surgery experienced more symptoms (P = .001), worse body image (P = .029), and more sexual worry (P = .004) than women who underwent surgery alone.[58]

Patient-related and treatment-related factors associated with sexual dysfunction

Risk factors for VS include higher radiation dose, age older than 50 years,[43, 49] lack of compliance with dilator use, and concomitant chemoradiation therapy.[49] Radiation doses >80 Gy have been associated with a 10% to 15% increased risk of grade 2 vaginal toxicity, including VS.[59] Several studies have demonstrated that VS can have a negative effect on patient sexual satisfaction because of vaginal dryness, vaginal shortness, tightness, and dyspareunia.

Treatment of sexual dysfunction

Menopausal symptoms, such as hot flashes and mood changes, may be treated with supplemental oral progesterone and/or estrogen or with serotonin-specific reuptake inhibitors. The most commonly used intervention to prevent VS is the use of vaginal dilators. In addition to dilators, other treatments for stenosis include topical estrogens and benzydamine, hyperbaric oxygen, and surgical reconstruction, although these are based on small, single-institution experiences.[60]

Vaginal necrosis (Fig. 6) may result from high doses of radiation, especially in patients who have undergone reirradiation. Patients who receive HDR, particularly those treated with interstitial brachytherapy to the distal vagina, may be at greater risk for vaginal necrosis.[61] Hydrogen peroxide douching with a dilution of at least 1:10 with saline, oral metronidazole, and hyperbaric oxygen may be considered.

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Figure 7. Avascular necrosis of the femoral head in a 50-year-old 13 years after chemoradiation for cervical cancer. The patient presented with 4 months of progressive right hip pain, and had a right femoral head/acetabulum pathologic fracture identified on (Left) x-ray and (Right) computed tomography.

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Hematologic Toxicity of Pelvic Radiation

Patient-related and treatment-related factors associated with hematologic toxicity

Higher doses of radiation may lead to chronic myelosuppressive effects and poor tolerance to subsequent chemotherapy by damaging the bone marrow (BM) microenvironment.[62] Large prospective studies have demonstrated that the rate of grade ≥3 hematologic toxicity with cisplatin-based pelvic chemoradiotherapy is approximately 20% to 25%. Extended-field RT leads to the irradiation of a larger proportion of the total BM and a correspondingly higher rate of hematologic toxicity.[63] Hematologic toxicity predisposes patients to infection, hospitalization, and requirements for transfusions and growth factors. Hematologic toxicity can also lead to delayed or missed chemotherapy cycles and treatment breaks, which potentially may compromise disease control. Furthermore, some patients with advanced disease may benefit from intensified treatment,[64] and hematologic toxicity is a major barrier to the use of intensified regimens, with up to 72% of patients experiencing grade ≥3 acute toxicity.

One important advantage of IMRT over conventional technology is that IMRT results in less BM irradiation, leading to lower rates of acute hematologic toxicity.[65] Dose-volume parameters of pelvic BM irradiation are associated with hematologic toxicity.[66] Other studies of pelvic radiotherapy have validated this relation.[67, 68]

Treatment approaches for limiting hematologic toxicity

Sparing functional BM subregions instead of the entire BM is one investigational approach to limiting hematologic toxicity. Functional imaging with positron emission tomography (PET), single positron emission CT (SPECT), and/or specialized MRI sequences has been proposed as a means to identify active BM subregions.[69-71] Irradiation of BM subregions with higher fluorodeoxyglucose (18F-FDG)-PET activity was associated with hematologic toxicity, whereas irradiation of subregions with lower FDG activity was not.[71]

Management of acute hematologic toxicity

Weekly blood counts are routinely obtained. Chemotherapy is typically held when the neutrophil count decreases below 1500/μL. RT is typically held when the neutrophil count approaches 500/μL to 1000/μL. Lymphopenia rarely leads to adverse events, and no specific management recommendations are made based on the lymphocyte count. Platelet counts typically are monitored weekly, and chemotherapy is held when counts fall below 100,000/μL. Radiation therapy is typically continued until the counts fall below 40,000/μL. Despite uncertainty, the standard recommendation for patients with cervical cancer is to transfuse to maintain a hemoglobin level above 10 mg/dL for patient quality of life and treatment tolerance in addition to the potential impact on outcomes.

Bone Complications From Pelvic Radiation

Although uncommon, important sequelae of radiation to bone, such as pathologic fractures, osteoradionecrosis, and second malignancies,[72] are associated with a decrease in quality of life[73] and increase in mortality.[74, 75] The factors that influence bone toxicity include radiation dose (>50 Gy)[76] as well as patient factors, such as age, menopausal status, presence of underlying bone weakness (such as osteopenia or osteoporosis), corticosteroid use, cigarette smoking, and vascular integrity. In addition, other risk factors have been identified for sustaining a pelvic insufficiency fracture (PIF), such as low body mass index, prior fractures, reirradiation, and prior hormone-replacement therapy.[77, 78]

The reported incidence of PIF in women with gynecologic tumors who receive RT ranges from 10% to 29%.[77, 79-81] The published 5-year cumulative rate of PIF ranges from 5.1 to 45%.[80-83] Greater than 60% of patients present with multiple fractures involving the sacrum, acetabulum, or pubic bone; up to 50% of fractures are bilateral, 10% to 20% occur in the pubic bone, and 5% occur in the acetabulum.[84] Grigsby et al[85] investigated 207 patients who received RT for gynecologic malignancies and observed an incidence of femoral neck fractures (FNFs) of 4.8%, with a 5-year cumulative rate of 11%. Avascular necrosis of the femoral head may occur in conjunction with pelvic fractures because of generalized bone weakness (Fig. 7).

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Figure 8. (A) Sacral insufficiency fracture 2 years after treatment. An axial computed tomography (CT) scan demonstrates a linear lucency that extends to the anterior cortex, with a mild associated cortical step-off and ill-defined sclerosis adjacent to the lucency. This region was mildly avid on fluorodeoxyglucose positron emission tomography (FDG-PET). (B) A pubic symphyseal fracture 1.5 years after treatment. The FDG-PET image reveals the hypermetabolic focus indicative of partial healing in the region of the fracture. (C) Axial CT slices reveal the fracture lucency with adjacent sclerosis. Both patients required conservative measures, including pain medication and weight-bearing as tolerated.

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Diagnosis of bone complications

The diagnosis of radiation-induced PIF (Fig. 8) or FNF is often delayed, because the clinical presentation and radiographic findings can mimic metastatic lesions, hip osteoarthritis, and spinal or lumbar stenosis. Common clinical features are usually nonspecific and include severe back, hip, and leg pain. Radiographic findings are usually equivocal and, in most patients, CT imaging is necessary.[86, 87] In the absence of radiographic evidence and an equivocal CT, MRI may aid in the diagnosis by depicting high signal intensity on T2-weighted images, representing BM edema, and a fracture line observed on T1-weighted images.[81, 88, 89] Bone scintigraphy is sensitive for detecting PIF. A common feature is an H-shaped pattern of increased radionuclide uptake occurring across the sacrum, representing symmetric sacral ala fractures.[88]

Treatment of bone complications

A 4-level instability classification system with subcategorization has been proposed to guide the management of PIF based on the ability of the bony and ligamentous pelvic structures to withstand physiologic loads without displacement. The amount of instability indicates operative versus nonoperative treatment measures.[90] The classification recommends nonoperative treatment for stable type I fractures, nonoperative or minimally invasive surgical fixation for type 2 fractures, and surgical stabilization for type 3 and 4 fracture patterns. Nonoperative treatment measures usually consist of a combination of nonsteroidal anti-inflammatory and pain medication and slow progression from bed rest to full mobilization with full weight-bearing on the affected side. A prolonged course of physical therapy ranging from 6 months to 12 months is often required. If the pain persists longer than 8 weeks, then repeat imaging of the pelvis is indicated to evaluate for fracture healing and new onset of instability.[91] For incomplete and isolated sacral ala fractures, sacroplasty may be considered.

Unlike PIF, FNF usually requires surgical intervention within 24 to 48 hours. FNF in irradiated bone has been initially treated with hemiarthroplasty, but published data demonstrate that 50% of patients developed protrusio acetabuli.[92] Therefore, the current treatment of choice is a total hip replacement with increased stabilization of the acetabulum because of a higher incidence of osteolysis.[93] Overall, PIF and FNF are complex and require a multidisciplinary team approach, including the radiation oncologist, gynecologist, radiologist, orthopedic surgeon, physiatrist, and physical therapist, to successfully manage the pathologic disease process.

Dermatologic Toxicity of Pelvic Radiation

Patient-related and treatment-related factors for dermatologic toxicity

The risk of skin toxicity as well as its onset, severity, and duration are strongly affected by clinical and treatment-related factors. Vascular disease, smoking, and poor nutrition may impair acute and long-term recovery of the dermis and subcutaneous tissues. Compromised wound healing after surgery may lead to delays both in the initiation of RT and during the actual treatment. A robust, radiation-induced skin reaction may occur in a patient with a high body mass index because of the presence of skin folds and may be compounded by concurrent fungal or bacterial infection. IMRT also may have an advantage in reducing acute skin toxicity in the treatment of vulvar cancer by lowering the radiation dose within the skin and subcutaneous tissues, particularly within the groin (Fig. 9).[94] For cases in which the distal vagina or vulva is not within the target volume, specific radiation techniques may be used to avoid flashing the skin of the perineum, perianal region, and gluteal fold.

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Figure 9. Shown are (A) intensity-modulated radiotherapy (IMRT) versus (B) 3-dimensional conformal radiotherapy treatment plans for a patient with vulvar carcinoma. The IMRT plan depicts femoral head sparing.

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Acute dermatologic effects of pelvic RT

Currently, the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer skin toxicity score is widely used in clinical practice and research. Grade 1 reactions include folliculitis, faint or dull erythema, epilation, dry desquamation, or decreased sweating. At a dose of 40 Gy, grade 2 reactions are typically observed, defined as tender and edematous erythema with patchy, moist desquamation in skin folds and associated pain. Grade 1 and 2 skin reactions are common in gynecologic RT, with an incidence of 10% to 50% in prospective randomized trials of cervical and endometrial cancer[3, 95] and 85% to 100% in the treatment of vulvar cancer.[94, 96, 97] Grade 3 skin reactions are associated with confluent moist desquamation when doses exceed 50 to 60 Gy with bolus placement. Grade 4 skin reactions include skin ulceration, hemorrhage, and necrosis. Severe skin reactions are rare (range, 1%-5%) in the treatment of endometrial and cervical cancer,[3, 95, 98] whereas patients with vulvar cancer are at significantly higher risk (range, 24%-53%) of moist desquamation and wound complication.[96, 97] Acute skin reactions typically peak within 1 or 2 weeks after treatment, with a relatively rapid healing time of 3 to 4 weeks. IMRT may decrease the risk of vulvar skin toxicity, and 1 series reported no grade 3 groin skin desquamation.[94]

Treatment of dermatologic toxicities

An acute skin reaction is generally apparent after 2 or 3 weeks of pelvic EBRT with conventional dose fractionation. With a 4-field beam arrangement, mild erythema is most commonly observed in the vulva, perineum, and the inguinal and gluteal folds. Mild skin reactions, such as erythema, may be treated with topical moisturizers without added perfumes or metals like zinc or silver, which can irritate the skin or enhance the reaction. Moisturizing creams may prevent the onset and severity of erythema, although this warrants further study. Daily use of a sitz bath with the addition of sodium bicarbonate, Epsom salts, or Domeboro soaks may provide symptomatic relief. Gentle cleaning with a mild, unperfumed soap is advised for folliculitis.

In patients with vulvar cancer, skin overgrowth of Candida is common and may be identified by white plaques over the skin. Daily treatment with fluconazole for the remainder of the treatment course may provide significant symptomatic relief and promote healing. The patient should also be encouraged to wear loose-fitting and cotton clothing and to avoid temperature extremes. In the setting of pruritis, 1% hydrocortisone cream may be helpful. Patients may develop skin warmth in the irradiated region without the presence of cellulitis; however, caution must be exerted with frequent skin checks to ensure that the area of redness is not rapidly progressing.

For patients with desquamation, the application of silver clear nylon,[99] nonadherent or hydrogel dressings, which have been used extensively for first-degree burns, creates a moist environment that stimulates wound healing. Vaseline gauze impregnated with antibiotics may also provide topical relief and prevent secondary infection, although the routine use of antibiotics has not been systematically studied. A treatment break should be considered to allow for skin healing as well as pain medications, such as nonsteroidal anti-inflammatory drugs or narcotics for symptom control. In the setting of a severe wound reaction, a wound-care referral may be considered.

Late dermatologic effects

The late effects of gynecologic RT may include hyperpigmentation or hypopigmentation, telangiectasia, textural changes (xerosis and hyperkeratosis), or thinning of the skin because of atrophy, with a reported incidence of 0% for cervical cancer (grade 3) and up to 20% in patients with vulvar cancer (grade ≥2).[100, 101] In the months after RT, folliculitis is common because of regrowth of occluded hair follicles, sweat glands, and sebaceous glands and may be relieved with warm compresses or occasionally may require antibiotics. Subcutaneous fibrosis with associated woody thickening of the skin may also be observed, although tissue retraction and pain are less common. Recurrent episodes of cellulitis, specifically erysipelas, are reported in 1% to 16% of patients who have vulvar cancer, and the greatest risk is reported after inguinal lymph node dissection and postoperative RT.[102] Patients who receive cumulative vulvar doses in excess of 60 to 70 Gy or an interstitial brachytherapy boost may be at higher risk for severe complications.[103, 104] Twice daily use of a 1:10 diluted hydrogen peroxide douche can prevent the formation of necrotic tissue, particularly in previously irradiated patients. Additional assessment tools for chronic skin toxicity are needed to describe the degree of skin reaction and pain and the impact on quality of life.

Surgical Implications of Radiation-Induced Toxicity

After radiation, subsequent postsurgical wound healing may be compromised. Prior RT can complicate not only abdominal wounds created to address intra-abdominal chronic radiation complications but also the surgical management of recurrent vulvar malignancies. Wound infection, dehiscence, and delayed wound healing are common and require prolonged management. This poor healing is likely because of poor vascularity or impaired regeneration capacity after radiation. In addition, repeat radical vulvar excisions often do not heal well and may require transposition, rotational, or advancement flaps. These flaps can be cutaneous or myocutaneous in nature.[105] For late wound breakdown, ulceration, or necrosis, hyperbaric oxygen should be considered.[106, 107]

Chemotherapy Implications of Radiation-Induced Toxicity

Although data on late toxicity are sparse and, thus, are insufficient for drawing firm conclusions, data from a meta-analysis[108, 109] and from individual studies (such as cervical cancer trial RTOG 900198) suggest that there may be no significant differences in the types or gravity of late effects between concurrent chemoradiation and RT alone.[108, 109] Specifically, only a small number of women across all trials (range, 1%-3%) experienced serious late toxicities (mainly late rectal, bladder, intestinal, and vaginal toxicities). Chemotherapy after pelvic RT is routinely administered in endometrial cancer, and this approach has been well studied in this disease.[110, 112] In those studies, increased hematologic toxicities were observed in patients who were receiving chemotherapy who had previously received radiation to the pelvis, although administration of platinum-based chemotherapy after pelvic RT was feasible. Growth factor support should be strongly considered for chemotherapy administered after pelvic RT. Modification and/or slow escalation of the doses of chemotherapy administered after pelvic RT should be considered, and this strategy has been used in the ongoing GOG 258 endometrial trial (4 cycles of carboplatin at an area under the concentration time curve [AUC] of 5 and escalated to an AUC of 6 if tolerated and paclitaxel 175 mg/m2 every 3 weeks with granulocyte-colony–stimulating factor support). Administration of sequential chemotherapy and RT as sandwich therapy (i.e., chemotherapy, followed by pelvic RT, followed by further chemotherapy) demonstrated the completion of all planned cycles of postradiation chemotherapy in approximately 75% of patients.[113, 114] The administration of future chemotherapy for metastases may be more difficult, depending on the tolerance of prior chemoradiotherapy.

Conclusions

Administering standard pelvic radiation results in the potential for toxicities. IMRT may reduce this risk in some instances. Major morbidities are relatively rare. Comorbidities play an important role in the risk of radiation-induced toxicities. Both during and after RT, careful management and long-term monitoring of patients who are treated for gynecologic malignancies are necessary. Future diagnostic testing may assist in determining which patients have the greatest risk for toxicity and will benefit most from frequent monitoring and early intervention.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICTS OF INTEREST DISCLOSURES
  6. REFERENCES

Dr. Viswanathan receives funding from the National Institutes of Health (grant R21 CA 167800).

CONFLICTS OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICTS OF INTEREST DISCLOSURES
  6. REFERENCES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. FUNDING SUPPORT
  5. CONFLICTS OF INTEREST DISCLOSURES
  6. REFERENCES
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