Clinical Therapeutics/Volume 37, Number 1, 2015

Original Resarch

Severe Gastrointestinal Complications in the Era of Image-guided High-dose-rate Intracavitary Brachytherapy for Cervical Cancer Daniel M. Trifiletti, MD1; W. Tyler Watkins, PhD1; Linda Duska, MD2; Bruce B. Libby, PhD1; and Timothy N. Showalter, MD, MPH1 1

Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, Virginia; and 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, Virginia ABSTRACT Purpose: The purposes of this analysis are to report a modern series of severe gastrointestinal toxic effects after definitive chemoradiotherapy in the treatment of locally advanced cervical cancer at our institution and to review the existing literature on factors that contribute to toxic effects and preventive strategies and management. Methods: Our institution’s cervical cancer cohort was evaluated for patients with late grade 3 to 4 gastrointestinal toxic effects who were retrospectively reviewed for clinical or dosimetric parameters that could have contributed to late toxic effects. A review of the published literature was performed to identify factors associated with late toxic effects, prophylactic agents, and corrective therapy. Findings: Five of 85 patients were identified as having late grade 3 to 4 gastrointestinal toxic effects with a median follow-up of 13.3 months. Two of 5 patients developed late grade 3 toxic effects, and 3 of 5 developed late grade 4 toxic effects. Three of the 5 patients reviewed ultimately required permanent colostomies. Cumulative median dose (in equivalent dose in 2-Gy fractions) of clinical target volume to the hottest 90% was 107.2 Gy, rectal dose to the hottest 2 cc (D2cc) was 81.7 Gy, sigmoid D2cc was 61.7 Gy, and bladder D2cc was 79.5 Gy. No patient

Accepted for publication November 6, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.11.003 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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had evidence of disease recurrence in the pelvis. One patient developed oligometastatic disease in the suprarenal gland and was successfully salvaged with adrenalectomy. Implications: Despite its risk of toxic effects, intracavitary brachytherapy remains a critical component of the treatment of locally advanced cervical cancer. Even with modern radiotherapy planning and delivery techniques, extra attention is warranted to continue to strive for optimal outcomes. (Clin Ther. 2015;37:49–60) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: brachytherapy, cervical cancer, gastrointestinal, high dose rate, rectum, toxicity.

INTRODUCTION Intracavitary brachytherapy has been used in the treatment of cervical cancer since the use of vaginal radium insertions more than a century ago.1,2 Since that time there have been numerous reports of late gastrointestinal (GI) toxic effects after radiotherapy. In more recent years, there has been a transition from low-dose-rate (LDR) to high-dose-rate (HDR) brachytherapy, with reported similar cancer-specific outcomes and improved safety profiles and logistics of administration with HDR brachytherapy.3 In addition Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.

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Clinical Therapeutics to these changes in brachytherapy delivery approaches, a considerable international effort has been made to improve target coverage and limit dose delivered to adjacent organs at risk (OARs). This effort has largely focused on the adaptation of 3-dimensional (3D) computerized treatment planning with computed tomography (CT) and magnetic resonance imaging (MRI). This approach allows for a more accurate optimization and calculation of dose delivery to target structures and OARs.4 Although the use of volumetric target optimization during brachytherapy is well described,5 late GI toxic effects remain a serious risk after definitive radiotherapy. Our goal is to evaluate the occurrence of severe GI toxic effects after definitive chemoradiotherapy with contemporary image-guided brachytherapy for the treatment of locally advanced cervical cancer at our institution. We also review existing literature on the topic.

REPORT OF INSTITUTIONAL PATIENT OUTCOMES From a cohort of 85 patients who received definitive chemoradiotherapy for locally advanced cervical cancer during 2011 to 2013, we identified 5 patients who developed late grade 3 to 4 GI toxic effects, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.6 The review was performed with approval from the Institutional Review Board for Health Sciences Research at the University of Virginia. Patient and treatment information was obtained through medical record review. Table I gives the baseline patient characteristics for the 5 patients who developed grade 3 to 4 GI toxic effects. The median follow-up time for the 5 patients who developed late GI toxic effects was 13.3 months. Mean age at presentation was 43.8 years, and mean initial clinical cervical tumor size was 6.5 cm. Patient conditions were staged based on current International Federation of Gynecology and Obstetrics7 and American Joint Committee on Cancer8 staging manuals. No patient had a recorded history of diabetes mellitus or a known connective tissue disorder. Four of 5 patients had a history of tobacco use, and 3 smoked tobacco while under treatment. All patients received external beam radiotherapy (EBRT) concurrent with weekly cisplatin chemotherapy (range, 45–50.4 Gy in 25–30 fractions). Para-aortic nodal basins were included in one patient. At the

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conclusion of whole pelvic radiotherapy, each patient was given general anesthesia and underwent suturing of a Smit Sleeve into the cervical os before tandem and ovoid applicator placement. Subsequent fractions were performed while the patient was conscious after premedication. For each HDR brachytherapy fraction, patients underwent imaging using an in-room CT onrails system9 after applicator insertion, and a new plan was followed for each fraction. An iridium-192 isotope was used in all HDR treatments. All contouring and optimization were performed with BrachyVision treatment planning software (Varian Medical Systems Inc, Palo Alto, California). For each fraction, a dose was prescribed to an isodose line and normalized to point A. Adverse events were graded by the CTCAE.6 To prevent further delays in total treatment duration, 1 patient received brachytherapy with the twice-daily schedule. Table II reports the cumulative biological effective dose and equivalent dose in 2-Gy fractions (EQD2) to the high-risk clinical target volume (CTV), rectum, sigmoid colon, and bladder. Cumulative doses were calculated under the linear-quadratic equation assuming an α/β ratio of 3 and 10 for OARs and CTV, respectively. In EQD2, the median CTV dose to the hottest 90% (D90%) was 107.2 Gy, rectal dose to the hottest 2 cc (D2cc) was 81.7 Gy, sigmoid D2cc was 61.7 Gy, and bladder D2cc was 79.5 Gy. Patients who received a parametrial or nodal external beam boost did not have boost doses included in these calculations because dose overlap was usually minimal and difficult to accurately predict. With a median follow-up of 13.3 months, all 5 patients are alive, and no patient has developed recurrent disease within the pelvis. The mean time to hospital admission or surgery from treatment-related toxic effects was 8.8 months. There was no grade 5 toxic effect. One patient developed a metastasis to the right adrenal gland found on 3-month posttreatment positron emission tomography–CT and received salvage surgery with adrenalectomy. She currently has no evidence of disease.

REVIEW OF LITERATURE AND RELEVANCE TO INSTITUTIONAL SERIES Incidence Several studies have reported on the incidence of GI complications after definitive radiotherapy and chemoradiotherapy with HDR brachytherapy for cervical cancer, and the reported incidences vary widely from approximately 5% to 30%. This is in

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Table I. Clinical characteristics of 5 patients who developed late grade 3 to 4 gastrointestinal toxic effects. Patient No. Characteristic

1

Age at 56 brachytherapy, y Follow-up duration, 20.6 mo Histologic subtype SCC Tumor size, cm 4.2 FIGO stage IB2 Tobacco use Former Toxicity grade 3 Toxic effect Proctosigmoiditis with hemorrhage Intervention Time to toxic effect, mo Result Pelvic EBRT dose Pelvic EBRT fraction Para-aortic EBRT EBRT boost

9.4 Grade 1 proctitis 45 Gy 25 Gy None None 27.5 Gy 5 Gy 5.50 Gy

46 8.1

3 31 9.4

SCC 6.2 IIB Never 3 Proctitis and cecal ulcer with hemorrhage

SCC 8 IB2 Concurrent 4 Necrotic sigmoid stricture

Argon therapy and sucralfate 7.1

Partial colectomy or ileostomy 8.2

Grade 1 proctitis 45 Gy 25 Gy None Bilateral parametrial 10 Gy 30 Gy 5 Gy 6.00 Gy

4

5

Mean

45

45

44.9

13.3

23.8

15.1

Adenocarcinoma 7.4 IB2 Concurrent 4 Proctitis and rectovaginal fistula Colostomy

SCC 6.7 IIB Concurrent 4 Rectal ulcer and rectovaginal fistula

4.5

Colostomy 14.6

Anastomotic leak, Chronic pain, FTT Chronic pain, FTT FTT 45 Gy 50.4 Gy 45 Gy 25 Gy 28 Gy 25 Gy None None Yes Pelvic lymph node None Bilateral parametrial 10 Gy 9 Gy 29 Gy 30 Gy 5 Gy 5 Gy 5 Gy 5.80 Gy 6.00 Gy 6.00 Gy

EBRT ¼ external beam radiation therapy; FTT ¼ failure to thrive; HDR ¼ high dose rate; SCC ¼ squamous cell carcinoma.

6.5

8.8

46.1 Gy 25.6 Gy

29 Gy 5.0 Gy 5.8 Gy

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D.M. Trifiletti et al.

Total HDR dose HDR fraction Mean HDR dose per fraction

Carafate enemas

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Clinical Therapeutics

Table II. Cumulative EQD2 doses to CTV and organs at risk in 5 patients with late grade 3 to 4 gastrointestinal toxic effects. Patient No. Dose HR CTV EQD2 D100% HR CTV EQD2 D90% HR CTV EQD2 V100% HR CTV EQD2 V150% HR CTV EQD2 V200% Rectal EQD2 D0.1cc Rectal EQD2 D1cc Rectal EQD2 D2cc Sigmoid EQD2 D0.1cc Sigmoid EQD2 D1cc Sigmoid EQD2 D2cc Bladder EQD2 D0.1cc Bladder EQD2 D1cc Bladder EQD2 D2cc

1

2

3

4

5

Mean

71.76 107.20 4522.99 3718.08 2556.43 104.22 85.43 78.09 98.45 69.15 60.72 169.18 112.61 94.66

85.86 113.76 4491.74 3406.68 1972.71 105.80 88.50 81.72 99.77 83.25 76.92 154.47 117.97 104.77

82.43 106.61 4612.24 3310.77 1644.26 93.98 79.43 74.71 79.37 65.80 61.67 63.03 56.10 53.11

73.17 97.40 4161.75 2822.09 1562.65 119.50 96.01 88.85 83.97 70.38 64.13 94.91 76.52 69.32

90.76 143.99 4617.46 4430.28 3360.40 107.41 89.78 83.54 69.29 60.43 56.98 112.80 87.77 79.51

80.80 113.79 4481.23 3537.58 2219.29 106.18 87.83 81.38 86.17 69.80 64.08 118.88 90.19 80.27

BED ¼ biologically equivalent dose; CTV ¼ clinical target volume; D90% ¼ dose to the hottest 90%; D100% ¼ dose to the hottest 100%; D0.1cc ¼ dose to the hottest 0.1 cc; D1cc ¼ dose to the hottest 1 cc; D2cc ¼ dose to the hottest 2 cc; EQD2 ¼ equivalent dose in 2-Gy fractions; HR ¼ high risk; V100% ¼ volume receiving 100% of the prescription dose; V150% ¼ volume receiving 150% of the prescription dose; V200% ¼ volume receiving 200% of the prescription dose.

part due to variability in detecting and reporting lowgrade toxic effects, but some additional factors warrant consideration. Early in the implementation of HDR brachytherapy for locally advanced cervical cancer, there was much controversy regarding the risks of toxic effects when compared with LDR brachytherapy.10–13 Most of the debate has centered on the radiobiological differences between HDR and LDR brachytherapy, with concerns that HDR brachytherapy would have higher rates of normal tissue injury. In a comparison of LDR and HDR techniques, Ferrigno et al14 found that late rectal toxic effects (all grades) were reduced from 16% with LDR brachytherapy to 8% with HDR brachytherapy (P ¼ 0.03). Notably, one patient (0.8%) in the HDR group died of uncontrolled rectal hemorrhage. Small-bowel toxic effects did not differ between groups (4.6% in the LDR group and 8.9% in the HDR group).14 In contrast, Chen et al15 reported a 29.7% rate of late rectal toxic effects, with 74% of these toxic effects being grade 1 in severity.15 Most other studies report Z5-year rectal toxic effect

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rates in the 10% to 20% range, with most toxic effects (approximately 80%) composed of grade 1 to 2 adverse effects, leaving an approximately 2% to 4% risk of severe late GI toxic effects.16–22 A recent comparative review by the Cochrane Database found that rectal and bladder toxic effects were no different after HDR or LDR brachytherapy but that HDR brachytherapy was associated with a small increase in the risk of bowel toxic effects.22 At our institution, considering the 85 patients treated with tandem and ovoid HDR brachytherapy for locally advanced cervical cancer between mid-2011and 2013, the 5 patients approximate a 5.8% rate of severe late GI toxic effects at our institution. In the literature, sigmoid and small-bowel toxic effects are less common than rectal toxic effects, but it is difficult to attribute GI toxic effects to a specific organ, and sigmoid or small-bowel complications may be grouped together with rectal toxic effects when reported.4,16,23 Sigmoid grade 2 to 4 toxic effects have been reported at rates of 3%16 and 2.1%.17 Smallbowel toxic effects have been reported at a slightly

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D.M. Trifiletti et al. higher rate of 8.9%14 and 10%.18 Notably, these numbers are small and difficult to draw meaningful conclusions from, considering that modern series incorporate intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy when treating paraaortic nodal basins. In a large review of factors related to toxic effects after cervical brachytherapy, Eifel et al24 reported on the results of 3489 patients and found rectal and small-bowel major complication rates of 3.2% and 4.2%, respectively. In their series, major complication was defined as a toxic effect that led to transfusion, hospitalization, surgery, or death or one that was not controlled with opioids and/or other medical management as identified by medical record review. Factors that predict adjacent organ damage from the treatment of cervical cancer can be largely grouped into 4 components. These components include baseline patient factors, systemic therapy, EBRT, and brachytherapy details.

BASELINE PATIENT FACTORS Several reports have reported that diabetes mellitus,25,26 tobacco use,24,25 hypertension,26 age,15,21 and history of pelvic inflammatory disease27,28 are associated with complications related to definitive radiotherapy in the treatment of cervical cancer. These factors are similar to those reported for radiotherapy morbidity in the treatment of prostate cancer.29 The largest report of patient factors related to cervical cancer treatment toxic effects came from a report from the MD Anderson Cancer Center in 2002.24 They investigated 3489 patients for late bladder, rectal, and small-bowel major complications and looked for correlating factors, including race, tobacco use, body mass index, age, diabetes, hypertension, and history of gynecologic infections, such as pelvic inflammatory or venereal disease. On multivariate analysis, they found that late major rectal toxic effects were more common among patients with a body mass index o22, African Americans, and current smokers (particularly 41 pack per day). Small-bowel toxic effects were more common in smokers and less common in Hispanics. A history of prior gynecologic infection increased the risk of having a major complication, but a history of hypertension or diabetes mellitus did not predict for late toxic effects. Notably, all patients were treated with LDR brachytherapy in their series.24

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It is generally accepted that age, diabetes mellitus, tobacco use, pelvic inflammatory disease, and hypertension contribute to late rectal toxic effects after radiotherapy. Of these, only tobacco use was prevalent among our described institutional cohort of late rectal complications (4 of 5 patients).

SYSTEMIC THERAPY In modern US practice, 480% of patients with locally advanced cervical cancer receive chemotherapy as a component of their treatment,30 with cisplatin as the generally recommended drug if tolerated.3 Although cisplatin concurrent with radiotherapy can increase the risk of acute toxic effects, it is generally not thought to contribute to late grade 3 or 4 GI or genitourinary complications. As an example, late toxic effects were similar (12% and 13%) between the chemoradiotherapy and radiotherapy alone arms of Radiation Therapy Oncology Group trial 90-01.31 A review of multiple trials on the effect of chemotherapy on late toxic effects was published in 2006.13 Regarding delivery of chemotherapy with respect to brachytherapy, general practice recommendations advise against brachytherapy and cisplatin administration on the same day for fear of increased normal tissue toxic effects by radiosensitization.3 In our series, all patients received concurrent chemotherapy in combination with radiation therapy.

EXTERNAL BEAM RADIOTHERAPY In a report from 1988, Stryker et al32 noted increased rectal toxic effects associated with an EBRT dose 450 Gy and recommended EBRT doses between 40 and 45 Gy when paired with 2 intracavitary LDR brachytherapy insertions. This EBRT dose has remained fairly stable over time, with current American Brachytherapy Society (ABS) guidelines noting 45 Gy in 25 fractions (1.8 Gy per fraction) as a recommended option in combination with brachytherapy.3 Extrapolating from a series in endometrial cancer, there is evidence that a 4-field box pelvic technique reduces late toxic effects when compared with 3-field or parallel-opposed photon techniques.33 This finding suggests that more conformal and homogeneous EBRT techniques may minimize the risk of toxic effects. Patients with clinical parametrial or nodal involvement commonly receive an EBRT boost in addition to pelvic EBRT and brachytherapy. There are sparse data

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Clinical Therapeutics comparing the effect of these boosts on GI toxic effects. Although the boost volume should have minimal overlap with the brachytherapy volume via a midline block or similar technique, a parametrial boost may increase the risk of late toxic effects. Huang et al18 evaluated the clinical outcomes of 203 patients who received a parametrial EBRT boost and found that a cumulative EBRT dose 454 Gy predicted for higher risk of enterocolitis (26%) and proctitis (17%) at 5 years. A similar study suggested 59 Gy as a cumulative EBRT limit, but results were not statistically significant.19 IMRT offers a technical advancement that may limit dose to bowel. However, given the proximity of the rectum to the cervix, it is unlikely that the cumulative volume of rectum exposed to high radiation doses would be reduced despite potential reduction in mean dose. Randomized clinical trials of IMRT versus other forms of EBRT have not been reported for the definitive treatment of locally advanced cervical cancer, but there are several early studies (including some prospective trials) that have reported favorable toxicity profiles with the use of IMRT.34–37 IMRT probably provides its greatest benefit by reducing small-bowel dose and dose inhomogeneity, particularly in patients who receive para-aortic nodal irradiation.36,38–40 In the era of costconscious medicine, however, any increase in cost of treatment must be met with a convincing improvement in clinical outcomes.41 In our series, 4 of 5 patients received whole pelvic radiotherapy using 3D conformal technique (4-field box). One patient received IMRT with extended field for para-aortic nodal irradiation.

BRACHYTHERAPY DETAILS After proper patient selection, quality brachytherapy begins with appropriate applicator selection. There is currently no preference given to any one applicator over the other, although proper placement and immobilization are critical with the chosen applicator.42 Current consensus remains that either tandem and ovoid or tandem and ring applicators provide adequate coverage in most cases,42 and the Vienna ring and tandem applicator43 or a similar combined intracavity and interstitial approach can permit improved target coverage without exceeding OAR doses in technically challenging cases.42 Several devices exist to physically separate the rectum from the high-dose volume by vaginal packing, balloon, or

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paddle. Although these devices are effective at lowering rectal dose, care should be taken to avoid displacement of the ring or ovoids and compromising anterior or posterior cervical target coverage. Several studies have found that proper applicator placement is critical to target coverage and acceptable dose to OARs,43–45 and a current ABS consensus statement includes step-by-step recommendations for applicator insertion.42 As previously stated, when intracavitary applicators provide inappropriate dose to OARs or inadequate target coverage, an interstitial implant can improve conformality.42 Interstitial cervical brachytherapy poses many technical challenges46,47 and should only be performed at centers with a volume high enough to ensure clinical expertise.42 On the basis of recent practice survey results,30 o1% of patients reviewed received interstitial brachytherapy as a component of their treatment, down from 7.8% in 1999. This finding could be due to improvements in intracavitary brachytherapy or EBRT technique, although the authors raise the point that physician inexperience and lack of comfort could also contribute to the decision to avoid brachytherapy in general. To this end, the brachytherapy portion of therapy should be limited to centers with adequate volume and expertise in these advanced technologies.3,5,45 Even among these centers, considerable interphysician variability exists in terms of target contouring and optimization.5 Dose and fractionation schedules vary among institutions, with no single schedule recommended over another.42 Some data suggest that 6 Gy in 5 fractions may result in increased toxic effects, but reported follow-up is relatively short in this group.48 Current ABS guidelines provide several acceptable schedules; notably, all are paired with an EBRT dose of 45 Gy in 25 fractions42 and provide a D90 of 480 Gy (EQD2). Individualized brachytherapy dosing is accepted, ranging from 5 to 6 Gy per fraction (total of 5 fractions), based on residual tumor volume at the time of brachytherapy.42 Some modern MRI-based series suggest that a higher total D90 dose (87 Gy, EQD2) predicts for improved local control.49 Modern facilities ultimately confirm proper applicator placement with 3D imaging by CT or MRI. All patients in our series had an in-room CT performed immediately after applicator placement with minimal patient movement, confirming appropriate position. Despite this, severe GI damage still occurred. Although proper applicator placement can minimize

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D.M. Trifiletti et al. dose to OARs and improve target coverage, it cannot prevent late toxic effects if normal tissue tolerances are not respected.

Total Cumulative Dose There have been several single-institution series reporting clinical outcomes after HDR brachytherapy for cervical cancer and proposing cumulative dose recommendations to reduce GI and genitourinary toxic effects.15–18,21,23,42 These recommendations and associated outcomes are listed in Table III. As previously discussed, sigmoid colon toxic effects are difficult to isolate, and there are no evidence-based recommendations for cumulative dose, although current ABS guidelines recommend similar constraints as for the rectum (D2cc o75 Gy in EQD2).42 Georg et al17 reported on 141 patients with cervical cancer treated at the Medical University of Vienna, with a median follow-up of 51 months. They found that the most import predictor of late rectal toxic effects was the D2cc and that D1cc and D0.1cc did not provide clinically meaningful additional information. In a separate study, however, their group

correlated the physical location of D0.1cc receiving the highest dose to mucosal ulcerations on the anterior rectal wall on endoscopy.50 A study by Koom et al23 followed up 71 patients treated with definitive chemoradiotherapy with a flexible sigmoidoscopy every 6 months for 2 years and then as needed afterward for symptoms. Their primary end point was mucosal changes by sigmoidoscopy. They found that a cumulative biological effective dose threshold of 125 and an EQD2 of 75 reliably predicted for mucosal changes, a threshold proposed by other groups based on clinical outcomes.21 In our series, rectal D2cc was 475 Gy (EQD2) for 4 of 5 patients with severe late toxic effects. Sigmoid D2cc was 475 Gy in 1 of 5 patients. One patient was treated twice daily, and the biologic effect of this strategy is not reflected in our calculations. Four of the 5 patients developed severe toxic effects within 1 year of brachytherapy.

Preventative Therapies and Management GI toxic effect prevention strategies generally focus primarily on careful patient selection, radiation dose

Table III. Proposed cumulative rectal dose recommendations, with associated source. Cumulative Dose Recommendation Source Chen et al15 Huang et al18 Hyun Kim et al21

BED ICRURP ICRURP ICRURP ICRURP ICRURP ICRURP

o110 4110 o100 Z100 o125 Z125

EQD2 Gy Gy Gy Gy Gy Gy

Koom et al23

D2cc o75 Gy D2cc 475 Gy D2cc o75 Gy

Georg et al17 ABS HDR consensus guidelines42 Current series median

D2cc Z73 Gy D2cc r75 Gy D2cc: 81.72 Gy

Georg et al16

BED: 104.3 Gy†

Late Toxic Effects* 19% 36% 4% 17% 5.4 36.1% 5% 20% Defined by grade Z2 endoscopic mucosal damage 10% …

ABS ¼ American Brachytherapy Society; BED ¼ biologically equivalent dose; D2cc ¼ dose to the hottest 2 cc; EQD2 ¼ equivalent dose in 2-Gy fractions; HDR ¼ high dose rate; ICRURP ¼ International Commission on Radiation Units and Measurements Rectal Point. * Toxic effect grades included vary among series. † Determined by rectal dose to the hottest 0.1 cc not ICRURP.

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Clinical Therapeutics and fractionation selection, brachytherapy technique, and IMRT. However, there are other potential medical approaches that have been explored as a means of preventing GI toxic effects from pelvic radiotherapy. For example, amifostine, which is a potential radioprotectant medication, has been evaluated in clinical trials for this indication. A study of prophylactic amifostine included 53 male and female patients with pelvic malignant tumors (11 with cervical cancer), but the study was not structured to detect the effect of amifostine against conservative management, and definitive conclusions are difficult to draw.51 Several cervical cancer–specific trials investigating amifostine have been published,52,53 but a clear and consistent benefit has yet to be found. Given that the dose-limiting toxic effect for amifostine is symptomatic hypotension, routine use of amifostine has been called into question.54 Regardless, the 2014 Multinational Association of Supportive Care in Cancer clinical practice guidelines recommend the use of intravenous amifostine at a dose of at least 340 mg/m2 to prevent radiation-induced proctitis.55 It is not clear what the rate of acceptance of this recommendation is among clinicians. Similar to amifostine, results are mixed regarding the use of rectal misoprostol56 and oral sucralfate57–59 in preventing late GI toxic effects, and they should not routinely be used as prophylactic therapy.55 Probiotic therapy may have a role in preventing GI toxic effects. Its optimal formulation remains to be seen, although most evidence exists for Lactobacillus species.55

The management of GI toxic effects after radiotherapy is highly patient specific. Typically, patients who develop severe toxic effects undergo endoscopy, and argon laser therapy at the time of endoscopy is an effective means of preventing rectal bleeding.60,61 Oral sulfasalazine, rectal corticosteroids, and rectal sucralfate have produced endoscopic improvement in proctosigmoiditis.62 Hyperbaric oxygen therapy also has produced promising results.63 In a study from 2002, Luna-Perez et al64 reported on 20 women with radiation-induced proctitis who received formalin instillation for symptom control (90% cervical cancer). Eighty-five percent of patients had immediate cessation of hemorrhage, with an overall 90% success rate. Notably, 25% of patients studied developed chronic pelvic pain, and 15% developed bowel necrosis that required colostomy or abdominoperineal resection.64 If conservative methods fail or the toxic effects are life threatening, definitive therapy includes surgical resection and possibly colostomy, while acknowledging that the adjacent bowel likely has some degree of microvascular damage and prolonged healing or anastomotic leaks are not uncommon.65 Indications for the surgical management of radiation-induced bowel injury have been described elsewhere.65 In our series of patients who developed severe GI toxic effects after treatment of locally advanced cervical cancer, 3 of 5 patients required permanent colostomies. One was for a bowel stricture, and 2 were for fistulae. The endoscopic and surgical findings

Figure. Endoscopic appearance (A) and gross specimen (B) of a sigmoid colon stricture and ulcer that developed in a patient who received definitive chemoradiation therapy for locally advanced cervical cancer. The patient underwent partial colectomy and colostomy. Review of her dosimetry revealed a sigmoid colon dose to the hottest 2 cc of 61.67 Gy. The arrows delineate the region of sigmoid colon injury following chemoradiation therapy.

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D.M. Trifiletti et al. for one of these patients are shown in the Figure. The remaining 2 patients developed severe rectal bleeding and were managed conservatively (Table I). Both these patients now have grade 1 proctitis. Although surgery plays a critical management role in the treatment of radiation injury, it should be viewed as a last resort when nonoperative measures fail.

CONCLUSIONS GI toxic effects pose a serious and sometimes lifethreatening risk in patients who receive definitive radiotherapy for locally advanced cervical cancer. Careful patient selection, EBRT technique, brachytherapy expertise, and cumulative dose-volume optimization are paramount in preventing late toxic effects. There are several medical therapies that are promising in the prevention and management of GI toxic effects, but it is likely that none will ever be as critical as the reduction of dose to OARs through improvements in radiotherapy technique. At our institution, we have incorporated several methods for reducing toxic effects associated with brachytherapy, including a record of cumulative dose to each OAR with each fraction of brachytherapy (accounting for EQD2 conversions), which is reviewed before plan approval for each fraction of brachytherapy and is part of the electronic medical record, and increased use of manual optimization of brachytherapy treatment plans to reduce dose to OARs. Our program has moved away from point A–based prescriptions to prioritize avoidance of normal tissue toxic effects, and treatment plans are instead prescribed to an isodose line after iterative treatment plan optimization. Furthermore, we are in the process of implementing MRI-based target volume delineation. These additional steps paired with advanced technology, such as IMRT, in-room CT simulation, and HDR optimization, are expected to contribute to decreased rates of late toxic effects. Our experience reveals the importance of continual quality improvement in the era of image-guided brachytherapy.

ACKNOWLEDGMENTS Dr. Trifiletti prepared the first draft of the manuscript. All authors contributed to the manuscript and approved the final version.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

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Address correspondence to: Timothy N. Showalter, MD, MPH, Department of Radiation Oncology, University of Virginia, 1240 Lee St, Box 800383, Charlottesville, VA 22908. E-mail: [email protected]

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