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Patient-reported Urinary, Bowel, and Sexual Function After Hypofractionated Intensity-modulated Radiation Therapy for Prostate Cancer: Results From a Randomized Trial

Hoffman, Karen, E., MD, MPH, MHSc; Skinner, Heath, MD, PhD; Pugh, Thomas, J., MD; Voong, Khinh, R., MD; Levy, Lawrence, B., MS; Choi, Seungtaek, MD; Frank, Steven, J., MD; Lee, Andrew, K., MD; Mahmood, Usama, MD; McGuire, Sean, E., MD, PhD; Schlembach, Pamela, J., MD; Du, Weiliang, PhD; Johnson, Jennifer, MS, MBA; Kudchadker, Rajat, J., PhD; Kuban, Deborah, A., MD

American Journal of Clinical Oncology: June 2018 - Volume 41 - Issue 6 - p 558–567
doi: 10.1097/COC.0000000000000325
Original Articles: Genitourinary

Objectives: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy.

Methods: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment.

Results: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains.

Discussion: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

Departments of Radiation Oncology and Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX

The authors declare no conflicts of interest.

Reprints: Karen E. Hoffman, MD, MPH, MHSc, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1202, Houston, TX 77030. E-mail: khofman1@mdanderson.org.

External beam radiation treatment is an important component of curative therapy for many patients with prostate adenocarcinoma. Clinical guidelines recommend administration of dose-escalated radiation therapy that improves prostate cancer control compared with lower dose radiation.1–4 However, dose-escalated radiation can take 9 weeks to complete when it is delivered with conventional fractionation (1.8 or 2 Gy per treatment). Hypofractionated prostate radiotherapy has the potential to deliver a higher biologically effective dose over a shorter period of time because the α/β ratio for prostate cancer is estimated to be low, approximately 1 to 3 Gy, indicating prostate cancer is more sensitive to radiation delivered with larger fractions.5–7 As the α/β ratio for prostate cancer is estimated to be equivalent or lower than the α/β ratio for adjacent normal tissues, in theory, delivery of fewer, larger radiation fractions can increase prostate cancer control without increasing toxicity. Shortening the duration of prostate radiation to 6 weeks using a moderate hypofractionation regimen (2.4 Gy per fraction) is more convenient for patients, decreases the cost of treatment, and may increase patient access to treatment.8,9

The exposure of tissues adjacent to the prostate to radiation including the rectum, prostatic urethra, bladder neck, and neurovascular bundles can cause urinary, bowel, and sexual symptoms that can impact health-related quality of life from the patient’s perspective. Data from institutional series and randomized trials suggest that delivery of prostate radiotherapy using a moderate hypofractionation regimen does not increase physician-assessed maximum urinary and bowel toxicity compared with conventionally fractionated prostate radiotherapy.10–12 However, patient’s self-assessment of symptoms after prostate cancer treatment can differ substantially from physician judgment.13 Patient-reported functional outcomes after moderate hypofractionation are lacking, therefore, we report patient-reported urinary, bowel, and sexual function after treatment on a randomized trial comparing dose-escalated hypofractionated prostate radiotherapy (72 Gy in 2.4 Gy fractions) to conventionally fractionated prostate radiotherapy (75.6 Gy in 1.8 Gy fractions) in men with localized prostate cancer.

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METHODS

Men with organ-confined prostate cancer were enrolled in an institutional review board–approved trial from January 2001 to January 2010, which randomized men to either a conventional fractionation regimen that delivered 75.6 Gy in 1.8 Gy fractions or to a dose-escalated moderate hypofractionation regimen that delivered 72 Gy in 2.4 Gy fractions. The moderate hypofractionaton regimen was biologically equivalent to delivering 85 Gy in 1.8 Gy, assuming an α/β ratio of 1.5 Gy for prostate cancer. Therefore, the hypofractionation regimen delivered a higher biologically effective dose than the conventional fractionation regimen.

Eligible patients had biopsy-proven prostate adenocarcinoma, good performance status (Zubrod <2), clinical tumor stage (cT) T1b-T3b disease (1992 AJCC staging system), PSA≤20, Gleason score <10, and no clinical, radiographic, or pathologic evidence of nodal or bone metastasis.11 Men were stratified at randomization by PSA (≤10 vs. >10 ng/mL), stage (cT1b-T2 vs. cT3a-b), Gleason score (≤7 vs. 8-9), and receipt of neoadjuvant androgen deprivation therapy (yes vs. no).

All men were treated with step-and-shoot intensity-modulated radiation therapy (IMRT) with daily prostate localization as previously described.11 The treatment target was the prostate and proximal seminal vesicles. Lymph nodes were not treated. The protocol recommended that for men treated on the conventional fractionation arm the proportion of rectum and proportion of bladder receiving 70 Gy be <20% and for men treated on the hypofractionation arm the proportion of rectum and proportion of bladder receiving 65 Gy be <20%; however, these constraints were not met in some patients. Nine men treated with conventional fractionation had ≥20% of the rectum receiving 70 Gy and 19 men treated with hypofractionation had ≥20% of the rectum receiving 64.6 Gy. Seven men treated with conventional fractionation had ≥20% of the bladder receiving 70 Gy and 9 men treated with hypofractionation had ≥20% of the bladder receiving 64.6 Gy.

Internally developed self-administered questionnaires designed to assess problems incurred by men treated with radiation therapy for localized prostate cancer were completed pretreatment (Supplemental Digital Content 1, http://links.lww.com/AJCO/A138), 2 years after treatment (Supplemental Digital Content 2, http://links.lww.com/AJCO/A139) and 3, 4, and 5 years after treatment (Supplemental Digital Content 3, http://links.lww.com/AJCO/A140). The questionnaires evaluated urinary, bowel, and sexual function. For each item, patients were instructed to mark the statement that best described their level of function.

After completion of radiotherapy, per protocol, men were seen at least every 6 months for the first 2 years and then annually. Physician-assessed toxicity was evaluated at each follow-up visit. Late genitourinary and gastrointestinal toxicity, starting 90 days after completion of radiotherapy, is reported utilizing modified Radiation Therapy Oncology Group (RTOG) toxicity grading (Supplemental Digital Content 4, http://links.lww.com/AJCO/A141).14

Descriptive statistics were generated to characterize the study cohort. Patients who completed the questionnaires were compared with those who did not complete them. Respondents in the conventional and hypofractionation arms were compared at each time point. For questions asked in both the pretreatment and posttreatment questionnaires, change in function from baseline to follow-up timepoint was categorized as decline, same, or improvement from baseline as outlined in Supplemental Digital Content 5 (http://links.lww.com/AJCO/A142). Distribution of patient-reported urinary and bowel function was compared with physician-assessed toxicity (categorized as grade <2 or ≥2). Fisher exact test and χ2 statistic were used to evaluate categorical variables. Wilcoxon-Mann-Whitney test and t test were used to compare continuous variables. For all analyses, to adjust for multiplicity while accounting for the correlated nature of the items, an α=0.01 was used when testing individual questions. An α=0.05 was used when testing all other comparisons. All data were analyzed with SAS (v9.2 for Windows; SAS Institute, Cary, NC).

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RESULTS

A total of 101 of 111 men randomized to the conventional fractionation arm and 101 of 111 men randomized to the hypofractionation arm completed treatment as planned and were alive at least 90 days after completion of radiation treatment for evaluation of late toxicity. One man allocated to 75.6 Gy actually received 72 Gy. Therefore, 203 men were eligible for analysis of late effects of treatment, 101 men who received conventional radiotherapy and 102 men who received hypofractionated radiotherapy (Supplemental Digital Content 6, http://links.lww.com/AJCO/A143).

A total of 185 (91%) out of 203 eligible patients completed at least 1 questionnaire. Pretreatment questionnaire compliance was 85% and then was consistently lower throughout follow-up; 50%, 48%, 35%, and 32% of patients completed assessments at 2, 3, 4, and 5 years, respectively. Completion was similar between arms at each time point (Supplemental Digital Content 7, http://links.lww.com/AJCO/A144). Patient demographics, tumor characteristics, receipt of androgen deprivation therapy, and maximum physician-assessed toxicity grade were not significantly different between those who did and did not complete any questionnaires (P>0.05). Thus, a missing at random mechanism can be assumed and minimal bias anticipated.

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Patient Characteristics and Baseline Patient-reported Function

The majority of analyzable patients had T1 disease (73%), Gleason 7 disease (65%), PSA<10 ng/mL (90%), and did not receive androgen deprivation therapy (76%). The median age was 67 years. Ninety-one of the 173 patients who completed the baseline questionnaire received hypofractionated radiation therapy. Patient demographics and clinical characteristics were well balanced between treatment arms at baseline (Table 1, P>0.05) and were well balanced between treatment arms for respondents at 2, 3, 4, and 5-year time points (P>0.05).

TABLE 1

TABLE 1

Pretreatment urinary and bowel function was well balanced between treatment arms (Table 2, P>0.01). Before radiation, 20% of all patients reported a problem with dripping or leaking urine, 6% reported getting up ≥4 times to urinate, 7% reported occasional hematuria, and 21% reported occasional or frequent burning with urination. Only 1% had ≥4 bowel movements per day, 4% were concerned because bowel movements were urgent, and 3% were not able to control bowel movements without accidents. Sexual function was also well balanced between treatment arms before radiation (Table 2, P>0.01), with 29% of men reporting erections usually or always firm enough to have intercourse and 46% reporting full erections when stimulated.

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

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Effect of Hypofractionation on Patient-reported Function

Urinary and bowel function reported by men 2 years after treatment with hypofractionated radiation therapy was similar to function reported by men treated with conventional fractionation (Table 2, P>0.01). Two years after treatment with hypofractionated radiation, 24% of men reported a problem with dripping or leaking urine, 4% reported getting up ≥4 times at night to urinate, 5% reported occasional hematuria, 18% reported occasional burning with urination, 4% had ≥4 bowel movements per day, 17% were concerned because bowel movements are urgent, and 4% were not able to control bowel movements without accidents. Similarly 2 years after treatment with conventional radiation, 17% of men reported a problem with dripping or leaking urine, 7% reported getting up ≥4 times at night to urinate, 9% reported occasional hematuria, 14% reported occasional burning with urination, 3% had ≥4 bowel movements per day, 12% were concerned because bowel movements are urgent, and 9% were not able to control bowel movements without accidents. Sexual function reported by men 2 years after treatment with hypofractionated radiation therapy was also similar to function reported by men treated with conventional fractionation (Table 2, P>0.01). About 36% of men treated with hypofractionation and 30% of men treated with conventional fractionation reported erections usually or always firm enough to have intercourse.

Urinary, bowel, and sexual function reported by men 3, 4, and 5 years after treatment with hypofractionated radiation therapy was also similar to function reported by men treated with conventional fractionation (Table 2, P>0.01).

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Change in Patient-reported Function After Hypofractionation

At 2 years after treatment, men treated with hypofractionation and men treated with conventional fractionation reported similar changes in urinary and bowel function from baseline (Table 3, P>0.01). Men treated with hypofractionation and men treated with conventional fractionation also reported similar changes in urinary and bowel function from baseline at 3, 4, and 5 years after treatment (Table 3, P>0.01).

TABLE 3

TABLE 3

TABLE 3

TABLE 3

TABLE 3

TABLE 3

At 2 years after treatment, men treated with hypofractionation and men treated with conventional fractionation reported similar changes in sexual function from baseline (Table 3, P>0.01). There was a nonsignificant numeric difference in decline in frequency of achieving erections firm enough for intercourse over time between men treated with hypofractionation and men treated with conventional fractionation. At 4 years, 58% of men treated with hypofractionation reported a decline in frequency of achieving erections firm enough for intercourse compared with 32% of men treated with conventional fractionation (P=0.05). At 5 years, 63% of men treated with hypofractionation reported a decline in frequency of achieving erections firm enough for intercourse compared with 36% of men treated with conventional fractionation (P=0.07). An analysis of the subset of men who did not receive androgen deprivation therapy demonstrated a similar nonsignificant numeric difference in decline in frequency of achieving erections firm enough for intercourse 4 and 5 years after treatment.

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Concordance Between Physician-assessed Toxicity and Patient-reported Function

Among the 185 men evaluable for patient-reported function, 13 had grade 2 or higher maximum GI toxicity by physician assessment and 22 had grade 2 or higher maximum GU toxicity by physician assessment (Table 1).

Men with grade 2 or higher physician-assessed gastrointestinal toxicity were more likely to report concern that bowel movements were urgent 2 (P=0.001) and 3 (P=0.004) years after treatment and were more likely to report blood with bowel movements 2 (P=0.003) through 5 (P<0.001) years after treatment (Supplemental Digital Content 8, http://links.lww.com/AJCO/A145). There was no association between grade 2 or higher physician-assessed gastrointestinal toxicity and patient-reported ability to control bowel movements without accidents, use of antidiarrheal pills, or number of bowel movements (Supplemental Digital Content 8, http://links.lww.com/AJCO/A145).

Men with grade 2 or higher physician-reported genitourinary toxicity were more likely to report problems of dripping or leaking urine (P=0.005) at 4 years. There was no association between grade 2 or higher physician-reported genitourinary toxicity and patient-reported nocturia, dysuria, or hematuria (Supplemental Digital Content 8, http://links.lww.com/AJCO/A145).

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DISCUSSION

In this prospective randomized trial, administration of dose-escalated hypofractionated prostate IMRT (72 Gy in 2.4 Gy fractions) did not increase patient-reported late urinary, bowel, or sexual symptom burden compared with conventionally fractionated prostate IMRT (75.6 Gy in 1.8 Gy fractions). There also was no significant difference in change in patient-reported late urinary, bowel, or sexual function from baseline at 2 though 5 years after treatment between the 2 treatment groups. Men with grade 2 or higher gastrointestinal toxicity by physician assessment were more likely to report concern that bowel movements were urgent and blood with bowel movements, whereas men with grade 2 or higher genitourinary toxicity by physician assessment were more likely to report problems of dripping or leaking urine. There was no association between grade 2 or higher physician-assessed toxicity and other patient-reported urinary and bowel functional domains.

Because the α/β ratio for prostate cancer is estimated to be equivalent or lower than the α/β ratio for adjacent normal tissues, in theory, using a moderately hypofractionated regimen that delivers fewer, larger radiation treatments can increase the effective radiation dose to the prostate without increasing toxicity.5–7 Clinical trials that evaluate hypofractionated prostate radiation treatment regimens often depend on physician evaluation of genitourinary and gastrointestinal toxicity. We previously reported that this moderately hypofractionated regimen did not increase physician-assessed grade 2 or higher genitourinary or gastrointestinal toxicity.11 Similar to our trial, the Fox Chase randomized trial found no difference in grade 2 or higher physician-assessed late toxicity in men who received a similar hypofractionated radiation (70.2 in 2.7 Gy fractions) compared with men who received conventionally fractionated radiation (76 Gy in 2 Gy fractions).12 Other trials evaluating alternative moderate hypofractionationated regimens (3 and 3.1 Gy fractions) also found no increase in physician-assessed late toxicity.15,16

Although studies suggest delivery of prostate radiotherapy using moderate hypofractionation does not increase physician-assessed late urinary and bowel toxicity, there are limited data on patient-reported functional outcomes. Men treated with hypofractionated radiation on the Fox Chase randomized trial reported less bowel symptoms than men treated with conventional fractionation17 and men treated with hypofractionation on this trial did not report increased bowel or urinary symptom burden. It is essential to consider outcomes from the patient’s perspective because patient self-assessment can differ substantially from the physician’s judgment.13,18,19 It is also important to evaluate functional outcomes after treatment over time because changes in urinary, bowel, and sexual function can occur several years after completion of radiation treatment.20,21

In this study, concordance between physician-assessed toxicity and patient-reported function varied across urinary and bowel domains. Physician-assessed gastrointestinal toxicity was scored by modified RTOG toxicity grading, which classifies men as having grade 2 or higher toxicity if they have received coagulations or steroids for bleeding, take antidiarrheals, use incontinence pads, or take narcotics for pain. It was not surprising that grade 2 or higher physician-assessed gastrointestinal toxicity was associated with patient-reported rectal bleeding, as nearly all men were assigned grade 2 or higher toxicity by physicians because of rectal bleeding.11 However, physician-assessed gastrointestinal toxicity was not associated with patient-reported ability to control bowel movements without accidents, use of antidiarrheal pills, or number of bowel movements. Therefore, patient-reported bowel function provided more detail and insight about patient experience after prostate radiation than the physician-assigned numeric toxicity score. Physician-assessed genitourinary toxicity was scored by modified RTOG toxicity grading, which classifies men as having grade 2 or higher toxicity if they have at least intermittent macroscopic hematuria, at least moderate frequency or nocturia, have required coagulations or blood transfusion, or take medicines for pain. Grade 2 or higher physician-assessed genitourinary did not reflect most of the patient-reported urinary domains including nocturia, dysuria, or hematuria. The fact that provider assessment of genitourinary and gastrointestinal toxicity correlated with only some aspects of patient-reported symptom burden in this trial highlights the importance of assessing patient-reported outcomes (PROs) in prostate cancer trials.

Although not statistically significant, men treated with hypofractionation were almost twice as likely to report a decrease in ability to achieve erections firm enough for intercourse at 4 and 5 years after treatment. Our ability to assess the impact of dose-escalated hypofractionated radiation on late sexual function was limited by the fact that 25% of men enrolled in the trial were impotent at baseline (unable to achieve an erection firm enough for intercourse) and by the fact that <40% of patients completed the 4 and 5 year questionnaires. It is important to keep in mind that the trial was designed as a dose-escalation study. Assuming an α/β ratio of 1.5 Gy for prostate cancer, the hypofractionated regimen evaluated in this study is biologically equivalent to delivering 85 Gy in 1.8 Gy fractions, which is considerably higher than the 75.6 Gy in 1.8 Gy fractions administered to men in the conventionally fractionated arm. The α/β ratio for the penile bulb is not well defined and this protocol did not specify penile bulb dose constraints. Previous studies have demonstrated that increased radiation dose to the penile bulb is associated with increased risk of erectile dysfunction after radiation therapy.22

Some patients enrolled in the trial did not complete the symptom questionnaires. It is possible that there are insufficient data to detect clinically meaningful differences between the treatment groups. There were some nonsignificant numeric differences in patient-reported function between the treatment groups. We previously reported that men with larger prostate size who receive more moderate to high-dose radiation to the anterior rectal wall are at increased risk of physician-reported gastrointestinal toxicity and the Fox Chase group reported that men with more urinary symptoms before treatment were at increased risk of physician-reported urinary toxicity.11,12 RTOG 0415 is a randomized cooperative group trial comparing moderate hypofractionation (70 Gy in 2.5 Gy fractions) to conventional fractionation (73.8 Gy in 41 fractions) delivered with 3D-conformal or IMRT in men with favorable-risk prostate cancer. Patient-reported urinary, bowel, and sexual function are being assessed by the Expanded Prostate Cancer Index Composite (EPIC). The results of RTOG 0415 will provide additional information about PROs after hypofractionated prostate radiation.

There are several points that deserve further consideration. First, the outcomes are from a single institution and only 1 hypofractionated regimen was analyzed. Second, some patients enrolled in the trial did not complete the symptom questionnaires. Patients seemed to be missing at random, but there may have been unaccounted differences between patients in the 2 treatment groups. Third, the study was designed in the 1990s before the EPIC and other PRO indices were commonly used in clinical trials. However, the questionnaires used in this study do assess 4 of the 5 domains recommended by the National Cancer Institute Symptom Management and Health-Related Quality of Life Steering Committee for localized prostate cancer: urinary incontinence, urinary obstruction and irritation, bowel-related symptoms, and sexual dysfunction.23 The questionnaires did not assess the fifth domain, hormonal symptoms; however, this study was not evaluating hormonal treatment. The questionnaires have good face validity and the wording for many questions is similar to the wording of questions in the validated EPIC questionnaire. Fourth, although we report toxicity outcomes for this trial, long-term cancer control rates are as yet forthcoming so at present readers cannot interpret the toxicity outcomes within the context of prostate cancer control for this dose-escalated hypofractionated regimen.

In conclusion, it seems that dose-escalated IMRT using a moderate hypofractionation regimen (72.0 Gy in 2.4 Gy fractions) can be delivered safely without adversely impacting urinary or bowel function from the patient’s perspective. However, it is possible that insufficient data were collected to detect clinically meaningful differences between the treatment groups. Patient-reported function provided more detail and insight about patient experience after prostate radiation than the physician-assigned numeric toxicity score. Additional research is needed to determine whether hypofractionated radiation adversely impacts long-term sexual function from the patient’s perspective relative to conventional fractionation.

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Keywords:

prostate cancer; radiation therapy; hypofractionation; patient-reported outcomes

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