Patient-reported quality of life during definitive and postprostatectomy image-guided radiation therapy for prostate cancer

    Patient-reported quality of life during definitive and post-prostatectomy image-guided radiation therapy for prostate cancer Kevin Diao BA, Emily A. Lobos, Eda Yirmibesoglu MD, Ram Basak PhD, Laura H. Hendrix MS, Brittney Barbosa BS, Seth M. Miller MD, Kevin A. Pearlstein MD, Gregg H. Goldin MD, Andrew Z. Wang MD, Ronald C. Chen MD, MPH PII: DOI: Reference:

S1879-8500(16)30154-0 doi: 10.1016/j.prro.2016.08.004 PRRO 660

To appear in:

Practical Radiation Oncology

Received date: Revised date: Accepted date:

14 April 2016 5 August 2016 8 August 2016

Please cite this article as: Diao Kevin, Lobos Emily A., Yirmibesoglu Eda, Basak Ram, Hendrix Laura H., Barbosa Brittney, Miller Seth M., Pearlstein Kevin A., Goldin Gregg H., Wang Andrew Z., Chen Ronald C., Patient-reported quality of life during definitive and post-prostatectomy image-guided radiation therapy for prostate cancer, Practical Radiation Oncology (2016), doi: 10.1016/j.prro.2016.08.004

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Patient-reported quality of life during definitive and post-prostatectomy image-guided radiation therapy for prostate cancer

RI P

T

Kevin Diao, BA1,3;* Emily A. Lobos1;* Eda Yirmibesoglu, MD; Ram Basak, PhD1; Laura H. Hendrix, MS1; Brittney Barbosa, BS1; Seth M. Miller, MD1; Kevin A Pearlstein, MD1; Gregg H. Goldin, MD1; Andrew Z. Wang, MD1; Ronald C. Chen, MD, MPH1,2 1

Department of Radiation Oncology, University of North Carolina at Chapel Hill, NC, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, 3Harvard Medical School, Boston, MA

NU

SC

2

MA

*contributed equally

Running title: Prostate cancer therapy quality of life

ED

Please send communications and reprint requests to:

AC

CE

PT

Ronald C. Chen, MD MPH Department of Radiation Oncology University of North Carolina at Chapel Hill 101 Manning Drive, CB #7512 Chapel Hill, NC 27516 Tel: 984-974-8428 Fax: 984-974-8607 E-mail: [email protected] CONFLICT OF INTEREST NOTIFICATION None of the authors report any conflict of interest. Word count: 1945

1

ACCEPTED MANUSCRIPT ABSTRACT Purpose: The importance of patient-reported outcomes is well-recognized. Long-term patient-

T

reported symptoms have been described for individuals who completed radiation therapy (RT)

RI P

for prostate cancer. However, the trajectory of symptom development during the course of treatment has not been well-described in patients receiving modern, image-guided RT.

SC

Methods and Materials: Quality of life data were prospectively collected for 111 prostate

NU

cancer patients undergoing radiotherapy using the validated Prostate Cancer Symptom Indices, which assessed 5 urinary obstructive/irritative and 6 bowel symptoms. Patients who received

MA

definitive radiotherapy (N=73) and post-prostatectomy radiotherapy (N=38) were analyzed separately. The frequency and severity of symptoms over multiple time points are reported.

ED

Results: An increasing number of patients had clinically-meaningful urinary and bowel

PT

symptoms over the course of radiotherapy. A greater proportion of patients undergoing definitive RT reported clinically-meaningful urinary symptoms at the end of RT compared to baseline in

CE

terms of flow (33% vs 19%) and frequency (39% vs 18%). Individuals receiving post-

AC

prostatectomy radiation also reported an increase in symptoms including frequency (29% vs 3%) and nocturia (50% vs 21%). Clinically-meaningful bowel symptoms were less commonly reported. Patients receiving definitive RT reported an increase in diarrhea (9% vs 4%) and urgency (12% vs 6%) at the completion of radiotherapy compared to baseline. Both bowel and urinary symptoms approached their baseline levels by the time of first follow-up after treatment completion. The majority of patients who had clinically-meaningful urinary or bowel symptoms during RT did not have them at 2 years or beyond, and development of new symptoms long-term was uncommon.

2

ACCEPTED MANUSCRIPT Conclusions: There is a modest increase in urinary and bowel symptoms over the course of treatment for individuals receiving definitive and post-prostatectomy image-guided radiotherapy.

T

These data can help inform both providers and patients regarding the trajectory of symptoms and

AC

CE

PT

ED

MA

NU

SC

RI P

allow for reasonable expectations regarding toxicity under treatment.

3

ACCEPTED MANUSCRIPT INTRODUCTION Patient-reported health-related quality of life (QOL) is increasingly recognized as an

T

important outcome measure after cancer treatment [1, 2]. While physician-assessed toxicity data

RI P

are valuable and traditionally considered a gold standard, multiple published studies have consistently demonstrated that physicians underestimate the frequency and severity of treatment-

SC

related symptoms compared to patient report [3-5]. For example, a study by Chen et al compared

NU

patient-reported symptoms and physician-assessed toxicity in 77 consecutive patients receiving concurrent chemoradiation therapy for rectal cancer; patients with the same grade level of

MA

diarrhea as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) had wide ranges of patient-reported diarrhea severities using a validated QOL instrument [4].

ED

Because treatment-related side effects are an important part of the patient decision-making

PT

process, it is important to have research that fully and accurately captures this information. In recent years, numerous studies have documented patient-reported symptoms after

CE

external beam radiation therapy (RT) for prostate cancer [6-9]. For the most part, these QOL

AC

studies have concentrated on long-term symptoms after RT; further, most studies included patients who received older forms of radiotherapy and may not reflect outcomes of modern patients. Symptom development during treatment, using modern intensity-modulated radiotherapy (IMRT) with image-guidance, is not well-described. While acute urinary and gastrointestinal (GI) symptoms are expected during RT, especially toward the end of the treatment course, the timing and severity of symptom development is unknown. Data on symptom trajectory and severity can assist physicians in counseling patients prior to treatment, ultimately allowing patients to make better informed decisions.

4

ACCEPTED MANUSCRIPT Within XXXX institution, QOL using a validated instrument[10] is prospectively captured during weekly treatment visits as part of the routine clinical work-flow. The goal of this

T

study is to describe the trajectory of patient-reported urinary and GI symptom development

SC

definitive or post-prostatectomy image-guided IMRT.

RI P

during the course of radiotherapy for patients, analyzed separately for patients who received

NU

Materials and Methods

Overall, 111 patients who received IMRT for prostate cancer at XXXX institution

MA

between 2010 and 2013 were included in this analysis. The cohort included 73 patients who received definitive RT and 38 who received post-prostatectomy RT. All patients received IMRT

ED

with image guidance.

PT

In general, image guidance for intact prostate radiotherapy used the Calypso® transponder system, and RT started 2-3 weeks after transponder placement. Treatment target was

CE

the prostate and seminal vesicles to 45 Gy, followed by prostate boost to a total dose of 75-79

AC

Gy. Margin expansions were 8-10 mm circumferentially, except posteriorly which was 3-5 mm. For post-prostatectomy RT, cone beam CT was used for image guidance; no fiducial markers were placed. Treatment target was the prostate bed, and standard prescription dose was 66.6 Gy. Margin expansions were 5 mm circumferentially. Among patients analyzed in this study, postprostatectomy RT was started at a median of 19 months following surgery (range 4 months to 12 years), and this included both adjuvant RT and salvage RT. Patients were treated in the supine position, and pelvic irradiation was not routinely used in definitive or post-prostatectomy RT at our institution. For patients who received RT along with androgen deprivation therapy (ADT),

5

ACCEPTED MANUSCRIPT ADT consisted of LHRH agonist with an anti-androgen for definitive RT, usually starting about 6-8 weeks before RT. For salvage treatment, LHRH agonist was used without anti-androgen.



Rectum: D10cc < 70Gy.

RI P

Bladder: mean bladder dose < 40Gy

SC



T

Dose constraints used were consistent across both types of patients, and included

These goals are consistently met at our institution, and no additional bladder or rectal dose

NU

constraints were used.

Quality of life data were collected prospectively. Patients completed the Urinary

MA

Obstruction/Irritation and Bowel Problems scales of the validated Prostate Cancer Symptom Indices[10] before starting RT, weekly during treatment visits, and at first follow-up which

ED

occurred within 6 months after treatment completion. Briefly, the symptom questions were rated

PT

on a Likert scale of 1 to 4 or 5, where 1 signified “not at all,” 2 signified “occasionally,” 3 signified “fairly frequently,” 4 signified “frequently,” and 5 signified “very frequently.” Based

CE

on prior methodologic work, a score of ≥3 represented clinical significance/meaningfulness [9,

AC

11, 12]. The five questions assessing urinary obstructive/irritative symptoms were: 1. In the past week, how easy has your urine flow been? (Urine flow)
 2. In the past week, how often did you urinate at night? (Nocturia) 3. In the past week, how often did you urinate? (Frequency) 4. In the past week, how often have you felt pain or burning during urination? (Dysuria) 5. In the past week, how often did you have the feeling that it is urgent to pass your urine? (Urgency) The six questions assessing bowel symptoms were: 1. In the past week, have you had diarrhea or loose watery stools? (Diarrhea)


6

ACCEPTED MANUSCRIPT 2. In the past week, have you had a sense of urgency that you move your bowels? (Urgency) 3. In the past week, have you had any tenderness or pain when you move your bowels?

T

(Rectal Pain)

RI P

4. In the past week, have you had bleeding with your bowel movements? (Bleeding) 5. In the past week, have you had abdominal cramping or pain? (Cramping)

SC

6. In the past week, have you had the urge to move your bowels, but had nothing to pass?

NU

(Tenesmus)

MA

This analysis included patients who completed QOL surveys at baseline, during treatment, and at a follow-up within 6 months of completing radiation treatment. Descriptive

ED

statistics were used to report the frequency and severity of individual urinary and bowel

PT

symptoms at each assessment time point. Analysis was performed separately for patients who received definitive RT, and for those who received post-prostatectomy RT. Statistical

CE

significance in the change of symptom severity from the last week of RT vs. baseline, and from

AC

follow-up vs. last week of RT, was assessed using the paired t-test. To explore whether patients who developed clinically meaningful symptoms (vs. those who did not) were more likely to have these symptoms long-term, we performed an additional analysis for the subgroup of 75 patients who had QOL data at 2 years or beyond, and examined each symptom separately. Due to limited sample size, patients who received definitive RT and post-prostatectomy RT were combined. The first QOL data point available at 2 years or beyond was used for this analysis. Statistical significance between groups was assessed using the McNemar’s test. The XXXXX Institution Review Board approved this study.

7

ACCEPTED MANUSCRIPT RESULTS Table 1 summarizes the patient and clinical characteristics of the 73 definitive RT and 38

T

post-prostatectomy RT patients. For definitive RT patients, median age was 67 years, median

RI P

radiation dose 79 Gy, and 92% received concurrent ADT. For post-prostatectomy RT patients, median age was 65 years, median radiation dose 66.6 Gy, and 55% received concurrent ADT.

SC

Table 2 presents individual urinary symptoms at different time points from before to after

NU

radiation treatment. Except for urinary urgency, the mean scores for each symptom progressively increased from baseline throughout the treatment course, with resolution by follow-up. For

MA

definitive RT patients, there was a statistically significant worsening from Baseline to Week 8 in urinary flow, nocturia, frequency, and dysuria; change from Week 8 compared to baseline was

ED

0.4-0.6 points on the 4-5 point Likert scale. All symptoms resolved to baseline levels by follow-

PT

up. Presented in another way (Figure 1), the proportion of patients who reported clinicallymeaningful symptoms (score ≥3) related to urinary flow increased from 17.8% (baseline) to

CE

32.8% (Week 8); nocturia 68.1% to 79.1%; frequency 17.8% to 38.8%, and dysuria 8.2% to

AC

25.4%. Importantly, a sizable proportion of patients had each of these urinary symptoms at baseline (prior to radiation treatment). For post-prostatectomy patients, there was a statistically significant worsening from Baseline to Week 7 in nocturia, frequency, and dysuria (Table 2); as well as significant improvement of these symptoms by follow-up (p<.05 for each symptom). The magnitude of symptom change for nocturia, frequency and dysuria from Week 7 compared to baseline was 0.4-0.6 points on the 4-5 point Likert scale. The proportions of patients who reported clinicallymeaningful nocturia increased from 21.1% (baseline) to 50.0% (Week 7); frequency from 2.7% to 29.4%; and urgency from 13.2% to 20.6% (Figure 1).

8

ACCEPTED MANUSCRIPT Table 3 presents individual bowel symptoms at different time points from before to after radiation treatment. Relative to the urinary symptoms scores, the magnitude of scores for bowel

T

symptoms is lower, and a small proportion of patients report bowel symptoms at baseline and

RI P

throughout the treatment course. For definitive RT patients, there were no statistically significant differences in mean scores comparing Week 8 to Baseline in diarrhea, urgency, rectal pain,

SC

bleeding, cramping, and tenesmus (Table 3). The proportion of patients reporting clinically

NU

meaningful bowel symptoms was also low, even during the last week of treatment (Figure 2) [12]. Diarrhea increased from 4.1% of patients at baseline to 9.0% in Week 8, urgency increased

MA

from 5.5% to 11.9%, and rectal pain from 5.5% to 9.0%.

Development of bowel symptoms in post-prostatectomy RT patients was similarly

ED

uncommon.

PT

To explore whether patients who had clinically-meaningful symptoms during RT were also more likely to have symptoms long-term, we performed an additional analysis for the

CE

subgroup of 75 patients who had data at 2 years or beyond. Only a small proportion of patients

AC

who reported clinically-meaningful urinary (Table 4) and bowel (Table 5) symptoms during RT continued to report this beyond 2 years. The only exception is nocturia (51.8% of patients who had this symptom during RT reported this long-term). Further, among patients who did not report clinically-meaningful symptoms during RT, development of symptoms long-term was uncommon – except nocturia (35.3%). Comparing patients who did vs. did not have symptoms during RT, the former group was more likely to have symptoms long-term in all eleven items assessed.

9

ACCEPTED MANUSCRIPT DISCUSSION This study presents the results of prospectively collected patient-reported outcomes of

T

acute urinary and bowel symptoms during receipt of modern definitive and post-prostatectomy

RI P

radiation therapy for prostate cancer. It describes the frequency, severity, and time course of 11 individual symptoms using a validated prostate cancer-specific QOL instrument. This study is

SC

unique because it describes in detail acute side effect development during the radiation treatment

NU

course, fulfilling a current knowledge gap because most of the published literature has focused on long-term QOL outcomes without capturing weekly changes during the treatment course.

MA

Therefore, this study provides important, patient-centered information which can be used to counsel patients about possible expectations of experiences during radiation therapy. Further,

ED

this study is unique in describing patient QOL effects from modern radiation therapy, with each

PT

patient treated by IMRT and daily image-guidance. This is in contrast to the published literature which consists of mostly QOL studies of patients treated with older radiation technologies. We

CE

found one prior published study which has documented symptom change during prostate cancer

AC

radiation treatment[9]. However, the authors acknowledged that their study was limited by patients treated in an older era using three-dimensional conformal radiation therapy to 72 Gy without image-guidance. Another recent publication reported the acute and late urinary toxicity in patients treated on prospective trials RTOG 94-08 (intact prostate) and RTOG 96-01 (prostate bed) using 2D- or 3D-confomal radiotherapy techniques[20]. Thus, results from these prior studies likely do not accurately represent patients treated today. Patient-reported QOL is becoming increasingly important in assessing the tolerance and effectiveness of various treatments [1-5]. There is a growing body of literature showing a discrepancy between physician-reporting and patient-reporting of their treatment-related side

10

ACCEPTED MANUSCRIPT effects, with physician reporting often under-capturing the prevalence and severity of toxicity [13, 14]. Thus, this study which recorded patient-reported outcomes prospectively during each

T

patient’s treatment course may more accurately capture patient experience.

RI P

Several important findings emerged from this study. One, baseline urinary symptoms are prevalent before prostate cancer patients start radiation therapy. For patients who received

SC

definitive RT, 68% reported clinically-meaningful nocturia at baseline, and 18-27% reported

NU

difficulty with flow, frequency and urgency. This is not surprising because elderly men can often have benign prostatic hypertrophy, which can cause these symptoms. These findings highlight

MA

the importance of prospectively capturing QOL, including baseline data, so that changes in patient symptoms attributable to radiation treatment can be ascertained. In general, baseline

ED

urinary obstructive and irritative symptoms were less commonly reported among post-

PT

prostatectomy individuals: no patient reported difficulty with urinary flow at baseline, while 13% reported urgency and 21% nocturia.

CE

Second, we documented changes in individual urinary and bowel symptoms during the

AC

treatment course. Indeed, there was a modest worsening of urinary symptoms from baseline to the last week of radiation treatment. For definitive RT patients, flow, nocturia, frequency and dysuria worsened – by an average of 0.4-0.6 points on a 4-5 point Likert scale. Figure 1 presents the findings in another way which can be used to counsel patients: comparing Week 8 to baseline, between 11.0 to 21.0% of patients developed each of these urinary symptoms to a clinically-meaningful level. Further, all symptoms resolved to baseline within 6 months after treatment. For post-prostatectomy RT patients, nocturia, frequency, and dysuria also worsened modestly, by an average of 0.4-0.6 points from Baseline to Week 7. In terms of prevalence, the proportions of patients who developed clinically-meaningful symptoms during the treatment

11

ACCEPTED MANUSCRIPT course were 29% (nocturia), 27% (frequency) and 12% (dysuria). These symptoms also improved during follow-up within 6 months, but not yet to baseline. In addition, urinary

T

symptoms were more commonly reported among patients receiving definitive RT than post-

RI P

prostatectomy treatment. This is expected as the symptoms assessed in this study related to urinary obstruction and irritation. However, a limitation of this study is that urinary incontinence

SC

was not assessed, and these symptoms would be expected to be more prevalent in post-

NU

prostatectomy patients [15].

Third, modern radiotherapy has relatively minimal impact on acute GI symptoms; data

MA

from this study compare favorably to published data of older treatment technologies [16,17]. For definitive radiotherapy given to a median dose of 79 Gy, average scores for each of the 6

ED

measured GI symptoms were not significantly different between Baseline and Week 8. In post-

PT

prostatectomy radiotherapy, rectal pain and bleeding scores were slightly higher at the end of treatment compared to baseline. Of note, pelvic radiotherapy was not standardly performed at

CE

our institution, and only 6 patients received pelvic radiotherapy – and in general this is done at

AC

our institution for patients with node positive disease. Given the small numbers of patients, it was not possible to assess whether these 6 patients experienced more bowel symptoms compared to the other patients. Overall, findings from this study of modern radiotherapy stand in sharp contrast to common patient and physician perceptions regarding the GI morbidity caused by radiation treatment for prostate cancer [18,19]. Lastly, the vast majority of patients who developed clinically-meaningful urinary or bowel symptoms during RT had resolution of symptoms long-term, and few patients (who did not report symptoms during RT) developed new clinically-meaningful symptoms. However,

12

ACCEPTED MANUSCRIPT longer-term follow-up is necessary to further evaluate development of late effects beyond 2

T

years.

RI P

Conclusions

In summary, we characterized the patient-reported urinary and GI symptoms at baseline,

SC

weekly during treatment, and at follow-up in a cohort of prostate cancer patients who received

NU

IMRT with image guidance. This study provides new information for both patients and physicians, which can be helpful during the treatment counseling and decision-making process.

MA

Indeed, these patient-reported outcomes stand in contrast to perceptions about radiation-related

AC

CE

PT

ED

morbidity from an older era.

13

ACCEPTED MANUSCRIPT REFERENCES 1. Sloan JA, Berk L, Roscoe J, et al. Integrating patient-reported outcomes into cancer

RI P

clinical trials networks. J Clin Oncol 2007;25(32):5070-7.

T

symptom management clinical trials supported by the National Cancer Institute-sponsored

SC

2. Wagner LI, Wenzel L, Shaw E, et al. Patient-reported outcomes in phase II cancer clinical trials: lessons learned and future directions. J Clin Oncol 2007;25(32):5058-62.

NU

3. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med 2010;362(10):865-9.

MA

4. Chen RC, Mamon HJ, Chen YH, et al. Patient-reported acute gastrointestinal symptoms during concurrent chemoradiation treatment for rectal cancer. Cancer 2010;116(8):1879-86.

ED

5. Flores LT, Bennett AV, Law EB, et al. Patient-Reported Outcomes vs. Clinician Symptom

2012;5(4):119-24.

PT

Reporting During Chemoradiation for Rectal Cancer. Gastrointest Cancer Res

CE

6. Conaglen HM, de Jong D, Hartopeanu C, et al. The effect of high dose rate brachytherapy in

AC

combination with external beam radiotherapy on men's health-related quality of life and sexual function over a 2 year time span. Clin Oncol (R Coll Radiol) 2013;25(3):197-204. 7. Denham JW, Wilcox C, Joseph D, et al. Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial. Lancet Oncol 2012;13(12):1260-70. 8. Frank SJ, Pisters LL, Davis J, et al. An assessment of quality of life following radical prostatectomy, high dose external beam radiation therapy and brachytherapy iodine

14

ACCEPTED MANUSCRIPT implantation as monotherapies for localized prostate cancer. J Urol 2007;177(6):2151-6; discussion 2156.

T

9. Chen RC, Zhang YY, Chen MH, et al. Patient-reported quality of life during radiation

RI P

treatment for localized prostate cancer: results from a prospective phase II trial. BJU International 2012;110(11):1690-1695.

SC

10. Clark JA, Talcott JA. Symptom indexes to assess outcomes of treatment for early prostate

NU

cancer. Med Care 2001;39(10):1118-30.

11. Talcott J, Clark J, Manola J, et al. Bringing prostate cancer quality of life research back to

MA

the bedside: translating numbers into a format that patients can understand. J Urol 2006;176(4):1558-64

ED

12. Chen RC, Clark JA, Talcott JA. Individualizing Quality-of-Life Outcomes Reporting: How

PT

Localized Prostate Cancer Treatments Affect Patients With Different Levels of Baseline Urinary, Bowel, and Sexual Function. Journal of Clinical Oncology 2009;27(24):3916-3922.

CE

13. Goldner G, Wachter-Gerstner N, Wachter S, et al. Acute side effects during 3-D-planned

AC

conformal radiotherapy of prostate cancer. Differences between patient's self-reported questionnaire and the corresponding doctor's report. Strahlenther Onkol 2003;179(5):320-7. 14. Stephens RJ, Hopwood P, Girling DJ, et al. Randomized trials with quality of life endpoints: are doctors' ratings of patients' physical symptoms interchangeable with patients' self-ratings? Qual Life Res 1997;6(3):225-36. 15. Sanda MG, Dunn RL, Michalski J et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. New Engl J Med 2008; 358(12):1250 16. Tsai HK, Manola J, Abner A, et al. Patient-reported acute gastrointestinal toxicity in men receiving 3-dimensional conformal radiation therapy for prostate cancer with or without

15

ACCEPTED MANUSCRIPT neoadjuvant androgen suppression therapy. Urologic Oncology-Seminars and Original Investigations 2005;23(4):230-237.

T

17. Pinkawa M, Fischedick K, Asadpour B, et al. Health-related quality of life after adjuvant and

RI P

salvage postoperative radiotherapy for prostate cancer - A prospective analysis. Radiotherapy and Oncology 2008;88(1):135-139.

SC

18. Lesperance RN, Kjorstadt RJ, Halligan JB, et al. Colorectal complications of external beam

NU

radiation versus brachytherapy for prostate cancer. American Journal of Surgery 2008;195(5):616-620.

MA

19. Kim S, Shen SH, Moore DF, et al. Late Gastrointestinal Toxicities Following Radiation Therapy for Prostate Cancer. European Urology 2011;60(5):908-16.

ED

20. Mak RH, Hunt D, Efstathiou JA, et al. Acute and late urinary toxicity following radiatoin in

PT

men with an intact prostate gland or after a radical prostatectomy: a secondary analysis of

AC

CE

RTOG 94-08 and 96-01. Urol Oncol 2016;ePub ahead of print.

16

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC

RI P

T

Figure 1: Proportion of patients who reported clinically-meaningful (score ≥3) urinary symptoms over time among individuals receiving definitive radiation (top) and postprostatectomy radiation (bottom) Abbreviations: RT, radiation therapy; post-RP, post-prostatectomy radiation therapy. *Week 7 is the last week of RT for post-prostatectomy radiation therapy patients. †Week 8-9 is the last week of RT for definitive radiation therapy patients.

Figure 2: Proportion of patients who reported clinically-meaningful (score ≥3) bowel symptoms over time among individuals receiving definitive radiation (top) and post-prostatectomy radiation (bottom) Abbreviations: RT, radiation therapy; post-RP, post-prostatectomy radiation therapy; std, standard deviation. *Week 7 is the last week of RT for post-prostatectomy radiation therapy patients. †Week 8-9 is the last week of RT for definitive radiation therapy patients

17

ACCEPTED MANUSCRIPT Table 1: Demographic and clinical characteristics

MA

T

RI P

NU

13 (17.8) 31 (42.5) 27 (37.0) 2 (2.7)

Post-Prostatectomy RT (N=38) (N, %) 65 (47-79)

SC

32 (43.8) 32 (43.8) 8 (11.0)

7 (18.4) 27 (71.1) 2 (5.3) 4 (10.5) 14 (36.8) 18 (47.4) 1 (2.6) 2 (5.3) 20 (52.6) 10 (26.3)

67 (91.8) 5 (6.9) 79 (45-80.02)

21 (55.3) 15 (39.5) 66.6 (45-66.6)

ED

2 (2.7) 37 (50.7) 33 (45.2)

CE

PT

Age at RT, years (median, range) Race African American Caucasian Other Year of RT 2010 2011 2012 2013 Risk group Low Intermediate High Concurrent androgen deprivation therapy Yes No Median Radiation dose delivered, Gy (range)

Definitive RT (N=73) (N, %) 67 (53-85)

AC

Abbreviations: RT, radiation therapy.

18

ACCEPTED MANUSCRIPT Table 2: Urinary symptom scores over time for definitive RT and post-prostatectomy RT patients Wee k2

Wee k3

Wee k4

Wee k5

Wee k6

Wee k 7*

Mean (std)

Mea n (std)

Mea n (std)

Mea n (std)

Mea n (std)

Mea n (std)

Mea n (std)

1.9 (1.0) 1.1 (0.3)

1.9 (1.1) 1.1 (0.4)

2.0 (1.0) 1.1 (0.3)

1.8 (0.9) 1.1 (0.2)

2.0 (0.9) 1.1 (0.3)

2.8 (1.0) 2.2 (0.8)

2.9 (0.9) 2.3 (0.9)

3.0 (0.8) 2.4 (0.9)

3.2 (0.9) 2.2 (1.0)

1.9 (0.7) 1.7 (0.6)

2.1 (0.8) 1.9 (0.7)

2.1 (0.8) 2.0 (0.8)

1.6 (1.0) 1.2 (0.7) 2.1 (1.0) 1.8 (0.8)

2.1 (1.1) 1.2 (0.6)

2.1 (1.0)

<.0.001

1.1 (0.3)

…

0.74

3.2 (0.9) 2.4 (1.1)

3.1 (0.9) 2.5 (1.0)

3.1 (0.8)

<.0.001

…

<0.001

2.2 (0.8) 1.9 (0.7)

2.3 (0.9) 2.1 (1.0)

2.3 (0.9) 2.1 (0.9)

2.3 (0.8)

0.005

…

0.003

1.7 (1.1) 1.1 (0.4)

1.7 (1.0) 1.2 (0.8)

1.9 (1.1) 1.4 (1.0)

1.8 (1.0) 1.5 (1.0)

2.0 (1.2)

<0.001

…

0.006

2.3 (1.1) 2.0 (1.0)

2.2 (1.3) 1.9 (0.9)

2.4 (1.3) 2.0 (1.0)

2.4 (1.1) 2.0 (1.0)

2.2 (1.2)

0.27

…

0.13

1.9 (0.8)

Frequenc y Definitive RT Post-RP

1.9 (0.8) 1.7 (0.5)

Dysuria

Post-RP

1.0 (0.2)

Urgency

1.4 (1.0) 1.1 (0.3)

CE

1.4 (0.8)

AC

Definitive RT

Definitive RT

2.2 (1.2)

Post-RP

1.8 (0.9)

ED

Post-RP

PT

2.7 (0.9)

2.1 (1.0) 1.6 (0.8)

MA

Nocturia Definitive RT

SC

Post-RP

RI P

(Last week of RT vs. Baseline )

NU

1.7 (0.8)

p-value

Mea n (std)

Flow Definitive RT

Wee k 8-9†

T

Baselin e

Follow -Up

p-value

Mean (std)

(Follow -Up vs. Last week of RT)

1.5 (0.7) 1.1 (0.5) 2.6 (0.9) 2.2 (0.8)

1.8 (0.7) 1.9 (0.9) 1.6 (1.1) 1.2 (0.8) 2.1 (1.1) 1.8 (0.9)

<0.001 0.32

<0.001 0.03

<0.001 0.2

0.03 0.03

0.06 0.13

Abbreviations: RT, radiation therapy; post-RP, post-prostatectomy radiation therapy; std, standard deviation. Flow, dysuria, and urgency questions were scored from 1 (not at all) to 5 (very frequently). Nocturia and frequency questions were scored from 1 (not at all) to 4 (very frequently). *Week 7 is the last week of RT for post-prostatectomy radiation therapy patients. †Week 8-9 is the last week of RT for definitive radiation therapy patients.

19

ACCEPTED MANUSCRIPT Table 3: Bowel symptom scores over time for definitive RT and post-prostatectomy RT patients

Rectal Pain Definitive RT Post-RP Bleeding Definitive RT Post-RP Cramping Definitive RT Post-RP Tenesmus Definitive RT Post-RP

Wee k6

Wee k7

Mean (std)

Mea n (std)

Mea n (std)

Mea n (std)

Mea n (std)

Mea n (std)

Mea n (std)

1.3 (0.7) 1.3 (0.5)

1.4 (0.8) 1.4 (0.6)

1.6 (0.9) 1.4 (0.7)

1.5 (0.9) 1.4 (0.7)

1.5 (0.8) 1.5 (0.9)

1.6 (0.9) 1.5 (0.9)

1.4 (0.8) 1.6 (0.8)

1.4 (0.9) 1.6 (0.8)

1.5 (1.0) 1.5 (0.8)

1.6 (0.8) 1.4 (0.6)

1.4 (0.8) 1.5 (0.9)

1.2 (0.7) 1.2 (0.7)

1.1 (0.4) 1.2 (0.6)

1.2 (0.5) 1.2 (0.8)

1.1 (0.5) 1.2 (0.6)

1.1 (0.2) 1.2 (0.6)

1.0 (0.1) 1.1 (0.2)

1.0 (0.2) 1.2 (0.6)

Wee k 8-9†

p-value

T

Wee k5

(Last week of RT vs. Baseline )

1.4 (0.8 1.6 (0.9)

1.5 (0.9)

0.23

…

0.12

1.5 (0.9) 1.6 (0.9)

1.4 (0.8) 1.6 (0.9)

1.7 (0.9)

0.12

…

0.61

1.3 (0.7) 1.4 (0.8)

1.3 (0.7) 1.3 (0.7)

1.2 (0.6) 1.3 (0.8)

1.4 (0.9)

0.14

…

0.02

1.1 (0.4) 1.1 (0.6)

1.1 (0.3) 1.2 (0.6)

1.1 (0.5) 1.1 (0.4)

1.0 (0.2) 1.4 (0.9)

1.1 (0.3)

0.26

…

0.04

SC

NU

MA

RI P Mea n (std)

ED

Post-RP

Wee k4

PT

Urgency Definitive RT

Wee k3

CE

Post-RP

Wee k2

AC

Diarrhe a Definitive RT

Baselin e

1.2 (0.8) 1.2 (0.5)

1.3 (0.7) 1.2 (0.4)

1.3 (0.6) 1.3 (0.5)

1.2 (0.5) 1.2 (0.4)

1.3 (0.7) 1.4 (0.7)

1.2 (0.5) 1.4 (0.8)

1.3 (0.7) 1.4 (0.9)

1.2 (0.7)

1

…

0.21

1.4 (0.6) 1.2 (0.5)

1.3 (0.6) 1.2 (0.4)

1.4 (0.8) 1.3 (0.6)

1.4 (0.8) 1.1 (0.4)

1.3 (0.6) 1.3 (0.6)

1.3 (0.5) 1.2 (0.5)

1.2 (0.5) 1.3 (0.6)

1.4 (0.8)

0.89

…

0.6

Follow -Up

p-value

Mean (std)

(Follow -Up vs. Last week of RT)

1.4 (0.7) 1.2 (0.5) 1.5 (0.9) 1.3 (0.5) 1.3 (0.8) 1.3 (0.7) 1.1 (0.4) 1.1 (0.3) 1.2 (0.5) 1.3 (0.8) 1.3 (0.5) 1.2 (0.5)

Abbreviations: RT, radiation therapy; post-RP, post-prostatectomy radiation therapy; std, standard deviation. All questions were scored from 1 (not at all) to 5 (very frequently). *Week 7 is the last week of RT for post-prostatectomy radiation therapy patients. †Week 8-9 is the last week of RT for definitive radiation therapy patients.

20

0.19 0.02

0.46 0.03

0.12 0.08

0.44 0.09

0.74 0.1

0.3 0.21

ACCEPTED MANUSCRIPT Table 4: Number of patients with long-term urinary symptoms by whether they developed acute symptoms during treatment Clinically meaningful symptom at ≥24mo N(%)

T

Clinically meaningful symptom during treatment

RI P

Flow Yes (N=27) No (N=46) Nocturia Yes (N=56) No (N=17) Frequency Yes (N=28) No (N=45) Dysuria Yes (N=27) No (N=46) Urgency Yes (N=30) No (N=43)

p-value <.001

SC

4 (14.8) 3 (6.5)

<.001

NU

29 (51.8) 6 (35.3) <.001

ED

MA

7 (25.0) 2 (4.4) 1 (3.7) 0 (0) <.001 8 (26.7) 1 (2.3)

AC

CE

PT

Total N added to different numbers due to rare missing data on some items.

21

<.001

ACCEPTED MANUSCRIPT Table 5: Number of patients with long-term bowel symptoms by whether they developed acute symptoms during treatment Clinically meaningful symptom at ≥24mo N(%)

T

Clinically meaningful symptom during treatment

RI P

Diarrhea Yes (N=17) No (N=57) Urgency Yes (N=19) No (N=55) Rectal pain Yes (N=18) No (N=56) Bleeding Yes (N=17) No (N=57) Cramping Yes (N=18) No (N=56) Tenesmus Yes (N=16) No (N=57)

p-value <.001

SC

1 (5.9) 1 (1.8)

<.001

NU

3 (15.8) 1 (1.8) <.001

ED

MA

1 (5.6) 3 (5.4) <.001

1 (5.9) 0 (0) <.001 1 (5.6) 1 (1.8) <.001

PT

1 (6.3) 0 (0)

AC

CE

Total N added to different numbers due to rare missing data on some items.

22

Figure 1

AC

CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

23

Figure 2

AC

CE

PT

ED

MA

NU

SC

RI P

T

ACCEPTED MANUSCRIPT

24