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Patient-reported Quality of Life After Proton Beam Therapy for Prostate Cancer: The Effect of Prostate Size
Accepted Manuscript Patient Reported Quality of Life Following Proton Beam Therapy for Prostate Cancer: The Impact of Prostate Size Anuj Goenka, Neil B. Newman, Hiral Fontanilla, Oren Cahlon, Brian Chon, Henry Tsai, Eugen Hug, C. Brown, Carlos Vargas, Rahul R. Parikh PII:
S1558-7673(17)30067-8
DOI:
10.1016/j.clgc.2017.03.005
Reference:
CLGC 806
To appear in:
Clinical Genitourinary Cancer
Received Date: 18 January 2017 Revised Date:
10 March 2017
Accepted Date: 10 March 2017
Please cite this article as: Goenka A, Newman NB, Fontanilla H, Cahlon O, Chon B, Tsai H, Hug E, Brown C, Vargas C, Parikh RR, Patient Reported Quality of Life Following Proton Beam Therapy for Prostate Cancer: The Impact of Prostate Size, Clinical Genitourinary Cancer (2017), doi: 10.1016/ j.clgc.2017.03.005. 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.
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Patient Reported Quality of Life Following Proton Beam Therapy for Prostate Cancer: The Impact of Prostate Size
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Anuj Goenka1, Neil B. Newman1, Hiral Fontanilla2, Oren Cahlon2, Brian Chon2, Henry Tsai2, Eugen Hug2, C. Brown2, Carlos Vargas2, Rahul R. Parikh3
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Department of Radiation Medicine, Northwell Health, New Hyde Park, NY
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Department of Radiation Oncology, Princeton Radiation Oncology.
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Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ,
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Running Title: Impact of Prostate Size on QOL following PBT
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Anuj Goenka, M.D. Attending Physician Department of Radiation Medicine North-Shore LIJ Health Systems Email: [email protected] Phone: 212-434-2919 Fax 212-434-2445
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Microabstract
INTRODUCTION
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This study assesses the impact of prostate gland size on patient assessed quality of life (QOL) following definitive treatment for prostate adenocarcinoma with proton beam therapy. Larger Prostate sizes, despite receiving greater radiation doses did not affect QOL at six months, which further supports unnecessary neoadjuvant cytoreductive treatments.
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Prostate cancer is the leading non-dermatological cancer and the second most common cause of cancer death in US males, with an estimated 233,000 new cases and 29,480 estimated deaths in 2014 [1]. Radiation therapy is one of the conventional curative treatment options for localized prostate adenocarcinoma. Proton beam therapy (PBT) is a highly conformal radiation therapy modality that has been shown to have
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dosimetric advantages of delivering lower doses to nearby organs at risk when compared to 3D conformal or intensity-modulated radiotherapy (IMRT) [2].
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There has been an increasing focus on toxicity outcomes when evaluating contemporary methods of treating prostate cancer. Early dose escalation studies that
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have incorporated PBT found that modern radiation doses were not associated with an increase in patient-reported symptoms [3]. Additional studies have suggested PBT may be associated with decreased rates of rectal and genitourinary toxicity, though long-term outcomes continue to be controversial [4-6]. It also remains unclear whether there is a specific subset of patients with prostate cancer in which PBT may be of increased benefit. An area we have been increasingly interested in is the role of PBT in patients with large prostate glands that are receiving dose-escalated radiotherapy. In this setting, pre-
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treatment prostate size has been shown to correspond with increased toxicity [7-9]. Aizer et al reported that patients with prostate size >50cc’s had significantly higher rates of acute genitourinary toxicity, but follow-up was limited to assess for late toxicity [10].
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Pinkawa et al studied patients with small prostates (11–43 cc’s) and large prostates (44– 151 cc’s), and found that the patients with larger prostates had more bothersome urinary symptoms pretreatment and on the last day radiation therapy. Given these concerns, it
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has been advocated that patients with large prostate glands be treated with neoadjuvant
androgen deprivation treatment [7, 8, 11]. It has been shown that with this approach, the
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volume of the bowel and bladder that receives high dose can be reduced, thereby improving the therapeutic ratio by reducing the potential morbidity of treatment [11, 12]. Given the favorable dosimetric profile of PBT over other contemporary modalities [2], we have not routinely prescribed androgen deprivation treatment for the purpose of
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cytoreduction. Instead, ADT is prescribed strictly based on the NCCN risk group. The aim of this study was to examine the effect of pretreatment prostate volume on proton dosimetry and the resulting post-treatment urinary and bowel quality of life. This study
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was performed on a series of consecutively enrolled men on an institutional protocol using prospectively completed EPIC questionnaires both pre-treatment and at time of
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follow up.
PATIENTS AND METHODS
Patient Selection
As part of an ongoing prospective clinical trial sponsored by the Proton Collaborative Group, Evaluation Tracking Project: A prospective Chart Review of Patients Treated with Proton Therapy REG001-09, patients treated for prostate
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adenocarcinoma with definitive proton beam therapy (PBT) completed an Expanded Prostate Cancer Index Composite questionnaire (EPIC) both pre-treatment and at time of follow-up. Between January 2012 and November 2013, eighty-one patients were
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identified at our single institution that were enrolled on this protocol and had reviewable EPIC completed both pre-treatment and at follow-up. The medical records for these
patients were reviewed and clinical, dosimetric, and quality of life data recorded. Risk
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group stratification was performed as per NCCN guidelines. Pre-treatment prostate size was calculated for all patients by prostate MRI, if performed within two weeks of
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simulation, or CT at time of simulation. Prostate size was calculated in accordance with spherical volume and simplified by multiplying the length, width, and height by π/6. Prostate size was categorized into three pre-defined groups: <30 cc; 30-49cc; and ≥50cc.
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Treatment Planning and Delivery
Simulation and treatment planning techniques were performed per departmental guidelines based on NCCN defined risk groups. Gold fiducial marker placement into the
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prostate was performed using ultrasound guidance prior to simulation. All patients underwent CT simulation in the supine position with a full bladder. Routine policy was
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to place 100 cc of rectal saline at time of simulation and daily prior to treatment. MRI obtained in the treatment position for staging and treatment planning purposes was fused with CT when available. For low risk patients, the clinical tumor volume (CTV-1) was defined as the prostate alone and was treated to a dose of 79.2 Gy (RBE). A relative biologic effectiveness (RBE-factor) of 1.1 of protons was assumed. For intermediate risk disease, CTV-1 was defined as the prostate and proximal seminal vesicles and was
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treated to 54 Gy followed by a boost to CTV-2, defined as the prostate alone, to 79.2 Gy. For high risk patients, CTV-1 was defined as the prostate, seminal vesicles +/- the pelvic lymph nodes, and was treated to 45 Gy, followed by a boost to CTV-2to 79.2 Gy. All
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treatments were delivered in 1.8 Gy fractions. Typically equally weighted lateral beams were utilized, treated with either one beam or two beams a day. All patients were treated with 3D-proton beam therapy using uniform scanning technology as described elsewhere
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review and again for evaluation of treatment plan.
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[13]. Each case was peer-reviewed prior to initiation of treatment, once for contour
Data Collection & Statistical Analysis
The rectum was contoured as the outer wall of the rectum from the rectosigmoid junction to the bottom of the ischial tuberosities. RectalEval was a structure representing
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a segment of the rectum limited to 1 cm of the PTV. Dosimetric values including PTV V98, Rectal V70, RectalEval V50, Bladder V80, and Bladder V70 were recorded.
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The EPIC-50 questionnaires were completed prospectively by all patients. We reviewed the American Urological Association Symptom Index (AUA score), EPIC-
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urinary domain score (UDS), and EPIC-GI domain score (GDS). Patient-reported outcomes were calculated according to the instrument instructions as validated by Wei et al [14]. Urinary bother was defined by question 14 of the UDS, which quantifies patient’s perception of urinary function during the previous four weeks. GI bother was defined by question 30 of the GDS, which similarly quantifies patient’s perception of bowel habits during the previous four weeks. To assess for patient-specific changes, we
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assessed the change in individual responses at 6 months post-treatment from baseline for each of the three tools. Differences in quality of life and dosimetric endpoints across measured time
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points were calculated using a one-way analysis of variance (ANOVA) test. The
significance of quality of life scores between any two-time points was assessed using the paired t-test. Clinically meaningful change in quality of life was defined as a change
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from baseline to follow-up that exceeded half the standard deviation of the baseline value [15]. All reported p values are two-sided. Statistical significance was considered at
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p<0.05. Statistical analysis was calculated using SPSS (Version 22.0. Armonk, NY: IBM Corp).
Descriptive statistics
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RESULTS
Eighty-one patients treated for prostate adenocarcinoma with PBT were identified
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that had completed a pre-treatment EPIC. Of these patients, 27 (33%) patients had completed a 3-month survey, 44 (54%) a 6 month survey, and 21 (26%) a 12 month
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survey. Clinico-pathologic characteristics are described in Table 1. Twenty-two (27%) patients had a prostate size ≤30cc, 36 (44%) patients between 30cc and 49cc, and 23 (28%) patients a prostate size ≥50cc (range 51cc-170cc). Of these 81 patients, 22 patients were prescribed androgen deprivation treatment (ADT) concurrently with radiation therapy, including 6 with intermediate risk disease and 16 with high-risk disease. Four of these 22 patients (18%) had a prostate size ≥50 cc. ADT was prescribed
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to these patients exclusively based on risk stratification and not for the purpose of cytoreduction. No patient received ADT for greater than two months prior to initiating
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radiation therapy.
Dosimetric Evaluation
The plans for all patients were reviewed. The median PTV V98 was 99.96%
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(Range 96.1%-100%), rectum V70 7.85% (Range 4.0%-13.8%), rectum eval V50 21% (3.1%-39.5%), and bladder V70 5.6% (Range 1.0% – 24.3%). As shown in Figure 1,
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larger prostate gland size was associated with greater rectal V70 (p=0.001), but not a greater rectalEval V50 (p=0.77). Larger prostate glands were also associated with a greater bladder V80 (p=0.04), and a greater bladder V70 (p=0.01, Figure 2).
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Urinary Function
The mean pre-treatment AUA survey score was 7.2, and at 6 months was 8.8. Patients with larger prostate glands were more likely to have a higher pre-treatment AUA
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score (≤30 cc, mean AUA=5.8; 30-49 cc, mean AUA=6.4; ≥50cc mean AUA=9.9; p=0.03, Figure 3). Prostate size was not associated with patient reported change in AUA
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at 6 months (<30 cc, ∆AUA +2.3 points; 30-49cc, ∆AUA +3.2 points; ≥50cc, ∆AUA +0.2 points; p=0.06). There were a total of 9 patients (20%) that had a clinically meaningful detriment in AUA at six months of ≥3 points, of which three patients had a prostate size <30 CC, 5 patients a prostate size between 30-49cc, and 1 patient a prostate size ≥50cc.
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The mean pre-treatment EPIC Urinary domain score (UDS) quality of life was 87.4 and at six months was 83.1. Patients with larger prostates had a lower pre-treatment UDS (≤30 cc, UDS=86.2; 30-49cc, UDS=82.8; ≥50, UDS=74.8; p<0.01; Figure 4a).
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Prostate size was not associated with patient reported change in UDS at six months (<30 cc, ∆UDS -3.6; 30-49cc ∆UDS -3.1 points; ≥50cc, ∆UDS +3.8 points; p=0.76). In total, 10 patients had a clinically meaningful decrease in UDS, calculated to be greater than 7
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points, of which 5 had a prostate size ≤30cc, 4 a prostate size of 30-49 cc, and 1 a
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prostate size of ≥50 cc.
The mean baseline urinary bother score was 78.2. Urinary bother score was associated with pre-treatment prostate gland size (≤30cc, 80.7; 30-49cc, 83.3; ≥50cc, 65.9; p<0.01). Prostate size was not associated with patient reported change in urinary
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bother score at six months (≤30cc, ∆ -4.7 points; 30-49cc ∆ -9.4 points; ≥50cc, ∆ +7.5 points; p=0.55). Six patients (14%) had a decrease in urinary bother score greater than two on the 1-5 scale, including two patients with prostate size ≤30cc, 3 patients 30-49cc,
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and 1 patient ≥50cc.
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Bowel Function
The mean pre-treatment EPIC GI domain quality of life score (GDS) was 93.1.
Prostate size was not related to baseline GI domain score (≤30 cc, GDS=95.5; 30-49 cc, GDS=92.7; ≥50 cc, GDS=91.7; p=0.36, Figure 5a). Prostate size was not associated with patient reported change in GDS at 6 months (≤30cc, ∆GDS -3.7; 30-49cc, ∆GDS -1.1; ≥50cc, ∆GDS -0.55; p=0.67). In total, 12 individual patients had a ∆GDS>6 points, of
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which 4 had a prostate size ≤30, 5 had a prostate size between 30-49 cc, and 3 had a prostate size ≥50 cc.
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Baseline GI bother score was different based on prostate size (≤30 cc, 95.5; 30-49 cc, 92.8; ≥50cc, 90.7; p<0.01). Prostate size was not associated with patient reported
change in GI bother at six months (≤30cc, ∆-7.8; 30-49cc, ∆0; ≥50cc, ∆+10, p=0.27).
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Overall, only one patient (2%) had a detriment in GI bother score greater than two points on the 1-5 scale filled in on the EPIC questionnaire. This patient had a prostate size of 55
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cc, a Rectal V70 of 8.41, and a RectalEval V50 of 18.68.
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DISCUSSION This study is the first to our knowledge that assesses the impact of prostate size on dosimetry with proton beam therapy (PBT), and correlates prostate size with patient
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assessed GU and GI quality of life following definitive proton beam therapy. We identified that larger prostate glands are associated with increased bowel and bladder
dose. Despite this, all patients, regardless of prostate size, were able to achieve excellent
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coverage of the planning tumor volume while maintaining bladder and rectal doses
reasonably low and within generally accepted constraints. All patients were treated with
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a rectal V70 <15%. Consistent with the favorable dosimetry, we did not find a correlation between increased prostate size and change in GU or GI quality of life 6 months following treatment.
Both dose and volume of rectum irradiated are well established risk factors for
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acute and late GI toxicity[16]. An MD Anderson trial showed that when at least 25% of the rectum was treated to more than 70 Gy, the grade 2+ complication rate significantly increased from 16% to 46%[17]. Preliminary results from RTOG 0126 further showed
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that if >15% of the rectum exceeded 70 Gy, there was an increase in late grade 2 rectal toxicity [16]. These tight rectal constraints can be difficult to achieve with photon based
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radiotherapy [18-23]. In the high dose arm in RTOG 0126, in which patients were prescribed a dose of 79.2 Gy, the median rectal V70 was 22.2% with 3D-CRT and 16.6% with IMRT[16]. This suggests that while IMRT is beneficial in reducing the volume of rectum that receives high doses of radiation compared to 3D-CRT, a subgroup of patients are still exposed to rectal doses in which the V70 is greater than15%. In our study, patients were exclusively treated with PBT, which has previously been shown to result in a favorable dosimetric profile compared to IMRT with reductions
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in both bowel and bladder dose [2]. We found that irrespective of prostate size, we were able to treat all patients to a rectal V70 dose <15 Gy (Range 4% - 13.8%). Importantly, this was achieved without sacrificing coverage of the planning tumor volume.
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To our knowledge, there is limited data in the literature examining whether prostate size is associated with an increased risk of achieving a plan with a rectal
V70>15%. Our data suggests that there is a dosimetric correlation between prostate
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gland size and rectal dose, in which patients with larger prostate glands are more likely to have a greater volume of their rectum exposed to doses greater than 70 Gy. While with
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protons we were able to keep the V70<15%, we hypothesize that it is these patients with large prostate glands that are least likely to meet this rectal constraint using photon based therapy. Therefore, it is logical that this subpopulation of patients may gain the greatest clinical benefit from the dosimetric advantages of proton beam therapy. However,
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further investigation is needed to confirm this hypothesis.
It is important to emphasize that our data has limitations. For one, we did not perform comparative IMRT planning, making it impossible to directly compare the
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dosimetric benefits of PBT with IMRT from this data alone. Secondly, our patient population is limited to 23 patients with prostate sizes ≥50 cc, of which 4 patients did
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receive ADT for clinical/pathologic risk factors. However, all 4 patients had prostate volumes ≥50 cc at time of treatment. This may be complemented by a larger, multiinstitutional study that incorporates additional patients with large prostate volumes. Third, patient compliance in completing the EPIC QOL surveys at six months was limited (54%), and may bias the results. And finally, longer-term follow up studies are needed to correlate the dosimetry with clinically meaningful outcomes.
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Some authors have advocated using androgen deprivation treatment for cytoreduction in patients with large prostate gland in order to improve the therapeutic ratio[24-26]. The concern with this approach is that androgen deprivation treatment itself
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can be poorly tolerated and result in permanent changes in overall quality of life [7, 2731]. Further, there is suggestion that concurrent ADT may result in greater urinary
toxicity [29]. For this reason and in context of the favorable dosimetry of PBT, we have
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not prescribed ADT for cytoreduction. Given this single-institutional experience, we believe that ADT for the purpose of cytoreduction in the setting of PBT may have a
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limited role, and may be considered on a case by case basis. Furthermore, we suggest that future multi-institutional efforts are aimed at the potential need [or lack thereof] for preradiotherapy cytoreduction with ADT in this select cohort of patients. Nevertheless, 27% of patients in our series were prescribed ADT based on NCCN risk group rather than
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prostate size. The majority of the patients that were prescribed ADT had prostate gland volume <50cc (82%), while only 4 patients with prostate gland volume ≥50 cc (17%) received ADT.
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While our study is limited in the number of patients with large prostate glands that were treated with PBT without ADT, our treatment approach may be further supported by
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the published experience from the University of Florida, in which they followed 186 men with prostates ≥60 cm3 that were treated with definitive PBT, of which only 14 received ADT for cytoreduction [26]. With a median follow-up of two years, they identified grade 3 genitourinary toxicities in only 14 men, grade 3 gastrointestinal toxicity in one man, and grade 2 gastrointestinal toxicity in 15 men.
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One concern in treating men with large prostate glands is the risk of acute urinary retention. Based on the methodology of our study, it is possible that we may not be adequately capturing this outcome. However, data presented in a study by McGee et al.
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found urinary retention to be relatively low in a similar population[26]. In their study, 2.1% of patients with prostate size >60 cc requiring temporary catherization during
treatment, and 6.4% of patients experienced a late grade 3 toxicity. However, we should
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caution generalizing the results of this study those patients with prostate gland volumes significantly larger than 50 cc.
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Our patient reported quality of life data adds to that published by Hoppe et al. [6] in which young men (≤60 years old) undergoing PBT for PC were followed for 12 months to evaluate changes in EPIC UDS and GDS. They reported excellent outcomes with respect to health-related quality of life parameters, including bowel and bladder
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function. They found the average decline from baseline to 12 months was 3.9 points and 5.9 points (using EPIC UDS and GDS tools, respectively). This study supports their data and adds to it by suggesting that patients with larger prostate glands did not suffer a
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detriment in AUA or GI/GU quality of life or bother compared to patients with smaller
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Our experience suggests that irrespective of prostate size, patients can be treated
safely and effectively with PBT with excellent urinary and bowel quality of life at six months. This supports our general treatment approach in which we do not routinely prescribe androgen deprivation treatment for cytoreduction for purposes of improved dosimetry. We propose that the favorable dosimetric profile of PBT may provide its greatest benefit in patients who have large prostate glands or have unfavorable anatomy.
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Clinical Practice Points The treatment of prostate cancer with proton beam therapy, routinely does
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not require neadjuvant cytoreduction, no matter the prostate size, unlike other modalities of radiation therapy. There are limited studies examining patient reported outcome with this favorable profile. This study details that despite the fact that patients with larger
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prostate sizes receive a higher dosimetric profile, there are limited long term adverse
affects. Multi-institutional analysis should be performed to verify the role of ADT prior
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to definitive PBT
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REFERENCES: Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29. Vargas, C., et al., Dose-volume comparison of proton therapy and intensitymodulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 70(3): p. 744-51. Talcott, J.A., et al., Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA, 2010. 303(11): p. 1046-53. Vargas, C., et al., Rectal dose-volume differences using proton radiotherapy and a rectal balloon or water alone for the treatment of prostate cancer. Int J Radiat Oncol Biol Phys, 2007. 69(4): p. 1110-6. Zietman, A.L., et al., Randomized trial comparing conventional-dose with highdose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09. J Clin Oncol, 2010. 28(7): p. 1106-11. Sheets, N.C., et al., Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA, 2012. 307(15): p. 1611-20. Pinkawa, M., et al., Toxicity profile with a large prostate volume after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 70(1): p. 83-9. Krupski, T., et al., The impact of prostate volume following neoadjuvant androgen deprivation on quality of life and voiding symptoms in patients undergoing permanent prostate brachytherapy. Eur Urol, 2003. 43(5): p. 467-72. Chevli, C., et al., Effect of pretreatment prostate volume on urinary quality of life following intensity-modulated radiation therapy for localized prostate cancer. Res Rep Urol, 2013. 5: p. 29-37. Aizer, A.A., et al., The impact of pretreatment prostate volume on severe acute genitourinary toxicity in prostate cancer patients treated with intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys, 2011. 79(2): p. 379-84. Zelefsky, M.J. and A. Harrison, Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer: reducing the potential morbidity of therapy. Urology, 1997. 49(3A Suppl): p. 38-45. Forman, J.D., et al., Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation. Cancer Invest, 1995. 13(1): p. 8-15. Vargas, C., et al., Proton therapy for prostate cancer treatment employing online image guidance and an action level threshold. Am J Clin Oncol, 2009. 32(2): p. 180-6.
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9.
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10.
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7.
11.
12.
13.
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19.
20.
21.
22.
23.
24.
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25.
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18.
SC
17.
M AN U
16.
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15.
Wei, J.T., et al., Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology, 2000. 56(6): p. 899-905. Sanda, M.G., et al., Quality of life and satisfaction with outcome among prostatecancer survivors. N Engl J Med, 2008. 358(12): p. 1250-61. Michalski, J.M., et al., Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial. Int J Radiat Oncol Biol Phys, 2013. 87(5): p. 932-8. Pollack, A., et al., Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys, 2002. 53(5): p. 1097-105. Kuban, D.A., et al., Long-term results of the M. D. Anderson randomized doseescalation trial for prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 70(1): p. 67-74. Zietman, A.L., et al., Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA, 2005. 294(10): p. 1233-9. Dearnaley, D.P., et al., Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol, 2007. 8(6): p. 475-87. Peeters, S.T., et al., Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol, 2006. 24(13): p. 1990-6. Peeters, S.T., et al., Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys, 2005. 61(4): p. 1019-34. Vargas, C., et al., Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys, 2005. 62(5): p. 1297-308. Zelefsky, M.J., et al., Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys, 1994. 29(4): p. 75561. Lilleby, W., et al., Changes in treatment volume of hormonally treated and untreated cancerous prostate and its impact on rectal dose. Acta Oncol, 2003. 42(1): p. 10-4. McGee, L., et al., Outcomes in men with large prostates (>/= 60 cm(3)) treated with definitive proton therapy for prostate cancer. Acta Oncol, 2013. 52(3): p. 470-6. Bolla, M., et al., Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med, 1997. 337(5): p. 295-300. Feigenberg, S.J., et al., Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional
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conformal radiation therapy. Int J Radiat Oncol Biol Phys, 2005. 62(2): p. 397405. Schultheiss, T.E., et al., Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys, 1997. 37(1): p. 3-11. Davis, J.W., et al., Quality of life after treatment for localized prostate cancer: differences based on treatment modality. J Urol, 2001. 166(3): p. 947-52. Hanks, G.E., et al., Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 9202. J Clin Oncol, 2003. 21(21): p. 3972-8.
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Table 1. Patient Clinicopathologic Characteristics.
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% N Risk Group Low Risk 32 40% Intermediate Risk 32 40% High Risk 17 21% Androgen Deprivation Treatment Yes 22 27% No 59 73% Pelvic LN Treated Yes 5 6.6% No 76 93.4% Prostate Size <30 cc 22 27% 30-49 cc 36 44% 50 cc 23 28%
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Patient Characteristics
Figure 1: Rectal Dose as a Function of Prostate Size. Larger prostate glands were associated with greater Rectal V70 (p=0.001), but not a greater Rectal V50Eval (p=0.77). 16
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Figure 2: Bladder Dose as a function of Prostate Size. Larger prostate glands were associated with a greater bladder V80 (p=0.04), and a greater bladder V70 (p=0.01).
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Figure 3. Baseline AUA by Prostate Size: Patients with larger prostate glands were more likely to have a higher pre-treatment AUA score (≤30 cc, mean AUA=5.8; 30-49 cc, mean AUA=6.4; ≥50cc mean AUA=9.9; p=0.03).
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85 80 75
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EPIC Urinary Doman
90
70 65
≤30 cc
30-49 cc
≥50 cc
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Prostate Size (cc's)
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EPIC Urinary Doman
87 86 85 84 83 82
80 0 months
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81 3 months
6 months
12 months
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Time (months)
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Figure 4. Baseline EPIC Urinary Domain by Prostate Size. Patients with larger prostates had a lower pre-treatment UDS (≤30 cc, UDS=86.2; 30-49cc, UDS=82.8; ≥50, UDS=74.8; p<0.01).
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90 85 80 75 70 30-49 cc
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<30 cc
Prostate Size (cc's)
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EPIC GI Domain
100 95 90 85
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6 months
12 months
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80 0 months
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EPIC GI Domain
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Figure 5. Baseline EPIC GI Domain by Prostate Size. Prostate size was not related to baseline GI domain score (≤30 cc, GDS=95.5; 30-49 cc, GDS=92.7; ≥50 cc, GDS=91.7; p=0.36).
S1558-7673(17)30067-8
DOI:
10.1016/j.clgc.2017.03.005
Reference:
CLGC 806
To appear in:
Clinical Genitourinary Cancer
Received Date: 18 January 2017 Revised Date:
10 March 2017
Accepted Date: 10 March 2017
Please cite this article as: Goenka A, Newman NB, Fontanilla H, Cahlon O, Chon B, Tsai H, Hug E, Brown C, Vargas C, Parikh RR, Patient Reported Quality of Life Following Proton Beam Therapy for Prostate Cancer: The Impact of Prostate Size, Clinical Genitourinary Cancer (2017), doi: 10.1016/ j.clgc.2017.03.005. 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.
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Patient Reported Quality of Life Following Proton Beam Therapy for Prostate Cancer: The Impact of Prostate Size
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Anuj Goenka1, Neil B. Newman1, Hiral Fontanilla2, Oren Cahlon2, Brian Chon2, Henry Tsai2, Eugen Hug2, C. Brown2, Carlos Vargas2, Rahul R. Parikh3
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Department of Radiation Medicine, Northwell Health, New Hyde Park, NY
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Department of Radiation Oncology, Princeton Radiation Oncology.
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Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ,
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Running Title: Impact of Prostate Size on QOL following PBT
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Anuj Goenka, M.D. Attending Physician Department of Radiation Medicine North-Shore LIJ Health Systems Email: [email protected] Phone: 212-434-2919 Fax 212-434-2445
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Microabstract
INTRODUCTION
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This study assesses the impact of prostate gland size on patient assessed quality of life (QOL) following definitive treatment for prostate adenocarcinoma with proton beam therapy. Larger Prostate sizes, despite receiving greater radiation doses did not affect QOL at six months, which further supports unnecessary neoadjuvant cytoreductive treatments.
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Prostate cancer is the leading non-dermatological cancer and the second most common cause of cancer death in US males, with an estimated 233,000 new cases and 29,480 estimated deaths in 2014 [1]. Radiation therapy is one of the conventional curative treatment options for localized prostate adenocarcinoma. Proton beam therapy (PBT) is a highly conformal radiation therapy modality that has been shown to have
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dosimetric advantages of delivering lower doses to nearby organs at risk when compared to 3D conformal or intensity-modulated radiotherapy (IMRT) [2].
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There has been an increasing focus on toxicity outcomes when evaluating contemporary methods of treating prostate cancer. Early dose escalation studies that
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have incorporated PBT found that modern radiation doses were not associated with an increase in patient-reported symptoms [3]. Additional studies have suggested PBT may be associated with decreased rates of rectal and genitourinary toxicity, though long-term outcomes continue to be controversial [4-6]. It also remains unclear whether there is a specific subset of patients with prostate cancer in which PBT may be of increased benefit. An area we have been increasingly interested in is the role of PBT in patients with large prostate glands that are receiving dose-escalated radiotherapy. In this setting, pre-
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treatment prostate size has been shown to correspond with increased toxicity [7-9]. Aizer et al reported that patients with prostate size >50cc’s had significantly higher rates of acute genitourinary toxicity, but follow-up was limited to assess for late toxicity [10].
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Pinkawa et al studied patients with small prostates (11–43 cc’s) and large prostates (44– 151 cc’s), and found that the patients with larger prostates had more bothersome urinary symptoms pretreatment and on the last day radiation therapy. Given these concerns, it
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has been advocated that patients with large prostate glands be treated with neoadjuvant
androgen deprivation treatment [7, 8, 11]. It has been shown that with this approach, the
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volume of the bowel and bladder that receives high dose can be reduced, thereby improving the therapeutic ratio by reducing the potential morbidity of treatment [11, 12]. Given the favorable dosimetric profile of PBT over other contemporary modalities [2], we have not routinely prescribed androgen deprivation treatment for the purpose of
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cytoreduction. Instead, ADT is prescribed strictly based on the NCCN risk group. The aim of this study was to examine the effect of pretreatment prostate volume on proton dosimetry and the resulting post-treatment urinary and bowel quality of life. This study
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was performed on a series of consecutively enrolled men on an institutional protocol using prospectively completed EPIC questionnaires both pre-treatment and at time of
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follow up.
PATIENTS AND METHODS
Patient Selection
As part of an ongoing prospective clinical trial sponsored by the Proton Collaborative Group, Evaluation Tracking Project: A prospective Chart Review of Patients Treated with Proton Therapy REG001-09, patients treated for prostate
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adenocarcinoma with definitive proton beam therapy (PBT) completed an Expanded Prostate Cancer Index Composite questionnaire (EPIC) both pre-treatment and at time of follow-up. Between January 2012 and November 2013, eighty-one patients were
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identified at our single institution that were enrolled on this protocol and had reviewable EPIC completed both pre-treatment and at follow-up. The medical records for these
patients were reviewed and clinical, dosimetric, and quality of life data recorded. Risk
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group stratification was performed as per NCCN guidelines. Pre-treatment prostate size was calculated for all patients by prostate MRI, if performed within two weeks of
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simulation, or CT at time of simulation. Prostate size was calculated in accordance with spherical volume and simplified by multiplying the length, width, and height by π/6. Prostate size was categorized into three pre-defined groups: <30 cc; 30-49cc; and ≥50cc.
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Treatment Planning and Delivery
Simulation and treatment planning techniques were performed per departmental guidelines based on NCCN defined risk groups. Gold fiducial marker placement into the
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prostate was performed using ultrasound guidance prior to simulation. All patients underwent CT simulation in the supine position with a full bladder. Routine policy was
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to place 100 cc of rectal saline at time of simulation and daily prior to treatment. MRI obtained in the treatment position for staging and treatment planning purposes was fused with CT when available. For low risk patients, the clinical tumor volume (CTV-1) was defined as the prostate alone and was treated to a dose of 79.2 Gy (RBE). A relative biologic effectiveness (RBE-factor) of 1.1 of protons was assumed. For intermediate risk disease, CTV-1 was defined as the prostate and proximal seminal vesicles and was
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treated to 54 Gy followed by a boost to CTV-2, defined as the prostate alone, to 79.2 Gy. For high risk patients, CTV-1 was defined as the prostate, seminal vesicles +/- the pelvic lymph nodes, and was treated to 45 Gy, followed by a boost to CTV-2to 79.2 Gy. All
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treatments were delivered in 1.8 Gy fractions. Typically equally weighted lateral beams were utilized, treated with either one beam or two beams a day. All patients were treated with 3D-proton beam therapy using uniform scanning technology as described elsewhere
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review and again for evaluation of treatment plan.
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[13]. Each case was peer-reviewed prior to initiation of treatment, once for contour
Data Collection & Statistical Analysis
The rectum was contoured as the outer wall of the rectum from the rectosigmoid junction to the bottom of the ischial tuberosities. RectalEval was a structure representing
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a segment of the rectum limited to 1 cm of the PTV. Dosimetric values including PTV V98, Rectal V70, RectalEval V50, Bladder V80, and Bladder V70 were recorded.
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The EPIC-50 questionnaires were completed prospectively by all patients. We reviewed the American Urological Association Symptom Index (AUA score), EPIC-
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urinary domain score (UDS), and EPIC-GI domain score (GDS). Patient-reported outcomes were calculated according to the instrument instructions as validated by Wei et al [14]. Urinary bother was defined by question 14 of the UDS, which quantifies patient’s perception of urinary function during the previous four weeks. GI bother was defined by question 30 of the GDS, which similarly quantifies patient’s perception of bowel habits during the previous four weeks. To assess for patient-specific changes, we
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assessed the change in individual responses at 6 months post-treatment from baseline for each of the three tools. Differences in quality of life and dosimetric endpoints across measured time
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points were calculated using a one-way analysis of variance (ANOVA) test. The
significance of quality of life scores between any two-time points was assessed using the paired t-test. Clinically meaningful change in quality of life was defined as a change
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from baseline to follow-up that exceeded half the standard deviation of the baseline value [15]. All reported p values are two-sided. Statistical significance was considered at
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p<0.05. Statistical analysis was calculated using SPSS (Version 22.0. Armonk, NY: IBM Corp).
Descriptive statistics
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RESULTS
Eighty-one patients treated for prostate adenocarcinoma with PBT were identified
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that had completed a pre-treatment EPIC. Of these patients, 27 (33%) patients had completed a 3-month survey, 44 (54%) a 6 month survey, and 21 (26%) a 12 month
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survey. Clinico-pathologic characteristics are described in Table 1. Twenty-two (27%) patients had a prostate size ≤30cc, 36 (44%) patients between 30cc and 49cc, and 23 (28%) patients a prostate size ≥50cc (range 51cc-170cc). Of these 81 patients, 22 patients were prescribed androgen deprivation treatment (ADT) concurrently with radiation therapy, including 6 with intermediate risk disease and 16 with high-risk disease. Four of these 22 patients (18%) had a prostate size ≥50 cc. ADT was prescribed
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to these patients exclusively based on risk stratification and not for the purpose of cytoreduction. No patient received ADT for greater than two months prior to initiating
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radiation therapy.
Dosimetric Evaluation
The plans for all patients were reviewed. The median PTV V98 was 99.96%
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(Range 96.1%-100%), rectum V70 7.85% (Range 4.0%-13.8%), rectum eval V50 21% (3.1%-39.5%), and bladder V70 5.6% (Range 1.0% – 24.3%). As shown in Figure 1,
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larger prostate gland size was associated with greater rectal V70 (p=0.001), but not a greater rectalEval V50 (p=0.77). Larger prostate glands were also associated with a greater bladder V80 (p=0.04), and a greater bladder V70 (p=0.01, Figure 2).
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Urinary Function
The mean pre-treatment AUA survey score was 7.2, and at 6 months was 8.8. Patients with larger prostate glands were more likely to have a higher pre-treatment AUA
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score (≤30 cc, mean AUA=5.8; 30-49 cc, mean AUA=6.4; ≥50cc mean AUA=9.9; p=0.03, Figure 3). Prostate size was not associated with patient reported change in AUA
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at 6 months (<30 cc, ∆AUA +2.3 points; 30-49cc, ∆AUA +3.2 points; ≥50cc, ∆AUA +0.2 points; p=0.06). There were a total of 9 patients (20%) that had a clinically meaningful detriment in AUA at six months of ≥3 points, of which three patients had a prostate size <30 CC, 5 patients a prostate size between 30-49cc, and 1 patient a prostate size ≥50cc.
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The mean pre-treatment EPIC Urinary domain score (UDS) quality of life was 87.4 and at six months was 83.1. Patients with larger prostates had a lower pre-treatment UDS (≤30 cc, UDS=86.2; 30-49cc, UDS=82.8; ≥50, UDS=74.8; p<0.01; Figure 4a).
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Prostate size was not associated with patient reported change in UDS at six months (<30 cc, ∆UDS -3.6; 30-49cc ∆UDS -3.1 points; ≥50cc, ∆UDS +3.8 points; p=0.76). In total, 10 patients had a clinically meaningful decrease in UDS, calculated to be greater than 7
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points, of which 5 had a prostate size ≤30cc, 4 a prostate size of 30-49 cc, and 1 a
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prostate size of ≥50 cc.
The mean baseline urinary bother score was 78.2. Urinary bother score was associated with pre-treatment prostate gland size (≤30cc, 80.7; 30-49cc, 83.3; ≥50cc, 65.9; p<0.01). Prostate size was not associated with patient reported change in urinary
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bother score at six months (≤30cc, ∆ -4.7 points; 30-49cc ∆ -9.4 points; ≥50cc, ∆ +7.5 points; p=0.55). Six patients (14%) had a decrease in urinary bother score greater than two on the 1-5 scale, including two patients with prostate size ≤30cc, 3 patients 30-49cc,
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and 1 patient ≥50cc.
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Bowel Function
The mean pre-treatment EPIC GI domain quality of life score (GDS) was 93.1.
Prostate size was not related to baseline GI domain score (≤30 cc, GDS=95.5; 30-49 cc, GDS=92.7; ≥50 cc, GDS=91.7; p=0.36, Figure 5a). Prostate size was not associated with patient reported change in GDS at 6 months (≤30cc, ∆GDS -3.7; 30-49cc, ∆GDS -1.1; ≥50cc, ∆GDS -0.55; p=0.67). In total, 12 individual patients had a ∆GDS>6 points, of
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which 4 had a prostate size ≤30, 5 had a prostate size between 30-49 cc, and 3 had a prostate size ≥50 cc.
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Baseline GI bother score was different based on prostate size (≤30 cc, 95.5; 30-49 cc, 92.8; ≥50cc, 90.7; p<0.01). Prostate size was not associated with patient reported
change in GI bother at six months (≤30cc, ∆-7.8; 30-49cc, ∆0; ≥50cc, ∆+10, p=0.27).
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Overall, only one patient (2%) had a detriment in GI bother score greater than two points on the 1-5 scale filled in on the EPIC questionnaire. This patient had a prostate size of 55
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cc, a Rectal V70 of 8.41, and a RectalEval V50 of 18.68.
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DISCUSSION This study is the first to our knowledge that assesses the impact of prostate size on dosimetry with proton beam therapy (PBT), and correlates prostate size with patient
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assessed GU and GI quality of life following definitive proton beam therapy. We identified that larger prostate glands are associated with increased bowel and bladder
dose. Despite this, all patients, regardless of prostate size, were able to achieve excellent
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coverage of the planning tumor volume while maintaining bladder and rectal doses
reasonably low and within generally accepted constraints. All patients were treated with
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a rectal V70 <15%. Consistent with the favorable dosimetry, we did not find a correlation between increased prostate size and change in GU or GI quality of life 6 months following treatment.
Both dose and volume of rectum irradiated are well established risk factors for
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acute and late GI toxicity[16]. An MD Anderson trial showed that when at least 25% of the rectum was treated to more than 70 Gy, the grade 2+ complication rate significantly increased from 16% to 46%[17]. Preliminary results from RTOG 0126 further showed
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that if >15% of the rectum exceeded 70 Gy, there was an increase in late grade 2 rectal toxicity [16]. These tight rectal constraints can be difficult to achieve with photon based
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radiotherapy [18-23]. In the high dose arm in RTOG 0126, in which patients were prescribed a dose of 79.2 Gy, the median rectal V70 was 22.2% with 3D-CRT and 16.6% with IMRT[16]. This suggests that while IMRT is beneficial in reducing the volume of rectum that receives high doses of radiation compared to 3D-CRT, a subgroup of patients are still exposed to rectal doses in which the V70 is greater than15%. In our study, patients were exclusively treated with PBT, which has previously been shown to result in a favorable dosimetric profile compared to IMRT with reductions
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in both bowel and bladder dose [2]. We found that irrespective of prostate size, we were able to treat all patients to a rectal V70 dose <15 Gy (Range 4% - 13.8%). Importantly, this was achieved without sacrificing coverage of the planning tumor volume.
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To our knowledge, there is limited data in the literature examining whether prostate size is associated with an increased risk of achieving a plan with a rectal
V70>15%. Our data suggests that there is a dosimetric correlation between prostate
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gland size and rectal dose, in which patients with larger prostate glands are more likely to have a greater volume of their rectum exposed to doses greater than 70 Gy. While with
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protons we were able to keep the V70<15%, we hypothesize that it is these patients with large prostate glands that are least likely to meet this rectal constraint using photon based therapy. Therefore, it is logical that this subpopulation of patients may gain the greatest clinical benefit from the dosimetric advantages of proton beam therapy. However,
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further investigation is needed to confirm this hypothesis.
It is important to emphasize that our data has limitations. For one, we did not perform comparative IMRT planning, making it impossible to directly compare the
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dosimetric benefits of PBT with IMRT from this data alone. Secondly, our patient population is limited to 23 patients with prostate sizes ≥50 cc, of which 4 patients did
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receive ADT for clinical/pathologic risk factors. However, all 4 patients had prostate volumes ≥50 cc at time of treatment. This may be complemented by a larger, multiinstitutional study that incorporates additional patients with large prostate volumes. Third, patient compliance in completing the EPIC QOL surveys at six months was limited (54%), and may bias the results. And finally, longer-term follow up studies are needed to correlate the dosimetry with clinically meaningful outcomes.
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Some authors have advocated using androgen deprivation treatment for cytoreduction in patients with large prostate gland in order to improve the therapeutic ratio[24-26]. The concern with this approach is that androgen deprivation treatment itself
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can be poorly tolerated and result in permanent changes in overall quality of life [7, 2731]. Further, there is suggestion that concurrent ADT may result in greater urinary
toxicity [29]. For this reason and in context of the favorable dosimetry of PBT, we have
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not prescribed ADT for cytoreduction. Given this single-institutional experience, we believe that ADT for the purpose of cytoreduction in the setting of PBT may have a
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limited role, and may be considered on a case by case basis. Furthermore, we suggest that future multi-institutional efforts are aimed at the potential need [or lack thereof] for preradiotherapy cytoreduction with ADT in this select cohort of patients. Nevertheless, 27% of patients in our series were prescribed ADT based on NCCN risk group rather than
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prostate size. The majority of the patients that were prescribed ADT had prostate gland volume <50cc (82%), while only 4 patients with prostate gland volume ≥50 cc (17%) received ADT.
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While our study is limited in the number of patients with large prostate glands that were treated with PBT without ADT, our treatment approach may be further supported by
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the published experience from the University of Florida, in which they followed 186 men with prostates ≥60 cm3 that were treated with definitive PBT, of which only 14 received ADT for cytoreduction [26]. With a median follow-up of two years, they identified grade 3 genitourinary toxicities in only 14 men, grade 3 gastrointestinal toxicity in one man, and grade 2 gastrointestinal toxicity in 15 men.
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One concern in treating men with large prostate glands is the risk of acute urinary retention. Based on the methodology of our study, it is possible that we may not be adequately capturing this outcome. However, data presented in a study by McGee et al.
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found urinary retention to be relatively low in a similar population[26]. In their study, 2.1% of patients with prostate size >60 cc requiring temporary catherization during
treatment, and 6.4% of patients experienced a late grade 3 toxicity. However, we should
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caution generalizing the results of this study those patients with prostate gland volumes significantly larger than 50 cc.
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Our patient reported quality of life data adds to that published by Hoppe et al. [6] in which young men (≤60 years old) undergoing PBT for PC were followed for 12 months to evaluate changes in EPIC UDS and GDS. They reported excellent outcomes with respect to health-related quality of life parameters, including bowel and bladder
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function. They found the average decline from baseline to 12 months was 3.9 points and 5.9 points (using EPIC UDS and GDS tools, respectively). This study supports their data and adds to it by suggesting that patients with larger prostate glands did not suffer a
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detriment in AUA or GI/GU quality of life or bother compared to patients with smaller
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Our experience suggests that irrespective of prostate size, patients can be treated
safely and effectively with PBT with excellent urinary and bowel quality of life at six months. This supports our general treatment approach in which we do not routinely prescribe androgen deprivation treatment for cytoreduction for purposes of improved dosimetry. We propose that the favorable dosimetric profile of PBT may provide its greatest benefit in patients who have large prostate glands or have unfavorable anatomy.
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Clinical Practice Points The treatment of prostate cancer with proton beam therapy, routinely does
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not require neadjuvant cytoreduction, no matter the prostate size, unlike other modalities of radiation therapy. There are limited studies examining patient reported outcome with this favorable profile. This study details that despite the fact that patients with larger
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prostate sizes receive a higher dosimetric profile, there are limited long term adverse
affects. Multi-institutional analysis should be performed to verify the role of ADT prior
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to definitive PBT
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REFERENCES: Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29. Vargas, C., et al., Dose-volume comparison of proton therapy and intensitymodulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 70(3): p. 744-51. Talcott, J.A., et al., Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA, 2010. 303(11): p. 1046-53. Vargas, C., et al., Rectal dose-volume differences using proton radiotherapy and a rectal balloon or water alone for the treatment of prostate cancer. Int J Radiat Oncol Biol Phys, 2007. 69(4): p. 1110-6. Zietman, A.L., et al., Randomized trial comparing conventional-dose with highdose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09. J Clin Oncol, 2010. 28(7): p. 1106-11. Sheets, N.C., et al., Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA, 2012. 307(15): p. 1611-20. Pinkawa, M., et al., Toxicity profile with a large prostate volume after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 70(1): p. 83-9. Krupski, T., et al., The impact of prostate volume following neoadjuvant androgen deprivation on quality of life and voiding symptoms in patients undergoing permanent prostate brachytherapy. Eur Urol, 2003. 43(5): p. 467-72. Chevli, C., et al., Effect of pretreatment prostate volume on urinary quality of life following intensity-modulated radiation therapy for localized prostate cancer. Res Rep Urol, 2013. 5: p. 29-37. Aizer, A.A., et al., The impact of pretreatment prostate volume on severe acute genitourinary toxicity in prostate cancer patients treated with intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys, 2011. 79(2): p. 379-84. Zelefsky, M.J. and A. Harrison, Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer: reducing the potential morbidity of therapy. Urology, 1997. 49(3A Suppl): p. 38-45. Forman, J.D., et al., Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation. Cancer Invest, 1995. 13(1): p. 8-15. Vargas, C., et al., Proton therapy for prostate cancer treatment employing online image guidance and an action level threshold. Am J Clin Oncol, 2009. 32(2): p. 180-6.
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6.
8.
9.
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10.
EP
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7.
11.
12.
13.
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19.
20.
21.
22.
23.
24.
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25.
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18.
SC
17.
M AN U
16.
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15.
Wei, J.T., et al., Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology, 2000. 56(6): p. 899-905. Sanda, M.G., et al., Quality of life and satisfaction with outcome among prostatecancer survivors. N Engl J Med, 2008. 358(12): p. 1250-61. Michalski, J.M., et al., Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial. Int J Radiat Oncol Biol Phys, 2013. 87(5): p. 932-8. Pollack, A., et al., Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys, 2002. 53(5): p. 1097-105. Kuban, D.A., et al., Long-term results of the M. D. Anderson randomized doseescalation trial for prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 70(1): p. 67-74. Zietman, A.L., et al., Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA, 2005. 294(10): p. 1233-9. Dearnaley, D.P., et al., Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol, 2007. 8(6): p. 475-87. Peeters, S.T., et al., Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol, 2006. 24(13): p. 1990-6. Peeters, S.T., et al., Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys, 2005. 61(4): p. 1019-34. Vargas, C., et al., Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys, 2005. 62(5): p. 1297-308. Zelefsky, M.J., et al., Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys, 1994. 29(4): p. 75561. Lilleby, W., et al., Changes in treatment volume of hormonally treated and untreated cancerous prostate and its impact on rectal dose. Acta Oncol, 2003. 42(1): p. 10-4. McGee, L., et al., Outcomes in men with large prostates (>/= 60 cm(3)) treated with definitive proton therapy for prostate cancer. Acta Oncol, 2013. 52(3): p. 470-6. Bolla, M., et al., Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med, 1997. 337(5): p. 295-300. Feigenberg, S.J., et al., Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional
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conformal radiation therapy. Int J Radiat Oncol Biol Phys, 2005. 62(2): p. 397405. Schultheiss, T.E., et al., Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys, 1997. 37(1): p. 3-11. Davis, J.W., et al., Quality of life after treatment for localized prostate cancer: differences based on treatment modality. J Urol, 2001. 166(3): p. 947-52. Hanks, G.E., et al., Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 9202. J Clin Oncol, 2003. 21(21): p. 3972-8.
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Table 1. Patient Clinicopathologic Characteristics.
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% N Risk Group Low Risk 32 40% Intermediate Risk 32 40% High Risk 17 21% Androgen Deprivation Treatment Yes 22 27% No 59 73% Pelvic LN Treated Yes 5 6.6% No 76 93.4% Prostate Size <30 cc 22 27% 30-49 cc 36 44% 50 cc 23 28%
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Patient Characteristics
Figure 1: Rectal Dose as a Function of Prostate Size. Larger prostate glands were associated with greater Rectal V70 (p=0.001), but not a greater Rectal V50Eval (p=0.77). 16
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Rectum V70 (%)
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Prostate100 Size (cc's) 150
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TE D
M AN U
0
SC
RI PT
45 40 35 30 25 20 15 10 5 0
AC C
Rectum V50 Eval (%)
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
10 8 6 4 2 0 0
50
100
150
200
Prostate Size (cc's)
SC
12 10 8 6 4 2 0 0
50
100
150
TE D
Prostate Size (cc's)
M AN U
Bladder V80 (%)
RI PT
Bladder V80 (%)
12
200
AC C
EP
Figure 2: Bladder Dose as a function of Prostate Size. Larger prostate glands were associated with a greater bladder V80 (p=0.04), and a greater bladder V70 (p=0.01).
ACCEPTED MANUSCRIPT
12
8
RI PT
6 4 2 0 ≤30 cc
30-49 CC
≥50 cc
Prostate Size (cc's)
M AN U
10
AUA Score
8 6 4
0 months
TE D
2 0
SC
Baseline AUA Score
10
3 months
6 months
12 months
Time (months)
AC C
EP
Figure 3. Baseline AUA by Prostate Size: Patients with larger prostate glands were more likely to have a higher pre-treatment AUA score (≤30 cc, mean AUA=5.8; 30-49 cc, mean AUA=6.4; ≥50cc mean AUA=9.9; p=0.03).
ACCEPTED MANUSCRIPT
85 80 75
RI PT
EPIC Urinary Doman
90
70 65
≤30 cc
30-49 cc
≥50 cc
SC
Prostate Size (cc's)
88
M AN U
EPIC Urinary Doman
87 86 85 84 83 82
80 0 months
TE D
81 3 months
6 months
12 months
EP
Time (months)
AC C
Figure 4. Baseline EPIC Urinary Domain by Prostate Size. Patients with larger prostates had a lower pre-treatment UDS (≤30 cc, UDS=86.2; 30-49cc, UDS=82.8; ≥50, UDS=74.8; p<0.01).
ACCEPTED MANUSCRIPT
100
90 85 80 75 70 30-49 cc
≥50 cc
SC
<30 cc
Prostate Size (cc's)
M AN U
EPIC GI Domain
100 95 90 85
3 months
6 months
12 months
TE D
80 0 months
RI PT
EPIC GI Domain
95
Time (months)
AC C
EP
Figure 5. Baseline EPIC GI Domain by Prostate Size. Prostate size was not related to baseline GI domain score (≤30 cc, GDS=95.5; 30-49 cc, GDS=92.7; ≥50 cc, GDS=91.7; p=0.36).