Abstract
Purpose/Objective(s):
Post-prostatectomy radiotherapy planning with fluciclovine (18F) PET/CT (PET) has demonstrated improved disease-free survival over conventional-only [CT or MRI-based] treatment planning. We hypothesized that incorporating PET would result in larger clinical target volumes (CTV’s) without increasing patient-reported toxicities.
Materials/Methods:
From 2012–2019, 165 post-prostatectomy patients with detectable PSA were randomized (Arm 1 [no PET]: 82; Arm 2 [PET]: 83). Prostate bed target volumes with (CTV1 [45.0–50.4 Gy/1.8Gy]) or without (CTV2/CTV [64.8–70.2Gy/1.8Gy]) pelvic nodes, as well as organ-at-risk doses, were compared pre- v post-PET (Arm 2) using the paired t-test and between Arms using the t-test. Patient-reported outcomes (PRO’s) utilized International Prostate Symptom Score (IPSS) & Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP). Univariate & multivariable analyses (MVA) were performed & linear mixed-models were fitted.
Results:
Median FU of the whole cohort was 3.52 years. All pts had baseline PRO’s, 1 pt in Arm 1 & 3 pts in Arm 2 withdrew, & 4 Arm 2 pts had extra-pelvic uptake on PET with XRT aborted, leaving 81 [Arm 1] & 76 pts [Arm 2] for toxicity analysis. Mean CTV1 (427.6cc v 452.2cc [p=0.462], Arm 1 v Arm 2) and CTV2/CTV (137.18cc v 134.2cc [p=0.669]) were similar prior to PET incorporation. CTV1 (454.57cc v 461.33cc; p=0.003) and CTV2/CTV (134.14cc v 135.61cc; p<0.001) were significantly larger following PET incorporation. While V40Gy (p=0.402 & p=0.522 for rectum & bladder, respectively) & V65Gy (p=0.157 & p=0.182 for rectum & bladder, respectively) were not significantly different pre- v post-PET, penile bulb dose significantly increased post-PET (p<0.001 for both V40Gy & V65Gy). On MVA, Arm was not significant for any EPIC-CP subdomain. IPSS & EPIC-CP LMMs were not significantly different between Arms.
Conclusion:
Despite larger clinical target volumes after incorporation of fluciclovine (18F) PET, we found no significant difference in patient-reported toxicities with long-term follow-up.
Introduction
Radical retropubic prostatectomy (RRP) and radiation (RT) remain the main curative treatments for localized prostate cancer.[1, 2] Following RRP, radiation therapy can be utilized in either the adjuvant or salvage settings [3–5] with long term disease control in up to two-thirds of patients. Given that the use of post-prostatectomy radiation increases both acute[3, 5] and late[5] toxicity, appropriate patient selection is imperative.
Consensus guidelines were recently updated to define post-prostatectomy RT target volumes.[6] However, certain targets, such as the pre-sacral space, remain without clear consensus.[6, 7] Additionally, the clinical factors indicating pelvic nodal treatment remain unclear.[8] While conventional imaging with CT may occasionally identify residual or recurrent disease, and bone scintigraphy may identify metastatic foci, the yield remains low.[9] Furthermore, the incremental benefit seen larger treatment volumes observed in RTOG 0534 suggest that increasing field size may offer disease-related improvements at the cost of increased acute GI and acute blood/bone marrow toxicity.[10] Thus, improvement in imaging modalities is necessary to define patient selection criteria and appropriate target volume delineation.
Advanced imaging using fluciclovine (18F) (anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid)-based PET/CT (hereafter 18F-fluciclovine-PET/CT) scanning has been incorporated into NCCN guidelines in the post-prostatectomy setting.[11] Compared to earlier imaging modalities, such as radioimmunoscinitgraphy, 18F-fluciclovine-PET/CT appears to have a high sensitivity and specificity.[12, 13] Early clinical reports have shown clinical decision changes in up to 30% of patients based on 18F-fluciclovine-PET/CT. [14] An additional tracer, prostate specific membrane antigen (PSMA) has demonstrated higher sensitivity. When consensus guideline target volumes were overlaid with PSMA based PET/CT scans, up to 35% of radiographically involved nodes were not contained in CTV volumes.[15] To date only a single trial has demonstrated an improvement in prostate cancer specific clinical outcomes with advanced imaging compared to standard anatomical imaging.[16]
Patient reported outcomes (PROs) have recently been incorporated in large, prospective, cooperative-group studies.[17, 18] An effort to consolidate patient reported scales into metrics that can be compared across studies has resulted in the measure of “minimal clinically important differences” (MCID). [19] However, no consensus has been established and various approaches have been utilized.[17, 18] Given the favorable life expectancy of patients receiving post-prostatectomy radiation, both acute and late treatment related toxicity may substantially affect patient quality of life.
Incorporating advanced PET/CT imaging in radiation planning may result in improved clinical outcomes at the cost of increased toxicity. In this analysis of a randomized, prospective, intention to treat, clinical trial our objective was to determine if integrating 18F-fluciclovine PET/CT scans into radiotherapy planning significantly altered target volumes for either salvage or early adjuvant treatment in the post-prostatectomy setting. We also sought to determine if treatment related toxicity, measured by provider or patient reported assessments, would differ between patients in each Arm. Our hypotheses were that: (1) integration of 18F-fluciclovine-PET/CT would result in significant alteration of radiation target volumes and (2) there would be no significant difference in provider or (3) patient reported acute or late toxicities between Arms.
Methods
Trial design
We conducted an IRB approved (IRB00057680) National Institutes of Health-funded prospective randomized controlled trial (NCT01666808) evaluating the incorporation of 18F-fluciclovine-PET/CT in post-prostatectomy patients planned for adjuvant or salvage radiotherapy. All subjects provided informed consent.
Eligibility criteria included patients with a detectable PSA at any time after prostatectomy (with or without pelvic lymph node dissection), and an initial imaging workup with a CT or MRI scan of the abdomen and pelvis, and bone scintigraphy confirming the absence of metastatic disease. Stratification factors included: (a) pre-radiotherapy PSA; (b) adverse pathologic features including: positive surgical margins, seminal vesical invasion, extracapsular extension, or positive lymph nodes; and (c) intent to initiate androgen deprivation therapy (ADT). Patients were then randomized (1:1) using random sequence number allocations to the control Arm (Arm 1) or the experimental Arm (Arm 2). All Arm 1 patients received standard imaging workup as detailed above while Arm 2 patients underwent 18F-fluciclovine-PET/CT scans in addition to standard imaging workup.
All patients received image guided radiation therapy with weekly toxicity assessments. After completion of treatment, patients were seen at 1, 6, 12, 18, 24, 30- and 36-months post-completion of radiation and had toxicity assessments (provider and patient-assessed) as well as PSA testing. The primary endpoint of the study was 3-year disease-free survival with failure defined by: serum PSA ≥0.2ng/mL over the post-radiation PSA nadir with subsequent continued elevation, a further increase in PSA despite radiotherapy, clinical progression, or initiation of systemic therapy after radiation treatment.
The accrual goal of 162 patients incorporated a 10% drop-out rate and assumed a 20% power to detect differences in disease-free survival at 3 years between the two cohorts.
Treatment failure was defined by: Stephenson salvage criteria of a PSA value 0.2ng/mL above post-radiation nadir followed by another higher value;[20] a continued rise in PSA despite radiation; or initiation of systemic therapy including ADT after radiation or clinical progression (digital rectal exam or imaging). Kaplan-Meier curves were generated for each Arm from time 0 to 4 years using log-rank tests, with time 0 defined as the end of radiation therapy.
CT simulation and target delineation
All patients were simulated in the supine position following patient-specific immobilization and with appropriate bladder filling and rectal emptying. CT images were obtained without intravenous, oral, or rectal contrast using 5mm slices and included, at minimum, the top of the L2 vertebral body to the mid femur (below the ischial tuberosities). All patients, unless contraindicated, received treatment planning multiparametric MRI scans (3-Tesla) of the pelvis to assist with target volume delineation. Prostate bed clinical target volumes were according to RTOG consensus guidelines for post-prostatectomy radiation[7] and pelvic nodal treatment volumes were according to the RTOG pelvic atlas.[21] MRI images were co-registered to CT simulation scans using Velocity software (Varian Medical Systems, Palo Alto, CA). Target and organ at risk (OAR) delineation, treatment planning and plan evaluation was completed in Eclipse (Varian Medical Systems, Palo Alto, CA). For all patients the planning target volume incorporated a 0.8cm (0.6cm posterior) planning target volume that accounted for both deformable registration uncertainty (0.2–0.3cm) and daily setup uncertainty.
Specifically, the pre-18F-fluciclovine-PET/CT volumes included a CTVpre with expansion, as detailed above, to create PTVpre volumes. Arm 2 patients also had CTVpost volumes incorporating 18F-fluciclovine-PET/CT uptake and had identical planning target volume expansions as Arm 1 to create PTVpost. For all patients CTV1/PTV1(pre/post) included prostate bed and pelvic nodes (when applicable) and was prescribed 45–50.4Gy at 1.8 Gy per fraction. CTV2/PTV2(pre/post) included the prostate bed and was prescribed 64.8–70.2 Gy at 1.8 Gy per fraction. For Arm 1 patients no CTV/PTVpost was generated.
Incorporation of 18F-fluciclovine-PET/CT in Radiotherapy Planning
In group B 18F-fluciclovine-PET/CT scans were incorporated in radiotherapy target delineation by the creation of iso-SUVs that accounted for previously reported positivity criteria[12, 22] and clinical factors. The process of integrating 18F-fluciclovine-PET/CT scan results into radiation treatment plans has previously been described.[16] Briefly, deformable registrations were created to fuse 18F-fluciclovine-PET/CT scans with CT images from radiation simulation and iso-SUVs were incorporated into radiation target volumes. The decision to include prostate bed alone, pelvic nodal treatment, or aborting treatment were specified per protocol. Briefly, four scenarios were expected: (1) patients with no pelvic nodal uptake and no pathologically confirmed nodal disease were treated to the prostate-bed alone; (2) patients with prostate bed alone uptake received only prostate bed radiation; (3) patients with nodal 18F-fluciclovine-PET/CT uptake or pathologically confirmed nodal disease were treated to the prostate bed and pelvic nodes, and (3) patients with extra-pelvic disease (clinically or radiographically) had radiation treatment aborted. Intent for ADT use was specified by providers prior to trial enrollment. Two-tailed paired t-test was employed to compare target volumes between pre and post scans to account for patients with planned pelvic nodal treatment pre-18F-fluciclovine-PET/CT who had smaller volumes post-18F-fluciclovine-PET/CT scan. Descriptive statistics were also used to summarize demographic, imaging, and plan characteristics.
Plan Evaluation
For all patients PTV coverage ≥95% of prescribed dose was mandated. Organ at risk (OAR) constraints were identical between Arms and were assessed by V40Gy and V65Gy to critical structures including: bladder, bladder-CTV, rectum, and penile bulb. Additionally, for small bowel, V45Gy volume (cc) was assessed but did not have a specified constraint.
Toxicity Assessment and Analysis
Chi-square tests were conducted to compare the provider reported RTOG maximum acute (with window defined from enrollment into the study till first post-treatment follow-up) GU and GI toxicity between those who had completed radiotherapy in the control group (Arm 1) and experimental group (Arm 2), respectively. The significance level was set at 0.05 for all tests.
Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP),[23] and International Prostate Symptom Scores (IPSS)[24] were collected at baseline and at each follow-up appointment. The average change over time was assessed for: total IPSS score (0–35), with higher scores representing more significant symptoms; and EPIC-CP total score (0–60) or sub-domain specific score (incontinence, irritation/obstruction, bowel, sexual function, and vitality; 0–12), with higher sores representing more significant symptoms. Linear mixed models (LMMs) were created for total IPSS as well as total EPIC-CP and EPIC-CP sub-domain scores that incorporate correlative patient and group specific analyses. Additionally, differences in scores at specified time intervals were assessed. Minimal clinically important difference (MCID) was defined based on a distributive approach and was equal to one half standard deviation at baseline for each PRO category: IPSS: 3.6; EPIC total: 4.6; EPIC incontinence: 1.4; EPIC irritative: 1.2; EPIC bowel 1.0; EPIC sexual 1.5; EPIC vitality: 0.9 (supplemental table 1). [19]
This trial is registered with ClinicalTrials.gov, NCT01666808.
Role of the funding source
The funders of the study had no role in design of the study, collection, analysis, or interpretation of data, or writing of the manuscript. Funding was provided by the National Institutes of Health NIH R01 CA169188, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University..
Results
Baseline
Between September 2012 and March 2019, a total of 165 patients were randomized, 82 in Arm 1 (no 18F-fluciclovine-PET/CT scan) and 83 in Arm 2 (with 18F-fluciclovine-PET/CT scan). One patient withdrew from Arm 1 post-randomization but before radiotherapy; three patients in Arm 2 withdrew post-randomization. Additionally, 1 patient in Arm 2 did not receive study intervention (18F-fluciclovine-PET/CT scan) due to technical difficulties. Thus, a total of 161 patients were evaluable for toxicity analysis and 79 patients were available for pre/post-18F-fluciclovine-PET/CT volumetric analyses.
Arms were well balanced for age, race, PSA, Gleason score, T stage, margin status, lymph node involvement, and both use and duration of ADT. Significantly more patients in Arm 2 received pelvic nodal irradiation (30.49% vs 42.17%, Arm 1 vs Arm 2, respectively; p=0.05) (Table 1).
Table 1 –
Baseline Patient Characteristics and Survey Completion
| Covariate | Level | Arm 1 (N=82) | Arm 2 (N=83) | Parametric P-value |
Non-Parametric P-value |
|---|---|---|---|---|---|
| Age (years) | Mean | 61.73 | 61.75 | 0.99 | 0.74 |
| Median | 61 | 61 | |||
| Range | 46–78 | 42–75 | |||
| Race | White | 52 (63.41%) | 52 (62.65%) | 0.92 | 1.00 |
| Androgen Deprivation | Yes | 53 (65.43%) | 49 (62.03%) | 0.65 | 0.74 |
| Fields | Pelvic nodes treated | 25 (30.49%) | 35 (42.17%) | 0.05 | 0.07 |
| T stage | ≤2 | 34 (41.46%) | 38 (45.78%) | 0.58 | 0.64 |
| Seminal Vesicle Invasion | Yes | 22 (26.83%) | 24 (28.92%) | 0.77 | 0.86 |
| ECE | Yes | 43 (52.44%) | 39 (46.99%) | 0.48 | 0.53 |
| Surgical Margins | Positive | 41 (50.00%) | 37(44.58%) | 0.49 | 0.53 |
| Chi square p-value | |||||
| Survey completion | Baseline | 82 | 83 | p=0.392 | |
| ≤2 months | 82 | 73 | |||
| >2 - ≤6 months | 8 | 8 | |||
| >6-≤12 months | 43 | 39 | |||
| >12- ≤18 months | 43 | 33 | |||
| >18-≤24 months | 7 | 10 | |||
| >24-≤30 months | 13 | 9 | |||
| >30 months | 39 | 59 | |||
Volumetric and Dosimetric Comparisons
Prior to 18F-fluciclovine-PET/CT-PET incorporation there was no significant difference in mean volume for CTV1 (427.6cc vs 452.2cc [p=0.462], Arm 1 vs Arm 2, respectively) or CTV2 (137.18cc vs 134.2cc [p=0.669], Arm 1 vs Arm 2, respectively) between Arms. Additionally, there was no difference between Arms in rectal V40Gy/V65Gy (p=0.990/p=0.440); bladder V40Gy/V65Gy (p=0.990/p=0.655); bladder-CTV V40Gy/V65Gy (p=0.632/p=0.710); penile bulb V40Gy/V65Gy (p=0.288/p=0.699); or small bowel V45Gy (p=0.087).
When comparing pre- vs. post- 18F-fluciclovine-PET/CT incorporation for Arm 2, CTV1 (454.57cc v 461.33cc; p=0.003) and CTV2/CTV (134.14cc v 135.61cc; p<0.001) were significantly larger following PET incorporation. There was no significant change in rectal V40Gy/V65Gy (p=0.402/p=0.157), bladder V40Gy/V65Gy (p=0.522/p=0.182), bladder-CTV V40Gy/V65Gy (p=0.522/p=0.182), or small bowel V45Gy (p=0.247) between pre- vs post- 18F-fluciclovine-PET/CT incorporation. Penile bulb mean V40Gy (47.43% vs 55.74%, pre- vs post-, respectively; p<0.001) and mean V65Gy (22.97% vs 30.81%, pre- vs. post-, respectively) significantly increased with 18F-fluciclovine-PET/CT incorporation.
Toxicity Analysis
Provider Reported outcome and Urinary Medication Use
Provider reported toxicity was not significantly different between Arms and has previously been reported. There were no grade 4+ toxicities and minimal grade 3 toxicities were noted in either Arm. When considering use of urinary medications, 14.63% of patients in Arm 1 vs 9.21% of patients in Arm 2 were on alpha antagonists prior to radiotherapy (p=0.295), 28.13% vs 23.68% of patients required alpha antagonist within 3 months of treatment (Arm 1 and Arm 2, respectively; p=0.795) and 45.12% vs 40.79% patients required an alpha antagonist at any point during follow-up (Arm 1 vs. Arm 2, respectively; p=0.583). At most recent follow-up 24 (29.27%) vs. 15 (19.74%) patients continued to utilize alpha antagonists (Arm 1 vs. Arm 2, respectively; p=0.165).
IPSS Total
There was no significant difference in total IPSS score between groups on UVA (p=0.216), or MVA (p=0.250). Gleason score ≥8 was associated with significantly increased IPSS scores over time on MVA with absolute difference greater than MCID threshold (absolute difference: +2.4; p=0.037).
EPIC-CP Total
Total EPIC-CP scores were similar between Arms on both UVA (p=0.117) and MVA (p=0.224). Gleason score ≥8, non-white race, and nodal treatment were also associated with increased total EPIC-CP scores on MVA (absolute difference +4.1 [p=0.010], absolute difference 3.4 [p=0.010], and absolute difference +5.0 [p=0.019], respectively). The magnitude of difference for all covariates surpassed the MCID threshold (supplemental table 1).
EPIC-CP Incontinence
There was no significant difference between Arms in EPIC-CP incontinence scores on UVA (p=0.529), MVA (p=0.650). Factors associated with increased EPIC-CP incontinence scores on MVA included non-white race (absolute difference +1.2; p=0.004), Gleason score ≥8 (absolute difference +1.2; p=0.018), and pre-RT PSA ≥1 (absolute difference +1.0; p=0.050). No covariate surpassed the MCID.
EPIC-CP Irritative
A trend towards lower EPIC-CP irritative scores was observed for Arm 2 on UVA (absolute difference −0.6 [p=0.062]; Figure 2) and MVA (absolute difference −0.6, p=0.075). On MVA, non-white race was associated with a trend towards a significant increase in EPIC-CP irritative score (absolute difference +0.7, p=0.051). No covariates surpassed the MCID threshold.
Figure 2:
Mean(standard deviation) for EPIC-CP: total (a), incontinence (b), irritative (c), bowel (d), sexual (e), and vitality (f) scores at specified time intervals for control (arm 1) and FACBC-incorporated (arm 2) patients with linear mixed-model defined significance value.
EPIC-CP Bowel
There was no significant difference in EPIC-CP bowel scores between Arms on UVA (p=0.282), MVA (p=0.402) and no covariates were significantly associated with EPIC-CP bowel scores.
EPIC-CP Sexual
There was no difference in EPIC-CP sexual scores between Arms on UVA (p=0.146) or on MVA (p=0.212). Factors associated with higher EPIC-CP sexual scores included non-white race (absolute difference +1.1; p=0.029) and Gleason score ≥8 (absolute difference +1.6; p=0.007), with only Gleason score surpassing the MCID threshold.
EPIC-CP Vitality
There was no significant difference in EPIC-CP vitality scores between Arms on UVA (p=0.416) or MVA (p=0.456). There was no difference between Arms at any other time interval.
On MVA, older age and nodal treatment were associated with an increase in EPIC-CP vitality scores (absolute difference +0.1 [p=0.011] and +0.9 [p=0.045], respectively). Neither covariate met the MCID threshold.
Discussion
In this prospective, randomized, phase III study we found that the incorporation of fluciclovine (18F) PET into post-prostatectomy radiation treatment planning resulted in a significant increase in target volumes without substantially increasing provider or patient reported toxicities with long term follow-up. Additionally, we found that the incorporation of 18F-fluciclovine-PET/CT scans resulted in no difference in most OAR doses including V40Gy & V65Gy dosimetry for: rectum, bladder(-CTV), and small bowel V45Gy. Penile bulb V45Gy and V65Gy was considerably increased with 18F-fluciclovine-PET/CT based radiation planning but did not result in increased patient-reported sexual toxicity.
The incorporation of advanced imaging modalities in treatment planning (18F-choline, 11C-choline, 68Ga-PSMA) has been shown to alter radiotherapy target volumes. [25] Additionally, increased radiation volumes have been associated with higher provider [10] and patient [26] reported toxicities. We found that a modest increase in pelvic (+6.76cc) and prostate-bed (+1.61cc) target volumes did not significantly impact either provider or patient-reported toxicities despite a significantly larger proportion of patients in the experimental arm receiving pelvic nodal radiotherapy. This observation is congruent with the capacity for Arm 1 and Arm 2 patients to achieve identical OAR constraints for: bladder(-CTV), rectum, and small bowel. Given the step-wise improvement in biochemical relapse-free survival (bRFS) shown in the SPPORT trial [10] as well as the demonstrated bRFS advantage shown with 18F-fluciclovine-PET/CT-PET incorporation[16]. Taken together, these observations suggest that incorporating 18F-fluciclovine-PET/CT-PET imaging in radiotherapy planning does increase target volumes and improve bRFS with no significant increase in associated provider or patient-reported toxicity. One important caveat is that although there were certain patients who received pelvic nodal radiation due to nodal uptake on 18F-fluciclovine-PET/CT-PET scans, there were also patients with high-risk pathologic features (i.e. high grade group or advanced T stage) who were spared pelvic nodal radiation if no 18F-fluciclovine-PET/CT-PET nodal uptake was present. Thus, the ability to appropriately disposition patients to pelvic nodal radiotherapy may explain the lack of difference in provider or patient-reported outcomes between Arms.
The heterogeneous use of PRO questionnaires is a major challenge in assessing toxicity. In prospective studies of definitive [17, 27, 28] or salvage [29–31] radiotherapy there are a number of questionnaires used with the EPIC-26 and EORTC QLQ-C30 being most widely adopted. Additionally, when interpreting the significance of changes in PRO scores, defining a threshold for each scoring system remains a challenge. Prior studies have defined the minimal clinically important difference (MCID) for EPIC-26 [19] using a distributive (standard deviation) and anchor-based (correlated to satisfaction with treatment) approach. Similarly, the PROSTQA consortium has analyzed EPIC-CP scoring and established an MCID for each sub-category.[32] Specifically, Chipman et al. defined the MCID for scores as follows: 1.0 (incontinence), 1.3 (urinary irritation/obstruction), 1.2 (bowel), 1.6 (sexual), and 1.0 (vitality/hormonal).[32] We included the EPIC-CP form for PROs in this study based on our institutional practice. Additionally, we calculated a study specific MCID using a distributive analysis as detailed in the methods section. Given our study-specific MCID thresholds, there were no clinically important differences in EPIC-CP incontinence, irritative/obstructive, bowel, sexual, or vitality scores between Arms on linear mixed models which incorporated patient specific and group specific correlations. Furthermore, the trend towards lower EPIC-CP irritative scores in Arm 2 (absolute difference −0.6; p=0.062, Arm 2 vs Arm1) may be viewed as clinically insignificant and may represent an artifact from non-blinded treatment group assignment. Importantly, given the increased number of patients in Arm 2 receiving pelvic nodal irradiation, there were no significant differences in patient or provider reported bowel toxicity. As would be expected, the use of ADT was associated with a clinically significant increase in EPIC-CP vitality scores on multivariable analysis (supplemental table 1).
To our knowledge, this manuscript is the first to explore the effect of 18F-fluciclovine-PET/CT-PET/CT based radiotherapy on patient-reported outcomes in a randomized prospective fashion. Our findings support the use of advanced imaging techniques to tailor radiotherapy target volumes and suggest the modest increase in radiation volumes may not significantly impact patient or provider-assessed toxicity.
Supplementary Material
Figure 1:
Mean(standard deviation) International Prostate Symptom Scores at specified time intervals for control (arm 1) and FACBC-incorporated (arm 2) patients with linear mixed-model defined significance value.
Table 2 –
Volumetric and Dosimetric Analysis of Arm 1 vs Arm 2 (pre-FACBC incorporation)
| Arm |
|||||
|---|---|---|---|---|---|
| Covariate | Level | Arm 1 N=82 |
Arm 2 (pre-FACBC) N=83 |
Parametric P-value* | |
|
| |||||
| CTV1 (cc) | N | 25 | 35 | 0.462 | |
| Mean | 427.63 | 452.21 | |||
| Median | 384.24 | 447.2 | |||
| Min | 195.4 | 165.54 | |||
| Max | 676.7 | 674.49 | |||
| Std Dev | 144.77 | 112.22 | |||
| PTV1 (cc) | N | 25 | 35 | 0.103 | |
| Mean | 972.93 | 1081.05 | |||
| Median | 975.36 | 1067.1 | |||
| Min | 295.3 | 542.81 | |||
| Max | 1508.9 | 1513.99 | |||
| Std Dev | 300.32 | 206.33 | |||
| CTV2/CTV (cc) | N | 81 | 78 | 0.699 | |
| Mean | 137.18 | 134.2 | |||
| Median | 130.9 | 126.97 | |||
| Min | 52.3 | 46.4 | |||
| Max | 289.3 | 275.4 | |||
| Std Dev | 51.36 | 45.31 | |||
| PTV2/PTV (cc) | N | 81 | 78 | 0.814 | |
| Mean | 327.71 | 324.56 | |||
| Median | 325.6 | 318.35 | |||
| Min | 175 | 145.8 | |||
| Max | 569.7 | 526.51 | |||
| Std Dev | 88.61 | 79.3 | |||
| Rectum, V40Gy (%) | N | 81 | 78 | 0.990 | |
| Mean | 45.03 | 45.01 | |||
| Median | 43.4 | 45.95 | |||
| Min | 20.9 | 22.7 | |||
| Max | 86.2 | 70.1 | |||
| Std Dev | 10.89 | 10 | |||
| Rectum, V65Gy (%) | N | 81 | 78 | 0.440 | |
| Mean | 19.31 | 18.35 | |||
| Median | 18.49 | 18.37 | |||
| Min | 4.4 | 3.2 | |||
| Max | 41.4 | 35 | |||
| Std Dev | 7.82 | 7.78 | |||
| Bladder, V40Gy (%) | N | 81 | 78 | 0.989 | |
| Mean | 68.95 | 68.92 | |||
| Median | 73.8 | 68.1 | |||
| Min | 26.5 | 39.1 | |||
| Max | 99.2 | 100 | |||
| Std Dev | 18.04 | 14.94 | |||
| Bladder, V65Gy (%) | N | 81 | 78 | 0.655 | |
| Mean | 50.99 | 49.68 | |||
| Median | 52.7 | 47.7 | |||
| Min | 14.39 | 19.34 | |||
| Max | 97.61 | 95.8 | |||
| Std Dev | 19.35 | 17.31 | |||
| Bladder-CTV, V40Gy (%) | N | 81 | 78 | 0.632 | |
| Mean | 58.36 | 56.98 | |||
| Median | 62.7 | 57.39 | |||
| Min | 1.7 | 0 | |||
| Max | 98.7 | 100 | |||
| Std Dev | 19.18 | 17.1 | |||
| Bladder-CTV, V65 Gy (%) | N | 81 | 78 | 0.707 | |
| Mean | 31.78 | 30.9 | |||
| Median | 33.9 | 30.05 | |||
| Min | 0 | 0 | |||
| Max | 68.6 | 85.4 | |||
| Std Dev | 14.86 | 14.69 | |||
| Penile Bulb, V40Gy (%) | N | 81 | 78 | 0.288 | |
| Mean | 42.44 | 47.56 | |||
| Median | 44.4 | 45.35 | |||
| Min | 0 | 0 | |||
| Max | 100 | 100 | |||
| Std Dev | 30.42 | 30.21 | |||
| Penile Bulb, V65Gy (%) | N | 81 | 78 | 0.699 | |
| Mean | 21.69 | 23.17 | |||
| Median | 12.8 | 19.45 | |||
| Min | 0 | 0 | |||
| Max | 90.1 | 100 | |||
| Std Dev | 24.01 | 24.24 | |||
| Small bowel, V45Gy (cc) | N | 81 | 75 | 0.087 | |
| Mean | 34.18 | 53.11 | |||
| Median | 0 | 1.67 | |||
| Min | 0 | 0 | |||
| Max | 238.76 | 311.56 | |||
| Std Dev | 61.17 | 75.61 | |||
The parametric p-value is calculated by independent samples t Test.
Arm 1: Control; Arm 2: Experimental pre-FACBC scan incorporation. V40/65Gy: Volume of structure receiving >/= 40/65 Gy
Table 3 –
Volumetric and dosimetric analysis for Arm 2 pre- vs post- FACBC incorporation
| Group |
|||||
|---|---|---|---|---|---|
| Covariate | Statistics | Preregistration N=82 | Postregistration N=82 | Parametric P-value* | |
| CTV1 | N | 34 | 34 | 0.003 | |
| Mean | 454.57 | 461.33 | |||
| Median | 452.25 | 456.68 | |||
| Min | 165.54 | 178.29 | |||
| Max | 674.49 | 723.2 | |||
| Std Dev | 113.02 | 117.03 | |||
| PTV1 | N | 34 | 34 | <.001 | |
| Mean | 1084.76 | 1109.16 | |||
| Median | 1073 | 1090.05 | |||
| Min | 542.81 | 607.46 | |||
| Max | 1513.99 | 1562.5 | |||
| Std Dev | 208.25 | 210.5 | |||
| CTV2/CTV | N | 77 | 77 | <.001 | |
| Mean | 134.14 | 135.61 | |||
| Median | 126.4 | 127.7 | |||
| Min | 46.4 | 46.4 | |||
| Max | 275.4 | 277.1 | |||
| Std Dev | 45.6 | 45.51 | |||
| PTV2/PTV | N | 77 | 77 | <.001 | |
| Mean | 324.5 | 329.54 | |||
| Median | 317.9 | 319.34 | |||
| Min | 145.8 | 145.8 | |||
| Max | 526.51 | 537.32 | |||
| Std Dev | 79.82 | 81.34 | |||
| Rectum, V40 | N | 77 | 77 | 0.402 | |
| Mean | 44.81 | 45.07 | |||
| Median | 45.4 | 46.5 | |||
| Min | 22.7 | 22.7 | |||
| Max | 70.1 | 71.31 | |||
| Std Dev | 9.91 | 9.78 | |||
| Rectum, V65 | N | 77 | 77 | 0.157 | |
| Mean | 18.14 | 18.48 | |||
| Median | 18.37 | 18.3 | |||
| Min | 3.2 | 3.2 | |||
| Max | 33.9 | 37.81 | |||
| Std Dev | 7.59 | 7.78 | |||
| Bladder, V40 | N | 77 | 77 | 0.522 | |
| Mean | 68.94 | 69.1 | |||
| Median | 68.8 | 69.7 | |||
| Min | 39.1 | 39.1 | |||
| Max | 100 | 100 | |||
| Std Dev | 15.04 | 14.79 | |||
| Bladder, V65 | N | 77 | 77 | 0.182 | |
| Mean | 50.03 | 50.29 | |||
| Median | 48.2 | 47.05 | |||
| Min | 19.34 | 24.91 | |||
| Max | 95.8 | 97.5 | |||
| Std Dev | 17.15 | 17.03 | |||
| Penile Bulb, V40 | N | 77 | 77 | <.001 | |
| Mean | 47.43 | 55.74 | |||
| Median | 45 | 56.8 | |||
| Min | 0 | 0 | |||
| Max | 100 | 100 | |||
| Std Dev | 30.38 | 31.62 | |||
| Penile Bulb, V65 | N | 77 | 77 | <.001 | |
| Mean | 22.97 | 30.81 | |||
| Median | 19.2 | 28.6 | |||
| Min | 0 | 0 | |||
| Max | 100 | 100 | |||
| Std Dev | 24.33 | 28.39 | |||
| Small bowel, V45 | N | 74 | 75 | 0.247 | |
| Mean | 53.83 | 54.26 | |||
| Median | 1.9 | 1.67 | |||
| Min | 0 | 0 | |||
| Max | 311.56 | 324.25 | |||
| Std Dev | 75.87 | 77.04 | |||
The parametric p-value is calculated by a paired t-test.
CTV1/PTV1= Clinical & planning target volume for pelvic nodal field (when applicable) CTV2/CTV & PTV2/PTV: Clinical and planning target volume for prostate bed field alone (CTV/PTV) or in association with pelvic nodal field (CTV2/PTV2).
Acknowledgements:
Research reported in this publication was supported in part by the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding
National Institutes of Health/National Cancer Institute (NIH R01 CA169188), Blue Earth Diagnostics, and Winship Cancer Institute of Emory University
Footnotes
ClinicalTrials.gov registration number: NCT01666808
Institutional Review Board number: IRB00057680
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