- Email: [email protected]
A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer
Accepted Manuscript A Comparison between Low Dose-Rate Brachytherapy +/- Androgen Deprivation, External Beam Radiotherapy +/- Androgen Deprivation, and Radical Prostatectomy +/- Adjuvant or Salvage Radiotherapy for High-Risk Prostate Cancer Jay P. Ciezki, M.D., Michael Weller, M.D., Chandana A. Reddy, M.S., Jeffrey Kittel, M.D., Harguneet Singh, Rahul Tendulkar, M.D., Kevin L. Stephans, M.D., James Ulchaker, M.D., Kenneth Angermeier, M.D., Andrew Stephenson, M.D., Steven Campbell, M.D., Georges-Pascal Haber, M.D., Ph.D., Eric A. Klein, M.D. PII:
S0360-3016(16)33554-4
DOI:
10.1016/j.ijrobp.2016.12.014
Reference:
ROB 23960
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 6 September 2016 Revised Date:
25 November 2016
Accepted Date: 7 December 2016
Please cite this article as: Ciezki JP, Weller M, Reddy CA, Kittel J, Singh H, Tendulkar R, Stephans KL, Ulchaker J, Angermeier K, Stephenson A, Campbell S, Haber G-P, Klein EA, A Comparison between Low Dose-Rate Brachytherapy +/- Androgen Deprivation, External Beam Radiotherapy +/Androgen Deprivation, and Radical Prostatectomy +/- Adjuvant or Salvage Radiotherapy for High-Risk Prostate Cancer, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2016.12.014. 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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A Comparison between Low Dose-Rate Brachytherapy +/- Androgen Deprivation, External Beam Radiotherapy +/- Androgen Deprivation, and Radical Prostatectomy +/- Adjuvant or Salvage Radiotherapy for High-Risk Prostate Cancer
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Jay P. Ciezki, M.D.*, Michael Weller, M.D.*, Chandana A. Reddy, M.S.*, Jeffrey Kittel, M.D.*, Harguneet Singh*, Rahul Tendulkar, M.D.*, Kevin L. Stephans, M.D.*, James Ulchaker, M.D.**, Kenneth Angermeier, M.D.**, Andrew Stephenson, M.D.**, Steven Campbell, M.D.**, GeorgesPascal Haber, M.D., Ph.D.**, and Eric A. Klein, M.D.**
*Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic
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**Glickman Urological and Kidney Institute, Department of Urology, Cleveland Clinic
Correspondence:
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Jay P. Ciezki, M.D.
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JPC serves as Senior Editor of the GU Section, CAR serves as Statistical Editor, and RT serves as Continuing Medical Education Editor of The International Journal of Radiation OncologyBiologyPhysics.
Desk T-28
9500 Euclid Avenue
Cleveland, OH 44195 USA
PH (216) 445-9465 FAX (216) 445-1068 Email: [email protected]
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Abstract Purpose: We compare the efficacy and toxicity among the three major modalities available
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used to treat high-risk prostate cancer (HRCaP). Methods and Materials: From 1996-2012, 2557 HRCaP patients were treated: 734 external beam radiation (EBRT) +/- androgen deprivation therapy (ADT), 515 low-dose-rate prostate brachytherapy (LDR) +/- ADT, and 1308 radical prostatectomy (RP) +/- EBRT. Biochemical
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relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer-specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology
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Criteria for Adverse Events, version 4.03 (CTCAE v4.03). The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray’s test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM.
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Results: The median follow-up and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (p=0.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73%
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for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (p=0.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and
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6.8% for RP (p=0.0004). The 10-year cumulative incidence of > grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (p<0.0001). The 10-year cumulative incidence of > grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, 1.0% for RP (p<0.0001).
Conclusion: HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.
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Introduction There is no level I evidence comparing major treatment modalities that defines a standard-ofcare for high-risk prostate cancer (HRCaP) patients.1 The data available for guidance is most
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voluminous within the area of external beam radiotherapy plus androgen deprivation therapy (EBRT)2-11, somewhat available within the radical prostatectomy plus adjuvant/salvage
radiotherapy (RP) literature12,13, and least explored using low-dose-rate prostate brachytherapy (LDR)14-16. Perhaps because of the distribution of these data, the National Comprehensive
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Cancer Network® (NCCN) has excluded low-dose-rate prostate brachytherapy as monotherapy from its guidelines for the treatment of HRCaP, implying that a standard among major therapies
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exists and that LDR was found to be lacking in efficacy or had excessive toxicity.17 As noted above however, there is little information on outcomes following LDR as monotherapy for the treatment of HRCaP to support its exclusion from the NCCN guidelines. Recently, The ASCENDE-RT trial has shown superior biochemical outcomes from the
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combination of LDR with EBRT + ADT over EBRT + ADT alone for intermediate-risk or HRCaP.15 Similar to the results seen in the RTOG 0232 phase III trial for intermediate-risk prostate cancer assessing the effect of adding LDR to EBRT18,19, the ASCENDE-RT trial also
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demonstrated an increased toxicity with the combination of LDR with EBRT.20 In appealing to the first principles of radiotherapy, one finds that it is well within the capabilities of LDR
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techniques to encompass the microscopic extent of HRCaP within the region of the prostate, making LDR monotherapy a logical alternative treatment for HRCaP.21 The use of LDR monotherapy takes on more promise when noting that a combination of EBRT with LDR yields toxicity that is greater than that of either EBRT20 or that of LDR as monotherapy.14 In this manuscript, we present the results of an inception cohort study in which HRCaP patients were treated with RP, EBRT, or LDR. Both efficacy and toxicity is reported in the hope that LDR may be considered for incorporation into future clinical trials of HRCaP.
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Methods and Materials Since 1993 we have maintained an IRB-approved inception cohort study for all prostate cancer patients treated definitively at our institution. We queried this database to identify patients with
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NCCN-defined HRCaP treated definitively with RP, EBRT, or LDR from 1996 to 2012. The pathologic grading conformed to the 2006 update of the Gleason grading system.22 Gleason grading reported here is from biopsy tissue. All EBRT patients were required to have received
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at least 78 Gy at 2 Gy per fraction or 70 Gy at 2.5 Gy per fraction with image guidance
(ultrasound or cone beam CT). Patients treated with LDR were planned so that the prostate
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and proximal seminal vesicles received 144 Gy with a 5 mm margin laterally, anteriorly, and inferiorly. No margin was planned superiorly (bladder) and posteriorly (rectum). RP patients underwent either an open, a pure laparoscopic, or a robotic-assisted prostatectomy. For those RP patients who received adjuvant or salvage EBRT, the median dose was 70 Gy at 2 Gy/ fraction. Choice of treatment modality was determined by the patient after being counseled on
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all three treatment modalities.
The primary efficacy end points were biochemical relapse-free survival (bRFS), clinical relapsefree survival (cRFS), and prostate cancer-specific mortality (PCSM). Biochemical failure was
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defined as a PSA value of at least 0.4 ng/mL for RP patients23 and the Phoenix Definition24 was used for EBRT and LDR patients. If a patient received post-operative EBRT prior to the post-
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RP PSA exceeding 0.4 ng/mL, he was counted as a biochemical failure. We defined cRFS as metastases identified via medical imaging (with or without co-localizing symptoms) or as biopsyproven local recurrence. For post-EBRT and post-LDR biopsies, the biopsy had to show adenocarcinoma with no evidence of radiation effect for the patient to be coded as having a local failure. PCSM was defined as death due to prostate cancer as noted on the death certificate (corroborated with biochemical and clinical information prior to death) or the presence of uncontrolled metastatic disease at time of death.
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The primary toxicity endpoints were defined via the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).25 A retrospective chart review is performed periodically to assess toxicity as documented in clinical notes contained in the electronic medical record as
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maintenance of the database, but a review specific to those subjects included here was completed for this report. We focused on gastrointestinal and genitourinary toxicity, but severe toxicity of any site was also recorded. We linked a clinical event as a toxicity if it was possibly,
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probably, or definitely associated with the initial treatment. Grade 2 toxicity was reported as any toxicity after 2 months from treatment (to exclude typical acute toxicity like catheter usage after
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RP) while grade 3 toxicity was reported at any time since therapy. Secondary malignancies were coded as being associated with treatment if they were within the treatment field. For all end points, factors thought or known to influence the endpoint were recorded and used in the analysis for the outcomes of interest. The Chi-square test and analysis of variance were used to evaluate differences in demographic and clinical characteristics among the modalities.
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The log-rank test was used to compare bRFS and cRFS among the modalities, and Cox regression was used to identify factors associated with bRFS and cRFS. The analyses for bRFS and cRFS were limited to patients who had at least two follow up PSAs post treatment.
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Gray’s test was used to compare differences in late toxicity and PSCM among the modalities. Competing risk regression was used to identify factors associated with PSCM. All analyses
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were done with SAS v. 9.4 (SAS Inst., Cary, NC) or R v. 3.3.1 (R Foundation, Vienna, Austria). A p-value of <0.05 was considered to be statistically significant.
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Results A total of 2557 patients were included comprising: 734 EBRT patients (29%), 515 LDR patients (20%), and 1308 RP patients (51%). The median follow-up for the entire group was 63.5
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months. The median age (years) of the patients was 65 overall and 68.5 for EBRT, 70 for LDR, and 62 for RP. At the last follow-up, 80% of patients were still alive. For the EBRT patients, 384 (52%) received 78 Gy at 2 Gy per fraction while 350 (48%) received 70 Gy at 2.5 Gy per
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fraction. For the RP patients, 732 (56%) received an open prostatectomy, 103 (7.8%) received a pure laparoscopic prostatectomy, and 473 (36.2%) received a robotic-assisted prostatectomy.
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The median 30-day D90 for the LDR patients was 149.39 Gy (one standard deviation = 21.31 Gy). Neoadjuvant or adjuvant androgen deprivation therapy (ADT) was administered to 93% of EBRT patients, 53% of LDR patients, and 19% of RP patients. Descriptive statistics are shown in Table 1. Patients treated with EBRT had longer follow-up, higher iPSA, more advanced T stage, and a higher preponderance of ISUP 5 disease; however, there is also a higher
cohort.
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preponderance of International Society of Urologic Pathology (ISUP) 1 disease in the EBRT
The bRFS for the RP patients is lower than LDR and EBRT (Figure 1A). On multivariable
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analysis of the entire cohort, RP vs. EBRT, clinical stage T3, biopsy Gleason Score 8-10, higher pre-treatment PSA, shorter ADT duration, and more frequent PSA testing post-therapy were
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associated with significantly worse bRFS (Table 2). The multivariable model did not show a significant difference between Gleason 6 vs. Gleason 8-10 but this is likely an artifact of the small number of patients with Gleason 6 . The log-rank test was not significant for cRFS among the modalities (Figure 1B). On multivariable analysis, EBRT vs. RP and LDR vs. RP, clinical stage T3, and biopsy Gleason Score 8-10 were associated with significantly worse cRFS (Table 2).
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The cumulative incidence of PCSM was higher for EBRT patients than for patients treated with LDR and RP (Figure 1C). On multivariable analysis, EBRT vs. RP, higher clinical stage, higher pre-treatment PSA, biopsy Gleason Score 8-10, and younger age were associated with
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significantly worse PCSM (Table 2). Figure 2A shows the cumulative incidence of grade >3 GU toxicity. The 10-year cumulative incidence of > grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for As seen in Table 3, the majority of the GU toxicities result from minor
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RP (p<0.0001).
procedures necessary to manage incontinence or obstruction. In keeping with some literature,26
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we also note a lower early complication rate for grade >3 GU toxicity with robotic-assisted prostatectomy, but this advantage dissipates with further follow-up (Figure 2B). The EBRT group had a greater incidence of >3 gastrointestinal (GI) toxicity (Figure 2C). The 10-year cumulative incidence of > grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, 1.0% for RP (p<0.0001).When examining grade >2 GI toxicities (more “bothersome” toxicities
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vs. those serious enough to require intervention) , one sees parallels with the PROST-QA trial in which near the 2-year mark, the EBRT patients experienced a greater amount of rectal bother (Figure 2D).27 The more “bothersome” GU toxicities are included in Figure 2E. In addition to
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the grade 5 GI and GU toxicities listed in Table 3, there were three other deaths resulting from some aspect of prostate cancertreatment: one fatal post-operative hemorrhage in the RP group,
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one neutropenic sepsis after salvage chemotherapy in the EBRT group, and one fatal case of diarrhea 8 hours after an infusion of chemotherapy in the EBRT group. The secondary malignancy rate is shown in Figure 2F.
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Discussion With the lack of prospective, randomized, comparative efficacy studies among modalities used to treat HRCaP, observational studies such as this serve as a significant source of clinical
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guidance. In addition to the efficacy data presented, we also supplemented our investigation with toxicity data. Our research effort forces us to conclude that LDR is highly competitive with EBRT and RP. We feel that a case can be made for considering all three major modalities for
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the treatment of HRCaP.
This report possesses several significant strengths. The two most important of which are its
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relatively long median follow-up and the use of modern treatment techniques. The 63.5-month median follow-up permits us to adequately assess all meaningful efficacy and toxicity end points. The use of high dose radiation in the EBRT arm and the fact that 93% of the EBRT patients received ADT, indicate that the EBRT techniques meet modern recommendations for this modality. All LDR patients were treated with an intraoperative planning technique
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minimizing set-up error.28 Most of the RP patients were offered adjuvant or salvage EBRT, but only 18.6% received it, similar to contemporary patterns of care.29,30 Finally, the percentage of high-risk patients treated at our institution over the period of this study has remained constant at
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15-20% of all newly-diagnosed CaP patients per year while the percentage of low-risk patients treated per year has decreased from ~50% to ~15%. This shift reflects our enthusiasm for
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active surveillance in appropriate patients as per most modern prostate cancer treatment guidelines.
The differences in the definition for biochemical failure in each modality make it a difficult end point to use for comparisons. Specifically, the bRFS for the RP patients is 43% at 10 years versus 52% and 53% for LDR and EBRT; we believe that this phenomenon is due to the more rigorous Phoenix definition of biochemical failure and not clinically significant. Comparisons between the ASCENDE-RT trial and this series for bRFS are challenging because only two-
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thirds of the patients in ASCENDE-RT had HRCaP while the remaining one-third had intermediate-risk disease. Yet, the control arm (EBRT+ADT) of ASCENDE-RT fared about 20% worse than the patients in any of the modalities in this series, depending on the bRFS definition
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used.15 The difference is difficult to explain because one would expect the reverse given the longer duration of ADT in ASCENDE-RT vs. this series (12 months vs. 6 months) and
underscores the hazards of using bRFS as an endpoint to evaluate treatment efficacy. Our
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shorter duration of ADT is primarily the result of the fact that most of our EBRT patients were treated 10 years ago when the optimal duration of ADT had not been as thoroughly
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investigated. As will be discussed in the following paragraphs, the ambiguous effect of ADT dosage on bRFS noted above is not observed when cRFS and PCSM are examined. This may be due to the higher doses of radiation in the LDR group overwhelming a positive effect of ADT or the vagaries of bRFS as an end point.
Overall, there was no significant difference among the modalities relative to cRFS (Figure 1).
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The surgical patients did have a better outcome in pair-wise comparisons (Table 2), and this may be due to differences in follow-up since many of the RP patients were followed from a distance while the EBRT and LDR patients were usually followed locally increasing the chance
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of knowing about a clinical failure. Also, due to the differences in definition for biochemical failure, it is possible that RP patients are observed to experience a biochemical failure sooner
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than EBRT or LDR patients, allowing for an earlier salvage therapy intervention. The PCSM results show that LDR is competitive with EBRT and RP. The slight differences seen between EBRT and RP in our series mimics that difference noted by Sooriakumaran P et al.31 Both investigations note that EBRT patients have an inferior PCSM compared to RP that persists after controlling for variables known to affect PCSM. In our series, one additional factor that may explain the difference in PCSM is that our EBRT patients had a longer median follow up than our LDR or RP patients. This results from our lower enthusiasm for EBRT over time
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because of the differences in rates of toxicity noted by ourselves and others.27 As a result, most of our EBRT patients were treated 10 years ago.
One assumes that the median follow-up did
not differ in Sooriakumaran P et al., but as far as can be determined from the manuscript, they
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did not include LDR, disclose the dose of EBRT, or note whether the EBRT patients in the highrisk group had ADT. It is unlikely that they would have known about the EBRT dose or ADT from their national database data source, but their omission of LDR could probably have been
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avoided. When LDR is included in an analysis of PCSM, as we have done here, one can see that the PCSM of LDR is equivalent to RP. Further, the disease aggressiveness of our RP and
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LDR groups are equally balanced and they have similar follow-up; the differences between LDR and RP vs. EBRT may be explained by the greater disease aggressiveness and longer followup in the EBRT group. In the EBRT cohort, 36% of patients had initial PSAs that were > 20ng/mL while the LDR cohort had and the RP cohort both had 15% of patients with an initial PSA > 20ng/mL. In addition, the EBRT group had a higher percentage of patients with a
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Gleason 9 or 10 (ISUP 5): 17% vs. 11.4% for LDR and 14.3% for RP. The EBRT group also had significantly more T3 patients (14%) vs. 0.4 % in LDR and 3% in RP. The longer PSA f/u in the EBRT patients could have biased the results against EBRT by knowing of biochemical
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failure more frequently than other groups, but we feel that we guarded against this eventuality (see Methods and Materials) by corroborating death certificate information with clinical data
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prior to death. The use of ADT did not improve the PCSM in the LDR group presented in this paper (p = 0.42; HR 1.97, 95% CI = 0.38-10.2, Figure 1D for cumulative incidence). Mirroring our results, D’Amico et al. noted that HRCaP patients treated with LDR alone had a PCSM similar to those treated with LDR plus ADT.16 Their report differs in that the PCSM rate at 5 years for their LDR-alone group is ~6% while our 5-year PCSM rate is 1.2% for the LDR-alone group. Our study lacks data on biopsy core positivity percent, but in high-risk disease this data appears to have limited significance.32
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The observed PCSM rates provide some insight into future directions for HRCaP clinical research. In particular, the question of local intensification vs. adjunctive systemic therapy gains importance. The local failure rate (Table 1) across all three cohorts is 2%. Since one of the
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three groups is RP +/- EBRT for adjuvant or salvage treatment, which is arguably the most intensive local treatment commonly used, it is unreasonable to expect much improvement of this end point. The equivalence of the local failure rates suggest that all three treatments are high
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on the “shoulder” of the classic dose-response curve for HRCaP. Additional effort to intensify locally in NRCaP patients, such as by combining EBRT with LDR, is likely to result in the same
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toxicity differences seen in RTOG 02-32 in which combining modalities (EBRT + LDR vs. LDR) for intermediate-risk prostate cancer was not noted to improve efficacy but did increase toxicity.19 When comparing combined modality therapy in HRCaP, as in ASCENDE-RT, to EBRT, again one sees increasing toxicity with the use of multi-modality treatment.20 In ASCENDE-RT, the multi-modaity arm did demonstrate an improved bRFS, but there has not
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been a reported advantage in PCSM.15 It has been recently noted that in the ISUP 5 category of HRCaP there is an advantage in cRFS with LDR + EBRT over EBRT and RP, but this did not translate into a PCSM improvement.33 This echos earlier data in which higher biologic effective
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dose, that the authors calculate as being higher in LDR + EBRT, shows better bRFS and cRFS but unfortunately did not assess PCSM.34 With unclear evidence for improvement in “hard”
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clinical outcomes like PCSM or local failure and the increased toxicity in multi-modality treatment, it seems more reasonable to focus on the other ~90% of treatment failures which we identify in this series as metastatic disease. Local intensification may affect metastatic spread, but this is not likely in a population with such good local control. The value of regional intensification such as nodal radiation, remains unknown after decades of study and this uncertainty has generated further studies to help clarify.35 Consequently, it seems that systemic therapy beyond the typical use of ADT should be the focus of attention for future investigation.
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Toxicity is important to note when making comparisons in observational studies. It is very difficult to compare toxicity using observational studies where data are sourced from a national database but, it is more readily performed from a single institution study such as this series.
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Here we compare GI and GU toxicities using CTCAE v4.03. The rate of grade 5 toxicity is very low. In addition, the rate of fistula formation after LDR is lower than prior reports although with such an uncommon event, comparisons are difficult.36 The overall grade 3 and higher GU
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toxicity is well within the expected range.37 The higher GI toxicity in the EBRT patients also tracks with prior reports and the assessment of the grade 2 GI toxicity (analogous to the “bothersome” toxicity noted in the EPIC questionnaire and shown here in Figure 2D) yields a
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very similar result to that noted in PROST-QA.27 In addition, despite the fact that they treated low and intermediate-risk patients, the grade 2 toxicity of our patients follows the toxicity profile of the patients treated on the ProtecT trial which scored toxicity in a manner similar to PROSTQA.38,39 We feel that this indicates that the larger margins that one expects when treating high-
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risk disease did not yield a toxicity profile that was substantially different from the population in ProtecT. The plateau seen in the RP and LDR patients’ cumulative incidence toxicity curves (Figure 2) may reflect the larger volume of tissue being irradiated vs. LDR and only 18.6% of the
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RP patients received EBRT which limited the potential of patients in that arm to express the late toxicity seen in the EBRT alone arm.
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The majority of both the higher grade >3 GI toxicity with EBRT and the higher grade >3 GU toxicity with RP only required minor procedures for treatment, but are still important to note. The use of robotic-assisted RP results in a transient reduction of GU toxicity, but this gap closes relative to the open and pure laparoscopic approaches with further follow-up (Figure 2B). The secondary malignancy rate is in keeping with prior reports.40
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Conclusions For HRCaP, there is no standard-of-care because of the near complete lack of randomized comparative efficacy studies. This report helps fill this gap by providing efficacy and toxicity
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outcomes in HRCaP patients treated with LDR, RP, or EBRT. They each have similar efficacy but different toxicity. Given the competitive LDR results reported here, it is reasonable to
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consider LDR for HRCaP.
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17. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer, Version 1.2106 Freatured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2016;14:19-30. 18. Lawton CA, Yan Y, Lee WR, et al. Long-term results of an RTOG Phase II trial (00-19) of external beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate. Int J Radiation Oncology Biol Phys 2012;82:e795-801. 19. Prestidge BR, Winter K, Sanda MG, et al. Initial report of NRG Oncology/RTOG 0232: A phase 3 study comparing combined external beam radiation and transperineal interstitial permanent brachytherapy with brachytherapy alone for selected patients with intermediate-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 2016;96:S4. 20. Rodda SL, Tyldesley S, Morris WJ. Toxicity outcomes in ASCENDE-RT: a multicenter randomized trial of dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2015;93:S121. 21. Sohyada C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000;55:382-6. 22. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL. Update on the Gleason grading system for prostate cancer: results of an international consensus conference of urologic pathologists. Adv Anat Pathol 2006;13:57-9. 23. Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006;24:29738. 24. Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiation Oncology Biol Phys 2006;65:965-74. 25. Common Terminology Criteria for Adverse Events version 4.03. 2010. (Accessed June 1, 2016, at evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03.) 26. Leow JJ, Chang SL, Meyer CP, et al. Robot-assisted versus open radical prostatectomy: a contemporary analysis of an all-payer discharge database. Eur Urol 2016. 27. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-61. 28. Wilkinson DA, Lee EJ, Ciezki JP, et al. Dosimetric comparison of pre-planned and or-planned prostate seed brachytherapy. Int J Radiation Oncology Biol Phys 2000;48:1241-4. 29. Sineshaw HM, Gray P, Efstathiou JA, Jemal A. Declining use of radiotherapy for adverse features after radical prostatectomy: results from the National Cancer Data Base. Eur Urol 2015;68:768-74. 30. Kalbasi A, Swisher-McClure S, Mitra N, et al. Low rates of adjuvant radiation in patients with nonmetastatic prostate cancer with high-risk pathologic features. Cancer 2014;120:3089-96. 31. Sooriakumaran P, Nyberg T, Akre O, et al. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality ouotcomes. BMJ 2014;348:g1502. 32. Ellis CL, Partin AW, Han M, Epstein JI. Adenocarcinoma of the prostate with Gleason Score 9-10 on core biopsy: correlation with findings at radical prostatectomy and prognosis. J Urol 2013;190:206873. 33. Kishan AU, Shaikh T, Wang PC, et al. Clinical ooutcomes for patients with Gleason score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis. Eur Urol 2016. 34. Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;73:341-6. 35. Roach III M, DeSilvio M, Valicenti R, et al. Whole-pelvis, "mini-pelvis", or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiation Oncology Biol Phys 2006;66:647-53.
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36. Leong N, Pai HH, Morris J, et al. Rectal ulcers and rectoprostatic fistulas after I-125 low dose rate brachytherapy. J Urol 2016;195:1811-6. 37. Jarosek SL, Virnig BA, Chu H, Elliott SP. Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both. Eur Urol 2015;67:273-80. 38. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016;375:1415-24. 39. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375:1425-37. 40. Abdel-Wahab M, Reis IM, Wu J, Duncan R. Secondary primary cancer risk of radiation therapy after prostatectomy for prostate cancer: an analysis of SEER data. Urology 2009;74:866-72.
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Figure Legends
Figure 1. Efficacy plots.
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A. Kaplan-Meier estimates of biochemical relapse-free survival for low-dose-rate brachytherapy (LDR) plus/minus, external beam radiation plus/minus androgen deprivation therapy (EBRT), and radical prostatectomy plus/minus adjuvant or salvage external beam radiotherapy (RP). Analysis limited to patients with a least two posttreatment PSAs. B. Kaplan-Meier estimates of clinical relapse-free survival for low-dose-rate brachytherapy (LDR) plus/minus, external beam radiation plus/minus androgen deprivation therapy (EBRT), and radical prostatectomy plus/minus adjuvant or salvage external beam radiotherapy (RP). Analysis limited to patients with a least two post-treatment PSAs. C. Cumulative incidence of prostate cancer-specific mortality for low-dose-rate brachytherapy (LDR) plus/minus, external beam radiation plus/minus androgen deprivation therapy (EBRT), and radical prostatectomy plus/minus adjuvant or salvage external beam radiotherapy (RP). D. Cumulative incidence of prostate cancer-specific mortality for low-dose-rate brachytherapy (LDR) by use of androgen deprivation therapy (ADT). Figure 2. Toxicity plots.
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A. Cumulative incidence of grade 3 or higher genitourinary toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). B. Cumulative incidence of grade 3 or higher genitourinary toxicity among radical prostatectomy sub-types (open, pure laparoscopic, and robotic-assisted), assessed with the Common Terminology Criteria for Adverse Events, version 4.03. ( Lap RP = laparoscopic non-robotic prostatectomy; Open RP = open radical prostatectomy; Robotic RP = robotic prostatectomy). C. Cumulative incidence of grade 3 or higher gastrointestinal toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). D. Cumulative incidence of grade 2 or higher gastrointestinal toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). E. Cumulative incidence of grade 2 or higher genitourinary toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). F. Cumulative incidence of secondary malignancies for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). All secondary malignancies occurred within the radiation field except one spindle cell malignancy (histologically indistinguishable from spindle cell malignancies seen in EBRT fields) in an RP patient who did not receive EBRT. This may suggest that spindle cell cancers seen after radiation may not be radiation-induced, but simply a persistent variant of cancer
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detected after primary treatment. Because we want to apply the same standards to each modality this patient was coded as a secondary malignancy due to its histologic appearance and location.
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Table 1. Descriptive Statistics
Factor
EBRT*
LDR**
RP***
n/median
%/range
n/median
%/range
n/median
734
29
515
20
1308
p-value
%/range
Count 51 <0.0001
68.5
40-86
70
44-89
Risk Sub-Grouping
RI PT
Age (y)
62
43-79
<0.0001
2 intermediate factors
207
28
248
48
>1 high-risk factor
527
72
267
52
582
45
726
55
459
62
458
89
779
60
11
489
37
0.4
40
3
<0.0001
T1 or T2A T2B or T2C
174
24
55
T3
101
14
2
<4
22
3
4 - <10
185
25
10 - <20
255
34
>20
271
36
1
0.1
76
10
unknown Biopsy Gleason (ISUP) 6 (1)
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Initial PSA (ng/mL)
SC
Clinical Stage
<0.0001
15
3
134
10
161
32
527
40
257
50
451
35
81
15
196
15
1
0.2
0
0
31
6
70
5
<0.0001
354
48
278
54
662
51
8 (4)
178
24
147
28
394
30
9 (5)
117
16
57
11
178
14
10 (5)
9
1
2
0.4
4
0.3
7
241
47
1061
81
93
274
53
247
19
Androgen Deprivation
TE D
7 (2 or 3)
54
Yes
680
Duration ADT (m) 0
EP
No
<0.0001
<0.0001
54
7
241
47
1061
81
487
66
241
47
197
15
193
26
31
6
24
2
0
0
2
0.4
26
2
6
3-78
6
1-32
3
0.25-86
94.6
1.2-242
48.9
0.1-201
55.6
0.1-238.7
No
444
65
305
75
715
65
Yes
240
35
104
25
378
35
1-6
AC C
>6
unknown
Duration ADT^ (m)
<.00001
Follow-up Time
<.00001
Biochemical Failure#
#
Clinical Failure
No
542
79
366
90
955
87
Yes
142
21
43
10
138
13
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Local Failure No
670
98
401
98
1074
98
Yes
14
2
8
2
19
2
Distant Metastases 550
80
370
91
967
89
134
20
39
9
126
12
Alive
463
63
444
86
Dead Other Cause
192
26
60
12
Yes
79
11
11
2
Prostate Cancer Death
RI PT
No Yes
1139
87
120
9
49
4
AC C
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*External beam radiotherapy; **Low dose-rate brachytherapy; ***Radical prostatectomy, † International Society of Urologic Pathology33, ^ADT duration for patients who received ADT; # analysis for biochemical and clinical failure limited to patients with >2 post-treatment PSAs
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Table 2. Univariate and Multivariable Analyses of Efficacy Factor
Univariate P-value HR* (95% CI**)
Multivariable P-value HR* (95% CI**)
Treatment
0.1257 0.1335 0.0003
0.83 (0.66-1.05) 1.22 (0.94-1.57) 1.43 (1.19-1.79)
1.05 (0.89-1.25) 1.73 (1.35-2.23) 1.64 (1.25-2.16)
0.1321 0.0001 0.0086
1.15 (0.96-1.37) 1.69 (1.29-2.20) 1.47 (1.10-1.96)
0.92 (0.69-1.23) 1.51 (1.14-2.00) 1.64 (1.40-1.90)
0.5478 0.1537 0.0003
0.92 (0.69-1.22) 1.24 (1.92-1.66) 1.36 (1.15-1.59)
1.01 (1.01-1.01)
<0.0001
1.01 (1.01-1.01)
0.99 (0.98-1.00)
0.0104
0.98 (0.97-1.00)
0.93 (0.79-1.08) 0.94 (0.73-1.21) 1.02 (0.79-1.31)
-
-
1.43 (1.38-1.48)
<0.0001
1.42 (1.38-1.48)
1.00 (1.01-1.01)
<0.0001
1.01 (1.01-1.01)
0.8455 0.1493 0.0668
0.97 (0.69-1.36) 0.78 (0.55-1.10) 0.80 (0.64-1.02)
0.0176 0.5278 0.0277
1.57 (1.08-2.27) 1.13 (0.78-1.65) 0.72 (0.54-0.97)
0.2436 <0.0001 0.0003
1.16 (0.90-1.49) 2.26 (1.62-3.14) 1.94 (1.35-2.79)
0.4610 <0.0001 0.0011
1.10 (0.85-1.44) 2.11 (1.48-3.00) 1.91 (1.30-2.81)
0.1191 <0.0001 <0.0001
1.56 (0.89-2.73) 4.12 (2.39-7.10) 2.64 (2.08-3.34)
0.0730 0.0001 <0.0001
1.68 (0.95-2.96) 3.03 (1.73-5.29) 1.81 (1.40-2.32)
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0.70 (0.56-0.87) 0.96 (0.76-1.21) 1.37 (1.17-1.61)
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LDR*** vs. RP† 0.0013 LDR*** vs. EBRT‡ 0.7214 RP† vs. EBRT‡ 0.0001 Clinical Stage T2B&C vs. T1&T2A 0.5546 T3 vs. T1&T2A < 0.0001 T3 vs. T2B&C 0.0004 Biopsy Gleason 7 vs. 6 0.5740 8-10 vs. 6 0.0044 8-10 vs. 7 <0.0001 Initial PSA <0.0001 ADT§ Duration (months) 0.1799 ADT§ Duration (months) 1-6 vs. 0 0.3422 >6 vs. 0 0.6497 >6 vs. 1-6 0.8899 PSA Frequency <0.0001 PSA Frequency x Time <0.0001
RI PT
Biochemical Relapse-Free Survival
Clinical Relapse-Free Survival Treatment
AC C
LDR*** vs. RP† LDR*** vs. EBRT‡ RP† vs. EBRT‡ Clinical Stage T2B&C vs. T1&T2A T3 vs. T1&T2A T3 vs. T2B&C Biopsy Gleason 7 vs. 6 8-10 vs. 6 8-10 vs. 7 Initial PSA
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0.0987
1.00 (1.00-1.01)
0.7134
1.00 (0.99-1.01)
0.0151
1.02 (1.00-1.03)
0.3797
0.99 (0.98-1.01)
0.0302 <0.0001 0.0121
1.31 (1.03-1.68) 1.96 (1.41-2.74) 1.49 (1.09-2.04)
-
-
<0.0001
1.56 (1.45-1.66)
<0.0001
1.54 (1.44-1.65)
<0.0001
1.01 (1.01-1.01)
<0.0001
1.01 (1.01-1.01)
ADT§ Duration (months) 1-6 vs. 0 >6 vs. 0 >6 vs. 1-6 PSA Frequency PSA Frequency x Time
SC
Prostate Cancer-Specific Mortality Treatment
ADT§ Duration (months)
0.68 (0.35-1.30) 0.37 (0.20-0.69) 0.54 (0.38-0.78)
0.6764 0.1069 0.0018
1.15 (0.60-2.23) 0.58 (0.30-1.13) 0.50 (0.32-0.77)
1.64 (1.13-2.39) 3.16 (2.00-4.98) 1.92 (1.18-3.12)
0.0038 0.0008 0.3033
1.77 (1.20-2.61) 2.33 (1.42-3.83) 1.32 (0.78-2.22)
2.23 (0.80-6.20) 6.06 (2.23-16.46) 2.72 (1.90-3.89)
0.0928 <0.0001 <0.0001
2.44 (0.86-6.92) 7.82 (2.80-21.89) 3.21 (2.22-4.61)
0.0009
1.01 (1.00-1.02)
0.0068
1.01 (1.00-1.01)
<0.0001
1.03 (1.03-1.04)
0.4906
1.01 (0.99-1.02)
<0.0001 <0.0001 0.0724
2.72 (1.75-4.22) 4.04 (2.35-6.92) 1.49 (0.96-2.29)
-
-
0.0026
0.97 (0.95-0.99)
0.0001
0.96 (0.94-0.98)
0.0089 <0.0001 0.0081 0.1259 0.0004 <0.0001
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0.2404 0.0018 0.0009
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LDR*** vs. RP† LDR*** vs. EBRT‡ RP† vs. EBRT‡ Clinical Stage T2B&C vs. T1&T2A T3 vs. T1&T2A T3 vs. T2B&C Biopsy Gleason 7 vs. 6 8-10 vs. 6 8-10 vs. 7 Initial PSA
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ADT§ Duration (months) 1-6 vs. 0 >6 vs. 0 >6 vs. 1-6 Age
RI PT
ADT§ Duration (months)
*Hazard ratio, **Confidence Interval, *** Low Dose-rate Brachytherapy, † Radical Prostatectomy, ‡ External Beam Radiotherapy, § Androgen Deprivation Therapy.
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Table 3. Tabulation of types of toxicity, grade >3, scored with Common Terminology Criteria for Adverse Events, version 4.03. EBRT* % n % Genitourinary
LDR** n %
2 1 1 4
50.0 25.0 25.0
1 1 1 3
33.3 33.3 33.3
0 0 0 0
0.0 0.0 0.0
1 0 0 1
100.0 0.0 0.0
1 7 1 11 5 1 2 5 33
3.0 21.2 3.0 33.3 15.2 3.0 6.1 15.2
0 2 0 3 4 0 1 1 11
0.0 18.2 0.0 27.3 36.4 0.0 9.1 9.1
0 0 0 0 0 0 0 1 1
0.0 0.0 0.0 0.0 0.0 0.0 0.0 100.0
1 5 1 8 1 1 1 3 21
4.8 23.8 4.8 38.1 4.8 4.8 4.8 14.3
2 47 4 117 1 1 1 1 30 204
1.0 23.0 2.0 57.4 0.5 0.5 0.5 0.5 14.7
0.0 2.0 0.0 57.1 0.0 0.0 0.0 0.0 40.8
0 1 0 15 0 0 0 0 4 20
0.0 5.0 0.0 75.0 0.0 0.0 0.0 0.0 20.
2 45 4 74 1 1 1 1 6 135
1.5 33.3 3.0 54.8 0.7 0.7 0.7 0.7 4.4
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Grade 5 fistula XRT‡ proctitis Total Grade 4 fistula obstruction perforation XRT‡ proctitis Total Grade 3 infection obstruction XRT‡ proctitis Total
0 1 0 28 0 0 0 0 20 49 Gastrointestinal
RP*** %
RI PT
n
2 1 3
66.7 33.3
2 1 3
66.7 33.3
0 0 0
0.0 0.0
0 0 0
0.0 0.0
8 4 2 1 22
53.3 26.7 13.3 6.7
4 1 0 1 6
66.7 16.7 0.0 16.7
1 0 0 0 1
100.0 0.0 0.0 0.0
3 3 2 0 8
37.5 37.5 25.0 0.0
2 1 28 31
6.5 3.2 90.3
1 0 24 25
4.0 0.0 96.0
0 0 3 3
0.0 0.0 100.0
1 1 1 3
33.3 33.3 33.3
EP
Grade 5 fistula renal failure XRT† cystitis Total Grade 4 anastamotic leak fistula incontinence infection necrotic tissue obstruction renal failure XRT† cystitis Total Grade 3 hernia incontinence infection obstruction pain spermatocele testicular infarct urgency XRT† cystitis Total
TE D
n
SC
All
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Description
*external beam radiotherapy; **low-dose-rate brachytherapy; ***radical prostatectomy; † radiotherapy-induced cystitis; ‡ radiotherapy-induced proctitis.
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Biochemical Relapse Free Survival by Treatment
RI PT
100
SC M AN U Treatment Number of Patients # at risk 5-yr surv (%) 95% CI (%) # at risk 10-yr surv (%) 95% CI (%) # at risk 15-yr surv (%) 95% CI (%)
20
EBRT 684 329 74 70-77 107 53 48-58 14 39 31-47
LDR 409 124 74 68-79 12 52 42-62 0 na na
EP
40
TE D
60
AC C
Cumulative Incidence (%)
80
RP 1093 306 65 61-68 85 47 43-52 12 39 33-46
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Clinical Relapse Free Survival by Treatment
RI PT
100
SC M AN U
60
EBRT 684 384 85 83-88 152 73 68-77 24 59 51-67
LDR 409 155 90 86-93 20 76 66-86 0 na na
TE D
Treatment Number of Patients # at risk 5-yr surv (%) 95% CI (%) # at risk 10-yr surv (%) 95% CI (%) # at risk 15-yr surv (%) 95% CI (%)
EP
40
20
AC C
Cumulative Incidence (%)
80
RP 1093 431 89 86-91 145 75 71-80 27 67 60-74 P-value= 0.1205
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Prostate Cancer Specific Mortality by Treatment
SC
RP 1308 612 2.8 1.7-3.9 241 6.8 4.7-8.9 69 9.8 6.6-12.9
TE D
60
LDR 515 211 3.2 1.2-5.1 40 3.6 1.5-5.8 3 3.6 1.5-5.8
EP
40
20
AC C
Cumulative Incidence (%)
80
EBRT 734 508 5.3 3.6- 7.1 261 11.2 8.6-13.9 77 15.8 12.3-19.3
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Treatment Number of Patients # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value= 0.0004
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Prostate Cancer Specific Mortality by Use of ADT for Patients Treated with LDR
LDR + ADT 374 163 4.2 1.5-6.9 26 4.2 1.5-6.9 3 4.2 1.5-6.9
SC
LDR Alone 241 48 1.2 0.0- 3.5 14 3.3 0.0-7.9 0 na na
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Treatment Number of Patients # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
TE D
60
EP
40
20
AC C
Cumulative Incidence (%)
80
RI PT
100
P-value= 0.3393
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Grade >3 GU Toxicity (Excluding Secondary Malignancies) by Treatment
SC
RP 1308 1072 5.7 4.4-7.0 558 12.7 10.7-14.8 223 16.4 13.8-19.0 64 17.2 14.4-20.0
EP
40
M AN U
60
LDR 515 436 0.9 0.0-1.8 202 4.4 2.4-6.5 35 7.2 3.4-11.0 3 7.2 3.4-11.0
20
AC C
Cumulative Incidence (%)
80
EBRT 734 699 0.3 0.0-0.7 491 4.4 2.8- 5.9 243 8.1 5.9-10.4 66 11.6 8.6-14.5
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Grade >3 GU Toxicity (Excluding Secondary Malignancies) by RP Technique
SC
Open RP 732 634 6.8 4.9-8.6 405 13.8 11.2-16.5 206 17.1 14.0-20.2 64 17.6 14.4-20.9
EP
40
M AN U
60
Robotic 473 359 3.5 1.8-5.3 106 11.3 7.9-14.8 3 15.5 8.1-22.9 0 na na
20
AC C
Cumulative Incidence (%)
80
Lap RP 103 73 6.8 1.5-12.1 47 9.2 3.1-15.3 14 16.6 6.5-26.2 0 na na
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value= 0.6028
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Grade >3 GI Toxicity (Excluding Secondary Malignancies) by Treatment
SC
RP 1308 1124 0.4 0.1-0.7 615 0.7 0.2-1.2 244 1.0 0.4-1.7 69 1.5 0.4-2.6
EP
40
M AN U
60
LDR 515 439 0.0 0.0-0.0 211 1.1 0.0-2.2 40 1.1 0.0-2.2 4 1.1 0.0-2.2
20
AC C
Cumulative Incidence (%)
80
EBRT 734 699 0.4 0.0-0.9 492 3.8 2.4- 5.2 253 4.6 3.0-6.2 76 5.7 3.6-7.7
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Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
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P-value <0.0001
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Cumulative Incidence for Grade >2 GI Toxicity (Excluding Secondary Malignancies) by Treatment
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RP 1308 1121 0.6 0.2-1.0 615 1.0 0.4-1.5 244 1.8 0.8-2.8 69 2.2 0.9-3.6
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LDR 515 439 0.0 0.0-0.0 211 1.1 0.0-2.2 40 1.1 0.0-2.2 4 1.1 0.0-2.2
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Cumulative Incidence (%)
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EBRT 734 692 1.5 0.6-2.5 475 7.0 5.1-8.9 246 8.4 6.2-10.5 72 9.9 7.3-12.5
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Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
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P-value <0.0001
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Cumulative Incidence for Grade >2 GU Toxicity (Excluding Secondary Malignancies) by Treatment 100
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RP 1308 972 8.5 6.8-10.1 491 19.0 16.6-21.5 199 25.7 22.5-28.9 60 28.0 24.4-31.5
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LDR 515 427 3.1 1.5-4.8 186 9.7 6.8-12.7 32 13.8 9.1-18.5 3 13.8 9.1-18.5
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Cumulative Incidence (%)
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EBRT 734 696 0.6 0.0-1.1 483 5.7 4.0-7.5 235 11.8 9.1-14.4 61 18.9 15.2-22.7
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Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
P-value <0.0001
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Cumulative Incidence for Secondary Malignancies by Treatment
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RP 1308 1129 0.1 0.0-0.3 616 0.2 0.0-0.4 244 0.2 0.0-0.4 68 0.9 0.0-2.0
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LDR 515 439 0.0 0.0-0.0 213 0.0 0.0-0.0 40 1.3 0.0-3.8 4 1.3 0.0-3.8
5
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Cumulative Incidence (%)
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EBRT 734 700 0.1 0.0-0.4 501 1.4 0.5-2.3 258 2.7 1.4-4.1 77 2.7 1.4-4.1
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Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
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P-value= 0.0011
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Summary There is no level I evidence defining a standard of care for patients with high-risk prostate cancer. Clinical trials comparing treatment variations within a modality exist but none compare
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outcomes among modalities. We present an inception cohort study in which we compare
efficacy and toxicity among the three major therapeutic modalities for high-risk prostate cancer: radical prostatectomy plus/minus adjuvant or salvage radiotherapy, external beam radiotherapy
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plus/minus androgen deprivation, and low-dose-rate prostate brachytherapy plus/minus
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androgen deprivation therapy.
S0360-3016(16)33554-4
DOI:
10.1016/j.ijrobp.2016.12.014
Reference:
ROB 23960
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 6 September 2016 Revised Date:
25 November 2016
Accepted Date: 7 December 2016
Please cite this article as: Ciezki JP, Weller M, Reddy CA, Kittel J, Singh H, Tendulkar R, Stephans KL, Ulchaker J, Angermeier K, Stephenson A, Campbell S, Haber G-P, Klein EA, A Comparison between Low Dose-Rate Brachytherapy +/- Androgen Deprivation, External Beam Radiotherapy +/Androgen Deprivation, and Radical Prostatectomy +/- Adjuvant or Salvage Radiotherapy for High-Risk Prostate Cancer, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2016.12.014. 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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A Comparison between Low Dose-Rate Brachytherapy +/- Androgen Deprivation, External Beam Radiotherapy +/- Androgen Deprivation, and Radical Prostatectomy +/- Adjuvant or Salvage Radiotherapy for High-Risk Prostate Cancer
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Jay P. Ciezki, M.D.*, Michael Weller, M.D.*, Chandana A. Reddy, M.S.*, Jeffrey Kittel, M.D.*, Harguneet Singh*, Rahul Tendulkar, M.D.*, Kevin L. Stephans, M.D.*, James Ulchaker, M.D.**, Kenneth Angermeier, M.D.**, Andrew Stephenson, M.D.**, Steven Campbell, M.D.**, GeorgesPascal Haber, M.D., Ph.D.**, and Eric A. Klein, M.D.**
*Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic
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**Glickman Urological and Kidney Institute, Department of Urology, Cleveland Clinic
Correspondence:
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Jay P. Ciezki, M.D.
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JPC serves as Senior Editor of the GU Section, CAR serves as Statistical Editor, and RT serves as Continuing Medical Education Editor of The International Journal of Radiation OncologyBiologyPhysics.
Desk T-28
9500 Euclid Avenue
Cleveland, OH 44195 USA
PH (216) 445-9465 FAX (216) 445-1068 Email: [email protected]
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Abstract Purpose: We compare the efficacy and toxicity among the three major modalities available
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used to treat high-risk prostate cancer (HRCaP). Methods and Materials: From 1996-2012, 2557 HRCaP patients were treated: 734 external beam radiation (EBRT) +/- androgen deprivation therapy (ADT), 515 low-dose-rate prostate brachytherapy (LDR) +/- ADT, and 1308 radical prostatectomy (RP) +/- EBRT. Biochemical
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relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer-specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology
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Criteria for Adverse Events, version 4.03 (CTCAE v4.03). The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray’s test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM.
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Results: The median follow-up and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (p=0.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73%
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for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (p=0.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and
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6.8% for RP (p=0.0004). The 10-year cumulative incidence of > grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (p<0.0001). The 10-year cumulative incidence of > grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, 1.0% for RP (p<0.0001).
Conclusion: HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.
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Introduction There is no level I evidence comparing major treatment modalities that defines a standard-ofcare for high-risk prostate cancer (HRCaP) patients.1 The data available for guidance is most
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voluminous within the area of external beam radiotherapy plus androgen deprivation therapy (EBRT)2-11, somewhat available within the radical prostatectomy plus adjuvant/salvage
radiotherapy (RP) literature12,13, and least explored using low-dose-rate prostate brachytherapy (LDR)14-16. Perhaps because of the distribution of these data, the National Comprehensive
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Cancer Network® (NCCN) has excluded low-dose-rate prostate brachytherapy as monotherapy from its guidelines for the treatment of HRCaP, implying that a standard among major therapies
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exists and that LDR was found to be lacking in efficacy or had excessive toxicity.17 As noted above however, there is little information on outcomes following LDR as monotherapy for the treatment of HRCaP to support its exclusion from the NCCN guidelines. Recently, The ASCENDE-RT trial has shown superior biochemical outcomes from the
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combination of LDR with EBRT + ADT over EBRT + ADT alone for intermediate-risk or HRCaP.15 Similar to the results seen in the RTOG 0232 phase III trial for intermediate-risk prostate cancer assessing the effect of adding LDR to EBRT18,19, the ASCENDE-RT trial also
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demonstrated an increased toxicity with the combination of LDR with EBRT.20 In appealing to the first principles of radiotherapy, one finds that it is well within the capabilities of LDR
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techniques to encompass the microscopic extent of HRCaP within the region of the prostate, making LDR monotherapy a logical alternative treatment for HRCaP.21 The use of LDR monotherapy takes on more promise when noting that a combination of EBRT with LDR yields toxicity that is greater than that of either EBRT20 or that of LDR as monotherapy.14 In this manuscript, we present the results of an inception cohort study in which HRCaP patients were treated with RP, EBRT, or LDR. Both efficacy and toxicity is reported in the hope that LDR may be considered for incorporation into future clinical trials of HRCaP.
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Methods and Materials Since 1993 we have maintained an IRB-approved inception cohort study for all prostate cancer patients treated definitively at our institution. We queried this database to identify patients with
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NCCN-defined HRCaP treated definitively with RP, EBRT, or LDR from 1996 to 2012. The pathologic grading conformed to the 2006 update of the Gleason grading system.22 Gleason grading reported here is from biopsy tissue. All EBRT patients were required to have received
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at least 78 Gy at 2 Gy per fraction or 70 Gy at 2.5 Gy per fraction with image guidance
(ultrasound or cone beam CT). Patients treated with LDR were planned so that the prostate
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and proximal seminal vesicles received 144 Gy with a 5 mm margin laterally, anteriorly, and inferiorly. No margin was planned superiorly (bladder) and posteriorly (rectum). RP patients underwent either an open, a pure laparoscopic, or a robotic-assisted prostatectomy. For those RP patients who received adjuvant or salvage EBRT, the median dose was 70 Gy at 2 Gy/ fraction. Choice of treatment modality was determined by the patient after being counseled on
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all three treatment modalities.
The primary efficacy end points were biochemical relapse-free survival (bRFS), clinical relapsefree survival (cRFS), and prostate cancer-specific mortality (PCSM). Biochemical failure was
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defined as a PSA value of at least 0.4 ng/mL for RP patients23 and the Phoenix Definition24 was used for EBRT and LDR patients. If a patient received post-operative EBRT prior to the post-
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RP PSA exceeding 0.4 ng/mL, he was counted as a biochemical failure. We defined cRFS as metastases identified via medical imaging (with or without co-localizing symptoms) or as biopsyproven local recurrence. For post-EBRT and post-LDR biopsies, the biopsy had to show adenocarcinoma with no evidence of radiation effect for the patient to be coded as having a local failure. PCSM was defined as death due to prostate cancer as noted on the death certificate (corroborated with biochemical and clinical information prior to death) or the presence of uncontrolled metastatic disease at time of death.
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The primary toxicity endpoints were defined via the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).25 A retrospective chart review is performed periodically to assess toxicity as documented in clinical notes contained in the electronic medical record as
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maintenance of the database, but a review specific to those subjects included here was completed for this report. We focused on gastrointestinal and genitourinary toxicity, but severe toxicity of any site was also recorded. We linked a clinical event as a toxicity if it was possibly,
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probably, or definitely associated with the initial treatment. Grade 2 toxicity was reported as any toxicity after 2 months from treatment (to exclude typical acute toxicity like catheter usage after
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RP) while grade 3 toxicity was reported at any time since therapy. Secondary malignancies were coded as being associated with treatment if they were within the treatment field. For all end points, factors thought or known to influence the endpoint were recorded and used in the analysis for the outcomes of interest. The Chi-square test and analysis of variance were used to evaluate differences in demographic and clinical characteristics among the modalities.
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The log-rank test was used to compare bRFS and cRFS among the modalities, and Cox regression was used to identify factors associated with bRFS and cRFS. The analyses for bRFS and cRFS were limited to patients who had at least two follow up PSAs post treatment.
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Gray’s test was used to compare differences in late toxicity and PSCM among the modalities. Competing risk regression was used to identify factors associated with PSCM. All analyses
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were done with SAS v. 9.4 (SAS Inst., Cary, NC) or R v. 3.3.1 (R Foundation, Vienna, Austria). A p-value of <0.05 was considered to be statistically significant.
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Results A total of 2557 patients were included comprising: 734 EBRT patients (29%), 515 LDR patients (20%), and 1308 RP patients (51%). The median follow-up for the entire group was 63.5
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months. The median age (years) of the patients was 65 overall and 68.5 for EBRT, 70 for LDR, and 62 for RP. At the last follow-up, 80% of patients were still alive. For the EBRT patients, 384 (52%) received 78 Gy at 2 Gy per fraction while 350 (48%) received 70 Gy at 2.5 Gy per
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fraction. For the RP patients, 732 (56%) received an open prostatectomy, 103 (7.8%) received a pure laparoscopic prostatectomy, and 473 (36.2%) received a robotic-assisted prostatectomy.
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The median 30-day D90 for the LDR patients was 149.39 Gy (one standard deviation = 21.31 Gy). Neoadjuvant or adjuvant androgen deprivation therapy (ADT) was administered to 93% of EBRT patients, 53% of LDR patients, and 19% of RP patients. Descriptive statistics are shown in Table 1. Patients treated with EBRT had longer follow-up, higher iPSA, more advanced T stage, and a higher preponderance of ISUP 5 disease; however, there is also a higher
cohort.
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preponderance of International Society of Urologic Pathology (ISUP) 1 disease in the EBRT
The bRFS for the RP patients is lower than LDR and EBRT (Figure 1A). On multivariable
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analysis of the entire cohort, RP vs. EBRT, clinical stage T3, biopsy Gleason Score 8-10, higher pre-treatment PSA, shorter ADT duration, and more frequent PSA testing post-therapy were
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associated with significantly worse bRFS (Table 2). The multivariable model did not show a significant difference between Gleason 6 vs. Gleason 8-10 but this is likely an artifact of the small number of patients with Gleason 6 . The log-rank test was not significant for cRFS among the modalities (Figure 1B). On multivariable analysis, EBRT vs. RP and LDR vs. RP, clinical stage T3, and biopsy Gleason Score 8-10 were associated with significantly worse cRFS (Table 2).
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The cumulative incidence of PCSM was higher for EBRT patients than for patients treated with LDR and RP (Figure 1C). On multivariable analysis, EBRT vs. RP, higher clinical stage, higher pre-treatment PSA, biopsy Gleason Score 8-10, and younger age were associated with
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significantly worse PCSM (Table 2). Figure 2A shows the cumulative incidence of grade >3 GU toxicity. The 10-year cumulative incidence of > grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for As seen in Table 3, the majority of the GU toxicities result from minor
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RP (p<0.0001).
procedures necessary to manage incontinence or obstruction. In keeping with some literature,26
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we also note a lower early complication rate for grade >3 GU toxicity with robotic-assisted prostatectomy, but this advantage dissipates with further follow-up (Figure 2B). The EBRT group had a greater incidence of >3 gastrointestinal (GI) toxicity (Figure 2C). The 10-year cumulative incidence of > grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, 1.0% for RP (p<0.0001).When examining grade >2 GI toxicities (more “bothersome” toxicities
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vs. those serious enough to require intervention) , one sees parallels with the PROST-QA trial in which near the 2-year mark, the EBRT patients experienced a greater amount of rectal bother (Figure 2D).27 The more “bothersome” GU toxicities are included in Figure 2E. In addition to
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the grade 5 GI and GU toxicities listed in Table 3, there were three other deaths resulting from some aspect of prostate cancertreatment: one fatal post-operative hemorrhage in the RP group,
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one neutropenic sepsis after salvage chemotherapy in the EBRT group, and one fatal case of diarrhea 8 hours after an infusion of chemotherapy in the EBRT group. The secondary malignancy rate is shown in Figure 2F.
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Discussion With the lack of prospective, randomized, comparative efficacy studies among modalities used to treat HRCaP, observational studies such as this serve as a significant source of clinical
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guidance. In addition to the efficacy data presented, we also supplemented our investigation with toxicity data. Our research effort forces us to conclude that LDR is highly competitive with EBRT and RP. We feel that a case can be made for considering all three major modalities for
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the treatment of HRCaP.
This report possesses several significant strengths. The two most important of which are its
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relatively long median follow-up and the use of modern treatment techniques. The 63.5-month median follow-up permits us to adequately assess all meaningful efficacy and toxicity end points. The use of high dose radiation in the EBRT arm and the fact that 93% of the EBRT patients received ADT, indicate that the EBRT techniques meet modern recommendations for this modality. All LDR patients were treated with an intraoperative planning technique
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minimizing set-up error.28 Most of the RP patients were offered adjuvant or salvage EBRT, but only 18.6% received it, similar to contemporary patterns of care.29,30 Finally, the percentage of high-risk patients treated at our institution over the period of this study has remained constant at
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15-20% of all newly-diagnosed CaP patients per year while the percentage of low-risk patients treated per year has decreased from ~50% to ~15%. This shift reflects our enthusiasm for
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active surveillance in appropriate patients as per most modern prostate cancer treatment guidelines.
The differences in the definition for biochemical failure in each modality make it a difficult end point to use for comparisons. Specifically, the bRFS for the RP patients is 43% at 10 years versus 52% and 53% for LDR and EBRT; we believe that this phenomenon is due to the more rigorous Phoenix definition of biochemical failure and not clinically significant. Comparisons between the ASCENDE-RT trial and this series for bRFS are challenging because only two-
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thirds of the patients in ASCENDE-RT had HRCaP while the remaining one-third had intermediate-risk disease. Yet, the control arm (EBRT+ADT) of ASCENDE-RT fared about 20% worse than the patients in any of the modalities in this series, depending on the bRFS definition
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used.15 The difference is difficult to explain because one would expect the reverse given the longer duration of ADT in ASCENDE-RT vs. this series (12 months vs. 6 months) and
underscores the hazards of using bRFS as an endpoint to evaluate treatment efficacy. Our
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shorter duration of ADT is primarily the result of the fact that most of our EBRT patients were treated 10 years ago when the optimal duration of ADT had not been as thoroughly
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investigated. As will be discussed in the following paragraphs, the ambiguous effect of ADT dosage on bRFS noted above is not observed when cRFS and PCSM are examined. This may be due to the higher doses of radiation in the LDR group overwhelming a positive effect of ADT or the vagaries of bRFS as an end point.
Overall, there was no significant difference among the modalities relative to cRFS (Figure 1).
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The surgical patients did have a better outcome in pair-wise comparisons (Table 2), and this may be due to differences in follow-up since many of the RP patients were followed from a distance while the EBRT and LDR patients were usually followed locally increasing the chance
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of knowing about a clinical failure. Also, due to the differences in definition for biochemical failure, it is possible that RP patients are observed to experience a biochemical failure sooner
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than EBRT or LDR patients, allowing for an earlier salvage therapy intervention. The PCSM results show that LDR is competitive with EBRT and RP. The slight differences seen between EBRT and RP in our series mimics that difference noted by Sooriakumaran P et al.31 Both investigations note that EBRT patients have an inferior PCSM compared to RP that persists after controlling for variables known to affect PCSM. In our series, one additional factor that may explain the difference in PCSM is that our EBRT patients had a longer median follow up than our LDR or RP patients. This results from our lower enthusiasm for EBRT over time
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because of the differences in rates of toxicity noted by ourselves and others.27 As a result, most of our EBRT patients were treated 10 years ago.
One assumes that the median follow-up did
not differ in Sooriakumaran P et al., but as far as can be determined from the manuscript, they
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did not include LDR, disclose the dose of EBRT, or note whether the EBRT patients in the highrisk group had ADT. It is unlikely that they would have known about the EBRT dose or ADT from their national database data source, but their omission of LDR could probably have been
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avoided. When LDR is included in an analysis of PCSM, as we have done here, one can see that the PCSM of LDR is equivalent to RP. Further, the disease aggressiveness of our RP and
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LDR groups are equally balanced and they have similar follow-up; the differences between LDR and RP vs. EBRT may be explained by the greater disease aggressiveness and longer followup in the EBRT group. In the EBRT cohort, 36% of patients had initial PSAs that were > 20ng/mL while the LDR cohort had and the RP cohort both had 15% of patients with an initial PSA > 20ng/mL. In addition, the EBRT group had a higher percentage of patients with a
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Gleason 9 or 10 (ISUP 5): 17% vs. 11.4% for LDR and 14.3% for RP. The EBRT group also had significantly more T3 patients (14%) vs. 0.4 % in LDR and 3% in RP. The longer PSA f/u in the EBRT patients could have biased the results against EBRT by knowing of biochemical
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failure more frequently than other groups, but we feel that we guarded against this eventuality (see Methods and Materials) by corroborating death certificate information with clinical data
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prior to death. The use of ADT did not improve the PCSM in the LDR group presented in this paper (p = 0.42; HR 1.97, 95% CI = 0.38-10.2, Figure 1D for cumulative incidence). Mirroring our results, D’Amico et al. noted that HRCaP patients treated with LDR alone had a PCSM similar to those treated with LDR plus ADT.16 Their report differs in that the PCSM rate at 5 years for their LDR-alone group is ~6% while our 5-year PCSM rate is 1.2% for the LDR-alone group. Our study lacks data on biopsy core positivity percent, but in high-risk disease this data appears to have limited significance.32
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The observed PCSM rates provide some insight into future directions for HRCaP clinical research. In particular, the question of local intensification vs. adjunctive systemic therapy gains importance. The local failure rate (Table 1) across all three cohorts is 2%. Since one of the
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three groups is RP +/- EBRT for adjuvant or salvage treatment, which is arguably the most intensive local treatment commonly used, it is unreasonable to expect much improvement of this end point. The equivalence of the local failure rates suggest that all three treatments are high
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on the “shoulder” of the classic dose-response curve for HRCaP. Additional effort to intensify locally in NRCaP patients, such as by combining EBRT with LDR, is likely to result in the same
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toxicity differences seen in RTOG 02-32 in which combining modalities (EBRT + LDR vs. LDR) for intermediate-risk prostate cancer was not noted to improve efficacy but did increase toxicity.19 When comparing combined modality therapy in HRCaP, as in ASCENDE-RT, to EBRT, again one sees increasing toxicity with the use of multi-modality treatment.20 In ASCENDE-RT, the multi-modaity arm did demonstrate an improved bRFS, but there has not
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been a reported advantage in PCSM.15 It has been recently noted that in the ISUP 5 category of HRCaP there is an advantage in cRFS with LDR + EBRT over EBRT and RP, but this did not translate into a PCSM improvement.33 This echos earlier data in which higher biologic effective
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dose, that the authors calculate as being higher in LDR + EBRT, shows better bRFS and cRFS but unfortunately did not assess PCSM.34 With unclear evidence for improvement in “hard”
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clinical outcomes like PCSM or local failure and the increased toxicity in multi-modality treatment, it seems more reasonable to focus on the other ~90% of treatment failures which we identify in this series as metastatic disease. Local intensification may affect metastatic spread, but this is not likely in a population with such good local control. The value of regional intensification such as nodal radiation, remains unknown after decades of study and this uncertainty has generated further studies to help clarify.35 Consequently, it seems that systemic therapy beyond the typical use of ADT should be the focus of attention for future investigation.
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Toxicity is important to note when making comparisons in observational studies. It is very difficult to compare toxicity using observational studies where data are sourced from a national database but, it is more readily performed from a single institution study such as this series.
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Here we compare GI and GU toxicities using CTCAE v4.03. The rate of grade 5 toxicity is very low. In addition, the rate of fistula formation after LDR is lower than prior reports although with such an uncommon event, comparisons are difficult.36 The overall grade 3 and higher GU
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toxicity is well within the expected range.37 The higher GI toxicity in the EBRT patients also tracks with prior reports and the assessment of the grade 2 GI toxicity (analogous to the “bothersome” toxicity noted in the EPIC questionnaire and shown here in Figure 2D) yields a
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very similar result to that noted in PROST-QA.27 In addition, despite the fact that they treated low and intermediate-risk patients, the grade 2 toxicity of our patients follows the toxicity profile of the patients treated on the ProtecT trial which scored toxicity in a manner similar to PROSTQA.38,39 We feel that this indicates that the larger margins that one expects when treating high-
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risk disease did not yield a toxicity profile that was substantially different from the population in ProtecT. The plateau seen in the RP and LDR patients’ cumulative incidence toxicity curves (Figure 2) may reflect the larger volume of tissue being irradiated vs. LDR and only 18.6% of the
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RP patients received EBRT which limited the potential of patients in that arm to express the late toxicity seen in the EBRT alone arm.
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The majority of both the higher grade >3 GI toxicity with EBRT and the higher grade >3 GU toxicity with RP only required minor procedures for treatment, but are still important to note. The use of robotic-assisted RP results in a transient reduction of GU toxicity, but this gap closes relative to the open and pure laparoscopic approaches with further follow-up (Figure 2B). The secondary malignancy rate is in keeping with prior reports.40
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Conclusions For HRCaP, there is no standard-of-care because of the near complete lack of randomized comparative efficacy studies. This report helps fill this gap by providing efficacy and toxicity
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outcomes in HRCaP patients treated with LDR, RP, or EBRT. They each have similar efficacy but different toxicity. Given the competitive LDR results reported here, it is reasonable to
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consider LDR for HRCaP.
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References
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1. Ciezki JP. High-Risk Prostate Cancer in the Modern Era: Does a Single Standard of Care Exist? Int J Radiat Oncol Biol Phys 2013;87:440-2. 2. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M.D. Anderson randomized doseescalation trial for prostate cancer. Int J Radiation Oncology Biol Phys 2008;70:67-74. 3. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:2516-27. 4. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11:1066-73. 5. D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer. JAMA 2008;299:289-95. 6. Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: Results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 2005;6:841-50. 7. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of Radiation Therapy Oncology Group protocol 92-02: A Phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497-504. 8. Lawton CA, DeSilvio M, Roach III M, et al. An update of the Phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen supression: Updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiation Oncology Biol Phys 2007;69:646-55. 9. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of Phase III RTOG 85-31. Int J Radiation Oncology Biol Phys 2005;61:1285-90. 10. Roach III M, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: Long-term results of RTOG 8610. J Clin Oncol 2008;26:585-91. 11. Zietman AL, Bae K, Slater JD, 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;28:1106-11. 12. Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after radical prostatectomy versus external beam radiotherapy for patients with high-risk prostate cancer. Cancer 2011;117:2883-91. 13. Nepple KG, Stephenson AJ, Kallogjeri D, et al. Mortality after prostate cancer treatment with radical prostatectomy, external-beam radiation therapy, or brachytherapy in men without comorbidity. Eur Urol 2013. 14. Kittel JA, Reddy CA, Smith KL, et al. Long-term efficacy and toxicity of low-dose-rate (125)I prostate brachytherapy as monotherapy in low-, intermediate-, and high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2015;92:884-93. 15. Rodda SL, Tyldesley S, Keyes M, et al. Low-Dose-Rate prostate brachytherapy is superior to doseescalated EBRT for unfavorable risk prostate cancer: the results of the ASCENDE-RT randomized control trial. Int J Radiat Oncol Biol Phys 2015;93:E191-E2. 16. D'Amico AV, Moran BJ, Braccioforte MH, et al. Risk of death from prostate cancer after brachytherapy alone or with radiation, androgen supression therapy, or both in men with high-risk prostate cancer. J Clin Oncol 2009;27:3923-8.
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17. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer, Version 1.2106 Freatured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2016;14:19-30. 18. Lawton CA, Yan Y, Lee WR, et al. Long-term results of an RTOG Phase II trial (00-19) of external beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate. Int J Radiation Oncology Biol Phys 2012;82:e795-801. 19. Prestidge BR, Winter K, Sanda MG, et al. Initial report of NRG Oncology/RTOG 0232: A phase 3 study comparing combined external beam radiation and transperineal interstitial permanent brachytherapy with brachytherapy alone for selected patients with intermediate-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 2016;96:S4. 20. Rodda SL, Tyldesley S, Morris WJ. Toxicity outcomes in ASCENDE-RT: a multicenter randomized trial of dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2015;93:S121. 21. Sohyada C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000;55:382-6. 22. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL. Update on the Gleason grading system for prostate cancer: results of an international consensus conference of urologic pathologists. Adv Anat Pathol 2006;13:57-9. 23. Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006;24:29738. 24. Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiation Oncology Biol Phys 2006;65:965-74. 25. Common Terminology Criteria for Adverse Events version 4.03. 2010. (Accessed June 1, 2016, at evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03.) 26. Leow JJ, Chang SL, Meyer CP, et al. Robot-assisted versus open radical prostatectomy: a contemporary analysis of an all-payer discharge database. Eur Urol 2016. 27. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-61. 28. Wilkinson DA, Lee EJ, Ciezki JP, et al. Dosimetric comparison of pre-planned and or-planned prostate seed brachytherapy. Int J Radiation Oncology Biol Phys 2000;48:1241-4. 29. Sineshaw HM, Gray P, Efstathiou JA, Jemal A. Declining use of radiotherapy for adverse features after radical prostatectomy: results from the National Cancer Data Base. Eur Urol 2015;68:768-74. 30. Kalbasi A, Swisher-McClure S, Mitra N, et al. Low rates of adjuvant radiation in patients with nonmetastatic prostate cancer with high-risk pathologic features. Cancer 2014;120:3089-96. 31. Sooriakumaran P, Nyberg T, Akre O, et al. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality ouotcomes. BMJ 2014;348:g1502. 32. Ellis CL, Partin AW, Han M, Epstein JI. Adenocarcinoma of the prostate with Gleason Score 9-10 on core biopsy: correlation with findings at radical prostatectomy and prognosis. J Urol 2013;190:206873. 33. Kishan AU, Shaikh T, Wang PC, et al. Clinical ooutcomes for patients with Gleason score 9-10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis. Eur Urol 2016. 34. Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;73:341-6. 35. Roach III M, DeSilvio M, Valicenti R, et al. Whole-pelvis, "mini-pelvis", or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiation Oncology Biol Phys 2006;66:647-53.
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36. Leong N, Pai HH, Morris J, et al. Rectal ulcers and rectoprostatic fistulas after I-125 low dose rate brachytherapy. J Urol 2016;195:1811-6. 37. Jarosek SL, Virnig BA, Chu H, Elliott SP. Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both. Eur Urol 2015;67:273-80. 38. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016;375:1415-24. 39. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375:1425-37. 40. Abdel-Wahab M, Reis IM, Wu J, Duncan R. Secondary primary cancer risk of radiation therapy after prostatectomy for prostate cancer: an analysis of SEER data. Urology 2009;74:866-72.
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Figure Legends
Figure 1. Efficacy plots.
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A. Kaplan-Meier estimates of biochemical relapse-free survival for low-dose-rate brachytherapy (LDR) plus/minus, external beam radiation plus/minus androgen deprivation therapy (EBRT), and radical prostatectomy plus/minus adjuvant or salvage external beam radiotherapy (RP). Analysis limited to patients with a least two posttreatment PSAs. B. Kaplan-Meier estimates of clinical relapse-free survival for low-dose-rate brachytherapy (LDR) plus/minus, external beam radiation plus/minus androgen deprivation therapy (EBRT), and radical prostatectomy plus/minus adjuvant or salvage external beam radiotherapy (RP). Analysis limited to patients with a least two post-treatment PSAs. C. Cumulative incidence of prostate cancer-specific mortality for low-dose-rate brachytherapy (LDR) plus/minus, external beam radiation plus/minus androgen deprivation therapy (EBRT), and radical prostatectomy plus/minus adjuvant or salvage external beam radiotherapy (RP). D. Cumulative incidence of prostate cancer-specific mortality for low-dose-rate brachytherapy (LDR) by use of androgen deprivation therapy (ADT). Figure 2. Toxicity plots.
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A. Cumulative incidence of grade 3 or higher genitourinary toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). B. Cumulative incidence of grade 3 or higher genitourinary toxicity among radical prostatectomy sub-types (open, pure laparoscopic, and robotic-assisted), assessed with the Common Terminology Criteria for Adverse Events, version 4.03. ( Lap RP = laparoscopic non-robotic prostatectomy; Open RP = open radical prostatectomy; Robotic RP = robotic prostatectomy). C. Cumulative incidence of grade 3 or higher gastrointestinal toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). D. Cumulative incidence of grade 2 or higher gastrointestinal toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). E. Cumulative incidence of grade 2 or higher genitourinary toxicity, assessed with the Common Terminology Criteria for Adverse Events, version 4.03 for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). F. Cumulative incidence of secondary malignancies for low-dose-rate brachytherapy (LDR), external beam radiation therapy (EBRT), and radical prostatectomy (RP). All secondary malignancies occurred within the radiation field except one spindle cell malignancy (histologically indistinguishable from spindle cell malignancies seen in EBRT fields) in an RP patient who did not receive EBRT. This may suggest that spindle cell cancers seen after radiation may not be radiation-induced, but simply a persistent variant of cancer
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detected after primary treatment. Because we want to apply the same standards to each modality this patient was coded as a secondary malignancy due to its histologic appearance and location.
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Table 1. Descriptive Statistics
Factor
EBRT*
LDR**
RP***
n/median
%/range
n/median
%/range
n/median
734
29
515
20
1308
p-value
%/range
Count 51 <0.0001
68.5
40-86
70
44-89
Risk Sub-Grouping
RI PT
Age (y)
62
43-79
<0.0001
2 intermediate factors
207
28
248
48
>1 high-risk factor
527
72
267
52
582
45
726
55
459
62
458
89
779
60
11
489
37
0.4
40
3
<0.0001
T1 or T2A T2B or T2C
174
24
55
T3
101
14
2
<4
22
3
4 - <10
185
25
10 - <20
255
34
>20
271
36
1
0.1
76
10
unknown Biopsy Gleason (ISUP) 6 (1)
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Initial PSA (ng/mL)
SC
Clinical Stage
<0.0001
15
3
134
10
161
32
527
40
257
50
451
35
81
15
196
15
1
0.2
0
0
31
6
70
5
<0.0001
354
48
278
54
662
51
8 (4)
178
24
147
28
394
30
9 (5)
117
16
57
11
178
14
10 (5)
9
1
2
0.4
4
0.3
7
241
47
1061
81
93
274
53
247
19
Androgen Deprivation
TE D
7 (2 or 3)
54
Yes
680
Duration ADT (m) 0
EP
No
<0.0001
<0.0001
54
7
241
47
1061
81
487
66
241
47
197
15
193
26
31
6
24
2
0
0
2
0.4
26
2
6
3-78
6
1-32
3
0.25-86
94.6
1.2-242
48.9
0.1-201
55.6
0.1-238.7
No
444
65
305
75
715
65
Yes
240
35
104
25
378
35
1-6
AC C
>6
unknown
Duration ADT^ (m)
<.00001
Follow-up Time
<.00001
Biochemical Failure#
#
Clinical Failure
No
542
79
366
90
955
87
Yes
142
21
43
10
138
13
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Local Failure No
670
98
401
98
1074
98
Yes
14
2
8
2
19
2
Distant Metastases 550
80
370
91
967
89
134
20
39
9
126
12
Alive
463
63
444
86
Dead Other Cause
192
26
60
12
Yes
79
11
11
2
Prostate Cancer Death
RI PT
No Yes
1139
87
120
9
49
4
AC C
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*External beam radiotherapy; **Low dose-rate brachytherapy; ***Radical prostatectomy, † International Society of Urologic Pathology33, ^ADT duration for patients who received ADT; # analysis for biochemical and clinical failure limited to patients with >2 post-treatment PSAs
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Table 2. Univariate and Multivariable Analyses of Efficacy Factor
Univariate P-value HR* (95% CI**)
Multivariable P-value HR* (95% CI**)
Treatment
0.1257 0.1335 0.0003
0.83 (0.66-1.05) 1.22 (0.94-1.57) 1.43 (1.19-1.79)
1.05 (0.89-1.25) 1.73 (1.35-2.23) 1.64 (1.25-2.16)
0.1321 0.0001 0.0086
1.15 (0.96-1.37) 1.69 (1.29-2.20) 1.47 (1.10-1.96)
0.92 (0.69-1.23) 1.51 (1.14-2.00) 1.64 (1.40-1.90)
0.5478 0.1537 0.0003
0.92 (0.69-1.22) 1.24 (1.92-1.66) 1.36 (1.15-1.59)
1.01 (1.01-1.01)
<0.0001
1.01 (1.01-1.01)
0.99 (0.98-1.00)
0.0104
0.98 (0.97-1.00)
0.93 (0.79-1.08) 0.94 (0.73-1.21) 1.02 (0.79-1.31)
-
-
1.43 (1.38-1.48)
<0.0001
1.42 (1.38-1.48)
1.00 (1.01-1.01)
<0.0001
1.01 (1.01-1.01)
0.8455 0.1493 0.0668
0.97 (0.69-1.36) 0.78 (0.55-1.10) 0.80 (0.64-1.02)
0.0176 0.5278 0.0277
1.57 (1.08-2.27) 1.13 (0.78-1.65) 0.72 (0.54-0.97)
0.2436 <0.0001 0.0003
1.16 (0.90-1.49) 2.26 (1.62-3.14) 1.94 (1.35-2.79)
0.4610 <0.0001 0.0011
1.10 (0.85-1.44) 2.11 (1.48-3.00) 1.91 (1.30-2.81)
0.1191 <0.0001 <0.0001
1.56 (0.89-2.73) 4.12 (2.39-7.10) 2.64 (2.08-3.34)
0.0730 0.0001 <0.0001
1.68 (0.95-2.96) 3.03 (1.73-5.29) 1.81 (1.40-2.32)
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0.70 (0.56-0.87) 0.96 (0.76-1.21) 1.37 (1.17-1.61)
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LDR*** vs. RP† 0.0013 LDR*** vs. EBRT‡ 0.7214 RP† vs. EBRT‡ 0.0001 Clinical Stage T2B&C vs. T1&T2A 0.5546 T3 vs. T1&T2A < 0.0001 T3 vs. T2B&C 0.0004 Biopsy Gleason 7 vs. 6 0.5740 8-10 vs. 6 0.0044 8-10 vs. 7 <0.0001 Initial PSA <0.0001 ADT§ Duration (months) 0.1799 ADT§ Duration (months) 1-6 vs. 0 0.3422 >6 vs. 0 0.6497 >6 vs. 1-6 0.8899 PSA Frequency <0.0001 PSA Frequency x Time <0.0001
RI PT
Biochemical Relapse-Free Survival
Clinical Relapse-Free Survival Treatment
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LDR*** vs. RP† LDR*** vs. EBRT‡ RP† vs. EBRT‡ Clinical Stage T2B&C vs. T1&T2A T3 vs. T1&T2A T3 vs. T2B&C Biopsy Gleason 7 vs. 6 8-10 vs. 6 8-10 vs. 7 Initial PSA
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0.0987
1.00 (1.00-1.01)
0.7134
1.00 (0.99-1.01)
0.0151
1.02 (1.00-1.03)
0.3797
0.99 (0.98-1.01)
0.0302 <0.0001 0.0121
1.31 (1.03-1.68) 1.96 (1.41-2.74) 1.49 (1.09-2.04)
-
-
<0.0001
1.56 (1.45-1.66)
<0.0001
1.54 (1.44-1.65)
<0.0001
1.01 (1.01-1.01)
<0.0001
1.01 (1.01-1.01)
ADT§ Duration (months) 1-6 vs. 0 >6 vs. 0 >6 vs. 1-6 PSA Frequency PSA Frequency x Time
SC
Prostate Cancer-Specific Mortality Treatment
ADT§ Duration (months)
0.68 (0.35-1.30) 0.37 (0.20-0.69) 0.54 (0.38-0.78)
0.6764 0.1069 0.0018
1.15 (0.60-2.23) 0.58 (0.30-1.13) 0.50 (0.32-0.77)
1.64 (1.13-2.39) 3.16 (2.00-4.98) 1.92 (1.18-3.12)
0.0038 0.0008 0.3033
1.77 (1.20-2.61) 2.33 (1.42-3.83) 1.32 (0.78-2.22)
2.23 (0.80-6.20) 6.06 (2.23-16.46) 2.72 (1.90-3.89)
0.0928 <0.0001 <0.0001
2.44 (0.86-6.92) 7.82 (2.80-21.89) 3.21 (2.22-4.61)
0.0009
1.01 (1.00-1.02)
0.0068
1.01 (1.00-1.01)
<0.0001
1.03 (1.03-1.04)
0.4906
1.01 (0.99-1.02)
<0.0001 <0.0001 0.0724
2.72 (1.75-4.22) 4.04 (2.35-6.92) 1.49 (0.96-2.29)
-
-
0.0026
0.97 (0.95-0.99)
0.0001
0.96 (0.94-0.98)
0.0089 <0.0001 0.0081 0.1259 0.0004 <0.0001
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0.2404 0.0018 0.0009
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LDR*** vs. RP† LDR*** vs. EBRT‡ RP† vs. EBRT‡ Clinical Stage T2B&C vs. T1&T2A T3 vs. T1&T2A T3 vs. T2B&C Biopsy Gleason 7 vs. 6 8-10 vs. 6 8-10 vs. 7 Initial PSA
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EP
ADT§ Duration (months) 1-6 vs. 0 >6 vs. 0 >6 vs. 1-6 Age
RI PT
ADT§ Duration (months)
*Hazard ratio, **Confidence Interval, *** Low Dose-rate Brachytherapy, † Radical Prostatectomy, ‡ External Beam Radiotherapy, § Androgen Deprivation Therapy.
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Table 3. Tabulation of types of toxicity, grade >3, scored with Common Terminology Criteria for Adverse Events, version 4.03. EBRT* % n % Genitourinary
LDR** n %
2 1 1 4
50.0 25.0 25.0
1 1 1 3
33.3 33.3 33.3
0 0 0 0
0.0 0.0 0.0
1 0 0 1
100.0 0.0 0.0
1 7 1 11 5 1 2 5 33
3.0 21.2 3.0 33.3 15.2 3.0 6.1 15.2
0 2 0 3 4 0 1 1 11
0.0 18.2 0.0 27.3 36.4 0.0 9.1 9.1
0 0 0 0 0 0 0 1 1
0.0 0.0 0.0 0.0 0.0 0.0 0.0 100.0
1 5 1 8 1 1 1 3 21
4.8 23.8 4.8 38.1 4.8 4.8 4.8 14.3
2 47 4 117 1 1 1 1 30 204
1.0 23.0 2.0 57.4 0.5 0.5 0.5 0.5 14.7
0.0 2.0 0.0 57.1 0.0 0.0 0.0 0.0 40.8
0 1 0 15 0 0 0 0 4 20
0.0 5.0 0.0 75.0 0.0 0.0 0.0 0.0 20.
2 45 4 74 1 1 1 1 6 135
1.5 33.3 3.0 54.8 0.7 0.7 0.7 0.7 4.4
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Grade 5 fistula XRT‡ proctitis Total Grade 4 fistula obstruction perforation XRT‡ proctitis Total Grade 3 infection obstruction XRT‡ proctitis Total
0 1 0 28 0 0 0 0 20 49 Gastrointestinal
RP*** %
RI PT
n
2 1 3
66.7 33.3
2 1 3
66.7 33.3
0 0 0
0.0 0.0
0 0 0
0.0 0.0
8 4 2 1 22
53.3 26.7 13.3 6.7
4 1 0 1 6
66.7 16.7 0.0 16.7
1 0 0 0 1
100.0 0.0 0.0 0.0
3 3 2 0 8
37.5 37.5 25.0 0.0
2 1 28 31
6.5 3.2 90.3
1 0 24 25
4.0 0.0 96.0
0 0 3 3
0.0 0.0 100.0
1 1 1 3
33.3 33.3 33.3
EP
Grade 5 fistula renal failure XRT† cystitis Total Grade 4 anastamotic leak fistula incontinence infection necrotic tissue obstruction renal failure XRT† cystitis Total Grade 3 hernia incontinence infection obstruction pain spermatocele testicular infarct urgency XRT† cystitis Total
TE D
n
SC
All
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Description
*external beam radiotherapy; **low-dose-rate brachytherapy; ***radical prostatectomy; † radiotherapy-induced cystitis; ‡ radiotherapy-induced proctitis.
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Biochemical Relapse Free Survival by Treatment
RI PT
100
SC M AN U Treatment Number of Patients # at risk 5-yr surv (%) 95% CI (%) # at risk 10-yr surv (%) 95% CI (%) # at risk 15-yr surv (%) 95% CI (%)
20
EBRT 684 329 74 70-77 107 53 48-58 14 39 31-47
LDR 409 124 74 68-79 12 52 42-62 0 na na
EP
40
TE D
60
AC C
Cumulative Incidence (%)
80
RP 1093 306 65 61-68 85 47 43-52 12 39 33-46
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Clinical Relapse Free Survival by Treatment
RI PT
100
SC M AN U
60
EBRT 684 384 85 83-88 152 73 68-77 24 59 51-67
LDR 409 155 90 86-93 20 76 66-86 0 na na
TE D
Treatment Number of Patients # at risk 5-yr surv (%) 95% CI (%) # at risk 10-yr surv (%) 95% CI (%) # at risk 15-yr surv (%) 95% CI (%)
EP
40
20
AC C
Cumulative Incidence (%)
80
RP 1093 431 89 86-91 145 75 71-80 27 67 60-74 P-value= 0.1205
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Prostate Cancer Specific Mortality by Treatment
SC
RP 1308 612 2.8 1.7-3.9 241 6.8 4.7-8.9 69 9.8 6.6-12.9
TE D
60
LDR 515 211 3.2 1.2-5.1 40 3.6 1.5-5.8 3 3.6 1.5-5.8
EP
40
20
AC C
Cumulative Incidence (%)
80
EBRT 734 508 5.3 3.6- 7.1 261 11.2 8.6-13.9 77 15.8 12.3-19.3
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Treatment Number of Patients # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value= 0.0004
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
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Cumulative Incidence for Prostate Cancer Specific Mortality by Use of ADT for Patients Treated with LDR
LDR + ADT 374 163 4.2 1.5-6.9 26 4.2 1.5-6.9 3 4.2 1.5-6.9
SC
LDR Alone 241 48 1.2 0.0- 3.5 14 3.3 0.0-7.9 0 na na
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Treatment Number of Patients # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
TE D
60
EP
40
20
AC C
Cumulative Incidence (%)
80
RI PT
100
P-value= 0.3393
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Cumulative Incidence for Grade >3 GU Toxicity (Excluding Secondary Malignancies) by Treatment
SC
RP 1308 1072 5.7 4.4-7.0 558 12.7 10.7-14.8 223 16.4 13.8-19.0 64 17.2 14.4-20.0
EP
40
M AN U
60
LDR 515 436 0.9 0.0-1.8 202 4.4 2.4-6.5 35 7.2 3.4-11.0 3 7.2 3.4-11.0
20
AC C
Cumulative Incidence (%)
80
EBRT 734 699 0.3 0.0-0.7 491 4.4 2.8- 5.9 243 8.1 5.9-10.4 66 11.6 8.6-14.5
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Cumulative Incidence for Grade >3 GU Toxicity (Excluding Secondary Malignancies) by RP Technique
SC
Open RP 732 634 6.8 4.9-8.6 405 13.8 11.2-16.5 206 17.1 14.0-20.2 64 17.6 14.4-20.9
EP
40
M AN U
60
Robotic 473 359 3.5 1.8-5.3 106 11.3 7.9-14.8 3 15.5 8.1-22.9 0 na na
20
AC C
Cumulative Incidence (%)
80
Lap RP 103 73 6.8 1.5-12.1 47 9.2 3.1-15.3 14 16.6 6.5-26.2 0 na na
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value= 0.6028
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Cumulative Incidence for Grade >3 GI Toxicity (Excluding Secondary Malignancies) by Treatment
SC
RP 1308 1124 0.4 0.1-0.7 615 0.7 0.2-1.2 244 1.0 0.4-1.7 69 1.5 0.4-2.6
EP
40
M AN U
60
LDR 515 439 0.0 0.0-0.0 211 1.1 0.0-2.2 40 1.1 0.0-2.2 4 1.1 0.0-2.2
20
AC C
Cumulative Incidence (%)
80
EBRT 734 699 0.4 0.0-0.9 492 3.8 2.4- 5.2 253 4.6 3.0-6.2 76 5.7 3.6-7.7
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Cumulative Incidence for Grade >2 GI Toxicity (Excluding Secondary Malignancies) by Treatment
SC
EP
40
RP 1308 1121 0.6 0.2-1.0 615 1.0 0.4-1.5 244 1.8 0.8-2.8 69 2.2 0.9-3.6
M AN U
60
LDR 515 439 0.0 0.0-0.0 211 1.1 0.0-2.2 40 1.1 0.0-2.2 4 1.1 0.0-2.2
20
AC C
Cumulative Incidence (%)
80
EBRT 734 692 1.5 0.6-2.5 475 7.0 5.1-8.9 246 8.4 6.2-10.5 72 9.9 7.3-12.5
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
100
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Cumulative Incidence for Grade >2 GU Toxicity (Excluding Secondary Malignancies) by Treatment 100
SC
RI PT
RP 1308 972 8.5 6.8-10.1 491 19.0 16.6-21.5 199 25.7 22.5-28.9 60 28.0 24.4-31.5
TE D
60
LDR 515 427 3.1 1.5-4.8 186 9.7 6.8-12.7 32 13.8 9.1-18.5 3 13.8 9.1-18.5
EP
40
20
AC C
Cumulative Incidence (%)
80
EBRT 734 696 0.6 0.0-1.1 483 5.7 4.0-7.5 235 11.8 9.1-14.4 61 18.9 15.2-22.7
M AN U
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
P-value <0.0001
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Cumulative Incidence for Secondary Malignancies by Treatment
SC
M AN U
RP 1308 1129 0.1 0.0-0.3 616 0.2 0.0-0.4 244 0.2 0.0-0.4 68 0.9 0.0-2.0
EP
10
LDR 515 439 0.0 0.0-0.0 213 0.0 0.0-0.0 40 1.3 0.0-3.8 4 1.3 0.0-3.8
5
AC C
Cumulative Incidence (%)
15
EBRT 734 700 0.1 0.0-0.4 501 1.4 0.5-2.3 258 2.7 1.4-4.1 77 2.7 1.4-4.1
TE D
Treatment Number of Patients # at risk 1-yr cum inc (%) 95% CI (%) # at risk 5-yr cum inc (%) 95% CI (%) # at risk 10-yr cum inc (%) 95% CI (%) # at risk 15-yr cum inc (%) 95% CI (%)
RI PT
20
P-value= 0.0011
0 0
1
2
3
4
5
6
7
8
9
10 Years
11
12
13
14
15
16
17
18
19
20
ACCEPTED MANUSCRIPT
Summary There is no level I evidence defining a standard of care for patients with high-risk prostate cancer. Clinical trials comparing treatment variations within a modality exist but none compare
RI PT
outcomes among modalities. We present an inception cohort study in which we compare
efficacy and toxicity among the three major therapeutic modalities for high-risk prostate cancer: radical prostatectomy plus/minus adjuvant or salvage radiotherapy, external beam radiotherapy
SC
plus/minus androgen deprivation, and low-dose-rate prostate brachytherapy plus/minus
AC C
EP
TE D
M AN U
androgen deprivation therapy.