Therapies for Clinically Localized Prostate Cancer: A Comparative Effectiveness Review
2020; Lippincott Williams & Wilkins; Volume: 205; Issue: 4 Linguagem: Inglês
10.1097/ju.0000000000001578
ISSN1527-3792
AutoresTimothy J Wilt, Kristen Ullman, Eric J. Linskens, Roderick MacDonald, Michelle Brasure, Elizabeth Ester, Victoria A. Nelson, Jayati Saha, Shahnaz Sultan, Philipp Dahm,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoYou have accessJournal of UrologyReview Article1 Apr 2021Therapies for Clinically Localized Prostate Cancer: A Comparative Effectiveness Review Timothy J. Wilt, Kristen E. Ullman, Eric J. Linskens, Roderick MacDonald, Michelle Brasure, Elizabeth Ester, Victoria A. Nelson, Jayati Saha, Shahnaz Sultan, and Philipp Dahm Timothy J. WiltTimothy J. Wilt †Correspondence: Minneapolis VA Healthcare System, Minneapolis, Minnesota E-mail Address: [email protected] Minneapolis VA Healthcare System, Minneapolis, Minnesota , Kristen E. UllmanKristen E. Ullman Minneapolis VA Healthcare System, Minneapolis, Minnesota , Eric J. LinskensEric J. Linskens Minneapolis VA Healthcare System, Minneapolis, Minnesota , Roderick MacDonaldRoderick MacDonald Minneapolis VA Healthcare System, Minneapolis, Minnesota , Michelle BrasureMichelle Brasure Minneapolis VA Healthcare System, Minneapolis, Minnesota , Elizabeth EsterElizabeth Ester Minneapolis VA Healthcare System, Minneapolis, Minnesota , Victoria A. NelsonVictoria A. Nelson Minneapolis VA Healthcare System, Minneapolis, Minnesota , Jayati SahaJayati Saha Minneapolis VA Healthcare System, Minneapolis, Minnesota , Shahnaz SultanShahnaz Sultan Minneapolis VA Healthcare System, Minneapolis, Minnesota , and Philipp DahmPhilipp Dahm Minneapolis VA Healthcare System, Minneapolis, Minnesota View All Author Informationhttps://doi.org/10.1097/JU.0000000000001578AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: We sought to identify new information evaluating clinically localized prostate cancer therapies. Materials and Methods: Bibliographic databases (2013–January 2020), ClinicalTrials.gov and systematic reviews were searched for controlled studies of treatments for clinically localized prostate cancer with duration ≥5 years for mortality and metastases, and ≥1 year for harms. Results: We identified 67 eligible references. Among patients with clinically, rather than prostate specific antigen, detected localized prostate cancer, watchful waiting may increase mortality and metastases but decreases urinary and erectile dysfunction vs radical prostatectomy. Comparative mortality effect may vary by tumor risk and age but not by race, health status, comorbidities or prostate specific antigen. Active monitoring probably results in little to no mortality difference in prostate specific antigen detected localized prostate cancer vs radical prostatectomy or external beam radiation plus androgen deprivation regardless of tumor risk. Metastases were slightly higher with active monitoring. Harms were greater with radical prostatectomy than active monitoring and mixed between external beam radiation plus androgen deprivation vs active monitoring. 3-Dimensional conformal radiation and androgen deprivation plus low dose rate brachytherapy provided small mortality reductions vs 3-dimensional conformal radiation and androgen deprivation but little to no difference on metastases. External beam radiation plus androgen deprivation vs external beam radiation alone may result in small mortality and metastasis reductions in higher risk disease but may increase sexual harms. Few new data exist on other treatments. Conclusions: Radical prostatectomy reduces mortality vs watchful waiting in clinically detected localized prostate cancer but causes more harms. Effectiveness may be limited to younger men and those with intermediate risk disease. Active monitoring results in little to no mortality difference vs radical prostatectomy or external beam radiation plus androgen deprivation. Few new data exist on other treatments. Abbreviations and Acronyms 3D-CRT 3-dimensional conformal radiation therapy ADT androgen deprivation therapy AHRQ Agency for Healthcare Research and Quality AM active monitoring AUA American Urological Association BT brachytherapy CLPC clinically localized prostate cancer COE certainty of evidence EBRT external beam radiation therapy HIFU high intensity focused ultrasound LDR-PB low dose rate prostate brachytherapy MRI magnetic resonance imaging PCa prostate cancer PDT photodynamic therapy PIVOT Prostate Cancer Intervention vs Observation Trial PSA prostate specific antigen RCT randomized controlled trial ROB risk of bias RP radical prostatectomy SPCG4 Scandinavian Prostate Cancer Group Study Number 4 WW watchful waiting In 2020, prostate cancer was estimated to be the most frequently diagnosed nondermatological malignancy (191,930 new cases) and the second leading cause of cancer death (33,330) among men in the United States.1 Treatment related medical costs were projected to rise to $16 billion per year by the end of 2020. In about 90% of men diagnosed with prostate cancer, the disease is confined to the prostate gland (clinically localized prostate cancer).2 Although disease progression can result in morbidity and mortality, most cases of clinically localized prostate cancer grow slowly and remain asymptomatic, even if untreated. Attention is turning to potentially lower risk focal therapies that focus treatment on the index lesion, such as HIFU and cryotherapy.3–5 Use of these options has also increased in response to advances in MRI technology, which allow for better detection of local lesions potentially treatable with "lesion targeted" interventions rather than whole-gland therapy. Awareness has increased regarding the slow growing nature of most prostate specific antigen detected tumors and the importance of weighing treatment benefits and harms to avoid treatment related complications.6 Thus, treatments for clinically localized prostate cancer aim to balance benefits with complications, burden and costs. The purpose of this review was to identify new information and update previous Agency for Healthcare Research and Quality and American Urological Association funded reviews7–9 evaluating treatments for CLPC. Findings can inform clinical guideline committees as they update guidelines. Materials and Methods We employed methods consistent with the AHRQ Evidence-Based Practice Center Program Methods Guidance (https://effectivehealthcare.ahrq.gov/topics/cer-methods-guide/overview). We describe these in the full report (https://effectivehealthcare.ahrq.gov/products/prostate-cancer-therapies/report). Randomized controlled trials ere assessed for risk of bias using the Cochrane ROB tool.10 The tool includes domains for random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other sources of bias. RCTs were classified as low, moderate or high ROB based on the collective ROBs across domains. We assessed observational studies using the ROBINS-1 tool.11 Observational studies were rated as low, moderate, serious or critical ROB based on the ROBIN-1 criterion. We referenced findings from the 2014 AHRQ8 and 2016 AUA9 funded reviews and included them in updated analyses if RCTs provided additional data on similar populations, interventions, comparators, and outcomes. We summarized and compared major findings from our review with those of the prior reports. We derived a priori thresholds defining "small," "moderate" and "large" effect sizes for benefits and harms (supplementary Appendix 1, https://www.jurology.com). Our searches covered publication dates from January 2013 to January 2020. We modified Grading of Recommendations Assessment, Development and Evaluation and Evidence-Based Practice Center tools for ROB and COE assessments (supplementary Appendix 2, https://www.jurology.com). We included controlled studies of CLPC (stages T1–T3a) treatments with duration ≥5 years for mortality and metastases and ≥1 year for quality of life and harms (supplementary Appendix 3, https://www.jurology.com). We extracted inclusion and exclusion criteria; sample size; participant age, race, clinical stage, Gleason score, and tumor risk classification and score; intervention and comparator characteristics; followup duration; and results for outcomes and adverse effects. We extracted data at 1 year and the longest followup for quality of life, health status, and harms; and we extracted data at 5-year intervals for mortality and metastases or at mean/median followup if that was the only way reported. One investigator extracted data to tables with verification by a second reviewer. One investigator rated ROB, extracted data and assessed COE, and a second checked accuracy. We analyzed English-language studies with low or medium ROB. We compiled results in evidence tables and synthesized evidence for each unique comparison with meta-analysis when appropriate. We assessed clinical and methodological heterogeneity to determine appropriateness of pooling data.12 When able to pool data, the Hartung-Knapp-Sidik-Jonkman method for random effects models was applied when there were at least 5 trials, and a fixed effect model was used when there were fewer than 5 trials and no between-study variance (tau2 at or near 0). When meta-analysis was not appropriate, we summarized findings. We calculated RRs or Peto ORs and absolute risk differences with the corresponding 95% CIs for binary outcomes. Mean differences and/or standardized mean differences with 95% CIs were calculated for continuous outcomes. Data were analyzed in Comprehensive Meta-Analysis™ version 3 or R software (package "meta") version 3.6.0 (R Project for Statistical Computing, Vienna, Austria). We assessed COE using the Grading of Recommendations Assessment, Development and Evaluation approach for key outcomes.13 This included assessing the applicability of results by analyzing the study population, diagnostic approaches, eligibility criteria, patient and intervention characteristics and other potential factors that may differ from current populations of treatment-naïve men with CLPC. For each comparison, one investigator rated the COE for each outcome as high, moderate, low or insufficient. COE was reviewed by a second investigator. We resolved discrepancies by consensus. Results Our search identified 11,327 references (fig. 1). Title and abstract screening eliminated 10,564 references leaving 763 references for full text review. We identified 67 eligible references, of which 17 were unique RCTs. A list of all eligible publications can be found in supplementary Appendix 4 (https://www.jurology.com). Supplemental searches of ClinicalTrials.gov and other grey literature sources did not yield additional eligible studies. Figure 2 illustrates intervention comparisons addressed in eligible RCTs according to study sample size.Table 1 summarizes findings by interventions and outcomes from the prior AHRQ and AUA funded reviews, and updated findings derived from our report. Intervention comparisons considered either "out of scope" for this review, or where we found no new data, are summarized in supplementary Appendix 5 (https://www.jurology.com). We provide a narrative summary of benefits and harms according to intervention and comparison. Additional information on effect estimates for individual studies and COE for all-cause mortality, prostate cancer mortality, and metastases are provided in tables 2–5. Effect estimates and COE for harms and quality of life data are provided in supplementary Appendix 6 (https://www.jurology.com). Figure 1. Literature flow diagram. SR, systematic review. Figure 2. Plot of comparisons addressed in RCTs identified in updated literature search. Node size reflects sample size. Width of lines reflects number of RCTs that evaluated that comparison. Within-category comparisons are not shown in figure. One RCT (ProtecT) was 3-arm trial. Active surveillance protocols varied. Prior systematic reviews identified 3 additional trials that compared external beam radiation alone with add-on androgen deprivation therapy. Table 1. Summary updates of comparisons between reviews Intervention/Comparison Outcome(s) Previous Findings from 2014 AHRQ or 2016 AUA Funded Reviews* Present Findings Derived from Studies Published after Prior Reviews and by Incorporating Prior RCT Data when Applicable† WW vs RP in men with clinically detected (SPCG4) or mainly clinically detected (PIVOT) CLPC† All-cause mortality, PCa-specific mortality, metastases harms Insufficient evidence on all-cause mortality, PCa-specific mortality, and erectile and bowel harms; RP probably reduces metastases; WW may reduce urinary harms; insufficient evidence for erectile and bowel harms‡ WW vs RP in men with clinically detected CLPC (SPCG4)—probably results in moderate increases in all-cause mortality and large increases in PCa-specific mortality and metastases at 25 yrs; mortality effects may be limited to men younger than age 65 yrs and men with intermediate risk CLPC; no new data for harms WW vs RP in men with mainly clinically detected CLPC (PIVOT)—probably results in moderate increase in all-cause mortality and large reduction in metastases, and small increase in PCa-specific mortality and at 20 yrs; mortality effects may be limited to men younger than age 65 yrs and men with intermediate risk CLPC; probably results in moderate reduction in erectile and urinary harms at 10 yrs AM (PSA based) vs EBRT+ADT All-cause mortality, PCa-specific mortality, metastases, harms Not addressed AM vs EBRT+ADT in men with PSA screen detected CLPC—probably results in little to no difference in all-cause mortality, may result in little to no difference in PCa-specific mortality and probably results in small increases in metastases at 10 yrs; results may not vary by patient or tumor characteristics; may result in small decrease in erectile dysfunction, probably results in small increase in urinary incontinence and may make little to no difference in fecal incontinence at 6 yrs AM (PSA based) vs RP All-cause mortality, PCa-specific mortality, metastases, harms Not addressed AM vs RP in men with PSA screen detected CLPC—may result in little to no difference in all-cause or PCa-specific mortality but probably results in small increase in metastases at 10 yrs; results may not vary by pt or tumor characteristics; probably results in large decrease in erectile dysfunction and moderate decrease in urinary incontinence, and may make little to no difference in fecal incontinence at 6 yrs AS (biopsy+PSA based) vs PDT Harms Not addressed AS vs PDT in men with PSA screen detected low risk CLPC—probably results in large decrease in erectile dysfunction and moderate decrease in urinary retention at 2 yrs RP vs EBRT+ADT All-cause mortality, PCa-specific mortality, metastases, harms Clinical outcomes not addressed Insufficient evidence on harms§ RP vs EBRT+ADT in men with PSA screen detected CLPC—may result in little to no difference in all-cause mortality, PCa-specific mortality and metastases at 10 yrs; results on PCa-specific mortality may not differ by age, PSA level, Gleason score or clinical stage; probably results in increase in erectile and urinary harms and decrease in bowel dysfunction at 6 yrs RP+ADT vs EBRT+HDR BT+ADT All-cause mortality, PCa-specific mortality, harms Insufficient evidence on harms for RP vs EBRT+BT§ RP+ADT vs EBRT+high dose rate BT+ADT in men with T1b–T3a PCa of any histological grade—may result in small increase in erectile dysfunction at 2 yrs; insufficient evidence on urinary or bowel harms at 2 yrs and all-cause or PCa-specific mortality through 10 yrs RP vs HIFU Harms Not addressed In men with Gleason score 7, <T2b CLPC, insufficient evidence on urinary, erectile and bowel harms at 1 yr Laparoscopic RP vs robot-assisted RP Harms Insufficient evidence on urinary and erectile harms at 1 yr‡ Laparoscopic RP vs robotic RP in men with PSA detected predominantly low to intermediate risk CLPC—may result in moderate increase in urinary incontinence and large increase in erectile dysfunction at 5 yrs Robot-assisted laparoscopic RP vs open retropubic RP All-cause mortality, PCa-specific mortality, metastases, harms Insufficient evidence on all-cause mortality, PCa-specific mortality, metastases and harms§ In men with predominantly low and intermediate D'Amico risk CLPC, insufficient evidence on erectile dysfunction; no data for mortality/metastases EBRT vs BT All-cause mortality, PCa-specific mortality, metastasis-free survival Insufficient evidence on all-cause mortality and PCa-specific mortality‡ In men with Gleason 6 or 7 CLPC, insufficient evidence on overall survival, PCa-specific survival and metastasis-free survival EBRT+BT vs BT All-cause mortality, PCa-specific mortality Insufficient evidence on PCa-specific mortality‡ In men with intermediate National Comprehensive Cancer Network risk CLCP, insufficient evidence on all-cause mortality in men Intensity modulated radiation therapy vs SBRT All-cause mortality Not addressed In men with predominantly Gleason 6–7, PSA<10 and T1C CLPC, insufficient evidence on all-cause mortality Conventionally fractionated EBRT vs ultrahypofractionated EBRT All-cause mortality, PCa-specific mortality, metastasis, harms Not addressed Conventionally fractionated EBRT vs ultrahypofractionated EBRT in men with predominantly intermediate risk CLPC—probably results in little to no difference in all-cause mortality, and may result in little to no difference in PCa-specific mortality and metastasis at 5 yrs; may result in little to no differences in urinary and bowel harms (except urinary harms at 1 yr); insufficient evidence on erectile function 3D-CRT+ADT+low dose rate BT vs 3D-CRT+ADT All-cause mortality, PCa-specific mortality, metastases, harms Insufficient evidence on PCa-specific mortality for EBRT+BT vs EBRT‡ 3D-CRT and ADT+low dose rate BT vs 3D-CRT and ADT in men with intermediate and high National Comprehensive Cancer Network risk CLPC—may result in small decrease in all-cause mortality and little to no difference in metastases at 5 yrs; insufficient evidence on PCa-specific mortality, urinary incontinence and erectile function EBRT+ADT vs EBRT‡ All-cause mortality, PCa-specific mortality, metastases, harms Inconsistent findings on all-cause mortality/survival and metastases but evidence consistently favored combination therapy on PCa-mortality§ EBRT+ADT vs EBRT in men with predominantly intermediate to high risk CLPC (using different risk classifications)—probably results in small reduction in all-cause mortality, and may result in small reduction in PCa-mortality and metastasis at 5–10 yrs. Mortality effects may be limited to intermediate to high risk men, and men with no or minimal comorbidity; may moderately increase sexual dysfunction; insufficient evidence on urinary incontinence and rectal bleeding EBRT+neoadjuvant and concurrent ADT vs EBRT plus concurrent and adjuvant ADT All-cause mortality, PCa-specific mortality, metastasis, harms Not addressed EBRT+neoadjuvant and concurrent ADT vs EBRT+concurrent and adjuvant ADT in men with predominantly intermediate risk CLPC—may result in little to no difference in all-cause mortality and PCa-specific mortality at 12 yrs; insufficient evidence on metastasis; may result in little to no difference in genitourinary toxicity at 3 yrs This table shows findings on mortality; PCa-specific mortality; metastases; sexual, urinary and bowel harms from treatment comparisons analyzed in this current systematic review; and previous findings from the 2014 AHRQ funded and 2016 AUA funded systematic reviews on those same treatment comparisons. We interpreted findings from the 2016 AUA funded report with level C evidence to be equivalent to insufficient evidence. For select treatment comparisons (WW vs RP and EBRT+ADT vs EBRT), our findings incorporate data/outcomes from the prior reviews (see Methods). Findings from 2014 AHRQ funded systematic review. Findings from 2016 AUA funded systematic review. Table 2. Certainty of evidence: watchful waiting vs radical prostatectomy (k=2 RCTs) Outcome (length of followup) Relative Effect (95% CI) % Absolute Effects WW (No./trial) % Absolute Effects RP % Absolute Effects Difference (95% CI) Certainty of Evidence What Happens All-cause mortality (∼20 yrs) SPCG4 RR 1.23 (1.10–1.38),14,15PIVOT RR 1.09 (0.98–1.22)16 SPCG4 70.9 (247/348), PIVOT 66.7 (245/367) 57.6 (200/347) 61.3 (223/364) SPCG4 13.3 (6.3–20.4), PIVOT 5.5 (−1.45–12.4) ⊕⊕◯◯ Low*,† WW may result in moderate to large increase in all-cause mortality vs RP All-cause mortality (∼25 yrs)15 RR 1.12 (1.03–1.2) 83.9 (292/348), 75.2 (261/347) 8.7 (2.7–14.6) ⊕⊕⊕◯ Moderate† WW probably results in moderate increase in all-cause mortality vs RP PCa-specific mortality (∼20 yrs) SPCG4 RR 1.57 (1.19–2.07),14,15PIVOT RR 1.54 (0.97–2.45)16 SPCG4 28.4 (99/348), PIVOT 11.4 (42/367) SPCG4 18.1 (63/347), PIVOT 7.4 (27/364) SPCG4 10.3 (4.05–16.5), PIVOT 4.0 (−0.19–8.25) ⊕⊕◯◯ Low*,† WW may result in small to large increase in PCa-specific mortality vs RP PCa-specific mortality (∼25 yrs)15 RR 1.54 (1.19–2.00) 31.6 (110/348) 20.5 (71/347) 11.1 (4.7–17.6) ⊕⊕⊕◯ Moderate† WW probably results in large increase in PCa-specific mortality vs RP Metastases (∼20 yrs)15 RR 1.54 (1.24–1.93) 39.7 (138/348) 25.6 (89/347) 14 (7.1–20.9) ⊕⊕⊕◯ Moderate† WW probably results in large increase in metastases vs RP Metastases (∼25 yrs)15 RR 1.63 (1.3–2.00) 43.1 (150/348) 26.5 (92/347) 16.6 (9.6–23.6) ⊕⊕⊕◯ Moderate† WW probably results in large increase in metastases vs RP Metastases/systemic progression (∼20 yrs)16 RR 1.45 (0.98–2.14) 14.7 (54/367) 10.2 (37/364) 4.5 (−0.3–9.4) ⊕⊕◯◯ Low‡ WW may result in small increase in metastases (systemic progression) vs RP Rated down 1 level for inconsistency. Rated down 1 level for imprecision. Rated down 2 levels for imprecision. Table 3. Certainty of evidence: active monitoring and active surveillance vs control (k=1 RCT) Comparison Outcome (length of followup) Relative Effect (95% CI) % Absolute Effects (No. AM/AS) % Absolute Effects Control (No./trial) % Absolute Effects Difference (95% CI) Certainty of Evidence What Happens PSA based AM vs EBRT+ADT17,18 All-cause mortality (10 yrs) RR 1.07 (0.8–1.5) 10.8 (59/545) 10.1 (55/545) 0.7 (−2.9–4.4) ⊕⊕⊕◯ Moderate* AM probably results in little to no difference in all-cause mortality vs EBRT+ADT PCa-specific mortality (10 yrs) Peto OR 1.96 (0.63–6.12) 1.5 (8/545) 0.7 (4/545) 0.7 (−0.5–1.9) ⊕⊕◯◯ Low† AM may result in little to no difference in PCa-specific mortality vs EBRT+ADT Metastases (10 yrs) RR 2.1 (1.15–3.7) 6.0 (33/545) 2.9 (16/545) 3.1 (0.67–5.6) ⊕⊕⊕◯ Moderate* AM probably results in small increase of metastases vs EBRT+ADT Rated down 1 level for imprecision. Rated down 2 levels for imprecision. Table 4. Certainty of evidence: radical prostatectomy vs control (k=1 RCT) Comparison Outcome (length of followup) Relative Effect (95% CI) % Absolute Effects RP (No./trial) % Absolute Effects Control (No./trial) % Absolute Effects Difference (95% CI) Certainty of Evidence What Happens RP vs AM17,18 All-cause mortality (10 yrs) RR 0.92 (0.65–1.30) 9.9 (55/553) 10.8 (59/545) −0.9 (−4.5–2.7) ⊕⊕⊕◯ Moderate* RP probably results in little to no difference in all-cause mortality vs AM PCa-specific mortality (10 yrs) Peto OR 0.62 (0.20–1.87) 0.9 (5/553) 1.5 (8/545) −0.6 (−1.8–0.7) ⊕⊕◯◯ Low† RP may result in little to no difference in PCa-specific mortality vs AM Metastases (10 yrs) Peto OR 0.40 (0.22–0.72) 2.4 (13/553) 6.4 (33/545) −4.0 (−6.1–−1.3) ⊕⊕⊕◯ Moderate* RP probably results in small reduction in metastases vs AM RP vs EBRT+ADT17,18 All-cause mortality(10 yrs) RR 0.99 (0.69–1.04) 9.9 (55/553) 10.1 (55/545) −0.1 (−3.7–3.7) ⊕⊕⊕◯ Moderate* RP probably results in little to no difference in all-cause mortality vs AM PCa-specific mortality (10 yrs) Peto OR 1.23 (0.33–4.58) 0.9 (5/553) 0.7 (4/545) 0.2 (−0.9–1.2) ⊕⊕◯◯ Low† RP may result in little to no difference in PCa-specific mortality vs EBRT+ADT Metastases (10 yrs) Peto OR 0.80 (0.38–1.67) 2.4 (13/553) 2.9 (16/545) −0.6 (−2.5–1.3) ⊕⊕◯◯ Low† RP may result in little to no difference in metastases vs EBRT+ADT Rated down by 1 level for imprecision. Rated down by 2 levels for imprecision and sparse data. Table 5. Certainty of evidence: external beam radiation therapy vs control (k=9 RCTs) Comparison Outcome (length of followup) No of Participants (studies) No. RCTs (No. pts) Relative Effect (95% CI) % Anticipated Absolute Effects EBRT (No./trial) % Anticipated Absolute Effects Control (No./trial) % Anticipated Absolute Effects Difference (95% CI) Certainty of Evidence What Happens 3D-CRT and ADT vs 3D-CRT and ADT with LDR-PB boost19–21 Mortality (5 yrs) 1 (398) RR 1.25 (0.81–1.94) 18.9 (38/200) 15.2 (30/198) 3.8 (−3.5–11.2) ⊕⊕◯◯ Low*,† 3D-CRT and ADT may result in small increase in mortality vs 3D-CRT and ADT with LDR-PB boost in higher risk disease Prostate-specific mortality (5 yrs) 1 (398) RR 1.56 (0.62–3.93) 5.5 (11/200) 3.5 (7/198) 2.0 (−2.1–6.0) ⊕◯◯◯ Insufficient*,‡ Evidence is very uncertain about effect of 3D-CRT and ADT with LDR-PB boost on prostate-specific mortality vs 3D-CRT and ADT in higher risk disease Metastatic disease (5 yrs) 1 (398) RR 1.05 (0.56–1.97) 9.0 (18/200) 8.6 (17/198) 0.4 (−5.1–6.0) ⊕⊕◯◯ Low*,† 3D-CRT and ADT with LDR-PB boost may result in little to no difference in metastatic disease vs 3D-CRT and ADT in higher risk disease EBRT+ADT vs EBRT22–28 Overall mortality (5.9–9.1 yrs) 5 (4,047) RR 0.86 (0.69–1.06) 27.3 (587/2,150) 32.4 (615/1,897) −3.7 (−9.8–2.4) ⊕⊕⊕◯ Moderate† EBRT+ADT probably results in small reduction in overall mortality vs EBRT in higher risk disease PCa mortality (7.2–9.1 yrs) 3 (3,004) Peto OR 0.51 (0.37–0.70) 3.53 (53/1,499) 6.9 (104/1,505) −3.4 (−4.95- −1.8) ⊕⊕◯◯ Low*,† EBRT and ADT may result in small reduction in prostate cancer mortality vs EBRT in higher risk disease Metastasis (5–10 yrs) 4 (4,664) RR 0.83 (0.71–0.97) 11.5 (284/2,461) 13.1 (289/2,203) −2.3 (−4.1–−0.4) ⊕⊕◯◯ Low*,† EBRT and ADT may result in small reduction in metastasis vs EBRT in higher risk disease EBRT+neoadjuvant and concurrent ADT vs EBRT+concurrent and adjuvant ADT29 Overall mortality (12.2 yrs) 1 (432) RR 1.05 (0.81–1.37) 34.9 (75/215) 33.2 (72/217) 1.7 (−7.2–10.6) ⊕⊕◯◯ Low‡ EBRT+neoadjuvant and concurrent ADT may result in little to no difference in overall mortality vs EBRT+concurrent and adjuvant ADT PCa mortality (12.2 yrs) 1 (432) Peto OR 1.01 (0.35–2.93) 3.3 (7/215) 3.2 (7/217) 0 (−3.3–3.4) ⊕⊕◯◯ Low*,† EBRT+neoadjuvant and concurrent ADT may result in little to no difference in PCa mortality vs EBRT+concurrent and adjuvant ADT Metastasis distant progression (12.2 yrs) 1 (432) Peto OR 1.36 (0.57–3.27) 5.6 (12/215) 4.1 (9/217) 1.4 (−2.6–5.5) ⊕◯◯◯ Insufficient*,‡ Evidence is very uncertain about effect of EBRT+neoadjuvant and concurrent ADT on
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