ASCO recommendation of SUO/AAU/ASTRO guidline 2018. EAU 2018 review. Evidence for guideline

1. Clinically localized Prostate
Cancer
Dr.Bhavin Vadodariya
Date- 17/11/2018

3. Outline
 Introduction
 Risk Stratification
 ASCO Guideline Summary
 Comparison with EAU
 ProTect Trial
 NC ProCess Trial
 Caesar Trial
 Conclusion

4. Introduction
 In the United States, prostate cancer remains the
most commonly diagnosed cancer in men, representing 19% of all newly
reported cases—an estimated 164,690 patients in 2018.
 It is also the second leading cause of cancer deaths in all men, with an
estimated mortality of 39,430 in 2018.
 For these reasons, there is great interest in maintaining the highest cancer
care quality and identifying optimal treatment, while considering such factors
as disease stage, risk, volume, age, and performance status.
.Siegel RL, Miller KD, Jemal A: Cancer statistics, 2018. CA Cancer J Clin 68:7-30, 2018

5. Staging

6. Clinically localized Prostate cancer

8. Recommendations

9. Shared decision making

10. Counseling of patients - (Strong recommendation;
Evidence level: grade A)
 Why?- to select a management strategy for localized prostate cancer should incorporate shared decision
making and explicitly consider
 Cancer severity (risk category),
 Patient values and preferences,
 Life expectancy,
 Pretreatment general functional and genitourinary symptoms,
 Expected post treatment functional status, and
 Potential for salvage treatment. (Strong recommendation; Evidence level: grade A)

11.  Modifiable health-related behaviors or risk factors, such as smoking and
obesity
 Should inform patients about suitable clinical trials and encourage patients to
consider participation in such trials based on eligibility and access. (Expert
Opinion)

12. Meet with different prostate cancer care
specialists –Uro,MO,SO,RO
 To know about morbidity and mortality
 Surgery- Urinary incontinence(25%), Erectile dysfunction
 RT- Enteritis, Proctitis, Erectile dysfunction ,Urinary frequency,dysuria,urgency
 Brachytherapy- Stricture, Retention,incontinence

13. Recommendations clinical

15. EAU 2018

16. EAU 2018

17. EAU 2018

18. Active Surveillance ASCO
 Accurate disease staging including systematic biopsy with ultrasound or magnetic
resonance imaging-guided imaging. (Clinical Principle)
 Routine surveillance prostate specific antigen testing and digital rectal exams.
(Strong recommendation; Evidence level: grade B)
 To have a confirmatory biopsy within the initial two years and surveillance biopsies
thereafter. (Clinical Principle)

19. Active Surveillance ASCO
 Clinicians may consider multiparametric prostate magnetic resonance imaging as a
component of active surveillance for localized prostate cancer patients. (Expert
Opinion)
 Tissue based genomic biomarkers have not shown a clear role in active
surveillance for localized prostate cancer and are not necessary for follow up.
(Expert Opinion)
 Definitive treatment -to localized prostate cancer patients undergoing active
surveillance who develop adverse reclassification. (Moderate recommendation;
Evidence level: grade B)

20. EAU 2018

21. Radical Prostatectomy ASCO
 Clinicians should inform localized prostate cancer patients that younger or
healthier men (e.g. 65 years of age or .10 year life expectancy) are more likely to
experience cancer control benefits from prostatectomy than older men. (Strong
recommendation; Evidence level: grade B)
 Clinicians should inform localized prostate cancer patients that open and robot-
assisted radical prostatectomy offer similar cancer control, continence recovery,
and sexual recovery outcomes. (Moderate recommendation; Evidence level:
grade C)

22. Radical Prostatectomy ASCO
 Clinicians should inform localized prostate cancer patients that robotic/laparoscopic
or perineal techniques are associated with less blood loss than retropupic
prostatectomy. (Strong recommendation; Evidence level: grade B)
 Clinicians should counsel localized prostate cancer patients that nerve-sparing is
associated with better erectile function recovery than nonnerve sparing.(Strong
recommendation; Evidence level: grade A).
 Clinicians should not treat localized prostate cancer patients who have elected to
undergo radical prostatectomy with neoadjuvant androgen deprivation therapy
or other systemic therapy outside of clinical trials. (Strong recommendation;
Evidence level: grade A)

23. Radical Prostatectomy ASCO
 Clinicians should inform localized prostate cancer patients considering
prostatectomy, that older men experience higher rates of permanent erectile
dysfunction and urinary incontinence after prostatectomy compared with
younger men. (Strong recommendation; Evidence level: grade B)
 Pelvic lymphadenectomy can be considered for any localized prostate cancer
patients undergoing radical prostatectomy and is recommended for those with
unfavorable intermediate-risk or high-risk disease.
 Patients should be counseled regarding the common complications of
lymphadenectomy, including lymphocele development and its treatment. (Expert
Opinion)

24. Radical Prostatectomy ASCO
 Clinicians should inform localized prostate cancer patients with unfavorable
intermediate-risk or high-risk prostate cancer about benefits and risks related to
the potential option of adjuvant radiotherapy when locally extensive prostate
cancer is found at prostatectomy. (Moderate recommendation; Evidence level:
grade B)

25. Radiotherapy ASCO
 Clinicians may offer single modality external beam radiotherapy or brachytherapy
for patients who elect radiotherapy for low-risk localized prostate cancer.
(Clinical Principle)
 Clinicians may offer external beam radiotherapy or brachytherapy alone or in
combination for favorable intermediate-risk localized prostate cancer. (Clinical
Principle)
 Clinicians should offer 24-36 months of androgen deprivation therapy as an
adjunct to either external beam radiotherapy alone or external beam
radiotherapy combined with brachytherapy to patients electing radiotherapy for
high-risk localized prostate cancer. (Strong recommendation; Evidence level:
grade A)

26. Radiotherapy ASCO
 ADT+RT- likelihood and severity of adverse treatment-related events on sexual
function in most men and can cause other systemic side effects. (Strong grade B) .
 Moderate hypofractionation when the localized prostate cancer patient (of any
risk category) and clinician decide on external beam radiotherapy to the prostate
(without nodal radiotherapy). (Moderate B)
 For localized prostate cancer patients with obstructive, non-cancer-related lower
urinary function, surgical approaches may be preferred.
 If radiotherapy is used for these patients or those with previous significant
transurethral resection of the prostate, low-dose rate brachytherapy should be
discouraged. (Moderate recommendation; Evidence level: grade C)

27. Radiotherapy ASCO
 Proton beam therapy that it offers no clinical advantage over other forms of
definitive treatment. (Moderate recommendation; Evidence level: grade C)
 Brachytherapy that it has similar effects as external beam radiotherapy with regard
to erectile dysfunction and proctitis but can also exacerbate urinary obstructive
symptoms. (Expert Opinion)

28. EAU 2018

29. HIFU and Focal Therapy ASCO
 These treatment options lack robust evidence of efficacy. (Expert Opinion)
 Even though HIFU is approved by the U.S. FDA for the destruction of prostate
tissue, it is not approved explicitly for the treatment of prostate cancer (Expert
Opinion).
 Tumor location may influence oncologic outcome.Limiting apical treatment to
minimize morbidity increases the risk of cancer persistence. (Moderate
recommendation; Evidence level: grade C)
 As prostate cancer is often multifocal, clinicians should inform localized prostate
cancer patients considering focal therapy that focal therapy may not be curative
and that further treatment of prostate cancer may be necessary. (Expert Opinion)

30. Whole Gland Cryosurgery ASCO non endorsed
 In low- and intermediate-risk localized prostate cancer patients who are not
suitable for either radical prostatectomy or radiotherapy due to comorbidities yet
have 10 year life expectancy. (Expert Opinion)
 Defects from prior transurethral resection of the prostate are a relative
contraindication for whole gland cryosurgery due to the increased risk of urethral
sloughing. (Clinical Principle)
 For whole gland cryosurgery treatment, clinicians should use a third or higher
generation, argon-based cryosurgical system for whole gland cryosurgery
treatment. (Clinical Principle)

31. Whole Gland Cryosurgery ASCO non endorsed
 Cryosurgery that it is unclear whether concurrent androgen deprivation therapy
improves cancer control, though it can reduce prostate size to facilitate treatment.
(Clinical Principle)
 Erectile dysfunction is an expected outcome. (Clinical Principle)
 The adverse events of urinary incontinence, irritative and obstructive urinary
problems. (Strong recommendation; Evidence level: grade B)

32. Treatment Side Effects and Health Related Quality of Life
 Erectile dysfunction occurs in many patients following prostatectomy or radiation,
and that ejaculate will be lacking despite preserved ability to attain orgasm,
whereas observation does not cause such sexual dysfunction. (Strong B)
 long-term obstructive or irritative urinary problems occur in a subset of patients
following observation or active surveillance or following radiation, whereas
prostatectomy can relieve pre-existing urinary obstruction. (Strong B)
 Whole-gland cryosurgery is associated with worse sexual side effects and similar
urinary and bowel/rectal side effects as those after radiotherapy. (Strong
recommendation; Evidence level: grade B)

33. Treatment Side Effects and Health Related Quality of Life
 Temporary urinary incontinence occurs in most patients after prostatectomy and
persists longterm in a small but significant subset, more than during observation
or active surveillance or after radiation. (Strong A)
 Temporary proctitis following radiation persists in some patients long-term in a
small but significant subset and is rare during observation or active surveillance or
after prostatectomy. (Strong A)

34. Post-Treatment Follow Up
 Prostate specific antigen, even though not all prostate specific antigen recurrences
are associated with metastatic disease and prostate cancer specific death. (Clinical
Principle)
 Clinicians should inform localized prostate cancer patients of their individualized
risk-based estimates of post treatment prostate cancer recurrence. (Clinical
Principle)
 Clinicians should support localized prostate cancer patients who have survivorship
or outcomes concerns by facilitating symptom management and encouraging
engagement with professional or community-based resources. (Clinical Principle)

35. Tissue-based genomic biomarker
 Tissue-based genomic biomarker investigations are moving the traditional
clinically based risk classification toward a combined genomic-clinical
classification system,particularly in the postprostatectomy setting.
 Nonetheless, patients selected for active surveillance using the Prostate
Cancer Research International Active Surveillance criteria(PRIAS) have low
likelihood of harboring high primary Gleason grade disease at prostatectomy.

37. Tissue-based genomic biomarker
 Multifocal spatial and intralesional genomic heterogeneity and discordance
between Gleason grading and biomarker findings may create greater
challenges using biopsy specimens alone compared with prostatectomy
tissue.
 Further research, particularly in cohorts from prospective clinical trials, is
essential to establish guidelines for routine clinical decision making.

38. For High-risk prostate cancer, ADT duration
 Duration as short as 18 months may be permissible based on the RADAR
(Randomized Androgen Deprivation and Radiotherapy) randomized trial
finding that 18 months of ADT reduced prostate cancer mortality compared
with 6 months,and the results of the PCS IV (Duration of Androgen Blockade
Combined With Pelvic Irradiation in Prostate Cancers) randomized trial, which
could not demonstrate that 36 months resulted in superior overall survival
compared with 18 months.

40. PCS IV
 Objective:
 The aim of this superiority randomized trial was to compare outcomes of RT
combined with either 36 or 18 mo of ADT.
 Design, setting and participants:
 From October 2000 to January 2008, 630 patients with HRPC were
randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm)
and 320 to the same RT with 18 mo (short arm) of ADT. ]
 Outcome measurements and statistical analysis:
 Overall survival (OS) and quality of life (QoL)

41. PCS IV Results
 With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143
short arm).
 The 5-yr OS rates (95% confidence interval) were 91% for long arm (88–95%)
and 86% for short arm (83–90%), p = 0.07.
 QoL analysis showed a significant difference (p < 0.001) in six scales and 13
items favoring 18 mo ADT with two of them presenting a clinically relevant
difference in mean scores of 10 points.

42. PCS IV Conclusion
 In localized HRPC, our results support that 36 mo is not superior to 18 mo
of ADT.
 ADT combined with RT can potentially be reduced to 18 mo in selected men
without compromising survival or QoL.
 Thus, 18 mo of ADT appears to represent a valid option in HRPC.

43. ProTect Trial- October 2016
The Prostate Testing for Cancer and Treatment (ProtecT) trial

44. ProTect Trial
Between 1999 and 2009, a total of 1643 men 50 to 69 years of age
patients were randomly assigned to one of three regimens:
 Active monitoring, (545)
 Radical prostatectomy, (553)
 External beam RT (74 Gy in 37 fractions) with neoadjuvant and concurrent
ADT for three to six months. (545)

45. End points
 The primary outcome
 Prostate-cancer mortality (DFS)at a median of 10 years of follow-up.
 Secondary outcomes
 Rates of disease progression(Clinical progression included the development of
metastatic disease, the diagnosis of clinical T3 or T4 disease, long-term ADT treatment,
ureteral obstruction, rectal fistula, or the need for a urinary catheter due to local tumor
growth.
 Development of metastases(bone, lymph node, or visceral metastases, or a serum PSA
>100 ng/mL)
 All-cause deaths. (OS)

46. Protect Trial
 Active monitoring used serum PSA levels measured every three months in the
first year and every 6 to 12 months thereafter to trigger patient reassessment
and consideration of a change in clinical management.
 Active monitoring is different from active surveillance in that it relies primarily
on grade progression, rather than an increase in serum PSA, to prompt
therapeutic intervention.

47. ProTect Trial
 Stage T1c disease- 76 %
 The Gleason score was 6 - 77 % and 7- 21%
 The median serum PSA was 4.6 ng/mL.
 Approximately 1 percent of the population had African or Caribbean ethnicity.

50. Patient reported outcomes(PRO)
 Sexual and urinary function declined gradually in the active-monitoring group.
 Bowel function was unchanged in the other groups.
 No significant differences were observed among the groups in measures of
anxiety, depression, or general health-related or cancer-related quality of life.

53. Prostatectomy- PROs
 Prostatectomy had the greatest negative effect on sexual function and urinary
continence, and although there was some recovery, these outcomes
remained worse in the prostatectomy group than in the other groups
throughout the trial.

54. Radiotherapy +ADT PROs
 The negative effect of radiotherapy on sexual function was greatest at 6 months, but
sexual function then recovered somewhat and was stable thereafter;
 Radiotherapy had little effect on urinary continence.
 Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but
then mostly recovered and were similar to the other groups after 12 months.
 Bowel function was worse in the radiotherapy group at 6 months than in the other
groups but then recovered somewhat, except for the increasing frequency of bloody
stools;

55.  Longer follow-up will be required to know whether the higher incidence of
metastatic disease with active monitoring compared with radical
prostatectomy or RT can affect cancer-specific or overall mortality, and what
impact subsequent treatment for metastatic disease has on quality of life and
survival.

56. Limitations
 The applicability of the results of this trial to older men (≥70 years at
diagnosis) or those of African or Caribbean ethnicity is unclear, and results
may differ.
 Both RT and surgical techniques have improved since the trial was initiated, as
have the criteria for patient selection for active surveillance.
 Prostate MRIs and genomic testing were not available;
 Prostate biopsies were not done in the active surveillance group, and the
trigger to consider a change in management was largely driven by PSA results.
This "surveillance" strategy is largely outdated

57. NC ProCESS
The North Carolina Prostate Cancer
Comparative Effectiveness &
Survivorship Study (NC ProCESS)
Population-based
prospective cohort of 1141
men with newly diagnosed
prostate cancer were
enrolled from January
2011 through June 2013

58. Outcome
 Quality of life using the validated instrument Prostate Cancer Symptom Indices was
assessed at baseline (pretreatment) and 3, 12, and 24 months after treatment.
 The instrument contains 4 domains—each scored from 0 (no dysfunction) to 100
(maximum dysfunction).
 Sexual dysfunction,
 Urinary obstruction
 Irritation,
 Urinary incontinence,
 Bowel problems

59. Results
 Median age was 66 to 67 years across groups, and
 77% to 80% of participants were white.
 Compared with active surveillance, mean sexual dysfunction scores worsened
by 3 months for patient who received radical prostatectomy (36.2 [95% CI,
30.4-42.0]), external beam radiotherapy (13.9 [95% CI, 6.7-21.2]), and
brachytherapy (17.1 [95% CI, 7.8-26.6]).

60. Results
 Compared with active surveillance at 3 months, worsened urinary
incontinence was associated with radical prostatectomy (33.6 [95% CI, 27.8-
39.2]);
 Acute worsening of urinary obstruction and irritation with external beam
radiotherapy (11.7 [95% CI, 8.7-14.8]) and brachytherapy (20.5 [95% CI, 15.1-
25.9]);
 Worsened bowel symptoms with external beam radiotherapy (4.9 [95% CI,
2.4-7.4]).

61. Conclusion Nc process
 By 24 months, mean scores between treatment groups vs active
surveillance were not significantly different in most domains.

62. CEASAR
Trial
The Comparative Effectiveness Analysis
of Surgery and
Radiation (CEASAR) study

63. CEASAR Trial
 Prospective, population-based, observational study
 Men with localized prostate cancer in 2011–2012.
 Among 2117 CEASAR participants who underwent RP or EBRT,
 817 had low-risk, (38%)
 902 intermediate-risk, (42%)
 398 high-risk disease. (20%)

64. Outcome
 Patient-reported, disease-specific function was measured using the 26-item
Expanded Prostate Index Composite (at baseline and 6, 12, and 36 mo).
 Predicted function was estimated using regression models and compared by
disease risk.

65. Results
 Low-risk EBRT patients reported 3-yr sexual function scores 12 points higher
than those of low-risk RP patients (RP, 39 points [95% confidence interval {CI},
37–42] vs EBRT, 52 points [95% CI, 47–56]; p < 0.001).
 The difference in 3-yr scores for high-risk patients was not clinically
significant (RP, 32 points [95% CI, 28–35] vs EBRT, 38 points [95% CI, 33–42]; p
= 0.03).

68. Results
 Binary definition of sexual function (erections firm enough for intercourse), no
major differences were noted between RP and EBRT at 3 yr across low-,
intermediate-, and high risk disease strata.
 No clinically significant interactive effects between treatment and cancer
severity were observed for incontinence, bowel, irritative voiding, and
hormone domains.

69. Conclusions
 For men with low-risk prostate cancer, EBRT was associated with higher sexual
function scores at 3 yr than RP;
 however, for men with high-risk prostate cancer, no clinically significant difference
was noted.
 Men with high-risk prostate cancer should be counselled that EBRT and RP carry
similar sexual function outcomes at 3 yr.
 The primary limitation is the lack of firmly established thresholds for clinically
significant differences in Expanded Prostate Index Composite domain scores

70.  For guideline statement 61: Clinicians should inform localized
prostate cancer patients that erectile dysfunction occurs in many
patients following prostatectomy or radiation, and that ejaculate will be
lacking despite preserved ability to attain orgasm, whereas observation does
not cause such sexual dysfunction (Strong recommendation; Evidence level:
grade B).

71.  For guideline statement 62: Clinicians should inform localized prostate cancer
patients that long-term obstructive or irritative urinary problems occur in a
subset of patients following observation or active surveillance or following
radiation, whereas prostatectomy can relieve pre-existing urinary obstruction
(Strong recommendation; Evidence level: grade B).

72. ASCO does not endorse Cryosurgery

73. Pelvic lymph node dissection
 Pelvic lymphadenectomy is optional in patients at low risk for lymph node
metastases.
 In fact, pelvic lymphadenectomy has been less frequently performed with
robotic prostatectomy (Gandaglia et al, 2014).

74. Pelvic lymph node dissection
 Some have argued that a more extensive pelvic lymphadenectomy yields
better outcomes, but compelling evidence for this is lacking (Weight et al,
2008), and more extensive lymphadenectomy carries a greater risk for
postoperative genital and lower extremity lymphedema and lymphocele
(Bader et al, 2002; Allaf et al, 2004; Musch et al, 2008).
 Thromboembolic events and reinterventions are more common in patients
with symptomatic lymphocele (Musch et al, 2008).

75. EAU

76. Kattan MSKCC Normogram

77. Briganti Normogram
Using a 5% nomogram
cut-off, 385 of 588 patients
(65.5%) would be spared ePLND.
and LNI would be missed in only
6 patients (1.5%).
The sensitivity, specificity, and
negative predictive value
associated with the 5%cut-off
were 87.8%, 70.3%, and 98.4%,
respectively.

78. Fossati -2016

79. Fossati meta analysis
 Comparing biochemical and clinical recurrence, while no significant
differences were observed among groups for survival.
 Conversely, the majority of studies showed that the more extensive the PLND,
the greater the adverse outcomes in terms of operating time, blood loss,
length of stay, and postoperative complications.
 No significant differences were observed in terms of urinary continence and
erectile function recovery.

80. Fossati meta analysis
Conclusions:
 Although representing the most accurate staging procedure, PLND and its
extension are associated with worse intraoperative and perioperative outcomes,
whereas a direct therapeutic effect is still not evident from the current literature.
 The current poor quality of evidence indicates the need for robust and adequately
powered clinical trials.

81. Take Home Message
 Distant metastatic workup can be avoided in Very low, low and favorable
intermediate risk group.
 Watchful waiting is recommended in patients with life expectancy less than 5 yrs
regardless of risk category
 Active Surveillance is best option for low risk patients but associated with disease
progression , development of metastasis and gradual deterioration of sexual and
urianary function.
 Radical prostatectomy or radiotherapy is the option in clinically localized prostate
cancer strongly recommended in intermediate and high risk disease

82. Take Home Message
 RP is preferred in patient with non cancerous obstructive uropathy and
previous TURP
 older men experience higher rates of permanent erectile dysfunction and
urinary incontinence after prostatectomy compared with younger men.
 Pelvic lymphadenectomy can be considered for any localized prostate cancer
patients undergoing radical prostatectomy and is recommended for those
with unfavorable intermediate-risk or high-risk disease.

83. Take home message
 Cryo,HIFU- lack of evidence , don’t use outside clinical trial.
 Neoadjuvant ADT before RP not recommneded
 RT with 18 month of ADT in high risk is recommended

84. Thank you