ca prostate dr naresh jakhotia
TRANSCRIPT
05/03/2023
Dr Naresh JakhotiaDepartment of Radiation Oncology
BMCHRC
Department of Radiation Oncology, Duke University Medical Center
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Prostate CancerStaging
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Risk Group
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Prostate CancerTreatment
PRINCIPLES OF THERAPY May include
Watchful waiting Androgen deprivation External beam radiotherapy Retropubic or perineal radical prostatectomy
with or without postoperative radiotherapy to the prostate margins and pelvis
Brachytherapy (either permanent or temporary radioactive seed implants)
with or without external beam radiotherapy to the prostate margins and pelvis.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment
Require individualization Must take into account
Patient's comorbidity Life expectancy Likelihood of cure Personal preferences
Based on an understanding of potential morbidity associated with each treatment
A multidisciplinary approach (recommended) Integrate
Surgery Radiation therapy Androgen deprivation Behavioral therapy
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment
Surgery Traditional Robotic
Radiation Brachytherapy External beam
Cryotherapy Androgen Deprivation Watchful waiting
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment - LOW/INTERMEDIATE RISK DISEASE
LOW/INTERMEDIATE RISK DISEASE Randomized trial
Under the age of 75 Clinical stage T1b, T1c, or T2 prostate cancer Radical prostatectomy
Reduced the relative risk of death by 50% (a 2% absolute risk reduction)
Compared with watchful waiting Despite a significant reduction in the risk of metastasis,
overall mortality was unchanged Adverse effects on quality of life
More dysfunction and urinary leakage after radical prostatectomy
More urinary obstruction with watchful waiting Nerve-sparing radical prostatectomy was not routinely
performed in this study Less advanced disease with newer surgical techniques are not
knownSmall, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment - LOW/INTERMEDIATE RISK DISEASE
Nonrandomized data Suggest that watchful waiting may be
judiciously used Gleason score 2, 3, or 4 tumors with life
expectancy of 10 years or less Watchful waiting is probably not appropriate for
young, otherwise healthy men with high-risk features as described earlier (PSA > 10, Gleason sum = 7, or clinical stage T3 or higher).
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment - LOW/INTERMEDIATE RISK DISEASE
External beam radiation therapy (EBRT) Three-dimensional conformal radiation therapy (3D-
CRT) IMRT/ IG-IMRT
Complications of external radiotherapy Cystitis Proctitis Enteritis Impotence Urinary retention Incontinence (7-10%)
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment - LOW/INTERMEDIATE RISK DISEASE
Brachytherapy Placement of permanent or temporary
radioactive seeds directly into the prostate Adequate for
Intracapsular disease No more than minimal transcapsular extension It can be combined with external beam radiation
therapy.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment – High-risk disease
HIGH-RISK DISEASE. Patients with adverse risk features (Gleason score 8 to 10, PSA > 10, stage T3)
Treated with Aggressive local therapy or Androgen deprivation
Synergistic with radiation therapy Trials
4 months of androgen deprivation with radiation therapy Improve local control and prolong progression-free survival in
patients with intermediate risk features Long-term androgen deprivation (up to 3 years)
Prolongs local control Prolongs progression-free survival and overall survival in
patients with high-risk features compared with radiation therapy.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment – Recurrent disease
RECURRENT DISEASE ~50% of men treated with radiation therapy or
prostatectomy develop evidence of recurrence Defined by a climbing PSA level
Local salvage therapy Selected patients with clear local recurrences
Surgery for patients previously treated with radiation Radiation for patients previously treated with surgery
and androgen deprivation Early hormone therapy
Appears to be better than hormonal salvage therapy in terms of survival.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment – Advanced disease
ADVANCED DISEASE Microscopic involvement of lymph nodes
Revealed by radical prostatectomy Immediate androgen deprivation prolongs survival
Should not wait until osseous metastases are detected Patients at high risk of nodal invasion and who undergo
external beam radiation Benefit from concurrent short-term hormonal therapy.
Newly diagnosed metastatic prostate cancer Androgen deprivation is the mainstay of treatment
Results in symptomatic improvement and disease regression in approximately 80 to 90% of patients
Androgen deprivation can be achieved by orchiectomy or by medical castration
Luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide acetate, goserelin acetate)
Safer and as effective as estrogen treatment.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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Prostate CancerTreatment – Advanced disease
Side effects of LHRH agonist LH and testosterone surge within 72 hours
Transient worsening of signs and symptoms during the first week of therapy An antiandrogen (flutamide, bicalutamide, or nilutamide) should be given with the
first LHRH injection to prevent a tumor flare Medical castration occurs within 4 weeks Hormone sensitivity
Duration 5 to 10 years for node-positive or high-risk localized (or recurrent) prostate
cancer 18 to 24 months in patients with overt metastatic disease
Side effects androgen ablation Loss of libido Impotence Hot flashes Weight gain Fatigue Anemia Osteoporosis
Bisphosphonates reduce bone mineral loss associated with androgen deprivation.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
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NRG ONCOLOGY RTOG 0415: A RANDOMIZED PHASE III NON-INFERIORITY STUDY COMPARING TWO FRACTIONATION SCHEDULES IN PATIENTS WITH LOW-RISK PROSTATE CANCER
W Robert Lee, James J Dignam, Mahul B Amin, Deborah W Bruner, Daniel Low, Gregory P Swanson, Amit B Shah, David D'Souza, Jeff M Michalski, Ian S Dayes, Samantha
A Seaward, William A Hall, Paul L Nguyen, Thomas M Pisansky, Sergio L Faria, Yuhchyau Chen, Bridget
Koontz, Rebecca Paulus, Howard M Sandler
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Processed as a Rapid Communication manuscript.
Supported by National Cancer Institute.
Presented in part at 57th Annual Meeting of the American
Society for Radiation Oncology, San Antonio, TX, September 18-21, 2015
2016 American Society of Clinical Oncology, Genitourinary Symposium, San Francisco, CA, January 7-9, 2016.
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Background• Conventional radiotherapy
involves 40-45 once daily treatments over 8-9 weeks
• Fractionation sensitivity of prostate cancer may favor hypofractionation
• Contemporary randomized trials have not demonstrated increased efficacy with hypofractionation
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Purpose of NRG Oncology RTOG 0415
To determine whether efficacy of hypofractionated treatment schedule was not worse than a conventional schedule in men with low-risk prostate cancer. This is first report of this study.
Advantage: Potentially increasing efficacy of RT, smaller number of treatments with hypofractionation increases convenience for patient and decreases use and health care costs.
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Trial Design & Participants
Men age >18 years with Prostate Adenocarcinoma – Eligibility Criteria Stage - cT1b to T2c cNo Mo Gleason score 2 to 6 S.PSA < 10 Zubrod performance status <2 No prior B/l orchidectomy, chemotherapy, RT,
cryosurgery, or definitive surgery for prostate cancer. No h/o another invasive cancer (except localised basal
or squamous cell skin carcinoma), unless continually free from that cancer for a minimum of 5 years.
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Before entry in study –
History Physical examination, including DRE S.PSA (within 180 days before registration) Androgen suppression was not allowed,
except as a salvage therapy All participants –
Written informed consent, before registration Receive protocol-specified care Follow-up at a member site Did not receive compensation No commercial support
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Random Assignment Multicenter, stratified, parallel group study with
1:1 random assignment approved and sponsored by the US National Cancer Institute.
Patients were stratified according to PSA level ( <4 ng/ml v 4 to 10 ng /ml) Gleason score (2 to 4 v 5 to 6) Radiation modality ( 3D-CRT v IMRT)
Participants were then randomly assigned by using the permuted block method to either a C-RT treatment schedule (73.8 Gy in 41 fractions over 8.2 weeks) or to an H-RT schedule (70 Gy in 28 fractions over 5.6 weeks).
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SchemaSTRATIFY
RANDOMIZE
Gleason 2-4Gleason 5-6
PSA <4PSA 4-<10
3DCRTIMRT
73.8 Gy/41 frof 1.8 Gy over
8.2 weeks70 Gy/28 fr of2.5 Gy over5.6 weeks
No androgen suppression
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Biologic Effective Dose (BED)
Biologic effective dose of each treatment arm according to alpha-beta assumption. This study was designed so that the two arms would be iso-effective assuming an alpha-beta of 10. If alpha-beta is lower, whether for prostate cancer or normal tissue, then hypofractionated arm would result in a higher BED.
10 5 3 1.5 10
50100150200250300
BED
α/β ratio
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Treatment RT was initiated within 6 weeks of registration. Daily field alignment with intraprostatic
fiducial markers or other means to the prostate was required.
CTV was prostate as identified on planning CT scan
A 3D expansion of CTV by 4 to 10 mm was used to create planning target volume (PTV).
Participants were assigned either to 73.8 Gy (C-RT) or to 70 Gy (H-RT) fraction, which was minimum dose to ≥ 98% of the PTV.
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Maximum dose to PTV could not exceed prescription dose by > 7%.
Maximum dose > 7% but < 10% was a minor, acceptable variation, and ≥ 10% was a major, unacceptable variation.
Dose constraints to normal tissues (bladder, rectum, penile bulb) as listed in the protocol were followed.
No attempt was made to treat seminal vesicles or pelvic lymph nodes.
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Results
The study opened in April 2006 and accrual was closed in December 2009 ahead of schedule
with 1115 men enrolled.
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Eligibility
1092 men analyzable
73.8 Gy 70.0 GyRandomized 558 557Ineligible 10 3Not evaluable
6 4
Eligible 542 550
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Patient CharacteristicsCharacteristic
73.8 Gy(n=542)
70.0 Gy(n=550)
Age ≤ 59 87 (16%) 95 (17%)60-69 239 (44%) 251 (46%)≥ 70 216 (40%) 204 (37%)
Race White 430 (79%) 436 (79%)Black 91 (17%) 99 (18%)Other 21 (4%) 15 (3%)
Zubrod 0 507 (94%) 504 (92%)1 35 (6%) 46 (8%)
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Tumor CharacteristicsCharacteristic
73.8 Gy(n=542)
70.0 Gy(n=550)
PSA < 4 106 (20%) 112 (20%)4 - <10 436 (80%) 438 (80%)
Gleason 2-4 2 (<1%) 0 (0%)5-6 540 (99%) 550 (100%)
T Stage T1 411 (76%) 442 (80%)T2 131 (24%) 108 (20%)
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DFS Event
73.8 Gy
(n=99)
70.0 Gy
(n=86)
Death w/o failure 49 46PSA Recurrence 46 36Non-protocol HT 4 2Distant Progression
0 2
Primary Endpoint
Median FU 5.8 years
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HR 0.85 (0.64,1.14)
86%85%
Disease-free Survival
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Secondary Endpoints
• Biochemical Recurrence
• Adverse Events
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Biochemical RecurrenceHR 0.77 (0.51,1.17)
8%6%
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73.8 Gy(n=533)
70.0 Gy(n=542)
73.8 Gy(n=533)
70.0 Gy(n=542)
Grade 2 52(9.8%) 54(10.0%) 132(24.8%) 129(23.8%)
Grade 3 3(0.6%) 3(0.6%) 13 (2.4%) 18(3.3%)
Grade 4 0(0%) 1(0.2%) 0 (0%) 0 (0%)
Acute Adverse EventsGI GU
GI p=0.80 GU p=0.66
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73.8 Gy(n=533)
70.0 Gy(n=542)
73.8 Gy(n=533)
70.0 Gy(n=542)
Grade 2 61(11.4%) 99(18.3%) 109(20.5%) 142(26.2%)
Grade 3 13(2.4%) 22(4.1%) 11(2.1%) 19(3.5%)
Grade 4 1(0.2%) 0(0%) 1(0.2%) 0(0%)
Late Adverse EventsGI GU
GI p=0.005 GU p=0.009
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Overall Survival Estimated 5-year overall survival
C-RT arm – 93.2 % H-RT arm – 92.5 % HR comparing OS between two arms – 0.95
Protocol specified noninferiority criteria was met (HR>1.54 rejected, p= 0.008).
Most frequent cause of death – Cardiovascular disease Second cancers
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Additional protocol-specified clinical end points
As a result of low frequency of these events, additional analyses are not presented.
C-RT ARM H-RT ARM
LOCAL PROGRESSION
7 2
Prostate cancer-specific survival
(deaths)2 1
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Discussion Many RCTs were started based on hypothesis that
higher dose per treatment, that is, hypofractionated external RT, would increase efficacy of RT compared with conventionally delivered external RT.
Results reported to date have not confirmed that hypothesis
This trial was designed to demonstrate that a shorter, more convenient treatment schedule could be accomplished without compromising cure or causing additional adverse effects.
Results indicate that shorter course provides similar efficacy, albeit with an increase in late GI and GU adverse events.
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This trial is unique in that it focused exclusively on patients with low-risk prostate cancer, using RT alone—androgen suppression was not allowed.
As such, this trial complements other research yet provides unique findings with generalizability and immediate relevance.
Coincidentally designed with a debate about use of early intervention compared with active surveillance for this group of patients.
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Noninferiority design was a prudent use of resources.
A noninferiority trial is typically warranted when an investigational treatment is hypothesized to have efficacy that is comparable to standard treatment, but with safety, convenience, cost, and/or other advantages.
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These findings have important implications for men with low-risk prostate cancer who are considered for external beam RT.
If disease control is similar, reducing number of treatments from 41 to 28 and reducing duration of therapy by 2.5 weeks (a nearly one-third reduction) provides greater patient convenience and reduced cost.
Observed increase in late GI and GU adverse events in H-RT arm suggests that increased convenience leads to more treatment-related toxicity.
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Several patient-reported outcomes, including health-related quality of life, anxiety, and depression, were collected as a component of this study but have not been analyzed to date.
It will be of great interest to determine whether patients themselves report differences according to assigned treatment.
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RTOG 9406 – Dose increase from 1.8 to 2 Gy may increase toxicity.
This trial analyze – Dose-volume relationships exist when fraction
size is further increased to 2.5 Gy IMRT has any effect on late toxicity compared
with 3D-CRT Pollack trial –
only study that reported excess toxicity with hypofractionation
Only observed for GU toxicity in
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Most important criticism is that many of these men with low-risk prostate may not need any treatment at all.
Active surveillance is an appropriate initial strategy for men with low-risk disease and has increased in use during the last 5 years.
This trial includes men with low-risk disease only; therefore, these results should not be extrapolated to men with intermediate or high-risk disease.
Criticism
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PTV included prostate only; seminal vesicles and pelvic lymph nodes were not irradiated.
Two other noninferiority trials that have completed accrual include men with intermediate- and high-risk disease treating larger volumes, and results are expected soon.
It is also important to note that all participants had low-risk disease and were allocated to immediate intervention. It may not be appropriate to extend these results to men who progress beyond low-risk disease after a period of active surveillance
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Conclusion In low-risk prostate cancer-
Efficacy of 70 Gy delivered in 28 fractions over 5.5 weeks is not inferior to 73.8 Gy delivered in 41 fractions over 8.25 weeks
Although an increase in late grade 2 and 3 GI and GU adverse events was observed.
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There is a growing body of evidence suggesting that prostate cancer has a low α/β-level of 1.4 Gy and therefore lower than that of surrounding organs at risk, such as rectum or bladder.
This poses a therapeutic rationale for hypofractionation with the possible result of a better tumor control at a lower toxicity rate.
Vital for a safe appliance of hypofractionated schemes are IMRT and IGRT
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So far, there are encouraging results for moderately as well as for higher hypofractionated schemes regardless of prostate cancer risk group.
Nevertheless there are still pending questions and ongoing trials, before hypofractionated radiotherapy can be generally recommended.
Therefore so far patients who are intended to be treated with a hypofractionated scheme should be enrolled in clinical trials.
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05/03/2023THANK YOU