Hypofractionation in Prostate Cancer: Is Less Enough?
1) The document discusses several studies that have compared hypofractionated radiation therapy (delivering larger doses of radiation in fewer treatments) to standard fractionation for prostate cancer. The PROFIT trial found equivalent 5-year outcomes for intermediate risk prostate cancer patients treated with either 60Gy in 20 fractions over 4 weeks or 78Gy in 39 fractions over 7-8 weeks, with less late gastrointestinal toxicity in the hypofractionated group.
2) The CHHiP trial also found non-inferior 5-year outcomes when comparing 60Gy in 20 fractions to 74Gy in 37 fractions for intermediate risk prostate cancer, with no difference in toxicity.
EBCTCG METAANALYSIS
INDICATION OF POST OP RADIOTHERAPY
Immobilization devices
Conventional planning
Alignment of the Tangential Beam with the Chest Wall Contour
Doses To Heart & Lung By Tangential Fields
EBCTCG METAANALYSIS
INDICATION OF POST OP RADIOTHERAPY
Immobilization devices
Conventional planning
Alignment of the Tangential Beam with the Chest Wall Contour
Doses To Heart & Lung By Tangential Fields
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
This slide explains the radiotherapy contouring guidelines for carcinoma esophagus. It has detailed explanations in a quite simple way, so that you need not go anywhere else for esophageal contouring guidelines.
The vmat vs other recent radiotherapy techniquesM'dee Phechudi
VMAT is a new type of intensity-modulated radiation therapy (IMRT) treatment technique that uses the same hardware (i.e. a digital linear accelerator) as used for IMRT or conformal treatment, but delivers the radiotherapy treatment using a rotational or arc geometry rather than several static beams.
This technique uses continuous modulation (i.e. moving the collimator leaves) of the multileaf collimator (MLC) fields, continuous change of the fluence rate (the intensity of the X rays) and gantry rotation speed across a single or multiple 360 degree rotations
This is a made easy summary of ICRU 89 guidelines for gynecological brachytherapy. Extra practical questions for MD/DNB Radiotherapy exams are also attached.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
This slide explains the radiotherapy contouring guidelines for carcinoma esophagus. It has detailed explanations in a quite simple way, so that you need not go anywhere else for esophageal contouring guidelines.
The vmat vs other recent radiotherapy techniquesM'dee Phechudi
VMAT is a new type of intensity-modulated radiation therapy (IMRT) treatment technique that uses the same hardware (i.e. a digital linear accelerator) as used for IMRT or conformal treatment, but delivers the radiotherapy treatment using a rotational or arc geometry rather than several static beams.
This technique uses continuous modulation (i.e. moving the collimator leaves) of the multileaf collimator (MLC) fields, continuous change of the fluence rate (the intensity of the X rays) and gantry rotation speed across a single or multiple 360 degree rotations
This is a made easy summary of ICRU 89 guidelines for gynecological brachytherapy. Extra practical questions for MD/DNB Radiotherapy exams are also attached.
Large patient cohort prospective study with more than 500 patients and more than 5
years follow up have shown that CyberKnife is equally effective as long coures RT
SBRT/ CyberKnife is now standard of care treatment for localized prostate cancer
Best of ASCO Metastatic Non-Small Cell Lung CancerH. Jack West
Dr. Jack West's presentation on highlights in advanced non-small cell lung cancer from ASCO 2014, focusing on new agents ramucirumab and necitumumab for broad NSCLC populations, crizotinib and ceritinib for ALK-positive NSCLC, EGFR inhibitor-options of afatinib and bevacizumab added to erlotinib for first line treatment of EGFR mutation-positive NSCLC, and AZD9291 or CO1686 for EGFR mutation-positive patients with acquired resistance.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
3. Epidemiology
• Most common cancer in men in the west
– Incidence- 30.7 per 100000 (Second most incident cancer next to ca lungs)
– Mortality- 7.8 per 100000
– Prevalence = 25.2% (most prevalent)
• Second most common malignancy in Indian men
– Incidence – 4.2 per 100000
– Mortality – 2.7 per 100000
– Prevalence = 9.6% (Second to ca lip and oral cavity)
• Slow growing tumors
• Multiple treatment options
3
Globocan, 2012
8. NCCN Risk stratification
Risk Category T Stage Gleason
Score
PSA Other
Very Low T1c ≤6 <10 <3 core positive
<50% in each core
PSA density <0.15 ng/mL/g
Low T1-T2a ≤6 <10 -
Intermediate T2b-T2c or 7 or 10-20 -
High T3a or ≥8 or >20 -
Very High T3b-T4 or - - Primary Gleason pattern 5
>4 core with Gleason score 8-10
8
9. Management options
• Active Surveillance
• Radical Prostatectomy ± Pelvic LN dissection
• Brachytherapy
• Radical EBRT
Low Risk
• Radical EBRT + Short term ADT
• EBRT + Brachytherapy boost + Short term ADT
• Radical Prostatectomy ± Pelvic LN dissection ± Adjuvant RT
• Brachytherapy
Intermediate Risk
• Radical EBRT + long term ADT
• EBRT + Brachytherapy boost + long term ADT
• Radical Prostatectomy + Post op RT
High Risk
9
10. Roach formulas
• Partin’s risk nomograms uses pretreatment PSA,
Gleason score, and T category for risk assessment.
• Seminal vesicle involvement - PSA +([GS-6] x 10)
– Cutoff is 13%
– If <13%, risk 7%; if >=13%, risk 37%.
• Lymph node involvement - 2/3 x PSA + ([GS-6] x 10)
– Cutoff is 15%.
– If calculated risk is <15%, actual risk 6%; if >=15%,
actual risk 40%.
• Extracapsular extension - 3/2 x PSA + ([GS-3) x 10)
– Approximates actual risk
10
11. Radiotherapy
• Definitive Radiotherapy
– Radical EBRT
– EBRT + Brachytherapy boost
• Adjuvant Radiotherapy: Patients with unfavorable risk factors
• pT3-prostate cancer-ECE/SV+
• Positive surgical margins
• High Gleason scores /PSA
• Salvage Radiotherapy: In case of a biochemical failure occurs
• EBRT
– 3D-CRT/ IMRT with image guidance
– SBRT
– Particle radiation – Proton, Carbon Ions
• Brachytherapy
– Permanent implant
– Temporary implant
Target Volumes
Low risk: Prostate ± Proximal SV
Intermediate risk: Prostate + SV
High risk: Prostate + SV ± Pelvic
LNs (External and internal iliac,
presacral and obturator LN)
11
13. Dose Escalation
Trial n Dose FU BCF OS
Heemsbergen et
al 2014
664 78 Gy vs 68 Gy 110 mo + -
Hoskin et al 2012 216 80 Gy vs 63 Gy 85 mo + -
Dearnaley et al
2011
843 74 Gy vs 64 Gy 120 mo + -
Beckendorf et al
2011
306 80 Gy vs 70 Gy 61 mo + -
Kuban et al 2007 301 78 Gy vs 70 Gy 114 mo + -
16. Introduction
• Hypo-fractionated RT: RT delivered over a shorter
time than standard RT with larger doses per fraction
• Mostly been studied in intermediate-risk prostate
cancers
ADVANTAGES
• Shorter treatment
• Increased patient convenience
• Lesser costs
• Optimized use of resources
CONCERNS
• ? Increased toxicity
16
17. Linear-quadratic model
• α and β are parameters defining the
radiation dose vs response curve
• (Gy-1)= irreparable ,linear term- gives initial
slope
• (Gy-2) = repairable, quadratic term- gives
final slope
17
22. Evidence
Trial Design HF dose Standard dose EQD2 Sample
size
F/up Efficacy Acute
toxicity
Late
Toxicity
PROFIT
(Canada)
Non-inf 60Gy/20#/4w 78Gy/39#/8w 77Gy 1206
Interm
6y 5y DFS
85% v 85%
GU same
≥G2 GI
more in
HF
GU same
≥G2 GI
more in
standard
CHHiP
(UK)
Non-inf 60Gy/20# or
57Gy/19#
74Gy/37#/8w 77Gy/
73.3G
3216
Interm
5y 5y DFS
90.6% v
85.9% v
88.3%
No diff No diff
Italian
(Arcagneli)
Non-inf 62Gy/20#/5w 80Gy/40#/8w 81.5 168
High
9y 10y DFS
72% v 65%
No diff No diff
HYPRO
(Dutch)
Sup. 64.6Gy/19#/6w 78Gy/39#/8w 90.4 820
High
5y 5y DFS
80.5% v
77.1%
GU same
GI more
in HF
≥G2 more
in HF
RTOG 0415
(US)
Non-inf 70Gy/28#/5.6w 73.8Gy/41#/8 80Gy 1115
Low
5.8y 5y DFS
86.3% v
85.3%
No diff G2, G3
more in
HF
25. Biochemical-clinical
failure (BCF)–free survival
• The 5-year BCF-DFS 85%
(95% CI, 82-88%) in both
arms
• HR (short v standard)
adjusted on stratification
factors 0.96 (90% CI, 0.77 to
1.20, p=0.16).
25
26. Freedom from prostate
cancer–related death
• Total 154 deaths in the
cohort (76 in the short arm
and 78 in the standard arm)
• Overall, 10 deaths as a
result of prostate cancer
observed in the short arm
vs 12 in the standard arm
(HR, 0.76; 95% CI, 0.32 to
1.82)
26
27. GU toxicities
• Similar in both treatment
arms.
Acute (14 weeks)
• only 4% of patients in both
arms had grade ≥ 3 GU
toxicity;
Late period (6 months onward)
• 3.0% of patients in standard
arm vs 2.1% in the short arm
experienced grade ≥ 3 toxicity.
27
28. GI toxicities
• A significant increase in acute
grade ≥ 2 toxicity occurred in the
short arm (16.7% v 10.5% p =
.003)
• Late grade ≥ 2 toxicity, a
significant increase occurred in
the standard arm (8.9% v 13.9% p
= .006)
28
29. Toxicity profile
• Late grade ≥ 3 toxicity was not significantly different between groups, but a trend
toward higher levels in the standard arm was observed.
• Significantly less grade ≥ 2 late GI toxicity in the HF arm
• BED (tumor) : 180 Gy v 182 Gy
• BED (Acute tox) : 78 Gy v 93.6 Gy
• BED (Late tox) : 120 Gy v 130 Gy
• The reduction in late toxicity with the hypofractionated regimen is consistent
with the linear-quadratic model
29
31. Trial Design
• Between Oct 18, 2002, and June 17, 2011, 3216 men enrolled from 71 centres and
randomly assigned, 74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy
group, 1077 patients
• Median follow-up 62·4 months (IQR 53·9–77·0)
• IRPC, PS 0-1, T1b–T3aN0M0 , GS <8, PSA < 30 ng/mL , Risk of SV invol < 30%
• All patients treated by IMRT with portal imaging/image guidance
• All received 6 months of androgen deprivation therapy before and during RT
• BED(74Gy/37#)= 88.8(early), 123.33(late), 172.67(tumor)
• BED(60Gy/20#)= 78(early), 120(late), 180(tumor)
• BED(57Gy/19#)= 74(early), 114(late), 171(tumor)
31
32. Results
• 60 Gy was non-inferior to 74 Gy
with HR 0.84 (90% CI 0.68–1.03),
pNI=0.0018
• Evaluation of the lower 57 Gy was
inconclusive: it cannot be stated to
be non-inferior to the 74 Gy but it
was inferior to the 60 Gy group
• No significant differences in OS
• The proportion of patients,
biochemical or clinical failure free
at 5 years 88·3% (95% CI 86·0–
90·2) in the 74 Gy group, 90·6%
(88·5–92·3) in the 60 Gy group,
and 85·9% (83·4–88·0) in the 57 Gy
group
32
33. Toxicity
• The estimated cumulative 5 year incidence of RTOG grade 2 or worse bowel and
bladder adverse events 13·7% (111 events) and 9·1% (66 events) in the 74 Gy
group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95
events) and 6·6% (57 events) in the 57 Gy group, respectively
• No treatment-related deaths reported
• No difference in bladder s/e except: wave of toxicity occurs earlier in HF arms
• No significant differences in late bowel toxicity
• No significant differences in sexual function domains
35. HYPRO trial design
• Aluwani, Incrocci et al Lancet Oncology, Mar-Jun 2016 (Dutch)
• Intermediate-risk to high-risk: T1b–T4NX–N0MX–M0 localised prostate cancer,
PSA < 60 μg/L, PS 0-2
• Hypofractionated radiotherapy: 64.6 Gy/19fr of 3.4 Gy, 3fr/week
• Concomitant ADT for 6 months: 67%
• Median f/u 60 mnths
• 95% :IMRT
• The primary endpoint to detect a 10% enhancement in 5-year relapse-free
survival with hypofractionation
• A key additional endpoint non-inferiority of hypofractionation in cumulative
incidence of grade 2 or worse acute and late genitourinary and gastrointestinal
toxicity
• Planned to reject inferiority of hypofractionation for late genitourinary toxicity if
the estimated HR less than 1.11 and for gastrointestinal toxicity was less than
1.13
35
36. Results
• Treatment failure reported in 169 (21%) of 804 patients, 80 (20%) in the
hypofractionation group and 89 (22%) in the conventional fractionation group
• 5-year relapse-free survival 80.5% (95% CI 75.7–84.4) for hypofractionation and
77.1% (71.9–81.5) for conventional fractionation (HR 0.86, 95% CI 0.63–1.16; log-
rank p=0.36)
• No treatment-related deaths
• Not superior
37. Toxicity
Parameter HF Arm (64.6
Gy)
Standard (78
Gy)
Remarks
Treatment Failure 20% 22%
5-yr RFS 80.5% 77.1% Adjusted HR:0.86, (95% CI 0.63–1.16;
p=0.36)
HF-RT was not superior
Acute ≥ 2 GU 60.5% 57.8% p=0.43
Acute ≥ 2 GI 42% 31.2% p=0.0015; non-inferiority not confirmed
≥G2 GU tox (3y) 41.3% 39% HR 1.16
≥G2 GI tox (3y) 21.9% 17.7% HR 1.19 (Significantly more in HFRT)
≥G3 GU toxicity 19% 12.9% p=0.021 (Significantly more in HFRT)
≥G3 GI toxicity 3.3% 2.6% p=0.55
37
BED (hypo#)=
211(tumor),90.4 (EQD2
tumor), 86.56(Early),
137.81(late)
Vs
BED(conv#)= 182(tumor),
93.6(early), 130(late)
39. Results
• 168 patients with high-risk Ca prostate
• Conventional(80 Gy/40#/8 weeks) vs Hypofractionated (62 Gy/20#/5 weeks)
• Median f/u 9 years
• No differences was observed in late ≥G2 gastro intestinal and genitourinary
toxicity (p=.68 and .57)
• 10-year FFBF rate was 72% in the hypofractionation group and 65% in the
conventional group (HR:1.62, p = .15)
• Ten-year OS rates were 75% in the hypofractionation group and 64% in the
conventional group(HR:1.45 , p= .22)
39
BED (hypo#)= 190.13(tumor),
81(Early), 126.06(late)
Vs
BED(conv#)= 186.67(tumor),
96(early), 133.33(late)
41. • Lee et al, JCO April 2016(US based)
• 1,115 men with low-risk prostate cancer (T1b to T2c,GS 2-6, PSA<10)
• C-RT (73.8 Gy/41#/8.2 wks) 1.8gy/# vs
• H-RT (70 Gy/28#/5.6 wks) 2.5Gy/#
• Median follow-up 5.8 years
• Trial designed to establish (with 90% power and an alpha of .05) that
treatment with H-RT results in 5-year disease-free survival (DFS) that is
not worse than C-RT by more than 7.65% (H-RT/C-RT hazard ratio [HR] ,
1.52
• BED (H-RT): Tumor=186.67, Early = 87.5, Late = 128.33
• BER (C-RT): Tumor= 162.36, Early = 87.08, Late = 118
41
RTOG 0415 Trial design
42. • 5-year DFS was 85.3% (95% CI, 81.9 to 88.1) in the C-RT arm and 86.3%
(95%CI, 83.1 to 89.0) in the H-RT arm
• DFS HR was 0.85 (95% CI, 0.64 to 1.14), and the predefined noninferiority
criterion was met (critical HR <1.52)(p<.001)
• No differences in early GI or GU adverse events were observed
• Late grade 2 and 3 GI and genitourinary adverse events were increased
(HR, 1.31 to 1.59) in patients who were treated with H-RT, but no
differences in severe toxic effects were recorded
42
RTOG 0415 Results
43.
44. Metaanalysis
• 9 studies with 5969 patients
• RevMan 5.3 software
• H-RT group obtained greater improvements in the 5-year biochemical or clinical
failure-free survival (RR = 1.04, 95% CI:1.01–1.08; P = 0.01) and 5-year disease-
free survival(RR = 1.04, 95% CI: 1.01–1.07, P = 0.02) than the C-RT group
• 5-year overall survival rates comparable in the two groups (RR = 1.02, 95% CI:
0.99–1.04; P = 0.18)
• Comparison of multiple secondary parameters, including grade 2-4 acute/late
gastrointestinal toxicity, grade 2–4 acute/late genitourinary toxicity, biochemical
failure, local failure, distant failure and prostate cancer-specific mortality
between the H-RT and the C-RT groups showed no statistical differences
• This meta-analysis thus indicates that in patients with localized prostate cancer,
moderate H-RT exerts a great beneficial effect on the primary parameters than C-
RT without enhancing adverse events
Cao et al. Oncotarget, 2017
47. Metaanalysis
• 6 of 341 studies fulfilled inclusions with 6931 patients
• No significant difference in BCDF between H-RT and C-RT (RR=0.94, 95%
CI: 0.83-1.06, p=0.31), with a moderate heterogeneity I2=36%).
• Dose-escalated H-RT significantly improved BCDF compared with C-RT
(RR=0.86, 95%CI:0.74-0.99, p=0.04)
• Patients who received H-RT showed a lower BF (RR=0.78, 95% CI: 0.63-
0.97, p=0.03), without heterogeneity (I2=0%).
• No significant difference in overall survival (RR=0.89, 95% CI: 0.76-1.03,
p=0.12) between H-RT and C-RT, also no heterogeneity noted ( I2=0%).
• No significant difference in late GI (RR=1.04, 95%CI: 0.88-1.23, p=0.63)
and GU toxicity (RR=1.10, 95% CI: 0.47- 2.40, p=0.26) at 5-years
• Dose-escalated H-RT increased in late GI toxicity (RR=1.80, 95%CI: 1.32-
2.43, p=0.0002) and GU toxicity (RR=1.38, 95%CI: 1.07-1.79, p=0.01)
significantly, while non dose-escalated H-RT (GI: RR=0.82, 95%CI: 0.68-
1.00, p=0.05; GU: RR=0.92, 95%CI: 0.72-1.16, p=0.46)
Yin et al. ESTRO, 2017
49. Pelvic LN Irradiation
• Prospective, Phase II trial, 2009 to 2012,
• 40 patients of high-risk prostate cancer (increased risk of microscopic lymph node
involvement)
• Helical IMRT (tomotherapy) of the pelvic lymph nodes (51.0 Gy) with HF-SIB (2.25
Gy/#) to the prostate (76.5 Gy) in 34 fractions
• Overall acute toxicity rates were low and no acute grade 3 or 4 GI / GU toxicity.
• No late grade ≥ 2 GI toxicity and 6.4 % late grade 2 GU toxicity.
• At median f/u 2 yrs: 34/37 patients free of a PSA recurrence
49
The combined irradiation
of both prostate and
pelvic lymph nodes
seems to be as well
tolerated as the
irradiation of the prostate
alone
53. SBRT- Low Risk
• Low-risk prostate cancer
• 67 patients
• 36.25 Gy in 5 fractions with CyberKnife system
• Median follow-up of 2.7 years
• Low rates of Late rectal and urinary toxicity - >G2 in 1 & 5 pts respectively
• The 4- year Kaplan-Meier PSA relapse-free survival was 94% and is similar to other
definitive treatments 53
54. • Multi-institutional pooled data
• N – 1100
• Median dose – 36.25 Gy in 5 fractions (35-40 Gy/4-5#)
• 3 yr median FU, 335 cases with a >4 years follow-up (median 53 mos)
• Risk group
– Low risk – 59%
– Intermediate risk – 30%
– High risk – 11%
• ADT – 14%
King et al Radiother Oncol 2013; 109:217-21
54
King et al
57. Design
• Prostate given 5 doses of 8 Gy each
• RT dose to bladder, rectum, testes &
penile bulb rigorously constrained
• Pts followed an average of 5.1 yrs
57
58. Results
Safety
• No grade 4-5 toxicities
• Grade 3 side effects occurred in 4 pts:
• Two low-risk pts (1.2%)
• Two interm-risk pts (1.5%),
p<0.001
Efficacy
Based on Nadir + 2 definition:
• 97.1% of pts free from recurrence at 5 yrs
58
72. UCLA HR SBRT Trial
8 Gy x 5 (40 Gy) to prostate PTV
5 Gy x 5 (25 Gy) to pelvic LN
72
73. Conclusion
• RT dose is important to control prostate cancer, even in low risk disease
• Hypofractionation offers an equal, if not superior rates of tumor control in
patients with low and intermediate risk prostate cancers
• The toxicity rates are similar if appropriate dose and patient selection criterias
are used
• IMRT and IGRT are pre-requisite tools for administering high doses
• Prostate SBRT is a faster, cheaper and better way of treating localized prostate
cancers
• Further follow-up of already conducted trials need to be awaited, before hypo-
fractionated radiotherapy can be generally recommended for high risk patients
and adjuvant settings
73
74. Thank You
“It is rare that nature hands us a cancer situation
where an improved treatment goes hand in hand with
a shorter and more convenient one.”
Editor's Notes
advanced radiotherapy techniques that are able to deliver high dose distributions to the prostate target and avoid the organs at risk is needed
NCCN old: 7
D’amico 3
RTOG:4
Estimates pathologic state based on original roach data
Absolute Indications
Positive Surgical Margin
Seminal Vesicle Invasion
Extra Capsular Extension
Failure of PSA to drop
Relative Indications
High PSA
High Gleason score
Pelvic LN involvement
In 2005, we reported the results of a Canadian trial that compared conventional RT (66 Gy in 33 fractions) with hypofractionated RT (52.5 Gy in
20 fractions) in prostate cancer.
The total doses of radiation in both arms were suboptimal by current standards and associated with high rates of recurrence
The curve of late reacting tissue is curvier than that of acute reacting tissues and a and b are………
A/b ratio is a quantitative measure of the sensitivity to changes in fraction size.
Low ratio signify high fraction sensitivity and high ratio signify low radiation sensitivity.
The proportion of patients with acute grade ≥ 3 toxicity was low in both arms.
that would predict a lower biologically equivalent dose for normal tissues with an a/b of 3 to 5.
Pelvic lymph nodes were not included in the target volumes
Biochemical failure was defined as PSA >2 ng/mL 6 months or more after the commencement of radiotherapy and a PSA rising by 50% or more from the nadir
5-year biochemical or clinical failure-free rates were 88.3% in the 74 Gy group, 90.6% in the 60 Gy group, and 85.9% in the 57 Gy group
The standard arm used a lower radiation dose (74 Gy) compared with the 78 Gy used in the standard arm in our trial, which is more commonly used in North America.
Superiority trial
Cumulative p value
Couldn’t confirm that hypofractionation was non-inferior wrt cumulative acute/ late genitourinary and gastrointestinal toxicity compared with standard fractionation.
This trial was designed to have a biologically higher dose in the experimental treatment arm, which likely accounts for these findings.
Patients in group 1 (risk of seminal vesicle
involvement <10%) received no dose to the seminal
vesicles. In group 2 (risk of seminal vesicle involvement
10–25%), seminal vesicles received a reduced dose.
With hypofractionation, the seminal vesicles received
16 fractions of 3.4 Gy (sequential boost technique) or
19 fractions of 3.04 Gy (simultaneously integrated
boost). With conventional fractionation, this dose was
administered with either a sequential boost technique,
delivering 34 fractions of 2.0 Gy to the prostate-plusvesicles
and a boost of fi ve fractions of 2.0 Gy to the
prostate only, or a simultaneously integrated boost
technique, delivering 39 fractions of 1.85 Gy to the
vesicles and 39 fractions of 2.0 Gy to the prostate. In
group 3 (risk of seminal vesicle involvement >25%),
seminal vesicles received the full prescribed dose of
64.6 Gy for hypofractionation and 78.0 Gy for
conventional fractionation. We did not allow elective
irradiation of the pelvic lymph nodes.
Current study is the first randomized trial reporting long-term results
RT to prostate and seminal vesicles.
All pt received 9mths ADT. 3D CRT used
Mean FFBF was 8.7 years vs 7.9 years with evidence of a significant benefit in the former compared with the latter group of 0.8 years (P,.001).
in the MVA models, for FFBF, hypofractionation was significant prognostic factor (P = .021), when adjusted for other factors, such as GS (P = .025), baseline PSA level (P,.001), and cT stage (P = .039)
Non-inferiority by 7.65% (HR 1.52)
542 patients were assigned to C-RT and 550 to H-RT
70 Gy in 28 fractions over 5.6 weeks is not inferior to 73.8 Gy in 41 fractions over 8.2 weeks, although an increase in late GI/genitourinary adverse events was observed in patients treated with H-RT.
In many jurisdictions, however, active surveillance is commonly used in low-risk prostate cancer.
The normal tissue dose constraints permitted for the hypofractionated arm were liberal compared with the other trials and may account for this finding
The observation of increased late toxic eff ects is perhaps not surprising, because the biological eff ective dose of the hypofractionated regimen in NRG Oncology 0415 (128·0 Gy) is slightly greater than that of the hypofractionated regimen in CHHiP (120·0 Gy), assuming the α/β ratio of rectum and bladder to be 3·0 Gy.
the fraction size has been shown to be an independent
prognostic factor for severe late urinary toxicity in the univariable and multivariable Cox analysis.
Tomotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate can be
performed safely and without excessive toxicity.
HF to prostate and SF to LNsScreen Shot 2017-03-31 at 1.07.20 AM
Gucke: IMRT equal results, DFS 82%
When retrospectively contouring the daily
CT-scans of patients, who developed a grade ≥ 2 rectal
toxicity, the combined average daily deviation of the actual
rectal volume from the planned volume was 12.7% and
88% of all fractions delivered a higher V70 than originally
planned. This study therefore showed that the addition of
ENI leads to a significant higher rate of late grade ≥ 2 rectal
toxicity and confirms the above mentioned hypothesis
that the dose exposure of the rectum increases with the irradiation
of larger volumes, like the inclusion of pelvic
lymph nodes.
Mostly for low and low/intermediate risk
UT SOUTHWESTERN SBRT PROSTATE PROTOCOL
Phase I 45 patients 5 fractions: 9 Gy , 9.5 Gy,10 Gy Phase II 50 patients
T1-T2b PSA ≤10 GS 6 and PSA <20 Boike et al, JCO, 2011, timmerman
Predictors of Gr4 rectal toxicity;
• Diabetes (trend p=0.07).
• > 35% of rectal wall at 39 Gy (p=0.03)
• Volume of rectal wall receiving 50 Gy (p=0.01)
Gr4 toxicity: All had > 3.5 cm3 of rectal wall > 50 Gy (p < .0001).
All patients with no rectal toxicity had < 3.5 cm3 rectal wall at 50 Gy.
Late RTOG Grade III, II and I bladder toxicities were seen in 2, 3 and 13 patients with no late urinary Grade IV toxicity.
Late rectal Grade III, II and I toxicities were seen in 0, 1 and 7 patients with no persistent rectal bleeding.
For 135 patients possessing a minimum of 5years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively.
Subset with longer follow-up:
335 cases with >4 years follow-up (median: 53 months)
5-year bRFS rates:
Low risk: 97%
Intermediate-risk: 89%
309 patients
G3 se: far below the 10% considered excessive:
• In low-risk pts, 97.3% free from recurrence
(superior to 93% historical control rate)
• In intermediate-risk pts, 97.1% free from recurrence at 5 yrs
Urinary Incontinence Score
EPIC Urinary Irritation or Obstruction Score
EPIC Bowel Score
EPIC Sexual Score
* Statistically significant
Both trials use IGRT, which permits reduced target margins around the prostate, and might reduce treatment side-effects.
The HYPO trial: (1200 men) comparing 43.7 Gy in seven fractions over 15–19 days with 78 Gy in 39 fractions over 7.8 weeks
The PACE trial: compares 36.25 Gy in five fractions over 1–2 weeks with 78 Gy in 39 fractions over 7.8 weeks.
Chhip 6mm and 3 mm
A total of 80 prostate cancer patients with the indication for adjuvant radiotherapy will be enrolled
SBRT: Not delivery platform specific.
CT/MRI planning
SV: Full dose or 5 Gy x 5 (respecting ROI constraints)
*Minimum dose, 30-50% heterogeneous ‘Hot Shell’
2. The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks.
3. Men with compromised urinary function/ baseline sexual function before treatment may not be ideal candidates for this approach.
3. Late rectal toxicity is minimal with hypofractionated RT (including SBRT). Urinary toxicity is pronounced early after RT and is self limited.
5. SBRT is considered an acceptable option for low and intermediate risk patients.