This document discusses castrate resistant prostate cancer (CRPC). It defines CRPC and outlines various treatment options including androgen receptor directed therapies like abiraterone and enzalutamide, cytotoxic chemotherapies like docetaxel and cabazitol, immunotherapies, and targeted therapies. It also discusses mechanisms of castration resistance like AR amplification and activation by alternative ligands.
diagnosis and outline of management of localized prostate cancer for non-urol...Dr Mayank Mohan Agarwal
a brief introduction of anatomy of prostate, screening of prostate cancer, measures to improve specificity of PSA screening, risk stratification of prostate cancer, treatment options - active surveillance, radical prostatectomy, radical radiotherapy
diagnosis and outline of management of localized prostate cancer for non-urol...Dr Mayank Mohan Agarwal
a brief introduction of anatomy of prostate, screening of prostate cancer, measures to improve specificity of PSA screening, risk stratification of prostate cancer, treatment options - active surveillance, radical prostatectomy, radical radiotherapy
Prostate cancer the androgenic fortified dogmaMohamed Abdulla
It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
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.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
3. DEFINITION
Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either;
a) Biochemical progression:
Three consecutive rises in PSA 1 week apart resulting in two
50% increases over the nadir, and a PSA > 2 ng/mL
b) Radiological progression:
The appearance of new lesions: either two or more new bone
lesions on bone scan or a soft tissue lesion
3
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
4. TERMINOLOGY
In the past
Hormone Refractory
Androgen Independent
Androgen Resistant
Now … Castrate Resistant Prostate Cancer (CRPC) – Why?
Even though patients have castrate levels of serum testosterone,AR signaling is
still happening
They are resistant to castration, but these tumors are still responding to AR
signaling
4
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
5. CLINICAL STATES OF PROSTATE CANCER 5
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
6. ANTIANDROGEN WITHDRAWL
Carefully observed discontinuation of antiandrogen in patients
progressing while on antiandrogens
Serial monitoring of PSA level for 4-8 weeks
Approximately 15% to 30% of men will exhibit a greater than
50% decline in serum PSA level.
When the PSA level begins to rise
Initiate treatment with a second-line antiandrogen 6
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
7. MOLECULAR BIOLOGY OF ANDROGEN AXIS
AR – member of nuclear receptor superfamily
Cause transcription of target genes within specific cells after ligands bind
to them
All forms of ADT act by reducing the ability of androgen to activate the
androgen receptors
By lowering levels of androgen
By blocking androgen AR binding 7
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
11. HYPERSENSITIVITY PATHWAY
Increase in sensitivity to available low androgen levels by
Increasing AR synthesis
and/or
Increasing AR sensitivity
11
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
12. AR GENE AMPLIFICATION
Stanbrough and colleagues - genomic segment of chromosome X encoding the AR
is amplified, up to 60-fold
Seen in 28-30%
Abundance of AR increases the total AR content of the tumor that is available for
ligand binding and allows seemingly androgen-independent cancer cells to
proliferate in an androgen depleted environment
12
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
13. PROMISCUITY OF AR
Ligands other than androgen activate AR
Non androgenic steroids
Antiandrogens
Mechanism
Mutations in the LBD
Through alterations in the coregulator profile
13
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
14. OUTLAW AR MODEL
Increase transcriptional activity in the absence of androgens by non steroidal
molecules
Growth factor peptides such as EGF, KGF and IGF-1
Cytokines – IL-6
Protein kinase A & C
Increased expression of AR coregulators – autonomous activation of AR pathway
14
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
15. BYPASS AR MODEL
Activation of parallel or alternative survival pathways independent of AR
transactivation
INHIBITINGAPOPTOSIS
Upregulate the antiapoptotic protein, Bcell lymphoma 2 (Bcl-2)
Inactivating the proapoptotic tumor suppressor gene Phosphatase and Tensin
Homologue (PTEN).
NEUROENDOCRINE DIFFERENTIATION
Neuroendocrine cells secrete neuropeptides, such as serotonin and bombesin
OVEREXPRESSION OF ER ALPHA 15
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
16. LURKER CELL MODEL
Outgrowth of castration resistant cells
Proliferates under the selective pressure of Androgen deprivation
Tumorigenic
Preexistent epithelial stem cells
16
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
19. TREATMENT
OPTIONS
Androgen Receptor Directed Approaches
• CYP 17 inhibition
• AR modulation
Cytotoxic chemotherapy
Immunotherapy
Targetted treatments
• PI3K/Akt/mTOR pathway
• Angiogenesis
• MET signaling
• Apoptosis pathway
19
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
20. AR DIRECTED APPROACHES – CYP 17 INHIBITION
Suppresses extragonadal androgen synthesis
Abiraterone – oral selective CYP17 inhibitor – inhibits both 17,20 lyase and 17 alpha
hydroxylase
Approved for all patients with mCRPC even in patients who have not received
docetaxel chemotherapy
Not currently approved for non metastatic CRPC
Other agents
High dose Ketaconazole – weak inhibitor
Orteronel,Seviteronel (17,20 lyase inhibitor), – not FDA approved
20
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
21. AR DIRECTED APPROACHES – CYP 17 INHIBITION
Improved PFS, OS
57% reduction in risk of radiographic progression
Significantly delayed initiation of cytotoxic chemotherapy
In predocetaxel setting – improved patient reported quality of life outcomes
21
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
25. AR MODULATION - ENZALUTAMIDE
AFFIRM TRIAL – mCRPC in docetaxel pretreated patients – survival benefit in
good performance status
PREVAIL TRAIL – mCRPC in Prechemotherapy setting – improved PFS, OS
Approved for all mCRPC irrespective of prior docetaxel therapy
PROSPER TRIAL – non-metastatic CRPC – significant 71% lower risk of
metastases, delay in the time to first use of antineoplastic therapy, no difference
in quality of life
Advantage: No concurrent steroid administration
25
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
26. FDA approval
- nm CRPC
(2018)
SPARTAN
TRIAL
APALUTAMIDE
26
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
27. CYTOTOXIC CHEMOTHERAPY
Mitoxantrone
Docetaxel
Cabazitaxel
Other cytotoxic agents are no longer used as they have not been associated with either
symptomatic improvements or extension of survival
27
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
28. MITOXANTRONE
Semisynthetic anthracycline - 12mg/m2 iv every 21 days
Modest symptomatic benefits with minimal objective antitumor activity
Maximal palliative effect in combination with low dose corticosteroids
Survival was not significantly improved
FDA approved (1997) – symptomatic CRPC
Still useful for patients
With docetaxel and cabzitaxel refractory disease
Marginal performance status where toxic taxane agents may not be well tolerated
28
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
29. DOCETAXEL
Taxane family – 75 mg/m2 iv every 21 days
Acts in cancer cells throughTP53
independent mechanism
By inhibition of microtubule
depolymerization
Blocakade of antiapoptotic signaling
By inducing apoptosis by BCL
phosphorylation 29
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
30. As of 2004,docetaxel has become the
agent of choice for treatment of
metastatic CRPC
TAX 327
30
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
32. DOCETAXEL TOXICITY
Myleosuppression
Fatigue
Peripheral edema
Neurotoxicity
Hyperlacrimation
Nail dystrophy
32
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
33. CABAZITAXEL
FDA approved in 2010 - 25mg/m2 every 21 days – docetaxel refractory mCRPC
Novel tubulin binding taxane – poor affinity for P-glycoprotein,the ATP dependent
drug efflux pump
Active in both docetaxel-sensitive and primary or acquired docetaxel resistant CRPC
Principal dose limiting toxicity – neutropenia administered along with G-CSF
33
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
34. TROPIC TRIAL
mCRPC progressed after docetaxel
based chemotherapy
Mitoxantone vs Cabazitaxel
Improved PFS, extended time to PSA
progression, OS
34
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
35. IMMUNOTHERAPY
Activating immune responses against malignant cells
Overcoming tumor induced tolerance
35
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
36. IMMUNOTHERAPY IN PROSTATE CANCER
Prostate cancer – IDEALTARGET
Slow growing
Allowing stimulated immune system the time to generate an anti-tumor response
Produces several tissue specific proteins – serve as tumor antigens
PSA, prostatic acid phosphatase, PSMA
36
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
37. IMMUNOTHERAPY IN PROSTATE CANCER
Dendritic cell based therapies
Adjuvants such as granulocyte macrophage colony stimulating factor
Viral carriers
Single antigen or whole cell vaccines
Genetically modified tumor cell vaccine
DNA plasmid vaccine
Incorporating costimulatory molecules, cytotoxicT lymphocyte antigen 4 (CTLA4)
blockade, PD1 blockade
Intracellular viral or bacterial mediators 37
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
38. IMMUNOTHERAPY IN PROSTATE CANCER
SipuleucelT
ProstVacVF
Immunecheck point inhibitior – Ipilimumab,Pembrolizumab
GVAC – allogeneic recombinant whole cell vaccine
38
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
39. SIPULEUCEL - T - PROVENGE
Personalised vaccine
Derived from autologous CD54+ dendritic cells – apheresed from individuals
Processed with recombinant fusion proteins composed of PAP & GM-CSF
PAP – prostate cell membrane localization prostate specific immune responses
39
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
41. SIPULEUCEL - T - PROVENGE
FDA approval in 2010 – asymptomatic / minimally
symptomatic CRPC
Statistically significant improvement in overall survival
Largest impact in prechemotherapy setting & early disease
Preparation & production in large quantities – challenging
Well tolerated & Minimal infusion related fevers and
rigors
Not recommended in – visceral disease or in severely
symptomatic mCRPC
Ongoing trials - for use in nm BCR, combination with AR
directed Rx
IMPACT
41
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
42. PROSTVAC -VF
PSA targeted poxviral based vaccine
Incorporates a DNA plasmid containing the PSA gene + 3 costimulatory molecules
Increase PSA specific immune responses
Not a personalized product
Relatively inexpensive to synthesize
Administration – subcutaneous injection through several months
Improved overall survival in mCRPC
Currently in phase III testing 42
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
44. IMMUNE CHECKPOINT INHIBITION
Prevents normal attenuation of antitumorT
cell responses
Ipilimumab – monoclonal anti CTLA4
antibody
Not currently FDA approved
Greatest benefit in pts without visceral
disease, normal hemoglobin and ALP levels
Immunological toxicity from unchecked
immune response
Colitis, hepatitis, adrenal insufficiency,
endocrinopathies, dermatitis,hypophysitis
44
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
46. TARGETED TREATMENTS – NON AR PATHWAYS
Phospahtidylinositol 3 kinase (PI3K)/Akt/mTOR pathway
EGFR signaling
Mitogen activated protein kinase (MAPK) signaling
IGF1R singaling
Endothelin, Hedgehog, Src kinase signaling and several others
46
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
47. PI3K/AKT/MTOR PATHWAY
Bidirectional talk between PI3K and AR
mTOR inhibitors – failed to demonstrate significant
clinical activity in mCRPC ; Can reverse
chemotherapy resistance in PTEN deficient CaP
Combined blockade – PI3K/mTOR: BEZ235 +
Enzalutamide/abiraterone
Akt inhibitor – MK2206, perifosine
PI3K inhibitors – BKM120, PX866
47
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
48. ANGIOGENESIS INHIBITORS
Bevacizumab – humanized monoclonal antibody toVEGF : 15mg/kd IV every 21 days
PFS improved but not approved by FDA – toxicities and treatment related mortality
Afilbercept – decoy receptor that bindsVEGF - No significant differences in PFS/OS + higher
toxicity rate
Sunitinib – promiscuous TKI inhibitor (blocksVEGFR2 & PDGbeta) - PFS ^; no ^ in OS; not
approved
Tasquinimod – in Phase III trial - Second generation quinolone-3-carboxamide analogue
Prevents upregulation of HIFalpha
Induces endogenous antiangiogenesis factor,thrombospondin 1
Inhibits S100A9 – protein involved in differentiation and cell cycle progression 48
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
49. APOPTOSIS PATHWAY
Clusterin – stress induced antiapoptotic chaperone protein expressed in CaP after
androgen ablation/chemotherapy
CUSTIRSEN – intravenous antisense oligonucleotide moiety that inhibits clusterin
at mRNA level, increasing sensitivity to androgen deprivation and chemotherapy
May reverse chemotherapy resistance
SYNERGY & AFFINITY – ongoing trials
49
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
53. EPIDURAL CORD COMPRESSION
First therapeutic intervention – High dose IV glucocorticoids - Dexamethosone
Loading dose - 10mg followed by 4-10mg every 6 hours
Maintenance -16-100 mg/day
Radiation therapy
Decompression surgery
Progressive signs and symptoms during radiation therapy
Unstable pathologic fractures that require stabilisation
Experience recurrence after RT 53
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
54. BONE TARGETED APPROACHES
Bisphosphonates
RANK L inhibitor
Radiopharmaceuticals
54
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
55. BISPHOSPHONATES
Reduce bone resorption by inhibiting osteoclastic activity and proliferation
Agents shown clinical benefit in patients with prostate cancer with bone metastasis
Zoledronate & Pamidronate
Other agents - – benefit in Prostate Cancer not established
Alendronate, Etidronate, Ibandronate, Clodronate
55
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
56. ZOLEDRONIC ACID
First approved for treatment of hypercalcemia and decreased bone mineral density in
postmenopausal women
Progressive CRPC with bone metastasis – 4mg iv repeated at 4 weeks interval
Side effects – fatigue, myalgia, fever,anemia, Sr. Creatinine elevation
Hypocalcemia – concomitant administration of oral calcium (1000mg/day) +Vitamin
D (800units/day)
Unusual complication – osteonecrosis of mandible – most frequently seen in patients
undergoing dental work/poor dentition / chronic dental disease
56
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
57. RANK L INHIBITORS
RANK L binds and activates RANK in osteoclasts osteoclastic activation
RANKL inhibitors
Recombinant osteoprotegerin – natural decoy receptor
Denosumab – monoclonal antibody against RANK L
Improved time to first skeletal related event but no difference in OS
DENOSUMAB - FDA approval (2010) – for prevention of skeletal related events in bone
metastases
Toxicities – hypophosphatemia, hypocalcemia, fatigue, nausea
Does not require dose adjustment or monitoring of renal impairment
Dose: 120 mg SC every 4 weeks
57
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
58. RADIOPHARMACEUTICALS
Beta emitters
Strontium 89
Samarium 153
Alpha emitters
Radium 223
Not only palliate but also improve OS
FDA approved for palliation of mCRPC
No improvement in overall survial
58
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
59. BONE TARGETING
Calcium-mimetic in the human body
Deposit in osteoblastic bone metastatic sites
Bone targeting occurs via hydroxyapatite Ca5(PO4)3(OH) binding
Hydroxyapatite is an essential portion of the inorganic matrix of bone and is inter-
mixed with cancer cells in lesions with an osteoblastic phenotype.
59
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
60. RADIUM 223
Alpha particles - 7000 times heavier than beta paritcles
Very short path length - <100 micrometer
50 KBq/kg iv every 4 weeks – 6 doses
FDA approval - Symptomatic bone metastatic CRPC
without visceral or bulky nodal metastases
Docetaxel refractory and/or ineligible or uninterested in
chemotherapy
Only radiopharmaceutical agent with improved OS &
quality of life 60
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
63. EVALUATINGTHE PATIENTSWITH CRPC
PSA 2ng/mL bone scan, CT chest,
Abdomen & Pelvis
PSA @ every 3 months for
asymptomatic patients
Repeat bone scan & CT @ 5ng/mL
Again after every PSA doubling
Symptomatic Relevant investigations
regardless of PSA
Negative for metastasis
Negative for metastasis
NON METASTATIC VS METASTATIC CRPC
PSMA PET/ wb MRI early mCRPC
63
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
66. INDEX PATIENT 1 – NON METASTATIC CRPC
STANDARD
Apalutamide or enzalutamide with continued androgen
deprivation (Grade A)
RECOMMENDATION
Observation with continued androgen deprivation
(Grade C)
OPTION
Second-generation androgen synthesis inhibitor
(abiraterone + prednisone) who do not want or cannot
have one of the standard therapies and are unwilling to
accept observation (Grade C)
66
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
67. INDEX PATIENT 1 – NON METASTATIC CRPC
RECOMMENDATION AGAINST
Systemic chemotherapy or immunotherapy outside the context of a clinical trial
(Evidence Level Grade C)
67
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
69. INDEX PATIENT 2 – METASTATIC CRPC
STANDARD
Abiraterone + prednisone (Grade A)
Enzalutamide(Grade A)
Docetaxel (Grade B)
Sipuleucel-T (Grade B)
Asymptomatic / minimally symptomatic with no prior docetaxel therapy
69
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
70. INDEX PATIENT 2 – METASTATIC CRPC
OPTION (Evidence Level Grade C)
First- generation anti-androgen therapy
Ketoconazole + steroid
Observation to patients who do not want or cannot have one of the standard
therapies
Asymptomatic / minimally symptomatic with no prior docetaxel therapy
70
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
72. INDEX PATIENT 3 – METASTATIC CRPC
STANDARD
Abiraterone + prednisone (Grade A)
Enzalutamide (Grade A)
Docetaxel (Grade B)
Radium-223 to patients with symptoms from bony metastases from mCRPC without
known visceral disease (Evidence Level Grade B)
Symptomatic good performance status with no prior docetaxel therapy
72
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
73. INDEX PATIENT 3 – METASTATIC CRPC
OPTION
Ketoconazole + steroid (Grade C)
Mitoxantrone (Grade B)
radionuclide therapy to patients who do not want or cannot have one of the standard
therapies (Evidence Level Grade C)
Symptomatic good performance status with no prior docetaxel therapy
73
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
74. INDEX PATIENT 3 – METASTATIC CRPC
RECOMMENDATION AGAINST
Estramustine or sipuleucel-T (Evidence Level Grade C)
Symptomatic good performance status with no prior docetaxel therapy
74
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
76. INDEX PATIENT 4 – METASTATIC CRPC
OPTION (Evidence Level Grade C)
Abiraterone + prednisone
Enzalutamide
Ketoconazole+ steroid
Radionuclide therapy
Symptomatic poor performance status with no prior docetaxel therapy
To patients who are unable or unwilling to receive
abiraterone + prednisone or enzalutamide
76
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
77. INDEX PATIENT 4 – METASTATIC CRPC
EXPERT OPINION
Docetaxel or mitoxantrone chemotherapy
In select cases, specifically when the performance status is directly related to the cancer
Radium-223
To patients with symptoms from bony metastases from mCRPC without known visceral
disease in select cases, specifically when the performance status is directly related to
symptoms related to bone metastases
Symptomatic poor performance status with no prior docetaxel therapy
77
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
78. INDEX PATIENT 4 – METASTATIC CRPC
RECOMMENDATION AGAINST
Sipuleucel-T (Evidence Level Grade C)
Symptomatic poor performance status with no prior docetaxel therapy
78
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
80. INDEX PATIENT 5 – METASTATIC CRPC
STANDARD
Abiraterone + prednisone (Grade A)
Cabazitaxel (Grade B)
Enzalutamide (Grade A)
If the patient received abiraterone + prednisone prior to docetaxel chemotherapy,he
should be offered cabazitaxel or enzalutamide
Radium-223 to patients with symptoms from bony metastases from mCRPC and
without known visceral disease (Evidence Level Grade B)
With prior docetaxel therapy & good performance status
80
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
81. INDEX PATIENT 5 – METASTATIC CRPC
OPTION
Ketoconazole + steroid if abiraterone + prednisone, cabazitaxel or enzalutamide is
unavailable (Evidence Level Grade C)
Retreatment with docetaxel to patients who were benefitting at the time of
discontinuation (due to reversible side effects) of docetaxel chemotherapy (Evidence
Level Grade C)
With prior docetaxel therapy & good performance status
81
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
83. INDEX PATIENT 6 – METASTATIC CRPC
EXPERT OPINION
Palliative care;
Alternatively, for selected patients, clinicians may offer treatment with abiraterone +
prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy
EXPERT OPINION AGAINST
Systemic chemotherapy or immunotherapy
With prior docetaxel therapy & poor performance status
83
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
84. BONE HEALTH
RECOMMENDATION
Preventative treatment (e.g. supplemental calcium, vitamin D) for fractures and
skeletal related events (Evidence Level Grade C)
OPTION
Choose either denosumab or zoledronic acid when selecting a preventative
treatment for skeletal related events for mCRPC patients with bony metastases
(Evidence Level Grade C)
84
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
85. SUMMARY
NM CRPC FIRST LINE SECOND
LINE
THIRD LINE
Apalutamide
Enzalutamide
Abiraterone
Enzalutamide
Docetaxel
Radium 223
Cabazitaxel
Pembrolizumab
Observation Docetaxel Cabazitaxel Abiraterone
Enzalutamide
Docetaxel
rechallenge
Mitoxantrone
Abiraterone
Enzalutamide
Radium 223
Cabazitaxel
Radium 223 Cabazitaxel
Abiraterone
Enzalutamide
Abiraterone Radium 223 Pembrolizumab
PARP inhibitors
SipuleucelT
85
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
86. MONITORING
PSA
RFT
LFT
ALP
BONE SCAN
CT chest, abdomen & pelvis
Repeat Blood profile every 2-3 months
& Bone scan + CT – every 6 months
even in the absence of clinical indication
STOPTREATMENT if two out of
three criteria present
PSA PROGRESSION
RADIOLOGICAL PROGRESSION
CLINICAL DETERIORATION 86
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
88. ANTIANDROGENWITHDRAWL PHENOMENON
Decline in PSA and even objective responses with
withdrawal of antiandrogen
Rapid PSA responses following androgen ablation –
higher rates of antiandrogen withdrawal phenomenon
88
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.