Prostate Flashcards
What is the epidemiology for prostate cancer?
Incidence (Australian statistics):
* 16700 cases annually
* Most common malignancy (excluding NMSC) in men
○ Second most common malignancy overall behind breast cancer
○ Lifetime risk = 1 in 8
* Incidence is increasing (particularly in younger men, due to increased screening)
* 5% present w/ distant mets
Primarily disease of the elderly (most cases >60yo)
* Incidence of latent CaP 20% for men in 50’s→ 70% for men between 70 – 80y.
Mixed genetic and geographic/lifestyle interplay
* Men living in high socioeconomic regions are at markedly increased risk (AUS, USA, Europe)
* Men who migrate adopt the new risk within one generation
What are the risk factors for prostate cancer?
- Advancing age (most important risk factor)
- Western diet
a. Red meat and animal fats (including dairy) are linked
b. Retinol, carotenoids, phytoestrogens and vitamin D are protective (high fruit/vegetable diet) - Androgen exposure
a. Exogenous testosterone can increase risk
b. Use of 5-α reductase inhibitors (e.g. dutasteride) can increase risk of high-grade disease - Metabolic syndrome
a. Single components assoicated with sig higher risk of Pca: HTN, waist circumference - Obesity and physical inactivity
a. Likely due to hyperinsulinaemia –> increased IGF –> increased androgens - Smoking
a. Increase risk of incidence, and worse prognosis - Race
a. African-Americans are at particular risk (up to 50x increased compared with Asians)
b. African-Americans also have particularly aggressive disease course - Genetic/familial causes
a. Involved first-degree relative increases risk by 2.5x
b. Multiple genes have been implicated (BRCA2, MYC, ATM, dMMR, PTEN)
§ BRCA1/2: RR 4.7 (BRCA2 assoc w/ ↑ Gleason & ↓ OS)
□ Incr risk progression on local therapy, decr OS
§ HPC1: hereditary prostate Ca 1
□ Androgen receptor gene: polymorphic CAG repeat
□ ↓ repeats = ↑ risk
§ ATM: RR: 6.3 for met PCa
§ GSTP1: Loss of glutathione S-transferase P1
§ Lynch syndrome: MLH1, MSH2, MSH6, PMS2
□ May lead to MSA (microsatellite instability), deficient mismatch repair (dMMR)
§ Homologous recombo genes: BRCA1, BRCA2, ATM, PALB2, CHEK2
§ Others: RAD51D, ATR, NBN, GEN1, RAD51C, MRE11A , BRIP1, FAM175A
§ If strong family hx, suggest testing for (Next generation sequencing):
□ BRCA1/2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2
- Western diet
List the differential diagnosis of a prostate lesion, including subtypes.
- Epithelial
a. Glandular
i. Acinar adenoca- 95%- see below
ii. Ductal adenoca- 1%- clinically aggressive, DM early, usually central location. Usually surgical Mx.
b. Urothelial- TCC- central, arise from urothelial lining of prostatic urethra + proximal prostatic ducts. Don’t secrete PSA, -ve for PAP (prostatic acid phosphatase), +ve CK7 + CK20, HMW keratin post.
c. Squamous- adenosquamous, SCC
d. Adenoid cystic ca- treat surgically- Neuroendocrine
a. Focal neuroendocrine differentiation
b. Carcinoid- well diff, no PSA
c. Small cell carcinoma- poorly diff, no PSA, short OS, early DM. Like lung.
d. Treatment related neuroendocrine prostatic carcinoma (occur within 2 years of duodart) - Mesenchymal (highly resistant to Rx)
a. LMS- older pts
b. RMS- kids
c. Carcinosarcoma
d. Leiomyoma, lyomeiosarcoma, prostate stromal sarcoma,
e. - Haematological- lymphoma
- Others- germ cell, clear cell, melanoma
- Neuroendocrine
Describe prostate intra-epithelial neosplasia and the differentiation from malignancy.
- Precursor lesion for invasive prostate cancer
○ Not required for development of malignancy (can be de-novo)- Consists of proliferation of atypical/dysplastic cells within ducts and acini (without invasion of basement layer - myoepthilium)
○ Normal architecture preserved
○ P16 positive differentiates from invasive - Low-grade PIN has a low risk of progression to malignancy
- High-grade PIN should prompt further investigation to exclude concomitant presence of invasive malignancy (generally associated with cancer)
○ Basement membrane breach leads to invasion
○ 30%will progress to invasive in 10 years - PIN plays a role in pathogenesis of invasive malignancy
○ Multifactorial development of telomere shortening + GSTP1 hypermethylation –> PIN
○ p27 loss of function mutation –> invasive malignancy
○ Loss of PTEN function +/- telomerase activation +/- p53/Rb mutation –> metastasis - Cribiform (ductal or intraductal histo): increased genomic instability
- Consists of proliferation of atypical/dysplastic cells within ducts and acini (without invasion of basement layer - myoepthilium)
Distinguishing Benign from Malignant
* Defining feature of malignant transformation is invasion through basement membrane/myoepithelial layer
○ However, not all prostate glands without basal cells are carcinoma
○ IHC: (triple antibody cocktail PIN4 - most widely used)
1. High molecular weight cytokeratin 34bE12 identifies basal cells- present in benign, absent in malignant
2. P63 - nuclear protein in basal cells = absent in malignant
3. AMACR/P504s (alpha-methylacy-CoA racemase) = positive in malignant ~80%
□ Often increased fatty acid metabolites by over expression of AMACR
▪ Over expression of ERG from TMP-RSS2:ERG gene re-arrangement; role in initiation of 50% of CaP
□ Highly specific (in the setting of absence of basal cells) but not sensitive for CaP
* Both: PSA (confirms prostatic origin of epithelial cells, although if positive in tissue from LNs and met sites = maligant)
Describe the pathology for Acinar prostate adenocarcinoma.
Acinar adenocarcinoma
* By far the most common histopathological subtype
* 70% arise in PZ posteriorly, majority are multifocal
* Synoptic report for core biopsy
○ Type
○ Grade/gleason score –prim, second, tert
○ Composite score
○ Intraductal (could be pattern 5)
○ Cribiform (grade 4) = more aggressive gr 4
○ Number of cores, percent of specimenCores
○ EPE
LVI
PNI
* Postprostetectomy: similar + margins for surgery, SV.
○ Microscopic extension in bladder neck = T3
○ Nodes, seminal vesicle involvement
○ TNM
▪ T3a extraprostatic: focal or established (1 HPF)
▪ T3b SV invasion
▪ T4 other organs
* Macroscopic ○ Poorly delineated tumour (often easier felt than seen) ○ Firm grey-yellow tumour with gritty texture * Microscopic ○ Appearance is heavily dependent on the Gleason grade ▪ Typically, defined by abnormal appearance to glandular structures (too many, too small and too crowded) ○ Typically forms gland structures that are smaller than normal ▪ Cells lining glands are usually cuboidal ○ Classic cytological features include ▪ High N:C ratio, prominent/large nucleoli & hyperchromatic nuclei (but not severe pleomorphism) ▪ Mitotic figures only in very high grade disease ▪ Classical amphophillic cytoplasm (stains for both H&E) ○ May present as single cell infiltration in high-grade disease ○ PNI is very common ○ IHC may be used to stain for basal layer cells (basal layer positive for high molecular weight keratin and p63 = benign), absent in malignant glands. * Immunohistochemistry ○ POS = NKX3.1 □ Prostatic transcription gene: Key role in the development of prostatic epithelium and ducts. □ Positive staining majority of primary prostate adenocarcinomas, downregulated in high grade disease and completely lost in metastatic disease □ Needs to have this transcription factor, but less expression than normal prostate tissue (loss of function contributes to prostate carcinogenesis), negative in basal ○ POS= PSA □ Prostatic origin of metastatic tumours, differentiates between prostate and urothelial carcinoma ○ POS=AR □ Androgen receptor ○ POS= AMACR (good marker of cancer vs benign, but not specific for prostate) □ Alpha methylacyl CoA racemase widely used as found in prostate carcinoma but not BPH ○ POS=PSMA □ Prostate specific membrane antigen, cytoplasmic marker of prostate adenocarcinoma less sensitive and specific than NKX3.1 □ Correlated with a higher Gleason grade ○ NEG = PAX8, TTF1, CK7 & CK20 ▪ p63, CD10, CK 5/6, CK 34bE12 (normal basal cells –lost in cancer),
Describe the pathology for ductal prostate adenocarcinoma.
Ductal carcinoma
* Rare subtype, more likely mixed with acinar than pure ductal
* Key differences
○ More locally aggressive than acinar type
○ Less PSA secretory than acinar
○ Usually near urethra
* Macroscopic ○ Unchanged * Microscopic ○ Typically forms glands which are larger than normal ○ Glands composed of tall columnar cells ▪ Can form cribriform, papillary, solid or PIN patterns (Gl 4) ○ Unlike acinar type, cribriform pattern is more slit-like * IHC: stains like colorectal or endometrioid ○ PSA, PAP positive, ○ CDX2 and CK20 pos (like colorectal) ○ CEA weak positive
Describe the gleason’s scoring system
Histological grading system based primarily on architecture (no cytology)
- Size of glands, separation, differentiation
- Resemblance to normal prostate and formation of glands
Histological appearances are separated into 5 pattern groups
* Gleason 1+2 –> no longer reported > normal
○ Circumscribed nodules of small uniform glands, more stroma between glands
* Gleason 3
○ Single, separate and well-formed glands; variable in size
○ Abnormal glands in appearance (small or irregular or ragged in appearance), open lumina
○ Tumour glands infiltrates between normal glands
○ Stroma intervening between glands (i.e. not fused)
○ May have nucleoli, blue cytoplasm
* Gleason 4
○ Glands coalesce and fuse (>1 lumen visible and no intervening stroma seen)
○ Cribriform pattern is always Gleason 4+ by definition
▪ coalescent sheet of glands with small lumina
○ Intraductal carcinoma within invasive malignancy should be characterized as Gleason 4
* Gleason 5
○ No glands –just tumour cells; large cells with atypia and pleomorphism
○ Two key patterns
▪ Comedonecrosis –> central necrosis with intraluminal necrotic cells
▪ Single cells –> can form cords/sheets/nests (sometimes with vacuoules) but without glandular lumina
Allocation of final Gleason scores depends on the specimen type:
1. Needle biopsy
a. Primary = most prevalent pattern
b. Secondary = any amount of the worst pattern present (irrespective of percentage) –> reflects possible sampling error regarding proportion of high-grade disease
2. Radical prostatectomy
a. Primary = most prevalent pattern
b. Secondary = worst pattern present (if >5%); otherwise, next most prevalent pattern
Tertiary = notes presence of high-grade disease if <5%
Discuss the significance of the gleason scoring system and also describe the ISUP system.
Significance of Gleason Score
* Grade is one of most important PFs in prostate cancer affecting: (clinical behaviour)
* Likelihood of organ confined dx Partin tables
* Alternatively, likelihood of ECE, SVI, LN+ & metastatic disease
* Likelihood of response to radical Rx D’Amico risk group
* Risk stratification + treatment intensification
* Prognosis
* Risk of death from CaP Albertson data
* Advantages
* Stratification into prognostic groups
* Uniformity in reporting, correlates with clinical behavior (as above)
* By assigning 2 Gleason grades»_space; more information
* Disadvantages
* Sampling error, accuracy of grading dec if small volume
* No information of each grade within combined score
* Interobserver interpretation, under and over grading
* Doesn’t allow for variant pathology
ISUP
Derived in 2014, to simplify explanation to patients about very low risk prostate cancer
Once the primary, secondary and tertiary grades are established, the Grade Group is assigned
* GG1 = 3+3
* GG2 = 3+4
* GG3 = 4+3
* GG4 = 8 = 4+4, 3+5 & 5+3
* GG5 = 9, 10 =4+5, 5+4 & 5+5
Groups prognostically similar gleason scores
Data eg. Data suggesting GS 4+3 is more aggressive than 3+4
GG4 quite heterogenous
Always report the percentage of any high-grade disease present
e.g. Gleason 3+4=7 (GG2; 20% pattern 4)
Original gleason only reported if >5%
* Biopsy with 97% pattern 3 and 3% pattern 4 would now be scored as 3 + 4 = 7 rather than as 3 + 3 = 6 in the classical Gleason
ISUP also scores every core individually
Describe the pathology for prostate small cell carcinoma.
Small Cell Carcinoma
* Rare subtype, more often combined with acinar adenocarcinoma (rather than pure)
○ May develop following previous treatment (esp ADT)
* Key differences:
○ Often non-PSA secreting
○ Highly aggressive disease course
○ Typically resistant to androgen deprivation
* True small cell carcinoma needs to be distinguished from adenocarcinoma with focal neuroendocrine carcinoma
○ True small cell –> chemo-based management (not ADT)
○ Focal NE differentiation –> manage as per acinar adenocarcinoma
* Microscopic ○ Resembles small cell lung cancer ▪ Classic description of "oat" cells ▪ Large numbers of apoptotic cells ▪ Not much cytoplasm ▪ Marked atypia --> high N:C ratio, frequent mitosis, pleomorphic nuclei ▪ Nuclear molding, ○ High Ki67 * Immunohistochemistry ○ POS = chromogranin, synaptophysin, CD56, NSE, TTF1 ○ NEG = PSA, PAP
Describe PSA
Prostate specific antigen
* Cytoplasmic marker that is sensitive and specific for prostatic tissue and adenocarcinoma of prostatic origin
* Produced by the secretory cells of prostatic ducts and acini, androgen regulated
Role in prostate- secreted into gland s and cleaves semenogelin 1 and II in the process of mediating semen formation.
* Limitations of measuring absolute level of PSA:
i) Specificity
○ Organ specific but not cancer specific: ↑ levels due to ↑ age, BPH, prostate inflammation/infection/trauma, post- ejaculation, post-DRE.
ensitivity
○ Small tumours may not produce adequate PSA to be considered high levels.
○ Poorly differentiated tumours produce less PSA per volume of tumour.
○ Some tumours do not produce PSA- e.g. small cell, neuroendocrine tumours.
* Non- malignant causes of PSA rise: BPH, prostatitis, urinary retention, recent ejaculation, recent trauma (DRE, Biopsy, TURP).
* Conversely 5 alpha reductase inhibitors can artificially lower the PSA (finasteride). 5αR inhibitors decrease PSA by 50% (if on for > 2.5 years, multiply by 2.5x).
* PSA Post treatment bounce
○ Spikes of PSA <2 can occur in hormone naïve patients, more commonly in younger men receiving EBRT
○ 10-40% of men, average of 12-18 months after Tx
* Post treatment PSA Nadir
○ Post prostatectomy: zero within 2-4 weeks
○ Post EBRT: Reached by ~1.5years with median PSA of 0.6
○ Post BT: Reached by ~2years with median PSA of <0.2
* Biochemical Recurrence
○ ASTRO Phoenix definition: Rise in PSA by 2 or more, above nadir
Describe the features of a prostate cancer synoptic report.
Describe the prognostic factors for prostate cancer.
Patient Factors
* Age (controversial)
○ Younger men may perform better following therapy
* Performance status and co-morbidity
* Life-expectancy
* Ethnicity
○ African-American population tend to have more aggressive disease
* 5-α reductase inhibitor use (risk for higher-grade disease)
○ Decrease PSA by 50%
Tumour Factors
* NCCN risk group
○ (incorporating Gleason grade, iPSA, T-stage)
○ Number/percentage of positive cores (i.e. volume of disease; >50% = ↑ aggressive )
○ PNI, EPE, intraductal component
○ PSAdt (<9months) and velocity
* N-stage & M-stage
○ The number of positive nodes influences risk of survival
* Histopathological features
○ LVI
○ p53 mutation
○ Ki67 -not usually done
○ Others (E-cadherin, IGF, AR expression, loss of PTEN)
○ SV invasion
○ PNI (associated with gleason score)
○ Margins -negative margin is 3mm. Gl 4 or 5 at margin higher recurrence risk.
○ Pathology = small cell = worse
Treatment Factors
* XRT dose/ Dose escalation for RT
* Duration of ADT
* ADT use (intermediate/high risk)
* Positive surgical margins
Describe the NCCN risk stratification for prostate cancer.
What are the methods of estimating risk of LN involvement and SV involvement in prostate cancer?
1) Lymph node involvement
* Roach formula (PSA + Gleason) % Risk of LN mets = 2/3 PSA + ((GS – 6) x 10)
* Partin tables (cT-stage + PSA + Gleason)
* MSKCC nomogram (cT-stage + PSA + Gleason + number of positive cores)
2) SV involvement
* Roach formula % Risk of SVI = PSA + 10 x (GS – 6)
* Partin tables
MSKCC nomogram
Describe the history and examination for prostate cancer.
Presentation/Natural History
- Often asymptomatic with increasing PSA - LUTSx
Consultation
- History ○ HPI + baseline function (urinary function, bowel and bladder, IPSS) § Screening PSA § Urinary symptoms (IPSS/AUA) □ Prostatic = hesitancy, reduced stream flow, intermittency & incomplete void □ Irritative = urgency, frequency, nocturia, dysuria □ AUA scored 0-5 (NEW-FUSH). Nocturia, Emptying, Weak stream, Frequency, Urgency, Strain, Hesitancy. § Haematuria § Rectal symptoms (bowel invasion): diarrhoea, pain, fistula § Erectile dysfunction § Haematospermia § Recent TURP (may have worse toxicity with SABR) § Pulmonary mets: SOB, cough § Bone mets: pain, compression fracture § Constitutional symptoms ○ PMHx: § Hip replacement (and what time of prosthesis) § Co-morbidities □ Cardiac (ADT) § Previous radiotherapy § Inflammatory bowel disease ○ Medications § Exogenous androgens ○ Family History § BRCA § Lynch ○ Social § Smoking - Examination ○ PR examination § Can only palpate post & lateral (65-75% of tuours) § Clinical T-stage □ No median raphe indicates bilateral disease, no lateral sulci indicates ECE § Rectal invasion § Blood
Discuss the work up for prostate cancer.
- PSA
○ Ideally serial levels
§ PSA, density (↑ρ = ↑ Ca)
§ Velocity: >2ng/ml per year associated with higher risk of GS ≥ 7
§ Free: complex ratio - <10% = ↑ risk; ratio >25% = ↓ risk
§ Doubling time <9 months is concerning for cancer
○ Ensure no recent DRE or instrumentation preceding
§ May be increased with prostatitis, BPH, Post biopsy, DRE, ejaculation
○ Pre-bx PSA 4-10 has risk of GS ≥ 7 ~50%, while PSA >10 has risk of GS ≥ 7 ~66%- Other bloods:
○ UEC, LFT, Testosterone, LFTs, ALP, Ca
○ Check LFTs and FBC prior to ADT initiation - Prostate MR
○ Multiparametric MR improves specificity (over CT)
§ PIRADS score
§ Better for delinating prostate & T stage
○ Helps to guide biopsy (MR fusion)
○ Prostate volume (<80cc for SBRT)
○ Look for EPE and SV invasion and can be used in RT planning
○ T2 weighted MRI + DWI, dynamic contrast enhanced (DCE)
§ Low signal on T2
§ Restricted diffusion DWI
§ Early and intense enhancement on DCE
○ 444ÍNodes + bony mets - Biopsy
○ TRUS-guided vs trans-perineal biopsy - Staging Imaging for >/= Unfavourable intermediate risk
○ Ga-68 PSMA-PET (preferred)
§ proPSMA trial (Hofman, 2020 - Peter Mac)
□ PSMA-PET was associated with improved specificity and sensitivity than conventional imaging
□ Higher radiation exposure for conventional imaging
§ + Consider in salvage EBRT post RT
§ 3-5% of prostate cancers are PSMA negative
§ For nodal mets
□ (Hope 2021) PSMA open label surgical trial 277pts - sensitive 40%, specificity 95%
□ PPV 0.75, NPV 0.8
□ Sensitivity poor if <6mm
○ CT CAP
§ CT AP: T3+ disease, normogram LN risk >10%
○ WBBS
§ PSA >10 (if <10 then positive in < 5%), T3-4, GS ≥ 8, unfavourable-intermediate, high, very high, symptoms
Rarely +ve if PSA>10 and asymptomatic
- Other bloods:
Discuss PSA screening for prostate cancer.
- Randomised evidence does not support a broad screening approach, harms of PSA testing including anxiety and overtreatment
- The harms of PSA testing may outweigh benefits, particularly men >70
- DRE not recommended for asymptomatic men as part of PSA screening, but important aspect of clinical work up (clinical T stage)
- Counsel prior to testing; re potential risks/benefits
- 50–69 with no family history of prostate cancer, PSA every 2 years
- If family history of prostate cancer, depending on RR may recommend from age of 40/45
- Referral to genetics for BRCA 1 and 2 testing (1-2% of prostate cancers)
○ A family history suggestive of BRCA 1 or BRCA 2 variant e.g. relatives breast/ovarian cancer, breast cancer <50 years, bilateral breast cancer, male breast cancer, Ashkeni Jewish ancestry
○ X3 1st or 2nd degree relatives with prostate cancer
or
○ X2 1st or 2nd degree relatives with prostate cancer, x1 diagnosed <50 years
Describe the different types of prostate biopsy and the advantages and disadvantages.
§ Trans-perineal superior
□ Better sampling of the gland (especially anteriorly)
□ Lower infection rate
○ MRI guided biopsies are less likely to detect clinically insignificant cancer, but standard biopsies are non-inferior at detecting clinically significant cancer
§ Cognitive biopsy
○ Identify suspicious region on MRI and visually direct biopsy (without fusion)
§ MRI-USS software fusion biopsy
○ Ridgid or elastic fusion of MRI and US to guide biopsy to suspicious segment
§ MRI in-bore guided biopsy
○ Pt in MRI bore, with active MRI guidance of needles
○ Consider Bx suspicious LN
What factors should be taken into account when managing patients with prostate cancer?
Patient:
- Life expectancy
- Comorbidities including cardiac, CI to surgery, RT
- CFS, G8 screening tool
- Age
- Preference (shared decision making)
Tumour = risk group
- GS
- PSA
- T stage
Treatment factors:
- Available options
- Toxicities
Describe the management options for ‘very low risk’ and ‘Low risk’ Prostate cancer
Very Low Risk
* Active Surveillance
* Less Preferred
* Prostatectomy
* LDR brachytherapy
* Hypofractionated EBRT
* Observation (WW) if LE <10 years
Low Risk
* Active Surveillance
* Less Preferred
* Prostatectomy
* LDR brachytherapy
* Hypofractionated EBRT
* SABR
* HDR
* Observation (WW) if LE <10 years
Describe staging for prostate cancer.
Describe the management options for ‘Favourable intermediate risk’ and ‘unfavourable intermediate risk’ Prostate cancer
Favourable Intermediate Risk
* Prostatectomy +/- PLND (if predicted prob LN+ is ≥ 20%)
* LDR brachytherapy
* HDR brachytherapy
* EBRT
* Hypofractionation
* SABR
* Less Preferred
Active Surveillance
Unfavourable Intermediate risk
* Prostatectomy + PLND (if predicted prob LN+ is ≥ 20%)
* EBRT with 4- 6mo ADT
* Hypofractionation
* SABR
Conventional fractionation EBRT with HDR boost (or LDR)
Describe the management options for ‘High risk’ and ‘Very high risk’ Prostate cancer
High risk
* Conventional fractionation EBRT with HDR boost
* With 18-24mo of ADT
* Dose escalated EBRT to ~79.2 Gy
* With 18-24mo of ADT
* +/- Include LN (roach >15%)
* NCCN 2024: offer hypoFx (if not treating LN)
* Less preferred:
Prostatectomy + ePLND
Very high risk
* Conventional fractionation EBRT with HDR boost
* With 24-36mo of ADT
Include LN
Consider Palliative ADT alone for pt with high risk prostate ca, local symptoms and limited LE
Describe the management options for node positive Prostate cancer
- EBRT (conventional fractionation, covering elective LNs and boosting involved LNs) + ADT (for 2 years) (+/- Abiraterone, but not on PBS)
- SEER data: EBRT inc 10yr OS, CSS (vs. no local therapy)
- Rusthove 2014: 10 yr OS benefit for local therapy in N+
- Radical prostatectomy + PLND -not recommended
§ Limited evidence that this approach is beneficial in the setting of node-positive disease - Non-curative options include:
- ADT +/- Abiraterone
Observation
Describe the management for small cell Prostate cancer
- Similar to lung
- Chemo as usually a systemic disease
- Consider XRT: localised disease or local onctrol
- No role for PCI
- Small cell alone: 60Gy/30Fx + pelvic LN + cisplat/etop x4
- Small cell w/ adeno: 70Gy/35Fx + PLN + cis/etop +/- ADT
Slight decrease in dose as giving concurrent chemo
Compare and contrast ‘watchful waiting’ vs ‘active surveillance’ for prostate cancer
Watchful waiting=Palliative, LE <10 years, aim to minimise treatment related toxicity
- Significant no. of screen detected CaP > clinically insignificant > overtreatment > morbidity without benefit
○ Aim to avoid Ses of local treatment or ADT
- High incidence of asymptomatic CaP on autopsy of men >70
- Reasonable approach with sig comordbities, LE<10 years + low risk/intermediate risk
○ Can use SSA life expectancy calculator; e prognosis
- ADT traditionally if symptoms; however evidence early ADT can prolong short term survival,
○ Locally advanced disease
○ PSAdt < 12 mo
○ PSA >30-50
- Thus can consider ADT before symptoms arise
- Individualised strategy
○ Monitor q6m
○ Only treat for Sx or PSA >50,
- Usually palliative ADT
- Supported by PIVOT & SPCG-4 studies
- Overall evidence: asymptomatic, clinically localised, LE <10 yrs; active treatment over WW unlikely relevant
Active surveillance= Curative, LE >10 years, Baseline MRI, 6 monthly PSA and 12 monthly biopsy
Active Surveillance (Aim to minimise treatment-related toxicity without compromising survival)
-Standard of care recommendation for very low and low-risk patients
- ProtecT and PRIAS trials
○ Low risk of progression to higher-risk disease whilst on surveillance
○ Cancer-specific survival > 99% at 10 years
- DECTECTIVE consensus study
○ EUA/ESTRO etc develop consensus statements for deferred treatment with curative intent for localised Pca, covering all domains of AS
-Factors such as younger age, prostate cancer volume, pt preference should be considered
For younger patients (e.g., < 62y): Consider MRI ± genomics (Decipher, Oncotype, Prolaris, Promark).
-Reasonable to consider for low-volume favourable intermediate risk disease
- Updated PRIAS protocol allows inclusion
-Transition to active therapy:
- Progression on Bx:
○ Reclassification to higher risk category eg. GS ≥ 7
○ Significant increases in tumour volume on subsequent biopsies
- Pt preference
PRIAS Surveillance Protocol
- Clinical review every six months for years 1-2
○ PSA q3mo
○ DRE each visit
○ = change = trigger for repeat MRI +/- Bx
- MRI + TRUS biopsy at 12mo, 48mo and 84mo
○ If doubling time is <10 years, then annual MR is indicated
Definitive Management
-Life expectancy >10 years is considered a mandatory threshold for patient to benefit from active treatment
-Definitive therapy is associated with improvement in CSS and OS
- Benefit most proven in intermediate or high-risk disease
- NCIC, Scandinavian and PIVOT studies
-There is no randomised comparisons comparing efficacy between prostatectomy and RT
- Decision for each should be made on the basis of toxicity profile
○ ProtecT trial provides guidance
Fixed T4 disease should not be operated on
Discuss indications, advantages and disadvantages for radical prostatectomy for prostate cancer
- Surgery traditionally indicated for low risk, organ confined prostate cancer
- Upgrading of Bx proven GS from ≤ 6 -> ≥7 , or from 7 -> ≥ 7 occurs in 25-30% (chun 2006)
Downgrading of GS is uncommon - Indications: LE >10 years, no contraindications to surgery
- Upgrading of Bx proven GS from ≤ 6 -> ≥7 , or from 7 -> ≥ 7 occurs in 25-30% (chun 2006)
Discuss pelvic lymph node dissection in prostate cancer treatment.
- Provides staging information which may guide further management,
- but does not have consistently documented improvement in MFS, CSS or OS
- Additionally 2 x RCTs = no benefit of extended approach vs. limited PLND
- Use nomogram to select pt for lymphadenectomy
○ Balance risk vs. benefit of identifying node positive disease
○ If performing PLND, should be extended - improved staging compared to limited
○ Limited = obtruator fossa
○ Std = limited + EI LN
○ Ext = std + II LN
○ Super-ext = extended + CI, PS, and/or other nodes - Pelvic LND often excluded if <2-7% probability of LN mets
- 40-60% of LN located in internal iliac & presacral nodes (Extended PLND can resect these)
Discuss radical prostatectomy techniques, recurrence, toxicity and post op PSA.
- Techniques: open, robotic, laparoscopic
○ Open
§ Radical retropubic prostatectomy
§ Perineal approach- typically sued less as higher change of erectile dysfunction and difficult to sample lymph nodes. Primary advantage is shorter operation, so may be used in patients with co morbidities that make retropubic difficult.
○ Laparoscopic
§ Robotic
□ Advantages of smaller incisions- less bleeding, quicker recovery, shorter hospital stay
□ Similar side effect profile to open surgery- Prostate removed from urethra to bladder vesicourethral anastomosis
- Locations of recurrence
○ Anastomosis 45%
○ Retrovesical 15-30%
○ SV 20% - Attempt to spare cavernous nerves (EF), nerve sparing aims to leave the neurovascular bundle in tact
○ Avoid if extensive Ca on Bx; ≥ 3 positive cores in 1 lobe, palpable T3/4, ED already
○ NVB lies between the levator fascial and prostatic capsule. Nerve sparing dissects the levator fascia and aims to spare the cavernous nerves that branch from the NVB to remain in tract. Prostate removed with prostatic capsule intact - Tox: bleeding, GI/GU/nerve injury, urinary leakage/fitula, VTE, UTI, lymphocele
○ Late: ED, incontinence/stricture - PSA should become undetectable <0.1 within 1 month
○ Recurrence = PSA ≥0.2ng/mL on 2 consecutive rises - Salvage RP after brachytherapy, if no metastatic disease potentially curative salvage RP if
○ Patient >12 months post completion of radiation
○ At least 10 year life expectancy
○ PSA <10
○ Peri-operative complications higher in this group: urinary incotinence 40-50%, rectal injury 10-15%
Discuss Post operative N1 disease for prostate cancer.
- Up to 37% of patients with positive LN at surgery remain free of disease long term without further surgery
- There is an OS benefit for immediate ADT after incidental N1 disease discovered at time of surgery (however, see below)
- Requires risk assessment: extent of node dissection, no. of lymph nodes, post op PSA, primary tumour factors
○ Subset of pt with limited +ve LN (1-2) - favourable outcomes and did not require further treatment - EUA/ESTRO/ISUP: pN1, post ePLND discuss based on nodal involvement characteristics:
○ 1. Offer adjuvant ADT;
○ 2. Offer adjuvant ADT with additional IMRT/VMAT plus IGRT;
○ 3. Offer observation (expectant management) to a patient after eLND and < 2 nodes and a PSA < 0.1 ng/mL. - AUA:
○ Persistent PSA
§ Consider Salvage + adjuvant ADT
○ Undetectable PSA options (AUA):
§ Adjuvant treatment (including immediate ADT)
§ PSA surveillance - Evidence: Messing NEJM 99, Lancet 06
○ Randomised, 98 pt; immediate ADT vs. delayed ADT (at time of symptomatic progression)
○ MFU 12yr immediate improved PFS, CSS, OS
○ Mostly high volume nodal disease and multiple adverse tumour favours
○ Note: did not assess comparative outcomes of adj ADT vs. ADT initiated at time of biochemical recurrence, thus thus the optimal timing to initiate postoperative ADT for patients with pN1+ remains unclear
○ Mixed findings in 6 cohort studies; 3 studies- no diff in oncological outcomes
Discuss dose escalation and dominant intraprostatic lesion boost in prostate cancer.
Dose Escalation
- EBRT dose escalation is associated with improved bPFS (10yr by ~10-20%) and DMFS ○ Mostly noted in IR group and high risk (not low risk) No OS benefit § Controversial evidence for improved OS (if Gleason 8-10) - Aim 78Gy/39F to the primary - Brachytherapy dose escalation is associated with improved bPFS (intermediate and high-risk) ○ Improvement in DMFS & CSS is seen in Grade Group 5 disease - Both LDR and HDR brachytherapy boost are reasonable options ○ HDR boost = 15Gy/1F HDR-BT with 46Gy/23F EBRT - Note that brachytherapy boost does NOT allow reduction or omission of ADT (as indicated) ○ ADT improves OS, but brachytherapy does not
Dominant intraporstatic lesion (DIL) boost
- Validated in FLAME trial - EUA IR and HR patients - 77Gy +/- DIL up to 18Gy, 65% ADT in both arms, duration unknown - Improvement in BFS, LC, regional + distant MFSnd distant MFS - Acceptable toxicity
Discuss moderate hypofractionation and ultra-hypofractionation/SABR in prostate cancer
Moderate Hypofractionation
- Reasonable option for most patients where nodal irradiation is not required (including high risk) ○ Concerns about toxicity when hypofractionating pelvic RT ○ Potential concerns for lack of support in higher-risk populations (majority of data in low/intermediate risk patients) ○ More convenience for patients, also radiobiological advantage (low a/b), resource utilisation - Similar PFS to conventional fractionation ○ Small increased acute GI toxicity - Caution when IPSS >12 ○ Consider mini-TURP/ conventional fractionation - Recommend 60Gy/20F to the prostate alone ○ CHHiP protocol (w/ ADT) ○ PROFIT (60/20, no ADT) ○ RTOG 70/28, no ADT)
Ultra-hypofractionation (SABR)
- ≥ 5 Gy/fx in 4-7 fractions. Example: 36.25/5 (7.25 Gy) or 50/5. ○ 5 treatments over 1.5 weeks - CaP - low a/b, w relatively higher a/b of surrounding tissues - Preliminary data are promising, with acceptable bPFS and toxicity data ○ Early follow-up only thus far - Only in low and favourable intermediate risk disease > lack of RCTs addressing nodal coverage - For now, should only be used in the context of a clinical trial (e.g. NINJA trial) - Caution if prostate>80ml or large median lobe, recent turp, IPSS>15 (?> GU toxicity), - NCCN guidelines: offer
Discuss radiotherapy options for low or favourable intermediate risk prostate cancer
- Low or favourable intermediate risk options offered as equivalent forms of treatment
○ Dose escalated HypoFx EBRT (mod or ultra)
○ Permanent LDR (I-125, 145Gy, others: Pd-103, 125Gy; Cs 115Gy)
○ Temporary HDR (19Gy/1Fx, 27Gy/2Fx)
No randomised trials comparing EBRT to brachytherapy
Describe ADT recommendations for the different prostate cancer risk groups.
- Common Ses: dec libido, ED, hot flushes, depression, mood chnages, fatigue, weight gain
Metabolic function: BMD, insulin resistance, blood lipids
Discuss elective nodal irradiation in prostate cancer
- Consider addition of elective nodal irradiation in high-risk patients where the Roach score > 15-20%
○ POP-RT trial (ENI and ADT, PSMA era) improved bPFS 14%
Recommend conventional fractionation whenever pursuing ENI
Describe the advantages and disadvantages of the different dose escalation strategies in prostate cancer.
Discuss the evidence for dominant intraprostatic lesion boost
Metanalysis: MRI is 77% accurate in determining DIL
FLAME (Focal Boost to the Intraprostatic Tumour in EBRT) trial (Kerkmeijer, 2021) ○ 571 men with intermediate or high-risk prostate cancer were randomised to § EBRT (77Gy/35F) +/- DIL boost (95Gy SIB) § conventional ○ Technique § GTV volumed based on mpMRI § No margin added § OAR constraints took priority over boost target ○ Aim for an "isotoxic" boost protocol ○ Outcomes: 5 year bcDFS increased from 85 to 92% in boost arm without significant increase in late GI or GU toxcities § 5 year bDFS is improved in boost arm (92% vs 85%; p<0.001) § No difference in CSS or OS § No statistically significant differences in toxicity or QoL □ late GU- or GI toxicity grade ≥ 2 (23% and 12% vs. 28% and 13%) □ grade ≥ 3 GU-toxicity 3.5% vs 5.6% HYPOFLAME (Draulans, 2020) ○ Phase 2, 100 pts, IR or HR 35/5# with SIB boost of dominant lesion up to 50Gy But need to watch urethra DELINEATE ○ Phase 2 ○ 74Gy/37# (+82Gy boost) vs 60Gy/20# (+67Gy Boost) ○ SIB to DIL seen on MRI ○ 5year late toxicity comparable between groups and when compared to contemporary series without boost
Discuss the management of locally recurrent prostate cancer, post prostate radiotherapy.
- Patient selection:
· Life expectancy >10 years,
· initial T1/2, GS≤7, PSA <10, PSA-DT >12 months (6-12 mo no unreasonable in presence of other favourable factors <6 mo likely disseminated)
· PSA at salvage <6 (lower the better, less bcF).
· Prefer at least 3-4 years post RT.
· No nodal or metastatic disease on imaging.
· Biopsy proven recurrence with minimal residual RT side effects- Option: RP, LDR Brachytherapy. Less defined role for Cryo ablation and SBRT
- EBRT SRS
- MASTER Systematic review + MA (Valle, 2021)
· Most common: Surgery (RP), ablation (cryo and High Intensity Focal Ultrasound - HIFU) and re-irradiation (SBRT, LDR, HDR)
· Efficacy similar at 2 & 5 years
· ~50% long term rates of bPFS with all techniques in appropriately selected pt
· RT methods less GU toxicity than RP; re-RT with HDR less severe GI than RP - Salvage RP
· Open or robotic; should include LND
· Challenging even in experienced
· Risks: rectal injury, bladder neck contractures, haemorrhage, urethral injury/stenosis, fistulas, chronic urinary incontinence
· 5yr BcPFS after salvage RP is around 50%
· Unclear oncological benefit of addition of lymphadenectomy; risk of lymphocele - Reirradiation
· Rates and severity of complications similar across techniques
· Similar GU and GI toxicity
· Compared to RP: lower urinary function toxicity ~ 5.6-9.6%
· Overall severe bowel dysfunction low - Brachytherapy
· LDR or HDR
· No randomised trials comparing brachy to other salvage
· ??? DOSE - Cryotherapy/surgery
· post-RT, PSA <5, Bx proven recurrence, init PSA <10, low/intermed risk Pro Ca
· Freezing with argon gas to ablate prostate
· Warming device to spare urethra
· CI: prior TURP w lrg defect, lrg prostate, prev rectal pathology, fistula, disrupted prostate anatomy (e.g. prev fracture), pubic arch interference
· Less invasive, fewer SE than RP
· Retrospective data only
· 5- & 10 yr recurrence free survival 63%, 35%; CSS 91%, 79%
· Tox: 40% rectal pain, 10% scrotal oedema, 10% incontinence; no GU retention/fistulas - HIFU
· Using acoustic energy to inc temp of prostate to 100 oC
· Tox: 20% urinary fistula, incontinence, stricture, perineal pain, ED 30-60% - Toxicity:
· Urinary incontinence after salvage BT / cryo / salvage RP of 6→ 36→ 41%.
· G3-4 GU complications and fistula risk after salvage BT of ~3.4%. - After brachy 70-80% 2 year biochemical control
· 1st decade major complication rate: 33%
· 2nd decade major complication rate 13%
· (rectal/urethral injury, bladder neck contracture, incontinence, vesicorectal/ vesicoperineal fistula) - EBRT SRS
- 50% 2 year biochemical control, G3 Toxicity 5% (limiter FU time)
Discuss management of distant prostate cancer recurrence after prostate RT/prostatectomy
Describe management of oligometastatic prostate cancer.
Radiotherapy to the Primary (Low-Volume Metastatic)
- Consider radiotherapy to the prostate in patients with de-novo low-volume metastatic disease ○ CHAARTED/STAMPEDE definition (1-3 bony metastases only anywhere, or any number of spine/pelvis mets) ○ STOPCAP Meta <5 bone or nodal mets - Radiotherapy can be delivered as ○ 36Gy/6F weekly ○ 55Gy/20F
Radiotherapy to Oligometastases
- Aggressive local therapy for oligometastases is a reasonable option, potentially may reduce further metastasis - Aim of therapy ○ Delay progression ○ Delay need for ADT/systemic therapy (do not commence immediately) - Should eradicate all PET-detectable disease - ?Repeat sabr for further oligomets - There is NO convincing OS advantage
Node only recurrence
Options:
SBRT if <3 nodes
ENRT -45Gy +- SIB
(STORM trial 3x10gy vs conventional, doubling time 6months)
Both well tolerated, g2 git 5%
bRFS 50 vs 70% -most failure locoregional -sbrt 25%, enrt 3%
Describe use of ADT in biochemical relapsed prostate cancer
- Time of commencement
○ Early
§ If long-term survival expected (>10 years)
§ Rapid PSAdt (<10mo)
§ High-risk features (Gleason 8+)
○ Late (before PSA 5-10ng/mL)
§ Elderly
§ Indolent disease- EAU recommendation for systemic treatment in non-metastatic BCR
○ Observation in low risk
§ In unselected relapsing patients the median actuarial time to the development of metastasis will be 8 years and the median time from metastasis to death will be a further five years. For patients with EAU Low-Risk BCR features, unfit patients with a life expectancy of less than ten years or patients unwilling to undergo salvage treatment, active follow-up may represent a viable option.
○ Treatment in High risk
§ Offer enzalutamide (This is not on PBS) with or without androgen deprivation therapy to M0 patients with high-risk BCR, defined as a PSA doubling time of ≤9 months and a PSA level of ≥2ng/ml above nadir after radiation therapy or ≥1 ng/ml after radical prostatectomy with or without postoperative radiation therapy - Method of administration
○ Intermittent
§ This is reasonable in the non-metastatic setting only
§ Multiple meta-analyses have investigated this
□ Demonstrated no OS detriment compared with continuous ADT
□ Improved physical and sexual function with intermittent ADT
○ Continuous
§ Preferred in higher-risk non-metastatic patients
§ Mandatory in metastatic patients
□ Intergroup INT 0162 trial/ SWOG 9346
® Non-inferiority trial with OS the key endpoint
Continuous therapy improves OS (5.8yrs vs 5.1 yrs)
- EAU recommendation for systemic treatment in non-metastatic BCR
Describe the mechanism behind castrate resistant prostate cancer and its management
Different mechanisms lead to castration resistance: Amplification, overexpression or mutation of the androgen receptor, constitutive activation of AR, alternative splicing events, intra-tumoral androgen synthesis or androgen synthesis by the adrenal glands, activation of other ligands, proliferation of prostate tumour cells independent of androgens
- First step is to introduce total androgen blockade (steroidal anti-androgen) ○ Bicalutamide 50mg daily - If ongoing progression, proceed to second line therapy as per below ○ Novel anti-androgen - Always continue the ADT regardless of additional therapy
Discuss the evidence against adjuvant prostate bed RT, in prostate cancer
EORTC 22911 phase 3 RCT 1000pt
Adjuvant vs salvage. Most PSA <0.2
10year improved BFS and local control. No difference in survival
ARO –9 year BFS but not OS
SWOG –T3N0 –improved MFS and OS. Significant toxicity.
Adverse features post RT
- Adverse pathology (GS 5/GG5, many cores +, ECE etc) +N0
- Node positive
- PSA + and no mets seen
Discuss adjuvant RT vs early salvage RT for prostate cancer
Adverse features post RT
- Adverse pathology (GS 5/GG5, many cores +, ECE etc) +N0
- Node positive
- PSA + and no mets seen
Summary
- Older studies have previously demonstrated the benefit of adjuvant radiotherapy vs “observation” (salvage RT at PSA +0.2, 0.7-1???)
○ (T3, EPE, positive margin, SV invasion)
○ SWOG 8794, ,EORTC 22911, ARO 96-02 (above)
○ Absolute 20% less biochemical failure, less metastasis (7%),
Given results from [RAVES], [RADICALS], and [ARTISTIC], It appears as if adjuvant RT is not necessary for SM+ or T3 disease, but keep in mind patients with GG4+ and pT3b are in limited numbers on the above trials. These groups are the highest risk groups.
- Based on new data, a strict protocol of surveillance and early salvage radiotherapy is not inferior ○ This should be prioritised due to better toxicity - Tendulkar Nomogram ○ Better bcPFS and DM with lower pre-salvage PSA ○ 2460 patients with pN0 biochemical recurrence after RP ○ 10y DM for Pre-RT PSA < 0.2 / 0.5 / 1 / > 2 of 9→ 15→ 19→ 37%. ARTISTIC meta-analysis (Vale, 2020) ○ 3 randomised trials investigating early salvage RT vs adjuvant RT § RAVES (Aus) * EPE/SVI/margin+ & PSA ≤ 0.10ng/mL * Early salvage at PSA ≥0.2 * Recurrence was 20%, * trial aborted for futility, low event rate; 50% had rise req XRT in salvage group * Adj = increased SU § GETUG- 17 * T3-4N0, margin + * All had 6 months of ADT. Trial aborted for futility * No diff EFS, better later GU, EF § RADICALS * pT3-4, GS7-10, margin +, PSA>10 * Early salvage –2 PSA >0.1 or 3 consecutive PSA rises * 1400pt 66Gy/33# or 52.5Gy/20#, pelvis allowed * 5 years no bPFS difference. * Slightly worse GU toxicity for adjuvant 6 vs 4% grade 3 ○ Outcomes § No difference in 5 year event-free survival □ bPFS, clinical progression, death, use of ADT § At this time-point, only 39% of patients in early-salvage arm had required RT § Spares patients from pelvic XRT with sig lower GU toxicity § No heterogeneity based on clinical factors (e.g. Gleason, SV invasion, surgical margins) □ Note low numbers of Gleason 5 and SV invasion
Discuss the evidence for using ADT with Salvage prostate RT
Summary:
- Use of 6mo ADT improves survival and bPFS in patients undergoing salvage radiotherapy
○ Limit use to patients with PSA > 0.6ng/mL (0.7) due to diminishing benefit and cardiac toxicity
- Metanalysis DADSPORT (RTOG9601/GETUG-16/SPPORT) 2022
○ Salvage + no ADT vs 6 months vs 24 months
○ 6months improved metastasis free survival, no duration of ADT improved OS
- Systematic review + MA (Yuan, 2021) including GETUG-16, RTOG9601 + 9 cohort: superior BCR- free survival and OS with concurrent ADT + salvage RT
RTOG 9601 trial (Shipley, 2016) ○ 706 patients planned for salvage radiotherapy (+ve margin/inc PSA) were randomised to § Bicalutamide (2 years) vs placebo § Over half PSA >0.5 at the time of treatment; ie mainly late salvage RT § Only ~20% had PSA 0.2-0.3, 50% persistently detectable PSA ○ Outcomes § 12 yr OS was improved in the ADT arm (76% vs 71%; p=0.04) § Improved bPFS, CSS and DMFS § Greatest DMFS benefit if PSA >1.5 ○ Subgroup analysis (Dess, 2020) § No OS improvement if PSA < 0.6ng/mL (only in 0.7-1.5ng/mL) § Clear detriment <0.3ng/mL § In this group, there was an increase in all-cause mortality ~9% and G3-5 cardiac toxicity GETUG-16 (Carrie, 2016) ○ 743 patients requiring salvage radiotherapy were randomised to § Goserelin for 6mo + RT vs RT alone § Mainly early salvage, also included pelvic RT (unlike RTOG9601) ○ Outcomes § Long-term 10 yr PFS was improved in ADT arm (64% vs 49%; p<0.0001) § DMFS improved (75 vs 69%, p=0.034) § No diff OS or CSS § No benefit if PSA <0.5 SPPORT trial (Pollack, 2022) *updated from old matt with trial data* ○ 1792 pts. pT2-3 and/or SM+ (50%) with rising PSA 0.1-2.0. SVI (15%), GS ≤ 9 (GS 8-9 16%), Pre-RT PSA (Median 0.35, ~30% with PSA > 0.5), pN0 (65% received PLND, median 6 LN examined). Staged with bone scan and CT. 2008-2015. MFU 8.2y. ○ requiring salvage radiotherapy were randomised to 3 arms § Prostate RT alone § Prostate RT + ADT (Short term, 2m nADT, 4-6 months total) § Prostate RT + ADT + Nodal RT § * *no WPRT alone arm** ○ Interim analysis - trial stopped RT alone. 18% inferior ○ Median FU 8.2 years ○ Outcomes § Rates of PFS were improved in each sequential arm □ 71% vs 82% vs 89% □ Improved biochemical failures, regional failure § Adding RT alone = no improvement in DM, CSS, OS § Adding ADT + WPRT = improved DM, CSS ○ i.e. both ADT and ENI both individually added to outcomes § Whole pelvis benefit if PSA >0.35*** ○ Toxicity: § Acute G2+ 18 > 36 > 44% § Late G2+ similar; more G2+ blood/marrow in group 3 vs. group 2 (addition of PLNRT) § Late GU, GI
How does ADT work in prostate cancer?
Testosterone→ potent DHT in target tissues, binding with high affinity to androgen receptor in PrCa cells. The DHT-Androgen receptor complex translocates to cancer cell nucleus, binding to DNA androgen response elements and facilitating many PrCa growth pathways.
Mechanisms:
· Better disease control locally
· Improved distant control
Castrate Testosterone
· Want testosterone level on hormones to be the same as if surgically castrated
· Testosterone: 0.7nmol/L or 20ng/dL ideal
· < 50ng/dL: Scher HI, J Clin Oncol 2008;26:1148-59.
· Found that levels above 20ng/dL have worse PSA PFS
Complete androgen blockade
· GnRH agonist (Leuprolide/ Goserelin) + anti-androgen (Bicalutamide)
· GnRH antagonist (Degarelix) - not associated with flare, as no initial stimulation of LH
· No evidence for adding at 5-α-reductase inhibitor
*Anti-androgen precedes/co-admin w/ GnRH agonist & continued as combo for at least 7-10d
· ↓ risk devel symp assoc w/ flare in testosterone w/ init GnRH agonist alone
· Anti-androgen monotherapy less effective than med/sx castration
· Monotherapy not recommended
Intermittent ADT
· May ↓ s/e w/o altering OS compared to continuous ADT (PR7)
· Equivalent to continuous (interim analysis) à unless presence of mets (then intermittent = ↓OS)
○ Good candidates have PSA <4 within 6 months, nonmetastatic disase or node only, older, long doubling time
Adeq suppress of testost (<50ng/mL, 1.7nmol/L) w/ med/sx castration not achieved
· Consider: add’nal horm manipulation: estrogen, anti-androgens, steroids or GnRH antagonist
· Clinical benefit not clear
· Ie: add casodex, dexamethasone…
· Testosterone recovery: approx. 50% recovery by 6mo, 75% by 12mo after cessation ADT
○ Time to recovery increases if ADT > 2yrs, older age, lower initial test
Discuss the mechanism and side effects for GNRH/LHRH agonists and antagonists. Discuss testosterone recovery after these medications
Testosterone Recovery:
· Younger pt = quicker recovery
· On average, it takes a median of 1 year to recover for around 70% of men to recover their testosterone after 6 mo of ADT, independent of sequencing with RT (i.e., at least 1.5 years from initial injection)
· On average, it takes a median of 2 years to recover for a little over half of men to recover their testosterone after 18 mo of ADT (i.e., at least 3.5 years from the initial injection).
On average, it takes a median of 4 years to recover for a little under half of men to recover their testosterone after 36 mo of ADT (i.e., at least 7 years from the initial injection).
Describe the radiation technique for hypofractionated prostate treatment (including SABR)
Moderately Hypofractionated (CHHiP)
Patients
1) All patients where nodal irradiation is not required
a. Mostly low/intermediate risk
2) Low volume M1
Pre-simulation
MDT discussion
Fiducials inserted (wait >5-7 days post for CT)
Consider rectal spacer gel
Simulation
Supine with arms on chest
Vacbag, knee-block and ankle-stocks
Bladder comfortably full
Fiducials inserted
Generous CT (2mm without contrast)
- L4 to below ischial tuberosity
Fusion
MR fusion (if available)
Dose prescription
Primary
- 60Gy/20F prescribed to the PTV
45Gy/20# to node
Low Vol M1
- 55Gy/20Fx
- 60Gy/20Fx
- 36Gy/6Fx q1w (Stampede)
VMAT technique
9 days per fortnight
Volumes
- CTV60
○ Entire prostate
○ Consider proximal SVs
○ EPE + 5mm
- PTV60
○ CTV + anisotropic margin
- Post = 5mm
- Others = 7mm
Target Verification
Daily CBCT
OARs
Bladder
- V40 < 50%
- V60 < 5%
Rectum
- V30 < 60%
- V40 < 40%
- V50 < 30%
Femoral Heads
- V50<5
- V40<50
- Dmax < 50Gy
Small Bowel
- ALARA (avoid hotspots)
Spinal Cord/Cauda Equina
- Dmax < 45Gy
Avoid urethral hot spots
Describe the radiation technique for prostate HDR-BT Boost
HDR-BT Boost
Patients
1) Unfavourable-intermediate and high-risk, v. high
* T1-T3b, select T4; N0M0
* No preplan required (cw LDR)
Pre-simulation
MDT Discussion
Anaesthetic assessment
IPSS and urodynamics
- IPSS < 15
- Peak flow > 15mL/sec and residual <100mL
Assess prostate volume (ideally < 50cc)
- Consider neoadjuvant ADT
- No pubic arch interference
Consider rectal spacer gel
Absolute Contraindications:
- Limited LE
- Unacceptable operative risks
- Distant mets.
- Large TURP defects
- ATM
Relative CI:
- Previous pelvic RT
- TURP
- Large median lobe, gland >60cc > ADT, MLR
- IBD (fistula)
Simulation
- 2-3 hour procedure
- Consent
- GA and in dorsal lithotomy
- Prophylactic ABx (cephazolin)
- IDC inserted
- Transrectal US and volumetric acquisition
* Every 5mm
* Prostate and SV contoured
* Placement of needles determined
- Fiducial marker insertion (for EBRT), apex and base;
each side
- Insertion of 12-20 catheters under TRUS guidance
* Template guided
* Stepper to guide depth
* Peripheral loaded first, then central
- Further TRUS volumetric acquisition
- Mapping of catheters
- Treatment planning and optimisation
* Inverse planned based on dose constraints
* Further optimisation manually
- Treatment delivery
- Bladder irrigation
- Catheter removal & TOV
- Discharge if passes and well
Dose prescription
15Gy/1F to cover prostate
- D95% > 15Gy (100%)
- V150% < 40%
I-192 via afterloader
EBRT usually starts 2-3 weeks after brachy
Volumes
CTV = GTV - prostate +/- SV and any EPE
PTV = CTV +0-5mm
Target Verification
TRUS-guided
OARs
PTV (brachy + EBRT)
V100: 95-99% (usually 80-90% d/t decr coverage of base near bladder)
V90: 99-100%
V150 < 35%
V200 < 11%
Rectum
- Dmax < 75%
- V12Gy < 0.5cc
Urethra
- Dmax < 130%
- D10cc < 120%
What is the follow up after prostate treatment. Discuss the biochemical free survival and cancer specific survival for prostate cancer risk groups?
PSA nadir
* After RP about 3 wks
* After EBRT 2-3 yrs (can be up to 4-5yrs)
* After brachy 3-4 yrs
After local therapy
* Median time from biochemical failure to symptomatic DM= 8 years
* Median time to death is 5 years after developing DM
* For PSA doubling time <3months, 50% of patients will die at 6 years
Follow up
- Tailored to disease risk
- PSA and clinical sympotms
- Initially more frequently; every 3-6 months for the first two years
- Subsequently every 6 months from 2-5 years
- Then annually
What are the acute and late toxicities for prostate EBRT?
Comparison b/w RP and EBRT
EBRT worse
· Irritative bowel (urgency) 15%
· Late sexual dysfunction
· Risk bladder Ca: 1%/10yrs
· Rectal Ca: RR 1.26
RP worse
· Urinary incont, use of absorptive pads (2x ↑)
○ Up to 46%
· Early sex dysfunction (almost 100% postop)
· Similar: Irritative bladder
What are the pro/cons to LDR/HDR brachytherapy for prostate?
