Metastatic Flashcards
Describe the Bilsky grading for spinal tumours
Discuss indications and contraindications for spinal SBRT
Indications:
- Local control
- Pain improvement
- Suitable for patients with favourable prognosis, controlled or controllable burden of distease with limited metastatic disease
- Indications:
○ Oligometastatic disease
○ Spinal mets from solit tumour
○ Symptomatic ≥2 pain score
○ Bilsky epidural disease G0-1
○ SINS ≤ 12
○ Oligoprogression in presence of controlled systemic disease
Contra-indications:
- Neurologically symptomatic spinal cord or cauda equina compression
○ In the form of motor, bowel or bladder dysfunction
- SINS score >12
- Treatment to ≥4 consecutive vertebral segments
Discuss the evidence for spine SBRT
OS benefit from Phase III trials lacking
There is no advantage to SABR over single dose conventional radiotherapy for pain response in oligometastatic bone disease
PAIN:
SC.24
Sahgal et al. 2021 (SC.24)
○ 229 pt EBRT 20Gy/5Fx vs,. SABR 24Gy/2Fx
○ 6.7 months median follow-up
○ 6 m OS: 73% cEBRT vs. 77% SABR
○ 3 complete pain repsonse 14 vs. 35% (20% higher)
○ Compression Fx lower 17 vs 11%, simialr G2
Palma et al 2020
- Phase II cEBRT 20/5 or 30/10 vs. SABR 20/1, 30/3, 35/5
- 51 months medial FU
- OS EBRT 28 months vs SABR 50 months
- 5 yr OS 18 vs. 42%
- mPFS 5.4 vs. 11.6 mo
Sprave et al 2018
- Compared 30Gy/10Fx
- No cghange in OS
- SABR significantly lower pain relieft at 6 months
- pain values decreased faster within this period in the SABR arm
SABR-COMET was a phase two study that demonstrated survival benefit for radical treatment of oligometastases, including spine metastases
LOCAL CONTROL
SC.24
- Zeng et al
○ Risk of local failure at 6, 12, 24 months
○ 6 months 3 vs 11%
○ 12 months 6.1 vs. 28.4%
○ 24 months 14.8 vs,. 35.6%
○ cEBRT and presence of paraspinal mass/epidural ext predicted local failure
Large single insititution experience 24Gy/2Fx
- Lopcal control 1 year 90%, 2 years 80%
TOXICITY:
- Acute: similar flare, fatigue, dysphagia, nausea; higher dermatitis with EBRT
- Late:
○ Vertebral compression Fx higher with single fraction, higher SINS score (7-12), mean time to fracture 3.3 months
○ Myelopathy (from Sahgal)
§ 24Gy/2Fx: a point maximum dose of 12.5, 14.6, 15.7, 16.4 and 17.0 Gy yielded an estimated risk of 1, 2, 3, 4 and 5% of RM, respectively.
Discuss the radiotherapy technique for spine SBRT
RT:
- Presim: review imaging, discussion SABR MDT (if available)
- Sim:
○ Supine
○ near-rigid immobiisation to aid reproducibility and restrict CTV/PTV margins
○ If treating above T5 = TPM and neck support, arms by side
○ If below: vaccum device, wingboard, knee syupports, ankle stocks; arms above head
○ Consider 4DCT for thoracic lesions - due to changes in path length caused by diaphragm and organ dosimetry
○ 2mm axial slices (at least), 10cm above and below and include whole organ OARs
○ Fusion (or sim) with MRI
§ delineation of the spinal cord, cauda equina/thecal sac, and the target volume
§ If MRI contraindicated then CT myelogram of at least 1 VB above and below
§ T1 (weighted) MRI +/- Gadolinium and T2 (weighted) MRI
- Dose/Px
○ 24Gy in 2 Fx
○ 16-24Gy in 1Fx
○ 24-30 in 3 Fx
○ 30-35Gy in 5Fx
- Target volume objectives:
○ GTV D100 >100 PD
○ GTV D0.1cc ≤140% PD (should fall within GTV)
○ Review near minimum dose in GTV at spinal cord (SC) interface to ensure no cold spots within GTV
○ PTV:
§ PTV coverage will be compromised to meet organs at risk (OAR) tolerance, including SC
§ D80-90 =100%
- Target volumes:
○ GTV = all availabnle imaging, include epidural and paraspinal extension
○ CTV
§ Include bony epxnasion to account for subclinical spread
§ Include abnormal marrow signal suspicious for microscopic invasion
○ PTV= 2-3mm margin
Toxicities:
- Acute: Dermatitis, oesophagitits, N/V, pain flare, fatigue
- Late: skin/fibrosis, vertebral compression fraction=, higher if >20Gy per fraction, peak 2-3 months after
○ Radiation myelpathy, plexopathy, esophagieal stricture/stenosis
OARs
eviQ guidelines
Dependent on clinical situation
Push of 17Gy if say anterior no epidural
19 if need to push dose, concerns for relapse etc
Image verification
- AP or PA kV initially with sup, inf
- Then CBCT
- Then verification CBCT - 1mm and 1degree tolerance
- Then mid treatment (prior to next arc)
Describe the management of bone metastasis.
Mirels score for consideration of prophylactic fixation
* Estimates fracture risk at 6 month's after radiation * >= 8 consider Radiotherapy * No sig difference in pain control, neuropathic pain, pain flare, pathological Fx, overall response rates and cord compression between SF vs MF * Chow et al 2019 MA, 29 trials, 5617 patients * Surgery – goals * Reduce pain * Improve functionality * Prevent risk of impending fracture
Post operative radiotherapy
* Lack of high level evidence and conflicting data benefits of post op RT for non-spinal bony mets
* All retrospective, no prospective
* Uncertainty regarding optimal field design
* Ideally cover full surgical implant – minimise risk of tumour progression
* Improved pain control, reduced risk of local recurrence
* Low toxicity,
* Townsend J Clin Oncol 2012
○ 35 pt PORT vs. 29 Surgery alone
○ Probabiliy of normal use of extremity 53% vs. 11%
○ Further procedures more frequent with surgery alone (3 vs. 15%)
○ Improved OS
○ Doses 30-45Gy, 14 days post op
* Rosen et al
○ Cover entire hardware: 12% versus 21% at one year, and 16% versus 41% at two years
* Review 2023 Cancers
○ 6 retrospective studies and other reviews
○ 20/5 or 30/10
○ Complete coverage of hardware = improved local control
○ Reduced time to PORT leads to decreased local recurrence
○ Improved functional status
* Dose/Technique
○ Ranges from 8/1 -30 to 45/10
○ Japanese survey 50% use 30Gy/10Fx
○ Felt longer course = improved LC
○ Also demonstrated by Rosen et al
○ ESTRO-ACROP guidelines – spinal decompression
▪ Randomised data benefit of 30Gy/10Fx as standard for PORT spinal
▪ Similar to spine setting – typically residual untreated disease following stabilisation, as not focusing on resection of disease
○ = 30Gy/10Fx
○ Shorter if poor performance status, minimise delays to systemic, travel
○ 8Gy/1Fx higher incidence of re-irradiation
* RT Volumes
○ Generally APPA
○ Cover entire resection cavity
○ Extend RT field to inlcude all hardware and any visible disease
○ Margin 1.5 -2cm around areas of interest -
▪ Accounts for penumbra + planning uncertainties (PTV)
○ MLCs to shield out
* Timing
○ Increased risk of LR with increasing time
○ Balance between prompt RT and wound healing
Long bone SBRT (femur, humerus)
Limited data -100pt retrospective study
90% local control, 10% fracture risk
35gy/5 most recommended
Describe the evidence for symptomatic bone palliative RT
Evidence for symptomatic bone palliative radiotherapy
* TROG96.05 (Roos RTO ’05)
○ Treatment of symptomatic bone metastasis causing pain with neuropathic components.
○ 8Gy/1# vs 20Gy/5#
○ Relatively small trend towards non-inferiority with 8Gy/1# vs 20Gy/5#
▪ Pain response at 2 months 53 vs 61% (p=0.16). Complete pain response ~25%
○ Time to treatment failure 2.4 vs 3.7 months (p=0.06)
* RTOG9714 (Hartsell JNCI ’05)
○ 8Gy/1# vs 30Gy/10# for treatment of symptomatic bone metastasis
○ Around 2/3 patients have response with 8Gy/1# or 30Gy/10#
○ 8Gy/1# appears to be equivalent to 30Gy/10#
* Meta-analysis for bone metastasis (Chow JCO ’12)
○ Single vs multifaction RT for symptomatic bone metastasis
○ There were no significant differences between single fraction and multifaction in regards to overall pain relief
○ There was a 2.6x increased retreat event rate with single fraction RT
If pain relief alone - data does not support SABR
Takes longer to start treatment
Resource intenseive
Requires MRI
More costly
However: good for local control (eg. Oligomet) SABR COMET
Describe the definitions for oligometastatic, oligorecurrent, oligoprogressive, and oligo persistent disease.
Oligometastatic = denovo
Oligorecurrent =<3 metastasis new after initial treatment
Oligoprogression = control of mets, but small no. progress (in context of systemic therapy)
- Aquired resistance, not in all, but some
Oligopersistence
In up front phase, response, but some persist
Describe the evidence for oligometastatic directed therapy
SABR-COMET
- 99 pt, controlled primary, 1-5 met lesions (lung, breast, CRC, prostate)
- Randomised to SOC or SOC +SABR
- Benefit for OS and PFS
○ 5 year OS 42% vs 18%
- Subset - took prostate out and still showed benefit
- Required surveillance and sequential salvage SABSR for oligoprogression
SABR-COMET3 + SABR-COMET 10 (4-10 mets)
Evidence for SBRT metachronous Oligomet disease
Higher LC and longterm control rates
- Many studies, MA and systematic review have showed that use of SBRT for met lung and liver met, and spinal/bone met, have provided high LC 80-95%. High LC rate translate into longterm disease stability for many patients
- Multiple Ph1 and ph 2 and HYTEC studies have shown that SBRT can provide high ablative dose to oligomet to provide high local disease control with 2-3 yr LC 70-95%, and improve OS comparable to surgery.
- However Median survival for hepatic mets in ACUP is poorer than others (6-8mo vs 12-18mo range
Survival Benefit:
- Many trials have demonstrated that aggressive treatment to oligometastatic have resulted in improved OS and PFS esp for treatment sensitive disease. Eg. Oligomet CRC have demonstrated
- SABR COMET demonstrated addition of SABR to standard therapy improved Os and PDS in oligomet disease.
Favourable tox profile and QoL improvement
- SBRT allows delivery of high ablating doses in small areas, esp in target adjacent to criticila structures, hence sparing severe toxicities when compared to standard treatment.
- Many SABR trials have showed that this technique is safe with minimal acute toxicities
- Given the high dose, SBRt is effective in improving symptoms management form oligo met. TROG study compared SBRT to conventional RT and demonstrated that pain response seem better with SBRT with lower LF rate
Delay chemotherapy/ systemic treatment
- Obsevational and SBRT studies have shown that timing of systemic therapy initiation in pt receving SABR are delayed hence delaying potential acute tox from pt and less disruption to their daily lives
Prostate RCT showed that SBRT in oligomet can delay or prevent the use of ADT, hence decrease the tox associated from ADT use.
What factors should be considered when selecting oligometastatic patients for local therapy?
Discuss the evidence for oligometastatic therapy in prostate cancer and lung cancer
Prostate Cancer: metastasis directed therapy to delay any systemic therapy
- STOMP
○ Good local control
○ Asymptomatic BC with up to 3 mets
○ Castrate senisitve
○ Difference in ADT free survival 5 years 8 vs 34%
○ 5 yr castrate resistance improved
- ORIOLE
○ Primary controlled with definitive
○ 1-3 mets on conventional
○ ADT included
○ Difference in bPFS
○ Most patients had PETs but werent included in protocol
○ If ablate all of mets - then better
- MA
○ Miszczyk 2024
○ 22 studies with 1137 patients
- 36% will progress with oligometastatic disease
Repeat treatments (retrospective registry) -25-40%
Prognosis of repeat course is similar to first course
Lung Cancer: consolidate therapy AFTER initial systemic therapy
- GOMEZ
○ Oligomet NSCLC
○ First line systemic therapy without prgression
○ 1-3 mets after
○ Repeat local therapy showed improved survival HR 0.44 vs 0.3
- SINDAS
○ Denovo oligomet,EGFR meutant
○ 1-5 mets
○ Started erlotinib
○ SBRT to all knonwn mets
○ RT to primary and nodal
○ PFS:superior LC, superior PFS, superiro median OS
○ Symptomatic pneumoints 32.1 G1-2, 7.4% G3-4
- CURB
Describe the epidemiology for malignancy of unknown primary
Epidemiology
* Unknown primary 2% of all invasive cancer presentations
* Carcinoma most common
○ Adenocarcinoma 70%
§ Lung, breast, upper Gi (pancreas, biliary), kidney and prostate
§ Demographics
□ Female w suspicion for breast ca, males s suspicion for prostate cancer
□ Heavy smoking history for lung ca, East-Asian Females non smoker
□ East-Asian BG for upper GI
○ SCC 5%
§ Head and neck - smoking and EtOH history
§ Lung or oesophageal- smoking and EtOH history
§ Ano-genital- Asian migrants, indigenous (cervical cancer)
§ Skin- Older, Caucasian, Australian, immunosuppressed
* Other: Neuroendocrine or poorly differentiated
○ Neuroendocrine 1%
§ Lung, bowel, SBO, UNP, Pancreas and stomach
§ Lung neuroendocrine typically younger age at diagnosis
§ Rare, affects all genders and races
○ Poorly Differentiated 20-25%
Describe the cytological, histological and IHC features for cancer of unknown primary
Cytological, histological and IHC features
* First get large biopsy material if possible
4 go-to IHC stains for UNP
* CK7
○ Epithelial marker, carcinoma origin
* CK 20
○ Epithelial marker, carcinoma origin
* TTF-1
○ Thyroid transcription factor 1, preferentially expressed in thyroid, lung and brain
○ Rule out between lung primary/metastases
○ Positive staining in Lung, Thyroid and brain
○ Negative staining: Breast, GI, SCC, Prostate
* CDX-2
○ Nuclear transcription factor for intestinal epithelium
○ Fairly specific for GI origin adenocarcinomas
○ Negative staining for breast and prostate adenocarcinom
Special Considerations/Additional Stains based on clinical correlation
* PSA- prostate
* Thyroglobulin and TTF1- Thyroid
* Melanocytic: S100, HMB45, MelanA
* Lymphoid: CD19/20 (B cells), CD15/30 (Hodgkin’s), CD 3 (T cells)
* Neuroendocrine: Synaptophysin, chromogranin, CD 56/7
Common situations strongly suggestive of primary site
CRC: CK7-/CK 20 + or CDX2 +
Lung adeno: CK7+/CK20-, TTF 1 positive
Prostate: PSA
Adenocarcinoma
* Most commonly lung, pancreas, hepatobiliary, kidney (two thirds of cases in autopsy series)
* Breast and prostate less common despite being the most common cancers in men and women respectively
* Perform PSA, ER/PR, CK7 and CK20
* CK7+/CK20-: above the diaphragm (plus female gynae - uterus, ovary)
* CK7-/CK20+: below the diaphragm CRC (plus Merkel)
* CK7+/CK20+: peridiaphragm - stomach, pancreas, biliary tree and urothelium
* CK7-/CK20-: simple visceral epithelia (except colon): liver, kidney, prostate, neuroendocrine
Role of Tumour markers
* Traditional tumour markers not very useful, unless significantly elevated.
* CEA, Ca 19.9, Ca 15.3, Ca 125, AFP, PSA
Describe history and work up for cancer of unknown primary
- Main tumours critical not to miss:
- M+F → lymphoma, myeloma, thyroid, GCT
- M → prostate, testis
- F → breast, ovary
- History
- Current symptoms, systemic symptoms (fever, weight loss, night sweats, anorexia, malaise)
- Systems review → skin, H&N, lung, UGI, LGI, GU, gynae, B symptoms (lymphoma)
- Risk factors → smoking, hepatitis, previous malignancy, FHx
- Previous screening tests → MMG, US, PAP, PSA, colonoscopy
- Examination
- As per systems review
- Investigations
- Biopsy - essential to establish tissue diagnosis (unless contraindicated - e.g. pheochromocytoma)
- Bloods - FBC, EUC, LFT, LDH
- Serum tumour markers
- PSA → prostate
- αFP, βHCG → GCT
- Others less useful as either diagnostic or prognostic tests. Serial measurement may be useful in following response to therapy for individual tumours.
- CEA
- CA125 → ovary, papillary serous endometrium
- CA19.9 → upper GI
- CA15.3 → breast
- Serum EPG, β2 microglobulin → myeloma
- Thyroglobulin - papillary/follicular thyroid
- Calcitonin - medullary thyroid
- Imaging
- CT CAP
- MMG, USS breast, MRI breast in women with axillayr lymphadenopathy compatible with metastatic breast cancer
- PET - isolated neck LN Useful in specific clinical settings, but in most patietns does not add substantially to the information obtained by CT scans.
- Others as indicated:
- Urine cytology, urinalysis, cystoscopy
- FOBT
- Gastroscopy, colonoscopy
- Bronchoscopy
- Testicular ultrasound
Discuss prognostic features for cancer of unknown primary
Metastatic | CUP | 2.2 | Prognostic factors
* Number of organs involved (burden of disease)
* Performance status
* Age
* Elevated LDH
* Ability to identify primary site
* Lymphoma, GCT
* Normal ALP, albumin, LN enlargement as presentation , administration of treatment
Describe the management of cancer of unknown primary for certain situations.
- A few special circumstances of CUP which are favourable → consider specific treatment
- Female with adenocarcinoma involving axillary LN
- Female with papillary adenocarcinoma of peritoneal cavity
- Poorly differentiated carcinoma, midline distribution
- Poorly differentiated neuroendocrine carcinoma
- SCC involving cervical LNs
- Adenocarcinoma with colon cancer profile (CK7-, CK20+)
- Isolated inguinal LN (SCC)
- One small, potentially resectable tumour
- Female with axillary lymphadenopathy alone
- Likely breast cancer with undetectable primary
- BUT also consider skin, lung, lymphoma
- Treat as per stage II breast cancer → ALNDx + modified radical mastectomy/RT +/- adjuvant chemotherapy / hormones
- Breast treated with either mastectomy or RT even if no breast primary found
- Female with peritoneal carcinomatosis
- Treat as per stage III ovarian cancer → surgical debulking + carboplatin / paclitaxel
- Poorly differentiated carcinoma with midline distribution
- Typically young male (<50 yo) with retroperitoneal or mediastinal disease with rapid growth
- Treat with chemotherapy for GCT
- Neuroendocrine carcinoma
- Poorly differentiated tumours, often responsive to cisplatin and etoposide, like SCLC
- Well-differentiated, consider octreotide (for carcinoid), sunitinib or everolimus (pancreatic or small intestine) based on clinical suspicion
- SCC of mid to high cervical LNs
- 3 important primary sites
○ Mucosal H&N
○ Skin
○ Thyroid - Workup:
○ Panendoscopy and blind biopsies of NPX, BoT and pyriform fossa and bilateral tonsillectomy
○ CT H&N +/- MRI and PET scan
○ Consider thyroid USS - Even if no primary identified → warrants aggressive Rx of neck with ipsilateral surgery and bilateral PORT to neck as well as RT to potential primary sites → oropharynx, hypopharynx +/- nasopharynx
- May exclude NPX if examined carefully and blind biopsy negative
- ⇒ RNSH approach in PET era (likelihood of emergent primary felt to be significantly lower than in older series) ⇒ neck dissection +/- adjuvant RT. No treatment of primary site.
- Poorly differentiated carcinoma
- Empiric chemotherapy - carboplatin/paclitaxel, carboplatin/gemcitabine, gemcitabine/irinotecan, oxaliplatin/irinotecan
- Controversial whether improves OS, evidence contradictory
- Others
- SCC over lower neck/SCF → ? lung
- SCC inguinal LN → ?anal, vulva, vagina, cervix, penile, skin
- Predominantly blastic lesions in men → trial of ADT even if PSA normal
- Malignant ascites (non-papillary serous adenocarcinoma) → ?GIT , esp. if mucin producing or signet ring cells
- Empirical Chemotherapy
- Cisplatin-based plus taxane, gemcitabine or irinotecan
- Median OS 7-10 months
- 2yr OS 20-25%
- RNSH - typically carboplatin plus gemcitabine or taxol (2016)
