Skin Flashcards
What is the epidemiology of NMSC?
BCC
I: Common, BCC comprises the majority of all NMSCs (75%)
900000 new diagnoses annually
A: Incidence increased with age
G: Male predominance up to 50, in older years incidence is similar.
R: White/Caucasian. Compared with people born in Aus, immigrants from UK show lower incidence rate (strong positive association between childhood sun exposure and lifetime risk of BCC). Rare in dark-skinned population.
Geographical location: Higher in areas with highest UV exposure
cSCC
I: Common, 271 per 10 000
A : Increasing age
G : Male predominance
R: White/Caucasian. Higher in people born in Aus.
Geographical: Higher in QLD, lowest in TAS
What is the aetiology for NMSC?
1) UV-B exposure–> Sunlight, artificial radiation (Tanning beds 75% increase lifetime risk of melanoma)
a. Photo damaged skin
b. Actinic keratosis
c. Telangiectasia
2) Advancing age
3) Ethnicity (fair-skinned) and skin type
a. Fitzpatrick phenotype
b. Light skin that burns or prone to freckles
c. Red hair and blue eyes
4) Immunosuppression
a. Iatrogenic (transplant)
b. Infective (e.g. HIV)
c. NHL, CLL
5) Other benign skin lesions
a. Chronic ulceration/trauma (Marjolin’s ulcer)
b. Bowen’s
c. Actinic keratosis
6) Environmental exposures
a. Arsenic
b. Smoking (MA evdience)
7) Personal history of NMSC
8) Genetic syndromes
a. Gorlin’s (basal cell naevus syndrome)
-Rare autosomal dominant disorder characterised by the development of multiple early-onset BCCs (mutations in PTCH1 TSG–> key regulator of the hedgehog signalling pathway)
b. Xeroderma pigmentosum
9) Chronic inflammation
a. Draining sinus 10 years Marjolin ulcer
What is Gorlin syndrome?
-‘Basal cell nauevus syndrome’
-<1 % of skin cancers attributed to Gorlins (1/30 000 incidence)
-Mutations in PTCH1 gene. Sonic hedgehog is the ligand for patched-1 receptor. Patched-1 blocks cell growth and division until Sonic Hedgehog is activated.
-PTCH1 is TSG, mutations result in uncontrolled/unchecked replication
-Autosomal dominant
-Second hit to develop BCC
Macrocephaly, skeletal abnormalities, early onset BCC
How does UV light induce carcinogenesis
Multi-step carcinogenic process which is driven by UV-mediated DNA damage
- Melanocytes are derived from the neural crest cells and can be found in dermis/epidermis. Melanin important role in giving skin pigment + filtering UV radiation
- Fitzpatrick scale is s semi-quantitative scale to describe skin colour, melanin level and sensitivity to UV
- UV falls between light and gamma rays on the spectrum
- UV C shortest wavelength, highest energy. UV A longest wavelength, lowers energy
- Sunburn/Acute UV exposure: Inflammatory response and increase cytokines. Keratinocytes are damaged--> activation of DNA repair mechanisms (p53 activation) and apoptosis - Protective/Sub-acute: Epidermal hyperkeratosis (epidermal growth factors to increase the thickness of the epidermis) _ adaptive melanisation 'tanning' - Oxidative damage: UV damage results in ROS, the base-excision repair pathway is the main pathway to repair free-radical DNA damage. - Nucleotide excision repair important pathway in repairing photodamage and bulky DNA lesions. In xeroderma pigmentosum (Rare UV hypersensitivity syndrome with homozygous defect in multiple common pathways that execute NER)
Tumour uv signature dna damage, c to t transitions on dna.
How does immunosuppression impact on skin cancer pathogenesis?
- NK cells and macrophages are cytotoxic, part of the innate immune system
- NK cells bind to cancer cells or virus infected cells and release cytotoxic granules that kill the cell
- T cells are part of the adaptive immune system, cytotoxic T cells can destroy cancer cells
- Prednisone bind to glucocorticoid receptors in cells, move to nucleus and block pro-inflammatory genes (e.g. NF kappa-B, A2) and inhibitors macrophages
- Azathioprine (solid organ transplants) inhibits pure synthesis, which is necessary for NK cells, T cells and B cells. Azothioprine inhibits the immune systems ability to repair UV DNA damage (Transplant patients that take azathioprine RR x2 SCC and 1.3x melanoma, compared with transplant patients who don’t take azathioprine therapy)
-TNF alpha inhibitors for rheumatological conditions, increased risk for non-melanoma skin cancers - In immunosuppressed patients:
Skin cancers grow more quickly, more likely to recur, metastasize and cause death
Oral B3 (nicotinamide) 500 mg BD reduces rate of skin cancer and acitinic keratosis by 23%
What genes are involved in cSCC and BCC carcinogenesis?
SCC
- Large number of genes with a large mutational burden
○ P53 mutation is an early event
○ NOTCH mutations facilitate HRAS carcinogenesis
- Chronic inflammation can also contribute to this
○ Trauma (e.g. burn)
○ HPV infection
BCC
- Multiple genes are implicated
○ SHH family are implicated in 90% of cases –> PTCH1 receptor (Gorlin’s)
§ PTCH TSG that blocks activation, until SHH signalling
○ P53 is also frequently implicated
Describe the histopathological features of Keratoacanthoma and SCC.
Ketatocanthoma
- Rapidly developing neoplasm that clinically & histologically mimics well diff SCC, but can regress spontaenously
- Macro: sun-exposed areas, flesh colour nodules with central keratin filled plug
- Micro: keratin filled cater surrounded by proiliferating epithelial cells, extend upward as a lip around the plug and downward into dermis
Squamous Cell Carcinoma
- Macroscopic ○ Pre-malignant in-situ lesions may appear as well-circumscribed erythematous and scaling plaques ○ Malignant lesions may be nodular with variable ulceration § Often raised nodular border with central ulceration ○ Variable amount of hyperkeratosis - Microscopic ○ Atypical keratinocytes, penetrating basement membrane → dermis, § Large cellular size, nuclear atypia, mitotic figures, intercellular bridges ○ Tumours with sheets of polygonal epithelial cells arranged in nests § Penetrates into the dermis ○ Evidence of keratinisation (keratin pearls, intercellular bridges) ○ Differentiation varies, such that no keratinisation may be evident § Well diff SCC→ atypical cells but with keratinisation present (keratin pearls) § Poorly diff SCC → keratinocytes anaplastic with little no no differentiation or keratinisation. Focal necrosis § Nuclear pleomorphism and mitoses also contribute to grading ○ May have PNI ~5-10% of excised SCCs but often asymptomatic ○ Variants § Low-risk □ Keratoacanthoma (WD) □ Verrucous carcinoma (minimal atypia) § High-risk □ Acantholytic (pseudoglandular, loss of intercellular adhesion) □ Spindle cell □ Desmoplastic i. Nb. Basaloid not skin, mucosal h+n or anal - Immunohistochemistry ○ POS = AE1/AE3, CK5/6, p40, p63 ○ NEG = CAM 5.2, CK20, S100, MelanA, SOX10
List the Subtypes of BCC and the macro, microscopic features of each. List the IHC for BCC
Immunohistochemistry
- POS = AE1/AE3 (epithelial origin- antibody cocktail for cytokeratin’s), p63 (Transcription factor, master regular of epidermal keratinocyte proliferation), BerEP4 (Epithelial cell adhesion molecule vs SCC), CAM5.2 (variable, low molecular weight keratin)
NEG = CK20, CK7, S100, MelanA, SOX10, CEA
What are the prognostic factors for NMSC?
Patient Factors
- Age and performance status
- Fitness for surgery
- Immunosuppression: Transplant, HIV, CLL
- Immunosuppressive Medications: Prednisone, azathioprine, TNF alpha inhibtors
Tumour Factors
- Histological subtypes
○ High risk BCC = morphoeic, infiltrative
- TNM stage
○ Size of primary
- Tumour location (H-zone of face & ear)
- Grade
- DOI (>5mm)
- PNI (especially >0.1mm diameter nerve OR symptomatic)
- LVI
- Multiplicity or recurrence
Treatment Factors
- R0 resection
Describe specific features of the work up for NMSC.
Full history, including:
- Lesion
○ Duration and rate of growth
○ Pain/bleeding/discharge
○ Neuropathic symptoms (incl paraesthesia)
- PMHx including contra-indications to RT
○ Immunosuppression
○ Consider Gorlin’s syndrome –> no RT
- Medications including contraindications to RT
- Social
○ Sun exposure
○ Particularly to establish ability to attend for fractionated therapy
○ Performance status
Examination:
- Characterise the primary lesion
○ Location and size
○ Depth and fixation
○ Ulceration
○ Borders
- Palpate for lymphadenopathy
- CN examination:
○ Paresis of facial muscles (motor CN7). Potential to spread to origin in midbrain base of skull destruction, meningeal carcinomatosis, parenchymal brain invasion.
○ CN V - sensory to scalp, face + tongue via 3 divisions. Emerges lateral to pons trigem ganglion 3 divisions
○ cavernous sinus Superior orbital fissure.
○ cavernous sinus foramen rotundum pterygopalatine fossa inferior orbital fissure infraorbital forarnen.
○ V3 foramen ovale.
○ CN Vll - motor to facial muscles, taste ant 2/3 tongue. Emerges from pons→ Internal auditory meatus→ bony facial canal→ stylomastoid foramen→parotid
Investigations
Need a biopsy prior to any treatment
Staging
- For cT1 cN0
○ No staging indicated
- For all others (i.e. cT2+ or cN+)
○ Minimum CT NCAP
○ Consider PET-CT (only funded if H+N primary)
If PNI is clinically suspected, consider MR
Describe the TNM Staging for NMSC
What factors guide your management decisions for NMSC?
I. Patient Factors:
○ Age: young should be treated with surgery due to longer life expectancy for RT late effects ie 2nd Ca, cosmesis
○ Co-morbidities: ability to undergo anaesthesia, although most are performed under LA, anti-coagulation. Skin specific: psoriasis, scleroderma, atropic skin (age, steroids), extensive contiguous actinic keratoses
○ Prior treatment history: prior RT may rule out re-irradiation
○ SHx: ability to care for wounds, dressings, apply topical treatments or compliance with therapy, daily attendance
○ Patient preferences
II. Tumour Factors: ○ Histologic Features: treat advanced lesions more aggressively & irregular borders with Moh’s to achieve clear margin ○ Site: CI to RT are hair-bearing areas or prone to trauma and poor healing- below knee, pretibial- esp. if PVD, varicosities, oedema. Ideal- surgery + graft+ strict bed rest. ○ CI to Sx include lip, nose, canthus for cosmesis ○ Size and depth of invasion: bone and cartilage invasion may be better served by surgery ○ Primary vs Recurrence: recurrence has worse prognosis, treat with surgery when possible & adjuvant RT III. Treatment Factors: ○ Cure & recurrence rates, SEs, cosmesis (younger pt, facial), cost, availability, physician expertise
Describe the non-radiotherapy options for NMSC.
I. Surgical Excision Preferred in young pts, and generally, where possible
○ A: margin control, one step procedure, good cosmesis if adequate skin for flap
○ D: invasive, may require GA, 2-step if margin+, disfiguring in functional or cosmetic sensitive areas (lip, eyelid, nose)
○ Surgical Margins: well-circumscribed BCC: 3mm; small (T1) & well-diff SCC: 4mm; larger lesions or poorly diff: 1cm
II. Moh’s Micrographic Surgery: Under LA, resect tumour + small rim of adjacent tissue; 100% of the margin is examined microscopically + mapped. Any +ve margins re-excised till clear. ○ A: achieves negative margin, high cure rate, removes minimum of normal tissue ○ D: expensive, prolonged, requires expertise ○ Indications: lesions with features that make clear margin difficult to obtain eg morpheic, recurrent, sensitive areas III. Curettage: lesion excised by curetting with 3-4mm margin from apparent tumour under LA ○ A: quick, single visit, good cosmesis, no sedation. Suitable for <1cm, superficial or nodular BCC, SCC-in-situ ○ D: margin not controlled, recurrence rates high with large lesions (>5mm) in high risk sites IV. Cryotherapy: compressed liquid nitrogen sprayed onto lesion until frozen then allowed to thaw & re-sprayed. Ice crystal formation and cell membrane disruption. Immediate erythema + oedema. Exudation (24h) + sloughing (7d). Healing 6w (face), 12w (trunk + extremities). ○ A: quick, cheap, single visit, non-invasive, excellent cosmesis, good for multiple lesions. Useful for AK or small/superficial BCC ○ D: not margin controlled, tendency to recur, some discomfort associated with procedure V. Topical Chemotherapy ○ Suitable for actinic keratoses, SCC in situ, superficial BCC. NOT for nodular BCC, deeply invasive or thick (b/c affects epidermis) § 5-FU (Efudix): Pyrimidine analogue, interferes with DNA synthesis by inhibiting thymidylate synthetase □ applied twice daily 6wks depending on clinical response (increase if no inflamm r/n) § Imiquimod (Aldara): immune response modifier, promotes apoptosis, circumvents anti-apoptotic pathways in Ca cells, activates langheran’s cells □ applied daily (BCC) or 2/week (AK) for 6-12 weeks. ○ A: non-invasive, good cosmesis. Clearance rates 70-80% ○ D: margin not controlled, may penetrate to depth required, SEs: burning, erythema, irritation, scabbing, (imiquimod – fatigue, flu-like, angioedema) VI. Photodynamic Therapy: contraindicated in thick lesions ○ Photosensitising porphyrin applied topically to lesion for hours, higher concentration & half-life within cancer cells ○ Area is then exposed to light (630nm), porphyrin becomes unstable & reactive causing cell death
What are the advantages, disadvantages and contraindications when comparing radiotherapy to surgery for NMSC?
- Radiotherapy vs. Surgery
Choice of Modality- Results of RT comparable to surgery
- Surgery is Rx of choice when lesions small + amenable to excision w/o sig morbidity.
- RT reserved minority of BCCs + SCCs w Mx problems for surgery where:
i) Surgery is not feasible
- Patient unfit for surgery
- Technically difficult to obtain margin clearance
- Patient refuses
- Anticoagulation problems
ii) Surgery will result in worse toxicity
- Functional/cosmetic morbidity unacceptable to pt + RT would have better cosmesis (e.g. loss of function lips/eyelids, rhinectomy, large tissue deficit, multiple lesions) - CI/relative CI to RT
○ CI: prior RT in field, RT hypersensitivity syndrome
○ Relative:
§ Young patients < 50-60yrs- 2nd malignancy
§ Poor blood supply, esp. pretibial, dorsum of hands (prone to trauma)- fully fractionate to aid healing
§ Sites- Hair bearing areas, overlying lacrimal gland, upper eyelid.
§ Advanced lesions invading bone/tendons. Def RT provide LC 50-75%, better LC if Surg+Adj RT
§ Cartilage involvement not a CI, but ↑ risk chondroradionecrosis. Avoided in large pinna lesions (or fully #ate for max cartilage repair)
What are the indications for treating BCC with Radiotherapy?
Radiotherapy for BCC:
I. Primary: limited role as surgery preferred but can be used for reasons mentioned above
II. Residual:
○ After RT: clinical resolution can take up to 4mths, confirm clinical persistence with biopsy & treat with excision
○ After Sx: Local recurrence after margin+ 33%-> re-excision or RT -> LR 9%
§ Other features high risk for recurrence: PNI, morphoeic, basosquamous, invasion of skeletal m/cartilage/bone
○ Review at MDT and consider further excision or adjuvant RT
III. Recurrent BCC
○ After definitive RT: 90% occur within 5y, treat with excision, recurrence after salvage Sx is 15%
○ After other treatment modalities: treat as for primary, may require wider resection or more aggressive RT
What are the indications for treating cSCC with Radiotherapy?
Primary:
○ solar keratosis & SCC in situ-> more readily treated by Sx, topical 5-FU or cryo
○ keratocanthoma: difficult to distinguish from SCC, excise if in doubt, if not in doubt RT can hasten resolution
○ invasive indications as above
II. Adjuvant RT to primary after surgical excision:
○ Absolute indications:
§ pT4
§ margin+ or close (if <2mm re-excision preferred otherwise 60Gy should achieve equivalent LC)
§ PNI (symptomatic or named nerve)
§ recurrent disease (when irradiating nodes for local failure within 12mths & primary is within 5cm from field)
○ Relative indications: ≥2 of:
§ pT2/3
§ >5mm depth
§ margin<5mm
§ poorly diff
§ extratumoural PNI of unnamed nerve
§ extratumoural LVSI
§ Immunosuppression
Adjuvant skin radiotherapy
○ Need a higher dose in general to compensate for tumour bed hypoxia.
When would you consider elective lymph node treatment in cutaneous SCC?
Incompletely excised SCC are at risk of higher LR and regional mets, up to 25-45% depending on the site. Adequate radiation margin 10-15mm
I. Elective Treatment of Regional Lymph Nodes in Primary Cutaneous SCC, N- ○ <5% of pt’s with primary skin SCC will develop LN mets ○ 5yr OS following nodal disease is markedly reduced to 40% ○ Pt’s are curable but are at increased risk of developing distant mets ○ Pt’s at high risk of LN mets due to features of primary should have elective nodal treatment (ENT) ○ Elective nodal treatment can be with lymphadenectomy or RT § Dose: 50Gy (undisrupted tissue) or 54Gy (surgically disrupted) IF Non-IMRT technique. IF IMRT technique, then 56Gy to disrupted and 54Gy (undisrupted) Risk factors for subclinical nodal mets: ENT may be of benefit when 1 or a combo of these are present: § DOI/thickness: >4-5mm or Clark 4+ (invasion of reticular dermis or subcutaneous tissues) § Size: tumours >2cm § Recurrent: 25-45% risk of LN spread § Site: ear & lip § Histology: poorly-diff, desmoplastic (aggressive variant with high propensity for regional mets) § PNI: increases regional & distant mets, ?LVI § Immunosuppression: higher risk of recurrent & metastatic SCC * Elective nodal irradiation based on location of the primary as per Porceddu below. Some centre opt to observe the nodal basin. In area where the first echelon node may be unclear, it may be more appropriate to observe the nodal regions rather than risk unnecessary toxicity from ENI.
How would you manage high risk NMSC?
Treatment of High-Risk NMSC
1) Surgical resection (preferred) a. Aim margins > 2mm b. Most will require adjuvant RT i. Absolute indications 1) T4 disease 2) N+ disease 3) Positive margins 4) Recurrent lesion (if no previous RT) ii. Usually if >/=2 high-risk features 1) T2/T3 2) DOI > 6mm 3) Poorly differentiated 4) Location (H-zone of face) 5) PNI (>0.1mm) 6) Multifocality or satellite lesions 7) LVI 2) Definitive RT a. Not the preferred approach May be considered in elderly patients not suitable for resection
How would you manage LN +ve cSCC?
1) Surgical resection of primary + nodal disease
a. Including parotidectomy or selective neck dissection if appropriate
i. ~25% regional failure without RT
a. Will require adjuvant RT to 60Gy to parotid bed
i. Virtually all cases (consider exclusion if single ipsilateral LN <3cm without ENE)
ii. If neck dissection negative no RT
iii. If no neck dissection then elective radiation (15% risk)
iv. No contralateral neck treatment.
Cervical Lymph Node Mets
* Surgery should be used if patient is fit and disease is resectable
* Post-op RT to 60Gy indicated IF >1LN+, ECE+, LN>3cm, SM+ or close <2mm, tumour spill, OR recurrence
* If there are LNs and RT is being used definitively, treat to 70Gy
* TROG 0501 POST trial: randomised to concurent carboplatin: no difference in 5 year recurrence or survival
* There is evidence in mucosal H&N SCC that adding chemo to RT in post-op RT is beneficial for DFS & OS
*
Axilla/Groin mets: Sx -> PORT IF >2LN+, ECE or LN>3cm
There is no evidence to support elective nodal irradiation
What are the systemic therapy options in cSCC?
What is the evidence to support definitive radiotherapy in NMSC?
- 2021 meta-analysis (Krauss, 2021)
○ Multiple retrospective series
○ 5 yr LC = 85-90%- Office-based radiation therapy for cutaneous carcinoma, 2007 -Hernandez-machin et al
○ Retrospective analysis of 604 BCCs and 106 SCC
○ Definitive radiotherapy with KV Photons
○ 5 year local control 94% BCC and 93% for SCC
○ 15 year local control 85% BCC and 78% for SCC
Predictors for local recurrence were size ≥10mm and tumour location in the nasolabial fold - Hypofractionated radiation treatment for BCC and SCC: A meta-analysis, 2018 -Zaorsky et al
○ Analysis of 21 studies assessing treatment with definitive RT, with primary endpoint of cosmesis
○ EBRT (9255 pts) and Brachytherapy (474 pts)
○ Median dose of 45Gy/11 fractions and median follow up of 3 years
Hypofractionated schedules produce similar cosmesis compared to conventional fractionation, for the same BED (alpha/beta 3)
- Office-based radiation therapy for cutaneous carcinoma, 2007 -Hernandez-machin et al
What is the evidence for adjuvant radiotherapy for NMSC?
- TROG 05.01 RCT (Porceddu, 2018)
○ Randomised high-risk cSCC to adjuvant RT +/- concurrent chemotherapy
○ 5-year LC = 85%
○ No benefit with chemotherapy (p=0.58)- LN + –> 2019 meta-analysis (Sahovaler, 2019)
○ 20 retrospective series + 1 RCT
Adjuvant RT improves OS and CSS
- LN + –> 2019 meta-analysis (Sahovaler, 2019)
Is there a role for concurrent chemotherapy when treating cSCC?
- TROG 05.01 RCT (Porceddu, 2018)
○ Randomised high-risk cSCC to adjuvant RT +/- concurrent chemotherapy
○ 5-year LC = 85%
○ No benefit with chemotherapy (p=0.58)
○ R0/1→ PORT 60-66 Gy ± Concurrent carboplatin.
○ This is the only reported prospective trial with a pre-defined RT protocol and a RT QA program.
○ There is no role for CCRT in SqCC. There is excellent FFLR in both arms.
Critique: Carboplatin was used, not cisplatin.
- 321 SqCC pts. ECE, ~50% SM+ 5-10%. PNI not in inclusion criteria. Mostly HR nodal.
○ HR SqCC: T3-4 H&N primary excluding nose, lip or in-transit nodal mets or HR nodal.
○ HR nodal: ECE, intra-parotid nodal dz, 2+ cervical nodes or >3 cm.
○ RT: PORT 60-66 Gy ± carboplatin AUC 2 q1w x6c.
- 2y FFLR ~88%, 5y FFLR ~85%.
- 5y DFS ~70%, 5y OS ~78%.
- Cetuximab may sometimes produce tumor regression in unresectable/metastatic SCC. May also consider H&N chemo such as CDDP ± 5-FU.
- SqCC: Typically no role for systemic therapy, but consider cetuximab or CDDP ± 5-FU.
What is the evidence for systemic management of BCC?
Unresectable BCC
Vismodegib and sonidegib - small molecule inhibitors of hedgehog pathway. Approved for non-surgery/RT candidates. ~30-65% response rate with median duration 7-10 mo.
* ERIVANCE [Sekulic JAAD ‘15, BMC ‘17]: Single arm phase II. Vismodegib.
○ 33 pts metastatic BCC with 30% response, 62 pts locally advanced BCC with 43% response.
§ Very low pCR 0-5%.
Response = decrease of at least 30% in externally visible or radiographic dimension of the lesion or complete resolution of ulceration.
What is the evidence for systemic treatment in metastatic cSCC?
Cemiplimab demonstrated to have 65% disease control and is approved in metastatic SCC
Cemiplimab is a highly protenant PD1 antibody
Approved on PBS for patients with metastatic or locally advanced cutaneous SCC in patients who are not candidates for curative surgery or RT
- Metastatic SqCC [Migden NEJM ‘18, Lanc Onc ‘20]: Phase I/II. Cemiplimab 3 mg/kg q2w (PD-1).
TBL: The PD-1 inhibitor cemiplimab is active in advanced cSCC.
Methodology: Most metastatic SqCC’s are immunosuppressed and often hypermutated.
○ 78 pts. Locally advanced or metastatic cutaneous SqCC. MFU 9 mo.
○ ORR nearly 50% with over half of these having a duration of response exceeding 6 mo.
○ Complete response in 13%, partial response in 31%.
○ G3-4 in 44%. Serious treatment emergent AEs in 29% of patients.
○ Durable disease response in 63% of patients (at least stable disease for at least 3.5 mo).
○ MPFS and MS have not been reached at 9 mo of followup.
Describe your radiotherapy technique for definitive management of NMSC with EBRT.
Alternative:
Brachytherapy
-Flat surface
-Alternative to SXRT in superficial tumours
-Selection of appropriate sized Valencia applicator at simulation
-36Gy/12F prescribed to 5mm depth
Describe your radiotherapy technique for adjuvant management of NMSC with VMAT.
Describe your radiotherapy technique for adjuvant management of NMSC with KV photons.
EviQ
* For a well-defined nodular BCC, a field margin of 0.5-1 cm beyond macroscopic disease or surgical site is usually adequate.
* For infiltrative/morphoeic BCC, a wider field margin of 1-1.5 cm is required to encompass surrounding subclinical spread.
There are numerous variations in defining an appropriate field margin, however for SCC, a field margin of 1-1.5 cm is required to encompass surrounding subclinical spread. T1/T2 SCC- 1-1.5cm radially and 0.5cm deep margin T3/T4 SCC- 1-1.5cm radially and 0.5-1cm deep margin * IF RF for LR, then use 2-3cm margin * Small electron fields (<4 cm) are associated with certain disadvantages (isodose constriction) when compared with superficial and orthovoltage treatment. Bowing of isodoses due to lateral electron scatter means this modality is less useful with tumours close to the eyes.
Margins
* Recent article in R+O (12) - looked at extent of microscopic disease after resection and made recommendations for margins:
○ < 2cm size BCC/SCC- use 1cm margin
○ > 2cm size BCC/SCC- use 1.5cm margin.
○ Consider 2cm for poorly diff/large (>3cm) SCC.
* Margins: ○ 0.5cm for small, well-defined BCC ○ 1cm for larger, superficial or ill-defined BCC & well-diff SCC 1.5-2cm for poorly diff or large (>3cm) SCC 1) Consider wax-coated lead for: a. Internal eye-shields (SXRT only - consider if 6meV electrons) b. Intraoral mandibular shields (SXRT and electrons) 2) Consider custom lead cut-out (collimation on skin) a. Especially if on face near eyes Minimum size of 4x4cm
What factors do you need to take into account with different radiation treatment modalities for treatment of skin cancers?
Modality: Factors to consider:
* Skin dose
* Dose at depth ie adequate coverage of tumour
* Dose to critical structures at depth: ie rate of dose drop-off
* Dose to critical structures lateral to PTV ie margins required for penumbra
* Dose to bone: higher in orthovoltage due to photoelectric effect
I. Superficial: 100-150kV
* suitable up to palpable tumour thickness of 5mm, max field diameter 10cm
* margin: 5mm for BCC, 10mm for large/superficial/ill-defined BCC, 15mm for SCC
* HVL (range 1-4mm Al) chosen to deliver 90% of dose to base of tumour
II. Orthovoltage: 150-300kV, can treat to max depth of 1.5cm
* Preferred when require narrow penumbra due to adjacent critical structure, or if irregular surface E inhomogeneity
* A: high skin dose, narrow penumbra, ease of collimation with lead cut-out on skin, ease of eye, alveolus and mucosal shielding. Shield is lead with wax to absorb backscatter
* D: high dose to underlying bone due to PEE, max depth 1.5cm, significant dose at depth
* HVL 0.5-1mm Cu to achieve 90% of surface dose at depth of tumour
III. Electrons: 6-15meV, max field size 25cm
* Preferred when require sparing of deeper structures due to rapid dose fall-off, more deeply infiltrating lesions (>1.5cm)
* Require wider margin due to penumbra (extra 1cm on above margins) and electron cut-out & bolus to ensure skin dose. Field size must be >4cm, need flat surface (obliquity < 30 degrees). Inhomogeneities (bone, air spaces) can be problematic although usually distal clinically. Eye protection more difficult than orthovoltage
-MeV: Dmax = E/4, D90% = E/3.2, D80% = E/2.8, D50% = E/2
IV. Megavoltage Photons: use for bony infiltration or where difficult to use KV/e- due to curvature of pt, penumbra issues. IMRT w 1cm bolus
Additional notes:
* Use bolus to bring skin dose up to 100%, ie 0.5-1.5cm depending on energy
* TLD: use when adjacent to critical structure (eg lens/cornea) or uncertainty re/ dosimetry (uneven surface, tissue inhomogeneity, junction)
* Do not hypofractionate >3Gy/#, esp for large lesions
* Use external eyeshield where required and internal eye shield when treating eyelid
* Pack the ear and nostril with vaz-gauze to flatten ala nasi & to provide shielding for underlying structures and from backscatter eg internal mouth shield wax coated to protect gingiva and minimize mucositis of lip
Keratin horns should be de-bulked
What are factors to consider when treating skin lesions on the nose and hands?
- Nose/ear- MV photons if bone/cartilage involved (generally larger tumour, KV ↑bone absorption). Wax coated lead shield in nasal cavity protects nose for DXRT/electrons. Tip of nose- consider E or parallel-opposed MV photons if unacceptable standoff.
- Dorsum hand- fully # as little subcut tissue (↑risk necrosis + ↓funcn). SXRT→ ↑ absorption in bone. Avoid exit dose on palmar aspect + no ↑absorption in bone.
How does PNI affect treatment of cSCC?
Perineural spread
* PNI is assoc with higher LR and worse OS, increase morbidities and mortality. Rarely salvageable if BOS recurrence
* Multiple retrospective studies showed Adj RT improve LC and decrease lethal BOS recurrence
* Incidental PNI has better outcome than symptomatic/gross PNI; 5yr LC 85 vs 55%
○ Microscopic PNI= histological finding of PNI > 0.1mm
○ Gross PNI= clinical or radiological evidence of PNI
* Dose:
○ IF Micro PNI, resected with neg margin -> 54Gy to the CN at risk (in column 2)
○ IF Gross PNI, resected with neg margin -> 60Gy to the CN at risk and inter nerve connections (in column 2 and 5)
IF Gross PNI, resected with pos margin on the nerve-> 66Gy in tumour bed and remaining course to 60Gy
**IF Micro PNI- cover the CN by anatomic proximity to BOS + relevant branches
**IF Gross PNI- cover the CN by anatomic proximity AND the elective CN via internerve connections
** Ensure to over 5mm CTV from the nerve
** For Malar Cheek, in the case of incidental PNI, they do not routinely cover the course of the nerve to the foramen rotundum
* PNI of CN should be considered for widefield RT to encompass potential neural pathway back to brainstem * Gross evidence of PNI on MRI should receive BoS resection + PORT to 50-60Gy Definitive RT may be attempted but is morbid & difficult to achieve doses of 70Gy close to brainstem
What are the side effects of skin radiotherapy?
a) Acute Effects
* Erythema (10-20Gy)
* Dry desquamation >20Gy
* Patchy then confluent Moist desquamation – epi cell death, exposing underlying dermis.
b) Late Effects
* Atrophy/fibrosis, telangiectasia
* Hypo/hyperpigmentation (larger #size→ ↑hypopigmentation)
* Skin appendage loss: epilation (>25Gy permanent), ↓sweating, ↓wax prodn (ear)
* Necrosis – <5% dt inability of residual epi to remain intact→ ulceration, commonly painful. Small may heal, but larger lesions →plastics repair w skin graft.
* ORN underlying bone, chondronecrosis (nose, ears)
Second malignancy
What is the expected local control after skin radiotherapy, with different T stages?
T1 LC = 95%
T2 LC = 85%
T3 LC = 60%
T4 LC = 50%
N+ OS = 40%
Describe the epidemiology for Melanoma.
Incidence (Australian statistics)
- 16900 cases in 2021
- 3rd most common malignancy
Median age 59
Slight male pre-dominance (1.5:1)
Geographical and ethnic disparity (increased in white skinned populations)
Immunosuppression
Moles>50
Presentation:
* Localised 84%
* Nodal 9%
Mets 4%
What are the risk factors for melanoma?
1) UV exposure
a. In addition to pale skin
2) Other benign skin lesions
a. Giant congenital naevus
b. Dysplastic naevi
3) Immunosuppression
4) Familial melanoma
a. CDKN2A gene (familial atypical multiple mole melanoma syndrome - FAMMMS)
b. CDK4 gene
5) Xeroderma pigmentosum
Impaired DNA repair
Describe the pathogenesis for melanoma.
Majority of cases are related to UV-induced carcinogenesis
- Can occur de-novo or within an existing naevus
Main oncogenic signalling pathways:
1) Mitogen activated protein kinase (MAPK) pathway (RAS / RAF / MEK / ERK)
2) PI3K / AKT / mTOR/ WNT / beta catenin signalling pathway
4 step model of carcinogenesis:
- Mitogenic driver mutation (BRAF)
- Escapes senescence (CDKN2A mutation)
- Overcoming apoptosis (p53)
- Immortalisation (TERT promoter mutation)
Growth typically occurs in two main phases
- Radial growth
Deep/vertical growth (potential for metastasis)
Describe the histopathological features of the following melanoma subtypes:
-Superficial spreading
-Lentigo maligna
Classic melanoma markers
- S100
- SOX10 (neural crest)
- MelanA (may be negative in desmoplastic)
- HMB45
Negative
- CKs
- P16 (loss of p16)
Describe the histopathological features of the following melanoma subtypes:
-Nodular melanoma
-Acral lentiginous
-Desmoplastic
Classic melanoma markers
- S100
- SOX10 (neural crest)
- MelanA (may be negative in desmoplastic)
- HMB45
Negative
- CKs
- P16 (loss of p16)
In relation to melanoma, describe the importance of BRAF, NRAS and cKIT.
BRAF
- 50% of melanomas with BRAF mutation, BRAF is a proto-oncogene
- Most common mutation in the BRAF gene is V600E (90%)
- Non-BRAF V600 mutations account 3-5% of melanomas
- BRAF critical role in the MAPK (RAS-RAF-MEK-ERK) pathway. Majority of BRAF mutations result in constitutive phosphorylation of MEK, independent of upstream activation. Results in promotion of cell growth and evasion of apoptosis
- Prior to targeted therapy, BRAF was a poor prognostic biomarker, patients tended to be younger, lack sun damage, trunk associated lesions and have worse OS compared with wild-type BRAF.
- BRAF V600 mutation is a predictive biomarker to targeted therapy
- daBRAFenib (BRAF inhibitor) and tRAMetinib (MEK inhibitor) in unresectable or metastatic melanoma
- Resistance: NRAS mutations and activation of the PI3K pathway
-BRAF also involved in -colorectal, NSCLC (adeno) and papillary thyroid cancers
NRAS
- RAS important role signal transduction pathway
- NRAS mutation in 20% of melanomas
- Poorer prognosis: Shorter time to progression, higher risk of CNS involvement
- Higher prevelance on arms and legs
cKIT
- KIT is a proto-oncogene encoding got the transmembrane receptor tyrosine kinase
- 3% of melanomas (Higher proportion in acral, mucosal and chronically sun damaged skin)
- C-kit activates downstream signalling pathways: MAPK and Pi3K pathways
- Often mutations in KIT almost never occur if BRAF or NRAS mutations present
- GIST, leukaemia, melanoma and lung cancer
- Tyrosine kinase inhibtors (TKIs) e.g. imatinib
What are the 2 ways to describe depth in melanoma?
Breslow depth = simple depth in mm
Clark level = discrete levels
- 1 = epidermis
- 2 = papillary dermis
- 3 = dermis
- 4 = reticular dermis
- 5 = subcut fat
What are the prognostic factors important in melanoma?
Patient Factors
- Age and performance status
- Gender (females are favourable)
- LDH high- worse prognosis
Tumour Factors
- Clinicopathological Type
○ Nodular has worst prognosis
- Pathological Features
○ DOI (Breslow) - higher risk of nodal+
○ Mitoses
○ Ulceration
○ Neurotropism
○ LVI
○ TILs & tumour regression (host immune reactivity)
○ Molecular mutations: BRAF, NRAS, cKIT
○ Microstatelitosis
- TNM stage
○ Nodal and distant metastases
○ Nodes: number, burden and size, ENE
- Location
○ Extremity is favourable
○ H+N or trunk is unfavourable
- In-transit metastases
Treatment Factors
- Margin of resection
- Sentinel node negative
What’s important in history and clinical examination for melanoma?
- Can occur anywhere on the skin surface, but predominate in sun-exposed areas
- Anatomic distribution:
- Caucasian male: Most common on face and back
- Caucasian female: Most common on face, shoulders and lower leg (knee to ankle)
- Lentigo maligna melanoma - sun-damaged areas, e.g. H&N
- Acatal lentiginous melanoma - palms, soles, nailbeds of darker skinned people
- 10% of patients present with LNs and no evidence of primary
- → better prognosis
- May have arisen from naevus cells in LN and when resected → nil residual disease
- Clinical features
- A: Asymmetry
- B: Border irregularities
- C: Colour variegation
- D: Diameter >5mm
- E: Enlargement
- F: Clinical features (itch / pain)
- G: Grown-ups / adults - new lesions in later life
- Changes in size, colour, shape, +/- inflammation, bleeding/crusting, sensory change
- Hx, exam, + dermoscopy in experienced hands
- Dermatoscopy (x10 magnification - 90% sensitive) evaluation
ABCD (asymmetric lesion, irregular border, irregular colour and differential structure - invading other structures)
How would you investigate melanoma?
Always biopsy the primary lesion.
Histopathology should have:
* Histological subtype
* Depth of invasion/ Breslow thickness
* PNI/neurotrophism
* LVI/ angiolymphatic invasion
* Molecular status (BRAF, PD-L1)
* Microsatellitosis (present or absent)
* Ulceration status (present or absent)
* Dermal mitotic rate (#/mm^2)
* Margins: deep and peripheral
pure desmoplasia if present
How would you stage melanoma?
Describe the management of Stage I+II Melanoma.
Management of primary:
* Surgical excision with adequate margins
○ Stage 2b consider adjuvant immunotherapy or observation (improved recurrence free survival)
Microscopic margins:
LM: for >3mm = 2-3% local recurrence, if <3mm =30%
* Definitive radiotherapy (60Gy/30F or 50Gy/20F) - considered non-curative ○ Indications: § Unresectable § Medically inoperable § Mucosal site § Lentigo maligna or lentigo maligna melanoma (50Gy/25F IF >5cm or 45Gy/10F if <5cm field size) * Adjuvant immunotherapy for locally advanced
Adjuvant RT to primary IF: (48Gy/20F ***** or 30Gy/5 twice weekly)
* Desmoplastic histology, esp. neurotropic
* Inadequate surgical margins, where further surgery difficult (e.g. Face, H&N area)
* Poor pathological response
* PNI/Extensive LVSI 90% relapse with in-transit / satellite lesions
* Recurrence
* Unresectable positive/close margin
* DOI >4mm, ulceration, satellosis
Evidence: No RCT data, but Ph2 TROG and MDACC showed improved LC with Adj PORT to High risk melanoma (>1 node, ENE, recurrent, tumour spill, Clark 4). For desmoplastic, 2 retrospective study (MIA and NCDB) showed improve OS and LC with Adj PORT
Describe the management for Stage III Melanoma.
Stage III (Clinically node positive) (PBS funded for Stage IIIB/C/D)
* Biopsy of node (FNA/excision), BRAF test.
- If node positive on biopsy and resectable then
○ -> Neoadjuvant immunotherapy (Pembrolizumab, Ipi/Nivo) improves EFS
§ Only neoadjuvant pembro on PBS in 2024
○ Can also proceed without neoadjuvant treatment (then would require adjuvant immunotherapy).
- WLE + nodal dissection
○ Overall 30% local recurrence, 50% metastasis
- Lymphoedema risk
○ Axilla 10%
○ Groin 10-15%
○ Pelvic +10%
- Adjuvant systemic therapy ○ (if had neoadjuvant doublet immuno and complete response or major response then no adjuvant therapy) ○ ONE YEAR DURATION then observation ○ PBS funded ○ Drug choice ® If BRAF mutant --> Dabrafenib / trametinib COMBI-AD: Improved OS/RFS cf. placebo. Use only if contraindications to immunotherapy and BRAFV600E mutant. § If BRAF wildtype --> single agent nivolumab, pembrolizumab –improved 3 year RFS 63 vs 50% □ Nivolumab x12 months CheckMate 238, improved 2yr RFS 63 vs. 50% cf. ipilimumab □ Pembrolizumab x 12 months KEYNOTE-054. Improved 3yr RFS 64 vs. 44% cf. placebo □ OS data immature but more durable response than BRAF Note: Note: There are no head to head comparison between BRAF/MEK therapy and anti-PDL1. However, BRAF/MEK inhib are more toxic than anti-PD1 therapy (G3 tox 40% vs 14%) and has higher discontinuation rate (26 vs <10%). - Satellite lesions(<2cm from primary)/ intransit mets (>2cm from primary) (stage IIIb/c/d): ○ Resectable § Neoadjuvant systemic therapy + Surgical resection + adjuvant therapy as per stage IIIb/c disease § Surgical resection + adjuvant therapy as per stage IIIb/c disease ○ Unresectable § Systemic therapy - preferred □ Immunotherapy □ BRAF/MEK inhibitors □ Topical DPCP (Diphencyprone) 40% overall response rate □ Pt sensitised (made allergic) to DPCP by applying to arm (contact dermatitis) □ Then applied to tumour field weekly for up to 3months. Cream strength titrated to g2 skin reaction. § Regional chemotherapy Should be followed by systemic immunotherapy □ Isolated limb perfusion ORR 56%, CR 22%; or □ Isolated limb infusion ORR 75%, CR 33% * RPA and Peter Mac units only * Intensive salvage treatment * 30min chemo in theatre. 1 week in hospital with swollen painful leg. Risk oedema, dead muscle, compartment syndrome. § Intralesional treatment (T-VEC) reserved for patients with injectable lesions in the setting of distant metastatic disease, ORR 17% □ Only IL2 and bleomycin available in Australia § Consider palliative RT if above not feasible (used infrequently) - Consider adjuvant RT to nodal basin after dissection ○ Regional control benefit 21% vs 36%. No survival benefit ○ 48Gy/20F (TROG trial) ○ Consider when risk factors § Extracapsular extension § Large nodal burden □ Parotid = 1+ LN □ Cervical = 2+ LN or >3cm size □ Axillary = 2+ LN or >4cm size □ Inguinofemoral = 3+ LN or >4cm size ○ Note this is questionable in the context of adjuvant immunotherapy/BRAF inhibition –use if patient has medical contraindications - If not well enough for a LN dissection ○ Ideally, aim for selective resection of macroscopic nodes ○ Completion RT to entire LN basin § 30Gy/6F twice per week
What is the management of Oligometastatic Melanoma?
- Oligometastatic disease (one or a very limited number of sites)
○ Resectable
§ Complete surgical resection of all disease
§ Adjuvant immunotherapy with induction ipi/nivo → maintenance nivolumab
○ Unresectable
§ Initial immunotherapy
§ Re-evaluate to determine suitability for resection of sites of residual disease
What is the management of Stage IV melanoma?
Stage IV
- Oligometastatic disease (one or a very limited number of sites)
○ Resectable
§ Complete surgical resection of all disease
§ Adjuvant immunotherapy with induction ipi/nivo → maintenance nivolumab
○ Unresectable
§ Initial immunotherapy
□ Palliative surg esp heart, gut (bleeding), brain surg/SRS if these mets are symptomatic and interfering with sysyemic
§ Re-evaluate to determine suitability for resection of sites of residual disease
- All other patients ○ Immunotherapy (preferred in all cases, even if BRAF mutants) § Combination immunotherapy □ Induction ipi/nivo (3-weekly x 4 doses)→ maintenance nivolumab (3-weekly) CheckMate 067 exploratory analysis: superior response rate and PFS (5yr PFS 36 vs. 29% SS) cf. nivolumab (5yr OS 52 vs. 44%, NS) * ORR 60% * Subgroup –particular benefit effective for BRAF mutants. □ Nivo + Relatlimab (LAG3 inhib) * Better than nivo alone, less toxic than ipi/nivo * G3 toxicity 20% (vs ipi/novo 60%) § PD-L1 inhibitor monotherapy: less toxicity □ Nivolumab CheckMate 066 improved OS cf. dacarbazine (mOS 38 vs, 11 months, 3yr OS 51 vs. 22%); or * ORR 40% □ Pembrolizumab for up to 2 years Keynote-006: improved OS (mOS 33 vs. 16 months; 5yr OS 39 vs. 31%) and mPFS (8.4 vs. 3.4 months) cf. ipilimumab. G≥3 toxicity 17% Ipilimumab (anti-CTLA-4 inhibitor) monotherapy → inferior to PD-L1: ○ Targeted therapy: * BRAFV600E mutation: □ Sequencing trial ipi/Nivo before BRAF had better overall survival § □ Dabrafenib + trametinib COMBI-D: cf. dabrafenib alone improved mPFS 11 vs. 9 months; improved mOS 25 vs. 19 months; improved objective response rate (68 vs. 55%) * Quicker onset of response * Not as durable as immunotherapy but still 20% long term response □ Encorafenib + Binimetinib □ Venmurafenib + cobimetinib § KIT mutation: Imatinib - Systemic therapy ○ Chemo has <10-15% response rate § Chemotherapy- minimal role now due to small response rate and median duration of effect 4-6mo. No OS benefit
What is the management of mucosal head and neck melanoma?
- Commonly nasal cavity, paranasal sinus, oral (hard palate, upper alveolus). Oral cavity often node positive 25%
* AJCC 8th edition staging - begins at stage III to reflect poor prognosis
* Resectable:
▪ WLE - LR rates high (30-80%) despite aggressive surgery
▪ Neck dissection for oral cavity (not sinonasal)
▪ + adjuvant RT as high rates of local recurrence.
® Improved local control with RT in retrospective case series
◊ No impact on OS
* Unresectable:
▪ Definitive RT
® Tumour control rates 60-85% in case series
® Optimal dose/fractionation not established
* Prognosis
○ Poor
○ 5yr OS 12-30%
What is the management of ocular melanoma?
○ ○ Uveal: ~95% of ocular melanomas
* Most common primary intraocular malignancy in adults, but ocular mets are more likely. GNAQ mutation –growth. BAP 1 mutation -malignant
* Can arise from any part of the uveal tract (iris, ciliary body, choroid)
□ Plaque brachytherapy with 125Iodine
® Dose rate 0.7-1Gy/h (Tx 4-7 days)
® Dose: 85Gy to the tumour apex or 5mm from internal surface of the sclera with 2mm margin around the tumour
® Not suitable if Thickness >5mm, blind painful eye, no light perception
□ SBRT
§ Dose/fractionation: Typically 50Gy/5#, PTV= GTV+1mm, have the pt focus on a red LED dot on the mounted camera, which tracks the eye movement and is gated to the treatment machine.. If the eye movement certain amount, the camera software stop the beam
□ Enucleation
§ Retrospective studies did not show a survival advantage over RT
§ QOL outcomes appear similar to RT
§ Generally reserved for patients who would not be expected to have a favourable outcome with RT
□ Large tumours
□ Marked extrascleral extension
□ Neovascular glaucoma
□ Extensive retinal detachment
□ Poor visual potential
□ Select patients who prefer enucleation
* Prognosis
* LC 95% with local treatment; BUT
* DM in 50%
What is the evidence for SLNBx in Melanoma?
- MSLT-I
○ 2001 patients randomised to SLNB or observation
○ SLNB is prognostic
§ Intermediate (1.2-3.5mm) and thick melanomas had worse survival if SNB positive
§ SLN management improves DFS in all melanoma patients. DMFS and CSS are also improved in intermediate thickness.
§ In thin melanoma, too few events to make conclusions
○ Did not show significant survival benefit with ∴ not considered therapeutic- MSLT-II
○ 1934 patients with positive SLNB
§ Randomised to LND or observation (US surveillance)
○ Outcomes
§ No change to melanoma-specific survival with upfront dissection
§ LND improves regional control and provides prognostic information, but has no benefit in CSS
§ Higher rate of lymphoedema if proceeding with dissection - DeCOG-SLT (2006-2014) [Leiter JCO ‘19]: SLNB(+)→ ± Completion LND.
TBL: Long-term results of the German DeCOG-SLT trial confirm that there is no improvement in OS, DMFS, or RFS with a completion lymph node dissection for melanoma.
There is an approximate 25% incidence of positive NSLNs after (+) SLNB. There is an improvement in regional recurrence.
○ 483 pts. Cutaneous melanoma of the trunk and extremities
○ MVA demonstrated tumor thickness > 2mm most impactful on DMFS, OS and RFS. 1 mm SLN mattered less.
○ G3+ toxicity 13% (mostly lymphedema).
- MSLT-II
In a Nutshell:
- Everyone with intermediate (>1mm) or thick melanoma (>4mm) should get SLNbx as MLTS I showed that SLNBx provided important prognostication and help decide on nodal mx. Improves DMFS and DSS esp in those with intermediate risk
- Once the SLNbx is Pos, The SOC is LND. However if SLNB <1mm then the option is for either immediate LND or obs with USS surveillance as per MSLTII trial and DeCOG. As immediate LND only provide LC benefit but no CSS, and increase risk of lymphaedema significantly
What would be your adjuvant radiotherapy technique in melanoma management for the primary and nodes?
What are the options for radiotherapy fractionation in definitive, adjuvant, regional and palliative management of melanoma?
What is the 5year OS for melanoma by stage?
What is the staging for Merkle cell carcinoma?
Is there a role for chemotherapy in Merkle cell carcinoma?
Adjuvant- controversial, but doesnt seem to have any benefit UNLESS male, T>3cm and pos margin.
- Rationale
§ ≥10mm primary
§ LN+ (62%)
§ residual dx post-sx
§ surgical recurrence
§ recurrence outside XRT field.
○ High metastatic potential of MCC
○ Responsive to CT
○ Improve OS
- Disadvantages
○ ↑XRT toxicity- esp. skin + CT toxicity- esp. neutropaenia
○ Short-lived responses 3-4mo, but clinically meaningful
Retrospective data showed incr OS if Pos margin, T >3cm, or male
What is the 5yr OS for Merkle cell carcinoma by stage?
OUTCOMES:
- Median Survival: Stage I/II – 40mo; Stage III – 13mo; Stage IV – 9mo
- Local Control with addition of RT
○ N0 50% -> 90%, 3yr OS 70-80%
○ N+ ve 50% -> 70-80%, 3yr OS 50%
○ RT alone in field control 75%, LRC 40%, 5yr OS 30-40%
- Possibly increase in DFS, OS- conflicting data
- Distant relapse in 50-60%
3yr OS 30% if DM
What is the staging for Kaposi sarcoma?
No widespread staging system
Generally use a qualitative approach
- Type of lesion (macule stage, nodular stage, etc.)
- Location and extent
Compare and contrast the biological behaviour and growth patterns of Merkel cell carcinoma and malignant melanoma. (3 marks)
