Skin Cancer — Board Review Summary

PART I — KERATINOCYTE CARCINOMA: EARLY-STAGE BCC AND SCC

BCC vs SCC: The High-Yield Contrast

FeatureBCCSCC
FrequencyMore commonLess common
Clinical tempoMonths to yearsWeeks to months
Metastatic risk<<<1%~4%
Relative radiosensitivityMore radiosensitiveLess radiosensitive
Most effective systemic therapy classHedgehog pathway inhibitors (vismodegib, sonidegib)PD-1 inhibitors (cemiplimab, pembrolizumab)

Subtype Matters

HistologyLower-risk subtypesHigher-risk subtypes
BCCNodular, superficial, pigmented, fibroepithelial, infundibulocysticMicronodular, infiltrating, sclerosing / morphoeic, sarcomatoid
SCCKeratoacanthoma, verrucousSpindle cell, acantholytic, adenosquamous, clear cell

Randomized RT Data for Early Keratinocyte Carcinoma

TrialDiseaseDose / techniqueOutcome
Hall 1986BCC35 Gy / 5, 41.5 Gy / 7, or 37.5 Gy / 10; 130 kVAbout 4% recurrence at 2y
Landthaler 1989BCC60 Gy / 20 or 48 Gy / 12; 50 kVAbout 10% and 8% recurrence at 3y+
Landthaler 1989SCC60 Gy / 20 or 48 Gy / 12; 50 kVAbout 4% and 15% recurrence at 3y+
Avril 1997BCCIr-192 brachy 60-70 Gy; 50 kV 36-40 Gy / 2; 250 kV 60 Gy / 15-304y recurrence about 9%, 7%, and 5%
Garcia-Martin 2011BCC40-70 Gy / 10-15; 50-100 kV0% recurrence at 2y in a small series
The slide set highlights that external-beam teletherapy remains the most common RT approach for early skin cancer, but brachytherapy is resurging. In Avril, the smallest tumors selected for interstitial brachytherapy paradoxically had the highest recurrence rate, so the choice of modality should not be reduced to "small lesion = brachy" without context.

How to Define the Target

GTV: relies on clinical assessment, biopsy-site confirmation, and inclusion of the entire visible skin abnormality.
CTV: depends on tumor size, histology, and subtype. General range is 5-15 mm.
Larger CTVs are favored when: tumor is >2 cm, histology is SCC, or the subtype is high risk.
Emerging skin imaging may further refine early-stage skin target delineation, but clinical examination remains the foundation.

PART II — HIGH-RISK TO LOCALLY ADVANCED, RESECTABLE cSCC

Primary-Site Local Recurrence Risk After Margin-Negative Excision

Risk factorObserved riskHigh-yield interpretation
Deep invasion12% if thickness >6 mmDepth is a major local and regional risk driver
Desmoplasia / PNI / LVI24% if desmoplasticDesmoplastic and neurotropic features are especially concerning

Adjuvant RT After Excision of High-Risk Primary cSCC

In the Barker/Yan/Kim/Ma series of 52 high-risk primary cSCC treated with surgery plus adjuvant RT, only 2 local recurrences were seen. Both recurred early, both were margin-positive, and both had received <60 Gy adjuvantly (56 Gy and 53 Gy). That is a practical board-style reminder that very high-risk disease may not be adequately covered by lower postoperative doses.

Ongoing Randomized Adjuvant RT Trial for Resected High-Risk SCC

EligibilityDose optionsBoard takeaway
R0 resected cSCC, high-risk by BWH staging (T2b/T3; at least 2 risk factors)45 Gy / 10, 55 Gy / 20, or 60 Gy / 30High-risk features include PNI ≥0.1 mm, depth beyond subcutaneous fat (>6 mm), diameter ≥2 cm, poor differentiation, or bone erosion

Can Genomics Refine Adjuvant RT Selection?

DecisionDx-SCC is a 40-gene expression profile with retrospective metastasis-risk estimates of roughly 5% (class 1), 20% (class 2A), and 60% (class 2B). Prospective validation is still pending. The slide set frames this as promising for risk stratification, but not yet something to treat as definitive standard-setting evidence.

Risk Factors for Regional Nodal Recurrence

FactorRisk
Thickness 2-6 mmAbout 4%
Thickness >6 mmAbout 16%
ImmunosuppressionAbout 16%
Diameter ≤2 cmAbout 2%
Diameter 2-5 cmAbout 8%
Diameter >5 cmAbout 20%
Ear primaryAbout 10%

Standard for Resectable High-Risk T3/4 or N+ cSCC

Standard approach: surgery plus adjuvant RT.
High-risk primary features: cartilage, bone, or muscle invasion; >4 cm tumor; in-transit metastases.
High-risk nodal features: 1 parotid node, >1 cervical node, node >3 cm, or extranodal extension.

Porceddu JCO 2018

Weekly adjuvant carboplatin did not improve outcomes in resected high-risk cSCC treated with postoperative RT. This is a classic "do not reflexively add chemotherapy" board point.

Neoadjuvant Immunotherapy in Resectable cSCC

Gross 2022/2023 showed promising pathologic responses with neoadjuvant immunotherapy, but the lecture explicitly notes that it remains unclear how much adjuvant RT contributes once strong pathologic response is achieved. NRG HN014 is testing neoadjuvant immunotherapy against the standard approach. In the protocol shown on the slide, postoperative RT indications are based on final pathology, and doses are 56.1-63 Gy / 30 fx; elective nodal irradiation is encouraged for lateralized tumors.

PART III — LOCALLY ADVANCED, UNRESECTABLE KERATINOCYTE CARCINOMA

RT Alone for Unresectable Advanced Primary Disease

SeriesPopulation / doseKey result
USC / Florida / Oklahoma / MSKCC retrospective seriesAdvanced T3/4 primaries; mean or median dose roughly 55-75 GyRT controls about half of advanced primary cSCC overall; BCC controls better than SCC

Prospective Chemoradiation for Unresectable cSCC

Nottage et al enrolled 21 patients with locally advanced unresectable cSCC. Patients received concurrent platinum with 70 Gy / 35 fx. Grade 3-4 adverse events occurred in 47%. Complete response at 3 months was seen in 10/19 assessable patients (52.6%), and response predicted disease-free survival.

Prospective RT + Immunotherapy Studies

StudyApproachBoard-style takeaway
UNSCARRed63-66 Gy / 30 + avelumab, then avelumabUnresectable stage I-IVA cSCC; formal prospective safety/efficacy evaluation
RAMPARTNeoadjuvant cemiplimab, then response-adapted RT 50-70 Gy / 25-35 + IOReflects response-adapted integration of RT and PD-1 blockade
CRIOPlatinum CRT + IO; RT 54-70 Gy / 35Explores trimodality systemic intensification in unresectable disease

Unresectable BCC: Vismodegib + RT

The phase II Barker 2024 study in unresectable head-and-neck BCC combined vismodegib with RT and achieved high response rates and durable local control. The lecture frames this as a real example where combined targeted therapy plus RT may help selected patients.
Bottom line for unresectable keratinocyte carcinoma: RT remains an important local therapy, but in modern practice the most interesting frontier is RT plus biologic therapy rather than simply escalating RT alone. Histology matters: unresectable BCC and unresectable cSCC are not interchangeable diseases.

PART IV — MELANOMA

Lentigo Maligna

TreatmentDiagnosisReported local recurrence
SurgeryLM5.6-15.4%
SurgeryLMM0-15.5%
RTLM1.6-38%
RTLMM7.4-15.6%
Hong 2025 randomized unresectable lentigo maligna to imiquimod vs RT. The RT arm used a median dose of 54 Gy in a median of 25 fractions, with 47% treated using superficial RT and 45% with electrons. The lecture takeaway is pragmatic: consider imiquimod or radiotherapy for unresectable lentigo maligna.
Reflectance confocal microscopy (RCM) may help both define extent and assess response in lentigo maligna. The slide example showed RT of 57.5 Gy / 23 fx using 100 kV with serial RCM response assessment.

Neurotropic Melanoma

  • Rare: <5% of cutaneous melanomas.
  • Typical phenotype: older patients, head and neck, frequently desmoplastic.
  • Biology: melanoma cells track along or into neural structures; local recurrence risk is high.
  • Desmoplasia: present in about 72% of neurotropic cases.
RTN2 / Pinkham 2024 randomized patients after narrow-margin excision to adjuvant RT vs observation. The study closed early at 50 of 100 planned. The deck's practical takeaway is conservative but clear: consider adjuvant primary-site RT after pathologic narrow-margin excision of neurotropic melanoma.

Adjuvant Nodal Basin RT After Lymphadenectomy for cN+ Melanoma

TrialDoseMain resultKey toxicity
Mayo Clinic50 Gy / 28 fxNo OS signal; historical support for regional controlMild lymphedema 22%, severe 7%
TROG 02.0148 Gy / 20 fxRegional recurrence 18% vs 33% at 5y; no OS benefitAcute grade 3-4 15%; late grade 2-4 high
Ukrainian NCI50-55 Gy / 25-28 fx + IFNa2bImproved 3y RFS/OS in a smaller studySignificant interferon toxicity
Board pearl: nodal basin RT after lymphadenectomy in melanoma is mainly a regional control strategy, not a survival strategy. The toxicity cost, especially lymphedema, matters.

Neoadjuvant Immunotherapy Era in Regionally Advanced Melanoma

StudyRegimenpCRGrade 3+ AE
Amaria 2018Nivolumab25%8%
Amaria 2018Nivolumab + ipilimumab45%73%
Huang 2019Pembrolizumab19%10%
OPACINNivolumab + ipilimumab39%90%
OPACIN-NeoNivo + ipi variants23-57%20-50%
PRADONivolumab + ipilimumab49%22%
SWOG 1801Peri-op pembrolizumabNot pCR-focusedSupports neoadjuvant-first strategy
NADINA 2024Nivolumab + ipilimumab59%30%
High-yield synthesis: multi-drug neoadjuvant regimens generally increase pathologic response but also increase toxicity. SWOG1801 supports the principle that neoadjuvant therapy can outperform purely adjuvant sequencing, and NADINA reinforces the prognostic importance of major pathologic response.

Where Does RT Fit After Neoadjuvant Immunotherapy?

In PRADO and OpACIN-neo, adjuvant RT was used at physician discretion mainly for pathologic non-response. The slide takeaway is direct: consider adjuvant nodal basin RT for high-risk lymphatic metastases after surgery and pathologic non-response.

Oligometastatic Melanoma

StudyDesignTakeaway
Spaas JAMA Oncol 2023Anti-PD1/PD-L1 +/- non-comprehensive SBRT 24 Gy / 3 fx to 1-3 lesionsNo significant overall benefit; melanoma subgroup had the largest relative signal, but RT to modulate immunotherapy remains investigational
Comprehensive metastatectomy / ablative seriesSelected oligometastatic patients treated to all known diseaseLong median survivals reported in carefully selected patients
AXIOMRandomized 2:1; immunotherapy-naive, extracranial melanoma with ≤5 mets; SBRT to all lesions with BED 48 GyImportant ongoing test of comprehensive metastasis-directed therapy + ICI

PART V — MERKEL CELL CARCINOMA

Localized Primary MCC: Surgery vs Definitive RT

ApproachEvidenceTakeaway
Wide excisionMSK series of 393 patients; local recurrence risk 2%Excellent local therapy; local-only failures were salvaged
Definitive primary-tumor RT13/171 crude local recurrences = 7.6%Also highly effective for selected patients
Board pearl: for the primary site, surgery or RT monotherapy can both be effective in MCC. Choice depends on anatomy, morbidity, function, and patient-specific considerations.

Metastatic / Unresectable MCC After Progression on Anti-PD1/L1

In a randomized study of ipi/nivo +/- non-comprehensive SBRT, MCC patients received 24 Gy / 3 fx to at least one but not all metastases. The overall response rate for second-line ipi/nivo was about 31% and was not improved by SBRT. All irradiated lesions were locally controlled, but this does not support limited-site SBRT as a reliable systemic immune modulator in this setting.

CARTA Phase II

FeatureCARTA
PopulationMetastatic or unresectable MCC progressing after first-line anti-PD1/L1
StrategyComprehensive ablative RT + avelumab
N17
ORR71% (95% CI 44-90)
Median follow-up18 months
Median PFS7 months
Median OSNot reached
Grade 3-4 treatment-related AEs12%
Why CARTA is interesting: the slide set strongly suggests that comprehensive ablative RT plus immunotherapy may be more promising in refractory MCC than partial, non-comprehensive "immunogenic" SBRT to a subset of lesions.

CROSS-CUTTING HIGH-YIELD POINTS

  • BCC vs SCC: BCC is more common, slower, rarely metastatic, and more radiosensitive; SCC metastasizes more often and is more PD-1 sensitive systemically.
  • Early-stage skin RT works well, with randomized-series recurrence rates often in the single digits.
  • CTV for early skin cancer is clinical: usually 5-15 mm, larger for SCC, lesions >2 cm, and high-risk subtypes.
  • High-risk local recurrence factors in cSCC: depth >6 mm, desmoplasia, PNI, LVI.
  • High-risk regional recurrence factors in cSCC: thickness, immunosuppression, larger diameter, and ear primary.
  • Resectable high-risk cSCC: surgery + adjuvant RT is standard; weekly carboplatin did not improve outcomes.
  • Ongoing adjuvant RT cSCC dose options: 45 Gy / 10, 55 Gy / 20, 60 Gy / 30.
  • NRG HN014: response-adapted neoadjuvant immunotherapy strategy in cSCC; postoperative RT per final pathology, typically 56.1-63 Gy / 30.
  • Unresectable cSCC: RT alone controls only about half of very advanced primaries; combined systemic strategies are the modern area of interest.
  • Nottage chemoRT: 70 Gy / 35 with platinum gave 47% grade 3-4 toxicity and CR in about half of assessable patients.
  • Unresectable BCC: vismodegib + RT is a real combined-modality option in selected head-and-neck cases.
  • Lentigo maligna: RT is a reasonable nonsurgical option; randomized data now support considering RT or imiquimod in unresectable cases.
  • Neurotropic melanoma: rare, locally aggressive, usually head and neck, often desmoplastic; consider adjuvant RT after narrow-margin excision.
  • Melanoma nodal basin RT: improves regional control, not OS; lymphedema cost is real.
  • Neoadjuvant melanoma IO: more drugs generally means higher pCR and higher toxicity.
  • SWOG1801 and NADINA: major reasons neoadjuvant sequencing is now central in regionally advanced melanoma.
  • Adjuvant RT after neoadjuvant melanoma IO: mainly consider in pathologic non-response / persistently high-risk nodal disease.
  • Oligometastatic melanoma: comprehensive treatment of all sites is conceptually different from single-site "immune-priming" SBRT; the latter remains investigational.
  • MCC primary site: surgery or RT monotherapy can both be highly effective.
  • Refractory metastatic MCC: limited-site SBRT did not clearly enhance ipi/nivo, whereas comprehensive ablative RT + avelumab in CARTA showed a strong response signal.

CONSOLIDATED DOSE TABLE

Clinical settingDose / regimenWhy it matters
Early BCC (Hall)35 Gy / 5, 41.5 Gy / 7, 37.5 Gy / 10Classic kV randomized experience
Early BCC / SCC (Landthaler)60 Gy / 20 or 48 Gy / 12High-yield historical skin RT fractionation
Early BCC (Avril, brachy)65-75 Gy / 5-7 dInterstitial brachy comparator
Early BCC (Avril, superficial RT)36-40 Gy / 2Very hypofractionated orthovoltage option
Early BCC (Avril, external beam)60-65 Gy / 15-35External-beam teletherapy benchmark
Ongoing adjuvant cSCC trial45 Gy / 10, 55 Gy / 20, 60 Gy / 30Modern postoperative dose options under study
NRG HN014 adjuvant RT56.1-63 Gy / 30Response-adapted postoperative cSCC framework
Unresectable cSCC chemoRT70 Gy / 35Prospective platinum chemoRT regimen
UNSCARRed63-66 Gy / 30RT + avelumab for unresectable cSCC
RAMPART50-70 Gy / 25-35Response-adapted cemiplimab + RT strategy
CRIO54-70 Gy / 35ChemoRT + IO intensification
Lentigo maligna (Hong 2025)54 Gy median / 25 fx medianRandomized nonsurgical RT benchmark
Lentigo maligna example (Hibler)57.5 Gy / 23Illustrative 100 kV regimen with RCM follow-up
Melanoma nodal basin RT (Mayo)50 Gy / 28Historical randomized nodal RT regimen
Melanoma nodal basin RT (TROG 02.01)48 Gy / 20Modern high-yield melanoma nodal-basin trial dose
Melanoma immunotherapy-modulation SBRT24 Gy / 3Non-comprehensive SBRT remains investigational
MCC partial-site SBRT24 Gy / 3Locally effective, not clearly systemically synergistic

KEY LANDMARK TRIALS (memorize)

Trial / studyDiseaseOne-line takeaway
Hall 1986Early BCCHistorical randomized kV RT data showing strong local control
Landthaler 1989Early BCC / SCC60/20 and 48/12 are classic skin RT fractionations
Avril 1997Early BCCBrachy and teletherapy produced similarly good control; modality choice matters
Garcia-Martin 2011Early periocular BCCSmall modern orthovoltage series with excellent short-term control
Brantsch 2008cSCC risk stratificationDepth, size, ear site, and immunosuppression drive recurrence risk
Yan / Kim / Ma / Barker 2019High-risk primary cSCCAdjuvant RT produced low local recurrence; sub-60 Gy failures stand out
Porceddu JCO 2018High-risk resected cSCCAdding weekly carboplatin to postoperative RT did not help
Gross 2022 / 2023Neoadjuvant cSCC immunotherapyMajor pathologic responses are achievable, but the exact role of adjuvant RT remains unsettled
Nottage 2017Unresectable cSCC70 Gy / 35 platinum chemoRT is feasible but toxic
Barker JCO 2024Unresectable BCCVismodegib + RT produced high response and durable local control
Hong 2025Lentigo malignaRandomized data support RT as a valid nonsurgical option
RTN2 / Pinkham 2024Neurotropic melanomaSupports considering adjuvant RT after narrow-margin excision
TROG 02.01Node-positive melanoma after dissectionNodal basin RT improves regional control, not survival, and increases toxicity
SWOG 1801Regionally advanced melanomaNeoadjuvant pembrolizumab sequencing beat purely adjuvant sequencing
NADINA 2024Regionally advanced melanomaMajor pathologic response after neoadjuvant nivo/ipi predicts excellent outcomes
PRADO / OpACIN-neoMelanoma response-adapted therapyAdjuvant RT is mainly considered for pathologic non-response
Spaas 2023Oligometastatic melanomaSingle-site immunomodulatory SBRT remains investigational
AXIOMExtracranial oligometastatic melanomaOngoing randomized test of SBRT to all lesions + ICI
Kavanagh 2025Primary MCCWide excision gave only 2% local recurrence in a large MSK series
Gunaratne 2017Primary MCC definitive RTDefinitive RT alone can achieve strong primary-site control
Kim 2023Metastatic MCC after ICIPartial-site SBRT did not clearly enhance ipi/nivo, although irradiated sites were controlled
CARTARefractory metastatic MCCComprehensive ablative RT + avelumab showed a strong response signal with manageable toxicity