Keratinocyte cancer

8.3 Radiotherapy for cutaneous squamous cell carcinoma

From Cancer Guidelines Wiki

Unless stated otherwise, tumour stage is according to the American Joint Committee on Cancer (AJCC) cancer staging manual 8th edition[1] and Union for International Cancer Control (UICC) TNM classification of malignant tumours 8th edition.[2]


Radiotherapy (RT) has been used for treating cutaneous squamous cell carcinoma (cSCC) for over a century. It is an efficacious alternative treatment for primary untreated cSCC in patients when surgery is disadvantageous:

  • when surgery is not feasible (e.g. in patients unfit for surgery, including those with significant coagulation risk)
  • when the patient declines surgery
  • when surgery will cause cosmetic or functional morbidity unacceptable to the patient (e.g. nasectomy, loss of function of lips or eyelids, large tissue deficits, multiple lesions).

Human papillomavirus infection, which is a risk factor for cSCC, may affect radiosensitivity.[3]

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In which patients with cutaneous squamous cell carcinoma does a radiotherapy modality achieve equal or better outcomes than conventional surgery?

A systematic review was undertaken to identify groups of patients with cSCC in whom a radiotherapy modality achieves outcomes equal to or better than those achieved with conventional surgery.

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

Systematic review evidence

Twenty-nine studies were identified that assessed outcomes in patients treated with RT for cSCC and met search criteria.[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] These include one study representing level II evidence,[30] 12 level III-2 evidence,[9][10][15][17][20][21][23][24][26][27][28][32] and 16 level IV.[4][5][6][7] [8][11][12][13][14][16][19][19][22][25][29][31]

All studies were at high risk of bias.

Participants were mainly patients in whom surgery was unsuitable. Many different RT techniques were used, including different types of external-beam radiotherapy (EBRT) and brachytherapy.

The single prospective randomised controlled trial (RCT)[30] was a phase III Trans-Tasman Radiation Oncology Group (TROG) study comparing postoperative concurrent chemoradiotherapy with postoperative radiotherapy in patients with high-risk cSCC of the head and neck. The remainder were retrospective studies.


Twenty-one studies reported survival outcomes in patients with cSCC treated with EBRT or brachytherapy, alone or in comparison to other treatment modalities.[4][5][6][14][9][10][11][15][8][17][18][19][20][21][22][23][27][28][30][31][32] Thirteen studies reported overall survival[5][10][11][15][17][19][20][21][28][27][30][31][32]

Two studies reported overall survival for patients treated with RT or chemoradiotherapy:

  • An Australian RCT[30] reported 5-year follow-up outcomes in patients treated with postoperative ERBT or chemoradiotherapy. There was no statistically significant difference between the EBRT and chemoradiotherapy groups for overall survival (76% versus 79%; p=0.86) or disease-free survival (67% versus 73%; p=0.44).
  • A US study[32] reported no significant difference in median overall survival time between patients treated by adjuvant RT (41.3 months) or adjuvant chemoradiotherapy (40.3 months). However, median recurrence-free survival time was significantly longer for patients treated with adjuvant chemoradiotherapy than those treated with adjuvant RT (40.3 months versus 15.4 months; hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.13–0.78, p=0.01).[32]

Five studies reported overall survival for patients who underwent surgery, surgery and adjuvant RT, or RT alone:

  • An Australian study[20] reported 5-year survival in a large (n=217) cohort of patients with cSCC of the lip treated by surgery alone (n=89), RT alone (n=89), or adjuvant RT (n=26). Overall survival was highest (83%) in those treated by EBRT alone, followed by surgery alone (79%) and adjuvant RT (68%).[20] Relapse-free survival was highest (92%) in those treated by adjuvant RT, followed by RT alone (87%), and then surgery alone (51%).[20]
  • A Greek study[28] compared 5-year overall survival between patients treated by surgery, adjuvant RT, or RT alone. The highest survival (83%) was reported in those who had surgery only (n=160), followed by the adjuvant RT group (66%), and then the RT only group (40%).
  • A small (n=36) US study[27] reported no statistically significant difference in 5-year overall survival or cause-specific survival rates between patients treated by RT with or without Mohs micrographic surgery.
  • An Australian study[15] reported survival outcomes in a small cohort of patients treated with EBRT definitively or as adjuvant therapy. At 1-, 2-, and 5-year follow-up there were no statistically significant differences in overall survival or relapse-free survival rates. Overall survival rates were numerically higher for the adjuvant RT group.[15]
  • A small (n=75) cohort study reported significantly higher 3- and 5-year disease-specific survival rates in patients treated by RT alone, compared with those treated with adjuvant RT (p=0.003).[4]
  • Another small (n=42) cohort study reported no significant difference in 5-year disease-free survival in patients treated with RT or adjuvant RT (90% versus 69%).[23]

Two studies reported overall survival for patients treated with different RT doses:

  • A large (n=385) Italian cohort study[21] reported significantly higher median overall survival time (months) among patients treated with 45 Gy RT than those treated with 36.75 Gy, at a median follow-up of 65.5 months. However, median disease-free survival time did not differ significantly between groups.[21]
  • A Japanese study[17] reported 5-year overall survival in a small cohort of 38 patients treated with EBRT <56 Gy (75% survival) or ≥56 Gy RT (83.3% survival).

Four other studies reported survival outcomes for patients with cSCC treated with EBRT:

  • An Australian study reported 2- and 5-year recurrence-free survival of 91% and 90%, respectively, in a cohort (n=93) of patients treated with RT only.[22]
  • A US study[19] reported survival outcomes for a cohort of 70 patients treated by EBRT and followed for a median of 13.2 months. Overall survival was 61.4% and recurrence-free survival was 57.1%.
  • Another study by the same investigators reported recurrence-free survival of 61.9% at median follow-up of 12 months in patients.[18]
  • A large (n=180) cohort study reported 1-, 2-, 5-, and 10-year relapse free survival of 95.8%, 91.5%, 86.2%, and 80.4%, respectively.[14]

Five studies reported overall survival of patients with cSCC treated with brachytherapy:

  • A French study[31] reported 5-year overall survival of 80% and disease-free survival of 82% in a cohort (n=86) of patients treated by brachytherapy.
  • A Spanish cohort study of 121 patients treated with brachytherapy for cSCC of the lip[5] reported 89.5% overall survival, 97.5% cause-specific survival, and 86.6%,disease-specific survival, at follow-up of up to 15 years.
  • A large (n=204) Spanish study[10] compared survival rates between 99 patients treated by low-dose-rate (LDR) brachytherapy and 104 patients treated by high-dose-rate (HDR) brachytherapy, followed for a median of 51–63 months. Overall survival rates were 76.7% and 64.4%, respectively, while cause-specific survival rates were 95.9% and 94.2%, respectively (nonsignificant differences).
  • A US study[11] reported 2- and 3-years overall survival in a cohort of 40 patients treated by HDR brachytherapy. Overall survival rates were 89% and 79%, after 2- and 3-year follow-up, respectively.
  • A very small (n=10) cohort study[6] reported disease-free survival of 90% following treatment by HDR brachytherapy, after a median of 39.5 months follow-up.

Recurrence rates

Seven studies reported recurrence rates.[6][7][12][16][20][21][26]

An cohort Australian study (n=204) reported 5-year follow-up recurrence rates of 43% for patients who underwent surgery only, 15% for those who received RT only, and 6% for those who received adjuvant RT.[20]

Two studies that compared RT doses[21][26] reported no significant difference in recurrence rates between groups after median follow-up of 65.5 months[21] and 42.8 months.[26]

In four other studies in which all patients received RT monotherapy, recurrence rates were:

  • 1.8% at 2-year follow-up and 5.8% at 5-year recurrence rates of and respectively, in a large cohort of 861 patients treated with EBRT[16]
  • 10% in a case series of 10 patients treated with HDR brachytherapy and followed for a median of 39.5 months[7]
  • 4.8% in a large cohort of 273 patients treated with HDR brachytherapy and followed for a median of 25 months.[12]

Control rates

Six studies reported control rates.[5][10][11][13][23][24]

Reported control rates at 5 years were above 85% in all studies that reported this outcome.[5][10][11][13][23][24]

Local control rates for patients treated with RT were:

  • 88% in a cohort of 25 patients treated with HDR brachytherapy, with 30 months median follow-up[11]
  • 86% and 89%, respectively, in a cohort of 42 patients treated with RT only, or adjuvant RT, at follow-up of 5 years[23]
  • 90% local control rate in a cohort of 121 patients treated with brachytherapy and followed for 15 years[5]
  • 94.9% and 95.2% in a cohort of 203 patients treated with either LDR or HDR brachytherapy, respectively, and followed for a median of 51–63 months[10]
  • 95% at 5- and 10-years following RT treatment in a large cohort of 720 patients[24]
  • 100% in a small cohort of 15 patients treated with RT and followed for a median of 42 months.[13]


Five studies reported acute toxicity outcomes of RT:[5][12][29][7][25]

  • A study comparing outcomes in patients receiving LDR brachytherapy or HDR brachytherapy reported no statistically significant differences in rates of grade 3 or grade 4 acute toxicities.[5]
  • A large cohort (n=297) of patients treated with HDR brachytherapy reported rash in 86% and pruritus in 27% of patients.[7]
  • In another large cohort of patients treated with HDR brachytherapy, less than 7% experienced grade 4 toxicities.[12]

Three studies reported late effects of RT:[4][25][7]

  • In a cohort of 75 patients treated with EBRT, grade 4 late toxicities were reported in 1.3%.[4]
  • In a large cohort of 297 patients treated with HDR brachytherapy, hyperpigmentation was reported in 6% of patients reported, and alopecia in 1%.[7] There were no cases of necrosis.
  • In as small (n=21) cohort of patients treated with helical tomotherapy, 66.6% experienced late toxicity.[25]There were no cases of necrosis.

Cosmetic outcomes

In studies that reported cosmetic outcomes, these were reported to be excellent or good for most patients.[7][8][10][26]

Overview of additional evidence (non-systematic literature review)

Outcomes of RT series and other relevant clinical findings were reported in additional studies that did not meet inclusion criteria.

Definitive treatment of primary squamous cell carcinoma

Reported outcomes of RT for primary cSCC are comparable to those reported for surgery.[33][34][35]

Five-year control rates of primary cSCC treated with curative doses of radiotherapy are 93% for T1 lesions, 65–85% for T2 lesions and 50–60% for T3–4 lesions (staging according to AJCC/UICC 6th edition).[36][37][38][39][40][41][34][42][43][19][14]

Together with the findings of the Australian study that reported a 5-year control rate of 90% for early-stage cSCC of the lip,[22] these findings raise the clinical question of whether surgery can be reserved for salvage.

Postoperative radiotherapy for residual tumours following incomplete excision

Incompletely excised cSCC carries a local recurrence rate of over 50%.[44][45][46] Overall, tumour control of all stages of previously untreated primary cSCC with radiotherapy is 87%, but the tumour control rate for recurrent cSCC treated with radiotherapy is 65%.[47]

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Evidence summary and recommendations

Evidence summary Level References
Overall survival and disease-free survival

Overall survival rates across reported studies were generally greater than 80%, with follow-up of 1–5 years for most studies.

Disease-free survival was lower than overall survival in the same studies (although some of these studies included cSCCs of the lip) and did not significantly vary between treatment modalities.

II, III-2, IV [4], [5], [6], [14], [9], [10], [11], [15], [8], [17], [18], [19], [20], [21], [22], [23], [27], [28], [30], [31], [32]
Acute and late toxicity and effects

Toxicity (acute and late effects) were reported by a significant proportion of patients and varied depending on tumour site. Dermatitis was the most common side effect reported.

IV [4], [5], [7], [25], [29], [12]
Control rate and recurrence

Local control rates following treatment with brachytherapy or RT were >88%, with most patients reporting >94% local control. Recurrence rates were less than 10% at 5 years of follow-up.

III-2, IV [13], [5], [6], [7], [16], [24], [10], [11], [20], [12], [21], [23], [26]
Cosmesis, complications, and functional outcomes

Cosmetic outcomes were generally ‘excellent’ or ‘good’ for approximately >80% of patients following brachytherapy or RT.

At least one-third of patients treated with RT experienced complications.

III-2, IV [13], [7], [8], [10], [26]
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 8.3.1 Radiotherapy using curative doses can be considered as an alternative to surgery for cutaneous squamous cell carcinomas if surgery is either declined by the patient or surgery is inappropriate.

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PP 8.3.1 If surgical excision of a cutaneous squamous cell carcinoma is not possible, referral for a radiotherapy opinion should be considered.

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PP 8.3.2 For patients with T3/T4 primary, persistent and recurrent cutaneous squamous cell carcinomas, a consideration should be given to obtaining an opinion from a radiation oncologist as part of multidisciplinary care.

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PP 8.3.3 Postoperative radiotherapy should be considered after complete excision for high-risk cutaneous squamous cell carcinomas, including when any of the following are present:

  • T3/T4 tumours
  • extradermal invasion beyond subcutaneous fat, bone
  • >6mm depth of invasion
  • rapidly growing tumour
  • recurrent disease
  • inadequate margins on excision when further surgery is problematic
  • poorly differentiated tumour
  • perineural invasion (major and minor nerves)
  • lymphovascular invasion
  • in-transit metastases
  • regional nodal involvement.

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PP 8.3.4 Following incomplete surgical excision of a cutaneous squamous cell carcinoma, radiotherapy can be considered as an alternative to re-excision if further treatment is deemed advisable and re-excision is disadvantageous or not feasible.

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PP 8.3.5 For recurrent and/or locally advanced cutaneous squamous cell carcinomas, the draining regional nodes must be examined (even after treatment of the primary site), because of the relatively higher propensity of cutaneous squamous cell carcinoma to metastasise, compared with basal cell carcinoma.

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Notes on the recommendations

Keratinocyte cancers occur predominantly in sun- exposed areas (e.g. face) and these can be in cosmetically sensitive areas where the tissue loss that is inherent in surgery is not acceptable to the patient. Definitive RT can then be considered, with oncological outcomes approximately equivalent to surgery. This type of RT does require fractionation, which necessitates multiple visits to a radiation facility.


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