8.1 Radiotherapy with or without surgical treatment for keratinocyte cancer

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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]


Background

Radiotherapy (RT) is used extensively in Australia to treat skin cancer. Definitive RT is an alternative to surgery. Radiotherapy is particularly helpful when tissue conservation for functional and cosmetic reasons are a priority, or when surgery is problematic, such as when it would result in unacceptable tissue loss or when comorbidity or medication would compromise safety (e.g. in patients taking anticoagulant therapy).

As the majority of basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (cSCCs) present early, surgery is the more common treatment because it usually requires a single treatment episode, is highly efficacious and delivers a complete specimen for pathology examination. Radiotherapy is reserved for lesions that present problems for conventional surgery and for cases of incompletely excised (persistent), recurrent or advanced BCC and cSCC[3][4][5][6][7][8][9][10][11][12][13][14] where multimodality treatment may be indicated.

The treatment of complex skin cancers should be managed by the multidisciplinary team. Ideally, all BCCs and cSCCs should be confirmed histologically by biopsy prior to RT.

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Systematic review evidence

When should radiotherapy be used alone, or in combination with surgical excision to treat those with keratinocyte cancers?

A systematic review was undertaken to evaluate the effects of radiotherapy when used alone or in combination with surgical excision to treat those with keratinocyte carcinomas.

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

Eight studies meeting search criteria were identified that assessed outcomes of RT as monotherapy or in combination with surgical excision for patients with a keratinocyte cancer (KC).[15][16][17][18][15][16][19][20][21][19][22] These included one systematic review,[15] one prospective longitudinal observational cohort study,[21] and six retrospective cohort studies.[16][22][19][17][20][18] All were level 2 evidence. Two studies were assessed to be at low risk of bias[16][18] and the remainder were at high risk of bias.

All studies used external-beam RT.

A systematic review of surgical monotherapy versus surgery plus adjuvant RT in for patients with high-risk cSCC identified no randomised controlled trials.[15] Of 2,449 cases documented in observational studies, 91 received surgery plus adjuvant RT.[15] Tumour stage and surgical margin status before adjuvant RT were generally not reported in the included studies.[15] In 74 cases of perineural invasion, outcomes were statistically similar between patients who received surgical monotherapy and those who received surgery and adjuvant RT.[15] The investigators concluded that it was not possible to identify high-risk features in which adjuvant RT may be beneficial, based on the available data.[15]

A Greek prospective observational cohort study of 315 consecutive patients (145 males and 170 females) presenting with primary cSCC of the head and neck was designed to identify any clinical-pathologic factors associated with reduced overall and recurrence-free survival.[21] At a mean follow-up time of 46.7 months (range 12–124 months) for 222 surviving patients, adjuvant irradiation was associated with a 92% reduced risk for recurrence[21] The investigators concluded that, after excision with negative margins, patients with head and neck cSCCs should be referred to specialised multidisciplinary oncology clinics for counselling on adjuvant RT and follow-up.

Of the retrospective cohort studies, one compared two electron beam fractionation schedules in patients with KC (BCC or cSCC),[18] one reported outcomes in patients with aggressive cSCC at any site,[22] two reported outcomes in patients with cSCC of the lip,[16][20] and two reported outcomes in patients with KC (cSCC or BCC) of the eyelid. [19][17]

In the study comparing RT fractionation schedules (Netherlands),[18] one reported outcomes in patients with aggressive cSCC at any site,[22] two reported outcomes in patients with cSCC of the lip,[16][20] and two reported outcomes in patients with KC (cSCC or BCC) of the eyelid.[19][17]

In the study comparing RT fractionation schedules (Netherlands),[18] 333 patients with 434 epithelial skin cancers (332 BCCs and 102 cSCCs) received either 54 Gy in 18 fractions (159 tumours) or 44 Gy in 10 fractions (275 tumours).[18] Three-year local recurrence-free survival rates were high for all groups (97–98% for BCC and 94–97% for cSCC) and were not significantly different between fractionation schedules.[18]

In the study of aggressive cSCC at any site (USA), 27 patients with high-risk (n=5) or very high-risk (n=22) cSCC were identified among 1591 cases treated at a single institution between 2000 and 2011.[22] Among those with high-risk cSCC, one patient received surgery and RT while four received surgery only. At median follow-up of 5 years, all remained disease-free.[22] Among those with very-high-risk cSCC, four received surgery alone, 11 received surgery and RT, six received surgery plus cetuximab, and one received the combination of surgery, cetuximab, and RT. At follow-up, 12 patients showed disease progression, including three treated with surgery alone, seven treated with surgery and RT (median time to recurrence 6 months), and two treated with surgery and cetuximab.[22] No clear conclusions about the comparable effects of regimens with and without RT can be drawn from these data due to the lack of randomisation or control, and the absence of a standardised treatment protocol.[22]

An Australian retrospective cohort study compared surgery alone with surgery and adjuvant RT as a definitive treatment in patients with T1 or T2 (staging according to AJCC/UICC 7th edition) cSCC of the lip.[16] The addition of local adjuvant RT in patients with a close or positive margin was associated with a significant improvement in relapse-free survival.[16] Compared with patients having any RT, those undergoing surgery experienced a higher rate of locoregional recurrence.[16] The investigators concluded that the addition of adjuvant RT in patients with inadequate excision significantly decreased the risk of recurrence.[16]

In a Brazilian retrospective study designed to evaluate three histologic grading methods using data from 53 patients with cSCC of lip, surgical treatment combined with RT was associated with lower recurrence-free survival when applying a model based on tumour budding and depth of invasion. However, this observation may be due to selection bias if only those judged to be at higher risk received RT.[20]

A small US retrospective cohort study compared definitive primary RT (n=32) versus wide local excision plus postoperative RT (n=10) in patients with cSCC of the eyelid.[19] At median follow-up of 76 months, there were no significant differences between the treatment groups in 5-year local, regional, and distant control rates, and there were no grade 3 or 4 complications. The investigators concluded that primary RT for cSCC of the eyelid provided excellent locoregional control with reasonable complication rates and should be considered an alternative to surgery in selected patients.

A Turkish retrospective cohort study analysed data from 311 patients treated for BCC of the eyelid, of which most common histologic subtypes were infiltrative, nodular, and basosquamousshowing evidence of squamatisation (descriptor applicable to basaloid tumours and indicating aggressive subtype) BCC.[17] Approximately 30% of the patients had previous tumour recurrence. The investigators noted outcomes were worse than previously reported due to delay in treatment and previous inadequate treatments.[17]

Local recurrence

Four studies reported recurrence related outcomes in those treated with surgery alone, compared with surgery and RT, or RT alone.[15][16][17][18]

A systematic review of 49 cohort studies reported lower recurrence rates for patients with cSCC treated by surgery alone (7%, n=1874) compared with those treated with adjuvant RT (12%, n=68), with a follow-up period ranging from 1 month to 26 years. This difference was nonsignificant (p=0.10).

In the Australian cohort with T1 or T2 (staging according to AJCC/UICC 7th edition) cSCC of the lip,[16] recurrence rates were highest among those treated by surgery (43%, n=89), lower in those who had RT only (15%, n=89), and lower still in those treated by adjuvant RT (6%, n=26) with a follow-up of 5 years. In this same cohort, 5-year relapse-free survival was approximately 90% for RT alone and adjuvant RT groups, and 51% in the surgery only group. None of these patients underwent Mohs micrographic surgery.

The retrospective cohort of patients treated for BCC of the eyelid[17] reported the lowest recurrence in those who had surgery alone (5.3%, n=244), higher recurrence in the adjuvant RT group (10%, n=20), and higher again (21%, n=19) in the RT-only group, with a median follow-up of 33 months.

The study comparing RT fractionation schedules in patients with KCs[18] reported local recurrence rates of 3.1% (n=386) in those treated by RT alone, and 6.4% (n=48) in those treated with RT postoperatively, after a median follow-up of 42.8 months (p=0.919).

Survival

Five studies reported survival outcomes in patients with cSCC and BCC treated by surgery or adjuvant RT.[15][16][19][20][21]

The systematic review[15] reported a higher rate of KC-specific deaths in those treated with adjuvant RT (10%, n=91), compared with those treated with surgery alone (4%, n=1772), for a follow-up period ranging from 1 month to 26 years.

The Australian cohort study of patients with cSCC of the lip[16] reported 5-year overall survival rates of approximately 80% in patients treated with either surgery alone (79%, n=89) or RT alone (83%, n=89), and 68% in those treated by adjuvant RT (n=26). In a subgroup of patients who had close or positive margins at surgical treatment (n=45), relapse-free survival was 40% in the surgery-only group (n=23), and 90% in the adjuvant RT group (n=22).

The US retrospective cohort of patients with cSCC of the eyelid[19] reported 5-year disease free survival of 90% in the RT-only group and 69% in the adjuvant RT group, after a median follow-up of 76 months.

The Brazilian retrospective study of patients with cSCC of the lip reported 5-year recurrence free survival of 81.2% in surgery only patients, compared to 44.4% in adjuvant RT patients. This difference was significant (p=0.03).

The Greek prospective observational cohort study of patients with cSCC of the head and neck[21] reported 5-year overall survival of 83% in those treated by surgery only (n=160), 66% in those treated by adjuvant RT (n=112), and 40% for those treated by RT alone (n=20).

Control rate

The US retrospective cohort of patients with cSCC of the eyelid[19] reported 5-year local and regional control rates.

Reported 5-year local control rates were similar between tumours treated with RT alone and treated with adjuvant RT (89% versus 86%; p=0.91).[19]

Reported 5-year regional control rates were 100% for patients treated with adjuvant RT and 93% for those treated by RT alone (p=0.45).[19]

Response rate

Complete response (disease free at >9 months after treatment) was reported in a single small study of patients with aggressive cSCC.[22] Response rates of 63% (n=8) were reported for those treated by surgery and 42% for those treated with adjuvant RT (n=12).[22]Back to top

Evidence summary and recommendations

Evidence summary Level References
Local recurrence rates at 5-year follow-up were similar between groups who received surgery alone, surgery with adjuvant RT, and RT alone. III-2 [15], [16], [17], [18]
In general, overall survival and recurrence-free survival rates were higher after surgery, with follow-up intervals of 5 years or longer. Survival rates were generally lower among patients who received RT alone, and lower still among those who received surgery and adjuvant RT (although the adjuvant RT group included patients who received postoperative RT only if residual disease was detected/suspected after surgery as well as patients who received planned postoperative RT). III-2 [15], [16], [19], [20], [21]
There is insufficient evidence to compare the control rate or response rate across treatment modalities (surgery alone, RT alone, or surgery plus adjuvant RT) for BCC or cSCC. III-2 [19], [22]
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 8.1.1. Radiotherapy can be used alone in the treatment of keratinocyte cancers when surgery is not possible or the patient declines surgery.
D
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 8.1.2. Radiotherapy may be used in combination with surgical excision with the aim of improving locoregional control.
D
Practice pointQuestion mark transparent.png

PP 8.1.1. Radiotherapy should begin within 6 weeks following surgery, as macroscopic recurrence at the start of radiotherapy will necessitate a higher dose, which is associated with a higher risk of poor cosmetic and functional outcomes.

Key point(s)

Histological assessment of margins and other associated pathological features by the histopathologist are essential for predicting the need for further therapy.

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Appendices

Jutta's magnifying glass icon.pngPICO question RT1 View Evidence statement form RT1Evidence statement form RT1 View Systematic review report RT1Systematic review report RT1

References

  1. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, et al. (Eds.). AJCC Cancer Staging Manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017 [cited 2016 Dec 28].
  2. Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell; 2017.
  3. Petrovich Z, Parker RG, Luxton G, Kuisk H, Jepson J. Carcinoma of the lip and selected sites of head and neck skin. A clinical study of 896 patients. Radiother Oncol 1987 Jan;8(1):11-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3809597.
  4. Mazeron JJ, Chassagne D, Crook J, Bachelot F, Brochet F, Brune D, et al. Radiation therapy of carcinomas of the skin of nose and nasal vestibule: a report of 1676 cases by the Groupe Europeen de Curiethérapie. Radiother Oncol 1988 Nov;13(3):165-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3146781.
  5. Lovett RD, Perez CA, Shapiro SJ, Garcia DM. External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 1990 Aug;19(2):235-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2394605.
  6. Lee WR, Mendenhall WM, Parsons JT, Million RR. Radical radiotherapy for T4 carcinoma of the skin of the head and neck: a multivariate analysis. Head Neck 1993 Jul;15(4):320-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8360054.
  7. Mendenhall WM, Parsons JT, Mendenhall NP, Million RR. T2-T4 carcinoma of the skin of the head and neck treated with radical irradiation. Int J Radiat Oncol Biol Phys 1987 Jul;13(7):975-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3597161.
  8. Ashby MA, Smith J, Ainslie J, McEwan L. Treatment of nonmelanoma skin cancer at a large Australian center. Cancer 1989 May 1;63(9):1863-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2702595.
  9. Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P, Benhamou E, et al. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer 1997;76(1):100-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9218740.
  10. CHURCHILL-DAVIDSON I, JOHNSON E. Rodent ulcers: an analysis of 711 lesions treated by radiotherapy. Br Med J 1954 Jun 26;1(4877):1465-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/13160499.
  11. Fitzpatrick PJ, Thompson GA, Easterbrook WM, Gallie BL, Payne DG. Basal and squamous cell carcinoma of the eyelids and their treatment by radiotherapy. Int J Radiat Oncol Biol Phys 1984 Apr;10(4):449-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6725035.
  12. Hall VL, Leppard BJ, McGill J, Kesseler ME, White JE, Goodwin P. Treatment of basal-cell carcinoma: comparison of radiotherapy and cryotherapy. Clin Radiol 1986 Jan;37(1):33-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3514075.
  13. McCombe D, MacGill K, Ainslie J, Beresford J, Matthews J. Squamous cell carcinoma of the lip: a retrospective review of the Peter MacCallum Cancer Institute experience 1979-88. Aust N Z J Surg 2000 May;70(5):358-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10830600.
  14. Wilder RB, Kittelson JM, Shimm DS. Basal cell carcinoma treated with radiation therapy. Cancer 1991 Nov 15;68(10):2134-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1913451.
  15. 15.0015.0115.0215.0315.0415.0515.0615.0715.0815.0915.1015.1115.12 Jambusaria-Pahlajani A, Miller CJ, Quon H, Smith N, Klein RQ, Schmults CD. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg 2009 Apr;35(4):574-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19415791.
  16. 16.0016.0116.0216.0316.0416.0516.0616.0716.0816.0916.1016.1116.1216.1316.1416.15 Najim M, Cross S, Gebski V, Palme CE, Morgan GJ, Veness MJ. Early-stage squamous cell carcinoma of the lip: the Australian experience and the benefits of radiotherapy in improving outcome in high-risk patients after resection. Head Neck 2013 Oct;35(10):1426-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22965889.
  17. 17.017.117.217.317.417.517.617.717.8 Soysal HG, Soysal E, Markoç F, Ardiç F. Basal cell carcinoma of the eyelids and periorbital region in a Turkish population. Ophthalmic Plast Reconstr Surg 2008 May;24(3):201-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18520835.
  18. 18.0018.0118.0218.0318.0418.0518.0618.0718.0818.0918.10 van Hezewijk M, Creutzberg CL, Putter H, Chin A, Schneider I, Hoogeveen M, et al. Efficacy of a hypofractionated schedule in electron beam radiotherapy for epithelial skin cancer: Analysis of 434 cases. Radiother Oncol 2010 May;95(2):245-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20334941.
  19. 19.0019.0119.0219.0319.0419.0519.0619.0719.0819.0919.1019.1119.12 Petsuksiri J, Frank SJ, Garden AS, Ang KK, Morrison WH, Chao KS, et al. Outcomes after radiotherapy for squamous cell carcinoma of the eyelid. Cancer 2008 Jan 1;112(1):111-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17963262.
  20. 20.020.120.220.320.420.520.6 Strieder L, Coutinho-Camillo CM, Costa V, da Cruz Perez DE, Kowalski LP, Kaminagakura E. Comparative analysis of three histologic grading methods for squamous cell carcinoma of the lip. Oral Dis 2017 Jan;23(1):120-125 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27667675.
  21. 21.021.121.221.321.421.521.6 Kyrgidis A, Tzellos TG, Kechagias N, Patrikidou A, Xirou P, Kitikidou K, et al. Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival. Eur J Cancer 2010 Jun;46(9):1563-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20338745.
  22. 22.0022.0122.0222.0322.0422.0522.0622.0722.0822.0922.10 O'Bryan K, Sherman W, Niedt GW, Taback B, Manolidis S, Wang A, et al. An evolving paradigm for the workup and management of high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2013 Oct;69(4):595-602.e1 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23871719.


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