Keratinocyte cancer

12.2 Systemic therapies for metastatic cutaneous squamous cell carcinoma

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Guideline contents > What should be the protocol to manage or treat locoregionally advanced cutaneous squamous cell carcinoma?

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A/Professor Alexander Guminski, Sydney Ch'ng, Cancer Council Australia Keratinocyte Cancers Guideline Working Party. Clinical question:Protocol to treat local regional SCC . In: Clinical practice guidelines for keratinocyte cancer. Sydney: Cancer Council Australia. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=208337, cited 2023 Sep 24]. Available from: https://wiki.cancer.org.au/australia/Guidelines:Keratinocyte_carcinoma.


Last modified:
25 November 2019 20:16:31

Background

Certain features of primary cutaneous squamous cell carcinoma (cSCC) are associated with a higher risk of recurrence and lymph node involvement. Different systems, including TNM (American Joint Committee on Cancer [AJCC] Cancer Staging Manual 8th edition)[1] and the Brigham and Women’s Hospital tumour staging system, are used to estimate risk and guide further management.[2]

When the primary lesion is on the head and neck there may be anatomical constraints to performing surgery with curative intent.

Perineural involvement (PNI) of the large nerves is associated with a higher risk of relapse. Patients may present sometime after excision of the index cSCC with facial nerve weakness or pain/numbness in part of the trigeminal nerve distribution. There is often a significant delay to diagnosis.

Special populations include patients with solid organ transplants and patients with concurrent haematological malignancy. Both these clinical circumstances present challenges in managing localised, high-risk and recurrent/metastatic cSCC.

Locoregional advanced cSCC represents a spectrum that comprises:

  • unresectable locally advanced disease presenting de novo
  • unresectable locally advanced disease recurring after prior surgery and radiotherapy (RT)
  • regional lymph node metastasis, usually presenting subsequent to treatment of a primary lesion.

Locoregionally advanced cSCC should be managed with the goals of clearing the local disease, preventing local recurrence and preventing regional or distant metastases, which may otherwise compromise patient survival.

However, treatment options may be limited by the location of the primary tumour and by comorbidities.

Adjuvant RT following surgery is widely practised for patients deemed to be at high risk of local or regional relapse. However, this approach has not been evaluated in randomised controlled trials (RCTs).

Systematic review evidence

What should be the protocol to manage or treat locoregionally advanced cutaneous squamous cell carcinoma?

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

Twenty-three studies were identified that reported treatment outcomes in patients with locally advanced or metastatic SCC treated by various modalities, including chemotherapy.[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] [21][22][23][24][25]

They include one RCT,[20] 16 cohort studies[3][4][5][6][7][8][9][11][12][13][14] [15][18][21][22][23] and six case studies[10][16][17][19][24][25]

Ten studies were at moderate risk of bias[7][8][11][13][14][22][23][24][25] 12 at high risk of bias[3][4][5][6][9][12][15][21][10][16][24][25] and one at unclear risk of bias.[20]

An Australian RCT[20] compared postoperative concurrent chemoradiotherapy with postoperative RT in patients with high-risk cSCC of the head and neck.

The observational studies included cohorts of patients with metastases of cSCC to the parotid,[3][10][13][14] metastases to the axilla or groin[7] cSCC of the head and neck,[5][8] as well as cohorts with a broader range of cSCC presentations.


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Recurrence

Locoregional control

One RCT[20], six retrospective cohort studies[5][6][8][11][13][14] and one case series[24] reported locoregional control outcomes.

The RCT[20] reported no significant difference in locoregional control rates between patients with high-risk cSCC of the head and neck who received postoperative RT and those who received postoperative concurrent chemoradiotherapy (83% versus 87%).

One retrospective cohort study with a moderate risk of bias[13] reported a superior locoregional control rate among patients with parotid cSCC metastasis who received postoperative RT compared with those who received either radiotherapy only or preoperative neoadjuvant RT (83% versus 53%, p=0.008).

Of the three retrospective cohort studies that reported local control rates,[6][8][12] none reported significant effects.

Progression-free survival

Six retrospective cohort studies[3][5][7][11][18][21] and one case series[16] reported progression-free survival/local recurrence-free survival/relapse-free survival.

One retrospective cohort study (high risk of bias) in patients with cSCC of the head and neck[21][10] reported a significantly higher proportion of patients without recurrence at 5-year follow-up among those treated with surgery plus adjuvant RT group than those treated with surgery alone (78% versus 30%; p=0.02).

A non-comparative study evaluating cetuximab in elderly patients with advanced cSCC reported median progression-free survival of 9 months.[19] Another non-comparative study evaluating gefitinib in patients with incurable cSCC amenable to curative therapy including surgery or RT reported median progression-free survival of 3.8 months.[25]

Overall survival

One RCT,[20] 10 retrospective cohort studies[4][5][6][7][8][11][14][15][18][21] and three case series[10][16][17] reported overall survival rates.

The RCT[20] reported no significant difference in 5-year overall survival rates between patients with high-risk cSCC of the head and neck who received postoperative RT and those who received postoperative concurrent chemoradiotherapy (76% versus 79%).

Three retrospective cohort studies reported significant differences in survival between treatment groups: a retrospective cohort study with a moderate risk of bias[8] reported a survival benefit with RT 240–250 cGy/fraction over other doses in patients with keratinocyte cancers of the head and neck, of which the majority were cSCCs.

Another study with a moderate risk of bias[11] reported a survival advantage for RT plus concurrent systemic chemotherapy, compared with RT alone, in patients with locally advanced cSCC of head and neck (median overall survival 20.9 months versus 34.4 months; p = 0.03).

A study with a high risk of bias[21] reported higher 5-year survival among patients with cSCC of head and neck treated with surgery plus adjuvant RT compared with surgery alone (79% versus 46%, p<0.05).

A non-comparative study evaluating cetuximab in elderly patients with advanced cSCC reported median overall survival of 13 months.[19]
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Survival time

Four retrospective cohort studies[8][9][11][22] and two case series[19][25] reported survival times.

One retrospective cohort study with a high risk of bias[9] reported significantly longer median survival among patients with regionally metastatic cSCC of head and neck treated with adjuvant RT than those treated with surgery alone (23 months versus 10 months, p=0.002).

Overview of additional evidence (non-systematic literature review)

Locoregional metastasis

Overall, the evidence for management of locoregional SCC is of low quality. It is estimated that less than 5% of primary cSCC give rise to local recurrence or regional lymph node metastasis (see: Prognosis).

Several risk factors for recurrence have been identified (Table 2).

Table 2. Tumour-specific factors associated with recurrence of keratinocyte cancers Table 2 KC guideline Tumour specific factors cSCC.png


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Currently used staging systems to identify patients at higher risk of relapse include the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (8th edition) [1] and the Brigham and Women’s Hospital staging system for cSCC.[26]

The head and neck region are the most common sites of primary cSCC and, therefore, the commonest lymph node metastasis sites are the parotid and cervical lymph nodes. Prognosis appears worse for patients with more extensive involvement of cervical lymph nodes.[27] Metastases to groin, axilla or epitrochlear lymph nodes should be managed surgically and adjuvant RT should be considered.[28]

Available evidence, albeit from non-randomised trials, consistently supports the use of adjuvant RT after surgery for patients with metastatic SCC involving the parotid or cervical lymph nodes. Adjuvant RT is associated with reduced local recurrence and improved disease-free and overall survival.[29][30]

Distant metastases

Distant metastases from cSCC are uncommon.[31] They rarely precede the development of regional metastases or occur in isolation from regional metastasis.

The time to occurrence after presentation with the original primary lesion is short, usually within 2 years. The lung and liver are the most common sites of spread, but bone and brain may also be involved. Radiotherapy is effective in controlling symptoms and delaying local progression of disease. Cisplatin-based chemotherapy protocols appear to be the most effective.[32] Survival is poor despite treatment, with few patients surviving more than 2 years.[32]

More recently, the efficacy of checkpoint inhibitor immunotherapy has been demonstrated in metastatic and locally advanced cSCC. Response rates of 47% and a high overall disease control rate have been reported, with prolonged responses seen in a proportion of patients.[33] First-line immunotherapy may become the standard of care for metastatic/inoperable locally advanced cSCC. However, this therapy is not currently funded by the Pharmaceutical Benefits Scheme in Australia.

Other systemic therapies

Epidermal growth factor receptor (EGFR) inhibitors have some activity in patients with cSCC.[17] In patients with other malignancies, EGFR inhibitors are typically used with other agents. Their role in combination with chemotherapy or checkpoint inhibitor immunotherapy in the treatment of cSCC remains to be clarified. EGFR inhibitors are not registered for use in cSCC in Australia currently and use would be off label.

Cetuximab is approved by the Australian Therapeutic Goods Administration for the treatment of SCC of the head and neck, either in combination with RT for locally advanced disease, or in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.[34] However, cetuximab is not subsidised by the PBS for the treatment of cSCC.

Patient selection

Patient performance status, comorbidities, social support and likely compliance with treatment, follow up and supportive interventions are important.

Managing side effects

Common adverse effects of checkpoint inhibitor immunotherapy include rash, itch, fatigue and thyroid disturbance. Less common effects include pneumonitis, colitis and other endocrinopathies. Rare adverse effects include renal and neurological autoimmune effects.[35]

Typical adverse effects of cisplatin include nausea, vomiting, fatigue, low blood cell counts, infection, renal toxicity, neurotoxicity and ototoxicity.[36] Carboplatin generally has fewer side effects than cisplatin and does not require intravenous hydration, unlike cisplatin. Typical carboplatin side effects include fatigue, nausea and thrombocytopenia.[37]

Common adverse effects of 5-fluorouracil include nausea, diarrhoea, fatigue, and rash. Rare effects include severe diarrhoea and coronary artery spasm. Continuous-infusion 5-fluorouracil requires placement of a venous access device and is given over a number of days via an infusion device.[36]

Chemotherapy

Systemic chemotherapy has been used for metastatic cSCC. It can be used alone or as part of multimodality therapy. Most phase II studies used cisplatin, often combined with doxorubicin.[38][39][40][41][42] Other drugs include methotrexate, 5-fluorouracil, bleomycin and vindesine.[43][44][31][45][46] Objective response rates of >80% have been reported, with complete response rates of around 30%.[44]

In some patients, locally advanced disease can be rendered operable with the combination of cisplatin-based chemotherapy and radiotherapy.[47]

Oral 5-fluoropyrimidine analogues are well tolerated and can achieve effective palliation in patients who are elderly and have significant comorbidities.[48]

Follow-up

The majority of relapses after lymph node metastasis resection and adjuvant radiotherapy occur within 2 years, so 3-monthly follow-up for the first 2 years has been suggested.[49]

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Evidence summary and recommendations

Evidence summary Level References
Local recurrence free survival/freedom from locoregional relapse/progression-free survival

Eight studies reported data for one or more of these outcomes.

Studies assessing surgery plus adjuvant radiotherapy as a treatment modality consistently reported survival rates of 70–90% range at follow-up of 3–5 years.

No treatment modality could be identified that consistently improved local recurrence-free survival, relapse-free survival or progression-free survival across all studies that reported these outcomes.

III-2, IV [3], [5], [7], [11], [16], [50], [23]
Overall survival/mean survival time

Eighteen studies reported data for overall and mean survival times. The addition of radiotherapy to surgery improved overall survival in three studies comparing these modalities.

Adding chemotherapy to radiotherapy only showed inconsistent improvements to overall survival.

Whether or not chemotherapy, in addition to adjuvant radiotherapy, improved overall survival cannot be ascertained from current evidence due to insufficient data and inconsistent findings.

Generally, overall survival was higher in patients who received adjuvant radiotherapy compared with those who received definitive radiotherapy only.

There were insufficient studies comparing modalities to ascertain the best treatment modality or combination with respect to mean survival time.

II, III-2, IV [4], [5], [6], [7], [8], [9], [10], [11], [14], [15], [16], [17], [18], [19], [20], [21], [22], [25]
Local control/locoregional control

Nine studies reported data for one or both outcomes.

The addition of chemotherapy to radiotherapy improved locoregional control rates, compared with radiotherapy only in four studies that reported this outcome.

Some studies reported that the addition of radiotherapy to surgery improved locoregional control rates, but data were inconsistent.

Adjuvant radiotherapy improved locoregional control, compared with radiotherapy alone.

There were too few studies and the data were too inconsistent data to enable conclusions about the best treatment modality for local control rates. The use of radiotherapy alone, or in combination with other modalities reported high (>80%) local rates, even up to 10 years post treatment.

II, III-2, IV [5], [6], [8], [11], [12], [13], [14], [20], [24]
Distant-metastasis free survival/distant control

Only single studies reported these outcomes, all of which reported similar rates between modalities reported.

III-2 [11], [12]
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 12.2.1. For patients with resected high-risk cutaneous squamous cell carcinoma, adjuvant radiotherapy to reduce the risk of locoregional recurrence should be considered. 		D
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 12.2.2. For patients with cutaneous squamous cell carcinoma metastatic to cervical lymph node(s) who have adverse factors such as multiple node involvement, extra-nodal extension or involved margin, neck dissection followed by adjuvant radiotherapy is recommended. 		D
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 12.2.3. For patients with cutaneous squamous cell carcinoma metastatic to the parotid, surgery or radiotherapy of the ipsilateral neck is recommended, even if clinically uninvolved. 		D
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 12.2.4. Patients with resected primary cutaneous squamous cell carcinoma should be assessed for high-risk features and referred for consideration of adjuvant treatment, if appropriate. 		D
Evidence-based recommendationQuestion mark transparent.png Grade
EBR 12.2.5. Do not routinely offer carboplatin chemotherapy in addition to adjuvant radiotherapy for patients who have undergone excision of high-risk head and neck cutaneous squamous cell carcinoma. 		B


Consensus-based recommendationQuestion mark transparent.png

CBR 12.2.1. Patients with cutaneous squamous cell carcinoma involving the parotid or cervical lymph nodes should be offered adjuvant radiotherapy after surgery.


Practice pointQuestion mark transparent.png

PP 12.2.1. Recurrences of cutaneous squamous cell carcinoma in the axillary, epitrochlear or inguinal lymph nodes should be treated with surgery and adjuvant radiotherapy.


Practice pointQuestion mark transparent.png

PP 12.2.2. Patients with resected lymph node metastases of cutaneous squamous cell carcinoma should be followed 3-monthly for the first 2 years after surgery.


Practice pointQuestion mark transparent.png

PP 12.2.3. Patients with unresectable local cutaneous squamous cell carcinoma can be considered for radiotherapy and, if fit for chemotherapy, platinum-based chemoradiation


Practice pointQuestion mark transparent.png

PP 12.2.4. Cemiplimab treatment should be considered for patients with unresectable locoregionally advanced cutaneous squamous cell carcinoma not suitable for surgery or radiotherapy.

Key point(s)

Patients with high-risk resected cutaneous squamous cell carcinoma should be encouraged to participate in clinical trials of adjuvant therapy including radiotherapy, chemotherapy and immunotherapy.

Notes on the recommendations

Overall the evidence for management of local-regional cSCC is of low quality.

Neck dissection followed by adjuvant radiotherapy has been advocated for patients with adverse features such as multiple involved nodes, extranodal extension or close/involved margins.[14][49] One series showed equivalent outcomes for elective neck node radiotherapy to 50–60Gy, and elective neck dissection followed by radiotherapy.[12]

Patients with resected cSCC who are most likely to benefit from adjuvant radiotherapy cannot be clearly identified based on current evidence. However, features may include:

  • lesion size over 2cm
  • tumour spread to local lymph nodes
  • PNI affecting large nerves.

Lymph node recurrences in the axilla, epitrochlear or groin should be managed with surgery and adjuvant radiotherapy, although the risk of lymphoedema following axillary and groin dissection needs to be considered.[28]

Although low dose carboplatin given concurrently with adjuvant radiotherapy for resected nodal metastases did not improve outcome over radiotherapy alone in patients with high-risk cSCC of the head and neck in a RCT,[20] a non-randomised series in which patients with high-risk cSCC received platinum-based chemotherapy reported an apparent improvement in risk of local relapse, compared with radiotherapy alone.[22] In this study, most patients received cisplatin (n=24) rather than carboplatin (n=10), and mostly at a relatively high dose.[22]

Patients with unresectable local disease can be considered for radiotherapy (platinum-based chemoradiation, if the patient is fit for chemotherapy).[47]

The EGFR agents cetuximab[17][19] and gefitinib[25] have been reported effective in palliative treatment for patients with unresectable or metastatic cSCC. Cetuximab is registered for use in metastatic or locally recurrent SCC of the head and neck but use at other anatomical sites, or use of oral EGFR inhibitors would be off label.


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Appendices

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References

  1. ↑ 1.0 1.1 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. ↑ Skin Tumours In: Brierley JD, Gospodarowicz MK, Wittekind C (eds).. TNM Classification of Malignant Tumours (8th edition). Oxford, UK: Wiley-Blackwell; 2017.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Aboziada MA, Eisbruch A. Parotid squamous cell carcinoma: Outcome of multidisplinary management. Journal of Solid Tumors 2012 Dec 10;3(1):14-20 Available from: http://dx.doi.org/10.5430/jst.v3n1p14.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Amoils M, Lee CS, Sunwoo J, Aasi SZ, Hara W, Kim J, et al. Node-positive cutaneous squamous cell carcinoma of the head and neck: Survival, high-risk features, and adjuvant chemoradiotherapy outcomes. Head Neck 2017 May;39(5):881-885 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28252823.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Apisarnthanarax S, Dhruva N, Ardeshirpour F, Tepper JE, Shores CG, Rosenman JG, et al. Concomitant radiotherapy and chemotherapy for high-risk nonmelanoma skin carcinomas of the head and neck. Int J Surg Oncol 2011;2011:464829 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22312508.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Balamucki CJ, Mancuso AA, Amdur RJ, Kirwan JM, Morris CG, Flowers FP, et al. Skin carcinoma of the head and neck with perineural invasion. Am J Otolaryngol 2012 Jul;33(4):447-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22185685.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Beydoun N, Graham PH, Browne L. Metastatic Cutaneous Squamous Cell Carcinoma to the Axilla: A Review of Patient Outcomes and Implications for Future Practice. World J Oncol 2012 Oct;3(5):217-226 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29147309.
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 Dundar Y, Cannon RB, Hunt JP, Monroe M, Suneja G, Hitchcock YJ. Radiotherapy regimens in patients with nonmelanoma head and neck skin cancers. Int J Dermatol 2018 Apr;57(4):441-448 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29355917.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Givi B, Andersen PE, Diggs BS, Wax MK, Gross ND. Outcome of patients treated surgically for lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Head Neck 2011 Jul;33(7):999-1004 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21284049.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Goh RY, Bova R, Fogarty GB. Cutaneous squamous cell carcinoma metastatic to parotid - analysis of prognostic factors and treatment outcome. World J Surg Oncol 2012 Jun 25;10:117 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22731750.
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 Goyal U, Prabhakar NK, Davuluri R, Morrison CM, Yi SK. Role of Concurrent Systemic Therapy with Adjuvant Radiation Therapy for Locally Advanced Cutaneous Head and Neck Squamous Cell Carcinoma. Cureus 2017 Oct 19;9(10):e1784 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29279810.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Herman MP, Amdur RJ, Werning JW, Dziegielewski P, Morris CG, Mendenhall WM. Elective neck management for squamous cell carcinoma metastatic to the parotid area lymph nodes. Eur Arch Otorhinolaryngol 2016 Nov;273(11):3875-3879 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27048521.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Hinerman RW, Indelicato DJ, Amdur RJ, Morris CG, Werning JW, Vaysberg M, et al. Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes. Laryngoscope 2008 Nov;118(11):1989-96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18849863.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 Hirshoren N, Ruskin O, McDowell LJ, Magarey M, Kleid S, Dixon BJ. Management of Parotid Metastatic Cutaneous Squamous Cell Carcinoma: Regional Recurrence Rates and Survival. Otolaryngol Head Neck Surg 2018 Aug;159(2):293-299 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29533706.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Kropp L, Balamucki CJ, Morris CG, Kirwan J, Cognetta AB, Stoer CB, et al. Mohs resection and postoperative radiotherapy for head and neck cancers with incidental perineural invasion. Am J Otolaryngol 2013 Sep;34(5):373-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23415573.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 Matthiesen C, Forest C, Spencer Thompson J, Ahmad S, Herman T, Bogardus C. The role of radiotherapy for large and locally advanced non-melanoma skin carcinoma. Journal of Radiotherapy in Practice 2013;12(1):56-65.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 Maubec E, Petrow P, Scheer-Senyarich I, Duvillard P, Lacroix L, Gelly J, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011 Sep 1;29(25):3419-26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21810686.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 Palmer JD, Schneider CJ, Hockstein N, Hanlon AL, Silberg J, Strasser J, et al. Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: A propensity score analysis. Oral Oncol 2018 Mar;78:102-107 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29496036.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 Picard A, Pedeutour F, Peyrade F, Saudes L, Duranton-Tanneur V, Chamorey E, et al. Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab. JAMA Dermatol 2017 Apr 1;153(4):291-298 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28259104.
  20. ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 Porceddu SV, Bressel M, Poulsen MG, Stoneley A, Veness MJ, Kenny LM, et al. Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial. J Clin Oncol 2018 May 1;36(13):1275-1283 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29537906.
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 Strassen U, Hofauer B, Jacobi C, Knopf A. Management of locoregional recurrence in cutaneous squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol 2017 Jan;274(1):501-506 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27498202.
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 Tanvetyanon T, Padhya T, McCaffrey J, Kish JA, Deconti RC, Trotti A, et al. Postoperative concurrent chemotherapy and radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck 2015 Jun;37(6):840-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24623654.
  23. ↑ 23.0 23.1 23.2 23.3 Wang JT, Palme CE, Wang AY, Morgan GJ, Gebski V, Veness MJ. In patients with metastatic cutaneous head and neck squamous cell carcinoma to cervical lymph nodes, the extent of neck dissection does not influence outcome. J Laryngol Otol 2013 Jan;127 Suppl 1:S2-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23046820.
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 Warren TA, Panizza B, Porceddu SV, Gandhi M, Patel P, Wood M, et al. Outcomes after surgery and postoperative radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma. Head Neck 2016 Jun;38(6):824-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25546817.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 25.7 William WN Jr, Feng L, Ferrarotto R, Ginsberg L, Kies M, Lippman S, et al. Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial. J Am Acad Dermatol 2017 Dec;77(6):1110-1113.e2 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28964539.
  26. ↑ Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol 2014 Feb 1;32(4):327-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24366933.
  27. ↑ O'Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck 2002 May;24(5):417-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12001070.
  28. ↑ 28.0 28.1 Goh A, Howle J, Hughes M, Veness MJ. Managing patients with cutaneous squamous cell carcinoma metastatic to the axilla or groin lymph nodes. Australas J Dermatol 2010 May;51(2):113-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20546217.
  29. ↑ Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY, Veness MJ. Predictors of outcome in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes: Improved survival with the addition of adjuvant radiotherapy. Head Neck 2012 Nov;34(11):1524-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22109745.
  30. ↑ Veness MJ, Palme CE, Smith M, Cakir B, Morgan GJ, Kalnins I. Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy. Laryngoscope 2003 Oct;113(10):1827-33 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14520114.
  31. ↑ 31.0 31.1 Ames FC, Hickey RC. Metastasis from squamous cell skin cancer of the extremities. South Med J 1982 Aug;75(8):920-3, 932 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7112196.
  32. ↑ 32.0 32.1 Cranmer LD, Engelhardt C, Morgan SS. Treatment of unresectable and metastatic cutaneous squamous cell carcinoma. Oncologist 2010;15(12):1320-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21147868.
  33. ↑ Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2018 Jul 26;379(4):341-351 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29863979.
  34. ↑
    Unable to find the reference "Merck Serono Australia Pty Ltd 2018"
  35. ↑ eviQ. Metastatic nivolumab. [homepage on the internet] NSW Government; Available from: https://www.eviq.org.au/medical-oncology/melanoma/metastatic/3555-metastatic-nivolumab#side-effects.
  36. ↑ 36.0 36.1 eviQ. Head and neck squamous cell carcinoma recurrent or metastatic ciSplatin (three weekly) and fluorouracil. [homepage on the internet] NSW Government; 2006 Jul 12 Available from: https://www.eviq.org.au/medical-oncology/head-and-neck/recurrent-or-metastatic/288-head-and-neck-scc-recurrent-or-metastatic-cisp.
  37. ↑ eviQ. Head and neck squamous cell carcinoma recurrent or metastatic cARBOplatin and fluorouracil. [homepage on the internet] NSW Government; 2006 Jun 21 Available from: https://www.eviq.org.au/medical-oncology/head-and-neck/recurrent-or-metastatic/280-head-and-neck-scc-recurrent-or-metastatic-carb.
  38. ↑ Suzuki T, Inoue Y, Kuramochi A, Kiyohara Y, Ikeda S. [Squamous cell carcinoma and basal cell carcinoma]. Gan To Kagaku Ryoho 1997 Jan;24(1):16-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9020940.
  39. ↑ Merimsky O, Neudorfer M, Spitzer E, Chaitchik S. Salvage cisplatin and adriamycin for advanced or recurrent basal or squamous cell carcinoma of the face. Anticancer Drugs 1992 Oct;3(5):481-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1450442.
  40. ↑ Guthrie TH Jr, Porubsky ES, Luxenberg MN, Shah KJ, Wurtz KL, Watson PR. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol 1990 Feb;8(2):342-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2405109.
  41. ↑ Ikegawa S, Saida T, Obayashi H, Sasaki A, Esumi H, Ikeda S, et al. Cisplatin combination chemotherapy in squamous cell carcinoma and adenoid cystic carcinoma of the skin. J Dermatol 1989 Jun;16(3):227-30 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2551943.
  42. ↑ Guthrie TH Jr, McElveen LJ, Porubsky ES, Harmon JD. Cisplatin and doxorubicin. An effective chemotherapy combination in the treatment of advanced basal cell and squamous carcinoma of the skin. Cancer 1985 Apr 15;55(8):1629-32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/4038911.
  43. ↑ Goldberg H, Tsalik M, Bernstein Z, Haim N. [Cisplatin-based chemotherapy for advanced basal and squamous cell carcinomas]. Harefuah 1994 Oct;127(7-8):217-21, 286 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7813942.
  44. ↑ 44.0 44.1 Sadek H, Azli N, Wendling JL, Cvitkovic E, Rahal M, Mamelle G, et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer 1990 Oct 15;66(8):1692-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1698529.
  45. ↑ Loeffler JS, Larson DA, Clark JR, Weichselbaum RR, Norris CM, Jr., Ervin TJ. Treatment of perineural metastasis from squamous carcinoma of the skin with aggressive combination chemotherapy and irradiation. J Surg Oncol 1985;29(3):181-183.
  46. ↑ delCharco JO, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Mendenhall NP. Carcinoma of the skin metastatic to the parotid area lymph nodes. Head Neck 1998 Aug;20(5):369-73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9663662.
  47. ↑ 47.0 47.1 Nottage MK, Lin C, Hughes BG, Kenny L, Smith DD, Houston K, et al. Prospective study of definitive chemoradiation in locally or regionally advanced squamous cell carcinoma of the skin. Head Neck 2017 Apr;39(4):679-683 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28032670.
  48. ↑ Cartei G, Cartei F, Interlandi G, Meneghini G, Jop A, Zingone G, et al. Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged. Am J Clin Oncol 2000 Apr;23(2):181-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10776981.
  49. ↑ 49.0 49.1 Schmidt C, Martin JM, Khoo E, Plank A, Grigg R. Outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center. Head Neck 2015 Dec;37(12):1808-15 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24995842.
  50. ↑
    Unable to find the reference "Citation:Palmer JD, Schneider CJ, Hockstein N, Hanlon AL, Silberg J, Strasser J, et al 2018Strassen U, Hofauer B, Jacobi C, Knopf A 2017"

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