12.2 Systemic therapies for metastatic cutaneous squamous cell carcinoma
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) and the Brigham and Women’s Hospital tumour staging system, are used to estimate risk and guide further management.
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. 
An Australian RCT 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, metastases to the axilla or groin cSCC of the head and neck, as well as cohorts with a broader range of cSCC presentations.
The RCT 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 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).
One retrospective cohort study (high risk of bias) in patients with cSCC of the head and neck 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. 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.
The RCT 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 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 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 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).
One retrospective cohort study with a high risk of bias 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)
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).
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)  and the Brigham and Women’s Hospital staging system for cSCC.
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. Metastases to groin, axilla or epitrochlear lymph nodes should be managed surgically and adjuvant RT should be considered.
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.
Distant metastases from cSCC are uncommon. 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. Survival is poor despite treatment, with few patients surviving more than 2 years.
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. 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. 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. However, cetuximab is not subsidised by the PBS for the treatment of cSCC.
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.
Typical adverse effects of cisplatin include nausea, vomiting, fatigue, low blood cell counts, infection, renal toxicity, neurotoxicity and ototoxicity. 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.
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.
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. Other drugs include methotrexate, 5-fluorouracil, bleomycin and vindesine. Objective response rates of >80% have been reported, with complete response rates of around 30%.
In some patients, locally advanced disease can be rendered operable with the combination of cisplatin-based chemotherapy and radiotherapy.
Oral 5-fluoropyrimidine analogues are well tolerated and can achieve effective palliation in patients who are elderly and have significant comorbidities.
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.
Evidence summary and recommendations
|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||, , , , , , |
|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||, , , , , , , , , , , , , , , , , |
|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||, , , , , , , , |
|Distant-metastasis free survival/distant control
Only single studies reported these outcomes, all of which reported similar rates between modalities reported.
|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|
|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|
|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|
|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|
CBR 12.2.1. Patients with cutaneous squamous cell carcinoma involving the parotid or cervical lymph nodes should be offered adjuvant radiotherapy after surgery.
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.
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.
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
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.
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. One series showed equivalent outcomes for elective neck node radiotherapy to 50–60Gy, and elective neck dissection followed by radiotherapy.
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.
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, 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. In this study, most patients received cisplatin (n=24) rather than carboplatin (n=10), and mostly at a relatively high dose.
Patients with unresectable local disease can be considered for radiotherapy (platinum-based chemoradiation, if the patient is fit for chemotherapy).
The EGFR agents cetuximab and gefitinib 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.
|PICO question MS1|| Evidence statement form MS1
| Systematic review report MS1
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