Immunosuppression and several other factors were associated with worse survival outcomes for patients with metastatic head and neck cutaneous squamous cell carcinoma (cSCC), results of a large meta-analysis found.
In the analysis of over 3,500 patients with regional lymph node metastases, immunosuppression was associated with worse disease-specific (HR 3.82, 95% CI 2.47-5.92) and overall survival (HR 2.66, 95% CI 2.26-3.13), reported Danielle MacNeil, MD, of London Health Science Centre in Ontario, Canada, and colleagues.
Additional risk factors were also linked with decreased overall survival, they wrote in JAMA Otolaryngology–Head & Neck Surgery:
- Extracapsular spread: HR 1.90, 95% CI 1.12-3.23
- Lymph node ratio: HR 1.91, 95% CI 1.09-3.35
- Advanced age: HR 1.03, 95% CI 1.00-1.07
By contrast, adjuvant radiotherapy was associated with improvements in both disease-specific survival (HR 0.52, 95% CI 0.33-0.84) and overall survival (HR 0.45, 95% CI 0.27-0.78).
“This meta-analysis provides robust evidence that in patients with metastatic cutaneous squamous cell carcinoma, those who are immunosuppressed and have extracapsular extension (spread of cancer outside of the lymph node) have a worse prognosis than those who don’t,” MacNeil told MedPage Today. “Furthermore, patients who receive radiation after surgery have an improved survival compared to those who don’t.”
In a linked editorial, Brittany Barber, MD, of the University of Washington in Seattle, said the study raises “important clinical questions regarding the significance of immune status and immunotherapy on prognosis” for these patients, including the nature of the immunosuppression (i.e., whether due to a clinical condition or use of medication), whether the immunosuppression is temporary or likely to become permanent, and whether treatment escalation with adjuvant chemoradiotherapy could improve outcomes in those with or without extracapsular spread.
While evidence supports offering systemic treatment to patients with mucosal squamous cancers, MacNeil noted, two studies of adjuvant chemoradiotherapy in this meta-analysis showed no overall survival benefit.
“More research is needed into the impact of immunosuppression, in particular whether the etiology of immunosuppression makes a difference to overall survival, and whether reversing immunosuppression, when possible, improves survival,” MacNeil said, opinions also expressed in Barber’s editorial.
“The role of adjuvant chemotherapy in addition to radiation needs to be further studied as this may improve survival in high-risk patients with extracapsular extension and immunosuppression,” MacNeil continued. “Further research should also focus on the role of immunotherapy in the adjuvant setting.”
The researchers also looked at sex, nodal classification, and perineural invasion, but none were significantly associated with overall survival. “We expected to find a significant association between nodal classification and overall survival,” they noted, hypothesizing that heterogeneous reporting of study endpoints and overlapping cohorts could explain why no link was found.
Extracapsular spread, which had the second highest hazard ratio associated with overall survival in the analysis, was included in the latest American Joint Committee on Cancer (AJCC) staging system, under the highest N classification. Immunosuppression is included “as an additional factor recommended for clinical care of patients,” the authors noted.
Of the 200,000 to 400,000 new cSCC cases in the U.S. each year, nodal metastases are present in approximately 5% of patients, with higher rates seen in the immunosuppressed, and those with recurrent disease or higher-stage tumors. Five-year survival in these patients ranges from 50% to 70% after surgery and adjuvant treatment.
Despite a comparatively low metastatic risk of cSCC versus other malignant tumors, its high prevalence “portends that the absolute number of patients harboring nodal metastases and dying from this disease is substantial,” the authors explained.
For their analysis, the researchers included 20 observational studies and one randomized trial, which in all included 3,534 patients with head and neck cSCC and regional lymph node metastases. The risk factors — age, sex, adjuvant radiotherapy, extracapsular spread, immunosuppression, lymph node ratio, nodal classification, and perineural invasion — had to be assessed in at least three studies for inclusion in the review.
Studies had to include at least 10 metastatic head and neck cSCC patients and have a minimum follow-up of 1 year. Analysis followed a prespecified protocol and used PRISMA guidelines for abstracting data.
The authors acknowledged study limitations, such as its inclusion of a heterogeneous sample of retrospective, single-cohort analyses with inherent biases, many of which had not adjusted for confounding factors and used various approaches to reporting of risk factors and outcomes.
No disclosures were reported by the study authors or editorialist.