Limitations
Several limitations must be considered in addition to those already
discussed. Firstly, diagnostic and treatment protocols varied
considerably both within and between studies. In some, treatment
approaches varied upon likely putative primary site (61), and others
reported a change in practice during the study period (60). Whilst some
studies identified which patients were not treated ‘per protocol’
(53,54) (usually due to patient refusal of adjuvant treatment), the
majority gave no explanation for decision making regarding treatments
given, leading to potential selection bias. The lack of clarity
regarding patients excluded, small sample sizes, and attrition rates in
several studies leads to potential concerns for reporting bias within
the studies. The geographical differences in incidence of disease (65)
and prognostic impact of p16 (66) mean that the tumour biology both
within and between these studies is likely to be variable, impacting on
the results and interpretability.