Discussion
In recent years, with the development of immunotherapy, there has been
an increasing number of immunotherapy studies on HNSCC, and there are
also drugs approved for treatment of recurrent/metastatic HNSCC after
platinum treatment failure. The two trials involved in this paper,
checkmate-141 [8] and keynote-012 [7], are the basis for the
approval of nivolumab and pembrolizumab, both of which are PD-1
inhibitors. PD-1 is a programmed death protein, which is an important
immune checkpoint for tumours with which they can evade immune
surveillance. It is expressed on the surface of activated T cells, B
cells and NK cells [11]. Like many solid tumours, HNSCC can evade
the immune response of host cells by expressing immunosuppressive
ligands. For example, PD-L1 has two major ligands, PD-L1/PD-L2, which
exist in tumour cells, antigen-presenting cells and stromal cells. The
tumour microenvironment induces infiltration of T cells with a high
expression of PD-1 and tumour cells with a high expression of
PD-L1/PD-L2. The combination of the two leads to the continuous
activation of the PD-1 pathway, the down-regulation of T cell function
and inhibition of the anti-tumour effect of the immune system. At
present, the main antibodies against PD-1 are nivolumab and
pembrolizumab, and the main antibodies against PD-L1 are atezolizumab,
avelumab and durvalumab.
Of the five articles, three were PD-1/PD-L1 inhibitor single drug
treatments compared with chemotherapy. The first article was a PD-L1
inhibitor single drug treatment compared with CTLA-4 inhibitor; the
second was a PD-L1 inhibitor single drug treatment compared with PD-L1
inhibitor combined with CTLA-4 inhibitor; the third article was a PD-L1
inhibitor single drug treatment compared with chemotherapy and a PD-1
inhibitor treatment combined with chemotherapy. Meta-analysis results
showed that there were differences in OS among the groups, but no
differences in PFS and ORR. In the article by Burtness et al. [10],
the ORR was 17% in the study group compared with 36% in the control
EXTREME group. Although immunotherapy is a promising treatment, its
efficacy in patients is limited. The effective rate of single drug
treatment in patients with HNSCC was only about 20%. The effective
rates in the five articles included in this paper were 14.6%, 13.3%,
26.1%, 9.2% and 17%. The median survival times in the five articles
were 8.4 months (6.4–9.4), 7.5 months (5.5–9.1), 9.5 months (9.1–NR),
6.0 months (4.0–11.3), and 14.9 months (no range reported) in the
groups with PD-L1 inhibitor single drug treatment. Apart from one
article, the median survival time was higher than that of the control
group, including the standard chemotherapy, single treatment with CTLA-4
inhibitor, but lower than that of PD-1 inhibitor combined with CTLA-4
inhibitor (6.0 vs 7.6 months).
The use of immunotherapy combined with other adjuvant therapies has been
increasing in recent years. For example, the sensitization effect and
mechanism of action of chemotherapy and radiotherapy are all supported
by the literature. Therefore, it is also hoped that the response rate
can be improved by combining immunotherapy with other therapies to
further extend survival time. In recent and ongoing clinical trials, in
addition to the use of PD-1/PD-L1 inhibitors as a single drug for
treatment, the trials include their combination with other
immunosuppressants, chemotherapy and radiotherapy, etc. Table 4 shows
the current stages of the ongoing phase III clinical trials (registered
at clinicaltrials.gov) for immunotherapy of HNSCC. In addition, a
clinical trial of neoadjuvant immunotherapy for patients with locally
advanced or operable HNSCC is also being carried out, combined with
radiotherapy and chemotherapy to regulate the immune environment and to
work alongside immunotherapy to improve the therapeutic effect [12].
These trials are expected to provide high-level clinical evidence to
support the management of future therapy.
Unlike other treatments, there are many immune-related adverse events
associated with immunotherapy such as anaemia, renal failure, pneumonia,
etc. [13]. In the five articles included in this paper, four of them
recorded adverse events including diarrhoea, asthenia, rash, fatigue,
anaemia, nausea, etc. Our meta-analysis showed that PD-1/PD-L1
inhibitors did not increase the risk of adverse events, but in fact,
reduced the risk of anaemia and gastrointestinal reactions. The main
reason may be because the control group was mainly composed of
chemotherapy or chemotherapy-based comprehensive treatments. No matter
what kind of treatment, the incidence of adverse events in patients was
more than 10%. In the articles included in this study, the adverse
events caused by immunotherapy included skin reaction, endocrine,
gastroenteric, therapeutic, pulmonary, infection reaction, renal injury,
hypothyroidism, and pneumatic events. In the four articles included in
this study and mentioning adverse reactions, the incidences of adverse
reactions in the PD-1/PD-L1 treatment groups were higher than those in
the immunotherapy combined with other auxiliary treatment groups (26%
vs 12%; 63.1% vs 55.4%/57.9%; 58.9% vs 37.5%; 26% vs 12%).
Therefore, from the point of view of adverse reactions, combination
therapy may improve the response rate and improve the therapeutic
effect. There are also no increased risks from the point of view of side
effects. It also provides help for the formulation of future treatment
plans and the improvement of intolerable treatments.