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.