New developments in radiation oncology for head and neck cancers

One possible option is to switch a cytotoxic agent like cisplatin to a less toxic agent as cetuximab while maintaining the standard radiotherapy dose prescription (70 Gy). Three prospective trials, the De-ESCALaTE HPV trial, RTOG1016 and TROG12.01 have evaluated the impact. In these trials non-inferiority of cetuximab was not achieved and cisplatin-based chemoradiotherapy (CRT) remained the standard of care in HPV-driven oropharyngeal squamous cell cancer (OPSCC) [4‐6].

RTOG1016 was a non-inferiority randomized controlled trial (RCT) randomizing 987 patients with p16-HPV-positive OPSCC to cisplatin or cetuximab with accelerated radiotherapy of 70 Gy in 35 fractions in 6 weeks (6 fractions/week). Reduced overall survival (OS) at 5 years and locoregional control (LRC) rates were shown in the cetuximab vs cisplatin arm (OS 77.9 vs 84.6%, p = 0.016, LRC 82.7 vs 90.1%, p = 0.0005). Moreover, in terms of toxicity, acute or late side effects were not significantly reduced [4]. The De-ESCALaTE HPV trial and the TROG12.01 trial showed similar results in terms of reduced tumour control without reduction of treatment-related toxicity [5, 6].

Another approach aims to apply lower doses of radiation and/or chemotherapy, possibly reducing side effects, without compromising the oncological outcome.

NCT01530997 and NCT02281955 trials in patients with HPV-positive OPSCC tumours with stages T0-T3, N0-N2c, M0 and < 10 pack–year (py) smoking history, showed encouraging results when reducing the radiation dose from 70 to 60 Gy, and decreasing the cisplatinum dose by 20–40% [7, 8]. Despite the lower radiation and chemotherapy dose, these two subsequent trials showed impressive tumour control with moderate toxicity. In 114 patients the complete response rate with positron emission tomography/computer tomography (PET/CT) was 93% and 80% at the primary tumour site and the neck. The 2‑year progression-free survival (PFS) and OS were 86 and 97% without any grade 3 or higher adverse late effects [7, 8].

NRG-HN002 studied the possible omission of simultaneous chemotherapy in HPV-positive patients. In this trial 316 patients were randomized to either 60 Gy intensity-modulated radiotherapy (IMRT) in 6 weeks with concomitant weekly cisplatin 40 mg/m² or accelerated stand-alone IMRT 60 Gy in 5 weeks [9]. Because of lower PFS in the IMRT alone arm at 5 years (87.6% vs. 90.5% in the combined arm), this study failed to meet acceptability criterion of non-inferiority.

The ongoing study NCT03799445 is evaluating the impact of dual treatment with nivolumab and ipilimumab followed by IMRT up to 50–66 Gy on disease outcome in advanced HPV-associated SCC.

NRG-HN005 (NCT03952585) is a prospective trial aiming to randomize 711 patients with p16-HPV-positive OPSCC to either reduced dose of radiotherapy (RT) (60 Gy in 6 weeks) with cisplatin, reduced dose of RT (60 Gy in 5 weeks) with nivolumab or standard of care RT of 70 Gy in 5 weeks with cisplatin.

The results of these studies are highly awaited, because of some cautions regarding negative results from the NCT02952586 and GORTEC 2017-01 studies [10, 11].

With technological improvements in RT delivery leading to better dose conformity, such as IMRT, volumetric arc radiotherapy (VMAT) and proton therapy, additional attention may be dedicated to reducing the overall RT dose to healthy tissue without compromising the tumour dose. A reduction in the dose to critical structures, e.g. the salivary glands, resulted in reduced long-term toxicity and improved quality of life [12]. Together with improved target definition using advanced imaging (magnetic resonance imaging [MRI], PET/CT), improved accuracy of radiation delivery using image-guided radiotherapy (IGRT) and even reacting to tumour volume changes during the treatment course through image-guided adaptive radiotherapy (IGART), the overall toxicity can be reduced without treatment de-intensification to the tumour site ([13], Figs. 2 and 3).

MRI-guided adaptive radiotherapy is a novel strategy using a magnetic resonance linear accelerator (MR-Linac) in order to track volume changes in the tumour in real time throughout the treatment course and adapt the RT volumes accordingly. This newest development in the treatment of head and neck cancers is being adopted in clinical practice. With the help of MRI guidance, both target volume reduction and safe dose de-escalation can be combined for primary and elective target areas [14‐17].

The JAVELIN Head and Neck 100 trial was aiming at improvement of outcomes in patients with locally advanced head and neck cancers by combination of avelumab (monoclonal PD-L1 antibody) with chemoradiotherapy [10]. In all, 697 patients with high-risk HNSCC who received radiochemotherapy with standard IMRT dose and 3 cycles of cisplatin at 100 mg/m² were randomized to receive avelumab 10 mg/kg biweekly followed by 12 month maintenance or placebo. Unfortunately, the trial was stopped at the time of preplanned interim analysis, because the study was unlikely to meet the primary objective of prolonging PFS [10].

The key factor in local or distant failure is treatment resistance. One possible mechanism is evasion of apoptosis enabling cancer cells to resist cell death. Inhibitors of apoptosis proteins (IAPs) are overexpressed in cancer, including HNSCC, increasing the resistance of cancer cells to apoptosis. Xevinapant is a small molecule IAP inhibitor, which restores cancer cells sensitivity to apoptosis. In a very promising double-blind randomized phase 2 study, xevinapant in addition to chemoradiation significantly improved local control [20]. Side effects did not differ between the two groups. With longer follow-up, the risk of locoregional failure was reduced by 54% in the xevinapant plus CRT arm versus the placebo plus CRT arm, but this did not reach statistical significance (p = 0.0893). The risk of death or disease progression was reduced by 67% for patients receiving xevinapant (p = 0.0019) [21]. The Trylinx phase III study investigating xevinapant in a larger population will show whether this approach could be practice changing.

The Keynote 412 study is a randomized phase III study evaluating the efficacy and safety of pembrolizumab or placebo given concomitantly with CRT followed by maintenance therapy in patients with locally advanced (LA) HNSCC. The rationale for this study was also to address the need for an effective treatment option with potential of improving patient outcome. The addition of pembrolizumab was associated with a favourable trend toward improved event free survival (EFS), however the difference did not reach statistical significance [22].

Meta-analysis of head and neck cancer patients > 70 years of age and with poor performance status treated with concurrent chemoradiotherapy showed higher noncancer-related mortality nullifying the beneficial impact of concurrent chemotherapy [23]. Especially the tolerability to cisplatin is lacking in older patients due to a low serum creatinine clearance and sensorineural hearing loss [24]. Docetaxel is a possible alternative in this frail population. To prove its efficacy over radiotherapy alone a randomized trial in this cisplatin-ineligible population was performed [25]. The study included 356 patients, randomized to receive radiation alone or with concurrent docetaxel 15 mg/m² once weekly for a maximum of 7 cycles. The disease-free survival (DFS) at 2 years was 30.3% versus 42% in the RT and docetaxel-RT arm (p = 0.002); the 2‑year overall survival was 41.7% versus 50.8% (p = 0.035). The locoregional control was 45.3% versus 58.2% in RT and docetaxel-RT arm at 2 years (p = 0.009). There was a higher incidence of ≥ grade 3 acute adverse events.