Efficacy
Concomitant chemoradiation therapy versus radiation therapy alone
The evidence supporting this protocol is provided by phase III trials by Bernier et al. 2004 (EORTC 22931), Cooper et al. 2004 (RTOG 9501), Bachaud et al. 1996, and Noronha et al. 2018.rrrr
Bernier et al. 2004 and Bachaud et al.1996 demonstrated that adjuvant concomitant chemotherapy in patients with high risk features for local and regional recurrence, compared with postoperative radiation alone, improved locoregional control, disease free survival and overall survival.rr
Cooper et al. 2004 randomised patients with head and neck cancer (oral cavity, oropharynx, hypopharynx, glottic) to radiation therapy (RT) alone (60-66Gy/30-33#) or ChemoRT (three weekly cisplatin).r The primary endpoint was locoregional control and secondary endpoints of overall survival (OS) and disease free survival(DFS). At a median follow up of 9.4 years, locoregional control rates, DFS and OS rates were not different between the two cohort groups. However, on subgroup analysis, in a subset of patients with extra capsular extension (ECE) and/or microscopically involved margins, concurrent chemotherapy and RT is associated with statistically significantly improved locoregional control and DFS.
In patients without ECE or positive surgical margins, combined analysis of EORTC 22931 and RTOG 9501 trials showed no statistically significant reduction in locoregional control or overall survival by the addition of chemotherapy.r Therefore, adjuvant RT alone is the standard treatment in patients without ECE and/or positive margins.
Noronha et al. 2018 randomised locally advanced head and neck patients (oral cavity, oropharynx, hypopharynx, larynx, or metastatic cervical lymphadenopathy of unknown primary) to weekly cisplatin (30 mg/m2) or three weekly cisplatin (100 mg/m2).r The study demonstrated that weekly cisplatin was inferior to three weekly cisplatin in prolonging locoregional control.
Optimal radiation therapy dose
The majority of randomised trials in the post-operative setting use doses of 66 Gy or higher in for microscopically positive margins at the site of the primary tumour or nodes. The minimum equivalent dose in 2 Gy fractions used for treatment for the elective nodal regions is 50 Gy. It is recognised that in order to sterilise the elective volume within the surgical bed, a higher dose is required due to a number of factors including risk of tumour spillage and postoperative hypoxia. Typically a minimum equivalent dose of 54 Gy (in 2 Gy fractions) to 57.6 Gy (in 1.8 Gy fractions) is given.rr When delivering treatment in a single phase, simultaneous integrated boost technique, additional dose is required to account for the lower dose per day received to lower dose regions and therefore treatment prolongation.
Optimal chemotherapy dose schedule
The optimal dose and schedule of cisplatin is controversial. The two largest trials addressing the role of radiation with concurrent cisplatin in the post-operative setting utilised a high dose cisplatin regimen.rr
It should be noted that this regimen is associated with a substantial increase in adverse effects and is often poorly tolerated, particularly post-operatively.
Bachaud et al.1996 provides evidence of efficacy of weekly concurrent cisplatin (50 mg/m2 total weekly dose).r Porceddu et al. 2004 reported similar outcomes with weekly cisplatin (40 mg/m2) compared to those previously reported with high dose cisplatin, but no comparative trials have been conducted.r There are two major advantages of a low dose weekly regimen. Treatment is more likely to be given as planned, compared indirectly to high dose regimens. A second major advantage of low dose cisplatin regimens is that chemotherapy can be stopped early if major acute toxicity is encountered that threatens completion of radiation therapy.
Human papillomavirus (HPV) status
The incidence of HPV related oropharynx squamous cell carcinoma (SCC) is increasing. These patients have a different profile to HPV unrelated head and neck SCC. HPV positive tumours carry a better prognosis than HPV negative tumours.rr This can be mitigated by their smoking history.r
There are preliminary results supporting treatment de-escalation in HPV positive patients, though this is not standard of care outside the context of a clinical trial.
MC1675 (DART) was a phase III randomised trial of patients with HPV associated oropharyngeal SCC, managed with surgery and adjuvant radiation.r Patients with intermediate risk factors (excluding T4 disease and positive margins) were assigned to either dose reduced radiation (30 Gy for no extranodal extension or 36 Gy for extranodal extension, with radiation therapy administered twice daily and given concurrently with docetaxel 15 mg/m2 weekly) or standard of care (60 Gy in 30 fractions given once daily with concurrent weekly cisplatin 40 mg/m2). Two year overall survival (OS) was 96.1% (dose-reduced arm) versus 97% (standard of care). Grade ≥3 adverse events (AEs) at 3 months were 1.6% (dose-reduced arm) versus 7.1% (standard of care).r
A randomised phase II trial (ECOG 3311) assigned Stage III-IV HPV positive oropharyngeal cancer to one of four adjuvant treatment arms based on risk.r Low risk patients were closely observed, with 3 year OS of 100%. Intermediate risk patients were randomly assigned to either low dose (50 Gy) or standard dose (60 Gy) adjuvant radiation. Three year OS was 95% vs 99% (50 Gy vs 60 Gy). Patients receiving 50 Gy had lower rates of grade 3 or greater toxicity (15% vs 25%) and improved quality of life (FACT-H&N) from baseline to six months post treatment (63% vs 49%).r
There are several ongoing de-intensification trials including PATHOS (NCT02215265), HNCUP (NCT04489212 ), DART 2.0 (NCT05541016) and ADAPT (NCT03875716).
Depth of invasion
There is evidence to suggest that pathological tumour thickness is a predictor for cervical lymph node involvement in SCC of the oral cavity. Huang et al. 2009 have indicated that the optimal tumour thickness cutoff point is 4mm.r