Concomitant chemoradiotherapy vs radiotherapy 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 RT alone (60-66Gy/30-33#) or ChemoRT (three weekly cisplatin).r The primary endpoint was locoregional control and secondary endpoints of overall survival and disease free survival. 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 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 radiation therapy alone is the standard treatment in patients without extracapsular extension 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 (30mg/m2) or three weekly cisplatin (100mg/m2).r The study demonstrated that weekly cisplatin was inferior to three weekly cisplatin in prolonging locoregional control.
Optimal radiotherapy dose
The majority of randomised trials in the post-operative setting use doses of 66Gy or higher in for microscopically positive margins at the site of the primary tumour or nodes. The minimum equivalent dose in 2Gy fractions used for treatment for the elective nodal regions is 50Gy. It is recognized that in order to sterilize 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 54Gy (in 2Gy fractions) to 57.6Gy (in 1.8Gy 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. This has been accounted for in the IMRT/VMAT dose prescription tables.
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 postoperative 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 postoperatively.
Bachaud et al.1996 provides evidence of efficacy of weekly concurrent cisplatin (50mg/m2 total weekly dose).r Porceddu et al. 2004 reported similar outcomes with weekly cisplatin (40mg/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 lowdose weekly regimen. Treatment is more likely to be given as planned, compared indirectly to highdose regimens. A second major advantage of lowdose cisplatin regimens is that chemotherapy can be stopped early if major acute toxicity is encountered that threatens completion of radiotherapy.
The incidence of HPV related oropharynx 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
MC1273 was a phase II non-randomised trial of patients with HPV-associated oropharyngeal squamous cell carcinoma.r The study explored an aggressive course of de-escalated adjuvant RT (30-36Gy) and once-per-week docetaxel after curative-intent surgery. They reported locoregional control rates comparable to historical controls. This phase II study requires confirmation from a randomised phase III trial before the results can be broadly applied.
At this stage there is no evidence to support treatment de-escalation in HPV positive patients and we await the results of de-intensification trials.
Peters et al. 2010 reported on the impact of radiotherapy quality on patient outcomes in a large international phase III trial (TROG 02.02).r In patients with major deficiencies in their radiotherapy treatment plan there was a significantly inferior outcome; 2-year overall survival of 50% vs 70%; hazard ratio (HR), 1.99; P< .001; and 2-year freedom from locoregional failure, 54% v 78%; HR, 2.37; <P .001, respectively. These results show the critical importance of radiotherapy quality on outcome of chemoradiotherapy in locally advanced head and neck cancer.
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