A Trial Evaluating Omission of Radiotherapy to Regional Lymphatic's

Patients of oral cavity squamous cell carcinoma (OCSCC) undergoing surgery are at risk of local as well as regional failure. Postoperative radiotherapy (PORT) is often added to radical surgery with intent to reduce loco regional recurrence and improve overall survival in patients with high-risk features. High risk feature include patients with extra capsular extension, positive/ close margins, more than one lymph node involved, pT3 or pT4 primary disease, lymphovascular invasion (LVI), perineural invasion (PNI). PORT alone or in combination with concurrent chemotherapy is associated with reductions in loco regional recurrence as well as improvement in overall survival (OS). Benefits associated with PORT often come at the expense of development of significant acute and late morbidities that include dysphagia, mucositis, xerostomia, dermatitis, ototoxicity, fibrosis, dental caries, osteoradionecrosis, change in voice changes, and hypothyroidism.

Radiotherapy (RT) portals for head and neck squamous cell carcinomas (HNSCC) have traditionally included primary disease plus treatment of bilateral neck. Larger RT treatment volumes generally correlate with increased incidence of radiation induced morbidity .There is potential to reduce radiation morbidity if RT portals can be reduced without compromising treatment outcomes. One such situation is pN0-pN1neck status. However, at present there is no definite consensus as regards to omission of PORT to regional lymphatic's in pN0 -pN1neck and the benefit of omission of PORT largely remains unknown.

In a non randomized prospective phase II trial, that eliminated PORT to pN0 necks for patients with locally advanced HNSCC, showed that omitting PORT resulted in excellent control rates in the unirradiated neck. This study included 19% patients with OCSCC. Several retrospective series for OCSCC have reported that RT to tumor bed alone in N0-1 neck is associated with similar treatment outcomes as compared to RT to loco-regional sites.The ongoing PRESERVE study is addressing this question and will generate high level evidence in terms of oncologic outcomes, quality of life and toxicity.The PRESERVE study is a multicentre phase II study randomizing 90 patients with T1-4 N0-2 OCSCC with at least one pN0hemi-neck in a 1:2 ratio between standard RT volumes and omission of RT to the pN0 hemi-neck(s). The Eliminate trial is similar to the PRESERVE study but will exclude patients with PN2-pN3 disease. Unlike the PRESERVE study, the ongoing trial will also consider omission PORT in patients with pN1 disease.

A risk of nodal recurrence of 15%-20% has traditionally an indication warrant radiation to a nodal basin. Involvement of two or more nodes is a definite indication for PORT. However, in patients in whom the metastases are limited to a single, ipsilateral positive lymph node not larger than 3 cm (ie, N1), and the routine use of PORT is controversial. In such situations PORT delivery is at discretion of the treating physician. This discrepancy (pN1 status) was also seen in EORTC trial 22931 and RTOG trial 9501criteria for definition of high risk disease. In the EORTC trial 43% of patients enrolled in the trial hadpN0-1 status whereas only 6% of the patients enrolled in the RTOG trial hadpN0-1. The RTOG used the criteria of two or more lymph nodes as indication of PORT whereas in the EORTC trial stage III -IV were one of the criteria for delivery of PORT. There is no prospective study that has considered omission of PORT in pN1OCSCC.

Large retrospective series have demonstrated the benefit of PORT for pN1 disease yet there is declining uses of PORT for pN1 OSCC .The ASCO guidelines also do not recommend PORT in pN1 after adequate neck dissection. A recently published study of the National Cancer Database that comprised 1909 OSCC patients with pN1 disease showed a statistically significant survival benefit in favour of PORT (adjusted HR 0.82). The study reported similar benefit in patients with inadequate and adequate neck dissections. In light of this background, the Eliminate trial is designed to test omission of regional RT in pN0-1 neck.

The aim of this study is evaluate feasibility of omission of RT to regional lymphatics in pN0/pN1 patients undergoing radical surgery with adequate lymph node dissection for oral cavity HNSCC.

Inclusion criteria

• Aged 18 or above and less than 70 years
• Stage pT1-4histological confirmed squamous cell carcinoma of oral cavity undergoing radical excision and ipsilateral/bilateral neck dissection.
• Patient with high risk features: positive or close (≤ 5mm) margin, presence of LVI or PNI, pT3-4
• At least one dissected hemi-neck (at least 12 nodes recovered in one dissected hemi-neck)
• Pathological N0/ N1 neck and high risk features undergoing radiotherapy for HNSCC of the oral cavity
• Brandwein-Gensler (BG) histological risk assessment in all patients
• Karnofsky performance score greater or equal 70
• Ability to complete the MD Anderson Dysphagia Inventory (MDADI) and EORTC quality of life questionnaires English or Hindi Version.
• Timely delivery of PORT preferable within 6weeks of surgery (upto 1-2 weeks of delay beyond 6 weeks is permissible to accommodate for delayed wound healing or other logistics)
• Written informed consent for treatment.
• Available to attend long term follow- up

Exclusion criteria

• Non squamous histology
• Presences of distant metastases
• pT1-2 disease and no high risk features
• Pathologically N2/N3 disease.
• Patients that require re-irradiation for recurrent disease
• Inadequate neck dissection (less than 12 nodes examined)
• Primary tumor reaching midline (within 1 cm from midline) and only ipsilateral neck dissection done
• Initiation of PORT after 8 weeks of radical surgery.
• Previous radiotherapy to the head and neck region
• Any invasive malignancy within previous 2 years (other than non melanomatous skin carcinoma or cervical carcinoma in situ).
• Age < 18 years or > 70 years
• Brandwein-Gensler (BG) histological risk not done