The oropharyngeal areas mainly comprises of the tonsil, base tongue (BOT), soft palate and the posterior pharyngeal wall. Traditionally, surgical resection of oropharyngeal cancers (OPC) was a standard procedure, often performed through mutilating incisions with mandibulotomies, rendering significant post-operative functional deficits. Over the past 2 decades, there has been a major shift in treatment strategy with a majority of these cancers now being treated by primary concurrent chemoradiation (CCRT) with a trend towards organ and function preservation.

The oropharyngeal region primarily comprises the tonsil, base tongue (BOT), soft palate and posterior pharyngeal wall. Traditionally, surgical resection of oropharyngeal cancers (OPC) was a standard procedure, often performed through mutilating incisions with mandibulotomies, rendering significant post-operative functional deficits. Over the past 2 decades, there has been a major shift in treatment strategy with a majority of these cancers now being treated by primary concurrent chemoradiation (CCRT) with a trend towards organ and function preservation. The landmark trial determining effective treatment options for OPCs was by the RTOG group (0129) that provided strong evidence for HPV status being an independent prognostic factor for overall survival (OS) and progression-free survival (PFS), with these patients having significantly improved outcomes. Furthermore, after adjusting for demographics, T stage, N stage and smoking status, the HPV positive population had a 58% reduction in the risk of death and a 51% reduction in risk of progression or death. Most of the discussion today in HPV positive OPC is based on treatment- intensification to improve quality of life (QOL) measures.

A more concerning issue is the poor outcome, both survival, and QOL, seen in the "high-risk" HPV negative OPCs. When treated with radical CCRT, HPV negative patients have substantially reduced survival, both in terms of locoregional control (LRC) and OS. In the RTOG 0129, the HPV negative population had a 25.1% reduction in OS at 3 years (57.1% vs 82.4%) when compared to patients with HPV positive tumors. The locoregional relapse rate at 3 years was 21% higher in these patients (35.1% vs 13.6% for HPV positive tumors). Moreover, the salvage rates in oropharyngeal cancers that have undergone radical CCRT are quite low with only a third of the recurrences being amenable for salvage surgery. This led to a trend of intensification of management for these HPV negative tumors with altered fractionation schema,CCRT, multi-drug induction chemotherapy and targeted molecular therapies. Even with all these efforts, simply altering the method of radiation delivery, dosing and/or adding different types of concurrent chemotherapy is not seeming to be sufficient to improve oncologic outcomes in HPV negative tumors.

In the contemporary literature, an approach to further intensify treatment would be the addition of upfront surgery on this high-risk HPV negative OPCs. The recent advances in head neck surgery incorporate minimally invasive techniques and some focus around a transoral approach. These include transoral laser microsurgery (TLM) and transoral robotic surgery (TORS). Compared to the open approaches, these have minimal or no external incisions and do not require morbid access procedures. TLM is a surgical technique used in combination with an endoscope or direct laryngoscopy, operating microscope and a carbon dioxide (CO2) laser. TORS is performed using a robotic system, the arms of which are placed within the patient's mouth but controlled by a surgeon sitting at a remote console. The surgeon is provided with an endoscopically derived 3-dimensional view used to perform an enblocresection of the oropharyngeal tumor. Open surgery today incorporates modified techniques in osteotomy design, fixation and reconstruction methods to reduce and/or eliminate the traditional complications and have the additional advantage of direct visualization of the tumor. To add to this, radiotherapy techniques have also improved with more concentrated dosing obtained with intensity-modulated radiotherapy (IMRT) resulting in fewer complications.

Irrespective of the management received, patients with oropharyngeal tumors have a significant impact on the swallowing function and quality of life (QOL). Multiple factors are thought to contribute to the severity of this dysphagia, including multimodality therapy (surgery, RT, chemotherapy), total radiation dose, dosimetry to organs at risk (OAR) and intrinsic patient radiosensitivity and susceptibility to fibrosis. Majority of the current data on QOL are from single institution studies. Sinclair et al found that patients undergoing TORS for early OPCs have an initial decrease in mean dysphagia scores using the MD Anderson Dysphagia Inventory-Head and Neck (MDADI-HN) in the immediate postoperative period when compared to baseline pre-operative scores, although a gradual increasing improvement was observed over time. The global and physical subscales were most affected in the immediate postoperative period with the recovery of scores observed at last follow up. Postoperative chemotherapy predicted gastrostomy tube dependence for greater than 3 months. Hurtuk et al have shown a decrease from baseline immediately after surgery in speech, eating, aesthetic, social, and overall QOL domains, using the Head and Neck Cancer Inventory (HNCI). However, at 1 year, the health-related QOL in the aesthetic, social, and overall domains were high. Eating function and attitude were the only variables not returning to the high domain. In another population-based analysis of head neck cancers, oropharyngeal cancers had the second-highest prevalence of dysphagia, with 31% of patients demonstrating elevated episodes of aspiration relative to baseline greater than 1 year after receiving treatment. Weinstein et al reported long-term dependence on tracheostomy and gastrostomy was seen in 2.4% and 5%, respectively.(21) Even in the RTOG study,43% of the patients had severe long-term Grade 3 or 4 toxicity requiring a feeding tube/gastrostomy for more than 2 years or longer and death without cancer progression. Nichols et al recently attempted to answer some of these questions (ORATOR trial) in a randomized trial for early OPCs treated with CCRT versus TORS. They found the MDADI scores at 1-year were statistically superior in the RT arm (p = 0.042), but not meeting the definition of a clinically meaningful change (powered to detect a 10-point improvement). For the other QOL metrics, outcomes were similar at 1-year. Feeding tube rates were 3% in the RT arm vs 0% in the TORS arm. Even the rates of treatment-related grade ≥2 adverse events (AEs) were similar, with more neutropenia, constipation, and tinnitus in the RT arm and more trismus in the TORS arm. The findings of aspiration on modified barium swallow (MBS) have been significantly predictive of pneumonia in many trials of chemotherapy and IMRT in oropharyngeal cancer (p=0.017, Sensitivity 80%, Specificity 60%), and silent aspiration was evident on MBS studies in 63% of patients who developed pneumonia. In addition, pharyngeal residue in MBS studies was significantly associated with the development of pneumonia after chemotherapy and IMRT (p<0.01). These results offer compelling support for the examination of objective swallowing impairment (ie, "airway protection" and "pharyngeal transit") as these health-related endpoints cannot be obtained by patient-reported outcome (PROs) measures alone. Even the long-term results of RTOG 9111 study showed unknown mortality in 30% of the patients who received chemo-radiation, possibly due to silent aspiration. Hence, a lot of unanswered questions remain in determining the optimum management of OPCS that have minimal complications and maximum survival advantage.

Inclusion Criteria:

1. Histopathology proven diagnosis of squamous cell carcinoma of the oropharynx, localized to the tonsil and/or lateralized tongue-base

2. ECOG Performance Status ≤2

3. Age ≥18 to 70 years

4. Anesthetic fitness obtained for surgery under general anesthesia

5. Resectable primary tumor with an anticipation of achieving resection free margins either by minimally invasive/open techniques

6. Clinical stage III or IV, i.e. T1-T2 or T3-T4 with N0-N3. Nodal disease withextranodal extension on clinical examination/imaging may be included at the surgeon's discretion, if the nodal disease is deemed resectable by the operating surgeon

7. HPV negative status determined by p16 status.

8. No distant metastases below the clavicles, based upon the following minimum diagnostic workup:

   1. History/physical examination by the physician.
   2. Imaging of the head and neck (Contrast enhanced MRI for local workup and Chest CT/PET-CT for distant metastatic workup)

9. Patients with no contraindications to Cisplatin chemotherapy and radiotherapy

10. Adequate organ function

    1. Hematological- Hb> 10 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L.
    2. Liver functions- bilirubin ≤ 2 x upper limit normal (ULN), AST/ALT/ ALP ≤ 2.5 x ULN, S. albumin ≥ 30 g/L.
    3. Renal function- Creatinine ≤ 1.5 ULN, Creatinine clearance > 50 mL/min.

11. Women of child bearing age should have a negative pregnancy test at the time of randomization and should be willing to use adequate contraception during the treatment phase of the trial

12. Patients who can be followed up and must be able to provide informed consent prior to study entry

Exclusion Criteria:

1. Prior head and neck malignancy

2. Prior invasive malignancy, unless disease free for a minimum of 3 years

3. Prior chemotherapy for a different cancer administered within 3 years prior to registration

4. Patients who have received any neoadjuvant/ induction chemotherapy

5. Prior radiotherapy to the region of the head and neck that would result in overlap of radiation therapy fields

6. Unresectable primary or nodal disease involving the carotid vessels, prevertebral fascia or skull base

7. Large soft palate involvement >1 cm

8. Deep extension into larynx, pre-epiglottic space and deep invasion into extrinsic muscles of tongue

9. Calculated GFR < 50 cc/min

10. Patients who have uncontrolled cardiac comorbidity

    1. QTc prolongation (a value of >450 milliseconds)
    2. Ejection fraction below 50%
    3. Presence of regional wall akinesia

11. Presence of previous episode of thrombosis or embolism or presence of a prothrombotic condition in last 1 year

12. Presence of severe malnutrition as defined by body mass index of below 16kg per m2 or presence of weight loss of greater than 20% in last 6 months

13. Severe active co-morbidities such as severe cardiac failure, severe pulmonary compromise, type 1or 2 diabetes mellitus (Hb1ac of > 8 mg/dl) severe and active infections or life expectancy less than 6 months

14. Prior allergic reaction to cisplatin

15. Radiographic evidence of retropharyngeal and/or level VI metastasis

16. Patients on other investigational drugs within last 30 days

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