Cervical metastasis is the single most important prognostic factor in head and neck cancers. Appropriate management of the neck is therefore of paramount importance in the treatment of these cancers. While it is obvious that the positive neck must be treated, controversy has always surrounded the clinically node negative neck with respect to the ideal treatment policy.The situation is difficult with regards to early cancers of the oral cavity (T1/T2). These cancers are usually treated with surgery where excision is through the per-oral route. Elective neck dissection in such a situation is an additional surgical procedure with its associated costs, prolonged hospitalization and may be unnecessary in as high as 80% of patients who finally turn out to be pathologically node negative. Should the neck be electively treated or there be a wait and watch policy? Current practice is that the neck is always addressed whenever there is an increased propensity to cervical metastasis or when patient follow-up is unreliable.

There is clearly a need therefore for a large randomized trial that will resolve the issue either way once and for all.

Primary Objective:

To demonstrate whether elective neck dissection (END) is equal or superior to the wait and watch policy i.e.

therapeutic neck dissection (TND) in the management of the clinically No neck in early T1 /T2 cancers of the oral cavity.

Secondary Objective:

1. Does Ultrasound examination have any role in the routine initial workup of a node negative patient?
2. How are patients ideally followed up -does sonography have a role or is clinical examination sufficient.
3. Is assessment of tumor thickness by the surgeon at the time of initial surgery accurate -Is there a correlation between tumor thickness as measured grossly by the surgeon, at frozen section versus final histopathology.
4. Identify histological prognostic factors in the primary that may help identify a sub-set of patients at an increased risk of cervical metastasis.

ELECTIVE VERSUS THERAPEUTIC NECK DISSECTION IN THE TREATMENT OF EARLY NODE NEGATIVE SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY

INTRODUCTION AND BACKGROUND INFORMATION:

Cervical metastasis is the single most important prognostic factor in head and neck cancers. Appropriate management of the neck is therefore of paramount importance in the treatment of these cancers. Should the neck be electively treated or there be a wait and watch policy?

Current practice is that the neck is always addressed whenever there is an increased propensity to cervical metastasis or when patient follow-up is unreliable. This is usually the case with large T staged cancers (T3/T4) and also when the neck is entered at the time of surgery for the primary.

The situation is however different with regards early cancers of the oral cavity (T1/T2). These cancers are usually treated with surgery where excision is through the per-oral route. Elective neck dissection in such a situation is an additional surgical procedure with its associated costs, prolonged hospitalization , morbidity and may be unnecessary in as high as 80% of patients who finally turn out to be pathologically node negative. There is considerable debate whether to treat the neck electively the world over and there is no definite evidence to support either the policy of wait and watch or elective neck treatment. Proponents of elective neck treatment cite the fact that in those patients whose necks are observed, nodal recurrences are detected at an advanced stage which is detrimental to the ultimate outcome of the patient.

The major draw back of all trials apart from the retrospective nature is the fact that the total numbers of patients in majority of them are very small (none more than 150, the majority less than 100) and over different time spans to draw meaningful conclusions. It would therefore be attractive to prove this point conclusively in a prospective randomized trial.

To date there have been three prospective trials conducted to address this issue, two were inconclusive while one showed a benefit towards elective neck dissection. The first and most widely cited study was from the Institute Gustave- Roussy in 75 patients with oral cavity cancers who had either elective or salvage RND.In this study, both groups of patients had similar survival rates . Fakih et.al. ,reported similar findings in a study from our institution where 100 patients were randomized into two groups, elective neck dissection versus wait and watch. Only 70 of these were evaluable. Disease free survival (median follow-up 20 months) was 52 % versus 63% in patients who underwent hemiglossectomy alone and those who underwent hemiglossectomy and radical neck dissection, respectively. This difference though slightly in favor of the elective neck dissection was not statistically significant . Finally a prospective trial conducted by Kligerman and co-workers in Brazil randomized 67 patients with T1-2 N0 SCC of the floor of mouth or oral tongue to receive resection of the primary alone or resection and elective neck dissection. Occult disease was seen in 21% of those who had received END and recurrence was seen in 24% of patients in this group. By comparison the recurrence rate was 42% in the resection only group. This translated into a 3.5-year disease free survival group of 49% in the resection only arm versus 72% in the arm that received END (7). It is obvious from the above that the major shortcoming in all three studies as in the retrospective studies was the relatively small number of patients recruited in these trials (75, 100 & 63).

Thus there is clearly a need for a large randomized trial that will resolve the issue either way once and for all. The origin of such a trial from the West is difficult due to the relative lack of such cancers in that part of the world. At the Tata hospital itself on conservative estimate 100-150 patients would be eligible for enrollment each year on such a trial. Moreover the trial design and treatment arms are simple and this is ideal for a multicentre trial in India as standardization and uniformity would be easily achievable across all participating centers.

Presently there is no global consensus on the management of early T1/T2 cancers with a clinically negative neck. As a consequence current practice the world over includes:

1. Elective neck dissection as a staging procedure . Clinical assessment of the lesion with respect to size and depth of infiltration.
2. Assessment of the neck with ultrasound or ultrasound guided FNAC or CT / MRI.
3. Wait and watch policy (in the belief that neck dissection is unnecessary in up to 80% of patients)
4. Interval neck dissection
5. Sentinel node biopsy. The trial proposed will help answer all the above questions except the last.

AIMS OF STUDY

Primary Objective:

To demonstrate whether elective neck dissection (END) is equal or superior to the wait and watch policy i.e.therapeutic neck dissection (TND) in the management of the clinically No neck in early T1 /T2 cancers of the oral cavity.

Secondary Objective:

1. Does Ultrasound examination have any role in the routine initial workup of a node negative patient?
2. How are patients ideally followed up -does sonography have a role or is clinical examination sufficient.
3. Is assessment of tumor thickness by the surgeon at the time of initial surgery accurate -Is there a correlation between tumor thickness as measured grossly by the surgeon, at frozen section versus final histopathology.
4. Identify histological prognostic factors in the primary that may help identify a sub-set of patients at an increased risk of cervical metastasis.

Stratification criteria:

1. Size
2. Sex
3. Site
4. Sonography

Ethical Concerns:

1. Should patients with ultrasonography findings suggestive of metastasis be removed from randomization

• Ultrasonography is a simple and often used method to detect neck metastasis. Sensitivity ranges from 50-75%. These figures are much higher in centers that routinely practice sonography to detect neck metastasis as in some centers in Europe. However it is not an accepted standard of care the world over including the USA and in India in the initial management of a patient with a node negative neck. Moreover an accurate ultrasound of the neck is extremely operator dependent and whether its routine use can be recommended particularly in a country may be difficult.
• Specificity of ultrasonography in the clinically node negative neck is only 50-70%. This can be increased by the addition of fine needle aspiration cytology of enlarged nodes. Doing this procedure routinely in all patients will be difficult or next to impossible given the expertise required both by the sonologist as well as the pathologist particularly in our country.
• Costs- Even though the ultrasound is relatively inexpensive there are significant costs and waiting periods involved given the number of patients with oral cancers in the country.
• There is no evidence in literature that sono detection of occult metastasis and immediate surgery translates into better control or survival.
• Interval neck dissection was performed in Vandenbrooks prospective series where the primary was treated with radiotherapy and patients randomized to either neck dissection or wait and watch six weeks later.

Randomization (I): All patients will be randomly allocated into one of the two arms: wait and watch policy group or elective neck dissection group. Both the arms will have similar wide excision of the primary tumor in the oral cavity per oral route.

Randomization (II): Following surgery and after complete recovery prior to discharge, patients will be randomized a second time for follow-up into two arms namely clinical examination versus clinical examination and ultrasonography of the neck.

SURGICAL PROCEDURE:

Primary: The tumor will be excised after proper exposure via the per-oral route.

• Emphasis will be to achieve a wide clearance with tumor free margins to obviate the need of subsequent radiotherapy to the primary, which would otherwise act as a confounding factor.

Neck: Patients randomized to neck dissection will undergo a standard supra-omohyoid neck dissection that will involve clearance of nodal Levels I, II, and III.Completion MND will be done as and when required. Patients who develop metastatic adenopathy on follow-up will undergo a modified neck dissection/radical neck dissection depending on the size of the metastatic disease. Those who have nodes suggestive of metastasis on follow-up sonography, will undergo a supraomohyoid dissection, frozen section followed by a modified neck dissection if positive.

The depth of tumor infiltration though probably the most important individual prognostic factor in deciding the likelihood of cervical metastasis, is unfortunately only available to the clinician with the final histopathology report. Had this parameter been present at the time of surgery the patient with an increased likelihood of metastasis could have undergone an elective neck dissection while those with a lower incidence could have been saved an unnecessary operation .This study would help find out the accuracy of correlation between the gross assessments of thickness by the surgeon, on frozen section with the final thickness on histopathology and would be of importance in a country like ours where oral cancers are very common and the facilities of frozen as well as the expertise to measure accurately tumor thickness at histopathology may be unavailable.

POST OPERATIVE RADIOTHERAPY:

The standard accepted criteria will be followed. Patients receiving post operative radiotherapy for the primary will not be included in the main analysis but will be analyzed separately (Escape clause).

END POINT OF STUDY:

The patients will be followed for a minimum of 24 months but an attempt will be made up to 60 months. The end point will be regional recurrence with a controlled primary or disease free survival at 24 months, whichever is earlier. Local failures, distant metastases and second primary will be documented. An attempt will be made to follow-up all patients till death / completion of a minimum of 24 months. (This assumption is based on the fact that 90% of recurrences in head & neck cancer occur within the first 24 months).

DATA COLLECTION, QUALITY CONTROL & ANALYSIS:

All data will be collected and kept at the Trial Office in the Clinical Research Secretariat. Data will be collected on separate protocol sheets (clinical, radiological, and pathological) and kept in the trial office along with the source documents. Trial coordinator will be responsible for the upkeep of the data.

Assuming the baseline overall survival of 60%, for expected improvement in treatment arm of 10% the no. of patients required will be is 710 (355 in each arm) with α=0.05 (one sided) & power of 80% (β=20). An interim analysis is planned at 250 events (death) occur.

Ultrasound in the routine follow-up of all patients will be labor intensive. However the median follow-up to recurrence in all studies both retrospective/prospective has been 9 months on an average (range 6 months- 13months). It will therefore be important to follow patients every vigilantly in the first 12 months from primary treatment. Follow-up schedules will be: First visit: 4 weeks;First 6 months: 4-6 weeks; 6-12 months: 6-8 weeks; 12 months- 2 years: 8-12 weekly; Thereafter: 3 monthly.

Patients will be encouraged and counseled to come for check up on the earlier date within the range allowed. All patients will be followed up by one of the investigators and entry made both in the source document as well as the central registration cell at the CRS with the study coordinator. At each examination patients will undergo a through head and neck examination as well as an ultrasound if randomized to that arm.

Inclusion Criteria:

1. Histologically proven T1 or T2 N0 M0 (clinical) squamous cell carcinoma of the buccal mucosa, lower alveolus, oral tongue and floor of mouth.
2. Surgery is the preferred treatment and the primary tumor can be excised with clear margins via the per-oral route.
3. No history of a prior malignancy in the head and neck region.
4. No prior malignancy outside the head and neck region in the preceding 5 years.
5. Patient will be reliable for follow-up
6. Age> 18 years and < 75 years.
7. No significant co-morbid conditions - ASA grade II and I.
8. Understands the protocol and is able to give informed consent.

Exclusion Criteria:

1. Prior radiotherapy or surgery for malignancy in the head and neck region.
2. Non squamous cell carcinomas of the oral cavity.
3. Upper alveolus and palatal lesions where there is a possibility of retropharyngeal node involvement.
4. Per-oral excision of tumor will compromise margins in the opinion of the treating surgeon.
5. Significant co-existing pre-malignant conditions like erytho-leucoplakia and oral sub mucous fibrosis that in the opinion of the clinician would interfere in the planned treatment management of the patient.