Elective vs Therapeutic Neck Dissection in Treatment of Early Node Negative Squamous Carcinoma of Oral Cavity

• 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.

• Role of ultrasound examination in routine initial workup of a node negative patient. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
• Role of ultrasonogrphy vs clinical examination in ideal follow up of patient. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
• Correlation between the tumour thickness assessment by surgeon on table , on frozen section and final histopathology. [ Time Frame: Within 2 weeks after surgery ] [ Designated as safety issue: No ]
• Identify histological prognostic factors in primary that may help identify a sub-set of patients at an increased risk of cervical metastasis. [ Time Frame: upto 5 years ] [ Designated as safety issue: Yes ]

• 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.

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
4. Identify histological prognostic factors in the primary that may help identify a sub-set of patients at an increased risk for 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 single most important prognostic factor in head and neck cancers. Appropriate management of neck is therefore of paramount importance in treatment of these cancers. Should neck be electively treated or there be a wait and watch policy? Current practice is that neck is always addressed whenever there is an increased propensity to cervical metastasis or when patient follow-up is unreliable. This is usually case with large T staged cancers (T3/T4) and also when the neck is entered at time of surgery for primary.

Situation is however different with regards early cancers of oral cavity (T1/T2). These cancers are usually treated with surgery where excision is through 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 neck electively world over and there is no definite evidence to support either policy of wait and watch or elective neck treatment. Proponents of elective neck treatment cite fact that in those patients whose necks are observed, nodal recurrences are detected at an advanced stage which is detrimental to ultimate outcome of patient.

Major draw back of all trials apart from retrospective nature is fact that total numbers of patients in majority of them are very small (none more than 150, 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. First and most widely cited study was from 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 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 floor of mouth or oral tongue to receive resection of 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 recurrence rate was 42% in resection only group. This translated into a 3.5-year disease free survival group of 49% in resection only arm versus 72% in arm that received END (7). It is obvious from above that major shortcoming in all three studies as in retrospective studies was 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 issue either way once and for all. Origin of such a trial from West is difficult due to relative lack of such cancers in that part of world. At Tata hospital itself on conservative estimate 100-150 patients would be eligible for enrollment each year on such a trial. Moreover 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 management of early T1/T2 cancers with a clinically negative neck. As a consequence current practice world over includes:

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

Primary Objective:

To demonstrate whether elective neck dissection (END) is equal or superior to wait and watch policy i.e.therapeutic neck dissection (TND) in management of clinically No neck in early T1 /T2 cancers of 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
4. Identify histological prognostic factors in the primary that may help identify a sub-set of patients at an increased risk for 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 world over including USA and in India in initial management of a patient with a node negative neck. Moreover an accurate ultrasound of neck is extremely operator dependent and whether its routine use can be recommended particularly in a country may be difficult.
• Specificity of ultrasonography in clinically node negative neck is only 50-70%. This can be increased by addition of fine needle aspiration cytology of enlarged nodes. Doing this procedure routinely in all patients will be difficult or next to impossible given expertise required both by sonologist as well as pathologist particularly in our country.
• Costs- Even though ultrasound is relatively inexpensive there are significant costs and waiting periods involved given number of patients with oral cancers in 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 primary was treated with radiotherapy and patients randomized to either neck dissection or wait and watch six weeks later.

Protocol amendment details:

Protocol amendment was accepted by Scientific ethics committee/Instititional Review board on 29/12/2008 as follows:

All patients will undergo a pre randomization ultrasonography of neck. If USG report suggests metastasis patients would be treated according to merit to avoid ethical concerns and if USG report is normal or indeterminate, patients would be randomized for trial. This protocol amendment is done in view of following 2 reasons.

Very often patients are uncomfortable to give consent when they are explained that initial ultrasonography report will be blinded and findings will not be considered in deciding patient's treatment plan. This resulted in lower recruitment of patients and it also raised ethical issues when blind was not adequately maintained especially if sonography suggested metastasis.

To overcome a difference of opinion amongst examining clinicians about a clinically significant node.

However, breaking blind would have no bearing on outcome / impact of this study.

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

SURGICAL PROCEDURE:

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

• Emphasis will be to achieve a wide clearance with tumor free margins to obviate need of subsequent radiotherapy to 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 size of 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.

Depth of tumor infiltration though probably most important individual prognostic factor in deciding likelihood of cervical metastasis, is unfortunately only available to clinician with final histopathology report. Had this parameter been present at time of surgery 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 accuracy of correlation between gross assessments of thickness by surgeon, on frozen section with final thickness on histopathology and would be of importance in a country like ours where oral cancers are very common and facilities of frozen as well as expertise to measure accurately tumor thickness at histopathology may be unavailable.

POST OPERATIVE RADIOTHERAPY:

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

END POINT OF STUDY:

The primary end point will be overall survival and secondary end point will be DFS. The patients will be followed up until death or study close whichever is earlier. Since overall survival is the primary endpoint, patients will be followed up until death. telephonic or mail contact is acceptable.

Local failures, distant metastasis and second primary will be documented.

DATA COLLECTION, QUALITY CONTROL & ANALYSIS:

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

Assuming baseline overall survival of 60%, for expected improvement in treatment arm of 10% 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 routine follow-up of all patients will be labor intensive. However 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 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 earlier date within range allowed. All patients will be followed up by one of investigators and entry made both in source document as well as central registration cell at CRS with study coordinator. At each examination patients will undergo a through head and neck examination as well as an ultrasound if randomized to that arm.

• Active Comparator: Elective Neck dissection
  Elective vs therapeutic neck dissection in early oral cancer
  Intervention: Procedure: Elective Vs Therapeutic neck dissection in early oral cancer
• Experimental: Wait and Watch
  Wait and Watch.
  Intervention: Procedure: Elective Vs Therapeutic neck dissection in early oral cancer

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.