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

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Brief Title

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

Official Title

Elective Versus Therapeutic Neck Dissection in the Treatment of Early Node Negative Squamous Cell Carcinoma of the Oral Cavity

Brief Summary

      Cervical nodal 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.
    

Detailed Description

      Stratification criteria:

        1. Size

        2. Sex

        3. Site

        4. Sonography

      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.

      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:

      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.

      SUMMARY OF PROTOCOL AMENDMENTS The first version of the protocol (hereafter called Version 1)
      received approval from the Institutional Ethics Committee in September 2003.The most recent
      version of the protocol (hereafter called Version 4) received approval from the Institutional
      Ethics Committee in June 2014.

      Version 1 dated: September 2003 Version 2 dated: December 2008 Version 3 dated: August 2011
      Version 4 dated: June 2014

      The number of prospective randomized controlled trials previously reported and reviewed is
      three in version 1 and the number of prospective Randomized controlled trial previously
      reported and reviewed has increased to four in version 4. The change was done in version 3.

      Pre randomization USG findings for lymph nodes were not considered for eligibility criteria.
      Therefore patients with normal, indeterminate and those suggestive of metastasis were
      eligible for trial inclusion in version 1 and Patients with pre randomization ultrasound neck
      findings suggestive of metastasis were excluded in version 4. The change was done in version
      2.

      Based on pre-randomization ultrasound neck findings, patients were stratified between those
      with normal versus indeterminate versus suspicious for metastasis in version 1 and Patients
      stratification was between normal versus indeterminate ultrasound findings in version 4. The
      change was done in version 2

      Patients and investigators blinded to pre- randomization ultrasound neck findings in version
      1 and Patients and investigators are no longer blinded to pre- randomization ultrasound neck
      findings in version4. The change was done in Version 2

      The end points are locoregional recurrence survival in version 1 and The secondary endpoint
      of the study has been explicitly clarified to be disease-free survival in version 4. The
      change was done in Version 3.

      'Nodal relapse' and 'Regional Recurrence' have been defined explicitly in version 4. The
      change was done in version 3.

      Ethical Concerns:

      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.
    


Study Type

Interventional


Primary Outcome

Overall Survival

Secondary Outcome

 Disease free survival

Condition

Oral Cancer

Intervention

Elective neck dissection in early oral cancer

Study Arms / Comparison Groups

 Wait and Watch
Description:  Therapeutic neck dissection on developing nodal relapse

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

710

Start Date

January 2004

Completion Date

June 2019

Primary Completion Date

June 2019

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Anil K D'cruz, MS,DNB, , 

Location Countries

India

Location Countries

India

Administrative Informations


NCT ID

NCT00193765

Organization ID

TMH/131/2003


Responsible Party

Principal Investigator

Study Sponsor

Tata Memorial Hospital


Study Sponsor

Anil K D'cruz, MS,DNB, Principal Investigator, Tata Memorial Hospital,Mumbai,India


Verification Date

June 2017