Elective Versus Therapeutic Neck Dissection in the Treatment of Early Node Negative Squamous Carcinoma of the Oral Cavity
Recruitment status was Recruiting
|First Received Date ICMJE||September 13, 2005|
|Last Updated Date||June 1, 2012|
|Start Date ICMJE||January 2004|
|Estimated Primary Completion Date||January 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Survival [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT00193765 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Elective Versus Therapeutic Neck Dissection in the Treatment of Early Node Negative Squamous Carcinoma of the Oral Cavity|
|Official Title ICMJE||Elective Versus Therapeutic Neck Dissection in the Treatment of Early Node Negative Squamous Cell Carcinoma of the Oral Cavity|
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.
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.
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:
AIMS OF STUDY
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.
1. Should patients with ultrasonography findings suggestive of metastasis be removed from randomization
Protocol amendment details:
Protocol amendment was accepted by the Scientific ethics committee/Instititional Review board on 29/12/2008 as follows:
All patients will undergo a pre randomization ultrasonography of neck. If the USG report suggests metastasis patients would be treated according to merit to avoid ethical concerns and if the USG report is normal or indeterminate, patients would be randomized for the trial. This protocol amendment is done in view of the following 2 reasons.
Very often patients are uncomfortable to give consent when they are explained that the initial ultrasonography report will be blinded and the findings will not be considered in deciding the patient's treatment plan. This resulted in lower recruitment of patients and it also raised ethical issues when the blind was not adequately maintained especially if the sonography suggested metastasis.
To overcome a difference of opinion amongst examining clinicians about a clinically significant node.
However, breaking the blind would have no bearing on the outcome / impact of this study.
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.
Primary: The tumor will be excised after proper exposure via the per-oral route.
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||Oral Cancer|
|Intervention ICMJE||Procedure: Elective Vs Therapeutic neck dissection in early oral cancer
Elective neck dissection in early node negative oral cancers
|Study Arm (s)||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||710|
|Estimated Completion Date||January 2014|
|Estimated Primary Completion Date||January 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 75 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||India|
|NCT Number ICMJE||NCT00193765|
|Other Study ID Numbers ICMJE||TMH/131/2003|
|Has Data Monitoring Committee||Yes|
|Responsible Party||A K D'Cruz, Tata Memorial Hospital|
|Study Sponsor ICMJE||Tata Memorial Hospital|
|Collaborators ICMJE||Not Provided|
|Information Provided By||Tata Memorial Hospital|
|Verification Date||June 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP