A meta-analysis of the randomized controlled trials on elective ND vs therapeutic ND in oral cavity cancers with clinically node-negative neck.pdf

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Review

A meta-analysis of the randomized controlled trials on elective neck dissection

versus therapeutic neck dissection in oral cavity cancers with clinically

node-negative neck

Ayotunde J. Fasunla a,c, Brandon H. Greene b, Nina Timmesfeld b, Susanne Wiegand a, Jochen A. Werner a,Andreas M. Sesterhenn a,

a Department of Otolaryngology, Head and Neck Surgery, Philipps-University of Marburg, Germanyb Institute for Medical Biometry and Epidemiology, Philipps-University of Marburg, Germanyc Department of Otorhinolaryngology, College of Medicine, University of Ibadan and University College Hospital, Ibadan, Nigeria

a r t i c l e i n f o

Article history:

Received 28 January 2011

Received in revised form 7 March 2011

Accepted 8 March 2011

Available online 2 April 2011

Keywords:

Elective neck dissection

N0 neck

Observation

Oral cancer

Therapeutic neck dissection

s u m m a r y

Thereis still no consensus on theoptimal treatment of theneck in oral cavitycancer patients with clinical

N0 neck. The aim of this study was to assess a possible benefit of elective neck dissection in oral cancers

with clinical N0 neck. A comprehensive search and systematic review of electronic databases was carried

out for randomized trials comparing elective neck dissection to therapeutic neck dissection (observation)

in oral cancer patients with clinical N0 neck. A meta-analysis of the studies which met our defined selec-

tion criteria was performed using disease-specific death as the primary outcome, and the relative risk

(RR) of disease-specific death was calculated for each of the identified studies. Both fixed-effects

(MantelHaenszel method) and random-effects models were applied to obtain a combined RR estimate,

although between-study heterogeneity was not found to be significant as indicated by an I2 of 8.5%

(p = 0.350). Four studies with a total of 283 patients met our inclusion criteria. The results of the

meta-analysis showed that elective neck dissection reduced the risk of disease-specific death (fixed-

effects model RR = 0.57, 95% CI 0.360.89, p = 0.014; random-effects model RR = 0.59, 95% CI 0.370.96,p = 0.034) compared to observation. This reduction in disease-specific death rate supports the need to

perform elective neck dissection in oral cancers with clinical N0 neck.

2011 Elsevier Ltd. All rights reserved.

Introduction

There is no greater controversy on the management of oral can-

cers than the optimal treatment for clinically node-negative neck

(N0 neck).19 Researchers have reported that P30% of oral cancer

patients with clinical N0 neck harbor occult metastases, depending

on the size and site of the primary tumor and the histological diag-

nostic methods.10,11 However, the greatest challenge faced by head

and neck oncologists and surgeons is the correct identification ofthe subset of these patients without cervical nodal micro metasta-

ses who do not require elective neck treatment. Clinical palpation

of the neck is grossly inadequate.1214 Available radiological inves-

tigative tools have shown some improvements in the detection of

neck metastasis but sensitivity ranged between 70% and 80%.1519

Although oral carcinoma is a locally aggressive disease with a

great tendency for loco-regional and distant metastasis, the reality

is that some patients with a clinical N0 neck do not actually have

cancer cells in the cervical lymphatics. Treating these necks may

mean incurring unnecessary costs, prolongation of hospital stay

and causation of avoidable morbidity. However, when a clinical

N0 neck with actual micro metastases is not included in the man-

agement plan for these patients, the implications are poor treat-

ment outcome with increased morbidity and mortality rates.

Unfortunately, there is still no consensus on the elective treat-

ment of the neck in oral cavity cancers with clinical N0 neck. Manyavailable retrospective studies on oral cancer patients with clinical

N0 necks have not been helpful in resolving this problem.3,5,20 A

few prospective studies are available, but there is still inconclusive

evidence on whether elective neck dissection is of any benefit over

therapeutic neck dissection.2,6,8,9 Most of these studies have small

sample sizes. A meta-analysis of randomized controlled trials could

help to answer questions regarding the possible benefit of elective

neck treatment in these patients. This study is therefore aimed at

systematically reviewing the available literature and carry out a

meta-analysis on the existing randomized controlled trials which

compared elective neck dissection with therapeutic neck dissec-

tion in oral carcinoma patients with clinical N0 neck.

1368-8375/$ - see front matter 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.oraloncology.2011.03.009

Corresponding author. Address: Department of Otolaryngology, Head and Neck

Surgery, University Hospital Giessen and Marburg GmbH, Standort Marburg,

Deutschhausstrasse 3, D-35037 Marburg, Germany. Tel.: +49 06421 58 66811;

fax: +49 06421 58 66367.

E-mail address: [email protected](A.M. Sesterhenn).

Oral Oncology 47 (2011) 320324

Contents lists available at ScienceDirect

Oral Oncology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / o r a l o n c o l o g y
http://dx.doi.org/10.1016/j.oraloncology.2011.03.009mailto:[email protected]://dx.doi.org/10.1016/j.oraloncology.2011.03.009http://www.sciencedirect.com/science/journal/13688375http://www.elsevier.com/locate/oraloncologyhttp://www.elsevier.com/locate/oraloncologyhttp://www.sciencedirect.com/science/journal/13688375http://dx.doi.org/10.1016/j.oraloncology.2011.03.009mailto:[email protected]://dx.doi.org/10.1016/j.oraloncology.2011.03.009


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Materials and methods

Search strategy and eligibility criteria

We carried out a comprehensive search (Fig. 1) for articles pub-

lished in the electronic databases MEDLINE (19662010), EMBASE

(19882010), Cochrane Central Register of Controlled Trials, Sco-

pus and Google scholar using the key terms randomized con-trolled trial, oral cavity cancers, elective neck dissection,

therapeutic neck dissection, observation and N0 neck. All,

and then some of these terms were used in combination for the

search. The reference list of each article obtained was checked

for further potential studies. Only randomized controlled trials

which compared elective neck dissection (END) with observa-

tion/therapeutic neck dissection (OBS) in patients with squamous

cell carcinoma of the oral cavity, which had no clinical or radiolog-

ical evidence of neck node metastasis (clinical N0 neck), were eli-

gible for inclusion in the meta-analysis. In all studies, the END

groups had primary neck dissection at the time of the treatment

of the primary tumor and the OBS groups had treatment of the pri-

mary tumor only, while the neck was put under close observation

during follow-up, and neck dissection was performed only when

neck node metastasis was detected (therapeutic neck dissection).

Data extraction

Data from the studies were first extracted and assessed by the

principal investigator (AF) and thereafter, independently by two

co-authors (BG, NT) using standardized data forms. In addition to

information about study design, patient characteristics (Table 1)

and sample size, numbers of disease-specific deaths in each group

and corresponding follow-up times were extracted. The overall

number of deaths and the number of neck recurrences and metas-

tases (Table 2) were also extracted. Disease-specific death as the

primary endpoint for meta-analysis was chosen. The authors of

one study9 were contacted to obtain information regarding

group-specific overall death rates.

Statistical analysis

The analysis was performed using the R program for statistical

computing (R 2.10.1; meta package). The relative risk (RR) of dis-

ease-specific death and 95% confidence interval (CI) were calcu-

lated for each individual study. However, due to the small

number of studies included, both fixed-effects (MantelHaenszel

method) and random-effects models (DerSimonian and Laird21

method) were applied to obtain a combined RR estimate, 95% CI

andp-value. The inverse variance method of weighting studies (re-

sults not shown) was also used, but the results of the meta-analysis

did not differ between these methods with regard to combined RR

estimates and significance.

Results

An in-depth review of all the randomized controlled trials in-

cluded in this meta-analysis showed that there were a few varia-

tions like race, period of study, and duration of follow-up in the

trials. Although the data used in this meta-analysis were from dif-

ferent parts of the world, between-study heterogeneity of the rel-

ative risk of disease-specific death in the trials were tested and

there was no statistical significant difference (I2 = 8.5%,p = 0.3504).

613 records identified through

database searching

8 additional records identified through the

reference lists of articles obtained

Total of 621 potentially relevant articles

identified

16 full text articles identified and assessed for

eligibility

605 articles excluded based

on title and abstracts

4 studies included in the meta-

analysis

10 full text articles

excluded because they

were retrospective studies

1 full text article excluded because

it was a preliminary report of one

of the included studies

1 full text article excluded because

it compared effect of two different

classes of neck dissection

Figure 1 Flowchart showing the process of study selection for the meta-analysis.

A.J. Fasunla et al. / Oral Oncology 47 (2011) 320324 321


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In the systematic review, four randomized controlled trials with

a total of 283 patients which were eligible for inclusion in the

meta-analysis (Table 1 and Fig. 1)2,6,8,9 were identified. Three of

these were single-center studies that took place in France8, India2

and Brazil6, respectively. The latest completed study from Yuen

et al. was performed as a multi-center trial in Hong Kong.9 These

trials took place over four decades with the first patients recruited

in 19668 and the last in 2004.9

All of the studies showed lower disease-specific death rates in

the END group compared with the OBS group, but only in the study

by Kligerman et al.6 was significance reached. The meta-analysis of

these four randomized trials showed that elective neck dissection

significantly reduced the risk of disease-specific death (Fig. 2),

(fixed-effects model RR = 0.57, 95% CI 0.360.89, p = 0.014; ran-

dom-effects model RR = 0.59, 95% CI 0.370.96, p = 0.034).

Discussion

Only four randomized controlled trials on oral cancers with

clinical N0 neck were included in this meta-analysis.2,6,8,9 The fact

that only four studies have been successfully performed and

published till date is a testament to the difficulties associated with

well designed prospective randomized controlled trials in oral cav-

ity cancers these can include adherence to the study protocol,

tracking or follow-up of patients and outcomes.

Cancer of the oral cavity commonly involves oral tongue and

floor of the mouth more than any other sub-sites in the oral cav-

ity.22,23 This may be the reason why the patients from the trials in-

cluded in this meta-analysis had tumors which involved only these

two sub-sites (Table 1). Typically, cancers of the oral tongue and

floor of the mouth are not readily recognized or detected until they

become symptomatic. Studies have shown that cancers which in-

volved oral tongue metastasize more than cancers of the floor of

the mouth.24,25 Presence of neck node metastasis is an important

prognostic factor in oral cancers and tumor site influence on nodal

metastasis affects survival outcome.26,27 However, cancers from

these two sub-sites have tendency to spread to the contra-lateral

side through their midline communications.28,29

The usual treatment of the primary tumor in all the studies was

surgical therapy2,6,9 except in the study by Vandenbrouck et al.8

where radiation therapy was used. Researchers have however

reported that the five-year survival rates in early stage (I and II)

oral carcinoma treated with either surgery or radiotherapy are

similar.3033

Table 1

Characteristics of the studies included in the systematic review.

M, male; F, female; AT, oral tongue (anterior two third of the tongue); FM, floor of the mouth.

Table 2

Characteristics of tumor recurrences and metastasis.

na: Data not available.a Five patients in total were reported to have developed primary site recurrence by Fakih et al.,2 but the authors did not identify in which group the recurrences were.b The overall number of deaths was not separated between END and OBS groups in the study by Yuen et al.9 However, the study reported a total number of 18 deaths; 4

patients in each group died from the disease and 10 others died from other conditions.

Figure 2 Forest plot showing relative risk (RR) of disease-specific mortality and 95% confidence interval (CI) in each of the studies and the combined estimates.

322 A.J. Fasunla et al./ Oral Oncology 47 (2011) 320324


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For the primary outcome of this meta-analysis, disease-specific

death rate was chosen as the most clinically meaningful endpoint

for measuring the benefit of elective neck dissection. Although

homogeneity in the relative risk between studies was statistically

indicated (p = 0.350), it was still observed that there was heteroge-

neity in the estimated disease-specific death rates within each

treatment group. In the OBS group, these range from 11% to 42%

and in the END group from12%to 30% (Table 2). This observed dif-

ference within each group might be due to the availability of more

sophisticated investigative tools for the early identification of neck

node metastasis with better sensitivity and specificity in recent

times.1519 Some of the occult metastases can now be better de-

tected during evaluation and properly staged. This is evident in

the most recent study by Yuen et al. that showed increased reduc-

tion in the incidence of disease-specific death rate when compared

to the other older studies within the OBS group (Table 2). In more

than 60% of oral tongue carcinoma patients, disease related death

is due to uncontrolled neck disease.34 However, the percentage of

these deaths that can be attributed to the policy of watchful wait-

ing or observation in patients with clinically N0 neck is still ob-

scured. It is also still very difficult to distinguish between the

actual deaths due specifically to neck pathology (nodal recurrences

or metastases) and oral cancers.

The benefits of elective neck dissection in patients with oral

cavity tumors with N0 neck are still not clear because the results

of numerous existing studies on the topic have been generally

inconclusive. Most studies have failed to show statistically signifi-

cant differences in survival outcome between the patients with

oral cavity cancers in END and OBS groups.1,2,5,8,9 However, there

have been few studies which showed significant survival benefit

in favor of elective neck dissection in oral carcinoma patients with

clinically N0 neck.35,7 Among prospective randomized trials, only

the study by Kligerman et al. showed evidence of statistically sig-

nificant disease-free survival benefit of elective neck dissection

over a policy of observation.6 However, our meta-analysis showed

that being in the END group significantly reduced the risk of death

due to the disease. It is possible that this observed pooled effect inthe meta-analysis between END and OBS might have been largely

influenced by the older studies. Perhaps, if similar studies are con-

ducted now that there are better investigative tools to detect and

stage neck node metastasis, this observed difference might be

absent.

In all of the four studies used in this meta-analysis, it was ob-

served that the elective neck dissection markedly improved the re-

gional control because fewer patients in the END group developed

neck nodal recurrences or metastasis than those in the OBS group.

In the END group, nodal recurrence was detected in 630% of the

patients while in the OBS group, nodal metastasis was detected

in 3758% of the patients (Table 2). This may not really be a sur-

prise as the patients in the END group already had the lymphatic

and fibro fatty tissues in their neck removed. It was because of thisexisting bias that neck node recurrence in the END group or metas-

tasis in the OBS group was not considered to be a reliable outcome

measure in this meta-analysis. The patients whose necks were

observed tended to have more regional recurrences1,35 and the

results of the salvage treatment of the neck were generally

poor.13,5,29 Nodal metastasis or recurrence has been considered a

significant prognostic factor in oral cavity cancers and other head

and neck malignancies.11,32,36 Even when the tumor is small and

considered to be at early stage, it is potentially aggressive and

the incidence of neck node metastases is very high. Patients with

T1N0 and T2N0 squamous cell carcinoma of the oral cavity have

been reported to have occult metastases in 1333% and 3753%,

respectively at the time of diagnosis.4,9,10,37,38 This is similar to

the findings from all the randomized controlled trials in thismeta-analysis (Table 2). Only Vandenbrouck et al. included T3N0

patients in their study and this may actually explain the reason

why they reported a higher rate of extra capsular nodal spread in

their study than in other trials. Presence of capsular rupture has

been demonstrated to be an ominous prognostic sign. 8 There has

been a decline in the death rate from oral cavity cancers till date

perhaps due to the improved methods of diagnosis and treatment

of oral cancers.39 The quality of life of these oral cancer patients has

also improved as compared to the past, even in those who eventu-

ally succumbed to distant metastasis or the disease progression.

Despite the advances in cancer therapies, it is only possible to

achieve an improved survival time or cure in oral cancer patients

with early disease or N0 neck if appropriate, optimal and adequate

therapy is offered. A few retrospective studies have reported on the

survival benefit of elective neck dissection in early stage oral carci-

noma.40,41 The survival rate in oral carcinoma patients is reduced

by 50% once there is a palpable cervical lymph node.4244 In this

systemic review and meta-analysis, the findings confirmed the re-

port that elective neck dissection in oral carcinoma with N0 neck

can significantly reduce disease-specific death rate. It can therefore

be concluded that the benefits of the statistically significant reduc-

tion in disease-specific death rates may justify the need for elective

neck dissection in oral carcinomas with N0 neck.

Conflict of interest

None declared.

References

1. Duvvuri U, Simental Jr AA, DAngelo G, Johnson JT, Ferris RL, Gooding W, et al.

Elective neck dissection and survival in patients with squamous cell carcinoma

of the oral cavity and oropharynx. Laryngoscope 2004;114:222834.2. Fakih AR, Rao RS, Borges AM, Patel AR. Elective versus therapeutic neck

dissection in early carcinoma of the oral tongue. Am J Surg1989;158:30913.3. Dias FL, Kligerman J, Matosde S G, Arcuri RA,Freitas EQ, Farias T, etal. Elective

neck dissection versus observation in stage 1 squamous cell carcinomas of the

tongue and floor of the mouth. Otolaryngol Head Neck Surg 2001;125:239.4. Haddadin KJ, Soutar DS, Oliver RJ, Webster MH, Robertson DG, MacDonard DG.

Improved survival for patients with clinically T1/T2, N0 tongue tumors

undergoing a prophylactic neck dissection. Head Neck 1999;21:51725.5. Keski-Sntti H, Atula T, Trnwall J, Koivunen P, Mkitie A. Elective neck

treatment versus observation in patients with T1/T2 N0 squamous cell

carcinoma of oral cavity. Oral oncol 2006;42:96101.6. Kligerman J, Lima RA, Soares JR, Prado L, Dias FL, Freitas EQ, et al.

Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell

carcinoma of oral cavity. Am J Surg1994;168:3914.7. Marchioni DL, Fisberg RM, do Rosario M, Latorre DO, Wunsch V. Diet andcancer

of the oral cavityand pharynx: a case-control study in SaoPaulo, Brazil. IARC SciPubl 2002;156:55961.

8. Vandenbrouck C, Sancho-Garnier H, Chassagne D, Saravane D, Cachin Y,

Micheau C. Elective versus therapeutic radical neck dissection in epidermoid

carcinoma of the oral cavity: results of a randomized clinical trial. Cancer1980;46:38690.

9. Yuen AP, Ho CM, Chow TL, Tang LC, Cheung WY, Ng RW, et al. Prospective

randomized study of selective neck dissection versus observation for N0 neckof

early tongue carcinoma. Head Neck 2009;31:76572.10. Byers RM, El-Naggar AK, Lee YY, Rao B,Fornage B,Terry NH, et al. Can wedetector predict the presence of occult nodal metastases in patients with squamous

cell carcinoma of the oral tongue? Head Neck 1998;20:13844.11. Po Wing Yuen A, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, et al. Prognostic

factors of clinically stage 1 and11 oral tongue carcinoma a comparative study

of stage, thickness, shape, growth pattern, invasive front malignancy grading,

MartinezGimeno score, and pathologic features. Head Neck 2002;24:51320.12. Moreau P, Goffart Y, Collignon J. Computed tomography of metastatic cervical

lymph nodes. Arch Otolaryngol Head Neck Surg 1990;116:11903.13. Schuller DE, Bier-Laning CM, Sharma PK, Siegle RJ, Pellegrini AE, Karanfilov B,

et al. Tissue-conserving surgery for prognosis, treatment, and function

preservation. Laryngoscope 1998;108:1599604.14. Don D, Yoshimi A, Lufkin R, Fu Y, Calcaterra T. Evaluation of cervical lymph

node metastasis in squamous cell carcinoma of the head and neck.

Laryngoscope 1995;105:66974.15. Akoglu E, Dutipet M, Bekis R, Degirmenci B, Ada E, Guneri A. Assessment of

cervical lymph node metastasis with different imaging methods in patients

with head and neck squamous cell carcinoma. J Otolaryngol 2005;34:38494.

16. Haberal I, Celik H, Gocmen H, Akmansu H, YorukM, Ozeri C. Whichis importantin the evaluation of metastatic lymph nodes in head and neck cancer:

A.J. Fasunla et al. / Oral Oncology 47 (2011) 320324 323


5/5

palpation, ultrasonography, or computed tomography? Otolaryngol Head NeckSurg2004;130:197201.

17. Krestan C, Herneth AM, Formanek M, Czerny C. Modern imaging lymph node

staging of the head and neck. Eur J Radiol 2006;58:3606.18. Yamazaki Y, Saitoh M, Notani K, Tei K, Totsuka Y, Takinami S, et al. Assessment

of cervical lymph node metastases using FDGPET in patients with head and

neck cancer. Ann Nucl Med 2008;22:17784.19. Yonn DY, Hwang HS, Chang SK, Rho YS, Ahn HY, Kim JH, et al. CT, MR, US, 18F-

FDG PET/CT, and their combined use for the assessment of cervical lymph node

metastases in squamous cell carcinoma of the head and neck. Eur Radiol

2009;19:63442.20. DCruz AK, Siddachari RC, Walvekar RR, Pantvaidya GH, Chaukar DA,

Deshpande MS, et al. Elective neck dissection for the management of the N0

neck in early cancer of the oral tongue: need for a randomized controlled trial.

Head Neck 2009;31:61824.21. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials

1986;7:17788.22. MashbergA, Meyers H. Anatomicalsite andsize of 222 early asymptomaticoral

squamous cell carcinomas: a continuing prospective study of oral cancer II.

Cancer1976;37:214957.23. Moore C. Anatomic origins and locations of oral cancer. Am J Sur g

1967;114:5103.24. Dias FL, Lima RA, Kligerman J, Farias TP, Soares JR, Manfro G, et al. Relevance of

skip metastases for squamous cell carcinoma of the oral tongue andthe floor of

the mouth. Otolaryngol Head Neck Surg 2006;134:4605.25. Jerjes W, Upile T, Petrie A, Riskalla A, Hamdoon Z, Vourvachis M, et al.

Clinicopathological parameters,recurrence, locoregional and distant metastasis

in 115T1T2 oral squamous cell carcinoma patients. Head Neck Oncol 2010;2:9.26. Woolgar JA. Histopathological prognosticators in oral and oropharyngeal

squamous cell carcinoma. Oral Oncol 2006;42:22939.27. Garzino-Demo P, DellAcqua A, Dalmasso P, Fasolis M, La Terra Maggiore GM,

Ramieri G, et al. Clinicopathological parameters and outcome of 245 patients

operated for oral squamous cell carcinoma. J Craniomaxillofac Surg2006;34:34450.

28. Vidic B, Suarez-Quian C. Anatomy of the head and neck. In: Harrison LB,

Sessions RB, Ki Hong W, editors. Head and neck cancer: a multidisciplinary

approach. 1st ed. Philadelphia: Lippincott-Raven; 1998. p. 79114.

29. Kowalski LP. Results of salvage treatment of the neck in patients with oral

cancer. Arch Otolaryngol Head Neck Surg 2002;128:5862.30. Ord RA, Blanchaert RH. Current management of oral cancer: a multidisciplinary

approach. J Am Dent Assoc 2001;132:1923.31. Nakashima T, Nakamura K, Shiratsuchi H, Yasumatsu R, Toh S, Shioyama Y,

et al. Clinical outcome of partial glossectomy or brachytherapy in early-stage

tongue cancer. Nippon Jibiinkoka Gakkai Kaiho 2010;113:45662.32. Perez CA,Brady LW, Halperin EC, editors. In:Principlesand practice of radiation

oncology. 4th ed. Lippincott: Williams and Wilkins; 2004. p. 1005.

33. Bhalavat RI, Mahantshetty UM, Tole S, Jamema SV. Treatment outcome with

low-dose-rate interstitial brachytherapy in early-stage oral tongue cancers. JCancer Res Ther 2009;5:1927.

34. Alvi A, Myers EN, Johnson JT. Cancer of the oral cavity. In: Myers EN, Suen JY,

editors. Cancer of the head and neck. Philadelphia: WB Saunders Co.; 1996. p.

32160.

35. Silverberg E, Lubera JA. Cancer statistics, 1986. CA Cancer J Clin 1986;36:925.36. Boyd D. Invasion and metastasis. Cancer Metastasis Rev 1996;15:7789.37. Andersen PE, Cambronero E, Shaha AR, Shah JP. The extent of neck disease

after regional failure during observation of the N0 neck. Am J Sur g 1996;172:68991.

38. Teichgraeber JF, Clairmont AA. The incidence of occult metastases for cancer of

the oral tongue and floor of the mouth: treatment rationale. Head Neck Surg1984;7:1521.

39. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin2010;60:277300.

40. Woolgar JA. T2 carcinoma of the tongue: the histopathologists perspective. Br JOral Maxillofac Surg 1999;37:18793.

41. Yamazaki Y, Saitoh M, Notani K, Tei K, Totsuka Y, Takinami S, et al. Assessment

of cervical lymph node metastases using FDGPET in patients with head and

neck cancer. Ann Nucl Med 2008;22:17784.42. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Regional lymph node

involvement and its significance in the development of distant metastases in

head and neck carcinoma. Cancer1993;71:4526.43. Fielding LP, Fenoglio-Preiser CM, Freedman LS. The future of prognostic

factors in outcome prediction for patients with cancer. Cancer 1992;70:236777.

44. Shah J. Head and neck surgery. 2nd ed. New York: Mosby-Wolfe; 1996.

324 A.J. Fasunla et al./ Oral Oncology 47 (2011) 320324

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A meta-analysis of the randomized controlled trials on elective ND vs therapeutic ND in oral cavity cancers with clinically node-negative neck.pdf