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ORIGINAL ARTICLE

ELECTIVE NECK DISSECTION FOR THE MANAGEMENT OF THE N0 NECK IN EARLY CANCER OF THE ORAL TONGUE: NEED FOR A RANDOMIZED CONTROLLED TRIAL Anil K. D’Cruz, MS, DNB,1 Ravichand C. Siddachari, MS, DNB, MRCS,1 Rohan R. Walvekar, MD,1,2 Gouri H. Pantvaidya, MS, DNB, MRCS,1 Devendra A. Chaukar, MS, DNB,1 Mandar S. Deshpande, MS, DNB,1 Prathamesh S. Pai, MS, DNB,1 Pankaj Chaturvedi, MS1 1 2

Division of Head Neck Surgery, Tata Memorial Hospital, Mumbai, India. E-mail: [email protected] Department of Otolaryngology–Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Accepted 1 August 2008 Published online 8 January 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20988

Abstract: Background. The aim of this study is to determine the need for a randomized controlled trial in order to define the role of an elective neck dissection (END) in the treatment of early tongue cancers. Methods. We present a large retrospective analysis of patients with T1-2 N0 squamous cell cancers of the oral anterior tongue treated at a single institution. A total of 359 eligible patients with early tongue cancers were divided into 2 groups: END and wait and watch (WW). An analysis for survival outcomes and prognostic factors was conducted. Results. The estimated 3- and 5-year disease-free survival for the END group was 76% and 74% versus 71% and 68% for the WW group, respectively (p 5 .53). The 3- and 5-year overall survival (OS) rate for the END group was 69% and 60% versus 62% and 60% for the WW group, respectively (p 5 .24). Tumor grade and perineural invasion were independent predictors of recurrence. Conclusion. END did not impact disease-free or OS. Current literature still remains divided on this issue emphasizing the C 2009 Wiley Periodineed for a randomized controlled trial. V cals, Inc. Head Neck 31: 618–624, 2009 Keywords: tongue cancer; elective neck dissection; N0 neck; oral cancer

Correspondence to: A. K. D’Cruz The data in this study were presented at the 6th International Head and Neck Conference (AHNS) Washington DC 2004. C V

2009 Wiley Periodicals, Inc.

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N0 Neck in Early Tongue Cancer

Early cancers of the oral anterior tongue (T1, T2) are usually treated with surgery performed via the per-oral route. To date, the management of the clinically node-negative neck (N0) in this context remains controversial. Elective neck dissection (END) in this situation is an additional procedure with associated morbidity. Should an END be performed or is a wait and watch (WW) policy safe and adequate? A recent national survey conducted in the United States found a lack of consensus within the otolaryngology community regarding the management of the N0 neck.1 A similar observation was noted in the European survey in Marburg, Germany.2 In an era of evidence-based medicine, this can only be explained by the lack of robust evidence to support a particular treatment policy. The American Head Neck Society (AHNS) conducted a systematic review to define the state of evidence in head neck surgery. Procedures studied included selective neck dissection, total thyroidectomy, and endoscopic laryngeal surgery. The systematic review of literature concluded that the level of evidence available for selective neck dissection was 2b (cohort studies and low-

HEAD & NECK—DOI 10.1002/hed

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quality randomized controlled trials [RCTs]) and the grade of recommendation based on a compilation of evidence-based literature was ‘‘B’’ (range with decreasing power, A through D).3 This further validates the divided stance within the otolaryngology community on this subject. In this situation a consensus could be achieved if a highquality RCT were conducted. We present a large retrospective analysis of patients with T1-2 N0 squamous cell cancers of the oral anterior tongue treated at a single institution in an effort to determine the need for a RCT.

PATIENTS AND METHODS

A retrospective chart review was performed of patients with T1/T2 N0 cancer of the oral anterior tongue who underwent a per-oral wide local resection of the primary lesion with or without neck dissection at a tertiary cancer care center between January 1, 1997, and December 31, 2001. A total of 359 cases with biopsy-proven squamous cell carcinoma (SCC) of the oral tongue were identified from our registry. Demographic data and information on clinical presentation, imaging, operative details, histopathology, and follow-up were documented for analysis using a preapproved proforma. We divided the patients into 2 groups: END and WW. The primary endpoint was to compare overall survival (OS) and disease-free survival (DFS) between 2 groups (END vs WW). The secondary endpoint was to identify prognostic factors in the primary tumor which would predict a higher probability of nodal metastases. DFS was calculated from the date of surgical intervention to the end-point being recurrence. In the END group, the first recurrence after treatment was considered as the event. For the WW group, events included patients who developed recurrence after primary tumor excision either at the primary site or in combination with the neck. Among the pure neck failures within the WW group, patients who were inoperable or who had a second recurrence after salvage surgery were included as events for calculating DFS. OS was calculated in the usual fashion with the end-point being the patient’s vital status at last follow-up. SPSS 11.5 software was used to perform the analysis. Survival curves were plotted by using the Kaplan–Meier method and compared by the log-rank test. A multivariate analysis to assess the impact of different variables

Statistical Analysis.


on nodal metastasis was performed using the Cox logistic regression test. RESULTS

The median age of the study population was 49 years (range, 20–83), with a men-to-women ratio of 2:1. All patients underwent per-oral excision of the primary lesion. Management of the neck was at the discretion of the treating physician’s preference, which was based on clinical staging, intraoperative findings, and patient compliance to follow-up. Of the 359 patients, 200 were in the WW group while 159 underwent an END (79 underwent a supra-omohyoid neck dissection and 80 underwent a modified radical neck dissection). Distribution of clinical and pathological data such as T stage, tumor grade, perineural invasion (PNI), surgical margins, and thickness of the tumor between the 2 groups is listed in Table 1. To analyze the value of tumor thickness in predicting neck metastasis, tumors were categorized into 3 groups: tumors with thickness less than or equal to 3 mm, tumors with thickness between 4 and 9 mm, and tumors with thickness more than or equal to 10 mm. There were more patients with T1 tumors (118 vs 69) and tumors with thickness less than 9 mm (154 vs 102) in the WW group when compared with the END group, respectively. This difference was not significant enough to suggest a preferential selection of favorable tumors in the WW group. Of 159 patients treated with an END, the incidence of nodal metastasis was 20.1% (32/ Table 1. Tumor characteristics: WW group versus END group. WW group Tumor size T1 T2 Grade of differentiation Well differentiated Moderately differentiated Poorly differentiated Perineural invasion No Yes Tumor thickness (mm)* 3 4–9 10 Surgical margins Positive Negative Close

END group

118 (59%) 82 (41%)

69 (43.4%) 90 (56.6%)

48 (24%) 132 (66%) 20 (10%)

30 (18.9%) 109 (68.6%) 20 (12.6%)

181 (90.5%) 19 (9.5%)

145 (91.2%) 14 (8.8%)

39 (19.5%) 115 (57.5%) 37 (18.5%)

13 (8.2%) 89 (56%) 52 (32.7%)

7 (3.5%) 184 (92%) 9 (4.5%)

4 (2.5%) 146 (91.8%) 9 (5.7%)

Abbreviations: WW, wait and watch; END, elective neck dissection. *Tumor thickness was unavailable in 14 patients.


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Table 2. Indications for adjuvant radiotherapy.

Positive cut margins Poor differentiation PNI Increasing T size Positive nodes

Table 3. Patterns of recurrence.

WW group (21/200)

END group (55/159)

3 6 7 5 –

5 12 6 12 20

Abbreviations: WW, wait and watch; END, elective neck dissection; PNI, perineural invasion.

159). Of these, 37.5% (12/32) metastatic nodes were found in T1 lesions, and 62.5% (20/32) in T2 lesions. Adjuvant radiotherapy (RT) was given to 21 (10.5%) patients in the WW group and to 55 (34.59%) patients in the END group. Adjuvant RT was recommended in both the groups for indications that are listed in Table 2. Only 20 of 55 patients in the END group received adjuvant RT for purely nodal factors. The remaining 35 patients had a combination of unfavorable tumor and nodal factors. The patterns of recurrences for patients in both the groups are listed in Table 3. Most nodal recurrences (59.5%) occurred within the first 6 months following surgery, and the median time to all recurrences was 6.18 months. In the WW group, 94 (47%) patients had recurrence in the neck; 91 patients (96.8%) had ipsilateral neck metastasis, 1 patient had a contralateral neck recurrence, and 2 patients had recurrence bilaterally in the neck. In the WW group, 50% of the patients had recurrence with advanced (N2, N3) nodal disease. Seventy-three (77.6%) of 94 patients could be offered definitive neck dissection. Of these, 51 patients required adjuvant RT. Forty-three (58.9%) of these 73 patients were disease free 1 year after salvage surgery. The median disease-free interval after salvage was 36 months (range, 12–77 months). Twelve patients with regional metastasis who were resectable refused surgery. Nine patients recurred with end-stage nodal disease and were treated with palliative intent only. In the END group, 9 patients (5.7%) recurred in the neck. Of these, 6 patients failed in the ipsilateral operated neck while 3 patients had contralateral recurrences. Six (66%) patients in this group were seen with advanced neck disease (N2, N3) after elective neck treatment. Among the patients with regional recurrence in this group, 5 patients had salvage neck surgery followed by adjuvant RT. However, all the patients (100%) had Recurrences.

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Site of recurrence

WW group

END group

Primary Neck Primary 1 Neck Second primary

9 94 3 1

18 9 2 2

(4.5%) (47%) (1.5%) (0.5%)

(11.3%) (5.7%) (1.3%) (1.3%)

Abbreviations: WW, wait and watch; END, elective neck dissection.

re-recurrences and none could be salvaged. The follow-up status for both the groups is listed in Table 4. The estimated 3- and 5-year DFS for the END group was 76% and 74% when compared with 71% and 68% for the WW group, respectively (p 5 .53) (Figure 1). OS rate for the END group was 69% and 60%, respectively, when compared with 62% and 60% for the WW group, respectively (p 5 .24). To facilitate a true comparison of OS between the WW group and the END group, patients who underwent adjuvant RT were eliminated by analyzing survival rates in a subset of patients in whom no adjuvant RT was given after the first surgery. There was no survival advantage while comparing the WW group (179 patients) with the END group (104 patients) (p 5 .29) (see Figure 2). OS was also calculated in a subset of patient’s who had neither adjuvant RT nor primary recurrences. This selection was directed to evaluate the impact of neck metastasis on OS. Patients in the END group showed a trend toward better survival when compared with patients in the WW group, although this was not statistically significant (p 5 .09). A univariate analysis and MVA of variables with prognostic importance for predicting nodal recurrences was performed in this subset of patients. Tumor grade and perineural invasion (PNI) were found to be independent predictors of nodal recurrences (Table 5). Increasing tumor size and tumor thickness were not found to be statistically significantly.

Survival Analysis.

Table 4. Status at last follow-up: WW group versus END group. WW group Disease-free status Alive with disease Died of disease Died of other causes Lost to follow-up

131 38 8 6 17

(65.5%) (19%) (4%) (3%) (8.5%)

END group 117 25 5 1 11

(73.6%) (15.7%) (3.1%) (0.6%) (6.9%)

Abbreviations: WW, wait and watch; END, elective neck dissection.


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Table 5. Univariate analysis.

Prognostic factors T size T1 T2 Tumor thickness 3 4–9 10 Tumor grade Well Moderately Poorly Perineural invasion Present Absent

Patients (n)

Nodal metastasis

105 65

53 (50.5%) 33 (50.8%)

.86 (NS)

43 101 26

20 (46.5% 51 (50.5%) 15 (57.7%

.29 (NS)

39 117 14

14 (35.9%) 61 (52.1%) 11 (78.6%)

.03*

11 159

9 (81.8%) 77 (48.4%)

.01*

p value

Abbreviation: NS, not significant. * Indicates statistical significance.

FIGURE 1. Disease-free survival END versus WW group. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

DISCUSSION

The controversy regarding the management of the clinically N0 neck primarily stems from the advantages and disadvantages of either observing or treating the neck electively. END gives us definitive information regarding the pathological nodal status and helps to direct appropriate use of adjuvant therapy. However, even selective neck dissections have a reported incidence of spinal accessory nerve-related disability in approximately 30% to 40% of cases.4 This morbidity may be expected considering the fact that dissection of the level IIb, which is associated with shoulder dysfunction, is recommended whenever the

FIGURE 2. OS in the WW group versus END group. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]


tongue is the primary site of oral cancer.5 There have been numerous retrospective trials both in favor of6–20 and against21–24 this issue. Those in favor of an END based their assumption on data from retrospective studies indicating better regional control and survival in electively treated necks. Apart from being retrospective, the major drawback of these studies was a lack of strength in numbers (Table 6). In addition, most studies contained a mixed population of tumors which included various other subsites within the oral cavity in addition to the oral tongue, and were conducted over different time spans which does not allow us to draw meaningful conclusions. To date, there have been 3 prospective RCTs conducted to address this issue; 2 of these were inconclusive while 1 showed a benefit toward an END. The first and widely cited study was from the Institute Gustave-Roussy,25 in which 75 patients with oral cavity cancers had either an elective or salvage radical neck dissections (RND). In this study, both groups of patients had similar survival rates. In a study of 70 patients from our institution, Fakih et al26 reported similar findings in which the DFS was 52% versus 63% in patients who underwent hemiglossectomy alone when compared with those who underwent hemiglossectomy and RND, respectively. Although the difference in DFS was slightly in favor of the END group, it was not statistically significant. A prospective trial conducted in Brazil27 randomized 67 patients with T1-2 N0 SCC of the floor of mouth or oral tongue into a WW group and END group after primary resection. The incidence of occult nodal disease and recurrence was 21% and 24% in the


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Table 6. Retrospective studies evaluating the management of the N0 neck. Occult metastasis, % Author

Date

Patients

T1

T2

T3

Recommendations

Spiro and Strong

1971

185

29.1

42.9

77

Cunningham et al7 Lee and Litton8

1986 1972

54 158

– 24

– 22

– 22

Mendelson et al9

1976

340

18

33

60

Whitehurst and Droulias10

1977

137

15.9

42.9

–

Hughes et al12 Teichgraeber and Clairmont13

1993 1984

233 136

– 33

– 37

– –

Franceschi et al16

1993

297

–

–

–

Jesse et al21

1970

584

23

26

White and Byers22

1980

152

O’Brien et al24

1986

167

Partial glossectomy for lesions 2 or with floor of mouth involvement T1, partial glossectomy alone; T2 and greater lesions, END or irradiation END Ipsilateral elective irradiation or MND in poorly differentiated T1 and T2 or greater lesions SOHND appears to be an adequate procedure for removing nodes at highest risk Complete elective neck treatment is not advocated. Irradiation of the proximal lymphatics is useful END not justified because most nodal metastasis subsequent to observation can be salvaged END not recommended. Patients with PNI should receive RT to primary site and neck. Close observation was recommended for the rest

6

29

25% for all stages

25

37

–

Abbreviations: RND, radical neck dissection; END, elective neck dissection; MND, modified radical neck dissection; SOHND, supra-omohyoid neck dissection; PNI, perineural invasion; RT, radiotherapy.

END group, respectively. By comparison the recurrence rate was 42% in the resection-only group. This translated into a 3.5-year DFS group of 49% in the resection only arm versus 72% in the arm that received END. However, the major shortcoming in all the 3 prospective studies was the relatively small study cohorts, as also seen in the retrospective literature. Weiss et al23 constructed a decision tree on a mathematical model using computer software and came to a conclusion that a patient with primary SCC of the head and neck and stage N0 neck status should be observed if the probability of the occult cervical metastasis is less than 20%. If the probability is greater than 20%, treatment of the neck is warranted. However, it must be remembered that such decision analyses are based on probabilities of cervical metastasis from current literature. These clinical and pathological data are often not available at surgery, which is a major limitation to clinical decision making (intraoperatively). In addition, such a decision

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analysis needs further validation because it is based on current evidence, which as we discussed earlier is not robust enough to make definitive recommendations regarding the management of the N0 neck. Current studies, retrospective as well as prospective, have been unable to give us definitive recommendation regarding the management of the N0 neck in patients with early oral cancers. In our opinion, current literature is lacking a high-powered RCT to help make definitive recommendations. Random surveys conducted in the otolaryngology community both in the United States and Germany showed that there was no consensus regarding the elective treatment of the N0 neck, which endorses the need for a high-powered RCT.1,2 Hence, we reviewed our data, which is larger than most published series, to see whether any clear guidelines can be obtained to address this issue. Despite a large study population, the DFS and OS between the 2 groups (END and WW) were not statistically significant in our series.


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FIGURE 3. Disease-free survival: correlation of tumor grade with nodal recurrence. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Further statistical analysis was conducted to identify the risk factors for nodal recurrence, the presence of which could indicate the need for END. In our series, grade of differentiation and PNI were found to be statistically significant (p 5 .01) on univariate analysis and multivariate analysis. Poorly differentiated tumors had higher incidence of neck metastasis compared with the well-differentiated and moderately differentiated (78.6% vs 52.1% and 35.9%, respectively) (p 5 .03) (see Figure 3). Okada et al also found a positive correlation between the pretreatment histological grade and incidence of cervical metastasis in oral SCC.28 Similarly, Umeda et al, Mendelson et al, and Frierson and Cooper reported a higher incidence of neck involvement in poorly differentiated than in welldifferentiated carcinomas.9,29,30 In our review the incidence of PNI was 6.5% (11/170 patients). The incidence of neck recurrence among patients with PNI was 81.8% (9/11) when compared with 48.4% (77/159) where PNI was absent (p 5 .01) (see Figure 4). Some investigators24,30 have reported a correlation between PNI at the primary site and neck metastasis while others have not.31 Other variables that have been investigated for their prognostic value include tumor size and thickness. Several investigators have reported a correlation of neck metastasis with the T stage9,10,32,33 while others have found no correlation.8,16,21,29,34 Spiro et al34 reported tumor thickness as an important factor predicting neck metastasis rather than T stage. The risk of neck metastasis approached 40% when the tumor


thickness was greater than 2 mm. They advocate END for patients with tumor thickness exceeding 2 mm. On analyzing tumor thickness in our study, there was a trend toward higher rate of neck metastasis with an increasing thickness of the tumor. However, this was not statistically significant (p 5 .29). In our series, we found no correlation of neck metastasis with regards the tumor size. This observation is validated in other studies as well.28 Because most of the prognostic information pertaining to the risk of nodal metastasis is obtained postoperatively, the decision to perform an END is usually based on the experience of the surgeon. Until we have evidence-based guidelines in the literature, existing imaging techniques such as ultrasonography, CT scan, MRI, and newer techniques such as positron emission tomography (PET), combined PET-CT scanning, and sentinel lymph node biopsy may play a role but needs further investigation in this context by identifying clinically undetectable cervical nodes. CONCLUSION

In conclusion, a high number of patients (47%) in the WW group required delayed therapeutic neck dissections. END did not improve DFS or OS. However, when patients receiving adjuvant radiation and primary recurrence were removed from the analysis to evaluate the impact of neck metastasis on survival, END did show a trend toward better OS (p 5 .09). Grade of the tumor and the presence of PNI can be considered to be independent prognostic factors for nodal recurrence. In view of a continued lack of consensus in literature

FIGURE 4. Disease-free survival: correlation of PNI with nodal recurrence. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]


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a high-powered RCT is necessary to determine whether an END improves survival.

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