The Laryngoscope C 2015 The American Laryngological, V
Rhinological and Otological Society, Inc.
Effectiveness of Selective Neck Dissection in Head and Neck Cancer: The Experience of Two Italian Centers Luigi Barzan, MD; Renato Talamini, PhD; Giovanni Franchin, MD; Marco Pin, MD; Marina Silvestrini, MD; Giuseppe Grando, MD; Stefania Galla, MD; Maria Gabriella Savignano, MD; Gianluca Armas, MD; Francesco Margiotta, MD; Valentina Vanoni, MD; Elena Magri, MD; Cesare Grandi, MD Objective: The aim of this study was to evaluate the oncologic outcomes after a selective neck dissection (SND), both in elective and therapeutic settings, with particular regard to regional recurrence rate. Methods: Retrospective analysis of 827 patients with head and neck primary tumors submitted to SND from 1999 to 2011 in two large hospital centers of northern Italy. Results: A total of 40 neck recurrences were found in the whole series, with the same incidence after primary or salvage surgery (4.4% and 5.2%, respectively), but only 22 neck recurrences occurred in the same side of the dissected neck (3.0%). Factors predicting an increase of ipsilateral neck relapse were pathologically positive nodes, number of positive nodes, and nodal ratio (ratio between positive nodes and total nodal removed), but the risk of regional relapse did not exceed 5.0% in any subgroups. A total of 320 patients (39%) had postoperative radiotherapy (52.0% and 22.0% after primary and salvage surgery, respectively). Considering the primary surgery group alone, postoperative radiotherapy produced only a light reduction of homolateral neck recurrence rate in patients with pathological positive nodes (2.4% vs. 5.0%), but it impacted significantly disease-specific survival, both in pathological classification of nodes (pN)1 and pN2–3 patients. Conclusion: The SND can be considered a safe and sound procedure both in primary surgery and in salvage setting. Postoperative radiotherapy adds minor advantage to regional control only in node-positive patients but may impact survival. Key Words: Selective neck dissections, regional recurrence, postoperative radiotherapy. Level of Evidence: 4. Laryngoscope, 125:1849–1855, 2015
INTRODUCTION
MATERIALS AND METHODS
Although selective neck dissection (SND) thus far has been generally accepted in the elective setting, the exact role of therapeutic SND is less clear; moreover, whether the patients undergoing this procedure have an increased risk of neck recurrence remains uncertain.1–3 The purpose of our study was to evaluate the oncologic outcome, in particular the neck recurrence rate of SND in different clinical settings, and eventually identify predicting factors for both survival and neck recurrence by reviewing a large series of patients who were treated in two Italian hospitals.
From January 1999 to September 2011, the clinical charts of 827 patients submitted to a SND for a squamous cell cancer of the upper aerodigestive tract were retrospectively reviewed at the otolaryngology units of two northeastern Italian hospital centers in Pordenone and Trento. The whole series was first divided in two main categories: neck dissections performed for initial cancer treatment and salvage or planned dissections performed for present or supposed persistence or recurrence of disease, after radiotherapy or chemoradiotherapy. All patients were staged by computed tomography. As a general rule, levels I, II, III, and often but not always IV, were dissected for tumors of the oral cavity, and levels II, III, and IV for tumors of the oropharynx, hypopharynx, and larynx. Level IIb was often left undissected in patients without preoperative (clinical or radiological) or intraoperative evidence of enlarged nodes at level II. Even with respect to level IV, as a general rule only for oral cavity cancer patients, it was sometimes spared when levels II and III were preoperatively or intraoperatively macroscopically negative. Nodes frozen section procedures were not routinely adopted. All neck dissections were conducted in accordance with the limits indicated by Robbins et al.,4 particularly with regard to the posterolateral extension of the dissection, usually performed along the posterior aspect of the sternocleidomastoid muscle, with accurate cleaning of the tissues located among the branches of the cervical plexus. Sex, age, type of surgery (primary treatment, salvage or planned surgery after radio 1/2 chemotherapy), clinical tumor classification (T), clinical nodal classification (N), side of dissection, dissected levels, and complications were recorded for each
Additional Supporting Information may be found in the online version of this article. From the Unit of Otolaryngology, Azienda Ospedaliera “S. Maria degli Angeli” (L.B., M.P., G.G., M.G.S., F.M.), Pordenone; Unit Oncologic Radiotharapy (R.T.); Unit of Epidemioplogy and Biostatistics, Centro di Riferimento Oncologico, IRCCS (G.F.), Aviano; Unit of Otolaryngology (M.S, S.G., G.A., E.M., C.G.); and the Unit of Radiotherapy, Azienda Ospedaliera “S. Chiara” (V.V.), Trento, Italy. Editor’s Note: This Manuscript was accepted for publication March 12, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Cesare Grandi, MD, S.C. Otorinolaringoiatria, Azienda Ospedaliera “S. Chiara”, Largo Medaglie d’Oro n.1 - 38100, Trento, Italy. E-mail: [email protected] DOI: 10.1002/lary.25296
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TABLE I. Demographic and Clinical Characteristics by Type of Treatment. Type of Treatment Planned/Salvage (No. 267) N (%)
Characteristics
Sex Male
Primary Surgery (No. 560) N (%)
220 (82.4)
415 (74.1)
47 (17.6)
145 (25.9)
63 (21–92)
62 (33–98)
Oral cavity Oropharynx
55 (20.6) 84 (31.5)
275 (49.1) 127 (22.7)
Larynx
83 (31.1)
114 (20.4)
45 (16.8)
44 (7.9)
T1
31 (11.6)
112 (20.0)
T2 T3
54 (20.2) 34 (12.7)
207 (37.0) 121 (21.6)
Female Age (years) Median (range) Site
Hypopharynx Tumor classification
T4
34 (12.7)
112 (20.0)
114 (42.8)
8 (1.4)
N0
127 (47.6)
341 (60.9)
N1 N2a
57 (21.4) 22 (8.2)
92 (16.4) 33 (5.9)
N2b
32 (11.6)
67 (12.0)
N2c 1 N3 v2 trend P value
30 (11.2)
27 (4.8)
18 (6.7) 106 (39.7)
44 (7.9) 318 (56.8)
G3
97 (36.3)
181 (32.3)
G4 1 Gx
46 (17.2)
17 (3.0)
T (previous treatment) Nodal classification
RESULTS
Tumor grading G1 G2
G 5 grade; classification.
N 5 clinical
nodal
classification;
T 5clinical
tumor
patient. The following histological parameters were also collected: tumor grading, presence of perineural and angiolymphatic invasion, number of examined nodes, pathological classification of nodes (pN), and presence of extracapsular spread (ECS1). All patients were evaluated for the presence of currently reported risk factors.5,6 As a general rule, cases with no risk factors received no further treatment; those with one or more “minor” risk factors (pT4, pN2-3 ECS-, angiolymphatic or perineural invasion) received postoperative radiotherapy (PORT) or no further treatment, according to institutional policy (mainly at the Hospital of Trento) or individualized decision (general conditions, age, patient’s preferences); whereas highrisk patients (neck metastases with ECS1 or positive or close surgical margins) usually underwent postoperative chemoradiotherapy (cisplatinum 100 mg/mq, day 1, 22, and 43) when age and general health status allowed it. When PORT was delivered, it usually involved both primary tumor site a bilateral neck, with high- and low-risk areas receiving in general 63 to 66 Gy and 55 Gy, respectively. The date and site of all recurrences were registered, together with the final outcome. Survival rates were calculated by the Kaplan-Meier method.7 The following endpoints were considered: death or last follow-up for
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overall survival (OS), death for cancer recurrence only for disease-specific survival (DSS), and neck relapse for neck recurrence-free survival. Differences among survival curves were assessed with the log-rank test. The following pathologic prognostic factors were correlated to neck relapse and DSS: nodal stage; presence of perineural and angiolymphatic invasion; total number of removed nodes; number of positive nodes; ECS; and lymph node ratio, which was defined as the ratio between the number of positive nodes and the number of dissected nodes.8 Differences were tested in univariate and multivariate analysis using the Cox proportional hazards model,9 computing the relative hazard ratios (HR) and corresponding 95% confidence interval (CI). The statistical analysis was performed by means of SAS 9.1 (SAS Institute Inc., Cary, NC) statistic software. All results were considered statistically significant for values of P 0.05 (two-tailed test).
A total of 827 cases with histologically confirmed squamous cell carcinoma of the first aerodigestive tract were identified (498 from the Hospital of Pordenone, Italy, and 329 from the Hospital of Trento, Italy). The most frequent tumor site was the oral cavity (no. 330 cases; 39.9%), followed by oropharynx (no. 211; 25.5%), larynx (no. 197; 23.8%), and hypopharynx (no. 89; 10.8%). A total of 560 patients had a selective neck dissection during a primary surgery, whereas 267 had a planned/salvage operation. Table I shows the distribution of demographic and clinical characteristics of all eligible patients according to type of treatment (primary or planned/salvage surgery). The rate of clinically N0 patients was 60.9% and 47.6% in primary and salvage/ planned surgery groups, respectively. Regarding the T stage, T2 cases were the most represented category in both groups. There were 778 (primary surgery) and 333 (planned/salvage) neck dissections. As a whole, 52.0% and 34.0% of the patients had unilateral or bilateral nodes removal, respectively, whereas 14.0% had a selective procedure on one side and a comprehensive one on the other side. The sublevel IIb was dissected in 76.0% and of dissections, whereas level IV was removed in 50% of patients with an oral cavity cancer. The median number of the removed nodes was 26 (range 2–114). A large majority of patients (93.1%) did not experience any complication. Among patients submitted to primary neck surgery, 282 patients (52.3%) had adjuvant radiotherapy. Of those, 81 cases (29.0% of irradiated cases) had concomitant chemotherapy. In the salvage surgery group, 54 patients (15.0%) had further postoperative radiation. Of those, 16 (30.0%) were associated with concomitant chemotherapy. The 3- and 5-year overall survival rates of the whole series were 67% (95% CI: 63–70) and 57% (95% CI: 53–61), respectively. As expected, 5-year DSS resulted significantly better in the primary surgery group: 82% (95% CI: 78–86) versus 63% (95% CI: 56–69) in the salvage surgery group. Table II summarizes the recurrence distribution by treatment group: primary tumor recurrence and distant metastases were the most frequent events in the salvage surgery group, whereas distant metastases and second primaries were the most frequent unfavorable events in the primary surgery group. In total, there were 40 neck relapses, 26 (4.7%)
Barzan et al.: Selective Neck Dissection in Head and Neck Cancer
TABLE II. Site of First Level of Recurrence by Type of Treatment. Type of Treatment
Site of first recurrence No recurrence
Planned/Salvage (No. 267) N (%)
Primary Surgery (No. 560) N (%)
150 (56.2)
389 (69.4)
Primary site
49 (18.3)
37 (6.6)
Regional* Primary 1 regional
14 (5.2) 6 (2.3)
26 (4.7) 10 (1.8)
Distant
25 (9.4)
41 (7.3)
II primary tumor
23 (8.6)
57 (10.2)
*A total of 22 neck recurrences occurred in the same side of neck dissection: 8 and 14, respectively, for planned/salvage and primary type of treatment.
and 14 (5.2%) in the primary surgery and salvage surgery groups, respectively. However, of those, only 22 of them, 14 (2.5%) and 8 (2.9%), respectively, occurred within the side of the selective dissection, and only 5 ipsilateral neck recurrences occurred outside of the dissected area. Overall, the actuarial ipsilateral neck recurrence risk was not significantly different in the two groups (3.0% and 5.0% for primary and salvage surgery, respectively, P 5 0.39). For this reason, the whole group of patients was considered for prognostic factors analysis. Considering all the patients, the 3-year actuarial neck recurrence rate increased with the pathological neck stage: 2.0%, 5.0%, and 6.0% for pN0, pN1, and pN2 to N3 patients, respectively (statistically significant differences). Considering only those tumors of the oral cavity, no difference emerged in ipsilateral neck recurrence rate whether level IV was dissected or not (P 5 0.35), also separately evaluating patients submitted or not to PORT. Conversely, when sublevel IIb was not removed, in the whole group there was a slight but significant increase in the neck recurrence rate (2.1% vs. 6.7%, P 5 0.006). More in detail, this difference regarded only oropharynx and supraglottic cancers and particularly those patients who did not receive PORT (1.7% vs. 10.5%, P 5 0.0002). With respect to pathological nodal stage, surprisingly, without sublevel IIb dissection there was an increased neck recurrence rate only in pN0 patients (6.06% vs. 0.9%, P 5 003), probably due to the effect of PORT in node positive ones. Sixteen out of 22 neck recurrences could be treated with a curative aim, but a definitive disease control was achieved only in five cases (23.0%). Univariate and multivariate HRs for ipsilateral neck recurrence were calculated according to different neck pathological prognostic factors (Supp. Table SI: available online). In univariate analysis, the risk of a neck relapse resulted significantly correlated with pathological nodal stage, number of pathological nodes, and lymph node ratio (2 ratio breakdown levels, > 1 and > 7, were arbitrarily fixed), whereas perineural tumor invasion, angiolympatic tumor invasion, and extranodal Laryngoscope 125: August 2015
spread were not significantly correlated to regional relapse. Nevertheless, in multivariate analysis, all three factors lost statistical significance, probably due to the few events that occurred. The same analysis is presented in terms of cause specific mortality (Supp. Table SII: available online). Here again the previous three predictors, plus the presence of extracapsular spread resulted significantly correlated to survival in univariate analysis, whereas at the multivariate one only pathological node classification, the number of pathological nodes and presence of extracapsular spread remained significant predictors of specific survival. Five-year DSS survival by pathological node classification was 87%, 75%, and 55% for pN0, pN1, and pN23 patients, respectively. The effect of PORT was investigated only in the primary surgery group. Table III summarizes the risk of neck recurrence according to neck pathological stage and status of PORT. In pN0 patients, the neck recurrence rate was substantially unchanged whether or not the PORT had been adopted (2.0% and 2.7%, respectively), whereas there was a reduction (although not statistically significant) of neck recurrences in pN1 patients who had received adjuvant treatment (2.4% vs. 5.0%, P 5 0.08). Considering DSS, the PORT did not improve the outcome in pN0 patients, but it significantly reduced cancer mortality both in pN1 and pN2 to N3 patients (Figs. 1–3). The effect, although not completely explained, was mainly related to a reduction of primary tumor recurrence rate, especially in N2 to N3 patients. After the appearance of any disease recurrences, the outcome was invariably poor independent of the site of recurrence (primary tumor, neck, or distant organs), with a median survival ranging from 8.8 months (neck recurrence) to 10.1 months (distant metastases).
DISCUSSION During the last decades, SND has become widely accepted by the head and neck surgeons community10–12; however, despite its popularity there remains a lack of complete evidence of efficacy in terms of oncological outcomes.1 Only two randomized studies, published by the Brazilian Head and Neck Cancer Study Group, compared SND to modified radical neck dissection (MRDD) for cancer of the oral cavity and larynx in clinical N0 patients.13,14 Both trials confirmed the efficacy of SND in terms of survival and neck failure, but all selective procedure were converted to a comprehensive dissection in case of intraoperative detection of nodal metastases. In addition, most of the cases had postoperative radiation. However, many retrospective studies have shown that SND provides control rates similar to that of MRND in N0 patients.15–21 Nevertheless, neck failure rates reported in previously published series ranged from 2.8% to 15.0%, making it difficult to assess the actual safety of this surgical procedure. Patients selection, small samples, different data reporting, different surgical technique, and variable criteria for PORT may explain this wide variability. The surgical management of patients with positive nodes is also more
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TABLE III. Hazard Ratio for Neck Recurrence According to Pathological Node Classification/Postoperative Radio-Chemotherapy Treatment: Primary Surgery Group. Neck Recurrence Yes (No. 14) N (%)
No (No. 525) N (%)
HR (95% CI)1
Pathological nodes/radio-chemotherapy treatment pN0/Yes RT 6 CT
2 (2.7)
72 (97.3)
12
pN0/No RT 6 CT
4 (2.0)
193 (98.0)
0.57 (0.09–3.38)
v2 P value pN1 1 pN2 a2b2c 1 pN3/Yes RT 6 CT
5 (2.4)
203 (97.6)
P 5 0.53 12
pN1 1 pN2 a2b2c 1 pN3/No RT 6 CT
3 (5.0)
57 (95.0)
2.34 (0.56–9.80)
v2 P value
P 5 0.24
(%) 5 row percentage. *HR 5 hazard ratios and 95% CI. †Reference category. CI 5 confidence interval; CT 5computed tomography; HR 5 hazard ratio; pN 5 pathological classification of nodes; RT 5radiotherapy.
controversial, mainly due to the higher regional recurrence rate reported by various authors.21–23 Traditionally, a comprehensive neck dissection has been the surgical standard for patients presenting with neck disease, but selective procedures have progressively gained popularity, with recent reports supporting the safety of these techniques even in this patient setting.20,21,24 Again the regional control rates significantly vary in different series and again the role of PORT needs to be clarified, especially in the N1 patient category.20,21 Conversely, the role of selective neck dissection as salvage or planned surgery after radiotherapy or chemoradiotherapy seems to be more established. Numerous authors reported very low regional failure rates after selective and also after super selective surgical procedures, confirming the safety of these procedures both in the presence and absence of gross residual disease.25–29 The value of the present study derives primarily from the large number of evaluated patients, which makes this review one of the largest ever published. The
most notable result is the very low rate of regional failures. The risk of relapse in the neck was not statistically different in primary and salvage settings, and it was only slightly positively correlated with the nodal stage. In clinical N0 patients, the regional recurrence occurred in about 2% of the cases, independent of the adoption of PORT. In patients with pathological evidence of neck metastases (pN1, pN2–3), the neck relapse rates resulted only slightly increased if PORT was not delivered (5%). These data compare favorably with other published reports.20,21,24 In addition, in agreement with other authors,21,24,30 of 22 total single ipsilateral neck recurrences, only five (14%) occurred outside the dissected areas (recurrences theoretically avoidable with a comprehensive neck dissection). In our opinion, an explanation for that, and also for the large variations in regional recurrences presented in the literature, may be found in the surgical technique. Most of the procedures of this study were performed by only two surgeons with a long training in neck surgery, and surgeon’s expertise
Fig. 1. Primary surgery group: 398 pN0 patients. Disease-specific survival according to radio-chemotherapy treatment. A 5 no; B 5 yes.
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Barzan et al.: Selective Neck Dissection in Head and Neck Cancer
Fig. 2. Primary surgery group: 137 pN1 patients. Disease-specific survival according to radio-chemotherapy treatment. A 5 no; B 5 yes.
has been shown to correlate to a more complete neck dissection.31 Our data regarding the preservation of sublevel IIb and level IV, although taken with caution due to the low numbers and the risk of selection biases, seem to give diversified indications. While removal of level IV did not significantly increase the regional control rate, this was not the case when sublevel IIb was spared, even in N0 patients, especially in oropharynx and supraglottic cancers and when PORT was not planned. These observations are only in partial agreement with current reports in the literature.32–37 The analysis of prognostic factors for regional relapse was strongly limited by the very low neck recurrence rate. Only the number of positive nodes, the pathological classification, and the lymph node ratio (the latter two strictly correlated) significantly influenced the regional risk of recurrence after multivariate analysis. Surprisingly, the presence of extracapsular spread did not significantly impact on neck relapse. We could not differentiate from our data macroscopic form microscopic ECS and this may be the first explanation for this result. In addition, a selection bias is also possible due
to the exclusion of patients with advanced metastases from selective dissection. In any case, again it is remarkable that the 5-year neck recurrence HR did not also exceed 5% in the most unfavorable categories. Concerning the neck prognosticators for DSS, only pathological nodal stage, extracapsular spread, and total number of metastatic nodes remained significant predictors after multivariate analysis, whereas all the other factors lost significance when compared. This result is in agreement with what was published by others.38 Indications for PORT in head and neck cancer patients are still debated. The adjuvant treatment is generally adopted in the presence of unfavorable prognostic factors from primary tumor and or neck metastases, but the real effectiveness of the treatment has not been definitively demonstrated. In fact, although the use of chemoradiotherapy has been shown to improve survival with respect to radiotherapy alone in high-risk patients (i.e., presence of extracapsular spread of positive clinical margins),39 the demarcation between low and higher risk patients, together with the need of treating low- and intermediate-risk patients with postoperative radiation,
Fig. 3. Primary surgery group: 244 pN2 to N3 patients. Disease-specific survival according to radio-chemotherapy treatment. A 5 no; B 5 yes.
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are not supported by strong evidence.6,40–43 In particular, the pN1 patient category is highly controversial. Of course, our data cannot be conclusive on this point, mainly because of the multiple indications for PORT (deriving both from primary tumor and neck nodes prognostic factors and not available in detail), with the consequent risk of selection biases. In our opinion, however, some interesting observations can be made. Primarily with respect to regional control after a correctly performed SLN, it is rather evident that PORT seems to add some advantage only in pN1 cases; in this category of patients, there is a 50% relative reduction of the HR for neck recurrence, but the small absolute value of the clinical benefit (only 3% risk reduction of neck relapse) could probably be compared with the adjunctive toxicity. Trying to draw conclusions about the influence of PORT on survival is even more difficult. Some recent large reports from the Surveillance, Epidemiology, and End Results database have shown a significant advantage in survival in patients with neck metastases submitted to PORT, with respect to patients with no further treatment and also independent of the tumor stage.44,45 Despite this, no information about the cause of this survival improvement was reported due to the data source. Our data appeared in agreement with these results. Even when PORT had only a minor effect on regional control, it significantly improved both OS and DSS in patients with pathological neck metastases. In this series, this effect seems to be at least partially because of a reduction of the primary tumor recurrence rate, especially in N2 to N3 patients. The observation could be to some extent explained by considering that PORT was usually delivered both on primary tumor bed and bilateral neck in the presence of any unfavorable risk factor related to primary tumor or neck nodes.
CONCLUSION Our results strongly support the safety of SNL in both primary and in planned/salvage surgery settings and N0 as well as N-positive patients, independent of the adoption of PORT. Only in pN-positive patients might PORT slightly reduce the regional relapse rate. Conversely, in agreement with other reports in the literature, PORT seemed to improve DSS in N-positive patients, but this result deserves further confirmation through prospective studies.
Acknowledgment The authors wish to thank Mrs. Luigina Mei for her editorial assistance.
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34. Ferlito A, Silver CE, Suarez C, Rinaldo A. Preliminary multi-institutional prospective pathologic and molecular studies support preservation of sublevel IIB and level IV for laryngeal squamous carcinoma with clinically negative neck. Eur Arch Otorhinolaryngol 2007;264:111–114. 35. Hoyt BJ, Smith R, Smith A, Trites J, Taylor SM. IIb or not IIb: oncologic role of submuscular recess inclusion in selective neck dissections. J Otolaryngol Head Neck Surg 2008;37:689–693. 36. Paleri V, Kumar Subramaniam S, Oozeer N, Rees G, Krishnan S. Dissection of the submuscular recess (sublevel IIb) in squamous cell cancer of the upper aerodigestive tract: prospective study and systematic review of the literature. Head Neck 2008;30:194–200. 37. Khafif A, Fliss DM, Gil Z, Medina JE. Routine inclusion of level IV in neck dissection for squamous cell carcinoma of the larynx: is it justified? Head Neck 2004;26:309–312. 38. Shrime MG, Ma C, Gullane PJ, et al. Impact of nodal ratio on survival in squamous cell carcinoma of the oral cavity. Head Neck 2009;31:129–136. 39. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843–850. 40. Lundahl RE, Foote RL, Bonner JA, et al. Combined neck dissection and postoperative radiation therapy in the management of the high-risk
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neck: a matched-pair analysis. Int J Radiat Oncol Biol Phys 1998;40: 529–534. 41. Mendenhall WM, Hinerman RW, Amdur RJ, et al. Postoperative radiotherapy for squamous cell carcinoma of the head and neck. Clin Med Res 2006;4:200–208. 42. Langendijk JA, Ferlito A, Takes RP, et al. Postoperative strategies after primary surgery for squamous cell carcinoma of the head and neck. Oral Oncol 2010;46:577–585. 43. Moergel M, Meurer P, Ingel K, Wendt TG, Al-Nawas. Effectiveness of postoperative radiotherapy in patients with small oral and oropharyngeal squamous cell carcinoma and concomitant ipsilateral singular cervical lymph node metastasis (pN1): a meta-analysis. Strahlenther Onkol 2011; 187:337–343. 44. Lavaf A, Genden EM, Cesaretti JA, Packer S, Kao J. Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck squamous cell carcinoma. Cancer 2008;112:535–543. 45. Kao J, Lavaf A, Teng MS, Huang D, Genden EM. Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage. Int J Radiat Oncol Biol Phys 2008;71:362–370.
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Rhinological and Otological Society, Inc.
Effectiveness of Selective Neck Dissection in Head and Neck Cancer: The Experience of Two Italian Centers Luigi Barzan, MD; Renato Talamini, PhD; Giovanni Franchin, MD; Marco Pin, MD; Marina Silvestrini, MD; Giuseppe Grando, MD; Stefania Galla, MD; Maria Gabriella Savignano, MD; Gianluca Armas, MD; Francesco Margiotta, MD; Valentina Vanoni, MD; Elena Magri, MD; Cesare Grandi, MD Objective: The aim of this study was to evaluate the oncologic outcomes after a selective neck dissection (SND), both in elective and therapeutic settings, with particular regard to regional recurrence rate. Methods: Retrospective analysis of 827 patients with head and neck primary tumors submitted to SND from 1999 to 2011 in two large hospital centers of northern Italy. Results: A total of 40 neck recurrences were found in the whole series, with the same incidence after primary or salvage surgery (4.4% and 5.2%, respectively), but only 22 neck recurrences occurred in the same side of the dissected neck (3.0%). Factors predicting an increase of ipsilateral neck relapse were pathologically positive nodes, number of positive nodes, and nodal ratio (ratio between positive nodes and total nodal removed), but the risk of regional relapse did not exceed 5.0% in any subgroups. A total of 320 patients (39%) had postoperative radiotherapy (52.0% and 22.0% after primary and salvage surgery, respectively). Considering the primary surgery group alone, postoperative radiotherapy produced only a light reduction of homolateral neck recurrence rate in patients with pathological positive nodes (2.4% vs. 5.0%), but it impacted significantly disease-specific survival, both in pathological classification of nodes (pN)1 and pN2–3 patients. Conclusion: The SND can be considered a safe and sound procedure both in primary surgery and in salvage setting. Postoperative radiotherapy adds minor advantage to regional control only in node-positive patients but may impact survival. Key Words: Selective neck dissections, regional recurrence, postoperative radiotherapy. Level of Evidence: 4. Laryngoscope, 125:1849–1855, 2015
INTRODUCTION
MATERIALS AND METHODS
Although selective neck dissection (SND) thus far has been generally accepted in the elective setting, the exact role of therapeutic SND is less clear; moreover, whether the patients undergoing this procedure have an increased risk of neck recurrence remains uncertain.1–3 The purpose of our study was to evaluate the oncologic outcome, in particular the neck recurrence rate of SND in different clinical settings, and eventually identify predicting factors for both survival and neck recurrence by reviewing a large series of patients who were treated in two Italian hospitals.
From January 1999 to September 2011, the clinical charts of 827 patients submitted to a SND for a squamous cell cancer of the upper aerodigestive tract were retrospectively reviewed at the otolaryngology units of two northeastern Italian hospital centers in Pordenone and Trento. The whole series was first divided in two main categories: neck dissections performed for initial cancer treatment and salvage or planned dissections performed for present or supposed persistence or recurrence of disease, after radiotherapy or chemoradiotherapy. All patients were staged by computed tomography. As a general rule, levels I, II, III, and often but not always IV, were dissected for tumors of the oral cavity, and levels II, III, and IV for tumors of the oropharynx, hypopharynx, and larynx. Level IIb was often left undissected in patients without preoperative (clinical or radiological) or intraoperative evidence of enlarged nodes at level II. Even with respect to level IV, as a general rule only for oral cavity cancer patients, it was sometimes spared when levels II and III were preoperatively or intraoperatively macroscopically negative. Nodes frozen section procedures were not routinely adopted. All neck dissections were conducted in accordance with the limits indicated by Robbins et al.,4 particularly with regard to the posterolateral extension of the dissection, usually performed along the posterior aspect of the sternocleidomastoid muscle, with accurate cleaning of the tissues located among the branches of the cervical plexus. Sex, age, type of surgery (primary treatment, salvage or planned surgery after radio 1/2 chemotherapy), clinical tumor classification (T), clinical nodal classification (N), side of dissection, dissected levels, and complications were recorded for each
Additional Supporting Information may be found in the online version of this article. From the Unit of Otolaryngology, Azienda Ospedaliera “S. Maria degli Angeli” (L.B., M.P., G.G., M.G.S., F.M.), Pordenone; Unit Oncologic Radiotharapy (R.T.); Unit of Epidemioplogy and Biostatistics, Centro di Riferimento Oncologico, IRCCS (G.F.), Aviano; Unit of Otolaryngology (M.S, S.G., G.A., E.M., C.G.); and the Unit of Radiotherapy, Azienda Ospedaliera “S. Chiara” (V.V.), Trento, Italy. Editor’s Note: This Manuscript was accepted for publication March 12, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Cesare Grandi, MD, S.C. Otorinolaringoiatria, Azienda Ospedaliera “S. Chiara”, Largo Medaglie d’Oro n.1 - 38100, Trento, Italy. E-mail: [email protected] DOI: 10.1002/lary.25296
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TABLE I. Demographic and Clinical Characteristics by Type of Treatment. Type of Treatment Planned/Salvage (No. 267) N (%)
Characteristics
Sex Male
Primary Surgery (No. 560) N (%)
220 (82.4)
415 (74.1)
47 (17.6)
145 (25.9)
63 (21–92)
62 (33–98)
Oral cavity Oropharynx
55 (20.6) 84 (31.5)
275 (49.1) 127 (22.7)
Larynx
83 (31.1)
114 (20.4)
45 (16.8)
44 (7.9)
T1
31 (11.6)
112 (20.0)
T2 T3
54 (20.2) 34 (12.7)
207 (37.0) 121 (21.6)
Female Age (years) Median (range) Site
Hypopharynx Tumor classification
T4
34 (12.7)
112 (20.0)
114 (42.8)
8 (1.4)
N0
127 (47.6)
341 (60.9)
N1 N2a
57 (21.4) 22 (8.2)
92 (16.4) 33 (5.9)
N2b
32 (11.6)
67 (12.0)
N2c 1 N3 v2 trend P value
30 (11.2)
27 (4.8)
18 (6.7) 106 (39.7)
44 (7.9) 318 (56.8)
G3
97 (36.3)
181 (32.3)
G4 1 Gx
46 (17.2)
17 (3.0)
T (previous treatment) Nodal classification
RESULTS
Tumor grading G1 G2
G 5 grade; classification.
N 5 clinical
nodal
classification;
T 5clinical
tumor
patient. The following histological parameters were also collected: tumor grading, presence of perineural and angiolymphatic invasion, number of examined nodes, pathological classification of nodes (pN), and presence of extracapsular spread (ECS1). All patients were evaluated for the presence of currently reported risk factors.5,6 As a general rule, cases with no risk factors received no further treatment; those with one or more “minor” risk factors (pT4, pN2-3 ECS-, angiolymphatic or perineural invasion) received postoperative radiotherapy (PORT) or no further treatment, according to institutional policy (mainly at the Hospital of Trento) or individualized decision (general conditions, age, patient’s preferences); whereas highrisk patients (neck metastases with ECS1 or positive or close surgical margins) usually underwent postoperative chemoradiotherapy (cisplatinum 100 mg/mq, day 1, 22, and 43) when age and general health status allowed it. When PORT was delivered, it usually involved both primary tumor site a bilateral neck, with high- and low-risk areas receiving in general 63 to 66 Gy and 55 Gy, respectively. The date and site of all recurrences were registered, together with the final outcome. Survival rates were calculated by the Kaplan-Meier method.7 The following endpoints were considered: death or last follow-up for
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overall survival (OS), death for cancer recurrence only for disease-specific survival (DSS), and neck relapse for neck recurrence-free survival. Differences among survival curves were assessed with the log-rank test. The following pathologic prognostic factors were correlated to neck relapse and DSS: nodal stage; presence of perineural and angiolymphatic invasion; total number of removed nodes; number of positive nodes; ECS; and lymph node ratio, which was defined as the ratio between the number of positive nodes and the number of dissected nodes.8 Differences were tested in univariate and multivariate analysis using the Cox proportional hazards model,9 computing the relative hazard ratios (HR) and corresponding 95% confidence interval (CI). The statistical analysis was performed by means of SAS 9.1 (SAS Institute Inc., Cary, NC) statistic software. All results were considered statistically significant for values of P 0.05 (two-tailed test).
A total of 827 cases with histologically confirmed squamous cell carcinoma of the first aerodigestive tract were identified (498 from the Hospital of Pordenone, Italy, and 329 from the Hospital of Trento, Italy). The most frequent tumor site was the oral cavity (no. 330 cases; 39.9%), followed by oropharynx (no. 211; 25.5%), larynx (no. 197; 23.8%), and hypopharynx (no. 89; 10.8%). A total of 560 patients had a selective neck dissection during a primary surgery, whereas 267 had a planned/salvage operation. Table I shows the distribution of demographic and clinical characteristics of all eligible patients according to type of treatment (primary or planned/salvage surgery). The rate of clinically N0 patients was 60.9% and 47.6% in primary and salvage/ planned surgery groups, respectively. Regarding the T stage, T2 cases were the most represented category in both groups. There were 778 (primary surgery) and 333 (planned/salvage) neck dissections. As a whole, 52.0% and 34.0% of the patients had unilateral or bilateral nodes removal, respectively, whereas 14.0% had a selective procedure on one side and a comprehensive one on the other side. The sublevel IIb was dissected in 76.0% and of dissections, whereas level IV was removed in 50% of patients with an oral cavity cancer. The median number of the removed nodes was 26 (range 2–114). A large majority of patients (93.1%) did not experience any complication. Among patients submitted to primary neck surgery, 282 patients (52.3%) had adjuvant radiotherapy. Of those, 81 cases (29.0% of irradiated cases) had concomitant chemotherapy. In the salvage surgery group, 54 patients (15.0%) had further postoperative radiation. Of those, 16 (30.0%) were associated with concomitant chemotherapy. The 3- and 5-year overall survival rates of the whole series were 67% (95% CI: 63–70) and 57% (95% CI: 53–61), respectively. As expected, 5-year DSS resulted significantly better in the primary surgery group: 82% (95% CI: 78–86) versus 63% (95% CI: 56–69) in the salvage surgery group. Table II summarizes the recurrence distribution by treatment group: primary tumor recurrence and distant metastases were the most frequent events in the salvage surgery group, whereas distant metastases and second primaries were the most frequent unfavorable events in the primary surgery group. In total, there were 40 neck relapses, 26 (4.7%)
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TABLE II. Site of First Level of Recurrence by Type of Treatment. Type of Treatment
Site of first recurrence No recurrence
Planned/Salvage (No. 267) N (%)
Primary Surgery (No. 560) N (%)
150 (56.2)
389 (69.4)
Primary site
49 (18.3)
37 (6.6)
Regional* Primary 1 regional
14 (5.2) 6 (2.3)
26 (4.7) 10 (1.8)
Distant
25 (9.4)
41 (7.3)
II primary tumor
23 (8.6)
57 (10.2)
*A total of 22 neck recurrences occurred in the same side of neck dissection: 8 and 14, respectively, for planned/salvage and primary type of treatment.
and 14 (5.2%) in the primary surgery and salvage surgery groups, respectively. However, of those, only 22 of them, 14 (2.5%) and 8 (2.9%), respectively, occurred within the side of the selective dissection, and only 5 ipsilateral neck recurrences occurred outside of the dissected area. Overall, the actuarial ipsilateral neck recurrence risk was not significantly different in the two groups (3.0% and 5.0% for primary and salvage surgery, respectively, P 5 0.39). For this reason, the whole group of patients was considered for prognostic factors analysis. Considering all the patients, the 3-year actuarial neck recurrence rate increased with the pathological neck stage: 2.0%, 5.0%, and 6.0% for pN0, pN1, and pN2 to N3 patients, respectively (statistically significant differences). Considering only those tumors of the oral cavity, no difference emerged in ipsilateral neck recurrence rate whether level IV was dissected or not (P 5 0.35), also separately evaluating patients submitted or not to PORT. Conversely, when sublevel IIb was not removed, in the whole group there was a slight but significant increase in the neck recurrence rate (2.1% vs. 6.7%, P 5 0.006). More in detail, this difference regarded only oropharynx and supraglottic cancers and particularly those patients who did not receive PORT (1.7% vs. 10.5%, P 5 0.0002). With respect to pathological nodal stage, surprisingly, without sublevel IIb dissection there was an increased neck recurrence rate only in pN0 patients (6.06% vs. 0.9%, P 5 003), probably due to the effect of PORT in node positive ones. Sixteen out of 22 neck recurrences could be treated with a curative aim, but a definitive disease control was achieved only in five cases (23.0%). Univariate and multivariate HRs for ipsilateral neck recurrence were calculated according to different neck pathological prognostic factors (Supp. Table SI: available online). In univariate analysis, the risk of a neck relapse resulted significantly correlated with pathological nodal stage, number of pathological nodes, and lymph node ratio (2 ratio breakdown levels, > 1 and > 7, were arbitrarily fixed), whereas perineural tumor invasion, angiolympatic tumor invasion, and extranodal Laryngoscope 125: August 2015
spread were not significantly correlated to regional relapse. Nevertheless, in multivariate analysis, all three factors lost statistical significance, probably due to the few events that occurred. The same analysis is presented in terms of cause specific mortality (Supp. Table SII: available online). Here again the previous three predictors, plus the presence of extracapsular spread resulted significantly correlated to survival in univariate analysis, whereas at the multivariate one only pathological node classification, the number of pathological nodes and presence of extracapsular spread remained significant predictors of specific survival. Five-year DSS survival by pathological node classification was 87%, 75%, and 55% for pN0, pN1, and pN23 patients, respectively. The effect of PORT was investigated only in the primary surgery group. Table III summarizes the risk of neck recurrence according to neck pathological stage and status of PORT. In pN0 patients, the neck recurrence rate was substantially unchanged whether or not the PORT had been adopted (2.0% and 2.7%, respectively), whereas there was a reduction (although not statistically significant) of neck recurrences in pN1 patients who had received adjuvant treatment (2.4% vs. 5.0%, P 5 0.08). Considering DSS, the PORT did not improve the outcome in pN0 patients, but it significantly reduced cancer mortality both in pN1 and pN2 to N3 patients (Figs. 1–3). The effect, although not completely explained, was mainly related to a reduction of primary tumor recurrence rate, especially in N2 to N3 patients. After the appearance of any disease recurrences, the outcome was invariably poor independent of the site of recurrence (primary tumor, neck, or distant organs), with a median survival ranging from 8.8 months (neck recurrence) to 10.1 months (distant metastases).
DISCUSSION During the last decades, SND has become widely accepted by the head and neck surgeons community10–12; however, despite its popularity there remains a lack of complete evidence of efficacy in terms of oncological outcomes.1 Only two randomized studies, published by the Brazilian Head and Neck Cancer Study Group, compared SND to modified radical neck dissection (MRDD) for cancer of the oral cavity and larynx in clinical N0 patients.13,14 Both trials confirmed the efficacy of SND in terms of survival and neck failure, but all selective procedure were converted to a comprehensive dissection in case of intraoperative detection of nodal metastases. In addition, most of the cases had postoperative radiation. However, many retrospective studies have shown that SND provides control rates similar to that of MRND in N0 patients.15–21 Nevertheless, neck failure rates reported in previously published series ranged from 2.8% to 15.0%, making it difficult to assess the actual safety of this surgical procedure. Patients selection, small samples, different data reporting, different surgical technique, and variable criteria for PORT may explain this wide variability. The surgical management of patients with positive nodes is also more
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TABLE III. Hazard Ratio for Neck Recurrence According to Pathological Node Classification/Postoperative Radio-Chemotherapy Treatment: Primary Surgery Group. Neck Recurrence Yes (No. 14) N (%)
No (No. 525) N (%)
HR (95% CI)1
Pathological nodes/radio-chemotherapy treatment pN0/Yes RT 6 CT
2 (2.7)
72 (97.3)
12
pN0/No RT 6 CT
4 (2.0)
193 (98.0)
0.57 (0.09–3.38)
v2 P value pN1 1 pN2 a2b2c 1 pN3/Yes RT 6 CT
5 (2.4)
203 (97.6)
P 5 0.53 12
pN1 1 pN2 a2b2c 1 pN3/No RT 6 CT
3 (5.0)
57 (95.0)
2.34 (0.56–9.80)
v2 P value
P 5 0.24
(%) 5 row percentage. *HR 5 hazard ratios and 95% CI. †Reference category. CI 5 confidence interval; CT 5computed tomography; HR 5 hazard ratio; pN 5 pathological classification of nodes; RT 5radiotherapy.
controversial, mainly due to the higher regional recurrence rate reported by various authors.21–23 Traditionally, a comprehensive neck dissection has been the surgical standard for patients presenting with neck disease, but selective procedures have progressively gained popularity, with recent reports supporting the safety of these techniques even in this patient setting.20,21,24 Again the regional control rates significantly vary in different series and again the role of PORT needs to be clarified, especially in the N1 patient category.20,21 Conversely, the role of selective neck dissection as salvage or planned surgery after radiotherapy or chemoradiotherapy seems to be more established. Numerous authors reported very low regional failure rates after selective and also after super selective surgical procedures, confirming the safety of these procedures both in the presence and absence of gross residual disease.25–29 The value of the present study derives primarily from the large number of evaluated patients, which makes this review one of the largest ever published. The
most notable result is the very low rate of regional failures. The risk of relapse in the neck was not statistically different in primary and salvage settings, and it was only slightly positively correlated with the nodal stage. In clinical N0 patients, the regional recurrence occurred in about 2% of the cases, independent of the adoption of PORT. In patients with pathological evidence of neck metastases (pN1, pN2–3), the neck relapse rates resulted only slightly increased if PORT was not delivered (5%). These data compare favorably with other published reports.20,21,24 In addition, in agreement with other authors,21,24,30 of 22 total single ipsilateral neck recurrences, only five (14%) occurred outside the dissected areas (recurrences theoretically avoidable with a comprehensive neck dissection). In our opinion, an explanation for that, and also for the large variations in regional recurrences presented in the literature, may be found in the surgical technique. Most of the procedures of this study were performed by only two surgeons with a long training in neck surgery, and surgeon’s expertise
Fig. 1. Primary surgery group: 398 pN0 patients. Disease-specific survival according to radio-chemotherapy treatment. A 5 no; B 5 yes.
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Fig. 2. Primary surgery group: 137 pN1 patients. Disease-specific survival according to radio-chemotherapy treatment. A 5 no; B 5 yes.
has been shown to correlate to a more complete neck dissection.31 Our data regarding the preservation of sublevel IIb and level IV, although taken with caution due to the low numbers and the risk of selection biases, seem to give diversified indications. While removal of level IV did not significantly increase the regional control rate, this was not the case when sublevel IIb was spared, even in N0 patients, especially in oropharynx and supraglottic cancers and when PORT was not planned. These observations are only in partial agreement with current reports in the literature.32–37 The analysis of prognostic factors for regional relapse was strongly limited by the very low neck recurrence rate. Only the number of positive nodes, the pathological classification, and the lymph node ratio (the latter two strictly correlated) significantly influenced the regional risk of recurrence after multivariate analysis. Surprisingly, the presence of extracapsular spread did not significantly impact on neck relapse. We could not differentiate from our data macroscopic form microscopic ECS and this may be the first explanation for this result. In addition, a selection bias is also possible due
to the exclusion of patients with advanced metastases from selective dissection. In any case, again it is remarkable that the 5-year neck recurrence HR did not also exceed 5% in the most unfavorable categories. Concerning the neck prognosticators for DSS, only pathological nodal stage, extracapsular spread, and total number of metastatic nodes remained significant predictors after multivariate analysis, whereas all the other factors lost significance when compared. This result is in agreement with what was published by others.38 Indications for PORT in head and neck cancer patients are still debated. The adjuvant treatment is generally adopted in the presence of unfavorable prognostic factors from primary tumor and or neck metastases, but the real effectiveness of the treatment has not been definitively demonstrated. In fact, although the use of chemoradiotherapy has been shown to improve survival with respect to radiotherapy alone in high-risk patients (i.e., presence of extracapsular spread of positive clinical margins),39 the demarcation between low and higher risk patients, together with the need of treating low- and intermediate-risk patients with postoperative radiation,
Fig. 3. Primary surgery group: 244 pN2 to N3 patients. Disease-specific survival according to radio-chemotherapy treatment. A 5 no; B 5 yes.
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are not supported by strong evidence.6,40–43 In particular, the pN1 patient category is highly controversial. Of course, our data cannot be conclusive on this point, mainly because of the multiple indications for PORT (deriving both from primary tumor and neck nodes prognostic factors and not available in detail), with the consequent risk of selection biases. In our opinion, however, some interesting observations can be made. Primarily with respect to regional control after a correctly performed SLN, it is rather evident that PORT seems to add some advantage only in pN1 cases; in this category of patients, there is a 50% relative reduction of the HR for neck recurrence, but the small absolute value of the clinical benefit (only 3% risk reduction of neck relapse) could probably be compared with the adjunctive toxicity. Trying to draw conclusions about the influence of PORT on survival is even more difficult. Some recent large reports from the Surveillance, Epidemiology, and End Results database have shown a significant advantage in survival in patients with neck metastases submitted to PORT, with respect to patients with no further treatment and also independent of the tumor stage.44,45 Despite this, no information about the cause of this survival improvement was reported due to the data source. Our data appeared in agreement with these results. Even when PORT had only a minor effect on regional control, it significantly improved both OS and DSS in patients with pathological neck metastases. In this series, this effect seems to be at least partially because of a reduction of the primary tumor recurrence rate, especially in N2 to N3 patients. The observation could be to some extent explained by considering that PORT was usually delivered both on primary tumor bed and bilateral neck in the presence of any unfavorable risk factor related to primary tumor or neck nodes.
CONCLUSION Our results strongly support the safety of SNL in both primary and in planned/salvage surgery settings and N0 as well as N-positive patients, independent of the adoption of PORT. Only in pN-positive patients might PORT slightly reduce the regional relapse rate. Conversely, in agreement with other reports in the literature, PORT seemed to improve DSS in N-positive patients, but this result deserves further confirmation through prospective studies.
Acknowledgment The authors wish to thank Mrs. Luigina Mei for her editorial assistance.
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