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Complications and oncologic outcomes following elective neck dissection with salvage laryngectomy for the N0 neck
AM ER IC AN JOURNAL OF OT OLA RYNGOLOGY–H E A D A N D NE CK M E D ICI N E AN D S U RGE RY 3 7 (2 0 1 6) 1 86 –1 9 4
Available online at www.sciencedirect.com
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Complications and oncologic outcomes following elective neck dissection with salvage laryngectomy for the N0 neck☆,☆☆ Monika E. Freiser, MD, MPH a, 1 , Rosemary B. Ojo, MD a, 2 , Kaming Lo, MPH b , Sandra Saint-Victor, MD a , Craig Bollig, MD a, 3 , Chetan S. Nayak, MD a , Zoukaa B. Sargi, MD, MPH a,⁎ a
Department of Otolaryngology, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 650D, Miami, FL Biostatistics Collaboration and Consulting Core, Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, 1120 N.W. 14th Street, Suite 1049, Miami, FL b
ARTI CLE I NFO
A BS TRACT
Article history:
Purpose: To investigate the difference in survival and complication outcomes between
Received 3 December 2015
patients with a clinically and radiologically N0 neck who received an elective neck dissection at the time of salvage total laryngectomy compared to those who had salvage total laryngectomy alone. Materials and methods: A retrospective chart review was performed on 125 salvage total laryngectomy patients who were clinically and radiologically N0 preoperatively. Performance of an elective neck dissection and other factors were tested for associations with various postoperative complications, disease-free survival, and overall survival. Results: Ninety-eight patients underwent elective neck dissection, of which ten had positive nodal pathology. Elective neck dissection was not significantly associated with complications or survival outcomes. Positive nodal disease was associated with worse disease-free and overall survival on multivariate analysis. Conclusions: In patients with clinically and radiologically N0 necks undergoing salvage total laryngectomy, an elective neck dissection can provide prognostic information but does not appear to be significantly associated with increased complications or improved survival. © 2016 Elsevier Inc. All rights reserved.
☆ Meeting Presentations: Poster at the Florida Medical Association (FMA) Annual Poster Symposium, “Incidence of postoperative complications in patients treated with salvage laryngectomy with radiologically negative neck”, Orlando, FL, July 27, 2013; poster at the Academy Annual Meeting, “Incidence of occult nodal disease in patients treated with salvage laryngectomy with radiologically negative neck”, Vancouver, Canada, September 29, 2013; oral presentation at the National Medical Association Meeting, “Incidence of occult nodal disease and complications in patients treated with salvage laryngectomy with radiologically negative neck”, Honolulu, Hawaii, August 4, 2014. ☆☆ None of the authors have any potential conflicts of interest to disclose. ⁎ Corresponding author at: Department of Otolaryngology, Division of Head and Neck Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 650D, Miami, FL 33136. Tel.: +1 305 243 6495; fax: + 1 305 243 1283. E-mail addresses: [email protected] (M.E. Freiser), [email protected] (R.B. Ojo), [email protected] (K. Lo), [email protected] (S. Saint-Victor), [email protected] (C. Bollig), [email protected] (C.S. Nayak), [email protected] (Z.B. Sargi). 1 Present address: Department of Otolaryngology, University of Pittsburgh Medical Center, 203 Lothrop Street, Pittsburgh, PA 15213. 2 Present address: Silverstein Institute, 1901 Floyd Street, Sarasota, FL 34239. 3 Present address: Department of Otolaryngology, University of Missouri School of Medicine, 1 Hospital Drive, MA 314, Columbia, MO 65212.
http://dx.doi.org/10.1016/j.amjoto.2016.01.004 0196-0709/© 2016 Elsevier Inc. All rights reserved.
AM ER IC AN JOURNAL OF OT OLARYNGOLOGY–H E A D A N D NE CK M E D IC IN E A ND S U RGE RY 3 7 (2 0 1 6) 1 86–1 9 4
1.
Introduction
Routine elective neck dissection (END) for the clinically and radiologically negative (N0) neck in the setting of recurrent laryngeal squamous cell carcinoma after previous radiotherapy or chemoradiotherapy remains controversial. Over the past five years, the incidence of occult nodal disease after salvage total laryngectomy (STL) with END reported in the literature ranges from 0% to 28.3% [1–10]. Many studies have failed to demonstrate a survival benefit with END in this setting [1,7–13], while others have noted a benefit for some patients [2,3,5]. A number of studies have found a higher complication rate after END [7–9,14] while others suggested no significant difference [4,15,16]. The present study represents to the best of our knowledge the largest retrospective review to date with the aim of elucidating the impact of performing an elective neck dissection during STL on survival and postoperative complication outcomes. Furthermore, we attempt to identify other factors that may be associated with increased complications, occult disease, or mortality in N0 patients undergoing salvage total laryngectomy.
2.
Materials and methods
The current study is a retrospective chart review performed with permission from the institutional review board at our institution. One hundred twenty-five patients who underwent salvage total laryngectomy (STL) with clinically and radiologically negative necks at presentation of recurrence were identified from an existing billing database of 424 patients treated with total laryngectomy at our institution between 2000 and 2012. Inclusion criteria were that patients must have had a salvage total laryngectomy performed after previous radiotherapy or chemoradiotherapy for squamous cell carcinoma of the larynx and they must have an N0 neck at time of recurrence as determined by physical exam and imaging with CT, MRI, PET, or PET/CT scan. For the purpose of this study, “recurrent” disease included tumor recurrence, persistence, or second primary in the larynx. Patients with laryngectomy for non-squamous cell carcinoma or nonmalignant disease, laryngeal metastasis from another primary, previous neck dissection, or documented evidence of nodal disease at any time prior to STL were excluded. Extensive pre- and post-operative demographic and clinical data were collected for each patient. Comprehensive review of all postoperative notes up to one year after surgery was performed in search for reported complications. Review of clinic notes up to the most recent available follow-up was performed in search for information regarding recurrent disease and survival status. Publically available death records were also checked for information beyond the follow up available in the medical records. Statistical analyses were performed using SAS version 9.3 (Cary, NC). Associations between age and each of the binary outcomes were explored with the Student's t-test. Each factor was assessed for potential bivariate associations with each complication under consideration using the chi-square or Fisher's exact tests as appropriate in order to determine which factors may be predictive of increased complications or
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occult nodal disease. Multivariable analysis was subsequently performed using logistic regression to investigate the associations with binary outcomes including: overall complications, fistula formation, and wound complications (defined as history of infection or dehiscence). The following patient factors were included as predictors in the logistic models: age, T-stage at recurrence, site of recurrence, neck dissection status, performance of a pectoralis flap, and initial treatment modality. For oncologic outcomes, disease-free survival and overall survival were estimated using Kaplan–Meier curves. Log-rank tests were used for bivariate comparisons for these variables: neck dissection, nodal disease status, recurrence site, recurrence T stage, initial treatment modality, and pathologic T stage. Cox proportional hazards regression models were fit for both survival outcomes to further investigate adjusted associations with nodal disease status controlling for age, recurrence site, initial treatment modality, and pathologic T stage. All statistical significance in the current study was based on an alpha level of 0.05.
3.
Results
3.1.
Patient characteristics
One hundred and twenty-five patients met the inclusion criteria out of the 424 laryngectomy patients identified. Median age was 70 years (ranging from 38 to 90 years). Initial therapy included radiation therapy in 104 (83.2%) and chemoradiation in 20 (16.0%) patients. Site of recurrence was the glottis in 90 patients (72.0%), the supraglottis in 17 patients (13.6%), and 18 patients had a transglottic tumor (14.4%). Ninety-eight patients (78.4%) underwent neck dissection and 27 (21.6%) did not have neck dissection. Within the neck dissection group, 47 (48.0%) underwent unilateral neck dissections while 51 (52.0%) had bilateral neck dissection. Patient and tumor characteristics are summarized in Table 1.
3.2.
Postoperative complications
Overall, 54 patients (43.2%) had postoperative complications. The most common complication was pharyngocutaneous fistula (PCF), which occurred in 34 (27.2%) patients. Fourteen patients (11.2%) and 20 patients (16.0%) developed wound infection and wound dehiscence respectively, with a total of 26 patients (20.8%) having at least one of these wound complications. There were two (1.6%) deaths within thirty days of surgery. Four (3.2%) patients developed carotid blowout within five months postoperatively, and three of them died of the blowout. Two blowout patients received bilateral ND, one received unilateral ND, and the fourth did not have a neck dissection. Within the END group, 41 of 98 patients (41.8%) developed postoperative complications as compared to 13 of 27 (48.1%) noEND patients, and this difference was not significant (p = 0.558). However, there was a significantly higher proportion of complications in the patients with a history of chemoradiation as compared to those who were radiated (65% vs. 39%, p = 0.0346). The difference in fistula formation was not significant (p = 0.169), but patients with chemoradiation were observed to
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Table 1 – Patient characteristics.
Mean age Standard deviation Median age Range Sex Male Female Initial T stage T1 T2 T3 T4 Unknown Initial treatment modality† Radiation Chemoradiation Recurrence site Supraglottic Glottic Transglottic Preoperative imaging modality† CT PET PET/CT MRI Recurrence T stage rT1 rT2 rT3 rT4 Pectoralis flap Microvascular flap Pathologic T stage T1 T2 T3 T4
All patients, n = 125
No neck dissection, n = 27
Elective neck dissection, n = 98
P value
69.0 10.7 70 38-90
73.1 9.4 74 54-90
67.8 10.8 70 38-90
0.0238*
118 (94%) 7 (6%)
24 3
94 4
0.1712
55 (44%) 35 (28%) 10 (8%) 4 (3%) 21 (17%)
14 10 1 0 2
41 25 9 4 19
104 (83%) 20 (16%)
24 3
80 17
17 (14%) 90 (72%) 18 (14%)
3 22 2
14 68 16
84 (67%) 11 (9%) 27 (22%) 2 (2%)
21 2 4 0
63 9 23 2
5 (4%) 24 (19%) 44 (35%) 52 (42%) 25 (20%) 7 (6%)
3 8 10 5 0 0
2 16 34 47 25 7
9 (7%) 22 (18%) 38 (30%) 56 (45%)
5 7 9 5
4 15 28 51
–
0.5606 0.4764
–
0.0085*
– – 0.0029*
An asterisk signifies statistical significance at p < 0.05. A dagger denotes that the category is missing one patient due to an unspecified status. Dashes indicate that the comparison was not performed due to the existence of zero counts.
Table 2 – Postoperative complications.
Total complications Salivary fistula/leak Wound infection Wound dehiscence Chyle leak Hematoma Revision procedure Flap failure (out of 33 flaps) Medical complications Carotid blowout Hospital stay <7 7–14 14–28 Two or more complications
All patients, n = 125
No neck dissection, n = 27
Elective neck dissection, n = 98
P value
54 (43%) 34 (27%) 14 (11%) 20 (16%) 0 5 (4.0%) 20 (16%) 3 (2.4%) 12 (9.6%) 4 (3.2%)
13 (48%) 9 (33%) 2 (7.4%) 2 (7.4%) 0 2 (7.4%) 5 (19%) 0 2 (7.4%) 1 (3.7%)
41 (42%) 25 (26%) 12 (12%) 18 (18%) 0 3 (3.0%) 15 (15%) 3 (3.1%) 10 (10.2%) 3 (3.1%)
0.5577 0.4186 0.7325 0.2396 – 0.2946 0.7675 – 1 1 0.6653
50 (40%) 60 (48%) 15 (12%) 25 (20%)
9 (33%) 15 (56%) 3 (11%) 6 (22%)
41 45 12 19
Dashes indicate that the comparison was not performed due to the existence of zero counts.
(42%) (46%) (12%) (19%)
0.7444
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Table 3 – Univariate analyses results relating categorical variables to overall complications, pharyngocutaneous fistula formation, and wound complications. Overall complications P value Fistula formation P value Wound complications P value Treatment modality Radiation Chemoradiation Site Supraglottic Glottic Transglottic Recurrent T stage rT1/rT2 rT3 rT4 Microvascular flap Yes No Positive nodal disease on pathology Yes No Pathologic T stage T1/T2 T3 T4 Laterality of neck dissection (n = 98) Bilateral Unilateral
0.0346*
0.169
41/104 (39%) 13/20 (65%)
0.0341*
26 (25%) 8 (40%) 0.6231
18 (17%) 8 (40%) 0.6227
7/17 (41%) 41/90 (46%) 6/18 (33%)
5 (29%) 26 (29%) 3 (17%) 0.556
0.828 4 (24%) 18 (20%) 4 (22%)
0.0905
10/29 (34%) 20/44 (45%) 24/52 (46%)
5 (17%) 17 (39%) 12 (23%) 0.4641
0.4906 4 (14%) 9 (20%) 13 (25%)
0.3886
4/7 (57%) 50/118 (42%)
3 (43%) 31 (26%) 0.3123
0.448 2 (29%) 24 (20%)
0.1175
6/10 (60%) 35/88 (40%)
5 (50%) 20 (23%) 0.3638
0.6952 3 (30%) 20 (23%)
0.2328
11/31 (35%) 15/38 (39%) 28/56 (50%)
5 (16%) 13 (34%) 16 (29%) 0.4954
0.1048 3 (10%) 7 (18%) 16 (29%)
0.6462
23/51 (45%) 18/47 (38%)
14 (27%) 11 (23%)
0.3326 14 (27%) 9 (19%)
An asterisk signifies statistical significance at p < 0.05.
have significantly higher proportions of wound complications as compared to those who were radiated (40% vs. 17%, p = 0.0341). However, after multivariable logistic regression analysis, chemoradiation was no longer significantly predictive of increased odds for overall complications (OR = 0.99, 95% CI = 0.95–1.02) nor wound complications (OR = 2.6, 95% CI = 0.77– 8.9). Complication demographics comparing no-END to END are summarized in Table 2, and Table 3 demonstrates associations between patient characteristics and complications.
3.3.
Occult nodal disease
Among the 98 patients undergoing elective neck dissection, 10 (10.2%) had pathological evidence of nodal disease. Table 4
describes characteristics of these patients. No preoperative patient characteristic was significantly predictive of occult nodal disease.
3.4.
Recurrence and disease-free survival
The median length of follow-up for the entire cohort was 24 months, the mean was 38 months, and the range was 1– 148 months. Thirty-one patients (24.8%) developed a recurrence, of which six were distant recurrences. The median time to recurrence was 9.9 months (mean = 16.6 months, range 1.5–112 months). Based on log-rank tests for survival homogeneity, the only patient and tumor factor associated with reduced time to recurrence was positive nodal disease on pathology (p = 0.0057); notably, neck dissection was not associated with time to recurrence (p = 0.759).
Table 4 – Characteristics of patients with positive nodal pathology.
Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient
1 2 3 4 5 6 7 8 9 10
Initial Initial T Recurrence Recurrence Preoperative Laterality of Status at last treatment stage site T stage imaging neck dissection follow up modality modality
Overall survival in months
XRT XRT XRT CHMXRT XRT XRT CHMXRT XRT XRT XRT
5.4 12.5 4.4 66.3 39.1 31.4 39.6 16 (last follow-up) 5.3 5.9
T1 T1 T2 T4 UN T2 UN T1 UN T1
UN indicates unknown value.
Transglottic Glottic Glottic Glottic Glottic Supraglottic Glottic Glottic Glottic Glottic
4 2 4 4 3 3 4 3 4 3
CT CT CT PET/CT CT MRI PET/CT CT PET CT
Unilateral Unilateral Unilateral Unilateral Unilateral Bilateral Unilateral Unilateral Bilateral Bilateral
Deceased Deceased Deceased Deceased Deceased Deceased Deceased Alive, with disease Deceased Deceased
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Fig. 1 – Disease-free survival. Kaplan–Meier curves demonstrating disease-free survival when comparing (A) patients with positive versus negative nodal pathology, p = 0.0057, and (B) comparing patients with neck dissection versus no neck dissection, p = 0.7589.
Disease-free survival was defined as survival with no evidence of disease or death. For the entire cohort, the disease-free survival at two years was 57%. In patients with positive nodal disease after END, disease-free survival at two years was 30%, and 50% of patients were alive with no evidence of disease at 24.3 months (SE: 10.6). In patients with negative nodal disease after END, disease-free survival at two years was 60.2%, and 50% of patients were alive with no evidence of disease at 55.7 months (SE: 5.5). This is demonstrated in Fig. 1A. In patients who received END, disease-free
survival at two years was 56.4%. In patients who did not receive END, disease-free survival at two years was 59.3%, and 50% of patients were alive with no evidence of disease 51.2 months (SE: 9.5). This is demonstrated in Fig. 1B. A Cox proportional hazard analysis revealed that nodal disease status was significant with a hazard ratio of 2.7 (95% CI: 1.4– 5.6) for disease-free survival, indicating that a patient with positive nodal disease is about 2.7 times more likely to develop a recurrence or die over the study period as compared to a patient with negative nodal disease.
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Fig. 2 – Overall survival. Kaplan–Meier curves demonstrating overall survival when (A) comparing patients with positive versus negative nodal pathology, p = 0.0002, and (B) comparing patients with neck dissection versus no neck dissection, p = 0.7186.
The following patient and tumor factors were not associated with disease-free survival: neck dissection, recurrence site, recurrence T stage, initial treatment modality and pathologic T stage.
3.5.
Overall survival
Overall survival was determined using all-cause mortality. The only measured patient and tumor factor associated with overall survival was positive nodal disease on pathology (p = 0.0002), and neck dissection was not associated with overall survival (p = 0.72), as demonstrated in Fig. 2A and B. The
overall survival of the entire cohort at one year was 82.2% and at five years was 53.8%. In patients with positive nodal disease after END, overall survival at one year was 60%, at two years was 50%, and at five years was 12.5%. Fifty percent of patients were alive at 25.0 months (SE: 7.1). In patients with negative nodal disease after END, overall survival at one year was 83.6%, at two years was 74.8%, and at five years was 60.0%. Fifty percent of patients were alive at 69.1 months (SE: 5.5). In patients who received END, overall survival at one year was 80.8%, at two years was 71.8% and at five years was 53.2%. Fifty percent of patients were alive at 62.6 months (SE: 5.2). In patients who did not receive END, overall survival at one year
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was 88.5%, at two years was 64.9%, and at five years was 53.1%. Fifty percent of patients were alive at 55.5 months (SE: 9.5). A Cox proportional hazard analysis revealed that nodal disease status was significant with a hazard ratio of 4.6 (95% CI: 2.0–9.9) for disease-free survival, indicating that a patient with positive nodal disease is about 4.6 times more likely to die over the study period as compared to a patient with negative nodal disease. The following patient and tumor factors were not found to have an association with overall survival: neck dissection, recurrence site, recurrence T stage, initial treatment modality and pathologic T stage.
4.
Discussion
The primary aim of this study was to investigate the difference in survival and complication outcomes between patients with a clinically and radiologically N0 neck who received versus those who did not receive an elective neck dissection at the time of salvage total laryngectomy. A secondary aim was to identify the patient and surgical factors that may be predictive of increased complications, occult disease, recurrence, and mortality. There are a variety of findings and viewpoints in the literature, leading to controversy over the optimal management of the N0 neck. As the largest series of patients to date, this study contributes to the conclusion that either approach is acceptable.
4.1.
Complications
We found that previous treatment with chemoradiation is predictive of increased overall complications and wound complications on univariate analysis but not on multivariate analysis. This may be due to the small number of patients in the chemoradiation group. Klozar et al. studied 208 STL neck dissection patients (preoperative nodal status not disclosed) and found that chemoradiation was associated with increased fistula formation [19]. Ganly et al. who studied postoperative complications of 70 salvage patients, of whom 55 were N0 preoperatively, compared them to 113 primary total laryngectomy patients and also found that chemoradiation was a predictor of increased local wound (45% vs. 25% p = 0.02) and fistula complications (32% vs. 12%, p = 0.012) on multivariate analysis while radiation alone was not [18]. Age, recurrence site, recurrence T stage, positive occult nodal disease, and pathological T stage were not predictive of any of complications on univariate analysis in our cohort. Other studies have noted predictive characteristics that we did not study [17-20]. Pezier et al. studied 28 N0 STL patients and found that alcohol consumption (p = 0.01) and preoperative albumin levels less than 3.2 g/l (p = 0.012) were associated with increased wound infection [4]. Yirmibesoglu et al. studied 26 N0 STL patients and found that flap reconstruction leads to increased length of hospital stay (p = 0.034) [7]. Basheeth et al. studied 41 N0 STL patients and found that performance of laryngectomy within one year of completion of radiotherapy (p = 0.006) was a risk factor for fistula formation [10].
In our cohort, neck dissection was not a predictor of increased overall complications (p = 0.558) or any particular measured complication (Table 2). Similarly, bilateral neck dissection was not a predictor of increased complications (p = 0.495). While we failed to note a difference in complications with neck dissection, other studies have demonstrated increased complications [7,9,14]. Bohannon et al. studied 71 N0 STL patients and found that the ND group had more complications (p = 0.04) [8]. Dagan et al. studied 34 N0 STL patients and found that the ND group had longer postoperative stays, higher rates of fistula, and higher likelihood of grade III/IV toxicity [9]. Basheeth et al. found that performance of a concomitant bilateral neck dissection was associated with increased fistula formation (p = 0.02) [10,14]. Given that the addition of a neck dissection did not significantly increase measured complications, our results suggest that concern for increased complications with neck dissection is not in itself a reason to refrain from performing a neck dissection, and that elective neck dissection can be safely performed with STL.
4.2.
Occult nodal disease
We found that ten out of 99 neck dissection patients (10.2%) had occult disease. This rate is consistent with those reported by other studies. Over the past ten years, five studies reported rates under 10% [2,4,8,10,11], six studies including ours reported rates between 10 and 20% [3,6,7,9,12], and two studies reported rates over 20% [5,21]. It is notable that the majority of studies noted rates under 20%, which is a percentage that has been used as a cutoff value in decision analyses [22–24]. The wide range may be attributable in part to differing protocols for establishing N0 status. We did not find imaging modality, treatment modality, recurrence T stage, recurrence site, or laterality of neck dissection to be associated with occult nodal disease, although only strong associations would be detectable given the small sample size of ten patients with occult disease. Koss et al. found supraglottic location as a predictor of increased occult disease (p = 0.02) in the recurrence setting [5]. They also found that the specific sub-site relates to specific occult neck levels. Farrag et al. found that recurrence staging is associated with occult disease (p = 0.006) [11]. The NCCN guidelines recommend END at primary total laryngectomy for patients with advanced stage supraglottic and glottic tumors as these tumor sites have been associated with occult nodal disease in the primary setting [4].
4.3.
Survival
We found that positive nodal disease on pathology was the only measured patient factor associated with survival; specifically, occult nodal disease was predictive of worse diseasefree survival (p = 0.0057) and worse overall survival (p = 0.0002). Neck dissection was not significantly associated with disease-free survival (p = 0.76) or overall survival (p = 0.72). Other factors that were not predictive included recurrence site, recurrence T stage, initial treatment modality, and pathologic T stage. This contrasts with Koss et al. who studied 68 N0 STL patients and found that transglottic location
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correlates with reduced survival (p = 0.02) and neck dissection leads to a trend of improved survival (p = 0.08) [5]. Yirmibesoglu et al. found that close/positive margin status led to worse local control (p = 0.02) and overall survival (p = 0.01) [7]. Dagan et al. found that positive margins were associated with worse survival [9]. Lee et al. studied 50 N0 STL patients and found that ND in patients who had N+ at initial treatment had better regional control rate (p = 0.044) and that ND led to better disease-specific survival in patients who recurred within one year after initial treatment (p = 0.043) [2]. Many studies have failed to note a survival benefit with neck dissection [1,7–13], but in many studies including our own, END is not performed equally across groups, as noted by Sanabria et al. in their review of 12 studies [1]. In our study, recurrence T stage was associated with the performance of an END (p = 0.0085) and patients with more advanced recurrent tumors (rT3-4) were observed to have a higher proportion of neck dissection than those with lower stages. Patients with END were on average younger than those without END (p = 0.0238). As Sanabria et al. point out, it is possible that END may offer a survival advantage for patients with more advanced recurrent tumors, leading to overall survival results that are statistically similar [1]. However, in our multivariate analysis, survival results were similar when comparing END and no-END even after controlling for differing T stage. Our study suggests that elective neck dissections do not increase complications but at the same time may not provide a survival benefit. A benefit that is obtained is prognostic information for about 10% of patients. One could argue for or against the END based on this result. We feel that this makes it all the more important to discuss this with the patient and base the final decision about neck management on that conversation.
4.4.
Limitations
This study has several limitations. One is that there were patient and tumor factors that we were not able to measure, and we could not analyze or control for these unmeasured covariates. Although this study has the largest sample of N0 salvage laryngeal cancer patients in published studies to date, the power to detect small magnitudes of effect is limited by small sample size, particularly in some of the event counts in the outcomes. While we were clearly able to demonstrate a difference in survival based on nodal disease, we may need larger numbers of patients to detect additional differences based on recurrence T stage, recurrence site, and other characteristics. Lastly, the study is prone to information and selection bias due to its retrospective design. Future prospective studies are warranted to better define the role of END and to identify predictive factors of relevant outcomes.
5.
Conclusion
In patients with N0 necks undergoing STL, neck dissection does not appear to be significantly associated with incidence of complications, disease-free survival or overall survival. In the hands of experienced surgeons, neck dissection with STL can be performed without an increase in complications for
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the benefit of obtaining significant prognostic information, as patients with positive nodal disease after neck dissection have significantly worse disease-free survival and overall survival. However, given that the END is not associated with increased survival, fewer than 20% of END patients have occult disease, and the prognosis remains poor for those with occult disease, it would also be reasonable to choose not to perform routine elective neck dissections. This study provides evidence to support the conclusion that either approach is reasonable and the decision can be individualized based on other factors such as patient and surgeon preference.
Acknowledgements The authors would like to thank Shari Messinger Cayetano, Ph.D., Associate Professor of Biostatistics at the University of Miami Miller School of Medicine, for her review of the statistical analyses. We would also like to thank Kauthar Carr for helping to retrieve pathology data. The University of Miami Department of Otolaryngology provided funding for this study.
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[12] Yao M, Roebuck JC, Holsinger FC, et al. Elective neck dissection during salvage laryngectomy. Am J Otolaryngol 2005;26:388–92. [13] Wax MK, Touma BJ. Management of the N0 neck during salvage laryngectomy. Laryngoscope 1999;109:4–7. [14] Basheeth N, O'Leary G, Sheahan P. Pharyngocutaneous fistula after salvage laryngectomy: impact of interval between radiotherapy and surgery, and performance of bilateral neck dissection. Head Neck 2014;36:580–4. [15] Furuta Y, Homma A, Oridate N, et al. Surgical complications of salvage total laryngectomy following concurrent chemoradiotherapy. Int J Clin Oncol 2008;13:521–7. [16] Scotton W, Cobb R, Pang L, et al. Post-operative wound infection in salvage laryngectomy: does antibiotic prophylaxis have an impact? Eur Arch Otorhinolaryngol 2012;269: 2415–22. [17] Cavalot AL, Gervasio CF, Nazionale G, et al. Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records. Otolaryngol Head Neck Surg 2000;123:587–92.
[18] Ganly I, Patel S, Matsuo J, et al. Postoperative complications of salvage total laryngectomy. Cancer 2005;103:2073–81. [19] Klozar J, Cada Z, Koslabova E. Complications of total laryngectomy in the era of chemoradiation. Eur Arch Otorhinolaryngol 2012;269:289–93. [20] Wakisaka N, Murono S, Kondo S, et al. Post-operative pharyngocutaneous fistula after laryngectomy. Auris Nasus Larynx 2008;35:203–8. [21] Solares CA, Fritz MA, Esclamado RM. Oncologic effectiveness of selective neck dissection in the N0 irradiated neck. Head Neck 2005;27:415–20. [22] Okura M, Aikawa T, Sawai NY, et al. Decision analysis and treatment threshold in a management for the N0 neck of the oral cavity carcinoma. Oral Oncol 2009;45:908–11. [23] Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg 1994;120:699–702. [24] Hilly O, Stern S, Horowitz E, et al. Is there a role for elective neck dissection with salvage laryngectomy? A decisionanalysis model. Laryngoscope 2013;123:2706–11.
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Complications and oncologic outcomes following elective neck dissection with salvage laryngectomy for the N0 neck☆,☆☆ Monika E. Freiser, MD, MPH a, 1 , Rosemary B. Ojo, MD a, 2 , Kaming Lo, MPH b , Sandra Saint-Victor, MD a , Craig Bollig, MD a, 3 , Chetan S. Nayak, MD a , Zoukaa B. Sargi, MD, MPH a,⁎ a
Department of Otolaryngology, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 650D, Miami, FL Biostatistics Collaboration and Consulting Core, Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, 1120 N.W. 14th Street, Suite 1049, Miami, FL b
ARTI CLE I NFO
A BS TRACT
Article history:
Purpose: To investigate the difference in survival and complication outcomes between
Received 3 December 2015
patients with a clinically and radiologically N0 neck who received an elective neck dissection at the time of salvage total laryngectomy compared to those who had salvage total laryngectomy alone. Materials and methods: A retrospective chart review was performed on 125 salvage total laryngectomy patients who were clinically and radiologically N0 preoperatively. Performance of an elective neck dissection and other factors were tested for associations with various postoperative complications, disease-free survival, and overall survival. Results: Ninety-eight patients underwent elective neck dissection, of which ten had positive nodal pathology. Elective neck dissection was not significantly associated with complications or survival outcomes. Positive nodal disease was associated with worse disease-free and overall survival on multivariate analysis. Conclusions: In patients with clinically and radiologically N0 necks undergoing salvage total laryngectomy, an elective neck dissection can provide prognostic information but does not appear to be significantly associated with increased complications or improved survival. © 2016 Elsevier Inc. All rights reserved.
☆ Meeting Presentations: Poster at the Florida Medical Association (FMA) Annual Poster Symposium, “Incidence of postoperative complications in patients treated with salvage laryngectomy with radiologically negative neck”, Orlando, FL, July 27, 2013; poster at the Academy Annual Meeting, “Incidence of occult nodal disease in patients treated with salvage laryngectomy with radiologically negative neck”, Vancouver, Canada, September 29, 2013; oral presentation at the National Medical Association Meeting, “Incidence of occult nodal disease and complications in patients treated with salvage laryngectomy with radiologically negative neck”, Honolulu, Hawaii, August 4, 2014. ☆☆ None of the authors have any potential conflicts of interest to disclose. ⁎ Corresponding author at: Department of Otolaryngology, Division of Head and Neck Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 650D, Miami, FL 33136. Tel.: +1 305 243 6495; fax: + 1 305 243 1283. E-mail addresses: [email protected] (M.E. Freiser), [email protected] (R.B. Ojo), [email protected] (K. Lo), [email protected] (S. Saint-Victor), [email protected] (C. Bollig), [email protected] (C.S. Nayak), [email protected] (Z.B. Sargi). 1 Present address: Department of Otolaryngology, University of Pittsburgh Medical Center, 203 Lothrop Street, Pittsburgh, PA 15213. 2 Present address: Silverstein Institute, 1901 Floyd Street, Sarasota, FL 34239. 3 Present address: Department of Otolaryngology, University of Missouri School of Medicine, 1 Hospital Drive, MA 314, Columbia, MO 65212.
http://dx.doi.org/10.1016/j.amjoto.2016.01.004 0196-0709/© 2016 Elsevier Inc. All rights reserved.
AM ER IC AN JOURNAL OF OT OLARYNGOLOGY–H E A D A N D NE CK M E D IC IN E A ND S U RGE RY 3 7 (2 0 1 6) 1 86–1 9 4
1.
Introduction
Routine elective neck dissection (END) for the clinically and radiologically negative (N0) neck in the setting of recurrent laryngeal squamous cell carcinoma after previous radiotherapy or chemoradiotherapy remains controversial. Over the past five years, the incidence of occult nodal disease after salvage total laryngectomy (STL) with END reported in the literature ranges from 0% to 28.3% [1–10]. Many studies have failed to demonstrate a survival benefit with END in this setting [1,7–13], while others have noted a benefit for some patients [2,3,5]. A number of studies have found a higher complication rate after END [7–9,14] while others suggested no significant difference [4,15,16]. The present study represents to the best of our knowledge the largest retrospective review to date with the aim of elucidating the impact of performing an elective neck dissection during STL on survival and postoperative complication outcomes. Furthermore, we attempt to identify other factors that may be associated with increased complications, occult disease, or mortality in N0 patients undergoing salvage total laryngectomy.
2.
Materials and methods
The current study is a retrospective chart review performed with permission from the institutional review board at our institution. One hundred twenty-five patients who underwent salvage total laryngectomy (STL) with clinically and radiologically negative necks at presentation of recurrence were identified from an existing billing database of 424 patients treated with total laryngectomy at our institution between 2000 and 2012. Inclusion criteria were that patients must have had a salvage total laryngectomy performed after previous radiotherapy or chemoradiotherapy for squamous cell carcinoma of the larynx and they must have an N0 neck at time of recurrence as determined by physical exam and imaging with CT, MRI, PET, or PET/CT scan. For the purpose of this study, “recurrent” disease included tumor recurrence, persistence, or second primary in the larynx. Patients with laryngectomy for non-squamous cell carcinoma or nonmalignant disease, laryngeal metastasis from another primary, previous neck dissection, or documented evidence of nodal disease at any time prior to STL were excluded. Extensive pre- and post-operative demographic and clinical data were collected for each patient. Comprehensive review of all postoperative notes up to one year after surgery was performed in search for reported complications. Review of clinic notes up to the most recent available follow-up was performed in search for information regarding recurrent disease and survival status. Publically available death records were also checked for information beyond the follow up available in the medical records. Statistical analyses were performed using SAS version 9.3 (Cary, NC). Associations between age and each of the binary outcomes were explored with the Student's t-test. Each factor was assessed for potential bivariate associations with each complication under consideration using the chi-square or Fisher's exact tests as appropriate in order to determine which factors may be predictive of increased complications or
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occult nodal disease. Multivariable analysis was subsequently performed using logistic regression to investigate the associations with binary outcomes including: overall complications, fistula formation, and wound complications (defined as history of infection or dehiscence). The following patient factors were included as predictors in the logistic models: age, T-stage at recurrence, site of recurrence, neck dissection status, performance of a pectoralis flap, and initial treatment modality. For oncologic outcomes, disease-free survival and overall survival were estimated using Kaplan–Meier curves. Log-rank tests were used for bivariate comparisons for these variables: neck dissection, nodal disease status, recurrence site, recurrence T stage, initial treatment modality, and pathologic T stage. Cox proportional hazards regression models were fit for both survival outcomes to further investigate adjusted associations with nodal disease status controlling for age, recurrence site, initial treatment modality, and pathologic T stage. All statistical significance in the current study was based on an alpha level of 0.05.
3.
Results
3.1.
Patient characteristics
One hundred and twenty-five patients met the inclusion criteria out of the 424 laryngectomy patients identified. Median age was 70 years (ranging from 38 to 90 years). Initial therapy included radiation therapy in 104 (83.2%) and chemoradiation in 20 (16.0%) patients. Site of recurrence was the glottis in 90 patients (72.0%), the supraglottis in 17 patients (13.6%), and 18 patients had a transglottic tumor (14.4%). Ninety-eight patients (78.4%) underwent neck dissection and 27 (21.6%) did not have neck dissection. Within the neck dissection group, 47 (48.0%) underwent unilateral neck dissections while 51 (52.0%) had bilateral neck dissection. Patient and tumor characteristics are summarized in Table 1.
3.2.
Postoperative complications
Overall, 54 patients (43.2%) had postoperative complications. The most common complication was pharyngocutaneous fistula (PCF), which occurred in 34 (27.2%) patients. Fourteen patients (11.2%) and 20 patients (16.0%) developed wound infection and wound dehiscence respectively, with a total of 26 patients (20.8%) having at least one of these wound complications. There were two (1.6%) deaths within thirty days of surgery. Four (3.2%) patients developed carotid blowout within five months postoperatively, and three of them died of the blowout. Two blowout patients received bilateral ND, one received unilateral ND, and the fourth did not have a neck dissection. Within the END group, 41 of 98 patients (41.8%) developed postoperative complications as compared to 13 of 27 (48.1%) noEND patients, and this difference was not significant (p = 0.558). However, there was a significantly higher proportion of complications in the patients with a history of chemoradiation as compared to those who were radiated (65% vs. 39%, p = 0.0346). The difference in fistula formation was not significant (p = 0.169), but patients with chemoradiation were observed to
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Table 1 – Patient characteristics.
Mean age Standard deviation Median age Range Sex Male Female Initial T stage T1 T2 T3 T4 Unknown Initial treatment modality† Radiation Chemoradiation Recurrence site Supraglottic Glottic Transglottic Preoperative imaging modality† CT PET PET/CT MRI Recurrence T stage rT1 rT2 rT3 rT4 Pectoralis flap Microvascular flap Pathologic T stage T1 T2 T3 T4
All patients, n = 125
No neck dissection, n = 27
Elective neck dissection, n = 98
P value
69.0 10.7 70 38-90
73.1 9.4 74 54-90
67.8 10.8 70 38-90
0.0238*
118 (94%) 7 (6%)
24 3
94 4
0.1712
55 (44%) 35 (28%) 10 (8%) 4 (3%) 21 (17%)
14 10 1 0 2
41 25 9 4 19
104 (83%) 20 (16%)
24 3
80 17
17 (14%) 90 (72%) 18 (14%)
3 22 2
14 68 16
84 (67%) 11 (9%) 27 (22%) 2 (2%)
21 2 4 0
63 9 23 2
5 (4%) 24 (19%) 44 (35%) 52 (42%) 25 (20%) 7 (6%)
3 8 10 5 0 0
2 16 34 47 25 7
9 (7%) 22 (18%) 38 (30%) 56 (45%)
5 7 9 5
4 15 28 51
–
0.5606 0.4764
–
0.0085*
– – 0.0029*
An asterisk signifies statistical significance at p < 0.05. A dagger denotes that the category is missing one patient due to an unspecified status. Dashes indicate that the comparison was not performed due to the existence of zero counts.
Table 2 – Postoperative complications.
Total complications Salivary fistula/leak Wound infection Wound dehiscence Chyle leak Hematoma Revision procedure Flap failure (out of 33 flaps) Medical complications Carotid blowout Hospital stay <7 7–14 14–28 Two or more complications
All patients, n = 125
No neck dissection, n = 27
Elective neck dissection, n = 98
P value
54 (43%) 34 (27%) 14 (11%) 20 (16%) 0 5 (4.0%) 20 (16%) 3 (2.4%) 12 (9.6%) 4 (3.2%)
13 (48%) 9 (33%) 2 (7.4%) 2 (7.4%) 0 2 (7.4%) 5 (19%) 0 2 (7.4%) 1 (3.7%)
41 (42%) 25 (26%) 12 (12%) 18 (18%) 0 3 (3.0%) 15 (15%) 3 (3.1%) 10 (10.2%) 3 (3.1%)
0.5577 0.4186 0.7325 0.2396 – 0.2946 0.7675 – 1 1 0.6653
50 (40%) 60 (48%) 15 (12%) 25 (20%)
9 (33%) 15 (56%) 3 (11%) 6 (22%)
41 45 12 19
Dashes indicate that the comparison was not performed due to the existence of zero counts.
(42%) (46%) (12%) (19%)
0.7444
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Table 3 – Univariate analyses results relating categorical variables to overall complications, pharyngocutaneous fistula formation, and wound complications. Overall complications P value Fistula formation P value Wound complications P value Treatment modality Radiation Chemoradiation Site Supraglottic Glottic Transglottic Recurrent T stage rT1/rT2 rT3 rT4 Microvascular flap Yes No Positive nodal disease on pathology Yes No Pathologic T stage T1/T2 T3 T4 Laterality of neck dissection (n = 98) Bilateral Unilateral
0.0346*
0.169
41/104 (39%) 13/20 (65%)
0.0341*
26 (25%) 8 (40%) 0.6231
18 (17%) 8 (40%) 0.6227
7/17 (41%) 41/90 (46%) 6/18 (33%)
5 (29%) 26 (29%) 3 (17%) 0.556
0.828 4 (24%) 18 (20%) 4 (22%)
0.0905
10/29 (34%) 20/44 (45%) 24/52 (46%)
5 (17%) 17 (39%) 12 (23%) 0.4641
0.4906 4 (14%) 9 (20%) 13 (25%)
0.3886
4/7 (57%) 50/118 (42%)
3 (43%) 31 (26%) 0.3123
0.448 2 (29%) 24 (20%)
0.1175
6/10 (60%) 35/88 (40%)
5 (50%) 20 (23%) 0.3638
0.6952 3 (30%) 20 (23%)
0.2328
11/31 (35%) 15/38 (39%) 28/56 (50%)
5 (16%) 13 (34%) 16 (29%) 0.4954
0.1048 3 (10%) 7 (18%) 16 (29%)
0.6462
23/51 (45%) 18/47 (38%)
14 (27%) 11 (23%)
0.3326 14 (27%) 9 (19%)
An asterisk signifies statistical significance at p < 0.05.
have significantly higher proportions of wound complications as compared to those who were radiated (40% vs. 17%, p = 0.0341). However, after multivariable logistic regression analysis, chemoradiation was no longer significantly predictive of increased odds for overall complications (OR = 0.99, 95% CI = 0.95–1.02) nor wound complications (OR = 2.6, 95% CI = 0.77– 8.9). Complication demographics comparing no-END to END are summarized in Table 2, and Table 3 demonstrates associations between patient characteristics and complications.
3.3.
Occult nodal disease
Among the 98 patients undergoing elective neck dissection, 10 (10.2%) had pathological evidence of nodal disease. Table 4
describes characteristics of these patients. No preoperative patient characteristic was significantly predictive of occult nodal disease.
3.4.
Recurrence and disease-free survival
The median length of follow-up for the entire cohort was 24 months, the mean was 38 months, and the range was 1– 148 months. Thirty-one patients (24.8%) developed a recurrence, of which six were distant recurrences. The median time to recurrence was 9.9 months (mean = 16.6 months, range 1.5–112 months). Based on log-rank tests for survival homogeneity, the only patient and tumor factor associated with reduced time to recurrence was positive nodal disease on pathology (p = 0.0057); notably, neck dissection was not associated with time to recurrence (p = 0.759).
Table 4 – Characteristics of patients with positive nodal pathology.
Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient
1 2 3 4 5 6 7 8 9 10
Initial Initial T Recurrence Recurrence Preoperative Laterality of Status at last treatment stage site T stage imaging neck dissection follow up modality modality
Overall survival in months
XRT XRT XRT CHMXRT XRT XRT CHMXRT XRT XRT XRT
5.4 12.5 4.4 66.3 39.1 31.4 39.6 16 (last follow-up) 5.3 5.9
T1 T1 T2 T4 UN T2 UN T1 UN T1
UN indicates unknown value.
Transglottic Glottic Glottic Glottic Glottic Supraglottic Glottic Glottic Glottic Glottic
4 2 4 4 3 3 4 3 4 3
CT CT CT PET/CT CT MRI PET/CT CT PET CT
Unilateral Unilateral Unilateral Unilateral Unilateral Bilateral Unilateral Unilateral Bilateral Bilateral
Deceased Deceased Deceased Deceased Deceased Deceased Deceased Alive, with disease Deceased Deceased
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Fig. 1 – Disease-free survival. Kaplan–Meier curves demonstrating disease-free survival when comparing (A) patients with positive versus negative nodal pathology, p = 0.0057, and (B) comparing patients with neck dissection versus no neck dissection, p = 0.7589.
Disease-free survival was defined as survival with no evidence of disease or death. For the entire cohort, the disease-free survival at two years was 57%. In patients with positive nodal disease after END, disease-free survival at two years was 30%, and 50% of patients were alive with no evidence of disease at 24.3 months (SE: 10.6). In patients with negative nodal disease after END, disease-free survival at two years was 60.2%, and 50% of patients were alive with no evidence of disease at 55.7 months (SE: 5.5). This is demonstrated in Fig. 1A. In patients who received END, disease-free
survival at two years was 56.4%. In patients who did not receive END, disease-free survival at two years was 59.3%, and 50% of patients were alive with no evidence of disease 51.2 months (SE: 9.5). This is demonstrated in Fig. 1B. A Cox proportional hazard analysis revealed that nodal disease status was significant with a hazard ratio of 2.7 (95% CI: 1.4– 5.6) for disease-free survival, indicating that a patient with positive nodal disease is about 2.7 times more likely to develop a recurrence or die over the study period as compared to a patient with negative nodal disease.
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Fig. 2 – Overall survival. Kaplan–Meier curves demonstrating overall survival when (A) comparing patients with positive versus negative nodal pathology, p = 0.0002, and (B) comparing patients with neck dissection versus no neck dissection, p = 0.7186.
The following patient and tumor factors were not associated with disease-free survival: neck dissection, recurrence site, recurrence T stage, initial treatment modality and pathologic T stage.
3.5.
Overall survival
Overall survival was determined using all-cause mortality. The only measured patient and tumor factor associated with overall survival was positive nodal disease on pathology (p = 0.0002), and neck dissection was not associated with overall survival (p = 0.72), as demonstrated in Fig. 2A and B. The
overall survival of the entire cohort at one year was 82.2% and at five years was 53.8%. In patients with positive nodal disease after END, overall survival at one year was 60%, at two years was 50%, and at five years was 12.5%. Fifty percent of patients were alive at 25.0 months (SE: 7.1). In patients with negative nodal disease after END, overall survival at one year was 83.6%, at two years was 74.8%, and at five years was 60.0%. Fifty percent of patients were alive at 69.1 months (SE: 5.5). In patients who received END, overall survival at one year was 80.8%, at two years was 71.8% and at five years was 53.2%. Fifty percent of patients were alive at 62.6 months (SE: 5.2). In patients who did not receive END, overall survival at one year
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was 88.5%, at two years was 64.9%, and at five years was 53.1%. Fifty percent of patients were alive at 55.5 months (SE: 9.5). A Cox proportional hazard analysis revealed that nodal disease status was significant with a hazard ratio of 4.6 (95% CI: 2.0–9.9) for disease-free survival, indicating that a patient with positive nodal disease is about 4.6 times more likely to die over the study period as compared to a patient with negative nodal disease. The following patient and tumor factors were not found to have an association with overall survival: neck dissection, recurrence site, recurrence T stage, initial treatment modality and pathologic T stage.
4.
Discussion
The primary aim of this study was to investigate the difference in survival and complication outcomes between patients with a clinically and radiologically N0 neck who received versus those who did not receive an elective neck dissection at the time of salvage total laryngectomy. A secondary aim was to identify the patient and surgical factors that may be predictive of increased complications, occult disease, recurrence, and mortality. There are a variety of findings and viewpoints in the literature, leading to controversy over the optimal management of the N0 neck. As the largest series of patients to date, this study contributes to the conclusion that either approach is acceptable.
4.1.
Complications
We found that previous treatment with chemoradiation is predictive of increased overall complications and wound complications on univariate analysis but not on multivariate analysis. This may be due to the small number of patients in the chemoradiation group. Klozar et al. studied 208 STL neck dissection patients (preoperative nodal status not disclosed) and found that chemoradiation was associated with increased fistula formation [19]. Ganly et al. who studied postoperative complications of 70 salvage patients, of whom 55 were N0 preoperatively, compared them to 113 primary total laryngectomy patients and also found that chemoradiation was a predictor of increased local wound (45% vs. 25% p = 0.02) and fistula complications (32% vs. 12%, p = 0.012) on multivariate analysis while radiation alone was not [18]. Age, recurrence site, recurrence T stage, positive occult nodal disease, and pathological T stage were not predictive of any of complications on univariate analysis in our cohort. Other studies have noted predictive characteristics that we did not study [17-20]. Pezier et al. studied 28 N0 STL patients and found that alcohol consumption (p = 0.01) and preoperative albumin levels less than 3.2 g/l (p = 0.012) were associated with increased wound infection [4]. Yirmibesoglu et al. studied 26 N0 STL patients and found that flap reconstruction leads to increased length of hospital stay (p = 0.034) [7]. Basheeth et al. studied 41 N0 STL patients and found that performance of laryngectomy within one year of completion of radiotherapy (p = 0.006) was a risk factor for fistula formation [10].
In our cohort, neck dissection was not a predictor of increased overall complications (p = 0.558) or any particular measured complication (Table 2). Similarly, bilateral neck dissection was not a predictor of increased complications (p = 0.495). While we failed to note a difference in complications with neck dissection, other studies have demonstrated increased complications [7,9,14]. Bohannon et al. studied 71 N0 STL patients and found that the ND group had more complications (p = 0.04) [8]. Dagan et al. studied 34 N0 STL patients and found that the ND group had longer postoperative stays, higher rates of fistula, and higher likelihood of grade III/IV toxicity [9]. Basheeth et al. found that performance of a concomitant bilateral neck dissection was associated with increased fistula formation (p = 0.02) [10,14]. Given that the addition of a neck dissection did not significantly increase measured complications, our results suggest that concern for increased complications with neck dissection is not in itself a reason to refrain from performing a neck dissection, and that elective neck dissection can be safely performed with STL.
4.2.
Occult nodal disease
We found that ten out of 99 neck dissection patients (10.2%) had occult disease. This rate is consistent with those reported by other studies. Over the past ten years, five studies reported rates under 10% [2,4,8,10,11], six studies including ours reported rates between 10 and 20% [3,6,7,9,12], and two studies reported rates over 20% [5,21]. It is notable that the majority of studies noted rates under 20%, which is a percentage that has been used as a cutoff value in decision analyses [22–24]. The wide range may be attributable in part to differing protocols for establishing N0 status. We did not find imaging modality, treatment modality, recurrence T stage, recurrence site, or laterality of neck dissection to be associated with occult nodal disease, although only strong associations would be detectable given the small sample size of ten patients with occult disease. Koss et al. found supraglottic location as a predictor of increased occult disease (p = 0.02) in the recurrence setting [5]. They also found that the specific sub-site relates to specific occult neck levels. Farrag et al. found that recurrence staging is associated with occult disease (p = 0.006) [11]. The NCCN guidelines recommend END at primary total laryngectomy for patients with advanced stage supraglottic and glottic tumors as these tumor sites have been associated with occult nodal disease in the primary setting [4].
4.3.
Survival
We found that positive nodal disease on pathology was the only measured patient factor associated with survival; specifically, occult nodal disease was predictive of worse diseasefree survival (p = 0.0057) and worse overall survival (p = 0.0002). Neck dissection was not significantly associated with disease-free survival (p = 0.76) or overall survival (p = 0.72). Other factors that were not predictive included recurrence site, recurrence T stage, initial treatment modality, and pathologic T stage. This contrasts with Koss et al. who studied 68 N0 STL patients and found that transglottic location
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correlates with reduced survival (p = 0.02) and neck dissection leads to a trend of improved survival (p = 0.08) [5]. Yirmibesoglu et al. found that close/positive margin status led to worse local control (p = 0.02) and overall survival (p = 0.01) [7]. Dagan et al. found that positive margins were associated with worse survival [9]. Lee et al. studied 50 N0 STL patients and found that ND in patients who had N+ at initial treatment had better regional control rate (p = 0.044) and that ND led to better disease-specific survival in patients who recurred within one year after initial treatment (p = 0.043) [2]. Many studies have failed to note a survival benefit with neck dissection [1,7–13], but in many studies including our own, END is not performed equally across groups, as noted by Sanabria et al. in their review of 12 studies [1]. In our study, recurrence T stage was associated with the performance of an END (p = 0.0085) and patients with more advanced recurrent tumors (rT3-4) were observed to have a higher proportion of neck dissection than those with lower stages. Patients with END were on average younger than those without END (p = 0.0238). As Sanabria et al. point out, it is possible that END may offer a survival advantage for patients with more advanced recurrent tumors, leading to overall survival results that are statistically similar [1]. However, in our multivariate analysis, survival results were similar when comparing END and no-END even after controlling for differing T stage. Our study suggests that elective neck dissections do not increase complications but at the same time may not provide a survival benefit. A benefit that is obtained is prognostic information for about 10% of patients. One could argue for or against the END based on this result. We feel that this makes it all the more important to discuss this with the patient and base the final decision about neck management on that conversation.
4.4.
Limitations
This study has several limitations. One is that there were patient and tumor factors that we were not able to measure, and we could not analyze or control for these unmeasured covariates. Although this study has the largest sample of N0 salvage laryngeal cancer patients in published studies to date, the power to detect small magnitudes of effect is limited by small sample size, particularly in some of the event counts in the outcomes. While we were clearly able to demonstrate a difference in survival based on nodal disease, we may need larger numbers of patients to detect additional differences based on recurrence T stage, recurrence site, and other characteristics. Lastly, the study is prone to information and selection bias due to its retrospective design. Future prospective studies are warranted to better define the role of END and to identify predictive factors of relevant outcomes.
5.
Conclusion
In patients with N0 necks undergoing STL, neck dissection does not appear to be significantly associated with incidence of complications, disease-free survival or overall survival. In the hands of experienced surgeons, neck dissection with STL can be performed without an increase in complications for
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the benefit of obtaining significant prognostic information, as patients with positive nodal disease after neck dissection have significantly worse disease-free survival and overall survival. However, given that the END is not associated with increased survival, fewer than 20% of END patients have occult disease, and the prognosis remains poor for those with occult disease, it would also be reasonable to choose not to perform routine elective neck dissections. This study provides evidence to support the conclusion that either approach is reasonable and the decision can be individualized based on other factors such as patient and surgeon preference.
Acknowledgements The authors would like to thank Shari Messinger Cayetano, Ph.D., Associate Professor of Biostatistics at the University of Miami Miller School of Medicine, for her review of the statistical analyses. We would also like to thank Kauthar Carr for helping to retrieve pathology data. The University of Miami Department of Otolaryngology provided funding for this study.
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