Kaplan-Meier overall survival curve for patients undergoing neck dissection (ND) less than 12 weeks (<12-wk ND group) and 12 weeks or longer (≥12-wk ND group) after chemoradiotherapy.
Kaplan-Meier progression-free survival curve for patients undergoing neck dissection (ND) less than 12 weeks (<12-wk ND group) and 12 weeks or longer (≥12-wk ND group) after chemoradiotherapy.
Goguen LA, Chapuy CI, Li Y, Zhao SD, Annino DJ. Neck Dissection After ChemoradiotherapyTiming and Complications. Arch Otolaryngol Head Neck Surg. 2010;136(11):1071-1077. doi:10.1001/archoto.2010.188
To determine the incidence of postchemoradiotherapy (post-CRT) neck dissection (ND) complications; to ascertain whether timing (<12 vs ≥12 weeks) from CRT to ND or other factors are associated with increased complications; and to determine whether ND timing influences disease control or survival.
Ten-year retrospective analysis.
Tertiary care center.
One hundred five patients with head and neck cancer undergoing ND after CRT.
Main Outcome Measures
Complications and survival variables compared between groups undergoing ND less than 12 weeks (less-than-12-weeks ND group) and 12 weeks or more (12-weeks-or-more ND group) after CRT.
Sixty-seven NDs were performed less than 12 weeks and 38 were performed 12 weeks or more after CRT. Patient characteristics, treatment, and ND pathology results were comparable between the 2 ND groups. The incidence of complications between the less-than-12-weeks and the 12-weeks-or-more ND groups included major wound complications in 8 of 67 (11.9%) vs 1 of 38 (2.6%; P = .15), minor wound complications in 11 of 67 (16.4%) vs 4 of 38 (10.5%; P = .56), airway complications in 7 of 67 (10.4%) vs 2 of 38 (5.3%; P = .48), and systemic complications in 9 of 67 (13.4%) vs 2 of 38 (5.3%; P = .32). The number of patients with at least 1 complication was significantly smaller in the 12-weeks-or-more ND group (P = .04). Multivariate analysis showed that radical ND was significantly associated with an increased number of complications, and higher radiation doses approached significance (P = .05). Induction chemotherapy was associated with fewer wound complications (P = .01). There were no significant differences in overall survival (P = .82), progression-free survival (P = .77), or regional relapse (P = .54) between groups. Positive ND findings were associated with diminished progression-free and overall survival.
These findings indicate that ND can be safely performed 12 weeks or more after CRT without adversely affecting surgical complications or survival variables.
Neck management after chemoradiotherapy (CRT) for head and neck cancer has become a controversial topic. At most institutions, planned neck dissections (NDs) after CRT are often no longer routinely performed.1- 3 Rather, the neck is assessed and, if findings suggest possible residual metastatic disease, ND is advised. Results of early neck dual-modality positron emission tomography/computed tomography (PET/CT) may be inaccurate owing to treatment-related inflammation, cancer in evolution toward death, and pockets of residual disease that are too small to detect on imaging.4,5 Several investigators have found improved accuracy when PET/CT is delayed until 3 months or more after treatment.1- 3,6 However, this time frame has conflicted with the traditional thinking that posttreatment ND should be performed within 4 to 12 weeks after radiation to lessen the risk of surgical complications.7
We undertook the following study to determine whether there was any increase in surgical complications or decrease in disease control or survival when ND was performed 12 weeks or more after CRT.
A retrospective review was undertaken of all consecutive and eligible patients with advanced-stage squamous cell carcinoma of the oral cavity, oropharynx, larynx, hypopharynx, or unknown primary site treated with CRT followed by ND at the Dana-Farber Cancer Institute and Brigham and Women's Hospital from January 1, 1998, through June 30, 2008. The protocol was approved by the institutional review board of Dana-Farber Cancer Institute. All patients had a complete response to CRT at the primary site (defined as no evidence of disease on physical examination and imaging results) at the time of ND. Patients with cancers of the sinonasal cavity, nasopharynx, or salivary glands were excluded because some cancers at these sites are not squamous cell carcinoma or because neck staging and management are different for these sites. Patients with recurrent disease or a history of other malignant neoplasms were excluded.
Neck dissection was advised for patients who did not achieve a complete clinical response in the neck or for patients with initial extensive N2b or N3 neck disease regardless of response to treatment. Neck dissections were radical ND (RND), modified radical ND (MRND), or selective ND (SND), depending on neck stage, response to CRT, and surgeon preference.
We assessed computer and hard-copy patient medical records and collected patient demographic information. The operative, inpatient, and outpatient notes were rigorously reviewed, and complications were identified. Categories of complications included major and minor wound complications, airway complications, and systemic complications. The categories were defined as follows: Major wound complications were those that required a return to the operating room, required hospital readmission, or involved any chyle leak. Minor wound complications included all other wound complications that did not require a return to the operating room or hospital readmission but necessitated outpatient treatment, such as minor wound infections and fluid collections, wound dehiscence, and minor flap necrosis. Airway complications included the need for tracheotomy, intubation, postoperative intensive care unit admission for airway observation, and any hospital readmission for airway observation. Systemic complications were nonwound and nonairway complications that required intervention, such as cardiac problems, the need for blood product transfusion, fever workup, non–wound site infections, and exacerbation of other underlying medical problems. Effort was made to capture the multiplicity of complications experienced by some patients. This was accomplished by tabulating the number of patients with at least 1 complication (≥1 major or minor wound complication or airway or systemic complication), multiple complications (>1 major or minor wound or airway or systemic complication), and at least 1 wound complication (≥1 major or minor wound complication). Relapse and survival variables were assessed.
The patient characteristics, treatment, and ND pathology results were compared between the groups undergoing ND less than 12 weeks (less-than-12-weeks ND group) and 12-weeks- or-more (12-weeks-or-more ND group) after CRT with the use of the Wilcoxon rank sum test (for continuous variables) or the Fisher exact test (for categorical variables). Univariate analysis was used to compare the incidence of complications between the less-than-12-weeks and the 12-weeks-or-more ND groups. The time origin for follow-up, overall survival (OS), progression-free survival (PFS), and regional relapse was each patient's ND surgery date. Survival curves were calculated using the Kaplan-Meier product limit method and were compared between the less-than-12-weeks and 12-weeks-or-more ND groups using the log-rank test. Multiple regression analysis was also performed. The complication categories of at least 1 complication and at least 1 wound complication were the most robust and were used as end points. Other end points were PFS and OS. Multivariate models were established by performing initial bivariate association analyses to screen out insignificant covariates, followed by model selections. Then we used multiple regression analysis (linear and logistic regressions or Cox proportional hazards regression) to determine whether the variables neck stage, positive lymph node at ND, type of ND, amount of nodal radiotherapy, radiation technique, or induction vs concurrent CRT were associated with complications (≥1 complication or ≥1 wound complication) or influenced PFS or OS. All analyses were performed using R statistical software (version 2.8.0; R Development Core Team, Vienna, Austria).
We identified 115 patients. Ten patients were eliminated for the following reasons: 5 patients had simultaneous bilateral NDs, 2 had staged NDs, and 3 had brachytherapy to the base of tongue at the time of their ND. Bilateral and staged NDs were excluded because the performance of 1 ND interfered with the interpretation of complications from the second ND. This resulted in 105 patients with appropriate data for analysis. Sixty-seven patients underwent ND less than 12 weeks after CRT and 38 patients underwent ND 12-weeks-or-more after CRT.
Patient characteristics are listed in Table 1. The less- than-12-weeks and 12-weeks-or-more ND groups were comparable for all patient characteristics (Wilcoxon rank sum test or Fisher exact test).
Patient treatment and ND pathology results are tabulated in Table 2. All treatment variables and ND pathology results were found to be similar between the less-than-12-weeks and 12-weeks-or-more ND groups (Wilcoxon rank sum test or Fisher exact test). All patients underwent primary CRT. Seventy-one of the 105 patients received induction CRT consisting of 3 cycles of platinum-based chemotherapy followed by concurrent CRT, with most receiving weekly carboplatin. The remaining 34 patients received concurrent CRT, with most receiving weekly carboplatin and paclitaxel or bolus cisplatin. External beam radiotherapy was delivered using a 3-field technique until 2004, after which intensity-modulated radiotherapy was used. Irrespective of technique, grossly involved nodes were treated with a total dose of 70 to 72 Gy at 1.8 to 2.0 Gy/d. Neck levels at high risk for microscopic disease were typically treated with total doses of 54 to 60 Gy in 1.8 to 2.0 Gy per fraction (3-field) or 60 to 64 Gy (intensity-modulated radiotherapy). Total radiation dose was not available for 24 patients, and radiation technique was not available for 13 patients.
Neck dissections were performed at a median time of 11 weeks after completion of CRT (range, 4-26 weeks). Thirty patients underwent RND and 75 underwent MRND or SND. The more limited NDs, MRND and SND, were combined because only 3 patients underwent SNDs. No patient required carotid artery coverage, and no patient sustained bleeding from the carotid artery. Neck drains were required for a median of 4 days postoperatively (interquartile range, 4-5), and hospital length of stay was a median of 4 days (interquartile range, 4-5), without significant differences between the 2 groups.
The incidence and type of complications are reported in Table 3. The incidence of major and minor wound complications was 9 of 105 (8.6%) and 15 of 105 (14.3%) for the overall group, 8 of 67 (11.9%) and 11 of 67 (16.4%) for the less-than-12-weeks ND group and 1 of 38 (2.6%) and 4 of 38 (10.5%) for the 12-weeks-or-more ND group. There were 24 major and minor wound complications, including abscess in 5, wound infection in 4, cellulitis in 3, wound dehiscence in 3, wound necrosis in 3, neck hematoma in 2, chyle leak in 2, and neck seroma in 2. Major and minor wound complications, airway complications, and systemic complications all occurred less frequently in the 12-weeks-or-more ND group, but univariate analysis did not reach statistical significance.
The number of complications experienced per patient is reviewed in Table 4. In each category, the incidence was lower in the 12-weeks-or-more ND group and reached statistical significance by univariate analysis for the patients experiencing at least 1 complication (P = .04).
Airway complications are further described in Table 5. There were fewer of each type of airway complication in the 12-weeks-or-more ND group, but this did not reach statistical significance.
Multivariate regression analysis found that, among the variables neck stage, positive lymph node at ND, type of ND, amount of nodal radiotherapy, radiation technique, and induction vs concurrent CRT, only RND (P = .04) was significantly associated with more patients having at least 1 complication, and higher nodal radiotherapy dose approached significance (P = .05). Only induction CRT (P = .01) was found to be associated with fewer patients having at least 1 wound complication.
At a median follow-up time for surviving patients of 56 (range, 3-136) months, 87 of 105 (82.9%) were alive and 86 of 105 (81.9%) were without recurrent disease. The 19 patients with recurrence included 9 of 105 (8.6%) with primary site failure, 2 (1.9%) with neck relapse, 6 (5.7%) with distant metastasis, and 2 (1.9%) with combined distant metastases and primary failure. Univariate analysis found no significant differences for local relapse (P = .74), regional relapse (P = .54), or distant metastasis (P > .99) between the 2 groups. The less-than-12-weeks and the 12-weeks-or-more ND, OS, and PFS Kaplan-Meier curves revealed no significant differences (Figure 1 and Figure 2). Multiple regression analysis found that, for neck stage, positive lymph nodes at ND, type of ND, amount of nodal radiotherapy, radiation technique, and induction vs concurrent CRT, only the finding of positive lymph nodes at ND was significantly associated with decreased PFS (P = .01) and decreased OS (P < .001).
This study found no increase in surgical complications or decrease in disease control or survival variables when ND was undertaken 12 weeks or more after CRT for head and neck cancer. This is, to our knowledge, the first study that compares ND complications between patients undergoing ND less than 12 weeks and those undergoing ND 12 weeks or more after CRT. These findings permit performance of later neck imaging after CRT and diminish concern that delaying ND until 12 weeks or more after CRT increases the risk of surgical complications and/or reduces disease control and survival.
Several factors have prompted the current increasingly delayed timing of ND after CRT. The biological effects of radiation are known to continue for 2 to 3 months after radiotherapy completion, and it is optimal to perform neck assessments after this period.8 In addition, there has been an evolving realization that posttreatment imaging studies, particularly dual-modality PET/CT, are more accurate when performed 3 months or more after CRT.1- 3,6 These issues now frequently lead to neck assessment, and the ensuing decision as to whether ND is indicated, being delayed until 3 months after CRT.
Competing with this 3-month time frame for post-CRT neck assessment has been concern regarding displacing potentially needed ND outside the safe surgical window, described as 4 to 12 weeks after CRT.7,9 Ideally, ND should be performed after resolution of acute-phase CRT toxic effects, including mucositis, pharyngeal and laryngeal edema, and neck dermatitis, but before chronic vascular radiation injury and fibrosis have developed.10,11 Contrary to the traditional safe surgical window, some authors12 have found the onset and impact of chronic radiation injury to be harder to predict. Hopewell et al12 describe vascular irradiation damage causing injury to endothelial cells and smooth-muscle cells. Based on the low turnover of these cells, the expression of damage is delayed. Endothelial injury, resulting in a reduction in the capillary bed, occurs 2 to 4 months after radiation. Manifestation of smooth-muscle injury is more variable and occurs 7 to 18 months after radiation.
Our findings challenge the dictum of ND being safer during the 4- to 12-week window after CRT. Despite the 2 ND groups being similar in terms of patient characteristics, treatment, and ND pathology results, the number of patients sustaining at least 1 complication was significantly smaller in the 12-weeks-or-more ND group compared with the less-than-12-weeks ND group. In addition, patients in the 12-weeks-or-more group had fewer wound, airway, and systemic complications, but this did not reach statistical significance. These results are perhaps attributable to increased morbidity resulting from acute CRT toxic effects in the less-than-12-weeks ND group and comparatively fewer than anticipated chronic CRT fibrosis–related complications in the 12-weeks-or-more ND group.
Several authors7,9- 11,13- 25 have reported on surgical complications with ND after CRT (Table 6). It is often challenging to compare results because of differences between the complications considered, the thoroughness of the medical record review, the manner in which complications are tallied and categorized, the CRT technique, and the neck disease management. Among these authors, the incidence of major complications (defined as requiring a return to the operating room, requiring hospital readmission, or involving any chyle leak) varies from 0 to 24%, with a median of 5% and a mean of 7%. Our major complications in the overall group, 8.6%, and in the 12-weeks-or-more ND group, 2.6%, compare favorably with this literature review, and our major complications in the less-than-12-weeks ND group, 11.9%, are slightly elevated. The type of major wound complications reported by the authors listed in Table 6 were chyle leak in 12, neck abscess in 8, neck hematoma in 7, wound dehiscence in 6, skin necrosis in 4, neck infection in 1, neck cellulitis in 1, and neck seroma in 1. Our findings similarly showed neck abscess, hematoma, and chyle leaks to represent the most common major wound complications. Airway and systemic complications are not routinely reported and are therefore challenging to compare. Among the authors reporting airway complications, they occurred in 2% to 11% of patients and tracheotomy was usually needed.
Delaying neck assessment and potential ND until 12 weeks or longer after CRT also raises concern regarding possible effect on neck disease control and survival. We found no significant difference in regional relapse, PFS, or OS in patients undergoing ND less than 12 weeks compared with 12 weeks or more after CRT. These findings suggest that an ND can be undertaken at 12 weeks or later without an increase in neck relapse or diminished survival. Multiple regression analysis found only the presence of a positive lymph node at ND to be associated with decreased PFS and OS.
There were several potential limitations in our study. Its retrospective nature may have resulted in some complications being missed. Long-term functional impairment, such as shoulder dysfunction was not reported. Unfortunately, shoulder function was not consistently or objectively monitored during this period.
In conclusion, we found no increase in complications or reduction in disease control or survival among patients undergoing ND 12 weeks or more after CRT. These findings suggest that neck imaging can be delayed and, if it is needed, ND can safely be undertaken 12 weeks or more after CRT.
Correspondence: Laura A. Goguen, MD, Division of Otolaryngology, Department of Surgery, Brigham and Women's Hospital, 45 Francis St, Boston, MA 02115 (email@example.com).
Submitted for Publication: March 29, 2010; final revision received July 19, 2010; accepted August 8, 2010.
Author Contributions: Drs Goguen, Chapuy, and Annino had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Goguen, Chapuy, and Annino. Acquisition of data: Goguen and Chapuy. Analysis and interpretation of data: Goguen, Chapuy, Li, Zhao, and Annino. Drafting of the manuscript: Goguen, Chapuy, Li, and Zhao. Critical revision of the manuscript for important intellectual content: Goguen, Chapuy, Li, Zhao, and Annino. Statistical analysis: Chapuy, Li, and Zhao. Administrative, technical, and material support: Goguen and Chapuy. Study supervision: Goguen and Annino.
Previous Presentation: This study was presented as a poster at the American Head and Neck Society Annual Meeting; April 28-29, 2010; Las Vegas, Nevada.
Financial Disclosure: None reported.