Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: Impact of upfront neck dissection on outcome, toxicity, and quality of life

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1 ORIGINAL ARTICLE Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: Impact of upfront neck dissection on outcome, toxicity, and quality of life Abrahim Al-Mamgani, MD, PhD, 1 * Cees A. Meeuwis, MD, PhD, 2 Peter H. van Rooij, MSc, 3 Robert Mehilal, MD, 1 Harie Basdew, MD, 1 Aniel Sewnaik, MD, PhD, 2 Peter C. Levendag, MD, PhD 1 1 Department of Radiation Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands, 2 Department of Otorhinolaryngology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands, 3 Department of Biostatistics, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. Accepted 28 May 2012 Published online 21 August 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. To investigate the impact of up-front neck dissection on the outcome of patients with node-positive hypopharyngeal cancer (HPC) treated with (chemo)radiation. Methods. Of 135 consecutive patients with node-positive HPC, 32 patients underwent up-front neck dissection followed by (chemo)radiation (group 1), and 103 patients received definitive (chemo)radiation (group 2). Results. The 3-year regional, local and distant control for groups 1 and 2 were 92% versus 87% (p ¼.37), 84% versus 72% (p ¼.15), and 80% versus 62% (p ¼.08), respectively. High T classification was the only significant predictor for poor overall survival on multivariate analysis (OR ¼ 3.0, p ¼.02). Acute and late toxicities and the prospectively assessed quality of life were comparable in both groups. Conclusion. Upfront neck dissection followed by (chemo)radiation did not negatively impact on oncologic outcomes, toxicity, or quality of life and therefore is to be regarded as a safe and effective treatment option for small HPC with bulky nodal disease, especially in busy radiation departments with unacceptably long waiting time for definitive (chemo)radiation. VC 2012 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: hypopharyngeal cancer, up-front neck dissection, radiotherapy, quality of life, toxicity INTRODUCTION Hypopharyngeal cancer (HPC) is relatively uncommon type of head and neck cancer accounting for approximately 3% to 5% of all head and neck squamous cell carcinomas (HNSCCs) and affecting 1.3 per 100,000 persons per year. 1 About 75% of the cases are presented at a locally advanced stage. Because of the abundant lymphatic pathways, at least one half of patients have nodepositive disease at presentation. Distant metastatic spread has been reported to occur in up to 60% of patients with HPC, either at presentation or during follow-up, and is more frequent compared with other HNSCCs. 2 With a view to laryngeal preservation, chemoradiation schemes are nowadays accepted as the standard of care in patients with locally advanced disease. 3,4 Furthermore, proper management of neck lymph nodes in patients with HPC is extremely important, because node-positive HPC is one of the most powerful prognostic factors predicting outcome. 5 Cervical metastasis is generally less responsive to (chemo)radiation than primary tumor, which therefore raises the question whether to perform neck dissection up front, followed by definitive treatment with (chemo)radiation. This treatment approach has been investigated for *Corresponding author: A. Al-Mamgani, MD, PhD., Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. a.al-mamgani@erasmusmc.nl head and neck cancer at different sites. Reddy et al 6 concluded that initial neck dissection followed by locoregional radiotherapy with or without chemotherapy is an effective therapy for small primary oropharyngeal cancers with N2 or greater cervical metastases. The available data on the impact of such treatment approach in patients with HPC are scarce. Prades at el 7 investigated the efficacy of pretreatment neck dissection as a part of a chemoradiation regimen for organ-preservation strategy for pyriform sinus carcinoma and showed an excellent regional control rate of 90%. Given the relative paucity of data regarding the indication for up-front neck dissection and the impact of such a treatment approach on oncologic outcomes of patients with HPC, our aim is to report our institutional experience with up-front neck dissection in node-positive HPC and to compare the outcome of such a treatment approach with standard definitive (chemo)radiation. MATERIALS AND METHODS From January 1996 to November 2010, 135 consecutive previously untreated patients with node-positive HPC were treated with curative intent at our institution and are the subject of this study. Pretreatment evaluations consisted of complete history and physical examination, including direct laryngoscopy. All patients underwent chest radiography, ultrasonography with fine-needle aspiration, head and neck CT, and, in some cases, MRI. All patients were presented at our weekly 1278 HEAD & NECK DOI /HED SEPTEMBER 2013

2 UPFRONT NECK DISSECTION FOR NODE-POSITIVE HYPOPHARYNGEAL CANCER multidisciplinary head and neck conference. On the basis of the joint recommendations of the multidisciplinary meeting, patients selected for the organ-preservation treatment protocol received radiotherapy either alone or in combination with chemotherapy. The standard larynxpreservation treatment schedule for HPC at our institution consists of definitive radiotherapy for T1 and T2, and chemoradiation for T3 and early T4. In cases of locally advanced T4 in which an attempt at larynx preservation is not realistic, laryngectomy with or without neck dissection followed by postoperative radiotherapy is advocated. Patients with locally advanced T4 disease who were technically inoperable or not fit to undergo a major surgical procedure received chemoradiation. Of the entire group, up-front neck dissection was given on the advice of the head and neck cancer board to 32 patients (24%) when the waiting time until starting the definitive (chemo)radiation exceeded 3 weeks (n ¼ 13) or because of bulky nodal disease in patients with T1 or T2 tumors (n ¼ 19). (Chemo)radiotherapy Patients were immobilized in the supine treatment position in a custom-made head and neck mask. CT scanning simulation was performed in all patients. The planning target volume included a margin of 5 mm beyond the clinical target volume to account for various targeting uncertainties. In case of node-negative disease, the elective neck irradiation consisted of 46 Gy of radiotherapy to levels II, III, and IV bilaterally. The intended radiation dose to the primary tumor and involved neck was 70 Gy in 35 fractions of 2 Gy, 6 times a week. In patients treated with up-front neck dissection (group 1), the total radiation dose was 70 Gy to the primary tumor and 66 Gy after surgery to the involved neck. Before 2000, patients were treated with a 3-dimensional conformal radiotherapy technique. From April 2000 onward, we have used intensity-modulated radiotherapy to treat all who have head and neck cancers at our institution. When chemotherapy was indicated, 2 cycles of cisplatin were given (100 mg on days 1 and 22 of radiotherapy). Creatinine clearance was checked before each administration. Application of chemotherapy was delayed or discontinued in case of neutropenia (count <1000/nL) or thrombocytopenia (count <100/nL) to prevent radiotherapy breaks. Endpoints End points of the study were rates of regional control, local control, distant metastasis free survival (DMFS), disease-free survival (DFS), overall survival (OS), acute and late toxicity, and quality of life (QOL). Regarding local and regional failure, the first time that recurrence was reported was used as the moment at which failure was registered. The ultimate local and regional control rates reflect the proportion of patients primarily cured by (chemo)radiotherapy added to those who were successfully salvaged after local or regional recurrence. DFS was measured from the date of completion of treatment to the date of first relapse (local, regional, or distant) or death. Patients who died of intercurrent disease without evidence of relapse were censored at the moment of death. Acute toxicity (90 days after treatment) was evaluated by the radiation oncologist during the weekly visit of patients to our outpatient department. Late toxicity (>90 days after treatment) scores were retrospectively collected from chart review by use of Common Terminology Criteria for Adverse Events v3.0. QOL was assessed prospectively in all patients treated from January 2006 onward. Two types of questionnaires were used: the EORTC QLQ-C30, and the EORTC QLQ- H&N35. 8 For the EORTC QLQ-C30 (functional scales); the higher the score, the better the QOL. For the EORTC QLQ-H&N35 (problem scales); the higher the score, the more problems the patient will have. Follow-up The treatment response was evaluated by clinical examination by the head and neck surgeon or radiation oncologist 6 to 8 weeks after completion of (chemo)radiation and by CT scanning of the head and neck, 12 weeks after treatment. Positron emission tomography scanning was performed if there was any suspicion about the locoregional response. In case of increased fluorodeoxyglucose (18 F) uptake at 1 or more cervical regional lymph nodes, ultrasonography with fine-needle aspiration was done to confirm residual disease. Subsequently, salvage neck dissection would be offered to these patients. After completion of treatment, patients were followed up every 2 months for the first year, every 3 months for the second and third year, and every 6 months thereafter. At each visit, history and clinical examination were performed, including flexible nasoendoscopy. Statistical analysis The incidences of toxicities were compared by use of logistic regression. The Mann-Whitney sign test was used for nonparametric significance tests. Univariate and multivariate analyses were performed to identify variables predicting outcome. Regression models were used to evaluate the impact of up-front neck dissection and definitive (chemo)radiation on QOL scores. A 2-tailed p <.05 was considered statistically significant. RESULTS Of the entire study population (135 consecutive patients with node-positive HPC), 32 patients (24%) underwent up-front neck dissection followed by (chemo)radiation (group 1), and 103 patients (76%) received definitive (chemo)radiation (group 2). Table 1 shows patient demographics of both groups. Significant differences were seen between both groups with regard to the tumor stage and the use of chemotherapy. Significantly more patients in group 2 had locally advanced disease (T3 and T4), compared with group 1 (68% vs 41%, p ¼.007, respectively), and significantly more patients in group 2 who were treated with chemoradiation, compared with group 1 (77% vs 28%, p <.0001, respectively). Table 2 shows characteristics of patients who underwent up-front neck dissection, as well as the pathologic findings of the performed neck dissections. The delays HEAD & NECK DOI /HED SEPTEMBER

3 AL-MAMGANI ET AL. TABLE 1. Pretreatment patient characteristics. Characteristic All patients (Total ¼ 135) Up-front ND Group 1 (Total ¼ 32) No up-front ND Group 2 (Total ¼ 103) p value Age, y NS Range Median Sex NS Male 112 (83%) 26 (81%) 85 (83%) Female 23 (17%) 6 (19%) 18 (17%) Follow-up, mo NS Range Median Nodal classification NS N1 30 (22%) 6 (19%) 26 (25%) N2 þ N3 105 (78%) 26 (81%) 77 (75%) Tumor classification.007 T1 þ T2 53 (39%) 19 (59%) 33 (32%) T3 þ T4 82 (61%) 13 (41%) 70 (68%) Chemotherapy <.0001 Yes 88 (65%) 9 (28%) 79 (77%) No 47 (35%) 23 (72%) 24 (23%) Abbreviations: ND, neck dissection; NS, not significant. Note: Significant p values are indicated in bold. from neck dissection to the start of the definitive treatment with (chemo)radiation were primarily to allow for wound healing, for CT simulation, and for treatment planning. No patient experienced clinically evident local progression or change in T classification during the interval between neck dissection and the start of definitive treatment. Radiotherapy was delivered to the neck according to the pathologic findings of the neck dissection. In 6 patients with N1 disease without extracapsular extension (ECE), only 46 Gy of radiotherapy was given. Patients with ECE (n ¼ 14) received 70 Gy of radiotherapy, and in 8 of them chemotherapy was also added because they had T3, T4, or N3 disease. In all other patients, 66 Gy of radiotherapy was delivered. In patients treated in group 2 with definitive (chemo)radiation, a mean dose of 70 Gy was delivered to the involved neck and 46 Gy to the uninvolved neck. After a median follow-up of 34 months (range, 5 158), the 3-year regional control, local control, DMFS, DFS, and OS for the entire group were 90%, 76%, 68%, 49%, and 46%, respectively (Figure 1). The figures for patients from group 1 compared with those from group 2 were 92% versus 87% for regional control (p ¼.37), 84%, versus 72% for local control (p ¼.15), 80% versus 62% for DMFS (p ¼.08), 64% versus 45% for DFS (p ¼.06), and 66% versus 42% for OS (p ¼.04), respectively (Figure 2 4). Regarding regional control, 14 patients (10%) had development of regional failure (RF), 2 patients in group 1 (6%) and 12 patients (12%) in group 2. In only 6 patients salvage neck dissection were attempted, with success occurring in only 2 of them, resulting in an ultimate regional control rate of 91% for the entire group. In all other patients with RF, the regional recurrence was either too advanced for surgery or was associated with distant metastasis (DM) or large inoperable local recurrence. With regard to local control, 30 patients had development of local failure (LF). However, in only 8 patients salvage laryngectomy was performed because most LFs were diagnosed at advanced stage or simultaneously with RF or DM. Nevertheless, the ultimate local control rate of the entire group was excellent (80%). Thirty-five patients had development of DM during the follow-up time; of them 24 patients had lung, 3 brain, 2 bone, 1 liver, 1 skin metastases, and 4 had DM at different sites. In only 3 patients DM were treated in curative setting, 2 lung metastases were treated with lobectomy and one patients with high-dose stereotactic radiotherapy by means of the CyberKnife (Accuray, Sunnyvale, CA) (60 Gy in 3 fraction of 20 Gy). All other patients with DM died because of uncontrollable disease progression. Of the entire group, 85 patients (63%) died. Significantly more patients died in group 2 compared with group 1, resulting in 3-year OS rates of 42% and 66%, respectively (p ¼.04). Also the cancer-related mortality rate was significantly higher in group 2 (44% vs 22%, p ¼.03), whereas non cancer-related mortality rates were similar in both groups (14%). Besides up-front neck dissection (treatment group 1), tumor stage and use of chemotherapy correlated significantly with OS on univariate analysis. However, on multivariate analysis high T classification was the only significant predictor for poor OS (OR 3.0, 95% CI , p ¼.02) (Table 3). Safety, feasibility, and acute toxicity Of 32 patients with up-front neck dissection, only 1 patient had development of wound healing problems as a result of underlying infected hematoma, requiring wound toilet and postoperative antibiotic course. The time between neck dissection and starting definitive chemoradiation for this patient was 40 days, compared with the mean interval of 32 days for the whole group. All patients received their planned dose of radiotherapy. When chemotherapy was indicated, all patients received the 2 planned courses of cisplatin. The treatment was 1280 HEAD & NECK DOI /HED SEPTEMBER 2013

4 UPFRONT NECK DISSECTION FOR NODE-POSITIVE HYPOPHARYNGEAL CANCER TABLE 2. Data of patients treated with up-front neck dissection followed by definitive (chemo)radiation (n 5 32). No. of patients (%) Tumor classification T1 6 (19%) T2 13 (40%) T3 7 (22%) T4 6 (19%) Nodal classification N1 6 (19%) N2a 5 (16%) N2b 17 (53%) N2c 1 (3%) N3 3 (9%) Type of ND Selective 13 (41%) Modified radical 15 (47%) Radical 4 (12%) Number LN removed Range 8 75 Median 25 Number LN involved Range 1 12 Median 2 Levels involved Level I 0 Level II 19 (59%) Level III 20 (63%) Level IV 7 (22%) Level V 1 (3%) ECE Yes 14 (44%) No 18 (56%) Time between ND and start RT, d Range Median 32 Time between ND and start CRT, d Range Median 32 Abbreviations: ND, neck dissection; LN, lymph node; ECE, extracapsular extension; RT, radiotherapy; CRT, chemoradiation. FIGURE 1. Kaplan-Meier curve of regional control (RC), local control (LC), distant metastasis free survival (DMFS), disease-free survival (DFS), and overall survival (OS) for the entire study population. group 1 and 2, respectively (p ¼.8). The figures for grade 3 late toxicity were 12% for the whole group and 12% and 13% for group 1 and 2, respectively (p ¼.8). Dysphagia and xerostomia were the most commonly reported types of grade 2 late toxicities (21% and 19%, respectively). The figures for group 1 and 2 were 18% vs 23% (p ¼.09) for dysphagia and 17% vs 20% (p ¼.16) for xerostomia, respectively (Table 4). Quality of life Fifty-five patients treated at our institution from January 2006 onward were eligible for this analysis. However, only patients with sufficiently long follow-up time (1 year) with NED who filled out the questionnaires at well tolerated because no treatment breaks and no grade 4 to 5 acute toxicities were reported. All patients experienced one or more types of acute side effects. The overall incidence of grade 2 acute toxicity was 92% for the whole group and 88% and 94% for group 1 and 2, respectively (p ¼.6) (Table 4). However, grade 3 acute toxicity was significantly higher in group 2 compared with group 1 (72% vs 50%, respectively; p ¼.02), because significantly more patients in group 2 received chemoradiotherapy (77% vs 28%, respectively; p <.0001). Also significantly more patients in group 2 had T3 or T4 tumors (68% vs 41%, respectively; p ¼.007) necessitating larger radiation fields and thus increasing the chances for development of serious acute toxicity. For the same reasons, the incidence of feeding tube dependence (grade 3 dysphagia) was also significantly higher in patients treated in group 2 compared with group 1 (46% vs 22%, p ¼.02). Late toxicity The overall 3-year incidence of grade 2 late toxicity was 32% for the whole group and 30% and 33% for FIGURE 2. Kaplan-Meier curve of regional control (RC) of both groups: Upf. Yes (up-front neck dissection), Upf. No (no up-front neck dissection). HEAD & NECK DOI /HED SEPTEMBER

5 AL-MAMGANI ET AL. TABLE 3. Logistic regression analysis: correlation between overall survival and patient demographics. Univariate analysis Multivariate analysis FIGURE 3. Kaplan-Meier curve of distant metastasis free survival (DMFS) of both groups: Upf. Yes (up-front neck dissection), Upf. No (no up-front neck dissection). baseline and at least on 3 moments thereafter are considered as responders and included in this analysis (n ¼ 48 [87%]). Patient demographics of the responders were fairly comparable with those of the entire group. Twentyone patients underwent up-front neck dissection and belong to group 1 and 27 to group 2. The median followup was 30 months. The median age was 60 years. Thirtyeight patients were male, and 10 were female. For the entire group (n ¼ 48), the baseline scores of the EORTC QLQ-C30 Global Health and the EORTC QLQ-H&N35 swallowing and dry mouth were 63, 22, and 17, respectively, which means that the patient population functioned reasonably within the tested domains at baseline but with relatively impaired scores on Global FIGURE 4. Kaplan-Meier curve of overall survival (OS) of both groups: Upf. Yes (up-front neck dissection), Upf. No (no up-front neck dissection). Sex (male vs female) p ¼.1 Age ( 60 vs >60 years) p ¼.8 Tumor stage (T1&T2 vs T3&T4) OR 3.5 (p ¼.007) Nodal Stage (N0-1 vs N2-3) p ¼.1 Chemotherapy (Yes vs No) OR 2.9 (p ¼.005) Upfront ND (Yes vs No) OR 2.4 (p ¼.03) Nodal irradiation 70 Gy (Yes vs No) Radiation technique (3DCRT vs IMRT) health, swallowing or dry mouth scales. QOL-scores on all scales and in both treatment groups deteriorated during treatment, reaching the worst scores around the end of treatment. The scores on all scales started to improve within 2 to 4 weeks and returned to baseline levels at 3 to 6 months after treatment. After 2-year follow-up, the scores on all scales of the EORTC QLQ-C30 and the EORTC QLQ-H&N35 had returned to or were even better than baseline levels, with the exception of EORTC QLQ-H&N35 dry mouth, dysphagia, and sticky saliva scales. The scores on these scales remained slightly worse than baseline levels. Slight differences were observed between both groups on some scales (Figure 5). However, the differences between both treatment groups were statistically not significant (p >.05). DISCUSSION p ¼.5 p ¼.1 OR 3.0 (95% CI: ), p ¼.023 OR 2.0 (95% CI: ), p ¼.090 OR 1.6 (95% CI: ), p ¼.317 Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval; ND, neck dissection; 3DCRT, 3-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy. It is generally accepted that patients with large primary head and neck cancer and bulky nodal disease benefit from chemoradiation followed by neck dissection only in case of residual neck disease. However, the timing of neck dissection (planned or salvage) is subject to continued debate. On the other hand, the available data are insufficient regarding when to perform a neck dissection in patients with small primary tumor and bulky cervical metastasis, because the ability of chemoradiation to control regional nodal metastasis is less clear. These patients may represent a subset of patients who would benefit from initial neck dissection followed by radiation therapy with or without chemotherapy. This treatment approach has frequently been investigated in patients with small oropharyngeal cancer and bulky nodal metastasis 6,9 but barely in patients with HPC. At our institution, patients with small HPC and bulky nodal disease were treated with up-front neck dissection followed by (chemo)radiation, especially when the waiting time for starting the definitive (chemo)radiation was longer than 3 weeks. This study demonstrates the 1282 HEAD & NECK DOI /HED SEPTEMBER 2013

6 UPFRONT NECK DISSECTION FOR NODE-POSITIVE HYPOPHARYNGEAL CANCER TABLE 4. The incidence of grade 2 acute and late toxicity, according to Common Terminology Criteria for Adverse Events version 3.0. All patients (n ¼ 135) Up-front ND Group 1 (n ¼ 32) No up-front ND Group 2 (n ¼ 103) p value Overall acute toxicity 124 (92%) 28 (88%) 97 (94%).6 Skin 121 (90%) 26 (81%) 96 (93%).06 Mucosal 121 (90%) 26 (81%) 96 (93%).06 Dysphagia 117 (87%) 25 (78%) 93 (90%).07 Sticky saliva 84 (62%) 19 (59%) 64 (62%).93 Pain 93 (69%) 20 (63%) 73 (71%).37 Overall late toxicity 43 (32%) 7 (30%) 34 (33%).8 Skin 18 (13%) 3 (10%) 14 (14%).57 Mucosal 15 (11%) 4 (13%) 9 (9%).09 Xerostmoa 26 (19%) 5 (16%) 21 (20%).16 Dysphagia 28 (21%) 6 (18%) 24 (23%).09 Trismus 7 (5%) 1 (3%) 6 (6%).12 Fibrosis 7 (5%) 2 (7%) 4 (4%).06 Pain 1 (1%) 0 (0%) 1 (1%).16 feasibility and favorable efficacy and toxicity profiles of performing up-front neck dissection before definitive (chemo)radiation for patients with node-positive HPC. Not only excellent local and regional treatment outcomes were achieved by this approach (group 1), but the impacts of this approach on toxicity and QOL were also comparable to those achieved by definitive (chemo)radiation (group 2). Furthermore, the local treatment outcomes in the present study are fairly comparable with the cohort of Prades et al., 7 who reported 90% regional control rates in patients with bulky nodal metastasis from HPC and with the study of Byers et al, 10 who reported a regional failure rate of 11% in 35 patients with T1 to T3 head and neck tumors with N2 or greater regional disease treated with initial neck dissection followed by radiation therapy. A theoretical concern about such treatment strategy is that the "delay in starting definitive (chemo)radiation after neck dissection could result in local tumor progression and might worsen the prognosis. In this study, no patient from group 1 experienced clinically evident local progression or change in T classification during the interval between neck dissection and the start of definitive treatment. Furthermore, the 3-year regional control and local control rates for group 1 and 2 were quite comparable (92% vs 87%, p ¼.37 for regional control, and 84% vs 72%, p ¼.15 for local control, respectively). Another concern about up-front neck dissection is that part of those patients probably would not have required a neck dissection afterward. In our study, only 6 patients with N1 disease have been treated with up-front neck dissection without postoperative radiotherapy to the involved neck, whereas patients with N1 disease primarily treated with (chemo)radiotherapy should receive 70 Gy to the involved neck. There is no strong evidence that morbidity of neck dissection is higher than that of 70 Gy of radiotherapy. Furthermore, the extent of up-front neck dissection will often require sacrifice of structures that we now rarely sacrifice after treatment. Some have also argued that patients who underwent upfront neck dissection might show a higher incidence of acute and late toxicities. In this study, neither acute nor late toxicity was significantly increased in patients treated with up-front neck dissection compared with definitive (chemo)radiation (Table 4). Furthermore, prospective QOL assessment of both groups showed no statistically significant differences on any scale, nor at any time point (Figure 5). The only significant difference between both groups was the incidence of grade 3 acute toxicity. This was significantly higher in patients treated with definitive (chemo)radiation (group 2) compared with group 1 (72% vs 50%, respectively; p ¼.02). This is because significantly more patients in group 2 received chemoradiotherapy (77% vs 28%, respectively; p <.0001). Furthermore, significantly more patients in group 2 had T3 or T4 tumors (68% vs 41%, respectively, p ¼.007) necessitating larger radiation fields, thus increasing the chances of developing serious acute toxicity. For the same reasons, the incidence of feeding tube dependence (grade 3 dysphagia) was also significantly higher in patients treated in group 2 compared with group 1 (46% vs 22%, p ¼.02). Upfront neck dissection has several advantages, such as providing detailed pathologic information about the extent of nodal disease and subsequently allowing one to tailor the dose of radiotherapy to these findings. In the present study, 57% of patients treated in group 1 received a dose 66 Gy to the involved neck, compared with 70 Gy given to all patients primarily treated with (chemo)radiation. The favorable regional control rates (92%) observed in patients treated in group 1 would suggest that irradiating the neck with a lower radiation dose after removal of gross disease may be sufficient to achieve such excellent outcomes. Reducing the dose and volume of the irradiated neck levels in the postoperative setting may reduce the incidence of radiation-induced complications. Davidson et al 11 found that the rate of wound complications after neck dissection increased from 29% in patients receiving <70 Gy to 58% in patients receiving >70 Gy. Another advantage of up-front neck dissection is to avoid operating an irradiated neck after a full course of chemoradiation in case of residual nodal disease (planned or salvage neck dissection). As reported by Stenson et al, 12 neck dissection after chemoradiation was associated with a 26% incidence of postoperative complications. Furthermore, Lango et al 13 showed that neck dissection may contribute to HEAD & NECK DOI /HED SEPTEMBER

7 AL-MAMGANI ET AL. FIGURE 5. The mean scores on different scales of the EORTC QLQ-C30 and the EORTC QLQ-H&N35 questionnaires of both groups; (--) for up-front neck dissection and ( ^ ) for no up-front neck dissection. chronic dysphagia in patients with HNSCC treated with primary radiation or chemoradiation followed by neck dissection, with a relatively high risk for feeding tube dependence of 7.7 (95% CI ) in these patients. Proponents of up-front neck dissection also argue that the ultimate success rate of salvage neck dissection in case of RF after a full-dose chemoradiation is small, 14,15 whereas the morbidity rate is high. 12,16 In this study, salvage neck dissection was attempted in only 6 of 14 patients with RF and succeeded in only 2 of them. In a series of 139 patients treated at the University of Florida with positive nodes treated with radiotherapy alone, 35 had development of RF; salvage surgery was attempted in 9 patients but was successful in only 2 of them. 14 Likewise, in the MD Anderson series, 1 of 7 attempted salvages was successful. 15 It is also believed that bulky nodal disease represents a higher risk of DM and should be addressed earlier in the course of treatment. In our study, patients treated by upfront neck dissection showed a tendency toward improved 1284 HEAD & NECK DOI /HED SEPTEMBER 2013

8 UPFRONT NECK DISSECTION FOR NODE-POSITIVE HYPOPHARYNGEAL CANCER DMFS, compared with those treated in group 2 with definitive (chemo)radiation (the 3-year actuarial incidence of 80% vs 62%, respectively; p ¼.08). However, this conclusion should be interpreted with great caution, because significantly fewer patients treated by up-front neck dissection in the current study had T3 and T4 tumors with subsequently less risk of having DM. For the same reason, DFS and OS rates were improved in patients treated with up-front neck dissection, because high T classification was the only significant predictor for poor OS on multivariate analysis. Another confounding factor contributed to better OS rates in group 1 is the selection of patients for up-front neck dissection. Patients selected for this treatment option generally had minimal comorbidities. Only 1 randomized study has addressed the role of upfront neck dissection in patients with advanced unresectable HNSCC. Carinci et al 17 randomly assigned these patients to either neck dissection followed by chemoradiotherapy (n ¼ 23) or chemoradiotherapy alone (n ¼ 31). The 2-year DFS rates were significantly better in the surgical arm (52% vs 29%, respectively). A Cox regression analysis reached a positive and significant odds ratio in association with the probability of death (p ¼.0366 in favor of neck dissection). Although this study had major methodologic shortcomings, it illustrated, at least, the noninferiority of this treatment approach in patients with bulky node-positive head and neck cancer with small primary tumor. Although a planned neck dissection performed after the completion of (chemo)radiation has been shown to improve regional control and survival in selected subgroups of patients with head and neck cancer, 18,19 a number of investigators have criticized this concept because of the demonstrated clinical and radiological complete response, primarily on the basis of negative histologic findings from posttreatment neck dissection pathology reports. 16,20 Opponents of such approach also argue that additional surgery will not reduce the risk of regional recurrence; rather, it will only increase morbidity. Furthermore, the timing of a planned neck dissection continues to be an issue of intense debate. In that respect, it is important to realize that the neck dissections performed within the first year after chemoradiation had a significantly higher complication rate compared with salvage neck dissection after the first year of follow-up (77% vs 20%). 21 The benefit of a planned neck dissection must therefore outweigh the risks associated with the surgical procedure. The role and the timing of posttreattment neck dissection for advanced head and neck cancer need to be further investigated in prospective, preferably, randomized clinical trials to differentiate more effectively those patients who still require additional surgical treatment and derive benefit from neck dissection after full course of chemoradiation from those who will not. According to the systemic review by Cheng et al, 22 the risk of LF increases significantly with increasing waiting times for radiotherapy for head and neck cancer (relative risk [RR] for LF/month ¼ 1.15). The observed RR translates into an absolute increase in the risk of recurrence of 3.7% per month of delay. There was a marginally significant decrease in survival (RR for death/month ¼ Given the fact that the probability of local control of head and neck cancer is inversely related to the volume of the tumor, 23 the treatment of bulky nodal disease in case of small primary HPC needs to be initiated as soon as reasonably achievable. Because the oncologic outcomes, toxicity and QOL of both groups in this study were fairly comparable, we would opt for up-front neck dissection followed by definitive (chemo)radiation in busy radiation departments with unacceptable long waiting times for the radiotherapy. However, it is difficult to define a threshold below which delay is safe. In our department, we have considered a waiting time >3 weeks as unacceptable. However, we can imagine that the threshold of 3 weeks is too short. Therefore, we believe it is ethically advisable to apply the principle that delays in radiotherapy should be as short as reasonably achievable. The limitations of the current study, including the selection bias inherent to the retrospective nature of the study are well recognized by the authors. Late toxicity was retrospectively scored using chart review only. Accurate assessment of less severe complications from the medical records is not entirely reliable because of the subjective nature of these endpoints. Therefore it is likely that some, especially mild, late toxicities were not captured. On the other hand, this study is, to our knowledge, the only one in which the oncologic outcomes of patients with node-positive HPC were combined with prospective analysis of QOL, including baseline scores. It should be emphasized that the present study is one of very few studies reporting on outcomes and toxicity of patients with HPC treated with an up-front neck dissection before the definitive (chemo)radiation, a treatment algorithm which deserves further investigation considering the favorable efficacy and toxicity profiles demonstrated in this study. In conclusion, 32 patients with node-positive HPC received up-front neck dissection before definitive treatment with (chemo)radiation at our institution, either because of having a small primary tumor and bulky nodal disease and/or because the waiting time before starting the definitive treatment was unacceptably long (>3 weeks). All other patients (n ¼ 103) were treated with definitive (chemo)radiation. Upfront neck dissection followed by (chemo)radiation for HPC did not negatively affect oncologic outcomes, toxicity or QOL, and therefore it is to be regarded as a safe and effective treatment option in selected subgroup of patients with node-positive HPC (small HPC with bulky nodal disease), especially in busy radiation departments with unacceptably long waiting time for the definitive (chemo)radiation, and it warrants further exploration. REFERENCES 1. Cooper JS, Porter K, Mallin K, et al. National Cancer Database report on cancer of the head and neck: 10-year update. Head Neck 2009;6: Kotwall C, Sako K, Razack MS, Rao U, Bakamjian V, Shedd DP. Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;154: Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;22: Lambert L, Fortin B, Soulières D, et al. 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