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Outcome of bimodality definitive chemoradiation does not differ from that of trimodality upfront neck dissection followed by adjuvant treatment for >6 cm lymph node (N3) head and neck cancer

Outcome of bimodality definitive chemoradiation does not differ from that of trimodality upfront... from that of trimodality upfront neck dissection followed by adjuvant treatment for>6 cm lymph Currently, data regarding optimal treatment modality, response, and outcome specifically node (N3) head and neck cancer. PLoS ONE 14 for N3 head and neck cancer are limited. This study aimed to compare the treatment out- (12): e0225962. https://doi.org/10.1371/journal. comes between definitive chemoradiotherapy (CCRT) to the neck and upfront neck dissec- pone.0225962 tion followed by adjuvant CCRT. Ninety-three N3 squamous cell carcinoma head and neck Editor: Randall J. Kimple, University of Wisconsin, cancer patients were included. Primary tumor treatment was divided to definitive CCRT UNITED STATES (CCRT group) or curative surgery followed by adjuvant CCRT (surgery group). Neck treat- Received: May 15, 2019 ment was also classified into two treatment modalities: definitive CCRT to the neck (CCRT Accepted: November 16, 2019 group) or curative neck dissection followed by adjuvant CCRT (neck dissection group). Published: December 3, 2019 Overall, the 2-year overall survival (OS), local recurrence-free survival (LRFS), regional Copyright:© 2019 Chen et al. This is an open recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were 51.8%, access article distributed under the terms of the 47.3%, 45.6%, and 43.6%, respectively. In both oropharyngeal cancer and nonoropharyn- Creative Commons Attribution License, which geal cancer patients, in terms of OS, LRFS, RRFS or DMFS no difference was noted permits unrestricted use, distribution, and regarding primary tumor treatment (CCRT vs. surgery) or neck treatment (CCRT vs. neck reproduction in any medium, provided the original author and source are credited. dissection). In summary, N3 neck patients treated with definitive CCRT may achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Caution Data Availability Statement: All relevant data are within the manuscript and its Supporting should be made to avoid overtreatment for this group of patients. Information files. Funding: This study was supported by research grants NTUH 104-M2861, NTUH 105-N3224 and NTUH 106-N3609 from National Taiwan University Introduction Hospital. Currently, data regarding optimal treatment modality, response, and outcome specifically Competing interests: The authors have declared that no competing interests exist. for N3 head and neck cancer are limited. Most studies included a combination of N2 and PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 1 / 12 Outcome of N3 head and neck cancer N3 head and neck cancers, with only approximately 10–15% of N3 patients in prospective clinical trials[1–4] or retrospective studies[4, 5]. Planned neck dissection after definitive chemoradiotherapy (CCRT) can be omitted, and salvage post-RT neck dissection can be performed only in incomplete response to CCRT[3, 6]. However, some physicians choose neck dissection as primary treatment because of concerns for poor radiation response of bulky necrotic lymph nodes, anatomical change of bulky lymph nodes during radiation, and avoidance of post radiation neck dissection. For N3 head and neck cancer, there is lim- ited data regarding whether direct neck dissection or definitive CCRT to the neck should be performed. This study aimed to compare the treatment outcomes between definitive CCRT to the neck and upfront neck dissection followed by adjuvant CCRT for N3 head and neck cancer patients. Materials and methods Patients and treatments The retrospective study protocol was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH: 201707061RINB) and IRB approved that patient consent was waived. All patient data were anonymized before researchers gained access. Between 2002 and 2015, 93 N3 (>6 cm, American Joint Committee on Cancer 7th edition) squamous cell carcinoma head and neck cancer patients with no distant metastasis who received curative treatment at National Taiwan University Hospital were included in this study. Nodal dimen- sions were defined by magnetic resonance imaging (MRI). The median diameter of confluent neck LNs was 7.5 cm (range 6–10). Among the 93 patients, 76 (81.7%) received induction che- motherapy, which included the following regimens: PF (cisplatin + 5-FU), EPF (Erbitux + PF), APF (Avastin + PF), TPF (Taxotere + PF), ATPF (Avastin + TPF), MEPFL (mitomycin, epiru- bicin, cisplatin, fluorouracil, and leucovorin), intra-arterial (IA) MPA (mitomycin, cisplatin, Avastin), IA-MTPF (mitomycin, Taxotere, cisplatin, 5FU), IA-MATPF (MTPF + Avastin), or their combinations. For patients receiving induction chemotherapy, the median cycles received were 2 (range, 1–8). The overall response rate to induction chemotherapy was 68%. Curative treatments were categorized into options 1–3 as follows: 1) definitive CCRT to pri- mary tumor and neck; 2) curative surgery for primary tumor and the neck followed by adju- vant CCRT; and 3) curative neck dissection followed by definitive CCRT for primary tumor and adjuvant CCRT for the neck. The treatments were summarized in the S1 Fig. Curative sur- gery for primary tumor comprised of wide tumor excision with flap reconstruction if neces- sary. Curative neck dissection includes modified radical neck dissection for bulky neck nodes with or without contralateral neck dissection at the discretion of the treating physician. Defini- tive CCRT irradiation dose was 70 Gy in 33–35 fractions, which was delivered concurrently with weekly 40 mg/m cisplatin. Sixty-seven (72%) patients completed all therapy. The median cycle of weekly cisplatin was 6 (range, 3–7) and 70 patients (75%) received cumulative dose of concurrent weekly cisplatin greater or equal to 200 mg/m . Adjuvant RT dose was set to 60–66 Gy in 30–33 fractions. Patients were routinely assessed 3–4 months after the completion of the treatment through clinical examination, chest X-ray, and head and neck MRI. For patients who received defini- tive CCRT, neck dissection was not routinely performed. Response evaluation in this study was done by both clinically local examination and MRI. Complete response was defined by undetectable primary tumor or shrinkage of neck lymph nodes to less than 1cm in short axis on T2 weighted and T1 weighted with contrast medium MRI. Salvage neck dissection or pri- mary tumor excision was considered only if an incomplete response occurred. PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 2 / 12 Outcome of N3 head and neck cancer Immunohistochemical analysis of p16 Primary tumor sections of 4 μm thickness were deparaffinized and pretreated for antigen retrieval through autoclave heating (121˚C) in 10 mM sodium citrate buffer (pH 6.0) for 10 min. These sections were blocked for endogenous peroxidase activity with 3% H2O2 in metha- nol for 10 min and then washed in phosphate-buffered saline. Thereafter, the sections were immersed in UltraVision Protein Block (Thermo Fisher Scientific, Fremont, LA, USA) for 10 min, covered with a primary rabbit monoclonal antibody specific for p16 (clone: EP1215Y, Epitomics, Abcam Company, Burlingame, CA, USA), and incubated for 1 h at room tempera- ture. Immunoreactions were performed using the UltraVision Quanto Detection System HRP DAB (Thermo Fisher Scientific, Fremont, LA, USA). Immunohistochemical evaluation of p16 in oropharyngeal cancer specimens was based on the intensity and extent of nuclear and cyto- plasmic reactivity. Positive p16 expression was defined as strong and diffuse nuclear and cyto- plasmic staining in 70% or more of the tumor cells. Statistical analysis Comparison of proportions across groups was performed using Chi-squared test or Fisher’s exact test when number <5. Unpaired Student’s t test was used to compare parametrically dis- tributed continuous data. The following endpoints were used for assessment: overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and dis- tant metastasis-free survival (DMFS). These endpoints were measured from the day of diagno- sis. Survival curves were estimated via the Kaplan-Meier method. Univariate and multivariate analyses were performed with log-rank test and Cox regression, respectively. A two-sided p value <0.05 was considered statistically significant. Statistical analysis was performed with SPSS 19.0. Results Table 1 shows the patients characteristics. The primary tumor sites included the oropharynx (n = 49) and nonoropharynx (n = 44; 26 hypopharynx, 14 oral cavity, and 4 larynx). The median smoking pack-year is 30 (range, 0–80). Patients with oropharyngeal malignancy were associated with more T1/T2 tumors (p = 0.030). Primary tumor treatment was divided to definitive CCRT (CCRT group; treatment options 1+3) or curative surgery followed by adju- vant CCRT (surgery group; treatment option 2). The oropharyngeal group had more patients receiving definitive CCRT to primary tumor sites (p = 0.030). Neck treatment was also classi- fied into two treatment modalities: definitive CCRT to the neck (CCRT group; treatment option 1) or curative neck dissection followed by adjuvant CCRT (neck dissection group; treat- ment option 2+3). The oropharyngeal group had more patients receiving definitive CCRT to the neck (p = 0.000). In addition, patients who received curative operation to primary tumors, compared to definitive CCRT to primary tumors, were associated with more advanced T3/T4 tumors (p = 0.019), better performance status ECOG 0 (p = 0.023), and more ono-oropharyn- geal cancer (p = 0.000). At presentation, 45% of nodes were considered unresectable. Patients who received curative neck dissection, compared to definitive CCRT to neck, were associated with better performance status ECOG 0 (p = 0.015) and ono-oropharyngeal cancer (p = 0.000). In our study, neck dissection was performed in 34 patients (36.3%). Among patients who received neck dissection, 30 out of 34 patients (88%) had pathological positive ECE. Clinical ECE was observed in 80 out of 93 patients (86%) according neck MRI. In addi- tion, matted nodes (defined as three nodes abutting one another with loss of intervening fat plane) [7] prevalence rate was 62%. Patients with matted nodes had inferior DMFS (p = 0.015). PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 3 / 12 Outcome of N3 head and neck cancer Table 1. Patient characteristics. Characteristics All patients No. (%) Oropharynx No. (%) (N = 49) Non- Oropharynx No. (%) (N = 44) P value (N = 93) Gender Male 89 (95.7) 48 (98.0) 41 (93.2) Female 4 (4.3) 1 (2.0) 3 (6.8) 0.341 Age (years old) (median, range) 52 (34–78) 53 (34–78) 51.5 (35–78) 0.870 T classification T1/T2 32 (34.4) 22 (44.9) 10 (22.7) T3/T4 61 (65.6) 27 (55.1) 34 (77.3) 0.030 Primary tumor treatment CCRT 71 (76.3) 45 (91.8) 26 (59.1) Surgery 22 (23.7) 4 (8.2) 18 (40.9) 0.000 Neck treatment CCRT 59 (63.4) 41 (83.7) 18 (40.9) Neck dissection 34 (36.6) 8 (16.3) 26 (59.1) 0.000 Radiotherapy Definitive to both primary and neck (option 1) 59 (63.4) 41 (83.7) 18 (40.9) Adjuvant (option 2) 22 (23.7) 4 (8.2) 18 (40.9) Definitive to primary and adjuvant to neck (option 3) 12 (12.9) 4 (8.2) 8 (18.2) 0.000 Induction chemotherapy No 17 (18.3) 5 (10.2) 12 (27.3) Yes 76 (81.7) 44 (89.8) 32 (72.7) 0.058 P16 positive rates 55% 14% 0.005 Abbreviation: CCRT = concurrent chemoradiation https://doi.org/10.1371/journal.pone.0225962.t001 Among patients who received definitive CCRT to primary tumor sites, oropharyngeal can- cer patients had higher complete response (CR) rate than nonoropharyngeal cancer patients. A total of 37 (82.2%) and 19 (73.1%) patients had oropharyngeal and nonoropharyngeal can- cer, respectively. The number (rate) of patients who achieved partial response (PR) was 8 (17.8%) and 7 (26.9%) in those with oropharyngeal and nonoropharyngeal cancer, respectively (p = 0.000). For patients who received definitive CCRT to the neck, the number of patients with oropharyngeal and nonoropharyngeal cancer who achieved CR were 31 (75.6%) and 12 (66.7%), respectively, and those who achieved PR were 10 (24.4%) and 6 (33.3%), respectively (p = 0.000). A total of 7 (22.6%) and 3 (25%) patients with oropharyngeal cancer and nonoro- pharyngeal cancer developed regional recurrence after CR was achieved post definitive neck CCRT, respectively. The median follow-up time for all patients was 21.1 months (range, 6.9–105.4 months). The median follow-up time for censored patients or survivors was 41.8 months (range, 10.6–105.4 months; IQR: 23.4–73.2 months). Overall, the 2-year OS, LRFS, RRFS, and DMFS were 51.8%, 47.3%, 45.6%, and 43.6%, respectively. For all patients combined, neck treatment (CCRT vs. neck dissection) did not affect 2-yr OS (55.5% vs. 46.4%; p = 0.236, S2 Fig), LRFS (47.9% vs. 46.5%; p = 0.419, S2 Fig), RRFS (45.2% vs. 46.7%; p = 0.854, S2 Fig) or DMFS (49.2% vs. 34.2%; p = 0.172, S2 Fig). Univariate and multivariate analyses for survival rate in oropharyngeal cancer patients are summarized in Table 2. In oropharyngeal cancer patients, in terms of OS, no difference was noted regarding primary tumor treatment (Surgery vs. CCRT) (HR: 0.607; 95% CI: 0.123– 3.000; p = 0.540) or neck treatment (neck dissection vs. CCRT) (HR: 2.199; 95% CI: 0.522– PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 4 / 12 Outcome of N3 head and neck cancer Table 2. Univariate and multivariate analysis for survival in oropharyngeal cancer patients. Univariate Multivariate Characteristics HR 95% CI P value HR 95% CI P value OS Gender (female vs. male) 0.047 0.000–1069.263 0.550 0.000 0.000- 0.980 T classification (T3/T4 vs. T1/T2) 2.391 1.043–5.482 0.039 3.337 1.312–8.488 0.011 Primary tumor treatment (Surgery vs. CCRT) 1.689 0.504–5.664 0.391 0.607 0.123–3.000 0.540 Neck treatment (Neck dissection vs. CCRT) 2.085 0.869–5.000 0.100 2.199 0.522–9.256 0.283 Induction chemotherapy (Yes vs. No) 0.514 0.192–1.373 0.184 0.557 0.128–2.242 0.410 P16 (Positive vs. Negative) 0.165 0.035–0.772 0.009 0.177 0.031–0.917 0.041 LRFS Gender (female vs. male) 0.047 0.000–824.709 0.540 0.000 0.000- 0.980 T classification (T3/T4 vs. T1/T2) 2.131 0.969–4.689 0.060 3.054 1.242–7.509 0.015 Primary tumor treatment (Surgery vs. CCRT) 1.486 0.446–4.947 0.519 0.446 0.079–2.536 0.363 Neck treatment (Neck dissection vs. CCRT) 1.971 0.832–5.671 0.123 2.689 0.448–16.145 0.280 Induction chemotherapy (Yes vs. No) 0.448 0.169–1.186 0.106 0.629 0.124–3.185 0.575 P16 (Positive vs. Negative) 0.165 0.035–0.772 0.009 0.197 0.036–0.985 0.048 RRFS Gender (female vs. male) 0.047 0.000–563.595 0.524 0.000 0.000- 0.978 T classification (T3/T4 vs. T1/T2) 1.873 0.878–3.993 0.104 2.354 1.037–5.342 0.041 Primary tumor treatment (Surgery vs. CCRT) 1.196 0.361–3.963 0.770 0.588 0.120–2.884 0.513 Neck treatment (Neck dissection vs. CCRT) 1.522 0.648–3.573 0.335 1.284 0.270–6.115 0.754 Induction chemotherapy (Yes vs. No) 0.508 0.193–1.335 0.169 0.457 0.098–2.132 0.319 P16 (Positive vs. Negative) 0.130 0.028–0.606 0.002 0.082 0.012–0.566 0.011 DMFS Gender (female vs. male) 0.047 0.000–785.047 0.538 0.000 0.000- 0.979 T classification (T3/T4 vs. T1/T2) 2.389 1.080–5.287 0.032 3.307 1.289–7.157 0.011 Primary tumor treatment (Surgery vs. CCRT) 1.710 0.513–5.697 0.382 0.706 0.150–3.322 0.660 Neck treatment (Neck dissection vs. CCRT) 1.940 0.819–4.597 0.132 1.962 0.503–7.660 0.322 Induction chemotherapy (Yes vs. No) 0.572 0.216–1.515 0.261 0.643 0.167–2.485 0.522 P16 (Positive vs. Negative) 0.157 0.031–0.737 0.007 0.131 0.020–0.844 0.032 https://doi.org/10.1371/journal.pone.0225962.t002 9.256; p = 0.283). Advanced T3/T4 stage was associated with worse OS (HR: 3.337; 95% CI: 1.312–8.488; p = 0.011). The 2-year OS rate for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) was 57.4% and 37.5%, respectively (Fig 1A). For LRFS, no difference was noted in terms of primary tumor treatment (surgery vs. CCRT) (HR: 0.446; 95% CI: 0.079–2.536; p = 0.363) or neck treatment (neck dissection vs. CCRT) (HR: 2.689; 95% CI: 0.448–16.145; p = 0.280). The 2-year LRFS rate for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) was 53.9% and 37.5%, respectively (Fig 1B). For RRFS, no difference was noted in terms of neck treatment (neck dissection vs. CCRT) (HR: 1.284; 95% CI: 0.270–6.115; p = 0.754). The 2-year RRFS for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) were 50.6% and 37.5%, respectively (Fig 1C). For DMFS, no difference was noted in terms of primary tumor treatment (surgery vs. CCRT) (HR: 0.706; 95% CI: 0.150–3.322; p = 0.660) or neck treatment (neck dissection vs. CCRT) (HR: 1.962, 95% CI: 0.503–7.660; p = 0.322). Advanced T3/T4 stage was associated with worse DMFS (HR: 3.307; 95% CI: 1.289–7.157; p = 0.011). The 2-year DMFS rate for definitive CCRT to the neck (CCRT group) and curative neck dissection followed by adjuvant CCRT (neck dissection group) was 56.3% PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 5 / 12 Outcome of N3 head and neck cancer Fig 1. Survival curve. (a) OS, (b) LRFS, (c) RRFS, and (d) DMFS for oropharyngeal cancer patients. (e) OS, (f) LRFS, (g) RRFS, (h) and DMFS for nonoropharyngeal patients. https://doi.org/10.1371/journal.pone.0225962.g001 and 37.5%, respectively (Fig 1D). Among 49 oropharyngeal cancer patients, 20 patients had adequate remaining pathology samples for IHC stain. Nine patients (45%) were p16+ and 11 patients (55%) were p16-. For 44 non-oropharyngeal cancers, 35 patients were tested for p16. However, only 5 patients (14%) were p16+. Significant differences in the 2-year OS (77.8% vs 45.5%, p = 0.009, respectively), 2-year LRFS (77.8% vs 45.5%, p = 0.009, respectively), 2-year RRFS (77.8% vs 27.3%, p = 0.002, respectively), and 2-year DMFS (77.8% vs 36.4%, p = 0.007, respectively) were observed between patients with HPV+ and HPV− oropharyngeal cancer. For nonoropharyngeal cancer patients, univariate and multivariate analyses for survival are summarized in Table 3. With regard to primary tumor treatment, (surgery vs. CCRT) no dif- ference was noted in terms of OS (HR: 0.940; 95% CI: 0.247–3.571; p = 0.927), LRFS (HR: 0.780; 95% CI: 0.227–2.675; p = 0.693), RRFS (HR: 1.033; 95% CI: 0.281–3.802; p = 0.961) or DMFS (HR: 0.665; 95% CI: 0.207–2.135; p = 0.493). Neck treatment (neck dissection vs. CCRT) did not affect OS (HR: 0.444; 95% CI: 0.127–1.549; p = 0.203), LRFS (HR: 0.473; 95% PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 6 / 12 Outcome of N3 head and neck cancer Table 3. Univariate and multivariate analysis for survival in non-oropharyngeal cancer patients. Univariate Multivariate Characteristics HR 95% CI P value HR 95% CI P value OS Gender (female vs. male) 0.989 0.234–4.177 0.988 0.621 9,142–2.725 0.528 T classification (T3/T4 vs. T1/T2) 2.466 0.853–7.132 0.096 2.899 0.862–9.746 0.085 Primary tumor treatment (Surgery vs. CCRT) 1.139 0.548–2.368 0.727 0.940 0.247–3.571 0.927 Neck treatment (Neck dissection vs. CCRT) 0.714 0.346–1.475 0.363 0.444 0.127–1.549 0.203 Induction chemotherapy (Yes vs. No) 0.602 0.286–1.269 0.182 0.306 0.100–0.932 0.037 LRFS Gender (female vs. male) 0.816 0.194–3.429 0.781 0.491 0.112–2.140 0.343 T classification (T3/T4 vs. T1/T2) 2.218 0.844–5.828 0.106 2.675 0.869–8.227 0.086 Primary tumor treatment (Surgery vs. CCRT) 0.950 0.466–1.933 0.087 0.780 0.227–2.675 0.693 Neck treatment (Neck dissection vs. CCRT) 0.638 0.316–1.289 0.210 0.473 0.149–1.503 0.204 Induction chemotherapy (Yes vs. No) 0.710 0.341–1.475 0.358 0.351 0.122–1.004 0.051 RRFS Gender (female vs. male) 0.958 0.227–4.037 0.954 0.626 0.143–2.751 0.535 T classification (T3/T4 vs. T1/T2) 1.745 0.662–4.603 0.261 1.927 0.640–5.085 0.244 Primary tumor treatment (Surgery vs. CCRT) 1.022 0.497–2.101 0.954 1.033 0.281–3.802 0.961 Neck treatment (Neck dissection vs. CCRT) 0.660 0.324–1.342 0.251 0.364 0.101–1.274 0.114 Induction chemotherapy (Yes vs. No) 0.602 0.288–1.259 0.178 0.307 0.103–0.915 0.034 DMFS Gender (female vs. male) 0.814 0.194–3.415 0.778 0.582 0.134–2.525 0.470 T classification (T3/T4 vs. T1/T2) 1.700 0.699–4.136 0.242 2.044 0.735–5.687 0.171 Primary tumor treatment (Surgery vs. CCRT) 0.896 0.447–1.797 0.758 0.665 0.207–2.135 0.493 Neck treatment (Neck dissection vs. CCRT) 0.758 0.383–1.500 0.426 0.717 0.248–2.077 0.540 Induction chemotherapy (Yes vs. No) 0.769 0.372–1.591 0.479 0.440 0.155–1.245 0.122 https://doi.org/10.1371/journal.pone.0225962.t003 CI: 0.149–1.503; p = 0.204), RRFS (HR: 0.364; 95% CI: 0.101–1.274; p = 0.114) or DMFS (HR: 0.717; 95% CI: 0.248–2.077; p = 0.540). The 2-year survival outcome in terms of OS, LRFS, RRFS, and DMFS for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) were 37.0% and 45.6% (Fig 1E), 27.8% and 45.2% (Fig 1F), 33.3% and 45.6% (Fig 1G), and 33.3% and 32.8% (Fig 1H), respectively. Among the 93 patients, 32 (34.4%) had disease-free recurrence at last follow-up. The first failure sites are summarized in Fig 2. In total, 30 out of the 61 patients experiencing recurrence had regional recurrence, whereas 27 had distant metastasis. Local recurrence occurred in 22 of the 61 patients. Among our patients, acute grade� 3 toxicities were observed in 82% of CCRT group and in 85% of neck dissection group. Late grade� 3 toxicities were 9% and 10% for CCRT and neck dissection, respectively. Discussion Studies focusing on the management of N3 head and neck patients are limited. The results of previous and current studies are summarized in Table 4. Adams et al.[8] reported outcomes for 33 N3 head and neck cancer patients treated with definitive CCRT and PET-guided neck management. Their patient cohort consisted of 25 (76%) cases of oropharyngeal; 4 (12%), nasopharyngeal; 1 (3%), laryngeal; and 1 (3%) hypopharyngeal malignancy. Overall PET CR rate was 64.5%, and subsequent nodal failure rate after PET CR was 10% (2 patients). The PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 7 / 12 Outcome of N3 head and neck cancer Fig 2. Pattern of first failure sites with numbers of patients. LR, local recurrence; RR, regional recurrence; DM, distant metastasis. https://doi.org/10.1371/journal.pone.0225962.g002 3-year nodal control rate and metastasis-free survival rate for all patients were 68.6% and 59.5%, respectively. For the patients with oropharyngeal cancer, the 3-year nodal control rate and metastasis-free survival were 64.8% and 59.1%, respectively. Karakaya et al. [10] reported on 40 N3 head and neck cancer patients treated with definitive CCRT. Of them, 24 (60%), 4 (10%), 6 (15%), 2 (5%), and 4 (10%) had oropharyngeal, laryngeal, hypopharyngeal, oral cavity, and unknown primary cancer, respectively. Twenty-seven (67.5%) patients achieved CR with subsequent nodal failure rate of 3/27 (11%). The 3-year overall survival and regional control in the whole cohort were 51.4% and 69.3%, respectively. Igidbashian et al.[9] reported on 70 N3 patients treated with definitive CCRT with neck dissec- tion only for those with incomplete response. Oropharyngeal patients comprised 56 (80.0%) of the cohort. The CR rate was 26/70 (37.1%), and the 2-year regional relapse-free survival was 87.8% for patients who achieved clinical CR. Our data showed that CR rate in the neck in patients with oropharyngeal and nonoropharyngeal cancer were 31/41 (75.6%) and 12/18 (66.7%), respectively. A total of 7/31 (22.6%) patients with oropharyngeal cancer and 3/12 (25%) patients with nonoropharyngeal cancer who achieved CR in the neck after definitive CCRT had subsequent regional recurrence. In our definitive CCRT to the neck cohort, the overall 2-year RRFS rate was 45.2%, while it was 50.6% and 27.8% in patients with oropharyn- geal and nonoropharyngeal cancer, respectively. Meanwhile, Zenga et al.[11] reported the outcomes of upfront neck dissection for 39 patients with N3 human papillomavirus (HPV)-related oropharyngeal cancers. Thirty-six (90%) underwent adjuvant therapy, with 69% of them receiving adjuvant CCRT. Isolated regional disease recurrence or persistence was found in two (5%) patients. Five-year OS, dis- ease-specific survival, and disease-free survival were 87%, 89%, and 84%, respectively. In our study, oropharyngeal cancer patients who received upfront neck dissection followed by adju- vant CCRT had 2-year OS and RRFS of 37.5% and 37.5%, respectively. The result probably reflects the effects of the combination of HPV-positive and HPV-negative oropharyngeal can- cer in our cohort. In our study, specifically for HPV (+) patients, 5yr OS for CCRT and neck dissection group were 80% and 68%, respectively. In the current study, the 2-year survival PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 8 / 12 Outcome of N3 head and neck cancer PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 9 / 12 Table 4. Summary of outcomes for N3 neck cancer patients in the literature. Study Igidbashian Karakaya et al. Adams et al. Zenga et al. Argiris Corry et al. Jung et al. [14] Ko et al. [15] Smyth et al. Jones et al. [17] Witek et al. Chen et al. et al. [9] [10] [8] [11] et al. [12] [13] [16] [18] (current study) Study period 1998–2006 2004–2010 2005–2012 1998–2013 1991–2000 1998–2002 2000–2010 2004–2012 1989–2009 1975–2005 1991–2015 2002–2015 No. of 70 40 33 39 25 total 102 total N2/ 121 N2; 70 N3 4867 100 275 (119 36 93 patients N2/N3 N3 (N3: 20 patients with (N3: 6 patients) radical patients) treatment) Primary 56 (80%) 24 (60%) 25 (76%) 16 (41%) Unknown 3 (3%) oral 30 (42.9%) 425 (8.7%) oral 53% 16 (13%) 67% 49 (52.7%) tumor site oropharynx, 8 oropharynx, 4 oropharynx, 4 base of primary cavity, 78 oropharynx, 18 cavity, 3275 oropharynx, 7% larynx, 27 oropharynx, oropharynx, 26 (11.4%) (10%) larynx, 2 (12%) tongue, 22 (76%) (25.7%) (67.3%) larynx, 15% (23%) 11% (27.9%) unknown, 2 (2.9%), 6 (15%) nasopharynx, (56%) oropharynx, 15 hypopharynx, oropharynx, hypopharynx, hypopharynx, Unknown, hypopharynx, 14 (2.9%) larynx, hypopharynx, 2 1 (3%) larynx, tonsil, and 1 (15%) 11 (15.7%) 538 (11.1%) 3% 30 (25%) 11% (15%) oral cavity, 2 (2.9%) oral (5%) oral and 1 (3%) (3%) hypopharynx, larynx, 8 hypopharynx, nasopharynx, oropharynx, 42 hypopharynx, and 4 larynx cavity, and 2 cavity, and 4 hypopharynx unknown 6 (6%) larynx (11.4%) 629 (12.9%) 8% oral cavity, 35%) oral 8% larynx, (4.3%) (2.9%) (10%) nasopharynx, 3 larynx 4% multiple cavity and 3% oral hypopharynx unknown (4.3%) oral sites, 11% cavity cavity unknown Neck Definitive Definitive Definitive Neck Definitive Definitive Definitive Definitive Definitive 119 patients: 20 (56%) Definitive CCRT management CCRT with CCRT without CCRT with dissection CCRT in 8 CCRT without CCRT 32 CCRT 3403 CCRT 76%, neck dissection definitive without planned neck planned neck PET-guided with or (32%) planned neck (45.7%), neck (70%), neck neck dissection + adjuvant CCRT, 8 neck dissection or dissection dissection management without patients, dissection dissection in 38 dissection in in 24% therapy (22%) RT upfront neck only for those at 12 weeks adjuvant neck (54.3%) 1464 (30%) alone, 8 (22%) dissection followed with therapy dissection surgery by adjuvant incomplete in 17 (64%) therapy response patients Overall 2-year at 3-year at 51.4% 3-year at 5-year at N3 NA for N3 N3: 5-year Propensity- Oropharynx: 5yr 26.6% 5yr 30%, no Oropharynx: survival 63.0% for cCR 48.4% 87% patients: disease-free adjusted 5-year 80% for difference in 2-year at 57.4% for and 79.4% 3-year 33% survival 36.3% median surgery, 46% definitive definitive CCRT and cPR-ND survival: 54.2 for CCRT CCRT or and 37.5% for neck and (p = 0.3); Non- surgery dissection. 44.8 months oropharynx: Non-oropharynx: for surgery and 58% for 2-year at 37.0% for CCRT, surgery, 15% definitive CCRT respectively for CCRT and 45.6% for neck (P = 0.06). (p = 0.02) dissection Neck control 2-year 3-year at 69.3% 3-year nodal Isolated NA N3: 40% nodal N3: 5-year NA NA NA no difference Oropharynx: regional control rate at regional CR rate at 12 local-regional in definitive 2-year at 50.6% for relapse-free 68.6% disease weeks post control rate CCRT or definitive CCRT survival at recurrence treatment 75.5% surgery and 37.5% for neck 87.8% for cCR or dissection. patients persistence Nonoropharynx: in two (5%) 2-year at 33.3% for patients definitive CCRT and 45.6% for neck dissection Distant 2-year distant NA 3-year NA NA NA N3: 5-year DM NA NA NA no difference Oropharynx: failure disease-free metastasis-free rate 60% in definitive 2-year at 56.3% for survival at survival at CCRT or definitive CCRT 67.1 for cCR 59.5% surgery and 37.5% for neck and 92.6% for dissection. cPR-ND Nonoropharynx: 2-year at 33.3% for definitive CCRT and 32.8% for neck dissection Abbreviations: cCR, clinically complete response; cPR-ND, neck dissection after achieving cCR at the primary site and clinically partial response in the neck; NA, not available; CCRT, concurrent chemoradiotherapy https://doi.org/10.1371/journal.pone.0225962.t004 Outcome of N3 head and neck cancer outcome in terms of OS and RRFS for definitive CCRT to neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) was 45.6% and 45.6%, respectively. Smyth et al.[16] analyzed 100 head and neck N3 patients. They found that for non-oropha- ryngeal cancer, those who underwent primary surgery (n = 14) had significantly better OS than those who had primary CCRT (n = 32, P = 0.02). Our data showed no difference between neck dissection or definitive CCRT. However, Smyth et al.[16] included 4% nasopharyngeal cancer, 8.5% multi-site primary cancer and 23% unknown primary carcinoma in non-oropha- ryngeal cancer. The outcomes for nasopharyngeal cancer, multi-site primary cancer and unknown primary carcinoma differ significantly from that of pure head and neck cancer squa- mous cell carcinoma, which might explain the difference between the 2 studies. Similar to our findings, Witek et al.[18] also showed that OS was similar between patients receiving primary surgery, radiotherapy, or chemoradiotherapy (p = 0.10). Patients with p16-positive tumors exhibited improved overall (p = 0.05). The largest N3 study so far was conducted by Ko et al[15]. They performed retrospective analysis of 4867 patients in National Cancer Database (NCDB). After adjusting for age, sex, and Charlson/Deyo comorbidity score, race, insurance status, income, location, patient vol- ume of treatment facilities, tumor subsite, tumor size, T classification, HPV status and radia- tion dose/technique by propensity score, median survival was 54.2 and 44.8 months for surgery and CCRT, respectively (P = 0.06). Distant failure is a major failure pattern for N3 head and neck patients. Our data showed a 2-year distant metastasis-free survival of around 35–40%. Jung et al. also showed a high 5-year DM rate of 60%[14]. In this extreme high risk patients, the potential role of induction chemo- therapy or chemotherapy regimen intensification should be further investigated. As for treatment toxicities, review article and meta-analysis comparing neck dissection fol- lowed by adjuvant therapy and definitive CCRT to neck showed that no difference in grade� 3 toxicities for acute (80% vs. 86%) and late toxicities (8% vs. 6%). Neck fibrosis rates of around 20% were reported for both groups[19]. For tri-modality therapy, Zenga et al.[11] showed a 5% pneumonia rate, 5% admission rate during adjuvant for acute kidney injury, and 8% other side effects (surgical site infection, pharyngocutaneous fistula, sepsis related to a gas- trostomy tube complication). Witek et al.[18] showed that acute toxicities were similar between surgery and definitive CCRT. Sixty-eight percent of patients in the neck dissection (68.4% v 68.0%; p = 0.98) groups required a feeding tube for a median of 6 months (range 2–42 months versus 3–33 months; p = 0.59). Unplanned hospitalization within 6 months from diagnosis was similar between surgery and CCRT groups (27.8% versus 36.0%; p = 0.57). Our study showed that the survival outcomes in terms of OS, LRFS, RRFS, or DMFS for N3 oropharyngeal and nonoropharyngeal cancer patients treated with bimodality definitive CCRT to the neck did not differ from those treated with trimodality curative neck dissection followed by adjuvant CCRT. The present study showed that even for bulky N3 neck, bimodal- ity definitive CCRT to the neck without planned neck dissection can be the treatment of choice. However, this study has some limitations. During the study period, PET-CT was not routinely performed in our institution. Response evaluation in this study was done by both clinically local examination and MRI. Complete response was defined by undetectable primary tumor or shrinkage of neck lymph nodes to less than 1cm in short axis on T2 weighted and T1 weighted with contrast medium MRI. However, it is not unusual to detect post-treatment mass, either as fibrosis or true residual tumors. This study had a 25% ultimate regional failure rate among CR patients. Adams et al.[8] and Karakaya et al.[10] reported a 10–11% subsequent nodal failure rate after CR. No routine use of PET in our study may be one of the reasons for higher nodal failure rate for differently defined CR patients. With more widespread PET-CT PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 10 / 12 Outcome of N3 head and neck cancer implementation in head and neck cancer, a more accurate staging, target definition, and treat- ment response evaluation can be achieved[20]. This study may also have treatment modality selection bias due to its retrospective nature. Adjusted Kaplan Meier analysis was used to account for unequal balance in factors. For oropharyngeal cancer, after adjusting for gender, T classification, primary tumor treatment (Surgery vs. CCRT), induction chemotherapy (Yes vs. No) and P16 status, there were no significant differences in terms of neck treatment (neck dis- section vs. CCRT) for OS (p = 0.379), LRFS (p = 0.775), RRFS (p = 0.510) and DMFS (p = 0.989). Although adjusted Kaplan Meier analysis might handle unequal balance in factors to some extent, limited numbers in subgroups was one of the weakness. Conclusion In summary, N3 neck patients treated with definitive CCRT can achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Bimodality definitive CCRT can be the primary treatment of choice for this group of patients with poor prognosis. Cautions should be made to avoid overtreatment for this group of patients. Supporting information S1 Fig. Treatment summary. (TIF) S2 Fig. Survival curve. (a) OS, (b) LRFS, (c) RRFS, and (d) DMFS for all patients. (TIFF) Acknowledgments This study was supported by research grants NTUH 104-M2861, NTUH 105-N3224 and NTUH 106-N3609 from National Taiwan University Hospital. The authors acknowledge sta- tistical assistance provided by the Center of Statistical Consultation and Research in the Department of Medical Research, National Taiwan University Hospital. Author Contributions Conceptualization: Wan-Yu Chen, Tony Hsiang-Kuang Liang, Chun-Wei Wang. Data curation: Wan-Yu Chen, Tseng-Cheng Chen, Shih-Fan Lai, Bing-Shen Huang. Methodology: Shih-Fan Lai, Tony Hsiang-Kuang Liang. Supervision: Chun-Wei Wang. Writing – original draft: Wan-Yu Chen, Tseng-Cheng Chen. Writing – review & editing: Shih-Fan Lai, Tony Hsiang-Kuang Liang, Bing-Shen Huang, Chun-Wei Wang. References 1. Cohen E.E., Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al., Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol, 2014. 32(25): p. 2735–43. https://doi.org/10.1200/JCO.2013.54.6309 PMID: 25049329 2. Haddad R., O’Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al., Induction chemotherapy fol- lowed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemora- diotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol, 2013. 14(3): p. 257–64. https://doi.org/10.1016/S1470-2045(13)70011-1 PMID: PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 11 / 12 Outcome of N3 head and neck cancer 3. Mehanna H., Wong WL, McConkey CC, Rahman JK, Robinson M, Hartley AG, et al., PET-CT Surveil- lance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med, 2016. 374(15): p. 1444–54. https://doi.org/10.1056/NEJMoa1514493 PMID: 27007578 4. Lorch J.H., Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, et al., Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell can- cer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol, 2011. 12(2): p. 153–9. https://doi.org/10.1016/S1470-2045(10)70279-5 PMID: 21233014 5. Huang S.H., O’Sullivan B, Xu W, Zhao H, Chen DD, Ringash J, et al., Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-and-neck cancer stratified by HPV sta- tus. Int J Radiat Oncol Biol Phys, 2013. 87(5): p. 1078–85. https://doi.org/10.1016/j.ijrobp.2013.08.049 PMID: 24210079 6. Hamoir M., Ferlito A, Schmitz S, Hanin FX, Thariat J, Weynand B, et al., The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease. Oral Oncol, 2012. 48(3): p. 203–10. https://doi.org/10.1016/j.oraloncology.2011.10.015 PMID: 22104248 7. Spector M.E., Chinn SB, Bellile E, Gallagher KK, Ibrahim M, Vainshtein J, et al., Matted Nodes Predict Distant Metastasis in Advanced Stage III/IV Oropharyngeal Squamous Cell Carcinoma. Head Neck, 2016. 38(2): p. 184–90. https://doi.org/10.1002/hed.23882 PMID: 25251643 8. Adams G., Porceddu SV, Pryor DI, Panizza B, Foote M, Rowan A, et al., Outcomes after primary che- moradiotherapy for N3 (>6 cm) head and neck squamous cell carcinoma after an FDG-PET—guided neck management policy. Head Neck, 2014. 36(8): p. 1200–6. https://doi.org/10.1002/hed.23434 PMID: 23893554 9. Igidbashian L., Fortin B, Guertin L, Soulieres D, Coulombe G, Belair M, et al., Outcome with neck dis- section after chemoradiation for N3 head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys, 2010. 77(2): p. 414–20. https://doi.org/10.1016/j.ijrobp.2009.05.034 PMID: 19775825 10. 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Corry J., Peters L, Fisher R, Macann A, Jackson M, McClure B, et al., N2-N3 neck nodal control without planned neck dissection for clinical/radiologic complete responders-results of Trans Tasman Radiation Oncology Group Study 98.02. Head Neck, 2008. 30(6): p. 737–42. https://doi.org/10.1002/hed.20769 PMID: 18286488 14. Jung J.H., Roh JL, Lee JH, Kim SB, Lee SW, Choi SH, et al., Prognostic factors in patients with head and neck squamous cell carcinoma with cN3 neck disease: a retrospective case-control study. Oral Surg Oral Med Oral Pathol Oral Radiol, 2014. 117(2): p. 178–85. https://doi.org/10.1016/j.oooo.2013. 09.010 PMID: 24268799 15. Ko H.C., Chen S, Wieland AM, Yu M, Baschnagel AM, Hartig GK, et al., Clinical outcomes for patients presenting with N3 head and neck squamous cell carcinoma: Analysis of the National Cancer Data- base. Head Neck, 2017. 39(11): p. 2159–2170. https://doi.org/10.1002/hed.24881 PMID: 28737019 16. Smyth J.K., Deal AM, Huang B, Weissler M, Zanation A, Shores C. Outcomes of head and neck squa- mous cell carcinoma patients with N3 neck disease treated primarily with chemoradiation versus surgi- cal resection. Laryngoscope, 2011. 121(9): p. 1881–7. https://doi.org/10.1002/lary.21968 PMID: 17. Jones A.S., Goodyear PW, Ghosh S, Husband D, Helliwell TR, Jones TM. Extensive neck node metas- tases (N3) in head and neck squamous carcinoma: is radical treatment warranted? Otolaryngol Head Neck Surg, 2011. 144(1): p. 29–35. https://doi.org/10.1177/0194599810390191 PMID: 21493383 18. Witek M.E., Wieland AM, Chen S, Kennedy TA, Hullett CR, Liang E, et al., Outcomes for patients with head and neck squamous cell carcinoma presenting with N3 nodal disease. Cancers Head Neck, 2017. 2. 19. Elicin O., Albrecht T, Haynes AG, Bojaxhiu B, Nisa L, Caversaccio M, et al., Outcomes in Advanced Head and Neck Cancer Treated with Up-front Neck Dissection prior to (Chemo)Radiotherapy. Otolaryngol Head Neck Surg, 2016. 154(2): p. 300–8. https://doi.org/10.1177/0194599815608370 PMID: 26450749 20. Cacicedo J., Navarro A, Del Hoyo O, Gomez-Iturriaga A, Alongi F, Medina JA, et al., Role of fluorine-18 fluorodeoxyglucose PET/CT in head and neck oncology: the point of view of the radiation oncologist. Br J Radiol, 2016. 89(1067): p. 20160217. https://doi.org/10.1259/bjr.20160217 PMID: 27416996 PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 12 / 12 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PLoS ONE Public Library of Science (PLoS) Journal

Outcome of bimodality definitive chemoradiation does not differ from that of trimodality upfront neck dissection followed by adjuvant treatment for >6 cm lymph node (N3) head and neck cancer

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Copyright: © 2019 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: This study was supported by research grants NTUH 104-M2861, NTUH 105-N3224 and NTUH 106-N3609 from National Taiwan University Hospital. Competing interests: The authors have declared that no competing interests exist.
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Abstract

from that of trimodality upfront neck dissection followed by adjuvant treatment for>6 cm lymph Currently, data regarding optimal treatment modality, response, and outcome specifically node (N3) head and neck cancer. PLoS ONE 14 for N3 head and neck cancer are limited. This study aimed to compare the treatment out- (12): e0225962. https://doi.org/10.1371/journal. comes between definitive chemoradiotherapy (CCRT) to the neck and upfront neck dissec- pone.0225962 tion followed by adjuvant CCRT. Ninety-three N3 squamous cell carcinoma head and neck Editor: Randall J. Kimple, University of Wisconsin, cancer patients were included. Primary tumor treatment was divided to definitive CCRT UNITED STATES (CCRT group) or curative surgery followed by adjuvant CCRT (surgery group). Neck treat- Received: May 15, 2019 ment was also classified into two treatment modalities: definitive CCRT to the neck (CCRT Accepted: November 16, 2019 group) or curative neck dissection followed by adjuvant CCRT (neck dissection group). Published: December 3, 2019 Overall, the 2-year overall survival (OS), local recurrence-free survival (LRFS), regional Copyright:© 2019 Chen et al. This is an open recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were 51.8%, access article distributed under the terms of the 47.3%, 45.6%, and 43.6%, respectively. In both oropharyngeal cancer and nonoropharyn- Creative Commons Attribution License, which geal cancer patients, in terms of OS, LRFS, RRFS or DMFS no difference was noted permits unrestricted use, distribution, and regarding primary tumor treatment (CCRT vs. surgery) or neck treatment (CCRT vs. neck reproduction in any medium, provided the original author and source are credited. dissection). In summary, N3 neck patients treated with definitive CCRT may achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Caution Data Availability Statement: All relevant data are within the manuscript and its Supporting should be made to avoid overtreatment for this group of patients. Information files. Funding: This study was supported by research grants NTUH 104-M2861, NTUH 105-N3224 and NTUH 106-N3609 from National Taiwan University Introduction Hospital. Currently, data regarding optimal treatment modality, response, and outcome specifically Competing interests: The authors have declared that no competing interests exist. for N3 head and neck cancer are limited. Most studies included a combination of N2 and PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 1 / 12 Outcome of N3 head and neck cancer N3 head and neck cancers, with only approximately 10–15% of N3 patients in prospective clinical trials[1–4] or retrospective studies[4, 5]. Planned neck dissection after definitive chemoradiotherapy (CCRT) can be omitted, and salvage post-RT neck dissection can be performed only in incomplete response to CCRT[3, 6]. However, some physicians choose neck dissection as primary treatment because of concerns for poor radiation response of bulky necrotic lymph nodes, anatomical change of bulky lymph nodes during radiation, and avoidance of post radiation neck dissection. For N3 head and neck cancer, there is lim- ited data regarding whether direct neck dissection or definitive CCRT to the neck should be performed. This study aimed to compare the treatment outcomes between definitive CCRT to the neck and upfront neck dissection followed by adjuvant CCRT for N3 head and neck cancer patients. Materials and methods Patients and treatments The retrospective study protocol was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH: 201707061RINB) and IRB approved that patient consent was waived. All patient data were anonymized before researchers gained access. Between 2002 and 2015, 93 N3 (>6 cm, American Joint Committee on Cancer 7th edition) squamous cell carcinoma head and neck cancer patients with no distant metastasis who received curative treatment at National Taiwan University Hospital were included in this study. Nodal dimen- sions were defined by magnetic resonance imaging (MRI). The median diameter of confluent neck LNs was 7.5 cm (range 6–10). Among the 93 patients, 76 (81.7%) received induction che- motherapy, which included the following regimens: PF (cisplatin + 5-FU), EPF (Erbitux + PF), APF (Avastin + PF), TPF (Taxotere + PF), ATPF (Avastin + TPF), MEPFL (mitomycin, epiru- bicin, cisplatin, fluorouracil, and leucovorin), intra-arterial (IA) MPA (mitomycin, cisplatin, Avastin), IA-MTPF (mitomycin, Taxotere, cisplatin, 5FU), IA-MATPF (MTPF + Avastin), or their combinations. For patients receiving induction chemotherapy, the median cycles received were 2 (range, 1–8). The overall response rate to induction chemotherapy was 68%. Curative treatments were categorized into options 1–3 as follows: 1) definitive CCRT to pri- mary tumor and neck; 2) curative surgery for primary tumor and the neck followed by adju- vant CCRT; and 3) curative neck dissection followed by definitive CCRT for primary tumor and adjuvant CCRT for the neck. The treatments were summarized in the S1 Fig. Curative sur- gery for primary tumor comprised of wide tumor excision with flap reconstruction if neces- sary. Curative neck dissection includes modified radical neck dissection for bulky neck nodes with or without contralateral neck dissection at the discretion of the treating physician. Defini- tive CCRT irradiation dose was 70 Gy in 33–35 fractions, which was delivered concurrently with weekly 40 mg/m cisplatin. Sixty-seven (72%) patients completed all therapy. The median cycle of weekly cisplatin was 6 (range, 3–7) and 70 patients (75%) received cumulative dose of concurrent weekly cisplatin greater or equal to 200 mg/m . Adjuvant RT dose was set to 60–66 Gy in 30–33 fractions. Patients were routinely assessed 3–4 months after the completion of the treatment through clinical examination, chest X-ray, and head and neck MRI. For patients who received defini- tive CCRT, neck dissection was not routinely performed. Response evaluation in this study was done by both clinically local examination and MRI. Complete response was defined by undetectable primary tumor or shrinkage of neck lymph nodes to less than 1cm in short axis on T2 weighted and T1 weighted with contrast medium MRI. Salvage neck dissection or pri- mary tumor excision was considered only if an incomplete response occurred. PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 2 / 12 Outcome of N3 head and neck cancer Immunohistochemical analysis of p16 Primary tumor sections of 4 μm thickness were deparaffinized and pretreated for antigen retrieval through autoclave heating (121˚C) in 10 mM sodium citrate buffer (pH 6.0) for 10 min. These sections were blocked for endogenous peroxidase activity with 3% H2O2 in metha- nol for 10 min and then washed in phosphate-buffered saline. Thereafter, the sections were immersed in UltraVision Protein Block (Thermo Fisher Scientific, Fremont, LA, USA) for 10 min, covered with a primary rabbit monoclonal antibody specific for p16 (clone: EP1215Y, Epitomics, Abcam Company, Burlingame, CA, USA), and incubated for 1 h at room tempera- ture. Immunoreactions were performed using the UltraVision Quanto Detection System HRP DAB (Thermo Fisher Scientific, Fremont, LA, USA). Immunohistochemical evaluation of p16 in oropharyngeal cancer specimens was based on the intensity and extent of nuclear and cyto- plasmic reactivity. Positive p16 expression was defined as strong and diffuse nuclear and cyto- plasmic staining in 70% or more of the tumor cells. Statistical analysis Comparison of proportions across groups was performed using Chi-squared test or Fisher’s exact test when number <5. Unpaired Student’s t test was used to compare parametrically dis- tributed continuous data. The following endpoints were used for assessment: overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and dis- tant metastasis-free survival (DMFS). These endpoints were measured from the day of diagno- sis. Survival curves were estimated via the Kaplan-Meier method. Univariate and multivariate analyses were performed with log-rank test and Cox regression, respectively. A two-sided p value <0.05 was considered statistically significant. Statistical analysis was performed with SPSS 19.0. Results Table 1 shows the patients characteristics. The primary tumor sites included the oropharynx (n = 49) and nonoropharynx (n = 44; 26 hypopharynx, 14 oral cavity, and 4 larynx). The median smoking pack-year is 30 (range, 0–80). Patients with oropharyngeal malignancy were associated with more T1/T2 tumors (p = 0.030). Primary tumor treatment was divided to definitive CCRT (CCRT group; treatment options 1+3) or curative surgery followed by adju- vant CCRT (surgery group; treatment option 2). The oropharyngeal group had more patients receiving definitive CCRT to primary tumor sites (p = 0.030). Neck treatment was also classi- fied into two treatment modalities: definitive CCRT to the neck (CCRT group; treatment option 1) or curative neck dissection followed by adjuvant CCRT (neck dissection group; treat- ment option 2+3). The oropharyngeal group had more patients receiving definitive CCRT to the neck (p = 0.000). In addition, patients who received curative operation to primary tumors, compared to definitive CCRT to primary tumors, were associated with more advanced T3/T4 tumors (p = 0.019), better performance status ECOG 0 (p = 0.023), and more ono-oropharyn- geal cancer (p = 0.000). At presentation, 45% of nodes were considered unresectable. Patients who received curative neck dissection, compared to definitive CCRT to neck, were associated with better performance status ECOG 0 (p = 0.015) and ono-oropharyngeal cancer (p = 0.000). In our study, neck dissection was performed in 34 patients (36.3%). Among patients who received neck dissection, 30 out of 34 patients (88%) had pathological positive ECE. Clinical ECE was observed in 80 out of 93 patients (86%) according neck MRI. In addi- tion, matted nodes (defined as three nodes abutting one another with loss of intervening fat plane) [7] prevalence rate was 62%. Patients with matted nodes had inferior DMFS (p = 0.015). PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 3 / 12 Outcome of N3 head and neck cancer Table 1. Patient characteristics. Characteristics All patients No. (%) Oropharynx No. (%) (N = 49) Non- Oropharynx No. (%) (N = 44) P value (N = 93) Gender Male 89 (95.7) 48 (98.0) 41 (93.2) Female 4 (4.3) 1 (2.0) 3 (6.8) 0.341 Age (years old) (median, range) 52 (34–78) 53 (34–78) 51.5 (35–78) 0.870 T classification T1/T2 32 (34.4) 22 (44.9) 10 (22.7) T3/T4 61 (65.6) 27 (55.1) 34 (77.3) 0.030 Primary tumor treatment CCRT 71 (76.3) 45 (91.8) 26 (59.1) Surgery 22 (23.7) 4 (8.2) 18 (40.9) 0.000 Neck treatment CCRT 59 (63.4) 41 (83.7) 18 (40.9) Neck dissection 34 (36.6) 8 (16.3) 26 (59.1) 0.000 Radiotherapy Definitive to both primary and neck (option 1) 59 (63.4) 41 (83.7) 18 (40.9) Adjuvant (option 2) 22 (23.7) 4 (8.2) 18 (40.9) Definitive to primary and adjuvant to neck (option 3) 12 (12.9) 4 (8.2) 8 (18.2) 0.000 Induction chemotherapy No 17 (18.3) 5 (10.2) 12 (27.3) Yes 76 (81.7) 44 (89.8) 32 (72.7) 0.058 P16 positive rates 55% 14% 0.005 Abbreviation: CCRT = concurrent chemoradiation https://doi.org/10.1371/journal.pone.0225962.t001 Among patients who received definitive CCRT to primary tumor sites, oropharyngeal can- cer patients had higher complete response (CR) rate than nonoropharyngeal cancer patients. A total of 37 (82.2%) and 19 (73.1%) patients had oropharyngeal and nonoropharyngeal can- cer, respectively. The number (rate) of patients who achieved partial response (PR) was 8 (17.8%) and 7 (26.9%) in those with oropharyngeal and nonoropharyngeal cancer, respectively (p = 0.000). For patients who received definitive CCRT to the neck, the number of patients with oropharyngeal and nonoropharyngeal cancer who achieved CR were 31 (75.6%) and 12 (66.7%), respectively, and those who achieved PR were 10 (24.4%) and 6 (33.3%), respectively (p = 0.000). A total of 7 (22.6%) and 3 (25%) patients with oropharyngeal cancer and nonoro- pharyngeal cancer developed regional recurrence after CR was achieved post definitive neck CCRT, respectively. The median follow-up time for all patients was 21.1 months (range, 6.9–105.4 months). The median follow-up time for censored patients or survivors was 41.8 months (range, 10.6–105.4 months; IQR: 23.4–73.2 months). Overall, the 2-year OS, LRFS, RRFS, and DMFS were 51.8%, 47.3%, 45.6%, and 43.6%, respectively. For all patients combined, neck treatment (CCRT vs. neck dissection) did not affect 2-yr OS (55.5% vs. 46.4%; p = 0.236, S2 Fig), LRFS (47.9% vs. 46.5%; p = 0.419, S2 Fig), RRFS (45.2% vs. 46.7%; p = 0.854, S2 Fig) or DMFS (49.2% vs. 34.2%; p = 0.172, S2 Fig). Univariate and multivariate analyses for survival rate in oropharyngeal cancer patients are summarized in Table 2. In oropharyngeal cancer patients, in terms of OS, no difference was noted regarding primary tumor treatment (Surgery vs. CCRT) (HR: 0.607; 95% CI: 0.123– 3.000; p = 0.540) or neck treatment (neck dissection vs. CCRT) (HR: 2.199; 95% CI: 0.522– PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 4 / 12 Outcome of N3 head and neck cancer Table 2. Univariate and multivariate analysis for survival in oropharyngeal cancer patients. Univariate Multivariate Characteristics HR 95% CI P value HR 95% CI P value OS Gender (female vs. male) 0.047 0.000–1069.263 0.550 0.000 0.000- 0.980 T classification (T3/T4 vs. T1/T2) 2.391 1.043–5.482 0.039 3.337 1.312–8.488 0.011 Primary tumor treatment (Surgery vs. CCRT) 1.689 0.504–5.664 0.391 0.607 0.123–3.000 0.540 Neck treatment (Neck dissection vs. CCRT) 2.085 0.869–5.000 0.100 2.199 0.522–9.256 0.283 Induction chemotherapy (Yes vs. No) 0.514 0.192–1.373 0.184 0.557 0.128–2.242 0.410 P16 (Positive vs. Negative) 0.165 0.035–0.772 0.009 0.177 0.031–0.917 0.041 LRFS Gender (female vs. male) 0.047 0.000–824.709 0.540 0.000 0.000- 0.980 T classification (T3/T4 vs. T1/T2) 2.131 0.969–4.689 0.060 3.054 1.242–7.509 0.015 Primary tumor treatment (Surgery vs. CCRT) 1.486 0.446–4.947 0.519 0.446 0.079–2.536 0.363 Neck treatment (Neck dissection vs. CCRT) 1.971 0.832–5.671 0.123 2.689 0.448–16.145 0.280 Induction chemotherapy (Yes vs. No) 0.448 0.169–1.186 0.106 0.629 0.124–3.185 0.575 P16 (Positive vs. Negative) 0.165 0.035–0.772 0.009 0.197 0.036–0.985 0.048 RRFS Gender (female vs. male) 0.047 0.000–563.595 0.524 0.000 0.000- 0.978 T classification (T3/T4 vs. T1/T2) 1.873 0.878–3.993 0.104 2.354 1.037–5.342 0.041 Primary tumor treatment (Surgery vs. CCRT) 1.196 0.361–3.963 0.770 0.588 0.120–2.884 0.513 Neck treatment (Neck dissection vs. CCRT) 1.522 0.648–3.573 0.335 1.284 0.270–6.115 0.754 Induction chemotherapy (Yes vs. No) 0.508 0.193–1.335 0.169 0.457 0.098–2.132 0.319 P16 (Positive vs. Negative) 0.130 0.028–0.606 0.002 0.082 0.012–0.566 0.011 DMFS Gender (female vs. male) 0.047 0.000–785.047 0.538 0.000 0.000- 0.979 T classification (T3/T4 vs. T1/T2) 2.389 1.080–5.287 0.032 3.307 1.289–7.157 0.011 Primary tumor treatment (Surgery vs. CCRT) 1.710 0.513–5.697 0.382 0.706 0.150–3.322 0.660 Neck treatment (Neck dissection vs. CCRT) 1.940 0.819–4.597 0.132 1.962 0.503–7.660 0.322 Induction chemotherapy (Yes vs. No) 0.572 0.216–1.515 0.261 0.643 0.167–2.485 0.522 P16 (Positive vs. Negative) 0.157 0.031–0.737 0.007 0.131 0.020–0.844 0.032 https://doi.org/10.1371/journal.pone.0225962.t002 9.256; p = 0.283). Advanced T3/T4 stage was associated with worse OS (HR: 3.337; 95% CI: 1.312–8.488; p = 0.011). The 2-year OS rate for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) was 57.4% and 37.5%, respectively (Fig 1A). For LRFS, no difference was noted in terms of primary tumor treatment (surgery vs. CCRT) (HR: 0.446; 95% CI: 0.079–2.536; p = 0.363) or neck treatment (neck dissection vs. CCRT) (HR: 2.689; 95% CI: 0.448–16.145; p = 0.280). The 2-year LRFS rate for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) was 53.9% and 37.5%, respectively (Fig 1B). For RRFS, no difference was noted in terms of neck treatment (neck dissection vs. CCRT) (HR: 1.284; 95% CI: 0.270–6.115; p = 0.754). The 2-year RRFS for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) were 50.6% and 37.5%, respectively (Fig 1C). For DMFS, no difference was noted in terms of primary tumor treatment (surgery vs. CCRT) (HR: 0.706; 95% CI: 0.150–3.322; p = 0.660) or neck treatment (neck dissection vs. CCRT) (HR: 1.962, 95% CI: 0.503–7.660; p = 0.322). Advanced T3/T4 stage was associated with worse DMFS (HR: 3.307; 95% CI: 1.289–7.157; p = 0.011). The 2-year DMFS rate for definitive CCRT to the neck (CCRT group) and curative neck dissection followed by adjuvant CCRT (neck dissection group) was 56.3% PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 5 / 12 Outcome of N3 head and neck cancer Fig 1. Survival curve. (a) OS, (b) LRFS, (c) RRFS, and (d) DMFS for oropharyngeal cancer patients. (e) OS, (f) LRFS, (g) RRFS, (h) and DMFS for nonoropharyngeal patients. https://doi.org/10.1371/journal.pone.0225962.g001 and 37.5%, respectively (Fig 1D). Among 49 oropharyngeal cancer patients, 20 patients had adequate remaining pathology samples for IHC stain. Nine patients (45%) were p16+ and 11 patients (55%) were p16-. For 44 non-oropharyngeal cancers, 35 patients were tested for p16. However, only 5 patients (14%) were p16+. Significant differences in the 2-year OS (77.8% vs 45.5%, p = 0.009, respectively), 2-year LRFS (77.8% vs 45.5%, p = 0.009, respectively), 2-year RRFS (77.8% vs 27.3%, p = 0.002, respectively), and 2-year DMFS (77.8% vs 36.4%, p = 0.007, respectively) were observed between patients with HPV+ and HPV− oropharyngeal cancer. For nonoropharyngeal cancer patients, univariate and multivariate analyses for survival are summarized in Table 3. With regard to primary tumor treatment, (surgery vs. CCRT) no dif- ference was noted in terms of OS (HR: 0.940; 95% CI: 0.247–3.571; p = 0.927), LRFS (HR: 0.780; 95% CI: 0.227–2.675; p = 0.693), RRFS (HR: 1.033; 95% CI: 0.281–3.802; p = 0.961) or DMFS (HR: 0.665; 95% CI: 0.207–2.135; p = 0.493). Neck treatment (neck dissection vs. CCRT) did not affect OS (HR: 0.444; 95% CI: 0.127–1.549; p = 0.203), LRFS (HR: 0.473; 95% PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 6 / 12 Outcome of N3 head and neck cancer Table 3. Univariate and multivariate analysis for survival in non-oropharyngeal cancer patients. Univariate Multivariate Characteristics HR 95% CI P value HR 95% CI P value OS Gender (female vs. male) 0.989 0.234–4.177 0.988 0.621 9,142–2.725 0.528 T classification (T3/T4 vs. T1/T2) 2.466 0.853–7.132 0.096 2.899 0.862–9.746 0.085 Primary tumor treatment (Surgery vs. CCRT) 1.139 0.548–2.368 0.727 0.940 0.247–3.571 0.927 Neck treatment (Neck dissection vs. CCRT) 0.714 0.346–1.475 0.363 0.444 0.127–1.549 0.203 Induction chemotherapy (Yes vs. No) 0.602 0.286–1.269 0.182 0.306 0.100–0.932 0.037 LRFS Gender (female vs. male) 0.816 0.194–3.429 0.781 0.491 0.112–2.140 0.343 T classification (T3/T4 vs. T1/T2) 2.218 0.844–5.828 0.106 2.675 0.869–8.227 0.086 Primary tumor treatment (Surgery vs. CCRT) 0.950 0.466–1.933 0.087 0.780 0.227–2.675 0.693 Neck treatment (Neck dissection vs. CCRT) 0.638 0.316–1.289 0.210 0.473 0.149–1.503 0.204 Induction chemotherapy (Yes vs. No) 0.710 0.341–1.475 0.358 0.351 0.122–1.004 0.051 RRFS Gender (female vs. male) 0.958 0.227–4.037 0.954 0.626 0.143–2.751 0.535 T classification (T3/T4 vs. T1/T2) 1.745 0.662–4.603 0.261 1.927 0.640–5.085 0.244 Primary tumor treatment (Surgery vs. CCRT) 1.022 0.497–2.101 0.954 1.033 0.281–3.802 0.961 Neck treatment (Neck dissection vs. CCRT) 0.660 0.324–1.342 0.251 0.364 0.101–1.274 0.114 Induction chemotherapy (Yes vs. No) 0.602 0.288–1.259 0.178 0.307 0.103–0.915 0.034 DMFS Gender (female vs. male) 0.814 0.194–3.415 0.778 0.582 0.134–2.525 0.470 T classification (T3/T4 vs. T1/T2) 1.700 0.699–4.136 0.242 2.044 0.735–5.687 0.171 Primary tumor treatment (Surgery vs. CCRT) 0.896 0.447–1.797 0.758 0.665 0.207–2.135 0.493 Neck treatment (Neck dissection vs. CCRT) 0.758 0.383–1.500 0.426 0.717 0.248–2.077 0.540 Induction chemotherapy (Yes vs. No) 0.769 0.372–1.591 0.479 0.440 0.155–1.245 0.122 https://doi.org/10.1371/journal.pone.0225962.t003 CI: 0.149–1.503; p = 0.204), RRFS (HR: 0.364; 95% CI: 0.101–1.274; p = 0.114) or DMFS (HR: 0.717; 95% CI: 0.248–2.077; p = 0.540). The 2-year survival outcome in terms of OS, LRFS, RRFS, and DMFS for definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) were 37.0% and 45.6% (Fig 1E), 27.8% and 45.2% (Fig 1F), 33.3% and 45.6% (Fig 1G), and 33.3% and 32.8% (Fig 1H), respectively. Among the 93 patients, 32 (34.4%) had disease-free recurrence at last follow-up. The first failure sites are summarized in Fig 2. In total, 30 out of the 61 patients experiencing recurrence had regional recurrence, whereas 27 had distant metastasis. Local recurrence occurred in 22 of the 61 patients. Among our patients, acute grade� 3 toxicities were observed in 82% of CCRT group and in 85% of neck dissection group. Late grade� 3 toxicities were 9% and 10% for CCRT and neck dissection, respectively. Discussion Studies focusing on the management of N3 head and neck patients are limited. The results of previous and current studies are summarized in Table 4. Adams et al.[8] reported outcomes for 33 N3 head and neck cancer patients treated with definitive CCRT and PET-guided neck management. Their patient cohort consisted of 25 (76%) cases of oropharyngeal; 4 (12%), nasopharyngeal; 1 (3%), laryngeal; and 1 (3%) hypopharyngeal malignancy. Overall PET CR rate was 64.5%, and subsequent nodal failure rate after PET CR was 10% (2 patients). The PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 7 / 12 Outcome of N3 head and neck cancer Fig 2. Pattern of first failure sites with numbers of patients. LR, local recurrence; RR, regional recurrence; DM, distant metastasis. https://doi.org/10.1371/journal.pone.0225962.g002 3-year nodal control rate and metastasis-free survival rate for all patients were 68.6% and 59.5%, respectively. For the patients with oropharyngeal cancer, the 3-year nodal control rate and metastasis-free survival were 64.8% and 59.1%, respectively. Karakaya et al. [10] reported on 40 N3 head and neck cancer patients treated with definitive CCRT. Of them, 24 (60%), 4 (10%), 6 (15%), 2 (5%), and 4 (10%) had oropharyngeal, laryngeal, hypopharyngeal, oral cavity, and unknown primary cancer, respectively. Twenty-seven (67.5%) patients achieved CR with subsequent nodal failure rate of 3/27 (11%). The 3-year overall survival and regional control in the whole cohort were 51.4% and 69.3%, respectively. Igidbashian et al.[9] reported on 70 N3 patients treated with definitive CCRT with neck dissec- tion only for those with incomplete response. Oropharyngeal patients comprised 56 (80.0%) of the cohort. The CR rate was 26/70 (37.1%), and the 2-year regional relapse-free survival was 87.8% for patients who achieved clinical CR. Our data showed that CR rate in the neck in patients with oropharyngeal and nonoropharyngeal cancer were 31/41 (75.6%) and 12/18 (66.7%), respectively. A total of 7/31 (22.6%) patients with oropharyngeal cancer and 3/12 (25%) patients with nonoropharyngeal cancer who achieved CR in the neck after definitive CCRT had subsequent regional recurrence. In our definitive CCRT to the neck cohort, the overall 2-year RRFS rate was 45.2%, while it was 50.6% and 27.8% in patients with oropharyn- geal and nonoropharyngeal cancer, respectively. Meanwhile, Zenga et al.[11] reported the outcomes of upfront neck dissection for 39 patients with N3 human papillomavirus (HPV)-related oropharyngeal cancers. Thirty-six (90%) underwent adjuvant therapy, with 69% of them receiving adjuvant CCRT. Isolated regional disease recurrence or persistence was found in two (5%) patients. Five-year OS, dis- ease-specific survival, and disease-free survival were 87%, 89%, and 84%, respectively. In our study, oropharyngeal cancer patients who received upfront neck dissection followed by adju- vant CCRT had 2-year OS and RRFS of 37.5% and 37.5%, respectively. The result probably reflects the effects of the combination of HPV-positive and HPV-negative oropharyngeal can- cer in our cohort. In our study, specifically for HPV (+) patients, 5yr OS for CCRT and neck dissection group were 80% and 68%, respectively. In the current study, the 2-year survival PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 8 / 12 Outcome of N3 head and neck cancer PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 9 / 12 Table 4. Summary of outcomes for N3 neck cancer patients in the literature. Study Igidbashian Karakaya et al. Adams et al. Zenga et al. Argiris Corry et al. Jung et al. [14] Ko et al. [15] Smyth et al. Jones et al. [17] Witek et al. Chen et al. et al. [9] [10] [8] [11] et al. [12] [13] [16] [18] (current study) Study period 1998–2006 2004–2010 2005–2012 1998–2013 1991–2000 1998–2002 2000–2010 2004–2012 1989–2009 1975–2005 1991–2015 2002–2015 No. of 70 40 33 39 25 total 102 total N2/ 121 N2; 70 N3 4867 100 275 (119 36 93 patients N2/N3 N3 (N3: 20 patients with (N3: 6 patients) radical patients) treatment) Primary 56 (80%) 24 (60%) 25 (76%) 16 (41%) Unknown 3 (3%) oral 30 (42.9%) 425 (8.7%) oral 53% 16 (13%) 67% 49 (52.7%) tumor site oropharynx, 8 oropharynx, 4 oropharynx, 4 base of primary cavity, 78 oropharynx, 18 cavity, 3275 oropharynx, 7% larynx, 27 oropharynx, oropharynx, 26 (11.4%) (10%) larynx, 2 (12%) tongue, 22 (76%) (25.7%) (67.3%) larynx, 15% (23%) 11% (27.9%) unknown, 2 (2.9%), 6 (15%) nasopharynx, (56%) oropharynx, 15 hypopharynx, oropharynx, hypopharynx, hypopharynx, Unknown, hypopharynx, 14 (2.9%) larynx, hypopharynx, 2 1 (3%) larynx, tonsil, and 1 (15%) 11 (15.7%) 538 (11.1%) 3% 30 (25%) 11% (15%) oral cavity, 2 (2.9%) oral (5%) oral and 1 (3%) (3%) hypopharynx, larynx, 8 hypopharynx, nasopharynx, oropharynx, 42 hypopharynx, and 4 larynx cavity, and 2 cavity, and 4 hypopharynx unknown 6 (6%) larynx (11.4%) 629 (12.9%) 8% oral cavity, 35%) oral 8% larynx, (4.3%) (2.9%) (10%) nasopharynx, 3 larynx 4% multiple cavity and 3% oral hypopharynx unknown (4.3%) oral sites, 11% cavity cavity unknown Neck Definitive Definitive Definitive Neck Definitive Definitive Definitive Definitive Definitive 119 patients: 20 (56%) Definitive CCRT management CCRT with CCRT without CCRT with dissection CCRT in 8 CCRT without CCRT 32 CCRT 3403 CCRT 76%, neck dissection definitive without planned neck planned neck PET-guided with or (32%) planned neck (45.7%), neck (70%), neck neck dissection + adjuvant CCRT, 8 neck dissection or dissection dissection management without patients, dissection dissection in 38 dissection in in 24% therapy (22%) RT upfront neck only for those at 12 weeks adjuvant neck (54.3%) 1464 (30%) alone, 8 (22%) dissection followed with therapy dissection surgery by adjuvant incomplete in 17 (64%) therapy response patients Overall 2-year at 3-year at 51.4% 3-year at 5-year at N3 NA for N3 N3: 5-year Propensity- Oropharynx: 5yr 26.6% 5yr 30%, no Oropharynx: survival 63.0% for cCR 48.4% 87% patients: disease-free adjusted 5-year 80% for difference in 2-year at 57.4% for and 79.4% 3-year 33% survival 36.3% median surgery, 46% definitive definitive CCRT and cPR-ND survival: 54.2 for CCRT CCRT or and 37.5% for neck and (p = 0.3); Non- surgery dissection. 44.8 months oropharynx: Non-oropharynx: for surgery and 58% for 2-year at 37.0% for CCRT, surgery, 15% definitive CCRT respectively for CCRT and 45.6% for neck (P = 0.06). (p = 0.02) dissection Neck control 2-year 3-year at 69.3% 3-year nodal Isolated NA N3: 40% nodal N3: 5-year NA NA NA no difference Oropharynx: regional control rate at regional CR rate at 12 local-regional in definitive 2-year at 50.6% for relapse-free 68.6% disease weeks post control rate CCRT or definitive CCRT survival at recurrence treatment 75.5% surgery and 37.5% for neck 87.8% for cCR or dissection. patients persistence Nonoropharynx: in two (5%) 2-year at 33.3% for patients definitive CCRT and 45.6% for neck dissection Distant 2-year distant NA 3-year NA NA NA N3: 5-year DM NA NA NA no difference Oropharynx: failure disease-free metastasis-free rate 60% in definitive 2-year at 56.3% for survival at survival at CCRT or definitive CCRT 67.1 for cCR 59.5% surgery and 37.5% for neck and 92.6% for dissection. cPR-ND Nonoropharynx: 2-year at 33.3% for definitive CCRT and 32.8% for neck dissection Abbreviations: cCR, clinically complete response; cPR-ND, neck dissection after achieving cCR at the primary site and clinically partial response in the neck; NA, not available; CCRT, concurrent chemoradiotherapy https://doi.org/10.1371/journal.pone.0225962.t004 Outcome of N3 head and neck cancer outcome in terms of OS and RRFS for definitive CCRT to neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group) was 45.6% and 45.6%, respectively. Smyth et al.[16] analyzed 100 head and neck N3 patients. They found that for non-oropha- ryngeal cancer, those who underwent primary surgery (n = 14) had significantly better OS than those who had primary CCRT (n = 32, P = 0.02). Our data showed no difference between neck dissection or definitive CCRT. However, Smyth et al.[16] included 4% nasopharyngeal cancer, 8.5% multi-site primary cancer and 23% unknown primary carcinoma in non-oropha- ryngeal cancer. The outcomes for nasopharyngeal cancer, multi-site primary cancer and unknown primary carcinoma differ significantly from that of pure head and neck cancer squa- mous cell carcinoma, which might explain the difference between the 2 studies. Similar to our findings, Witek et al.[18] also showed that OS was similar between patients receiving primary surgery, radiotherapy, or chemoradiotherapy (p = 0.10). Patients with p16-positive tumors exhibited improved overall (p = 0.05). The largest N3 study so far was conducted by Ko et al[15]. They performed retrospective analysis of 4867 patients in National Cancer Database (NCDB). After adjusting for age, sex, and Charlson/Deyo comorbidity score, race, insurance status, income, location, patient vol- ume of treatment facilities, tumor subsite, tumor size, T classification, HPV status and radia- tion dose/technique by propensity score, median survival was 54.2 and 44.8 months for surgery and CCRT, respectively (P = 0.06). Distant failure is a major failure pattern for N3 head and neck patients. Our data showed a 2-year distant metastasis-free survival of around 35–40%. Jung et al. also showed a high 5-year DM rate of 60%[14]. In this extreme high risk patients, the potential role of induction chemo- therapy or chemotherapy regimen intensification should be further investigated. As for treatment toxicities, review article and meta-analysis comparing neck dissection fol- lowed by adjuvant therapy and definitive CCRT to neck showed that no difference in grade� 3 toxicities for acute (80% vs. 86%) and late toxicities (8% vs. 6%). Neck fibrosis rates of around 20% were reported for both groups[19]. For tri-modality therapy, Zenga et al.[11] showed a 5% pneumonia rate, 5% admission rate during adjuvant for acute kidney injury, and 8% other side effects (surgical site infection, pharyngocutaneous fistula, sepsis related to a gas- trostomy tube complication). Witek et al.[18] showed that acute toxicities were similar between surgery and definitive CCRT. Sixty-eight percent of patients in the neck dissection (68.4% v 68.0%; p = 0.98) groups required a feeding tube for a median of 6 months (range 2–42 months versus 3–33 months; p = 0.59). Unplanned hospitalization within 6 months from diagnosis was similar between surgery and CCRT groups (27.8% versus 36.0%; p = 0.57). Our study showed that the survival outcomes in terms of OS, LRFS, RRFS, or DMFS for N3 oropharyngeal and nonoropharyngeal cancer patients treated with bimodality definitive CCRT to the neck did not differ from those treated with trimodality curative neck dissection followed by adjuvant CCRT. The present study showed that even for bulky N3 neck, bimodal- ity definitive CCRT to the neck without planned neck dissection can be the treatment of choice. However, this study has some limitations. During the study period, PET-CT was not routinely performed in our institution. Response evaluation in this study was done by both clinically local examination and MRI. Complete response was defined by undetectable primary tumor or shrinkage of neck lymph nodes to less than 1cm in short axis on T2 weighted and T1 weighted with contrast medium MRI. However, it is not unusual to detect post-treatment mass, either as fibrosis or true residual tumors. This study had a 25% ultimate regional failure rate among CR patients. Adams et al.[8] and Karakaya et al.[10] reported a 10–11% subsequent nodal failure rate after CR. No routine use of PET in our study may be one of the reasons for higher nodal failure rate for differently defined CR patients. With more widespread PET-CT PLOS ONE | https://doi.org/10.1371/journal.pone.0225962 December 3, 2019 10 / 12 Outcome of N3 head and neck cancer implementation in head and neck cancer, a more accurate staging, target definition, and treat- ment response evaluation can be achieved[20]. This study may also have treatment modality selection bias due to its retrospective nature. Adjusted Kaplan Meier analysis was used to account for unequal balance in factors. For oropharyngeal cancer, after adjusting for gender, T classification, primary tumor treatment (Surgery vs. CCRT), induction chemotherapy (Yes vs. No) and P16 status, there were no significant differences in terms of neck treatment (neck dis- section vs. CCRT) for OS (p = 0.379), LRFS (p = 0.775), RRFS (p = 0.510) and DMFS (p = 0.989). Although adjusted Kaplan Meier analysis might handle unequal balance in factors to some extent, limited numbers in subgroups was one of the weakness. Conclusion In summary, N3 neck patients treated with definitive CCRT can achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Bimodality definitive CCRT can be the primary treatment of choice for this group of patients with poor prognosis. Cautions should be made to avoid overtreatment for this group of patients. Supporting information S1 Fig. Treatment summary. (TIF) S2 Fig. Survival curve. (a) OS, (b) LRFS, (c) RRFS, and (d) DMFS for all patients. 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