N3 (> 6 cm) squamous cell carcinoma of the head and neck: outcomes and predictive factors in 104 patients
Objective. To report outcome and predictive factors in patients with N3 (> 6 cm) nonmetastatic locally advanced head and neck squamous cell carcinoma (LAHNSCC) treated with a conservative approach or with initial surgery. Methods. 104 patients were included: 69 treated with radiotherapy (RT) chemotherapy (CT) and 35 with nodal surgery with or without primary tumour resection, which was completed in 30 patients by adjuvant RT CT. Positron-emission tomography-computed tomography (PET-CT) guided surveillance after RT CT was standard. Results. Two-year overall survival (OS) and locoregional control (LRC) were 39.4% and 37.5%, respectively. In univariate analysis, body mass index (BMI), performance status (PS), p16 status and haemoglobin value influenced OS and disease-free survival (DFS). In multivariate analysis, p16 positive status and BMI ≥ 25 remained independent prognostic factors for better OS (p = 0.023) and DFS (p = 0.002). Only under/normal weight remained an independent and adverse significant prognostic factor in multivariate analysis for regional control (RC). Patients treated with primary RT CT had slightly better 2-year OS (43.5% versus 33.3%, p = 0.31).
Conclusions. Patients with N3 LAHNSCC have poor prognosis, but long term LRC is achievable, especially in overweight patients and those with a good PS.
Two-thirds of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) present with locally advanced stage III-IV disease at diagnosis. Among these, patients with metastatic lymph nodes measuring > 6 cm have a poor prognosis with a 2-year disease-free survival (DFS) of approximately 30%, especially because of a high rate of distant metastases 1. Although it is generally appreciated that the prognosis of such patients is poor, aggressive treatment improves survival and should be considered even in patients with high tumour burden. However, the optimal treatment strategy for large neck disease remains a controversial issue 2. Chemoradiotherapy (CRT) has now been established as one of the standard of care for unresectable locally-advanced HNSCC (LAHNSCC) in multiple randomised trials 3, but outcome of patients with N3 (> 6 cm) are poorly defined as these patients represent only 10% of patients with LAHNSCC and are routinely combined with patients with smaller nodes (N1-2) in clinical trials.
In this study, we aimed to report outcomes of patients with N3 LAHNSCC treated with definitive radiotherapy (RT) and with upfront surgery to find prognostic factors in this population.
Materials and methods
All patients with histologically N3 LAHNSCC according to the 7th American Joint Committee on Cancer (AJCC) and treated with curative intent between 2005 and 2016 were retrospectively identified at our two institutions. As the TNM classification was updated in December 2016, surgical patients were restaged following the 8th version: in case of extracapsular extension, patients were classified as pN3b, while the others were classified pN3a. Patients with nasopharyngeal or salivary gland cancer were not considered. The need for informed consent was waived by the medical ethics of our institution because of the retrospective nature of the study at the time it was designed.
Treatment decisions were made at the weekly multidisciplinary team meeting. Of note, p16 status was not routinely performed at the time patients were treated and was retrospectively analysed for oropharyngeal tumours for the purpose of this study. As such, the fact that some tumours were human papillomavirus (HPV)-driven did not influence the therapeutic management.
- Surgery Surgery consisted of a unilateral or bilateral neck dissection with or without a resection of the primary tumour.
- Chemotherapy Induction CT (ICT) was considered in patients with good performance status (ECOG: 0-1). Standard ICT consisted of 2-3 cycles of PF (cisplatin (CDDP) and 5-fluorouracil (5FU) 800 mg/m2 every 3 weeks) or from 2011 TPF (docetaxel 75 mg/m2, CDDP 75 mg/m2 and 5FU, 750 mg/m2 every 3 weeks) in selective fit patients. Regarding concomitant CT, CDDP delivered every three weeks (100 mg/m2) was the standard regimen from 2011. In case of contraindications to CDDP, weekly carboplatin (area under curve 2) or cetuximab were substituted. Before 2011, patients received either a FP regimen consisted of 5-FU and CDDP at a 3 week interval.
- Radiotherapy The standard biologically equivalent dose in 2 Grays (Gy) fractions to the primary tumour and involved nodes was typically 70 Gy. Prophylactic dose to uninvolved nodes was 56 Gy in 28 fractions, although dose regimens could slightly vary at the clinician’s discretion. Postoperative delivered dose was 66 Gy in case of extracapsular extension or positive margins. Patients were irradiated using a three-dimensional (3D) conformal RT or, from 2014, Intensity Modulated Radiotherapy (IMRT).
Response assessment and follow-up
To assess therapeutic response, computed tomography (CT) was performed 3 months after treatment completion until 2008, when these imaging modalities were substituted with 18-flurodeoxyglucose (18FDG) positron emission tomography (PET)-CT. Tumour response was accordingly assessed based on the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) or the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 4.
Salvage neck dissection was considered after RT only in the case of incomplete nodal response alongside with complete response (CR) at the primary site.
Clinical follow-up consisted of physical examination every second month until 2 years after diagnosis, every four months during the third year, and every six months up to 5 years.
Isolated neck failure was defined as recurrence in the neck after completion of treatment (i.e., including neck dissection if done) or as unresectable persistent neck disease after treatment, with primary and distant disease control.
Chi-square and Fisher’s exact tests were used to compare variables between groups. Survival curves were plotted based on the Kaplan-Meier method, and compared using the log-rank test. Impact of clinical variables (gender, age, body mass index (BMI), performance status (PS), smoking habit, haemoglobin value (Hb), primary site, T stage, presence of extracapsular extension according to the 8th AJCC version for patients treated with surgery, p16 status and primary treatment modality (RT versus surgery) on overall survival (OS), regional control (RC), locoregional control (LRC) and DFS was analysed by univariate (UVA) and multivariate analysis (MVA). Statistical significance was defined as a p value of < 0.05. A subgroup analysis on patients with oropharyngeal tumours was also performed.
Patient and tumour characteristics
One hundred and four patients with N3 (> 6 cm) LAHNSCC were indentified and included in the analysis. The majority of patients were male (93.3%) and had oropharyngeal (38.5%) or hypopharyngeal (40.4%) cancer. Median age was 61.7 years (range, 40.4-85.9). There were no significant differences in baseline characteristics between patients treated with definitive radio(chemo)therapy and those treated with initial surgery, except for tumour size which was larger in patients who underwent RT (p =< 0.001; Tab. I). Median maximal lymph node diameter was 6.7 cm (range 6-15).
Two main groups of patients were identified: group 1 included patients who were not suitable for surgery (poor performance status, nodes or primary tumour unresectable) and were treated with concomitant CRT (n = 28, 40.6%), RT alone (n = 11, 15.9%), ICT followed by CRT (n = 23, 33.4%), or ICT followed by RT alone (n = 7, 10.1%). Patients in group 2 were treated by surgery, including surgery alone (n = 5, 14.3%) because of adjuvant treatment refusal (n = 1), dramatically rapid tumour progression (n = 1), postoperative complications (n = 2) or both (n = 1), surgery followed by CRT (n = 15, 42.9%) or RT alone (n = 11, 31.4%), and surgery preceded by ICT and followed by post-operative CRT (n = 4, 11.4%; Tab. II).
At the first evaluation 3 months after treatment completion, all but 2 patients could be analysed for therapeutic response. Among these, 43 had a PET and 59 had a CT to assess therapeutic response. Thirty-two patients (46.4%) and 26 (34.8%) patients in group 1 and 14 (38.9%) and 14 (38.9%) patients in group 2 achieved a CR in the primary and nodal sites, respectively. Among the 40 patients who achieved a nodal CR, 7 relapsed regionally during follow-up. Thirty-eight patients (36.5%) (25 in group 1 and 13 in group 2) achieved a CR at the primary site and the neck [including 8 carcinoma of unknown primary (CUP)], 21 (20.2%) achieved CR at the primary site only (including 5 CUP) and 35 (33.7%) did not achieve CR at either the primary site or in the neck.
Among the 21 patients who did achieve CR at the primary site but not in the neck, 5 were diagnosed with metastatic disease and therefore did not proceed to neck dissection, 8 patients were not eligible to neck dissection as the mass was deemed unresectable, and 8 had a neck dissection which showed proliferating cancer cells.
Overall survival and disease-free survival
Median follow-up of surviving patients was 49.0 months (range, 23.2-133.9). At last follow-up, 69 (66.3%) patients had died of HNSCC, 5 following treatment complications (4.8%), 10 (9.6%) of an unrelated cause (including 5 for other cancers), 4 (3.8%) were alive with disease and 16 (15.4%) were alive and free of disease.
The 2- and 5-year OS rates were 39.4% and 20.0%, respectively, while the median OS was 16.0 months (95% CI, 10.4-21.6). The 2- and 5-year DFS rates were 29.0% and 18.3% respectively, and the median DFS was 6.2 months (95% CI, 4.2-8.1).
Patients treated with primary RT ± CT had slightly better OS than those treated with primary surgery with a 5-year OS of 23.2% (95% CI 12.4-34.0) vs 13.0% (IC95%, 0.8-26.8) and a median survival of 18.2 months (IC95 9.7-26.7) vs 14.9 months (95% CI, 9.0-20.9), but this difference was not statistically significant (p = 0.308).
Locoregional and distant control
At last follow up, 74 of all patients (71.2%) exhibited treatment failure: 61 patients (58.7%) experienced neck failure, 56 (53.8%) primary site failure and 37 (35.6%) distant metastasis. Only 4 patients (3.8%) had isolated neck failure (Tab. III). In summary, 82.4%, 75.7% and 50.0% of all cases of failures involved regional relapse, local relapse and distant metastasis, respectively. The 2- and 5-year LRC rates were 37.5% (95% CI, 27.7-47.3) and 29.8% (95% CI, 19.2-40.4), respectively.
Neither RC nor LRC were influenced by the therapeutic modality (p = 0.963 and 0.857 respectively).
On UVA, BMI ≥ 25, PS 0-1, positive p16 status and Hb values ≥ 13.5 for men and ≥ 12.5 for women were found to significantly influence OS, with a median survival of 89.7 months (95% CI, 0.0-182.9) versus 9.9 months (95% CI, 7.8-12.0) in favour of patients with p16 positive oropharyngeal cancer. On MVA, p16 positive status remained independently correlated with better OS (p = 0.023; Fig. 1; Tab. IV).
Regarding DFS, the same prognostic factors for better survival were found, while only overweight/obesity remained an independent prognostic factor in MVA (p = 0.002).
The UVA for RC showed that BMI ≥ 25, PS 0-1 and haemoglobin values were statistically significant, while being overweight (p = 0.001) and having a good general state (p = 0.009) remained independent prognostic factors in MVA, with a 5-years RC of 59.5% (95% CI, 42.7-76.3) for overweight/obese patients vs 28.6% (95% CI, 15.0-42.2) for normal/underweight patients (Fig. 2).
LRC was significantly better in overweight/obese patients, in patients with PS 0-1, in those having haemoglobin values ≥ 13.5-12.5g/dl and in case of p16 positive status, but only BMI ≥ 25 remained an independent prognostic factor (55.0% vs 15.3% at 5-year (p = 0.002); supplementary Tab. I).
We also studied prognostic factors in patients treated with definitive RT. Age ≥ 62 years, BMI ≥ 25, PS 0-1, haemoglobin value and p16 positive status conferred significantly better OS. On MVA, age, PS and p16 status remained independent prognostic factors for survival. Regarding LRC, only BMI ≥ 25 remained an independent factor on MVA. Neither OS nor LRC was influenced by the administration of ICT (p =0.339 and p = 0.837, respectively).
In the subgroup analysis, among patients diagnosed with oropharyngeal cancer, we found a significant difference for patients with p16 positive tumours in terms of OS for group 1 (62.5% vs 6.3% at 5 years, p = 0.011) whereas this survival advantage was not found for patients treated with primary surgery (p = 0.363).
We found a relatively poor 5-year OS of 20% in this large cohort of patients treated for HNSCC with N3 (> 6 cm). This is consistent with previous series reporting on outcomes after CRT 2,5,6 and surgery 7. Primary surgery does not seem to influence outcomes compared to RT ± CT. As such, radiation-based conservative treatment with PET-guided surveillance does seem appropriate even in very advanced regional disease.
This is in agreement with a retrospective series of 69 patients with N3 (> 6 cm) treated with definitive RT ± CT (n = 42) or surgery (n = 27), without any significant difference in 3–year OS (48% vs 41%, respectively) 2.
Because nodes > 6 cm were deemed to be unlikely eradicated by non-surgical means alone, neck dissection after RT was historically recommended in patients with N2-N3 disease. More recently, the integration of PET-CT has improved the accuracy of response assessment in the setting of residual nodal disease thanks to its high negative predictive value 8. On the basis of data from the recent British phase III PET-NECK trial, the strategy of systematic planned neck dissection after RT is no longer justified in patients who achieve a CR on PET-CT at 3 months following RT completion 9. However, N3 (> 6 cm) patients represented only 17 of the 564 patients included in this trial, making it difficult to draw any conclusion on this subgroup of patients.
In our study, the rate of isolated neck failure (3.8%) was low. These results suggest the high negative predictive value of PET still seems to be maintained with nodes > 6 cm and that planned neck dissection is unnecessary even in patients with large nodes > 6 cm if they achieve metabolic CR. This is in agreement with other studies 8,10.
The majority of failures were locoregional in our cohort, and the rate of distant metastasis (35.6%) was the same to that found in other series 1,2,5,10-12. Indeed, these patients are at high risk of having clinically occult micrometastatic disease on presentation and this raises the question on the benefit of ICT to reduce the rate of distant metastasis. We did not find any benefit of ICT and this is in line with recent randomised trials which failed to show a survival benefit of ICT in combination with CRT 13-15. The recent phase III trial of the French GORTEC group which tested the benefit of induction TPF chemotherapy followed by RT associated with cetuximab over CRT specifically in N2b-N3 patients suggests that the rate of distant metastases is decreased by the use of ICT, but without improvement in OS (p = 0.48) 16.
Many other therapeutic strategies are currently being tested with the aim to improve outcomes in patients with LAHNSCC, such as RT dose escalation, gemcitabine-based chemoradiation 17, altered fractionation with hypoxic cells radiosensitiser (NCT01880359) and, more recently, immunotherapy in combination with RT. Indeed, immune checkpoint inhibitors have become a standard in the treatment of recurrent or metastatic HNSCC and are now being tested prospectively in the locally-advanced setting. Through immunogenic cancer cell death and effect on the tumour microenvironment and vasculature, RT may enhance the effect of immune checkpoints inhibitors 18.
The role of PS is widely known to predict response to treatment and survival 19. More surprising is the positive impact of BMI ≥ 25 kg/m2 on outcomes. Historically, studies have demonstrated that patients with low BMI have worse outcome 20, an expected finding given the poor nutritional status of underweight patients. However, those studies did not address whether overweight patients have better survival rates than normal weight patients. We found that being overweight (BMI ≥ 25) at diagnosis conferred a significantly better prognosis with a 5-years LRC of 55% versus 15% in favour of overweight patients.
This observation has already been reported in a study of 578 patients with HNSCC, showing that higher BMI was associated with drastically better survival (p < 0.001) with 5-year OS rates ranging from 33.8% in underweight to 74.8% and 76.0% in overweight and obese patients, respectively. This study also showed that overweight and obese patients had equivalent survival, and these two groups were then combined in subsequent analyses 21.
The relationship between poor survival and normal/underweight may represent underlying patient’s comorbidity, frailty, or poor baseline nutritional health. However, BMI may not be the right measure to assess body composition, as the worse prognosis seems to be seen in patients with sarcopenic obesity 22.
HPV status has now been established as a reliable prognostic biomarker for oropharyngeal cancer 23. We found that patients with HPV/p16 positive oropharyngeal cancer had better prognosis compared to patients with HPV/p16 negative tumours, with a 5-year OS of 62.5% vs 6.3% (p = 0.004). HPV positive oropharynx cancer had a significantly better OS (p = 0.011) in the RT group, specifically reflecting the higher radiosensitivity of this disease subtype 24. This contributes to the notion that HPV-positive and HPV-negative HNSCC are two distinct diseases, which may require individual treatment optimisation.
We acknowledge that this study has the limitation of its retrospective design and therefore inherent bias. A major limitation is the heterogeneity of treatment modalities and post-treatment assessments, over a long period of time during which several specialists with possibly different levels of expertise were involved. Moreover, assessment of N3 (> 6 cm) disease was sometimes difficult in case of continuity between nodes and primary tumours. This work was also performed before the revision of the TNM classification. In case of surgery, CUPs are now classified as HPV-related oropharynx cancer in case of p16 positivity, or as nasopharyngeal tumours in case of presence of Epstein-Barr virus. The two patients with resected HPV-related oropharyngeal cancer in our study would now be classified as pN2 disease, reflecting the better prognosis of these patients. Finally, although not statistically different, the two groups were not perfectly balanced in terms of tumour locations: more patients with CUP and fewer with oropharyngeal tumours were treated with initial surgery, and p16 positive tumours were also more represented in the RT group, and this may have influenced outcomes.
Patients with N3 (> 6 cm) LAHNSCC have poor prognosis, but long term LRC is achievable, especially in those with a good performance status and BMI ≥ 25, and long term survival is possible for patients with HPV-related oropharyngeal cancer.
Figures and tables
|Characteristics||Radiotherapy group||Surgery group|
|n = 69||%||n = 35||%|
|Age: years and (range)||62.1 (46.9-85.9)||63 (40.4-81.3)|
|BMI before treatment|
|18.5 -< 25||26||37.7||15||42.9|
|25 -< 30||22||31.9||5||14.3|
|Hb before CRT|
|≥ 13.5 (M) or 12.5 (F)||20||28.9||7||20|
|< 13.5 or 12.5||32||46.4||9||25.7|
|Primary tumour site|
|pN3 stage for group 2 (n = 35)|
|p16 status for OPC (n = 40)||n = 29||n = 11|
|Treatment||Radiotherapy group||Surgery group|
|n = 69||%||n = 35||%|
|30/10 + 25/10||2||3.0||0||0|
|Planned but not made*||3||4.3||-||-|
|Radiation technique (n = 96)||n = 66||n = 30|
|Status at last follow-up||Radiotherapy group||Surgery group||All|
|Progression / Site of failure||49 (71.0%)||25 (71.4%)||74 (71.7%)|
|Primary and nodal||20#||6||26|
|Primary and nodal (without distant reassessment)||3||3||6|
|Primary nodal and distant||13 *||4||17|
|Primary and distant||3 *||3||6|
|Nodal and distant||4||4||8|
|Isolated distant||2||4 *||6|
|Without failure||20 (29%)||10 (28.6%)||30 (28.3%)|
|After completion of initial treatment||10||4||14|
|After salvage ND||2||0||2|
|Death due to treatment’s complications||2||3||5|
|Death – other reasons||6||3||9|
|Variables||Univariate analysis||Multivariate analysis|
|HR||95% IC||p||HR||95% IC||p|
|Sex (male versus female)||0.70||(0.26-1.92)||0.494|
|Age (> 62 vs ≤ 62)||1.36||(0.88-2.11)||0.162|
|BMI (< 25 vs ≥ 25)||2.45||(1.43-4.18)||0.001||1.36||(0.30-6.15)||0.686|
|PS (≥ 2 vs 0-1)||3.82||(2.36-6.18)||< 0.001||2.48||(0.85-7.25)||0.095|
|Smoking (active vs none or past)||1.33||(0.84-2.12)||0.226|
|Hb (< 13.5 or 12.5)||2.21||(1.23-3.98)||0.008||0.79||(0.22 2.78)||0.714|
|Site (others vs oropharynx)||0.97||(0.62-1.52)||0.911|
|T stage (T3-4 vs T1-2)||1.22||(0.77-1.92)||0.397|
|N stage (pN3b vs pN3a)||1.95||(0.46-8.31)||0.366|
|p16 status (+ vs -)||0.26||(0.09-0.70)||0.008||0.17||(0.04-0.78)||0.023|
|Surgery vs radiotherapy||1.22||(0.78-1.92)||0.383|
|Regional control||Univariate analysis||Multivariate analysis|
|HR||95% IC||p||HR||95% IC||p|
|Sex (male vs female)||0.66||(0.20-2.09)||0.477|
|Age (> 62 vs ≤ 62)||1.15||(0.69-1.92)||0.585|
|BMI (< 25 vs ≥ 25)||2.59||(1.39-4.81)||0.003||3.93||(1.69-9.12)||0.001|
|PS (≥ 2 vs 0-1)||3.62||(2.11-6.23)||< 0.001||2.60||(1.27-5.33)||0.009|
|Smoking (active vs none or past)||1.18||(0.68-2.06)||0.549|
|Hb (< 13.5 or 12.5)||2.05||(1.03-4.05)||0.039||1.39||(0.66-2.90)||0.384|
|Site (others vs oropharynx)||0.90||(0.54-1.51)||0.701|
|T stage (T3-4 vs T1-2)||1.48||(0.86-2.55)||0.161|
|N stage (pN3b vs pN3a)||0.94||(0.21-4.11)||0.931|
|p16 status (pos vs neg)||0.37||(0.12-1.12)||0.079|
|Surgery vs radiotherapy||0.96||(0.55-1.67)||0.894|
|Locoregional control||Univariate analysis||Multivariate analysis|
|HR||95% IC||p||HR||95% IC||p|
|Sex (male vs female)||0.57||(0.18-1.83)||0.348|
|Age (> 62 vs ≤ 62)||1.17||(0.72-1.90)||0.525|
|BMI (< 25 vs ≥ 25)||2.67||(1.47-4.85)||0.001||6.87||(2.01-23.45)||0.002|
|PS (≥ 2 vs 0-1)||3.35||(2.01-5.58)||< 0.001||1.80||(0.55-5.84)||0.328|
|Smoking (active vs none or past)||1.20||(0.72-2.02)||0.486|
|Hb (< 13.5 or 12.5)||1.91||(0.12-3.57)||0.042||0.84||(0.19-3.81)||0.826|
|Site (others vs oropharynx)||0.92||(0.57-1.50)||0.741|
|T stage (T3-4 vs T1-2)||1.50||(0.90-1.51)||0.118|
|N stage (pN3b vs pN3a)||1.01||(0.23-4.40)||0.992|
|p16 status (pos vs neg)||0.30||(0.10-0.89)||0.03||0.41||(0.07-2.53)||0.337|
|Surgery vs radiotherapy||1.05||(0.62-1.76)||0.857|
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