Less is enough : outcome of bimodality definitive concurrent chemoradiation does not differ from that of trimodality upfront neck dissection followed by adjuvant treatment for > 6 cm bulky lymph node ( N 3 ) head and neck cancer

Currently, data regarding optimal treatment modality, response, and outcome specifically for N3 head and neck cancer are lacking. This study aimed to compare the treatment outcomes between definitive concurrent chemoradiotherapy (CCRT) to the neck and upfront neck dissection followed by adjuvant CCRT. 93 N3 squamous cell carcinoma head and neck cancer patients were included. Primary tumor treatment was divided to definitive CCRT (CCRT group) or curative surgery followed by adjuvant CCRT (surgery group). Neck treatment was also classified into two treatment modalities: definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group). Overall, the 2-year overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were 51.8%, 47.3%, 45.6%, and 43.6%, respectively. In both oropharyngeal cancer and nonoropharyngeal cancer patients, in terms of OS, LRFS, RRFS or DMFS no difference was noted regarding primary tumor treatment (CCRT vs. surgery) or neck treatment (CCRT vs. neck dissection). In summary, N3 neck patients treated with definitive CCRT can achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Cautions should be made to avoid overtreatment for this group of patients. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 27 March 2019 doi:10.20944/preprints201903.0249.v1


Introduction
Currently, data regarding optimal treatment modality, response, and outcome specifically for N3 head and neck cancer are lacking.Most studies included a combination of N2 and N3 head and neck cancers, with only approximately 10-15% of N3 patients in prospective clinical trials [1][2][3] or retrospective studies [4,5].Planned neck dissection after definitive concurrent 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 postradiation neck dissection.For N3 head and neck cancer, whether direct neck dissection or definitive CCRT to the neck should be performed remains unsolved.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.

Patients and treatments
The study protocol was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH: 201707061RINB).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.
After induction chemotherapy, curative treatments were categorized into options 1-3 as follows: 1) definitive CCRT to primary tumor and neck; 2) curative surgery for primary tumor and the neck followed by adjuvant CCRT; and 3) curative neck dissection followed by definitive CCRT for primary tumor and adjuvant CCRT for the neck (Figure 1).Curative surgery for primary tumor comprised of wide tumor excision with flap reconstruction if necessary.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.Definitive CCRT irradiation dose was 70 Gy in 33-35 fractions, which was delivered concurrently with weekly cisplatin or IA chemotherapy.Adjuvant RT dose was set to 60-66 Gy in 30-33 fractions.
Figure 1: Treatment for tumors with different primary sites.
Patients were routinely assessed 3-4 months after the completion of the treatment through clinical examination, chest X-ray, and head and neck magnetic resonance imaging.For patients who received definitive CCRT, neck dissection was not routinely performed.Salvage neck dissection or primary tumor excision was considered only if an incomplete response occurred.

Statistical analysis
The variables were compared using Chi-squared test, Fisher's exact test, or student's t-test.The following endpoints were used for assessment: overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS).These endpoints were measured from the day of diagnosis.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.

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 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.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, disease-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 adjuvant 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 cancer in our cohort.
In the current study, the 2-year survival 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.
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, bimodality definitive CCRT to the neck without planned neck dissection can be the treatment of choice.However, this study has some limitations.First, during the study period, PET-CT was not routinely performed in our institution.With more widespread PET-CT implementation in head and neck cancer, a more accurate staging, target definition, and treatment response evaluation can be achieved [12].Second, our cohort lacked HPV-related biomarkers.HPV-related oropharyngeal cancer has better radiation response and survival outcome [13][14][15].
Whether outcomes of definitive CCRT or upfront neck dissection for N3 neck will differ according to HPV status should be further investigated.

Conclusion
In summary, N3 neck patients treated with definitive CCRT can achieve similar outcomes to those treated with upfront 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.

Figure 3 :
Figure 3: Pattern of first failure sites with numbers of patients.LR, local recurrence;

Figure 1 :
Figure 1: Treatment for tumors with different primary sites.

Figure 3 :
Figure 3: Pattern of first failure sites with numbers of patients.LR, local recurrence;

Table 2
Univariate and multivariate analysis for survival in oropharyngeal cancer

Table 3
Univariate and multivariate analysis for survival in non-oropharyngeal cancer

Table 4
Summary of outcomes for N3 neck cancer patients in the literature