Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for head and neck cancer 2018 (English version).

1.  Principles of diagnosis and treatment of head and neck cancer

During the diagnosis and treatment of head and neck cancer, a multidisciplinary team (MDT) is desired. This is especially important for patients with locally advanced head and neck squamous cell carcinoma. The principle of MDT should be applied throughout the treatment process. During the implementation of MDT, experts from multiple disciplines can evaluate the clinical presentation, images, pathology, and molecular biology data from the patients; and comprehensively assess the performance status, diagnosis, cancer stages/metastasis, development, and prognosis. Based on current national and international treatment standards and guidelines, as well as evidence-based medicine combined with existing treatment options, a treatment strategy tailored to an individual patient can be developed. During the treatment course, the MDT team should adjust the treatment strategy according to changes in the patient’s condition and tumor response, to maximize the survival of the patient, increase the cure rate, and improve the quality of life.

2.  Diagnosis principles of head and neck cancer

2.1  Image diagnosis ()

Head and neck cancer is one of the most common malignant tumors. Its incidence rate ranks sixth in males and the mortality rate ranks seventh in China (2). The most common pathological type is squamous cell carcinoma. With the exception of nasopharyngeal carcinoma, which is mainly caused by Epstein-Barr virus, most other head and neck squamous cell carcinomas are due to cigarette smoking and alcohol abuse (3). In recent years, the incidence of oropharyngeal cancer has significantly increased in Europe and the United States, mainly due to human papillomavirus (HPV) infection, but its exact infection rate is still unclear in China (4).

Enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans of the primary lesion are common methods for diagnosing head and neck cancer, both of which have advantages and disadvantages. CT has the advantages of simplicity, rapidity, and wide availability. On the other hand, it has the disadvantage of radiation exposure, which is not appropriate for patients with iodine allergy or severe renal insufficiency. MRI can show soft tissue with higher resolution than CT and provides a variety of imaging measurements. It is especially useful for tumors originating from the oral cavity, oropharynx, and nasopharynx, and has excellent resolution for the skull base and nerves. While, the disadvantage of MRI is that it is time-consuming and relatively expensive, and is not suitable for patients with metal implants or with claustrophobia. In addition, for the laryngeal and hypopharyngeal organs, it is easy to cause artifacts due to involuntary swallowing during MRI examination. The neck is the most common area for lymph node metastasis from head and neck cancer. Neck-enhanced CT is a standard staging method, especially during the characterization of typical features of lymph node necrosis. The lung is the most common site for distant metastasis from head and neck cancer. Chest CT is the standard staging method that also helps assess other pulmonary diseases such as chronic bronchitis.

Positron emission tomography (PET)/CT mainly uses 18F-FDG as the tracer, and has been extensively investigated for the management of head and neck cancer in recent years (5). For primary lesions, because PET/CT is commonly performed with low-dose plain CT, its resolution is not as good as that in enhanced CT and can result in false positive or false negative results. For cervical lymph node and distant metastases, some meta-analyses have shown that PET/CT had certain advantages (6,7). A prospective study showed that the combination of PET/CT with conventional staging methods changed the treatment strategy in 13.7% of patients (8). Currently, the National Comprehensive Cancer Network (NCCN) recommends PET/CT for pre-treatment examination in patients with stage III/IV cancer (9).

The diagnosis of primary head and neck cancer mainly depends on oral or endoscopic mass biopsy, whereas lymph node puncture or biopsy is helpful in cancer staging. Other countries usually advocate upper gastrointestinal endoscopy (panendoscopy) under general anesthesia for biopsies on suspicious lesions, which helps to increase the accuracy of diagnosis and the possibility of identifying a second primary cancer.

References

Lewis-Jones H, Colley S, Gibson D, et al. Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S28-31.

Pan R, Zhu M, Yu C, et al. Cancer incidence and mortality: A cohort study in China, 2008-2013. Int J Cancer 2017;141:1315-23.

Argiris A, Karamouzis MV, Raben D, et al. Head and neck cancer. Lancet 2008;371:1695-709.

Gillison ML, Chaturvedi AK, Anderson WF, et al. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol 2015;33:3235-42.

Goel R, Moore W, Sumer B, et al. Clinical practice in PET/CT for the management of head and neck squamous cell cancer. AJR Am J Roentgenol 2017;209:289-303.

Yongkui L, Jian L, Wanghan, et al. 18FDG-PET/CT for the detection of regional nodal metastasis in patients with primary head and neck cancer before treatment: a meta-analysis. Surg Oncol 2013;22:e11-6.

Gao S, Li S, Yang X, et al. 18FDG PET/CT for distant metastases in patients with recurrent head and neck cancer after definitive treatment. A meta-analysis. Oral Oncol 2014;50:163-7.

Lonneux M, Hamoir M, Reychler H, et al. Positron emission tomography with [18F]fluorodeoxyglucose improves staging and patient management in patients with head and neck squamous cell carcinoma: a multicenter prospective study. J Clin Oncol 2010;28:1190-5.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Head and Neck Cancers, Version 2, 2017.

2.2  Pathological diagnosis

The pathology of head and neck cancer is critical for identifying stages and deciding treatment strategies (1). For both biopsy and punctured specimens, it is essential to distinguish the benign lesion from the malignant tumor, and determine its histological type. If necessary, immunohistochemical staining should be applied. For surgical specimens obtained from radical resection of head and neck squamous cell carcinoma, information including tumor size, differentiation, margin, vascular invasion, peripheral nerve infiltration, bone or cartilage infiltration, site, number of lymph node metastases, and extracapsular invasion is required. For oral cancer, it is necessary to clarify the depth of tumor invasion, which is helpful in guiding the follow-up treatment strategy (2). For oropharyngeal cancer, immunohistochemical examination of p16 can be performed if possible, to determine whether it is associated with HPV infection, although current guidelines do not recommend that individualized treatment strategy be based on this test result (2).

References

Helliwell TR, Giles TE. Pathological aspects of the assessment of head and neck cancers: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S59-S65.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Head and Neck Cancers, Version 2, 2017.

2.3  Staging

Current guidelines apply the Union for International Cancer Control/American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis staging system (7th edition), due to its popularity. The 8th edition was published on January 1, 2018, but we did not use it here, as it recommends an HPV test in patients with oralpharynx cancer and requires the detection of the depth of invasion in patients with oral cancer, which are not routine tests performed in China.

3.  Treatment principles of early and locally advanced head and neck squamous cell carcinoma

3.1  Treatment of oral cancer

3.1.1  Treatment of early oral cancer ()

The main radical treatment method for early oral cancer should be surgery. Local radiation therapy is only considered for patients who do not meet the criteria for surgery. During surgery, a safe resection margin of at least 5 mm should be ensured; otherwise, treatment outcomes may be affected (2). Early oral cancer also carries a certain risk of cervical lymph node metastasis. Although a phase III randomized trial confirmed the survival benefit of preventive cervical lymph node selective clearance (zones I−III), it is still inconclusive if all patients with early oral cancer should receive cervical lymph node clearance (3). In recent years, several studies have shown that the depth of tumor invasion correlates with cervical lymph node metastasis and prognosis, which also contributes to the 8th edition of the AJCC staging system to include the depth of invasion in the T staging criteria for oral cancer (4-6). The NCCN guideline recommends ipsilateral or bilateral cervical lymph node clearance in zones I−III for patients with tumor invasion depth >4 mm (when the tumor is located at or close to the midline). For patients with invasive depths between 2 mm and 4 mm, whether to perform lymph node clearance based on the actual clinical situation is recommended by NCCN guidelines (7). Sentinel lymph node biopsy is a method to replace cervical lymph node clearance, but it has to be performed in an experienced center (8). Postoperative radiation therapy or chemoradiation therapy should be performed in patients with high risk factors suggested by postoperative pathological or histological examinations. For a small number of patients with early stage oral cancer who do not meet the criteria for surgery due to their physical conditions, radiation therapy, especially brachytherapy, is another option, but it needs to be performed in an experienced center and according to guidelines from relevant authorities (9,10).

3.1.2  Treatment of locally advanced oral cancer ()

For patients with advanced oral cancer, surgery is still a main radical treatment method. The surgical methods are the oral or mandibular lingual release and mandibular incision approaches, and include the necessary repair and reconstruction of the defects from the surgery. Cervical surgery should be performed with selective or radical clearance of the lymph nodes. For N2c or primary lesions located at or close to the midline, contralateral cervical lymph node clearance should be considered. Postoperative adjuvant radiation therapy should be performed within 6 weeks after surgery. It is recommended that patients with high risk factors (e.g., T3−4, lymph node metastasis, vascular invasion, peripheral nerve infiltration) receive postoperative radiotherapy alone. Patients with positive/incomplete resection margins or exnodal extension should receive concurrent chemoradiation therapy. Studies have shown that patients with exnodal extension and/or resection margin <1 mm under microscopic examination had a better survival outcome if they received postoperative concurrent chemoradiation therapy compared with radiation therapy alone (18). For patients with advanced oral cancer who do not meet the criteria for surgery, radiation therapy combined with cisplatin is a common treatment option. For patients who are not suitable for cisplatin or for elderly patients (>70 years old), radiation therapy alone can be given. For patients with a large unresectable tumor mass, sequential therapy with induction chemotherapy combined with radiation therapy may also be considered. The commonly used induction chemotherapy regimen is 5-fluorouracil (TPF), but randomized studies have not demonstrated superior survival outcomes compared with concurrent chemoradiation therapy (14-16).

References

Kerawala C, Roques T, Jeannon JP, et al. Oral cavity and lip cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S83-9.

Nason RW, Binahmed A, Pathak KA, et al. What is the adequate margin of surgical resection in oral cancer? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:625-9.

D’Cruz AK, Vaish R, Kapre N, et al. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. N Engl J Med 2015;373:521-9.

O’Brien CJ, Lauer CS, Fredricks S, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer--but what thickness? Head Neck 2003;25:937-45.

Huang SH, Hwang D, Lockwood G, et al. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies. Cancer 2009;115:1489-97.

International Consortium for Outcome Research (ICOR) in Head and Neck Cancer. Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study. JAMA Otolaryngol Head Neck Surg 2014;140:1138-48.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Head and Neck Cancers, Version 2, 2017.

Schilling C, Stoeckli SJ, Haerle SK, et al. Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer. Eur J Cancer 2015;51:2777-84.

Nag S, Cano ER, Demanes DJ, et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2001;50:1190-8.

Kovács G, Martinez-Monge R, Budrukkar A, et al. GEC-ESTRO ACROP recommendations for head & neck brachytherapy in squamous cell carcinomas: 1st update — Improvement by cross sectional imaging based treatment planning and stepping source technology. Radiother Oncol 2017;122:248-54.

Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949-55.

Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.

Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011;100:33-40.

Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.

Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.

Ahn MJ, D’Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on chemoradiotherapy: A literature review. Oral Oncol 2016;53:10-6.

Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-50.

3.2  Oropharyngeal cancer

3.2.1  Treatment of early oropharyngeal cancer ()

Early oropharyngeal cancer should be treated with either surgery or radiation therapy alone. Retrospective analyses have shown that the overall efficacy of these two methods is similar (2,3). The selection of management should be based on the tumor size and location, possible postoperative dysfunction, and the skills and experience of the surgeon or radiologist. It is strongly recommended that the MDT perform a comprehensive assessment of quality of life and treatment outcomes (e.g., efficacy, function maintenance, and complications) and select the most appropriate management. The surgery can be performed by an open or oral approach to remove the primary lesion. An oral approach can provide a better functional outcome. Laser microsurgery or robotic surgery through the oral approach can be selected for appropriate patients. Early oropharyngeal cancer can have occult cervical lymph node metastasis. Thus, ipsilateral selective cervical lymph node clearance is required in addition to primary lesion resection. Lymph node clearance should include the ipsilateral II−IV zones, which may have to include zone I when the cancer shows signs of forward invasions (4). If the primary lesion is located at or close to the midline, such as the soft palate, the base of the tongue, or the posterior pharyngeal wall, the contralateral clearance should be considered for obtaining accurate staging of the contralateral cervical lymph nodes. A retrospective analysis found that there was no need to perform cervical clearance in the IIb zone, when there was no invasion in the neck IIa zone before surgery. Patients with high risk factors suggested by postoperative pathological or histological examinations will require postoperative radiation therapy or chemoradiation therapy. The oral cavity, diet, and speech of patients should be assessed before radical radiation therapy. Delineation of the target volumes for radiation therapy should be based on enhanced CT, and MRI scan can be used for further reference. The target volumes for the radiation therapy commonly include the primary cancer and cervical lymph nodes at zones II−IV, as well as the Ib zone when the tumor invades forward and/or involves the anterior tonsil pillars. Prophylactic radiation of the ipsilateral cervical lymph nodes is recommended if the primary lesion is unilateral (such as tonsil). If the primary lesion is located at or close to the midline, such as the soft palate, tongue root, or posterior pharyngeal wall (midline structure invasion >1 cm), bilateral prophylactic radiation therapy should be performed. At least the three-dimensional conformal radiation therapy is used for radiotherapy, and the intensity-modulated radiation therapy (IMRT) is recommended.

3.2.2  Treatment of locally advanced oropharyngeal cancer ()

For patients with stage T1−2N1−2 oropharyngeal cancer, the outcome of surgery (usually combined with postoperative radiation therapy or chemoradiation therapy) is similar to that of chemoradiation therapy, but the latter provides functional protection. When the size of the primary tumor is too large or surgery may cause significant loss of function, concurrent chemoradiation therapy should be considered. Surgery can be performed through an oral approach or via open resection of the primary lesion, although an oral approach can provide better functional protection. Oral laser microsurgery or robotic surgery can be selected for appropriate patients. Cervical surgery should be performed with selective or radical lymph node clearance. If the N2c or primary lesion is located at or near the midline, such as the soft palate, tongue root, or posterior pharyngeal wall, the lymph node clearance at the contralateral side should be considered. Postoperative radiation therapy is required after surgery. For patients with stage T3−4 cancer, only a small number of patients with T3 may undergo surgery, and most of them should choose concurrent chemoradiation therapy to preserve functions. Postoperative adjuvant radiation therapy should be performed within 6 weeks after surgery. It is recommended that patients with high risk factors (e.g., T3−4, lymph node metastasis, vascular invasion, peripheral nerve infiltration) receive postoperative radiation therapy alone. It is also recommended that patients with positive/incomplete resection margins or exnodal extension receive concurrent chemoradiation therapy. Studies have shown that patients with exnodal extension and/or resection margin <1 mm under microscopic examination have a better survival advantage if they receive postoperative concurrent chemoradiation therapy compared with those who receive radiation therapy alone (12). For advanced oropharyngeal cancer, radiation therapy combined with cisplatin is the standard treatment method (5). For patients in whom cisplatin is not appropriate, radiation therapy combined with cetuximab can be given (6,7). Patients with advanced stage cancer who are not candidates for concurrent chemotherapy, especially elderly patients (>70 years old) who have unclear survival benefits during the same period, can receive radiation therapy alone (13). For patients with stage T4 or N2c−N3 cancer, induction chemotherapy may be considered to reduce tumor mass and also reduce the risk of distant metastasis, although randomized studies have not demonstrated its superiority to concurrent chemoradiation therapy (8-10). A commonly used induction chemotherapy regimen is TPF (10). For patients with N2−3 cancer and undergoing radical radiation therapy, if the PET/CT shows complete remission 3 months after radiation therapy, cervical lymph node clearance is not required (14). For patients with residual or local recurrence after radiation therapy/concurrent chemoradiation therapy, it is recommended that eligible patients receive salvage surgery (15).

References

Mehanna H, Evans M, Beasley M, et al. Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S90-6.

Cosmidis A, Rame JP, Dassonville O, et al. T1-T2 NO oropharyngeal cancers treated with surgery alone. A GETTEC study. Eur Arch Otorhinolaryngol 2004;261:276-81.

Mendenhall WM, Morris CG, Amdur RJ, et al. Definitive radiotherapy for tonsillar squamous cell carcinoma. Am J Clin Oncol 2006;29:290-7.

Lim YC, Koo BS, Lee JS, et al. Distributions of cervical lymph node metastases in oropharyngeal carcinoma: therapeutic implications for the N0 neck. Laryngoscope 2006;116:1148-52.

Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69-76.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8.

Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.

Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.

Ahn MJ, D’Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on chemoradiotherapy: A literature review. Oral Oncol 2016;53:10-6.

Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-50.

Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.

Mehanna H, Wong WL, McConkey CC, et al. PET/CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J Med 2016;374:1444-54.

Mehanna H, Kong A, Ahmed SK. Recurrent head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S181-90.

3.3  Treatment of laryngeal cancer

3.3.1  Treatment of early laryngeal cancer ()

Early-stage laryngeal cancer should be treated with a single method of either surgery or radiation therapy alone. A systematic review showed that the overall efficacy of the two methods was similar (2). The selection of a treatment method should be based on the tumor volume, location (for example, tumors with anterior commissure involement usually are treated with radiation therapy), possible postoperative dysfunction, and the skills and experience of the surgeon or radiologist. It is strongly recommended that the MDT perform a comprehensive assessment of the pronunciation function, quality of life, and treatment outcomes (e.g., effectiveness of treatment, function preservation, and complications) before selecting the most appropriate method. The surgery can be performed by an open or trans-oral approach to remove the primary lesion. Trans-oral surgery can provide better function preservation. Trans-oral laser microsurgery or robotic surgery can be selected if possible. Early-stage glottic laryngeal carcinoma rarely causes cervical lymph node metastasis; thus, it is not necessary to perform cervical lymph node dissection. For supraglottic laryngeal cancer, selective cervical lymph node dissection should be performed in the bilateral cervical zones II−IV. Patients with high risk factors suggested by postoperative pathological or histological examinations require postoperative radiation therapy or chemoradiation therapy.

Patients should be assessed for diet, speech, and oral cavity before the radical radiation therapy. Delineation of the target area for the radiation therapy should be based on the enhanced CT or MRI scan, which usually provide good reference. For early-stage glottic laryngeal laryngeal carcinoma, the target area for the radiation therapy generally only includes the primary tumor, and it is not necessary to perform prophylactic radiation therapy to the cervical lymph node drainage area. For supraglottic laryngeal cancer, the target area for the radiation therapy includes the primary tumor and bilateral lymph nodes in the cervical zones II−IV. Radiation therapy should be performed at least with three-dimensional dosimetry and IMRT is recommended.

3.3.2  Treatment of locally advanced laryngeal cancer ()

For patients with locally advanced laryngeal cancer, most of them, except T1−2 and some T3 lesions (please refer to the previous section for the surgical treatment), require surgical treatment including total laryngectomy, which usually should be combined with postoperative radiation therapy or chemoradiation therapy. Surgery on the neck should choose either selective or radical bilateral cervical lymph node dissection according to the sites of cervical lymph node metastasis and should include at least zones II−IV, and zone V if necessary (such as T4). Postoperative adjuvant radiation therapy should be performed within 6 weeks after the surgery. It is recommended that patients with gernal high risk factors (T3−4, lymph node metastasis, vascular invasion, peripheral nerve infiltration) receive postoperative radiation therapy alone. It is also recommended that patients with positive/incomplete resection margins or lymph node capsular invasion receive concurrent chemoradiation therapy. Studies have shown that patients with lymph node capsular invasion and/or resection margin <1 mm under microscopic examination have clear survival advantage if they receive postoperative concurrent chemoradiation therapy compared with those receiving radiation therapy alone (17). For patients with primary tumor staging of T4, surgical treatment is strongly recommended for patients who have potential for surgical resection, as radiation therapy has poor throat function preservation and efficacy in these patients. In addition, the recently published American Society of Clinical Oncology guideline recommends that total laryngectomy might provide better survival chances and quality of life in patients with extensive T3, T4 cancers or patients with severely impaired laryngeal function before the treatment (18). For other patients who desire to preserve the throat function, radiation therapy combined with cisplatin is a common treatment choice (3,4). For patients who are not candidates for cisplatin treatment, radiotherapy combined with cetuximab can be given (7,8). For patients with locally advanced cancer who are not suitable for concurrent chemotherapy, especially for elderly patients (>70 years old) who have unclear survival benefits with concurrent treatment, radiation therapy alone may be used (14). For patients with N2−3 undergoing radical radiation therapy, if the PET/CT shows complete remission 3 months after the radiation therapy, cervical lymph node dissection is not required (19). For patients with residual or local recurrence after the radiation therapy/concurrent chemoradiation therapy, it is recommended that eligible patients receive salvage surgery, usually with total laryngectomy (20).

Induction chemotherapy is another treatment strategy for preserving laryngeal functions. If patients reach complete or partial remission after chemotherapy, they could receive follow-up radiation therapy with or without concurrent cetuximab; otherwise they should receive total laryngectomy (5,6,9). The standard induction chemotherapy regimen is TPF. In addition, patients with a unresectable large tumor volume or stage T4 or N2c−N3 cancer may also consider sequential therapy with induction chemotherapy combined with follow-up radiation therapy. This approach may reduce the risk of distant metastasis while reducing tumor mass. The commonly used chemotherapy regimen is again TPF, but randomized studies have not demonstrated that survival results are superior to concurrent chemoradiation therapy (10-12).

References

Jones TM, De M, Foran B, et al. Laryngeal cancer: United Kingdom National Multidisciplinary guidelines. J Laryngol Otol 2016;130:S75-82.

Warner L, Chudasama J, Kelly CG, et al. Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer. Cochrane Database Syst Rev (in Portuguese) 2014:CD002027.

Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-8.

Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845-52.

Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498-506.

Janoray G, Pointreau Y, Garaud P, et al. Long-term results of a multicenter randomized phase III trial of induction chemotherapy with cisplatin, 5-fluorouracil, ±docetaxel for larynx preservation. J Natl Cancer Inst 2015;108:1-7.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8.

Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 2013;31:853-9.

Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.

Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.

Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949-55.

Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.

Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011;100:33-40.

Ahn MJ, D’Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on chemoradiotherapy: A literature review. Oral Oncol 2016;53:10-6.

Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-50.

Forastiere AA, Ismaila N, Lewin JS, et al. Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Oncol Pract 2018;14:123-8.

Mehanna H, Wong WL, McConkey CC, et al. PET/CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med 2016;374:1444-54.

Mehanna H, Kong A, Ahmed SK. Recurrent head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S181-90.

3.4  Treatment of hypopharyngeal cancer

3.4.1  Treatment of early hypopharyngeal cancer ()

Early-stage hypopharyngeal cancer should be treated with a single treatment method of either surgery or radiation therapy alone. Retrospective analysis has shown that the overall efficacy of these two methods is similar (2,3). The selection of a treatment method should be based on the tumor volume and location, possible postoperative dysfunction, and the skills and experience of the surgeon or radiologist. It is strongly recommended that the MDT perform a comprehensive assessment of quality of life and treatment outcomes (e.g., efficacy, function preservation, and complications) before selecting the most appropriate method. The surgery can be performed by an open or trans-oral approach to remove the primary lesion. The trans-oral approach can provide better function preservation. Trans-oral laser microsurgery or robotic surgery can be selected if possible. Early-stage hypopharyngeal cancer can have occult cervical lymph node metastasis. Thus, ipsilateral selective cervical lymph node dissection in zones II−IV is required in addition to primary lesion resection. If the primary lesion is located at or close to the midline, such as the posterior pharyngeal wall, posterior sulcus, or the inner wall of the piriform fossa, contralateral lymph nodes dissection should be considered to obtain the accurate staging of the contralateral cervical lymph nodes. Patients with high risk factors suggested by the postoperative pathological or histological examinations require postoperative radiation therapy or chemoradiation therapy. Patietns should be assed for diet, speech and oral cavity before the radical radiation therapy. Delineation of the target area for radiation therapy should be based on the enhanced CT or MRI scan that can usually provide good References. The target area for radiation therapy commonly includes the primary cancer and the cervical lymph nodes at zones II−IV. Prophylactic radiation of ipsilateral cervical lymph nodes is recommended if the primary lesion is unilateral. If the primary lesion is located at or close to the midline, such as the posterior pharyngeal wall, the posterior sulcus, or the inner wall of the piriform fossa, bilateral prophylactic radiation therapy should be performed. The radiation therapy should be performed with at least three-dimensional dosimetry and IMRT is recommended.

3.4.2  Treatment of locally advanced hypopharyngeal cancer ()

Surgical resection for most patients with locally advanced hypopharyngeal cancer should include total laryngectomy, except those with T1 or some T2 lesions (please refer to the previous section for the surgical treatment), which usually should combine with postoperative RT or concurrent chemoradiation. Selective or radical neck dissection should be performed. Bilateral neck dissection would be considered for an N2c or primary lesions located at or close to the midline, such as the posterior pharyngeal wall, the posterior sulcus, or the inner wall of the piriform fossa. Postoperative adjuvant radiotherapy should be performed within 6 weeks after surgery. It is recommended that patients with adverse features (e.g., T3−4, lymphatic metastasis, vascular embolism, perineural invasion) receive single postoperative radiotherapy, while those with positive margins and/or extranodal extension receive concurrent chemoradiation. For patients with extranodal extension and/or resection margin <1 mm under microscopic examination, studies have shown that those received chemoradiation has a better survival than those received RT alone after surgical resection (16).

For T4 primary leisions, surgical resection is strongly recommended, since radiation therapy does poor in larynx-preserving and treatment efficiency. For others desiring to preserve throat function, RT combined with cisplatin is a common choice (4-6). Cetuximab is an alternative for cisplatin in patients intolerable with cisplatin (9,10). Single radiotherapy may be used in patients with locally advanced cancer unfit for concomitant chemotherapy, especially in the elderly (>70 years old) who may not benefit from concomitant chemotherapy (5). Neck dissection is not required for N2−3 patients showing complete remission (CR) by PET/CT 3 months after radical RT (17). For patients with locoregional recurrence after the radiation therapy/concurrent chemoradiation therapy, salvage surgery is recommended if resectable (18).

Induction chemotherapy is another strategy for larynx-preserving patients. Patients reaching complete or partial remission after induction chemotherapy will receive RT with or without concurrent cetuximab; otherwise, they will receive total laryngectomy (7,8,11). TPF is the standard induction chemotherapy. In addition, patients with unresectable big tumor burden or staging T4 or N2c−N3, sequential therapy may be considered with induction chemotherapy followed by radiation therapy. This approach may reduce tumor mass and the risk of distant metastasis. The commonly used chemotherapy regimen is still TPF, although randomized studies have not demonstrated a prolonged survival compared with concurrent chemoradiation therapy (12-14).

References

Pracy P, Loughran S, Good J, et al. Hypopharyngeal cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S104-10.

Martin A, Jäckel MC, Christiansen H, et al. Organ preserving transoral laser microsurgery for cancer of the hypopharynx. Laryngoscope 2008;118:398-402.

Rabbani A, Amdur RJ, Mancuso AA, et al. Definitive radiotherapy for T1-T2 squamous cell carcinoma of pyriform sinus. Int J Radiat Oncol Biol Phys 2008;72:351-5.

Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949-55.

Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.

Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011;100:33-40.

Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498-506.

Janoray G, Pointreau Y, Garaud P, et al. Long-term results of a multicenter randomized phase III trial of induction chemotherapy with cisplatin, 5-fluorouracil, ± docetaxel for larynx preservation. J Natl Cancer Inst 2015;108:1-7.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8.

Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 2013;31:853-9.

Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.

Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-9.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.

Ahn MJ, D’Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on chemoradiotherapy: A literature review. Oral Oncol 2016;53:10-6.

Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-50.

Mehanna H, Wong WL, McConkey CC, et al. PET/CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med 2016;374:1444-54.

Mehanna H, Kong A, Ahmed SK. Recurrent head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S181-90.

4.  Treatment of recurrent or metastatic squamous cell carcinoma of head and neck ()

Patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) may receive locoregional treatment for a small part, such as surgery or re-irradiation. Most of them relied on systemic therapy [performance status (PS) 0−1] or appropriate supportive treatments (PS≥2), similar to the management for metastatic patients. Cisplatin combined with 5-fluorourcacil (5-FU) or paclitaxel is a commonly used first-line chemotherapy strategy. Carboplatin will be an alternative option for patients not amenable to cisplatin. The ECOG 1395 study indicated that cisplatin combined with 5-FU or paclitaxel had similar efficacies, with the former having a higher risk for oral mucositis and the latter having a higher incidence of peripheral neurotoxicity (2). Epidermal growth factor receptor (EGFR) is an important prognostic factor and therapeutic target in SCCHN (12). EXTREME, a prospective phase III randomized study, demonstrated that the addition of cetuximab to the combination of a platin and 5-FU had significantly prolonged overall survival and improved patients’ quality of life (4,13). For patients unable to tolerate 5-FU as the first-line treatment, a combination of cisplatin, docetaxel, and cetuximab may be considered (3). Cisplatin plus cetuximab is a reasonable chioce for patients unbearable combination chemotherapy (5,6). For patients who cannot tolerate platinum agents (such as patients with advanced age), paclitaxel monotherapy combined with cetuximab is a reasonable option (7).

Thus far, there was no standard treatment regimen in China for patients with recurrent or metastatic SCCHN progressing after first line treatment, while methotrexate is commonly used in other countries (8). For these patients treated without taxane in their first-line therapy, paclitaxel or docetaxel may have certain salvage effects as second-line treatment (9,10). Cetuximab is also appropriate for patients who have not been exposed to this agent or have a poor PS score (11). In recent years, immunological checkpoint inhibitors, such as anti-programmed cell death protein 1 (PD-1) inhibitors, have been developed rapidly in advanced SCCHN. In 2016, the US Food and Drug Administration (FDA) consecutively approved pemrolizumab and nivolumab as the salvage treatment for recurrent or metastatic SCCHN. In a prospective phase III randomized controlled trial CheckMate-141, when compared with the control, nivolumab significantly prolonged the median overall survival time and improved the quality of life of patients progressing within 6 months after treatment with platinum (14,15). To date, pemizumab and nivolumab have not gone on the market in China. Thus, clinical trials containing anti-PD-1/programmed death ligand 1 (PD-L1) antibodies may be benefiting as second-line therapy after failure of first-line platinum-based chemotherapy.

References

Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10:1245-51.

Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23:3562-7.

Guigay J, Fayette J, Dillies AF, et al. Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study. Ann Oncol 2015;26:1941-7.

Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.

Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646-54.

Bossi P, Miceli R, Locati LD, et al. A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2017;28:2820-6.

Hitt R, Irigoyen A, Cortes-Funes H, et al. Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol 2012;23:1016-22.

Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27:1864-71.

Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol 2013;31:1405-14.

Soulières D, Faivre S, Mesía R, et al. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol 2017;18:323-35.

Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171-7.

Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 2006;24:2666-72.

Mesía R, Rivera F, Kawecki A, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010;21:1967-73.

Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-67.

Harrington KJ, Ferris RL, Blumenschein G Jr, et al. Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol 2017;18:1104-15.

5.  Follow-up

Post-treatment follow-up in head and neck cancer is very important for the purpose of evaluating the therapeutic effects, detecting early recurrent lesions, identifying second primary tumor, monitoring and managing treatment-related complications, and promoting functional rehabilitation (1). The recommended follow-up includes physical examination and endoscopy evaluation for the primary lesions. Futher reimaging is recommended for areas inaccessible to clinical examination. If there are signs or symptoms indicating tumor recurrence, PET/CT examination should be considered (2). For patients undergoing radical treatment, especially those receiving radiation therapy, tumor assessment should be conducted 3 months after treatment. For those staging with N2−3, PET/CT should be performed 3 months post treatment to determine whether neck dissection is required (3). About 3%−5% patients will develop a second primary tumor on account of the high proportion of patients with smoking/alcohol history. Thus, examination of the entire upper digestive tract was required during follow-up (4). Chest CT is recommonded for patients with smoking history to detect early stage lung cancer (5). For patients undergoing neck radiation therapy, thyroid function should be regularly evaluated to prevent hypothyroidism and regular dental function examinations should be conducted as well. For head and neck cancer, both surgery or radiation therapy may damage the important physiological functions of the head and neck organs. It is recommended that regular functional assessments of pain, language, hearing, swallowing, and nutrition, as well as active participation in the rehabilitation be provided to patients if possible.

References

Simo R, Homer J, Clarke P, et al. Follow-up after treatment for head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S208-11.

Sheikhbahaei S, Taghipour M, Ahmad R, et al. Diagnostic accuracy of follow-up FDG PET or PET/CT in patients with head and neck cancer after definitive treatment: A systematic review and meta-analysis. AJR Am J Roentgenol 2015;205:629-39.

Mehanna H, Wong WL, McConkey CC, et al. PET/CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med 2016;374:1444-54.

Argiris A, Karamouzis MV, Raben D, et al. Head and neck cancer. Lancet 2008;371:1695-709.

National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.

Working group members

Consultant: Pingzhang Tang

Group leader: Ye Guo

Associate group leader: Chaosu Hu, Zhengang Xu, Chenping Zhang, Liang Zhou

Group members (listed alphabetically by last name) (

Jianhui Ding　 Shanghai Cancer Center, Fudan University

Ye Guo* 　 Shanghai East Hospital, Tongji University

Xiaohui He　 Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Chaosu Hu　 Shanghai Cancer Center, Fudan University

Qinghai Ji　 Shanghai Cancer Center, Fudan University

Jiang Li　 The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine

Zhiming Li　 Sun Yat-sen University Cancer Center

Yan Sun　 Peking University Cancer Hospital & Institue

Lei Tao* 　 Eye and ENT Hospital, Fudan University

Shengzi Wang　 Eye and ENT Hospital, Fudan University

Yunfei Xia　 Sun Yat-sen University Cancer Center

Zhengang Xu　 Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Ankui Yang　 Sun Yat-sen University Cancer Center

Junlin Yi　 Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Aimin Yu　 Jiangsu Subei People’s Hospital

Bin Zhang　 Peking University Cancer Hospital & Institue

Chenping Zhang　 The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine

Laiping Zhong　 The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine

Jundong Zhou　 Suzhou Municipal Hospital, Nanjing Medical University

Liang Zhou　 Eye and ENT Hospital, Fudan University

Guopei Zhu* 　 The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine

1

Image diagnosis

Content	Level I expert recommendation	Level II expert recommendation
CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.
Diagnosis	Primary lesion enhanced CT Primary lesion enhanced MRI Neck enhanced CT	PET/CT
Image staging (1)	Primary lesion enhanced CT Primary lesion enhanced MRI Neck enhanced CT Chest enhanced or plain CT Abdominal ultrasound	PET/CT
Technique to obtain tissue or cytology analysis	Oral or endoscopic mass biopsy Cervical lymph node puncture or biopsy	Endoscopic examination and biopsy under general anesthesia

2

Treatment of early oral cancer

Staging	Patient classification	Level I expert recommendation	Level II expert recommendation
T1−2N0	Patients who meet criteria for surgery	Surgery (1) (class 2A evidence)	—
	Patients who do not meet criteria for surgery	Radiation therapy alone (1) (class 2A evidence)	—

3

Treatment of locally advanced oral cancer

Staging	Patient classification 1	Patient classification 2	Level I expert recommendation	Level II expert recommendation
Patients not suitable for surgery: poor physical condition, reject opreration for various reasons, or heavy tumor burden. Patients not appropriate for cisplatin treatment: age >70 years, performance status (PS) >2, loss of hearing, renal dysfunction (creatinine clearance <50 mL/min), or > level 1 neuropathy (17).
T1−2N + T3−4 with different N	Patients who meet criteria for surgery	—	Surgery (1) (class 2A evidence)	—
	Patients who do not meet criteria for surgery	Appropriate for cisplatin treatment	Radiation therapy + cisplatin (11-13) (class 1A evidence)	Induction chemotherapy → radiation therapy alone (14-16) (class 1B evidence)
		Not appropriate for cisplatin treatment	Radiation therapy alone (1) (class 2A evidence)	—

4

Treatment of early oropharyngeal cancer

Staging	Patient classification	Level I expert recommendation	Level II expert recommendation
T1−2N0	Patients who meet criteria for surgery	Surgery (1) (class 2A evidence) Radiation therapy alone (1) (class 2A evidence)	—
	Patients who do not meet criteria for surgery	Radiation therapy alone (1) (class 2A evidence)	—

5

Treatment of locally advanced oropharyngeal cancer

Staging	Patient classification 1	Patient classification 2	Level I expert recommendation	Level II expert recommendation
Patients not suitable for surgery: poor physical condition, reject opreration for various reasons, or heavy tumor burden. Patients not appropriate for cisplatin treatment: age >70 years, performance status (PS) >2, loss of hearing, renal dysfunction (creatinine clearance <50 mL/min), or > level 1 neuropathy ( 11).
T1−2N1−2	Patients who meet criteria for surgery	Appropriate for cisplatin treatment	Surgery (1) (class 2A evidence) Radiation therapy + cisplatin (5) (class 1A evidence)	Radiation therapy + cetuximab (6,7) (class 1B evidence)
		Not appropriate for cisplatin treatment	Surgery (1) (class 2A evidence)	Radiation therapy + cetuximab (6,7) (class 1B evidence) Radiation therapy alone (1) (class 2A evidence)
	Patients who do not meet criteria for surgery	Appropriate for cisplatin treatment	Radiation therapy + cisplatin (5) (class 1A evidence)	Radiation therapy + cetuximab (6,7) (class 1B evidence)
		Not appropriate for cisplatin treatment	Radiation therapy alone (1) (class 2A evidence)	Radiation therapy + cetuximab (6,7) (class 1B evidence)
T3−4N0−3/ T1−2N3	—	Appropriate for cisplatin treatment	Radiation therapy + cisplatin (5) (class 1A evidence) Induction chemotherapy → radiation therapy alone (8-10) (class 1B evidence)	Radiation therapy + cetuximab (6,7) (class 1B evidence)
	—	Not appropriate for cisplatin treatment	Radiation therapy alone (1) (class 2A evidence)	Radiation therapy + cetuximab (6,7) (class 1B evidence)

6

Treatment of early laryngeal cancer

Staging	Patient classification	Level I expert recommendation	Level II expert recommendation
T1−2N0	Patients suitable for surgery	Surgery (1) (class 2A evidence) Radiation therapy alone (1) (class 2A evidence)	—
	Patients not suitable for surgery	Radiation therapy alone (1) (class 2A evidence)	—

7

Treatment of locally advanced laryngeal cancer

Staging	Patient classification 1	Patient classification 2	Level I expert recommendation	Level II expert recommendation
Patients not suitable for surgery: poor physical condition, reject opreration for various reasons, or heavy tumor burden. Patients not appropriate for cisplatin treatment: age >70 years, performance status (PS) >2, loss of hearing, renal dysfunction (creatinine clearance <50 mL/min), or > level 1 neuropathy ( 16).
T1−2N1−3/ T3 any N	Patients suitable for surgery	Patients suitable for cisplatin treatment	Surgery (1) (class 2A evidence) Radiation therapy + cisplatin (3,4) (class 1A evidence) Induction chemotherapy → radiation therapy alone (5,6) (class 1A evidence)	Radiation therapy + cetuximab (7,8) (class 1B evidence) Induction chemotherapy → radiation therapy + cetuximab (9) (class 2A evidence)
		Patients not suitable for cisplatin treatment	Surgery (1) (class 2A evidence)	Radiation therapy + cetuximab (7,8) (class 1B evidence) Radiation therapy alone (1) (class 2A evidence)
	Patients not suitable for surgery	Patients suitable for cisplatin treatment	Radiation therapy + cisplatin (3,4) (class 1A evidence) Induction chemotherapy → radiation therapy alone (10-12) (class 1B evidence)	Radiation therapy + cetuximab (7,8) (class 1B evidence)
		Patients not suitable for cisplatin treatment	Radiation therapy alone (1) (class 2A evidence)	Radiation therapy + cetuximab (7,8) (class 1B evidence)
T4 with different N	Patients suitable for surgery	—	Surgery (1) (class 2A evidence)	—
	Patients not suitable for surgery	Patients suitable for cisplatin treatment	Radiation therapy + cisplatin (13-15) (class 1A evidence) Induction chemotherapy → radiation therapy alone (10-12) (class 1B evidence)	Radiation therapy + cetuximab (7,8) (class 1B evidence)
		Patients not suitable for cisplatin treatment	Radiation therapy alone (1) (class 2A evidence)	Radiation therapy + cetuximab (7,8) (class 1B evidence)

8

Treatment of early hypopharyngeal cancer

Staging	Patient classification	Level I expert recommendation	Level II expert recommendation
T1−2N0	Patients suitable for surgery	Surgery (1) (class 2A evidence) Radiation therapy alone (1) (class 2A evidence)	—
	Patients not suitable for surgery	Radiation therapy alone (1) (class 2A evidence)	—

9

Treatment of locally advanced hypopharyngeal cancer

Staging	Patient classification 1	Patient classification 2	Level I expert recommendation	Level II expert recommendation
Patients not suitable for surgery: poor physical condition, reject opreration for various reasons, or heavy tumor burden. Patients not appropriate for cisplatin treatment: age >70 years, performance status (PS) >2, loss of hearing, renal dysfunction (creatinine clearance <50 mL/min), or > level 1 neuropathy ( 15).
T1−2N1−3/ T3 any N	Patients suitable for surgery	Patients suitable cisplatin treatment	Surgery (1) (class 2A evidence) Radiation therapy + cisplatin (4-6) (class 1A evidence) Induction chemotherapy → radiation therapy alone (7,8) (class 1A evidence)	Radiation therapy + cetuximab (9,10) (class 1B evidence) Induction chemotherapy → radiation therapy + cetuximab (11) (class 2A evidence)
		Patients not suitable for cisplatin treatment	Surgery (1) (class 2A evidence)	Radiation therapy + cetuximab (9,10) (class 1B evidence) Radiation therapy alone (1) (class 2A evidence)
	Patients not suitable for surgery	Patients suitable for cisplatin treatment	Radiation therapy + cisplatin (4-6) (class 1A evidence) Induction chemotherapy → radiation therapy alone (12-14) (class 1B evidence)	Radiation therapy + cetuximab (9,10) (class 1B evidence)
		Patients not suitable for cisplatin treatment	Radiation therapy alone (1) (class 2A evidence)	Radiation therapy + cetuximab (9,10) (class 1B evidence)
T4 with different N	Surgery candidates	—	Surgery (1) (category 2A)	—
	Patients unfit for surgery	Appropriate for cisplatin treatment	Radiation therapy + cisplatin (4-6) (category 1A) Induction chemotherapy →RT (12-14) (category 1B)	Radiation therapy + cetuximab (9,10) (category1B)
		Not appropriate for cisplatin treatment	Radiation therapy (1) (category 2A)	Radiation therapy + cetuximab (9,10) (category 1B)

10

Treatment of recurrent or metastatic squamous cell carcinoma of head and neck

Staging	Treatment selection	Level I expert recommendation	Level II expert recommendation
5-FU, 5-fluorourcacil.
Recurrence or Metastasis	First-line therapy	Cisplatin + 5-FU (1) (category 1A) Carboplatin + 5-FU (1) (category 1A) Cisplatin + paclitaxel (2) (category 1A) Cisplatin + docetaxel (3) (category 2A)	Cisplatin + 5-FU + cetuximab (4) (category 1A) Carboplatin + 5-FU + cetuximab (4) (category 1A) Cisplatin + docetaxel + cetuximab (3) (category 2A) Cisplatin + cetuximab (5,6) (category 2A) Paclitaxel + cetuximab (7) (category 2A)
	Salvage therapy	Methotrexate (8) (category 2A) Docetaxel (9) (category 2A) Paclitaxel (10) (category 2A)	Cetuximab (11) (category 2A) Clinical trials (category 2A)