Approach

Treatment regimens vary depending on the stage of the cancer. Early localized cancers (T1/T2, N0) can be treated with surgery or radiation with similar survival.[57][75][76]​ The choice of treatment modality is often dependent on size of the primary tumor and location within the oropharynx. Locoregionally advanced cancers can be treated with surgery followed by postoperative radiation with or without chemotherapy, or concurrent chemoradiation, with equal outcome.[77] Unresectable cancers are treated with chemoradiation, while cancers with distant metastases are treated with chemotherapy for palliation. Consideration should be given to combination therapy of immunotherapy plus platinum-based chemotherapy in the setting of recurrent/metastatic head and neck cancer, as this has been shown to provide a survival benefit.[78]​ 

Patients should be managed in specialized head and neck centers by a multidisciplinary team that includes otolaryngologists, medical and radiation oncologists, and speech and language pathologists to optimize oncologic and functional outcomes.[39]

Complete blood count, chemistry panel, albumin, and prealbumin should be measured to assess the patient's nutritional status before treatment because of the expected mucositis with radiation or dysphagia after surgery.

The National Comprehensive Cancer Network (NCCN) recommends keeping the number of treatment modalities minimum so as to minimize treatment-related toxicity and to preserve function.[2]​ For this reason, evidence of extranodal extension or multiple lymph nodes that will warrant addition of chemotherapy are often used as rationale to offer upfront nonsurgical treatment.

When using radiation, the NCCN recommends intensity-modulated radiation therapy to minimize damage to critical structures.[2]​ 

Treatment deintensification for p16+ oropharyngeal cancer warrants consideration, but at this stage, it should only be done as part of a clinical trial.[79]​ Patients with human papillomavirus (HPV)-associated tumors are more responsive to treatment and are thus being investigated for de-escalated therapy.[7][80][81]​​​ With a few exceptions, the treatment regimens for HPV-negative and HPV-positive cancers are similar.[2]

HPV-negative oropharyngeal cancer management

Early-stage (T1/T2, N0, M0 disease)

Patients may be treated with either upfront surgery or radiation.[2]​ Even though no randomized study has compared the two modalities, retrospective studies reported similar local control and survival rates ranging from 80% to 90%.[57][75][76]​​​ The choice of treatment modality is dependent on size of the primary tumor and location within the oropharynx. Tumors at or approaching the midline (i.e., tumors in the base of the tongue, posterior pharyngeal wall, soft palate, and tonsil invading the tongue base) are at risk of contralateral metastasis and warrant bilateral treatment.[2]

Historically, surgery for oropharyngeal cancer required splitting of the mandible or a pharyngotomy to provide access to the inferior tonsillar fossa or base of tongue.[Figure caption and citation for the preceding image starts]: Large base of tongue tumor not amenable to transoral robotic surgery, required open transhyoid approach to the base of tongueFrom the collection of Dr Linda X. Yin; used with permission [Citation ends].com.bmj.content.model.Caption@2f1cf2a9[Figure caption and citation for the preceding image starts]: Transhyoid open approach to a large base of tongue tumorFrom the collection of Dr Linda X. Yin; used with permission [Citation ends].com.bmj.content.model.Caption@6a86ea3c

Transoral robotic surgery (TORS) is an innovative technique for early-stage oropharyngeal cancer that allows sparing of the mandible compared with conventional surgery.[82][Figure caption and citation for the preceding image starts]: Robotic wide-field tonsillectomy using the Da Vinci SP robotFrom the collection of Dr Linda X. Yin; used with permission [Citation ends].com.bmj.content.model.Caption@3f1e898e[Figure caption and citation for the preceding image starts]: Robotic base of tongue resection using the Da Vinci SP robotFrom the collection of Dr Linda X. Yin; used with permission [Citation ends].com.bmj.content.model.Caption@3dba0d85

Preliminary results are promising; however, more data are warranted.[83][84]​​ TORS is widely thought to be associated with significantly better postoperative functional outcomes, related to speech, swallowing, and need for tracheostomy.

Locally advanced: resectable (T1-T2, N1-N3 disease or T3-T4a, N0-N3 disease, M0 disease)

Patients with resectable locally advanced oropharyngeal cancer can be treated with either surgery followed by postoperative radiation with or without chemotherapy, or with concurrent chemoradiation without surgery.[2]​ One randomized study of locally advanced head and neck cancer demonstrated similar local control and survival by either modality.[77] Even though the number of patients with oropharyngeal cancers was small, the study corroborated the equal effectiveness of both modalities reported in retrospective studies.[85][86][87]​​ Survival ranges from 50% to 60% at 3-5 years because of the high rate of distant metastases (20% to 40%).[77][85][86][87][88]​ The benefit of adding chemotherapy to radiation has been reported by one meta-analysis for all head and neck cancer anatomic sites. Patients with oropharyngeal cancers had an 8.1% improvement in survival at 5 years.[89] The increased toxicity of the combined modality may be lessened with modern radiation therapy techniques that decrease the radiation dose to the normal organs. Cisplatin is the preferred first-line chemotherapy agent given concurrently with radiation.[2][90]

There are many chemotherapy regimens used for concurrent chemoradiation, and it is not known which one is superior. Concurrent chemoradiation can be given without or following induction chemotherapy depending on the medical oncologist's preference.[2] Some physicians prefer a triple drug induction chemotherapy, even though the risk of toxicity is increased.

Locally advanced: unresectable (T4b, any N, M0 disease)

​Patients with locally advanced unresectable head and neck cancer should be treated with concurrent chemoradiation if feasible. Randomized studies and one meta-analysis demonstrate better survival and local control with concurrent chemoradiation therapy than with radiation therapy alone.[2][91][92][93][94][95][96][97][98]​​ The most common combinations of chemotherapy were fluorouracil and cisplatin, fluorouracil and carboplatin, and fluorouracil and mitomycin.[91][92]​​​​[93][94][95][96][97][99]​​​ Three-year survival in the concurrent chemoradiation group ranged from 40% to 55%, and locoregional control was 58% to 70% for the combined modality.[92][96][97]​​ However, concurrent chemoradiation is associated with significant grade 3 to 4 toxicity, predominantly mucositis (up to 71%) and hematologic adverse effects (up to 32%).[92][96]​​​ It is unclear which chemotherapy regimen or radiation therapy fractionation is optimal. Doses of fluorouracil, cisplatin, and carboplatin vary although the dose for mitomycin is fixed. Radiation therapy dose ranged from 70 Gy (once a day) to 75 Gy (twice a day).

In summary, the standard of care for patients with unresectable tumors is platinum-based chemotherapy concurrent with radiation. A standard is high-dose cisplatin every 21 days concurrent with radiation, although poor performance status patients may require low-dose weekly cisplatin or carboplatin. Another option is triple-drug induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by concurrent chemoradiation with weekly cisplatin or carboplatin.[99][100]​​​ The addition of docetaxel to induction cisplatin and fluorouracil resulted in a median survival of 71 months compared with 30 months for induction cisplatin and fluorouracil followed by concurrent chemoradiation. Local control was also superior in the triple-drug induction arm, although more hematologic toxicity was reported. One meta-analysis confirmed the superiority of the triple induction regimen.[101] However, the optimal chemoradiation regimen remains unclear, as these regimens have not been directly compared.

Distant metastases at presentation (any T, any N, M1 disease)

Patients with distant metastases should be treated with targeted therapy if amenable, and chemotherapy if not amenable to targeted therapy. Consideration should be given to combination therapy of immunotherapy plus platinum-based chemotherapy in the setting of metastatic head and neck cancer, as this has been shown to provide a survival benefit.[78]​ Conventional chemotherapy is usually a platinum agent combined with fluorouracil. As a result of the KEYNOTE-048 trial, chemoimmunotherapy is now the standard of care in recurrent or metastatic unresectable head and neck cancers. In patients with metastatic disease with high PD-L1 staining (CPS score >1), immunotherapy alone can also be considered as the first-line treatment.[102]

The immune checkpoint inhibitor pembrolizumab as a single agent or in combination with platinum chemotherapy and fluorouracil is the preferred first-line treatment in this patient group.[2]

HPV-positive oropharyngeal cancer management

Early-stage (T0-T2, N0 or N1, M0 disease)

Patients may be treated with either upfront surgery or radiation.[2]​ Even though no randomized study has compared the two modalities, retrospective studies reported similar local control and survival rates ranging from 80% to 90%.[57][75][76]​​​​ The choice of treatment modality is dependent on size of the primary tumor and location within the oropharynx. Tumors at or approaching the midline (i.e., tumors in the base of the tongue, posterior pharyngeal wall, soft palate, and tonsil invading the tongue base) are at risk of contralateral metastasis and warrant bilateral treatment.[2]

Historically, surgery for oropharyngeal cancer required splitting of the mandible or a pharyngotomy to provide access to the inferior tonsillar fossa or base of tongue.​

TORS is an innovative technique for early-stage oropharyngeal cancer that allows sparing of the mandible compared with conventional surgery.[82]​​​

Preliminary results are promising; however, more data are warranted.[83][84]​​​ TORS is widely thought to be associated with significantly better postoperative functional outcomes, related to speech, swallowing, and need for tracheostomy.

With HPV-positive patients presenting with better functional status and having better survival, surgery-first approaches are often considered with the idea that radiation, as a treatment modality, may be reserved for a future recurrence. In addition, these patients have longer to live with the late effects of radiation therapy.

Locally advanced: resectable (T3/T4 or presence of nodal disease beyond single lymph node <3 cm)

Patients with resectable locally advanced oropharyngeal cancer can be treated with either surgery followed by postoperative radiation with or without chemotherapy, or with concurrent chemoradiation without surgery.​ One randomized study of locally advanced head and neck cancer demonstrated similar local control and survival by either modality.[77] Even though the number of patients with oropharyngeal cancers was small, the study corroborated the equal effectiveness of both modalities reported in retrospective studies.[85][86][87]​​​

Survival ranges from 50% to 60% at 3-5 years because of the high rate of distant metastases (20% to 40%).[77][85][86][87][88]​​ The benefit of adding chemotherapy to radiation has been reported by one meta-analysis for all head and neck cancer anatomic sites. Patients with oropharyngeal cancers had an 8.1% improvement in survival at 5 years.[89] The increased toxicity of the combined modality may be lessened with modern radiation therapy techniques that decrease the radiation dose to the normal organs. Cisplatin is the preferred first-line chemotherapy agent given concurrently with radiation.[2][90]

There are many chemotherapy regimens used for concurrent chemoradiation, and it is not known which one is superior. Concurrent chemoradiation can be given without or following induction chemotherapy depending on the medical oncologist's preference.[2] Some physicians prefer a triple drug induction chemotherapy, even though the risk of toxicity is increased.

Evidence from randomized controlled trials that enrolled patients with HPV-positive oropharyngeal cancer demonstrated that cetuximab plus radiation therapy was inferior to cisplatin plus radiation therapy (in terms of overall survival).[2][103][104]​ Thus, cetuximab plus radiation is no longer recommended for this patient group.

Distant metastases at presentation (any T, any N, M1 disease)

Patients with distant metastases should be treated with targeted therapy if amenable, and chemotherapy if not amenable to targeted therapy. Consideration should be given to combination therapy of immunotherapy plus platinum-based chemotherapy in the setting of metastatic head and neck cancer, as this has been shown to provide a survival benefit.[78]​ Conventional chemotherapy is usually a platinum agent combined with fluorouracil. As a result of the KEYNOTE-048 trial, chemoimmunotherapy is now the standard of care in recurrent or metastatic unresectable head and neck cancers. In patients with metastatic disease with high PD-L1 staining (CPS score >1), immunotherapy alone can also be considered as the first-line treatment.[102]

The immune checkpoint inhibitor pembrolizumab as a single agent or in combination with platinum chemotherapy and fluorouracil is the preferred first-line treatment in this patient group.[2]

Patients with recurrent disease

In patients with recurrent disease after previous local therapy without any evidence of distant metastases, salvage with surgery, radiation, or chemoradiation may be considered on an individual basis, while bearing in mind treatment toxicity.[105][106]​​ Patients with recurrent disease after definitive treatment should undergo salvage treatment with immunotherapy (with or without chemotherapy) if they are not a candidate for definitive surgery or chemoradiation. Consideration should be given to combination therapy of immunotherapy plus platinum-based chemotherapy in the setting of recurrent head and neck cancer, as this has been shown to provide a survival benefit.[78]

The immune checkpoint inhibitor pembrolizumab is approved in the US as first-line treatment of metastatic or unresectable, recurrent head and neck squamous cell carcinoma in adults in combination with platinum chemotherapy and fluorouracil, or as a single agent in those whose tumors express PD-L1 with a combined positive score (CPS) ≥1. It is also approved in the US as a single agent for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma with disease progression, on or after platinum-containing chemotherapy. The NCCN supports these recommendations.[2] In Europe, pembrolizumab is approved, as a single agent or in combination with platinum chemotherapy and fluorouracil, as first-line treatment of metastatic or unresectable, recurrent head and neck squamous cell carcinoma in adults whose tumors express PD-L1 with a CPS ≥1. It is also approved in Europe as a single agent for the treatment of recurrent or metastatic head and neck squamous cell carcinoma in adults whose tumors express PD-L1, with a ≥50% tumor proportion score and progressing on, or after, platinum chemotherapy. The approvals were based on results from the KEYNOTE-048 trial.[102]

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