Treatment Protocols

Treatment protocols for pharyngeal cancers are provided below, including the following:

Generalized first-line therapy based on stage
Chemoradiation therapy and induction chemotherapy for locally advanced disease
First-, second-, and third-line chemotherapy for metastatic or recurrent disease

Generalized treatment recommendations for pharyngeal cancers

See the list below:

Treatment plans for all disease stages should be discussed at a multidisciplinary tumor conference involving ear, nose, throat (ENT) surgeons; radiation oncologists; and medical oncologists
Selected patients with advanced or metastatic disease may receive surgical resection of their primary tumors, depending on their response to first-line therapy

Surgery or radiation therapy for early or localized pharyngeal cancers

Stages I-II^{[1, 2]}:

Primary treatment for oropharyngeal cancers is surgical resection or definitive radiation therapy
Surgery is the preferred approach, except for some patients who may have early lip, retromolar trigone, and soft palate cancers
Radiation therapy is preferred for patients who may not be able to tolerate surgery
The radiation dose depends on tumor size; however, for early stage disease, doses of 66-72Gy may be used with adequate results

Chemotherapy with radiation therapy for locally advanced pharyngeal cancers

Stages III-IVB^{[1, 2]}:

Surgery should be considered for locally advanced disease; however, definitive radiation therapy, concurrent chemoradiation, and induction therapy are alternative options for patients who are not candidates for surgery
Concurrent chemoradiation therapy is the current standard of care for patients with locally advanced squamous cell carcinoma of the head and neck^[3]
Chemotherapy is given for the duration of radiation therapy unless otherwise stated; definitive radiation doses used are 66-72 Gy
Conventional fractionation for concurrent chemoradiation up to 72 Gy
Postoperative radiation dose is 60-66 Gy (2.0 Gy/fraction); preferred interval between resection and postoperative radiation therapy is 6 wk
The decision to treat the patient with concurrent chemoradiation therapy rather than surgery, radiation, or chemotherapy individually should be made by a multidisciplinary tumor board (including a medical oncologist, a radiation therapist, and an ENT surgeon)

Acceptable chemotherapy regimens for primary systemic therapy with concurrent radiation include:

Cisplatin 100 mg/m² IV on days 1, 22, and 43^{[1, 2, 4, 5]}or 40 mg/m² IV weekly for 6-7wk^[6]or
Cetuximab 400 mg/m² IV loading dose 1 wk before the start of radiation therapy, then 250 mg/m² weekly^{[7, 8]}; or
Cisplatin 20 mg/m² IV on day 2 weekly for up to 7 wk plus paclitaxel 30 mg/m² IV on day 1 weekly for up to 7 wk^[9]or
Cisplatin 20 mg/m²/day IV on days 1-4 and 22-25 plus fluorouracil (5-FU) 1000 mg/m²/day by continuous IV infusion on days 1-4 and 22-25^{[10, 11, 12]}or
5-FU 800 mg/m² by continuous IV infusion on days 1-5 given on the days of radiation plus hydroxyurea 1 g PO q12 h (11 doses per cycle); chemotherapy and radiation given every other week for a total of 13 wk^[9]or
Carboplatin 70 mg/m²/day IV on days 1-4, 22-25, and 43-46 plus 5-FU 600 mg/m²/day by continuous IV infusion on days 1-4, 22-25, and 43-46^[13]or
Carboplatin area under the curve (AUC) 1.5 IV on day 1 weekly plus paclitaxel 45 mg/m² IV on day 1 weekly^[14](see also the Carboplatin AUC Dose Calculation [Calvert formula] calculator)

Acceptable chemotherapy regimens for patients receiving postoperative concurrent chemoradiation:

Cisplatin 100 mg/m² IV on days 1, 22, and 43^{[4, 5]}or 40 mg/m² IV weekly for 6-7wk^[6]

Induction chemotherapy for locally advanced pharyngeal cancers

Stages III-IVB:

Induction chemotherapy is typically given to patients with stage III-IVB disease in order to shrink a primary tumor to reduce its bulkiness in preparation for future surgery or radiation therapy
The decision to treat the patient with induction chemotherapy rather than concurrent chemoradiation or surgery, radiation, or chemotherapy alone should be made by a multidisciplinary tumor board (including a medical oncologist, a radiation therapist, and an ENT surgeon)^{[1, 2]}

Acceptable chemotherapy regimens for induction chemotherapy:

Docetaxel 75 mg/m² IV on day 1 plus cisplatin 100 mg/m² IV on day 1 plus 5-FU 100 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk for three cycles; then 3-8 wk later, carboplatin AUC 1.5 IV weekly for up to 7wk during radiation therapy; then 6-12 wk later, pursue surgery, if applicable^{[15, 16]}; or
Docetaxel 75 mg/m² IV on day 1 plus cisplatin 75 mg/m² IV on day 1 plus 5-FU 750 mg/m²/day by continuous IV infusion on days 1-4 every 3wk for four cycles; then 4-7wk later, radiation; surgical resection can be pursued before or after chemotherapy^[17]
Paclitaxel 175 mg/m² IV on day 1 plus cisplatin 100 mg/m² IV on day 2 plus 5-FU 500 mg/m²/day by continuous IV infusion on days 2-6 every 3 wk for three cycles; then radiation with cisplatin 100 mg/m² IV on days 1, 22, and 43^[18]
Induction chemotherapy can be followed by concurrent chemoradiation with carboplatin or cisplatin as listed above or by concurrent chemoradiation with weekly cetuximab ^[2]

First-line chemotherapy for metastatic or recurrent pharyngeal cancers

Stage IVC:

Treatment recommendations include the use of single-agent or combination chemotherapy
Platinum-based combination chemotherapy regimens are preferred if the patient can tolerate these agents; if not, single agents have been used in this setting^{[1, 2]}
Below are first-line chemotherapy options for metastatic disease or recurrent squamous head and neck cancers (after surgery and/or radiation)

Acceptable chemotherapy regimens in patients with metastatic (incurable) head and neck cancers include (unless otherwise stated, goal is to complete at least six cycles):

Cisplatin 100 mg/m² IV on day 1 every 3 wk for six cycles plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk for six cycles plus cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly until disease progression (premedicate with dexamethasone, diphenhydramine, and ranitidine)^[19]; or
Carboplatin AUC 5 IV on day 1 every 3 wk for six cycles plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk for six cycles plus cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly until disease progression (premedicate with dexamethasone, diphenhydramine, and ranitidine)^[19] or
Cisplatin 100 mg/m² IV or carboplatin AUC 5 IV on day 1 every 3wk for six cycles plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3wk for six cycles plus pembrolizumab 200 mg IV over 30 min every 3wk until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression^{[20, 21]}
Pembrolizumab 200 mg IV over 30 min every 3wk until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression, in patients whose tumors express programmed death–ligand 1 (PD‑L1)(Combined Positive Score [CPS] ≥1), as determined by an FDA‑approved test^{[20, 21]} or
Cisplatin 75 mg/m² IV on day 1 plus docetaxel 75 mg/m² IV on day 1 every 3 wk^{[22, 23]}or
Cisplatin 75 mg/m² IV on day 1 plus paclitaxel 175 mg/m² IV on day 1 every 3 wk^{[24, 25]} or
Carboplatin AUC 6 IV on day 1 plus docetaxel 65 mg/m² IV on day 1 every 3 wk^[26]or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m² IV on day 1 every 3 wk^[27] or
Cisplatin 75-100 mg/m² IV on day 1 every 3-4 wk plus cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly^{[28, 29, 30]}or
Cisplatin 100 mg/m² IV on day 1 plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk^{[12, 25, 31, 32, 33]}or
Methotrexate 40 mg/m² IV weekly (3-wk cycle)^{[12, 31]} or
Paclitaxel 200 mg/m² IV every 3 wk^{[34, 35]} or
Docetaxel 75 mg/m² IV every 3 wk^{[36, 37, 38]}or
Cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly until disease progression (premedicate with dexamethasone, diphenhydramine, and ranitidine)^[39] or
Platinum doublet therapy with docetaxel or paclitaxel can be combined with weekly cetuximab for a three-drug regimen option ^{[40, 41]}

Second- and third-line chemotherapy for metastatic or recurrent pharyngeal cancers

Stage IVC:

Second-line chemotherapy is given after disease progression or recurrence following completion of first-line therapy
Third-line therapies are given after disease progression or recurrence following completion of first-line and second-line therapies
Second- and third-line regimens are similar to regimens used as first-line therapy but usually offer lower response rates and survival benefits
Patients should be treated with platinum-based chemotherapy regimens if they have not previously received a platinum-based drug

Acceptable chemotherapy regimens in patients with recurrent head and neck cancers include (unless otherwise stated, goal is to complete at least six cycles):

Cisplatin 100 mg/m² IV on day 1 every 3 wk for six cycles plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk for six cycles plus cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly until disease progression (premedicate with dexamethasone, diphenhydramine, and ranitidine)^[19] or
Carboplatin AUC 5 IV on day 1 every 3 wk for six cycles plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk for six cycles plus cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly until disease progression (premedicate with dexamethasone, diphenhydramine, and ranitidine)^[22] or
Cisplatin 75 mg/m² IV on day 1 plus docetaxel 75 mg/m² IV on day 1 every 3 wk^[22] or
Cisplatin 75 mg/m² IV on day 1 plus paclitaxel 175 mg/m² IV on day 1 every 3 wk^{[24, 25]} or
Carboplatin AUC 6 IV on day 1 plus docetaxel 65 mg/m² IV on day 1 every 3 wk^[26] or
Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m² IV on day 1 every 3 wk^[27] or
Cisplatin 75-100 mg/m² IV on day 1 every 3-4 wk plus cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly (premedicate with dexamethasone, diphenhydramine, and ranitidine)^{[28, 29, 30]} or
Cisplatin 100 mg/m² IV on day 1 plus 5-FU 1000 mg/m²/day by continuous IV infusion on days 1-4 every 3 wk^{[12, 25, 31, 32, 33]}or
Methotrexate 40 mg/m² IV weekly (3-wk cycle)^{[12, 31]} or
Paclitaxel 200 mg/m² IV every 3 wk^{[2, 35]} or
Docetaxel 75 mg/m² IV every 3 wk^{[36, 37, 38]} or
Cetuximab 400 mg/m² IV loading dose on day 1, then 250 mg/m² IV weekly until disease progression (premedicate with dexamethasone, diphenhydramine, and ranitidine)^{[39, 42]} or
Platinum doublet therapy with docetaxel or paclitaxel can be combined with weekly cetuximab for a three-drug regimen option ^{[40, 41]} or
Capecitabine 1250 mg/m²PO BID on days 1-14, then off 7 days (3-wk cycle)^[43]or
Afatinib 40 mg PO daily until disease progression^[44] or
Nivolumab 240 mg IV q2wk or 480 mg IV q4wk until disease progression^[45] or
Pembrolizumab 200 mg IV every 3 wk until disease progression^{[46, 47, 20, 48]}

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