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Treatment of metastatic and recurrent head and neck cancer
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Treatment of metastatic and recurrent head and neck cancer
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Literature review current through: Jul 2017. | This topic last updated: Jul 06, 2017.

INTRODUCTION — The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer is generally poor. The median survival in most series is 6 to 12 months depending upon patient and disease-related factors.

Systemic therapy is indicated in conjunction with best supportive care for most patients with metastatic or advanced recurrent head and neck cancer. The choice of a systemic regimen is influenced by whether patients have received prior treatment as part of a combined modality approach postoperatively or for functional organ preservation as part of their initial management or whether they had previously received systemic therapy for metastatic or recurrent locoregional disease.

Treatment options include single-agent therapy and combination regimens using either conventional cytotoxic chemotherapy and/or molecularly targeted agents combined with best supportive care. Checkpoint inhibitor immunotherapy is an option for patients with progressive disease after their initial chemotherapy regimen. The approach to patients requiring palliative systemic therapy is reviewed here, along with the management of oligometastatic disease.

The use of chemotherapy as a component of initial definitive therapy is discussed separately, as is the use of systemic chemotherapy in other malignancies of the head and neck region:

(See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

(See "Treatment of recurrent and metastatic nasopharyngeal carcinoma".)

(See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease".)

(See "Head and neck sarcomas".)

GENERAL APPROACH — The general approach to a patient with recurrent or metastatic squamous cell carcinoma of the head and neck is summarized in the algorithm (algorithm 1).

Clinical settings — Additional treatment may be indicated for patients with advanced squamous cell carcinoma of the head and neck in the following settings:

No prior systemic therapy (see 'Previously untreated patients' below)

Previous systemic therapy as part of a combined modality approach (see 'Previous systemic therapy as part of initial treatment' below)

As second-line therapy (see 'Second-line therapy' below)

For oligometastatic disease (see 'Oligometastatic disease' below)

For locally recurrent disease (see 'Locally recurrent disease' below)

Active agents — Conventional cytotoxic drugs, checkpoint inhibitor immunotherapy, and molecularly targeted compounds have activity in metastatic and recurrent head and neck cancer. Historically, the most widely used agents include platinum compounds (cisplatin, carboplatin) [1-8], taxanes (docetaxel, paclitaxel, abraxane) [9-13], methotrexate [4,9,14], fluorouracil [15], and cetuximab [16].

Pembrolizumab and nivolumab, checkpoint inhibitors of programmed cell death protein 1 (PD-1), have shown clinically significant activity in patients who progressed on or after platinum-based regimens, and these agents are approved for this indication [17-19].

Other agents that may possess activity but have been less extensively evaluated include etoposide [20], gefitinib [21-25], gemcitabine [26,27], capecitabine [28], and pemetrexed [29-32].

Comparison of earlier studies versus more recent studies must be interpreted in light of the lead time bias that results from more sensitive diagnostic techniques, leading to earlier detection of asymptomatic metastases in patients receiving radiological monitoring, and in light of the inclusion of patients with more favorable prognosis (ie, human papillomavirus [HPV] related metastatic tumors in more recent studies).

Cisplatin versus carboplatin — The platinum agents are used both as single agents and to form the backbone for most combination regimens. Although carboplatin is often considered to be less effective than cisplatin in head and neck cancer, there is little direct evidence. Carboplatin may be preferred in some cases since it is associated with less neurotoxicity, nephrotoxicity, ototoxicity, and nausea and vomiting compared with cisplatin, although carboplatin causes more myelosuppression [33-36].

Adequately powered randomized trials directly comparing cisplatin with carboplatin as single agents and in multidrug regimens are lacking in this patient population.

Of the three studies that have compared the combination of cisplatin or carboplatin and fluorouracil for induction chemotherapy in patients with locally advanced disease [33,34,37], only one showed a statistically increased response rate and survival with the use of a cisplatin-based rather than carboplatin-based regimen [34]. Quality of life and treatment-related toxicity are considerations for patients who did not have a curative option.

Similarly, indirect evidence from the phase III trial assessing the role of cetuximab in combination with a platinum-based regimen supports the use of carboplatin [38]. In that trial, there was a similar improvement in progression-free survival attributable to cetuximab in patients treated with cisplatin plus fluorouracil and those given carboplatin plus fluorouracil, and there was no apparent difference in results between patients treated with the two platinum regimens.

A Southwest Oncology Group (SWOG) trial showed similar survival for a regimen of cisplatin plus fluorouracil versus carboplatin plus fluorouracil in the metastatic recurrent setting, with a nonstatistically significant improvement in response rate (32 versus 21 percent) and overall survival (7 versus 5 months) for the cisplatin-containing regimen [14].

Prognostic factors — Patient-specific factors that influence prognosis need to be considered when choosing therapy. Factors associated with longer survival in patients include [14,15,39-41]:

Ambulatory performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1 versus 2) (table 1)

Poorly differentiated histology

Response to chemotherapy

HPV associated oropharyngeal cancers

In contrast, factors associated with a poor prognosis include:

Weight loss

Poor performance status

Prior radiation therapy

Active smoking

Significant comorbidity

Increasing age is often associated with increasing comorbidity. However, evidence suggests that healthy older adult patients with metastatic and recurrent head and neck cancer have survival outcomes comparable to younger patients, but they may experience increased toxicity [42].

The role of age in determining the efficacy and tolerability of palliative chemotherapy was retrospectively reviewed using data from two cooperative group phase III trials that compared cisplatin doublets in patients with metastatic and recurrent head and neck cancer [42,43]. Objective response rates, median time to progression, and two-year survival were similar in patients greater than versus less than age 70 years. The older adult patients, however, experienced significantly higher rates of grade 3 to 5 thrombocytopenia, diarrhea, and renal complications. Furthermore, the older adult patients included in these trials may represent a highly selected subset with a better performance status and less comorbidity compared with the general population of older adult patients.

PREVIOUSLY UNTREATED PATIENTS — The choice of appropriate therapy for patients with advanced head and neck cancer who have not received prior systemic therapy is affected by the patient's performance status and comorbidities. This includes patients who initially present with advanced disease and are not candidates for definitive therapy, as well as those who develop metastatic or incurable locally recurrent disease following local treatment (surgery and/or radiation therapy [RT]) without chemotherapy.

For patients with a good performance status and without serious comorbidity, doublet cytotoxic chemotherapy regimens, generally with a platinum-based regimen, increase the objective response rate compared with single-agent chemotherapy, although no improvement in overall survival has been demonstrated. (See 'Combination cytotoxic chemotherapy' below.)

The addition of cetuximab to cisplatin plus fluorouracil increases overall survival compared with cisplatin plus fluorouracil alone. However, whether the use of single-agent cetuximab when patients progress following chemotherapy with a platinum-based doublet can achieve the same prolongation of survival is not known. (See 'Platinum-based chemotherapy plus targeted therapy' below.)

For patients with a poor performance status or significant comorbidities, cisplatin or carboplatin-based combinations are generally contraindicated. Typically single-agent therapy (eg, carboplatin, paclitaxel, cetuximab) is used in this setting. Immunotherapy may also represent an option, but it has not been well evaluated in this patient population. (See 'Second-line therapy' below.)

Combination cytotoxic chemotherapy — A number of combination chemotherapy regimens without cetuximab have been evaluated in patients with advanced head and neck cancer, most of which include a platinum compound. Although these regimens significantly improve response rates compared with a single agent, an improvement in overall survival has not been demonstrated compared with single-agent chemotherapy.

Platinum and fluorouracil — Cisplatin (100 mg/m2 intravenous, day 1) and fluorouracil (1000 mg/m2 per day, continuous infusion, for four days) is a standard combination chemotherapy regimen for use in the palliative setting. In phase III trials, this regimen produced response rates around 30 percent, which is significantly better than with single-agent cisplatin or methotrexate [5,14,15,44].

As an example, a Southwest Oncology Group (SWOG) trial randomly assigned 261 patients with advanced head and neck cancer to one of three regimens: cisplatin plus fluorouracil, carboplatin plus fluorouracil, or single-agent methotrexate [14]. The overall response rate was greater for the two combination regimens compared with methotrexate (32 and 21 versus 10 percent, respectively). However, the median survival was similar with all three regimens (6.6, 5.0, and 5.6 months, respectively). The percentage of patients with any grade 3 or 4 toxicity was greatest for those treated with the cisplatin regimen compared with the carboplatin regimen or single-agent methotrexate (33 versus 26 and 16 percent, respectively).

Because of the toxicity of this regimen and the need for prolonged infusion, we often prefer to use a platin plus taxane combination or single agents as first-line treatment in the palliative setting.

Platinum plus taxane — Both cisplatin and carboplatin have been combined with either paclitaxel or docetaxel in various combination regimens. None of these regimens have demonstrated superiority compared with cisplatin plus fluorouracil.

The most extensive data on the role of a platinum-taxane regimen come from a phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG), in which 204 patients were randomly assigned to cisplatin plus fluorouracil or cisplatin plus paclitaxel [44]. With a median follow-up of eight months, there were no statistically significant differences in overall survival (median survival 8.7 versus 8.1 months and one-year survival rate 41 versus 32 percent) or objective response rate (27 versus 26 percent). Gastrointestinal and hematologic toxicities were more common in patients receiving cisplatin plus fluorouracil.

Combinations of docetaxel (75 to 100 mg/m2) plus cisplatin (70 to 75 mg/m2) given every three weeks have been evaluated in phase II studies that included both previously treated and chemotherapy-naïve patients. Overall response rates ranged from 32 to 55 percent, with median response durations around five months [45-48]. These higher response rates were associated with severe side effects in up to 70 percent of patients. Weekly therapy with this combination may have similar efficacy and a more favorable toxicity profile [49]. Docetaxel plus cisplatin has not been compared with cisplatin plus fluorouracil in a randomized phase III trial.

The substitution of carboplatin for cisplatin simplifies administration and is associated with less nephrotoxicity, neurotoxicity, ototoxicity, and emesis. Carboplatin has also been combined with either paclitaxel or docetaxel in phase II trials [50-52]. Reported response rates ranged from 25 to 43 percent. These combinations have not been adequately assessed in randomized trials.

Cisplatin plus pemetrexed — Although the combination of cisplatin plus pemetrexed may have activity in some patient subsets, this regimen is not recommended for the initial treatment of patients with recurrent or metastatic head and neck cancer.

In a phase III trial, 795 patients were randomly assigned to either cisplatin plus pemetrexed or cisplatin alone [32]. Overall survival, the primary endpoint of the trial, was not significantly improved with the combination compared with cisplatin alone (median 7.3 versus 6.3 months, hazard ratio [HR] 0.87, 95% CI 0.75-1.02). In preplanned subset analyses, overall survival was significantly improved in patients with performance status 0 or 1 and in those with an oropharyngeal primary; however, these results require confirmation and comparison with the current standard of care (a platinum-based combination).

Three- or four-drug regimens — Three- or four-drug regimens have been associated with high response rates but also with significant toxicity, particularly neutropenic fever, in patients with recurrent or metastatic head and neck cancer. Regimens that have been studied in phase II studies include paclitaxel, cisplatin, and fluorouracil [53-55]; docetaxel, cisplatin, and fluorouracil [56,57]; methotrexate, vinblastine, doxorubicin, and cisplatin [58]; and paclitaxel, ifosfamide, and cisplatin or carboplatin [59,60]. There is no evidence that these regimens are superior to single-agent or doublet chemotherapy.

Non-platinum-based regimens — Other combinations may be useful in patients who are not candidates for platinum-based chemotherapy.

In a SWOG study in 57 patients with metastatic or recurrent head and neck cancer, the combination of gemcitabine (3000 mg/m2) plus paclitaxel (150 mg/m2) on days 1 and 15 of 28-day cycles was associated with a 28 percent objective response rate [61]. Median progression-free survival and overall survival were four and eight months, respectively. However, it is not clear if this is superior to single-agent taxane therapy.

In a prospective first-line study of paclitaxel and cetuximab, both delivered weekly, the response rate was similar (54 percent), as were the progression-free and overall survivals (4.2 and 8.1 months) [62].

Platinum-based chemotherapy plus targeted therapy

Cetuximab — Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR). The addition of cetuximab to a platinum-based doublet regimen has resulted in a significant increase in overall survival compared with doublet chemotherapy alone. Cetuximab is approved for first-line use in combination with platinum-based chemotherapy.

In the phase III EXTREME trial, 442 patients with recurrent or metastatic head and neck cancer were assigned to a platinum (cisplatin 100 mg/m2 on day 1 or carboplatin area under the concentration x time curve [AUC] 5 day 1) plus fluorouracil (1000 mg/m2 per day for four days) every three weeks, with or without cetuximab (400 mg/m2 for the initial dose, followed by subsequent weekly 250 mg/m2) [38]. Overall, 39 percent of patients had received systemic cytotoxic chemotherapy at least six months prior to randomization as part of their initial definitive management. Chemotherapy was given for a maximum of six cycles, although cetuximab could be continued as maintenance therapy until disease progression or toxicity. Crossover to include cetuximab was not allowed in the chemotherapy arm of the trial.

Chemotherapy plus cetuximab significantly prolonged overall survival compared with chemotherapy alone (median 10.1 versus 7.4 months, HR for death 0.80, 95% CI 0.64-0.99). Significant improvements were also seen in the progression-free survival and objective response rates (median 5.6 versus 3.3 months and 36 versus 20 percent, respectively). In a retrospective analysis of the trial, the improvements seen with cetuximab appeared to be similar in those whose tumor was human papillomavirus (HPV) related compared with those whose tumor was HPV negative [63].

Crossover was not allowed. Thus, this trial does not exclude the possibility that sequential use of cisplatin plus fluorouracil followed by cetuximab at the time of failure would be equivalent in survival with the three-drug regimen.

The overall incidence of severe (grade 3 or 4) adverse events with the cetuximab regimen was not significantly increased compared with chemotherapy alone (82 versus 76 percent). However, treatment with cetuximab resulted in a significant increase in the incidence of severe hypomagnesemia (5 versus 1 percent), severe skin reactions (9 versus <1 percent), and sepsis (4 versus <1 percent). Severe infusion-related reactions to cetuximab occurred in 3 percent of cases. (See "Infusion reactions to therapeutic monoclonal antibodies used for cancer therapy" and "Cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy".)

Panitumumab — Panitumumab is another monoclonal antibody that targets the EGFR. Panitumumab does not have an established role in the treatment of advanced squamous cell carcinoma of the head and neck, and it should not be substituted for cetuximab.

In the SPECTRUM phase III trial, 657 patients were treated with cisplatin plus fluorouracil, with or without panitumumab, another monoclonal antibody targeting the EGFR receptor [64]. There was a statistically nonsignificant trend toward increased overall survival, the primary objective of the trial, with the addition of panitumumab (median 11.1 versus 9.0 months, HR 0.87, 95% CI 0.73-1.05). Progression-free survival was significantly prolonged (median 5.8 versus 4.6 months, HR 0.78, 95% CI 0.66-0.92). As with the EXTREME trial using cetuximab, there was slightly more toxicity in the panitumumab arm than in the control arm. Secondary treatment with available EGFR monoclonal antibodies, however, was allowed, and approximately 10 percent of control patients received treatment after progression, perhaps modifying the overall survival results.

Tissue was available to impute HPV status by p16 immunohistochemistry in 443 cases (67 percent). This prospectively defined retrospective analysis suggested that there was a greater benefit in terms of progression-free and overall survival for the p16 negative patients than for those who are p16 positive [65].

Conclusions regarding the sensitivity of p16 positive tumors to EGFR monoclonal antibodies in patients with locoregionally advanced disease, rather than recurrent or metastatic disease, cannot be extrapolated from these data, nor can they be for HPV positive tumors, as patients with recurrent or metastatic p16 or HPV positive disease may represent a distinct (more aggressive) subtype among untreated patients with locoregionally advanced disease.

The role of immunotherapy in the first-line setting is currently being investigated in first-line trials comparing immunotherapy with chemotherapy (NCT02358031, NCT02551159). Currently, first-line immunotherapy should be limited to clinical trial participation.

Bevacizumab — Bevacizumab has shown some evidence of activity in combination with platinum-based chemotherapy, but bevacizumab does not have a role in the management of advanced or metastatic head and neck squamous cell carcinoma outside of a clinical trial setting.

The most extensive data with bevacizumab come from the E1305 trial, in which 403 patients were randomly assigned to platinum-based chemotherapy with or without bevacizumab [66]. Patients had not received prior systemic therapy for advanced head and neck cancer. Chemotherapy consisted of investigators' choice of one of four regimens (cisplatin with either fluorouracil or docetaxel, or carboplatin with either fluorouracil or docetaxel). The primary endpoint was overall survival.

Results were presented at the 2017 American Society of Clinical Oncology (ASCO) meeting with a median follow-up of 23 months. The difference in overall survival with the addition of bevacizumab was not statistically significant (median 12.6 versus 11.0 months, HR 0.84, 95% CI 0.67-1.05). Progression-free survival was increased (6.1 versus 4.4 months, HR 0.71, 95% CI 0.58-0.87). The objective response rate was significantly increased (36 versus 25 percent).

PREVIOUS SYSTEMIC THERAPY AS PART OF INITIAL TREATMENT — Concurrent and/or induction chemotherapy is frequently used in combination with radiation therapy (RT) for definitive therapy in patients who present with locoregional disease. Although such treatment has the potential to cure some patients, many will eventually relapse, either with recurrent disease in the head and neck region or with distant metastases. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

Some patients who relapse may be candidates for salvage therapy with curative intent, using either surgery or reirradiation. However, most patients who recur ultimately require palliative systemic therapy. The optimal regimen for these patients has not been defined in randomized trials. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)

Key factors that need to be considered in choosing a treatment include:

The response to the initial chemoradiotherapy regimen and the specific agents originally used.

The interval between initial treatment and evidence of progressive disease.

The overall condition of the patient, and the presence or absence of comorbidities should be integrated into the patient treatment plan.

Patients who had a relatively prolonged period of disease control following their initial cisplatin-based chemoradiotherapy and whose overall condition is good may be candidates for retreatment with a platinum-based combination. In the cetuximab trial in which the tested therapies were for the initial management of recurrent or metastatic disease, 61 percent of patients had received no prior systemic therapy, while 39 percent had received prior induction chemotherapy and/or concurrent chemoradiotherapy at least six months before randomization [38]. There was no significant difference in progression-free survival between those who had received prior systemic therapy and those who had not. (See 'Platinum-based chemotherapy plus targeted therapy' above.)

In contrast, patients who failed to respond to their initial treatment regimen or relapsed shortly thereafter are presumed to be refractory to those agents and should be managed with second-line therapy. (See 'Second-line therapy' below.)

SECOND-LINE THERAPY — Immunotherapies using checkpoint inhibitors, cytotoxic chemotherapy, and targeted agents have all been evaluated as second-line therapy and have activity in some patients. Key factors in choosing a treatment regimen include the prior treatment history, the patient's performance status and comorbidities, and the potential toxicities of a proposed regimen.

PD-1 inhibitor immunotherapy — Both nivolumab and pembrolizumab target the programmed cell death protein 1 (PD-1) and have important clinical activity in patients with head and neck squamous cell carcinoma; both are approved by the US Food and Drug Administration (FDA) for patients who have previously been treated for metastatic or recurrent squamous cell carcinoma the head and neck. The toxicity associated with these agents is similar to that observed with their use in other indications. (See "Principles of cancer immunotherapy" and "Toxicities associated with checkpoint inhibitor immunotherapy".)

Pembrolizumab — The activity of pembrolizumab was established in two large, nonrandomized studies in previously treated patients:

In the KEYNOTE-012 study, patients were treated with pembrolizumab on one of two schedules: 10 mg/kg every two weeks or a fixed dose of 200 mg every three weeks [18,67,68]. Objective responses were observed in 28 of 174 patients (16 percent). The response rate was similar in human papillomavirus (HPV) positive and HPV negative patients.

In the KEYNOTE-055 study, 171 patients were treated with pembrolizumab 200 mg every three weeks [69]. All patients had platinum- and cetuximab-refractory head and neck cancer. The objective response rate was 16 percent, and the median duration of response was eight months. Response rates were similar in patients who were HPV positive and HPV negative, and in the various PD-1 ligand (PD-L1) subgroups.

In both trials, the toxicity was similar to that reported with pembrolizumab in other indications, except for a higher incidence of hypothyroidism (15 percent). (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Two phase III clinical trials with pembrolizumab are ongoing (NCT02252042 and NCT02358031).

Nivolumab — In the Checkmate-141 phase III trial, 361 patients with platinum-refractory, recurrent or metastatic disease were randomly assigned to either nivolumab (3 mg/kg every two weeks) or a single-agent investigator's choice of therapy (methotrexate, docetaxel, or cetuximab) [19,70].

With a median follow-up of 5.1 months, overall survival for the entire study population was significantly longer in patients treated with nivolumab (median 7.5 versus 5.1 months, one-year survival rate 36.0 versus 16.6 percent, hazard ratio [HR] 0.70, 97.7% CI 0.51-0.96). The objective response rate was also increased with nivolumab (13.3 versus 5.8 percent).

In a prespecified exploratory analysis, overall survival was significantly increased with immunotherapy in patients with PD-L1 expression ≥1 percent (8.7 versus 4.6 months, HR 0.55, 95% CI 0.36-0.83). Overall survival was not significantly increased in patients with PD-L1 expression <1 percent (HR 0.89, 95% CI 0.54-1.45).

In a post hoc exploratory analysis, overall survival was significantly increased in patients with HPV positive tumors treated with immunotherapy (median 9.1 versus 4.4 months, HR 0.56, 95% CI 0.32-0.99). The difference in overall survival was not statistically significant in those with HPV negative tumors (median 7.5 versus 5.8 months, HR 0.73, 95% CI 0.42-1.25).

Nivolumab was not routinely available for those patients randomized to chemotherapy, and routine use of nivolumab after second-line chemotherapy could negate or minimize the survival benefit of immediate nivolumab.

Patient-reported outcomes on a quality of life questionnaire found that there was no clinically meaningful deterioration associated with treatment with nivolumab immunotherapy, in contrast to chemotherapy, where quality of life significantly decreased in 8 of 15 domains [70].

Based upon the results of this phase III trial, nivolumab was approved by the FDA [71].

Other checkpoint inhibition antibodies — A phase III trial of durvalumab (a PD-L1 inhibitor), alone or in combination with tremelimumab (a CTLA-4 inhibitor), versus chemotherapy is completing accrual (NCT02369874).

Cytotoxic chemotherapy — After failure of first-line chemotherapy, objective responses to second-line cytotoxic chemotherapy are uncommon, particularly when contemporary response criteria are applied, and there is no evidence that second-line treatment prolongs survival. For patients who are candidates for second-line cytotoxic chemotherapy, the choice of agent is based upon prior treatment history and the overall condition of the patient.

The limited activity of chemotherapy in this setting is illustrated by a phase III trial that compared weekly intravenous methotrexate with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in a heavily pretreated population [25]. The overall response rate was 4 percent in 152 patients treated with methotrexate, and the median overall survival was seven months [25]. Other single agents have produced higher response rates, but this has generally been associated with increased toxicity, and these agents have not been shown to affect survival [3-5,9].

Toxicity profiles for different chemotherapy agents vary widely and may be an important consideration when choosing a regimen. As an example, single-agent methotrexate causes more mucositis than cisplatin (38 versus 0 percent) but less vomiting (10 versus 87 percent) [3]. When weekly docetaxel was compared with methotrexate, docetaxel was associated with grade 3 or 4 neutropenia (12.5 percent), febrile neutropenia (1 percent), anemia (19 percent), mucositis (9 percent), and ungual (nail) toxicity (pain and ungual loss, 9 percent), whereas methotrexate was associated with grade 3 or 4 anemia (15 percent) and mucositis (5 percent) [9].

Gemcitabine also has shown evidence of activity in previously treated patients [26,27] and may represent an option for some patients.

Anti-EGFR monoclonal antibodies — Cetuximab is a monoclonal antibody that targets the EGFR, which is overexpressed in most squamous head and neck cancers. The activity of cetuximab in patients refractory to platinum-based chemotherapy has been demonstrated in several multicenter phase II trials, all of which observed an objective response rate of approximately 10 percent [16,72,73]. (See "Treatment protocols for squamous cell carcinoma of the head and neck".)

The activity of cetuximab is illustrated by a series of 103 patients with progressive disease following two to six cycles of platinum-based therapy [16]. Cetuximab was given with an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly. Overall, 17 patients (13 percent) had an objective response, including 8 of 79 (10 percent) who had had progression with the cisplatin chemotherapy and 9 of 51 (18 percent) who had had stable disease. The median survival from the initiation of cetuximab therapy was 7.5 months.

The standard schedule for cetuximab is 250 mg/m2 weekly, and further dose escalation does not appear to be beneficial. Another study in 35 patients evaluated cetuximab at a dose of 500 mg/m2 every two weeks; treatment was well tolerated and had similar efficacy (response rate 11 percent) [74]. Further dose escalation (750 mg/m2) on the every-two-week schedule did not result in any improvement in efficacy in another 26 patients (response rate 8 percent).

Small molecule tyrosine kinase inhibitors — A number of small molecule tyrosine kinase inhibitors have been tested in patients with advanced head and neck cancer, including afatinib, gefitinib, sunitinib, erlotinib, and lapatinib. No clear clinical role has yet been established for this approach [21,23-25,75-77].

Large phase III trials have compared two EGFR inhibitors, gefitinib and afatinib, both alone and in combination with docetaxel, with standard chemotherapy [25,76,77]. None of these have demonstrated a significant increase in overall survival.

OLIGOMETASTATIC DISEASE — Patients with head and neck cancer with one or a limited number of distant metastases at presentation or relapse may benefit from aggressive treatment that includes eradication of all known sites of disease.

The most extensive data come from small series of patients with oligometastatic disease in the lungs, in whom disease in the primary site and regional lymph nodes has been completely controlled. In this setting, surgical metastasectomy can result in prolonged disease-free survival in a significant percentage of appropriately selected patients. Data on oligometastatic disease involving sites other than the lung are more limited. (See "Second primary malignancies in patients with head and neck cancers", section on 'Distinguishing second primary lung malignancies from distant metastasis' and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

In a series that included 97 patients with squamous cell carcinoma from primary sites other than the oral cavity, the five-year overall survival rate was 32 percent [78]. Similarly, in a series of 83 patients from one institution, the five-year survival was 34 percent for the 41 patients with squamous cell carcinoma [79].

The primary site is an important factor influencing outcome. Patients with oligometastatic disease from a primary tumor of the oral cavity appear to have a significantly worse prognosis. As an example, in one series of 23 patients with a primary lesion of the oral tongue, 22 (96 percent) relapsed, with a median time to death of 10 months [80]. Similar poor results were seen in another series of 17 patients with oral cavity primary tumors, in which there were no five-year survivors [78].

Other approaches to disease eradication, such as stereotactic body radiation therapy, have also been used to treat one or a limited number of pulmonary metastases [81]. However, long-term follow-up data are more limited compared with surgical resection. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

No clinical trials have been conducted to assess the role of adjuvant chemotherapy following surgical resection of all metastatic disease sites. Although there may be benefit to adjuvant chemotherapy, there is no evidence to make a recommendation for its use in this situation.

LOCALLY RECURRENT DISEASE — Patients with locally recurrent head and neck cancer present a therapeutic challenge. Treatment options are limited, and morbidity can be substantial. Nevertheless, selected patients with recurrent disease may achieve long-term survival. The treatment of locally recurrent disease is discussed separately. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)

SUMMARY AND RECOMMENDATIONS — For patients with metastatic or recurrent head and neck squamous cell carcinoma, the prognosis is generally poor. The overall approach to a patient with recurrent or metastatic squamous cell carcinoma of the head and neck is summarized in the algorithm (algorithm 1).

Carefully selected patients with a good performance status and locally recurrent disease may benefit from salvage surgery and/or reirradiation. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)

The management of patients who have not received prior systemic treatment for squamous cell head and neck cancer is influenced by the patient's performance status, comorbidities, and related prognostic factors:

For otherwise healthy patients with a good performance status, we suggest combination chemotherapy using a platinum compound (cisplatin or carboplatin) plus fluorouracil, with or without cetuximab, or a platinum plus a taxane, rather than single-agent chemotherapy (Grade 2C). Although the addition of cetuximab increases overall survival compared with a platinum plus fluorouracil when cetuximab is not subsequently used, there is no evidence that this is more effective than using cetuximab sequentially as second-line therapy. (See 'Previously untreated patients' above.)

For patients who have not received previous treatment for recurrent or metastatic head and neck cancer but whose condition is not adequate to permit combination chemotherapy, we suggest single-agent therapy. Options include single-agent therapy with a taxane, a platinum (cisplatin, carboplatin), methotrexate, or cetuximab (Grade 2C). (See 'Active agents' above.)

Patients with severe comorbidities or a poor performance status may be best treated with supportive care.

For patients whose initial definitive therapy included systemic therapy with a platinum-based regimen with or without cetuximab:

We suggest a platinum-based combination for those who had a relatively prolonged period of disease control following their initial chemoradiotherapy and whose overall condition is good (Grade 2A). When rapid response of symptomatic recurrence is not required, sequential single agents may also be an option, with a minimal decrease in benefit but more acceptable toxicity, or checkpoint inhibition immunotherapy may be used. (See 'Previously untreated patients' above and 'Previous systemic therapy as part of initial treatment' above.)

For patients who recur or develop metastases during or shortly after their initial chemoradiotherapy, we suggest checkpoint inhibition immunotherapy with a programmed cell death protein 1 (PD-1) antibody (nivolumab or pembrolizumab, or inclusion in a formal clinical trial) (Grade 2C). Single-agent or combination therapy with a taxane, a platinum (cisplatin, carboplatin), methotrexate, or cetuximab is an alternative. Patients with severe comorbidities and/or a poor performance status may be best treated with supportive care. (See 'PD-1 inhibitor immunotherapy' above and 'Previous systemic therapy as part of initial treatment' above and 'Second-line therapy' above.)

For patients who have progressed after initial palliative systemic treatment for recurrence or metastasis, we suggest checkpoint inhibition immunotherapy with a PD-1 antibody (nivolumab or pembrolizumab) (Grade 2A). Single-agent therapy with a taxane, platinum compound (cisplatin, carboplatin), methotrexate, afatinib, gemcitabine, or cetuximab is an alternative. Patients with severe comorbidities and/or a poor performance status may be best treated with supportive care. (See 'Second-line therapy' above and "Treatment protocols for squamous cell carcinoma of the head and neck".)

Whenever possible, patients should be enrolled in clinical trials in both the first- and second-line setting.

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