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Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy

Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy
Authors:
Bruce E Brockstein, MD
Everett E Vokes, MD
Avraham Eisbruch, MD
Section Editors:
Marshall R Posner, MD
David M Brizel, MD
Marvin P Fried, MD, FACS
Deputy Editor:
Sonali Shah, MD
Literature review current through: Dec 2022. | This topic last updated: Dec 14, 2022.

INTRODUCTION — In an effort to improve cure rates and functional outcomes for patients with locally advanced squamous cell carcinoma of the head and neck, chemotherapy has been integrated into various multimodality approaches. These approaches have been applied for patients with unresectable cancers and those with resectable disease in whom a functional organ-preservation technique is either of equivalent oncological benefit or preferred. (See 'Available techniques' below.)

The general application of these approaches to patients with locoregionally advanced head and neck cancer arising in the oral cavity, oropharynx, hypopharynx, and larynx will be reviewed here. More detailed discussions for locoregionally advanced cancer of each of these sites, plus a review of the management of advanced nasopharyngeal carcinoma, are presented separately:

(See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oral cavity".)

(See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx".)

(See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx".)

(See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma".)

APPROACH TO FUNCTIONAL ORGAN PRESERVATION

Available techniques — In patients with locoregionally advanced head and neck cancer, combined modality functional organ-preservation approaches that are nonsurgical include:

Concurrent chemoradiation – Chemotherapy is administered at the same time as radiation therapy (RT). This approach has also included various schedules in which cycles of induction chemotherapy are alternated with RT [1]. (See 'Chemotherapy plus definitive locoregional therapy' below.)

Induction chemotherapy – Chemotherapy administered prior to definitive RT. (See 'Induction chemotherapy' below.)

Sequential therapy – Induction chemotherapy followed by concurrent chemoradiation. (See 'Sequential therapy' below.)

Advantages — The key advantages of integrating chemotherapy with radiation therapy (RT) in a functional organ-preservation approach include the following:

Induction chemotherapy prior to RT may reduce tumor volume, increase locoregional control, and improve organ function prior to RT or concurrent chemoradiation, thereby permitting more effective and less toxic local therapy. However, even with significant tumor volume reduction, the target volume should be based upon the anatomic compartments that encompass the pretreatment sites of gross disease.

Induction chemotherapy could treat subclinical distant metastatic disease without delay, especially in patients with advanced disease in the lymph nodes who are at risk of distant failure.

A favorable initial response to induction chemotherapy can predict efficacy for further functional organ-preserving therapy such as chemoradiation. In contrast, an unfavorable response to induction chemotherapy may signal some form of primary tumor resistance, and alternative treatments may be necessary. (See "Treatment of metastatic and recurrent head and neck cancer", section on 'Subsequent therapy'.)

The administration of chemotherapy concurrently with RT may sensitize tumor cells to the effects of radiation and thus overcome radiation resistance. Reduction of repopulation between radiation treatment fractions may also contribute to the benefits of concurrent chemotherapy. This could improve locoregional control and organ preservation. If systemically active doses of chemotherapy are administered, it may also have direct cytotoxic effects. (See "Methods to overcome radiation resistance in head and neck cancer".)

Sequential therapy, the combination of induction chemotherapy followed by concurrent chemoradiation, may combine the benefits of both induction chemotherapy and concurrent chemoradiation.

However, in some patients, concurrent chemoradiation alone may be preferred over induction chemotherapy. Induction chemotherapy is most appropriate for patients with good performance status and minimal comorbidities who are able to manage treatment-related toxicities. However, such toxicity may limit patient compliance and delay or prevent the completion of subsequent chemoradiation.

When the tumor has already destroyed the organ, functional organ-preservation approaches are usually not appropriate, and surgery is generally preferred. This situation occurs most frequently in patients with far advanced laryngeal or oral cavity cancers. (See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx", section on 'Total laryngectomy' and "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oral cavity".)

Patient selection — Combined approaches using chemotherapy and definitive RT are used in patients with both resectable and unresectable disease. The definitions of resectable and unresectable disease vary among practitioners and a large fraction of resectable patients can be treated nonsurgically in an effort to preserve organ anatomy and function:

For patients whose disease is considered resectable, concurrent chemoradiation with or without induction chemotherapy may be useful as an approach for functional organ preservation.

If the disease is unresectable then concurrent chemoradiation with or without induction chemotherapy or (in patients not considered to be candidates for multimodality therapy) RT alone are the only treatment options. Such treatment may render the patient free of disease and may result in functional organ preservation. In some cases with persistent disease following completion of chemoradiation, salvage surgery can be performed.

Induction chemotherapy and/or concurrent chemoradiation for locally advanced head and neck cancer are associated with significant toxicity that can result in treatment delays or interruptions. Appropriate patient selection is critical to successfully complete therapy. The patient's performance status, comorbidities, age, and psychosocial support network are important factors that need to be considered prior to proceeding with a combined modality approach.

Key factors to consider in selecting appropriate treatment for an individual patient include the following:

Most randomized clinical trials limited enrollment to patients with minimal comorbidities and a good performance status (Eastern Cooperative Oncology Group [ECOG] 0 and 1 (table 1)).

Although older adults have been successfully treated, the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) meta-analysis found that older patients are less likely to benefit from the addition of chemotherapy to definitive locoregional treatment and the meta-analysis could not demonstrate a benefit in those over 70 years. In fact there is suggestion that in those over 80, the addition of chemotherapy may be harmful [2-4]. Age alone should not be used as a criterion in selecting treatment approaches; rather comorbidities and performance status should be critically assessed in all patients, especially in older adults [5]. (See 'Chemotherapy plus definitive locoregional therapy' below and "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

Patients with a poor performance status, significant comorbidities, or psychosocial issues that limit their ability to participate in their treatment may be best managed with definitive RT alone or laryngectomy for larynx cancer. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations" and "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx", section on 'Total laryngectomy'.)

Chemotherapy plus definitive locoregional therapy — A combined modality approach incorporating both chemotherapy and RT improved results compared with RT alone and achieved improved or equivalent overall survival (OS) compared with definitive locoregional therapy alone (surgery and/or RT). This is based upon data from multiple randomized trials [6,7] as well as the MACH-NC [2-4]. This approach applies to head and neck squamous cell carcinoma in general and for tumors of specific anatomic sites. (See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx", section on 'Nonsurgical functional organ preservation versus surgery' and "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Concurrent chemoradiation'.)

The MACH-NC pooled individual patient data from 107 randomized trials and 19,805 patients with resectable or unresectable squamous cell carcinoma of the head and neck; a majority (90 percent) had stage III or IV disease [2-4]. In all trials, patients were randomly assigned to definitive locoregional therapy alone (surgery and/or RT) or definitive locoregional therapy in combination with chemotherapy (either induction, concurrent, or adjuvant). The trials included patients with oral cavity, oropharyngeal, hypopharyngeal and laryngeal cancers; trials that were limited to patients with primary nasopharyngeal tumors were excluded. Importantly, these data were analyzed from studies that preceded the routine identification of patients as human papillomavirus (HPV) positive or stratification of oropharyngeal patients by HPV status.

Updated results from this meta-analysis include the following [4]:

Concurrent chemoradiation – In 71 trials that included 10,680 patients, at median follow-up of 9.2 years, concurrent chemoradiation significantly improved OS compared with definitive local therapy alone (five- and ten-year absolute OS benefit of 6.5 and 3.6 percent, respectively; hazard ratio [HR] 0.83, 95% CI 0.79-0.86).

The OS benefit was due to a decrease in cancer-related deaths, which was influenced by reduced rates of locoregional (but not distant metastatic) failure. No increase in non-cancer deaths was observed with concurrent chemotherapy, although longer follow-up is necessary to evaluate for long-term treatment related complications. (See "Overview of approach to long-term survivors of head and neck cancer", section on 'Late and long-term complications'.)

No differences in OS were observed with different RT schedules (once daily versus altered fractionation) [3].

The OS benefit for concurrent chemoradiation over definitive locoregional therapy decreased with increasing patient age, and no OS benefit was observed in those over age 70 years (HR 0.97, 95% CI 0.81-1.16).

Induction chemotherapy – In 45 trials that included 7054 patients, at median follow-up of 5.7 years, the addition of induction chemotherapy did not improve OS compared with surgery and/or RT alone (HR 0.96, 95% CI 0.90-1.01). There was also no clear OS benefit even when specific induction chemotherapy regimens were assessed.

Concurrent chemoradiation versus induction chemotherapy – In eight trials that included 1214 patients, at median follow-up of 9 years, concurrent chemoradiation improved OS (five-year absolute OS benefit of 6.2 percent; HR 0.84, 95% CI 0.74-0.95) and locoregional failure (LRF; five-year absolute benefit of 5.8 percent; HR 0.86, 95% CI 0.76-0.97) compared with various induction chemotherapy regimens followed by definitive locoregional therapy.

However, extended follow-up of one randomized trial (Intergroup RTOG 91-11) in patients with laryngeal cancer suggested worse OS for concurrent chemoradiation compared to induction chemotherapy plus RT. This finding was attributed to an increase in non-cancer related causes of death, potentially from long-term toxicity from chemoradiation [8]. Further details of this trial are discussed separately. (See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx", section on 'Comparison of combined chemotherapy and radiation therapy approaches'.)

Adjuvant chemotherapy – In 14 trials with 2915 patients, at median follow-up of 5.4 years, the addition of adjuvant chemotherapy to definitive local therapy did not improve OS (HR 1.02, 95% CI 0.92-1.13).

Sequential therapy — The optimal timing and integration of chemotherapy with RT remains uncertain. Based upon the demonstrated benefit of concurrent chemoradiation over RT alone and the decrease in distant metastases seen with induction chemotherapy [3], sequential therapy (ie, induction chemotherapy followed by concurrent chemoradiation) has been proposed as the optimal way to incorporate chemotherapy with locoregional therapy.

Multiple clinical trials have studied the question of whether sequential therapy offers a significant benefit compared with concurrent chemoradiation alone [2-4,9-13]. These are illustrated by the four largest trials, which are heterogenous in design and treatment and which resulted in different conclusions:

In a trial conducted by the Spanish Head and Neck Cancer Cooperative Group, 439 patients with stage III or IV squamous cell carcinoma of the head and neck were randomly assigned to concurrent chemoradiation alone (seven weeks of RT plus cisplatin on days 1, 22, and 43) or induction chemotherapy with three cycles of one of two regimens (docetaxel, cisplatin, fluorouracil [TPF (table 2)] or PF), followed by the same concurrent chemoradiation [10].

There were no statistically significant differences in the progression-free survival (PFS), time-to-treatment failure, or OS between the three treatment arms. Notably completion of therapy as planned on the two sequential arms involved the administration of 525 mg/m2 or 600 mg/m2 total cisplatin. A substantial number of patients treated with induction chemotherapy also did not complete therapy due to toxicity, and mortality rates were high in this study. Perhaps for this and other reasons, approximately half of patients did not complete radiation and/or concurrent chemotherapy as planned, and analysis by intention to treat showed no survival benefit. A secondary analysis restricted to patients who completed treatment per protocol showed a statistically significant benefit in PFS in those patients receiving induction chemotherapy with TPF.

In a phase II/III Italian trial, 421 patients with locally advanced (stage III or IV) squamous cell carcinoma of the head and neck were randomly assigned to induction chemotherapy with three cycles of TPF (table 2) followed by chemoradiation, or to immediate chemoradiation, and 414 were fully evaluable [12]. Within each group, patients were secondarily randomized to concurrent chemotherapy with two cycles of PF or to concurrent cetuximab. Thus, two groups received concomitant chemoradiation alone, with either PF or cetuximab, and two groups received induction chemotherapy with TPF, followed by concomitant chemoradiation with either PF or cetuximab.

At a median follow-up of 44.8 months, treatment with induction chemotherapy followed by concurrent chemoradiation significantly improved OS compared with concurrent chemoradiation alone (median 54 versus 30 months, three-year survival rate 58 versus 47 percent, HR 0.74, 95% CI 0.56-0.97). Similarly, PFS was also significantly improved with induction chemotherapy followed by concurrent chemoradiation (median 30 versus 19 months, three-year survival rate 47 versus 39 percent, HR 0.72, 95% CI 0. 56-0.93).

LRF was also lower in the induction chemotherapy arm, but unlike in other studies, distant failure was not reduced. While not powered to make such conclusions, there was a trend to more benefit when induction chemotherapy was added to cetuximab chemoradiation. While there may be a biological explanation for this difference, this may reflect inferiority of the cetuximab chemoradiation regimen. (See 'Cetuximab versus cisplatin for definitive chemoradiation' below.)

Additionally, there was a trend towards more benefit in non-oropharynx sites. It should be noted that by eligibility this was a poor prognosis group with nearly 75 percent of patients having T3 or T4 disease. It was notable that neutropenia was higher during chemoradiation in the induction chemotherapy groups, but nonhematologic toxicity was not increased. Notably, no data are available differentiating benefit in HPV versus non-HPV associated disease.

In the DeCIDE trial, 280 treatment-naïve patients with N2 or N3 squamous cell carcinoma of the head and neck were randomly assigned to induction with two cycles of TPF (table 2) followed by chemoradiation or chemoradiation alone [11]. Chemoradiation consisted of docetaxel, fluorouracil, and hydroxyurea (given as five "cycles" in combination with RT at 150 cGy twice daily, repeated every other week).

The primary endpoint was OS. The original statistical plan was to include 400 patients; this was subsequently amended to 280 patients because of slower than expected accrual, but duration of the study was extended to allow for additional events. With a minimum follow-up of 2.5 years, OS was significantly better than originally anticipated, with similar mortality rates in the two arms (28 percent with induction chemotherapy plus chemoradiation versus 31 percent in the chemoradiation alone arm at 3.5 years). There were no statistically significant differences in OS, the primary endpoint of the study (HR 0.91, 95% CI 0.59-1.41), in recurrence-free survival, or disease-free survival.

The goal of this trial was to improve OS through a decrease in the incidence of distant metastases in high-risk (N2/N3) patients. The incidence of distant metastases was reduced, but the absence of an improvement in survival may have been due to the difference in treatment-related mortality (5 versus 0 percent in the sequential and concurrent treatment groups, respectively).

In a phase III French trial (the Groupe d'Oncologie Radiothérapie Tête et Cou [GORTEC] 2007-02 trial), 370 patients with nonmetastatic, locally advanced squamous cell carcinoma of the head and neck with bulky nodal spread (N2b, N2c, or N3) were randomly assigned to receive concurrent chemoradiation alone (seven weeks of RT plus carboplatin and fluorouracil) or induction therapy with three cycles of TPF (table 2) followed by concurrent cetuximab plus RT [13].

TPF induction was given with prophylactic ciprofloxacin and growth factor support. Induction was complicated by febrile neutropenia in 30 patients (17 percent) and treatment-related mortality in 12 patients (6.6 percent). Of those assigned to TPF, 30 patients did not receive RT as planned (20 did not complete TPF, and 10 had progressive disease).

After a median follow-up of 2.8 years, induction therapy resulted in lower rates of distant metastases (HR 0.54, 95% CI 0.30-0.99), but similar rates of locoregional control, PFS, and OS. On subset analysis, the impact of the treatment arm on outcome did not differ by p16 status.

Interpretation of this trial is complicated by the population studied, which was mostly tobacco- and alcohol-related oropharyngeal cancer; the majority were p16 negative. Among those assigned to induction therapy, the high treatment-related mortality rate and number of patients who did not receive RT as planned illustrate the complexity and toxicity of this approach. The similar survival rates suggest that the addition of TPF induction obviates the decrease in efficacy expected with a switch from concurrent platinum-based chemoradiation to concurrent cetuximab plus RT.

The role of induction chemotherapy followed by concurrent chemoradiation (sequential therapy) versus concurrent chemoradiation alone as assessed in these and other trials remains controversial due to the conflicting results. Some of the factors that contribute to the difficulties in interpretation include differences in trial design, intensity, and choice of induction chemotherapy and concurrent chemotherapy (eg, inferiority of cetuximab compared with platinum) regimens. (See 'Cetuximab versus cisplatin for definitive chemoradiation' below.)

Differences in patient populations (especially the proportion of patients with HPV associated disease who may have a better prognosis and thus require less aggressive therapy to maximize tumor control) and patient selection are also likely to have had an impact.

Although the Spanish trial rightly used intention to treat in concluding no benefit, the Italian trial demonstrated higher induction and chemoradiation treatment completion rates than the Spanish trial, and their PFS difference was similar to the per protocol patient analysis in the Italian trial. Finally, in the DeCIDE trial, there was in total seven cycles of systemically active chemotherapy in the induction group (counting the TFHX [paclitaxel, infusional fluorouracil, hydroxyurea, and RT]) versus five in the chemoradiation group. This large total amount of chemotherapy in both groups may have dampened the difference and led to high survival numbers in both groups.

The use of sequential therapy should be an individual clinician/patient decision but generally is reserved for those very healthy patients at high risk for both distant and locoregional recurrence treated at a high-volume center that can give optimal supportive care. The subgroup of patients that may benefit most are those with bulky N2b, N2c low nodes or N3 nodal stage, and perhaps the T3 and T4 populations, as suggested by subgroup analysis of the DeCIDE trial and Italian trial. These treatment intensification approaches are also most relevant for non-HPV associated disease. Deintensification strategies for HPV associated disease are discussed separately. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Is there a role for treatment deintensification?'.)

SYSTEMIC THERAPY REGIMEN — Agents with proven activity in squamous cell head and neck cancer that are most commonly included in either induction or concurrent chemotherapy regimens include the platinum compounds (cisplatin, carboplatin), fluorouracil, and taxanes (docetaxel, paclitaxel). (See "Treatment of metastatic and recurrent head and neck cancer".)

Induction chemotherapy — Multiple clinical trials have established that three drug combinations of cisplatin, fluorouracil, plus a taxane are the preferred approach for induction chemotherapy.

Initial clinical trials found that cisplatin and fluorouracil (PF; cisplatin, 100 mg/m2, and fluorouracil, 1000 mg/m2/day continuous 24-hour infusion for five days) given every three weeks as induction chemotherapy induced higher rates of complete response and better survival compared with two cycles of an earlier cisplatin and bleomycin-based regimens or regimens using two cycles of cisplatin with shorter infusions of fluorouracil [14].

Subsequent randomized trials found that the addition of a taxane (docetaxel, paclitaxel) to PF induction chemotherapy enhanced the effectiveness of induction chemotherapy used with radiation therapy (RT) alone or with RT plus concurrent chemoradiation [15-19]. In contrast, a small randomized trial in larynx/hypopharynx cancer did not show a benefit from the addition of cetuximab to induction chemotherapy that included docetaxel and cisplatin followed by accelerated RT with or without concurrent cetuximab [20].

The TAX 324 and EORTC 24971/TAX 323 trials illustrate the potential benefits of adding a taxane to the induction chemotherapy regimen with locoregionally advanced cancer of the oral cavity, oropharynx, hypopharynx, and larynx:

The most extensive data come from the TAX 324 trial, in which 501 patients were randomly assigned to induction with docetaxel, cisplatin, plus fluorouracil [TPF (table 2)] or PF [16,17]. Both induction regimens were given every three weeks for three cycles. The TPF induction regimen administered docetaxel 75 mg/m2 day 1, cisplatin 100 mg/m2 day 1, and fluorouracil 1000 mg/m2/day by continuous infusion on days 1 to 4. This was followed by concurrent chemoradiation using weekly carboplatin (dosed at an area under the concentration X time curve [AUC] of 1.5). With a median follow-up of 72 months, overall survival (OS) was significantly better with TPF compared with PF (hazard ratio [HR] 0.74, five-year survival 52 versus 42 percent, 95% CI 0.58-0.94). Similar improvement in progression-free survival (PFS) was observed.

Acute toxicity associated with TPF induction chemotherapy in the TAX 324 trial was substantial. Severe myelosuppression was manifested by grade 3 or 4 neutropenia, febrile neutropenia, and neutropenic infection in 83, 12, and 12 percent of cases, respectively, during induction chemotherapy. Severe nonhematologic toxicities included stomatitis (mucositis), nausea, esophagitis, and anorexia in 21, 14, 13, and 12 percent of cases, respectively. Treatment delays due to toxicity occurred in 29 percent of patients during induction chemotherapy and were less frequent on the TPF arm.

The EORTC 24971/TAX 323 trial randomly assigned 358 patients to four cycles of a slightly different TPF (table 3) induction regimen or the same PF regimen used in the TAX 324 trial [18]. The TPF regimen consisted of docetaxel (75 mg/m2), cisplatin (75 mg/m2), and fluorouracil (750 mg/m2/day by continuous intravenous infusion for five days). Chemotherapy was not administered concurrently with RT. OS was significantly improved with this TPF regimen compared with PF (median 18.8 versus 14.5 months; three-year survival 37 versus 26 percent).

An individual patient data meta-analysis that incorporated data from 1772 patients in five trials confirmed that taxane containing induction chemotherapy regimens were associated with a significantly decreased risk of death (OS 42 versus 35 percent at five years, HR 0.79, 95% CI 0.70-0.89) [21]. The rate of locoregional failure (LRF) was also significantly decreased (five-year local failure rate 44 versus 52 percent, HR 0.79, 95% CI 0.66-0.94).

The protocols for these chemotherapy regimens are presented separately. (See "Treatment protocols for squamous cell carcinoma of the head and neck".)

Concurrent chemotherapy — Although multiple clinical trials and the MACH-NC meta-analysis demonstrated a survival benefit from chemoradiation [2-4], the optimal concurrent regimen has not been defined. The MACH-NC meta-analysis found a greater benefit for platinum-based as compared with other chemotherapy regimens. The various regimens have not been directly compared with each other in adequately powered, randomized trials. The benefit of concurrent chemoradiation appears to be age-related with a loss of benefit in older adult patients, and substituting concurrent chemoradiation for altered fractionation may be similarly detrimental in ill or older adult patients [22,23]. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'Clinical trial results'.)

For those treated with concurrent chemoradiation, we prefer platinum-based chemotherapy to other agents. When given as a single agent concurrently with RT, the efficacy of platinum is dose dependent and higher cumulative doses are more effective, regardless of the schedule used. Cisplatin is generally preferred for patients with a good performance status who did not receive induction chemotherapy with a cisplatin-containing regimen. For patients with a good performance status and contraindications to cisplatin, carboplatin is an acceptable, yet less effective, alternative; cetuximab is a less preferred sensitizing agent for chemoradiation in this population. Many older adults and those with significant comorbidities are not good candidates for concurrent chemoradiation; we treat such patients with RT alone. While multiple randomized studies have demonstrated significant improvements in locoregional tumor control with altered-fractionation RT versus standard-fractionation RT given without chemotherapy, it is not clear that older adults benefit from altered-fractionation RT [23]. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'Hyperfractionation'.)

Cisplatin — Two main schedules of cisplatin administration are used clinically (bolus and weekly). For patients receiving cisplatin as a radiosensitizer, we suggest cisplatin 40 mg/m2 weekly rather than bolus cisplatin 100 mg/m2 every three weeks. In a randomized trial, weekly cisplatin as part of definitive chemoradiation had noninferior locoregional control (LRC) and was better tolerated compared with bolus cisplatin [24].

The efficacy of cisplatin is also dose dependent when given as a single agent concurrently with RT, and total doses >200 mg/m2 are more effective than lower doses, regardless of the schedule used [24-28]. Data from these and other studies also support the use of weekly cisplatin in all primary tumor sites (including oral cavity tumors) and other pathologic subtypes (eg, human papillomavirus [HPV] associated oropharyngeal tumors); the latter is discussed separately. (See 'Cetuximab versus cisplatin for definitive chemoradiation' below and "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Choice of sensitizing agent with chemoradiation' and "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Radiation versus chemoradiation'.)

Retrospective studies initially suggested similar efficacy and an improved toxicity profile with weekly administration of cisplatin [25,28-30]. However, interpretation of these indirect comparisons was limited by differences in patient populations, with a greater percentage of older, less fit patients receiving weekly administration. Randomized trials conducted in various tumor sites subsequently confirmed similar efficacy and improved safety for weekly compared with bolus dosing of cisplatin in the setting of definitive and adjuvant chemoradiation. Data are as follows:

Efficacy of cisplatin with definitive chemoradiation – An open-label, randomized controlled phase III trial (conCERT) conducted in India compared the different dosing schedules of cisplatin in the setting of definitive chemoradiation [24]. In this study, 270 patients with locally advanced (stage III, IVA, or IVB) squamous cell carcinoma of the head and neck were randomly assigned to definitive chemoradiation with either cisplatin administered at 40 mg/m2 weekly for seven doses or bolus cisplatin administered at 100 mg/m2 every three weeks for three doses. Primary tumor sites included the oropharynx (60 percent), larynx (18 percent), hypopharynx, and oral cavity (11 percent each). Among patients with oropharyngeal cancer, a minority (approximately 13 percent) had HPV associated disease. Most patients also received a cumulative dose of cisplatin ≥200 mg/m2 in both treatment arms (80 versus 77 percent for weekly versus bolus cisplatin, respectively).

In preliminary results, at median follow-up of 26 months, compared with bolus cisplatin, weekly cisplatin demonstrated noninferior LRC (cumulative two-year LRC 53 versus 47 percent, HR 0.84, 95% CI 0.58-1.20), PFS (median 21 months each), and OS (median 26 versus 30 months). Grade ≥3 toxicity was more frequent for bolus cisplatin compared with weekly cisplatin including mucositis (54 versus 41 percent), kidney toxicity (18 versus 4 percent), and vomiting (13 versus 5 percent). Patients treated with bolus cisplatin were also more likely to have treatment interruptions and require supportive care (such as intravenous fluids or hospitalization). Similar toxicities for bolus cisplatin have also been seen in other trials [31-33].

Efficacy of cisplatin with adjuvant chemoradiation – We also prefer weekly dosing of cisplatin in the setting of adjuvant (postoperative) chemoradiation for all tumor sites. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Cisplatin'.)

Although randomized trials comparing weekly versus bolus cisplatin in the adjuvant setting have conflicting results, we prefer weekly cisplatin based on its efficacy and tolerability as demonstrated by the JCOG1008 trial and extrapolating from randomized trials conducted in the setting of definitive chemoradiation (conCERT) [24]. While other randomized trials suggest that weekly cisplatin is inferior to bolus cisplatin in the setting of adjuvant chemoradiation, one study used a lower, less preferable dose of weekly cisplatin and primarily enrolled patients with oral cavity tumors [34], and another closed early due to slow recruitment [35].

In one randomized phase II/III trial (JCOG1008), weekly cisplatin demonstrated noninferior OS and improved toxicity profile for weekly cisplatin compared with bolus cisplatin in patients treated with postoperative chemoradiation. Notably, this trial enrolled patients with a variety of primary tumor sites, including approximately one-half with oral cavity tumors. These data are discussed separately. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Cisplatin'.)

In another randomized phase III trial conducted at Tata Memorial Center in India, 300 patients with locally advanced disease were randomly assigned to cisplatin 30 mg/m2 weekly versus cisplatin 100 mg/m2 every three weeks [34]. At a median follow-up of 22 months, weekly cisplatin demonstrated worse locoregional control (two-year control rate 58 versus 73 percent, HR 1.76, 95% CI 1.11-2.79) but similar OS (median 39.5 months versus not reached, HR 1.14, 95% CI 0.79-1.65). Grade ≥3 toxicities were less frequent in the weekly cisplatin group (72 versus 85 percent).

However, inferiority of weekly versus bolus cisplatin is difficult to conclude from this study because of dosing and patient population. This trial used a lower, less-preferred dose of cisplatin at 30 mg/m2 weekly, whereas many centers generally use 40 mg/m2 weekly. In addition, this particular study population was enriched mainly with oral cavity tumors (87 percent) treated with adjuvant (postoperative) chemoradiation (93 percent), decreasing generalizability to other primary tumor sites and the use of chemoradiation as definitive therapy. Finally, while locoregional control suffered, OS was similar between the two dosing schedules, with less frequent toxicity with weekly cisplatin.

Carboplatin-based regimens — Weekly carboplatin (AUC of 1.5 to 2) is an acceptable agent for concurrent chemoradiation in patients with a good performance status who are ineligible for cisplatin [36]. The combination of carboplatin plus fluorouracil may also represent another option when cisplatin is not feasible [37,38]. Carboplatin has also been combined with paclitaxel [39,40]. Importantly, many older adults and those with significant comorbidities are not good candidates for concurrent chemoradiation; we treat such patients with RT alone.

Carboplatin is more acutely myelosuppressive than cisplatin but causes less neurotoxicity, nephrotoxicity, and nausea and vomiting [41-43]. Carboplatin is not as effective as cisplatin for its direct antitumor effect. Whether carboplatin is as effective as cisplatin as a radiation sensitizer is not clear [44,45]. At least one trial suggested that carboplatin is not as effective as high-dose cisplatin [41].

Concurrent chemoradiation using carboplatin demonstrated comparable efficacy and better tolerability when compared with concurrent chemoradiation with cisplatin in one randomized study in patients with locally advanced nasopharyngeal cancer [46]. There was no significant difference in three-year disease-free survival (61 versus 63 percent for carboplatin and cisplatin regimens, respectively) or OS (79 versus 78 percent). However, it is not clear that this can be extrapolated to biologically distinct non-nasopharyngeal squamous cell carcinoma.

In another randomized trial (Groupe d'Oncologie Radiothérapie Tête et Cou [GORTEC] 2007-01), the addition of concurrent carboplatin plus fluorouracil improved PFS and locoregional control over that seen with concurrent cetuximab and RT alone, supporting carboplatin as a radiation sensitizer [47]. In this study, 406 patients with locally advanced squamous cell carcinoma of the head and neck were randomly assigned to concurrent weekly cetuximab plus once-daily RT (up to 70 Gy) with or without three cycles of concurrent carboplatin and fluorouracil [47]. The majority of tumors were p16 negative, tobacco- and alcohol-related oropharyngeal cancer. At a median follow-up of 4.4 years, the addition of carboplatin and fluorouracil resulted in the following:

Superior three-year PFS (52 versus 41 percent, HR 0.73, 95% CI 0.57-0.94).

Better locoregional control (HR 0.54, 95% CI 0.38-0.76) and similar rates of distant metastases.

Numerically higher three-year OS that did not reach statistical significance (61 versus 55 percent, HR 0.80, 95% CI 0.61-1.05).

Higher rates of severe mucositis, feeding tube insertion, and hospitalization during treatment.

These results support the role of carboplatin and fluorouracil as a radiation sensitizer. The lack of a chemoradiation-only arm precludes assessment of concurrent cetuximab. (See 'EGFR inhibitors plus chemoradiation' below.)

Docetaxel — Docetaxel is an option for definitive chemoradiation in patients with non-HPV associated tumors who are ineligible for cisplatin.

Docetaxel is an active radiosensitizer in head and neck cancer [48]. In a phase III trial of patients with squamous cell carcinoma of the head and neck who were ineligible for cisplatin, the addition of docetaxel to RT improved OS [49], but was associated with increased toxicities such as mucositis, dysphagia, odynophagia, scarring, and fibrosis. Docetaxel has not been directly compared with carboplatin-based regimens in randomized trials, so the choice between these chemosensitizing agents is based upon clinician or institutional preference, patient characteristics, and toxicity profile. For example, docetaxel may be one appropriate option for patients with good performance status and kidney insufficiency who are not candidates for cisplatin. However, we do not offer docetaxel to older adults or patients who are frail and/or have significant comorbidities due to the higher toxicity risk; such patients are usually treated with RT alone. (See 'Chemotherapy plus definitive locoregional therapy' above.)

The efficacy of docetaxel compared with other chemosensitizers, including cisplatin, in the adjuvant (postoperative) setting is discussed separately. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Docetaxel'.)

In an open-label phase III trial conducted in India, 356 patients with locoregionally advanced squamous carcinoma of the head and neck who were ineligible for cisplatin were randomly assigned to either RT plus weekly docetaxel at 15 mg/m2 or RT alone [49]. Patients received RT either as definitive (66 to 70 Gy; 60 percent) or adjuvant (60 Gy; 40 percent) treatment. Criteria for cisplatin ineligibility included Eastern Cooperative Oncology Group (ECOG) performance status of 2 (table 1); any grade ≥2 organ dysfunction such as hearing loss, tinnitus, or neurologic disorder; cisplatin hypersensitivity; creatinine clearance <50 ml/min; borderline organ function or comorbidities that precluded cisplatin use; loss of 10 percent or more of baseline body weight within the past six months; malnourishment (body mass index [BMI] <15 kg/m2); or the concurrent use of drugs toxic to the kidney. Tumor sites mostly involved the oral cavity (37 percent) or oropharynx (29 percent), but also included larynx (14 percent), hypopharynx (17 percent), and cancers of unknown primary (2 percent). Most patients had either non-HPV associated tumors or were not tested; a minority had HPV associated disease (four percent).

In preliminary results, the addition of weekly docetaxel to RT alone improved DFS (two-year DFS 42 versus 30 percent, HR 0.67, 95% CI 0.52-0.87) and OS (two-year OS 51 versus 42 percent, HR 0.75, 95% CI 0.57-0.98). DFS and OS benefit were also consistent across all clinical subgroups, including the various tumor sites [49]. The addition of docetaxel to RT demonstrated higher grade ≥3 acute toxicity rates including mucositis (50 versus 22 percent), odynophagia (53 versus 34 percent), and dysphagia (50 versus 33 percent), but it did not worsen quality of life at six-month follow-up.

Cetuximab plus radiation therapy — Epidermal growth factor receptor (EGFR) is highly overexpressed in head and neck squamous cell carcinoma and is associated with a poor prognosis [50,51]. EGFR activation facilitates tumor growth by promoting angiogenesis and proliferation and metastasis by increasing motility and adhesion of tumor cells [52]. Cetuximab is a monoclonal antibody that binds to and inhibits EGFR. Data for the efficacy of concurrent cetuximab plus RT are as follows:

Addition of cetuximab to radiation therapy alone — Cetuximab is a less preferred sensitizing agent for chemoradiation in patients with a good performance status who are not candidates for cisplatin (eg, those with significant renal insufficiency). While the addition of cetuximab to RT alone improved OS in a randomized trial [53], its efficacy has not been directly assessed in this population, as patients who would typically be ineligible for cisplatin were excluded from this study. The efficacy of cetuximab plus RT has also not been directly compared to other more preferred carboplatin-based regimens. Additionally, available data do not support the use of cetuximab with RT in older adults and those with significant comorbidities; we treat such patients with RT alone. (See 'Carboplatin-based regimens' above.)

Cetuximab was evaluated in a multinational trial in which 424 patients with locoregionally advanced cancers of the oropharynx, hypopharynx, or larynx were randomly assigned to RT with or without concurrent weekly cetuximab. Patients enrolled in this study were medically suited for definitive radiotherapy, had a Karnofsky performance score (KPS (table 4)) of at least 60, and normal hematopoietic, hepatic, and renal function. Patients with oral cavity cancers were not enrolled [53]. Cetuximab was administered at a dose of 400 mg/m2 over two hours one week prior to RT, followed by 250 mg/m2 over one hour weekly during RT. RT was administered to 70 Gy in 2 Gy fractions using either an accelerated schedule (over six weeks using six fractions per week) or a conventional schedule (over seven weeks using five fractions per week).

With a median follow-up of 54 months, the cetuximab-treated group had significantly better OS compared with those receiving RT alone (three-year survival 55 versus 45 percent, HR 0.73). Locoregional control rates were also significantly better (50 versus 41 percent) [54]. An underpowered retrospective subset analysis suggested the benefit of cetuximab plus RT was restricted to patients under the age of 65 years and with a KPS 90 to 100 (table 4) and those with oropharyngeal cancer. In another subset analysis, the improvement with cetuximab plus RT, compared with RT alone, was present in both those with and without HPV associated disease (as assessed by p16 protein expression) but was more pronounced in the p16 positive group [55]. Patients 65 years of age and older and those with KPS 60 to 80 had an OS that favored RT alone, although the difference was not statistically significant. Treatment benefit was observed in patients receiving RT via accelerated fractionation but not conventional fractionation but the study was not designed to assess the role of fractionation [54].

Patients receiving concurrent cetuximab had a greater incidence of Grade 3 or 4 radiation dermatitis [54,56]. The management of radiation dermatitis is discussed in more detail separately. (See "Radiation dermatitis".)

Cutaneous side effects and infusion reactions associated with cetuximab are discussed in more detail separately. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'EGFR inhibitors' and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

Cetuximab versus cisplatin for definitive chemoradiation — For patients with HPV associated tumors receiving definitive chemoradiation, we recommend cisplatin rather than cetuximab as a chemosensitizer, provided patients are appropriate candidates for cisplatin-based chemotherapy. For patients with non-HPV associated tumors receiving definitive chemoradiation, we also suggest cisplatin rather than cetuximab, although we recognize that these two chemosensitizers have not been compared in this population.

However, carboplatin-based regimens plus RT are reasonable alternatives for patients who are not candidates for cisplatin (eg, patients with significant renal insufficiency, or preexisting hearing loss or neuropathy). Cetuximab is a less preferred sensitizing agent with RT since its efficacy has not been directly assessed in this patient population or compared to more preferred carboplatin-based regimens. (See 'Carboplatin-based regimens' above.)

Several randomized trials have compared cetuximab plus RT versus cisplatin plus RT in HPV associated oropharyngeal cancer. In this population, cetuximab plus RT results in inferior survival compared to cisplatin plus RT, regardless of the administration schedule of cisplatin (bolus versus weekly). Cetuximab also has a similar degree of severe toxicity compared with cisplatin, although with a different toxicity profile. These agents have not been directly compared in HPV negative or non-oropharyngeal populations.

The following trials provide a direct comparison of cetuximab versus cisplatin (bolus dosing) administered concurrently with RT [32,57]:

In an international trial (De-ESCALaTE HPV), 334 patients with locally advanced, low-risk (nonsmoker or <10 pack-year smoking history), HPV associated oropharyngeal squamous cell carcinoma were randomly assigned to receive cisplatin plus RT (administered at 100 mg/m2 on days 1, 22, and 43 with 7000 cGy in 35 fractions) versus cetuximab plus RT [57]. Compared to cisplatin plus RT, cetuximab plus RT resulted in the following:

Decreased OS (89 versus 98 percent at two years, HR 5.0, 95% CI 1.7-14.7)

Increased disease recurrence (16 versus 6 percent at two years, HR 3.4, 95% CI 1.6-7.2)

Similar quality of life and swallowing outcomes

A different spectrum of toxicity, with more cutaneous toxicity and infusion reactions, and less gastrointestinal toxicity, hearing loss, tinnitus, and vertigo

A randomized, multicenter, noninferiority phase II trial (RTOG 1016) compared cisplatin plus RT (two cycles of cisplatin at 100 mg/m2 with 7000 cGy in 35 fractions over six weeks) versus cetuximab plus the same RT in 849 patients with locally advanced, HPV associated oropharyngeal cancer [32]. After a median follow-up of 4.5 years, compared to cisplatin plus RT, cetuximab plus RT resulted in the following:

Decreased OS (78 versus 85 percent at five years, HR 1.45, 95% CI 1.03 to 2.04).

Inferior PFS (67 versus 78 percent at five years, HR 1.72, 95% CI 1.29-2.29), with greater LRF (17 versus 10 percent at five years, HR 2.05, 95% CI 1.35-3.10).

Similar rates of moderate to severe acute and late toxicities, with less gastrointestinal toxicity, myelosuppression, kidney injury, and hearing loss, but more cutaneous toxicity. The two treatment groups had similar feeding tube requirements.

Randomized trials also suggest that cetuximab plus RT has inferior OS and locoregional control compared to cisplatin administered on a weekly schedule plus RT [58,59]. Data are as follows:

In a phase III trial (ARTSCAN III), 298 patients with AJCC seventh edition stage III-IV locoregionally advanced squamous cell carcinoma of the head and neck were randomly assigned to concurrent chemoradiation with either cetuximab or cisplatin (administered at 40 mg/m2 weekly) [59]. A majority (approximately 90 percent) of patients had HPV associated oropharyngeal cancer. Patients with cT3-T4 disease were further randomly assigned to either standard RT (68 Gy) or dose-escalated RT (73.1 Gy). Although the trial was terminated early after an unplanned interim analysis at a median follow-up of 3.2 years, cetuximab plus RT resulted in greater LRF (23 versus 9 percent, HR 2.49, 95% CI 1.33-4.66) compared to cisplatin plus RT. There was also a trend towards worsened OS outcomes that did not achieve statistical significance (three-year OS rates of 78 versus 88 percent, HR 1.63, 95% CI 0.93-2.86). The cumulative incidence of distant failures was similar between the two treatment groups (9 versus 6 percent for cetuximab and cisplatin, respectively). Dose escalation in patients with cT3-T4 disease also did not improve local control. Acute toxicity rates were similar between the two treatment arms, and the unique toxicity profiles for each agent were similar to those noted in other studies [32,57]. Patients receiving cisplatin experiencing higher rates of nausea, vomiting, acute kidney injury, neutropenia, tinnitus, and dysphagia, whereas those receiving cetuximab experienced more mucositis, skin reactions, and acneiform rashes.

Another randomized phase II trial not restricted to patients with HPV associated disease that compared cetuximab plus RT versus weekly cisplatin plus RT suggested that cetuximab was associated with more acute toxicity (cutaneous, need for supplemental nutrition, and fatalities, but less hematologic and renal toxicity), worse compliance (more RT treatment interruptions), and a trend towards worse survival outcomes [58]. However, the trial was terminated early and was underpowered to draw definitive conclusions.

Investigational approaches — The combination of concurrent chemoradiation with other systemic therapies such as checkpoint inhibitor immunotherapy, EGFR inhibitors, and other agents remains investigational in patients with locally advanced squamous cell carcinoma of the head and neck.

Immunotherapy plus chemoradiation — We do not offer concurrent immunotherapy plus chemoradiation for patients with locally advanced squamous cell carcinoma of the head and neck. Data are as follows:

Avelumab – The addition of the programmed cell death ligand (PD-L1) inhibitor avelumab to cisplatin-based chemoradiation did not demonstrate a PFS benefit in a phase III randomized trial [60].

Pembrolizumab – While pembrolizumab plus concurrent chemoradiation were combined safely in an early phase clinical trial [61], this approach failed to improve event-free survival over chemoradiation alone, based on preliminary results from a randomized phase III trial (KEYNOTE-412) [62].

EGFR inhibitors plus chemoradiation — Cetuximab, panitumumab, and nimotuzumab (where available) are monoclonal antibodies that bind to and inhibit EGFR. Erlotinib is an inhibitor of the EGFR tyrosine kinase. The combination of such EGFR inhibitors plus chemoradiation remains investigational.

Cetuximab – We do not offer concurrent cetuximab plus chemoradiation as definitive locoregional therapy for locally advanced squamous cell carcinoma of the head and neck. In a phase III trial (RTOG 0522), the addition of cetuximab to concurrent cisplatin plus RT did not confer an OS advantage [63].

Additionally, while the addition of carboplatin plus fluorouracil to concurrent cetuximab plus RT resulted in superior locoregional control in one randomized trial [47], this combination has not been compared with concurrent carboplatin and fluorouracil plus RT. This study is discussed in detail separately. (See 'Carboplatin-based regimens' above.)

Nimotuzumab – Nimotuzumab is a monoclonal antibody targeting EGFR that is approved and available in China [64]. Nimotuzumab is not available in the United States. We do not offer concurrent nimotuzumab with chemoradiation for definitive locoregional treatment, as this approach has not demonstrated an OS benefit and increases toxicity (eg, mucositis), and we have concerns about the design of the clinical trial.

In an open-label, phase III, randomized trial of 536 patients (70 percent HPV negative) with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, and larynx, the addition of nimotuzumab to definitive chemoradiation with cisplatin improved PFS at two years (62 versus 50 percent, HR 0.69, 95% CI 0.53-0.89) and disease-free survival (60 versus 49 percent, HR 0.71, 95% CI 0.55-0.92) [65]. While there was a trend towards improved OS at two years, this did not reach statistical significance (64 versus 58 percent, HR 0.84, 95% CI 0.65-1.08), even among those who received a total cumulative cisplatin dose ≥200 mg/m2. Grade ≥3 mucositis was higher in those receiving nimotuzumab plus chemoradiation versus chemoradiation alone (67 versus 56 percent). Importantly, the dose of cisplatin used (30 mg/m2 weekly) was lower than the dose used by most centers (40 mg/m2 weekly).

Panitumumab Panitumumab is another monoclonal antibody targeting the EGFR receptor. At this time there is no indication for the use of panitumumab in head and neck cancer [66].

A randomized phase II trial involving patients with advanced head and neck cancer evaluated the addition of panitumumab to chemoradiation using cisplatin and reported increased toxicity with no improved survival or PFS [67]. A phase III trial comparing RT (standard fractionation) plus cisplatin versus accelerated fractionation RT plus panitumumab also failed to demonstrate an advantage from panitumumab [68]. Another randomized phase II trial directly compared chemoradiation using cisplatin with RT plus panitumumab alone and suggested inferior outcome using the monoclonal antibody [69].

Erlotinib Erlotinib is a small molecule inhibitor of the EGFR tyrosine kinase. Erlotinib was combined with cisplatin in a phase II trial in which 205 patients with locally advanced squamous cell carcinoma of the head and neck were randomly assigned to either cisplatin alone or cisplatin plus erlotinib, both given concurrently with definitive RT [70]. The addition of erlotinib did not significantly improve either the complete response rate or PFS.

Other agents

Debio 1143 – The addition of Debio 1143, an orally available antagonist of inhibitor of apoptosis proteins (IAPs), demonstrated clinical efficacy in a randomized phase II trial [71]. However, further data are necessary before incorporating this approach into routine clinical practice.

Is there a role for adjuvant therapy after chemoradiation? — Regular posttreatment follow-up is an essential part of the care of patients after potentially curative treatment of head and neck cancer. There is no established role for adjuvant treatment in patients who achieve a complete response after chemoradiation or chemoradiation followed by surgery. (See 'Posttreatment surveillance' below.)

Afatinib, an irreversible inhibitor of EGFR, was compared with placebo as an adjuvant in a phase III trial in 617 patients who had been rendered disease free for locoregionally advanced head and neck cancer with chemoradiation or chemoradiation followed by surgery [72]. There was no difference in disease-free survival with increased drug-related adverse events. The trial was stopped for futility after a planned interim analysis.

RADIATION THERAPY PLANNING

Initial assessment — Induction chemotherapy and concurrent chemoradiation are intensive and require multidisciplinary input to be successful. A multidisciplinary team is needed to coordinate care, prevent treatment delays, and provide optimal radiation therapy (RT) planning. Planning should begin prior to initiation of therapy (eg, induction chemotherapy or conformal RT [73]).

Specific pretreatment evaluations for patients undergoing RT include the following:

Evaluation of metastatic disease – Evaluation for distant metastases should include chest imaging, as well as any other studies indicated by symptoms.

Comorbidities – Comorbid medical issues should be addressed prior to treatment, since several months of rigorous treatment may exacerbate underlying illnesses.

Nutrition and swallowing – A nutritional evaluation should be carried out prior to initial treatment, and nutritional support should be provided as needed during and after treatment. We avoid prophylactic gastric feeding tubes in patients without an immediate need, as many patients can be supported through treatment without the need for a tube. However, some centers routinely insert prophylactic feeding tubes to supplement nutrition support throughout chemoradiation. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Head and neck cancer'.)

Some studies suggest that a policy of prophylactic feeding tubes has an advantage in retaining weight and improving quality of life compared with feeding tubes inserted when patients cannot maintain their weight. However, prophylactic tubes prolong the use of enteral feeding compared with reactive insertion and are associated with a higher rate of late pharyngeal/esophageal strictures [74]. This may be related to avoidance by patients of any swallowing during the period when feeding tubes are inserted.

Even after insertion of a feeding tube, patients should be encouraged to swallow liquids/soft food as much as possible to reduce rate of late dysphagia. (See "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

Dental evaluation – Patients' dental issues should be considered, and treated if necessary, as soon as possible after diagnosis so that the RT component of therapy does not have to be delayed and to avoid late complications related to dental extractions or osteoradionecrosis of the jaw. (See "Management of late complications of head and neck cancer and its treatment".)

Other evaluations – Other pretreatment evaluations to contemplate include intravenous (IV) access, speech and swallow evaluation, and supportive care including pain management. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Pretreatment evaluation'.)

Radiation therapy treatment plan — RT uses a treatment plan based upon the tumor's initial size, location, and relation to normal organs (in order to reduce the potential for long-term toxicities such as xerostomia or dysphagia). Contrast-enhanced CT or MRI should be obtained prior to induction chemotherapy to serve as a reference for post-induction RT planning [73]. (See "Management of late complications of head and neck cancer and its treatment".)

Changes in body weight, neck contours, and tumor volumes may necessitate treatment replanning following completion of induction chemotherapy but prior to RT initiation, as well as during the course of RT. Pretreatment primary tumor and gross nodal tumor volumes should be used for treatment planning even though tumor shrinkage may have occurred. All structures involved by tumor prior to induction chemotherapy should be included in the final treatment plan, even if gross tumor is no longer identifiable.

Significant weight loss and/or tumor shrinkage may increase radiation doses to the parotid gland and/or reduce the effectiveness of the immobilization mask built before RT started. Replanning may be required and is based on the pre-RT (or pre-induction) tumor volumes.

Radiation therapy schedule — The MARCH meta-analysis included individual patient data from 11,423 patients in 33 trials of RT as single modality comparing altered fractionation with conventional fractionation [75]. Hyperfractionation resulted in better locoregional control and overall survival (OS) when compared with once-daily RT as a single-modality treatment. In contrast, accelerated RT regimens did not have a significant effect on OS compared with conventional fractionation. However, the added cost and logistical challenges of multiple RT fractions per day have limited the widespread utilization of these techniques. Furthermore, altered fractionation schedules given alone were inferior to conventional fractionation given in conjunction with concurrent chemotherapy. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

At least two randomized trials have not observed a benefit from altered RT fractionation schedules when the RT is given in combination with concurrent chemotherapy. One of these trials also strongly suggests that standard fractionation concurrent chemoradiation is superior to accelerated fractionation RT alone:

In the Radiation Therapy Oncology Group (RTOG) 0129 trial, 721 patients with locoregionally advanced head and neck cancer were randomly assigned to once-daily fractionation RT (70 Gy in 35 fractions over seven weeks) or to accelerated boost RT (70 Gy in 42 fractions over six weeks) [33]. Patients receiving once-daily fractionation RT were to receive cisplatin (100 mg/m2) on days 1, 22, and 43, while those receiving accelerated boost RT were to receive the same dose of cisplatin on days 1 and 22. There was no statistically significant difference in OS (the primary endpoint of the trial) when the two radiation schedules were compared (eight-year survival rate 48 percent with both schedules, hazard ratio 0.96, 95% CI 0.79-1.18); there were also no significant differences in progression-free survival (PFS), locoregional failure (LRF), or rate of distant metastases.

In the Groupe d'Oncologie Radiothérapie Tête et Cou (GORTEC) 99-02 trial, 840 patients were randomly assigned to one of three regimens: conventional chemoradiation (70 Gy in 7 weeks with three cycles of carboplatin fluorouracil), accelerated chemoradiation (70 Gy in 6 weeks with two cycles of carboplatin fluorouracil), or very accelerated RT alone (64.8 Gy in 3.5 weeks) [76]. With a median follow-up of five years, there was no benefit from accelerated chemoradiation compared with conventional chemoradiation (three-year PFS 34 versus 38 percent, p = 0.88). There was a trend for conventional chemoradiation to do better than very accelerated RT alone (three-year PFS 38 versus 32 percent, p = 0.06). Similar results were observed for OS.

Duration of treatment — Although the benefits of induction chemotherapy or concurrent chemotherapy have been demonstrated in randomized clinical trials, breaks in therapy and the transition between induction and concurrent therapy should be minimized whenever possible.

The use of induction and/or concurrent chemotherapy may delay or prevent the delivery of a full course of RT. This issue is especially prevalent in studies of induction chemotherapy followed by concomitant chemoradiation, where 20 to 30 percent of patients starting induction chemotherapy did not complete the subsequent concurrent therapy, which is the most important part of the treatment course [10,16,18]. For example, the Spanish randomized study comparing two induction regimens followed by concurrent chemoradiation versus concurrent chemotherapy alone had 74 percent and 69 percent rates of therapy completion in the induction arms compared with 92 percent in the concurrent chemoradiation alone arm [10]. The loss of patients receiving induction and not proceeding with concurrent chemoradiation may contribute to the difficulty in demonstrating a benefit for induction chemotherapy.

Interval between induction chemotherapy and radiation therapy — Mathematical modeling and retrospective studies indicate that delays in instituting RT may be associated with poorer tumor control [77-79]. Time is required for the mucosa and bone marrow to recover from induction chemotherapy, but concurrent chemoradiation should be initiated whenever possible within three to five weeks after the last dose of induction chemotherapy [73]. Delays beyond this period of time may increase the risk of LRF. Additional chemotherapy should not be used as a "holding plan."

Radiation therapy delivery time — The RT component of treatment should be completed without unnecessary delay. A post hoc analysis of the TAX 324 trial analyzed outcome as a function of the duration required to complete the entire course of RT [80]. A multivariate analysis of outcomes in the 333 patients who completed all three cycles of induction chemotherapy and received a full course of radiation found that prolonging the duration of RT beyond eight weeks was an independent predictor of inferior survival.

ROLE OF SURGERY — The indications for surgery to treat persistent or recurrent primary tumor and regional lymph node disease depend upon the extent of pretreatment disease and subsequent response to therapy.

Surgery should be considered for resectable patients with poor responses in the primary site or neck after induction chemotherapy and for all patients with residual disease after concurrent chemoradiation.

Neck dissection, if feasible, is generally planned for patients with proven residual disease in the neck following concurrent chemoradiation.

The clinical examination is critical for the assessment of residual disease after concurrent chemoradiation and sequential therapy. Computed tomography (CT) and positron emission tomography (PET) scans augment the clinical evaluation. However, if PET imaging is performed too soon after the completion of concurrent chemoradiation, it can be difficult to distinguish residual disease from posttreatment inflammation. Therefore, we typically obtain PET/CT imaging approximately 12 weeks after treatment completion to reduce the possibility of equivocal imaging results [81]. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck" and "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma", section on 'Functional imaging'.)

Primary tumor — Surgery for the primary tumor provides good locoregional control and prolonged survival for some patients with residual disease after concurrent chemoradiation, although it is associated with considerable morbidity [82,83]. Residual or recurrent disease often contains multiple foci of tumor rather than a concentric tumor mass [84]. Thus, the salvage operation is typically the procedure that would have been performed prior to chemoradiation even for tumors that showed some response to therapy.

Overall complication rates of 30 to 50 percent and pharyngocutaneous fistula rates of 30 percent are common in this setting [82,85]. Many of these complications occur because of the poor tissue quality at the surgery site which results in poor wound healing and postoperative function. The use of free flap reconstruction brings nonirradiated, well-vascularized tissue into the site and results in a decreased incidence of wound complications.

For patients who undergo evaluation for salvage surgery, it is preferable to wait for approximately 12 weeks after completion of concurrent chemoradiation before assessing for residual tumor on PET-CT imaging (in the absence of clinically documented progression or persistent disease). This approach reduces the possibility of equivocal imaging results and allows patients time to recover appropriately from chemoradiation prior to resection. (See 'Posttreatment surveillance' below.)

Management of the neck — For patients with locally advanced head and neck squamous cell carcinomas, management of residual abnormalities in the neck can be a particularly difficult issue. For patients with complete response as documented clinically and by structural (CT, magnetic resonance imaging [MRI]) and functional (PET) imaging, observation is generally indicated, whereas salvage surgery is indicated in the absence of an adequate response (algorithm 1).

Management of the neck, including the extent of surgery, in patients treated with radiation therapy (RT) or chemoradiation is discussed separately. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

COMPLICATIONS AND SUPPORTIVE CARE — The complications associated the treatment of locoregionally advanced head and neck cancer are discussed in detail separately:

(See "Management of late complications of head and neck cancer and its treatment".)

(See "Management and prevention of complications during initial treatment of head and neck cancer".)

Topics that require particular consideration when chemotherapy and radiation therapy (RT) are combined include the prevention of infection due to severe myelosuppression and the maintenance of adequate nutrition.

Prevention of infection

Choice of prophylaxis — Intensive chemotherapy results in severe myelosuppression in the majority of patients. As an example, in the TAX 324 trial, induction chemotherapy with docetaxel, cisplatin, and fluorouracil resulted in grade 3 or 4 neutropenia, febrile neutropenia, and neutropenic infection in 83, 12, and 12 percent of cases, respectively [16,17]. (See 'Induction chemotherapy' above.)

Prophylactic medication has become routine to minimize the consequences of myelosuppression. While granulocyte colony-stimulating factor (G-CSF) is commonly used with myelosuppressive induction chemotherapy (docetaxel, cisplatin, fluorouracil), some experts advocate the use of a fluoroquinolone antibiotic during induction chemotherapy and avoid the use of hematopoietic colony-stimulating factors in general since there are some data to suggest a negative impact, at least when G-CSF is given during RT.

Granulocyte colony-stimulating factor — G-CSF should be used cautiously during RT, and G-CSF may have a possible tumor-protective effect in head and neck cancer. Because of the increasing frequency of human papillomavirus (HPV) associated tumors, it is unclear if this is disease specific or a generalization for all squamous cancers of the head and neck. There are no data on granulocyte-macrophage colony-stimulating factor (GM-CSF).

The observed incidence of febrile neutropenia observed in the TAX 324 trial does not meet the criterion for considering the use of G-CSFs to prevent febrile neutropenia according to guidelines from a variety of expert groups including the American Society of Clinical Oncology (ASCO), the European Organization for Research and Treatment of Cancer (EORTC), and the Infectious Disease Society of America, all of which recommend the use of primary prophylaxis if the risk of febrile neutropenia with a specific regimen is ≥20 percent. Primary prophylaxis with G-CSF was not permitted in the TAX 324 trial evaluating docetaxel, cisplatin, plus fluorouracil induction chemotherapy. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Indications, benefits, and guidelines'.)

Furthermore, the use of G-CSFs as primary prophylaxis during induction chemotherapy and/or concurrent chemoradiation may adversely affect treatment outcome. In one trial of concurrent chemoradiation with hyperfractionated accelerated RT, patients randomized to prophylactic G-CSF experienced significantly reduced locoregional tumor control [86].

Prophylactic antibiotics — Prophylactic antibiotics, such as ciprofloxacin, have been routinely used during induction chemotherapy; these typically are initiated on day 5 of each cycle and continued for 10 days. The merits of antibiotic prophylaxis to prevent infection and infection-related complications in cancer patients at risk because of severe neutropenia remain controversial. Nevertheless, fluoroquinolone prophylaxis, in particular, has been shown to reduce the risk of febrile episodes in neutropenic outpatients with solid tumors and potentially decrease mortality [87,88]. (See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications", section on 'Antibacterial prophylaxis'.)

Nutrition — Nutritional status should be monitored throughout the course of therapy, and feeding tubes or gastrostomy tubes are frequently required (table 5) [89]. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Head and neck cancer'.)

Gastrostomy or percutaneous endoscopic gastrostomy (PEG) tubes preferably should not be placed prior to induction chemotherapy due to complications that may occur during this phase of therapy. If the nutritional status is such that the patient requires a prophylactic gastrostomy or PEG tube prior to or during induction therapy, then such individuals may not be candidates for aggressive induction chemotherapy. If a prophylactic gastrostomy or PEG tube is placed prior to induction chemotherapy, then initiation of chemotherapy should be delayed for two weeks to allow the tract to mature, and proton pump inhibitors may be prescribed during induction chemotherapy therapy to prevent wound problems.

Gastrostomy or PEG tube placement prior to concurrent chemoradiation is less problematic than insertion prior to induction chemotherapy. However, aggressive analgesic use, nutritional counseling and support, intravenous fluid support, and optimal nursing care can prevent the need for tubes in many patients undergoing functional organ-preservation therapy.

POSTTREATMENT SURVEILLANCE — Regular posttreatment follow-up is an essential part of the care of patients after potentially curative treatment of head and neck cancer. Patients should be educated about possible signs and symptoms of tumor recurrence, including hoarseness, pain, dysphagia, bleeding, and enlarged lymph nodes.

In general, the intensity of follow-up is greatest in the first two to four years, since approximately 80 to 90 percent of all recurrences will occur within this timeframe. Continued follow-up beyond five years is generally suggested since the risk of recurrence remains elevated beyond the first five years, especially for cancers of the hypopharynx, larynx, nasopharynx, and salivary glands and there is a high rate of development of second primary malignancies, particularly with carcinogen-related cancers. Because of the higher risk of recurrence and second primary malignancy in those who continue tobacco use, many schedule more frequent surveillance visits for these patients and continue for longer duration (ie, beyond five years).

Details regarding posttreatment surveillance of head and neck cancer, including screening for treatment-related complications, is reviewed separately. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

SUMMARY AND RECOMMENDATIONS

Approaches for functional organ preservation – For patients with locally advanced squamous cell carcinoma of the head and neck, functional organ-preservation approaches include administering chemotherapy with radiation therapy (RT; concurrent chemoradiation); induction chemotherapy prior to RT; or induction chemotherapy prior to concurrent chemoradiation (sequential therapy). (See 'Available techniques' above.)

Rationale – The combination of chemotherapy with definitive RT improved results compared with RT alone and achieved improved or equivalent overall survival (OS) while preserving organ function compared with definitive locoregional therapy alone (surgery and/or RT). (See 'Chemotherapy plus definitive locoregional therapy' above.)

Patient selection – Treatment regimens combining chemotherapy and RT can be associated with toxicity. Appropriate patient selection is critical to successfully complete therapy. The patient's performance status, comorbidities, age, and psychosocial support network are important factors. (See 'Advantages' above and 'Patient selection' above.)

Concurrent chemoradiation for most patients – For most patients with locoregionally advanced head and neck cancer, we recommend concurrent chemoradiation (with or without induction therapy) rather than definitive locoregional therapy (surgery and/or RT) alone (Grade 1B). (See 'Chemotherapy plus definitive locoregional therapy' above.)

Radiation alone for many older adults – However, for many adults age 70 years or older, we suggest RT alone rather than chemoradiation (Grade 2B), as the addition of concurrent chemotherapy to RT did not confer an OS benefit in this population. However, other functional organ-preserving approaches may also be appropriate; shared decision making about therapy is necessary, taking into account clinical factors such as performance status, comorbidities and general health, and tumor characteristics. (See 'Chemotherapy plus definitive locoregional therapy' above.)

Sequential therapy for select patients – The use of induction chemotherapy followed by concurrent chemoradiation (sequential therapy) may offer additional advantages over concurrent chemoradiation alone in select situations. (See 'Sequential therapy' above and 'Approach to functional organ preservation' above.)

-Sequential therapy may be preferable for select patients with a very good performance status and high risk of distant metastases (more extensive lymph node disease, including bulky N2b, N2c, and N3) or advanced primary disease (T3 or T4). Patients should receive therapy at a center that can give optimal supportive care.

-Induction chemotherapy may provide a long-term survival advantage for larynx cancer patients when compared with concurrent chemoradiation alone.

-Concurrent chemoradiation without induction is preferable for patients less likely to have distant metastases (N0 and N1 presentations).

Selection of induction chemotherapy regimen – For patients treated with induction chemotherapy, we recommend the combination of docetaxel, cisplatin, and fluorouracil (TPF (table 2)) chemotherapy rather than cisplatin plus fluorouracil (PF (Grade 1A)), as this approach significantly improved local control and OS. However, the decision to offer induction chemotherapy should be individualized, as data are mixed for whether sequential therapy provides a survival advantage over concurrent chemoradiation alone. (See 'Induction chemotherapy' above and "Treatment protocols for squamous cell carcinoma of the head and neck".)

Because of the high frequency of severe neutropenia during TPF (table 2 and table 3) induction chemotherapy, we suggest primary prophylaxis with a fluoroquinolone, granulocyte colony-stimulating factor (G-CSF), or both (Grade 2B). (See 'Prevention of infection' above.)

HPV associated tumors receiving definitive chemoradiation – For most patients with HPV associated tumors receiving definitive chemoradiation, we recommend cisplatin-based regimens rather than cetuximab for chemosensitization (Grade 1B). When combined with RT in this population, cisplatin has demonstrated superior survival compared with cetuximab, regardless of its administration schedule (weekly or bolus); it has a similar rate of severe toxicity, although with a different toxicity profile. (See 'Concurrent chemotherapy' above and 'Cetuximab versus cisplatin for definitive chemoradiation' above.)

Ineligible for cisplatin – However, for patients with HPV associated tumors who are not eligible for cisplatin, we suggest carboplatin-based regimens (eg, weekly carboplatin, weekly carboplatin and paclitaxel, or carboplatin plus fluorouracil) over cetuximab (Grade 2C) as a radiation sensitizer. (See 'Carboplatin-based regimens' above.)

Non-HPV associated tumors receiving definitive chemoradiation – For patients with non-HPV associated tumors receiving definitive chemoradiation, we also suggest platinum-based regimens rather than cetuximab (Grade 2C), although we recognize that these chemosensitizers have not been directly compared in this population. (See 'Cisplatin' above and 'Cetuximab versus cisplatin for definitive chemoradiation' above.)

Choice of cisplatin dosing – For patients receiving cisplatin as a radiosensitizer, we suggest weekly rather than bolus cisplatin (Grade 2C). In a randomized trial, weekly cisplatin as part of definitive chemoradiation had noninferior locoregional control and was better tolerated compared with bolus cisplatin. Weekly cisplatin is administered at 40 mg/m2, given concurrently with RT, to achieve a total dose of ≥200 mg/m2. (See 'Cisplatin' above.)

Choice of chemosensitizer after induction chemotherapy – For patients who received induction chemotherapy with TPF (table 2) or another cisplatin-containing regimen, we suggest concurrent chemotherapy with low-dose weekly carboplatin (dosed at an area under the concentration X time curve [AUC] of 1.5), as was done in the TAX 324 trial (Grade 2C). (See 'Induction chemotherapy' above.)

Ineligible for cisplatin – For patients who are ineligible for cisplatin, options include a carboplatin-based regimen (eg, weekly carboplatin, weekly carboplatin and paclitaxel, or carboplatin plus fluorouracil) or docetaxel. (See 'Carboplatin-based regimens' above and 'Docetaxel' above.)

Older adults – Older adults and those with significant comorbidities are treated with RT alone rather than cetuximab plus RT or a platinum plus RT. (See 'Chemotherapy plus definitive locoregional therapy' above and "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

RT planning and schedule – Careful RT planning is required to ensure that an adequate course of definitive RT is administered in a timely fashion; delays or an incomplete course of treatment may lead to an increased risk of locoregional recurrence. (See 'Radiation therapy planning' above.)

We recommend once-daily fractionation of RT in combination with concurrent chemotherapy rather than a hyperfractionated or accelerated regimen (Grade 1A). Although alternative RT schedules improve outcomes when administered without concurrent chemotherapy, altered fractionation does not compensate for the lack of concurrent chemotherapy. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

Intensity-modulated RT – We use intensity-modulated RT or associated technologies, in conjunction with frequent imaging of the treatment fields and volumes during the course of RT. These techniques enable high conformality of radiation doses to the targets and spare organs that were previously included in the high-dose fields, such as the salivary glands and important swallowing structures. Clinical benefits in reducing xerostomia and dysphagia have been observed. (See "General principles of radiation therapy for head and neck cancer", section on 'Intensity-modulated RT'.)

Role of surgery after chemotherapy and RT – Surgery should be offered to patients with poor responses in the primary site or neck after induction chemotherapy and is indicated for patients with proven residual disease after RT or concurrent chemoradiation. (See 'Role of surgery' above.)

Neck dissection is indicated for patients with clinically detectable residual disease or a positive positron emission tomography (PET) scan 12 weeks after concurrent chemoradiation. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

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