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Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer

Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer
Literature review current through: Jan 2024.
This topic last updated: Apr 17, 2023.

INTRODUCTION — Selected high-risk patients with head and neck squamous cell carcinoma receive adjuvant (ie, postoperative) radiation therapy (RT), with or without concurrent chemotherapy, following primary surgical resection with the aim of improving locoregional control and survival. The rationale for this approach is that RT may eradicate microscopic deposits of cancer cells that would progress and lead to a locoregional recurrence.

The role of adjuvant RT for head and neck cancer, usually given with concurrent chemotherapy, will be reviewed here. Other relevant topics are discussed separately:

(See "General principles of radiation therapy for head and neck cancer".)

(See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

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

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

APPROACH TO ADJUVANT MANAGEMENT — Patients who have undergone gross total resection of their primary tumor may be at high risk of recurrent disease, depending on the specific clinicopathologic features of their tumor. In this situation, adjuvant radiation therapy (RT), generally in conjunction with chemotherapy, can improve the likelihood of disease-free survival. The approach described below is in general agreement with guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) [1-3].

Adjuvant chemoradiation is generally restricted to patients thought to be at highest risk of locoregional recurrence. It should be used with caution and only in those at high risk because of the morbidity of adding chemotherapy to adjuvant RT and the uncertainty regarding a survival benefit [4]. RT alone remains an alternative for patients with intermediate levels of increased risk or for those who cannot tolerate concurrent chemotherapy.

Factors that have been associated with an increased risk of locoregional recurrence after surgery include the following:

Advanced tumor stage (T3/T4)

Positive resection margins or tumor close to the resection margin

Tumor extension through the lymph node capsule (extranodal extension)

Two or more pathologically positive lymph nodes

Perineural invasion

Lymphovascular space invasion

Positive margins and extracapsular extension are the two most unfavorable parameters, both of which are associated with significant increases in locoregional recurrence and mortality [5-8]. These two features constitute the typical indication(s) for the addition of chemotherapy to RT. The definition of positive margins is not standardized; however, invasive tumor within 5 mm of the resection margin is commonly used [9]. Metastases in a single ipsilateral lymph node, 3 cm or less in greatest dimension (ie, N1 lymph node stage), is not considered a high-risk feature in the absence of other adverse factors [10].

Extranodal extension may also have prognostic significance in the patient with human papillomavirus (HPV) associated oropharyngeal cancer. Initial retrospective data suggested that extranodal extension is not a negative prognostic feature in these patients, not affecting disease-free or disease-specific survival [11,12], unlike carcinomas originating in the oral cavity and hypopharynx/larynx. However subsequent observational and prospective studies found that extranodal extension was associated with inferior survival in patients with HPV associated tumors [13-15]. Other traditional risk factors, advanced T stage and number of nodal metastases, were also associated with decreased survival. While clinical trial data evolves, it is important to maintain current adjuvant treatment protocols in those patients who will have a stage change under the eighth edition American Joint Committee on Cancer (AJCC) staging system for HPV associated oropharyngeal carcinoma (table 1A-B).

ADJUVANT CHEMORADIATION — Clinical trials have demonstrated that adjuvant concurrent chemoradiation is more likely than adjuvant radiation therapy (RT) alone to control locoregional disease and improve disease-free survival for patients at high risk of recurrent disease. Thus, we recommend adjuvant concurrent chemoradiation over adjuvant RT alone for patients at highest risk (ie, those with positive surgical margins and/or extranodal extension).

Chemoradiation versus radiation therapy alone — Two cooperative group trials compared adjuvant chemoradiation with adjuvant RT alone and provide insights into which patient subsets benefit from a combined approach:

In the European Organization for Research and Treatment of Cancer (EORTC) trial 22931, 334 patients with resected high-risk head and neck cancer were randomly assigned to RT alone (66 Gy in 33 daily 2 Gy fractions) or the same dose with concomitant cisplatin (100 mg/m2, on days 1, 22, and 43 of RT) [16]. High-risk disease was defined as a T3 or T4 primary with any nodal stage (except T3N0 laryngeal cancer), positive surgical margins, extranodal extension, perineural invasion, vascular invasion, or oral cavity/oropharyngeal primary sites with involvement of level IV or V lymph nodes. With a median follow-up of 60 months, adjuvant concurrent chemoradiation significantly improved five-year progression free survival, locoregional control, and overall survival compared with adjuvant RT alone (47 versus 36 percent, 82 versus 69 percent, and 53 versus 40 percent, respectively).

The Radiation Therapy Oncology Group (RTOG) 9501 trial randomly assigned 459 patients with resected high-risk head and neck cancer to RT alone (60 to 66 Gy in 30 to 33 fractions) or the same dose of RT with concomitant cisplatin (100 mg/m2, on days 1, 22, and 43 of RT) [17]. High-risk patients were limited to those with positive resection margins, involvement of two or more lymph nodes, or extranodal extension. In an initial report with a median follow-up of 46 months, concurrent chemoradiation improved two-year locoregional control and disease-free survival compared with RT alone (82 versus 72 percent and 54 versus 45 percent, respectively). However, the increase in overall survival was not statistically significant (64 versus 57 percent).

In both trials, the incidence of acute severe mucosal toxicity was significantly greater with adjuvant concurrent chemoradiation compared with RT alone (77 versus 34 percent in the EORTC trial), but late complications were comparable for both treatments.

The failure of these two trials to reach the same conclusion (ie, that concurrent chemoradiation improves locoregional control, disease-free survival, and overall survival) has been attributed to the different patient populations included in these two trials [4,18]. When comparative analyses were performed on pooled data from these trials (including selection criteria, clinical and pathologic risk factors, and treatment outcomes), extranodal extension and microscopically involved surgical margins were the only risk factors for which the impact of adjuvant concurrent chemoradiation was significant in both trials [18].

In extended follow-up of RTOG 9501 at 10 years, compared with RT alone, chemoradiation did not improve locoregional failure (22 versus 29 percent), disease-free survival (20 versus 19 percent), or overall survival (29 versus 27 percent) [19]. However, in an unplanned subgroup analysis of patients with extranodal spread or positive margins, chemoradiation improved locoregional control and disease-free survival and trended towards improved overall survival.

Consequently, we and others recommend adjuvant concurrent chemoradiation over adjuvant RT alone primarily for patients with positive surgical margins and/or extranodal extension [18,20]. Whether concurrent chemoradiation should be routinely added to adjuvant RT for patients with locoregionally advanced head and neck cancer and other adverse features is less clear. However, one large retrospective study suggests the effects of adjuvant chemoradiation on overall survival differed according to the number of positive lymph nodes, with the greatest absolute benefit in patients with two to four, or five or greater lymph nodes [21]. chemoradiation

Patients at elevated risk for recurrence based on perineural or vascular invasion, two or more involved lymph nodes, or T3 and T4 tumors are considered to be at intermediate risk and are commonly treated with adjuvant RT alone. The phase III RTOG 0920 trial is comparing RT alone versus RT plus cetuximab in patients with intermediate risk disease (NCT00956007). Likewise, the Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) Cancer Research Group phase III trial is comparing RT alone with RT plus weekly cisplatin in patients with disruptive p53 mutations after primary surgical resection with negative surgical margins, no extranodal extension, and no gross residual disease (NCT02734537). (See 'Adjuvant radiation therapy alone' below.)

It is also important to note the primary site of disease, such as human papillomavirus (HPV) associated oropharyngeal cancer. The approach to adjuvant RT and chemoradiation in these patients is discussed separately. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Adjuvant RT with or without chemotherapy'.)

It has not been clearly established in prospective clinical trials that adjuvant chemoradiation provides greater benefit than RT alone in HPV associated head and neck cancer. A randomized trial (NCT01687413) attempted to answer this question, but was terminated due to poor accrual and funding issues. Further details on clinical trials evaluating treatment deintensification in HPV associated oropharyngeal cancer are discussed separately. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Is there a role for treatment deintensification?'.)

Concurrent chemotherapy regimen

Platinum-based chemotherapy

Cisplatin — For patients who are eligible for platinum-based chemotherapy, we recommend administering weekly dosing of cisplatin (40 mg/m2 weekly) rather than bolus dosing (100 mg/m2 every 21 days for three cycles) concurrently with adjuvant RT. In a randomized trial, weekly cisplatin demonstrated non-inferior overall survival and an improved toxicity profile when compared with bolus cisplatin [22]. Bolus dosing of cisplatin is associated with considerable severe acute and late toxicities and is no longer the preferred regimen for patients receiving adjuvant chemoradiation [16,17].

For patients who are ineligible for cisplatin-based chemotherapy, we suggest treatment with RT alone rather than concurrent chemoradiation with carboplatin. (See 'Carboplatin' below.)

While previous randomized studies suggested potential clinical benefit for weekly cisplatin in patients receiving adjuvant chemoradiation [23-25], the cisplatin dosing in these studies were not consistent (ranging between 30 mg/m2 to 50 mg/m2 weekly). Additionally, one randomized study of chemoradiation in the adjuvant setting did not confirm superior locoregional control with weekly cisplatin compared with bolus cisplatin [26]. However, this study consisted exclusively of patients with oral cavity disease, limiting its applicability to other disease sites, and demonstrated more toxicity for the bolus regimen.

The clinical benefits of weekly dosing of cisplatin at 40 mg/m2 were confirmed in an open label phase II/III trial (JCOG1008) of 261 patients with resected high-risk pathologic AJCC seventh edition stage III-IVB disease (eg, positive surgical margins and/or extranodal extension). Patients enrolled had primary tumors of the oral cavity, larynx, oropharynx, or hypopharynx; notably, approximately half (121 patients) had oral cavity primary tumors. In this study, patients were randomly assigned to adjuvant chemoradiation (66 Gy) with either weekly cisplatin (40 mg/m2 weekly for six to seven doses) or bolus cisplatin (100 mg/m2 every three weeks) [22]. At median follow-up of 2.2 years, compared with bolus cisplatin, weekly cisplatin demonstrated non-inferior overall survival (OS), relapse-free survival (RFS), and local relapse-free survival (LRFS) at three years (OS, 72 versus 59 percent, HR 0.69, 95% CI 0.37-1.27; RFS, 64 versus 53 percent, HR 0.71, 95% CI 0.48-1.06; LRFS 70 versus 60 percent, HR 0.73, 95% CI 0.47-1.13). Both groups achieved the crucial cumulative cisplatin dose ≥200 mg/m2 (230 versus 280 mg/m2), as data suggest this threshold is more effective than lower cumulative doses, when given concurrently with RT [27-29].

Weekly cisplatin had a more favorable toxicity profile compared with bolus cisplatin, which is associated with severe acute and late toxicities [16,17]. Grade ≥3 toxicities were lower in the weekly cisplatin group than the bolus cisplatin group, including neutropenia (35 versus 49 percent), dysphagia (12 versus 18 percent), nausea (5 versus 13 percent), and infection (7 versus 12 percent). Specific platinum-related toxicity of any grade were also lower in the weekly cisplatin group, including hyponatremia (82 versus 92 percent), renal impairment (30 versus 40 percent), hearing impairment (7 versus 17 percent), and peripheral neuropathy (2 versus 5 percent).

The use of cisplatin as a chemosensitizing agent in patients receiving definitive chemoradiation is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cisplatin'.)

Carboplatin — For patients are ineligible for cisplatin-based therapy, we suggest treatment with RT alone rather than alternative platinum agents (eg, carboplatin), particularly for those who are ineligible due to age, comorbidities, and/or performance status. While we offer this same approach to those who are ineligible for cisplatin-based therapy due to other conditions (eg, kidney disease, neuropathy, sensorineural hearing loss, congestive heart failure) but otherwise have good performance status or minimal comorbidities, the additive benefit of other chemosensitizing regimens to RT remains under investigation. (See 'Other regimens' below.)

When carboplatin (50 mg/m2 twice weekly) rather than cisplatin was used as the concurrent chemotherapy in a clinical trial of patients with lymph node-positive head and neck cancer, no significant improvement in locoregional control or overall survival was seen compared with RT alone [30]. Whether this was due to the chemotherapy regimen or other factors, such as patient selection, is unclear.

The approach to the optimal chemotherapy regimen in patients receiving definitive concurrent chemoradiation is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Concurrent chemotherapy'.)

Other regimens — Both weekly docetaxel and cetuximab have demonstrated activity in patients with head and neck cancer in other clinical settings and are being investigated as alternatives to cisplatin in the adjuvant setting.

Cetuximab — Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has established efficacy when given concurrently with RT, as opposed to RT alone, in the primary treatment of locoregionally advanced head and neck cancer not including the oral cavity. However, the role of cetuximab is not established in the adjuvant setting and should only be used as part of an adjuvant strategy in the context of a clinical trial. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cetuximab plus radiation therapy'.)

In a randomized phase II trial, patients were randomly assigned to weekly low-dose cisplatin plus cetuximab or weekly docetaxel plus cetuximab following gross total resection of tumor [25,31]. Both combinations were feasible, with expected increased toxicity attributable to the addition of cetuximab and favorable outcomes compared with historical controls. In addition, the trial provided preliminary evidence that taxanes may be as effective as cisplatin in head and neck cancer.

Phase III clinical trials assessing the role of cetuximab include the following:

RTOG 0920, in which patients with intermediate-risk locally advanced, resected head and neck cancer are being randomly assigned to adjuvant intensity-modulated RT (IMRT) with or without cetuximab (NCT 01311063).

RTOG 1216, in which patients with high-risk, locally advanced, resected head and neck cancer are being randomlyhttps://www.clinicaltrials.gov/ct2/home assigned to IMRT plus weekly cisplatin, IMRT plus weekly docetaxel and cetuximab, or weekly cisplatin plus atezolizumab (NCT01810913).

Docetaxel — Weekly docetaxel, in conjunction with weekly cetuximab, has been studied as a concurrent regimen with adjuvant RT in patients with high-risk head and neck cancer. Results from the randomized phase II RTOG 0234 study have suggested that this may be an alternative to cisplatin; RT concomitantly given with weekly docetaxel in combination with cetuximab is being compared against a weekly cisplatin regimen and a weekly cisplatin in combination with atezolizumab regimen in the phase II/III RTOG 1216 trial (NCT01810913).

ADJUVANT RADIATION THERAPY ALONE — Adjuvant radiation therapy (RT) without concurrent chemotherapy is inferior to concurrent chemoradiation following gross tumor resection for high-risk disease. However, RT alone may retain a role for patients with intermediate-risk disease and for those whose overall condition cannot tolerate a concurrent therapy.

Data supporting the use of adjuvant RT without concurrent chemotherapy to improve locoregional control and survival are limited to two randomized trials and retrospective observational data:

One trial of 51 patients with advanced head and neck cancer found that the addition of RT to surgery decreased the overall recurrence rate [32]. However, no difference in overall survival was observed.

A second trial, limited to 140 patients, all with squamous cell carcinoma of the buccal mucosa, did observe a statistically significant increase in disease-free survival at three years with adjuvant RT compared with surgery alone [33].

Retrospective studies suggest that adjuvant RT improves survival after surgery, although this benefit may be limited to carefully selected high-risk patients. As an example, a Surveillance, Epidemiology and End Results (SEER) database study analyzed outcomes in 8795 patients with lymph node-positive head and neck cancer diagnosed between 1988 and 2001 [34]. All patients were treated with surgery and RT or surgery alone. On univariate analysis, the addition of adjuvant RT to surgery was associated with a significantly improved five-year overall survival (43.2 versus 33.4 percent) and cancer-specific survival (50.9 versus 42.1 percent). More detailed analyses of other observational series also support a role for adjuvant RT [35,36].

Adjuvant RT can cause important acute and late toxicity, which is related to the dose of radiation. For example, in a series of patients treated with either lower dose (57.6 Gy over 6.5 weeks) or higher dose (63 Gy over five weeks) adjuvant RT, confluent mucositis was present in the low- and high-dose cohorts in 5 and 47 percent of patients, and tube feeding was required in 12 and 39 percent of patients, respectively [37]. In addition, the five-year actuarial rates of late grade 3 and 4 toxicity (ulcer/soft tissue necrosis, fibrosis, dysphagia, fistula/osteonecrosis) were 17 and 38 percent for the low- and high-dose groups. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management of late complications of head and neck cancer and its treatment".)

Additional data may be derived from the phase III Radiation Therapy Oncology Group (RTOG) 0920 trial, which is comparing RT alone with RT plus cetuximab in patients with intermediate-risk disease (NCT00956007), or from EA3132, which is comparing RT alone with weekly cisplatin plus RT in patients with disruptive p53 mutations (NCT02734537).

ADMINISTRATION — The total dose, timing, and duration of therapy may all affect outcomes in patients with head and neck squamous cell carcinoma receiving adjuvant radiation therapy (RT) or concurrent chemoradiation [37,38].

Initiation and treatment delays — In the absence of wound healing issues or medical contraindications, adjuvant RT should be started no later than six weeks after surgery and should be completed in a timely manner.

The time interval between surgery and initiation of RT as well as the duration of adjuvant RT also appear to have an impact on outcome [37-39]. Patients who begin RT more than six weeks after surgery are more likely to develop a local recurrence [38]. Locoregional control is also better for patients who complete adjuvant RT within 100 days or less from the date of surgery compared with patients treated over a longer period of time [37,39].

Dose and treatment volume — The treatment parameters of adjuvant RT for head and neck cancer vary with the clinical and pathologic findings. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'Paradigms of dose and fractionation modification'.)

If all gross disease is resected with negative surgical margins in patients with advanced primary lesions (T3/4), adjuvant RT doses of 56 to 60 Gy to the primary tumor bed are recommended. For patients with microscopically positive margins or extracapsular extension, a 6 Gy boost in three fractions for a total dose of 66 Gy to that region is recommended. For those with grossly positive margins, the site of residual disease should be boosted to a total dose of 70 Gy.

Patients with high-risk features (positive surgical margins, extranodal extension) who are not candidates for adjuvant concurrent chemoradiation are treated with doses of at least 60 Gy. Dose-response relationships are less well understood when concurrent chemotherapy is utilized, but most high-risk volumes typically receive doses ≥60 Gy in 2 Gy daily fractions.

The neck is usually included with adjuvant RT. A notable exception is that the neck is not included when treating patients with oral cancer in which the primary tumor has no high-risk characteristics and is either pathologically node negative or has a single pathologically positive node without adverse features after high-quality neck dissection.

Subclinical regions (ie, clinically negative neck) that have not been dissected are electively treated to the equivalent of 50 Gy in 25 fractions, which would be 54 Gy if 30 fractions are delivered at 1.8 Gy per fraction to the dissected neck. Operated but non-tumor-bearing areas typically receive 56 to 57 Gy. Involved nodal regions receive 60 Gy in 30 fractions, and regions of extranodal extension may receive an additional boost of 4 to 6 Gy in two to three fractions.

In an early clinical trial that aimed to establish the optimal dosing for conventionally fractionated adjuvant RT and that provided the initial evidence for a dose-response relationship, 261 evaluable patients were randomly assigned to one of three dose levels (57.6, 63, or 68.3 Gy, all given with 1.8 Gy/day fractionation) [7,40]. In an initial interim analysis, 17 patients treated with a dose of ≤54 Gy had a significantly higher primary failure rate compared with those treated with higher doses, and that group was dropped from the trial. In a final analysis with more than 20 years follow-up, no significant dose response was demonstrated at doses ≥57.6 Gy in the final analysis in either the intermediate- or high-risk groups. On multivariate analysis, negative surgical margins, the absence of extracapsular extension, and total treatment time <85 days were independently associated with better locoregional control and overall survival. However, it is important to note that many of the high-risk patients included in this trial would receive concurrent chemoradiation in the contemporary treatment era, and it is therefore difficult to know how these data apply to such patients.

Schedule — Conventional adjuvant RT schedules typically deliver 54 to 66 Gy in 2 Gy daily fractions, over five to seven weeks.

Altered-fractionation RT schedules, including accelerated RT and hyperfractionation, have been investigated to overcome accelerated repopulation and to safely escalate the dose. These strategies when compared with conventional, once-daily RT have demonstrated improved locoregional control, but a survival benefit has not been established [41-43]. The added cost and logistical challenges of multiple fractions per day RT have limited their implementation. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'Hyperfractionation' and "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'Accelerated fractionation RT'.)

Radiation therapy techniques — A standard approach for patients treated with adjuvant RT is to use conventional fractionation external beam RT (EBRT) using three-dimensional conformal treatment planning (3D-CRT). Intensity-modulated RT (IMRT) and refinements, such as image-guided RT (IGRT), are used wherever available. The dosimetric advantages of protons over IMRT in the treatment of head and neck cancer are related to reduced doses to noninvolved tissues, but controlled trials comparing observer and patient-reported outcomes in the adjuvant setting are lacking [44]. (See "General principles of radiation therapy for head and neck cancer", section on 'External beam radiation therapy'.)

3D-CRT usually starts with large fields covering all areas at risk to 50 Gy, followed by shrinking fields to boost higher risk areas. The spinal cord is excluded after 40 Gy. A final boost treatment to the primary tumor bed and neck regions with involved lymph nodes may be administered using either EBRT or brachytherapy.

Retrospective studies suggest that a treatment boost with brachytherapy may improve local control for patients with positive tumor margins [45,46]. However, brachytherapy is used less frequently since the majority of patients with positive margins typically receive chemotherapy concurrently with adjuvant RT, and the brachytherapy catheters must be available to be placed at the time of surgery.

IMRT typically delivers a dose of 60 Gy in 30 fractions. CTV1 (high-risk areas) gets 60 Gy, CTV2 gets 57 Gy (intermediate-risk operated areas), and CTV3 (non-operated, elective areas, eg, N0 contralateral neck) gets 54 Gy. A boost for extracapsular extension or positive microscopic margins, as described above, can be used to 66 Gy.

Adjuvant versus neoadjuvant radiation therapy — RT is used almost exclusively as adjuvant therapy for head and neck cancer. Neoadjuvant (eg, preoperative) RT is no longer used due to concerns about operating in an irradiated field, the poorer local control in one older trial, the ability to use pathologic findings to guide high-dose RT planning, and the use of functional organ preservation approaches (chemoradiation). In the RTOG 7303 trial, preoperative RT used a dose of 50 Gy and the local control was worse than adjuvant RT with a dose of 70 Gy [47]. There was no difference in overall survival. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

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

Goals of adjuvant radiation therapy (RT) – Selected patients with head and neck squamous cell carcinoma treated with primary surgical resection who are at increased risk for locoregional recurrence are treated with adjuvant (ie, postoperative) radiation therapy (RT), with or without concurrent chemotherapy, with the aim of improving locoregional control and survival. (See 'Introduction' above.)

Clinicopathologic features indicating risk of recurrence – For patients who have undergone surgery for locoregionally advanced head and neck cancer, we recommend adjuvant RT for those with the following high-risk features (Grade 1B) (see 'Approach to adjuvant management' above):

Advanced tumor stage (T3/T4).

Positive or close margins.

Two or more positive lymph nodes (N2/N3).

Extranodal extension – There are not enough data to reduce the adjuvant radiation dose or eliminate chemoradiation in patients with human papillomavirus (HPV) associated versus non-HPV associated oropharyngeal cancer.

Perineural or lymphovascular invasion.

Indications for adjuvant chemoradiation – For patients with positive surgical margins or extranodal extension, we suggest adjuvant concurrent chemoradiation rather than adjuvant RT alone (Grade 2C). We offer this approach regardless of the HPV status of the tumors. (See 'Adjuvant chemoradiation' above and "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Adjuvant RT with or without chemotherapy'.)

However, further data on the benefits of adjuvant chemoradiation versus adjuvant RT in HPV associated tumors with extranodal extension are necessary, as observational studies are mixed and prospective clinical trials are limited. (See 'Approach to adjuvant management' above and "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Is there a role for treatment deintensification?'.)

Additionally, data do not show a clear benefit to adding chemotherapy to adjuvant RT for those with two or more positive lymph nodes in the absence of extranodal extension or positive margins. The use of chemotherapy for these patients should be determined on an individual basis, although retrospective data suggest that chemoradiation may provide a survival benefit.

For patients eligible for platinum-based chemotherapy, we recommend weekly cisplatin (40 mg/m2 weekly) rather than bolus cisplatin (100 mg/m2 every three weeks for three doses) concurrent with RT (Grade 1B). (See 'Platinum-based chemotherapy' above.)

For patients who are not candidates for cisplatin-based therapy, we suggest RT alone rather than concurrent chemoradiation with carboplatin or other systemic agents. (See 'Carboplatin' above and 'Other regimens' above.)

Indications for adjuvant RT – For patients with an increased risk of recurrence, but without positive surgical margins or extranodal extension, we suggest adjuvant RT without systemic therapy (Grade 2C). (See 'Adjuvant radiation therapy alone' above.)

Timing of adjuvant RT – In the absence of wound healing issues or medical contraindications, adjuvant RT should be started within six weeks after surgery and completed in a timely manner. (See 'Administration' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Shruti Jolly, MD, who contributed to an earlier version of this topic review.

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Topic 3374 Version 45.0

References

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