Treatment of human papillomavirus associated oropharyngeal cancer

INTRODUCTION — Human papillomavirus (HPV) infection, a common sexually transmitted disease, has been associated with the development of many cancers, including oropharyngeal squamous cell carcinoma (OPSCC) of the head and neck. (See "Virology of human papillomavirus infections and the link to cancer".)

While traditional, environmentally related OPSCC rates have declined, there has been a dramatic rise in OPSCC related to high-risk types of HPV. Patients with locoregionally confined HPV associated OPSCC typically have highly curable cancers and a better prognosis than those with non-HPV associated OPSCC.

The treatment approach to HPV related OPSCC will be reviewed here. Details on the epidemiology, staging, and clinical presentation of HPV related head and neck squamous cell carcinoma, as well as the treatment of non-HPV associated oropharyngeal head and neck cancer are discussed separately.

●(See "Epidemiology and risk factors for head and neck cancer", section on 'Human papillomavirus'.)

●(See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

●(See "Treatment of early (stage I and II) head and neck cancer: The oropharynx".)

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

CLINICAL PRESENTATION — The clinical presentation of HPV associated oropharyngeal squamous cell carcinoma (OPSCC) is distinct from non-HPV associated OPSCC (table 1). These features are discussed in detail separately. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Clinical presentation'.)

STAGING — The eighth edition American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging systems (table 2A and table 2B) were modified from the previous seventh edition to address the improved outcomes of HPV related oropharyngeal squamous cell carcinoma (OPSCC) relative to those with non-HPV associated disease [1-8]. The most notable changes to the staging system are the reassignments of the cervical nodal metastasis groupings [9].

This was the direct result of data which demonstrated improved outcomes in this disease relative to its non-HPV related counterpart, and the fact that the prior AJCC staging system was inadequate to properly stratify this population [2-5,10]. The revised eighth edition staging system appears to offer superior discrimination when compared with the previous staging system [6,7]. Despite the improvements in the staging system, additional data are required to validate and refine this new system, and results of clinical trials designed and stratified according to the revised staging will provide insights into the system's performance [8]. For example, smoking imparts a negative effect on outcome in HPV associated OPSCC but is not incorporated into the staging system. Most clinical trials, in particular those evaluating treatment deintensification, exclude or stratify by patients who smoke.

The purpose of the AJCC eighth edition stage group is to provide prognostic value and not necessarily to guide treatment decision making. Rather, treatment decisions should continue to employ the AJCC seventh edition staging system and match the staging criteria which determined eligibility for enrollment into the trials which established each relevant standard of care. As an example, some patients classified as stage I in the eighth edition of the AJCC staging system would have been stage III or IVA in the seventh edition of the AJCC staging system and therefore included in the pivotal trials of chemoradiation. While stage I HPV mediated oropharynx cancer has an excellent prognosis as described in the eighth edition of the AJCC staging manual, the existing evidence supports multimodality treatment for a subset of these patients.

Our treatment approach is generally consistent with the American Society of Clinical Oncology (ASCO) Provisional Clinical Opinion on the Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer [11]. (See "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'General principles' and 'Is there a role for treatment deintensification?' below.)

Further details on the staging system for HPV associated head and neck cancer are discussed separately.

PRETREATMENT EVALUATION — The pretreatment evaluation of patients with HPV associated head and neck cancer is similar to that of non-HPV associated cancers, and should include the following:

●Nutrition consultation – Patients with HPV related oropharyngeal squamous cell carcinoma (OPSCC) who are underweight prior to therapy have worse overall survival (OS) [12]. Therefore, patients should be evaluated by a nutritionist to ensure appropriate nutritional intake during and after therapy. The evaluation should include intake of oral nutrition, use of liquid nutritional supplements, and consideration of enteral nutrition (eg, tube feeds) with placement of a gastrostomy tube only when indicated. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Head and neck cancer'.)

●Evaluation for intravenous (IV) access and gastrostomy tube placement – We evaluate all patients for IV access and potential placement of a subcutaneous port (depending upon the expected treatment received) and their need for gastrostomy tube. (See "Gastrostomy tubes: Placement and routine care" and "Central venous access in adults: General principles", section on 'Subcutaneous ports'.)

●Dental evaluation – Patients undergoing surgery or radiation should receive a complete dental evaluation. All dental procedures (eg, tooth extractions, root canals) should be completed prior to initiation of therapy, when feasible. Changes to the teeth and jaw from these procedures may affect treatment planning. Additionally, poor dental health may lead to long-term complications after therapy is completed. (See "Overview of approach to long-term survivors of head and neck cancer", section on 'Dental complications and oral health'.)

●Speech and swallowing evaluation – Many patients have baseline tumor-related dysphagia, and a significant number develop treatment-related dysphagia. Early identification of dysphagia and early intervention with swallowing therapy may minimize the risk of muscle atrophy, aspiration pneumonia, and malnutrition. (See "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

●Pain management and supportive care – Patients may have pain related to their tumor or cervical lymphadenopathy; others develop treatment-related symptoms that require pain management and extensive supportive care. Early consultation with pain management and/or other supportive care teams is encouraged. (See "Management and prevention of complications during initial treatment of head and neck cancer".)

INITIAL TREATMENT — The treatment of HPV related oropharyngeal squamous cell carcinoma (OPSCC) may include surgery, radiation therapy (RT), and chemotherapy, either as single modalities or in combination. In particular, nonsmoking patients with early-stage HPV associated OPSCC are highly curable with these treatment modalities.

Treatment for patients with HPV associated OPSCC is similar to those with HPV negative OPSCC, except in the context of a clinical trial. Although testing for HPV association provides prognostic information, there are insufficient phase III data to alter therapy based on HPV status [13]. Given the excellent long-term prognoses of these patients, the approach to treatment must take into consideration oropharyngeal function preservation, the potential for late treatment-related toxicities, and avoidance of unnecessary intensification of therapy, if possible. (See "Management of late complications of head and neck cancer and its treatment".)

Improved surgical techniques, often utilizing transoral approaches, are an important option for selected patients with locoregional disease. Surgery can potentially lead to decreased use of adjuvant RT or chemoradiation, based on pathologic features, although this approach remains under investigation in deintensification trials. The potential complications of surgery should be weighed against a potential decrease in adjuvant therapy. (See 'Is there a role for treatment deintensification?' below and "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Surgery'.)

T1-T2, node negative

Selection of therapy: Surgery versus radiation — For patients with HPV associated early-stage, node-negative (eg T1-T2, N0) disease, we offer initial treatment with either minimally invasive surgery or RT (algorithm 1). This approach is similar to that of patients with non-HPV associated OPSCC. (See "Treatment of early (stage I and II) head and neck cancer: The oropharynx".)

It is uncommon for patients with HPV associated disease to present with early-stage, node-negative tumors, as most present with nodal involvement (table 1). Therefore, data are limited for the optimal treatment approach in this patient subgroup, and clinical trials are ongoing. (See 'Is there a role for treatment deintensification?' below.)

The choice of therapy should be based on a clinical risk-benefit discussion in a multidisciplinary setting and take into account functional outcomes and potential toxicities of each treatment modality, as well as patient comorbidities and preferences for therapy.

●Surgery – Surgery alone is appropriate when the primary tumor appears amenable to margin-negative resection and good functional outcomes (ie, well-lateralized T1-T2 disease without significant soft palate involvement). As an example, patients with tonsillar cancers (which are lateralized by definition) who meet these criteria may be more appropriate surgical candidates than those with a base of tongue cancer (which is typically located more centrally in the oropharynx).

For patients who choose surgery, we suggest minimally invasive transoral surgery rather than more invasive surgical techniques (eg, transmandibular or transcervical open surgery). These patients also should undergo elective neck dissection. Some patients may prefer surgery over other treatment approaches such as RT, as resection offers both immediate diagnosis and treatment. However, not all patients are candidates for surgery due to anatomic considerations or comorbidities. Patients should take into account potential surgical risks and complications, (eg, anesthesia, bleeding, operative morbidity, potential for functional impairment). A thorough evaluation by an experienced, high-volume surgeon is needed to assess these possibilities, as surgical outcomes are superior with such surgeons. As well, careful radiographic evaluation is warranted, as pathologic findings often indicate the need for postoperative radiation or chemoradiation, with the attendant risks of multimodality therapy. (See 'Surgical technique' below.)

One randomized trial (ECOG-ACRIN 3311) suggested excellent survival outcomes in patients with no nodal involvement (or one node without extranodal extension) treated with transoral robotic surgery (TORS) alone [14], further confirming the efficacy of surgery as a single modality in patients with HPV-associated, early-stage, node-negative disease. In this study, the subset of patients with HPV associated OPSCC treated with TORS followed by observation demonstrated excellent survival outcomes. Further details for this trial in the context of treatment deintensification are discussed below. (See 'Dose-reduced adjuvant radiation' below.)

However, only a minority of patients enrolled in this trial received surgery as a single modality, despite a deintensification strategy that withheld postoperative radiation for patients with a single node or initially positive margins. While carefully selected patients treated with initial primary surgery may potentially avoid the use of additional postoperative RT or chemoradiation, others may require such additional therapy. This raises the possibility that initial surgery will sometimes lead to treatment intensification and greater morbidity, and clinicians offering surgery should discuss this possibility with patients. (See 'Adjuvant RT with or without chemotherapy' below.)

●Radiation therapy (RT) – Another appropriate option is RT alone. RT is delivered to both the primary tumor and to cervical lymph nodes. RT is the preferred option for patients who are ineligible for or who wish to avoid the potential complications of surgery, or in situations where expertise in transoral resection is not available.

Radiation is often given with elective treatment of the bilateral neck. However, unilateral RT should be offered to patients with well-lateralized primary tonsillar cancers that do not invade >1 cm beyond the mucosa of soft palate or tongue base and do not extend to the posterior pharyngeal wall. Successful completion of an RT course requires adherence to a daily treatment schedule; furthermore, radiation carries risks of short- and long-term toxicities, which must be taken into account. (See 'Radiation' below.)

Surgical technique — For patients with well-lateralized T1-T2 disease with no clinical or radiographic evidence of multiple or bilateral nodes or extranodal extension that appears amenable to margin-negative resection, we suggest minimally invasive transoral surgery rather than more invasive surgical techniques (eg, transmandibular or transcervical open surgery).

Two minimally invasive techniques, transoral robotic surgery (TORS) and transoral laser microsurgery (TLM), are equally effective and well tolerated [15]. For patients who are not eligible for these minimally invasive approaches, we avoid the use of more aggressive surgical approaches (eg, transmandibular or transcervical open surgery), as these patients can be treated effectively using RT with or without chemotherapy with superior functional outcomes and high cure rates. The functional outcome of minimally invasive surgical techniques, on the other hand, can be very similar to RT. (See "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'General principles'.)

Patients treated with resection of the primary tumor should also receive selective neck dissection, as those with a clinically negative neck are still at risk of occult metastases [16-19]. The laterality of the neck dissection and the treated lymph node levels are dependent upon the location of the primary tumor. This approach is discussed in more detail separately. (See "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'Management of the neck'.)

A majority of patients treated with initial primary surgery will require additional postoperative RT or chemoradiation, either due to unexpected pathologic upstaging or uncertainty about the completeness of the resection. The likelihood of needing this type of adjuvant therapy is important to take into account during presurgical planning, as patients who receive postoperative chemoradiation will undergo treatment "intensification" by receiving three major modalities of treatment. These patients are at risk for more significant swallowing impairment, unless they are receiving de-escalated RT or more limited fields. (See 'Adjuvant RT with or without chemotherapy' below and 'Is there a role for treatment deintensification?' below.)

Short-term risks (eg, those associated with anesthesia, tumor resection, and elective neck dissection) and long-term toxicities (eg, swallowing difficulties) of surgery are discussed in more detail separately. (See "Anesthesia for head and neck surgery" and "Speech and swallowing rehabilitation of the patient with head and neck cancer", section on 'Postsurgical complications'.)

Radiation — RT monotherapy is an effective treatment strategy for patients with limited disease burden (eg T1-T2, N0 disease) [20]. Treatment with intensity-modulated radiation therapy (IMRT) is well tolerated with good functional outcomes. In addition to treatment of the primary tumor, patients with a clinically negative neck should also receive elective neck irradiation to address potential microscopic disease. This approach is discussed in more detail separately. (See "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'Radiation therapy'.)

Unilateral RT may be an appropriate strategy in patients with well-lateralized tonsillar tumors that do not invade >1 cm beyond the mucosa of the soft palate or tongue base and do not extend to the posterior pharyngeal wall [21].

Limitations to RT includes logistical issues (eg, adherence to a daily treatment schedule for up to six or seven weeks; supportive care for significant, severe short-term toxicities) and the potential for long-term toxicities associated with RT. Intensification of RT-based treatments (eg, aggressive altered fractionation schedules or the addition of chemotherapy) should be avoided in these patients with limited disease burden, because these approaches may also increase the risk and severity of short- and long-term toxicities [22]. RT-related toxicities are discussed in detail separately. (See "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects' and "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".)

T1-T2, single involved node (≤3 cm) — For patients with early-stage (T1-T2) disease with a single involved node ≤3 cm, acceptable treatment options include single-agent RT, definitive chemoradiation, or surgery (with or without adjuvant RT-based therapy). The choice between these options is based on clinical and radiographic characteristics of the tumor and involved node, patient comorbidities, and the ability of the chosen therapy to optimize functional outcomes, as discussed below.

Single-agent radiation versus definitive chemoradiation — For patients with early-stage (T1-T2) disease with a single involved node ≤3 cm who are eligible for RT-based therapies, the choice between single-agent RT and definitive chemoradiation is as follows:

●Single-agent radiation therapy – For nonsmoking patients with one small single involved node ≤3 cm without adverse features on clinical evaluation and high-quality imaging (eg, no radiographic evidence of extranodal extension), we offer single-agent RT.

In such patients with limited nodal involvement, RT is typically administered using IMRT. Careful anatomic delineation of target volumes is critical to optimize outcomes [23-25]. (See "General principles of radiation therapy for head and neck cancer".)

●Definitive chemoradiation – We offer definitive chemoradiation rather than single-agent RT to patients who are active smokers (ie, one cigarette per day over the past five years), heavy smokers (ie, >20 pack-year history of tobacco use), or have one involved node with certain high-risk features suspicious for a more advanced primary tumor or advanced nodal disease on clinical evaluation or radiographic imaging. Examples of such high-risk features include:

•Endophytic, ulcerated primary tumor

•Radiographic evidence of extranodal extension or nodal matting

•Additional highly suspicious clustered or small lymph nodes

•Retropharyngeal, level IV or V lymph node involvement (figure 1)

Additionally, chemoradiation should be offered to patients where these features are indeterminant (or cannot be determined accurately) on imaging. Further details on chemoradiation for squamous cell carcinoma of the head and neck is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Concurrent chemotherapy'.)

In patients with HPV associated OPSCC with limited primary and nodal disease burden, data are evolving for the relative risks and benefits of single-agent RT versus definitive chemoradiation, and the preferred approach remains to be defined. Prospective randomized trials are ongoing to address this issue, with some studies evaluating these approaches in the setting of treatment deintensification. (See 'Radiation versus chemoradiation' below.)

Some observational studies suggest that survival outcomes are similar for the two approaches, although such studies are subject to selection bias [26,27]. As an example, one retrospective study of approximately 1000 patients with oropharyngeal carcinoma included a cohort of 218 patients treated for HPV associated disease [27]. Among these patients, overall survival (OS; hazard ratio [HR] 0.95) and disease-specific survival (HR 1.08) were similar for those treated with radiation compared with chemoradiation. However, patients treated with chemoradiation are at higher risk for treatment-related toxicities including increased risk of hospitalization, need for gastrostomy tubes, and other platinum-based chemotherapy-related toxicity [27,28].

Surgery — Surgical resection is an acceptable alternative to single-agent RT in select nonsmoking patients with T1-T2 disease and a single involved node ≤3 cm without adverse features on clinical evaluation or high-quality imaging (eg, no extranodal extension) who can achieve good functional outcomes postoperatively. However, some UpToDate contributors prefer RT-based therapies rather than surgery in these patients. Most patients with node-positive disease who undergo surgery may still ultimately require adjuvant RT (with or without chemotherapy) due to the presence of high-risk pathologic features on postoperative pathology. (See 'Adjuvant RT with or without chemotherapy' below.)

Additionally, we administer initial RT-based therapies rather than surgery to patients in whom initial surgical resection would result in poor functional outcomes (based on the stage and extent of disease) or those with clinical or radiographic evidence of certain high-risk features suspicious for a more advanced primary or advanced nodal disease. (See 'Single-agent radiation versus definitive chemoradiation' above.)

●TORS versus RT – In patients with HPV associated OPSCC with early-stage disease and limited nodal involvement, data from one meta-analysis of 44 observational studies and randomized trials comparing TORS to RT-based therapy suggest that both approaches have similar survival outcomes [14,29,30].

As an example, a randomized phase II trial (ORATOR) directly comparing RT versus surgery in patients with early-stage disease with limited nodal burden suggested similar survival and functional outcomes, but different toxicities for each approach [29,31]. However, definitive interpretation of the results of this study are limited by the small numbers of patients enrolled as well as the use of other therapies in addition to RT and surgery monotherapy (eg, definitive chemoradiation in some patients treated with RT and adjuvant RT-based therapy in some patients treated with surgery). Larger randomized trials comparing these treatment modalities are needed. Further details on the ORATOR trial are discussed below. (See 'Selection of therapy: Surgery versus radiation' above.)

●Clinical versus pathologic staging in patients treated with surgery – For patients with HPV associated OPSCC, clinical and imaging characteristics do not always correspond to final pathologic staging on surgical specimens. Some patients with small primary tumors but known nodal disease who undergo surgery may have higher-risk pathologic features on postoperative pathology that ultimately require adjuvant RT (with or without chemotherapy). (See 'Adjuvant RT with or without chemotherapy' below.)

As an example, one observational study evaluated 92 patients with OPSCC (a majority of whom had HPV associated disease) who underwent clinical and radiographic staging followed by TORS with neck dissection [32]. Among the 32 patients who presented with no nodal disease or with a single metastatic node on imaging, postoperative pathology resulted in a higher stage in 22 percent, suggesting that those with node-positive disease may be at higher risk of needing adjuvant RT.

Minimally invasive surgery — Although minimally invasive surgery is an alternative to single-agent RT for these patients, most patients receiving surgery will need further adjuvant therapy (eg, RT alone or chemoradiation) if high-risk features are found on postoperative pathology [33]. Therefore, clinicians who offer surgery should discuss the potential risks and benefits of this treatment approach, including the need for adjuvant therapy.

The majority of patients selected for minimally invasive surgery (eg, TORS and TLM) will have eighth edition AJCC stage I disease (table 2A-B), and data indicate excellent oncologic control and functional outcomes in this highly selected population [34-37]. High-quality surgery is the goal, and tenets of surgery (including negative margins, high-quality neck dissections with appropriate nodal yields, and acceptable complication rates) must be achieved by centers offering these approaches.

By contrast, negative prognostic features in patients with a single involved node being evaluated for surgery include clinical or radiographic extranodal extension, matted nodes, low nodes, or unlikely ability to achieve a negative margin due to pharyngeal wall, tongue, or palatal or mid-tongue involvement. These patients should be offered initial RT-based therapy instead. (See 'Single-agent radiation versus definitive chemoradiation' above.)

For patients who have already undergone an open-neck biopsy, RT has been used to sterilize the surgically operated neck; however, one study suggested acceptable outcomes with surgical management in these patients [38].

Adjuvant RT with or without chemotherapy — For patients treated with surgery, the use of adjuvant (postoperative) therapy depends upon the presence of high-risk features on surgical pathology. Omission or reduction of radiation therapy (RT) dose or indicated chemotherapy in the adjuvant setting remains investigational (see "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer"):

●For tumors with close margins, perineural or lymphovascular invasion, or one involved node >3 cm, we suggest adjuvant RT rather than observation [39,40]. Active smokers or those with less than a 20 pack-year smoking history may especially benefit from adjuvant RT [41].

●For tumors with positive margins but no other high-risk factors, reresection can be offered if it is safe and feasible [42], although there are no high-quality data comparing outcomes in those with negative margins at initial versus reresection. For patients who are ineligible for further surgery, we suggest adjuvant chemoradiation rather than RT alone.

●For those with extranodal extension with or without positive margins, or a high number of involved lymph nodes, we suggest adjuvant chemoradiation rather than radiation alone [43]. Although some UpToDate contributors define a high number of lymph nodes as ≥3, the exact number in HPV associated OPSCC is not based on strong evidence and remains controversial.

Despite the excellent prognosis for HPV associated OPSCC, positive margins and extracapsular extension are associated with worse oncologic outcomes, including the risk of developing systemic disease [44,45]. As an example, the outcomes using surgery in 117 patients with HPV related OPSCC were retrospectively compared with those in 172 patients with HPV negative disease, all of whom were treatment naïve [44]. In the overall series, a majority had a primary lesion of the tonsil/base of the tongue or had seventh edition AJCC stage III or IV disease (92 percent each) and approximately two-thirds had seventh edition AJCC stage T1 or T2 primary. Treatment consisted of surgery combined with adjuvant RT or chemoradiotherapy in 90 percent of cases and surgery alone in 10 percent. Data are as follows:

●The five-year OS for the entire cohort was 65 percent and was better in those with HPV associated disease (82 versus 40 percent in those with HPV negative disease).

●On multivariable analysis, extranodal extension, and T3/T4 disease were independent predictors of a worse outcome. For those with HPV associated OPSCC, factors significantly associated with a worse outcome included an open, rather than transoral, surgical approach and positive surgical margins, as both factors are more likely to occur with T3/T4 disease.

Locoregionally advanced disease

Chemoradiation — For patients with locoregionally advanced disease (eg, clinical/radiographic evidence of T3-4 disease or any T stage with one node greater than 3 cm, multiple involved nodes, or evidence of extranodal extension), we suggest definitive chemoradiation alone rather than surgery followed by adjuvant chemoradiation ("trimodality therapy"), as this approach offers both organ preservation and excellent oncologic outcomes (algorithm 1). The use of chemoradiation in these patients is an established treatment approach for those with non-HPV related OPSCC, and a similar treatment approach is used in those with HPV associated OPSCC. (See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Nonsurgical versus surgical approaches'.)

Patients with locoregionally advanced HPV related OPSCC manifesting as a large primary tumor, or bulky, multiple, contralateral, or bilateral nodal spread require multimodality therapy. Adverse clinicopathologic features may predispose patients to a higher risk of both locoregional recurrence and distant metastasis [46,47]. Such adverse features include a large primary tumor; numerous cervical lymph nodes, and clinical or radiographic evidence of extranodal extension or matted lymph nodes. Additionally, an increasing number of cervical nodes is associated with extranodal spread and disease recurrence [48,49]. These clinical findings should be incorporated into the choice of therapy of each individual patient, even though these patients are staged as having N1 disease based on the AJCC eighth edition staging system (table 2A-B).

There are limited randomized data directly comparing definitive chemoradiation to "trimodality therapy" (including surgery) specifically in patients with HPV related OPSCC and increased nodal disease burden. In observational studies, while OS is similar for those receiving either surgery or chemoradiation, most patients treated with surgery are at risk for functional morbidity and still require postoperative chemoradiation due to high-risk pathologic features [23,48]. Additionally, the oncologic benefits of "trimodality therapy" in patients with HPV associated OPSCC remain a topic of debate and its use should be minimized or avoided, if possible [50].

Examples of studies comparing chemoradiation with "trimodality therapy" in those with locoregionally advanced HPV associated OPSCC are as follows:

●One observational study of 233 patients with AJCC seventh edition stage III/IV oropharyngeal carcinoma treated with either surgery or radiation included a cohort of 51 patients with HPV associated (p16 positive) disease [23]. Among the 139 patients who underwent surgery, 95 (68 percent) received adjuvant chemoradiotherapy; among the 94 patients treated with definitive RT, 84 (89 percent) received concurrent chemotherapy. When patients were stratified by p16 status, two-year recurrence-free survival rates were similar between the two approaches (86 versus 81 percent). Using the AJCC eighth edition staging system, many of these tumors would be classified as lower stage disease.

●In an observational study from the National Cancer Database (NCDB) of 116 patients with HPV associated node-positive OPSCC and a high number of pathologically involved lymph nodes, OS was similar for those treated with primary surgery compared with primary brachytherapy (three-year OS 91 versus 87 percent) [48]. Additionally, a higher number of involved lymph nodes (≥5) was associated with increased rates of three-year locoregional recurrence (22 versus 6 percent) and distant metastases (53 versus 12 percent). However, all patients underwent neck dissection and over one-half of patients treated with primary surgery still required postoperative chemoradiation based on high-risk pathologic findings, emphasizing the difficulty in selecting patients suitable for primary surgical management with reduced-intensity adjuvant postoperative therapy. Data evaluating the potential role for treatment deintensification is discussed below. (See 'Is there a role for treatment deintensification?' below.)

Induction chemotherapy — Select patients with locoregionally advanced disease may be candidates for induction chemotherapy followed by chemoradiation; specific indications and details for this approach are discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Sequential therapy'.)

Choice of sensitizing agent with chemoradiation — Definitive chemoradiation should employ cisplatin as a chemosensitizing agent for all cisplatin-eligible patients with HPV associated OPSCC. The use of cisplatin with RT is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cisplatin'.)

For patients with HPV associated OPSCC who are not cisplatin-eligible, an alternative option is a concurrent carboplatin-based regimen. Examples of such regimens include single-agent carboplatin or a carboplatin-based doublet (eg, carboplatin plus either paclitaxel or fluorouracil). (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Carboplatin-based regimens'.)

For patients with HPV associated tumors treated with concurrent chemoradiation, cisplatin-based chemotherapy is preferred over cetuximab. More detailed information on randomized trials comparing these agents is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cetuximab versus cisplatin for definitive chemoradiation'.)

IS THERE A ROLE FOR TREATMENT DEINTENSIFICATION?

Treatment approaches to deintensification — Deintensification is an emerging treatment approach for patients with HPV associated oropharyngeal squamous cell carcinoma (OPSCC) that aims to preserve superior oncologic outcomes while minimizing treatment-related toxicity. The role of treatment deintensification, including risk-adapted approaches, remains investigational, and patients interested in this approach should enroll in clinical trials, where available [51-53]. (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".)

Treatment deintensification of radiation therapy (RT) and/or chemotherapy has shown encouraging results in various phase II trials conducted in both the definitive and adjuvant settings [54-58]. Given the excellent prognosis for these patients following standard therapy, further randomized trials are required to better assess efficacy and safety before incorporating treatment deintensification into the standard of care [53,59]. Many different approaches have been or are being studied (eg, surgical resection, a lower dose of adjuvant RT, induction chemotherapy to de-escalate definitive RT dosing, dose-reduced definitive RT alone, or substitution of a potentially less toxic drug than cisplatin).

Surgical resection — The use of surgical resection to deintensify RT in patients with HPV associated OPSCC remains an experimental approach, and larger randomized studies are needed.

One randomized phase II trial (ORATOR) comparing surgery versus definitive RT in patients with HPV associated OPSCC suggested similar survival and functional outcomes, but different toxicities, for each approach [29,31].

In this study, 68 patients with mostly HPV related (88 percent, T1-2N0-2, with nodal disease ≤4 cm) resectable disease were randomly assigned to initial treatment with either definitive RT (70 Gy) or transoral robotic surgery (TORS) plus elective neck dissection. Patients in the definitive RT group with node-positive disease also received concurrent chemotherapy. Patients in the surgery group also received adjuvant RT (without deintensification), with or without chemotherapy, as clinically indicated (based on the presence of intermediate- or high-risk pathologic features).

At median follow-up of 45 months, overall survival (OS) and progression-free survival (PFS) were similar for definitive RT and surgery (three-year OS 87 versus 88 percent; three-year PFS 87 versus 85 percent) [31]. Grade ≥2 toxicities were also similar (97 versus 91 percent), but toxicity profiles varied based on the treatment approach [29,31]. For example, compared with TORS, definitive RT showed a statistically significant improvement in swallowing-related quality of life (QOL) relative to surgery, based on the MD Anderson Dysphagia Inventory (MDADI); however, the difference was not clinically meaningful, based on predetermined outcomes. In addition, an accurate comparison of dysphagia from surgery versus RT was further hampered by the need for elective temporary tracheostomies in those treated with TORS for airway protection in case of swelling and/or bleeding.

However, among those treated with TORS in this study, a majority still received full-dose adjuvant RT (71 percent) for intermediate- to high-risk pathologic features, so whether TORS could effectively allow for overall deintensification remains unclear. Additionally, while the proportion of patients receiving adjuvant chemoradiation (24 percent) was lower than that reported in other studies (approximately 60 percent) [30,60], this study population was small and may have underestimated the need for adjuvant chemoradiation in clinical practice.

A subsequent study (ORATOR-2) evaluating dose-reduced definitive radiation versus primary TORS plus dose-reduced adjuvant radiation is discussed below. (See 'Dose-reduced definitive radiation' below.)

Dose-reduced adjuvant radiation — Among patients with HPV associated OPSCC treated with surgery, it is unclear if there is clinical benefit from standard adjuvant therapy in the presence of high-risk pathologic findings on postoperative pathology [6,48,61]. Clinical trials suggest a role for deintensification of adjuvant RT or chemoradiation after surgical resection [14,41,56,62-64]. This approach is still experimental and continues to be evaluated in randomized clinical trials. (See 'Clinical trials' below.)

●ECOG 3311 – In a randomized phase II trial (ECOG 3311) of 519 patients with American Joint Committee on Cancer (AJCC) seventh edition stage III-IV HPV associated OPSCC without matted nodes and treated with transoral surgery, 360 eligible and treated patients were assigned to one of four treatment arms based on risk [14,63].

•Among those with low-risk disease (ie, negative margins [>3 mm], no nodes or one node without extranodal extension and no perineural invasion or lymphovascular invasion), 38 of 360 patients (11 percent) received no further postoperative therapy and were observed.

•Among those with intermediate-risk disease (ie, close margins [<3 mm], two to four positive nodes or a single node >3 cm and ≤6 cm, extranodal extension ≤1 mm, or perineural/lymphovascular invasion), 209 of 360 patients (58 percent) were randomly assigned to receive either low-dose (50 Gy) or standard-dose (60 Gy) adjuvant RT.

•Among with high-risk disease (eg, positive margins, five or more positive nodes, one node >6 cm, or extranodal extension >1 mm), 113 of 360 patients (31 percent) received adjuvant chemoradiotherapy (60 to 66 Gy of RT) with weekly cisplatin 40 mg/m².

Three-year PFS and OS were 97 and 100 percent, respectively, among the patients with low-risk disease and 91 and 93 percent, respectively, among the patients with high-risk disease [63]. Among the patients with intermediate-risk disease, patients receiving either 50 Gy or 60 Gy of RT demonstrated three-year PFS of 95 and 94 percent, respectively, and three-year OS of 99 and 95 percent, respectively. Compared with 60 Gy of RT, treatment with 50 Gy of RT lowered rates of grade ≥3 treatment-related toxicity (15 versus 25 percent), and improved patient-reported outcomes for head and neck cancer-specific QOL (FACT-H&N) from baseline to six months post-treatment (63 versus 49 percent) [14].

These data support the potential use of TORS alone in surgically eligible patients with low-risk disease and TORS plus deintensified adjuvant RT (ie, 50 Gy) in those with intermediate-risk disease. Further randomized studies are needed to directly compare TORS plus deintensified adjuvant RT to other definitive nonsurgical therapies (eg, definitive radiation or chemoradiation) in patients with intermediate-risk disease.

●MC1675 – A separate randomized phase III trial (MC1675) failed to demonstrate decreased toxicity ≥3 months after completion of RT (the primary endpoint) for dose-reduced RT versus standard-dose adjuvant RT [65]. However, further follow-up is necessary, as there were additional secondary analyses for toxicity, QOL, OS, and PFS that, albeit underpowered, may be informative for future studies.

Based on results from a phase II trial (MC1273) [56], a phase III trial (MC1675) was conducted in 194 patients with surgically resected HPV associated OPSCC, negative margins, and an indication for postoperative RT [65]. Patients were randomly assigned to receive either dose-reduced adjuvant RT (either 30 Gy for no extranodal extension or 36 Gy for extranodal extension, with RT administered twice daily and given concurrently with docetaxel 15 mg/m² weekly) or standard-dose adjuvant RT (60 Gy of RT given concurrently with cisplatin at 40 mg/m² weekly). Patients with T4 disease or those who required more than two surgical attempts to clear margins were excluded from the study.

In preliminary results, grade ≥3 adverse events three months or more after RT for dose-reduced versus standard-dose RT were approximately 2 and 7 percent, respectively [65]. Dose-reduced adjuvant RT improved other secondary outcomes including formal swallowing function one month after RT, overall QOL, pain, xerostomia, and need for gastrostomy tubes. At median follow-up of 25 months, in the entire study population, PFS for dose-reduced versus standard-dose RT was 87 and 95 percent; OS was 96 and 97 percent, respectively.

Dose-reduced definitive radiation — Studies have focused on reducing the dose of definitive RT in an effort to reduce or eliminate the risk of long-term toxicity from RT [66-72] or avoid surgical complications [73] in patients with HPV associated OPSCC. As examples:

●A randomized phase II trial (ORATOR-2) of 61 patients with HPV associated OPSCC compared dose-reduced definitive radiation (60 Gy of RT given concurrently with weekly cisplatin) with TORS plus neck dissection and dose-reduced adjuvant RT [73]. At median follow-up of 17 months, compared with TORS plus dose-reduced adjuvant RT, dose-reduced definitive RT improved two-year OS (100 versus 89 percent) and PFS (100 versus 84 percent). Grade ≥2 toxicity rates (67 versus 71 percent) and overall QOL at one year were similar between the two treatment arms. However, the trial was closed early due to two treatment-related deaths from TORS (one oropharyngeal bleed and one cervical osteomyelitis following adjuvant RT).

●In a nonrandomized phase II trial, 43 patients with T0-3,N0-2c, M0 HPV associated OPSCC were treated with deintensified chemoradiation (60 Gy of intensity-modulated radiation therapy [IMRT]) concurrent with cisplatin (30 mg/m² weekly) [66,67]. All patients subsequently underwent biopsy of the primary tumor and lymph node dissection of previously determined involved nodes at 6 to 14 weeks, regardless of clinical and radiographic response to treatment. The pathologic complete response rate was 86 percent. The three-year local control, regional control, cause-specific survival, and OS rates were 100, 100, 100, and 95 percent, respectively. It should be noted that this trial essentially treated patients using trimodality therapy that included limited surgical resection.

Radiation versus chemoradiation — Based on the results of a randomized trial (NRG-HN002) that showed higher locoregional relapse with RT alone, many studies continue to use RT plus chemotherapy rather than RT alone as the control arm in studies evaluating treatment deintensification in HPV associated OPSCC.

In a phase II trial (NRG-HN002), 306 non- or light-smokers with HPV associated seventh edition AJCC stage III or locoregionally advanced stage IV OPSCC were randomly assigned to either dose-reduced accelerated RT alone (60 Gy in five weeks) or dose-reduced RT (60 Gy in six weeks) administered concurrently with weekly cisplatin (40 mg/m²) [74]. Compared with chemoradiation, RT alone had similar PFS (two-year PFS 88 and 91 percent) and OS (two-year OS 97 percent each), but higher rates of locoregional failure at two years (10 versus 3 percent). Of note, the RT arm did not meet the target PFS.

Dose-reduced chemosensitizing agent with radiation — Data suggest that a subset of patients with low-volume, low-risk HPV associated OPSCC may have good disease control when definitive RT is combined with lower cumulative doses of cisplatin or RT given as a single modality.

In a single-arm, nonrandomized phase II trial, 114 patients with seventh edition AJCC stage I to IVA (T0 to T3, N0 to N2, clinical M0) HPV associated OPSCC and a limited smoking history were treated with definitive RT (60 Gy over six weeks) with or without concurrent weekly cisplatin at a reduced dose of 30 mg/m² for six doses [58]. Patients with T0-2N0-1 disease received RT alone, others received concurrent chemotherapy. Using this approach, two-year locoregional control and distant metastasis-free survival were 95 and 91 percent; two-year progression-free and OS rates were 86 and 95 percent. Approximately 9 percent (11 patients) had residual disease on end-of-treatment positron emission tomography (PET)/computed tomography (CT) requiring neck dissection. Treatment was well tolerated, with no grade ≥3 adverse events reported. Approximately one-third of patients required feeding tubes during treatment, none of which was permanent.

Induction chemotherapy — Induction chemotherapy has been studied in single-arm nonrandomized trials for its role in organ preservation. Data suggest that induction chemotherapy may allow for the deintensification of RT. However, given the toxicities, it is unknown to what extent induction chemotherapy constitutes deintensified treatment. Further data are needed to determine the optimal induction regimen, dosing of RT, and concurrent chemosensitizing agent regimen.

●ECOG 1308 – In a multicenter, nonrandomized phase II trial (Eastern Cooperative Oncology Group [ECOG] 1308), 80 patients with seventh edition AJCC stage III or IVA HPV associated OPSCC received induction chemotherapy with three cycles of cisplatin, paclitaxel, and cetuximab [54]. Lower-dose RT (54 Gy in 27 fractions) was given to patients who achieved a clinical complete response to induction chemotherapy at the primary site. Full-dose RT (69 Gy in 33 fractions) was delivered to the neck for those patients without a complete response in the cervical nodes and in patients with a clinical partial response or stable disease at the primary site. In both groups, RT was administered in conjunction with weekly cetuximab. A total of 56 patients (70 percent) had a primary site clinical complete response, and 51 of 56 patients proceeded to 54 Gy of RT.

For the 51 patients who had a complete response to the initial induction therapy and received reduced-dose RT to 54 Gy, the two-year progression-free and OS rates were 80 and 94 percent. Patients with T4 cancers or significant tobacco histories were more likely to experience recurrence. By contrast, among patients with (AJCC seventh edition) less than T4, less than N2 disease, and less than a 10 pack-year history of tobacco use, there were no recurrences and two-year OS was 96 percent. However, these data are difficult to interpret because different RT doses were administered to the primary site and lymph nodes.

●ECOG 2399 – The results from ECOG 1308 are similar to an earlier ECOG trial (E2399), in which the two-year PFS for HPV fluorescent in situ hybridization (FISH)-positive patients was 84 percent after carboplatin and paclitaxel induction chemotherapy followed by standard-dose RT (70 Gy in 35 fractions) with weekly paclitaxel (30 mg/m²), an alternative chemosensitizing agent [55]. In a subset analysis, compared with those with HPV negative tumors, patients with HPV associated tumors had improved response rates to induction chemotherapy (82 versus 55 percent), chemoradiation (84 versus 57 percent), and two-year OS (95 versus 62 percent) [75].

●UCLA/UC-Davis study – Another nonrandomized study evaluated the use of two cycles of induction chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m²) in 45 patients with p16-positive, AJCC seventh edition stage III to IV OPSCC [76]. Patients with a complete or partial response to induction chemotherapy were treated with lower-dose RT (54 Gy RT in 27 fractions) concurrent with weekly paclitaxel (30 mg/m²), while those with less than a partial response were treated with 60 Gy in 30 fractions. Of the 44 evaluable patients, 24 (55 percent) achieved a complete or partial response to induction and were treated with 54 Gy RT, while 20 (45 percent) achieved a less than partial response and were treated with 60 Gy RT. At a median follow-up of 30 months, two-year PFS was 92 percent. Three patients developed locoregional recurrence, and one developed distant metastases.

●OPTIMA – In a nonrandomized phase II trial (OPTIMA), 62 patients with HPV associated OPSCC were treated with induction chemotherapy using three cycles of carboplatin plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) followed by chemoradiotherapy with paclitaxel, fluorouracil (FU), hydroxyurea, and 1.5 Gy twice-daily RT every other week [77]. Treatment was stratified by risk:

•Low-risk patients – Patients were classified as low risk by AJCC seventh edition stage ≤T3N2b and ≤10 pack-year smoking history. Low-risk patients with ≥50 percent response were treated with single-agent RT at 50 Gy (RT50), while low-risk patients with 30 to 50 percent response received 45 Gy RT plus concurrent chemotherapy (CRT45). Patients with a lesser response received 75 Gy RT plus concurrent chemotherapy (CRT75). In this cohort, 71 percent were treated with single-agent RT50, while 21 percent received CRT45. At median follow-up of 29 months, in the low-risk group, two-year progression-free and OS were 95 and 100 percent, respectively.

•High-risk patients – Patients were classified as high risk by AJCC seventh edition stage T4 or ≥N2c or >10 pack-year smoking history. High-risk patients with ≥50 percent response received 45 Gy RT plus concurrent chemotherapy (CRT45). Patients with a lesser response received 75 Gy RT plus concurrent chemotherapy (CRT75). In this cohort, 71 percent received CRT45. At median follow-up of 29 months, two-year progression-free and OS were 94 and 97 percent, respectively.

•Toxicity – Toxicity rates and the need for enteral feeding increased with escalation of definitive RT. As an example, grade ≥3 mucositis rates were 30, 63, and 91 percent in the RT50, CRT45, and CRT75 groups; rates of gastrostomy tube use were 0, 31, and 82 percent, respectively.

Clinical trials — RT deintensification is actively being investigated in both the adjuvant and definitive setting. Examples of ongoing randomized clinical trials include the following:

●In a phase II/III trial (PATHOS; NCT02215265) of HPV associated OPSCC treated with transoral surgery, patients are randomly assigned to one of five adjuvant treatment arms based on risk. Patients with low-risk disease receive no adjuvant therapy; those with intermediate-risk disease are assigned to either low-dose (50 Gy) or standard-dose (60 Gy) adjuvant RT alone; those with high-risk disease (eg, positive margins and/or extranodal extension) are assigned to either 60 Gy of adjuvant RT alone or administered concurrently with cisplatin.

●In a randomized phase III trial (Trans-Tasman Radiation Oncology Group [TROG] 12.01; NCT01855451) of HPV associated OPSCC, weekly cetuximab with RT is compared with weekly low-dose cisplatin with RT. However, in randomized trials (RTOG 1016 and De-ESCALaTE HPV), cetuximab plus RT resulted in inferior OS and increased toxicity compared with cisplatin plus RT. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cetuximab versus cisplatin for definitive chemoradiation'.)

●In a phase II/III trial (NRG-HN005; NCT03952585) of HPV associated OPSCC, patients are randomly assigned to dose-reduced RT (60 Gy) administered concurrently with either cisplatin or nivolumab, or chemoradiation (70 Gy) with concurrent cisplatin.

SURVEILLANCE — After completion of therapy, patients should undergo surveillance for recurrent or metastatic disease. The approach to surveillance of patients with HPV associated oropharyngeal squamous cell carcinoma (OPSCC) is similar to that of other head and neck cancers. This topic is discussed in detail separately. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

A randomized trial (PET/NECK) supported the use of observation using positron emission tomography (PET)/computed tomography (CT) imaging at 12 weeks post-treatment completion rather than neck dissection, for select patients treated with radiation therapy (RT) [78]. This trial, which included a majority of patients with either HPV associated disease (75 percent) or oropharyngeal cancer (84 percent), demonstrated noninferiority in terms of overall survival (OS) and decreased rates of surgical complications. Further details on the outcomes for this trial are discussed separately. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma", section on 'Planned surgery versus PET/CT surveillance' and "Posttreatment surveillance of squamous cell carcinoma of the head and neck", section on 'Imaging of the head and neck'.)

Surveillance may also include the following considerations:

●Treatment-related toxicity – Surveillance is also important for the identification and management of short- and long-term treatment-related toxicities. These may be especially significant from a long-term functional standpoint given the younger age and better prognosis in patients with HPV associated OPSCC. (See "Management of late complications of head and neck cancer and its treatment".)

Clinicians should also be aware that many patients with HPV associated OPSCC and their families need unique formal educational strategies during and after therapy [79,80]. This includes promoting awareness of the association with HPV and cancer development related to head and neck cancer as well as other cancers, and addressing patient concerns about transmission of HPV infection to their sexual partners. Issues related to transmissibility, risks and benefits of vaccination of family members, alteration of sexual behavior are common questions after the diagnosis and should be addressed with the family when indicated. (See "Virology of human papillomavirus infections and the link to cancer" and "Human papillomavirus vaccination" and "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'HPV vaccination'.)

●Smoking cessation – Smoking cessation should also be encouraged, as data demonstrated inferior progression-free survival (PFS) for patients with HPV associated disease who smoke [10]. (See "Overview of smoking cessation management in adults".)

●Is there a role for cell-free HPV DNA in surveillance? – While there is not yet any established role for the use of cell-free (cf; ie, circulating tumor) HPV DNA in posttreatment surveillance, promising negative and positive predictive values for detecting recurrences have been reported using this biomarker technique. As an example, in one prospective study, 115 patients with HPV associated OPSCC treated with definitive chemoradiation were followed with cfHPV DNA on blood samples every six to nine months [81]. These patients were monitored for recurrence with a PET/CT three months after treatment completion, chest imaging every six months, and clinical evaluation for five years. The negative predictive value of cfHPV DNA for detecting disease recurrence was 100 percent; the positive predictive value for recurrence of two consecutive positive tests was 94 percent. This approach may become more clinically relevant as further validation studies emerge [82].

LOCALLY RECURRENT DISEASE — Due to the excellent prognosis following therapy for HPV related oropharyngeal squamous cell carcinoma (OPSCC), recurrences occur less frequently compared with other head and neck malignancies. Patients with locoregional recurrences are typically treated with comprehensive salvage approaches, the choice of which is dependent upon previous therapy. The approach to locally recurrent head and neck cancers is discussed separately. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)

Salvage therapy with either chemoradiation or surgery is associated with improved survival outcomes in patients with HPV associated OPSCC [83-86]. As an example, in a retrospective analysis of HPV associated and HPV negative patients enrolled in cooperative group trials, two-year survival after disease progression exceeded 50 percent for patients with HPV associated OPSCC [87]. Furthermore, the survival of the HPV associated patients was consistently better than that of HPV negative patients who had recurred, despite the presence of distant metastases or not having salvage surgery.

METASTATIC DISEASE — The approach to the treatment of metastatic disease (both isolated lung metastases [88] and more distant disease) in HPV associated oropharyngeal squamous cell carcinoma is similar to that of other head and neck cancers. Meta-analyses and randomized trial data suggest similar benefits to systemic therapy (eg, immunotherapy and combined chemotherapy plus immunotherapy) regardless of HPV status [89,90]. This is discussed in detail separately. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Treatment of metastatic and recurrent head and neck cancer".)

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

●Good prognosis of HPV associated oropharyngeal cancer – Human papillomavirus (HPV) infection has been associated with the development of oropharyngeal squamous cell carcinoma (OPSCC) of the head and neck. Patients with HPV associated OPSCC typically have more curable cancers and a better prognosis than those with non-HPV associated OPSCC. (See "Epidemiology and risk factors for head and neck cancer", section on 'Human papillomavirus'.)

●Pretreatment evaluation – The pretreatment evaluation of patients with HPV associated OPSCC includes nutrition consultation, intravenous access, and gastrostomy tube placement only when clinically indicated, dental assessment, speech and swallowing evaluation, pain management, and supportive care. (See 'Pretreatment evaluation' above.)

●T1-T2, node-negative – For patients with HPV associated early-stage, node-negative (eg, T1-T2, N0) disease, we offer initial treatment with either minimally invasive surgery (eg, transoral robotic surgery [TORS] and transoral laser microsurgery [TLM]) or radiation therapy (RT). The choice between such monotherapy treatments is individualized to the patient. (See 'T1-T2, node negative' above and 'Selection of therapy: Surgery versus radiation' above.)

●T1-T2, single node involved disease – For patients with T1-T2 disease with a single involved node ≤3 cm, options including single-agent RT, definitive chemoradiation, or surgery (with or without adjuvant RT-based therapy). In the absence of high-quality data, we use the following approach. (See 'T1-T2, single involved node (≤3 cm)' above.)

•Single-agent RT – For nonsmoking patients with one small single involved node ≤3 cm without adverse features on clinical evaluation or high-quality imaging (eg, no clinical or radiographic evidence of extranodal extension), we suggest single-agent RT (Grade 2C). (See 'Single-agent radiation versus definitive chemoradiation' above.)

•Definitive chemoradiation – For patients who are active smokers, heavy smokers, or have one involved node with certain high-risk features suspicious for a more advanced primary tumor or advanced nodal disease on clinical evaluation or radiographic imaging, we suggest definitive chemoradiation rather than single-agent RT (Grade 2C).

Examples of such high-risk features include endophytic, ulcerated primary tumors; radiographic evidence of extranodal extension or nodal matting; highly suspicious clustered or small lymph nodes; or involvement of retropharyngeal, level IV, or level V lymph nodes (figure 1). (See 'Single-agent radiation versus definitive chemoradiation' above.)

•Surgery – Surgery is an acceptable alternative to single-agent RT in select nonsmoking patients with one small single involved node ≤3 cm without adverse features on clinical evaluation or high-quality imaging (eg, no extranodal extension) who can achieve good functional outcomes postoperatively. However, some UpToDate contributors prefer RT-based therapy rather than surgery in these patients, as many who undergo surgery may still ultimately require adjuvant RT with or without chemotherapy, due to presence of high-risk pathologic features. (See 'Surgery' above and 'Adjuvant RT with or without chemotherapy' above.)

●Locoregionally advanced disease – For patients with locoregionally advanced disease (eg, clinical/radiographic evidence of T3-T4 disease or any T stage with one node greater than 3 cm, multiple involved nodes, or evidence of extranodal extension), we suggest definitive chemoradiation alone rather than "trimodality therapy" (ie, surgery followed by adjuvant chemoradiation) (Grade 2C), as this approach offers both organ preservation and excellent oncologic outcomes. (See 'Locoregionally advanced disease' above and 'Chemoradiation' above.)

Definitive chemoradiation should employ cisplatin as a chemosensitizing agent for cisplatin-eligible patients. (See 'Choice of sensitizing agent with chemoradiation' above.)

●Is there a role for deintensification? – Deintensification is an emerging treatment approach that aims to preserve oncologic outcomes while minimizing treatment-related toxicity. The role of treatment deintensification remains investigational, and patients interested in this approach should enroll in clinical trials, where available. (See 'Is there a role for treatment deintensification?' above.)