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The New Face of Head and Neck Cancer: The HPV Epidemic: Page 3 of 3

The New Face of Head and Neck Cancer: The HPV Epidemic: Page 3 of 3

Figure 1. Human papillomavirus (HPV) is a sexually transmitted virus a...
Figure 2. Imaging Studies of HPV-Positive OPSCC
Figure 3. Risk Stratification for Oropharyngeal Squamous Cell Carcinom...
Table 1. Comparison of HPV-Negative and HPV-Positive Head and Neck Cancers
Table 2. Notable Ongoing Deintensification Trials in HPV-OPSCC
Table 3. Summary: Management and Treatment Options in HPV-OPSCC

Treatment Options

Treatment of HNSCC is aimed at reducing the risk of locoregional and distant failure and may employ surgery, radiation therapy, and/or chemotherapy. In patients with HPV-OPSCC, triple-modality therapy should be avoided to minimize toxicity; single-modality therapy should be provided if possible. Of interest, prognosis of HPV-OPSCC seems to be generally favorable, independent of treatment modality.[35]

Early-stage OPSCC, defined as T1-2N0, is associated with an excellent prognosis; therefore, single-modality treatment with either surgery or radiation alone is considered optimal.[33] Although no studies have yet specifically addressed this issue, patients with HPV-positive, stage III, T1-2N1 OPSCC may also qualify for single-modality treatment. This group of HPV-positive patients is of particular interest in the current clinical trials aimed specifically at OPSCC.

The majority of patients with HPV-OPSCC present with nodal metastasis, and therefore advanced stage III or IV disease. As a result, combination therapies are indicated. Given the favorable prognosis for patients with HPV-OPSCC, ongoing clinical trials are examining the efficacy of risk-stratified treatment de-escalation strategies (Table 2). Until evidence supports such an approach, current national guidelines caution against any such treatment modifications outside the context of institutional review board–approved protocols.[33] The current standard of care for HNSCC is driven by site and TNM stage, and for now remains independent of HPV status.

Radiation therapy

Early studies attempted to establish the optimal fractionation of radiation delivered as treatment for HNSCC. Neither RTOG 9003[36] nor RTOG 0129[37] identified a survival advantage for altered fractionation over standard once-daily fractionation. In general, radiotherapy alone should be reserved for patients with early-stage (stage I/II) HNSCC tumors. Radiation monotherapy may eventually prove sufficient for a broader group of patients with HPV-OPSCC, although this remains to be determined (see Table 2).

Chemoradiation therapy

The efficacy of chemoradiotherapy in advanced head and neck cancers has been well established, irrespective of HPV status.[38] Chemotherapy can be given either as induction therapy or concurrently with radiotherapy, and both options offer improved survival over radiation alone in advanced-stage disease. The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) showed an absolute survival benefit of 6.5% at 5 years associated with concurrent or induction administration of chemotherapy with radiation therapy.[38,39] Concurrent chemoradiotherapy proved superior to induction chemotherapy followed by radiation in the setting of initial definitive treatment for patients with advanced OPSCC.[36] Chemotherapy is also given concurrently with radiation in the adjuvant high-risk setting (ie, positive/close surgical margins, significant extracapsular nodal extension).[40-42] In the European Organisation for Research and Treatment of Cancer (EORTC) 22931 and RTOG 9501 studies, the combined treatment arm was notable for improved locoregional control and disease-free survival.[43]

High-dose cisplatin has been widely accepted as the standard concurrent agent in patients with HNSCC, although comparative studies with other agents have not been completed. In the Intergroup study for patients with locally advanced (M0) head and neck cancer, the treatment group with the best survival rate received radiation plus concurrent cisplatin.[44] Although the survival benefit of cetuximab delivered concurrently with radiotherapy was established by Bonner et al, who demonstrated a 10% survival advantage at 3 years with this regimen in stage III/IV HNSCC,[45] no completed trials to date have directly compared cetuximab with cisplatin.

TO PUT THAT INTO CONTEXT

Marshall Posner, MD
Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, New York, New York

WHAT DON’T WE KNOW?
HPV-related oropharynx cancer (HPVOPC) has become a well-recognized entity and a growing health problem. While we have knowledge of the demographics of HPVOPC (especially its relationship to sexual behavior), its clinical presentation, and differences in prognosis compared with other oropharynx cancers, we know little of the real biology of the cancer. Almost all data on HPVOPC derive from clinical experience and retrospective analysis, and there are still huge gaps in our knowledge. Why is HPVOPC highly responsive? What is the immunology of this cancer, and can immunotherapy be refined enough to cure the cancer without drugs or radiotherapy?

HPVOPC also presents a number of conundrums. For example, although p16 is far more prevalent in HPV-positive OPC than in HPV-negative cancers, p16 is not sufficient to identify HPV-positive OPC. Tests for p16 will be falsely positive in 6% of cases. Also, while the disease is highly responsive, it also appears to be highly aggressive, with a high rate of metastases that are not amenable to treatment with surgery or chemoradiotherapy (CRT).

WHAT ISSUES MOST NEED TO BE ADDRESSED?
Radiotherapy dose de-escalation is critical. The major short- and long-term morbidity for patients is related to radiation dose and extent. The vast majority of HPVOPC patients will live 30 to 50 years and therefore are especially at risk for long-term consequences of radiotherapy. Thus, every effort should be made to leverage surgery and chemotherapy to reduce radiotherapy dose and field size. Encouraging clinical trials that examine de-escalating radiotherapy is the most important priority for our patients today.

In the HPVOPC subgroup of RTOG 0129, progression-free survival (PFS) at 3 years was only 70%, and at 8 years it was 64%. This is not high, given the curability of this disease. In TAX 324, the 5-year PFS in HPVOPC patients with advanced disease was 78%. Our experience is that there is an increasing rate of late metastases in patients treated with CRT only. We need to be able to determine who is at risk and needs systemic therapy.

Unfortunately, there is a clear risk of added acute and late toxicities with concurrent chemoradiation regimens for locoregionally advanced head and neck cancers, especially in the setting of cisplatin therapy. Some patients, specifically the elderly, do poorly after chemoradiotherapy.[46] RTOG trials defined severe late toxicity as chronic grade 3/4 pharyngeal or laryngeal toxicity, feeding tube dependence for 2 or more years after registration, and/or potential treatment-related deaths (eg, caused by pneumonia) within 3 years, which occurred in 43%, 20%, and 10% of patients, respectively.[47] In the GORTEC trial, which compared chemoradiation to radiation alone for advanced-stage OPSCC, concurrent chemoradiation proved superior in both locoregional control and OS but at the cost of a higher rate of mucositis, an increased need for feeding tubes, and a higher rate of late complications.[48] The treatment-related mortality rate for chemoradiation therapy for head and neck cancers in randomized clinical trials is reported to be approximately 3% to 4%.[47]

Toxicity may prove to be less problematic with modern intensity-modulated radiation therapy, and it may perhaps be further ameliorated by the frequent substitution of cetuximab for cisplatin. Cetuximab, a chimeric antibody directed against the epidermal growth factor receptor, is the only biologic agent currently approved by the US Food and Drug Administration for the treatment of HNSCC. With the exception of acneiform rash and infusion reactions, the addition of cetuximab to radiation therapy is not associated with an increased risk of grade 3/4 toxic side effects.

To date, the precise role of chemotherapy for patients with advanced-stage HPV-OPSCC has not been defined. This issue is especially important in this younger patient subgroup with a generally favorable prognosis because the toxicity of concurrent chemotherapy may not be justifiably offset by any meaningful clinical benefit. The benefit of chemotherapy in addition to radiation therapy, both in the upfront and adjuvant settings, needs to be carefully calibrated through future clinical trials aimed at this patient subpopulation.

Surgical treatment

Technologic advances, including transoral robotic surgery (TORS) and transoral laser microsurgery (TLM), have pushed surgery back into the discussion for frontline treatment of HNSCC. Small primary tumors—as are common in HPV-OPSCC—with resectable nodal disease lend themselves to surgical resection. Transoral surgery (TOS) has changed the way these small tumors can be treated. Traditional surgical treatment involved large operations that required mandibulotomies and free flap reconstructions. TOS allows for less invasive surgical approaches, shorter hospital stays, avoidance of tracheotomy and gastrostomy tubes, less pain, faster recovery with fewer complications, and less cost compared with traditional surgical techniques.[49] In addition, the functional deficits are manifest upfront with minimal long-term sequelae. A direct comparison with nonsurgical treatment of HNSCC is lacking; however, a review of early data from TORS resections showed an 80% to 90% 2-year OS.[50] Oncologic results following TLM are equally impressive: Local control rates reached 85% in earlier studies,[51] and more recent studies reported a 5-year OS of 78% and a local control rate of 97%.[52]

As surgeons gain more experience with new technologic approaches, some are now operating on more locally advanced tumors. Weinstein et al achieved excellent outcomes with TORS in stage III/IV oropharyngeal carcinomas: the 2-year DSS was 90%.[53] In a group of 47 patients, 38% avoided chemotherapy and 11% avoided both chemotherapy and radiation therapy; only one patient required a long-term gastrostomy tube. The same group of investigators further validated the TORS technique in HPV-positive patients and demonstrated outcomes comparable to those achieved in HPV-negative patients.[54]

Haughey et al reported similar results with the TLM technique.[52] In their study, 90% of patients demonstrated p16 positivity and 34% of patients presented with advanced T-stage disease. Despite these findings, local, locoregional, and distant disease control each exceeded 90%. Forty-eight percent of patients avoided primary tumor bed radiation therapy, 84% avoided chemotherapy, and 26% of patients received no adjuvant therapy at all. Furthermore, most patients (87%) had excellent swallowing scores. Severe long-term swallowing difficulty occurs mainly in patients with large T4 tumors, especially those that involve the base of the tongue. These data regarding functional outcomes after surgery are promising.

Haughey et al also found that outcomes sequentially worsen with each additional adjuvant modality after surgery.[52] TOS should be reserved for the anatomically amenable patient in whom a safe operation may be performed and unnecessary adjuvant therapy can be avoided, with predicted favorable postoperative functioning.

Management of at-risk or involved neck nodes is a common concern in patients with HPV-OPSCC. The best approach to lymphadenopathy is often multidisciplinary; it may include surgical resection or radiation to the involved neck compartments.[33] A neck dissection may be either staged or performed at the same time as TOS. In early tumors with no clinically apparent lymph node involvement, selective neck dissection should be performed. With clinically involved nodes, an ipsilateral, modified radical neck dissection is usually sufficient in most oropharyngeal tumors, whereas bilateral neck dissection is advised in larger base-of-tongue primary tumors that approach or cross midline. The extent of node dissection is often adjusted based on nodal location and volume, but levels II–IV should be included in the lymphadenectomy because level IV node involvement is common, especially in base-of-tongue tumors, and predicts a worse prognosis.[55]

Extracapsular spread from nodal disease is traditionally a prognostic indicator in head and neck cancer that is used to determine whether chemotherapy should be used in addition to adjuvant radiation. A recent finding that patients with p16-positive OPSCC have no difference in 5-year DSS despite extracapsular spread has significant implications for therapy.[56] In patients with p16-positive OPSCC who have nodal extracapsular spread, the addition of chemotherapy to radiation therapy seems to offer no survival advantage.[57] The ADEPT trial is a randomized phase III study actively investigating the role, if any, of nodal extracapsular spread in HPV-OPSCC (see Table 2).

In summary, HPV-oropharyngeal tumors frequently lend themselves to minimally invasive surgical treatment. Surgery is likely to play a larger role in HPV-OPSCC, since the surgeons’ experience in treating these tumors is growing and preliminary reports have been favorable. The traditional approach of postoperative chemoradiation therapy for nodal extracapsular extension within lymph nodes in patients with HPV-OPSCC is being challenged.

Posttreatment Expectations and Prognosis

Disease progression within 3 years of treatment occurs in 10% to 25% of patients with HPV-OPSCC.[58] The majority of recurrences are locoregional and occur in the first year after completion of treatment. In general, patients with HPV-OPSCC have decreased rates of locoregional failure but similar rates of distant metastasis compared with patients who have non–HPV-OPSCC.[58] The lung is the most common site of distant relapse in both groups. In disease relapse, p16 status continues to be a favorable prognosticator. Timely detection and salvage intervention for relapsed disease are beneficial.

There is currently no recommendation for any change in the posttreatment surveillance algorithm based on p16 status. During surveillance, second primary tumors are quite rare in patients with HPV-OPSCC compared with those who have tobacco-mediated oropharyngeal cancers.[59,60] This is thought to result from the intact genetic constitution of HPV-mediated tumors in contrast to tobacco-mediated tumors.

Future Directions

Although there are currently no recommended treatment modifications for HPV-OPSCC, several current trials are evaluating this precise issue. The concept of deintensification developed after demonstration of the excellent prognosis of HPV-positive tumors, many of which are likely being overtreated (see Figure 3).[34] In addition, a shift in patient demographics toward younger patients who survive longer after treatment has led to consideration of the long-term complications of chemoradiation therapy.

Such complications drive several ongoing trials directed specifically at HPV-OPSCC (see Table 2). These trials address deintensification through various strategies: (1) radiation alone in risk-stratified OPSCC, (2) decreased dose of radiation, (3) substitution of cetuximab for cisplatin, and (4) surgical resection followed by a reduction/elimination of chemotherapy or radiation therapy. The results of these studies will likely be critical in defining optimal treatment strategies.

In summary, a multidisciplinary approach is required for the optimal treatment of patients with HPV-positive OPSCC. As of now, there are no treatment guidelines directed specifically at this population (Table 3). Ideally, all patients should be directed toward clinical trials in order to answer important questions regarding prognosis and treatment. Furthermore, all patients should be stratified according to surgical resectability. There is an emerging trend toward minimally invasive surgical resection that may prove to decrease overall treatment-related morbidity. Both ECOG 3311 and ADEPT are national surgical trials that are actively investigating risk-adjusted adjuvant therapies in the HPV-OPSCC patient population. These trials will clarify pertinent risk factors in HPV-OPSCC and will refine treatment strategies accordingly, such that excellent oncologic and functional outcomes can be simultaneously realized.

Conclusion

The incidence of HPV-OPSCC is growing rapidly in the United States. Affected patients have unique risk profiles and presentations. HPV imparts a favorable prognosis for those with oropharyngeal cancer. Treatment modifications to optimize both oncologic and functional outcomes are currently being investigated, with results of ongoing trials expected to define optimal therapeutic strategies in the years ahead.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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