Oropharyngeal squamous cell carcinoma (OPSCC) has seen a dramatic rise in incidence over
the last two decades. This is largely due to the increased incidence of human
papillomavirus-positive (HPV+) malignancy within the oropharynx. In fact, HPV-positive
(HPV+) OPSCC has surpassed cervical cancer as the most common HPV related malignancy in
the United States. Thus, with the current widespread prevalence of HPV infection, OPSCC
will continue to be a major factor in cancer treatment in the national healthcare
landscape for years to come.
Fortunately, patients with HPV+ OPSCC have substantially improved treatment response and
overall survival (OS) compared to those with HPV-negative malignancy. Prior surgical
procedures to remove tumors within the oropharynx were very invasive and highly morbid,
requiring face and neck incisions along with mandibulotomy and pharyngotomy approaches.
Therefore, treatment paradigms shifted to favor concurrent chemoradiation as the primary
treatment modality over primary surgery. However, the acute and long-term toxicity of
chemoradiation can be significant, including swallow dysfunction, speech disturbance,
taste disturbance, mucositis, xerostomia, fibrosis, osteoradionecrosis, neutropenia,
neurotoxicity, and dental disease. With improved survival rates associated with HPV+
OPSCC, more patients are surviving their disease and experiencing these side effects,
negatively impacting quality of life (QOL).
With early studies establishing the more favorable prognosis associated with HPV+ OPSCC9,
the staging system for OPSCC was completely changed, with HPV+ OPSCC given its own
separate system from its HPV negative counterpart. Even with higher nodal burden, HPV+
OPSCC has lower stages, reflecting improved treatment response of this disease. Notably,
this reclassification omitted extranodal extension (ENE) as a component of the N staging.
The advent of transoral robotic surgery (TORS) via the da Vinci Surgical System, and
other minimally invasive techniques, has reaffirmed surgical therapy as a primary
treatment option, as these approaches provide quicker recovery times and confer less
morbidity to patients. The safety and oncologic efficacy of TORS has been
well-established for the treatment of OPSCC. For example, in one large
multi-institutional study of 410 patients undergoing TORS, the 2-year locoregional
control rate was 91.8%, disease-specific survival rate 94.5%, and overall survival 91%13.
Now, the majority of patients undergo surgery for T1-T2 disease (82%) in the United
States according to an analysis of the National Cancer Data Base.
The goal of primary surgical therapy is to minimize long term toxicity by eliminating the
need for chemotherapy, decreasing radiation intensity to adjuvant doses, and in some
cases, obviating the need for adjuvant therapy altogether while still providing
equivalent or even superior oncologic results compared to standard chemoradiation. The
resulting effects are improvement in functional outcomes and QOL for patients surviving
their disease. The prevailing treatment philosophy within head and neck oncology is that
further deintensifying treatment could still provide equivalent oncologic outcomes, while
further lowering toxicity profiles and improving functional outcomes even more. There are
now numerous trials investigating deintensification in an attempt to minimize the
morbidity incurred by patients, and strategies have varied greatly. But still, there is
no level I evidence for deintensification, and certainly, no consensus on the best
strategies for treatment moving forward in the near future.
One such trial focusing on surgical therapy with de-escalated radiotherapy is ECOG-3311,
a randomized phase II trial which focuses on a primary surgical approach for cT1-2 N1-2b
(as per AJCC 7th edition) HPV+ OPSCC. The study de-escalates the adjuvant radiation dose
to 50 gray for intermediate risk patients based on surgical pathology results. But even
in this study, nearly a third of the patients received adjuvant chemoradiation therapy
which raises concerns for even worse functional outcomes in those patients receiving
triple modality therapy (surgery, radiation, and chemotherapy). The final results of this
study are still pending.
In another phase II trial, the Mayo Clinic group randomized patients to either standard
adjuvant treatment or deintensified treatment after TORS, administering between 30 to 36
Gray of radiation along with concurrent docetaxel infusion in the latter group. In that
study, the most important risk factors for progression were higher T stage, pN2 disease
(5 or more positive nodes), and the presence of ENE. Moreover, those with pN2 and ENE
were at high risk for distant failure. The 3-year progression-free survival (PFS) rate
for the deintensified cohort was 87%, compared to the standard cohort PFS of 90%. The
group still concluded that even patients with high risk features could still benefit from
deintensification as both groups did poorly from a distant disease standpoint.
Other studies have shown the significance of having pN2 disease, as well, with associated
higher risk for distant disease. In a large multi-institutional study, patients with HPV+
OPSCC who underwent primary surgical therapy and found to have 4 or fewer positive nodes
had improved 5-year overall survival compared to those with 5 or more positive nodes (89%
vs 71%, respectively). This was the basis for the change in staging for the AJCC 8th
edition in which pN1 was designated for 1 to 4 positive nodes and pN2 for 5 or more
positive nodes. Moreover, ENE was removed as a stratifying factor in the N staging for
HPV+ OPSCC, as previously mentioned. The significance of ENE remains a point of
contention, and there is currently no level I evidence for the optimal management of ENE
in the adjuvant setting for surgically managed HPV+ OPSCC. Often times, chemotherapy is
recommended if ENE is identified, but the addition of the third modality significantly
worsens toxicity profile without assuredly providing benefit. Recent NCCN guidelines
recommend adjuvant radiation of 44 to 50 gray in low risk, 54 to 63 gray in intermediate
risk, and 60 to 66 gray for high risk patients, with or without the addition of
chemotherapy.
There is no doubt about the clinical impact of HPV+ OPSCC in the future of the national
healthcare system. Despite this, there is still no consensus on the best treatment
strategies for this disease. The investigators at IU have performed over 125 TORS
operations in the last four years since the inception of the Robotic Head and Neck
Surgery Program with excellent oncologic outcomes. The investigators anticipate the
surgical volume to continue to grow as the treatment paradigm shifts back to primary
surgery and the incidence of HPV+ OPSCC continues to rise. Thus, the purpose of this
phase II prospective trial is to assess the safety and efficacy of deintensification
after surgical therapy in early stage HPV+ OPSCC by evaluating oncologic outcomes,
toxicity profiles, functional outcomes, and QOL measures, and compare these factors to
historical controls. This protocol also seeks to more clearly define the setting and
safety of eliminating of chemotherapy in the adjuvant setting after transoral surgery for
HPV+ OPSCC.
