Sinai Robotic Surgery Trial in HPV-related Oropharyngeal Squamous Cell Carcinoma (SIRS 2.0 Trial)

The incidence of oropharyngeal (middle part of the throat) cancer has steadily increased across North America in recent years. Studies have found that this trend is largely associated with the increased number of tumors containing the human papillomavirus virus (HPV), specifically HPV16, which is the most common strain. HPV-related carcinoma (HPVOPSCC) now accounts for at least 80% of oropharyngeal squamous cell cancer nationwide and an increasing incidence in Europe. The Sinai Robotic Surgery (SIRS) 2.0 Trial will assess the efficacy of a less aggressive and significantly de-intensified therapeutic approach among patients who present with HPVOPSCC versus the standard of care.

SIRS 2.0 builds on the findings of the earliest SIRS 1.0 study, a non-randomized phase II study, which found that patients with early-stage HPVOPSCC who underwent Transoral Robotic Surgery (TORS) followed by reduced-dose radiation had favorable survival with excellent function. The goal of the SIRS 2.0 Trial is to further de-intensify post-operative therapy by using HPV circulating tumor DNA (ctDNA) as a biomarker for microscopic residual disease.

Rationale for the SIRS 2.0 Trial

Studies have found that most patients with early-stage HPVOPSCC have an excellent prognosis. This raises questions about the need for aggressive concurrent chemoradiotherapy as the standard of care among these patients, given its toxicity and impacts on quality of life. Recently, a new test was developed to measure ctDNA in the blood, offering a potential biomarker to predict treatment response and likelihood of cancer recurrence among patients with HPVOPSCC. Data suggest that a negative test during the surveillance period following treatment is highly accurate for predicting remission.

Investigators at the Head and Neck Cancer Research Program at the Icahn School of Medicine at Mount Sinai are wondering if it is possible to conduct TORS alone or combined with greatly reduced doses of radiation and chemotherapy to treat HPV-related oropharyngeal squamous cell carcinoma for patients with an undetectable postoperative HPV circulating tumor DNA test. Thus, these patients might be able to obtain cancer control and survival rates while reducing toxicity, as compared to outcomes achieved through standard therapy.

Transoral Robotic Surgery and HPV-related Cancer

Traditionally, the standard of care for patients with HPVOPSCC has been aggressive concurrent chemoradiotherapy—the same therapeutic approach administered to patients who present with environmentally related oropharyngeal squamous cell carcinoma from smoking and alcohol consumption. Although the cure rates are high, the toxicity of this treatment approach can result in lifelong, negative impacts such as osteoradionecrosis (bone death) of the jaw, fibrosis, difficulty swallowing, dry mouth, and even cranial nerve deficits including vocal fold paralysis. Given that many of the patients who present with HPVOPSCC are young, they are at potential risk for long-term toxicity and quality of life decrements from this therapy.

As a result, researchers have focused attention on how to de-escalate therapy to address quality-of-life issues without compromising patient outcomes. TORS is an effective platform to achieve that objective among patients who present with HPV-related oropharynx cancer, especially since Mount Sinai was one of the pioneers (Mount Sinai surgeons performed the first TORS for oropharyngeal cancer in the State of New York more than a decade ago). The minimally invasive procedure uses a surgical robot to resect oropharyngeal tumors through the mouth without external incisions.

Supporters of TORS maintain that the procedure results in improved functional outcomes when compared with nonsurgical treatment involving chemoradiotherapy and the long-term toxicities associated with that approach. Moreover, pathologic data gathered from patients who have undergone TORS and neck dissection can provide invaluable information for customizing therapy, such as eliminating chemoradiotherapy or taking a more aggressive course for individuals who have an unfavorable diagnosis.

Studies have reported favorable swallowing outcomes among patients who have undergone TORS, with recovery of a normal diet within a few weeks. Studies also show high survival rates and a low incidence of cancer recurrence among these patients, with figures that compare favorably to reports of oropharyngeal cancer treated with chemoradiotherapy.

In the SIRS 2.0 trial, Mount Sinai investigators will assess recurrence within the first two years of surgery among two groups of patients with early-stage HPVOPSCC and undetectable ctDNA: those with early-stage disease who are treated with surgery alone (low-risk group), and those with more advanced disease who received a de-intensified adjuvant protocol following surgery (high-risk group).

Assessing a Promising Biomarker for HPVOPSCC

Advances in testing have identified ctDNA as a promising biomarker for HPVOPSCC, not just in terms of its ability to predict treatment response among patients with localized and metastatic HPVOPSCC, but also the risk of cancer recurrence. As a result, it has potential as a risk stratification tool that could enable customization in treatment approaches and intensity. For example, patients who present with undetectable levels of ctDNA post-surgery may be candidates for chemoradiotherapy at a much lower dose than standard or for the elimination of this therapy altogether.

SIRS 2.0 Trial Criteria

Mount Sinai investigators are enrolling patients In the SIRS 2.0 trial, who have been diagnosed with HPVOPSCC and who have not received any prior chemotherapy, radiation therapy, or surgery for their cancer. Participants:

Must also be p16 positive and high-risk HPV positive on PCR or RNA testing
With a history of more than 20 pack years of smoking and recent (within five years) tobacco use will be excluded, as this is a known negative prognostic factor

There is also little understanding as to the biological factors that influence the growth and response of HPVOPSCC tumors to treatment. Research strongly suggests that multiple pathways may account for the difference in HPVOPSCC tumor growth and treatment response versus non-HPVOPSCC tumors.

Furthermore, research has also identified several mechanisms that may factor into different survival rates among HPVOPSCC patients. The advantage of a surgical study, such as the SIRS 2.0 trial is the availability of high-quality tissue specimens for analysis and exploration of the biological factors that influence tumor growth and survival rates. Mount Sinai investigators will collect blood and tumor samples from participants to further explore the diagnostic potential of these mechanisms.