Study Tests Preoperative Therapy for Easing Resection Burden in Rare Cancer

Nabil F. Saba, MD

A recently launched clinical trial aims to improve outcomes and quality of life for patients with nasal and paranasal squamous cell carcinoma (NPNSCC), a rare type of head and neck cancer that is challenging to treat and carries significant morbidity.

The current preferred treatment for patients with advanced NPNSCC is surgical resection, followed by radiation and chemotherapy, depending on the surgical outcome.¹ Because of the critical location of these tumors, patients who undergo surgery suffer from loss of the orbit or risk damage to the base of the skull.

The phase II study, which began recruiting patients in April 2018, seeks to evaluate the impact of administering chemotherapy before surgery and radiation (NCT03493425). Investigators hope the approach prevents disfiguring surgeries and improves overall survival (OS), thus establishing a course of treatment that will improve the quality of life for this patient population (Figure 1).

Study Design

“This cancer is very taxing on the patient because it develops in critical areas,” principal investigator Nabil F. Saba, MD, said in an interview with OncologyLive^®. “For patients who undergo orbital resection, it is a lifelong disfiguring treatment that also affects their quality of life, given that they are losing a major organ—their eye. “Other possible adverse effects include facial disfigurement if they get a big surgical resection, or patients may experience complications including cerebral spinal fluid leaks if they have a base-of-skull resection,” said Saba, director of the Head and Neck Medical Oncology Program at Winship Cancer Institute of Emory University in Atlanta, Georgia.Overall, an estimated 3% to 5% of patients with head and neck cancers have primary tumors of the sinonasal tract, accounting for approximately 2000 people a year in the United States.^2,3 There are several histological subtypes of NPNSCC, with the most common being squamous cell carcinoma. The study will focus on patients with a diagnosis of stage T3 or T4a advanced NPNSCC (Figure 2). These categories include tumors that have invaded the bone of the posterior wall of the maxillary sinus, the ethmoid sinuses, or the anterior orbital contents, according to the American Joint Committee on Cancer staging system.⁴ To participate in the trial, patients must be candidates for surgical resection.

Patients will be randomized into 2 arms. Arm A will provide standard-of-care surgery followed by postoperative image-guided intensity-modulated radiation therapy (IMRT) at 5 fractions per week for 30 fractions, beginning 4 to 6 weeks after surgery. Those with positive margins or positive extracapsular spread (ESC) in the lymph nodes will receive 66 Gy with weekly cisplatin or carboplatin.

Participants in the experimental arm B will receive an intensification of docetaxel plus cisplatin, or docetaxel plus carboplatin for patients who are cisplatin ineligible, for up to three, 21-day cycles. Patients will undergo standard- of-care surgery within 6 weeks of their last dose of chemotherapy, followed by IMRT at 5 fractions per week for 30 fractions. Additional cisplatin or carboplatin also will be administered to those with positive margins or ESC.

The primary outcome of the study is structure preservation rate defined as both skull base and orbit being preserved; the secondary outcome is OS. Additionally, administering chemotherapy prior to surgery may shrink the tumor and reduce the amount of normal tissue that needs to be removed and treated with radiation, Saba said.

Following the completion of treatment, patients will commit to follow-up appointments for 5 years. Because most treatment failures for NPNSCC occur within the first 2 years following therapy, patients should adhere to a meticulous follow-up schedule. Follow-up monitoring should take place every 3 months for 2 years and then every 6 months for years 2 to 5 after the study.⁵

Because of the rarity of this disease, there is a lack of uniformity, with no clear guidelines for treating these patients, Saba said. The results of this trial will also, hopefully, answer an important clinical question for changing the standard of care, he noted.

Difficulties of Launching the Trial

“This protocol is trying to focus specifically on these 2 scenarios and asking whether we can avoid disfiguring surgeries in patients who basically are doomed to have or deemed to need orbital resection or base-of-skull resection,” Saba said.Investigators faced a long roard in taking this trial from concept to action. Again, because of the rarity of NPNSCC, the disease has not been a priority for multicenter or cooperative group studies. Research conducted in North America and Europe is infrequent and tends to comprise case reports that are not part of a sanctioned clinical trial evaluation, Saba said.

Moreover, it is difficult to gain approval for a trial design from the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI), Saba explained. Questions of expenditure versus benefit arise. “People are asking, ‘Are you really sure you have to open this trial? Is it something that will be of value given the frequency of the disease?’” he said.

As a result, it took investigators nearly 7 years to gain the necessary approvals for the trial. After several committee reviews at the Eastern Cooperative Oncology Group, the consensus was that it was time to make a change for the patient population given the complications of the disease. The study is being sponsored by the ECOG-ACRIN Cancer Research Group in collaboration with the NCI.

Gaining approval to conduct the trial, however, was only the first step. “Besides the fact that this is a rare disease, the challenges also have been that we need participation of high-volume centers that have the surgical expertise and because of this it has been hard to move on with accrual on this study,” said Saba.

In an effort to streamline communications, a surgical steering committee of prominent base-of-skull surgeons will oversee the resection process in both arms of the study. The committee will examine whether resection is appropriate, especially in patients who have residual cancer following chemotherapy in arm B.

Patient Accrual

“This trial is focused only on patients who are going to have surgery. Engaging our surgical colleagues in this study is crucial because without their participation I don’t think this trial can succeed,” said Saba.The trial must enroll a minimum of 134 patients. Because of the rarity of the disease, investigators submitted an amendment concerning the treatment options for patients to allow proton therapy. “Some of the large centers, specifically for these types of tumors, focus on proton therapy because they think this is more beneficial for patients,” Saba said.

Large-volume centers in the United States include Emory University Hospital, Moffit Cancer Center in Tampa, Florida, and Smilow Cancer Hospital at Yale-New Haven in Connecticut. Saba noted that trial organizers are also reaching out to Canadian sites.

“Even though we are seeing a lot of improvement for patients with head and neck cancers, whether it is in novel treatments or metastatic disease, these trials have somewhat excluded patients with sinal nasal cancers,” concluded Saba. “I think this is the first step to try to impact the outcome for these patients, following which hopefully there will be other efforts and other steps taken to improve outcomes.” For more information, please visit the clinical trial website clinicaltrials.gov/ct2/show/NCT03493425.

References

1. Cracchiolo JR, Patel K, Migliacci JC, et al. Factors associated with primary surgical approach for sinonasal squamous cell carcinoma. J Surg Oncol. 2018;117(4):756-764. doi: 10.1002/jso.24923.
2. Lewis JS. Sinonasal squamous cell carcinoma: a review with emphasis on emerging histologic subtypes and the role of human papillomavirus. Head Neck Pathol. 2016:10(1):60-67. doi: 10.1007/ s12105-016-0692-y.
3. Nasal cavity and paranasal sinus cancer: statistics. Cancer.Net website. cancer.net/cancer-types/nasal-cavity-and-paranasal-sinus-cancer/statistics. Updated May 5, 2017. Accessed February 8, 2019.
4. PDQ paranasal sinus and nasal cavity cancer treatment (adult). National Cancer Institute website. Updated November 30, 2018. cancer.gov/types/head-and-neck/hp/adult/paranasal-sinus-treatment- pdq. Accessed February 1, 2019.
5. EA3663 — Education materials. ECOG-ACRIN cancer research group website. ecog-acrin.org/clinical-trials/ea3163-educational-materials. Updated January 19, 2019. Accessed February 1, 2019.