Trans-Frontal Five-Fluorouracil (TraFFF): a novel technique for the application of adjuvant topical chemotherapeutic agents in sinonasal adenocarcinoma

Abstract

Sinonasal adenocarcinoma has traditionally been treated with surgery (craniofacial or endoscopic) and adjuvant radiotherapy. Two large series have demonstrated favourable 5-year survival using surgery with adjuvant topical chemotherapy applied repeatedly over several weeks. The authors describe a novel, transnasal application of topical 5-fluorouracil. However, complete coverage of the frontal region of the anterior skull base can be difficult to achieve with a purely transnasal approach in an outpatient setting. We present a novel adjunct method of delivering chemotherapeutic agents into this key area used in a 37-year-old man with T2N0M0 ethmoid adenocarcinoma. The procedure was well tolerated in an outpatient setting and remains disease free at 3 years postoperatively. We suggest that frontal trephination is a useful adjunct to aid accurate placement of adjuvant topical chemotherapeutic agents in the treatment of sinonasal adenocarcinoma.

Background

Sinonasal adenocarcinoma is an uncommon malignancy. Management traditionally involves surgical resection (craniofacial or endoscopic) with adjuvant radiotherapy. The tendency for local recurrence without distant metastases has led some authors to recommend surgical resection followed by adjuvant topical chemotherapy (5-fluorouracil (5-FU), applied repeatedly over several weeks), with radiotherapy reserved for treatment failure. Two large series have demonstrated the efficacy of this approach with a reported 5-year disease-free survival of 86% and 87%, respectively.^{1 2} This compares favourably with surgery with adjuvant radiotherapy, including several large series involving craniofacial resection^{3 4} and more recent analysis of endoscopic resection.^{5 6} The chemotherapeutic agent is typically applied transnasally in the outpatient department² or in the operating theatre.¹ In this technique, it is critical that the chemotherapeutic agent achieve complete coverage of the exposed surfaces of the anterior skull base. The case series reported both describe transnasal application of the agent. It can be technically difficult to achieve complete coverage of the frontal region of the anterior skull base through a purely transnasal approach. Therefore, in conjunction with transnasal application, we propose an additional novel method of application that more accurately delivers the chemotherapeutic agent to the frontal region of the anterior skull base.

Case presentation

Institutional Review Board approval was obtained for this study.

At the primary endoscopic resection, frontal mini-trephines⁷ (Mini-Trephination Set, Medtronic, Minneapolis, Minnesota, USA) are placed to aid in the identification and clearance of one or both frontal recesses, often in the form of a Draf IIA/IIB frontal recess clearance⁸ or a modified endoscopic Lothrop procedure.⁹ At the end of the procedure, the trephine cannulas were removed.

At subsequent visits, the nasal cavity was toileted, with removal of crusts, clots and necrotic material. The residual mini-trephine site was identified by palpating for the presence of a depression in the bone, in the expected area. The skin over the residual mini-trephine site is disinfected and infiltrated with local anaesthetic (lignocaine 1%+1:100 000 epinephrine). A temporary 19-gauge cannula is placed through the residual frontal mini-trephine bone defect (figure 1) and 5% 5-FU emulsion (Efudex, Valeant Pharmaceuticals, Quebec, Canada) applied through the cannula (figures 2–4). A 4 mm 30° or 70° rigid Hopkins rod endoscope is used transnasally to aid in accurate placement of the chemotherapeutic agent. In addition to Trans-Frontal Five-Fluorouracil (TraFFF), 5-FU is applied transnasally with endoscopic guidance using a 4 mm 0° or 30° rigid Hopkins rod telescope.

Figure 1.

Outpatient Trans-Frontal Five-Fluorouracil (TraFFF) technique. Following local anaesthesia, a 19-gauge cannula is inserted through the mini-trephine bone defect (simulated photo, not actual patient).

Figure 2.

Outpatient endoscopic view of frontal sinuses/anterior skull base 1 week after excision, prior to 5-fluorouracil (5-FU) application.

Figure 3.

5-Fluorouracil (5-FU) entering frontal sinuses via Trans-Frontal Five-Fluorouracil (TraFFF) cannula.

Figure 4.

5-Fluorouracil (5-FU) coating anterior skull base via Trans-Frontal Five-Fluorouracil (TraFFF) cannula.

This procedure was repeated twice weekly for 4 weeks, according to the protocol described by Knegt et al.² 5-FU was initially applied intraoperatively at conclusion of the surgical resection. The first postoperative application was performed in the operating theatre under general anaesthesia, with subsequent applications performed in the outpatient department. Oral analgesia or light sedation may be required. At 3 months postoperatively, repeat examination was performed under general anaesthesia and multiple biopsies performed.

Treatment

The TraFFF technique was successfully used for one patient, a 37-year-old male woodworker with a right T2N0M0 ethmoid adenocarcinoma (intestinal type, moderately differentiated). Initial endoscopic resection incorporated a modified endoscopic Lothrop procedure, with mini-trephines, for improved access and postoperative surveillance. Oral analgesia (1 g paracetamol with 60 mg codeine) was administered 30 min prior to each outpatient procedure. Biopsies taken at 3 months were negative. No complications related to the TraFFF technique were observed.

Outcome and follow-up

The patient continues to undergo regular outpatient follow-up observed with nasendoscopic examination of the treatment area. The patient was reviewed every 3 months for the first year and every 6 months thereafter. The patient remains disease free at 3 years postoperatively.

Discussion

Two large studies of sinonasal adenocarcinoma have demonstrated that surgery with adjuvant topical 5-FU provides an equal or better 5-year survival, compared with surgery with adjuvant radiotherapy.^{1 2}

In both reported series, the chemotherapeutic agent was applied transnasally. Knegt et al followed a twice-weekly regimen for 4 weeks, performed under general anaesthesia initially, with all subsequent procedures as an outpatient, whereas Almeyda and Capper recommend a once-weekly regimen for 6 weeks, performed in the operating theatre under general anaesthesia.

Our endoscopic technique for sinonasal tumour resection often incorporates a Draf IIA/IIB frontal recess clearance or modified endoscopic Lothrop procedure (Draf III), to provide complete clearance of the anterior skull base and to allow for improved postoperative surveillance. Application of 5-FU to the anterior sinonasal cavity through a purely transnasal approach may be technically difficult to effectively achieve, particularly in an outpatient setting. Using TraFFF, in addition to the transnasal approach, the chemotherapeutic agent may be delivered more accurately and more thoroughly to this key area.

Learning points.

• Sinonasal adenocarcinoma, while traditionally treated with surgery and adjuvant radiotherapy, has recently also been treated with topical outpatient chemotherapy with similar 5-year survival.

• Transnasal topical chemotherapy can be difficult when disease lies in the frontal region of the anterior skull base in an outpatient setting.

• In our study, we describe our technique Trans-Frontal Five-Fluorouracil ‘TraFFF’ where frontal mini-trephines are placed at primary endoscopic resection to aid in finding the frontal recess, and cannulas removed at conclusion of the procedure. At subsequent visits for chemotherapy, a 19-gauge cannula is placed into the mini-trephine bone defect to deliver the chemotherapeutic agent under direct transnasal vision.

• The TraFFF technique was successful in one patient with T2N0M0 adenocarcinoma and remains disease free by the end of the follow-up period.