• 6/12/2005
  • Oxford, England
  • Rupan Banga et al.
  • Red Nova (rednova.com)

Abstract

We present the first reported case of a squamous cell carcinoma recurrence on a reconstructed flap in the pharynx treated successfully with topical chemotherapy. The patient, treated for a pharyngeal cancer with resection and reconstruction with a free radial forearm flap, and post-operative radiotherapy, developed a tumour on the flap more than two years after surgery. The recurrence was also squamous carcinoma, but there was only superficial infiltration. This was treated with 5-fluorouracil paste placed in the pharynx, with resolution of the tumour. The patient was alive and well more than 28 months after this treatment, with no sign of disease recurrence. Topical chemotherapy for treatment of oral cancer is well described for early disease, but we show that it may be a useful treatment in recurrent disease in selected patients.

Case history

A 76-year-old male ex-smoker was referred to the Oxford Head and Neck Centre with a T^sub 4^ N^sub 1^ post-cricoid carcinoma. He had been treated 22 years previously with primary external beam radiotherapy for a tongue-base squamous cell carcinoma. The post- cricoid tumour presented within the field of the previous external beam radiotherapy.

This tumour was treated with intent to cure in February 2000 with a total laryngectomy, partial pharyngectomy, left hemi- thyroidectomy, left radical neck dissection and a right selective neck dissection. The pharyngeal defect was reconstructed with a left radial forearm free flap.

A salivary fistula through the posterior wall of the trachea complicated the post-operative course, although this healed spontaneously.

Twenty-one months post-operatively, the patient developed a small patch of superficial leukoplakia to the right side of the soft palate, at the base of the uvula. This was observed, but at 29 months he also developed a granular area on the posterior pharyngeal wall on the surface of the radial forearm reconstruction of the neopharynx. He underwent laser excision to the leukoplakia of the soft palate and a biopsy of the granular area. Histologically, the granular area was invasive squamous cell carcinoma on the surface of the radial forearm flap in the neopharynx.

Unusually in this case, the recurrence occurred on the surface of the radial forearm free flap reconstruction. External beam radiotherapy could not be used as the recurrence lay within previous treatment fields. In view of the patient’s age and wishes, removal of the flap and a new reconstruction with further tissue transfer was not appropriate.

After multidisciplinary discussions the patient was treated with a course of topical 5-fluorouracil (5-FU) packing to the neopharynx.

The protocol consisted of five applications of ribbon gauze coated with 20 g of 5 per cent Efudix(TM) (5-FU ointment) at three- weekly intervals. The gauze was placed over the lesion under general anaesthetic and left in situ for 24 hours. As the patient already had a tracheal end stoma, the airway was protected and the packing tolerated without sedation. He experienced no side effects of the treatment and 28 months post-treatment he was clinically and histologically disease-free.

Discussion

This is the first reported case of a topical chemotherapy protocol used to treat squamous cell carcinoma recurrence on a reconstructive free flap in the pharynx. This case presented a difficult management decision and the final treatment choice was discussed between consultants of several specialties and the patient. Some of the other options that were considered as treatment modalities included brachytherapy, systemic chemotherapy and photodynamic therapy. After multidisciplinary discussions and considering the patient’s wishes, treatment with topical 5-FU was deemed the most suitable option.

5-Fluorouracil is a chemotherapeutic agent that can be used both topically and intravenously. At a cellular level its mechanism of action is to inhibit thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. When used topically, the local side effects include pain, pruritis. hypcrpigmcntation, irritation, inflammation and burning at the site of application, allergic contact dermatitis, scarring, soreness, tenderness, suppuration, scaling, and swelling. More rarely, haematological side effects have been reported, including leukocytosis, thrombocytopenia, toxic granulation and eosinophilia.

5-Fluorouracil has been used to treat localized skin cancers and urological cancers, with a good response. It causes selective inflammation, erosion and disappearance of cutaneous neoplasms.1 It has the advantage of being an out-patient treatment and it is less toxic than systemic chemotherapy (hence can be used if there are other significant co-morbidities). It is also useful as a local treatment to effect tumour shrinkage prior to surgical resection.2

Topical chemotherapy has been shown to be effective in the treatment of pre-cancerous and cancerous lesions of the oral cavity. Bleomycin has been shown to prevent progression of leukoplakia to squamous cell carcinoma.3 Previous reports have also shown that topical 5-FU has useful applications in the management of head and neck cancer, either alone or in conjunction with other treatment modalities. Maxson et al. described a case of extensive multicentric areas of oral squamous cell carcinoma-in-situ treated by topical 5- FU.4 In this case, 0.5 per cent 5-FU cream was applied (with the aid of an oral prosthesis) on a daily basis by the patient for 45 minutes. This treatment resulted in shrinkage but not total disappearance of the lesion, but treatment was completed with CO2 laser surgery and the patient was reported to be disease-free at three years.

Umsawasdi and Sawarnkatata had success with 5-FU as a mouthwash in the treatment of relapsing or residual cancer of the lip and buccal mucosa.5

In other head and neck cancer patients, topical 5-FU has been used to shrink carcinomas of the nasal floor and alae prior to undertaking surgical resection. This is limited to difficult and complex lesions that would ordinarily require extensive reconstructive surgery, or where surgery is contraindicated due to co-morbid disease.2 The largest series comes from Rotterdam, Netherlands, comprising a 23-year experience in 73 patients, with the use of topical 5-FU in ethmoidal adenocarcinoma.6 This was in conjunction with surgical debulking and was reserved for those patients who had no evidence of invasion through the orbit or anterior cranial floor. Patients were treated with a medial maxillectomy and spheno-ethmoidectomy via a sub-labial approach. The cavity was liberally covered with 5 per cent FU emulsion and packed with gauze impregnated with 3 per cent tetracycline hydrochloride. Post-operatively, the patients underwent eight twice-weekly pack changes and necrocectomies in the outpatient department. At 12-16 weeks the cavities were inspected and biopsied endoscopically to determine whether further surgical treatment was necessary. This protocol was felt to give good control of local recurrence.

In summary, topical 5-FU appears to be a useful treatment modality for a small group of patients. It is relatively well tolerated and has minimal toxic side effects. A great advantage is that topical treatment may have applications in the out-patient setting. Parenteral chemotherapy, in comparison, has numerous toxic side effects and can necessitate an expensive in-patient stay for the patient. Although the great majority of squamous head and neck cancer requires surgery and/or chemo-radiation, there is a place for topical chemotherapy in carefully selected patients.

* This case reports squamous carcinoma in a reconstructed pharynx

* The disease was successfully treated with topical 5- fluorouracil

References

1 Dillaha CJ, Jansen GT, Bradford AC. Selective cytotoxic effect of topical 5-fluorouracil. Arch Dermatol 1963;88:247-56

2 Ryan RF, Marks MW. Topical 5-fluorouracil in treatment of carcinoma of nasal floor and nasal alae. Annals of Plastic Surgery 1998;20:48-54

3 Epstein JB, Gorsky M, Wong FL, Milner A. Topical bleomycin for the treatment of dysplastic oral leukoplakia. Cancer 1998;83:629-34

4 Maxson BB, Scott RF, Headington JT. Management of oral squamous cell carcinoma in situ with topical 5-fluorouracil and laser surgery. Oral Surg Oral Med Oral Pathol 1989;68:44-8

5 Umsawasdi T, Sawarnkatata P. Intraoral topical application of 5- fluorouracil as a ‘mouthwash’ in the treatment of residual or relapsing cancer of the lip or buccal mucosa. Cancer Chemother Rep 1975:59:1052-3

6 Knegt PP, Ah-see KW, Velden LA, Kerrebijin J. Adenocarcinoma of the ethmoidal sinus complex: surgical debulking and topical fluorouracil may be the optimal treatment. Arch Otolaryngol Head Neck Surg 2001;127:141-6

Authors:
Rupan Banga,MRCS, James Ramsden,MRCS,PHD, Graham Cox,FRCS

Authors’ Affiliation:
Department of Otolaryngology – Head and Neck Surgery, Radcliffe Infirmary, Oxford, UK.