4 lnternal Medicine (Section 2), internal Medicine

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1 Retropharyngeal Abscess after Radiation Therapy and Cis-platinum, 5-Fluorouracil Treatment for Nasopharyngeal Carcinoma with Collagen Disease: Report of Two Patients and a Review of the Literature Masato Hareyama 1, Hisayasu Nagakura 1, Mitsuharu Tamakawa 1, Kazusa Hyodo 1, Kohji Asakura 2, Takashi Horikoshi 3, Shigemichi Tanaka 4, Kohzoh Imai 5, Atsuo Hattori 6, Atsushi Oouchi 1, Mitsuo Shido 1, Hirofumi Koshiba 1, Koh-ichi Sakata 1 and Kazuo Morita 1 Departments of 1 Radiology, 2 Otolaryngology, 3 Dermatology, (Section 1) and 6 Pathology (Section 2), Sapporo Medical University, Sapporo 4 lnternal Medicine (Section 2), internal Medicine Collagen disease are frequently associated with malignant tumors. Recently, radiotherapy combined with chemotherapy has been recommended for improving the efficacy of treatment for nasopharyngeal carcinoma. Two patients with nasopharyngeal carcinoma complicated by collagen diseases (dermatomyositis in one, and Sjogren's syndrome with mixed connective tissue disease in the other) were given radiotherapy combined with chemotherapy consisting of / cis-platinum and 5-fluorouracil. Following this combination therapy, both patients developed retropharyngeal abscess and ulceration of the mucosal membrane on the posterior wall of the oropharynx; there was no tumor cell involvement. Because these injuries were more severe than would have been expected from radiotherapy alone, it is recommended that special attention be paid to combination therapy in patients with nasopharyngeal carcinoma complicated by collagen disease. (Jpn J Clin Oncol 26: , 1996) Key words: Nasopharyngeal carcinoma Collagen disease Radiotherapy Chemotherapy Complications Introduction It is well known that collagen diseases are frequently associated with malignant tumors. I ~ 4) Furthermore, several investigators have documented adverse reactions to radiotherapy in patients with collagen diseases. 5 " 8 ' Teo et al. 9) reported exaggerated reactions to radiation in seven patients with nasopharyngeal carcinoma (NPC) complicated by dermatomyositis (DM). Radiotherapy combined with chemotherapy has recently been recommended as an efficacious therapy for NPC.' - 12) However, to the authors' knowledge, there are no published reports on the use of this combination therapy for NPC complicated by collagen diseases such as DM. We have encountered two patients with NPC complicated by collagen disease who developed se- Received: October 6, 1995 Accepted: January 18, 1996 For reprints and all correspondence: Masato Hareyama, Department of Radiology, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060 vere reactions to radiotherapy combined with chemotherapy using both cis-platinum (CDDP) and 5-fluorouracil (5-FU). Case 1 Case Reports In June 1987, a 45-year-old woman developed erythema on both hands; this was soon followed by itching on the back and buttocks. From December 1988 she also experienced muscle weakness of the extremities, nasal bleeding, left-sided migraine, left ear hearing loss, and nasal phonation. She was hospitalized at the Department of Dermatology, Sapporo Medical University, in May A diagnosis of DM was immediately made on the basis of the diffuse erythema over the whole body, muscle weakness, myogenic patterns in the electromyogram, and loss of striation and lymphocytic infiltration evident in a muscle biopsy specimen. Prednisone was prescribed at a dose of 30 mg/day, but no other immunosuppressive drugs were given. She then underwent a more detailed examination 189

2 HAREYAMA ET AL. :?;..*,. «Fig. 1. A lateral fluoroscopic view shows passage of barium through an oropharyngeal perforation (arrows) into the retropharyngeal space, and accumulation of air bubbles (clear arrows). Fig. 2. Axial contrast-enhanced CT scan shows a large amount of gas in the retropharyngeal space at the level of the upper neck (arrows). because of left cervical lymph node swelling, and was found to have a swelling that extended from the left lateral wall to the superior wall of the nasopharynx. A biopsy specimen revealed poorly differentiated squamous cell carcinoma, and she was transferred to our department. The primary lesion had infiltrated into the sphenoid sinus, clivus, left cavernous sinus, and nasal cavity (T4N1M0, Stage IV). She was treated with external beam irradiation using "Co 7-ray to an area extending from the nasopharynx to the lower neck through opposing lateral portals at a rate of 2 Gy/day. Using the shrinkage technique, a total dose of 64 Gy was delivered to the primary lesion, 60 Gy to the upper and middle neck, and 40 Gy to the lower neck. An analgesic agent was given to palliate the pharyngeal pain, and oral feeding was possible during the period of radiotherapy. The skin exposed to the radiation developed mild moist desquamation, but no exaggerated radiation reactions were noted. After 3 weeks, chemotherapy was initiated by intravenous drip of 100 mg of CDDP on the first day and continuous intravenous drip of 5-FU at 1000 mg/day from the 2nd to the 5th day. One week after the start of chemotherapy,- the patient complained of posterior cephalalgia and high fever. A lateral fluoroscopic view showed passage of barium through an oropharyngeal perforation into the retropharyngeal space and accumulation of air bubbles (Fig. 1). Axial contrast-enhanced CT scan showed a large amount of gas in the retropharyngeal space at the level of the upper neck (Fig. 2). A retropharyngeal abscess was diagnosed and emergency surgery was performed; a mucosal fistula measuring 8x 15 mm was found in the middle portion of the retropharyngeal wall. Surgery was completed by irrigation and drainage of the absess. The DM improved gradually during radiotherapy and steroid therapy, and the diffuse erythema disappeared 10 months after completion of the therapy for NPC, in spite of the fact that no prednisone was administered for the last 7 months. Examination by fiberscopy revealed no recurrence of NPC. However, pelvic bone metastases occurred one year after radiotherapy, and the patient died 35 months after the start of the therapy. 190 Jpn J Clin Oncol 26(3) 1996

3 RETROPHARYNGEAL ABSCESS AFTER TREATMENT FOR NPC Fig. 4. Ulceration of the mucosal membrane in the middle portion of the retropharyngeal wall 13 weeks after completion of the combination therapy (arrows). Fig. 3. The irradiated skin, showing indurated subcutaneous fibrosis, pigmentation, depigmentation, ulceration (arrow), and some crusting (clear arrows) 5 weeks after compleltion of combination therapy. Case 2 Following a tooth extraction in January 1988, a 64-year-old man noticed a painless lymph node swelling in the right middle neck. In October 1988 he noted right hearing loss, and consulted an otolarygologist who diagnosed otitis media. The symptoms were followed by dryness of the mouth in May In December of the same year, the patient experienced dull pain in the neck, shoulder, and finger joints, Raynaud's phenomenon, muscle weakness, as well as rubor, swelling, and a sensation of constriction of the fingers. Physicians at the Department of Internal Medicine at our hospital diagnosed Sjogren's syndrome (based on post-inflammatory sialectasis found in a parotid sialogram and a positive reaction in the Schirmer test) and mixed connective tissue disease (MCTD, based on positivity for (n)-rnp antibody, swollen hands, and Raynaud's phenomenon). Lobenzarit disodium and piroxicam were prescribed for 6 months at a daily dose of 80 mg and 20 mg, respectively. Neither corticosteroid nor immunosuppressive agent was given. Pathological examination of a biopsy specimen from the diffuse swelling in the posterior wall of the nasopharynx revealed squamous cell carcinoma (T2N2M0, Stage IV). Chemotherapy was started with an intravenous drip of 120 mg of CDDP on the first day and continuous intravenous drip of 5-FU at 1000 mg/day from the 2nd to the 5th day. Two weeks after completion of this regimen, radiotherapy was initiated with "Co 7-ray at 1.8 Gy daily through opposing lateral portals. Using the shrinkage technique, 66.6 Gy was applied to the nasopharynx, 61.2 Gy to the upper and middle neck, and 48.6 Gy to the lower neck. The NPC and the cervical lymph node metastasis had disappeared 5 weeks after completion of the radiotherapy; however, the irradiated skin developed indurated subcutaneous fibrosis, pigmentation, depigmentation, ulceration, and some crusting as an acute skin reaction (Fig. 3). There were also pronounced acute mucosal reactions, with markedly yellowish mucosa appearing on the middle portion of the retropharyngeal wall. Later, oral intake became impossible due to pharyngeal pain. The mucosal membrane in the middle portion of the retropharyngeal wall became ulcerated 13 weeks after the completion of radiotherapy (Fig. 4); this was treated using modalities such as hyperbaric oxygenation, without success. The patient suddenly lost consciousness and developed respiratory arrest 5 months after the end of radiotherapy. An axial CT examination through the middle neck showed accumulation of mottled gas in the retropharyngeal and anterior epidural spaces (Fig. 5). 191

4 HAREYAMA ET AL. Fig. 5. Axial CT examination through the middle neck shows accumulation of mottled gas in the retropharyngeal (arrows) and anterior epidural space (clear arrows) 5 months after completion of the combination therapy. He was diagnosed as having retropharyngeal abscess, and antibiotics were administered; consciousness was restored but he continued to suffer motor paralysis below the neck and could not be weaned from the respirator. Later, disseminated intravascular coagulation (DIC) developed and the patient died in June At autopsy, the pharynx and cervical lymph nodes were found to be free of tumor cells and there was no evidence of distant metastases. The symptoms of collagen disease had improved with radiotherapy. Discussion In has been reported that the frequency of malignant tumors complicating DM is high (25 to 37%); the types of tumors follow fairly closely the general incidence of malignant tumors in each country.3"4' In Japan, the most frequent complication is stomach cancer, whereas NPC is relatively infrequent.13' In contrast, Wong14) reported that the incidence of NPC in patient with DM was as high as 75% in Hong Kong. It has also been reported that exaggerated skin 192 reactions develop after radiotherapy in patients with malignant tumors complicated by collagen disease. Toe et al.9) analyzed patients with DM and NPC. They reported that acute confluent mucositis necessitating interruption of radiotherapy occurred in eight of nine patients suffering from DM. In the same group, two patients suffered from chronic radiation skin necrosis with ulceration at 7 and 9 months after radiotherapy, respectively. The development of severe moist desquamation of the irradiated breast as an acute reaction and chest wall necrosis as a late effect has been recorded in three of four patients who underwent radiotherapy for breast conservation in breast cancer preceding or simultaneous with collagen vascular disease.6' Similarly, Urtasun8' described severe skin reactions and intense mucositis in the treated area in epidermoid carcinoma of the buccal mucosa complicated by chronic discoid lupus. It has recently been reported that radiotherapy combined with chemotherapy improves the local control rates of NPC, and several trials have been performed.10"12' Since 1989 we have attempted a combination of two courses of CDDP and 5-FU and radiotherapy. However, in two cases where NPC was associated with collagen disease, combination therapy produced retropharyngeal abscess and ulceration of the mucosal membrane on the posterior wall of the oropharynx; there was no tumor cell involvement. In Case 2, the irradiated skin showed a severe reaction. The radiation dose was 60 Gy in Case 1 and 61.2 Gy in Case 2, neither of which was excessive compared with the usual dosage for NPC. In Case 2, the standard 2-course chemotherapy was replaced by a conservative, single course of chemotherpy, but even then the patient developed severe reactions. These could have been phlegmon, occurring after a tiny infection of the frail mucous membrane of the posterior oropharyngeal wall following the chemoradiotherapy, which was later exacerbated due to the impaired immunoreactivity of the host, who suffered from collagen disease. It is generally understood that the radiosensitivity of normal tissue is enhanced in patients with collagen disease, and that radiation causes damage to vascular endothelial cells. However, the pathogenetic mechanism involved has not been elucidated.7' Because the incidence of NPC complicated by collagen disease is quite low in Japan, it is difficult to carry out a definitive study. At this stage, it seems advisable to avoid a combination of radiotherapy and chemotherapy consisting of CDDP and 5-FU for the treatment of NPC. It is interesting that the collagen disease symptoms improved with radiotherapy in these two cases. Hidano et c/.13) evaluated patients with DM complicated by Jpn J Clin Oncol 26(3) 1996

5 RETROPHARYNGEAL ABSCESS AFTER TREATMENT FOR NPC malignant disease and reported that the clinical symptoms improved in 22 patients (37.3%) who had undergone excision surgery for their cancers. This finding suggests that malignant tumor cells produce a lymphokine which triggers the development of DM. We are currently studying the lymphocytes and serum collected from the patient in Case 2. 15) Acknowledgments The authors thank Mr. D. Day (Sapporo Medical University) for editorial assistance and Ms. E. Sudo for secretarial assistance. References 1) Arundell FD, Wilkinson RD, Haserick JR: Dermatomyositis and malignant neoplasms in adults: a survey of twenty years' experience. Arch Dermatol 82: , ) Barnes BE: Dermatomyositis and malignancy: a reivew of the literature. Ann Intern Med 84: 68-76, ) Callen JP, Hyla JF, Bole GG Jr, Kay DR: The relationship of dermatomyositis and polymyositis to internal malignancy. Arch Dermatol 116: , ) Okayasu I, Mizutani H, Kurihara H, Yanagisawa F: Cancer in collagen disease: a statistical analysis by reviewing the Annual of Pathological Autopsy Cases (Nippon Boken Shuho) in Japan. Cancer 54: , ) Fleck R, McNeese MD, Ellerbroek NA, Hunter TA, Holmes FA: Consequence of breast irradiation in patients with pre-existing collagen vascular diseases. Int J Radiat Oncol Biol Phys 17: , ) Ransom DT, Cameron FG: Scleroderma: a possible contra-indication to lumpectomy and radiotherapy in breast carcinoma. Australas Radlol 31: , ) Robertson JM, Clarke DH, Pevzner MM, Matter RC: Breast conservation therapy: severe breast fibrosis after radiation therapy in patients with collagen vascular disease. Cancer 68: , ) Urtasun RC: A complication of the use of radiation for malignant neoplasia in chronic discoid lupus erythematosus. J Can Assoc Radiol 22: , ) Teo P, Tai TH, Choy D: Nasopharyngeal carcinoma with dermatomyositis. Int J Radiat Oncol Biol Phys 16: , ) Al-Sarraf M, Pajak TF, Cooper JS, Mohiuddin M, Herskovic A, Ager PJ: Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: a radiation therapy oncology group study. / Clin Oncol 8: , ) Atichartakarn V, Kraiphibul P, Clongsusuek P, Pochanugool L, Kulapaditharom B, Ratanatharathorn V: Nasopharyngeal carcinoma: result of treatment with cis-diamminedichloroplatinum II, 5 fluorouracil, and radiation therapy. Int J Radiat Oncol Biol Phys 14: , ) Kish J, Drelichman A, Jacobs J, Hoschner J, Kinzie J, Loh J, Weaver A, Al-Sarraf M: Clinical trial of cisplatin and 5-FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep 66: , ) Hidano A, Kaneko K, Arai Y, Kikuchi R: Survey of the prognosis for dermatomyositis, with special reference to its association with malignancy and pulmonary fibrosis. J Dermatol 13: , ) Wong KO: Dermatomyositis: a clinical investigation of twenty-three cases in Hong Kong. Er J Dermatol 81: , ) Kozutsumi D, Matsuura A, Sato N, Hareyama M, Nagakura H, Morita K, Koshiba H: B cell growth factor from human T-cell hybridoma. Abstract of "8th International Congress of Immunology" in Hungary p203,