there have been no reports of endoprosthesis insertion for the treatment of cholangitis and jaundice as a result of complicated biliary hydatid disease. Percutaneous transhepatic cholangiography has been used as a diagnostic procedure in intra-biliary rupture before surgical exploration without complication. 15 CT scan, although useful for diagnosing the presence of intra-hepatic hydatid cysts, is less useful in demonstrating intra-biliary cyst rupture. The traditional method of treating ruptured intrabiliary hydatid cysts is by surgical excision and bile duct exploration. Dadoukis et al. 16 reported 45 patients with rupture of the hydatid cyst into the intra-hepatic biliary tree with successful surgical excision of the cyst in 40 cases. Omentoplasty was performed in three patients to close the ruptured cavity, and, in two patients, resection or drainage was not possible. In this series, there was one death in a patient operated on as an emergency. When rupture of a hydatid cyst is diagnosed, treatment with albendazole should be initiated in an attempt to prevent'dissemination ofthe cysts, especially if rupture is into the pleural or abdominal cavity. The use of albendazole may also help to reduce the effect of anaphylaxis. To our knowledge, this is the first case of insertion of an endoprosthesis in the treatment of cholangitis due to both intrabiliary rupture of a hydatid cyst and simultaneous compression of the common hepatic duct by the cyst. This form of management is valuable in the acutely ill patient, allowing deferral of more definitive surgery.

REFERENCES 1. Shemesh E, Friedman E. Radiologic and endoscopic appearance of intrabiliary rupture of hydatid liver disease. Digestion

Photodynamic therapy for completely obstructing esophageal carcinoma Howard M. Likier, MD Jeffrey G. Levine, MD Charles J. Lightdale, MD

Photodynamic therapy (PDT) is an experimental treatment that uses a photosensitizing chemical which is activated by light to selectively destroy neoplastic tissue. I - 4 In the past decade, PDT has been used to treat a variety of tumors including cancers of the esophagus, stomach, and rectum. 5. 6 The most favoraFrom the Gastroenterology Service of the Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York. Reprint requests: Charles J. Lightdale, MD, Memorial Hospital, 1275 York Avenue, New York, New York 10021. VOLUME 37, NO. 1, 1991

1987;36:96-100. 2. AI-Hashami HM. Intrabiliary rupture of hydatid cysts of the liver. Br J Surg 1971;58:228-32. 3. Kattan YB. Intrabiliary rupture of hydatid cyst of the liver. Br J Surg 1975;62:885-90. 4. Camunez F, Simo G, Robledo R, et al. Ultrasound diagnosis of ruptured hydatid cyst of the liver with biliary obstruction. Gastrointest Radiol 1986;11:330-3. 5. Subramanyam BR, Balthazar EJ, Naidich DP. Ruptured hydatid cyst with biliary obstruction: diagnosis by sonography and computed tomography. Gastrointest RadioI1983;8:341-3. 6. Marti-Bonmati L, Menor F, Ballesta A. Hydatid cyst of the liver: rupture into the biliary tree. Am J Roentgenol 1988;150:1051-3. 7. Cottone M, Amuso M, Cotton PB. Endoscopic retrograde cholangiography in hepatic hydatid disease. Br J Surg 1978;65:1078. 8. Moreira VF, Merono E, Simon MA, et al. Endoscopic retrograde cholangiopancreatography in Echinococcus (hydatid) cysts of the liver. Gastrointest RadioI1985;10:123-8. 9. McCorkell SJ. Echinococcal cysts in the common bile duct: an uncommon cause of obstruction. Gastrointest Radiol 1985; 10:390-3. 10. Vicente VFM, Garcia EM, Marco MAS. Endoscopic retrograde cholangiography (E.R.C.P.) and complicated hepatic hydatid cyst in the biliary tree. Endoscopy 1984;16:124-6. 11. Ibrahim MAH, Kawanishi H. Endoscopic retrograde cholangiography in the evaluation of complicated echinococcosis of the liver. Gastrointest Endosc 1981:27:20-3. 12. Shemesh E, Klein E, Abramowich D, Pines A. Common bile duct obstruction caused by hydatid daughter cysts-management by endoscopic retrograde sphincterotomy. Am J Gastroenterol 1986;81:280-2. 13. Al Karawi MA, Mohamed ARE, Yasawy I, Haleem A. Nonsurgical endoscopic trans-papillary treatment of ruptured echinococcus liver cyst obstructing the biliary tree. Endoscopy 1987;19:81-3. 14. Magistrelli P, Masetti R, Coppola R, et al. Value of ERCP in the diagnosis and management of pre- and post-operative biliary complications in hydatid disease of the liver. Gastrointest RadioI1989;14:315-20. 15. Farrelly C, Lawrie BW. Diagnosis of intrabiliary rupture of hydatid cyst of the liver by fine-needle percutaneous transhepatic cholangiography. Br J Radiol 1982;55:372-4. 16. Dadoukis J, Gamvros 0, Aletras H. Intrabiliary rupture of the hydatid cyst of the liver. World J Surg 1984;8:786-90.

ble results have been in superficial, early stage malignancies. Esophageal cancer presents most frequently in an advanced, incurable stage, and therapy is primarily for palliation of dysphagia. 7- 9 Current options for palliation include surgery, radiation, chemotherapy, dilation, intubation, and thermal ablation by electrocautery or Nd:YAG laser. Treatment with Nd:YAG laser has limited effectiveness in large tumors, in infiltrating submucosal tumors, and in those affecting the upper esophagus.1O-12 Feeding via surgical or percutaneous endoscopic gastrostomy can be used to successfully maintain nutrition in patients with esophageal cancer. However, the cancer may progress locally to cause continuous aspiration of secretions, again most commonly in the 75

upper esophagus. We report two patients with completely obstructing cancers of the upper esophagus who were maintained on gastrostomy feedings and were successfully palliated with PDT. PATIENTS AND METHODS

We applied PDT to patients with esophageal carcinomas as part of a multicenter cooperative study. Patients with biopsy-proven esophageal cancer stages Tl to T3 not directly invading an adjacent organ who were unsuited for, failed, or refused surgery, chemotherapy, and/or radiation therapy were eligible for PDT. Patients were considered completely obstructed if a guide wire was unable to pass through the existing lumen. These patients were entered into a PDT protocol for completely obstructed patients which did not require randomization. Other inclusion criteria included no contraindication to endoscopy, post-menopausal or sterile female, or a female practicing birth control. Patients also must have had a Kamofsky performance status of greater than or equal to 30 (severely disabled, hospitalized, death not imminent).13 Patients were excluded if they had tracheal or carinal involvement (as documented by bronchoscopy for upper esophageal tumors), porphyria or hypersensitivity to porphyrins, previous PDT, WBC of 3 mg/ dl, and alkaline phosphatase, and/or SGOT >3 times the upper limit of normal were also excluded. In addition, patients were excluded if they were receiving concurrent chemotherapy or radiation therapy. Patients who had received chemotherapy or radiation therapy were required to be off these treatments for at least 4 weeks before enrollment. Patients received 2 mg/kg porfimer sodium (Photofrin®; Quadra Logic Technologies Inc., Vancouver, B.C., Canada) by intravenous bolus injection over a 3- to 5-min period. Patients were advised to stay away from direct or reflected sunlight and to remain indoors whenever possible. If it was necessary to go outside, they were told to be completely covered. Laser light treatment was performed 40 to 50 hours after Photofrin® injection. If necessary, laser light treatment was repeated 96 to 120 hours after injection. Patients could receive two laser light treatments per Photofrin® injection and a maximum of three Photofrin® injections at least 30 days apart, with a maximum of six laser light treatments. Laser light treatments were performed with a tunable argon-pumped dye laser (Innova 200; Coherent, Inc., Palo Alto, Calif.). Patients were endoscoped at baseline for measurement of the tumor length and width, and minimal diameter of the lumen as measured by the open biopsy forceps technique. Laser light 76

Figure 1. The 2.5-cm cylindrical diffusing fiber used in both patients. The fiber was connected to the argon-pumped dye laser emitting red light at a wave length of 630 nm. Figure 2. Endoscopic photograph of the esophageal lumen of patient in case 1 after PDT. There was extensive tumor necrosis (white material) with relative sparing of the normal mucosa. The entire tumor was necrotic and soft. An open biopsy forceps (8 mm) was used to estimate lumenal diameter.

treatment was performed with an Olympus GIF XQ10 endoscope (Olympus Corporation of America, Lake Success, N.Y.). A cylindrical diffuser fiber was placed through the biopsy channel of the endoscope and embedded in the tumor to the point where it could no longer be advanced. The power output of the fiber delivering the red laser light at a wave length of 630 nm was kept constant at 400 milliwatts for each centimeter of the cylindrical diffuser tip. A 2.5-cm cylindrical diffuser tip was used in the two patients reported here (Fig. 1). A laser light dose of 300 joules/ em of diffuser tip was given, requiring a treatment time of 12 min and 30 sec per application. Patients were re-endoscoped 2 to 3 days later for debridement and evaluation. If visible tumor was found, the patient was retreated with laser light. A baseline history and physical, electrocardiogram, CBC, SMAC-20, urinalysis, chest x-ray, CT scan of the chest and abdomen with contrast, barium esophagram, and upper gastrointestinal endoscopy were performed. Dysphagia grade, Kamofsky performance status, and weight were noted. All measurements with the exception of the electrocardiogram and CT scans of the chest and abdomen were repeated at 1 week, GASTROINTESTINAL ENDOSCOPY

and all tests with the exception of the CT scans were repeated at 1 month post-Photofrin® injection. This cycle was repeated if a second injection was given. Tumor response was evaluated at each endoscopy and recorded as (1) complete response, absence of visible and biopsy evidence of esophageal malignancy; (2) partial response, decrease of greater than or equal to 50% in the maximum diameter of the tumor or any improvement in dysphagia grade; (3) stable disease, no objective evidence of increase or decrease in tumor dimensions and/or in esophageal lumen; and (4) progressive disease, an increase in any of the tumor margins, a marked decrease in diameter of the lumen, or reappearance of tumor. Dysphagia grade was as follows: grade 1, able to swallow all foods without difficulty; grade 2, difficulty swallowing some solid foods but able to swallow semi-solid foods; grade 3, unable to swallow solids but able to swallow liquids; grade 4, difficulty in swallowing liquids; grade 5, unable to swallow anything, including saliva. CASE REPORTS Case 1

A 54-year-old white woman developed squamous cell cancer of the larynx in 1988. She subsequently underwent a supraglottic laryngectomy and radical neck dissection with a finding of negative lymph nodes. Her post-operative course was uneventful until progressive dysphagia developed in May 1989. She sought medical attention 4 months later, when she was no longer able to swallow anything. Upper gastrointestinal endoscopy showed a completely obstructing tumor mass at 20 cm from the incisors that was biopsy positive for squamous cell carcinoma. At exploratory surgery, the tumor was found to be unresectable and a surgical gastrostomy tube was placed. Chemotherapy with 5-fluorouracil and interferon brought no response, and chemotherapy was discontinued. In February 1990, she was referred to the Gastroenterology Service at Memorial Sloan-Kettering Cancer Center. At presentation, she was unable to swallow anything, including saliva (dysphagia grade, 5). The patient was entered in the phase III study for patients with completely obstructing esophageal carcinoma as described above. Photofrin® was administered at a dose of 2 mg/kg by slow intravenous injection. Photoactivation was achieved with the argon-pumped dye laser at 48 hours after injection. Upon re-endoscopy 48 hours after photoactivation, the tumor appeared necrotic and a new lumen was appreciated. The Olympus GIF-XQI0 endoscope (9.8 mm in diameter) was passed into the stomach. By the end of the first week, the patient was tolerating a full liquid diet (dysphagia grade, 3). After 14 days, she was eating a solid diet with minimal symptoms (dysphagia grade, 2). Endoscopy showed a partial response with a fully patent lumen approximately 14 mm in diameter and extensive tumor necrosis (Fig. 2). One month after initial PDT, repeat endoscopy revealed some tumor regrowth, and a second cycle of PDT was given. She continues to tolerate a soft diet (dysphagia grade, 2) and has now survived for 8 months. VOLUME 37, NO.1, 1991

Case 2

The patient was a 60-year-old white woman diagnosed with squamous cell carcinoma of the esophagus diagnosed in February 1989, after the development of progressive dysphagia. Upper gastrointestinal endoscopy revealed a highgrade obstruction at 21 cm from the incisors that could not be passed. The patient refused surgery and underwent chemotherapy with cis-platinum and 5-fluorouracil, followed by 2000 rads of external beam radiation. Her dysphagia improved initially but, by July 1989, progressed to a point where only liquids could be tolerated. A surgical gastrostomy tube was placed in August 1989, and enteral feeding was begun. The patient was referred to our service in November 1989 for photodynamic therapy. At that time, she was unable to swallow anything, including saliva (dysphagia grade, 5). Repeat upper gastrointestinal endoscopy revealed a totally obstructing tumor mass at 21 cm. A guide wire could not be passed beyond the tumor. Photofrin® was injected at a dose of 2 mg/kg, and photoactivation was achieved 48 hours later with the argon-pumped dye laser. One week after treatment, there was evidence of a partial response with the tumor appearing necrotic on endoscopic evaluation and the patient was able to tolerate small amounts of liquids (dysphagia grade, 4). A guide wire was passed through the neo-Iumen, and the esophagus was dilated to 13 mm. Afterwards, the patient tolerated a full liquid diet (dysphagia grade, 3). In December 1989, she was reinjected with Photofrin® for the second cycle of PDT. One week after laser photoactivation, the tumor again appeared largely necrotic with a luminal diameter of 10 mm. She continued to tolerate a full liquid diet, but, 1 week later, she was admitted to a local hospital where she died because of progression of pulmonary metastases and pneumonia.

DISCUSSION

PDT with porfimer sodium or dihematoporphyrin ethers (DHE) is dependent on the selective retention of the photosensitizer in malignant tissue. As early as 1942, it was demonstrated that animal tumors would concentrate porphyrins. 14 , 15 In 1960, Lipson introduced hematoporphyrin derivative (HPD), which was produced by treating crude hematoporphyrin with glacial acetic and sulfuric acids, with subsequent alkalization. 16 It was demonstrated that neoplastic tissues would concentrate more HPD than hematoporphyrin. 16 Kinsey et al.,17 working at the Mayo Clinic, described the use of HPD in the localization of early bronchogenic cancer in 1978. The same year, Dougherty et al. 1 used light-activated HPD to successfully treat skin metastases from breast and other solid tumors. They also reported the development of DHE or porfimer sodium, the most photoactive portion of HPD, containing porphyrins linked by ether and ester bonds. The exact cytocidal mechanisms of PDT remain unknown, but there are important effects on tumor microvasculature and the reaction has been found to be oxygen dependent. 2,18 77

Several groups have previously reported successful treatment of esophageal cancer with PDT, with clinical remissions seen in early-stage tumors. Hayata et al. treated six early-stage esophageal cancers with clinical remissions in four patients 7 to 41 months after therapy.3 Of 12 patients with advanced disease, there were no complete remissions. Partial or significant remissions were observed in all, but they also received additional radiation therapy. McCaughan et al. 19 treated 40 patients with esophageal tumors with PDT. Two patients with stage I adenocarcinomas were free of disease at 11 and 23 months. Another patient survived 18 months free of disease but developed a recurrence above the original treatment area. Of nine patients who were completely obstructed at first treatment, all had improved dietary intake. However, complete obstruction was not clearly defined. One month after PDT, only two patients could be re-evaluated by endoscopy. Ofthe nine completely obstructed patients, two died, one tolerated a regular diet, two tolerated a soft diet, and four tolerated a liquid diet. The major toxicity of PDT is skin photosensitivity that can last up to 6 weeks after treatment. 20 Our patient (case 1), who was physically active and who was treated over the summer months, experienced two episodes of minor sunburn. Significant skin toxicity is seen in approximately 25% of patients treated with Photofrin®, but no deaths have been attributed to its direct effects. 21 Photodynamic therapy with porfimer sodium or DHE appears to be an effective, palliative approach in patients with esophageal cancer, even in completely obstructed patients. At 48 hours after the first application of laser light, a new lumen was present in both of our patients. In addition, both patients had almost immediate improvement in dysphagia and dietary intake. Although the patient described in case 2 died 2 months after initial treatment with advanced pulmonary metastases, the patient in case 1 continues to survive at 8 months. Both of our patients had lesions involving the upper esophagus just below the cricopharyngeus muscle where Nd:YAG therapy is technically difficult and less effective. 10- 12 The patients had large infiltrating tumors where the course of the lumen was difficult to establish. Possible angulation could not be assessed as the patients could not swallow x-ray contrast. This made antegrade Nd:YAG laser therapy potentially more dangerous. In addition, a guide wire for dilation could not be passed to permit the use of retrograde Nd:YAG laser technique. The ideal patient for photodynamic therapy has an early-stage cancer, perhaps inoperable because of other medical conditions or refusal of surgery. How-

78

ever, our experience demonstrates that PDT can be successfully used for palliation in the desperate setting of complete esophageal obstruction.

REFERENCES 1. Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A. Photoradiation therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628-35. 2. Manyak MJ, Russo A, Smith PD, Glatstein E. Photodynamic therapy. J Clin Oncol 1988;6:380-91. 3. Hayata Y, Kato M, Okitsu M, et al. Photodynamic therapy with hematoporphyrin derivative in cancer of the upper gastrointestinal tract. Semin Surg OncoI1985;1:1-11. 4. Okuda S, Mimura S, Otani T, et al. Experimental and clinical studies on HPD-photoradiation therapy for upper gastrointestinal cancer. In: Andreoni A, Cubedda R, eds. Porphyrin in tumor phototherapy. New York: Plenum Press, 1983:413. 5. McCaughan JS, Hicks W, Laufman L, et al. Palliation of esophageal malignancies with photoradiation therapy. Cancer 1984;55:2905-10. 6. Patrice T, Foultier MT, Yactayo S, et al. Endoscopic photodynamic therapy with hematoporphyrin derivative for primary treatment of gastrointestinal neoplasms in inoperable patients. Dig Dis Sci 1990;35:545-52. 7. Postlethwait RW. Complications and deaths after operations for esophageal carcinoma. J Thorac Cardiovasc Surg 1983;85:827-31. 8. Kelsen DP, Fein R, Coonley C, Heelan R, Bains M. Cisplatin, Vindesine, and Miroguazone in the treatment of esophageal cancer. Cancer Treat Rep 1986;70:255-9. 9. Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma: II. A critical review of radiotherapy. Br J Surg 1980;67:457-61. 10. Fleischer D, Sivak MW Jr. Endoscopic Nd:YAG laser therapy as palliation for esophagogastric cancer: parameters affecting initial outcome. Gastroenterology 1985;89:827-31. 11. Mellow M, Pinkas H. Endoscopic laser therapy for malignancies affecting the esophagus and gastroesophageal junction. Analysis of technical and functional efficacy. Arch Intern Med 1985;145:1443-6. 12. Lightdale CJ, Zimbalist E, Winawer SJ. Outpatient management of esophageal cancer with endoscopic Nd:YAG laser. Am J GastroenteroI1987;82:46-50. 13. Coscarelli C, Heinrich R, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol 1984;2:187-93. 14. Auler H, Banzer G. Unterssuchungen uber die rolle der Porphine bie Geschwelstkrawken Menschen und Tieren. Z Krebsforsch 1942;53:65-8. 15. Figge FHJ, Weiland GS, Marganiello LOJ. Cancer detection and therapy. Affinity of neoplastic embryonic and traumatized regenerating tissues for porphyrins and metalloporphyrins. Proc Soc Exp Bioi Med 1948;68:640-1. 16. Lipson RL, Baldes EJ. The photodynamic properties of a particular hematoporphyrin derivative. Arch Dermatol 1960;82:508-16. 17. Kinsey JH, Cortese DA, Sanderson DR. Detection of hematoporphyrin fluorescence during fiberoptic bronchoscopy to localize early bronchogenic carcinoma. Mayo Clin Proc 1978;53:594-600. 18. Lee See K, Forbes IJ, Betts WHo Oxygen dependency of phototoxicity with haematoporphyrin derivative. Photochem PhotobioI1984;39:631-4. 19. McCaughan JS, Nims TA, Guy JT, et al. Photodynamic therapy for esophageal tumors. Arch Surg 1989;124:74-80. 20. Ash D, Brown SB. Photodynamic therapy-achievements and prospects. Br J Cancer 1989;60:151-2. 21. Investigator's brochure-Photofrin II@ (dihematoporphyrin ethers) in Photodynamic therapy. Pearl River, NY: American Cyanamid Company, Lederle Laboratories, 1987.

GASTROINTESTINAL ENDOSCOPY

Photodynamic therapy for completely obstructing esophageal carcinoma.

there have been no reports of endoprosthesis insertion for the treatment of cholangitis and jaundice as a result of complicated biliary hydatid diseas...
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