Photodiagnosis and Photodynamic Therapy (2006) 3, 87—92
HOW-TO-DO-IT
Bare fiber photodynamic therapy using porfimer sodium for esophageal disease Herbert Wolfsen MD a,b,c,d,e,f,g,h,i,j,∗, Marcia Canto a,b,c,d,e,f,g,h,i,j, Bob Etemad a,b,c,d,e,f,g,h,i,j, Bruce Greenwald d, Frank Gress a,b,c,d,e,f,g,h,i,j, Drew Schembre a,b,c,d,e,f,g,h,i,j, V. Raman Muthusamy a,b,c,d,e,f,g,h,i,j, Afonso Ribeiro a,b,c,d,e,f,g,h,i,j, Virender Sharma a,b,c,d,e,f,g,h,i,j, Gregory Ginsberg a,b,c,d,e,f,g,h,i,j a
Divisions of Gastroenterology and Hepatology, Mayo Clinic, 6A Davis Bldg., 4500 San Pablo Road, Jacksonville, FL 32224, USA b Divisions of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA c Divisions of Gastroenterology and Hepatology, Ochsner Clinic, New Orleans, LA, USA d Divisions of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD, USA e Divisions of Gastroenterology and Hepatology, Duke University, Durham, NC, USA f Divisions of Gastroenterology and Hepatology, Virginia Mason Medical Center, Seattle, WA, USA g Divisions of Gastroenterology and Hepatology, University of California, San Francisco, CA, USA h Divisions of Gastroenterology and Hepatology, University of Miami, Miami, FL, USA i Divisions of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA j Divisions of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA Available online 2 May 2006 KEYWORDS Endoscopic ultrasound; Endobronchial ultrasound; Phototoxicity; Stricture; Lung cancer
∗
Summary During Digestive Disease Week 2005 in Chicago, Illinois, our group of 10 gastrointestinal photodynamic therapists met to discuss variations in procedural technique and treatment protocols. An extensive review of the use of photodynamic therapy (PDT) for esophageal disease has recently been published elsewhere [Wolfsen HC. Present status of photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. J Clin Gastroenterol 2005;39(3):189—202]. This report, based mostly on clinical experience and common sense rather than evidence-based medicine, is a detailed discussion of pragmatic issues. In summary, our centers treat patients with Barrett’s dysplasia, Barrett’s or squamous cell carcinoma using the photosensitizer porfimer sodium (2 mg/kg total body weight) and bare fiber PDT (no fiber centering devices). Aggressive suppression of gastric acid is uniformly emphasized. The most common technique variables were the light energy source, light dosimetry and the amount of Barrett’s mucosa treated during a course of PDT. Standardization of porfimer sodium PDT procedures and light dosimetry may enhance treatment outcomes. © 2006 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +1 904 953 2221; fax: +1 904 953 7260. E-mail address: [email protected] (H. Wolfsen).
1572-1000/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2006.03.004
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Photodynamic therapy for esophageal disease All our centers used porfimer sodium (Photofrin, Axcan Scandipharm, Mont St. Hilaire, Quebec, Canada) exclusively for photodynamic therapy (PDT) at the 2 mg/kg dosage in patients treated for Barrett’s high grade dysplasia, Barrett’s adenocarcinoma and squamous cell carcinoma. Porfimer sodium is the drug of choice and the only photosensitizer that has received Canadian and USA regulatory approval for gastrointestinal disease with consistent expense reimbursement from government health care systems such as Medicare and other third party payers [2]. Use of porfimer sodium is supported by extensive clinical experience including long-term studies as well as the recently published multi-center, prospective randomized controlled trial [3]. Although the prolonged photosensitivity produced by porfimer sodium is problematic, the depth of light penetration and degree of mucosal necrosis is critically important to the treatment success in patients with Barrett’s high grade dysplasia and mucosal carcinoma [2]. In our view, this clinical efficacy more than justifies the risk of stricture. Simply stated, it is preferable to tell a patient that they have developed a stricture that will require a course of multiple dilations compared with having to explain to a patient that PDT has failed to destroy their cancer that is now hidden beneath squamous epithelium and must be resected at esophagectomy to assure its complete removal. Previously, investigators have attempted to reduce the prolonged photosensitization of porfimer sodium by reducing the drug dose. This approach, unfortunately, was associated with decreased clinical efficacy [4]. Similarly, studies do not support the use of PDT for earlier stage Barrett’s disease and none of our centers are using PDT for the treatment of Barrett’s metaplasia or low grade dysplasia. While other photosensitizers such as amino levulinic acid or m-tetrahydroxyphenyl chlorin may be more efficient photosensitizers with less photosensitivity compared with porfimer sodium [5—7], they have failed or not been subjected to the rigorous Canadian and USA regulatory evaluation process [1]. Other ablation devices are currently being studied for the treatment of patients with Barrett’s metaplasia and low grade dysplasia, such as the radiofrequency balloon or low-pressure cryotherapy using liquid nitrogen [8]. Porfimer sodium PDT utilizes laser light activation with 630 nm red light. Most of our centers (6) are now using Diomed solid state diode lasers (Andover Massachusetts, USA, and Cambridge, Eng-
H. Wolfsen et al. land, UK; www.diomed-lasers.com) because of their compact size, ease of operation, reliability and lower acquisition and maintenance costs. The maximum power output of these lasers, however, is limited to 2000 mW. The other four centers continue to use the 630 XP dye module powered by the KTP-YAG model 800 laser system (Laserscope, San Jose, CA, USA) or the Lambda Plus photodynamic therapy laser manufactured by Coherent (Santa Clara, CA, USA). The majority of our centers (9) rely on the internal power meters and calibration units of their lasers. Only one center routinely uses an external power meter for light dosimetry calibration. Quartz cylindrical light diffuser fibers are used in the 1, 2.5 and 5 cm lengths (available from FibersDirect, a subsidiary of Diomed; www.fibersdirect.com) [9]. These fibers are also available in combination with a disposable, reflective-capped balloon device (Xcell photodynamic therapy balloon; Cook Endoscopy, WinstonSalem, NC, USA) [9]. Although three centers used these initially, the use of the balloon use has subsequently been abandoned because of their expense, cumbersome use, and lack of clinical efficacy. None of our centers currently use a fiber centering device, preferring to use the bare fiber technique. The diagnostic evaluation of patients for PDT is similar in all 10 centers (Fig. 1). Endosonography (EUS) is performed in all cases of Barrett’s high grade dysplasia and early esophageal carcinoma to ensure that the disease is limited to the mucosa. A variety of mucosal resection techniques (EMR) are used to remove any suspicious nodules or plaque lesions [10]. PDT is delayed for 6—8 weeks after EMR so that the mucosal defect has completely healed. Fine needle aspiration (FNA) is used to sample suspicious appearing lymph nodes to detect microscopic metastasis. This technique is problematic in patients with long segment Barrett’s disease since the sampling needle must traverse glandular epithelium. To deal with these cases, our group has developed the use of endobronchial ultrasound (EBUS) with fine needle aspiration to sample abnormal appearing para-esophageal lymph nodes [11—13]. Histologic mapping studies performed in patients with Barrett’s disease have found a mosaic of dysplastic and neoplastic changes [14]. The only way to ensure that all areas of dysplasia have been eradicated is by treating the entire segment of Barrett’s glandular mucosa [15]. The length of Barrett’s disease to be treated during a single PDT course, however, varied among our centers. Two centers treat no more than 5 cm glandular mucosa at one session while one center treats up to 8 cm. Four other centers treated up to 12 cm during one course of PDT
Bare fiber photodynamic therapy using porfimer sodium
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Figure 1 Proposed diagnostic approach to patients with Barrett’s high grade dysplasia and mucosal carcinoma.
while another three centers had no pre-determined treatment limitation. The maximum length treated at one session thus far was 16 cm. The PDT treatment format was similar in our centers (Fig. 2). All treatments are done at endoscopy centers on an out-patient basis and the vast majority of patients (90%) are able to convalesce at home, without the need for hospitalization. After informed consent, patients undergo infusion of porfimer sodium via peripheral intravenous catheter over 5 min. Two days later, patients return for upper endoscopy with laser light application. Adequate sedation is imperative for these procedures using intravenous conscious sedation with titrated doses of midazolam (typically 4—12 mg) and fentanyl (50—250 mg) or meperidine (50—250 mg) and supplemental oxygen (2 L/min via nasal canula). With the patient’s oxygen saturation level usually around 90%, a rise in the heart rate is an important early indicator of inadequate sedation or excessive gastric distention. Endoscopy is performed using a standard video endoscope (GIF-Q160, Olympus, Tokyo, Japan) although some favor using a sigmoi-
doscope (CF-140S, Olympus, Tokyo, Japan) because it is shorter, stiffer and has a larger suction channel. After intubation, there is a focused examination of the esophagus, hiatal hernia and cardia. A meticulous, detailed endoscopic examination including inspection and measurement of the Barrett’s segment should have been performed previously by the photodynamic therapist themselves to avoid any ‘‘surprises’’ or unexpected findings. Starting distally, the laser light fiber is inserted into the accessory channel of the endoscope and placed in the distal esophagus with 5—10 mm fiber extending into the hiatal hernia. As the fiber extends from the accessory channel of the endoscope, the position of the endoscope is noted and the laser is activated. During light application, it is important to apply low-level steady air insufflation to distend the esophageal lumen and maintain the position of the fiber in the center of the lumen. This can be challenging when the laser light ‘‘whites out’’ the endoscopes video chip although this problem is avoided by using high definition narrow band image endoscopes with their faster image processors and blue
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H. Wolfsen et al.
Figure 2 Typical one week patient evaluation and PDT treatment course.
light illumination (XGIF-H160Y2, Olympus, Tokyo, Japan). To treat additional segments, the endoscope is carefully repositioned to avoid over-lapping (and double treating) and the laser light application is repeated. Using the Diomed laser, it is important to not allow the laser to ‘‘time out.’’ When this occurs, the system software requires recalibrating the light fiber before additional light treatment can be programmed into the system. Since the cuvette used for light fiber calibration must be kept in pristine condition, it is important to avoid stopping the procedure to prevent the need for system recalibration. During a typical light application of 175 J/cm fiber length (437 s), the procedure is interrupted approximately every 75—100 J to prevent depletion of mucosal oxygen and ‘‘photobleaching’’ [16,17]. The light dose required for effective ablation may be quite variable among individual patients. Splitdose light treatment is used with the initial laser light treatment 48 h after porfimer sodium infusion and a second ‘‘touch up’’ light application at 72 or 96 h later. This second light application allows the treatment of areas that may have been ‘‘skipped’’ or inadequately treated during the initial treatment. The median initial light dose was 200 J/cm fiber length for Barrett’s high grade dysplasia (range 160—250 J/cm fiber length). All our
centers used at least 200 J/cm length as the initial light dose for T-1 mucosal carcinoma (median initial dose = 200 J/cm fiber length; range 200—250 J/cm fiber length). When additional ‘‘touch up’’ light application was used, the median light doses for both Barrett’s high grade dysplasia and mucosal carcinoma patients were 100 J/cm fiber length (range 50—200 J/cm fiber length). During and after PDT, profound suppression of gastric acid and control of gastro-esophageal reflux is considered critically important for optimal mucosal ablation and the regrowth of a stable squamous epithelium [18]. All our centers utilize high doses of proton pump inhibitors (PPI) starting at twice daily dosing and increasing to three times daily or double-dose twice daily, as necessary [19]. At endoscopy, litmus paper pH analysis of gastric juices may be used for PPI dose titration. After the ‘‘second look’’ PDT procedure, patients then return home. Depending on the length of Barrett’s disease treated, patients can expect chest discomfort and painful swallowing for at least 5—7 days. With the help of friends and family, most patients are able to manage at home with the use of an elixir or suppository form of narcotic pain medication (e.g. hydrocodone elixir, 16 oz (480 mL) bottle taken 1—3 teaspoons (5—15 mL) every 2—4 h as needed), high doses of proton pump
Bare fiber photodynamic therapy using porfimer sodium inhibitors, antiemetic suppositories (e.g. prochlorperazine suppositories 25 mg taken every 8—12 h as needed to control nausea and prevent vomiting and retching) and an esophageal cocktail called ‘‘Magic Mouthwash’’ that is a mixture of diphenhydramine, nystatin, viscous lidocaine and hydrocortisone. We also encourage patients to use acetominophen for pain and fever and osmotic laxatives with a stool softener to avoid constipation. In the first weeks after PDT, patients are advised to increase their fluid intake especially with noncitrus fruit juices and salty broth. Use of carbonated beverages, coffee and chocolate drinks is not recommended. We ask patients to eat smaller meals more frequently and avoid dry breads and meat filets (chicken breast and steak). The painful swallowing and anorexia after PDT typically results in a 5—8 kg weight loss [20]. Home visiting nurses are sometimes asked to provide supplementary intravenous fluids and to help administer medications. If patients develop severe chest pain or refractory nausea and vomiting that prevents adequate intake of fluids and medications then hospitalization is necessary. This occurs in approximately 10% of our patients. After this initial course of PDT, patients return home to convalesce while the photosensitivity resolves and then return for surveillance examinations including upper endoscopy with extensive Seattle protocol-type surveillance biopsies of the neo-squamous esophageal mucosa [21]. The most important complications associated with porfimer sodium PDT are phototoxicity reactions, the development of stricture and the persistence of sub-squamous dysplasia or neoplasia [22—25]. It is important to educate the patient and their family regarding the benefits and limitations of this form of PDT including the avoidance of direct sunlight exposure for 4—6 weeks to prevent severe sun burn-like reactions. A short course of corticosteroids may be required to relieve painful swelling in patients who inadvertantly receive excessive light exposure. Severe phototoxic reactions requiring hospitalization are unusual [23]. The development of stricture after PDT appears to be related to numerous local and systemic factors that alter esophageal blood flow and tissue remodeling [16]. The risk of stricture increases dramatically when PDT is performed in area previously treated with PDT, surgery or external beam radiation [26]. Stricture is also more common with the application of excessive PDT light doses but this ‘‘stricture toxicity light threshold’’ is difficult to predict and seems to vary from person to person. Use of split-dose laser light application avoids over-treatment that may cause stricture. We have not found that the
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balloon fiber centering devices have prevented or even decreased the rate of stricture. Narrow band imaging is being studied for improved laser fiber localization and for enhanced detection of residual Barrett’s after PDT and research continues toward the development an optical model of the esophagus during PDT in order to predict depth of mucosal injury to optimize clinical outcomes (more ablation, less stricture). The importance of endoscopic therapy for patients with Barrett’s high grade dysplasia is the prevention of esophageal carcinoma without the serious morbidity and mortality associated with esophageal resection surgery. This requires the complete ablation of all Barrett’s glandular mucosa to prevent the development of metachronous carcinoma as well as control of gastro-esophageal reflux disease to prevent the recurrence of Barrett’s dysplasia and carcinoma. The most serious complications after PDT, therefore, are the persistence and recurrence of sub-squamous Barrett’s dysplasia or neoplasia [24]. While visible disease may be retreated with endoscopic methods, partially treated disease hidden under squamous mucosa requires esophageal resection to assure complete removal. Since patients diagnosed with Barrett’s high grade dysplasia may have co-existent mucosal carcinoma [27], the use of porfimer sodium is favored for greater depth of tissue necrosis to decrease this risk. After porfimer sodium PDT, there are persistent areas of Barrett’s metaplasia in approximately 50% of patients [3,21]. Further, we have found that the detection of residual Barrett’s mucosa is enhanced using advanced endoscopic imaging with high definition endoscopes and narrow band imaging capability. This residual glandular tissue is usually destroyed using ‘‘point and shoot’’ thermal methods such as the argon beam coagulator, heater probe or Nd:YAG laser. More recently, we have also begun using radio frequency balloon ablation and low-pressure liquid nitrogen cryotherapy ablation. Patients with refractory GERD represent a particularly difficult clinical challenge. The unstoppable reflux of bile and gastric juices, seen in patients with large hiatal hernias or after esophagectomy and despite aggressive suppression of gastric acid, often prevents the successful regeneration of squamous epithelium after Barrett’s ablation. Instead, the glandular mucosa continues to regenerate. Since long-term GERD control is critically important both to stabilize the neo-squamous esophageal mucosa and prevent the development of recurrent Barrett’s dysplasia and carcinoma, we have increasingly sent patients for laparoscopic antireflux surgery after PDT.
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References [1] Wolfsen HC. Present status of photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. J Clin Gastroenterol 2005;39(3):189—202. [2] Wolfsen HC. Carpe luz-seize the light: endoprevention of esophageal adenocarcinoma when using photodynamic therapy with porfimer sodium. Gastrointest Endosc 2005;62(4):499—503. [3] Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62(4):488—98. [4] Laukka MA, Wang KK. Initial results using low-dose photodynamic therapy in the treatment of Barrett’s esophagus. Gastrointest Endosc 1995;42(1):59—63. [5] Prosst RL, Wolfsen HC, Gahlen J. Photodynamic therapy for esophageal diseases: a clinical update. Endoscopy 2003;35(12):1059—68. [6] Lovat LB, Jamieson NF, Novelli MR, et al. Photodynamic therapy with m-tetrahydroxyphenyl chlorin for high-grade dysplasia and early cancer in Barrett’s columnar lined esophagus. Gastrointest Endosc 2005;62(4):617—23. [7] Mlkvy P, Messmann H, Regula J, et al. Photodynamic therapy for gastrointestinal tumors using three photosensitizers— –ALA induced PPIX, Photofrin and m-THPC. A pilot study. Neoplasma 1998;45(3):157—61. [8] Sharma VK, Fleisher DE, Wang KK, Overholt B, Fennerty B. A randomized trial of radio-frequency ablation of specialized intestinal metaplasia of the esophagus. Gastrointest Endosc 2004;59:AB113. [9] Panjehpour M, Overholt BF, Haydek JM. Light sources and delivery devices for photodynamic therapy in the gastrointestinal tract. Gastrointest Endosc Clin N Am 2000;10(3):513—32. [10] Wang KK, Wongkeesong M, Buttar NS. American gastroenterological association technical review on the role of the gastroenterologist in the management of esophageal carcinoma. Gastroenterology 2005;128(5):1471—505. [11] Wallace MB, Perelman LT, Backman V, et al. Endoscopic detection of dysplasia in patients with Barrett’s esophagus using light-scattering spectroscopy. Gastroenterology 2000;119(3):677—82. [12] Noh KW, Raimondo M, Wallace MB, Wolfsen HC, Woodward TA. Fine needle aspiration of peritumoral lymph nodes in esophageal cancer with endobronchial ultrasound. Am J Gastroenterol 2005;100:S262.
H. Wolfsen et al. [13] Noh KW, Woodward TA, Wallace MB. Emerging endoscopic techniques in oncology. Gastrointest Endosc Clin N Am 2005;15(3):615—29, x—xi. [14] Cameron AJ, Lomboy CT, Pera M, Carpenter HA. Adenocarcinoma of the esophagogastric junction and Barrett’s esophagus. Gastroenterology 1995;109(5):1541— 6. [15] Wang KK. Current Strategies in the management of Barrett’s esophagus. Curr Gastroenterol Rep 2005;7(3):196— 201. [16] Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Inst 1998;90(12):889—905. [17] Georgakoudi I, Nichols MG, Foster TH. The mechanism of Photofrin photobleaching and its consequences for photodynamic dosimetry. Photochem Photobiol 1997;65(1):135—44. [18] Sampliner RE. Endoscopic ablative therapy for Barrett’s esophagus: current status. Gastrointest Endosc 2004;59(1):66—9. [19] Overholt BF. Acid suppression and reepithelialization after ablation of Barrett’s esophagus. Dig Dis 2000;18(4):232—9. [20] Ukleja A, Scolapio JS, Wolfsen HC. Nutritional consequences following photodynamic therapy. Gastrotenterology 1999;116(4, Part 2):A-582. [21] Ban S, Mino M, Nishioka NS, et al. Histopathologic aspects of photodynamic therapy for dysplasia and early adenocarcinoma arising in Barrett’s esophagus. Am J Surg Pathol 2004;28(11):1466—73. [22] Hemminger LL, Wolfsen HC. Photodynamic therapy for Barrett’s esophagus and high grade dysplasia: results of a patient satisfaction survey. Gastroenterol Nurs 2002;25(4):139—41. [23] Wolfsen HC, Ng CS. Cutaneous consequences of photodynamic therapy. Cutis 2002;69(2):140—2. [24] Wolfsen HC, Hemminger LL, Wallace MB, Devault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett’s dysplasia or cancer. Aliment Pharmacol Ther 2004;20(10):1125—31. [25] Wang KK, Nijhawan PK. Complications of photodynamic therapy in gastrointestinal disease. Gastrointest Endosc Clin N Am 2000;10(3):487—95. [26] Panjehpour M, Overholt BF, Phan MN, Haydek JM. Optimization of light dosimetry for photodynamic therapy of Barrett’s esophagus: efficacy vs. incidence of stricture after treatment. Gastrointest Endosc 2005;61(1):13—8. [27] Sujendran V, Sica G, Warren B, Maynard N. Oesophagectomy remains the gold standard for treatment of high-grade dysplasia in Barrett’s oesophagus. Eur J Cardiothorac Surg 2005;28(5):763—6.
HOW-TO-DO-IT
Bare fiber photodynamic therapy using porfimer sodium for esophageal disease Herbert Wolfsen MD a,b,c,d,e,f,g,h,i,j,∗, Marcia Canto a,b,c,d,e,f,g,h,i,j, Bob Etemad a,b,c,d,e,f,g,h,i,j, Bruce Greenwald d, Frank Gress a,b,c,d,e,f,g,h,i,j, Drew Schembre a,b,c,d,e,f,g,h,i,j, V. Raman Muthusamy a,b,c,d,e,f,g,h,i,j, Afonso Ribeiro a,b,c,d,e,f,g,h,i,j, Virender Sharma a,b,c,d,e,f,g,h,i,j, Gregory Ginsberg a,b,c,d,e,f,g,h,i,j a
Divisions of Gastroenterology and Hepatology, Mayo Clinic, 6A Davis Bldg., 4500 San Pablo Road, Jacksonville, FL 32224, USA b Divisions of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA c Divisions of Gastroenterology and Hepatology, Ochsner Clinic, New Orleans, LA, USA d Divisions of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD, USA e Divisions of Gastroenterology and Hepatology, Duke University, Durham, NC, USA f Divisions of Gastroenterology and Hepatology, Virginia Mason Medical Center, Seattle, WA, USA g Divisions of Gastroenterology and Hepatology, University of California, San Francisco, CA, USA h Divisions of Gastroenterology and Hepatology, University of Miami, Miami, FL, USA i Divisions of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA j Divisions of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA Available online 2 May 2006 KEYWORDS Endoscopic ultrasound; Endobronchial ultrasound; Phototoxicity; Stricture; Lung cancer
∗
Summary During Digestive Disease Week 2005 in Chicago, Illinois, our group of 10 gastrointestinal photodynamic therapists met to discuss variations in procedural technique and treatment protocols. An extensive review of the use of photodynamic therapy (PDT) for esophageal disease has recently been published elsewhere [Wolfsen HC. Present status of photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. J Clin Gastroenterol 2005;39(3):189—202]. This report, based mostly on clinical experience and common sense rather than evidence-based medicine, is a detailed discussion of pragmatic issues. In summary, our centers treat patients with Barrett’s dysplasia, Barrett’s or squamous cell carcinoma using the photosensitizer porfimer sodium (2 mg/kg total body weight) and bare fiber PDT (no fiber centering devices). Aggressive suppression of gastric acid is uniformly emphasized. The most common technique variables were the light energy source, light dosimetry and the amount of Barrett’s mucosa treated during a course of PDT. Standardization of porfimer sodium PDT procedures and light dosimetry may enhance treatment outcomes. © 2006 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +1 904 953 2221; fax: +1 904 953 7260. E-mail address: [email protected] (H. Wolfsen).
1572-1000/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2006.03.004
88
Photodynamic therapy for esophageal disease All our centers used porfimer sodium (Photofrin, Axcan Scandipharm, Mont St. Hilaire, Quebec, Canada) exclusively for photodynamic therapy (PDT) at the 2 mg/kg dosage in patients treated for Barrett’s high grade dysplasia, Barrett’s adenocarcinoma and squamous cell carcinoma. Porfimer sodium is the drug of choice and the only photosensitizer that has received Canadian and USA regulatory approval for gastrointestinal disease with consistent expense reimbursement from government health care systems such as Medicare and other third party payers [2]. Use of porfimer sodium is supported by extensive clinical experience including long-term studies as well as the recently published multi-center, prospective randomized controlled trial [3]. Although the prolonged photosensitivity produced by porfimer sodium is problematic, the depth of light penetration and degree of mucosal necrosis is critically important to the treatment success in patients with Barrett’s high grade dysplasia and mucosal carcinoma [2]. In our view, this clinical efficacy more than justifies the risk of stricture. Simply stated, it is preferable to tell a patient that they have developed a stricture that will require a course of multiple dilations compared with having to explain to a patient that PDT has failed to destroy their cancer that is now hidden beneath squamous epithelium and must be resected at esophagectomy to assure its complete removal. Previously, investigators have attempted to reduce the prolonged photosensitization of porfimer sodium by reducing the drug dose. This approach, unfortunately, was associated with decreased clinical efficacy [4]. Similarly, studies do not support the use of PDT for earlier stage Barrett’s disease and none of our centers are using PDT for the treatment of Barrett’s metaplasia or low grade dysplasia. While other photosensitizers such as amino levulinic acid or m-tetrahydroxyphenyl chlorin may be more efficient photosensitizers with less photosensitivity compared with porfimer sodium [5—7], they have failed or not been subjected to the rigorous Canadian and USA regulatory evaluation process [1]. Other ablation devices are currently being studied for the treatment of patients with Barrett’s metaplasia and low grade dysplasia, such as the radiofrequency balloon or low-pressure cryotherapy using liquid nitrogen [8]. Porfimer sodium PDT utilizes laser light activation with 630 nm red light. Most of our centers (6) are now using Diomed solid state diode lasers (Andover Massachusetts, USA, and Cambridge, Eng-
H. Wolfsen et al. land, UK; www.diomed-lasers.com) because of their compact size, ease of operation, reliability and lower acquisition and maintenance costs. The maximum power output of these lasers, however, is limited to 2000 mW. The other four centers continue to use the 630 XP dye module powered by the KTP-YAG model 800 laser system (Laserscope, San Jose, CA, USA) or the Lambda Plus photodynamic therapy laser manufactured by Coherent (Santa Clara, CA, USA). The majority of our centers (9) rely on the internal power meters and calibration units of their lasers. Only one center routinely uses an external power meter for light dosimetry calibration. Quartz cylindrical light diffuser fibers are used in the 1, 2.5 and 5 cm lengths (available from FibersDirect, a subsidiary of Diomed; www.fibersdirect.com) [9]. These fibers are also available in combination with a disposable, reflective-capped balloon device (Xcell photodynamic therapy balloon; Cook Endoscopy, WinstonSalem, NC, USA) [9]. Although three centers used these initially, the use of the balloon use has subsequently been abandoned because of their expense, cumbersome use, and lack of clinical efficacy. None of our centers currently use a fiber centering device, preferring to use the bare fiber technique. The diagnostic evaluation of patients for PDT is similar in all 10 centers (Fig. 1). Endosonography (EUS) is performed in all cases of Barrett’s high grade dysplasia and early esophageal carcinoma to ensure that the disease is limited to the mucosa. A variety of mucosal resection techniques (EMR) are used to remove any suspicious nodules or plaque lesions [10]. PDT is delayed for 6—8 weeks after EMR so that the mucosal defect has completely healed. Fine needle aspiration (FNA) is used to sample suspicious appearing lymph nodes to detect microscopic metastasis. This technique is problematic in patients with long segment Barrett’s disease since the sampling needle must traverse glandular epithelium. To deal with these cases, our group has developed the use of endobronchial ultrasound (EBUS) with fine needle aspiration to sample abnormal appearing para-esophageal lymph nodes [11—13]. Histologic mapping studies performed in patients with Barrett’s disease have found a mosaic of dysplastic and neoplastic changes [14]. The only way to ensure that all areas of dysplasia have been eradicated is by treating the entire segment of Barrett’s glandular mucosa [15]. The length of Barrett’s disease to be treated during a single PDT course, however, varied among our centers. Two centers treat no more than 5 cm glandular mucosa at one session while one center treats up to 8 cm. Four other centers treated up to 12 cm during one course of PDT
Bare fiber photodynamic therapy using porfimer sodium
89
Figure 1 Proposed diagnostic approach to patients with Barrett’s high grade dysplasia and mucosal carcinoma.
while another three centers had no pre-determined treatment limitation. The maximum length treated at one session thus far was 16 cm. The PDT treatment format was similar in our centers (Fig. 2). All treatments are done at endoscopy centers on an out-patient basis and the vast majority of patients (90%) are able to convalesce at home, without the need for hospitalization. After informed consent, patients undergo infusion of porfimer sodium via peripheral intravenous catheter over 5 min. Two days later, patients return for upper endoscopy with laser light application. Adequate sedation is imperative for these procedures using intravenous conscious sedation with titrated doses of midazolam (typically 4—12 mg) and fentanyl (50—250 mg) or meperidine (50—250 mg) and supplemental oxygen (2 L/min via nasal canula). With the patient’s oxygen saturation level usually around 90%, a rise in the heart rate is an important early indicator of inadequate sedation or excessive gastric distention. Endoscopy is performed using a standard video endoscope (GIF-Q160, Olympus, Tokyo, Japan) although some favor using a sigmoi-
doscope (CF-140S, Olympus, Tokyo, Japan) because it is shorter, stiffer and has a larger suction channel. After intubation, there is a focused examination of the esophagus, hiatal hernia and cardia. A meticulous, detailed endoscopic examination including inspection and measurement of the Barrett’s segment should have been performed previously by the photodynamic therapist themselves to avoid any ‘‘surprises’’ or unexpected findings. Starting distally, the laser light fiber is inserted into the accessory channel of the endoscope and placed in the distal esophagus with 5—10 mm fiber extending into the hiatal hernia. As the fiber extends from the accessory channel of the endoscope, the position of the endoscope is noted and the laser is activated. During light application, it is important to apply low-level steady air insufflation to distend the esophageal lumen and maintain the position of the fiber in the center of the lumen. This can be challenging when the laser light ‘‘whites out’’ the endoscopes video chip although this problem is avoided by using high definition narrow band image endoscopes with their faster image processors and blue
90
H. Wolfsen et al.
Figure 2 Typical one week patient evaluation and PDT treatment course.
light illumination (XGIF-H160Y2, Olympus, Tokyo, Japan). To treat additional segments, the endoscope is carefully repositioned to avoid over-lapping (and double treating) and the laser light application is repeated. Using the Diomed laser, it is important to not allow the laser to ‘‘time out.’’ When this occurs, the system software requires recalibrating the light fiber before additional light treatment can be programmed into the system. Since the cuvette used for light fiber calibration must be kept in pristine condition, it is important to avoid stopping the procedure to prevent the need for system recalibration. During a typical light application of 175 J/cm fiber length (437 s), the procedure is interrupted approximately every 75—100 J to prevent depletion of mucosal oxygen and ‘‘photobleaching’’ [16,17]. The light dose required for effective ablation may be quite variable among individual patients. Splitdose light treatment is used with the initial laser light treatment 48 h after porfimer sodium infusion and a second ‘‘touch up’’ light application at 72 or 96 h later. This second light application allows the treatment of areas that may have been ‘‘skipped’’ or inadequately treated during the initial treatment. The median initial light dose was 200 J/cm fiber length for Barrett’s high grade dysplasia (range 160—250 J/cm fiber length). All our
centers used at least 200 J/cm length as the initial light dose for T-1 mucosal carcinoma (median initial dose = 200 J/cm fiber length; range 200—250 J/cm fiber length). When additional ‘‘touch up’’ light application was used, the median light doses for both Barrett’s high grade dysplasia and mucosal carcinoma patients were 100 J/cm fiber length (range 50—200 J/cm fiber length). During and after PDT, profound suppression of gastric acid and control of gastro-esophageal reflux is considered critically important for optimal mucosal ablation and the regrowth of a stable squamous epithelium [18]. All our centers utilize high doses of proton pump inhibitors (PPI) starting at twice daily dosing and increasing to three times daily or double-dose twice daily, as necessary [19]. At endoscopy, litmus paper pH analysis of gastric juices may be used for PPI dose titration. After the ‘‘second look’’ PDT procedure, patients then return home. Depending on the length of Barrett’s disease treated, patients can expect chest discomfort and painful swallowing for at least 5—7 days. With the help of friends and family, most patients are able to manage at home with the use of an elixir or suppository form of narcotic pain medication (e.g. hydrocodone elixir, 16 oz (480 mL) bottle taken 1—3 teaspoons (5—15 mL) every 2—4 h as needed), high doses of proton pump
Bare fiber photodynamic therapy using porfimer sodium inhibitors, antiemetic suppositories (e.g. prochlorperazine suppositories 25 mg taken every 8—12 h as needed to control nausea and prevent vomiting and retching) and an esophageal cocktail called ‘‘Magic Mouthwash’’ that is a mixture of diphenhydramine, nystatin, viscous lidocaine and hydrocortisone. We also encourage patients to use acetominophen for pain and fever and osmotic laxatives with a stool softener to avoid constipation. In the first weeks after PDT, patients are advised to increase their fluid intake especially with noncitrus fruit juices and salty broth. Use of carbonated beverages, coffee and chocolate drinks is not recommended. We ask patients to eat smaller meals more frequently and avoid dry breads and meat filets (chicken breast and steak). The painful swallowing and anorexia after PDT typically results in a 5—8 kg weight loss [20]. Home visiting nurses are sometimes asked to provide supplementary intravenous fluids and to help administer medications. If patients develop severe chest pain or refractory nausea and vomiting that prevents adequate intake of fluids and medications then hospitalization is necessary. This occurs in approximately 10% of our patients. After this initial course of PDT, patients return home to convalesce while the photosensitivity resolves and then return for surveillance examinations including upper endoscopy with extensive Seattle protocol-type surveillance biopsies of the neo-squamous esophageal mucosa [21]. The most important complications associated with porfimer sodium PDT are phototoxicity reactions, the development of stricture and the persistence of sub-squamous dysplasia or neoplasia [22—25]. It is important to educate the patient and their family regarding the benefits and limitations of this form of PDT including the avoidance of direct sunlight exposure for 4—6 weeks to prevent severe sun burn-like reactions. A short course of corticosteroids may be required to relieve painful swelling in patients who inadvertantly receive excessive light exposure. Severe phototoxic reactions requiring hospitalization are unusual [23]. The development of stricture after PDT appears to be related to numerous local and systemic factors that alter esophageal blood flow and tissue remodeling [16]. The risk of stricture increases dramatically when PDT is performed in area previously treated with PDT, surgery or external beam radiation [26]. Stricture is also more common with the application of excessive PDT light doses but this ‘‘stricture toxicity light threshold’’ is difficult to predict and seems to vary from person to person. Use of split-dose laser light application avoids over-treatment that may cause stricture. We have not found that the
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balloon fiber centering devices have prevented or even decreased the rate of stricture. Narrow band imaging is being studied for improved laser fiber localization and for enhanced detection of residual Barrett’s after PDT and research continues toward the development an optical model of the esophagus during PDT in order to predict depth of mucosal injury to optimize clinical outcomes (more ablation, less stricture). The importance of endoscopic therapy for patients with Barrett’s high grade dysplasia is the prevention of esophageal carcinoma without the serious morbidity and mortality associated with esophageal resection surgery. This requires the complete ablation of all Barrett’s glandular mucosa to prevent the development of metachronous carcinoma as well as control of gastro-esophageal reflux disease to prevent the recurrence of Barrett’s dysplasia and carcinoma. The most serious complications after PDT, therefore, are the persistence and recurrence of sub-squamous Barrett’s dysplasia or neoplasia [24]. While visible disease may be retreated with endoscopic methods, partially treated disease hidden under squamous mucosa requires esophageal resection to assure complete removal. Since patients diagnosed with Barrett’s high grade dysplasia may have co-existent mucosal carcinoma [27], the use of porfimer sodium is favored for greater depth of tissue necrosis to decrease this risk. After porfimer sodium PDT, there are persistent areas of Barrett’s metaplasia in approximately 50% of patients [3,21]. Further, we have found that the detection of residual Barrett’s mucosa is enhanced using advanced endoscopic imaging with high definition endoscopes and narrow band imaging capability. This residual glandular tissue is usually destroyed using ‘‘point and shoot’’ thermal methods such as the argon beam coagulator, heater probe or Nd:YAG laser. More recently, we have also begun using radio frequency balloon ablation and low-pressure liquid nitrogen cryotherapy ablation. Patients with refractory GERD represent a particularly difficult clinical challenge. The unstoppable reflux of bile and gastric juices, seen in patients with large hiatal hernias or after esophagectomy and despite aggressive suppression of gastric acid, often prevents the successful regeneration of squamous epithelium after Barrett’s ablation. Instead, the glandular mucosa continues to regenerate. Since long-term GERD control is critically important both to stabilize the neo-squamous esophageal mucosa and prevent the development of recurrent Barrett’s dysplasia and carcinoma, we have increasingly sent patients for laparoscopic antireflux surgery after PDT.
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References [1] Wolfsen HC. Present status of photodynamic therapy for high-grade dysplasia in Barrett’s esophagus. J Clin Gastroenterol 2005;39(3):189—202. [2] Wolfsen HC. Carpe luz-seize the light: endoprevention of esophageal adenocarcinoma when using photodynamic therapy with porfimer sodium. Gastrointest Endosc 2005;62(4):499—503. [3] Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62(4):488—98. [4] Laukka MA, Wang KK. Initial results using low-dose photodynamic therapy in the treatment of Barrett’s esophagus. Gastrointest Endosc 1995;42(1):59—63. [5] Prosst RL, Wolfsen HC, Gahlen J. Photodynamic therapy for esophageal diseases: a clinical update. Endoscopy 2003;35(12):1059—68. [6] Lovat LB, Jamieson NF, Novelli MR, et al. Photodynamic therapy with m-tetrahydroxyphenyl chlorin for high-grade dysplasia and early cancer in Barrett’s columnar lined esophagus. Gastrointest Endosc 2005;62(4):617—23. [7] Mlkvy P, Messmann H, Regula J, et al. Photodynamic therapy for gastrointestinal tumors using three photosensitizers— –ALA induced PPIX, Photofrin and m-THPC. A pilot study. Neoplasma 1998;45(3):157—61. [8] Sharma VK, Fleisher DE, Wang KK, Overholt B, Fennerty B. A randomized trial of radio-frequency ablation of specialized intestinal metaplasia of the esophagus. Gastrointest Endosc 2004;59:AB113. [9] Panjehpour M, Overholt BF, Haydek JM. Light sources and delivery devices for photodynamic therapy in the gastrointestinal tract. Gastrointest Endosc Clin N Am 2000;10(3):513—32. [10] Wang KK, Wongkeesong M, Buttar NS. American gastroenterological association technical review on the role of the gastroenterologist in the management of esophageal carcinoma. Gastroenterology 2005;128(5):1471—505. [11] Wallace MB, Perelman LT, Backman V, et al. Endoscopic detection of dysplasia in patients with Barrett’s esophagus using light-scattering spectroscopy. Gastroenterology 2000;119(3):677—82. [12] Noh KW, Raimondo M, Wallace MB, Wolfsen HC, Woodward TA. Fine needle aspiration of peritumoral lymph nodes in esophageal cancer with endobronchial ultrasound. Am J Gastroenterol 2005;100:S262.
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