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Lecture Syllabus on Photodynamic Therapy

Anthony Infantolino, M.D., F.A.C.P.
Clinical Director of Endoscopic Ultrasound
Assistant Clinical Professor of Medicine
Thomas Jefferson University Hospital
Digestive Disease Institute

Esophageal cancer in the United States has recently exceeded 12, 000 cases. The number of deaths from this disease is similar. The majority of patients present with dysphagia and weight loss. The problem with esophageal cancer is that most patients presenting with dysphagia already have advanced disease. With the use of endoscopic ultrasound many of these patients are now deemed non-resectable and the search for palliative measures is ongoing. In the past most cancers of the esophagus were squamous cell, but more recently there has been a dramatic increase in cancers at the esophagogastric junction (adenocarcinoma). Most of the cancers seem to be related to underlying Barrett's esophagus which is a result of chronic gastroesophageal reflux. The risk factors for squamous cell cancer continue to be smoking and alcohol. The typical palliative tools available for esophageal cancer include radiation and chemotherapy, standard dilation with bougie's or balloons or more recently with expandable metal stents. Traditional thermal therapy includes bipolar electrocautery and high power Nd:YAG:laser. Chemical methods include injection of sclergoldnts and more recently photodynamic therapy (PDT). Many of the other palliative tools other than photodynamic therapy have limitations based on the location of the esophageal tumor. Up to 10.4% are located in the upper third, which is a very difficult area to treat. Stents are relatively contraindicated high in the esophagus due to pressure in the airway and a constant foreign body sensation. Nd:YAG is also difficult due to smoke accumulation and risk of aspiration. Tumors of the middle third are much more amenable to standard treatment with stent, Nd:YAG and PDT. Tumors located in the distal third are problematic for stents since they must cross the EG junction. Therefore, position and tumor morphology is an important factor in choosing a palliative tool for esophageal cancer. Certainly, very long tumors are more difficult to treat with standard Nd:YAG and also with stents. ND:YAG will typically require more sessions initially and then more frequent sessions to maintain luminal patency.

Photodynamic therapy has been studied for many years in many different specialties including GI, Dermatology, Urology, Gynecology etc. PDT with Photofrin is indicated for the palliation of patients with completely obstructing esophageal cancer or patients with partially obstructing esophageal cancer who have been determined by their physician not to be able to be adequately treated by other means. PDT is based on the principal that a drug will be taken up by dysplastic and neoplastic tissue. Subsequently, when this chemical is exposed to non-thermal laser light, singlet oxygen is created. This leads to tissue destruction directly and indirectly through ischemic necrosis by destruction of the blood vessels supplying the tumor. Other possible chemicals involved in tumor destruction include superoxide and hydroxyl radicals which also causes tumor damage and possibly thromboxane II which contributes to the ischemic damage. Patients who are considered for PDT receive an intervenous injection of Photofrin at 2 mg/kg. This is given by slow IV infusion over three to five minutes on day one. On day three, which is approximately 40-50 hours after their IV infusion the tumor is exposed to laser light. This is performed by passing a laser fiber through the biopsy channel of a standard endoscope. A 50 hour time window allows for the Photofrin to be selectively retained in dysplastic and neoplastic tissue and cleared from a variety of other non-neoplastic tissue. The wavelength of non-thermal light that is utilized is 630 nm. The fiber is a cylindrical fiber optic diffuser. Because the activating light is non-thermal, high intrathoracic temperatures are not generated. The second application is sometimes delivered 96-120 hours after injection (i.e. day five) after gentle debridement of the tumor with the endoscope. No additional injection of Photofrin is required for re-treatment. A true "second course" of PDT can be delivered but the time interval must be at least 30 days. Patients must be evaluated by barium swallow to rule out tracheoesophageal or bronchoesophageal fistula which can occur. The mechanisms by which dysplastic and neoplastic tissue selectively retain Photofrin remain unclear but the possibilities include leaky vasculature and poor lymphatic drainage characteristic of most tumors. This allows for extended exposure of tumor cells to plasma protein bound Photofrin and increased time for drug internalization. Acidic pH which is present in many tumors may also be contributory. The light source that generates the wavelength of 630 nm (red light) include Argon dye lasers or KTP driven dye lasers. Both lasers function as two lasers in one. An excitation laser, which is either the Argon or the KTP excites a circulating dye in the second laser which subsequently generates the light. Although all wavelengths cannot be achieved, changing the dye or filters can allow for additional "tuning" to emit laser light of a required wavelength. Experimentation is ongoing with wavelengths in the green light spectrum (365nm).However, presently the wavelength of 630 nm has been determined to be optimal for light penetration into tissue and activation of Photofrin. Once the Photofrin has been delivered, it is the job of the endoscopist to maintain the cylindrical diffusing fiber tip within the center of the lumen in an attempt to deliver equal light distribution throughout the tumor circumference. There are also varying lengths of the cylindrical diffuser fibers. If the length of the tumor is excessively long and the scope can be passed to the distal margin retrograde treatment is preferred. In cases of total obstruction, the proximal margin of the tumor can be treated by placing the fiber above the area of obstruction and then retreating two days later. The average light dose delivered is approximately 300 joules/cm and this is calculated by maintaining light intensity at 400 mW/cm for approximately 12.5 minutes. If the tumor is excessively long (i.e. 5 cm or greater) each 2.5 cm segment can be treated in two 12 minute sessions. PDT has been compared to Nd:YAG. There appears to be improved dysphagia scores and also longer period with which the patient is able to swallow effectively. Dysphagia is basically graded on a scale of 1 to 5, 1 being normal swallowing and 5 being unable to swallow saliva. In a recent small study of 17 patients with a completely obstructing esophageal cancer with a mean dysphagia grade of 4.6, there was statistically significant improvement in the mean dysphagia score at one month. Of the 17 patients treated, 11 received clinically significant benefit from PDT. Importantly, the median duration of benefit of these patient was 69+ days and the median survival was 115 days.

What are the side effects of PDT?

The most important side effect of note is the photosensitivity experienced by patients from direct sunlight or bright indoor light from all sources for 30 days. This is due to residual drug which will be present in all parts of the skin. Typical UV protectants are of no value against photosensitivity. Therefore, patients must be strictly instructed to avoid all direct sunlight or bright indoor light from all sources for 30 days. Therefore, the impact of photosensitivity on a patients individual lifestyle should be considered. For instance, if a patient is an avid bike rider or involved in construction, that activity will need to be eliminated for at least a 30 day time period. Other adverse effects reported in patients that have undergone treatment with Photofrin include nausea (24%), fever (31%), constipation (24%), and local effects characteristic of an inflammatory response we could include pleural effusion, some mild chest pain, etc. Chest pain is uncommon during the procedure. Perforation of the esophagus, although rare, has been reported. Transient increased dysphagia immediately post-procedure has also been reported. Esophageal strictures can form but are uncommon. Tumors of the mid-esophagus treated with PDT have also been associated with atrial arrhythmias given the location of the left atrium to the esophagus. Patients with tumors greater than 10 cm were more likely to experience anemia.

In summary, the significant aspects of PDT as relates to treatment of esophageal cancer include that it is a non-thermal procedure that is relatively pain free. There is no thermal damage to the equipment and no smoke generation. Lower power light sources utilized are simple and easy to perform with less risk. Less sedation is also required. Patients are not as nearly uncomfortable as they are with Nd:YAG. Response to therapy is independent of tumor histology (ie, adenocarcinoma versus squamous), and there is significant amelioration of dysphagia. If the dysphagia free period is too short PDT can also enable placement of esophageal stents in those who are completely obstructed. Other treatments such as XRT and chemotherapy can also continue to be utilized with little interference from PDT. In addition, up to three courses may be given at 30 day intervals. The only absolute contraindication include tumors eroding into major blood vessels (which can be evaluated by endoscopic ultrasound), tumors eroding into the tracheal or bronchial tree, tracheoesophageal or bronchoesophageal fistula, known allergies to porphyrins or those carrying a diagnosis of porphyria.

Although only FDA approved for esophageal cancer, there is exciting preliminary data utilizing PDT for Barrett's esophagus in patients with dysplasia. Barrett's esophagus occurs as a result of chronic acid reflux bathing the lower esophagus. The normal squamous mucosa is replaced by specialized columnar epithelium resembling intestine. It is estimated that the incidence of carcinoma in Barrett's is 30-40 times that of the normal population occurring in approximately 10% of the cases. Until recently esophagectomy was recommended for Barrett's adenocarcinoma and in patients with high-grade dysplasia. Until the present time there has been no effective therapy to completely reverse Barrett's esophagus and therefore avoid high-risk surgery with significant morbidity and mortality. Some thermal therapies have been shown in small trials to potentially cause reversal of Barrett's, however these have not been large studies and subsequent biopsies have revealed superficial squamous mucosa with underlying Barrett's esophagus. No matter which thermal therapy has been utilized controlling acid subsequently is critical to maintaining any improvement in the length of Barrett's esophagus. Overholt, M.D. et al. and others have studied PDT combined with acid suppression in patients with Barrett's mucosa and dysplasia or superficial cancer. PDT was performed and patients were maintained on omeprazole. Extensive mucosal ablation was observed after PDT. There was extensive reduction in the extent of Barrett's mucosa in all patients with an estimated 75%-80% of treated mucosa being replaced by normal squamous epithelium. Some patients actually had a complete endoscopic and biopsy disappearance of Barretts mucosa following PDT. Dysplasia was also eliminated in 29 of the 36 patients studied by Dr. Overholt. Superficial cancer (ie. T1 lesions) documented by endoscopic ultrasound were also destroyed with PDT. Of the 14 patients with 15 superficial cancers an average follow-up of 22 months ranging from 7-62 months no patients revealed recurrence. The problem faced in this initial study published in 1997 was that the 21 patients developed esophageal strictures out of a total of 36. Several required multiple dilatations to return swallowing function to normal, but 4 patients had severe strictures that persisted. This high stricture rate of 58% was felt to be secondary to the deep injury required to abolish the high grade dysplasia and superficial cancer.

There is a national PDT trial on now beginning which will look at other dose ranges in an attempt to accomplish the same goal with less stricture formation. Whether PDT will ever become standard for high grade dysplasia or eventually Barrett's esophagus without dysplasia remains unclear. Other thermal therapies such as the Argon plasma coagulator are presently being investigated at many centers around the country including Jefferson in an attempt to eliminate Barrett's safely and effectively before dysplasia ever develops. However, I do believe that based on the data available as of 1998, that patients who refuse surgery or whom are at excessive risk for surgery who are found to have a high grade dysplasia confirmed by a second opinion pathologist should be considered for PDT. Other indications for PDT as it relates to the GI tract include peritoneal carcinomatosis and other potential superficial GI malignancies.

In summary, I believe PDT is an exciting tool that has come of age. New oral photosynthesize are presently in development which have little if any skin sensitivity. This will help to further expand the use of PDT and improve its overall safety profile. Whether it will become standard of care for Barrett's esophagus and other GI and non-GI malignancies remains yet to be determined.

I do believe we have seen the light!