Medicine Section - Photodynamic Therapy for Oncologic Applications including Barrett’s Esophagus

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

As a treatment of cancer, photodynamic therapy (PDT) consists of the use of a photosensitizing agent and subsequent exposure of tumor cells to a laser light source in order to induce cellular damage. Several different photosensitizing agents have been used: including porfimer sodium (Photofrin), administered intravenously 48 hours before light exposure, and 5-aminolevulinic acid (5-ALA) administered orally four to six hours before the procedure. ALA is metabolized to protoporphyrin X, which is preferentially taken up by the mucosa. Clearance of porfimer occurs in a variety of normal tissues over 40-72 hours, but tumors retain porfimer for a longer period. All patients who receive porfimer become photosensitive and must avoid exposure of skin and eyes to direct sunlight or bright indoor light for 30 days. After administration of the photosensitizing agent, the target tissue is exposed to light using a variety of laser techniques. For example, a laser fiber may be placed through the channel of the endoscope, or a specialized modified diffuser may be placed via fluoroscopic guidance. Treatment of Barrett's esophagus may be enhanced by the use of balloons containing a cylindrical diffusing fiber. The balloon is designed to compress the mucosal folds of the esophagus, thus increasing the likelihood that the entire Barrett's mucosa is exposed to light. Tumor selectivity in treatment occurs through a combination of selective retention of photosensitizing agent and selective delivery of light.

The indications of the U.S. Food and Drug Administration (FDA) label for porfimer sodium are as follows:

• Palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer, who in the opinion of their physician, cannot be satisfactorily treated with Nd:YAG laser therapy.
• Reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial non-small cell lung cancer. (NSCLC)
• Treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy are not indicated.
• Treatment of high grade dysplasia in Barrett’s esophagus.

Oral 5-ALA has not yet received FDA approval for any indication. Topical 5-ALA is used for the treatment of actinic keratoses and is addressed in Regence, Medicine, Policy No. 99.

Lung Cancer Stages

Photodynamic therapy with Photofrin has also been investigated for use in a wide variety of tumors, including other gastrointestinal tumors, prostate, bladder, lung, breast, brain, skin, and head and neck cancers. Barrett’s esophagus has also been treated with photodynamic therapy.

Photodynamic therapy is also called phototherapy, photoradiation therapy, photosensitizing therapy, or photochemotherapy. This policy only addresses the oncologic applications of photodynamic therapy, and does not address its use as a treatment of age-related macular degeneration (see Regence, Medicine, Policy No. 87) or photodynamic therapy with topical 5-aminolevulinic acid for actinic keratosis (see Regence, Medicine, Policy No. 99). In addition, photodynamic therapy should not be confused with extracorporeal photopheresis, which is used in the treatment of certain skin malignancies (e.g., Sézary's syndrome, leukemia cutis). Extracorporeal photopheresis involves withdrawing blood from the patient, irradiating it with ultraviolet light, and then returning the blood to the patient (see Regence, Medicine, Policy No. 84).

Policy/Criteria

One or more courses of photodynamic therapy may be considered medically necessary for the following oncologic applications:

1. Palliative treatment of obstructing esophageal cancer
2. Palliative treatment of local recurrent esophageal cancer in patients who are not candidates for salvage esophagectomy
3. Palliative treatment of obstructing endobronchial lesions
4. Treatment of early stage non-small cell lung cancer in patients who are ineligible for surgery and radiation therapy
5. Treatment of high-grade dysplasia in Barrett’s esophagus

Other oncologic applications of photodynamic therapy, including but not limited to, other malignancies and Barrett’s esophagus without associated high grade dysplasia, are considered investigational.

Note: This policy does not address the use of photodynamic therapy as a treatment of age-related macular degeneration or actinic keratoses. See separate policies Medicine 87 and Medicine 99, respectively.

Scientific Background

Obstructing and Recurrent Esophageal Tumors

When used for palliative treatment, relevant outcomes include short-term resolution of symptoms, such as dysphagia or improvement in swallowing. Long-term outcomes, such as disease-free survival, may not be relevant in the palliative setting. The product insert for Photofrin describes a multicenter, single-arm study of the use of photodynamic therapy in 17 patients with obstructing esophageal cancer. (2) Patients received from one to three monthly treatments of photodynamic therapy. Of the 17 treated patients, 11 (65%) received clinically important benefit from photodynamic therapy, defined as either complete tumor response, normal swallowing, or improvement in dysphagia. Endoscopic debridement of the esophagus may be required after the photodynamic therapy. At this time, the residual tumor can also be retreated.  Response is quite low to second-line chemotherapy and radiation therapy in patients with local recurrent esophageal tumors.  Salvage esophagectomy carries higher morbidity and mortality rates than primary esophagectomy.  One series of 13 patients showed a 12 month disease-free survival of 46% and overall survival of 68.3% with PDT for recurrent tumors. (3)

Obstructing Endobronchial Tumors

Similar to obstructing esophageal tumors, short-term outcomes are also relevant for photodynamic therapy as a treatment of endobronchial tumors. At the present time, laser ablation is commonly used to treat endobronchial lesions and thus the relative efficacy of photodynamic therapy and laser ablation is also relevant. The product insert cites two studies totaling 211 patients with obstructing endobronchial tumors who were randomized to receive photodynamic therapy or Nd: YAG laser therapy. The response rates (i.e., the sum of complete and partial response rates) for the two treatments were similar at one week (59% photodynamic therapy, 58% laser therapy) with a slight increase in response rates for photodynamic therapy at six weeks (60% photodynamic therapy, 41% laser therapy). Clinical improvement, as evidenced by improvements in dyspnea, cough, and hemoptysis, were similar in the two groups at one week (25-29%), however at one month or later 40% of patients treated with photodynamic therapy reported clinical improvement compared to 27% treated with laser therapy. Due to missing data in the studies, statistical comparisons were not performed.

In another small, published, randomized study comparing photodynamic therapy and Nd:YAG laser therapy in patients with airway obstruction, Diaz-Jimenez and colleagues reported that the two techniques had similar effectiveness over a 24-month period. (4) The authors noted a better immediate response rate associated with laser therapy and suggested that laser therapy may be particularly appropriate for those requiring rapid relief of symptoms. Results of a larger case series of 100 patients with unresectable lesions also report that photodynamic therapy is associated with successful palliation. (5)

Similar to treatment of obstructing esophageal lesions, repeat endoscopy may be required for tumor debridement, at which time repeat photodynamic therapy may be performed to treat residual tumor.

Early Stage Lung Cancer

It is anticipated that only a minimal number of patients with non-obstructing lung cancer will be appropriate candidates for photodynamic therapy. Of the 178,000 new cases of lung cancer annually, only 15% are detected with early-stage lung cancer. Of these, approximately 60% are treated with surgery and another 25% are treated with radiation therapy. Candidates for photodynamic therapy are limited to those patients who cannot tolerate surgery or radiation therapy, most commonly due to underlying emphysema, other respiratory disease, or prior radiation therapy. In this primary treatment setting, long-term outcomes such as response rates and disease-free survival are important. The product insert for Photofrin refers to three case series totaling 62 patients with microinvasive lung cancer. The complete tumor response rate, biopsy-proven, at least three months after treatment was 50%, median time to tumor recurrence was more than 2.7 years, median survival was 2.9 years, and disease-specific survival was 4.1 years. (2) In another case series of 95 early-stage lung cancers, the complete response rate was 83.2%. (6)

The labeled indication suggests that photodynamic therapy for early-stage lung cancer should be limited to those who are not candidates for either surgery or radiation therapy. However, Cortese and colleagues reported on a case series of 21 patients with early-stage squamous cell cancer of the lung who were offered photodynamic therapy as an alternative to surgery. (7) Patients were followed closely with repeat endoscopy, with surgical resection if cancer persisted after no more than two courses of photodynamic therapy. A total of nine patients, (43%) had a complete response at a mean follow-up of 68 months (range 24-116 months) and thus were spared surgical treatment.

It should be noted that Nd:YAG laser therapy, electrocautery, and endobronchial brachytherapy are also considered treatment options for early-stage lung cancer. However, unlike obstructing endobronchial lesions, there are no controlled studies comparing the safety and efficacy of these techniques.

Barrett’s Esophagus with High Grade Dysplasia

The FDA labeled indications for treatment of high grade dysplasia is based on a multicenter, partially blinded, study that randomized 199 patients to receive either photofrin plus omeprazole or omeprazole alone. (8) Initially, 485 patients with high-grade dysplasia were screened for the trial; 49% were subsequently excluded because high-grade dysplasia was not confirmed on further evaluation. As noted in the package insert, the high patient exclusions rate re-enforces the recommendation by the American College of Gastroenterology that the diagnosis of dysplasia I Barrett’s esophagus be confirmed by an expert gastrointestinal pathologist. Patients randomized to the treatment group received up to three courses of photodynamic therapy separated by 90 days. The primary efficacy endpoint was the complete response rate at any one of the endoscopic assessment time points. Complete response was defined, at a minimum, as ablation of all areas of high-grade dysplasia but with some areas of low-grade dysplasia. A total of 76.8% of patients in the treatment group achieved a complete response compared to 38.6% in the control group. At the end of 24 months of follow up, patients in the treatment group had an 83% chance of being cancer free compared to a 54% chance in the control group.

Cholangiocarcinoma

There has been ongoing research interest in photodynamic therapy as an adjunct to endoscopic management of cholangiocarcinoma, primarily as a palliative strategy. In addition, percutaneous biliary drainage is a frequent management strategy for cholangiocarcinoma and PDT can thus be administered percutaneously. Several case series have reported positive results, as measured by quality of life studies. (9-11) Two small randomized studies have reported both palliative effects and an increase in median survival. For example, Ortner and colleagues conducted a trial of 39 patients with nonresectable cholangiocarcinoma who were randomized to receive either endoscopic stenting alone or in conjunction with PDT. (12) The median survival of the 20 patient in the PDT group was 493 days compared to 98 days in the 19 patients who underwent stenting alone. The trial was terminated prematurely due to the favorable results. Zoepf and colleagues randomized 32 patients with cholangiocarcinoma to stenting with and without PDT. (13) The median survival for the PDT group was 21 months compared to 7 months in the control group. The NCI-sponsored Phase III randomized study comparing stent placement with and without PDT has closed; however, results have not yet been published. Currently the National Comprehensive Cancer practice guidelines for the treatment of hepatobiliary cancer do not list photodynamic therapy as one of the treatment options. (14)

Other Indications

There continues to be research interest in a variety of applications of photodynamic therapy, including cervical neoplasia, bladder cancer, and soft tissue sarcoma, using a variety of sensitizers. However, the published data still consists of case series and phase I studies. (15, 16) A May 2006 search of the clinical trials database maintained by the National Institutes of Health identified several phase I and phase II trials involving oncologic applications of photodynamic therapy. (17) One trial focused on the safety and effectiveness of a novel light sensitizer, texafin lutetium, and one trial involved the use of a probe to deliver photodynamic therapy directly into liver metastases. Two trials focused on intraoperative photodynamic therapy as an adjunct to surgical resection of brain tumors.

An updated search of the literature focusing on clinical trials published through June 2007 did not identify any published studies that would prompt reconsideration of the policy statement; therefore, the policy is unchanged.

References

1. Blue Cross and BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.06
2. Product insert, Photofrin (Sanofi Pharmaceuticals)  www.sanofi-synthelabo.us/ (Verified 6/11/07)
3. Yano T, Muto M, Minashi K, et al. Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer. Gastrointest Endosc. 2005 Jul;62(1):31-6
4. Diaz-Jimenez, Martinez-Ballerin JE, Llunell A et al. Efficacy and safety of photodynamic therapy versus Nd: YAG laser resection in NSCLC with airway obstruction. Eur Resp J 1999;14:800-05
5. Moghissi K, Dixon K, Stringer M et al. The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer; Experience of 100 cases. Eur J Cardio-thoracic Surg 1999;15:1-6
6. Kato H, Okunaka T, Shimatani H. Photodynamic therapy for early stage bronchogenic carcinoma. J Clin Laser Med Surg 1996;14:235-38
7. Cortese DA, Edell ES, Kinsey JH. Photodynamic therapy for early stage squamous cell carcinoma of the lung. Mayo Clin Proc 1997;72:595-602
8. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93(7):1028-32
9. Shim CS, Cheon YK, Cha SW et al. Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy 2005; 37(5):425-33
10. Harewood GC, Baron TH, Rumalla A et al. Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol 2005; 20(3):415-20
11. Berr F. Photodynamic therapy for cholangiocarcinoma. Semin Liver Dis 2004;24(2):177-87
12. Ortner ME, Caca K, Berr F et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003; 125(5):1355-63
13. Zoepf T, Jakobs R, Arnold JC et al. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 2005; 100(11):2426-30
14. National Comprehensive Cancer Network 2007 Practice Guidelines:  www.nccn.org  (Verified 6/11/07)
15. Yamaguchi S, Tsuda H, Takemori M et al. Photodynamic therapy for cervical intraepithelial neoplasia. Oncology 2005; 69(2):110-6
16. Kusuzaki K, Murata H, Matsubara T et al. Clinical trial of photodynamic therapy using acridine orange with/without low dose radiation as new limb salvage modality in musculoskeletal sarcoma. Anticancer Res 2005; 25(2B):1225-35
17. PDQ National Cancer Institute Clinical Trials:  www.nci.nih.gov  (Verified 6/11/07)

Cross References

Photodynamic Therapy for Subfoveal Choroidal Neovascularization, Regence Medical Policy Manual, Medicine, Policy No. 87

Photodynamic Therapy for the Treatment of Actinic Keratoses and Other Skin Lesions, Regence Medical Policy Manual, Medicine, Policy No. 99

Photopheresis as a Treatment of Autoimmune Disease and Graft versus Host Disease, Regence Medical Policy Manual, Medicine, Policy No. 84

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