1. Esophageal Cancer
   
   Aetna considers photodynamic therapy with light-activated porfimer sodium (Photofrin) medically necessary for esophageal cancer in members with any of the following:
   
   
   1. Completely obstructing esophageal cancer; or
   2. Partially obstructing esophageal cancer, in members who cannot be satisfactorily treated with Nd:YAG laser therapy; or

   3. Barrett's esophagus carcinoma in situ and high grade disease in members who are not candidates for esophagectomy.

   Aetna considers photodynamic therapy for esophageal cancer experimental and investigational when these criteria are not met.

2. Lung Cancer
   
   Aetna considers photodynamic therapy with light-activated porfimer sodium medically necessary for members with any of the following:
   
   
   1. Microinvasive endobronchial non-small cell lung cancer at an early stage, for whom surgery and radiotherapy are not indicated; or
   2. Completely obstructing endobronchial non-small cell lung cancer; or

   3. Partially obstructing endobronchial non-small cell lung cancer.

   Aetna considers photodynamic therapy for lung cancer experimental and investigational when these criteria are not met.

3. Non-Melanoma Skin Tumor
   
   Aetna considers photodynamic therapy using topical photosensitizers (e.g.,topical methylaminolevulinate, topical 5-fluorouracil, aminolevulinic acid (Levulan Kerastik)) medically necessary for members with any of the following non-melanoma skin tumors (including pre-malignant and primary non-metastatic skin lesions):
   
   
   1. Refractory actinic keratoses (see CPB 567 - Actinic Keratoses Treatments ); or
   2. Cutaneous lesions of Bowen's disease; or

   3. Basal cell carcinoma.

   Photodynamic therapy is considered experimental and investigational for other skin tumors.
   
   Photodynamic therapy using intravenous photosensitizers (e.g., porfimer sodium) is considered experimental and investigational for these indications.

4. Cholangiocarcinoma

   Aetna considers photodynamic therapy medically necessary as an adjunct to stenting for palliation of inoperable cholangiocarcinoma.

   Aetna considers photodynamic therapy of cholangiocarcinoma experimental and investigational when these criteria are not met.

5. Prostate Cancer 

   Aetna considers interstitial motexafin lutetium-mediated photodynamic therapy for prostate cancer experimental and investigational.

For photodynamic therapy for ocular conditions, see CPB 594 - Visudyne (Verteporfin) Photodynamic Therapy. See CPB 091 - Endometrial Ablation for photodynamic endometrial ablation.

The United States Food and Drug Administration (FDA) has approved the use of Laserscope's laser systems with QLT PhotoTherapeutics' light-activated porfimer sodium (Photofrin) for injection in treating early-stage, microinvasive lung cancer. In clinical studies of photodynamic therapy for lung cancer, no candidates for photodynamic therapy had metastatic lesions, nodal involvement or cancer recurrence, and surgery or irradiation was contraindicated because they had an underlying respiratory disease, such as emphysema.

The FDA also recently approved the use of light-activated porfimer sodium for relief of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial non-small cell lung cancer.  Photodynamic therapy also shows promise as an alternative to esophageal resection for treatment for Barrett's esophagus, a pre-malignant lesion.

Photodynamic therapy has also been evaluated as an adjunct to stenting and drainage as a palliative treatment for unresectable bile duct cancer. Small randomized controlled studies have demonstrated improvements in survival, and the results of a Phase III study sponsored by the National Cancer Institute is pending publication. Zoepf, et al. (2005) conducted a randomized controlled clinical trial (Phase IIb) of photodynamic therapy in persons with advanced bile duct cancer. Thirty-two patients with nonresectable cholangiocarcinoma were randomized. Light activation was performed in the patients assigned to photodynamic therapy 48 hours after intravenous application of 2 mg/kg body weight of Photosan-3, an oligomier of hematoporphyrin that has been approved for use in the European Union but is not approved by the U.S. Food and Drug Administration. In the control group, patients were treated with stenting and drainage without photodynamic therapy. The investigators stated that the photodynamic therapy group and the control group were comparable due to age, gender, performance status, bilirubin level, and bile duct cancer stage. The investigators reported that the median survival time after randomization was 7 months for the control group and 21 months for the photodynamic therapy group (p = 0.0109). The investigators noted that, in half of the initially percutaneously treated patients, they were able to change from percutaneous to transpapillary drainage after photodynamic therapy. The investigators noted that phtodynamic therapy was associated with a considerable rate of cholangitis: four patients showed infectious complications after photodynamic therapy versus one patient in the control group.

Ortner, et al. (2003) reported on a prospective, open-label, randomized study with a group sequential design comparing photodynamic therapy plus stenting (n = 20) to stenting alone (n = 19) in patients with nonresectable cholangiocarcinoma. For photodynamic therapy, 2 mg/kg porfirin sodium (Photofrin) was injected intravenously 2 days before intraluminal photoactivation. Further treatments were performed in cases of residual tumor in the bile duct. The investigators reported that photodynamic therapy resulted in prolongation of survival, with median survival of 493 days in persons assigned to photodynamic therapy plus stenting, compared to a median survival of 98 days in persons assigned to stenting alone (p < 0.0001). The investigators noted that photodynamic therapy also improved biliary drainage and quality of life. The investigators noted that this study was terminated prematurely because photodynamic therapy proved to be so superior to simple stenting treatment that further randomization was deemed unethical.

Photodynamic therapy for tumors other than obstructing esophageal cancer, inoperable cholangiocarcinoma, and endobronchial non-small cell lung cancer is considered investigational, because it has not been proven to improve the survival of patients with other tumors.  Photodynamic therapy is being investigated as a treatment for cancers of the breast and brain.

Photodynamic therapy has been extensively studied for the treatment of various superficial nonmelanoma skin cancers. For photodynamic therapy for superficial skin cancers, a photosensitizing porphyrin (5-aminolevulinic acid, methyl aminolevulinate) is generally applied topically to the lesion . Although a porphyrin (porfimer sodium, Photofrin) can be administered systemically, this approach is avoided since systemic for treatment of skin cancers as such therapy can be associated with prolonged photosensitivity.

A recently published study found that photodynamic therapy had good cosmetic results, but had a significantly higher recurrence rates than excision. Rhodes, et al. (2007) reported on the results of a prospective, multicenter, randomized study where 97 patients with 105 nonpigmented nodular basal cell carcinomas (BCCs) were treated with two to four courses of methylaminolevulinate (MAL) photodynamic therapy (PDT) or with excision using 5-mm margins. The patients were followed for 5 years.The raw 5-year recurrence rate among successfully treated MAL-PDT patients was 14%, significantly higher than the 4% recurrence rate among excision patients. When initial treatment failures were included, the 5-year cure rates dropped to 66.0% in the MAL-PDT group and to 91.5% in the excision group. The overall cosmetic outcome at 5 years was rated as good or excellent in 87% of the MAL-PDT patients, which was significantly better than the 54% rated as good or excellent in the surgery patients.

In a prospective, multi-center, non-comparative study, Vinviullo et al (2005) examined the safety and effectiveness of photodynamic therapy using topical methyl aminolaevulinate (MAL) for basal cell carcinoma (BCC) defined as 'difficult to treat', i.e., large lesions, in the H-zone (located in the mid-face), or in patients at high risk of surgical complications.  Patients were assessed 3, 12 and 24 months after the last photodynamic therapy treatment.  A total of 102 patients with 'difficult-to-treat' BCC were treated with MAL PDT, using 160 mg g(-1) cream and 75 J cm(-2) red light (570 to 670 nm), after lesion preparation and 3 hours of cream exposure.  A total of 95 patients with 148 lesions were included in the final analysis.  The histologically confirmed lesion complete response rate at 3 months was 89 % (131 of 148).  At 12 months, 10 lesions had re-appeared, and therefore the cumulative treatment failure rate was 18 % (27 of 148).  At 24 months, an additional 9 lesions had re-appeared, resulting in a cumulative treatment failure rate of 24 % (36 of 148).  The estimated sustained lesion complete response rate (assessed using a time-to-event approach) was 90 % at 3 months, 84 % at 12 months and 78 % at 24 months.  Overall cosmetic outcome was judged as excellent or good in 79 % and 84 % of the patients at 12 and 24 months, respectively.  Follow-up is continuing for up to 5 years.  These investigators concluded that photodynamic therapy by means of MAL is an attractive option for 'difficult-to-treat' BCC.

Other photosensitizers are under investigation for skin cancers. In a clinical trial, Kaviani, et al. (2005) examined the use of photodynamic therapy for the treatment of various pathological types of BCC.  Six patients with 30 lesions underwent photodynamic therapy.  The photosensitizer used was Photoheme, a hematoporphyrin derivative IX.  It was injected intravenously at the dose of 2 to 3.25 mg/kg.  After 24 hours, the lesions were illuminated by laser light (lambda = 632 nm, light exposure dose = 100-200 J/cm2).  Lesions were evaluated pre and post-operatively and at follow-up sessions (of up to 6 months).  After a single session of photodynamic therapy, the average response rate in different histopathological types of BCC (e.g., ulcerative, superficial, nodular, and pigmented forms) were 100 %, 62 %, 90 %, and 14 %, respectively.  In patients who responded completely, the cosmetic results were excellent and there were no recurrence at 6th month of follow-up.  These researchers concluded that although photodynamic therapy seems to be an effective treatment modality for superficial, ulcerative, and nodular BCC, it is not recommended for pigmented lesions.

In a phase I clinical trial, Chan, et al. (2005) examined the pharmacokinetic properties of Npe6 and clinical response to photodynamic therapy with this photosensitizer.  A single intravenous dose of Npe6 was administered to 14 cancer patients with superficial malignancies (BCC = 22 lesions, squamous cell cancer = 13 lesions, papillary carcinoma = 14 lesions).  Patients received one of five ascending doses (0.5 mg/kg (n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n = 1)) 4 to 8 hours prior to light activation.  The total light dose (range 25 to 200 J/cm2) depended on the tumor shape and size.  Light was delivered using an argon-pumped tunable dye laser.  Serum NPe6 concentrations were measured over a 28-day period.  The toxicity and cutaneous clinical efficacy of NPe6 were observed.  Four weeks after photodynamic therapy, 20 of 22 BCC tumors (91 %) showed a complete response; 18 of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56 %) or partial (n = 3/27, 11 %) response.  Fewer non-responders were seen at an Npe6 dose level of 1.65 mg/kg or higher.  Only 2 of 14 patients experienced an adverse event that was definitely related to NPe6 administration.  Photosensitivity resolved within 1 week of NPe6 dosing in 12 of 14 patients.  Analysis of serum levels of 11 patients indicated that a 2-compartment model with a residual phase best fits the data.  The mean alpha, beta, and terminal half-lives were 8.63 +/- 2.92, 105.90 +/- 37.59 and 168.11 +/- 53.40 hours (+/- 1 SD), respectively.  The observed mean volume of distribution was 5.94 +/- 2.55 liters, and the mean clearance was 0.0394+/-0.0132 liters/hour.  These values were independent of the dose administered.  The authors concluded that the photosensitizer, NPe6, was well-tolerated with minimal phototoxic side effects, and demonstrated preliminary effectiveness against cutaneous malignancies.

In a review on photodynamic therapy for non-melanoma skin cancer, Szeimies, et al. (2005) stated that photodynamic therapy is a treatment modality that has been shown to be effective mainly for the dermato-oncological conditions such as actinic keratoses, cutaneous lesions of Bowen's disease, in situ squamous cell carcinoma, and BCC.  This is in agreement with the observations of Babilas, et al. (2005).  Garcia-Zuazaga, et al. (2005) noted that photodynamic therapy has been approved by the FDA to treat actinic keratoses.  In Europe, photodynamic therapy is currently being used in the treatment of actinic keratoses and BCC.  Other off-label uses of photodynamic therapy include cutaneous lesions of Bowen's disease, and cutaneous T-cell lymphoma.  The Finnish Medical Society’s guideline on skin cancer (2005) included photodynamic therapy a treatment option for basilomas (e.g., BCC). 

The National Institute for Health and Clinical Excellence (NICE, 2006) guideline on photodynamic therapy for non-melanoma skin tumors (including pre-malignant and primary non-metastatic skin lesions) stated that “evidence of efficacy of this procedure for the treatment of basal cell carcinoma, Bowen’s disease and actinic (solar) keratoses is adequate to support its use for these conditions …. Evidence is limited on the efficacy of this procedure for the treatment of invasive squamous cell carcinoma”.  The specialist Advisors of this report noted that photodynamic therapy is appropriate for large superficial lesions of Bowen’s disease, actinic keratoses, and BCC, especially where there are multiple lesions and where repair would otherwise require extensive surgery.  This report also stated that a Cochrane review is being developed on photodynamic therapy for localized squamous cell carcinoma of the skin and its precursors.

Du et al (2006) stated that interstitial PDT is an emerging modality for the treatment of solid organ disease.  These investigators have performed extensive research that showed the feasibility of interstitial PDT for prostate cancer.  This study reported their pre-clinical and clinical experience in this therapeutic approach.  These researchers have treated 16 dogs in pre-clinical studies, as well as 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma.  Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed.  They reported the safe and comprehensive treatment of the prostate using PDT.  However, there was significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate.  The authors concluded that PDT is an attractive option for the treatment of prostate adenocarcinoma.  However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility.  Their future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.