Coverage Policy Manual
Policy #: 2000038
Category: Medicine
Initiated: August 2017
Last Review: February 2019
  Photodynamic Therapy for Malignancy

Description:
Photodynamic therapy (PDT) is a treatment for cancer that consists of an intravenous injection of a photosensitizing agent and subsequent exposure of tumor cells to a laser light source in order to induce cellular damage.  Porfimer sodium (Photofrin) is the only FDA approved photosensitizing agent at this time but other agents are being investigated.  Clearance of porfimer occurs in a variety of normal tissues over 40-72 hours, but tumors retain porfimer for a longer period.  Between 40 and 50 hours after the injection of porfimer sodium, the tumor is exposed to 630-nm wavelength laser light.  Tumor selectivity in treatment occurs through a combination of selective retention of porfimer and selective delivery of light.  The procedure is done in conjunction with endoscopy when treating esophageal cancer and in conjunction with bronchoscopy when treating lung cancer.  A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection of porfimer and after debridement of the tumor.
 
Photodynamic therapy is also called phototherapy, photoradiation therapy, photosensitizing therapy or photochemotherapy.  It should not be confused with extracorporeal photopheresis which is not addressed in this policy.
 
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.
 
Photodynamic therapy has been investigated for use in a wide variety of tumors including other gastrointestinal tumors, prostate, bladder, lung, breast, skin, and head and neck cancers.  Its use has also been studied in Barrett's esophagus without dysplasia  to eliminate the associated cancer risk, and the treatment of dysplasia  associated with Barrett's esophagus.  There is inadequate data published in the peer reviewed literature to permit scientific conclusions about the role of photodynamic therapy for the treatment of patients with Barrett's esophagus either with or without dysplasia.  In patients without dysplasia photodynamic therapy does not reliably eliminate Barrett's esophagus such that patients will be unable to forego ongoing endoscopic surveillance.  Larger studies are needed to determine if the cancer risk is truly reduced in patients who have photodynamic therapy to eliminate the associated dysplasia.
 
On December 20, 2011 porfimer sodium (Photofrin) obtained Orphan Drug designation for the treatment of malignant mesothelioma.

Policy/
Coverage:
Effective, January 2012
Photodynamic therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following FDA approved indications and orphan drug designations:
 
    • Palliative treatment of obstructing esophageal cancer;
    • Treatment of early stage non small cell lung cancer in patients who are ineligible for surgery or radiation therapy;
    • Palliative treatment of obstructing endobronchial lesions;
    • Treatment of high-grade dysplasia in Barrett's esophagus.
    • Treatment of malignant mesothelioma (orphan drug designation)
    • Palliative treatment of unresectable cholangiocarcinoma when used with stenting  
 
Patients may receive a second course of photodynamic therapy a minimum of thirty (30) days after the initial therapy.
 
Other applications of photodynamic therapy do not meet member benefit certificate primary coverage criteria for effectiveness.
 
For contracts without primary coverage criteria, other applications of photodynamic therapy are considered investigational.  Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Effective prior to January 2012
Photodynamic therapy meets primary coverage criteria for effectiveness and is covered for its FDA-approved labeled indications:
    • Palliative treatment of obstructing esophageal cancer;
    • Treatment of early stage non small cell lung cancer in patients who are ineligible for surgery or radiation therapy;
    • Palliative treatment of obstructing endobronchial lesions;
    • Treatment of high-grade dysplasia in Barrett's esophagus.
 
Patients may receive a second course of photodynamic therapy a minimum of thirty (30) days after the initial therapy.
 
Other applications of photodynamic therapy do not meet member benefit certificate primary coverage criteria for effectiveness.
 
For contracts without primary coverage criteria, other applications of photodynamic therapy are considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
Obstructing 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.  Patients received from 1 to 3 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.
 
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 2 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 or complete and partial response rates) for the 2 treatments were similar at 1 week (59% photodynamic therapy, 58% laser therapy) with a slight increase in response rates for photodynamic therapy at 6 weeks (60% photodynamic therapy, 41% laser therapy). Clinical improvement, as evidenced by improvements in dyspnea, cough, and hemoptysis, were similar in the 2 groups at 1 week (25-29%), however at 1 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 2 techniques had similar effectiveness over a 24-month period.  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.
 
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 cites also refers to 3 case series totaling 62 patients with microinvasive lung cancer. The complete tumor response rate, biopsy-proved, at least 3 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.  In another case series of 95 early-stage lung cancers, the complete response rate was 83.2%.
 
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.  Patients were followed closely with repeat endoscopy, with surgical resection if cancer persisted after no more than 2 courses of photodynamic therapy. A total of 9 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, no controlled studies have compared the safety and efficacy of these techniques.
 
Other Indications
Although photodynamic therapy has been investigated for a number of years in the treatment of other cancers, such as bladder and other superficial cancers, a search of the National Cancer Institute’s Physician Data Query database revealed only 9 ongoing trials. All were either Phase I, Phase I/II, or Phase II studies; there were no Phase III clinical trials.
 
2002 Update
This policy is updated with a specific focus on the use of photodynamic therapy to treat Barrett’s esophagus with or without associated dysplasia.
 
Background
Barrett’s esophagus is defined by the American College of Gastroenterology as follows:
 
“Barrett’s esophagus is a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia at biopsy.”
 
Barrett’s esophagus is one of the most recognizable risk factors for the subsequent development of adenocarcinoma, whose incidence has increased rapidly over the past decade. Therefore, periodic endoscopic surveillance is recommended for those patients found to have Barrett’s esophagus, frequently diagnosed as part of a work-up of gastroesophageal reflux disease (GERD). While the symptoms of GERD may be effectively treated with acid suppression therapy, and acid reflux addressed by various surgical approaches, it is still unclear as to whether these therapies predictably result in a regression of Barrett’s esophagus, thus eliminating the cancer risk. Therefore, various mucosal ablative therapies have been investigated as a treatment of Barrett’s esophagus, on the theory that reinjury of the metaplastic epithelium may result in the regeneration of normal squamous mucosa from a pluripotential stem cell. Two applications of photodynamic therapy in the treatment of Barrett’s esophagus have been investigated.
 
Treatment of Barrett’s esophagus without dysplasia, to eliminate the associated cancer risk such that the patient can forego surveillance endoscopy.
In this setting, the final health outcome would be a reduction in the incidence of esophageal adenocarcinoma. However, since the risk of cancer in the overall population of patients with Barrett’s esophagus is low, investigation of this outcome would require a very large controlled clinical trial, comparing the incidence of Barrett’s esophagus in those treated or not treated with photodynamic therapy. As an alternative, a relevant intermediate outcome is the incidence of complete resolution of Barrett’s esophagus, such that the patient can forego routine endoscopic surveillance.
 
Treatment of dysplasia associated with Barrett’s esophagus.
While Barrett’s esophagus itself is considered a risk factor for the esophageal adenocarcinoma, the presence of dysplastic cells within intestinal metaplastic epithelium is considered a premalignant lesion. Patients with dysplasia may be treated with ongoing endoscopic surveillance, ablation therapy, or esophagectomy. Ablation therapy, including photodynamic therapy, may be undertaken as a technique to either “down grade” the dysplasia, or to entirely eliminate the dysplasia and/or the Barrett’s mucosa.  Once again, the final health outcome would be a decrease in the incidence of esophageal adenocarcinoma. Given the higher incidence of adenocarcinoma in this population of patients, it might be possible to study this outcome in a controlled clinical trial, comparing those with dysplasia treated with photodynamic therapy, compared to those followed with continued endoscopic surveillance. In addition, one could study the subsequent cancer incidence in patients considered to be candidates for esophagectomy but who elect to undergo photodynamic therapy as an alternative. An alternative intermediate outcome could be the elimination of dysplasia, theoretically eliminating or at least delaying the evolution to cancer.
 
As with any procedure, the benefits associated with photodynamic therapy must be balanced against the associated risks. Reported risks have included esophageal stricture formation, chest pain or cardiac arrhythmias, nausea and vomiting. In the largest series of 100 patients, the mortality rate was 3%.
 
Reported Data
The published literature predominantly consists of case series, focusing either on technical issues and intermediate outcomes.  The largest case series was reported by Overholt and colleagues who reported on the outcomes of 100 patients with Barrett’s esophagus with associated dysplasia or superficial esophageal cancer who were treated with photodynamic therapy using porfimer.  Patients were maintained on acid suppression therapy (omeprazole) and were followed up 4 to 84 months. Conversion of approximately 75%–80% of treated Barrett’s mucosa to normal squamous epithelium was found in all patients, with complete elimination in 43%. Dysplasia was eliminated in 78%, but developed during follow up in 11 patients. Ten of the 13 malignancies were ablated. However, esophageal stricture developed in 34% of patients. This trial, along with other trials, suggests that photodynamic therapy can rarely eliminate all of Barrett’s esophagus, and that the persistence or emergence of dysplasia is still a threat. Of particular concern was the occurrence of high-grade dysplasia beneath normal-appearing squamous epithelium in 3 patients. Other studies suggest that it is common to find residual Barrett’s mucosa underlying endoscopically normal appearing squamous mucosa. The cancer risk associated with this Barrett’s mucosa, which cannot be detected visually, is unknown.  Therefore, photodynamic therapy cannot be considered curative, and it is likely that all patients undergoing photodynamic therapy will still require ongoing endoscopic surveillance.
 
One small, randomized trial, focusing on intermediate outcomes, has been reported.  Ackroyd and colleagues randomized 36 patients with Barrett’s esophagus with dysplasia to undergo either photodynamic therapy with ALA or placebo, followed by laser endoscopy. Patients were followed for up to 12 months. Of the 18 patients in the treatment group, 16 patients had a decrease in the extent of Barrett’s esophagus, but none had complete eradication. In the placebo group, 2 of 18 patients showed a 10% decrease in the extent of Barrett’s esophagus. While dysplasia was eradicated in the treatment group, it persisted in 12 of 18 patients in the placebo group. There were no short- or long-term side effects.
 
Summary
There are inadequate data published in the peer-reviewed literature to permit scientific conclusions regarding the role of photodynamic therapy in the management of patients with Barrett’s esophagus either with or without associated dysplasia. In patients without dysplasia, photodynamic therapy does not reliably eliminate Barrett’s esophagus, such that the subsequent management of patients will remain unchanged; i.e., patients will be unable to forego ongoing endoscopic surveillance. While photodynamic therapy can eliminate associated dysplasia, it is uncertain how this might affect the cancer risk. Larger studies are needed to determine whether or not the cancer risk is truly reduced. Special consideration may be appropriate for patients with severe dysplasia in whom surgery is contraindicated due to co-morbidities.
 
Barrett’s Esophagus with High-Grade Dysplasia
Since this policy was developed, Barrett’s Esophagus with high-grade dysplasia was approved by the FDA as a labeled indication for photodynamic therapy. The FDA-labeled indication for treatment  is based on a multicenter, partially blinded, study that randomized 199 patients to receive either photofrin plus omeprazole or omeprazole alone.  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 exclusion rate re-enforces the recommendation by the American College of Gastroenterology that the diagnosis of dyplasia in Barrett’s esophagus be confirmed by an expert gastrointestinal pathologist. Patients randomized to the treatment group received up to 3 courses of photodynamic therapy separated by 90 days. The primary efficacy endpoint was the complete response rate at any 1 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.
 
2006 Update
A search of the literature focusing on clinical trials published between 2003 through December 2005 did not identify any published studies that would prompt reconsideration of the policy statement; therefore, the policy is unchanged. 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 consist of case series and phase I studies. A search of the clinical trials database maintained by the National Institutes of Health identified several phase I or phase II trials involving oncologoic applications of photodynamic therapy.  One trial focused on the safety and effectiveness of a novel light sensitizer, texafin lutetium, and 1 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.
 
2007 Update
A literature search was conducted using MEDLINE through June 2007. None of the articles identified led to a change in the policy statement. Many of the articles identified describe results for current indications. For example, Prasad reports similar outcomes between 2 groups (non-randomized) of patients who received either PDT (N=129) or surgery (N=70) for high-grade dysplasia in Barrett’s esophagus (Prasad, 2007).  Other publications describe early and/or preliminary results for use of PDT for other cancers such as head-and-neck, prostate, and pancreatic cancer. In a review article, Chahal describes that PDT in addition to biliary stent placement appears to be a promising step toward the management of locally unresectable cholangiocarcinoma and that randomized trials are needed to further evaluate these therapies (Chahal, 2006).
 
2008 Update
The policy was updated with a literature search using the MEDLINE database through September 2008. A phase II European trial with 20 patients of imiquimod and photodynamic therapy for vulval intraepithelial neoplasia reported by Winters demonstrated an overall response rate of 55% by intention to treat analysis (Winters, 2008).  Symptom response at 52 weeks was 65% asymptomatic versus 5% at baseline. The potential benefit of the treatment is its ability to treat multifocal disease. Results from this small trial need to be replicated in additional larger studies before changes are made to the policy statement. Recent reports of phase I and II trials of photodynamic therapy of prostate cancer are also small, involving less than 20 patients.
 
In a 2008 review, Biel reports his own experience with 276 patients treated with Photofrin PDT for early oral and laryngeal cancers over a period of nearly 16 years and summarizes previously published small case series (Biel, 2007).  Of 115 patients in the author’s series with recurrent or primary carcinoma-in-situ, T1N0 and T2N0, there were 10 recurrences (5-year cure rate 100%) at mean follow-up of 91months. Five-year cure rate for 113 patients with recurrent or primary CIS and T1N0 squamous cell carcinomas of the oral cavity was 100% with 6 recurrences within 8 months of initial treatment salvaged with either repeat PDT or surgical resection. Two patients withT1 tongue tumors developed positive regional lymph nodes within 3 months of PDT, had conventional neck dissection, and have been free of disease for at least 5 years. In the 48 patients treated for superficial T2N0 and T3N0 squamous cell carcinomas of the oral cavity, there were 5 recurrences, all salvaged with repeat PDT or surgical resection. Three-year cure rate was 100% (mean follow-up 56 months). Again, these data need to be replicated in larger, multi-centered studies that include a comparison group. Thus, the policy statement regarding this indication is not changed.
 
The National Institutes of Health clinical trials database lists a large number of trials involving photodynamic therapy.  Trials at U.S. centers include PDT for diagnoses of superficial bladder cancer, cutaneous AIDS-related Kaposi’s sarcoma, locally recurrent prostate cancer, primary or recurrent head and neck cancer, recurrent dysplasia or recurrent in situ or stage I cancer of the mouth or throat, resectable non-small cell lung cancer that has spread to the pleura, PDT plus brachytherapy for lung cancer, malignant mesothelioma, newly diagnosed or recurrent malignant supratentorial gliomas, refractory brain tumors, esophageal, bile duct, gall bladder, and pancreatic cancer.
 
2011 Update
A literature search was conducted for this policy through February 2011.  There was no evidence from well-controlled, randomized studies that would prompt a change in the coverage statement.  The identified literature is summarized below.
 
Fayter and others produced a systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett’s esophagus and cancers of the biliary tract, brain, head and neck, lung, esophagus and skin published in 2010 for the Health Technology Assessment (HTA) program of the United Kingdom’s National Institute for Health Research (NIHR) (Fayter, 2010). The review included literature published through June 2009 and included 88 trials. The authors note a number of limitations in the body of evidence including that there were few well-conducted, adequately powered randomized controlled trials (RCTs) and methodological limitations and gaps in the evidence base make drawing firm conclusions difficult. The authors’ conclusions are summarized as follows: for Barrett’s esophagus, PDT in addition to omeprazole appeared to be more effective than omeprazole alone at long-term ablation of high-grade dysplasia and slowing/preventing progression to cancer. No firm conclusions could be drawn for esophageal cancer. Further research into the role of PDT in lung cancer is needed. For cholangiocarcinoma, PDT may improve survival when compared with stenting alone. There was limited evidence on PDT for brain cancer and cancers of the head and neck. A wide variety of photosensitizers were used and, overall, no serious adverse effects were linked to PDT.
 
EsophageaI Cancer
In a retrospective study from China, 90 patients with esophageal cancer underwent photofrin PDT (n=27), PDT combined with chemotherapy (n=33) or chemotherapy alone (n=30) from 2004-2007 (Li, 2010). Rates of symptomatic palliation (85.2%, 93.9%, and 60.0%, respectively) were not significantly different. The differences in median survival rate at 2 years were statistically significant.
 
Barrett’s Esophagus with High-Grade Dysplasia
Badreddine and colleagues performed a retrospective analysis of a cohort of Barrett’s esophagus patients seen at a specialized Barrett’s esophagus clinic in the U.S. to identify risk factors for recurrence of dysplasia after ablative treatment including PDT (Badreddine, 2010). Three-hundred sixty-three patients underwent PDT with or without endoscopic mucosal resection. Forty patients were lost to follow-up, 46 had residual dysplasia, and 12 had no dysplasia at baseline. Indications for ablation were low-grade dysplasia in 53 patients, high-grade dysplasia in 152 patients, and intramucosal cancer in 56 patients. Median follow-up was 36 months. Recurrence occurred in 45 patients, and median time to recurrence was 17 months. Significant predictors of recurrence on the multivariate model were older age, presence of residual nondysplastic Barrett’s, and a history of smoking. The authors note that the possibility of missing prevalent dysplasia despite aggressive surveillance is a limitation in the study.
 
The Society of Thoracic Surgeons published practice guidelines for the management of Barrett’s esophagus with high-grade dysplasia in June 2009 (Fernando, 2009). The guideline states that, based on grade B evidence, “photodynamic therapy (PDT) should be considered for eradication of high-grade dysplasia (HGD) in patients at high risk for undergoing esophagectomy and for those refusing esophagectomy” and that “it is reasonable to use photodynamic therapy (PDT) to ablate residual intestinal metaplasia after endoscopic mucosal resection (EMR) of a small intramucosal carcinoma in high-risk patients”.
 
Cholangiocarcinoma
Gao and colleagues performed a systematic review of the literature on PDT for unresectable cholangiocarcinoma (Gao, 2010). The authors reviewed 2 randomized, controlled trials, 2 comparative trials with concurrent controls, 1 comparative trial with historical controls, and 15 case series. The 2 randomized trials were rated of moderate quality and the other available studies were of low to moderate quality. The mean number of subjects was 27 (range: 1–184 subjects). Porfimer sodium (Photofrin) was the photosensitizer used in all but 2 of the included studies.
 
Gynecological Malignancies
Istomin and colleagues reported on 112 patients with morphologically proven cervical intraepithelial neoplasia grades II and III with at least 1-year follow-up after treatment with Photolon PDT (Istomin, 2010). Complete regression of neoplastic lesions was seen in 104 of the treated women. Of 88 patients infected with HPV of highly oncogenic strains, 47 had complete eradication of the HPV infection 3 months after treatment.
 
Head and Neck Cancers
A U.S. cancer center enrolled 30 patients in a trial to determine efficacy and safety of Photofrin PDT for primary or recurrent moderate to severe oral or laryngeal dysplasia, CIS, or T1NO carcinoma (Rigual, 2009). Twenty patients had a complete response, one had a partial response, and one had no response. Three patients with oral dysplasia with and initial complete response experienced recurrence. All patients with no response or partial response or recurrence after initial response underwent salvage treatment. No patient required airway intervention, and all complications resolved without permanent sequelae.
 
A retrospective review of Photofrin PDT of 30 patients with early stage (TisT2N0M0) squamous cell carcinoma of oral cavity and oropharynx found that 24 patients demonstrated complete remission (follow-up 3-144 months) (Schweitzer, 2010). Six patients who had partial remission with recurrence at were subsequently treated with conventional therapy. Eleven of 24 patients were cancer disease free at 2 years after PDT.
 
Brain
Aziz and others describe using intraoperative Photofrin photodynamic therapy in 14 metastatic brain cancers (7 originating in the lung and 7 from a variety of sources) (Aziz, 2009). Of the patients with lung cancer metastases, 1 died of unrelated cause and 6 were free of brain disease until their deaths. Two of the remaining patients (one with metastatic bowel cancer and 1 with unknown primary) died of local brain recurrence. A review of the literature on PDT applications in brain tumors relied largely on unpublished data and was not reviewed for this policy (Eljamel, 2010).
 
2013 Update
A literature search was conducted through January 2013.  There was no new literature identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
McCann and colleagues, in 2011, reported on a systematic review of traditional non-endoscopic and endoscopic treatments for early esophageal cancer, including 26 PDT studies (McCann, 2011).  The reviewers noted the lack of evidence from large, randomized trials and found the quality of evidence available overall was generally low. While the evidence did demonstrate that endoscopic techniques reduced morbidity and mortality compared to esophagectomy, outcomes from endoscopic treatments were similar, and no single endoscopic technique could be identified as a recommended treatment approach. The review focused on tumor response and recurrence and disease-specific and overall survival and did not examine quality-of-life outcomes.
 
In 2011, Rupinski and colleagues reported on a randomized study of 93 patients with inoperable cancer of the esophagus or esophageal junction to compare argon plasma coagulation (APC) alone to PDT with APC or high-dose rate brachytherapy (HDR) with APC (Rupinski, 2011). Both combination therapies were more effective than APC alone in median time to recurrence of dysphagia (85, 59, and 35 days for HDR with APC, PDT with APC, and APC alone, respectively). Overall survival was not significantly different between groups. However, complications occurred more often in the PDT with APC and APC alone groups than the HDR with APC group.
 
2018 Update
 
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
EARLY-STAGE LUNG CANCER
Less than one-third of lung cancer patients present with early-stage disease. For patients with early-stage disease, surgery is the standard treatment. For inoperable early non-small-cell lung cancer, treatment guidelines from the National Comprehensive Cancer Network recommend stereotactic ablative radiotherapy (NCCN, 2017). The guidelines reference a 2009 phase 2 multicenter noncomparative trial of stereotactic body radiotherapy assessing 57 patients with inoperable stage I non-small-cell lung cancer, the results of which demonstrated a 3-year overall survival of 88% (Baumann, 2009). For patients who are not surgical candidates or who refuse surgery and are ineligible for radiotherapy, other ablative techniques (eg, PDT) are options.
 
CHOLANGIOCARCINOMA
 
Systematic Reviews
Lu et al (2015) reported on a meta-analysis of controlled trials of PDT for unresectable cholangiocarcinoma published through December 2013 (Lu, 2015). Eight controlled trials (total N=642 patients) were included; the two RCTs were the same RCTs identified in Gao (2010). In the 7 trials (n=602 patients) of PDT plus stent vs stent-alone, OS was significantly longer in PDT plus stent (hazard ratio, 0.49; 95% CI, 0.33 to 0.73; p<0.01). Two studies reported that Karnofsky Performance Status scores were higher in patients receiving PDT but quantitative summaries were not given. Cholangitis was reported in 36% of patients who received PDT and 34% of patients who did not. Eleven percent of patient receiving PDT had a phototoxic reaction.
 
Randomized Controlled Trials
Hauge et al (2016) reported results of a phase 2 safety and feasibility RCT for combination chemotherapy plus stenting with and without temoporfin (Foscan) PDT in the treatment of biliary tract cancer (Hauge, 2016). Eligible patients had unresectable or recurrent/metastatic biliary tract cancer, no previous chemotherapy or radiotherapy for the current cancer, and no other cancers in the previous 5 years. Twenty patients were enrolled; 17 had hilar cholangiocarcinoma. In the PDT group, one PDT treatment was given following stenting and before chemotherapy. Chemotherapy was given until progression or for 12 courses. No serious, procedure-related adverse events were observed in either group. The number of grade 3 and 4 adverse events was similar in both groups. Three patients in each group developed cholangitis within 30 days. Following chemotherapy, mean quality of life as measured by the EORTC QLQ-C30 symptom score (range, 0-100) was 33 vs 24 for the fatigue domain, 14 vs 19 for the nausea and vomiting domain, and 14 vs 10 for the pain domain for PDT vs no PDT, respectively. Precision estimates were not given. Median progression-free survival was 139 days (range, 26-600 days) vs 96 days (range, 56- 422 days) in PDT vs no PDT, respectively. Median OS was 238 days (range, 178-1060) in the PDT group and 336 days (range, 110-690 days) in the no-PDT group.
 
HEAD AND NECK CANCERS
 
Systematic Reviews
Gondivkar et al (2017) published a systematic review of PDT for the management of potentially malignant oral disorders and head and neck squamous cell carcinoma (Gondivkar, 2017). Twenty-six studies (total N=988 patients; range, 2-147 patients) of several different photosensitizers were included (ALA, metatetrahydroxyphenylchlorin, Foscan, hematoporphyrin derivatives, Photofrin, Photosan, and chlorin e6). Reviewers stated that the studies were all prospective; only 1 study was comparative. In the studies reporting response rates, complete, partial, and no response rates to PDT ranged from 23% to 100%, 4% to 66%, and 0% to 39%, respectively, for potentially oral malignant disorders, and complete response rates ranged from 16% to 100% for head and neck carcinoma. The recurrence rate for potentially malignant oral disorders ranged from 0% to 36% in 12 studies.
 
Noncomparative Studies
Ahn et al (2016) reported outcomes of a phase 1 study of PTD with ALA for premalignant and early-stage head and neck tumors (Ahn, 2016). Thirty-five patients were enrolled and 30 received PDT ranging from 50 to 200 J/cm2. The median follow-up was 42 months. The most common toxicity was grade 3 mucositis (52%). One patient developed grade 5 sepsis and died, which might have been related to treatment. The complete response rate at 3 months was 69%. Including all follow-up, 34% of patients developed local recurrence and 34% developed recurrence adjacent to the treated field.
 
SUPPLEMENTAL INFORMATION
 
European Association of Urology
European Association of Urology updated its guidelines on non-muscle-invasive bladder cancer in 2017 (Babjuk, 2017). PDT was not included as a treatment option.   
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Cervical Intraepithelial Neoplasia
 
Zhang et al conducted a systematic review on PDT for cervical intraepithelial neoplasia (CIN) and
human papilloma virus (HPV) infection (Zhang, 2018). The literature search, conducted in May 2017, identified 4 RCTs comparing PDT (n=292) with placebo (n=141). The quality of the trials was considered very low. Metaanalyses found a significant increase in complete remission rate among patients with CIN (OR 2.5, [95% CI, 1.2 to 5.1]) and HPV infection (OR 3.8, [95% CI, 1.9 to 7.7]) receiving PDT compared with placebo. However, adverse events rates were significantly higher for patients receiving PDT compared with patients receiving placebo.
 
Soft Tissue Sarcoma
 
A 2013 retrospective, single-center study from Japan examined PDT in high-grade soft tissue sarcoma.65
Acridine orange, a non-FDA-approved fluorescent dye, was used as the photosensitizer in 51 PDT treated patients. Compared with 119 patients who underwent conventional wide-margin resection for limb
salvage surgery, there was no statistical difference in 10-year OS (p=0.75) or 10-year local recurrence
(p=0.36).

CPT/HCPCS:
31641Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with destruction of tumor or relief of stenosis by any method other than excision (eg, laser therapy, cryotherapy)
43229Esophagoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed)
96570Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); first 30 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and gastrointestinal tract)
96571Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); each additional 15 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and gastrointestinal tract)
J9600Injection, porfimer sodium, 75 mg

References: Ackroyd R, Brown NJ, Davis MF, et al.(2000) Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomized, placebo controlled trial. Gut 2000; 47:612-617.

Ahn PH, Quon H, O'Malley BW, et al.(2016) Toxicities and early outcomes in a phase 1 trial of photodynamic therapy for premalignant and early stage head and neck tumors. Oral Oncol. Apr 2016;55:37-42. PMID 26865261

Aziz F, Telara S, Moseley H et al.(2009) Photodynamic therapy adjuvant to surgery in metastatic carcinoma in brain. Photodiagnosis Photodyn Ther 2009; 6(3-4):227-30.

Baas P, van Zandwijk N.(1995) Endobronchial treatment modalities in thoracic oncology. Ann Oncol 1995; 6:523-531.

Babjuk M, Compérat E, Gontero P, et al.(2017) Non-muscle-invasive Bladder Cancer (European Association of Urology). 2017; http://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. Accessed August 9, 2017.

Badreddine RJ, Prasad GA, Wang KK et al.(2010) Prevalence and predictors of recurrent neoplasia after ablation of Barrett’s esophagus. Gastointest Endosc 2010; 71(4):697-703.

Barr H, Shepherd NA, Dix A, et al.(1996) Eradication of high-grade dysplasia in columnar-lined (Barrett’s) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX. Lancet 1996; 348(9027):584-5.

Baumann P, Nyman J, Hoyer M, et al.(2009) Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. Jul 10 2009;27(20):3290-3296. PMID 19414667

Berr F.(2004) Photodynamic therapy for cholangiocarcinoma. Semin Liver Dis 2004; 24(2):177-87.

Biddlestone LR, Barham CP, Wilkinson SP, et al.(1998) The histopathology of treated Barrett’s esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy. Am J Surg Pathol 1998; 22(2):239-45.

Biel MA.(2007) Photodynamic therapy treatment of early oral and laryngeal cancers. Photochem Photobiol 2007; 83(5):1063-1068.

Biesalski HF, de Mesquita BB, Chesson A, et al.(1998) European consensus statement on lung cancer: risk factors and prevention. Cancer J Clin 1998; 48:167-176.

Buttar NS, Wang KK, Lutzke LS, et al.(2001) Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus. Gastrointest Endosc 2001; 54(6):682-8.

Chahal P, Baron TH.(2006) Endoscopic palliation of cholangiocarcinoma. Curr Opin Gastroenterol 2006; 22(5):551-60.

Cohen S, Parkman HP.(1999) Heartburn—a serious symptom. NEJM 1999; 340(11):878-879.

Cortese DA, Edell ES, Kinsey JH.(1997) Photodynamic therapy for early stage squamous cell carcinoma of the lung. Mayo Clin Proc 1997; 72:595-602.

Corti L, Toniolo L, Boso C, et al.(2007) Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med. Jun 2007;39(5):394-402. PMID 17565719

Diaz-Jimenez JP, Martinez-Ballarin JE , Llunell A, et al.(1999) Efficacy and safety of photodynamic therapy versus Nd-YAG laser resection in NSCLC with airway obstruction. Eur Respir J 1999; 14(4):800-5.

Dougherty TJ, Gomer CJ, Henderson BW, et al.(1998) Photodynamic therapy. J Natl Cancer Inst 1998; 90:889-905.

Eljamel S.(2010) Photodynamic applications in brain tumors: a comprehensive review of the literature. Photodiagnosis Photodyn Ther 2010; 7(2):76-85.

Endo C, Miyamoto A, Sakurada A, et al.(2009) Results of long-term follow-up of photodynamic therapy for roentgenographically occult bronchogenic squamous cell carcinoma. Chest. Aug 2009;136(2):369-375. PMID 19318660

Fayter D, Corbett M, Heirs M et al.(2010) A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett’s oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin. Health Technol Assess 2010; 14(37):1-288.

Ferguson MK, Naunheim KS.(1997) Resection for Barrett’s mucosa with high-grade dysplasia: implications for prophylactic photodynamic therapy. J Thorac Cardiovasc Surg 1997; 114:824-829;.

Fernando HC, Murthy SC, Hofstetter W et al.(2009) The Society of Thoracic Surgeons practice guideline series: guidelines for the management of Barrett’s esophagus with high-grade dysplasia. Ann Thorac Surg 2009; 87(6):1993-2002.

Friedberg JS, Simone CB, 2nd, Culligan MJ, et al.(2017) Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a median survival of nearly three years. Ann Thorac Surg. Mar 2017;103(3):912-919. PMID 27825687

Furukawa K, Kato H, Konaka C, et al.(2005) Locally recurrent central-type early stage lung cancer < 1.0 cm in diameter after complete remission by photodynamic therapy. Chest. Nov 2005;128(5):3269-3275. PMID 16306036

Gao F, Bai Y, Ma SR et al.(2010) Systematic review: photodynamic therapy for unresectable cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2010; 17(2):125-31.

Gondivkar SM, Gadbail AR, Choudhary MG, et al.(2017) Photodynamic treatment outcomes of potentially- malignant lesions and malignancies of the head and neck region: A systematic review. J Investig Clin Dent. May 08 2017. PMID 28480637

Gossner L, May A, Sroka R, et al.(1999) Photodynamic destruction of high grade dysplasia and early carcinoma of the esophagus after the oral administration of 5-aminolevulinic acid. Cancer 1999; 86:1921-1928.

Gossner L, Stolte M, Sroka R, et al.(1998) Photodynamic ablation of high-grade dysplasia and early cancer in Barrett’s esophagus by means of 5-aminolevulinic acid. Gastro 1998; 114(3):448-455.

Harewood GC, Baron TH, Rumalla A et al.(2005) Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol 2005; 20(3):415-20.

Hauge T, Hauge PW, Warloe T, et al.(2016) Randomised controlled trial of temoporfin photodynamic therapy plus chemotherapy in nonresectable biliary carcinoma--PCS Nordic study. . Photodiagnosis Photodyn Ther. Mar 2016;13:330-333. PMID 26415549

Istomin YP, Lapzevich TP, Chalau VN et al.(2010) Photodynamic therapy of cervical intraepithelial neoplasia grades II and III with Photolon. Photodiagnosis Photodyn Ther 2010; 7(3):144-51.

Kato H, Okunaka T, Shimatani H.(1996) Photodynamic therapy for early stage bronchogenic carcinoma. J Clin Laser Med Surg 1996; 14:235-238.

Kato H.(1997) Photodynamic therapy for early stage central type of lung cancer. Mayo Clin Proc 1997; 72:688-690.

Kusuzaki K, Murata H, Matsubara T et al.(2005) 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.

Lagergren J, Bergstrom R, Lindgren A, et al.(1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. NEJM 1999; 340(11):825-831.

Li LB, Xie JM, Zhang XN et al.(2010) Retrospective study of photodynamic therapy vs photodynamic therapy combined with chemotherapy and chemotherapy alone on advanced esophageal cancer. Photodiagnosis Photodyn Ther 2010; 7(3):139-43.

Lightdale CJ, Heier SK, Marcon NE, et al.(1995) Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 1995; 42:507-512.

Lu Y, Liu L, Wu JC, et al.(2015) Efficacy and safety of photodynamic therapy for unresectable cholangiocarcinoma: A meta-analysis. Clin Res Hepatol Gastroenterol. Dec 2015;39(6):718-724. PMID 26070572

Maier A, Tomaselli F, Gebhard F, et al.(2000) Palliation of advanced esophageal carcinoma by photodynamic therapy and irradiation. Ann Thorac Surg 2000; 69:1006-1009.

McCann P, Stafinski T, Wong C et al.(2011) The safety and effectiveness of endoscopic and non-endoscopic approaches to the management of early esophageal cancer: a systematic review. Cancer Treat Rev 2011; 37(1):11-62.

McCaughan JS Jr, Ellison C, Guy JT, et al.(1996) Photodynamic therapy for esophageal malignancy: a prospective twelve-year study. Ann Thorac Surg 1996; 62:1005-1010.

McCaughan JS Jr, Williams TE.(1997) Photodynamic therapy for endobronchial malignant disease: a prospective fourteen-year study. J Thorac Cardiovasc Surg 1997; 114:940-947.

Miller M.(2001) Barrett’s esophagus: major issues uncertain and unsolved. J Natl Cancer Inst 2001; 93(9):674-675.

Moghissi K, Dixon K, Hudson E, et al.(1997) Endoscopic laser therapy in malignant tracheobronchial obstruction using sequential Nd YAG laser and photodynamic therapy. Thorax 1997; 52:281-283.

Moghissi K, Dixon K, Stringer M, et al.(1999) The place of bronchoscopic photodynamic therapy in advanced unresectable lung cancer: experience of 100 cases. Eur J Cardiothorac Surg 1999; 15:1-16.

Moghissi K, Dixon K, Thorpe JA, et al.(2000) The role of photodynamic therapy (PDT) in inoperable oesophageal cancer. Eur J Cardiothorac Surg 2000; 17:95-100.

Moghissi K, Dixon K, Thorpe JA, et al.(2007) Photodynamic therapy (PDT) in early central lung cancer: a treatment option for patients ineligible for surgical resection. Thorax. May 2007;62(5):391-395. PMID 17090572

Nishioka NS.(1998) Drug, light, and oxygen: a dynamic combination in the clinic. Gastro 1998; 114(3):604-606.

Ortner ME, Caca K, Berr F et al.(2003) Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003; 125(5):1355-63.

Overholt BF, Panjehpour M, Haydek JM.(1999) Photodynamic therapy for Barrett’s esophagus: follow-up in 100 patients. Gastrointest Endosc 1999; 49(1):1-7.

Overholt BF, Panjehpour M.(1995) Barrett’s esophagus: photodynamic therapy for ablation of dysplasia, reduction of specialized mucosa and treatment of superficial esophageal cancer. Gastrointest Endosc ; 1995b;42:64-70.

Overholt BF, Panjehpour M.(1995) Photodynamic therapy in Barrett’s esophagus: reduction of specialized mucosa, ablation of dysplasia, and treatment of superficial esophageal cancer. Semin Surg Oncol; 1995a;11:372-376.

Overholt BF, Panjehpour M.(1996) Photodynamic therapy for Barrett’s esophagus: clinical update. Am J Gastro 1996; 91:1719-1723.

Panjehpour M, Overholt, BF, Haydek JM, et al.(2000) Results of photodynamic therapy for ablation of dysplasia and early cancer in Barrett's esophagus and effect or oral steroids on stricture formation. Am J Gastro 2000; 95:2177-2184.

Prasad GA, Wang KK, Buttar NS et al.(2007) Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2007; 132(4):1226-33.

Reynolds T.(1997) Photodynamic therapy expands its horizons. J Natl Cancer Inst 1997; 89:112-114.

Reynolds T.(1998) Using lasers and light-activated drugs, researchers home in on early lung cancers. J Natl Cancer Inst 1998; 90:417-418.

Rigual NR, Thankappan K, Cooper M et al.(2009) Photodynamic therapy for head and neck dysplasia and cancer. Arch Otolaryngol Head Neck 2009; 135(8):781-8.

Rowe PM.(1998) Photodynamic therapy begins to shine. Lancet 1998; 351:1496.

Rupinski M, Zagorowicz E, Regula J et al.(2011) Randomized comparison of three palliative regimens including brachytherapy, photodynamic therapy, and APC in patients with malignant dysphagia (CONSORT 1a) (Revised II). Am J Gastroenterol 2011; 106(9):1612-20.

Sampliner RE.(1998) Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastro 1998; 93(7):1028-32.

Schuitmaker JJ, Baas P, van Leengoed HLLM, et al.(1996) Photodynamic therapy: a promising new modality for the treatment of cancer. Photochem Photobiol B 1996; 34:3-12.

Schweitzer VG, Somers ML.(2010) PHOTOFRIN-mediated photodynamic therapy for treatment of early stage (TisT2N0M0) SqCCa of oral cavity and oropharynx. SqCCa of oral cavity and oropharynx. Lasers Surg Med 2010; 42(1):1-8.

Sharma P.(2001) An update on strategies for eradication of Barrett's mucosa. Am J Med 2001; 111:147S-152S.

Shim CS, Cheon YK, Cha SW et al.(2005) 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.

Sibille A, Lambert R, Souquet JC, et al.(1995) Long-term survival after photodynamic therapy for esophageal cancer. Gastro 1995; 108:337-344.

Stables GI, Ash DV.(1995) Photodynamic therapy. Cancer Treat Rev 1995; 21:311-323.

Sutedja TG, Postmus PE.(1996) Photodynamic therapy in lung cancer: A review. J Photochem Photobiol B 1996; 36:199-204;.

Wang KK, Geller A.(1995) Photodynamic therapy for early esophageal cancers: light versus surgical might. Gastro 1995; 108:593-607.

Wang KK.(1999) Current status of photodynamic therapy of Barrett’s esophagus. Gastrointest Endosc 1999; 49(3 Pt 2):S20-S23.

Winters U, Dayana S, Lear JT et al.(2008) Clinical and immunologic results of a phase II trial of sequential imiquimod and photodynamic therapy for vulval intraepithelial neoplasia. Clin Cancer Res 2008; 14(16):5292-9.

Yamaguchi S, Tsuda H, Takemori M et al.(2005) Am J Gastroenterol 2005; 100(11):2426-30. Oncology 2005; 69(2):110-6.

Zhang W, Zhang A, Sun W, et al.(2018) Efficacy and safety of photodynamic therapy for cervical intraepithelial neoplasia and human papilloma virus infection: A systematic review and meta-analysis of randomized clinical trials. Medicine (Baltimore). May 2018;97(21):e10864. PMID 29794788

Zoepf T, Jakobs R, Arnold JC et al.(2005) Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 2005; 100(11):2426-30.


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