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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2192-2201 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.097 Phase II Trial of Pleural Photodynamic Therapy and Surgery for Patients With Non–Small-Cell Lung Cancer With Pleural SpreadFrom the Department of Surgery, Thomas Jefferson University Hospital; and the Departments of Biostatistics and Epidemiology, Medicine, and Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA Address reprint requests to Stephen M. Hahn, MD, 3400 Spruce St, 2 Donner, Philadelphia, PA 19104-4283; e-mail: hahn{at}xrt.upenn.edu
PURPOSE: Non—small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy. METHODS: We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm2. Photosensitizer levels in tumor and surrounding normal tissue were measured. RESULTS: Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42. CONCLUSION: Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.
Lung cancer is the leading cause of cancer death in the Western hemisphere for both men and women, eclipsing the combined mortalities from breast, colon, and prostate cancers. It was estimated that 171,900 people were diagnosed with lung cancer and 157,200 died as a result of it in 2003.1 Historically, 80% to 85% of lung cancer cases have been non–small-cell lung cancer (NSCLC).2 Local spread of NSCLC to the pleura, as either bulky disease or a malignant effusion, is a common clinical event.3-5 In the absence of distant metastases the presence of pleural dissemination confers an International System for Staging Lung Cancer stage of IIIB, based on the pleural disease being considered a T4 tumor.6 The median survival for patients with stage IIIB NSCLC, on the basis of pleural dissemination, has been reported from 2 months to greater than 1 year, but is generally considered to be within the 6 to 9 month range.3,7,8 The survival rate for this subset of stage IIIB patients is so poor that it has been suggested that this disease should be upstaged to stage IV because of the similar survival rates.9 Conventional treatment for patients with malignant pleural effusion is palliative, consisting of talc pleurodesis for control of the effusion and combination chemotherapy. Radiotherapy is rarely administered to these patients because of the pulmonary toxicity from hemithoracic radiotherapy.10 Surgery has been shown to have little impact on survival and is accompanied by a local failure rate as high as 90%.11-16 There are anecdotal reports of long-term survivors, but it is generally held that there is no role for surgery in treating patients with NSCLC with pleural dissemination. Photodynamic therapy (PDT) is an anticancer treatment that combines a photosensitizer, oxygen, and visible light.17 PDT cytotoxicity occurs when photosensitizers capture light energy and transfer that energy to oxygen. It is the excited species of oxygen that are responsible for the antitumor activity and can take the form of direct tumor-cell kill, damage to the tumor's blood supply, or a combination of both.17 In this study we used Porfimer sodium (Photofrin; Axcan Pharma Inc, Birmingham, AL), a first-generation photosensitizer, that is a mixture of porphyrin monomers and oligomers and is activated by 630 nm red light.17 PDT offers several potential advantages for treating surface tumors compared with other cancer therapies. First, preclinical studies demonstrate greater retention of photosensitizers in tumor compared with normal tissues.18 Second, visible light only penetrates several millimeters into tissue. This phenomenon results in surface cell kill with sparing of underlying tissues, making PDT well suited for treatment of cancers that have spread to serosal surfaces.19 Last, PDT is a local therapy that can be administered intraoperatively. Surgery has been ineffective in treating lung cancer with pleural dissemination because of residual microscopic disease remaining in the chest cavity, even after what appears to be a "complete" resection. Our hypothesis was that if all gross disease could be resected, then immediate intraoperative PDT might be effective in treating the residual microscopic disease. Intrapleural PDT was first performed in a phase I study of porfimer sodium-mediated PDT in patients who had undergone maximal surgical debulking for pleural malignancies.20 Serious toxicities were intraoperative hemorrhage, bronchopleural fistula, and esophageal perforation. The dose limiting toxicity of porfimer sodium-mediated PDT was determined to be esophagopleural fistula.21 The maximally tolerated dose (MTD) of PDT was 30 J/cm2 of 630nm light delivered 24 hours after a porfimer sodium dose of 2.0 mg/kg. That study established the feasibility of intrapleural PDT in combination with radical surgery. We conducted a stratified phase II trial of intrapleural porfimer sodium-mediated PDT, at the previously established MTD, in cancers that were metastatic to the pleura. The primary goal was to assess the efficacy of this treatment in a number of diseases, including breast cancer, ovarian cancer, sarcomas, and NSCLC. Our interim results revealed that this subset of stage IIIB (based on pleural dissemination) NSCLC patients was achieving durable local control after PDT and appeared to have a significant extension of life. In this population, surgery and intraoperative PDT may have a role in a multimodal treatment plan that also includes chemotherapy and, possibly, mediastinal radiation. This report includes our phase II findings of porfimer sodium-mediated PDT for NSCLC patients with pleural dissemination. The clinical and preliminary pharmacologic (sensitizer uptake) results of this trial are presented.
Trial Design The primary objective of this study was to evaluate the effectiveness and toxicity of pleural PDT in patients with NSCLC metastatic to the pleura. Efficacy parameters included local control rate at 6 months as well as progression-free and overall survival. Twenty-two patients were enrolled onto this phase II study. All patients were treated with the same PDT regimen. Porfimer sodium 2 mg/kg was administered intravenously approximately 24 hours before the planned thoracotomy. Surgical resection and light delivery were performed as described further herein. The protocol permitted light administration to any patient whose pleural disease was resected to a thickness of 5mm or less, but it was the goal at every operation to have no visible or palpable disease remaining at the conclusion of the debulking. Toxicity was scored using the National Cancer Institute Cooperative Group Common Toxicity Criteria, version 1.0. Operative mortality was defined as death within 30 days of patients leaving the hospital or at any time for patients who never left the hospital. The investigators saw patients every 3 months after surgery. At these visits a computed tomography (CT) scan of the chest, laboratory studies, and a physical exam were performed.
Patient Selection
Patients were excluded based on the following criteria: HIV positivity, WBC less than 3,500/mm3, or platelet count less than 100,000/mm3, serum creatinine Patients underwent a preoperative evaluation that included a history and physical examination, imaging studies of the chest CT and/or magnetic resonance imaging, pulmonary function tests, quantitative ventilation perfusion scans, and laboratory studies. A CT scan of the abdomen and pelvis, bone scan, and imaging studies of the brain were performed to evaluate for distant metastatic disease as clinically indicated. All patients underwent an endoscopy and bronchoscopy before surgery. Preoperative staging, performed by two investigators (J.S.F. and S.M.H.), was based on physical examination and a review of radiographic studies. A mediastinoscopy was not performed, because N2 disease was not an exclusion criterion. Any patient with clinically suspicious N3 disease underwent a preoperative mediastinoscopy and/or Chamberlain procedure. Minimal pleural disease was defined as per the Japan Lung Cancer Society.12 Using this definition, more than "minimal pleural disease" was defined as a pleural effusion greater than 300mL or a large number of pleural nodules. The protocol was conducted under an investigator-sponsored investigational new drug with the US Food and Drug Administration. This study was performed in accordance with the Declaration of Helsinki and had approval from the institutional review boards of both the University of Pennsylvania and Thomas Jefferson University.
Chemotherapy and Radiotherapy Radiotherapy was recommended based on standard clinical indications. In general, postoperative radiotherapy was delivered to the mediastinum for patients who had N2 disease. More comprehensive radiotherapy was administered to three patients who had gross residual nodal or primary site disease after resection.
Surgical Procedures A thoracotomy was performed on all patients under the direction of the attending thoracic surgeon (J.S.F.). The goal was to have no visible or palpable tumor remaining in the affected hemithorax at the conclusion of the surgical resection. The criteria for selecting a particular pulmonary resection for the primary tumor were the same as those used with resections performed with curative intent in patients with early stage NSCLC. Anatomic resections, ranging from segmentectomy to pneumonectomy, were performed in all patients in whom it was possible to resect all gross disease. The frequency of each pulmonary resection employed for the primary tumor is shown in Table 1. The majority of cases were performed by entering the chest through the bed of the resected seventh rib. This lower approach provided adequate access for anatomic pulmonary resections and allowed better access to the diaphragm for tumor debulking, commonly a difficult part of the operation. After completing the pulmonary resection, the parietal pleura was stripped from the bony hemithorax. The mediastinum was debulked of all gross tumor. Usually, it was possible to strip and preserve the phrenic nerve, even when it traversed through bulk tumor. The pericardial fat almost always required resection. Every effort was made to strip tumor from the diaphragm and pericardium, but to maintain these structures as intact barriers to prevent tumor seeding of their bordering cavities. Debulking gross tumor from the diaphragm ranged from using a using a CO2 laser to ablate small implants to resection of nearly the entire diaphragm, preserving only the underlying peritoneum. In every case, a complete mediastinal lymphadenectomy was performed. The chest cavity was irrigated, hemostasis was achieved, and the light-delivery portion of the procedure was then initiated. If enough diaphragm was resected to potentially compromise breathing mechanics, then it was reconstructed with a 2mm-thick Gore-Tex patch (Gore, Inc, Flagstaff, AZ) before closure of the chest.
Intraoperative Photodynamic Therapy The light delivery and dosimetry system were similar to the technique previously described.22 Flat photodiodes were sewn into seven regions of the pleural cavity: apex, anterior chest wall, posterior chest wall, posterior mediastinum, posterior costophrenic sulcus, anterior costophrenic sulcus, and pericardium. A dosimetry system provided both real-time fluence and the cumulative light dose for each site. After placement of the photodiodes, the chest cavity was filled with dilute intralipid solution (0.01%) to act as a scattering agent to allow more homogeneous light delivery. The light was delivered with an optical fiber sheathed within a modified endotracheal tube. The balloon cuff was inflated and filled with a 0.1% intralipid solution. This delivery system was moved around the chest cavity until a measured dose of 30 J/cm2 of 630 nm light was recorded at all seven sites. The chest retractors were removed during the light delivery portion of the procedure to avoid shielding. Up to 20L of intralipid solution was used to keep the intrathoracic area as clear as possible and minimize absorption of light by hemoglobin. Following administration of the light the sterile photodiodes were removed from the pleural cavity. The light delivery portion of the procedure usually took approximately 1 hour. Laser light was generated using a KTP/532 Laser System to pump a model 630 XP Dye Module (Laserscope, Inc, San Jose, CA). Eye protection was worn by operating room personnel to attenuate light to 10–4 of incident intensity. Patients received one course of light therapy at the time of surgery.
Postoperative Care
Porfimer Sodium Concentration in Tissue Samples
Statistical Considerations
The clinical characteristics of all 22 patients who were eligible and enrolled onto this trial are shown in Table 1. Thirteen patients had preoperative clinical stage T4N2 disease, one patient had clinical stage T4N1 disease, and seven patients had clinical stage T4N0 disease. Eighteen of 20 patients who underwent resection of gross tumor had pathologic T4N2 disease. Twenty-one patients had pleural spread of NSCLC as their initial presentation. One patient presented with a pleural relapse after prior resection of a primary NSCLC. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Nineteen patients were treated with at least one cycle of chemotherapy before the thoracotomy. One patient was treated with preoperative chemoradiotherapy. Chemotherapy regimens consisted of carboplatin in combination with paclitaxel, taxotere or gemcitabine. Two patients received no systemic preoperative therapy. Pleural PDT was administered to 20 patients (Fig 1). Resection of gross tumor was defined as no visible or palpable disease remaining at the conclusion of the resection. Seventeen patients underwent resection of the primary tumor, gross nodal disease, and gross pleural disease followed by PDT. Three patients underwent resection of the gross pleural disease, but with only partial resection of either the pulmonary disease or nodal disease. Two patients did not receive pleural PDT treatment; one was found to have unsuspected intraperitoneal disease, and one was found to have unsuspected intrapericardial disease.
Postoperative mediastinal radiation was administered to 13 patients based on involvement of N2 lymph nodes. Of these 13 patients, postoperative chemoradiotherapy was administered in three because of gross residual nodal or primary site disease. Eight other patients did not receive postoperative radiotherapy because of N0 disease or necrotic tumor in lymph nodes (three patients), postoperative mortality (two patients), rapid onset of recurrent disease (one patient), and unresectable disease (two patients). The median follow-up for all patients was 33.6 months and 10.3 months for the patients alive at last contact. Fourteen patients have developed recurrent disease. Sixteen patients have died. Overall survival (Fig 2) and progression-free survival (Fig 3) were calculated for all 22 patients enrolled and for the 20 patients who underwent PDT. The median overall survival was 21.7 months (95% CI, 17.7 to 25.8 months) and the 1-year survival rate was 68%. The median progression-free survival was 6.6 months (95% CI, 0.3 to 13.0 months) and the 1-year progression-free survival rate was 28%. Of the 22 patients enrolled, seven were not assessable for local control due to death without relapse (three patients), unresectable disease (two patients), or recurrent disease outside the ipsilateral pleural space (two patients).
Local control 6 months after the completion of treatment was achieved in 11 of 15 patients (73.3%; 95% CI, 44.9 to 92.2%). Three patients are currently alive without evidence of disease (6, 10, and 34 months after surgery and PDT). The pattern of treatment failure for all patients is shown in Table 2. The local failure reported in Table 2 represents any local failure observed at the last follow-up or at the time of death. Isolated local failure was observed in only one patient. Four patients had local failure in association with either distant and/or regional failure. Distant metastases were identified in 11 patients.
The three patients who received PDT but who had only partial resection of all gross nodal or primary site disease were all treated with chemoradiotherapy postoperatively. They all exhibited rapid development of distant metastatic disease within 3 to 5 months of surgery and PDT. Two of these patients also had evidence of concurrent local failure. Toxicities that were scored as definitely, probably, or possibly related to PDT are shown in Table 3. The operative mortality from surgery and PDT was 9% (two of 22 patients). One patient died in the immediate postoperative period as a result of adult respiratory distress syndrome (ARDS), which developed rapidly after a pneumonectomy and PDT. Despite aggressive supportive measures, the patient died as a result of multiorgan failure. This patient had grade 4 elevations of liver function tests, acidosis, as well as hyperglycemia, thrombocytopenia and coagulopathy. One additional patient with a history of Hodgkin's disease treated with chemotherapy, radiation, and an autologous bone marrow transplantation died during a prolonged hospitalization approximately 2 months after a pneumonectomy and PDT. She died as a result of pneumonia in her remaining lung, resulting in sepsis and respiratory failure. This patient also had associated hypotension, acidosis, hypothermia, adrenal insufficiency, thrombocytopenia, hyperglycemia, and coagulopathy. Other PDT-related toxicities included transient thrombocytopenia, postoperative fever, peripheral edema, and skin photosensitivity.
Toxicities unlikely to be related or unrelated to PDT are shown in Table 4. The mean operative time for surgical resection and light delivery was 8.4 hours (range, 1.75 to 12.5 hours). Common toxicities included deep venous thrombosis, pulmonary embolism, atrial dysrhythmias, hyperglycemia, hypocalcemia, and postoperative fever. One patient developed herniation through a diaphragm repair on the first postoperative day and was taken back to the operating room for correction. This patient developed the rapid onset of contralateral malignant pleural disease after discharge from the hospital and subsequently died. One patient had persistent postoperative nausea and vomiting, as well as transient grade 4 confusion postoperatively. Another patient had an intraoperative hemorrhage related to the surgical resection as well as mucous plugging with associated grade 4 hypotension. Grade 4 thrombocytopenia was observed postoperatively in one patient who did not complete treatment with PDT. The thrombocytopenia was felt to be medication-related. Last, one patient had grade 3 hypotension related to epidural delivery of pain medications.
Porfimer sodium levels were measured in the tissues from three patients (Table 5). Levels of porfimer sodium in tumor were greater than those measured in normal pleura, fat, and diaphragm muscle, with tumor-to-normal-tissue ratios ranging from 1.19 to 22.42. The tumor-to-normal-tissue ratios for normal lung tissue generally showed a greater amount of porfimer sodium in tumor and ranged from 0.76 to 1.77.
The standard treatment for patients with stage IIIB NSCLC in the United States is nonoperative.24-26 Patients with a good performance status are usually treated with palliative chemotherapy and are rarely rendered disease-free. Currently, surgery is not considered part of the treatment for these patients. The survival of NSCLC patients with pleural spread who have a good performance status is reported to be in the range of 6 to 9 months.3,7,8 This is in contrast with other stage III patients with locally advanced NSCLC, who are typically treated with chemoradiotherapy and who have a median survival of 15 to 18 months.25 Intraoperative pleural PDT was used in this study as part of a multimodality approach for treating patients with NSCLC and pleural carcinomatosis. The results of this analysis appear promising. This is based on the minimal observed toxicities, the high rate of local control, and the median survival of 21.7 months, calculated from the time of surgery and PDT, not diagnosis or enrollment, which commonly preceded surgery and PDT by 3 to 6 months. This median survival compares very favorably to the historical control values of 6 to 9 months for similar patients treated with the nonoperative standard of care. Previous reports of surgery in patients with NSCLC and pleural carcinomatosis have reported some examples of prolonged survival, but only in patients with very limited involvement of the pleura and generally with only very limited nodal disease.11,12 A survey of patients treated by the Japan Clinical Oncology Group found that patients with minimal pleural disease—patients in this study had a mean pleural fluid volume of 37.1 mL and a mean number of pleural nodules of 5.6—had prolonged survival, with 3- and 5-year survival rates of 31.8 and 22.8%, respectively. Female sex and clinical N0 nodal staging were associated with improved prognosis.12 In this study an extrapleural pneumonectomy was performed in 11 patients with minimal pleural carcinomatosis; four of 11 patients were alive without evidence of disease 20 to 149 months after resection. Three of these four patients had pathologic N0 disease, and one patient had N1 disease. The authors concluded that an extrapleural pneumonectomy could be performed safely in patients with pleural carcinomatosis and minimal disease and that prolonged disease-free survival could be observed in patients without N2 disease.11 Our study differs from these reports in several key respects. First, we made no attempt to limit enrollment to patients with minimal pleural disease. The only requirement was that the disease appeared confined to one hemithorax and appeared to be surgically resectable. We were not able to quantify the amount of pleural disease, but our cohort included patients with dissemination ranging from malignant effusions to bulky pleural tumor masses, with the majority of patients falling into the latter group. Only one of 22 patients had minimal pleural disease as defined by the Japan Lung Cancer Society. Second, the majority (90%) of our resected patients had pathologic N2 disease which, as previously stated, is a negative prognostic factor.11 Last, our protocol did not mandate pneumonectomy, which was routinely performed in other series. Lung-sparing surgical procedures were performed in 45% of the patients in our study. Certainly in the setting of an experimental protocol, the option of performing a parenchymal-sparing procedure is intuitively attractive. The toxicity associated with surgery and PDT was acceptable. ARDS occurred in one patient in the immediate postoperative period. We did not observe damage to other intrathoracic organs or even the remaining lung in patients who underwent parenchymal sparing procedures. We conclude that, with careful light dosing, it is possible to perform intraoperative hemithoracic PDT with acceptable morbidity. Porfimer sodium levels were measured in the tissue samples from three patients. This series represents the first report of porfimer sodium levels in tumor and normal tissue from lung cancer patients. Greater levels of porfimer sodium were observed in tumor compared with normal pleura and muscle. This finding is encouraging and underscores the importance of similar pharmacologic evaluations in future studies. In conclusion, a multimodality approach including surgery and PDT is feasible in patients with NSCLC who have pleural carcinomatosis. Definitive conclusions regarding the impact of PDT in NSCLC patients with pleural spread cannot be made on the basis of this nonrandomized trial. It is possible that this group of patients might have had a similar outcome with surgery and systemic therapy alone. Furthermore, the relatively heterogeneous patient population and varying standard treatments used in these patients complicates interpretation. We believe, however, that the local control and survival results from this approach are encouraging and warrant further investigation in a multicenter setting.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received less than $2,000 a year from a company for either of the last 2 years: Stephen M. Hahn, Axcan Pharma Inc.
Supported in part by National Institutes of Health grant PO1 CA 87971. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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26. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial [see comments]. J Natl Cancer Inst 88:1210–1215, 1996 Submitted July 14, 2003; accepted February 16, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2.5 mg/dL, severe liver disease including cirrhosis, grade 3 to 4 elevations in liver function studies, or bilirubin in excess of 1.5 mg/dL, and pregnant or lactating patients. Patients who had undergone prior surgery or talc pleurodesis were not excluded. 
ex of 405 nm and 
