PDT and Synergy: The Effects of Combination Treatment in the Lung Carter JH Childs, MD Pulmonary and Critical Care Medicine Brody School of Medicine at ECU PDT’s Role in Treating Advanced Stage Lung Cancer-a Team Player or the Lone Wolf? Outline • To review the basis for PDT and other interventional therapies in advanced stage lung cancer. • To review the synergistic effects between PDT and: – Chemotherapy. – Radiation Therapy. – Other interventional therapies. PDT Clinical Capabilities-Lung • Early Disease – Carcinoma-in-situ • Advanced Disease – Local regional palliation – Maintaining organ function • Pleural disease Rationale for airway interventions in non-operable lung cancer • Schmassman et al. AJG 1996; 91(4):654-659 » 165 patients with acute biliary obstruction » Treated with plastic or metal stents » Dramatic survival advantage in reversing acute obstruction » Take home message: Maintaining normal organ physiology has a positive influence on outcomes in patients with malignancy. Rationale continued • Cavaliere S. et al. Chest 1996:110:1536-1542 » 13 year experience with 2008 patients, all with malignant airway obstructions. » Interventional modalities including Nd:YAG laser, Brachytherapy and Stent placement, patency was achieved in 93%. » Most had improved quality : decreased dyspnea, improved ABG’s, resolution of post-obstructive pneumonia's. » Mean airway patency was 102 days. Rationale continued • Marasso A., et al. 1998 Thorax;53:10-109 » 98 patients with 3b or 4 NSCCA were studied retrospectively. » 50 pts. treated first with ChemoRx, XRT, then interventional techniques. » 48 pts. treated first with interventional techniques, then ChemoRX and XRT. » Second group demonstrated longer mean survival (14 months compared to 5months). Rationale continued • Marasso and Cavaliere: Take home message » Interventional techniques are excellent methods to achieve airway patency. » Maintaining airway patency may have a positive effect on lung physiology and performance status. » Survival may be influenced in non-operable lung cancer Interventional Pulmonology Techniques • Bronchoscopy – Rigid bronchoscopy – Flexible bronchoscopy • Tumor ablation/airway restoration techniques – Thermal • Nd:YAG laser • Endobronchial Cryotherapy • Endobronchial Electrocautery/APC – Mechanical • Stents/Balloons • Core out • Rotoblator Tumor Ablation-continued – Non-thermal, Non-mechanical • Brachytherapy. • Photodynamic Therapy. Which one to Choose? • Choice of interventional technique is based on: – Lesion • Size, Site, Significance, Single/Multiple, Type. – Patient’s status – Physician • Training, Comfort, Costs, Availability. Lung Cancer: Palliation of Advanced Airway Carcinoma • Moghissi et al 1999: 100 pts with inoperable NSCCa were Tx with PDT • 82 % had previous chemo/XRT • Stages 3a to 4, Tx with 2 mg/kg photofrin, interstitial placement of fibers at 200J/cm2 • No Tx related morbidity or mortality • At 8 weeks: ^PFT’s. ^Performance status, Obstruction form 85% to 18% • Mean survival 9 months, with 53% > 2 years Lung Cancer: Palliation of Advanced Airway Carcinoma • McCaughan et al 1997: 152 pts with inoperable stage 3a to 4 NSSCa were Tx with PDT over 14 years • Both superficial and interstitial TX used, variable laser light doses were employed • Advocates treatment ASAP to any size lesions • No stats difference between efficacy of PDT and other tumor ablation modalities (YAG laser) Why choose just one? • Multimodality therapy has a long history in Medicine. – Multiple antibiotics for infectious diseases(esp. TB and HIV). – Cardiac “cocktail” for CAD/CHF. – Multi-agent chemotherapy for lung cancer. – Multidisciplinary approach to regionally advanced lung cancer. Rationale behind Multimodality Therapy • Maximize the treatment effect by hitting the disease from multiple angles, while minimizing side effects by reducing the amounts of any single therapy. PDT, can be Synergistic with • Chemotherapy. • Radiation Therapy. – External Beam. – Internal (Brachytherapy). • Other Interventional Therapies. Potential Mechanisms for Synergy • Blood supply to tumor. • Oxygen content of tumor. • Treatment field augmentation/definition. • Immunologic destruction of tumor. • ???????? PDT and Chemotherapy • Baas et al in 1996 studied PDT using Photophrin and it’s synergy with mitomycin C in patients with skin recurrences from breast cancer. • 4 patients were given Photophrin and light was applied to their lesions on days 1-2, and the amount of energy needed to achieve a response was determined. Baas, et al, Br. J Cancer, 1996 PDT and Chemo-continued • On day 3, MMC was injected and light was applied 20 and 40 minutes later on areas not previously treated, at ½ of the previously noted light dose. • Found equivalent responses between the two treatments. • No differences in wound healing. • Theory: PDT causes tissue hypoxia, which is further treated by MMC. Baas, et al, Br. J Cancer, 1996 PDT and Radiation Therapy • Schaffer, et al studied Photophrin and other porphyrins in mice implanted with human bladder carcinoma cells treated with XRT. • Only Photophrin had any significant effect, it reduced the doubling time of the cancer cells from 6.2 days to 10.9 days. • Higher doses of RT (5 vs 15 Gy) did not improve this effect. Schaffer et al, J of Photochemistry and Photobiology 2002 PDT and XRT • Madsen, et al studied PDT’s and XRT’s effects on Human Glioma Spheroids. • Found that Photophrin was not a radiosensitizer by itself. • Spheroids treated with both PDT and XRT had a larger fraction of apotototic cells. Madsen, et al, Photochemistry and Photobiology, 2002 Fraction of cells in apoptosis as a function of treatment type 1 0.8 Apoptotic Fraction 0.6 0.4 0.2 0 8 Gy + 150/50 PDT (150/50) 8 Gy + 25/25 PDT (25/25) + Control - Control 16 Gy 8 Gy Madsen, et al, Photochemistry and Photobiology, 2002 PDT and Brachytheapy • Freitag, et al studied sequential PDT, followed by brachytherapy in patients with non-small cell carcinoma. • 32 patients were treated initially with PDT, 2 mg/kg photophrin, and 630nm light. • 200J/cm for interstitial treatment, 100J/cm2 for surface treatment. Freitag, et al, Thorax 2004 PDT and Brachytherapy- continued • Brachytherapy was then performed, 5 treatments at 4 Gy = total dose of 20 Gy at a distance of 10 mm from the source. • Complete histological response rate of 97% was seen after the combination. (75% after PDT alone). • 1 patient (3%) had continued disease, and was treated with additional brachytherapy. • No significant side effects requiring additional interventions. Freitag, et al, Thorax 2004 PDT and Stenting • Stents can: – Define treatment field. – Make treatment field more uniform. – Cause tumor death from radial traction. – Control Bleeding PDT Combined with other Modalities • TUMOR ABLATION AFTER SELF-EXPANDABLE METAL STENT PLACEMENT IN LUNG CANCER Imtiaz Khurshid, MB,BS, Ron R. Allison, MD, Rosa E. Cuenca, MD, Gordon H. Downie MD, Ph.D. • Material and methods: five consecutive patients … 8 self-expandable metal stents… One to twelve months post-placement, refractory tumor required direct ablation. PDT at a median dose of 100 joules/cm2 • Results: Serial bronchoscopies demonstrated uniform tumor ablation in all five patients. Random biopsies showed no viable tumor in any field, including tissue from behind metal. Examination of all eight stents revealed no displacement, fracture, deformity or occlusion of any stents. Too Much Synergy? Multidisciplinary Approach • Advantages • Clinical debate • Dosimetry, patient prognosis, oncologic options, light delivery options, wound care issues • Coverage • Patient support; financial, psychological, nutritional • United front • Opportunities for clinical research • Disadvantages • Initial planning, up front energy, money and patience The Future • Develop multidisciplinary approach at centers. • Develop a body of prospective randomized trials supporting PDT. • Bring Dosimetry up to XRT standards. • Continue to develop new drugs and devices. • Continue to study PDT’s synergistic effects with other modalities.