A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest-ever mesothelioma PT experience (n = 10). PDT photosensitizers included porfimer sodium (2 mg-kg−1; 24 h drug-light interval) or 2-[1-hexylox-yethyl]-2-devinyl pyropheophorbide-a (HPPH) (4 mg m−2; 48 h) with wavelengths of 630 nm to 60Jcm−2 and 665 nm to 15–45Jcm−2, respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III-IV disease (100%). PT was delivered to a median of 55.0 CGE/1.8–2.0 CGE (range 50–75 CGE) adjuvantly (n = 8) or as salvage therapy (n = 2) following extended pleurectomy/decortication (ePD)/PDT. Two-year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and four received immunotherapy. Surgical complications included atrial fibrillation (n = 3), pneumonia (n = 2), and deep vein thrombosis (n = 2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1-and 2-year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade ≥2 acute or late toxicity. Our prolonged survival in very advanced-stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect.

Photodynamic Therapy: A Brief History

“…Fortunately, a formulation modification can add lysosomes to the targeting profile of BPD, as described below. Other groups have established the ability of PDT to enhance the efficacy of chemotherapy and ionizing radiation [35,36,37]. There have been recent advances relating to the ability of PDT to promote immunologic responses [38,39,40].…”

The Use of Radiation Therapy for the Treatment of Malignant Pleural Mesothelioma: Expert Opinion from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation

“…1 Here we present general guidelines for this approach. 25 Pencil beam scanning (PBS) proton therapy may be the optimal proton delivery choice for MPM. PBS involves the use of steering magnets to "paint" proton beam "spots" layer by layer over the target volume, which can provide better dose coverage than passive scattering proton therapy for volumes of complex shape and also allows the delivery of intensity-modulated proton therapy (IMPT), 26 which is especially useful for treating the large, irregularly shaped volumes involved in hemithoracic radiotherapy after EPP or whole pleural radiotherapy after extended P/D.…”

“…No patient experienced Common Terminology Criteria for Adverse Events, version 4, grade 2 or higher acute or late toxicity. 25 Investigators from the University of Washington School of Medicine reported outcomes for three patients with MPM treated with PBS to 54 to 66 Gy (RBE) after EPP in contrast with the outcomes of to proton therapy delivered to intact lungs. Compared with volumetricmodulated arc therapy photon plans, PBS produced lower doses to organs at risk.…”

Thomas J. Dougherty: An Appreciation

“…There continues to be support for three major PDT research groups (University of Pennsylvania, Massachusetts General Hospital/Harvard and Roswell Park Cancer Center). There are implications for use of PDT in otherwise poorly‐responsive tumors, for example, pancreatic cancer and mesothelioma . At this point, an appreciation for what PDT can do appears to be limited to a few centers in the US.…”