Intrapleural Photodynamic Therapy in a Multimodal Treatment for Patients With Malignant Pleural Mesothelioma
Condition: Malignant Pleural Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Study type: Interventional
Phase: Phase 2

Summary: 
      Malignant pleural mesothelioma (MPM) is an aggressive tumour with poor prognosis (median
      survival <13 months), and high resistance to chemotherapy. Extended pleurectomy/decortication
      (eP/D) is a debulking surgery of MPM but cannot be considered as a curative treatment.
      Therefore it has been suggested that eP/D may be of interest if combined with intra-operative
      treatment and adjuvant therapies.

      Photodynamic Therapy (PDT) is an innovative treatment based on the rationale that tumour
      cells, if previously treated with photosensitizing drugs (Photofrin), will die when exposed
      to light at a particular wavelength. Interestingly PDT might also stimulate anti-tumour
      immune response through the release of tumour antigens and induced inflammation.

      PDT was tested in phase I-II trials for MPM in combination with EPP or eP/D, and
      chemotherapy. US studies from J Friedberg et al found very promising survival results in MPM
      when combining eP/D, but not EPP, intra-operative PDT and chemotherapy
      (cisplatin-pemetrexed), with a median overall survival of 31.7 months.

      However, the definitive value of intra-pleural PDT combined to eP/D in the treatment of MPM
      still need to be validated. The same multimodal treatment has been established in Lille, the
      French national expert centre for MPM, with the help of our american colleagues. Therefore,
      this phase II trial proposes to patients to benefit from the combination of eP/D,
      intra-operative PDT then chemotherapy by cisplatin-pemetrexed and prophylactic radiotherapy.

      Primary endpoint is the feasibility for the patients to have the full multimodal treatment of
      MPM including intrapleural PDT without unacceptable or unexpected grade III-IV toxicities.
      Secondary endpoints are PFS, OS, ORR, and quality of life. If the feasibility of such
      treatment would be confirmed in France, a multicentric, randomized trial comparing this
      experimental treatment vs control arm (same multimodal treatment without PDT) is planned.
    

Detailed description: 
      phase II trial assessing the feasibility of an experimental multimodal treatment combining:

        -  surgery of the MPM: extended pleurectomy/decortication (eP/D)

        -  intra-operative (intrapleural) photodynamic therapy (PDT). Briefly, each patient will
           receive porfimer sodium (PHOTOFRIN®) (2 mg/kg) 24 hours before eP/D (IV injection on 3-5
           minutes). Cutaneous light precautions will be instituted immediately and for the next 4
           weeks.

      then:

        -  prophylactic chest radiotherapy of surgical scars to prevent tumor seeding (3 x 7 Gray)

        -  adjuvant standard chemotherapy by (cis)platin 75 mg/m2 and pemetrexed 500 mg/m2 up to 6
           cycles (1 cycle every 3 weeks), with oral folic acid (400 μg daily) and vitamin B12
           (1000 μg Q9W) supplementation

        -  follow-up
    

Intervention name(s): photodynamic therapy (PDT); thoracic surgery Pleurectomy / extended Decortication; Adjuvant chemotherapy
Intervention type(s): Device; Procedure; Drug
Intervention description(s): Intra-operative (intrapleural) photodynamic therapy (PDT): briefly, each patient will receive porfimer sodium (PHOTOFRIN®) (2 mg/kg) 24 hours before eP/D (IV injection on 3-5 minutes). Cutaneous light precautions will be instituted immediately and for the next 4 weeks.
After complete macroscopic resection of the tumour, the thoracic surgeon and his team will set isoprobes (7 at least) in the "pleural" cavity to monitor by a dosimetry device the correct illumination of the cavity with a visible red light (wavelength of 630 nm; laser source). PDT-related postoperative considerations include light precautions, intensive focus on perioperative nutrition, and a greater than normal fluid requirement in the immediate postoperative period.; extended P/D is intended to remove any macroscopic tumor including the parietal and visceral pleura when the diaphragm and / or the pericardium was resected; Chemotherapy should begin up to three months after surgery. It consists of pemetrexed 500 mg / m2 followed 30 minutes later by cisplatin 75 mg / m2 (in the usual manner from the center to the chemotherapy) on day 1 (J1) of each cycle every 3 weeks, for up to 6 cycles.
Other intervention name(s): Photofrin; pemetrexed / cisplatin
Intervention MeSH terms: Cisplatin; Pemetrexed; Dihematoporphyrin Ether
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: mesothelioma; multimodal treatment; PDT; pleura