1 PRODYNOV Targeted Photodynamic Therapy of Ovarian Peritoneal Carcinomatosis ONCO-THAI Image Assisted Laser Therapy for Oncology
2 Inserm ONCO-THAI «Image Assisted Laser Therapy for Oncology» Inserm ONCO-THAI "Image Assisted Laser Therapy for Oncology is developing minimally invasive therapies using laser light. These therapies employ multimodality imaging in preoperative phase (simulation, planning), intraoperative (interventional imaging) or postoperative (monitoring, therapeutic evaluation) Main research programs concern: - Localized cancers such as Prostate, Brain, (glioblastoma), Breast, using interstitial (focal) laser therapies - Diffuse cancers of the peritoneal cavity (carcinomatosis of ovarian origin) and the pleural cavity (mesothelioma) using intracavitary laser therapies. Research is carried out using ONCO-THAI technical platforms (hardware and software) based on mathematical modeling, imaging, and simulation development tools. These platforms are constantly improved, and are used extensively for pre-clinical or clinical studies and for industrial technology transfer
3 The PRODYNOV project s main theme is to develop strategies based on photodiagnosis and photodynamic therapy of peritoneal lesions of ovarian origin. The unit s main objective is to complete epithelial ovarian cancer cytoreductive surgery with a photodynamic therapy session. The objective would be to diminish the incidence of peritoneal recurrence by destroying the microscopic lesions beyond the reach of surgery. This new paradigm imposes perfecting peritoneal cavity modelisation techniques and the development of new illumination techniques, the latter needing to adapt to the constraints of the cavity and the use of next generation photosensitizers (PS) specifically targeting carcinomatosis lesions. Background One out of six cancers in women is of gynecological origin. Ovarian cancer is the leading cause of death from gynecological cancer in the US and Western Europe. In France, ovarian cancer is responsible for 3500 deaths every year. It has been shown that the 5-year survival rate critically depends on the stage of disease progression at the time of diagnosis. Despite the improvements in diagnostic tools, more than two thirds of women with the disease are diagnosed only at advanced stages, which 5-year survival rates are about 30%. Therapeutic modalities are complete cytoreductive surgery followed by platinum-based chemotherapy for adjuvant treatment. Complete macroscopic cytoreduction improved survival in patients of stage IIIC ovarian cancer. Many patients with advanced cancer (stage III and IV) initially respond, but 60% of these cases will recur and die. The relapse and associated lethality of ovarian cancer is mainly attributed to the dissemination of hardly visible micrometastasis in the entire peritoneal cavity, which are suboptimally removed during primary treatment. Thus, the development of new diagnostic and therapeutic approaches is mandatory to improve the outcome of this disease.
4 This cancer induces invasion of the peritoneum by secondary malignant tumors under the form of peritoneal carcinomatosis. The peritoneum is a serous membrane (constituted by a simple epithelial cell layer) that line the abdomen, the pelvis and the internal organs. It delimits a virtual cavity: the peritoneal cavity. It contains two leafs adjacent to each other i) the visceral peritoneum (lining the outer wall of the organs) ii) the parietal peritoneum (lining the inner wall of the abdomen). Stage IIIC Ovarian Cancer The major prognosis factor is the absence of macroscopic residual lesions after surgery. High peritoneal recurrence rate after optimal treatment of advanced ovarian cancer by the association of platinum-based chemotherapy and complete cytoreductive surgery raises the issue of peritoneal microscopic disease management and requires the development of additional locoregional treatment strategies, as this microscopic lesions may be ignored during surgical procedure alone, even with the help of photodiagnosis and fluorescence-guided surgery. Our objective is to provide another option to improve the completion of cytoreductive surgery by inducing necrosis of micrometastasis by targeted photodynamic therapy (PDT) and so to decrease the incidence of recurrence. Human peritoneal carcinomatosis of ovarian origin
5 Photodiagnosis of ovarian peritoneal carcinomatosis Photodiagnosis is based on the principle that abnormal tissues absorb light and fluoresce differently from normal tissues at specific light wavelengths. Autofluorescence takes advantage of this principle. Fluorescence can be enhanced by the use of exogenous markers (photosensitizers). This technique, which has been evaluated in preclinical and clinical studies, has shown a good accuracy to detect peritoneal metastasis of ovarian origin, increasing the number of lesion detected by more than a third, and allowing easier detection of submillimeric lesions. As a feasible application, photodiagnosis could be an efficient decisionsupport technology to help the surgeon to take a decision during explorative laparoscopy before cytoreductive surgery for peritoneal carcinomatosis in ovarian cancer. The Dutch team lead by van Dam (van Dam et al. Nature Med 2011) has performed for the first time a clinical application of fluorescence-guided surgery mediated by a folate-targeted PS (folate-fitc) with promising results and good accuracy to detect peritoneal lesions. An Innovative strategy: Photodynamic therapy of ovarian peritoneal micrometastasis. Nevertheless, the therapeutic impact of fluorescence guided surgery remains uncertain, as it is not possible to treat the entire peritoneal cavity surgically, even if more lesions are removed. Photodiagnosis will always be limited by optical detection device performances. Photodynamic therapy mechanism
6 Photodynamic therapy is an efficient treatment already applied in other medical indications: After administration of a PS, which accumulates in cancer cells, its illumination with a light of adequate wavelength may induce photochemical reaction with tissue oxygen, which lead to reactive oxygen species production and cytotoxic phenomenon. Its ability to treat superficial lesions disseminated on large area makes it an excellent candidate to insure destruction of microscopic residual disease. This strategy is presenting numerous advantages: diagnostic input, specific targeting of tumor cells, and possible association with other treatments. Perspectives: targeted approaches Development of intraperitoneal PDT has been confronted with poor tolerance related to the lack of specificity of PS and the proximity of intraperitoneal organ. First generation photosensitizer Porfimer sodium is the only PS which has been clinically evaluated in intraperitoneal indication in phases I and II trials. In these studies, the author s rapport high grade morbidity as digestive perforation, capillary leaks syndrome and no benefit has been observed neither on progressionfree survival nor on global survival. This narrow therapeutic window has been attributed to a narrow differential in drug selectivity between tumor and normal tissues of the peritoneal cavity. Targeted photosensitizers have a strong clinical potential and are needed to improve therapeutic index of intraperitoneal PDT. Specific promising targets, as folate receptor, could enhance tolerance of intraperitoneal photodynamic therapy using targeted PS.
7 Innovative illuminative solutions Another aspect of photodynamic therapy development is illumination using an optimal scheme and light administration monitoring. Innovative illumination solutions are available, like textile light diffusers that offer the possibility to apply a homogenous distribution of light on large surface areas, as parietal peritoneum or direct and cylindrical diffusing fibres which are easy to handle and allow reaching spaces that are difficult to attain. Homogeneity of light distribution inside the peritoneal cavity can be improved by filling it with a dilute intralipid solution which acts as an optical diffusing medium. Oxygen depletion is the major reason of relative treatment failure. Besides fractionation of light, numerous studies have clearly demonstrated that PDT efficacy can be enhanced by instillation of hyperoxygenated fluids during light irradiation. The fluence rate and the wavelength must be adapted to exposed organs to limit light penetration and to reduce the risk of deep visceral injuries. Light emission monitoring and source tracking are feasible to ensure a complete and homogenous illumination of any anatomical cavity as it is already performed for pleural mesothelioma treatment with promising results. Moreover, the combination of this spatial tracking and imaging modalities allows a real-time feedback and display of applied doses. Intraperitoneal PDT in a prophylactic intent Patients presenting an early-stage ovarian cancer have a high risk of developing peritoneal carcinomatosis in the short or long term, after surgery and chemotherapy. Additional treatment may reduce this risk and constitute a significant progress in the management of these patients. There are presently no imaging methods reliable enough to detect those lesions. Systematic peritoneal PDT, with or without visible carcinomatosis lesions could have a prophylactic effect.
8 Contacts Henri Azaïs Nacim Betrouni (nacim. Pierre Collinet Serge Mordon Unité U1189 Onco-THAI 1 avenue Oscar Lambret Lille Cedex