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A Phase I Trial of Continuous Low-Irradiance Photodynamic Therapy for Post-Mastectomy Chest Wall Recurrences of Breast Cancer
The goal of this research is to conduct a Phase I clinical study to assess the toxicity, safety and feasibility of a novel cancer treatment, Continuous Low Irradiance Photodynamic Therapy (CLIPT). This research will provide translation of recent promising preclinical work to human subjects with recurrent breast cancer. BACKGROUND: Patients who develop post-mastectomy chest wall skin/subcutis recurrence and fail conventional radiation therapy have few therapeutic options that can result in durable disease control. High-irradiance photodynamic therapy (PDT) has shown efficacy in patients with chest-wall progression of breast cancer that have failed radiation, surgery, and chemotherapy. However its clinical application has been severely limited as currently employed methods of PDT result in virtually 100% of patients developing skin necrosis, large areas of full-thickness ulceration, slow healing and chronic wound pain. In the rat and rabbit-brain tumor models, reducing the laser irradiance and increasing the exposure time to achieve a similar total fluence (fluence = irradiance x time) to standard PDT, avoids tissue necrosis while inducing apoptosis in the tumor but not normal tissue. HYPOTHESIS: Low dose-rate (low irradiance) PDT may reduce or eliminate skin toxicity and enables treatment of skin/subcutaneous chest wall metastases in skin previously subjected to ionizing radiation. SPECIFIC AIMS: 1) determine the fluence of CLIPT resulting in toxicity (maximum tolerated dose), defined as ulceration or necrosis of previously irradiated skin (non-tumor bearing skin within the prior ionizing radiation field) or normal skin, 2) evaluate the feasibility, ergonomics and safety of performing CLIPT via a proprietary electronically targetable fiber-optic ?patch? placed directly on tumor-bearing, surrounding uninvolved previously irradiated skin and normal integument 3) study the tumor-bearing integument for clinical response to therapy by measuring complete, partial and no response to CLIPT. STUDY DESIGN: We will perform a standard dose (laser fluence) escalation trial (holding drug level constant) in human subjects with post-mastectomy skin recurrences that have failed ionizing radiation therapy and assess toxicity in previously irradiated and normal integument. POTENTIAL OUTCOMES & BENEFITS: Therapeutic options for post-mastectomy cutaneous recurrences failing conventional radiotherapy are limited and irradiated skin is particularly vulnerable to injury. If the pre-clinical results are replicated in human subjects, Phase II studies to evaluate CLIPT would be warranted. The long-term goal is to develop an unobtrusive, large-area CLIPT system in the form of a fiberoptically woven ?garment? that can be worn by the patient outside the hospital setting to deliver the therapy for repeated and extended periods without causing skin breakdown or pain.
Local recurrence of breast cancer in the skin or subcutaneous tissues of the chest wall can occur months to years following mastectomy. Overall this occurs in 5% to 8% of women treated for breast cancer in the United States. However, the risk of local recurrence in the chest wall after mastectomy is stage-dependent and is as high as 60% in some patient groups. Although patients with small areas of chest wall disease can be effectively managed with a combination of surgery and radiation therapy, many have extensive disease that cannot be adequately controlled. Radiation therapy often combined with chemotherapy and/or hormonal therapies are the recommended treatments for these patients, but failure rates are between 30% and 55%. Skin that has received therapeutic radiation is often fragile, prone to break down and form open sores and, usually cannot receive further radiation or surgical treatment. The recurrent disease is often painful, unsightly with oozing and bleeding requiring frequent dressing changes and rigorous wound care, greatly impeding quality of life. Cutaneous recurrence causes tremendous anxiety, because the patients are presented with a continuous visual reminder of their uncontrolled cancer. For patients that fail following conventional radiation therapy there are few therapeutic options available that can offer a high probability of long-term control. Photodynamic Therapy (PDT) is a technique by which the patient takes a medicine that is preferentially is taken up by the cancer cells. The medicine by itself has no effect. When these tissues are exposed to light of a particular wavelength, the medicine is activated and kills the cell. PDT has demonstrated remarkable clinical efficacy in patients with chest-wall progression of breast cancer that have failed all other treatments. However, virtually 100% of these patients develop large and deep skin wounds that may require reconstructive surgery to repair, chronic pain and slow-healing skin sores as a side effect of the treatment. These side effects and the complexity of administering the PDT limit the number of Centers offering this treatment modality. Recent experiments in animals have demonstrated that by reducing the intensity (irradiance) of the light used to activate the medicine in the PDT reaction and prolonging the exposure time, the tumor cells undergo a programmed cell death while normal tissues are spared. The goal of this proposal is to explore whether these promising findings in animals can translate into a new treatment for patients. We call this treatment, ?Continuous Low-Irradiance Photodynamic Therapy,? or CLIPT. The technique of CLIPT will be evaluated in people, using a novel light delivery system, to assess its side effects and the benefit it has in treating breast cancer that has spread to the skin of the chest. Our long-range goal is to develop a safe and effective therapy that can be given in the doctor?s office or possibly at home on a repeated basis.