Squamous cell carcinoma of the anus (SCCA) is strongly increasing in incidence, with a 2.2% increase annually between 1992 and 2010. Treatment of early stage invasive disease with chemoradiotherapy is effective, but hindered by substantial toxicity. Once spread to the lymph nodes, cure rates for SCCA drop to less than 50%. The development of effective but minimally toxic methods to treat anal disease while it is high grade anal intraepithelial neoplasia (HGAIN) or microinvasive cancer is the proactive approach toward avoiding a need for more toxic therapy at its later stages. We propose photodynamic therapy (PDT) with systemic administration of the photosensitizing pro-drug aminolevulinic acid (ALA) for treatment of HGAIN or microinvasive cancer, postulating that its superficial cytotoxicity will provide for safe and effective treatment. Vitamin D3 will be added to the treatment regimen, based on knowledge that vitamin D3 can increase levels of ALA-induced photosensitizer in premalignant/malignant tissue and evidence of immunomodulatory effects in cancer therapy. We plan a clinical trial of PDT plus vitamin D3 to test our hypothesis that this therapy can be applied to treat anal (pre)malignancy with acceptable toxicity and light dose. A desired superficial effect is expected due to limited tissue penetration of the wavelength of illumination (630 nm) and preferential accumulation of ALA-induced photosensitizer in mucosal tissues (including tumor), relative to the underlying musculature. Moreover, reported destruction of Human Papilloma Virus (HPV) (a common initiator of anal cancer) by PDT lends even greater significance to the development of PDT for treatment of anal (pre)malignacy due to a potential preventive effect.
Aim 1 will be to conduct a Phase I trial of ALA-PDT plus vitamin D3 in patients with HGAIN/microinvasive anal cancer. Toxicity will be a primary endpoint, and effect of therapy on positive cytology and HPV expression will be secondary endpoints. There is increasing evidence that the inflammation created by PDT (or other cancer therapies) can both stimulate and impede adaptive immunity. Moreover, the anti-apoptotic effects of inflammation can attenuate direct cytotoxicity by PDT. Thus, a comprehensive understanding of the role for inflammation in modulating cytotoxic and immune response to therapy is crucial.
Aim 2 will be to quantify inflammation induced by PDT plus vitamin D3 of premalignant/microinvasive anal cancer and explore mechanisms linking innate immunity with anti-tumor immunity and therapeutic outcome. Comprehensive analysis of innate immunity and adaptive immune response to a known tumor antigen (HPV) will be possible, lending significance to this work while also filling basic knowledge gaps in the clinical translation of PDT, especially in combination with vitamin D3. Guided by results of the proposed Phase I trial, we will design a Phase II trial of efficacy. Informed by Phase I results, Phase II will additionally consider other factors such as the potential benefit of personalizing doses of vitamin D3 based on measured vitamin D3 levels and detected immunological endpoints.

Public Health Relevance

Incidence of squamous cell carcinoma of the anus (SCCA) is on the rise due in part to the increased life expectancy of individuals infected with human immunodeficiency virus (HIV), who are also frequently positive for infection with human papilloma virus (HPV), a known initiator of anal carcinogenesis. Effective methods of treating high grade anal neoplasia or microinvasive anal cancer with acceptable toxicity are lacking, yet they are needed in order to avoid disease progression and the substantial toxicities associated with treatment of more advanced disease. We are developing photodynamic therapy (PDT) plus vitamin D3 for the treatment of anal (pre)malignancy based on evidence that PDT with the photosensitizing pro-drug aminolevulinic acid can provide for superficial damage of diseased mucosal surfaces and may eradicate the HPV virus, whereas vitamin D3 can augment photosensitizer accumulation and may modulate anti-tumor immunity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1)
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Buchsbaum, Jeffrey
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University of Pennsylvania
Schools of Medicine
United States
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