Therapy For Nonmelanoma Skin Cancer Research Articles

Abstract 123: A novel J-series prostamide mediates D-series prostamide-induced apoptosis in skin cancer: receptor-independent signaling

Abstract Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. The absence of selective toxicity is a major problem that limits the utility of chemotherapeutic and radiation therapy for NMSCs. Our previous data showed that the endocannabinoid, anandamide, selectively induced apoptosis in non-melanoma skin cancer (NMSC) cells which overexpress cyclooxygenase-2. The cytotoxic effect of anandamide was mediated by the production of ethanolamide-conjugated D- and J-series prostaglandins (PGs), also known as prostamide D2 (PMD2) and prostamide J2 (PMJ2), respectively. The aim of the current study was to determine if tumorigenic keratinocytes are more sensitive to PMD2 than non-tumorigenic cells and to examine whether the cytotoxicity of PMD2 is mediated by its downstream metabolite PMJ2. To determine if PMD2 demonstrates preferential toxicity, tumorigenic (JWF2) and non-tumorigenic (HaCaT) keratinocytes were utilized. A significant reduction in cell viability was observed in JWF2 but not in HaCaT cells treated with PMD2. In tumorigenic keratinocytes, PMD2 induced apoptotic cell death, oxidative stress and increased the expression of apoptotic ER stress protein, C/EBP homologous protein-10 (CHOP10). In addition, use of the antioxidant, trolox, and ER stress inhibitor, salubrinal, inhibited the cytotoxic effect of PMD2. Furthermore, the use of prostaglandin D receptor (DP1 and DP2) antagonists did not inhibit PMD2-induced apoptosis indicating that the activity was mediated by a receptor-independent pathway. Similar effects were observed in keratinocytes treated with the structurally-related arachidonic acid metabolite, prostaglandin D2 (PGD2). Interestingly, PMD2 increased the production of J-series prostaglandins in both tumorigenic and non-tumorigenic keratinocytes. LC-ESI-MS/MS analysis detected ethanolamide- conjugated J series PG (15-deoxy, Δ12,14 prostamide J2, 15d-PMJ2) in PMD2-treated cell culture media. Since selective inhibitors of the J-series prostaglandins are not available, 15d-PMJ2 was synthesized to examine its direct activity. Exogenous 15d-PMJ2 mimicked the activity of PMD2 demonstrating preferential cytotoxicity towards tumorigenic compared to non-tumorigenic keratinocytes. In addition, 15d-PMJ2 induced oxidative stress, ER stress and apoptosis in tumorigenic keratinocytes. These findings suggest that the cytotoxicity of PMD2 is mediated by 15dPMJ2. Since PMD2 and its metabolite 15d-PMJ2 are preferentially toxic towards tumorigenic cells, PMD2 or 15d-PMJ2 may be an ideal topical treatment for NMSC that will elicit minimal toxicity in healthy surrounding skin cells. Citation Format: Eman Soliman, Daniel Ladin, Hussam Albassam, Ahmed E. Elhassanny, Andrew Morris, Allison Danell, Rukiyah Van Dross. A novel J-series prostamide mediates D-series prostamide-induced apoptosis in skin cancer: receptor-independent signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 123. doi:10.1158/1538-7445.AM2017-123

Oral therapy for nonmelanoma skin cancer in patients with advanced disease and large tumor burden: a review of the literature with focus on a new generation of targeted therapies.

Nonmelanoma skin cancer (NMSC) is the most common cancer in patients and includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Treatments useful for SCC and BCC include surgical, topical, and in advanced cases systemic chemo-radiation. This review of the literature aims to describe previous and current treatment options for oral therapy in locally advanced and metastatic NMSC otherwise unamenable to standard treatment. Oral Smoothened (Smo) inhibitors Vismodegib, Sonidegib, and Taladegib have shown to be effective in several trials. Oral tyrosine kinase inhibitors Erlotinib and Gefitinib, which target epidermal growth factor receptor (EGFR), have early supporting data and are currently undergoing large multicenter trials. Other less studied oral therapies which have shown at least partial efficacy include 5-Fluorouracil, capecitabine, and picropodophyllin. In vitro studies have elucidated new targets for dual combination oral therapy targeting both EGFR and insulin-like growth factor 1 receptor (IGF-1R). It is important to stratify treatment options based on patient risk of advanced disease, failure of conservative treatment, and ill-tolerated intravenous chemotherapy adverse events. Oral therapy in NMSC is useful in high risk patients with recurrent and aggressive disease who may not tolerate other systemic therapies.

Combined Treatments with Photodynamic Therapy for Non-Melanoma Skin Cancer.

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population. Among NMSC types, basal cell carcinoma (BCC) has the highest incidence and squamous cell carcinoma (SCC) is less common although it can metastasize, accounting for the majority of NMSC-related deaths. Treatment options for NMSC include both surgical and non-surgical modalities. Even though surgical approaches are most commonly used to treat these lesions, Photodynamic Therapy (PDT) has the advantage of being a non-invasive option, and capable of field treatment, providing optimum cosmetic outcomes. Numerous clinical research studies have shown the efficacy of PDT for treating pre-malignant and malignant NMSC. However, resistant or recurrent tumors appear and sometimes become more aggressive. In this sense, the enhancement of PDT effectiveness by combining it with other therapeutic modalities has become an interesting field in NMSC research. Depending on the characteristics and the type of tumor, PDT can be applied in combination with immunomodulatory (Imiquimod) and chemotherapeutic (5-fluorouracil, methotrexate, diclofenac, or ingenol mebutate) agents, inhibitors of some molecules implicated in the carcinogenic process (COX2 or MAPK), surgical techniques, or even radiotherapy. These new strategies open the way to a wider improvement of the prevention and eradication of skin cancer.

Superficial X-ray Therapy for Non-Melanoma Skin Cancer of the Head and Neck: Comparative Analysis of H-Zone Versus Non-H-Zone Lesions

Superficial X-ray Therapy for Non-Melanoma Skin Cancer of the Head and Neck: Comparative Analysis of H-Zone Versus Non-H-Zone Lesions

A prospective study of pain control by a 2-step irradiance schedule during topical photodynamic therapy of nonmelanoma skin cancer.

Topical photodynamic therapy (PDT) for selected nonmelanoma skin cancer using 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) has yielded high long-term complete response rates with very good cosmesis. Pain during light activation of the photosensitizer can be a serious adverse event. A 2-step irradiance protocol has previously been shown to minimize ALA-PDT pain. To determine the irradiance-dependent pain threshold for MAL-PDT, to adapt the 2-step protocol to a light-emitting diode (LED) light source, and assess clinical response. In this prospective study, 25 superficial basal cell carcinoma (sBCC) received an initial irradiance by laser at 40 or 50 mW/cm², or LED at 35 mW/cm² followed by an irradiance at 70 mW/cm² for a total of 75 J/cm². Pain levels were recorded for both irradiance steps. Efficacy was assessed at 6, 12, or 24 months. Pain was mild in the 40/70 mW/cm² laser cohort. Three instances of irradiance-limiting pain occurred at 50/70 mW/cm². Pain was minimal in the 35/70 mW/cm² LED cohort. Clinical response rates were 80% in the 50/70 mW/cm² laser cohort and 90% in the 35/70 mW/cm² LED cohort. Topical PDT can be effectively delivered to sBCC with minimal treatment-related pain by a 2-step irradiance protocol.

A Light Emitting Diode (LED) Based Spatial Frequency Domain Imaging System for Optimization of Photodynamic Therapy of Nonmelanoma Skin Cancer: Quantitative Reflectance Imaging

Photodynamic therapy (PDT) offers the potential for enhanced treatment of nonmelanoma skin cancer (NMSC) with minimal scarring. Yet, PDT has not achieved consistent long term effectiveness to gain widespread clinical acceptance for treatment of skin cancer. Therapeutic response varies between practitioners, patients and lesions. One important contributing factor is the absence of quantitative tools to perform in vivo dosimetry. To this end, we have developed a new quantitative imaging device that can be used to investigate parameters related to optimizing dosimetry. We present a spatial frequency domain imaging (SFDI) based device designed to: (1) determine the optical properties at the therapeutic wavelength, which can inform variations in light penetration depth and (2) measure the spatially resolved oxygen saturation of the skin cancer lesions and surrounding tissue. We have applied this system to a preliminary clinical study of nine skin cancer lesions. Optical properties vary greatly both spatially [101%, 48% for absorption and reduced scattering, respectively] and across patients [102%, 57%]. Blood volume maps determined using visible wavelengths (460, 525, and 630 nm) represent tissue volumes within ∼1 mm in tissue (1.17 ± 0.3 mm). Here the average total hemoglobin concentration is approximately three times greater in the lesion than that detected in normal tissue, reflecting increased vasculature typically associated with tumors. Data acquired at near infrared wavelengths (730 and 850 nm) reports tissue blood concentrations and oxygenations from the underlying dermal microvasculature (volumes reaching 4.36 ± 1.32 mm into tissue). SFDI can be used to quantitatively characterize in vivo tissue optical properties that could be useful for better informing PDT treatment parameters. Specifically, this information provides spatially resolved insight into light delivery into tissue and local tissue oxygenation, thereby providing more quantitative and controlled dosimetry specific to the lesion. Ultimately, by optimizing the execution of PDT, this instrument has the potential to positively improve treatment outcomes.

Risk of acute postoperative hypertension after topical photodynamic therapy for non‐melanoma skin cancer

Topical photodynamic therapy with methyl aminolevulinate (MAL-PDT) is a non-surgical treatment for actinic keratoses, Bowen's disease and basal cell carcinoma. MAL-PDT is particularly useful in elderly patients, who often present co-morbidities and/or in whom surgical excision could be contraindicated. MAL-PDT is generally well tolerated; the most frequent acute adverse events include pain and burning sensation localized to the treatment area. We describe our observation of the occurrence of acute postoperative hypertension (APH) and hypertensive crisis, after a MAL-PDT. BP measurement was taken twice at 2-min intervals, both before and shortly after the MAL-PDT session. APH was defined as an increase in systolic BP by more than 20% or an increase in diastolic BP to above 110 mmHg. Hypertensive crisis was defined as a systolic BP ≥ 180 mmHg or a diastolic BP ≥ 110 mmHg, with or without acute target organ involvement. Prevalence of post-MAL-PDT APH was 22%; 11% of patients developed hypertensive crisis after MAL-PDT, requiring immediate treatment. We highlight the importance of blood pressure measurement both before and after MAL-PDT session to identify high-risk patients and to prevent potentially severe organ involvement subsequent to hypertensive crisis.

Weather conditions and daylight-mediated photodynamic therapy: protoporphyrin IX-weighted daylight doses measured in six geographical locations

Photodynamic therapy (PDT) is an attractive therapy for nonmelanoma skin cancers and actinic keratoses (AKs). Daylight-mediated methyl aminolaevulinate PDT (daylight-PDT) is a simple and painless treatment procedure for PDT. All daylight-PDT studies have been performed in the Nordic countries. To be able to apply these results in other parts of the world we have to compare the daily protoporphyrin IX (PpIX) light dose in other countries with the PpIX light doses found in Nordic countries. To calculate where and when daylight-PDT of AKs was possible in six different geographical locations using ground stations measuring PpIX-weighted daylight doses. PpIX-weighted daylight doses were measured using a dosimeter with a customer-specific photodiode with a detector sensitivity that mimics the PpIX absorption spectrum and measures in 'PpIX doses'. The dosimeters were built into ground stations that were placed in six geographical locations measuring from July to December 2008. Temperature data for each location were obtained from the internet. The maximal ultraviolet (UV) index for Copenhagen was obtained for the measuring period of the dosimeters. If the PpIX light dose should be above 8Jcm(-2) and the maximum temperature of the day at least 10°C, it was possible to treat patients on nearly all days until the middle of September in Reykjavik and Oslo, until the last week of October in Copenhagen and Regensburg, until the middle of November in Turin and all year in Israel. Where and when to perform daylight-PDT depends on the PpIX light dose and outdoor temperature. The PpIX light dose was influenced by the geographical location (latitude), weather condition and time of year. The UV index was not more suitable than temperature and weather to predict if the intensity of daylight would be sufficient for daylight-PDT.

Fluoreszcens diagnosztika és in vivo konfokális mikroszkópia hámeredetû bôrtumorok fotodinámiás terápiája során

Fluoreszcens diagnosztika és in vivo konfokális mikroszkópia hámeredetû bôrtumorok fotodinámiás terápiája során

Electron Therapy for Nonmelanoma Skin Cancers: Computer Simulated Bolus Versus Actual Physical Bolus for Treatment Planning

Electron Therapy for Nonmelanoma Skin Cancers: Computer Simulated Bolus Versus Actual Physical Bolus for Treatment Planning

Monte Carlo simulations for optimal light delivery in photodynamic therapy of non-melanoma skin cancer

The choice of light source is important for the efficacy of photodynamic therapy (PDT) of non-melanoma skin cancer. We simulated the photodynamic dose (PDD) delivered to a tumour during PDT using theoretical radiation transfer simulations performed via our 3D Monte Carlo radiation transfer (MCRT) model for a range of light sources with light doses up to 75 J cm−2. The PDD delivered following superficial irradiation from (A) non-laser light sources, (B) monochromatic light, (C) alternate beam diameters and (D) re-positioning of the tumour within the tissue was computed. (A) The final PDD deposited to the tumour at a depth of 2 mm by the Paterson light source was 2.75, 2.50 and 1.04 times greater than the Waldmann 1200, Photocure and Aktilite, respectively. (B) Tumour necrosis occurred at a depth of 2.23 mm and increased to 3.81 mm for wavelengths 405 and 630 nm, respectively. (C) Increasing the beam diameter from 10 to 50 mm had very little effect on depth of necrosis. (D) As expected, necrosis depths were reduced when the tumour was re-positioned deeper into the tissue. These MCRT simulations show clearly the importance of choosing the correct light source to ensure optimal light delivery to achieve tumour necrosis.

Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study

Photodynamic therapy (PDT) is an attractive therapy for nonmelanoma skin cancers and actinic keratoses (AKs). Daylight-mediated PDT is a simple and tolerable treatment procedure for PDT. Methyl aminolaevulinate (MAL)-PDT is approved for the treatment of thin or nonhyperkeratotic AKs on the face and scalp. However, thick AK lesions are often treated as well when present in the field-cancerized treatment area. In a randomized multicentre study to evaluate efficacy of daylight-mediated PDT for different severity grades of AKs. One hundred and forty-five patients with a total of 2768 AKs (severity grades I-III) of the face and scalp were randomized to either 1½ or 2½ h exposure groups. After application of a sunscreen (sun protection factor 20) and gentle lesion preparation, MAL was applied to the entire treatment area. Patients left the clinic immediately after application and exposed themselves to daylight according to randomization. Daylight exposure was monitored with a wrist-borne dosimeter. No difference in lesion response was found between the 1½ and 2½ h exposure group. The mean lesion response rate was significantly higher in grade I lesions (75·9%) than in grade II (61·2%) and grade III (49·1%) lesions (P < 0·0001). Most grade II (86%) and III AKs (94%) were in complete response or reduced to a lower lesion grade at follow-up. Large variations in response rate of grade II and III AKs were found between centres. No association was found between response rate and light dose in patients who received an effective light dose of > 3·5 J cm(-2). Daylight-mediated PDT of moderate to thick AKs was less effective than daylight-mediated PDT of thin AKs especially in some centres. However, nearly all thicker lesions (grades II and III) were reduced to a lower lesion grade at 3 months after a single treatment of daylight-mediated PDT.

Photodynamic Therapy of Non-melanoma Skin Cancer with Methyl Aminolaevulinate is Associated with Less Pain than with Aminolaevulinic Acid

Photodynamic Therapy of Non-melanoma Skin Cancer with Methyl Aminolaevulinate is Associated with Less Pain than with Aminolaevulinic Acid

Daylight photodynamic therapy for actinic keratosis: an international consensus

Photodynamic therapy (PDT) is an attractive therapy for non-melanoma skin cancers including actinic keratoses (AKs) because it allows treatment of large areas; it has a high response rate and results in an excellent cosmesis. However, conventional PDT for AKs is associated with inconveniently long clinic visits and discomfort during therapy. In this article, we critically review daylight-mediated PDT, which is a simpler and more tolerable treatment procedure for PDT. We review the effective light dose, efficacy and safety, the need for prior application of sunscreen, and potential clinical scope of daylight-PDT. Three randomized controlled studies have shown that daylight-mediated PDT is an effective treatment of thin AKs. Daylight-mediated PDT is nearly pain-free and more convenient for both the clinics and patients. Daylight-mediated PDT is especially suited for patients with large field-cancerized areas, which can easily be exposed to daylight. Further investigations are necessary to determine at which time of the year and in which weather conditions daylight-mediated PDT will be possible in different geographical locations.

The role of the EP receptors for prostaglandin E2 in skin and skin cancer

One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE2. In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE2 and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE2 synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.

Plesiotherapy for non-melanoma skin cancer: Innovating to overcome!

Background:The non-surgical management of non-melanoma skin cancers is an area requiring clinical investigation. Radiotherapy has a role in treatment for a defined subset of patients.Aims:The application of radiotherapy is subject to availability of proper equipment, non-availability of which precludes appropriate radiotherapy in most centers in third world countries.Materials and Methods:The introduction of innovations is needed to circumvent this. Plesiotherapy is such a mode of therapy for non-melanoma skin cancer.Methods:The introduction of innovations is needed to circumvent this. Plesiotherapy is such a mode of therapy for non-melanoma skin cancer.Results:In this paper we present successful management of a cohort of non-melanoma skin cancer patients with plesiotherapy using stepping source192 Ir HDR source.Conclusions:Plesiothrapy is an effective mode of therapy for non-melanoma skin cancer.

Photodynamic Therapy of Nonmelanoma Skin Cancer with Topical Hypericum perforatum Extract—A Pilot Study

Hypericin, the photoactive compound of Hypericum perforatum, is probably the most powerful photosensitizer found in nature. This compound has shown high potency in the photodynamic treatment of tumor cells. However, there is only limited knowledge regarding the photodynamic effect of hypericin on nonmelanoma skin cancer cells. The aim of this prospective study was to investigate the efficacy of photodynamic therapy with topical application of an extract of H. perforatum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ). The study was carried out on 34 patients--eight with actinic keratoses (AKs), 21 with BCC and five with Bowen's disease. The extract of H. perforatum was applied on the skin lesions under occlusion and that was followed by irradiation with 75 J cm(-2) of red light 2 h later. The treatment was performed weekly for 6 weeks on average. The percentage of complete clinical response was 50% for AKs, 28% in patients with superficial BCC and 40% in patients with Bowen's disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumor cells was found in the histologic preparation of 11% of patients with superficial BCCs and 80% in the patients with Bowen's disease. All patients complained of burning and pain sensations during irradiation. Although the results of this first clinical trial could be regarded as disappointing, there are still possibilities for improvement. Better preparation of the lesions, enhancement of hypericin delivery and other types of light exposure procedures could significantly improve the clinical outcomes of this relatively inexpensive treatment modality.

Photodynamic Therapy for Non-Melanoma Skin Cancer

Photodynamic therapy (PDT) involves the administration of a photosensitizing drug and its subsequent activation by light at wavelengths matching the absorption spectrum of the photosensitizer. Because the skin is readily accessible to light-based therapies, PDT with systemic and particularly with topical agents has become important in treating cutaneous disorders. Topical PDT is indicated for treating actinic keratosis, superficial or thin non-melanoma skin cancer, including some cases of nodular basal cell carcinoma, and some cutaneous lymphomas. Advantages of aminolevulinic acid/methyl aminolevulinate PDT include the possibility of simultaneous treatment of multiple tumors and large surface areas, good cosmesis, and minimal morbidity, such as bleeding, scarring, or infection.

Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: An international consensus

Topical photodynamic therapy (PDT) is used to treat nonmelanoma skin cancers, such as actinic keratoses, Bowen's disease, and basal cell carcinoma (superficial and nodular). This article presents up-to-date, practical, evidence-based recommendations on the use of topical PDT using 5-aminolevulinic acid or methyl aminolevulinate for the treatment (and prevention) of nonmelanoma skin cancers. A systematic literature review was conducted (using MEDLINE), and recommendations were made on the basis of the quality of evidence for efficacy, safety/tolerability, cosmetic outcome, and patient satisfaction/preference. Topical PDT is highly effective in the treatment of actinic keratoses, Bowen's disease, superficial and thin nodular basal cell carcinomas, with cosmesis typically superior to that achieved with existing standard therapies. PDT may also be a means of preventing certain nonmelanoma skin cancers in immunosuppressed patients.

Photodynamic therapy for non-melanoma skin cancer

Photodynamic therapy is a treatment modality that has been shown to be effective mainly for the dermato-oncologic conditions: actinic keratosis, Bowen's disease, in situ squamous cell carcinoma and basal cell carcinoma. Recent work has focused on the development and evaluation of topical photosensitizers like the haem precursor 5-aminolevulinic acid or its methyl ester, both inducing photosensitizing porphyrins. These drugs do not induce strong generalized cutaneous photosensitization, unlike the systemically applied porphyrins or their derivatives. For dermatological purposes incoherent lamps or light-emitting diode arrays can be used for light activation. Cure rates reported for very superficial lesions (tumour thickness <2-3 mm) are comparable to those achieved by other therapeutic modalities. Photodynamic therapy is a minimally invasive therapy associated with excellent cosmetic results. For actinic keratosis and basal cell carcinoma, methyl aminolevulinate-photodynamic therapy is already approved in Europe, Australia and New Zealand, and is now also approved for actinic keratosis in the US.