Effect of Topical Diclofenac on Clinical Outcome in Breast Cancer Patients Treated With Capecitabine

Study Overview
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Brief Summary
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The aim of the study is to evaluate the efficacy of using combination of Urea-based cream (CARBAMIDE®) and topical diclofenac (VOLTAREN®) Emulgel 1% for improving the incidence of Hand-foot syndrome in histologically proven breast cancer Egyptian patients receiving single agent chemotherapy Capecitabine (XELODA ®) and Its effect on improving patients' quality of life.

Detailed Description
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Breast cancer (BC) is the most common cancer in women and the leading cause of death associated with cancer in females worldwide. BC, like most cancers, is a heterogeneous disease with a variety of molecular subtypes. Basal-like, Luminal-A, Luminal-B, HER2-positive/HER2-enriched/HER2-overexpressing BC, and normal-like tumors are the major subclasses identified by genetic profiling. Depending on the size, stage, grade, metastatic behavior, aggressiveness and intrinsic molecular subtyping of the tumor, age, menopausal status, overall health, comorbidities, and preferences of the patient, clinicians now have numerous options for breast cancer treatment. Treatment options include chemotherapy, hormone therapy, immunotherapy, radiotherapy, and surgery. The primary treatment option is usually surgery with the goal of complete resection of the major tumor mass. Surgery may be preceded by systemic neoadjuvant therapies to shrink the tumor in preparation for effective surgery and to maximize breast conservation. The United States FDA has approved a number of drugs for breast cancer therapy, including Capecitabine (Xeloda). However, these drugs are very pricey and have numerous side effects. Patients frequently report decreased appetite, dehydration, diarrhea, Hand-foot syndrome (HFS), irregular periods, mouth and throat sores, nausea, and vomiting as side effects of Capecitabine. These side effects are difficult for patients who are already weakened by the disease to tolerate. Eventually these also affect the decision for further choice of treatment and impair the quality of life. This necessitates the development of novel drugs for the treatment of breast cancer and This is the role of drug repurposing. The drug repositioning (aka drug repurposing, drug reprofiling, drug re-tasking, drug redesigning, drug resorting, drug reindication, indication switching, therapeutic switching) can be defined as exploring the new uses for an old clinically approved drug, with reduced risk, time and cost. Methotrexate, Raloxifene and Vinblastine are examples of Drug repurposing in breast cancer. Hand-foot syndrome (HFS) also Known as palmoplantar erythrodysesthesia, is a common side effect of the fluoropyrimidine chemotherapy drug capecitabine. According to reports, 43 % to 71 %of patients receiving single-agent capecitabine chemotherapy have hand-foot syndrome of any grade. It is characterized initially by palmoplantar numbness, tingling, or burning pain. These symptoms are usually accompanied by clearly defined erythema with or without edema, cracking, or desquamation. Blistering and ulceration may occur in the advanced stages. HFS may manifest as macular hyperpigmentation rather than erythema in people with darker skin (Fitzpatrick skin types V-VI). Symptoms can range from mildly to severely painful. The pathogenesis of HFS is unclear, but it is assumed to be different for each drug class HFS causes a variety of toxic skin damage, ranging from non-specific scattered keratinocyte necrosis with basal vacuolar degeneration to full epidermal layer necrosis and (sub)epidermal blistering. In addition to eccrine squamous syringometaplasia, inflammation at the dermo-epidermal junction with papillary dermal edema, blood vessel dilation, and a lymphocytic infiltrate has been reported. The unique physiology of the palms and soles may clarify why the effects of these drugs are concentrated in these areas. The palms and soles are highly vascular, with higher rates of skin cell division than other skin areas, as well as high concentrations of eccrine glands and unique temperature modulation. Unfortunately, no specific guidelines exist for HFS, and only a few randomized trials demonstrating the benefit of topical treatments are available. The most effective way to manage HFS once it has developed is to modify dose intensity in the form of a dose delay or dose reduction, which will affect patients' treatment outcomes and quality of life such as daily activities like walking or using of hands. The treatment of choice for symptomatic HFS is determined by the severity of symptoms and their impact on Quality of Life (QoL). Vitamin E, steroids (oral dexamethasone), and analgesics are among the systemic treatment options. Current topical treatments are corticosteroids and emollients such as urea-based creams. Capecitabine and its metabolites are thought to cause COX-2-mediated inflammation; COX-2 inhibition has been shown to be effective in the prevention of HFS. Topical non-steroidal anti-inflammatory inhibitors (NSAIDs), such as diclofenac, can inhibit COX-2 locally and may have a role in reducing HFS, without systemic side effects. However, no study has been conducted to date evaluating the role of topical COX inhibitors in reducing capecitabine-induced HFS. Hence, this study aimed to evaluate the efficacy and safety of topical diclofenac in reducing capecitabine-induced HFS.

Official Title
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Effect of Topical Diclofenac on Clinical Outcome in Breast Cancer Patients Treated With Capecitabine: A Randomized Controlled Trial.

Conditions
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Hand and Foot Syndrome

Intervention / Treatment
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* Drug: (CARBAMIDE®)
* Drug: (VOLTAREN®) Emulgel 1%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 18 years and above. Females. Histologically proven breast cancer patients receiving Capecitabine (XELODA ®) chemotherapy. life expectancy greater than 18 weeks. Exclusion Criteria: Hypersensitivity to diclofenac, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS). History of Urticaria. History of acute rhinitis Asthmatic Patients.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study consists of 2 Arms, A control arm which will only receive standard of care (CARBAMIDE) and an intervention arm which will receive (CARBAMIDE and VOLTAREN)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm<br>Standard of care Urea-based cream (CARBAMIDE®) will be applied to hands and feet 2-3 times daily for 14 days starting from the first dose and cycle of Capecitabine (XELODA ®). Each Capecitabine (XELODA ®) cycle lasts for 21 days. Capecitabine (XELODA ®) dose :2g/m2 daily divided into 2 doses after breakfast and dinner for 14 days followed by 7 days Capecitabine free. Capecitabine (XELODA ®) dose will be modified according to treatment related side effects (26). This regimen will be repeated at each cycle of Capecitabine (XELODA ®) and lasts for 6 cycles (18 weeks) and preventive measures of Hand-foot syndrome will be applied (Avoid mechanical stress | Drug: (CARBAMIDE®)<br>* Urea is used to treat dry/rough skin conditions (such as eczema, psoriasis, corns, callus) and some nail problems (such as ingrown nails). It may also be used to help remove dead tissue in some wounds to help wound healing. Urea is known as a keratolytic. It increases moisture in the skin by softening/dissolving the horny substance (keratin) holding the top layer of skin cells together. This effect helps the dead skin cells fall off and helps the skin keep more water in.<br>* Other names: Urea-based cream;|
| Active Comparator: Intervention Arm<br>Standard of care Urea-based cream (CARBAMIDE®) will be applied to hands and feet twice daily for 14 days starting from the first dose and cycle of Capecitabine (XELODA ®). Each Capecitabine (XELODA ®) cycle lasts for 21 days. Capecitabine (XELODA ®) dose: 2g/m2 daily divided into 2 doses after breakfast and dinner for 14 days followed by 7 days Capecitabine free. Capecitabine (XELODA ®) dose will be modified according to treatment related side effects (26). This regimen will be repeated at each cycle of Capecitabine (XELODA ®) and lasts for 6 cycles (18 weeks) and preventive measures of Hand-foot syndrome will be applied (Avoid mechanical stress Plus Topical diclofenac (VOLTAREN®) Emulgel 1% 2-4g (2g = 4 fingertip Units (FTU)) twice daily 2 hours away from Urea-based cream (CARBAMIDE®) for 14 days starting from the first cycle and dose of Capecitabine. This regimen will be repeated at each cycle of Capecitabine (XELODA ®) and lasts for 6 cycles (18 weeks). | Drug: (CARBAMIDE®)<br>* Urea is used to treat dry/rough skin conditions (such as eczema, psoriasis, corns, callus) and some nail problems (such as ingrown nails). It may also be used to help remove dead tissue in some wounds to help wound healing. Urea is known as a keratolytic. It increases moisture in the skin by softening/dissolving the horny substance (keratin) holding the top layer of skin cells together. This effect helps the dead skin cells fall off and helps the skin keep more water in.<br>* Other names: Urea-based cream;Drug: (VOLTAREN®) Emulgel 1%<br>* (VOLTAREN®) Emulgel 1% contain the active ingredient diclofenac which belongs to the NSAIDS.it has analgesic and anti-inflammatory properties and due to its alcohol base it has a cooling effect.<br>* Other names: Diclofenac Sodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Incidence of HFS between control arm (Urea-based cream (CARBAMIDE®)) and intervention arm (Combination of Urea-based cream (CARBAMIDE®) and (VOLTAREN®) Emulgel 1%) measured by (CTCAE v 5.0). | • Incidence of HFS between control arm (Urea-based cream (CARBAMIDE®)) and intervention arm (Combination of Urea-based cream (CARBAMIDE®) and (VOLTAREN®) Emulgel 1%) measured by (Common Terminology Criteria for Adverse Effects CTCAE v 5.0). | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Capecitabine, Breast Cancer, Hand and Foot Syndrome, Diclofenac Sodium