A Randomized Phase II Study of the Administration of Prebiotics and Probiotics During Definitive Treatment With Chemotherapy-radiotherapy for Patients With Squamous Cell Carcinoma of the Anal Canal (BISQUIT)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 75
- 试验地点
- 2
- 主要终点
- Response rate (clinical and radiological)
研究概览
简要总结
Phase II randomized study of the use of pre-and probiotics during the definitive treatment of chemotherapy-radiotherapy (Ch-RT) for patients with localized anal canal squamous cell cancer (ACSCC) with the objective of increasing the effectiveness of conventional treatment based on the assumptions of that there is a need for research that increases the cure rates of the definitive treatment of Ch-RT in the ACSCC; ACSCC is a virus-associated tumor in many cases and therefore potentially immunogenic; immunotherapy is a promising strategy in ACSCC; and that pre- and probiotics can stimulate the immune system through modulation of the intestinal microbiota, and improve oncological outcomes.
详细描述
Although anal canal squamous cell carcinoma (ACSCC) is rare in developed countries, it has shown an annual increase of 4% in its incidence in Brazil, and according to data from the Oncocenter Foundation of São Paulo (FOSP), 2,338 cases were diagnosed in 2000 and 2016.
The standard treatment for localized ACSCC (without distant metastases) is definitive chemo-radiotherapy (Ch-RT) concomitant with administration of a fluoropyrimidine (5FU or capecitabine) combined with mitomycin or cisplatin, which provides cure rates of 60-80 % depending on the staging. When there is no complete remission, surgical rescue through anal amputation is the only potentially curative modality. However, this strategy is associated with great morbidity, besides negative emotional and social impacts, with consequent reduction of quality of life. Therefore, interventions that may increase the chance of cure in ACSCC should be investigated.
The main risk factors for ACSCC are human papillomavirus (HPV) infections and immunosuppression, including human immunodeficiency virus (HIV) infection. Chronic HPV infection and HIV-induced immunosuppression point to research strategies that strengthen the immune system to reduce the risk of developing ACSCC. In the metastatic setting, the use of immune checkpoint inhibitors, such as anti-programmed death protein-1 (PD1) antibodies, were shown to be promising in ACSCC patients, promoting response rates of approximately 25%. However, there is no evidence of modulation interventions of the immune system in patients with localized ACSCC.
Recently, studies have shown that the composition of the intestinal microbiota influences the onset of colorectal cancer, and may even disrupt the effects of chemotherapy in this neoplasm. A preclinical study in animal model showed that E. coli impaired the antitumor effect of fluoropyrimidines, drug used in colorectal cancer and ACSCC. The intestinal microbiota also participates in a large set of metabolic processes (such as reduction, hydrolysis, dehydroxylation, etc.) involved in drug metabolism. For example, some intestinal bacteria have β-glucuronidases that cleave glucuronide from the inactive metabolite of irinotecan (SN-38G), a drug used in gastrointestinal tumors, releasing active metabolite (SN38) in the intestine, causing diarrhea and colitis. Ciprofloxacin has been shown to inhibit this enzyme by suppressing the diarrhea associated with irinotecan in an experimental model of mice. Mycoplasma hyorhinis encodes a thymidine phosphorylase that strongly restricts the cytostatic activity of pyrimidine nucleoside analogues.
On the other hand, the replacement of the intestinal microbiota "carcinogenic" (Fusobacterium spp and Bacteriodes fragilis) by a protective microbiota (Bifidobacterium and Lactobacillus) has been the reason of numerous investigations with prebiotics and probiotics. According to the International Scientific Association of Probiotics and Prebiotics, probiotics are composed of living organisms which, when administered, promote health benefits, such as antimicrobial action against intestinal pathogens, modulation of the immune system, reduction of cholesterol levels, reduction of colitis and prevention of colorectal cancer. Kefir is an example of probiotic. Already prebiotics are inert ingredients that promote alteration in the composition or activity of the gastrointestinal microflora, conferring health benefits. Example of prebiotic is polysaccharide inulin. Studies with these compounds have been conducted, showing promising results. A small placebo-controlled trial using B. breve breve (Yakut®) in children undergoing chemotherapy for a variety of neoplasms has shown that this group had fewer episodes of fever and less frequency of use of intravenous antibiotics compared to controls. There are also studies that suggest that the alteration of the intestinal flora can increase the effectiveness of immunotherapy as a form of modulation of the immune system in several animal models of colorectal cancer. In addition, the use of this strategy could have a modulatory effect on local and systemic toxicity of the treatment, possibly reducing the morbidity of the treatment, as already suggested by studies in cervical carcinomas.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Investigator, Outcomes Assessor)
盲法说明
The researchers will identify the patients through a unique number and through the initials of the name. Randomization will be simple and conducted independently by clinical trial support staff who are not participating in the study. The random sequence will be generated by computer program.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients older than 18 years;
- •Confirmed histological diagnosis of squamous cell carcinoma / squamous cell carcinoma of the anal canal (ACSCC);
- •Patients with localized ACSCC (≥ T2N0M0, according to American Joint Committee on Cancer (AJCC) 8th edition) staged by conventional imaging methods according to institutional routine;
- •Indication of starting definitive treatment with Ch-RT in the institution. HIV-positive patients may be included;
- •Free and informed consent signed by the patient or legal representative
排除标准
- •Diagnosis of perianal squamous cell carcinomas;
- •Clinical condition leading to difficulty in swallowing;
- •Patients with a contraindication to receiving Ch-RT, ie receiving only radiotherapy or not receiving polychemotherapy;
- •Clinical condition that, due to the investigator's judgment, prevents adherence to the study
- •Active infection requiring antibiotic therapy
结局指标
主要结局
Response rate (clinical and radiological)
时间窗: Six to eight weeks from the end of Ch-RT
absence of visible disease at the clinical examination and magnetic resonance imaging (MRI) of the pelvis (or pelvic tomography, if contraindicated to MRI) and without disease at a distance, through tomography of the chest and abdomen.
次要结局
- Complete clinical and radiological response rate(Six months)
- Metabolic response by 18-FDG PET-CT(Six to eight weeks from the end of Ch-RT)
- Incidence of HPV in tumor tissue(through study completion, an average of 3 years)
- Variation of systemic immune parameters(through study completion, an average of 3 years)
- Progression / disease free survival(through study completion, an average of 5 years)
- Incidence of Adverse Events Treatment-related(through study completion, an average of 5 years)
- Proportion of patients without colostomy(Twelve months)
研究者
Rachel Riechelmann
Head of Departament of Clinical Oncology
AC Camargo Cancer Center