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.
Despite the strong scientific rationale, there are no studies that have evaluated the use of
probiotics or prebiotics in order to increase the effectiveness of conventional Ch-RT
treatment in ACSCC. Therefore, based on the assumptions that there is a need for research
that increases the cure rates of the definitive treatment of Ch-RT in 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, the
investigators propose a randomized phase II study of the use of pre-probiotics during
definitive treatment of Ch-RT for patients with ACSCC located.
The primary hypothesis of this study is that addition of pre- and probiotics increases the
proportion of patients with complete clinical and radiological response after Ch-RT to ACSCC.
Secondary hypotheses are that pre- and probiotics increase the metabolic response measured by
positron emission computed tomography (PET-CT) with 18F-2-fluoro-2-deoxy-D-glucose
fluorodeoxyglucose (18-FDG) and promote greater control of local disease after Ch-RT; and
reduce local and systemic toxicity of treatment.