|Year : 2019 | Volume
| Issue : 6 | Page : 1383-1391
A phase 2 randomized controlled trial of oral resistant starch supplements in the prevention of acute radiation proctitis in patients treated for cervical cancer
Balu Krishna Sasidharan1, Balamurugan Ramadass2, PN Viswanathan1, Prasanna Samuel3, Mahasampath Gowri3, Srinivasan Pugazhendhi4, Balakrishnan S Ramakrishna5
1 Department of Radiation Oncology, Wellcome Research Unit, Christian Medical College Hospital, Vellore, Tamil Nadu, India
2 Department of Biochemistry, Wellcome Research Unit, Christian Medical College Hospital, Vellore, Tamil Nadu; Department of Biochemisry, All India Institute of Medical Sciences, Bhubhaneswar, Orrisa, India
3 Department of Biostatistics, Christian Medical College Hospital, Vellore, Tamil Nadu, India
4 Department of Biochemistry, Wellcome Research Unit, Christian Medical College Hospital, Vellore, Tamil Nadu, India
5 Department of Gastroenterology, Christian Medical College Hospital, Vellore; Department of Medical Gastroentrology, Institute of Gastroenterology, Hepatobiliary Science and Transplantation SRM Institutes for Medical Science, Chennai, Tamil Nadu, India
|Date of Submission||05-Mar-2019|
|Date of Decision||16-May-2019|
|Date of Acceptance||03-Sep-2019|
|Date of Web Publication||24-Dec-2019|
Dr. Balu Krishna Sasidharan
Department of Radiation Oncology, Unit 2, Christian Medical College Hospital, Ida Scudder Road, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Radiation induced proctitis is frequently encountered during the radiation therapy of cervical and prostate cancers that causes pain and occasionally with bleeding and may affect the continuity of radiation therapy.
Aims and Objectives: The purpose of the study is to look at the benefit of administration of an oral prebiotic amylase resistant starch in reducing the incidence of acute radiation proctitis, a distressing symptom in patients receiving radiation therapy for cancer of the cervix.
Material and Methods: The study was conducted between 2011 and 2014 in 104 patients receiving radical chemo-radiotherapy for carcinoma cervix. Patients were randomized in to two arms, one receiving 30 gm of resistant starch and the other digestible starch on a daily basis throughout the course of the external radiotherapy. All patients received standard 4-field box radiation portals, 50 Gy in 25 fractions with 4 cycles of weekly concurrent Cisplatin. At completion of external beam radiotherapy, all patients underwent LDR/HDR brachytherapy. The study was double blinded and allocation was concealed from the investigators. The investigator recorded the radiotherapy related toxicity of the patients according to CTC V 3.0. The incidence and severity of grade 2-4 diarrhoea and proctitis were documented on a weekly basis and compared across the two groups and analyzed. Stool short chain fatty acid concentrations were measured at baseline at 2nd and 4th week and after 6 weeks of completion of radiotherapy in both study placebo arms and reported. The pattern of microbiota in the stool were also estimated in all patients at 4 time points. Two patients who progressed during therapy were not included in the analyses and two patients discontinued the intervention. A per protocol analyses was done.
Results: At analysis there were 50 patients in each arm. The severity of clinical proctitis was found to be similar in both groups of patients with 12.2 % of patients experiencing toxicity of grade 2 and above in digestible starch group versus 14.6% in the resistant starch group. Functional proctitis was similarly graded and it was found that 16.3 % patients in digestible starch group experienced toxicity against 10.2 % patients in the resistant starch group. This difference was seen at 4th week and continued in the subsequent weeks till the end of radiation. Both groups had similar reported toxicity at 6 weeks post intervention and similar incidence of grade 2 and above diarrhea. The resistant starch group was found to have 8% incidence as compared to 2% in the other group at the 5th and 6th week. The short chain fatty acid concentrations were not significantly different in the groups at any point.
Conclusion: The study did not demonstrate a significant benefit in administering resistant starch over and above normal diet to patients receiving pelvic radiotherapy. The reasons may be attributed to concurrent use of chemotherapy and decrease in intestinal probiotics. The use of digestible starch in the control arm may have contributed to lower incidence of the toxicity endpoints as well.
Keywords: Butyrate, gut microbiome, prebiotics, radiation toxicity, short-chain fatty acids
|How to cite this article:|
Sasidharan BK, Ramadass B, Viswanathan P N, Samuel P, Gowri M, Pugazhendhi S, Ramakrishna BS. A phase 2 randomized controlled trial of oral resistant starch supplements in the prevention of acute radiation proctitis in patients treated for cervical cancer. J Can Res Ther 2019;15:1383-91
|How to cite this URL:|
Sasidharan BK, Ramadass B, Viswanathan P N, Samuel P, Gowri M, Pugazhendhi S, Ramakrishna BS. A phase 2 randomized controlled trial of oral resistant starch supplements in the prevention of acute radiation proctitis in patients treated for cervical cancer. J Can Res Ther [serial online] 2019 [cited 2020 Mar 28];15:1383-91. Available from: http://www.cancerjournal.net/text.asp?2019/15/6/1383/273789
| > Introduction|| |
Radical intent chemoradiotherapy is often the preferred treatment for curable stages of advanced cervical cancer that would include Stages IB–IVA. Radiation commonly refers to photon beam or X-rays from linear accelerators or gamma rays from cobalt 60 teletherapy machines. Therapeutic radiation beam kills cancer cells by inducing DNA breaks that divert the cells to apoptosis as they approach the cell cycle check points. Though radiation can be focused to target the tumor, it does not completely spare the normal tissues surrounding it and leads to radiation toxicity.
In the case of cervical and prostate cancer treatment, the close proximity of mucosa-lined structures such as bowel, bladder, and rectum poses serious concerns to the oncologist when planning radiation to these tumors. The mucosa in the path of the radiation is often damaged resulting in the accumulation of inflammatory cells and the toxicity may become manifest as enteritis, colitis, cystitis, and proctitis., Radiation-induced proctitis is frequently encountered during the radiation therapy of cervical and prostate cancers. It often presents with pain and occasionally with bleeding and may affect the continuity of radiation therapy.
Proctitis may be seen acutely during the course of radiation therapy or may occur much after cessation of radiation therapy. Acute radiation proctitis usually develops during or shortly after the course of radiation therapy, and is secondary to epithelial cell loss, damage to vascular endothelial cells, acute inflammation in the lamina propria, and eosinophilic crypt abscess formation., Chronic radiation proctitis occurs months or years after completion of radiation therapy and is characterized by ischemia and bleeding secondary to vascular endothelial damage and telangiectasias. Reduced radiation dose to the rectal mucosa is beneficial in decreasing the incidence of these side effects. However, in low-income countries, particularly for the economically disadvantaged patients, conventional teletherapy is often used to treat cervical cancer. In this technique, it is often impossible to reduce the dose to the rectum. The incidence of acute radiation proctosigmoiditis after pelvic radiotherapy is between 50% and 60% immediately after radiation therapy.,
Butyrate, administered as retention enema, was found to be useful in reducing the symptoms of acute radiation proctitis., Butyrate is a short-chain fatty acid (SCFA) produced by carbohydrate fermentation in the large intestine and has multiple beneficial properties in the gut, including reduction of mucosal inflammation and facilitation of epithelial restitution following physical or chemical injury.,,,, Luminal concentrations of butyrate in the colon can be augmented by increasing the intake of amylase-resistant starch, which escapes digestion in the small intestine and is fermented by colonic bacteria to SCFA. Oral administration of amylase-resistant starch increases faecal butyrate concentration both in health and in diarrheal disease.,
We hypothesized that daily administration of high-amylose maize starch (HAMS), containing a high proportion of amylase-resistant starch, would prevent symptomatic radiation proctitis in patients undergoing pelvic radiation therapy for carcinoma of the cervix, and undertook a clinical trial to test this hypothesis.
| > Methods|| |
Study design and participants
This double-blind, randomized clinical trial was registered at the Clinical Trials Registry of India and conducted at a single institution. The study protocol and consent forms were approved by the institutional review board, and all patients gave written informed consent.
To be eligible to be part of the study, patients had to be women aged between 18 and 70, diagnosed with carcinoma cervix Stage IIB–IVA, and who had been planned to undergo radical treatment with chemoradiotherapy. Patients were excluded from the study if they had preexisting gastrointestinal disorders such as Crohn's disease, ulcerative colitis, or irritable bowel syndrome. Other exclusion criteria were rectal extension of carcinoma, intestinal obstruction, previous diversion surgery of the colon, and previous pelvic irradiation. Between August 2011 and April 2014, eligible patients were randomized into two groups to receive digestible starch and nondigestible amylase-resistant starch. The study design is shown schematically in [Figure 1]a.
|Figure 1: (a) Summary of trial design. (b) Consolidated Standards of Reporting Trials flow diagram indicating participant flow in the study|
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Standard radiotherapy protocol followed for the patients was 50 Gy in 25 fractions prescribed to 95% isodose delivered over 5 weeks using the four-field box technique with shaped beams. Shielding in conventional box fields was limited to standard corner shields for anteroposterior-posteroanterior fields and anteroinferior and posterosuperior corner shields for lateral fields. Midline shields were not included for any of the patients in the study. Weekly concurrent chemotherapy with 40 mg/m 2 cisplatin (3–4 cycles) followed by low-dose rate or high-dose rate brachytherapy boost was delivered. The chemotherapy was limited to four cycles of cisplatin as per the standard practice at the institution at the time of conduct of the trial. This also ensured uniform chemotherapy cycles in both groups. The patients were treated with cobalt 60 gamma rays or 6 MV/15 MV beams from a linear accelerator.
The patients were randomly assigned into blocks of 10 using the “ralloc” module from the STATA software (StataCorp LLC, Texas, USA). In each block, the patients were assigned the randomization codes (A or B), and the allocation was concealed in a sealed envelope that was held with the biostatistician. Treatment allocation was concealed from both the patient and the clinician, with only the study dietician being aware of the choice. The randomization codes were broken only after the data analysis by the biostatistician.
The intervention group received 30 g of HAMS (Hylon VII, National Starch, UK) twice daily, whereas the control group received 30 g of commercially available maize starch (Weikfield Products, India) twice daily. Hylon VII contained 72% amylose, whereas regular maize starch contains around 25% amylose. The high amylose content of Hylon VII makes it quite resistant to amylase digestion. Under appropriate in vitro conditions, it has been shown that 88% of regular maize starch can be digested by alpha-amylase, whereas only 30% of Hylon VII is digested under the same conditions., Both starches were mixed with 150 ml milk or water and administered orally every day during the course of radiotherapy. The study dietician supervised the administration of starch based on the allocation of the patient and ensured compliance and documented noncompliance, if any. The intervention continued throughout the course of radiotherapy for 6 weeks and was stopped when radiotherapy was completed for the patient.
Clinical analysis – incidence of acute radiation proctitis
The investigator recorded the bowel toxicity of the patients through the course of therapy, using Common Toxicity Criteria version 3.0 and Radiation Therapy Oncology Group toxicity scales., The severity of diarrhoea and proctitis was documented at baseline, throughout the treatment, and at the first follow-up. These were compared across the two randomized groups and analyzed.
Biochemical analysis – Fecal short-chain fatty acid estimation
Four sets of stool samples were collected from the patients at different time points – baseline, at 2nd and 4th weeks during radiation, and 6 weeks after completing therapy. Fecal samples were transported immediately to the laboratory and stored at −80°C. At the time of analysis, they were removed from the freezer and diluted using saline to a 20% homogenate solution based on the wet weight (wt/vol). To 500 μl of the fecal homogenate, an equal volume of internal standard solution containing isobutyric acid and isovaleric acid was added. Then, a 500 μl of the mixture was treated with 75 μl of 6M sodium hydroxide solution for hydrolysis and incubated at room temperature for 2 h with mixing at every 30 min. The pH of the mixture was adjusted to 2 using phosphoric acid, and the mixture centrifuged for 10 min at 12,000 rcf in a cooling centrifuge. The clear supernatant was transferred into a gas chromatography vial and then loaded into an auto-sampler. The SCFA analysis was carried out using a gas chromatograph coupled to a mass spectrometer (gas chromatography–mass spectrometry [GCMS]-QP2010 plus, Shimadzu, Japan) using Stabilwax-DA capillary column (Restek ® Japan). Before the SCFA analysis of the fecal samples, the calibration method file was created using standards of acetic acid, propionic acid, and butyric acid along with internal standards isobutyric acid and isovaleric acid. 1 μl of the fecal samples were injected into GCMS and analyzed using the previously created calibration file. The quantitation was carried out using the proprietary software provided by the instrument manufacturer. The quantitative values were adjusted for the initial dilution by multiplying with a factor of 5. The quantitative values were expressed as μmoles/g wet weight of the fecal sample. The stool fatty acid concentration was analyzed for both groups. A full analysis of data of stool fatty acid concentration for the study and control groups was conducted after data collection was completed.
Microbiological analysis – Pattern of fecal micobiota
We investigated whether pelvic radiation for carcinoma of cervix may cause aberration to the gut microbiota during and after radiotherapy, and whether resistant starch supplementation would ameliorate this effect. Fecal samples collected from all the study patients at sequential time points were stored at −80°C. Paired fecal samples representing basal (0 week) and postfeeding (4th or 6th week) samples were taken for analysis. DNA was isolated from the samples using double-bead beating coupled with QIAamp DNA Stool Mini Kit (Qiagen, Germantown, MD) and checked for quality and quantified using Qubit dsDNA BR assay kits (Invitrogen, Carlsbad, CA) in a Qubit fluorometer (Invitrogen) and until analysis stored at −20°C. Fecal DNA was subjected to quantitative polymerase chain reaction (PCR) using primers [Table 1] targeted at 16s rRNA genes specific to microbial communities at the species, genus, or group level.,,,, The microbial communities targeted include Atopobium genus, Bacteroides-Prevotella group, Bifidobacterium genus, Clostridium coccoides up, Escherichia More Details coli, Faecalibacterium prausnitzii, and Lactobacillus group. These microbial communities were targeted because of their significance to human health. The DNA sequence of interest was amplified using SYBR green Master Mix (Eurogentec, Liege, Belgium) in Chromo4 instrument (Bio-Rad, CA, USA). DNA of bacteria of interest was expressed as the relative abundance, relative to the amplification of “universal” DNA sequences, conserved throughout the domain bacteria. Melting curve analysis was always done to check specificity of the amplification. PCR conditions and results were expressed as described by Kabeerdoss et al. Quantitative patterns of microbial communities were computed to understand the interrelationship between changes in microbiome before, during, and after radiation treatment and resistant starch supplementation.
|Table 1: Primers used for quantitative PCR amplification of the bacterial communities|
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Assuming 35% baseline incidence of acute proctitis in the group of patients recruited in the trial (a conservative estimate based on the reported incidence of 50%–60%,), and assuming a desired effect of 25% reduction in the incidence of proctitis in the treatment group, with alpha of 0.05 and beta of 20% (80% power), the required sample size per group was calculated as 43. Allowing for dropouts, we planned to recruit fifty patients in each arm, with a total sample size of 100.
The primary outcomes were change in the proctitis score and diarrhea score, and these were classified as dichotomous variables both below Grade 2, or Grade 2 and above. The change of grade over time between the two groups was compared. Generalized estimated equations analysis was used to find the change between time points for the two types of starch. The secondary outcomes were fecal SCFA concentration and microbial community abundance calculated as relative difference proportion, both of which were treated as continuous variables.
| > Results|| |
The study was designed to recruit 100 patients, 50 each in intervention and control arms, over a period of 2 years. The study did achieve the planned recruitment. Although the study was expected to be completed within 2 years, it was extended because of delay in the start of recruitment. There were no major setbacks in the planned conduct. The compliance of all patients to the intervention and the control was more than 80%, and this was monitored by the dietician. There were two patients who progressed in their disease, carcinoma cervix, and succumbed to it, and hence they were ineligible for analyses. They did not complete the planned intervention or follow-up. There were two others who after recruitment and start of intervention decided to opt out of the trial due to personal reasons. They continued their treatment outside the trial and completed it. The participants' demographics are shown in [Table 2].
|Table 2: Patient demographics: Women with Stage IIB-IVA cervical cancer scheduled for radical chemo-radiotherapy were recruited|
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The enrolled patients were randomly assigned to receive either resistant or digestible starch [Figure 1]a. [Figure 1]b shows the trial profile in a Consolidated Standards of Reporting Trials statement. The study screened 160 patients from August 2011 to April 2014, and 104 eligible patients were enrolled to the trial.
[Table 3] shows the incidence of clinical proctitis, functional proctitis, and diarrhea at baseline and followed up until 6 weeks post intervention. The severity of clinical proctitis was found to be similar in both groups of patients, with 12.2% of patients experiencing Grade 2 and above toxicity in control group versus 14.6% in the intervention group. There was no significant difference between digestible and nondigestible starch groups at any stage of treatment. The test of significance revealed P = 0.094. Functional proctitis was similarly graded, and it was found that 16.3% patients in digestible starch group reported Grade 2 and above toxicity, whereas 10.2% patients in the amylase-resistant starch group reported the same at the 4th week. This difference continued in the subsequent weeks till the end of radiation, but both groups had similar toxicity at 6 weeks post intervention [Table 3]. The severity of diarrhea during the radiotherapy was also recorded for both groups. Both groups were found to have similar incidence of Grade 2 and above diarrhea. The nondigestible starch group was found to have 8% incidence as compared to 2% in the other group at the 5th and 6th weeks.
|Table 3: A summary of outcomes/efficacy measures and the number of patients with Grade 2 or more toxicity is mentioned across the different time points for both the study arms|
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[Figure 2]a shows the patterns of the estimated commensals across time points and between two groups. The predominant microbe at each time point in each sample in both groups of patients is presented as a snapshot in [Figure 2]b.
|Figure 2: (a) Dominant microbial community in both arms across the four time points. (b) Predominant microbial pattern at four time points baseline (1), week 2 (2), week 4 (3), and post treatment (4) in two allocation Groups A (digestible starch) and B (resistant starch). The predominant group of bacteria in each sample at a given time point is plotted|
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[Figure 3] shows fecal SCFA concentration in the two groups over the course of the study. Although propionate and acetate concentration showed some difference, the butyrate concentrations remained similar for both groups' at all four time points.
|Figure 3: Fecal concentrations of acetate, propionate, and butyrate in the two trial arms at different time points through the course of the study. Values shown are mean (standard error)|
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The predominant microbial communities in the gut were estimated quantitative PCR of 16s rRNA gene targets and the relative abundance of each microbial community before and after ingestion of digestible or resistant starch show no statistically significant difference [Figure 4].
|Figure 4: Seven microbial communities or classes were estimated by quantitative polymerase chain reaction of 16S rRNA gene targets as described, and the relative abundance of each microbial community was expressed as the relative difference (Y axis) relative to quantification of universal sequences belonging to domain bacteria. This composite graph shows the relative abundance of each microbial community beforeand after 4–6 weeks of ingestion of digestible starch or resistant starch. None of the differences between pre-and post feeding samples was statistically significantly different (Wilcoxon-paired rank test)|
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None of the participants reported adverse events with either starch. Grade 1 nausea and vomiting was reported; however, none of the patients required intervention for these events.
| > Discussion|| |
This clinical trial joins a list of studies which have attempted to prevent or ameliorate radiation proctitis in individuals undergoing pelvic radiation therapy. The rationale behind this study was that oral resistant starch, by providing a substrate for the colonic generation of butyrate, would prevent radiation proctitis. However, we did not find a significant effect of the starch in preventing or ameliorating acute radiation proctitis.
Butyrate has a marked cytoprotective effect on the colorectal mucosa and epithelium.,,, Several trials in the literature have evaluated the utility of butyrate enemas in acute radiation proctitis. In a small (12 patients) crossover pilot study, butyrate enemas did not have a therapeutic effect in radiation proctitis. On the other hand, an randomized controlled trail (RCT) demonstrated clinical benefit of butyrate enemas in ameliorating symptoms, endoscopic findings, and histology in twenty patients with acute radiation proctitis, while another RCT demonstrated clinical benefit in 19 patients with chronic radiation proctitis. One preliminary report suggested that butyrate enemas prevented the development of radiation proctitis, but a larger trial recruiting 166 patients did not find any preventive effect of butyrate enemas in the prevention of acute radiation proctitis. As amylase-resistant starch is broken down to SCFA including butyrate in the colon, we had hoped that administration of oral amylase-resistant starch (HAMS) would result in the prevention or amelioration of radiation proctitis, but this was not borne out by the present study.
HAMS contains a high proportion of amylose and because of its high amylose content, it is estimated that about two-thirds of the starch in HAMS escapes amylase digestion. By contrast, only 20% of the control intervention – corn flour – is likely to escape small intestinal digestion. As the dose of starch was 60 g/day, it follows that perhaps 40 g of resistant starch in the HAMS arm would be matched with 12 g of resistant starch in the control arm. Whether this provided sufficient substrate for adequate butyrate generation will remain unanswered. Fecal butyrate concentrations were similar in both groups of participants. However, even if butyrate had been generated by HAMS, it is likely to have been rapidly absorbed by the colonic epithelium as it is well known that SCFA is rapidly absorbed from the colon and only a fraction of the SCFA production is excreted in stool. Butyrylated HAMS is more effective in raising colonic luminal butyrate levels than HAMS,, and may be potentially considered in future trials.
The study was designed to find a 25% reduction in the incidence of toxicity in the intervention arm, assuming a baseline incidence of 35%. In retrospect, this could be considered as an overestimate or the incidence of toxicity could have been lower in both arms due to a daily intake of starch. An improved nutrition in both groups of patients in the study setting, while supervised by dietician, would have resulted in a global reduction of toxicity. This prompts us to suggest that a third arm with no dietary intervention should have been planned ahead. Overall, of the 50 participants in each arm, 17 patients in each arm experienced diarrhea of some grade; 15 participants in the digestible starch arm and 12 in the resistant starch arm had some degree of mucositis; and 19 in the digestible starch arm and 12 in the resistant starch arm developed some degree of proctitis. The percentage of patients developing some degree of proctitis was in line with our projected expectation prior to the study.
To our knowledge, the initiative to establish the profile of fecal bacterial flora in the intestine pre- and postradiotherapy is the first of its kind. In 2016, Venkataraman et al. have reported an increase in the concentration of colonic butyrate and fecal butyrate levels when resistant starch type 2 was fed to twenty healthy volunteers. They have also reported an increase in the growth of beneficial gut microbiome. However, this has not been observed in our study in a set of patients undergoing treatment.
There were some limitations to the study. Perhaps, the differences between the two arms were dampened by the fact that we used another starch in the control group. It is possible that the use of vehicle alone without starch in the control arm could have provided evidence of some benefit. Second, as far at the microbiome analysis is concerned, we did not use next-generation sequencing, but instead used targeted real-time PCR assays. This could have led to nondetection of microbiota changes in the intervention arm compared to control arm. The collection of stool samples and transport posed technical difficulties that led to only 50% compliance in the cohort. The stools were frozen within 30 min of the sample collection. We acknowledge that time-dependent changes can affect SCFA concentration and the flora. However, as the groups were randomized and the difference between the groups was studied, this effect should be similar in both the arms. The study was originally powered to show a difference of 25%. As the intake of dietary starch would not be very easy for most patients, taking into consideration the potential additional costs and compliance to the supplementation, the team intended to set 25% as the quantum of difference to warrant a daily dietary intake of starch. Therefore, differences lesser than 25%, if any, could not be studied and reported.
The effects of radiation continue well beyond the completion of radiotherapy. Hence, ideally, the starch supplementation should have continued for another 6 weeks post radiation. However, the difficultly to continue monitored supplementation for the dietary intervention beyond 6 weeks when majority of the patients return to their hometown before the first review was strongly considered. To avoid loss of data points at analyses due to noncompliance and to reduce nonuniformity of starch intake among the two groups, the intervention was limited to the duration of radiotherapy. This study was also not designed to assess the effects due to late toxicity, as we were unsure about follow-up beyond the first review post radiation treatment.
| > Conclusion|| |
The study aimed to look at the benefit of prebiotic starch in reducing the incidence of acute radiation proctitis, a distressing symptom in patients receiving radiation therapy for cancer of the cervix. The study did achieve the planned recruitment objective. However, it did not show any significant difference in the incidence of proctitis or diarrhea or pain in both the study and control groups. There was no difference in stool SCFA concentrations in both arms either. There was a general decrease in the incidence of toxicity in both groups as compared to earlier estimates, which could be attributed to increased intake of starch, but this could not be established by this trial. The knowledge of the pattern of change in quality and quantity of microbiome in the bowel during radiation may help us introduce better prebiotic/probiotic supplements in future.
BS acknowledges Dr. Venkata Krishna Reddy, Dr. Sunitha Susan Varghese, Ms. Lavanya B, and Ms. Babee Ann Varghese for their help in the conduct of this trial.
Financial support and sponsorship
Department of Biotechnology, Ministry of Science and Technology, Government of India supported this clinical trial.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]