INTRODUCTION:

The uncontrolled proliferation or growth as well as the spread of the cells are known as cancer. Cancer can affect any part of the human body¹. For the treatment of pelvic cancer, radiotherapy or chemotherapy or a combination of both are also taken into consideration. Surgery is also considered at times. Radiotherapy or radiation therapy is a type of cancer treatment modality that uses beams of intense energy like ionising radiation in order to kill the malignant tumor cells².

Received on 28.07.2020 Modified on 30.09.2020

Research J. Pharm. and Tech. 2021; 14(8):4029-4034.

DOI: 10.52711/0974-360X.2021.00698

Various urological, gastrointestinal as well as gynecological cancers can be treated by pelvic radiotherapy. Pelvic radiotherapy however plays a significant role in the treatment of female and male malignancies such as anal, rectal, prostate, vulva, cervix, endometrium, vagina and ovary³.

During the treatment of radiotherapy to the tumors of the pelvic as well as abdomen, the important organ at high risk is the intestine. Apart from other organs, toxicity due to intestinal radiation can be categorized as acute (early) which occurs during the treatment or within 3 months of the radiotherapy treatment as well as chronic (delayed) that occurs after the 3 months of the radiotherapy⁴. Acute symptoms consist of diarrhea, nausea, abdominal pain, rectal bleeding, bloating, and urgency which usually occur during the second week of the radiotherapy treatment and peaks within four to five weeks of the treatment⁵. Chronic symptoms consists of fecal incontinence, flatulence, urgency, abdominal pain and rectal bleeding which occurs after the acute symptoms or can occur on their own after the continued treatment with radiotherapy⁶. The symptoms after radiation usually arises because there will be an alteration in one or more than one physiological functions in different parts of the gastrointestinal tract that rest in the pathway of the radiotherapy beam^7,8.

One of the methods to manage radiation induced gastro-intestinal symptoms is by modifying the diet. Dietary modification aims at limiting the acute inflammatory processes so that the subsequent fibrotic processes can be inhibited. In order to achieve this, manipulation of fat, fibre, and lactose in diet is advocated. In case of fat, low or modified fat diet is preferred. Foods low in long chain triglycerides must be taken. Low fibre content in food is preferred to reduce bloating. Exposure to intestinal irradiation may result in severe damage to the intestinal villi.^9,10. Lactose restriction is also advised because as a result of radiotherapy, there is a damage to the mucosa of the intestine and hence breakdown of brush border enzymes, in this case, lactase¹¹. Many studies have proved that lactose and fibre-confined diet have diminished the radiotherapy induced gastrointestinal toxicity in patients undergoing pelvic radiotherapy^12,13,14,15. Elemental nutrition formula can be provided to patients which supplies proteins as peptides or amino acids, carbohydrates largely as maltodextrins and fats primarily as medium chain triglycerides^16,17,18.

Patients receiving pelvic radiotherapy may experience many side effects which can significantly affect their Quality of Life. Some of the major side effects due to radiotherapy may include radiation enteritis^19,20,21 along with diarrhea and abdominal pain which can further affect the quality of life of patients^22,23,24,25. Radiation induced nausea and vomiting also influence the quality of life of patients^26,27,28,29. Pelvic irradiation may cause constipation and diarrhea which also have significant impact on the quality of life of patients^19,20,21.

MATERIALS AND METHODS:

The study period was from August 2018 to April 2019 and data collection form was carried out for a period of six months from September 2018 to March 2019 at the Radiation Oncology Department, Amrita Institute of Medical Sciences and Research Centre, Kochi.

Study Patients:

We selected patients who were diagnosed with prostate and rectal cancer, patients with gynecologic malignancies (endometrium, cervix, vagina, ovary), patients referred to local curative radiotherapy and those patients receiving neo-adjuvant chemo-radiotherapy of rectum with a dose of 50Gy in 25 fractions or Carcinoma prostate radiation therapy in patients involving pelvic nodal irradiation with a dose of 50.4Gy in 28 fractions or carcinoma of endometrium, cervix, vagina or ovary with a dose of 50Gy in 25 fractions. We excluded those patients diagnosed with inflammatory bowel diseases, patients with cognitive function impairment and those patients who are unwilling to give consent form. A total of 106 eligible patients participated in our study who satisfied the inclusion-exclusion criteria.

Study Description:

We conducted observational prospective follow up study on the effect of dietary modification in decreasing the radiation induced acute gastrointestinal toxicity. The patients were selected based upon the inclusion and exclusion criteria. A standard dietary instruction was provided to the patients by the physician, before initiation of radiotherapy. Patients continued their normal diet but distinction was made between foods that should be eaten and foods to be avoided (high fat, high fibre (insoluble) and lactose restriction) in order to reduce the symptoms. Foods that could be included were moderate protein, high calorie foods, medium chain triglyceride, calcium rich food, medium fibre content. All vegetables need to be consumed in steamed or cooked form. Foods to be avoided include lactose (milk and milk products) and high fat containing foods. Curd and cheese could be taken in small quantities as they contain less lactose than milk. These patients were then assessed on a weekly basis.

In order to assess the ability of dietary modification in decreasing or delaying the acute gastrointestinal adverse events, we observed the incidence of the symptoms and graded it in accordance with the CTCAE Version 5 and RTOG (Pelvis), during the weekly follow up. Global health status, functioning as well as symptoms were evaluated using EORTC QLQ-C30 form. The patients were asked to fill the EORTC QLQ C30 questionnaire before initiation of radiotherapy and then after the completion of the treatment. The pre as well as post treatment scores within the groups were compared.

Statistical Analysis:

The collected data were compiled using Microsoft Word, Microsoft Excel and were presented in graphical format using pie chart, bar diagram etc. All the statistical analysis carried out for this study was done on SPSS software version 20.0. Descriptive statistical methods were used to calculate mean, median and range. The data were tabulated, analysed and compared with relevant studies which are described in detail in the result and discussion section.

Statistical analysis was performed using IBM SPSS version 20.0 software. Categorical variables are expressed using frequency and percentage. Continuous variables are presented using mean and standard deviation. To test the statistical significance of the mean difference in the EORTC QLQ-C30 scores before and after results, paired t-test was used.

RESULTS:

There were 106 patients in our study who satisfied the inclusion and exclusion criteria during the study period and received radiotherapy for pelvic malignancies. Table 1 shows the baseline characteristics of the selected patients.

Table 1: Study Patient’s Baseline Characteristics

Characteristics	Patients Details
Mean Age (years)	63.44 ± 10.7
Gender (%)
Male	42.50%
Female	57.50%
Mean Height (cm)	159.91±7.965
Mean Weight (kg)	63.575±9.17
Life Style (% of patinets)
Smoking	15.10%
Alcohol	11.30%
Type of Cancer (%)
Prostate	33.00%
Rectum	17.00%
Cervix	23.60%
Ovary	1.90%
Vagina	0..9%
Endometrium	23.60%
Other Treatments (%)
Chemotherapy	100%
Surgery	32.10%

Assessment of Gastrointestinal Adverse Events using RTOG Grade:

The weekly grading of the ADRs in study patients was done using RTOG grading scale in Table 3 and in Figure 3. Statistically, there was a remarkable reduction in the number of patients experiencing grade 0 toxicity from 80.2% in week 1 to 57.54% in week 4 but an increase in the number of patients experiencing grade 1 toxicity from 10.4% in week 1 to 37.73% in week 4. None of the patients experienced grade 4.

Assessment of Gastrointestinal Adverse Events based on CTCAE:

The grading of gastrointestinal adverse events in patients was done using CTCAE V 5.0. The weekly grading of 14 most commonly seen adverse events are described below:

Abdominal Distension: None of the patients who adopted dietary modifications had abdominal distension in the first week of treatment. But by the end of the treatment, 1.9% of the patients experienced abdominal pain.

Abdominal Pain: In the first week of treatment, 9.4% of the patients developed abdominal pain. By the end of fourth week, 12.5% patients had abdominal pain of grade 1 and 2

Belching: In the first week, 46.22% patients developed belching, but by the end of treatment. 57.54% patients had belching.

Bloating: During the first week of treatment, about 50% patients had bloating. But by the fourth week, 64% patients had bloating.

Constipation: During week 1, 19% patientshad constipation. By the fourth week, 20.7% patients still had constipation.

Diarrhea: During week 1, 20.7% patients had diarrhea of varying grades. By the fourth week, 33.9% patients had diarrhea.

Dyspepsia: During week 1, only 3% patients had dyspepsia. By the fourth week, about 10.3% of the patients had dyspepsia.

Flatulence: During the first week of treatment, 27% patients had flatulence. By the fourth week, 36.8% patients had flatulence.

Nausea: It was experienced by 16.9% patients in the first week of the treatment. But by the fourth week, 33.9% patients in had nausea.

Rectal Hemorrhage: During week 1, 2.8% patients had rectal hemorrhage but by the fourth week, 7.54% patients had rectal hemorrhage.

Rectal Pain: During the first week, 3.7% patients had rectal pain. By the end of the treatment, 5.6% patients had rectal pain.

Vomiting: During the first week, 3.7% patients experienced vomiting. But by the fourth week, 4.7% patients had vomiting.

Quality of Life of Study Patients:

The QOL of the patients before and after the radiotherapy was assessed using the EORTC QLQ C-30 scale. In our study patients, the mean score of global health status/QOL decreased after RT from 68.55±15.91 to 66.12±18.70, which was statistically significant (p<0.05). There was a statistically significant decrease in the physical functioning from 92.51±10.35 to 89.18±16.00 (p=0.020) and in role functioning from 95.59±11.57 to 92.13±15.80 (p=0.011). The decrease in the emotional functioning from 87.73±16.55 to 86.71±22.02 (p=0.624) and cognitive functioning from 96.06±8.77 to 94.81±13.28 (p=0.287) were clinically significant but was not statistically significant. The decrease in social functioning score from 95.59±11.33 to 91.66±16.30 was statistically significant (p=0.022). These data are represented below in Tables 5 and in Figures 3-7.

Table 4: EORTC QLQ C30 Mean Scores

Parameter	Before RT			After RT		p value
Parameter	Mean		SD	Mean	SD	p value
Global Health Status/ QOL	68.55		15.91	66.12	18.70	0.00045
Functional Scales
Physical Functioning	92.51		10.35	89.18	16.00	0.020
Role Functioning	95.59		11.57	92.13	15.80	0.011
Emotional Functioning	87.73		16.55	86.71	22.02	0.624
Cognitive Functioning	96.06		8.77	94.81	13.28	0.287
Social Functioning	95.59		11.33	91.66	16.30	0.022
Symptoms Scale
Fatigue	84.48	16.56		78.40	23.44	0.016
Nausea and Vomiting	95.75	11.28		91.82	17.09	0.027
Pain	89.62	13.88		83.96	20.81	0.011
Dyspnoea	94.65	13.90		92.45	18.56	0.276
Insomnia	85.22	24.37		83.33	21.20	0.525
Appetite Loss	89.30	20.85		83.33	21.20	0.036
Constipation	89.30	22.32		89.93	20.66	0.672
Diarrhea	94.96	15.11		87.42	24.96	0.001
Financial Difficulties	87.42	23.66		88.36	23.92	0.670

DISCUSSION:

To our knowledge, there are only a few dietary modification studies that are concerned with decreasing the gastrointestinal side effects after radiotherapy. Our study was designed to assess the effect of dietary modifications in reducing the radiation induced acute gastrointestinal toxicities. The departmental dietary counseling provided to the patients was in compliance with the limited number of studies that assessed the efficiency of dietary intervention that could reduce the gastrointestinal adverse events in patients receiving pelvic radiotherapy^15,16,17,18.

The maximum RTOG score obtained during week 1 was 3 but from week 2 to 4, the maximum score obtained was 2. Even though the maximum score was 2, the only 8.5% of the patients had score 2. 80.2% of the patients were having score 0, which indicate diet modification could control the adverse events in study patients. In a study conducted by McGough et al³⁰, the maximum score obtained at any point of time was 2.

Earlier published studies suggest that, without any intervention patients experience higher grades of gastrointestinal adverse events during and by the end of radiotherapy. We assessed 12 most commonly reported symptoms by the patients and graded it as per CTCAE v.5.

Radiation induced diarrhea is one of the major potential lethal complication of radiotherapy for pelvic cancers. One of the reasons for radiation induced diarrhea is lactose malabsorption leading to osmotic diarrhea. Too much of fibre in the diet can increase the fecal mass also. Hence limiting the fibre and lactose might be the reason for the lower prevalence of people with diarrhea. In a study conducted by Pettersson A et al³², by the fourth week of RT, 30% of the study patients had diarrhea. In contradictory to these studies, Stryker JA et al³³ demonstrated a failure of lactose restricted diet to prevent radiation induced diarrhea. Their study suggest that lactose malabsorption might not be a significant factor contributing to the radiation induced diarrhea and bile acid malabsorption probably might be one reason of diarrhea. They suggest that diarrhea might be occurring due to damage to colon and rectum.

Bloating might be the reason of acute epithelial damage resulted from radiation. In the study conducted by Pettersson A et al³², 33% of the patients had bloated abdomen during the fourth week of RT which was contrary to our result. In our study, most patients developed nausea. Unlike our study result, in a study conducted by Ravasco P et al³⁴, by the end of RT, 72.9% of the patients had grade 1 nausea and 18.9% of the patients had grade 2 nausea. Grade 3 and 4 nausea was not observed anytime during our study which was similar to the observations from the study conducted by Ravasco P et al³⁴.

The quality of life of the patients is a major factor to be considered during a disease time or treatment, because the symptoms can negatively affect the QOL of patients. In our study, the quality of life of patients has decreased after the radiotherapy significantly (p=0.00045). All the functional scale scores have also decreased after RT. In a study conducted by Pettersson A et al³², the prevalence of symptoms post radiotherapy was higher when compared to baseline, i.e., the QOL decreased. They concluded in their study that the dietary modification did not have an effect on QOL. Isenring EA et al³¹, in his study explained that physical functioning can impact the QOL of patients due to its impact on activities of daily living and in his study, contrary to ours, the QOL of the patients had increased. Ravasco P et al³⁴, showed in their study that dietary counselling improved all the QOL function scores due to adequate dietary intake and nutritional status.

The study patients showed a statistically significant reduction in the Global Health Status/QOL (p=0.00045) which indicates that the quality of life of the study patients has significantly reduced. The study patients also showed reduction in the physical functioning (p=0.020) and social functioning (p=0.022) scales after RT but were statistically significant. There was a reduction in the role functioning (p=0.011) and was statistically significant whereas cognitive functioning showed a reduction but they were not statistically significant. There was a reduction in the emotional functioning scale but was statistically insignificant. There was tremendous improvement in the symptoms scale and showed a mean reduction of symptoms including pain, fatigue, insomnia, nausea and vomiting, appetite loss, dyspnoea, constipation, diarrhea. Out of all these symptoms, fatigue (p=0.016), nausea and vomiting (p=0.027), pain (p=0.011), appetite loss (p=0.036) and diarrhea (p=0.001) was statistically significant. The characteristic problems and certain bowel symptoms did not completely recover at the last assessment. These variations in functioning and symptoms showed an association with the radiotherapy.

CONCLUSION:

Radiotherapy to the pelvis is associated with many acute gastrointestinal adverse events in patients. Our study demonstrates that dietary modifications appear to be promising option to control these adverse events. The dietary restriction of fat, fibre and lactose also helped in reducing the grades of adverse events during the radiotherapy. In study patients, the QOL life was found to be decreased when compared to the baseline. Even though they couldn’t completely prevent moderate to severe adverse events, we suggest that diet modification are beneficial in reducing the severity of symptoms. With limited number of studies conducted till date, our study will provide a light to the present scenario of gastrointestinal adverse events occurring from pelvic radiotherapy and for future studies in this field. The results from our study can provide a preliminary data for the future studies to be conducted in the Indian population.

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