The Effect of Locally Made Nutritional Supplementation on Cancer Cachexia in Bangladesh: A Quasi-experimental Study.

Cancer is one of the major societal, public health, and economic problems of the 21st century. It encompasses a diverse group of diseases characterized by uncontrolled proliferation of abnormal cells, which can invade surrounding tissues and metastasize to distant organs. Despite advances in diagnostic modalities and therapeutic interventions, the burden of cancer continues to rise, particularly in low- and middle-income countries (LMICs). The global burden of cancer presents a formidable challenge to public health in the 21st century. According to the International Agency for Research on Cancer, the world witnessed approximately 20 million new cancer cases and 9.7 million deaths attributed to cancer in 2022 . In the South-East Asia region cancer also poses a significant public health challenge. In 2022, World Health Organization (WHO) reported approximately 2.37 million new cancer cases and 1.53 million deaths attributed to the disease in the South-East Asia region. Moreover, the burden of cancer is projected to rise, with an increase of new cases by 85.7% by 2050. According to estimates from the World Health Organization (WHO), the leading causes of cancer-related mortality worldwide in 2020 were lung cancer (1.80 million deaths), followed by colorectal cancer (916,000 deaths), liver cancer (830,000 deaths), stomach cancer (769,000 deaths), and breast cancer (685,000 deaths). Solid tumors accounts for approximately 90% of adult human cancer. Surgery is often the primary treatment for solid tumors, especially in early stages. It is estimated that by 2030 annually 45 million surgical procedures will be needed worldwide.

With a population of 171.2 million, Bangladesh is the world's eighth most populous country. The Global Cancer Observatory reported 156,775 new cancer cases and 108,990 cancer-related deaths occurred in Bangladesh in 2020. The age-standardized rates of 106.2 and 75.3 per 100,000 for cancer incidence and mortality, respectively.

As cancer prevalence increases, so does the incidence of cancer-associated complications, among which cancer cachexia is one of the most significant.

Cancer cachexia is a multifactorial syndrome characterized by progressive weight loss, skeletal muscle wasting and metabolic dysregulation in patients with cancer. It has been reported that conventional nutritional supplementation alone is not enough to combat cancer cachexia. Recent research has highlighted the potential role of specialized nutritional strategies in mitigating the impact of cancer cachexia. A positive protein balance is required to increase skeletal muscle mass. A recent study showed that patients with low serum albumin level had markedly poorer prognosis than those in the high serum marker group. Consistent with this, the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend a daily protein intake should be 1.0-1.5 gm/kg. In terms of multivitamin, vitamin B complex plays a crucial role in managing cancer cachexia. Vitamin B particularly B3 (niacin), B6, and B12, are essential cofactors for various enzymes involved in energy production and metabolism. Studies showed that decreased levels of B vitamin-related enzymes in the liver, along with alterations in one-carbon metabolism, are hallmarks of cancer cachexia.

The National Institute of Cancer Research & Hospital (NICRH) is a 500-bed tertiary specialized located in Dhaka, Bangladesh. NICRH is the only government hospital, dedicated to comprehensive cancer care, education, and research. They offer a comprehensive range of specialties including surgical oncology, radiation oncology, medical oncology, cytopathology, histopathology. The department of surgical oncology provides surgical interventions for various cancers. Surgical patients typically stay in the hospital for 15 to 20 days. These patients often present after prolonged periods of inadequate nutritional intake, frequently with hypoalbuminemia. In the context of limited access to advanced nutritional support, many patients at NICRH infrequently consume rice water mixed with egg as a locally available nutritional supplement. This low-cost locally developed nutritional formula improve energy intake and protein status. Rice starch water is culturally accepted, low cost, easily digestible source of complex carbohydrate. Unlike milk, rice-based water avoids lactose intolerance and is less likely to provoke nausea/vomiting. It also provides hydration and a slow-release energy source critical for cachectic patients with poor appetite. Moreover, the effectiveness of this combination remains uncertain, particularly in terms of essential micronutrients. The purpose of this study is to analyse the role of evidence-based nutritional interventions in cancer cachexia with an affordable cost.

Study design - This study will employ a quasi-experimental design with a control arm.

Study site - Surgical oncology ward, National Institute of Cancer Research & Hospital (NICRH).

Study population - The investigator will recruit patients with cancer cachexia admitted to the surgical oncology ward at the National Institute of Cancer Research & Hospital (NICRH).

Study duration- 12 months.

Eligibility Criteria Screening will be conducted among the hospitalised patients. Inclusion criteria-

1. Age- ≥18 years.
2. Either sex
3. Diagnosed case of cancer who met Fearon et al's criteria for cancer cachexia.
4. Informed written consent.

Exclusion criteria-

1. Patients with severe organ dysfunction, such as renal failure (chronic kidney disease stage 4 and above), advanced hepatic failure (child-pugh score class B or C), severe cardiac dysfunction (heart failure, arrythmia, acute coronary syndrome).
2. Patient with stage 4 (metastasis) cancer
3. Patients with active gastrointestinal obstruction or any complication that will interfere with oral and tube feeding.
4. Patients who are already getting commercially available nutritional formula or multivitamin, multimineral therapy.
5. Patients with a recent history (e.g., <3 months) of participation in another nutritional intervention study.
6. Patients who require exclusive parenteral feeding.
7. Patients with a known allergy to egg protein.

Study procedure: This is a proposal for a quasi-experimental study design to determine effect of locally made formula to combat cancer related cachexia among the patients in National Institute of Cancer Research & Hospital (NICRH).The patients will be recruited from surgical oncology department. Surgical oncology department has four wards for their patient management. All the patients fulfilling the inclusion and exclusion criteria will be our study participant. Participants will be enrolled consecutively from the four eligible wards. To minimize contamination, two wards will be designated a priori as intervention wards and two as control wards for the half of recruitment period. After 50% of patient enrolment, there will be a swap of the intervention and control wards. Upon discharging the 50th patient from the respective wards, a washout period of 2-3 days before swapping the interventions will be implemented. If a new patient is admitted to an intervention ward shortly before a scheduled swap day (e.g., two days prior), investigator will defer the swap. That patient will first complete their full scheduled intervention period before proceeding with the washout and ward swap.All eligible patients admitted to the intervention wards will receive the nutritional intervention in addition to standard care, while all eligible patients admitted to the control wards will receive standard care only. Ward designation will be finalized before enrolment begins and will not be changed during the study; baseline characteristics will be compared between groups and key prognostic variables will be adjusted for in the primary analysis. The baseline blood parameters (serum haemoglobin, serum albumin) and quality of life measurements will be collected before the nutritional intervention and follow-up measurements will be taken after the intervention. Eligibility criteria, screening procedures, laboratory methods, and outcome assessment will be identical for both groups.

Nutritional assessment and Study intervention: In this Fearon et al's criteria will be used for diagnosing and enrolment for our study. This criterion has following points- Table 01 - Fearon's criteria with translation in the study

Fearon et al's criteria Translation in our study Weight loss >5% in past 6 months without starvation and/or Weight loss >2% with either BMI<20 or sarcopenia Modified Sarcopenia Scoring System (Based on European Working Group on Sarcopenia in Older People (EWGSOP2))

After initial screening those who have cachexia as per Fearon et al's criteria, will be approached for participation. The investigator or his/her representative will explain the study to the participants and answer all questions regarding the study. The participants must be informed that their participation is voluntary. Participant will be told that they are free to refuse to participate or withdraw their consent at any time and for any reason during the study period. After enrolment, a locally made formula, consisting of rice starch water, egg, multivitamins, multimineral will be administered to patients. Rice starch water is the liquid that remains after boiling rice. To prepare a moderate to thick consistency, approximately 2.5 to 3 litres of water are mixed with 1 kilogram of rice before boiling. After boiling, around 700 millilitres of moderate to thick rice starch water can be collected.

After collecting rice starch water from the kitchen, egg and multivitamin, multimineral will be added by our trained health workers. The formula will be heated and blended to ensure proper mixture. Our trained health worker will involve every step and will ensure feeding within two hours of cooking. Proper hygiene will be maintained during the food preparation and distribution. In intervention arm, each patient will receive 500 ml of this liquid preparation two times daily for 14 days along with the hospital diet. The control arm will receive the hospital diet.

Investigations:

Biomarkers Serum albumin and haemoglobin are recognized biomarker for cancer cachexia, with lower levels often correlating with the severity of the condition. To assess the biomarker study endpoints, serum samples will be collected from the participants at the beginning and endpoint of the study in both control and intervention group. These serum samples will be tested for serum albumin and serum haemoglobin level. The maximum amount of blood collected from each participant will not exceed approximately 6ml at a given time.

Quality of life assessments - One of our outcome variables is sense of wellbeing. Sense of wellbeing will be measured by functional assessment of anorexia/cachexia treatment (FAACT) questioner. It was developed and tested by the functional assessment of chronic illness therapy (FACIT) group. FAACT was designed to measure general aspects of quality of life (QOL) as well as specific anorexia/cachexia-related concerns.

It includes the 27-item functional assessment of cancer therapy-general (FACT-G) and a 12-item subscale that specifically measures the symptoms and concerns of patients with anorexia/cachexia (A/CS). Patients rate each item from 0 to 4 (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; and 4 = very much). FAACT anorexia/cachexia-specific subscale ranges from 0-4, the range of possible scores is 0-48, with 0 being the worst possible score and 48 the best. To obtain the 0-48 score each negatively worded item response is recoded so that 0 is a negative response and 4 is a favourable response. All responses will be added with equal weight to obtain the total score. FAACT scales having a high score is good.

Sample size -

The sample size was calculated based on the primary outcomes, serum albumin and serum haemoglobin, with serum albumin used as the reference variable for estimation. Effect size assumptions were informed by a previous intervention study conducted in a comparable population (n = 60) with cancer cachexia, where the mean (SD) values of albumin increased from 33.2 (5.4) at baseline to 35.3 (2.9) post-intervention. Assuming a within-subject correlation coefficient of 0.6, the standardized effect size (Cohen's d) was estimated to be 0.48.

For the proposed study, a similar effect size was anticipated. Sample size estimation was performed using an analysis of covariance (ANCOVA) framework, with post-intervention serum albumin as the outcome and baseline serum albumin included as a covariate. The calculation assumed 80% statistical power, a two-sided alpha level of 0.05, an effect size of 0.48, one covariate, and a correlation coefficient of 0.6 between baseline and follow-up measurements. Using the pwr package in R, the required sample size to detect this effect is 45 participants per group.

To account for an anticipated attrition rate of 15%, the sample size is inflated to 53 participants per group, resulting in a total required sample size of 106 participants.

Outcome measures/variables:

Primary: Mean change in serum albumin and haemoglobin after supplementation.

Secondary:

Change in Body mass index (BMI) (kg/m²) Change in quality of life score from baseline to end line. Proportion rating acceptability of the diet Incidence of gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal pain), Mean change in daily energy intake (kilocalories/day) and protein intake (gm/kg/day) from baseline to the end line

Data analysis - Data will be entered into STATA (Version 15) or IBM SPSS (Version 25) from the pre-tested clinical record forms (CRFs). The socio-demographic characteristics of the study population, including age, sex, residence, education, family income, body weight, serum albumin, serum hemoglobin, quality of life score will be described.

The categorical variables will be reported as frequency (%). Distribution of the continuous variables will be examined using histogram and Shapiro-Wilk test. Continuous variables will be reported using mean with standard deviation (SD) or median with interquartile range (IQR), based on the type of distribution. During bi-variate analysis for categorical variables. Chi-square test or Fisher's exact test, and asymptomatic McNemar's test or exact McNemar's test will be applied where as appropriate. For continuous variables, ANCOVA will be applied with baseline information as covariate.

The current study will also use a multiple linear regression model to explore association between the dependent and independent variables. Covariates will be selected based on theoretical relevance and bi-variate screening with a p-value <0.25 considered as significant. To account for the ward-specific and time-specific effects, these variables will be included in the model. However, due to a small sample size (n=106), exploring interaction terms using mixed effects models is not considered to avoid the chances of overfitting.

Data safety and monitoring plan - Data safety monitoring will be rigorously performed throughout the study. All forms will be reviewed again by the study physician after enrolment and data collection followed by the supervisor for completeness, legibility, and internal consistency. The supervisor will perform random checks to ensure the validity of the collected data by the study physician. The study physician will be trained to conduct patient screening, enrolment, data collection, sample collection, and study patient follow up according to the standardized operating procedures (SOPs). All aspects of specimen accession, processing, and interpretation will also be performed according to SOPs.

Adverse events and serious adverse events The patients/legal guardian will be asked about any adverse event that occurred since the enrolment of the study. The investigators are responsible for detecting, documenting, and recording events that meet the definition of an adverse event (AE) or serious adverse event (SAE) and remain responsible for following up AEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study intervention or the study. The investigator is solely responsible for assessment, including assignment of causality and intensity, reporting and management. All AEs and SAEs will be collected from the time the informed consent. The investigator will inform the sponsor of any SAE data within 24 hours of its availability. Investigators are not obligated to actively seek AE or SAE information after conclusion of the study participation.

Events that will be considered as AE - An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavourable and unintended symptoms signs like acute gastroenteritis, vomiting, urticaria, rash that associated with study intervention.

Events that will not be considered as AE - Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

All AE will be recorded in separate case record form. A SAE will be defined as any untoward medical occurrence that results in death.

Ethical assurance for protection of human rights - The study will be performed in compliance with the 'Declaration of Helsinki' (2000), the international conference on harmonization (ICH), tripartite guidelines, guideline for good clinical practice (GCP). These procedures ensure the protection of the rights and the integrity of the study participants, adequate and correct conduct of all study procedures, adequate data collection, adequate documentation, and adequate data verification.

The supervisors will conduct regular monitoring visits and recheck ~10% of the data. Weekly meetings will be organized to discuss data quality issues and specific gaps observed during routine monitoring visits. The study will only be initiated after it has been approved by the Research Review Committee (RRC) and the Ethical Review Committee (ERC) of icddr,b. Before enrolment, a signed informed consent will be obtained from each patient. The consent form will be written and formatted in Bengali. It will be easily understandable for patients, even those with little or no formal education. The consent form will be read out to the patients of the study subject. Signed consent or the left thumb impression will be obtained from the patients for participation in the study. Patients who do not consent to participate in the study, will still receive this standard medical and dietary management.

Risk - This study does not introduce major risks to participants beyond what they would normally face in their normal condition. Blood samples for serum haemoglobin and serum albumin will be taken at the onset of enrolment and after 14 days of intervention. Breaching medical confidentiality is a risk. Training and standard operating procedure (SOPs) will be implemented to help avoid these problems.

Implications of the research findings - This research finding can help to combat cancer related cachexia to the hospitalized patient in low- and middle-income countries. Partnering with local and international organizations to support hospital-based nutritional support to the patients with cancer. Developing hospital based nutritious food by rice water along with egg and multivitamins, multimineral which are cost effective, easy to prepare and nutritionally rich.

Benefits to the Patients and Community as a whole - All patients in the study will benefit from frequent close monitoring by the research group along with the standard care provided by the hospital. Moreover, all patients may be benefited by the standardization of the procedure and additional supervision.

This study will also generate findings to understand the nutritional management of cancer cachexia. It also helps us develop a locally available, low-cost, and nutritious food using kitchen leftovers-rice water combined with egg, multivitamins, and multimineral.

Confidentiality Every effort will be taken to maintain normal medical confidentiality. All records will be kept in a locked filing cabinet at the appropriate site, which is accessed only by the investigators and the study staff. All computer entry and networking programs will be done with coded numbers and participant's initials only. Only the investigators and the clinical monitor will have access to these records. De-identified data may be shared with the funder or other investigators, as specified in the data sharing policy. No information concerning the study or the data will be released to any unauthorized third party, without prior written approval of the sponsor.

Feedback of information Results of the study will be fed back to the study community through icddr,b's community representatives or community liaison group, public meetings, and hospital. Results will be shared through presentation at local and international scientific meetings