The present single-arm prospective interventional study was conducted in the Radiation Oncology OPD, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India, from September 2022 to May 2024. Approval was taken from the Institutional Ethics Committee (IEC) (approval number is SNMC/IEC/2024/197). Study was conducted on patients with gallbladder carcinoma after obtaining informed consent from all patients and their attendants after explaining the disease stage, prognosis and palliative treatment options.

Patients were staged according to the American Joint Committee on Cancer (AJCC) edition 8 GBC staging guidelines, utilising clinical examination and imaging via Contrast-enhanced Computed Tomography (CECT) of the abdomen [11]. All eligible patients with stage IIIB, IVa, and IVb GBC who met the inclusion criteria were enrolled in the study.

Inclusion criteria:

Exclusion criteria:

Before starting treatment, performance status was assessed based on the KPS. All patients were evaluated according to their activity levels and medical assistance requirements [12], and QoL assessments were conducted based on the EORTC QLQ-C30 and BIL-21 [13-15].

Patients received a total radiation dose of 30 Gray (Gy) delivered in 10 fractions over two weeks (five fractions per week) using two Dimensional (2D) conventional planning, delivered by a Cobalt-60 Theratron^® Phoenix teletherapy machine. This dose was planned for palliative treatment {Equivalent Dose in 2 Gy fractions (EQD2)=32.5 Gray, Biological Effective Dose (BED)=39 Gray}. Based on the diagnostic CECT, a 2 cm margin was added to the tumour volume and marked on the skin of the anterior right abdomen according to the right subcostal margin. The medial field was extended 2 cm to the left of the midline of the patient’s body to include the coeliac lymph node, provided the lymph node size was >1 cm and its appearance was heterogeneous. Two treatment fields, an anterior and a right lateral field, were defined based on the simulation scan. A 15-degree wedge filter was applied after drawing beam profiles using an isodose chart on the patient’s contour for homogeneous dose distribution.

Toxicity and QoL evaluation: The National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, was utilised to evaluate nausea, vomiting, anaemia, neutropenia, thrombocytopenia, diarrhoea and cholangitis during treatment [16].

The QLQ was evaluated mid-treatment, specifically after five fractions. The EORTC QLQ-C30 is a widely used tool that includes five functional scales assessing physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning; as well as, nine multi and single-item scales assessing fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties, and a global health status/QoL scale [13]. Additionally, the BIL-21 questionnaire focuses specifically on 21 questions: three single-item assessments relating to treatment side-effects, difficulties with drainage bags/tubes, and concerns regarding weight loss, along with 18 items grouped into five proposed scales: eating symptoms (four items), jaundice symptoms (three items), tiredness (three items), pain symptoms (four items), and anxiety symptoms (four items) [15]. A high score on a functional scale represents a high/healthy level of functioning; similarly, a high score on the global health status/QoL represents a high QoL, but a high score on a symptom scale/item indicates a high level of symptomatology/problems [14].

Tumour response was evaluated using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria 1.1 after four weeks of treatment completion [17].

Post-treatment follow-up: Following treatment completion, all patients were followed-up at two-week intervals in the OPD until disease progression. A comprehensive assessment of quality of life and performance status was conducted post-treatment (four weeks after completion). A CT scan was performed four weeks post-treatment to assess tumour response and identify any potential indicators of disease progression. Patients whose tumours exhibited Stable Disease (SD) or Partial Response (PR), along with effectively managed symptoms (e.g., pain, jaundice), were assigned a two-week follow-up schedule. Conversely, patients presenting with Progressive Disease (PD) or a recurrence of symptoms were placed on an alternative treatment regimen.

Statistical data analysis was performed using the Statistical Package for Social Sciences (SPSS) version 28.0.1 software. Descriptive statistics were used to examine patient demographics, baseline characteristics, treatment details and toxicity profiles. A paired t-test was used to assess tumour response, while an ANOVA test was employed to evaluate quality of life. A p-value of <0.05 was considered statistically significant.

Total 24 patients were included in the present study, out of which four defaulted before treatment. Twenty patients completed the treatment. All patients had unresectable GBC. Cholelithiasis was present in 9 (45%) patients. The most common symptom was loss of appetite, reported by 17 patients. Sixteen patients complained of pain, 15 patients experienced weight loss and 18 patients reported fatigue. Twelve patients complained of nausea and vomiting. Fifteen patients had obstructive jaundice. Among these fifteen patients, interventional biliary drainage was impossible in nine patients due to anatomical constraints. The other six patients declined referral to higher centres for interventional biliary drainage, as this facility was unavailable at the study Institute. All patients completed two weeks of radiation treatment. One patient expired one week post-RT due to persistent hyperbilirubinemia, and another patient defaulted after the first follow-up (one month post-RT). Thus, 18 patients survived at the one-month follow-up.

The majority of patients were in the 30-60 years age group, with a mean age of 49.48±5.2 years. Among 24 patients, 7 (29.2%) were males and 17 (70.8%) were females. The majority of patients were classified as stage IV A, i.e., 16 (66.6%) [Table/Fig-1].

Distribution of patients according to Karnofsky Performance Score (KPS): KPS improved from 62.5±4.44 to 74.0±5.03, with a p-value of <0.001 [Table/Fig-2].

Toxicity assessment during treatment: Only two patients with cholangitis were admitted for conservative treatment, while the rest were treated on an outpatient basis [Table/Fig-3].

Assessment of quality of life and subjective response: There was an improvement in overall QoL and overall health, but the results were statistically insignificant. There was a substantial improvement in pain, jaundice and nausea/vomiting. Most patients, 18 (90%), needed assistance to answer both questionnaires [Table/Fig-4,5].

The drain score was not evaluated, as only those patients were included for whom interventional biliary drainage was not feasible or who could not afford it. In the present study, tumour response was observed in 10 (55.5%) patients, with PR in 4 (22.2%) patients, and SD in 6 (33.3%) patients. Progressive disease was observed in 8 (44.4%) patients [Table/Fig-6].

In the present study, most patients were aged 30-60 years, with a mean age of 49.48±5.2 years. This age data can be supported by an epidemiological study by Dutta U et al., in which the average age at diagnosis of GBC was 51±11 years in India [2]. The gender proportion of patients mirrored the established epidemiological pattern of GBC in India, with a higher prevalence observed in females (17, 70.8%) compared to males (7, 29.2%). This finding aligns with the data presented by Phadke PR et al., who documented a female-to-male incidence ratio of 6.04:3.17 in the Gangetic plains region of India [18].

Improvement in Karnofsky Performance Status (KPS) post-treatment was statistically significant, with a p-value of <0.001 in the current study. This result can be supported by a case study by Eleftheriadis N and Pistevou-Gompaki K, who documented the palliative management of unresectable gallbladder carcinoma. The RT dose was followed, and the patient’s performance status remained favourable and alive for one year post-diagnosis [19].

Strikingly minimal treatment-related toxicities were observed in the present study. Ranjan A et al., also observed a lower incidence of vomiting compared to the chemotherapy arm [10]. In their research, grade 3 vomiting was experienced by 22.2% of patients in the RT arm. In the same study, grade 1 anaemia was found in 33.33% of patients in the RT arm, and 5.5% had grade 2 anaemia. Grade 1 leukocytopenia was reported in 5.5% of patients in the RT arm, with no cases of thrombocytopenia reported.

Palliative care options for unresectable GBC remain limited. Current approaches primarily focus on managing symptoms like obstructive jaundice through endoscopic or percutaneous biliary drainage. Chemotherapy and Concurrent Chemoradiotherapy (CTRT) are used to address disease progression and symptom palliation; however, these treatments often require extended durations and are associated with adverse effects. Dierks J et al., studied chemotherapy in patients with unresectable GBC, noting that grade 3 and 4 neutropenia was observed in 32.8% of patients, and thrombocytopenia was observed in 13.1% of patients [20]. In a study by Sinha S et al., CTRT was compared with chemotherapy in treating patients with unresectable GBC. Although tumour control was better with CTRT, it was associated with grade 3 neutropenia in 16% of patients [21].

Therefore, while radical approaches can offer significant benefits, they can also be associated with potential risks and challenges. The present study was designed to address the need for a palliative approach that can fulfill the requirement for a short and localised treatment option, aiming for better quality of life while addressing the need for tumour control and symptom management.

The financial difficulty score was important as all patients came from low-income groups. Upon analysing the financial difficulty score using the EORTC QLQ-C30, the results were as follows: the pretreatment score was 84±18, the mid-treatment score was 72.5±15, and the post-treatment score was 67±1.8, indicating a decreasing trend in financial difficulty. In the present study Institute, patients were offered 2D radiotherapy using the Theratron^® Phoenix Co 60 for INR 350 for 10 fractions. However, some supportive medications that were unavailable in our institute still cost less than INR 500, despite requiring minimal supportive care. As evidenced by the scores for some patients, even spending this small amount was a difficult task for them to manage.

The present study showed improving trends in the overall quality of life score. This result can be supported by a study by Ranjan A et al., where quality of life was evaluated between the RT and chemotherapy groups using the University of Washington criteria. In the RT arm, with 30 Gray in 10 fractions, the majority of patients, 38.88%, had a fair quality of life, followed by 77.77% with a good quality of life [10]. Adding to the evidence, a study by Sekar V et al., found that symptomatic responses in the RT arm after one month of treatment were 61.4%, indicating a positive treatment response [22].

Tumour response was assessed four weeks after treatment completion. A total of 4 (20%) patients achieved a PR, 6 (30%) had SD, and 8 (40%) had Progressive Disease (PD). Similar results were reported in a study by Sekar V et al., [22]. A complete response was seen in 1 (3.8%) patient each in the RT and chemotherapy arms, and a PR was seen in 6 (23%) patients in the RT arm and 9 (34.6%) patients in the chemotherapy arm. SD was reported in 9 (34%) patients in the RT arm and 11 (42.3%) patients in the chemotherapy arm; PD was seen in 10 (38.4%) patients in the RT arm and 5 (19.2%) patients in the chemotherapy arm [22]. The study by Ranjan A et al., found a higher PR rate in the RT arm at two months (94.44%) compared to chemotherapy (82.35%), but again, this difference lacked statistical significance (p-value=0.52) [10].

Therefore, RT can be considered a palliative treatment option for patients with unresectable GBC. It was observed that there was an improvement in overall quality of life, performance status and tumour control. Adverse effects related to RT rarely tempered quality of life. Only two patients required hospitalisation to manage adverse effects.

The small sample size, the absence of a control group for comparison with standard treatment modalities, and the fact that it is a single-institution study are prominent limitations of the present study.

For patients with advanced unresectable gallbladder cancer who are not candidates for surgery or biliary stenting, palliative radiation therapy may be considered. However, a detailed comparative study with a large sample size should be performed for a better understanding of palliative RT in unresectable GBC. By implementing a thorough research plan, a personalised treatment strategy can be selected that optimises patient outcomes. Therefore, improving quality of life, tumour response, and minimising adverse effects is the important goal for palliation.