Patient reported change in pain outcome among stage IV cancer patients with bone metastases following palliative radiotherapy: A prospective study from Ethiopia.

Acronyms

AA - Addis Ababa

AAU - Addis Ababa University

Ca - Cancer

CRC - Colorectal cancer

EBRT - External Beam Radiotherapy

GI - Gastrointestinal

Gy - Gray

Hg - Hemoglobin

IV - Intravenous

IM – Intramuscular

LMIC – Low Middle-Income Country

NHL - Non-Hodgkin Lymphoma

NRR – Non-Response Rate

OPD - Out Patient Department

ORR – Overall Response Rate

P/E – Physical Examination

PO - Per Os

PRN - Per Need

QOL - quality of life

RT – Radiotherapy

RTOG – Radiotherapy Oncology Group

TASH - Tikur Anbessa Specialized Hospital

Tel - Telephone

Wks - Weeks

Introduction

Cancer has emerged as one of the most significant healthcare burdens worldwide, challenging the capacities of both high-income and low- to middle-income countries (LMIC). In 2016, non-communicable diseases (NCDs) were the leading cause of death globally, with cancer accounting for the second highest fatalities, preceded only by cardiovascular diseases. Notably, cancer's impact has expanded beyond traditionally affluent nations, imposing heavy burden on LMIC, especially in Asia and Africa. Alarmingly, adults in these regions face double the risk of dying from cancer compared to their counterparts in high-income countries (HIC) [ 1 ]. The Global Cancer Observatory (GLOBOCAN) projected that in 2018, there were 18.1 million new cancer cases and 9.6 million cancer-related deaths worldwide. Lung cancer emerged as the most diagnosed and fatal form of cancer, followed closely by breast cancer, prostate cancer, and colorectal cancer for incidence; and colorectal, stomach, and liver cancers for mortality. Gender-specific patterns reveal that breast, colorectal, and lung cancers rank highest among females, while lung, prostate, and colorectal cancers dominate in males [ 2 ]. The disparity in cancer patterns between HIC and LMIC raises critical concerns. Variations in risk factors, access to early diagnosis, and treatment modalities contribute to different cancer profiles in these regions [ 3 ]. For instance, in Africa, breast, cervical, and head-and-neck cancers represent the most prevalent cases, influenced by economic, healthcare access, and socio-cultural factors. In Sub-Saharan Africa, cervical cancer predominates, whereas breast cancer is most common in North Africa [ 4 ]. The treatment landscape is starkly different across Africa; while patients in North Africa often receive curative treatment, only 20 % to 45 % of patients in Sub-Saharan Africa do, with many presenting at advanced stages of the disease where palliative care becomes the primary focus of cancer treatment [ 5 ].

Ethiopia, the second most populous nation in Africa, faces a similar trajectory. With a population exceeding 120 million, the nation grapples with rising NCDs, including cancer. A population-based registry from 2015 estimated that 21,563 new cancer cases in men and 42,722 in women were diagnosed in Ethiopia. This burgeoning incidence compounds the existing healthcare challenges of infectious diseases, placing a strain on a still-developing health system. In Ethiopia, the top cancers diagnosed among women are breast, cervical, and ovarian cancers, while men primarily face colorectal, non-Hodgkin lymphoma, and prostate cancers [ 6 ].

Several factors contribute to the challenges of cancer control in Ethiopia, including limited public awareness, insufficient healthcare facilities, and a serious lack of trained professionals. Consequently, the majority of cancer patients often present at advanced stages of the disease, significantly reducing their chances of a cure [ 7 ].

A retrospective study conducted at Tikur Anbessa Specialized Hospital (TASH) revealed that most patients were diagnosed with stages III/IV and only 10 % presented at earlier stages (I/II) [ 8 ].

Cancer treatment encompasses various modalities, including classical methods such as surgery, chemotherapy, and radiotherapy. These methods have laid the foundation of cancer management for many years. Recent advancements, such as targeted therapies, bone modifying agents and high-technology radiotherapy techniques, have evolved the landscape of cancer treatment that hold promise for improving cancer management and outcomes including disease with skeletal and visceral metastases [ [9] , [10] , [11] ]. Targeted treatment in breast cancer, one of the most common cancer types with propensity to metastasizing to bone, has shown continuous advancement in using hormonal agents, HER-2 targets, angiogenesis targets, CDK4/6 targeted agents to the recent antibody-drug conjugate ladiratuzumab vedotin for metastatic breast cancer management [ 11 ]. Studies show bisphosphonates reduce skeletal-related events (SREs) in metastatic breast cancer and multiple myeloma [ 12 ]. Bisphosphonates can also provide pain relief for bone metastases, but evidence is insufficient for their immediate use or as first-line therapy. Their effectiveness varies among primary neoplasms. They should be considered when analgesics and radiotherapy do not adequately manage painful bone metastases [ 13 ].

In summary, the management of pain resulting from bone metastasis remains a significant challenge necessitating a thorough exploration of treatment modalities. Palliative radiotherapy has emerged as a cornerstone in alleviating this pain, yet the optimal fractionation schedules and their comparative effectiveness are not fully understood in our setting. This manuscript aims to address this gap by investigating the various fractionation regimens of radiotherapy and their impact on pain relief. By doing so, we hope to contribute valuable insights that can enhance clinical decision-making and ultimately improve patient outcomes in the context of metastatic bone disease.

Literature review

Pain remains one of the most debilitating and feared symptoms experienced by cancer patients, significantly compromising their quality of life (QOL). This pain may arise from the disease itself or because of its treatments. Notably, patients diagnosed with advanced stages of cancer report experiencing more pain than those diagnosed at an earlier stage, particularly due to the high propensity for bone metastases. Research indicates that 60 % to 70 % of patients in advanced stages of cancer experience pain, with approximately one-third of these individuals suffering from severe pain [ 14 ]. For a substantial number of cancer patients, bone metastasis emerges as a critical contributor to both chronic pain and reduced QOL, often being the first site of metastatic progression. Certain cancer types exhibit a greater tendency to metastasize to bone tissue. The most prevalent primary cancers associated with bone metastases include breast, lung, and prostate cancers. Autopsy studies have demonstrated that the prevalence of bone metastases originating from these primary sites can reach up to 85 %, while ante mortem analyses indicate a prevalence rate of around 50 % [ [15] , [16] , [17] ].

Pain management strategies for bone metastases typically encompass a multi-faceted approach, which may include analgesics, external beam radiotherapy (EBRT), chemotherapy, surgical interventions, and the use of radiopharmaceuticals. The selection of a specific treatment modality is influenced by a variety of patient-specific and tumor-related factors [ 16 , 18 , 19 ]. Treatment aims generally focus on alleviating pain, providing sustainable relief, preventing complications, improving QOL, and, when feasible, prolonging survival. Radiotherapy constitutes a fundamental component of this treatment landscape, serving as the most commonly employed modality for addressing pain related to bone metastases across both high-income and low- and middle-income countries (LMICs) [ 17 , 20 ]. The efficacy of radiotherapy in the management of bone metastases has been rigorously assessed in numerous studies, with findings consistently indicating its effectiveness in pain relief. For instance, a prospective study by Van der Velden et al. enrolled approximately 500 patients, targeting pain response between 2 and 12 weeks following EBRT. Patients received radiotherapy according to departmental protocols, with some receiving 30 Gy delivered in 10 fractions, while others were administering a single fraction of 8 Gy. Patients were classified as responders based on achieving either complete or partial relief at any of the follow-up assessments. Pain response in the total treated population was recorded at 61 %, with a response of 67 % observed in assessable patients at the two-week mark. Patients receiving longer courses of radiotherapy exhibited greater pain relief than those undergoing single-fraction therapy. The rates of retreatment proved comparable between the two fractionation schedules, although a shorter interval to reirradiation was noted among patients receiving single-fraction 8 Gy radiotherapy. The median time to pain response was 4 weeks, with a median duration of response spanning 21 weeks [ 21 ].Scholarly discourse has suggested that multifractionation regimens may offer superior efficacy in managing bone metastases compared to the single-fraction 8 Gy approach. This has led to a series of comparative studies designed to assess whether single-fraction treatment is superior or inferior to multifractionation. A pivotal randomized phase III trial conducted by Hartsell WF et al. involved nearly 1,000 patients and compared short-course radiotherapy (SFRT 8 Gy) against long-course radiotherapy (30 Gy) for the palliation of one to three painful bone metastases. Pain response was evaluated at three months, with an overall response rate (ORR) of 65 % in the SFRT group and 66 % in the long-course group, indicating no significant difference. No discrepancies in pain response were detected based on treatment site, weight-bearing status, bisphosphonate usage, or pretreatment pain scores, although retreatment rates were statistically significantly higher in the 8 Gy cohort, which received retreatment at roughly twice the rate of those on the longer regimen [ 22 ]. The RTOG 74-02 trial also compared varying dose levels of radiotherapy for bone metastases palliation, administering doses between 1500 cGy to 3000 cGy for multiple metastatic sites, and from 2000 cGy to 4050 cGy for single metastasis. Pain was classified into mild, moderate, and severe categories, with 89 % of patients eventually achieving at least minimal pain relief, noting no significant differences in outcomes across the various dose schedules [ 23 ]. Another randomized phase III trial evaluated SFRT of 8 Gy against 20 Gy delivered in five fractions, revealing no discernible differences in pain relief, duration of relief, or the necessity for reirradiation, with minor toxicity recorded across both treatment arms.

In conclusion, evidence suggests that single-fraction radiotherapy of 8 Gy is comparably effective to multifractionation in the management of patients with painful bone metastases [ 24 ]. Despite the extensive body of literature addressing this topic, the variability in outcome measures complicates efforts to establish an optimal radiotherapy regimen. Differences in pain assessment methodologies, with some studies using simpler four- or five-point scales compared to more recent ten- or eleven-point complexities, further obscure the ability to draw definitive conclusions. Compounding this, many of the studies do not account for confounding factors such as analgesic use, emotional and psychological aspects, and the potential benefits of achieving partial responses. There is also a noted trend among clinicians to prescribe multifractionated radiotherapy to patients with better performance status and limited metastases while reserving single-fraction treatment for more debilitated individuals, potentially biasing outcome comparisons [ 25 ].

Although recent evidence suggests that single-fraction radiotherapy is as effective as multifractionated approaches, a lack of standardization in radiotherapy regimens persists globally. Various cancer treatment institutions employ disparate regimens, leading to the existence of over 100 different fractionation schedules for managing bone metastases. Moreover, many centers favor multifractionation over single-fraction treatments, a trend reflected in patient preferences as well, as individuals with bone metastases often opt for multifractionation [ 24 , [26] , [27] , [28] ].

In Africa, there is a dearth of data addressing the efficacy and uncertainty surrounding radiotherapy dosing and fractionation. A study evaluating 23 centers on palliative radiotherapy practices for bone metastases revealed that 61 % adopted a single radiotherapy regimen, while the remainder utilized multiple regimens. Notably, only five centers reported using single-fraction 8 Gy radiotherapy for pain palliation, reflecting a lack of consensus on optimal treatment protocols in the region [ 20 ].

In Ethiopia, the absence of specific data evaluating the efficacy of radiotherapy for bone metastases complicates efforts to ascertain its effectiveness. Observations from clinical practices at Tikur Anbessa Specialized Hospital (TASH) indicate a trend towards increased utilization of single-fraction radiotherapy over multifractionation in current treatment practices. Continued research is imperative to establish effective treatment guidelines that optimize pain management for this patient population.

Statement of the problem

Radiotherapy (RT) plays a pivotal role as a primary treatment modality for cancer, effectively used in both curative and palliative care settings. In developed nations, it is reported that almost half of all cancer patients will receive palliative RT at some point, aiming to alleviate symptoms and significantly enhance their quality of life (QOL) [ 17 ]. This is essential because effective symptom management is a cornerstone of cancer care, providing relief and improving the overall well-being of patients during their treatment journeys. However, the situation in Africa differs markedly. In Sub-Saharan regions, a staggering 55 % to 80 % of cancer patients present with advanced-stage disease at diagnosis, with treatment intentions focused primarily on palliation [ 8 ].

This troubling trend is particularly pronounced in Ethiopia, where a multitude of factors contributes to patients presenting at advanced disease stages. Key challenges include low socioeconomic status, lack of health insurance coverage, inadequate oncology facilities, excessively long waiting times for access to radiotherapy and chemotherapy, and a significant gap in public awareness regarding cancer symptoms, diagnosis, and treatment options. Data from Tikur Anbessa Specialized Hospital (TASH), the nation's premier cancer treatment facility, indicate that 64 % of patients present with either advanced or unknown stages of disease upon their initial consultation ([ 7 , 8 ]).(10,11)n A recent retrospective study conducted at TASH further revealed that three-quarters of cancer patients are diagnosed at inoperable advanced stages (III/IV), necessitating a focus on palliative RT; among these, 50 % present with overt metastasis, underscoring the urgent need for effective palliation [ 29 ].

Throughout the course of cancer, patients contend with a variety of distressing symptoms, chief among them being pain. Out of the various sources of pain, bone metastasis emerges as the leading cause for many cancer patients, contributing significantly to their discomfort and diminished quality of life [ 16 , 20 ]. An analysis of RT administration patterns at TASH indicates that a significant majority of treatments—62.4 %—are administered for palliative purposes, while only 37.6 % are with a curative intent. Critically, pain management is the primary indication for administering palliative RT, with over 55 % of these treatments aimed specifically at alleviating cancer-related pain. This highlights the considerable burden of pain management on the only RT facility in the country. Additionally, nearly 50 % of patients with late-stage disease receive palliative RT for either bone or brain metastases, largely utilizing multifractionation schedules [ 29 ]. Notably, current practices at TASH indicate a potential shift toward the use of single fractions of 8 Gy for treating bone metastases. If this practice were to be included in prior studies, the estimated proportion of palliative RT dedicated to bone metastases at TASH would likely be even higher. Despite the evident prevalence of bone metastases among cancer patients and the resulting pressure on RT resources, there is a significant lack of studies that comprehensively evaluate the optimal treatment approaches for these patients.

Research has shown that single-fraction (SF) RT can be just as effective as conventional multifractionation in terms of alleviating pain and improving QOL in patients suffering from bone metastases [ 24 , 27 ] Nevertheless, the global landscape of RT reveals a bewildering variety of over one hundred different fractionation schedules employed for managing bone metastases, leading to significant inconsistencies across treatment centers. Despite the clear evidence supporting the effectiveness of single-fraction treatments, many centers continue to underutilize this more efficient approach [ 28 ]. In the United States, studies concerning the efficacy of RT for pain relief associated with bone metastasis have demonstrated that 90 % of patients achieve some level of symptomatic response, with half achieving complete relief from pain [ 23 ].

In the context of Africa, and particularly in Ethiopia, robust data on the efficacy of RT for treating bone metastases is alarmingly scarce. Although a considerable number of patients at TASH receive palliative RT for bone metastases to manage their pain and improve their quality of life, the actual effectiveness of these treatments remains unverified by empirical research. Consequently, there is a pressing need to determine whether current palliative RT practices are indeed effective in relieving pain among patients with bone metastases. Moreover, the absence of an institutional treatment protocol leads to inconsistent and potentially ineffective RT regimens, even at the only dedicated radiation treatment center in the country. Therefore, conducting a study to explore the efficacy of palliative RT in our setting is essential. Such research would not only validate current practices but also inform the development of standardized treatment protocols that may assist in improving patient outcomes, ultimately providing valuable insights that could benefit other African countries facing similar challenges. Additionally, this investigation could spur ongoing evaluations of everyday clinical practices, promoting a culture of continuous improvement in cancer care.

While alternative treatment options exist for managing painful bone metastasis—including analgesics, chemotherapy, bone-modifying agents, radiopharmaceuticals, and surgical interventions—the availability of these therapies in Ethiopia is often limited, characterized by inconsistencies in supply [ 15 , 18 , 19 ]. In stark contrast, external beam radiotherapy (EBRT) is readily accessible at TASH for palliative patients, with minimal waiting times for treatment [ 29 ].

Therefore, evaluating the efficacy of EBRT is critical for optimizing treatment strategies for this vulnerable patient population, ensuring that they receive the best possible care despite the myriad challenges that they face.

Objectives

General objectives

To assess patient reported change in pain status following palliative radiotherapy at 2,4 and 8 wks post treatment when compared to pretreatment pain status

Specific objects

To evaluate pain relief at 2 wks following palliative radiotherapy

To evaluate pain relief at 4 wks following palliative radiotherapy

To evaluate pain relief at 8 wks following palliative radiotherapy

To evaluate pain relief post 8gy Vs 20 gy in 5 fractions

Primary end point

Response rate of pain at 2wks, 4 wks & 8 wks following palliative RT

Secondary endpoints

Pain relief post 8gy SFVs 20gy in 5 fractions

Reirradiation status at 6 months

Survival at 6 months,12months,24 months

Materials and methods

Study setting

The study was conducted at an oncology center in Tikur Anbessa specialized hospital, AAU. TASH is the largest referral and teaching hospital, giving training in most preclinical and clinical disciplines. It is also giving postgraduate training in clinical oncology. There are five clinical oncologists, one functional cobalt teletherapy machine and one high dose brachytherapy for 110 million Ethiopian populations.

The oncology unit in TASH provides both radiotherapy and chemotherapy service and it is the only RT center in the country and therefore it is the only cancer referral hospital in the country. Currently, more than 10,000 cancer patients visit this center each year and therefore the waiting time for RT and Chemotherapy is too long with nine to ten months and four to five months, respectively.

Study design

This study was an institution based prospective observational cohort study at RT center of TASH. Patients who full fill the inclusion criteria were recruited consecutively from Feb 10 – Sep10, 2020. The study was conducted from Feb 10, 2020, up to September 10, 2022. The first data was collected from Feb 10, 20 20 up to Sep 10, 2020. The second data is collected from Sep 10, 2020, up to September 10, 2022. Survival analysis at 6 months,12 months and 2 years will be presented separately.

Target population

All patients with bone metastasis treated at TASH

Source population

All patients with bone metastasis booked at RT center of TASH

Study population

Patients with histopathologically confirmed cancer or radiologically diagnosed metastatic cancer with radiologically confirmed bone metastasis which is painful, and were booked to take RT to the bone at TASH.

Inclusion and exclusion criteria

Inclusion criteria: Patients who are /or older than 18 years, with histologically proven cancer or radiologically (CT/MRI) alone are suggestive of bone metastases, with painful bone metastasis, different pain scores on two painful bone metastases sites for patients with multiple metastatic bone sites, and who were able to give written informed consent were included in the study.

Exclusion criteria: Patients with primary bone tumor, metastasis to skull bone, previously irradiated to the bone, very extensive bone metastasis (> 5 contiguous vertebra metastases or sum diameter > 15 cm), patients with cord compression, septic patients and patients with psychiatric problems were excluded from the study.

Sample size

Sample size was calculated from Ahrens single stage phase II sample size determination table which is based on binomial distribution using BINOMIDST excel

Po is the minimum RR not worth giving the treatment and is taken 20 %

P1 is clinically meaningful RR and is taken minimum 40 % from literature

Type 1 error (α) is taken as 0.05

power (1- β) is 80 % to exclude a RR of ≤ 20 % with 5 % significance level

The trial tests the null hypothesis: Ho P≤ po against alternative hypothesis H1: P≥P1

Hence the binomial distribution formula

From Ahrens single phase sample size calculation table, a sample size of 35 patients was needed. In addition to the usual reasons to consider a dropout rate, here considering a network problem for a phone call in rural parts of Ethiopia and for inclusion of more debilitated patients with PS of ECOG 3,4 and extensive metastases sites,30 % drop out rate is assumed. Therefore, a final sample size was calculated as follows: N=n/ (1-d), where N is final sample size, n is initial calculated sample size and d is assumed dropout rate. N= 35/ (1-0.3) N= 50.

Sampling procedure

Eligible patients were consecutively enrolled in the study until the required sample size was attained.

Study variables

Dependent variable

Change in pain status and reirradiation status.

Independent variables

Age, sex, site of bone metastasis, radiotherapy administration, presence of visceral metastasis, histopathology of the primary cancer (breast cancer, prostatic cancer and other histologies) and use of bone modifying agent and duration of pain.

Operational definition

Pain: Unpleasant physical sensation due to illness.

Four-Point Scale Pain Score: 0 is no pain; 1 is mild pain; 2 is moderate pain, 3 is severe pain.

Mild pain ( pain score of 1 ) - nagging, annoying but doesn't interfere with daily activity. E.g., you don't spend much of your time thinking about it, mild pain which mostly can be ignored although sometimes it may get worse, and the pain could be adapted.

Moderate pain (pain score of 2) - Pain interferes significantly with daily living activity. e.g., with effort, pain can be ignored for a while; patient could participate in some social relations, Distraction while working, unable to concentrate.

Severe pain (pain score of 3) – disabling and unable to perform daily activity. E.g., limited activity to extent of chair confined or bedridden, affecting social relationships, sleep interference, patients have little effort to converse, crying out or shouting.

Complete response - Response in pain from initial pretreatment severe, moderate or mild pain to no pain and it is regardless of analgesics use. In another term it is a pain score reduction from 3or 2 or 1 to 0

Partial response – response in pain from pretreatment severe pain to moderate or mild pain and response in pain of from moderate pain to mild pain and it is regardless of analgesics use. In another term it is a pain score reduction from 3 to 2 or 3 to 1 or 2 to 1.

No response – no change in pain status when compared before and following treatment. It means the patient will have the same pain score as before treatment.

Worse response – state of pain following treatment worsens compared to initial pretreatment state. It is any increase in score of pain.

Analgesics use – any analgesics use before a day of presentation to RT planning session.

Patients with two painful sites are considered as if they are two different patients and their response is assessed differently and when they die, they will be considered as a single patient and only the most painful site at presentation was analyzed.

Morphine conversion - those patients who converted from morphine to other less strength analgesics on subsequent follow ups were considered as if they reduced morphine by one third.

Analgesics frequency - those patients who were taking analgesics on PRN base, the most usual frequency they take was taken as their fixed schedule.

Data collection tool and procedure

Data collection procedure

Data was extracted and collected by two oncology residents who were working at the radiation planning outpatient department. Baseline data abstraction format will be prepared and filled during actual planning for treatment or the time after planning but before the treatment is given to patients. After patients took palliative RT to the indicated bone site, patients were reached by phone at 2, 4 and 8 wks following RT. Data were filled in the data abstraction format.

Data collectors

The principal investigator briefed the data collectors on the importance of the study and trained them in how to properly collect data and explain each word and meaning on data abstraction format

Data quality control

Two days of training was given for the oncology resident on how to collect data. The principal investigator supervised the data collectors and checked if the data extraction was complete and consistent. The original paper of the data abstraction format was kept with the principal investigator.

Data processing and analysis

Data was coded, cleaned and then entered into SPSS version 21 to analyze it. Descriptive analysis like mean, median and percentage was done and for variables with two possible outcome binary logistics regression was done. Chi-square test was done to test correlation using level of significant set at 5 %.

Ethical consideration

Ethical clearance was obtained from the ethical review committee of the department. Data collection was started once the study was approved by the clinical oncology department. Written informed consent was taken from the patient. The patients’ history confidentiality was protected as data was collected by residents working at oncology department.

Results

The study enrolled sixty patients, of whom sixteen were lost to follow-up. Consequently, forty-four patients were included in the final analysis ( Fig. 1a ). Among these forty-four patients, six received palliative radiotherapy for bone metastases at two distinct sites. Since each site in these six patients presented with a different pain score, the pain response to radiotherapy was evaluated separately for each site, and the analysis was conducted accordingly.

A little more than half (52 %) of the patients are older than 49 years of age. On the other hand, about half are female. The majority of patients live in Addis Ababa and most patients are also urban dwellers (data not shown). More patients (68 %) are either secondary or tertiary school graduates. On the other hand, 68 % are working force while 26 % are retired. ( Table 1 )

Breast and prostate ca are the two most common cancer of primary site. Vertebra was the commonest site of bone metastases (92 %) followed by pelvic bone (36 %), ribs (14 %) and other sites (10 %). Ninety percent of patients were planned for RT based on information acquired both on imaging and P/E. whereas only 8 % and 2 % of patients were planned based on imaging only and P/E only respectively (data not shown). Although seventy percent of the patients showed multiple sites of bone metastasis, only 12 % of them received treatment at two sites. On the other hand, among those patients who had visceral metastases, half of them had more than one site of metastases. The majority of the participants in this study did not have any comorbidity. Among those patients with comorbidity, diabetes was the most common. Sixty percent of the study participants had either I or II performance score while only 4 % had a performance score of IV. Half of the patients experienced severe bone pain at baseline and on the remaining patients more patients presented with mild pain and less patients with moderate pain. Moreover, the majority of the patients had pain for 3 months or longer and only two patients (4 %) had less than one month duration of pain at the time of enrollment ( Table 2 ).

The proportion of patients who experienced severe pain were seen to be lower dramatically at 2 weeks post-radiotherapy. The percentage of patients having severe pain remained low at week-4 and week_8. A slight increase was seen at week-8 compared to week-4 and week_2. On the other hand, there is not much reduction in the proportion of patients who experienced mild and moderate bone pain at baseline compared to post-radiotherapy ( Fig. 1b ). At baseline, 16 %, 2 %, and 36 % of patients with mild, moderate and severe pain, respectively were females. On the other hand, 20 %, 12 %, and 14 % of the patients who had mild, moderate, and severe pain, respectively were males (data not shown). This indicates that significantly higher proportion of patients who experienced severe pain at presentation were females (p< 0.05). The difference was not found to be significant in the subsequent follow-up weeks post-radiotherapy. Seventy percent of patients with visceral metastases presented with severe pain at baseline while only 28 % of patients with no visceral metastases (p = 0.039) (data not shown).

Statistically significant association were seen between radiation administration and reduction in pain severity status at weeks -2, -4, -8 following palliative radiation administration to painful metastatic bone sites with Pearson chi-square value of 34.1829,26.5245, 28.8314 and P value of < 0.001, < 0.001, < 0.001, respectively.

The majority of patients (about 80 %) who had severe pain at baseline improved and experienced mild pain or no pain while a portion of these patients experienced moderate pain. About 20 % of these patients remained to experience severe pain regardless of time mark following radiation treatment; similar p value of < 0.001 at weeks -2, -4, -8 ( Fig. 2 ).

Overall response rate (ORR) was calculated as complete response (CR) plus partial response (PR) that each CR and PR from each bone pain score subgroup analysis was calculated and summed up as a total ORR for each week following palliative RT. The same calculation was used for calculating no response rate (NRR) and it was the sum of no change plus worsening in pain status. At week_2, ORR and NRR were 65 % and 35 % respectively. At week_4, ORR and NRR were 66.7 % and 33.3 % respectively. At week_8, ORR and NRR were 78 % and 23 % respectively. CR was seen to increase as weeks go by post RT so also ORR. On the other hand, worsening in pain status was seen to subsequently decrease as weeks go by post RT so also NRR. The highest ORR and the lowest NRR were seen at week_8 post RT, p value < 0.01( Fig. 3 ).

The allocation to 8gy or 20gy of radiotherapy was done by the decision of treating and consultant physician taking into consideration of the site, PS and primary disease control. Thirty-three (66 %) of the patients received 8gy while 17 (34 %) of the patients received 20gy radiotherapy. Among the patients who received 8gy of RT, more patients had severe pain, whereas less patients of those who received 20 gy of RT had severe pain at baseline. The observed change in the total percentage of patients at wk-2 was due to the death of few patients in the subsequent wks following treatment. At week-2 post-radiotherapy, the proportion of patients with severe pain were 13 % and 0 % among patients who took 8gy and 20gy, respectively showing no significant association between pain reduction and dose of prescribed radiation, P value of 0.340 ( Fig. 4 ).

AT wk-4 following radiation the same trend that was observed at wk-2 continued, with more patients attained complete pain response regardless of the prescribed dose of radiation. At baseline, among patients who received palliative radiotherapy, 48 % of those assigned to a single dose of 8 Gy experienced either severe or moderate pain. In contrast, only 16 % of patients who received fractionated 20 Gy RT reported similar pain levels. Four weeks after radiation treatment, the percentages changed significantly: 9.52 % and 2.38 % of patients in the single-dose 8 Gy and fractionated 20 Gy groups, respectively, were still experiencing severe or moderate pain. The observed change in the total percentage of patients at wk-4 was due to the death of few patients in the subsequent wks following treatment. At the wk-4 mark, there was no statistically significant association observed between dose of radiation and pain response following treatment, P value of 0.176 ( Fig. 5 )

AT wk-8 following radiation the same trend that was observed at wk-2 and -4 continued, with more patients attained complete pain response regardless of the prescribed dose of radiation. At baseline, among patients who received palliative radiotherapy, 48 % of those assigned to a single dose of 8 Gy experienced either severe or moderate pain. In contrast, only 16 % of patients who received fractionated 20 Gy RT reported similar pain levels. Eight weeks after radiation treatment, the percentages changed significantly: 17.95 % and 5.12 % of patients in the single-dose 8 Gy and fractionated 20 Gy groups, respectively, were still experiencing severe or moderate pain. The observed change in the total percentage of patients at wk-8 was due to the death of few patients in the subsequent wks following treatment. At the wk-8 mark, there was no statistically significant association observed between dose of radiation and pain response following treatment, P value of 0.342 ( Fig. 6 )

We looked into the daily average dose of morphine use of patients excluding other forms of analgesics at baseline. Eighty four percent of patients were taking morphine at baseline. Ninety-six percent of patients were not told they need adjustment in their use of anti-pain type or dose depending on change in pain status after they receive RT. Among patients who were prescribed to morphine, 16 % of them either discontinued or changed to other analgesics modality by themselves post RT. At baseline, patients with severe pain received the highest dose of morphine and more or less patients with moderate and mild pain status received similar dose. But, in the subsequent follow-up weeks, the pattern somehow was seen reversed in which patients with mild or no pain received the highest dose while those with severe or moderate pain received the least Fig. 7 .

Discussion

The findings from our prospective study highlighted a significant aspect of cancer care in Ethiopia, where the majority of patients present with advanced stages of the disease, particularly stage IV cancer associated with painful bone metastases. This scenario necessitates a focus on palliative radiotherapy (RT), which serves as a critical treatment option for alleviating pain and improving quality of life. One of the notable advantages of the RT program at Tikur Anbessa Specialized Hospital (TASH) is the absence of waiting time for patients to receive palliative radiation treatment, facilitating timely interventions [ 10 , 11 , 15 , 29 ]. In our study, the mean and median ages of patients receiving palliative RT were 51 and 52 years, respectively, with an age range of 18 to 82 years. This demographic data contrasts with findings from studies conducted in Italy and the United States, where the median age of patients is significantly higher at 67 years. This discrepancy could be attributed to differences in life expectancy, variations in healthcare access, and the age at which cancer is diagnosed in these populations. In Ethiopia, the delayed presentation of cancer may reflect lower awareness of cancer symptoms and a lack of preventive healthcare measures.

A striking feature of our findings is that 70 % of patients exhibited multiple sites of bone metastases, a significantly higher proportion than the 40 % reported in studies from the US [ 22 , 30 ]. This discrepancy may be indicative of delayed presentations where patients are diagnosed with more advanced disease due to limited access to healthcare services. The most common sites of vertebral metastases were identified as the thoracic and lumbar regions, representing 60 % of cases.

Our results also indicated that half of the patients presented with severe baseline pain. Female patients and those with visceral metastases were more likely to experience severe pain upon presentation (p < 0.05). However, it is noteworthy that this correlation did not remain significant in subsequent follow-up weeks post-RT. Among the different radiation dose regimens, patients receiving 8 Gy were diagnosed with severe pain at baseline at rates significantly higher than those receiving 20 Gy (p = 0.026). This finding is discordant with studies by Sharma et al. and Fairchild et al., which may be due to the inclusion of patients with poorer performance status in our cohort [ 20 , 28 ]. Significantly, there is a lack of data regarding the optimal radiotherapy regimen for metastatic bone disease in resource-limited settings like Ethiopia. In such contexts, where other adjunct treatment options are either unavailable or not accessible in a timely manner, identifying the most effective RT approach becomes crucial. In this regard, our study has evaluated the correlation between dose of radiation and response in pain status in which no significant correlation was observed between the two RT fractionation schedules during the post-RT follow-up weeks.

Additionally, our analysis explored correlations between age, the number of metastatic bone sites, performance status, and depth of RT with a depth point of 5 cm, with all being non-significant. This suggests that these factors may not effectively predict pain outcomes in the context of palliative RT for advanced cancer. We noted that a majority of patients were diagnosed with either primary breast or prostate cancer, which is consistent with epidemiological trends observed in other countries [ [15] , [16] , [17] ].

Considering patients who exhibited a drop in pain score by one or more compared to their baseline as responders, our findings revealed a positive effect of RT on improving patient-reported pain status at 2-, 4-, and 8-weeks post-treatment. Specifically, 65 %, 67 %, and 78 % of patients reported favorable changes in pain status at 2, 4, and 8 weeks, respectively (p < 0.05). The most pronounced improvement in pain status was observed at the 8-week mark, with complete resolution of pain noted in 32 %, 45 %, and 51 % of patients at 2, 4, and 8 weeks, respectively. These outcomes are consistent with previous international studies, where 50 % to 85 % of patients reported pain relief following RT [ [21] , [22] , [23] ].

Different studies have employed varying time intervals following RT to evaluate patient responses. For instance, Nielsen et al. assessed pain response in bone metastatic cancer patients at intervals including 4, 8, 12, and 20 weeks, revealing an increasing trend in pain response over time [ 22 , 24 , 27 ].

Notably, patients with severe pain at baseline showed a higher likelihood of responding positively to treatment compared to those with moderate or mild pain. The benefit of palliative radiation was also seen in patients with performance status of ECOG-3 and – 4, our analysis did not show significant correlation between pain response to radiation and performance status of patients. Therefore, palliative radiation can be given for patients regardless of performance status which gives good generalizability of our study's result to regular patients. While a higher percentage of patients receiving 8 Gy were found to present with severe pain, no significant correlation between RT dose and pain scores at follow-up weeks was established, which aligns with similar findings from abroad [ [23] , [24] , [25] ]. We believe this is an important observation that needs further evaluation if single fraction 8gy RT is an even more appropriate regimen for subgroups of patients with severe pain at presentation. Majority of patients were not started on any form of systemic bone modifying agents throughout the follow up weeks which we identify it as an area that needs improvement in the treatment of such patients in Ethiopia. (Data not shown here).

An important observation in our study pertains to the utilization of analgesics during the post-RT follow-up weeks. It was evident that the administration of analgesics was not systematically adjusted based on patients’ pain statuses. Many patients persisted with their baseline medication regimens, while others made alterations independently without medical guidance. Based on the result of this study, the pronounced effect of RT in alleviating pain was observed at 8-weeks post RT, therefore, we recommend close follow up of patients with antipain adjustment at least till 8-weeks post radiation period. Regardless of their reported pain status, the average maximum morphine dosage used per day was 66 mg, suggesting a gap in pain management optimization. To our knowledge our study is the first of its kind evaluating the efficacy of radiation and the role of different radiation dose regimens in the treatment of metastatic bone diseases in Ethiopian setting. We acknowledge that this study has limitations in having a small sample size and a relatively short follow up time to evaluate the longer treatment effect of radiation. We could not also use the 10- point visual analogue scale of pain score due to our observation that most of our patients had difficulty in grading their pain using such scale. Therefore, we used the four-point pain scale. An updated analysis of this study on reirradiation and survival status at - 6, -12, - 24 months will be reported separately.

Conclusion

In conclusion, our study has shown palliative radiotherapy to be effective in alleviating pain severity among majority of stage IV cancer patients in Ethiopian cancer setting. Moreover, it reveals that the majority of patients with bone metastases, primarily from breast or prostate cancer, had multiple metastatic sites, with half presenting severe baseline pain, especially among females and those with visceral metastases. Most patients received a single 8 Gy fraction of radiotherapy, which demonstrated comparable effectiveness in reducing pain severity when compared to patients who received fractionated 20 Gy doses. Notably, significant pain reduction was observed around the 8-week mark after radiation treatment. Importantly, those with severe pain at baseline were more likely to respond positively to treatment. These findings underscore the urgent need for enhanced pain management protocols in Ethiopia, particularly for advanced cancer patients. We recommend close follow-up and adjustments to analgesic therapy based on patient-reported pain levels for at least 8 weeks post-radiotherapy. While our study provides valuable insights, further research is needed to evaluate the feasibility and effectiveness of the 8Gy regimen to refine optimal treatment strategies for Ethiopian patients.

CRediT authorship contribution statement

Haimanot Kasahun Alemu: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Ahmedin Jemal: Writing – review & editing, Visualization, Supervision, Resources, Methodology, Funding acquisition, Conceptualization. Mathewos Assefa: Writing – review & editing, Visualization, Supervision, Resources, Methodology, Funding acquisition, Conceptualization. Edom Seife: Writing – review & editing, Visualization, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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