Introduction

Development of distant metastasis is seen with progression of cancer, and once distant spread occurs, the disease becomes more advanced, mostly incurable, and fatal¹. Among different organs involved by metastatic cancer cells, bone seems to be third in order, only after lung and liver²,³. The frequent primary malignancies those usually cause bone involvement as distant spread are breast, prostate, lung, kidney, and multiple myeloma¹,³,⁴. Bone metastasis can be osteoblastic or osteolytic or mixed type, depending on the interaction between circulating cancer cells and bone formation mechanism⁵. Osteoblastic deposits are predominantly seen in prostate cancer; osteolytic lesions mainly occur in multiple myeloma, renal cell carcinoma, and mixed type lesion can be seen in primary breast cancer, gastrointestinal malignancies, and so on⁶. Long-term and diffuse, multiple bone involvement by secondary deposits leads to a few typical sign and symptoms, collectively known as skeletal related-event (SRE)⁴,⁷. These can be pathological fracture, compression of spinal cord, impairment in movement, bone marrow depression leading to anemia or pancytopenia, hypercalcemia, and most importantly severe, refractory pain⁴,⁶,⁷. Majority of patients having bone metastasis presented with chief complain of severe bone pain not relieving by routine analgesics and thus having decreased daily performance and poor quality of life (QoL)⁸.

The appearance of bone metastasis in any malignancy denotes poor prognosis and in most of the cases, the treatment intent becomes palliation⁹,¹⁰. The treatment of bone metastasis includes an inter-disciplinary multimodality effort with contributions from various fields such as involvement of orthopedic surgeon, radiation and medical oncologists, nuclear medicine specialists, interventional radiologists, pain specialist, and often neurovascular surgeons⁹. Therapeutic strategy includes but not limited to external beam radiotherapy (EBRT), systemic therapy consisting of chemotherapy, targeted agents and hormonal drugs, targeted radionuclide therapy, surgical and orthopedic intervention, and associated conservative therapies with bone-targeted agents such as bisphosphonates and receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors⁴,⁸. EBRT provides dramatic relief in localized metastatic bone pain and is considered the reference treatment in palliation of pain and other SRE caused by bone metastasis⁶. After EBRT, rapid pain relief usually occurs in majority of the patients with more than 50% of patients had complete pain relief⁶,¹¹. Historically, multifractional dose-schedules were considered appropriate for palliation of bone metastasis¹⁰,¹². However, a few analyses, in different parts of world, comparing single versus multifraction have concluded that single fraction dose-schedule is as effective as traditional multifraction regimen¹³-¹⁷. The same has been assessed in this study in bone metastasis patients of Indian origin. The purpose of this study was to compare three schedules of palliative radiotherapy (6 Gy single session [SS], 8 Gy SS, and 10 Gy in 2 fractions, 1 week apart) with respect to pain-relieving and functional status improving in patients of painful bone metastases from any primary.

Materials and methods

This is a prospective and randomized study, which was conducted on patients of painful bone metastases from any solid tumor primary. Bone metastasis was confirmed by either histopathology (biopsy or cytology) or by modern imaging technique (magnetic resonance imaging, bone scintigraphy or positron emission tomography). All the patients had histopathological proven primary malignancy and most of them received treatment for primary earlier. The pre-treatment evaluation was done in all patients which included complete history, general physical, and systemic examination. The assessment of the patient’s functional outcome was done by Eastern Cooperative Oncology Group (ECOG) performance status score. The pain score in each patient was calculated using the Glasgow pain scale. Based on the initial evaluation, those patients were considered eligible for the study, who were having ≥ 18 years of age, pain intensity on a numeric rating scale of 4-10, and were ready for palliative EBRT to metastatic site(s). Those patients were excluded from the study, who had been treated before with radiotherapy to the concerned region and patients having any serious comorbid conditions to which the patient’s symptoms could be attributed. Patients having single-site bone metastasis, with controlled primary and could be taken for curative treatment were also excluded from the study.

The study was conducted after getting informed consent from all the enrolled patient and approval of the institutional review board. All the enrolled patients were randomly divided into three groups equally with the help of computer-generated randomization. In all three groups, all the patients received palliative EBRT to involved site (single or multiple bones). Patients were given 6 Gy SS, 8 Gy SS, and 10 Gy in two fractions (5 Gy/fraction, 1 week apart) in Group I, II, and III, respectively. EBRT was given on megavoltage cobalt-60 teletherapy machines in 2-dimensional conventional technique, taking appropriate margin as per standard guidelines. Treatment position was prone or supine depending on the involved bone(s) and treatment technique. EBRT was combined with associated conservative treatment as needed. Radiation therapy to primary site and systemic therapy, that is, chemotherapy and targeted agents (intravenous or oral metronomic) were administered to patients as indicated, to reduce the primary and metastatic disease burden. Repeat palliative radiation to the same site was offered if pain did not subside significantly, a minimum of 3 months after first radiation. Patients were followed up after radiotherapy for a total period of 6 months, that is, bi-weekly for 1 month, and then monthly for 5 months. At each follow-up, patients were assessed for pain palliation using the Glasgow pain scale and functional outcome using the ECOG score.

Primary objectives were to assess overall pain response and improvement in functional or performance status. Secondary objectives measured were complete pain relief, duration of overall pain response, analgesic requirement, and need of reirradiation. Overall pain response was defined as decrease in pain score by at least two points with respect to the pre-treatment value. Improvement in performance status was defined as a decrease in ECOG score by at least one grade with respect to pre-treatment value. Complete pain response was defined as achieving a pain score of 0 at any point during follow-up. Duration of overall pain response was defined as time from initial response till return of pain to its baseline value.

The data thus received were entered in Microsoft Excel (version 2019) and analyzed with Statistical Package for the Social Sciences software version 26.0. Patient characteristics were summarized using descriptive statistics. Quantitative data were presented as mean and standard deviation, while qualitative data were presented as ratios and proportions. A comparison of quantitative data was done by analysis of variance test after confirming the normality of the data. Chi-square test and Fisher’s exact test were used for qualitative data whenever two or more than two groups were used to compare. The level of statistical significance was set as p < 0.05.

Results

Over a period of 1 year, a total of 60 patients, fulfilling inclusion criteria, were enrolled in this study, after getting informed consent and were equally randomized into three groups as mentioned earlier, that is, each group having 20 patients each. Details of patients’ characteristics were depicted in tabulated format (Table 1) and there was no significant difference among the three groups. The mean and median age of presentation was 56.9 years and 60 years, respectively; the range was from 27 to 85 years (Fig. 1). Baseline tumor profiles, both primary and metastatic, were also illustrated in table 2. Tumor characteristics appeared to be well-balanced among the study groups, with the majority of patients having lung cancer as primary lesion.

Figure 1 Age-wise distribution of bone metastasis patients in all the three groups. 

Post-treatment observation for primary and secondary endpoints in all three groups was depicted in tabulated format (Table 3). Maximum patients got pain relief at 4^th week (1 month) post-radiotherapy, and all patients had sustained pain relief, that is, pain score less than pre-treatment pain score anytime during 6^th month of follow-up. The mean baseline pain score was significantly reduced after 4^th week of post-radiotherapy in all three groups (Fig. 2). From the 4^th week (1 month) to 4 months, almost a similar mean pain score was observed. From the 5^th month follow-up, there was an increase in mean pain score in each group but never equal to or above pre-treatment values. Mean ECOG performance status was improved after radiation therapy in all three groups (Fig. 3). Most patients of all three groups had decrease analgesic requirement at 1-month follow-up. Furthermore, a downward shift in analgesic uses, that is, from use of opioids to non-opioid, simple non-steroidal-anti-inflammatory-drugs (NSAIDs), was also noticed in all the groups. However, an increasing trend of analgesic requirement was observed 5^th month follow-up onward, and this was true for all three groups.

Figure 2 Mean pain score in patients of bone metastasis in all the three groups before and after radiation therapy. 

Figure 3 Mean ECOG (Eastern Cooperative Oncology Group) performance status of bone metastasis patients in all the three groups before and after radiation therapy. 

Discussion

Bone is very common sites for secondary deposits in advanced solid tumor. Most of the time, skeletal metastasis is seen in multiple bones⁶. Pain is the most common presenting symptoms in patients having bone metastasis. It may be localized or diffuse, progressive with time, and often worsen with daily routine activities; at first relived by conventional analgesics, that is, NSAIDs; but later opioids and other modalities of management are needed for pain relief¹⁸. Efficacy of bone-targeted agents such as bisphosphonates (zoledronate, ibandronate, pamidronate etc.), RANKL inhibitor (denosumab) in bone metastasis by reducing pain, decreasing fractures incidence, and less chance of developing new skeletal lesions and thus improve the QoL is well established¹⁹,²⁰. Howbeit, in practical situation many patients did not get the expected benefits from this treatment; thus, to prevent further disease progression and also for more palliation benefit additional treatments for bone metastasis needed²¹. Radiotherapy, both EBRT and radionuclides, can be used in the management of analgesic-refractory pain arising from skeletal metastasis¹⁸,²². Local site EBRT, using either small-to-medium field radiation or large-field like hemibody irradiation, is established treatment for palliation of bone metastasis²²-²⁴. Conventionally, 30Gy in 10 fractions was the most widely used dose-fractionation schedules in achieving palliation of these patients¹⁰,¹²,²³. However, various other dose fractionations were widely explored and used as routine practice globally (Table 4)¹³-¹⁷,²⁵-²⁷. Two large-scale meta-analyses also confirmed the pain-relieving efficacy of different single dose-fractionation schedules²⁸,²⁹. Practice of single fraction RT was also increased during the COVID pandemic as it decreased number of hospital visit without hampering effective pain control³⁰.

Our analysis revealed an equal incidence of bone metastasis among male and female. In general, gender-wise incidence of bone metastasis depends on the primary tumor site; more female patients if breast tumor is the most common primary, while male predominance if prostate cancer primary found to be more. A few studies documented male majority in bone metastasis, whereas female preponderance also noticed in some analyses¹³,²⁷,³¹-³³. Three-fourths of our patients were from rural background. This data strongly matched with the data from Korean study, both India and Korea are Asian country with majority of people living in rural region³². Our analysis showed that lung cancer was the most common primary site (37%) followed by breast and prostate in decreasing frequency. These data were different from that were mentioned in the literature, where either breast or prostate was the most common primary²⁴,²⁵,³¹-³³. However, other studies from the same country also denoted lung cancer as the most common primary metastasizing to bone⁷,²⁶. Around 40% of patients in our study had bone metastasis initially, that is, at the time of primary cancer diagnosis. This also matched nearly with the similar data from another Asian country³². Nearly two-third of patients (65%) of our study cohort had bone metastasis in vertebrae and pelvis, bones rich in red bone marrow. This finding is in consistent with existing literature²¹. Overall reirradiation rate (13.33%) in our analysis matched closely with the reirradiation rate of single fraction RT (14%) in a 5-year retrospective study conducted in Belgium³⁴.

A few limitations are there in our study. Among these, the significant drawback was very small sample size, that is, only 60 patients. Another limiting factor could be not evaluating the association of other treatment modalities such as systemic therapies and bisphosphonates along with radiation in assessing the primary objectives. On contrary, the interesting fact of our study was that all three groups have nearly equal schedules in terms of fractions and radiobiological perspective. Inclusion of all metastatic bony site irrespective of subsite specification is also unicity of our analysis.

Conclusion

It was observed that all three schedules provided good palliation in the painful bone metastases. However, Schedules II and III were found to be more effective in comparison to Schedule I with better overall pain relief, complete pain relief, and improved performance status. In conclusion, it can be stated that all three schedules of palliative EBRT can be given in painful bone metastasis patients depending on patient tolerability and compliance. This single or two fractions’ schedules in palliation of bone metastasis in limited resource settings are very useful, both for patients and health-care providers