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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
Faculty of Medicine
Oncology and Hematology department
Palliative radiotherapy treatment effect on patients with metastatic
bone disease:
Systematic review
Master's Thesis
Thesis author:
Ilana Reznikov
Kaunas, 2019 Thesis Supervisor:
Assoc.Prof. Dalia Skorupskienė MD, PhD
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TABLE OF CONTENTS
1. SUMMARY 3
1.1. Santrauka 4
2. CONFLICT OF INTEREST 5
3. ETHICS COMMITTEE APPROVAL 6
4. ABBREVIATIONS LIST 7
5. TERMS 8
6. INTRODUCTION 9
7. AIM AND OBJECTIVES OF THE THESIS 11
8. RESEARCH METHODOLOGY AND METHODS 12
9. RESULTS AND THEIR DISCUSSION 14
9.1 The effect of palliative radiotherapy fractionation schedule on pain response in patients with bone metastases 14
9.2 Palliative radiotherapy treatment effect on different age groups on patients with bone metastases 16
9.3 The developing toxicities after palliative radiotherapy treatment on painful bone metastases 18
9.4 Palliative radiotherapy effect on quality of life of patients with metastatic bone disease 22
9.5 Palliative radiotherapy treatment effect on survival prognosis in patients with bone metastases 24
9.6. Palliative radiotherapy treatment effect on complicated bone metastases 26
10. CONCLUSIONS 28
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1. SUMMARY
Author’s name and surname: Ilana Reznikov
Research title: Palliative radiotherapy treatment effect on patients with metastatic bone disease, a systematic review.
Introduction: Palliative radiotherapy treatment for bone metastases skeletal related events, among all other treatment methods, has been proven to be the most efficient treatment. The outcome is up to 70% symptoms relief [6, 7]. Optimization of palliative radiotherapy treatment has been further investigated in order to produce the best results possible. In this study we are going to systematically review the most recent studies that provide information regarding the most optimal and efficient usage of palliative radiotherapy on bone metastases.
Research Aim: To review the most recent literature and guidelines about the influence and use of palliative radiotherapy treatment on patients with metastatic bone disease.
Objectives: 1. Review the latest studies regarding the optimal utilization of palliative radiotherapy treatment dosage and fractionation quantity on patients with bone metastases. 2. Review the latest studies outcomes of patients with bone metastases undergoing palliative radiotherapy treatment.
3. To give an update about the treatment of complicated bone metastases with palliative radiotherapy according to the latest studies.
Methodology: In this study PRISMA guidelines for reporting systematic review were implemented. 34 of the most relevant and recent studies in the last 10 years were cited.
Research results: Single fraction radiotherapy regimen was compared to the multi-fraction radiotherapy regimen on patients with bone metastases in several studies, pain relief was evaluated. Special consideration was noted to age as an influencing variable. Further assessment of the adverse effects produced after palliative radiotherapy treatment were recorded, in concomitance with patients quality of life, and post radiotherapy survival rates. Influence of palliative radiotherapy treatment on complicated bone metastases was also reviewed as a variable for future relevance.
Conclusions: In this systematic review we concluded that a single fraction radiotherapy regimen found to be as efficient as multi-fraction radiotherapy treatment and independent of age. The outcomes presented were significant pain relief, quality of life improvement; minimum adverse effects and no life threatening events after palliative treatment.
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1.1. SANTRAUKA
Autorius, vardas ir pavarde: Ilana Reznikov
Pavadinimas: Paliatyvios spindulinės terapijos efektyvumas gydant pacientus su metastazėmis kauluose: sisteminė apžvalga.
Įžanga: Paliatyvi spindulinė terapija yra laikoma vienu iš efektyviausių metodų, gydant metastatinę kaulų ligą. Simptomų (skausmo ir kt.) kontrolė pasiekiama 70 procentų atvejų [6,7]. Norint pasiekti geriausių rezultatų,tikslingi tolimesni paliatyvios spindulinės terapijos tyrimai, jos optimizacija. Šiame tyrime bus sistemiškai apžvelgtos visos naujausios klinikinės studijos, kuriose pateikti duomenys apie optimalų ir efektyvų paliatyvios spindulinės terapijos naudojimą, gydant metastazes kauluose.
Tyrimo tikslas: apžvelgti naujausią medicininę literatūrą, kurioje nagrinėjamas paliatyvios spindulinės terapijos naudojimas ir jos efektyvumas, gydant pacientus su metastazėmis kauluose. Uždaviniai: 1. Peržiūrėti naujausių klinikinių studijų duomenis apie paliatyvios spindulinės terapijos dozės ir jos frakcionavimo optimizaciją, gydant pacientus su metastazėmis kauluose. 2. Apžvelgti paskutinėse klinikinėse studijose nurodomus paliatyvios spindulinės terapijos poveikius (efektą) pacientams su metastazėmis kauluose.
3. Įvertinti naujausių klinikinių tyrimų duomenis apie komplikuotos metastazinės kaulų ligos gydymą paliatyvia spinduline terapija.
Tyrimo metodika: šiame tyrime panaudotos PRISMA metodinės rekomendacijos, skirtos pristatyti.sisteminėms literatūros apžvalgoms. Cituojamos 34 iš naujausių ir svarbiausių klinikinių studijų, vykdytų paskutinių 10 metų laikotarpiu.
Rezultatai: Keliuose klinikiniuose tyrimuose lygintos vienos ir kelių frakcijų spindulinės terapijos metodikos, gydant pacientus su metastazėmis kauluose, vertintas poveikis skausmui. Atsižvelgta į pacientų amžių, kaip faktorių, galintį turėti įtakos gydymo efektyvumui. Vertintas šalutinis (nepageidaujamas) paliatyvios spindulinės terapijos poveikis gydymo metu ir po jo, atsižvelgiant į pacientų gyvenimo kokybę, gyvenimo trukmę po spindulinio gydymo.Apžvelgtas ir paliatyvios spindulinės terapijos efektas, gydant komplikuotas metastazes kauluose, kaip tolimesnių tyrimų, stebėjimo ateityje objektas.
Išvados: Remiantis šios sisteminės apžvalgos duomenimis, galima daryti išvadą, kad vienos frakcijos spindulinė terapija yra tokia pat efektyvi, kaip ir daugia (multi)frakcijinis paliatyvus spindulinis gydymas, nepriklausomai nuo paciento amžiaus.Paliatyvios spindulinės terapijos poveikis buvo: ryškus skausmo sumažėjimas, gyvenimo kokybės pagerėjimas. Stebėtas minimalus šalutinis poveikis be gyvybei pavojingų komplikacijų.
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2. CONFLICT OF INTEREST
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3. CLEARANCE ISSUED BY THE ETHICS COMMITTEE
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4. ABBREVIATIONS
ADL- activities of daily living
BPI- brief pain inventory
ECOG- Eastern Cooperative Oncology Group
EORTC QLQ-BM22- European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases Module
KPS- Karnofsky performance scale
MESCC- metastatic epidural spinal cord compression
MFRT- multiple fraction radiotherapy
MTD- maximum tolerated dose
NRS- numeric rating scale
PRO- patient reported outcome
QOL- quality of life
QLQ-C30- Quality-of-life Questionnaire Core 30
RINV- radiotherapy induced nausea and vomiting
SFRT- single fraction radiotherapy
SRE- skeletal related events VAS- visual analogue scale
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5. TERMS
Acute toxicity symptoms- symptoms which appear up to 90 days after radiotherapy treatment
Grade 1/2/3/4 toxicity- indicates the severity of a symptom appearing by relaying on an agreed international classification and scales.
Gy (also known as Gray)- unit of ionizing radiation dose in the international system of units, measured based on the amount of radiation absorbed by the tumor in the patient.
Hazard ratio- a term used in survival analysis, the stronger the hazard ratio the more influence it has.
Katagiri scoring system- a score used to predict the survival in patients with bone metastases who undergo palliative radiotherapy. The system was constructed by investigating 808 patients with symptomatic bone metastases. It uses primary lesion, visceral or cerebral metastases, abnormal laboratory data, poor performance status, previous chemotherapy and multiple skeletal metastases as predictive factors.
Late toxicity symptoms- symptoms which appear later than 90 days after radiotherapy treatment
Pain flare- a temporary sudden worsening in bone pain, in a previously irradiated metastatic bone.
Performance status- in cancer patients certain scales are filled, those scales are given a score, the score calculated is representing the well being of the patient and his/her ability to ambulate and perform daily life activities without needing the help of others.
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6. INTRODUCTION
Bone metastases are spreading of the primary tumor site to the bone, occurring in advanced cases of the disease. There are certain types of malignancies which develop bone metastases more common than others such as: prostate (70%), breast (70%) and lung cancer (15-30%) [1], the less common malignancies are: thyroid, kidney, uterus and urinary bladder cancer [2]. Involvement of the bone may further complicate the course of the disease and result in skeletal-related events (SREs) such as bone pain, bone fractures, impaired mobility or joint function, spinal cord compression, hypercalcemia and decreased bone marrow function [3]. With the progression of the disease and development of bone metastases patient’s life expectancy and future prognosis worsens, with median survival rate of 7 months [4]. Patient’s quality of life and activities of daily living (ADL) worsens subsequently and result in physical and psychological difficulties, with consideration to social and demographical determinants which seem to contribute [5].
The goal in these patients is not eradicating the disease but rather giving the patient palliation to his current state and to allow the best possible life quality, by reducing pain, returning functional abilities and preventing further complications. Many methods exist in the field for that particular purpose: pain medication, bone modifying agents as bisphosphonates and Denosumab, orthopedic stabilization, chemotherapy agents, radiopharmaceuticals, and palliative radiotherapy [3].
Palliative radiotherapy for bone metastases SREs among all other treatment methods has been proven to be the most efficient treatment, which result in up to 70% symptoms relief [6, 7]. Optimization of palliative radiotherapy treatment has been further investigated in order to produce the best results possible. Palliative radiotherapy dosages: 8 Gy versus 20 Gy/30 Gy, number of treatment cycles given: single fraction radiotherapy (SFRT) versus multiple fraction radiotherapy (MFRT), symptoms response predictors as age, genetic markers, and life expectancy were compared. Post radiotherapy adverse effects were summarized and further investigated on how to prevent them. Patient’s quality of life (QOL) were assessed and evaluated concomitantly as a palliative radiotherapy treatment response. The aim of this study is to
10 systematically review the most recent studies that show the most optimal and efficient usage of palliative radiotherapy on bone metastases.
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7. AIM AND OBJECTIVES OF THE THESIS
Research Aim: To review the most recent literature and guidelines about the influence and use of palliative radiotherapy treatment on patients with metastatic bone disease.
Objectives: 1. Review the latest studies regarding the optimal utilization of palliative radiotherapy treatment dosage and fractionation quantity on patients with bone metastases. 2. Review the latest studies outcomes of patients with bone metastases undergoing palliative radiotherapy treatment.
3. To give an update about the treatment of complicated bone metastases with palliative radiotherapy according to the latest studies.
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8. RESEARCH METHODOLOGY AND METHODS
Data collection process and strategy:
In this study PRISMA guidelines for reporting systematic review were implemented as an
outline. A detailed criteria checklist and a specifically designed outflow chart as seen in Figure 1. was used.
Information sources:
- The searches were conducted between 2017 up to March 2019. - https://www.ncbi.nlm.nih.gov/pubmed/ - PUBMED database - https://scholar.google.lt/ - Google scholar
- https://www.sciencedirect.com/ - ScienceDirect
- https://www.cochrane.org/ - Cochrane controlled trials register Search:
- Keywords\terms used: bone metastases, bone pain, palliative radiotherapy, dose response, quality of life, social determinants, advanced cancer, fractionation, brief pain inventory, survival.
- Sentances used: „Palliative radiotherapy treatment on bone metastases“ „Pain response in patients recieving radiotherapy for bone metastases“
„Survival prognosis in patients undergoing radiotherapy for metastatic bone diseases“ „Complicated bone metastases and their management“
„palliative radiotherapy for bone metastases in elderly“
„Adverse effects in patients recieving palliative radiotherapy for bone metastases“
„ Quality of life assesment in patients recieving radiotherapy for metastatic bone disease“ The search was limited in the search engine for articels from the last 10 years.
Eligibility criteria:
- Finished status studies published between the years 2009-2019.
- Studies published in English language or translated to English language from the original source.
13 - Prospective types of studies were used: prospective cohort studies and randomized
control trials.
- Study population must have evidence of bone metastases, symptoms related to bone metastases and treated by radiotherapy.
Exclusion criteria and risk of bias: - Studies published before 2009.
- In order to avoid attrition bias, studies which had large amount of dropouts from it, due to any reason were excluded.
- In order to avoid sample bias, studies with very small population sample were excluded. - Absence of crucial information, or an important variable such as evidence of bone
metastases, bone metastases related symptoms and treatment by radiotherapy. - Studies designed without control groups.
- Studies with a less pertinent headline and abstract description.
Figure 1. PRISMA flow chart displaying how articles was being excluded and included in the data collection processes
1452 Studies were identified through database search
hing keywords
4905 Additional records were identified through other sources
1164 studies were left after duplicates and exclusion criteria was applied
451 studies were screened due to their
relevancy (n = )
406 studies were excluded
45 Full-text articles were assessed for eligibility
11 Full-text articles were excluded, due to specific
reasons
34 studies were included in the systematic review
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9. RESULTS AND THEIR DISCUSSION
9.1. The effect of palliative radiotherapy fractionation schedule on
pain response in patients with bone metastases
Radiotherapy is the main treatment for pain relief and palliation in patients with metastatic bone disease [8, 12]. Two main approaches are used nowadays, the single fraction radiotherapy (SFRT) of 8 Gy or the multiple fraction radiotherapy (MFRT) of different regimens 20 Gy in 5 fractions over one week, or 30 Gy in 10 fractions over two weeks. When considering performing radiotherapy certain characteristics have to be taken into consideration prior to the procedure, in order to decide which type of approach is more suitable. Patient's performance status (according to performance status scales used in cancer (oncological) patients), life expectancy, and
treatment compliance will decide whether the patient will be able to withstand the whole treatment prescribed or not. Bone metastases localization, histology, presence of symptoms, presence of complications (pathologic fractures, neurological compromise), expected
toxicity/adverse effects post radiation will decide which regimen is more beneficial. Treatment cost, and family assistance are also taken into consideration [9]. In medical practice MFRT is used more frequently then SFRT [1, 11], although there is evidence that demonstrates the
benefits of single fraction radiotherapy. This subject has been widely investigated and compared in many studies.
In a study performed by Conway et al [10] 968 patients from six cancer centers have participated and completed the study tasks. The study aim was to compare patient reported outcomes post SFRT versus MFRT; the researchers used 8 Gy for SFRT and 20 Gy of 5 fractions for MFRT. For evaluation Patient Reported Outcome (PRO) scale was assessed at the time of CT simulation and 3-4 weeks following the completion of radiotherapy treatment. The results found no significant statistical difference between SFRT and MFRT influence in overall pain response (74% and 75% respectively), symptom frustration (78% and 80% respectively) and function restoration (73%and 79% respectively). Another study performed by Nongkynrih et al [2] also compared single versus multi-fraction palliative radiotherapy on painful bone metastases, 60 patients have participated, they were divided into three equal groups, one group
15 received a treatment of 8 Gy in one fraction, the second group received 20 Gy in 5 fractions and the third group received 30 Gy in 10 fractions. The patients were assessed by visual analogue scale (VAS), Eastern Cooperative Oncology Group (ECOG) scale, and by Karnofsky performance scale (KPS) for 6 months. The results showed no significant statistical difference in complete pain response (group I, II and III 20% each), overall pain response (group I- 80%, group II- 75%, group III-85%), and decreased analgesic (pain medication) requirements (group I, II and III 65% each). In a prospective study conducted by Anter [11] 88 patients have completed the study. The patients were divided randomly into two equal groups by characteristics, one group received 8 Gy of radiotherapy in a single fraction and the second group received 20 Gy of radiotherapy in 5 fractions. They were assessed by numeric rating scale (NRS) for pain intensity prior to the procedure and 3 months post radiotherapy. The results obtained showed no significant statistical difference between the groups pain scores; complete pain relief was 18% in group A and 22% in group B, similar results appeared in partial pain relief. In another prospective study performed by Jilla et al [12] 45 patients participated and completed the study. They were divided into three groups of different radiotherapy regimens randomly and equally, group A received 8 Gy in a single fraction, group B received 20 Gy in 5 fractions and group C received 30 Gy in 10 fractions. The patients were assessed by Pain score, ECOG performance scale, and analgesic requirement questioner for 3 months of follow up after radiotherapy. The results once again showed no significant statistical difference between the different regimens; pain relief: group A 78%, group B 80%, group C 80%, improvement in performance status results has given the same percentages as in pain relief respectively, and decrease in analgesic requirements: group A 85.7%, group B 86.6%, group C 80%. Rades et al [13] compared a single fraction of 8 Gy versus 20 Gy in 5 fractions radiotherapy treatment influence on metastatic epidural spinal cord compression (MESCC). Although the study was analyzing data only regarding the MESCC complication it also evaluated treatment outcome, the need for re-irradiation, post radiotherapy motor function improvement and overall survival. As in previous studies mentioned no difference was found between the fractions regimens in all fields. Majumder et al [14] concluded the same regarding radiotherapy regimens for palliation of painful bone metastases; the study compared 30 Gy in 10 fractions with 8 Gy in a single fraction. The only statistically significant finding was pain response initiation time, which started earlier in patients undergoing 30 Gy in 10 fractions treatment (P=0.0281). However Cacicedo et al [17]
16 who investigated whether patient's age has influence on pain response after receiving palliative radiotherapy for bone metastases found that patients receiving multiple fraction regimen of 20 Gy in 4 or 5 fractions had a better pain response then those receiving a single 8 Gy fraction (70.5% and 45.9% respectively), it found to be statistically significant. From the studies reviewed only one demonstrated the superiority of one radiotherapy regimen over the other.
9.2. Palliative radiotherapy treatment effect on different age groups
on patients with bone metastases
Table 1. Palliative radiotherapy effect on pain response in different age groups
Author/year Pain Response Statistically
significant (p-value<0.05)
yes/not <65 years 65-75 years >75 years
Paulin G. Westhoff/2014 78% 74% 67% No 405/520 303/410 152/227 Sarak Campos/2010 49.55% 53.6%* - No 111/224 179/334* - Jon Cacicedo/2018 53.6% 60.9% 80.8% Yes 30/56 28/46 21/26 Ronald Chow/2017 <70 years >/=70 years No 28.4% 32.5% 108/382 60/185 * >/= 65 years
Advances in technology have led with time to a growth in the life expectancy; elderly population grew in percentage with more than 50% over the age of 65 years [15]. Cancer
17 incidence increases with age, with majority of cases discovered between the ages of 60 and 69 years, so does the incidence of metastatic bone disease, which is found more often in the older population with advanced disease. The new modern possibilities allow a better diagnosis of cancer, and the enhanced discovery of bone metastases. Elderly population exhibits multiple comorbidities, poor performance status, fragility, and decreased cognitive abilities compared to the younger population. Physicians also take into consideration the multi-morbidities and take precaution of possible toxicities which may appear after radiotherapy treatment [16]. These facts have led to the under treatment of cancer and under representation of the older patients in clinical trials. These patients are referred less for such treatments as palliative radiotherapy for pain relief. Many studies have been conducted upon the question whether age should be taken into the consideration for further treatment.
Table-1 summarizes the studies mentioned in this section and their results regarding pain response in different age groups. A study performed by Westhoff et al [15] investigated whether age affects the response to palliative radiotherapy on painful bone metastases and changes in quality of life. 1099 patients have completed the study and were randomized into three groups by age; group A- were patients under 65 years, group B- 65-74 years and group C- patients older than 75 years. After a period of two years, no significant differences were noted between the three age groups, group B and C which consisted of elderly population patients have demonstrated 74% and 67% pain response respectively. The response to palliative radiotherapy was found to be higher than expected and independent of age; pain reduction led to improvement in quality of life, according to questionnaires filled and summary results. There must be also noted that patients with breast cancer or prostate cancer more frequently had improvement than those with lung cancer and other tumors. Hence type of primary tumor has to be considered instead of age. Campos et al [16] conducted a study which investigated the efficacy of palliative radiotherapy on painful bone metastases in the elderly population according to age groups. 558 patients have completed the study, they were divided according to their age and other demographical characteristics, groups of <65 versus >/=65 years, <70 versus >/=70 years and <75 versus >/=75 years were formed and evaluated at 1, 2 and 3 months after radiotherapy treatment. One of the evaluating methods was Karnofsky performance status (KPS), KPS score was found to correlate with patient's age, with younger patients having a better higher score. The researchers found that the KPS score and the treatment outcome after one month was related, the
18 higher was the initial KPS score at baseline the higher was the response outcome. Although at the second and third month no such relation was established. Average worst pain score has significantly improved over time for all age group patients and the response rate did not differ significantly. Equivalent pain relief after palliative radiotherapy for elderly patients was achieved. Cacicedo et al [17] conducted a prospective study, with 128 patients which have completed the study requirements. Patients as in the studies mentioned above, were divided into three main age groups, under 65 years, 65-75 years and above 75 years. The results yielded interesting findings; it found that in patients over the age of 75 years the response rate was significantly better then in younger patients (80.8% and 56.9% respectively) unlike in previous studies which found no difference, but in the multivariate analysis these results did not achieve statistical significance. Also in patients' filled (during the study) Brief Pain Inventory (BPI), those with higher pain scores between 8 to 10 prior to radiotherapy treatment had 70.8% pain response, while those with a score under 8 had only 50% pain response. In a randomized trial conducted by Chow et al [18] 847 admitted patients were divided by age, with special consideration for gender, and by other demographical criteria. The trial focused on age and gender influence on pain response for patients undergoing palliative radiotherapy for bone metastases, especially when doing re-irradiation. Although re-irradiation was of interest the research kept the conditions similar to those performed in other studies. The initial data showed that older patients reported better emotional/social functioning, less pain and sleep disturbances and less financial worries prior to treatment compared to the younger patients. Although after treatment the younger patients reported better improvement in life enjoyment and in BPI scores. As for the most crucial criteria, both age groups responded to radiotherapy treatment similarly (<70 years old: 28.4%, >/=70 years old 32.5) with similar survival rates. None of the studies reviewed have demonstrated age as a hindrance factor for the further use of palliative radiotherapy.
9.3. The developing toxicities after palliative radiotherapy treatment
on painful bone metastases
19 Table 2. A representation of the toxicity incidence
Author/year Toxicity Statistically
significant (p-value<0.05) yes/not Amanda Hird et-al/ 2009 Pain flare
Symptomatic Duration Yes
1-5 days after 6-10 days after Mean 40% (44/111) 80% 20% 1.5 days Alfonso Gomez-Iturriaga et-al/2015 37.7% (51/135) 88.2% 11.8% 3 days Yes Paul M. Cheon et-al/2015 Fatigue Yes
After 1 month After 2 months
After 3 months
35% 36% 36%
Dawn Owen et-al/2015 - - 39% Yes Dipanjan Majumder et-al/2012 Gastrointestinal No
Grade 1 Grade 2 Grade 3 Grade 4
none 12.1% (8/64) 3% (2/64) none Abeer Hussein Anter/2015 17% (15/88) 8% (7/88) 2.2% (2/88) none No
-was not evaluated
“Primum non nocere” which in Latin means “First of all, do not harm”, is one of the foundation stones of medicine, when giving treatment to a patient we have to be aware of the adverse effects the treatment may evoke and we need to consider whether the treatment is more
20 beneficial or harmful. Palliative radiotherapy has been known to be the main treatment for painful metastases in the bones, it outcomes and adverse effects known as toxicities have been widely investigated. Several studies conducted researches in order to show what are the most common adverse effects, how harmful are they, and what factors influence their development in order to know what specific factors should be especially noticed and addressed accordingly. Table-2 summarizes the studies mentioned in this section and their results regarding toxicity incidence. Previous studies have found that after palliative radiotherapy treatment to the bone was induced, pain flare appeared in certain patients afterwards. It was determined to be 2%-44%, but the diversity in this percentage was too high and inconclusive, researchers couldn't find a linkage between the patients having the symptom. Hird et al [19] conducted a study with the aim to confirm the incidence of pain flare after receiving palliative radiotherapy for symptomatic bone metastases. 111 patients have completed the study requirements, the patients were asked to fill in a daily diary during the treatment, and for 10 days after. They have written in their BPI, analgesic (pain medication) consumption and current pain status (e.g.- worse, same, better). Overall pain flare appeared in 40% (44/111), it lasted for a median time of 1.5 days, with majority of episodes occurring in the first 5 days post radiotherapy (80%), and the rest (20%) on the 6-10 days. No statistically significant difference was found in patients experiencing the pain flare versus those who did not in variables such as age, sex, radiotherapy dose, fractionation, analgesic consumption or radiotherapy target, but the significant difference found was the primary cancer site, 52% from those who had breast cancer had pain flare, and only 25% and 23% with prostate and lung cancer respectively. The occurrence itself of the symptom does not predict the future response of the patient to the radiotherapy but the primary cancer site may predict the possibility of the patient developing the symptom in order to take prior measures accordingly. However in a prospective study performed by Gomez-Iturriage et al [20] no connection was found between the primary cancer site and the other baseline characteristics to the incidence of pain flare episodes. The study established that 51 out of the 135 patients participating in the study have experienced a pain flare episode (37.7%), a similar data as in the previous mentioned study, 88.2% of the episodes occurred in the first 5 days after radiotherapy treatment, and 11.8% in the 6-10 day. Mean pain duration lasted for 3 days. Despite the results, BPI scores drastically reduced in all patients after radiotherapy compared to the pre-treatment results (p<0.001).
21 Another symptom commonly associated with advanced cancer is fatigue, which is defined as subjective feeling of lack of energy, this symptom may arouse and correlate to various reasons such as; pre existing co-morbidities, anti-cancer therapies, psychological status, and pain. Cheon et al [21] performed a prospective study to indicate what the fatigue ratios are in patients receiving palliative radiotherapy for their painful bone metastases. 881patients have participated, they were divided into two groups, group one contained 399 patients and group two 482 patients. Each group completed 3 different questionnaires which followed their health status up to 3 months. In group 1 fatigue scores showed to be increasing significantly during the time period from baseline and after receiving radiotherapy, 35% at the first month after radiotherapy, 36% at second and third month. Unlike fatigue scores, quality of life scores have shown to be significantly improving by each month, with 33% in the first and second month and 37% in the third month. This finding further indicated that the lower was the fatigue scores the higher was the quality of life. No correlation was found between fatigue and other demographical characteristics. Upon analyzing KPS scores it was additionally found that the higher the KPS score was at baseline, the less fatigue patient had after receiving radiotherapy treatment in both groups. However group 2 findings had shown no statistically significant changes in fatigue scores over 3 months follow up unlike in group 1. In group 1 quality of life significantly improved compared to baseline scores, and demonstrated the same correlation to fatigue scores. KPS data has shown the same conclusion as in group 1, the higher the KPS score, the lower the fatigue after receiving radiotherapy treatment. Owen et al [22] conducted a study which aim was to investigate how palliative radiotherapy to non- spinal metastases affects the patient and which toxicities it may produce, 25% of patients (18/72) experienced acute toxicity symptoms, from that group 39% (7/18) of patients experienced fatigue, which was the most common adverse effect. It was found that quantity of radiotherapy fractions was associated with early toxicity development (p=0.03).
Gastrointestinal toxicities were also reported and of interest, in Majumder et al [14] study which investigated the effect of palliative radiotherapy fractions number on the toxicities developing after treatment induction, 12.1% (8/64) of patients had mild grade 2 gastrointestinal toxicity, 3% (2/64) of patients had moderate grade 3 gastrointestinal toxicity. Toxicities were similar between the groups in the study, no additional toxicities were reported and no influencing characteristic or causes were found to be correlated. Anter [11] study’s aim was the same, he
22 investigated whether one radiotherapy regimen produce more toxicities then the other, the results exhibited 22.7% gastrointestinal adverse effects in group A (8 Gy single fraction treatment) and 31.8% in group B (20 Gy in 5 fractions), moreover hematological adverse effects were observed 9% in group A and 15% in group B. No grade 4 toxicities were present in both groups and the differences were insignificant comparing radiation toxicity to fraction number. Owen et al [22] (mentioned in the above section) reported 16% (3/18) of patients having nausea out of the 25% of patients affected by toxicities after radiotherapy. A study performed by Dennis et al [23] investigated the prophylaxis of palliative radiotherapy induced nausea and vomiting (RINV). Of 59 patients who were enrolled in the study, 54% (32/59) experienced nausea or vomiting, it was found to be a common toxicity. According to other literature data it is usually estimated to be 40%-80% and is considered to be dependent on the anatomical region irradiated, although no such connection was investigated in this study.
Other adverse effects which are seen in rare cases: fractures which are usually asymptomatic, lymphedema, pulmonary fibrosis, neuralgia, chest wall pain, and dyspnea. Most cases are categorized as late toxicity and are much harder to predict [22].
9.4. Palliative radiotherapy effect on quality of life of patients with
metastatic bone disease
Radiotherapy treatment success is measured not only by reduction of pain but also by patient’s quality of life aspects improvement and decrease in other complaints. Those life aspects are measured by many different scales which usually involve physical, psychological, social, cognitive and emotional criteria, together with symptom description and scoring of each. Quality of life (QOL) tend to deteriorate in advanced cancer patients with bone metastases, many studies have investigated the level of change after palliative radiotherapy treatment and whether or not QOL is improved and in which domains. The studies which were reviewed in this systematic review found that in patients who had pain response, their QOL had significantly improved. The
23 studies divided the characteristics influencing QOL into more detailed factors in order to be able to provide a more effective symptom management insight in future treatments [5].
A study conducted by Zeng et al [24] researched how QOL would be influenced in patients after receiving palliative radiotherapy treatment for bone metastases. The study used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases Module (EORTC QLQ-BM22) and Quality-of-life Questionnaire Core 30 (QLQ-C30) for assessment and evaluation; they are bone metastases specific evaluative instruments. 59 patients completed the research requirements, for up to 1 month of follow up. No patient had a complete response after radiotherapy, which may serve as a limitation to this study, due to other expected results. At baseline the results of all participating patients were similar and had shown no significant differences in QOL. After 1 month of follow up 37% (22/59) have responded to radiotherapy, although only partially. Responders had lower scores of pain, better physical functioning, less functional interference and reduced constipation, when comparing the results to non-responding patients, results were statistically significant. Another performed study by Westhoff et-al [25] divided 956 patients into 3 main groups according to primary cancer site; breast, prostate, lung and other cancer types which did not fit into any of the groups mentioned, 722 patients (76%) have responded to palliative radiotherapy treatment, their results were compared to the non-responders. At baseline significant statistical difference was found in activity level between the groups, but in none of the other parameters compared. After 12 weeks non-responders got higher scores in all domains, which means increased number of complaints; psychological distress, and deterioration in the activity level. An interesting finding was that non-responders had more frequently lung cancer than other types; order of response was breast (82%), prostate (79%) and lung (62%) cancer. Best responders were the prostate cancer group which had the best QOL scores. Lam et-al [5] study hypothesized that QOL is not only dependent on whether or not the patient is responding to the radiotherapy treatment, but it also depends on patient life situation and surroundings, 397 patients were studied, 75.8% were females and only 24.2% were males, which may serve as a limitation due to the inequality and inaccurate population representation. It was shown that patients who were employed had a better physical functioning during the follow up compared to unemployed patients, they had especially less insomnia and more social functioning. Moreover the higher was the KPS score the better was QOL the patient had. In this study especially prominent result was breast cancer patients
24 having significantly higher physical, social and rule functioning, it was statistically significant, but it may contribute to the fact that majority of the participating in the study were female patients.
9.5. Palliative radiotherapy treatment effect on survival prognosis in
patients with bone metastases
Table 3. Median survival rates of patients who underwent palliative radiotherapy treatment
Palliative radiotherapy is a time consuming treatment, short course treatment consist of 8 Gy in a single fraction or 5 Gy in 4 fractions and it takes up to a week to complete. The long course of radiotherapy treatment consists of 3 Gy in 10 fractions over 2 weeks or 2 Gy in 20 fractions over 4 weeks duration, it may occupy patients remaining lifetime. A patient with metastases in bones is in advanced stage of the disease, his state may serve as a restriction and prevent full therapy completion [34]. In order to adjust treatment to patient’s remaining life span; few studies investigated life expectancy by using different scoring systems to be able to determine the most optimal and suitable treatment duration [28-29].
Author/Year Median survival Statistically
significant (p-value<0.05)
yes/not
Dirk Rades/2015 3 months No
Hikaru Kubota/2019
Low risk group Intermediate risk group
High risk group Yes
27 months 6 months 2 months
Wen-Yi Zhang/2016
25 Table-3 summarizes the studies presented in this section; it presents the results of each study on the median survival rates after the admission of palliative radiotherapy treatment. Rades et al [13] investigated different fraction regimens of radiotherapy on patients with bone metastases complication having MESCC and their influence on patient’s survival prognosis. Patients having MESCC are in advanced stages of cancer, and already have a poor survival prognosis; they differ by survival rates from patients with uncomplicated metastatic bone disease who do not have bone fractures or neurological compromise. This characteristic may serve as a limitation and has to be taken into consideration since it shortens patient’s life expectancy. Two groups containing 121 patients each were formed, one group was receiving 8 Gy regimen in a single fraction, and the other group 5 Gy in 4 fractions. Patients were followed until death; median survival was 3 months after treatment (range: 5-16 months), the more time passed the more overall survival rate decreased after radiotherapy treatment; at 3 months 50%, at 6 months 24%, at 9 months 16% and at 12 months 11%, no correlation was found between the regimen type and survival prognosis. A retrospective study performed by Berger et al [26] contributed to the subject by researching 22 patients with bone metastases, who died during treatment or shortly after. While calculating the remaining lifetime the study took into consideration the time from treatment indication, treatment awaiting, and treatment duration, it concluded that majority of patients who died in that time period had previous severe co-morbidities, or were referred too late, and without consideration of their remaining survival time. Kubota et al [27] explored patient’s life expectancy by applying the Katagiri scoring system unlike previous studies mentioned, the study wanted to validate the scoring system and try to predict as accurately as possible patients life expectancy after palliative radiotherapy treatment. 356 patients were assessable, survival rates were shown to decrease with time at 3, 6, 12 and 24 months, survival rates were 52.6%, 34.9%, 20%, and 10.6% respectively. Patients were divided into three groups according to their prognostic factors; the higher number of prognostic factors the higher the risk group. Low risk group survival rate was 27 months, intermediate risk group survival rate was 6 months and high risk group survival rate was only 2 months (p<0.001). The higher was the Katagiri prognostic score the lower was the survival rate. Similarly Zhang et al [28] investigated another scoring system which was based on the same prognostic variables idea; the calculation was performed by calculating the hazard ratio of each of the variables in the scoring system, according to them the patients were further divided into 3 groups. Group 1 with the highest
26 score (14/125 patients) had 4.9 months survival, group 2 with intermediate score (65/125 patients) had 10.5 months survival, and group 3 (46/125 patients) with lowest score had 29.7 months of survival, the results showed significant statistical difference between the groups. Certain variables were proven to have stronger influence on the survival of the patient, especially primary esophageal or colorectal cancer. The more variables and the more influential they were, the lower the survival rate of the patient.
9.6. Palliative radiotherapy treatment effect on complicated bone
metastases
When talking about metastases in the bone, the metastases sites and outcomes are investigated as a whole, although metastases in the bone can be divided into two categories: complicated and uncomplicated. Complicated- which means that the metastases have caused a further complication at site, as pathological bone fracture or neurological compromise, although diversity exist in literature in regarding of the exact definition. If no complications such as this exist, the bone metastases are referred to as 'uncomplicated'. Up to this day, palliative radiotherapy was indicated in consideration to life expectancy, patient's clinical status and his QOL. Only few studies have investigated whether or not bone metastases should be categorized prior to treatment, as the literature indicates regarding bone metastases classification [30]. Despite the studies, up to this day the optimal fractionation dose of radiotherapy treatment remains debatable for complicated bone metastases [31].
In a study performed by Tiwana et al [30] participated 880 patients who had bone metastases and had undergone palliative radiotherapy treatment. The study established what was the incidence of complicated bone metastases was; they found out that out of all participants 34.4% (303/880) had complicated bone metastases, which pointed them to be an often present complication. Out of them 42.1% (127/303) had pathological fracture and 36.3% (110/303) had a neurological compromise. Patients with complicated bone metastases were less commonly
27 treated with SFRT (39.4%) unlike patients with uncomplicated bone metastases (70.4%), moreover age, primary tumor site and metastases location influenced the decision making. Older patients, prostate cancer patients, and those having pelvis, extremities and ribs metastases were more commonly seen in SFRT regimen. Response to treatment was not mentioned, but the incidence of complicated bone metastases was established. After the incidence establishment the first and second phase trials performed by Capuccini et al [32] investigated which dose of palliative radiotherapy is more appropriate for patients with complicated bone metastases. The study examined the toxicities developing and pain response. A total of 45 patients have participated in the trial, 20 in phase I and 25 in phase II. 31 patients received 20 Gy in 4 fractions, 2 per day in 2 consecutive days which was found to be the maximum tolerated dose (MTD) in such a short duration. Only 3.2% (1/31) had grade 3 acute toxicity, and the rest of the patients had grade 1-2 acute toxicities which were considered tolerable. Overall pain response was 84% which lasted for a median duration of 4 months; this data is comparable with previous studies conducted using 30 Gy regimen in 10 fractions on patients with bone metastases without a clear bone metastases classification. 20 Gy in 4 fractions in only 2 days was found to be effective and tolerable. Another phase II trial by Silva et al [33] found that 16 Gy in 2 fraction of 8 Gy each by 1 week apart also produce satisfactory pain relief results, is safe, and statistically significantly seen functional improvement. Further trials are being performed nowadays.
28
10. CONCLUSIONS
Radiotherapy is an already proven treatment for palliation of symptoms caused by metastases in the bones, although many opinions exist regarding its usage, application and influence on patients health. This study reviewed the latest articles in the past 10 years regarding the matter, in order to create an updated and clear view of the subject.
1. Fractionation- SFRT of 8 Gy was shown to be equally effective for palliation of pain, use of analgesics (pain medication) decrease and function improvement as MFRT regimen. The treatment consumes less time, cost is beneficial for both patient and the hospital. SFRT should be offered more often for palliation. As every study uses different scales for evaluation of both regimens, in order to have a more precise comparison between the studies, uniform scales should be applied.
2. Response to treatment-
2.1. Older age has been shown in the past to influence negatively pain relief results, yet during this study review pain response was shown to be higher than expected in elderly and independent of age, all age groups had a similar outcome. Age should not be a criterion for further palliative treatment referral and palliative radiotherapy should be offered to all age groups equally.
2.2. Patients who suffer from greater pain prior to palliative radiotherapy treatment will more likely respond better with greater relief; pain intensity scales may serve as predictors to pain response.
3. Treatment adverse effects-
3.1. Pain flare was found to be a frequent adverse effect of palliative radiotherapy treatment, occurring in approximately 40% of patients, mostly in the first five days after treatment. No variable was found to be related to symptom development. Patients should be informed about the possibility of developing pain flare, in order for them to seek for the appropriate treatment, and for doctors to treat accordingly.
29 3.2. Palliative radiotherapy treatment was found to be a safe procedure with minimal toxicities and no life threatening conditions, regardless of the regimen used (SFRT or MFRT).
4. Quality of life- is significantly improved in those patients who respond to treatment, palliative radiotherapy increases physical functioning, decreases functional interference, psychological distress, pain scores and constipation. Although it promises a better life quality, an even better response is expected for those patients who had a higher and better KPS score initially at baseline.
5. Life expectancy-
5.1. There was found to be a strong correlation between the quantity of prognostic factors a patient had prior to therapy, to the life expectancy he/she had left after palliative radiotherapy treatment, regarding the regimen used. The more factors exist the lower the life expectancy despite the treatment.
5.2. Life expectancy after palliative radiotherapy treatment in patients with bone metastases ranges from 3 months up to 28.4 months. Population with bone metastases who did not receive palliative radiotherapy treatment have life expectancy of 3.5 months up to 12.5 months, depending on the primary tumor type and variables which were used in studies scales mentioned. We might assume that palliative radiotherapy treatment is the cause of life expectancy prolongation, despite the fact that its main purpose is palliation. However no studies were performed comparing the two groups, it may serve as a future research objective.
6. Complicated bone metastases- one third (34.4%) of patients with bone metastases will develop complicated bone metastases. Combining dosages of SFRT treatment, while using multiple fractions but shortening the duration between them and their quantity, was found to be effective and safe with high pain response for complicated bone metastases. Further studies should be performed in the future in order to establish a more precise approach.
7. Primary lung cancer- bone metastases arising from primary lung cancer were mentioned several times in different literatures and objectives, they were of special interest. They
30 were found to be the least responsive to palliative radiotherapy treatment, with the lowest improvement results, and the lowest median survival rates.
31
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