Pain control with palliative radiotherapy in patients with bone metastases

Introduction

Approximately 50% of cancer patients will receive palliative radiotherapy (RT) during the course of their disease [ ]. Bone metastases (BMs) remain a significant concern in the radiation oncology setting, and 70% of BMs occur in the axial skeleton [ ]. RT is frequently employed with palliative intent in order to minimize tumor-related symptoms. RT delivery can be broadly classified as via an external beam (“teletherapy”) or via radioactive sources implanted or inserted into a body surface, tissue, or cavity near or into the tumor itself (“brachytherapy”). The most common RT treatment, external beam radiation therapy (EBRT), utilizes high-energy gamma rays produced by a linear accelerator or X-rays given off by a radioactive cobalt source housed within the head of a treatment machine. The delivery of EBRT, either in local or wide fields, will be a focus of this chapter.

Principles of palliative radiation therapy

RT exposes cancerous and noncancerous cells in the treatment field to ionizing radiation, which can penetrate and cause damage to individual cells. Direct DNA damage comes in the form of base deletions, as well as single- and double-strand breaks. Indirect damage occurs when radiation ionizes water molecules, which produces free radicals and in turn damages DNA. Both normal cells and cancer cells have the aptitude to repair their DNA; however, cancer cells have less capacity to do so. Dividing the total dose of radiation into a number of smaller doses (“fractions”) delivered over time allows normal tissues to repair damage [ , ]. This schedule has evolved empirically to balance normal tissue repair with tumor cell kill, although there are clinical scenarios in which more than one treatment is given per day, or is administered on weekends. Radiation dose is measured in units of the Gray (Gy); 1 Gy is 1 J of absorbed energy per kilogram.

Tumors usually do not have to be completely eradicated in order to relieve symptoms [ ]; as such, doses lower than required for total lesion ablation are often utilized in palliative settings. This use of a lower dose still achieves symptom control and has several advantages: the risk of acute side effects is minimized, which increases patient quality of life (QOL) and acceptance of treatment; the administration of RT can be given in fewer fractions, thus decreasing transportation and hospital admission requirements; patient discomfort with positioning is decreased; resources are freed for others; and the cost associated with lost opportunities for patients to spend their remaining days as they choose is decreased [ ].

Mechanism of action in relief of painful bone metastases

There is still uncertainty regarding the exact dosage of EBRT needed to relieve pain secondary to metastatic bone lesions; however, tumor cell kill may be an important contributor. Rapid responses and poor correlation of symptom relief with tumor regression suggest that an effect on host mechanisms of pain could also be important. Radiosensitive host cells (i.e., osteoclasts and macrophages) may be damaged by RT, and in turn inhibit both bone breakdown and the chemical mediators of pain, such as prostaglandins. Disturbance of neuronal transmission by RT may destroy or exhaust resources for neurotransmission of the pain signal [ ].

Pain monitoring

The frequency, severity, and impact of symptoms, including pain, vary tremendously in patients with incurable cancers and can affect the patient's sense of physical and social functioning, as well as their overall well-being. The clinical assessment for pain from BM can be achieved through one of the three methods: numerical rating scales, visual analogue scales, and verbal rating scales. Although verbal rating scales (i.e., none, mild, moderate, or severe) are the easiest to use, the merit of such scales over others is questionable.

The Brief Pain Inventory (BPI) is a commonly exercised measure of pain intensity and functional interference in cancer-related research [ ]. Developed by Cleeland and Ryan [ ], this validated patient-based assessment tool evaluates pain in the past 24 h on three dimensions: current pain, average pain, and worst pain. Furthermore, seven indicators of functional interference are surveyed: general activity, normal work, walking ability, mood, sleep, relationships with others, and enjoyment of life [ ]. Both components of the BPI utilize an 11-point scale with “0” representing an absence of pain/functional interference, and “10” signifying the worst pain imaginable/complete functional interference. Multiple studies have shown that the intensity of the worst pain rating correlates substantially to functional interference [ ]. Hence, a patient's worst pain score should be used in the assessment of overall RT response [ ].

Validation attempts on developed pain measurement instruments have been made in an effort to advance the clinical management and research of cancer pain. Additionally, the absence of universally accepted endpoints for the evaluation of partial response, complete response, and pain progression has prevented a detailed assessment of the overall efficacy of palliative RT. Response rate is a function of endpoint [ ], and thus different conclusions can be reached based solely on the methods of data interpretation employed. Specifically, this has contributed to the barriers surrounding the establishment of optimal dose fractionation in the palliative care setting [ ].

In 2002, the Bone Metastases Consensus Working Party introduced the International Consensus Endpoints for the evaluation of palliative response to RT [ ]; the endpoints were then updated in 2012 [ ]. Evaluation of pain response at 1, 2, and 3 months following completion of RT was recommended. Complete response was defined as a pain score of zero at the radiated site with no simultaneous increase in analgesic consumption employing daily oral morphine equivalents (OMED). Partial response was defined as one of the following:

• i.

  decrease in pain score of 2 or more, on a 0–10 scale, without analgesic increase;

• ii.

  analgesic reduction of 25% or more from baseline without an increase in pain.

Pain progression was defined as an increase in pain score of 2 or more points above the reported baseline pain score at the radiated site with a stable OMED, or an increase in daily OMED of 25% or more compared with baseline with a stable pain score or an increase in pain by one point [ ].

Assessment of quality of life

For patients receiving RT for painful uncomplicated bone metastases (UBMs), QOL may help in establishing an appropriate radiation treatment regimen. Currently, three assessment modules are widely used and have been validated for the evaluation of QOL in BMs patients: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for patients with bone metastases (EORTC QLQ-BM22) [ ], the Bone Metastases Quality of Life Questionnaire (BOMET-QOL) [ ], and the Functional Assessment of Cancer Therapy Quality of Life Measurement in patients with bone pain (FACT-BP) [ ].

The EORTC QLQ-BM22 consists of four subscales of well-being: painful sites, pain characteristics, functional interference, and psychosocial aspects. Although the items on the BM22 appear on the questionnaire as 22 unrelated questions, they are grouped according to the subscale assessed. Items are all formatted as questions in which response options utilize a Likert-like scale (1–4 inclusive). Along with the core EORTC QLQ-C30 questionnaire, administration of the BM22 is 52 questions long (30 questions of the C30 in addition to the 22 questions of the BM22). Recall period of the BM22 is 7 days.

Contrary to the EORTC QLQ-BM22, the BOMET-QOL was not developed with the intention of being coupled to a general cancer questionnaire; rather, developers of the module recommended that the assessment tool be combined with cancer-specific tools. The BOMET-QOL encompasses 10 items and is therefore by itself much shorter than the BM22. The BOMET-QOL utilizes a 0–4 Likert-like scale as response options, and, like the BM22, recall period for the questionnaire is the past 7 days. All of the questions on the BOMET-QOL are unrelated and all items appear as statements. Unlike the BM22, items within the BOMET-QOL are not grouped into subscales.

The FACT-BP is comprised of three distinct subscales: general functioning, physical functioning, and bone pain. When coupled with the general cancer questionnaire, the FACT-G, QOL assessment is 43 items long (27 FACT-G items in addition to 16 FACT-BP items). The FACT-BP uses a 0–4 inclusive Likert-like scale; recall period of the questionnaire is 7 days. Only one item is a statement on the questionnaire, while 15 other items are structured as questions. All items on the module are organized based on the subscale assessed.

Two separate literature reviews have compared the development and characteristics of the BM22 to the FACT-BP [ ] and to the BOMET-QOL [ ]. Both works recommended that the choice between the tools is dependent on the specific needs of the investigation [ , ]. In future, direct clinical comparison between the three QOL tools available for BMs patients will facilitate for the establishment of a standardized QOL module in this patient population [ ].

Local field radiation therapy: clinical evidence

A growing body of empirical evidence describes results of randomized controlled trials (RCTs) of different dose-fractionation schedules for UBM [ , ]. The vast majority of published RCTs have shown that single fraction (SF) palliative RT provides equivalent pain relief for UBM as multiple fractions (MFs) [ ]. This topic has been controversial for more than two decades, with analysis of one of the first randomized studies performed twice, each coming to different conclusions [ , ]. It was not until the late 1990s that more consistent and conclusive data began to emerge from several large, multicenter, phase III RCTs, supported by the results of four meta-analyses [ , , ].

In general, no differences have been found to date in the proportion of patients achieving complete or partial pain relief from RT, regardless of dose employed [ , , , ]. No significant differences in QOL, time to first improvement in pain, time to complete pain relief, time to pain progression, nausea, vomiting, or spinal cord compression have been found [ , , , ]. However, in two trials, fewer patients on the SF arm experienced toxicity [ , ]. Grades 2–4 acute toxicity, for example, was experienced by 10% in the SF arm compared to 17% in the MF arm (p = .002) [ ] ( Table 59.2 ). The data on pathologic fracture are less consistent. In two publications, for example, patients receiving SF RT had higher fracture rates [ , ]. However, in two others, incidence was higher in the MF arms [ , ] ( Table 59.1 ).

An updated meta-analysis in 2018 reviewed 26 randomized trials which compared SF and MF schedules in patients with UBM [ ]. Included studies totaled 3059 randomizations to SF arms and 3040 to MF arms. The overall response rate to SF RT was 61%, and complete response rate was 23%. These response rates were not significantly different from the 62% and 24% experienced by patients randomized to MF RT, respectively, thus confirming the conclusions of previous systematic reviews. Generally, no differences in acute toxicity, pathologic fracture, risk of pathologic fracture, or spinal cord compression incidence were found. It was determined that 4% of patients fractured after SF versus 3.0% after MF (p = .42).

Among the use of MF RT, there is no documented dose–response for pain relief from randomized data or systemic review data. A systematic review conducted in 2017 included 17 studies found that 2.5Gy/5 had the highest overall response, 30Gy/15 had better complete response while 20Gy/2 better partial response. And the acute toxicities and gastrointestinal toxicities did not differ greatly between various schedules [ ].

Patient preferences of RT schedules were studied in only three studies [ ]. In one study, participants generally considered medical appointments to be physically demanding, and rated sustained pain relief and reduced risk of future complications as their highest priorities [ ]. Convenience was acknowledged, but factors such as traveling distance and brevity of treatment were considered of secondary importance to overall QOL and treatment efficacy. Most patients favored SF RT, assuming equivalent outcomes. Patients in Singapore and Canada were interviewed using the same patient-preference instrument, which presented differences and similarities between SF and MF RT [ , ]. A study by Shakespeare et al. conducted in Singapore reported that 85% of patients would choose extended courses of RT (24Gy/6 fractions) compared to a single treatment due to lower retreatment rates and decreased fracture risk; choice did not seem to depend on age, performance status, primary cancer site, cost, or pain score [ ]. On the contrary, 76% of Canadian patients would choose a single 8Gy, as opposed to 1 week of RT, due to greater convenience [ ]. Older and retired patients were more likely to select SF. Differences in the above three studies may be explained in part by cultural differences and potentially by differences in the decision aid instrument [ ]. Common among all studies were the high patient acceptance and preference of participation in the treatment decision-making process, which highlights the importance of good communication and patient-centered care.

Despite the overwhelming amount of randomized evidence and obvious advantages for patients, there has been reluctance to adopt SF schedules as global standard practice to date. One article reviewed surveys published between 1988 and 2006 on RT prescription patterns for patients with BMs [ ]. American respondents indicated an overwhelming preference for the 30Gy/10 schedule, and 90%–100% of radiation oncologists preferred multiple to single fractions. Approximately 85% of Canadian Radiation Oncologists preferred MFs, with the most common dose being 20Gy/5 over 1 week. MFs were again commonly used in the United Kingdom, Western Europe, Australia and New Zealand, and India; however, oncologists in these countries would consider SF schedules in up to 42% of cases [ ]. A more recent review on the international practice by McDonald et al. also confirmed similar finding with large variation of the rate of SFRT from 3% to 75% [ ]. Underutilization most often seen in America with prevalence ranged from around 4% in community and 13.5% in academic centers. Northern and Western Europe and Canada were less reluctant in which around 20%–50% of patients were treated with SF within these regions.

Nonetheless, first indications of a shift in prescription patterns have begun to appear. In 2008, it was reported that the use of SF RT increased at an outpatient RT clinic in Canada [ ]. A recent audit in 2019 demonstrated a high compliance rate in a single Canada academic center with 85.4% RT courses were delivered using SFRT [ ], although cultural effect still affect physician use of SFRT as shown by the variation in practice ranging from 25.5% to 73.4% across five regional cancer centers in a Canadian province [ ]. Performance status (ECOG) was found to be the most significant predictor for fractionation choice. In the United Kingdom, a practice audit performed in 2003 revealed the most common palliative RT schedule to be the delivery of a SF [ ]. Swedish, Dutch, and Scandinavian radiation oncologists have also modified their treatment regimens [ , , ]. Even in America, a recent assessment using the National Cancer Database also showed a slight increase in the use of SFRT 8Gy from 3.4% in 2005 to 7.5% in 2011, although further efforts still needed to address the issue [ ].

Wide-field radiation therapy: clinical evidence

Patients with BMs can have multiple sites of disease, which may cause diffuse symptoms. Wide-field or hemi-body irradiation (HBI) is usually delivered either to the upper half (base of skull to iliac crest) or to the lower half (iliac crest to ankles) of the body, to a total dose of 6 and 8Gy, respectively [ ].

SF HBI has been shown to provide pain relief in 70%–80% of patients [ ]. Poulter et al. reported the result of a randomized trial of 499 patients comparing local radiation alone versus local RT and SF HBI. A lower incidence of new BMs (50% vs. 68%) and fewer patients requiring further retreatment at 1 year (60% vs. 76%) were reported for the local RT and SF HBI arm [ ].

In a randomized trial of 156 patients, Salazar et al. investigated the choice of dose-fractionation schedules for HBI [ ]. Among the three trial arms (15Gy/5 over 1 week, 8Gy/2 fractions in 1 day, 12Gy/4 over 2 days), the 15Gy/5 arm not only provided equivalent pain relief, but also a longer survival duration compared with the other schedules.

Side effects of local field radiotherapy

It is imperative to minimize adverse side effects in palliative RT. This can be accomplished by treating the tumor while limiting dose to surrounding normal tissue [ ]. As local EBRT is a focused treatment modality, benefits and potential side effects are site-specific, except for fatigue [ ]. Acute side effects arise within 90 days of RT, while late toxicities occur following this cutoff point.