Abstract
Background/Aim: The study aim was to analyze the feasibility and efficacy of palliative radiotherapy in patients receiving advanced/interventional pain therapy, such as epidural or spinal anesthesia or subcutaneous pump delivery of opioids. Endpoints such as pain relief, treatment in the last month of life and survival were evaluated. Patients and Methods: Different baseline parameters including but not limited to age and Eastern Cooperative Oncology Group performance status (ECOG PS) were assessed. Outcomes were abstracted from electronic health records. The Edmonton Symptom Assessment System (ESAS) was utilized to score pain intensity. Results: The study included 48 patients, 44 of whom completed radiotherapy as prescribed. Device malfunction was not observed. Overall, 31 patients (65%) had journal notes available allowing for evaluation of pain relief. Twenty-six of 31 experienced pain relief (54% in the intention-to-treat population of 48 study patients). Twelve patients (25%) stopped interventional pain therapy and were converted to transdermal or oral drugs. Median survival was 1.6 months. Forty-four percent had received radiotherapy during the last month of life. Sixty-four percent of patients with ECOG PS 3-4 had received radiotherapy during the last month of life, compared to 22% of those with ECOG PS <3, p=0.004. Conclusion: Palliative radiotherapy was feasible in this setting, but given the short median survival and high likelihood of treatment during the last month of life, patient selection and choice of fractionation regimen should be optimized. The record review identified several patients who experienced worthwhile pain relief, sometimes leading to conversion of pain therapy back to non-invasive oral or transdermal application.
Palliative radiotherapy often aims at pain relief, particularly in patients with bone metastases or multiple myeloma (1-3). Extraosseous lesions, such as lymph node metastases and abdominal or pelvic primary tumors, e.g., pancreatic or rectal cancer, may also cause serious pain, which results in referral for palliative radiotherapy (4-9). Pain intensity varies widely and so does prescription of different types of analgesics and co-analgesics (10). Commonly, oral or transdermal analgesics are utilized and outpatient radiotherapy is feasible. However, some patients require intense, multimodal pain management, which often is supervised by a dedicated palliative care team (PCT) and also may require temporary hospital administration.
Palliative radiotherapy often results in gradual pain improvement. For example, a systematic review and meta-analysis of conventional irradiation for bone metastases assessed using international consensus pain response endpoints demonstrated response in 60% of evaluable patients (n=4,775) and 45% of intent-to-treat patients (n=6,775) (11). Due to limited survival and difficult follow-up of patients with reduced performance status (PS), most studies had high rates of non-evaluable patients. Little research has focused on patients who needed advanced/interventional pain therapy such as pump-delivered continuous analgesics. Such approaches are often the final step after insufficient titration of standard oral or transdermal drugs (12, 13).
Over a long period of time, our group has studied the feasibility and appropriateness of palliative radiotherapy in different settings with or without involvement of a PCT (14-17). The present retrospective analysis was undertaken to specifically address the feasibility and efficacy in patients who received advanced/interventional pain therapy.
Patients and Methods
In 2022 a single-institution database (2009-2016) was evaluated, which includes information about the type of pain management at the start of palliative radiotherapy. Forty-eight consecutive patients managed with standard palliative external beam radiotherapy regimens, such as a single fraction of 8 Gy, 5 fractions of 4 Gy or 10 fractions of 3 Gy (3-D conformal; no stereotactic ablative body radiotherapy) who had advanced/interventional pain therapy were analyzed. The latter included epidural or spinal anesthesia or subcutaneous pump delivery. Pain management and setting (in- or outpatient) were at the discretion of the PCT. Symptom severity was classified according to the Edmonton Symptom Assessment System (ESAS) (18, 19), e.g., at the time of radiotherapy planning (score 10: maximum pain, score 0: no pain). Radiotherapy fractionation was at the discretion of the treating oncologist. Interrupted or permanently discontinued radiotherapy series were included to comply with the intention-to-treat principle. The patients received standard-of-care systemic anticancer treatment as indicated (tailored to organ function, Eastern Cooperative Oncology Group (ECOG) PS, frailty etc.). Follow-up was individualized and tailored to patients’ needs, but many patients continued care in close contact with the PCT.
The review-board approved database is regularly updated for survival and has been previously utilized for different quality-of-care projects (15, 16). Data were extracted from the regional hospitals’ shared electronic health records (6 hospitals in Nordland county). We did not have access to the records of health care providers outside of the hospitals, e.g., primary health care or nursing home physicians. Standard descriptive analyses were employed. Overall survival (time to death) from the first day of radiotherapy was calculated employing the Kaplan-Meier method (SPSS 28, IBM Corp., Armonk, NY, USA). In one case, survival was censored after eight years of follow-up (newly diagnosed multiple myeloma). Kaplan-Meier curves were compared by means of log-rank tests. Outcomes of interest, e.g., death within 30 days of last radiation treatment were dichotomized (alive/dead) and the chi-square test (2-sided) was utilized for further analyses. p-Values ≤0.05 were considered statistically significant.
Results
As indicated in Table I, the study included 21 female and 27 male patients (56%), whose median age was 63 years (range=42-84 years). More than half had ECOG PS 3-4 (52%) and 81% were inpatients. As shown in Table II, a wide range of malignancies was treated, including hematological diagnoses (12%) such as multiple myeloma (10%). Most patients were irradiated for bone metastases from solid primary tumors (73%), others for painful pelvic tumors.
Baseline characteristics and selected outcomes for 48 patients.
Tumor characteristics for 48 patients.
Commonly, 3- or 4-Gy fractions were employed (Table III). Some patients received additional radiotherapy for non-pain indications, e.g., brain or skin metastases, in the same course. Four patients (8%) were unable to complete the prescribed course of radiotherapy, all with ECOG PS 3-4. Deviation from routine ESAS utilization before radiotherapy was observed in 21 patients. Only a small subgroup of 11 patients had ESAS data available during follow-up (Table IV). Based on 27 patients with baseline ESAS, median pain score was 4 (resting) and 6 (activity), respectively. A reduction after radiotherapy was observed (after 4-6 weeks median 1 and 3, respectively).
Radiation treatment characteristics for 48 patients.
Pain and management characteristics for 48 patients.
Overall, 31 patients (65%) had journal notes available allowing for evaluation of pain relief, even if not documented by ESAS and therefore not always quantifiable. Several patients were discharged to nursing homes or home without documented pain status. Twenty-six of 31 experienced some degree of pain relief (54% in the intention-to-treat population of 48 study patients), and 17 (35%) had less pain for at least one month. Twelve patients (25%) stopped interventional pain therapy by pump and were converted to transdermal or oral drugs.
Median survival was 1.6 months (95% confidence interval=0.3-3.1; Figure 1). After 6 months, 17% were still alive. Thirty-three percent died within 30 days of last radiation treatment. Forty-four percent had received radiotherapy during the last month of life. Interestingly, 64% of patients with ECOG PS 3-4 had received radiotherapy during the last month of life, compared to 22% of those with PS <3, p=0.004. None of the other baseline parameters displayed in the Tables correlated significantly with this endpoint. Patients scheduled to receive at least 10 fractions survived for a median of 1.6 months and those scheduled to receive fewer fractions survived for a median of 1.9 months, p=0.5. Patients with ECOG PS 3-4 survived for a median of 1.0 months and those with better PS for a median of 3.0 months, p=0.03. Survival was longest in patients with multiple myeloma (median 6.9 months) and breast cancer (median 4.4 months) and shortest in those with lung cancer (median 1.5 months) and colorectal cancer (median 1.2 months), p=0.09.
Overall survival after start of palliative radiotherapy.
Discussion
Even in prospective clinical trials, many patients with painful bone metastases could not be assessed for pain response [2,000 out of 6,775 (30%) in a recent meta-analysis (11)]. We were aware of this challenge and expected an equal or bigger drop-out rate in a retrospective setting like the present one, and indeed only 65% of our patients had journal notes available allowing for evaluation of pain relief, although quantification of this endpoint was elusive. Ideally, the international consensus pain response endpoints should be reported (20), however limited information could be abstracted from the electronic health records, e.g., regarding longitudinal drug dose titration. A disappointingly low percentage of patients had serial ESAS pain scores documented. Despite anticipating challenges with missing data and limited follow-up consistency, we decided to perform this study, because the previous literature gives little if any guidance on what to expect when irradiating patients with advanced/interventional pain therapy.
Our retrospective study included 48 patients with a very heterogeneous status at baseline before radiotherapy, ranging from newly diagnosed multiple myeloma with excellent systemic treatment options to chemotherapy-resistant widely metastasized colorectal cancer with poor ECOG PS. Also, type of pain therapy varied widely (subcutaneous continuous opioids via pump, spinal anesthesia etc.). Due to the small size of the study, we could not account for these different scenarios by looking into subgroups. Given that Odell et al. already have reported that radiotherapy can be administered safely to patients with intrathecal drug delivery systems without malfunction [total measured dose to the device ranged from 0 to 18 Gy (median 0.2 Gy) with a median dose of 0.04 Gy/fraction (range=0-3.2 Gy/fraction)] (21), the main research questions were related to efficacy and prognosis. Reassuringly, malfunction was not reported and the fact that 8% of patients did not complete radiotherapy could be explained by adverse baseline characteristics such as poor ECOG PS, leading to rapid clinical deterioration and short survival. The rate of 8% is not unusual in the palliative radiotherapy literature (16, 22, 23).
The record review identified several patients who experienced worthwhile pain relief that would have been classified as response according to the international consensus pain response endpoints, sometimes leading to conversion of pain therapy back to non-invasive oral or transdermal application. Durable relief was sometimes observed, but only 17% survived for at least six months. The rate of 35% who had less pain for at least one month (intention-to-treat) is not tremendously different from the reported response rate of 45% of intent-to-treat patients in the bone metastases meta-analysis (nota bene: different patient populations, different assessments) (11). It would thus not be justified to advice against palliative radiotherapy in all patients with interventional pain therapy. However, improved selection appears necessary, given that 33% died within 30 days of last radiation treatment. In a recent large meta-analysis (24), 16% of patients with advanced cancer who had received palliative radiotherapy died within 30 days of treatment. In the present study, ECOG PS 3-4 was the only statistically significant predictor of death within 30 days. The clinical picture is too complex to base decision making on PS alone, although PS is a well-known, robust predictor identified in numerous studies (16, 24, 25). Ideally, prediction of survival would be complemented by prediction of pain response. Much larger studies than ours are needed to decipher factors predicting pain response. In theory, a well-responding, initially bedridden inpatient may regain an ECOG PS <3 and qualify for initiation of life-prolonging systemic therapy. In the light of sometimes disappointing record quality and variable PCT involvement during follow-up in this retrospective study, we can only advocate for prospective clarification of response rates and predictors.
In the absence of better selection criteria, administration of 10 or more fractions in patients with median survival of 1.6 months appears to violate the principles of Choosing Wisely. Based on the knowledge generated by our retrospective analysis, we are now trying to complete radiotherapy in a shorter time frame, prioritizing single fraction and 4-5 fraction regimens. Besides the number of patients (suboptimal statistical power), limitations of the present work include its retrospective single-institution design and selection bias, because a proportion of poor-prognosis patients referred to palliative radiotherapy may have died before the planned start of treatment or opted out of treatment due to discomfort during treatment planning. A stringent definition of pain response at narrowly defined follow-up time points could not be applied. Endpoints such as pain flare, nausea, and other side-effects were not assessable. Nevertheless, the study cohort represents an understudied real-world patient population of cancer patients who may have been excluded from many clinical trials due to survival expectation <3 months and/or poor PS.
Despite recent progress in prognostic stratification, survival predictions in oncology tend to be overly optimistic (16, 17, 22, 24-28). Not all patients initially thought to represent suitable candidates for palliative radiotherapy are able to complete their treatment and derive net benefit. The large meta-analysis by Kutzko et al. identified multiple treatment sites, hepatobiliary primary, inpatient status, and ECOG PS 3-4 as predictors of 30-day mortality (24). In contrast to these results, Wu et al. performed a multivariate analysis suggesting that breast or prostate primary tumor, ECOG PS, body mass index, liver metastases, more than five active metastases (dichotomized, radiographically identified), albumin level, and hospitalization within three months of radiotherapy consult were associated with 30-day survival (22). Tools preferred by palliative care providers (29) may be relevant in a setting like ours, where inpatient care, PCT involvement, and short survival were common.
Conclusion
Palliative radiotherapy was feasible in this setting, but given the short median survival and high likelihood of treatment during the last month of life, patient selection and choice of fractionation regimen should be optimized. The record review identified several patients who experienced worthwhile pain relief, sometimes leading to conversion of pain therapy back to non-invasive oral or transdermal application.
Footnotes
Authors’ Contributions
SMJ and SN: Collected the related data, contributed to analysis of the data, investigated the study results. CN and ECH: Interpreted data and wrote the manuscript. All Authors contributed to the article and approved the submitted version.
Funding
None.
Conflicts of Interest
The Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Received July 15, 2024.
- Revision received July 30, 2024.
- Accepted July 31, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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