Association between Opioid Requirement and Overall Survival in Patients with Spinal Metastases.

Introduction

Management of cancer-related pain is an essential aspect of maintaining the quality of life. The prevalence of chronic pain in patients with cancer is 15%-75%, depending on the type of cancer, the extent of disease, and other factors 1 ) . There is a broad consensus that opioid therapy is a first-line strategy for treating moderate or severe chronic cancer-related pain 2 , 3 ) , although some experimental and clinical studies revealed that opioids might be associated with shorter survival in cancer patients 4 - 10 ) .

Bone is the third most common site of metastases, following lung and liver 11 ) , with the spine being the most common site for bone metastasis 12 , 13 ) . Unlike appendicular bone, the spine presents a highly complex environment in which to assess tumor-related instability. The mechanical integrity of the spine is a key component of treatment decision making in patients with metastatic disease, along with tumor histology and neurological status. Therefore, a reliable, valid grading system for assessing neoplastic stability in the spine has been developed 14 ) .

Evaluation of prognosis in patients with spinal metastases is also important in decision making for surgical treatment. Therefore, many prognostic factors have been reported in patients with spinal metastases, including histology, systemic status, the extent of metastatic disease, and the extent of previous treatment 15 - 20 ) . However, few clinical studies have evaluated whether opioid use is associated with overall survival in patients with spinal metastases. This study therefore aimed to investigate the association between pain severe enough to require opioids and survival. We also evaluated the association between opioid requirement and tumor-related spinal instability.

Materials and Methods

Study population

This retrospective study included 451 patients who had been diagnosed with spinal metastases at Yodogawa Christian Hospital from February 2009 to May 2017. Spinal metastases were diagnosed radiologically using computed tomography, magnetic resonance imaging, and/or positron emission tomography. The minimum follow-up period after diagnosis of spinal metastasis was 6 months, except in cases of death before 6 months.

Opioid requirement

The use of opioids was decided by doctors in charge of primary cancer or palliative care physicians. The decision to start opioids was left to the discretion of each doctor. Patients with an oral and/or transdermal opioid prescription during the first 1 month after diagnosis of spinal metastases were included. The total amount of opioid prescription was converted to oral morphine equivalents (OME) using an equianalgesic conversion table 21 ) . Patients needing >5 mg OME/day were categorized as the opioid requirement group, and those who needed <5 mg OME/day were categorized as the nonopioid group. This 5 mg OME cutoff value was based on results of a previous study 10 ) . We then subdivided the opioid requirement patients into two further groups: a high opioid requirement group (≥30 mg OME/day) and a low opioid requirement group (5-30 mg OME/day).

Spinal instability due to metastases was evaluated using the Spinal Instability Neoplastic Score (SINS) 14 ) , which is based on six parameters: location of the lesion, presence and type of pain, nature of the lesion (lytic or blastic), radiographic alignment, vertebral body collapse, and posterior element involvement. A high score indicates a potentially unstable spine.

Prognostic factors

Based on the findings of previous studies and clinical judgment, variables that were considered to be related to the outcome were selected for analysis. The following variables were analyzed as covariates, each categorized into two or three groups according to the modified Katagiri scoring system as follows: sex, age (<70 or ≥70 years), opioid use (<5 or ≥5 mg OME/day) at the time of spinal metastasis diagnosis; primary cancer type (slow, moderate, or rapid growth); presence/absence of abnormal laboratory data; presence/absence of visceral or cerebral metastasis; Eastern Cooperative Oncology Group performance status (0-2 or 3-4); history of previous chemotherapy; presence/absence of multiple skeletal metastases; and presence/absence of appendicular bone metastasis. The primary cancer type was divided into three prognostic groups, as previously reported 15 ) . Abnormal laboratory data were defined as C-reactive protein ≥0.4 mg/dL, lactate dehydrogenase ≥250 IU/L, serum albumin <3.7 g/dL, platelet count <100,000/μL, serum calcium (albumin-adjusted) ≥10.3 mg/dL, and total bilirubin ≥1.4 mg/dL 15 ) .

Statistical analysis

Categoric variables were analyzed using the chi-square test. Survival was estimated using the Kaplan-Meier method. The log-rank test as a univariate analysis was used to test the association between overall survival and the prognostic factors of each group. Multivariate analysis was performed using the Cox proportional hazards regression model. We used a t test to compare average SINS results between (1) the opioid requirement and nonopioid groups and (2) the high opioid requirement group (≥30 mg OME/day) and the low opioid requirement group (5-30 mg OME/day).

Data were censored on September 30, 2018. Patients who were lost to follow-up were censored at the date of the last contact/follow-up. Patients who were alive on September 30, 2018, were censored for overall survival analysis. Overall survival was calculated from the date of spinal metastasis diagnosis to the date of death.

IBM SPSS Statistics, version 19 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses; p<0.05 was considered to indicate statistical significance.

Results

Demographics

Among the 451 patients with spinal metastases, we excluded 23 because of incomplete clinical or radiological data. The remaining 428 patients were included in this study, and 347 patients (81%) were dead at the time of censoring. Table 1 shows the patients' demographic and clinical data. The mean±SD patient age was 67.7±11.3 years, and 52% of the patients were men. The most frequent primary site was the lung in 159 patients, followed by the breast in 75 and the prostate in 46. The most frequent metastatic site was the thoracic spine, followed by the lumbar spine and the cervical spine. Fig. 1 shows overall survival according to the total points of the modified Katagiri score.

Opioid requirement and prognosis

Table 2 , 3 show the patients' baseline characteristics and the distribution of prognostic factors for patients with spinal metastasis. The main reasons for opioid use were pain from spinal metastases in 119 patients, pain from a primary cancer in 41 patients, and pain from bone metastases other than spinal metastases. The median overall survival time was significantly shorter in the opioid requirement group than in the nonopioid group, although the median overall survival time was not significantly different between the high and low opioid requirement groups ( Fig. 2 ). Multivariate analyses showed that the opioid requirement group (≥5 mg OME/day) was approximately twofold more likely to be at an increased risk of death than the nonopioid group (<5 mg OME/day) ( Table 4 ). The opioid requirement patients were significantly more likely to have severe spinal instability (high SINS) than the nonopioid patients ( Fig. 3 ).

Discussion

We investigated overall survival and prognostic factors, including the presence/absence of opioid utilization, in patients with spinal metastases. Opioid requirement was stratified by the cutoff point of 5 mg OME/day. The results showed that opioid requirement at the time of spinal metastases diagnosis was associated with shorter survival, independently of known prognostic factors. Patients who used opioids were significantly more likely to have tumor-related spinal instability than those who did not.

A retrospective study of patients with stage IV malignancy showed that a greater opioid requirement was also associated with shorter survival 9 ) . Two large Phase III trials in men with castration-resistant prostate cancer showed that the use of opioids for pain was associated with poor survival 8 ) . These studies, however, did not focus on patients using opioids for bone metastases. In the present study, 119 of 193 patients (62%) taking opioids for pain due to spinal metastases showed that the opioid requirement was associated with shorter survival.

To date, many prognostic factors have been reported in patients with spinal metastases, including histology, systemic status, the extent of metastatic disease, and the extent of previous treatment. Hence, several prognosis-evaluation systems have been developed 15 - 20 ) , although none of them evaluated the influence of opioid use on overall survival. We evaluated the modified Katagiri scoring system, because it is characterized, unlike in other scoring systems, by incorporating the indication for molecular targeted therapy for lung cancer and hormone therapy for breast and prostate cancers. To the best of our knowledge, this is the first study to examine the association between opioid requirement and overall survival in patients with spinal metastases.

The present study revealed that patients with opioid use are at a twofold risk of shorter survival than those without opioid use. However, the prognosis prediction via opioid use does not have advantages over the modified Katagiri score, because the modified Katagiri score consists of multiple prognostic factors.

Experimental studies in transgenic mice with breast cancer revealed that opioid use was associated with shorter survival and with cancer progression 4 , 5 ) . A systematic literature review offered no definitive conclusion as to whether opioids affect survival in cancer patients because no study was powered to assess the effect of opioids on survival as a primary endpoint 22 ) . Therefore, to confirm or deny an association between opioid use and a poor prognosis in patients with spinal metastases, prospective studies with survival as a primary endpoint are required.

The opioid users in the present study, however, were significantly more likely to have tumor-related spinal instability than those without opioid use. Tumor-related spinal instability is defined as the loss of spinal integrity due to a neoplastic process that is associated with movement-related pain, symptomatic or progressive deformity, and/or neural compromise under physiological loads 14 ) . Even in the absence of obvious vertebral body collapse or deformity, some clinical instability is assumed to be present when a mechanical pain syndrome is present. Therefore, some patients with spinal instability could be candidates for surgical stabilization not only to prevent the progression of the destructive process but also to avoid opioid administration.

There are several limitations in the present study. First is its retrospective nature. Additionally, the cancer type and the systemic treatments for the cancers were not uniform. Second, the analyses remain subject to biases resulting from potential confounding factors, although a multivariate analysis should reduce bias in prognostic estimates. Finally, pain was not included in the analyses. Several reports have revealed an association between pain and shorter survival in cancer patients 8 , 23 , 24 ) . Nevertheless, opioid requirement could be considered a surrogate marker for pain.

In conclusion, opioid use was associated with shorter survival in patients with spinal metastases, independently of known prognostic factors. Patients with opioid requirement were significantly more likely to have spinal instability due to metastases than those without opioid requirement. Prospective studies with survival as a primary endpoint are needed to confirm or deny an association between opioid use and a poor prognosis in patients with spinal metastases.

Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

Sources of Funding: None.

Author Contributions: S. Dohzono wrote and prepared the manuscript, and all of the authors participated in the study design. All authors have read, reviewed, and approved the article.

Ethical Approval: This study was approved by the Institutional Review Board of Yodogawa Christian Hospital (approval number 2019-035).

Informed Consent: The requirement for written informed consent was waived because of the study's retrospective design.

Acknowledgement

We thank Nancy Schatken, BS, MT(ASCP), from Edanz Group ( www.edanzediting.com/ac ), for editing a draft of this manuscript.

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