Outcomes of Patients With Advanced Gastrointestinal Cancer in Relationship to Opioid Use: Findings From Eight Clinical Trials (2024)

Background

Opioid analgesia is an integral part of pain management among patients with advanced cancer.^1,2 A potential correlation between opioid analgesics and cancer progression has been previously hypothesized.^3,4 However, most of the published data evaluating this correlation have focused on the impact of perioperative opioid anesthetics on cancer recurrence and progression.^5,6 These studies were confounded, however, by small sample size, retrospective data collection (with the potential of missing data or bias), and little attention to patients with advanced disease who received opioids for pain management rather than as a perioperative anesthetic. To provide a better assessment of the impact of opioid use on outcomes of patients with advanced cancer, this question needs to be addressed through a prospectively collected dataset using a meticulous gathering of patient and treatment data to minimize the risk of bias and confounding factors.

Project Data Sphere is a recently launched platform that allows researchers access to deidentified clinical trial datasets.⁷ It thus represents an excellent opportunity to examine this question with limited confounders. To minimize heterogeneity of the sample used for this analysis, we focused only on patients with advanced gastrointestinal cancer. Our working hypothesis was that patients with advanced gastrointestinal cancers who received opioids have poor overall survival (OS) and progression-free survival (PFS). The aims of this study were to assess the patterns of opioid use among patients with advanced gastrointestinal cancers who were included in 8 clinical trials and to evaluate the impact of opioid use on survival outcomes of those patients.

Methods

Results

Discussion

The aim of this study was to evaluate the patterns and impact of opioid use among patients with advanced gastrointestinal cancer recruited into 8 clinical trials. Our data suggest that opioid use is variable among patients with different gastrointestinal cancers, with those with pancreatic cancer being the most likely to use opioids. Importantly, our data show that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers.

Several possible mechanisms might explain the association between opioid use and poor survival outcomes in the current study. One possible explanation might relate to the fact that opioid analgesics have been shown to have protumor effects in preclinical studies.¹⁴ These protumor effects have been partly linked to their inhibition of humoral and cell-mediated immunity and their proangiogenic effects.^15,16 Along the lines of the current study, an interesting post hoc analysis of 2 randomized controlled studies evaluated the impact of methylnaltrexone (a peripherally acting μ-opioid receptor antagonist used to treat opioid-induced constipation) on the survival of patients with advanced cancer. This study has suggested that treatment using this agent (and, more so, response to this drug) is associated with improved survival.¹⁷ A second explanation might relate to the correlation between pain and poor survival outcomes among patients with different solid tumors.^18,19 The presence of pain may be associated with more advanced local or metastatic disease, and thus poorer OS. A third explanation might be related to the fact that severe pain itself has been correlated with poor OS in patients with advanced cancer.²⁰ Opioid use might be only a surrogate marker for that severe pain. Notably, patients who used opioids in our study were more likely to have a high ECOG PS. This supports the assumption that opioid use is a culprit of poor patient-/disease-related factors rather than the real underlying reason for poorer survival.

It is also notable that opioid use has been linked to poor survival among patient populations without cancer.^21,22 Thus, it is possible that a negative relationship between opioid use and survival does exist outside of cancer-mediated pathways.

Our study has several limitations. First, opioid use was not the primary research question in any of the included trials. Thus, although the current study is based on a prospectively collected dataset, the research question is retrospective. Second, this pooled analysis spans 4 different cancers, and therefore there is heterogeneity in the current dataset. To mitigate the impact of this heterogeneity, survival analyses were conducted for each disease entity independently. Third, the included clinical trial datasets reported information about opioid use during first-line systemic treatment without providing detailed information about subsequent opioid use. Fourth, although the included clinical trials reported data regarding opioid use among patients with advanced gastrointestinal cancer, they did not clarify the degree or form of pain these patients experienced. Thus, it is not possible to isolate the prognostic impact of opioids from the prognostic impact of pain on survival outcomes in the studied cohort. These limitations need to be weighed against the clear strengths of the current analysis. Most important is the reliance on clinical trial datasets in generating this pooled analysis. This should indicate greater credibility of the results of the current analysis than those in previously conducted retrospective studies evaluating the same research question.

Furthermore, it is important to note that the current study evaluated patients recruited within the context of a clinical trial. Thus, included patients are more likely to have less comorbidity and better PS than the general population. Caution should therefore be exercised when generalizing the results of the current analysis to real-world settings.

Findings of the current study have several implications for clinical practice and research directions. Although opioid analgesia can be an indispensable part of the analgesic regimen for some patients with advanced gastrointestinal cancer and intractable pain, physicians should not rush to use it in patients with milder pain symptoms that can be controlled with other pharmacologic or nonpharmacologic interventions (eg, local radiotherapy for bone metastases). Although our study suggests an association between opioid use and poorer outcomes, it falls short of establishing causation. Future research should focus on the potential mechanisms underlying opioid-induced cancer progression and whether this is universal to all opioid analgesics or pertinent only to certain subtypes; the impact of specific types/doses of opioids on oncologic outcomes in the current dataset cannot be assessed, due to the small number of patients receiving individual opioid medications.

Conclusions

Results of our study suggest that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers. Whether this results from a genuine negative impact of opioid use on survival or opioid use serves merely as the surrogate marker for poor patient-/disease-related conditions is unclear. Further studies are needed to study the mechanisms underlying this observation.