ABSTRACT
Objective : Recent increased awareness and research studies reflect possible associations between opioid exposure and cancer outcomes. Children with neuroblastoma (NB) often require opioid treatment for pain. However, associations between tumor response to chemotherapy and opioid exposure have not been investigated in clinical settings.
Methods : This is a single institution retrospective review of patients with NB treated between 2013 and 2016. We evaluated opioid consumption quantified in morphine equivalent doses (mg/kg) based on nurse- or patient-controlled analgesia during antibody infusions. We also analyzed their associations with change in tumor volume and extra-adrenal tumor burden.
Results : Of 42 patients given opioids for pain related to anti-GD2 mAb, data completion was achieved for 36 and details of statistical analyses were entered. Median total weight-based morphine equivalent (over 8 days) was 4.71 mg/kg (interquartile range 3.49-7.96). We found a statistically insignificant weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (correlation coefficient -0.0103, p-value 0.9525) and a statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score (correlation coefficient 0.1096, p-value 0.5247).
Conclusion: Our study found no statistically significant correlation between opioid consumption and NK cell-mediated killing of NB cells as measured by effects on tumor volume/tumor load.
INTRODUCTION
Opioid therapy is the cornerstone of pain treatment for patients with cancer.1 Increased awareness of the potential impact of opioids on the immune system and oncological outcomes has been developing, particularly in the context of newer chemotherapy agents that engage the body’s immune system in the fight against cancer cells.2 Cancer treatment has entered an era of immunotherapy,3 and newly-designed immunotherapies harness the immune system to fight cancer cells.
NB is the most common extracranial solid tumor in childhood.4 Standard therapy for NB has historically consisted of three phases of treatment: (1) induction with intensive multi-agent chemotherapy; (2) consolidation with myeloablative therapy and stem cell rescue; and (3) treatment of minimal residual disease (MRD) with isotretinoin.5 However, after a period of regression, patients may experience a recurrence secondary to drug-resistant cancer cells. Researchers have postulated that more effective treatment of MRD with anti-disialoganglioside monoclonal antibodies (antiGD2-mAb) would reduce the rate of recurrence.5-8 NB cells show a uniform expression of GD2 receptors on their surface, whereas there is a minimal presence of GD2 receptors on some non-tumor cells (predominantly neurons, melanocytes, and peripheral sensory nerve fibers).5-7Dinutuximab and Naxitimab, two antiGD2-mAbs, are immunotherapy agents used in the treatment of neuroblastoma (NB).9 The use of anti-GD2 mAb has become the standard of care in the treatment of NB. The initial form of this mAb (ch14.18) was partly murine (i.e. chimeric) and caused significant pain in patients during intravenous infusion.5,8 A second-generation antibody hu14.18 (humanized) was developed to reduce the adverse effects of the chimeric antibody.8,10 A point mutation was inserted in a newer anti-GD2 mAb (hu14.18K322A) to reduce complement-mediated pain, as research suggested that complement pathway activation played a significant role in pain development.8,11 Although higher doses of the mAb are now tolerated following this mutation, pain is still common10 given the ongoing binding of mAb to normal peripheral sensory nerve fibers.5,12
An effective approach to the treatment of anti-GD2 mAb-related pain has been opioid patient/controlled analgesia (PCA) administered as a parenteral opioid infusion prior to initiation of anti-GD2 mAb and continued throughout the mAb infusion.10 However, there is reason to be skeptical with the use of opioids in this setting. Research has brought to light the potential interaction of opioid analgesics with the proliferation of cancer cells.13,14 Although the clinical significance of in vitro data have been inconclusive to date, it is clear that opioids modulate the immune system and have an in vitro effect on cancer cells. It appears that both endogenous and exogenous opioids can stimulate angiogenesis, thus prompting enhanced tumor growth and metastasis.14 This has implications for both primary treatment and treatment of MRD and later metastatic disease. Studies have demonstrated an upregulation of the mu opioid receptor (MOR) on tumor cells. Lennon et al. evaluated MOR expression in non-small cell lung cancer tissue and found that cells having MOR overexpression had a 2.5-fold increase in primary tumor growth rate compared to control cells.14 Multiple theories on the effect of opioids on immunity have been postulated, including stimulation of epithelial-mesenchymal transformation and an inhibitory effect on both innate and acquired immune responses, specifically natural killer (NK) cells,15,16 as well as decreasing phagocytic functioning of granulocytes.17 In preclinical and animal studies, morphine and fentanyl have been shown to reduce NK cell activity, the main cellular defense against oncogenic cells.16,18,19 Anti-GD2 mAb relies on NK cells as the effector cells of NB tumor cell killing.6,7 Therefore, suppression of NK cell activity could theoretically decrease the efficacy of anti-GD2 mAb treatment.
This study assessed the possible impact of opioids on the effectiveness of anti-GD2 mAb (hu14.18K322A) in facilitating the eradication of NB cells. We performed a retrospective review of medical records of patients undergoing NB treatment as part of an institutional phase II clinical trial.20 Patients on the clinical trial receive two identical courses of chemoimmunotherapy and then their tumor response is assessed by imaging. This study will attempt to determine the impact of opioids on tumor response using two outcome measures: 1) cumulative opioid consumption (mg/kg) and 2) degree of tumor reduction (primary tumor volume and extra-primary location tumor burden as determined by the Curie score) during the first two courses of induction chemoimmunotherapy. These measures will be used to assess the relationship between opioid exposure and tumor reduction response to chemotherapy.
METHODS