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