3.2 RELATIONSHIP BETWEEN EXPOSURE TO OPIOIDS AND TUMOR RESPONSE
Spearman’s Rank Correlation coefficient was performed to determine the strength and direction of the linear relationship between the total weight-based morphine equivalents and tumor response. The correlation coefficient of -0.0103 and P-value of 0.9525 indicates a statistically insignificant, weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (Figure 1). The correlation coefficient of 0.1096 and p-value 0.5247 indicates statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score (Figure 2).
DISCUSSION
The impact of opioids on cancer outcomes has been an ongoing topic of considerable debate and investigation.22-26Cell-mediated immunity is critical for the eradication of tumor cells and prevention of metastases development.27,28Multiple preclinical studies have demonstrated the suppressive effects of opioids on the immune system in general and NK cells specifically,18,22-25,29 but this effect is variable amongst different types of opioids.22 Clinical studies have been equivocal and results are inconsistent across different types of cancers.2,30,31 This observation likely suggests that the impact (if any), is unique to certain subtypes of cancer and cannot be applied to cancer generally. For this reason, it is important to investigate the impact of opioids on cancer outcomes within specific diagnoses, such as NB. It is known that NB treatment with anti-GD2 mAb relies on NK cells as the effector cells of the tumor cell killing.6,7 Therefore, one would expect that increased opioid consumption would correlate with decreased tumor killing.
Our findings did not conclusively support the general hypothesis that the magnitude of opioid exposure negatively impacts anti-GD2 mAb-directed tumor reduction. However, this does not indicate that there is no correlation, as we did find a weakly negative correlation (as hypothesized) between primary tumor volume reduction and total weight-based morphine equivalents. Interestingly, we found the opposite correlation (weakly positive) between tumor reduction outside the primary tumor (as measured by Curie score) and total weight-based morphine equivalents. This was the opposite of what was hypothesized. However, neither measure achieved statistical significance. It is likely that the impact on tumor reduction may be too minimal to be detected by our study methodology. While the study design is novel (the use of tumor reduction as a marker of opioid impact on chemotherapy effectiveness), it may not be sensitive enough. If opioids suppress NK cell activity in vivo, as seen in vitro, the clinical significance is likely too minimal to be detected by tumor volume reduction at the primary tumor site or other locations. The current anti-tumor therapies may be effective enough that small variations in the tumor response in relationship to opioid exposure may not be detected by this study design and with this small sample size. Still, this study design is unique in that it investigated the impact of more than just a single perioperative opioid exposure, as is the design seen in most investigations of the impact of opioid/anesthesia on cancer outcomes.30-33 While the opioid exposure in this study was more than perioperative, it can still be classified as an acute opioid exposure (8 total days). It is possible that since there is a different mechanism by which acute versus chronic opioid administration modulates the immune system,15,16 the duration of opioid therapy in our patient population did not have as significant an impact on their tumor progression as a patient population with a more chronic exposure to opioid therapy would have.
Not only does the impact of opioids on cancer likely vary with duration of opioid exposure, but also opioid dose. Studies have shown that higher doses of morphine affect NK cells differently than do lower doses. Higher doses lose specificity for MOR and can bind to delta opioid receptors, which may increase NK cell activity.15,16
A potential limitation of this study may be the lack of accounting for differences in immunosuppression by opioid type , as all opioid doses were converted to morphine equivalent doses. Justifiably, this choice was based on the small number of patients and occurrences of pain treatment with opioids other than morphine. It is known that different drugs within the opioid class inhibit NK cells to different degrees16,22 and our study was not powered enough to detect differences based on the type of opioid used. Finally, another potential limitation of this study is related to the role of interleukin-2 (IL-2). All patients on the institutional protocol received IL-2 on days following the anti-GD2 mAb infusion (following course 1 and course 2), which has a pro-NK cell effect.34 It is conceivable that the pro-NK cell effect of the IL-2 counteracted or masked any potential anti-NK cell effect of the opioid.
Although our results do not suggest a clinically significant correlation between opioids converted to morphine equivalent doses and adverse effects on tumor reduction, it should not be presumed that opioids can be used without limitation. The warnings from preclinical studies that demonstrate the immunosuppressive effects of opioids can be heeded without compromising patient care. It may be prudent to favor the use of opioids that have been shown to cause lesser degrees of immunosuppression (e.g., hydromorphone, oxycodone, tramadol).16,22 Additionally, it is advisable to maximize the use of non-opioid analgesics to minimize opioid consumption, particularly if a non-opioid analgesic such as lidocaine has been shown to have anti-tumor effects.35-38 This approach to the management of pain associated with anti-GD2 mAb has been demonstrated previously.12 Gorges et al. reported that dexmedetomidine and hydromorphone (both drugs that are not known to affect NK cells) can be safely and effectively used to treat pain in this patient population.12 Regardless, the effective treatment of pain is essential as untreated pain shows similar immunosuppressive effects.39,40
In conclusion, our study did not find a statistically significant correlation between the consumption of opioids and the NK cell mediated killing of NB cells as measured by effects on tumor volume/tumor load. Although our findings do not endorse indiscriminate or excessive opioid utilization, it is reassuring that the doses used in this study to ameliorate the severe pain that accompanies antibody treatment do not have adverse effects on tumor response to antibody. Opioid sparing measures can and should be employed, when possible, given the untoward secondary effects of prolonged opioid use, regardless of any potentially negative influence on cancer biology.
CONFLICTS OF INTERESTS
The authors report no conflicting interests.
ACKNOWLEDGEMENTS
The authors thank Vani Shanker, PhD, ELS for scientific editing of the manuscript.
FUNDING
National Cancer Institute Cancer Center Support Core Grant; Grant Number: 2P30CA021765; ALSAC
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request.