Elimination of Perioperative Octreotide Does Not Increase Rate or Duration of Carcinoid Crisis in NETs

Prophylactic octreotide can be safely discontinued in patients with neuroendocrine tumors (NETS) undergoing operation, as stopping its use has not been shown to increase the rate or duration of carcinoid crisis, according to data from a study presented during the 2021 NANETS Annual Symposium.^1,2

Results from the study showed that among 171 patients who underwent 195 operations without receiving perioperative octreotide, crisis was reported in 25% (n = 49) of operations, with a mean duration of 3 minutes. Additionally, it was found that carcinoid crisis was more likely to occur in patients with small bowel primary tumors (P = .012), older age (P = .015), and carcinoid syndrome (P < .001). Furthermore, those who experienced crises were more likely to experience major postoperative complications (P = .003).

“Based on the results of this prospective study, we conclude that use of prophylactic octreotide may be safely discontinued owing to inefficacy without concern for increased incidence of crisis,” lead study author Sarah M. Wonn, MD, of Oregon Health & Science University, and colleagues, wrote. “Similarly, treatment of crisis with octreotide should be replaced with intravenous fluids and vasopressors, which address the actual pathophysiology of crisis, without concern for increasing crisis duration or rates of major postoperative complications.”

Patients with neuroendocrine tumors are at increased risk for carcinoid crisis, which is described as a sudden event of hemodynamic instability that occurs in those undergoing invasive procedures. Because the nature of crisis is unpredictable, sudden, and life-threatening, these events have proven to be difficult to research. Moreover, an exact definition for carcinoid crisis has not been established. As such, investigators have created their own descriptions for these events, which makes comparability between studies particularly challenging. 

In previous studies, the somatostatin analog octreotide was found to inhibit the release of vasoactive hormones, which serves to rapidly reverse a carcinoid crisis. As such, the drug has been used prophylactically to reduce crisis rates and treat crises that still occur. However, guidance regarding the optimal timing, dosage, route of administration, and duration of the agent have varied. Even with the routine use of octreotide, studies have demonstrated crisis rates still range from 24% to 35%.

To understand whether the use of perioperative octreotide should be recommended, investigators sought to study patients with NETs who underwent operations without the agent. The goal of the study was to determine whether the rate of carcinoid crisis was higher than what has been reported in previous studies, if the duration of crisis was longer, and if these patients experienced additional harm.

The study examined patients with NETs who had undergone a major abdominal operation under general anesthesia with a single surgeon at Oregon Health & Science University between January 2017 and May 2020. Those with pancreatic primary tumors were excluded. Notably, the preoperative use of long-acting somatostatin analogs for symptom and/or tumor control was permitted.

In this study, criteria for carcinoid crisis was defined as a sudden and significant change in hemodynamic parameters without another attributable cause like blood loss, compression of the inferior vena cava, or insufficient intravenous fluid resuscitation. Additionally, hemodynamic instability was considered to be significant if systolic blood pressure was less than 80 mm Hg or more than 180 mm Hg, heart rate was higher than 120 beats per minute, or if the patient exhibited physiology that could cause end organ dysfunction. 

Moreover, both the surgeon and anesthesiologist had to agree that there was no other plausible cause to declare a carcinoid crisis. If declared, treatment was initiated immediately, and it could include intravenous fluids, bolus injections, or continuous intravenous infusions of vasopressors or vasodilators, per anesthesiologist discretion.

Duration of crisis was measured from the time of onset of hemodynamic instability to the time when systolic blood pressure was restored to more than 80 mm Hg and less than 180 mm Hg, heart rate was less than 120 beats per minute, and ventilatory pressures were normal.

A total of 195 operations done on 171 patients happened during the study period. Operations included hepatic metastases resection and bowel resection (n = 66), bowel resection with no hepatic metastases resected (n = 47), hepatic metastases resection with no bowel resected (n = 45), and other (n = 37). Of the carcinoid crises reported during 49 operations, 35 were hypertension alone, 11 were tachycardia and hypotension, 2 were hypotension and flushing, and 1 was tachycardia and flushing.

Forty-one patients had a single operation with crisis. “The remaining 8 crisis occurrences were observed in the following scenarios: in 1 patient who had 2 operations both with crisis, and 6 other patients with multiple operations, with at least 1 of whom had a crisis,” study authors wrote.

Additional data showed that patients with carcinoid crisis were less likely to have grade 1 primary tumor than those without crisis, at 59% vs 77%, respectively (P = .015), and they were more likely to have a higher median age at operation, at 67 years vs 64 years, respectively (P = .021). Those with crisis also had a longer median anesthesia time (333 minutes vs 245 minutes; P < .001), higher median estimated blood loss (400 mL vs 200 mL; P < .001), and a higher percentage of receiving at least 1 intraoperative transfusion (22% vs 6%; P= .006).

Furthermore, in the 49 operations where crises were observed, the median number of crises experienced during an operation was 2 (range, 1-14), the maximum number of crises observed in a single patient was 14, and the median duration of the first carcinoid crisis was 3 minutes (range, 2-4).

In those patients who experienced a second carcinoid crisis (n = 35), the median duration of that crisis was 2 minutes (range, 2-4). Similarly, for patients who had a third carcinoid crisis (n = 23), the median duration of crisis was also 2 minutes (range, 2-4). The median duration of crisis increased to 3 minutes (range, 2-4) in patients who had a fourth carcinoid crisis (n = 14). No crisis was documented to occur for longer than 10 minutes.

Those who experienced carcinoid crisis were more likely than those who did not to have post-operative complications (43% vs 26%; P = .034), as well as a longer median hospital stay (8 days vs 6 days; P < .001). Additionally, patients who experienced crisis were more likely than those who did not to experience major complications (29% vs 11%; P = .003). No difference in rates of postoperative mortality was observed between the 2 groups.

“This only serves to emphasize the importance of continuing the search for ways to reduce the incidence of carcinoid crisis,” the study authors concluded. “However, despite the renewed correlation, the 29% rate of major complications for patient with crises in this study was actually lower than the rates of 39% and 36% reported in our previous series using octreotide.”

References

1. Wonn SM, Ratzlaff AN, Pommier SJ, et al. A prospective study of carcinoid crisis with no perioperative octreotide. Presented at: 2021 NANETs Annual Symposium; November 3-6, 2021; virtual. Abstract 163.
2. Wonn SM, Ratzlaff AN, Pommier SJ, et al. A prospective study of carcinoid crisis with no perioperative ocreotide. Surgery. Published online July 3, 2021. doi:10.1016/j.surg.2021.03.063