Stereotactic Body Radiation Therapy Facilitating Debulking Surgery in Metastatic VIPoma with Severe Diarrhea and Hypovolemic Shock

Introduction

Neuroendocrine tumors (NETs) exhibit variable malignant potential and typically originate from the entero-pancreatic endocrine system. These tumors may be functional, producing a variety of hormones, including insulin, glucagon, vasoactive intestinal peptide (VIP), calcitonin, somatostatin, and renin. VIPoma, also known as Verner-Morrison syndrome, is a rare functional NET that arises from the pancreas and secretes VIP. Its estimated incidence is approximately 1 case per 10 million person-years [1]. It is often referred to by the acronym WDHA syndrome, for watery diarrhea, hypokalemia, and achlorhydria.

The symptoms are mediated by VIP, which increases intracellular cyclic AMP (cAMP) in intestinal epithelial cells, leading to excessive fluid secretion, electrolyte imbalance, and inhibition of gastric acid production. VIP also exerts systemic effects, including vasodilation and increased cardiac output [1].

At the time of diagnosis, most VIPomas are found to be metastatic (59%), predominantly located in the body or tail of the pancreas (72%), and secretory diarrhea is nearly universal at presentation [2]. The severity of symptoms may be associated with disease burden, and conventional locoregional or systemic therapies may be insufficient for symptom control.

We report a case of metastatic VIPoma with refractory secretory diarrhea, in which stereotactic body radiation therapy (SBRT) to the primary tumor resulted in rapid symptom relief, enabling the patient to undergo subsequent debulking surgery.

Case Report

A 54-year-old man presented with severe watery diarrhea and metabolic acidosis in July 2020. An abdominal MRI revealed a heterogeneous, centrally necrotic pancreatic body mass measuring 12.0 cm, with involvement of the splenic artery, peripancreatic lymphadenopathy, and multiple liver lesions. Fine-needle aspiration of the pancreatic and liver masses confirmed a well-differentiated NET with strong expression of CAM5.2, synaptophysin, and chromogranin, and a Ki-67 index of less than 1%. His serum VIP level was elevated at 129 pg/ml (normal range: 0–64 pg/ml), while chromogranin A, gastrin, and 5-HIAA levels were normal. His clinical, histopathologic and biochemical findings were consistent with a metastatic VIPoma. Due to the multifocal liver lesions involving both lobes, he had been deemed unsuitable for curative surgical intervention. In August 2020, treatment was initiated with short-acting octreotide at 100 mcg 3 times a day. Due to a suboptimal response, the dosage was increased to 200 mcg 3 times daily, and long-acting release octreotide was added at 30 mg every 4 weeks. Despite these actions, his diarrhea persisted, requiring escalation of short-acting octreotide to 400 mcg 3 times daily. Although he initially showed some improvement, he was admitted to the ICU in September 2020 with severe diarrhea, hypovolemia, and hypotension requiring pressor support. Long-acting release octreotide was increased to 60 mg, which temporarily improved his symptoms. However, he was readmitted to the ICU within 1 month with worsening diarrhea exceeding 3 liters per day. Short-acting octreotide was further increased to 500 mcg, then 667 mcg 3 times daily, and finally transitioned to an intravenous infusion due to persistent symptoms.

After achieving clinical stability, he underwent trans-arterial chemoembolization (TACE) of the liver in December 2020 and Yttrium-90 (Y90) radioembolization in January 2021. Attempts to wean him off short-acting octreotide were unsuccessful. In February 2021, everolimus was initiated but discontinued within a few weeks due to drug fever and oral mucositis, with no significant improvement in his diarrhea.

He was readmitted on March 7th, 2021, and quickly transferred to the ICU due to profuse watery diarrhea unresponsive to intravenous (IV) therapy. His stool output was recorded as 9.6 liters on admission, decreasing to 5 liters later that day. By March 11th, his output had increased to 11.4 liters and remained at that level for 4 days despite aggressive fluid resuscitation with lactated Ringer’s solution and bicarbonate supplementation. On March 12th, 2021, his stool output exceeded 5 liters per day and his hemodynamic stability was tenuous. In consideration of persistent volume loss refractory to continuous IV octreotide, SBRT was initiated, targeting the primary pancreatic tumor.

The patient underwent 4D computed tomography (CT) simulation in the supine position with arms above the head using a custom immobilization device to ensure reproducibility and to account for respiratory motion. A contrast-enhanced CT scan was acquired and registered with the 4D data to aid in target delineation and identify adjacent critical structures, particularly the surrounding bowel. The gross tumor volume was defined based on the visible tumor across respiratory phases to create an internal target volume (ITV) and a uniform 0.5 cm margin was added to generate the planning target volume, accounting for setup variability. The prescribed dose was 30 Gy in 5 fractions of 6 Gy each (Figure 1).

Treatment planning was performed using inverse-planned SBRT techniques to optimize conformality and steep dose gradients. The highest priority during treatment planning was the dose delivered to the small bowel. We constrained the maximum dose to the bowel to less than 105% of the prescription dose. Daily cone-beam CT (CBCT) was used prior to each fraction to verify tumor localization.

At the start of radiation treatment, he required 12 liters of fluid intake to compensate for an output of 8.9 liters. Unexpectedly, the diarrhea promptly abated within a day. Radiation therapy had provided short-term stabilization and temporary relief of his severe diarrhea (Figure 2).

However, although his symptoms improved, the diarrhea persisted. He was then re-evaluated for surgical debulking and subsequently underwent subtotal spleno-pancreatectomy, liver metastasectomy, and intraoperative radiofrequency ablation for tumor debulking with pathology showing a well-differentiated grade 2 NET in the pancreas, portal vein thrombus, and liver. This extensive debulking surgery resulted in long-term stability and resolution of his debilitating diarrhea. Clinically, he recovered without SBRT-related toxicity and was stable for discharge by post-operative day 7. His serum VIP level decreased to undetectable on post-operative day 26 and remained undetectable.

Postoperatively, short-acting octreotide was gradually tapered to 125 mcg 3 times daily, while long-acting release octreotide was maintained at 60 mg every 4 weeks. Following the debulking surgery, he has remained stable for the past 2 years, with no further hospitalizations related to diarrhea and hypovolemic shock and no need for dose escalation of octreotide. A timeline from diagnosis to the current time is shown in Figure 3.

Discussion

The management of NETs requires a nuanced, multidisciplinary approach that considers tumor extent, location, resectability, and functional status. While many NETs present with metastatic disease at diagnosis, the presence of metastases does not necessarily preclude surgical intervention. Surgical resection – whether curative or palliative – can significantly improve quality of life and may extend survival in selected patients [3,4]. Consequently, all NET patients, including those with metastatic disease, should be evaluated for potential surgical options.

In our case, the patient presented with life-threatening, recurrent hypovolemic shock due to a functional VIPoma, despite aggressive medical therapy with somatostatin analogs and systemic treatments. While his metastatic burden initially made him a poor surgical candidate, the severity and refractory nature of his symptoms necessitated a more aggressive treatment strategy.

A stepwise approach was employed, beginning with liver-directed therapies – TACE and Y90 radioembolization – to reduce tumor burden and mitigate hormone-related symptoms. Although these interventional radiology-guided treatments likely provided transient hormonal control, the primary pancreatic tumor remained a substantial source of VIP secretion, perpetuating his life-threatening diarrhea.

Given the ineffectiveness of IV octreotide and the need for urgent symptom control, SBRT was employed as a bridging strategy. Currently, there is limited data on the efficacy of SBRT in the treatment of NETs [5,6], particularly for VIPomas. Historically, well-differentiated NETs were considered radio-resistant; however, recent data have shown them to respond to higher doses of radiation given with SBRT.

Published data from retrospective studies [6–8] have demonstrated SBRT to be an effective strategy for symptom control for liver metastasis in NETs, often in combination with other treatments such as systemic therapy and peptide receptor radionuclide therapy. The use of multimodal treatment appears to be more effective in achieving disease control, likely due to underlying tumor heterogeneity.

The application of SBRT in NETs is an evolving approach and warrants more attention in this arena. Although the specific data on SBRT in VIPoma is scarce, promising results have been reported in other functioning pancreatic NETs such as insulinoma [9,10]. A patient with refractory hypoglycemia due to insulinoma attained optimal glycemic control following SBRT (50 Gy/5 fractions) after failure of other treatments [9]. This patient had mild fatigue as the only side effect of SBRT. Similarly, another study documenting 2 cases (first case: 35 Gy/5 fractions; second case: 30 Gy/3 fractions) of insulinoma demonstrated adequate symptom alleviation following SBRT, without acute or delayed adverse effects from the SBRT. Although these examples pertained to insulinoma instead of VIPoma, they indicate that SBRT may serve as a viable option for functioning pancreatic tumors, including VIPoma [10].

Radiation therapy is not traditionally used for VIPomas; however, in this case, the high dose per fraction delivered via stereotactic technique led to rapid attenuation of fluid loss. This unexpected clinical response stabilized the patient, making him eligible for definitive surgical intervention.

Abdominal and pancreatic SBRT requires careful consideration to minimize toxicity. We utilized 4-dimensional CT simulation to assess respiratory-induced tumor motion, allowing for accurate delineation of both the target and nearby organs at risk across all respiratory phases. This enabled precise creation of the ITV. We also adhered to established organ-specific dose constraints. For this patient, special attention was paid to the surrounding small bowel, given its proximity to the target. We limited the maximum bowel dose to less than 105% of the prescription dose (30 Gy in 5 fractions), consistent with published SBRT safety guidelines. During inverse planning, we optimized dose fall-off using multiple beam angles and highly conformal dose distributions to improve sparing of the small bowel. Additionally, daily image guidance using cone-beam CT was employed to ensure accurate treatment delivery.

This case highlights the importance of considering all available treatment options, even those not traditionally employed, when managing complex cases with refractory symptoms. The debulking surgery, which included subtotal spleno-pancreatectomy, liver metastasectomy, and intraoperative radiofrequency ablation, proved to be the definitive treatment for his debilitating diarrhea. This case underscores the potential value of debulking surgery, even in the setting of metastatic disease, when medical therapies fail to control life-threatening symptoms. It also emphasizes the need to recognize and address the potential heterogeneity in tumor biology between the primary tumor and metastases, as even low-grade NETs can have life-threatening functional consequences.

Conclusions

VIPoma can present with uncontrollable aggressive diarrhea, and when other therapies fail. SBRT to the primary tumor can be employed as a bridge to debulking surgery and to prevent hypovolemic shock. This case highlights the importance of considering all available treatment options, even those not traditionally employed, when managing complex cases with refractory symptoms.