A Peptide Meets a Radionuclide to Combat a Rare Tumor

Background: Neuroendocrine carcinomas (NECs) are rare malignancies with limited treatment options beyond surgery. Peptide receptor radionuclide therapy (PRRT) is a process by which a somatostatin analog (octreotate) is combined with a chelator (DOTA) and a radionuclide (lutetium-177 [177Lu-dotatate]). This therapy targets receptors on neuroendocrine cells, causing internalization of the radionuclide by the tumor cell, which results in cellular damage and apoptosis. Case Report: We describe the clinical and therapeutic course of a 69-year-old male with a metastatic rectal NEC in whom progressive disease was noted after multiple therapies were attempted. After PRRT with 177Lu-dotatate, the patient was asymptomatic and demonstrated a near-complete radiologic response. Conclusion: This case illustrates that treatment with PRRT may improve the outcome of patients with metastatic rectal NEC. Our case highlights the importance of further research into the use of PRRT in patients with a Ki-67 <55% and uptake on somatostatin receptor imaging.


INTRODUCTION
Neuroendocrine tumors (NETs) are rare malignancies that increased 6.4-fold between 1973 (1.09 per 100,000) and 2012 (6.98 per 100,000). 1 These malignancies occur most commonly in the gastrointestinal tract. Beyond surgery, treatment options are limited to chemotherapy. In patients with high-grade, poorly differentiated (PD) tumors, termed neuroendocrine carcinomas (NECs), therapeutic options are even more limited.
Peptide receptor radionuclide therapy (PRRT) provides another therapeutic option for patients with advanced, progressive, somatostatin receptor (SSTR)-positive NETs of the midgut. 2 By combining a somatostatin analog (SSA) (octreotate) with a chelator (DOTA) and a radionuclide (lutetium-177 [ 177 Lu-dotatate]), PRRT takes advantage of the SSTRs that are expressed on the surface of most NETs. 3 This therapy targets the SSTRs on NET cells, allowing internalization of the radionuclide by the tumor cell. Once inside the tumor cell, beta emission from the radionuclide results in cellular damage. 3 *Dr Ramirez is now affiliated with the Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN.
We describe a patient with a metastatic rectal NEC who had a near-complete response with 177 Lu-dotatate treatment.

CASE REPORT
A 69-year-old male with a history of a metastatic rectal NEC was referred to our center for evaluation. The patient had been diagnosed in October 2014 after developing rectal bleeding. Colonoscopy had shown a fungating, infiltrative, ulcerating, nonobstructive mass measuring 3 cm in length within the rectum. Pathology identified a PD NEC. The tumor was present within the lamina propria and muscularis mucosa, no small-cell features were seen, and the Ki-67 proliferative index was 40%. Computed tomography (CT) showed asymmetric wall thickening involving approximately 50% of the circumference of the rectum and enlarged adjacent perirectal lymph nodes abutting the mesorectal fascia ( Figure 1A). CT also revealed innumerable hepatic masses, bilateral pulmonary nodules, and a sclerotic lesion in the right ilium (Figure 2A). Fluorodeoxyglucose positron emission tomography (PET) CT confirmed uptake in multiple liver metastases, which were too numerous to count, as well as uptake in the rectal neoplasm and perirectal lymph node. In January 2015, the patient began treatment with carboplatin area under the curve 5 and etoposide 100 mg/m 2 every 3 weeks and completed 6 cycles of therapy. Treatment was interrupted because surgery was needed for an expanding meningioma. Scans revealed stable disease, and the patient was judged to be a candidate for prophylactic cranial irradiation. The patient underwent 25 Gy in 10 fractions in August 2015.
Because of progressive disease in the liver, the patient was started on topotecan 1.5 mg/m 2 on days 1 through 5 every 3 weeks in October 2015. Following the first cycle of treatment, he developed symptomatic hypoglycemia, and insulin was elevated at 67.7 μU/mL (reference range, 0-30 μU/mL). Hypoglycemia was hypothesized to be related to his metastatic liver disease, and the patient underwent transarterial chemoembolization (TACE). Symptoms improved, and he started a second cycle of topotecan in December 2015. In January 2016, the patient started combination capecitabine 750 mg/m 2 twice daily on days 1 through 14 of a 28-day cycle and temozolomide 200 mg/m 2 on days 10 through 14 of a 28-day cycle (CAPTEM), along with lan-reotide, and was noted to have uptake on somatostatin scintigraphy.
The patient underwent repeat TACE in July 2016 and continued CAPTEM until November 2016 when he was noted to have progression in the liver. In December 2016, the patient was started on treatment with fluorouracil (5-FU) 400 mg/m 2 followed by a 2,400 mg intravenous infusion over 2 days, leucovorin 400 mg/m 2 , and oxaliplatin 85 mg/m 2 every 2 weeks (FOLFOX). The patient's disease remained stable until November 2017, when he again had progression in the liver. In December 2017, the patient was started on ipilimumab 1 mg/kg for 30 minutes daily on day 1 and nivolumab 3 mg/kg for 30 minutes daily on days 1, 15, and 29 through a clinical trial. Following 4 cycles of treatment, the patient was noted to have progression of disease and declining performance status. The last treatment was in May 2018.
The patient sought follow-up in our clinic in May 2018. At that time, he was extremely symptomatic with fatigue, weight loss, and abdominal and rectal pain, and he required assistance to ambulate. After nutritional support and pain control, he was judged to be a candidate for further treatment. Gallium-68 dotatate PET/CT scan in June 2018 showed uptake in diffuse metastatic disease throughout the liver causing hepatomegaly ( Figure 3A). Uptake in metastatic lymph nodes in the left lower neck, mediastinum, and rectum was also noted. Axial fused pretreatment gallium-68 dotatate PET/CT scan demonstrated SSTR-rich primary rectal tumor and hepatic metastatic lesions with index lesion (Figures 1C  and 2C).
In August 2018, the patient was initiated on 177 Lu-dotatate and received 200 mCi. He repeated this treatment every 8 weeks for 4 cycles. During this time, his symptoms improved, and he gained weight. By February 2019, when he received his final cycle, the patient was completely asymptomatic. Repeat imaging that included a gallium-68 dotatate PET/CT scan in April 2019 revealed a nearcomplete response to therapy (Figures 1D, 2D, and 3B). CT of the abdomen and pelvis also revealed partial response ( Figures 1B and 2B). A subsequent scan showed responsive disease.  Our patient differed from patients in the NETTER-1 study, as he was classified as having an NEC (Ki-67 40%) with PD morphology, and he had a hindgut tumor. The data on high-grade tumors are scarce, and thus, PRRT is not currently a recommended treatment for NEC. 4 The majority of research on the effectiveness of PRRT has been in lowor intermediate-grade NETs because of the demonstrated inverse relationship between grade and SSTR expression. [5][6][7] As previously described, PRRT uses the SSTRs to gain internal access to the cell; therefore, the more SSTRs that a tumor cell expresses, the more successful PRRT is. The current (2019) National Comprehensive Cancer Network treatment guidelines for PD NECs state that somatostatin scintigraphy is not recommended in the evaluation of NECs unless evidence suggests well-differentiated morphology. 4 Contrary to the current guidelines, however, studies have demonstrated high SSTR expression in certain patients with NEC, despite concomitant PD morphology. 8,9 For example, Welin et al reported that 62% of patients with NECs had a positive SSTR expression, and Binderup et al described 69% of patients with PD NECs as SSTR positive during their initial evaluation. 8,9 Congruently, our patient demonstrated SSTR expression and an excellent response to PRRT, despite both a high proliferation rate and PD morphology.

DISCUSSION
Our patient's response was in line with a patient described by Garske and collegues. 10 The patient with an NEC of unknown primary with liver metastasis and a Ki-67 10% to 50% had a successful response to PRRT after progression of disease on 2 chemotherapies. 10 Similarly, our patient was pretreated with multiple lines of chemotherapy, with the addition of liver-directed therapy and immunotherapy.
The current first-line treatment for unresectable NEC is chemotherapy using a platinum-based treatment in combination with etoposide. 4 The NORDIC (Neuro-Ophthalmology Research Disease Investigator Consortium) NEC trial demonstrated a median overall survival (OS) of 11 months and a median PFS of 4 months in patients when first-line chemotherapy was used in NECs. 11 Thang et al conducted a recent (2018) retrospective study examining PRRT in NEC and reported more favorable results than the NORDIC NEC trial, with a median OS of 19 months and a median PFS of 9 months in patients who underwent PRRT. 12 Patients with a Ki-67 <55% did remarkably better with PRRT (46 months vs 14 months) compared to chemotherapy treatment; however, those with a Ki-67 ࣙ55% had a shorter OS with PRRT compared to treatment with chemotherapy (7 months vs 10 months, respectively). 11,12 In line with the results reported by Thang and colleagues, Carlsen et al conducted a retrospective cohort study of 149 patients with NEC treated with PRRT and found that those with a Ki-67 21% to 54% experienced longer PFS and OS compared to patients with a Ki-67 ࣙ55% (16 vs 6 months [P<0.001] and 31 vs 9 months [P<0.001], respectively). 13 Parallel to our patient, the majority of subjects examined by Thang et al and Carlsen et al failed prior treatment with chemotherapy (79% and 69.8%, respectively) but responded favorably to PRRT. 12,13 177 Lu-dotatate is indicated for SSTR-positive gastroenteropancreatic NETs, including foregut, midgut, and hindgut in adults. 4 As of October 2020, no grade is specified as a cutoff. Although the NETTER-1 study did not include these patients, considering this treatment for patients with widespread SSTR-positive disease is reasonable.
Our patient demonstrated an excellent response to PRRT, perhaps because of his lower proliferation rate, in spite of having PD morphology. These results demonstrate that, conceivably, PRRT is a more advantageous therapy than chemotherapy for patients with NEC who have a proliferation rate <55%.
Not only did our patient have a dramatic radiologic improvement, but he also improved clinically and became symptom-free. When compared to chemotherapy, PRRT appears to be tolerated well with less adverse effects. The safety of 177 Lu-dotatate was studied in 504 patients with NETs and was found to produce digestive (such as diarrhea, vomiting, and abdominal pain) and hematologic (neutropenia, anemia, thrombocytopenia [World Health Organization grades 3 or 4]) side effects in 25% and 3.6% of administrations, respectively. 14 Serious adverse effects, including myelodysplastic syndrome and nonfatal liver toxicity, were reported in <1% of patients. 14 The side effect profile of PRRT illustrates that 177 Lu-dotatate may serve as a well-tolerated therapy for patients with NEC.

CONCLUSION
Our case accentuates the importance of further investigation of PRRT in NEC, specifically in patients with a Ki-67 <55% and uptake on SSTR imaging.