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Published in: CardioVascular and Interventional Radiology 1/2024

06-12-2023 | Neuroendocrine Tumor | Clinical Investigation

Integrated Capecitabine–Temozolomide with Radioembolization for Liver-Dominant G2 NETs: Long-Term Outcomes of a Single-Institution Retrospective Study

Authors: Michael C. Soulen, Ursina R. Teitelbaum, Rosemarie Mick, Jennifer Eads, Jeffrey I. Mondschein, Mandeep Dagli, Diana van Houten, Nevena Damjanov, Charles Schneider, Keith Cengel, David C. Metz

Published in: CardioVascular and Interventional Radiology | Issue 1/2024

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Abstract

Purpose

Capecitabine–Temozolomide (CapTem) is an oral chemotherapy regimen for NETs. Both drugs are radiosensitizers. Integrating CapTem and Y90 transarterial radioembolization (TARE) in patients with grade 2 neuroendocrine tumor (NET) liver metastases achieved an encouraging objective response rate (ORR) and progression-free survival (PFS) in a feasibility study. This study expands that report to a larger cohort with longer follow-up.

Methods

Therapy consisted of monthly cycles of capecitabine 600 mg/m2 twice daily for 14 days and temozolomide 150–200 mg/m2 on day 10–14. Simulation angiography was performed during the initial cycle. The dominant lobe was treated with 90Y-resin microspheres using BSA dosimetry on day 7 of the second cycle of CapTem. Patients with bilobar disease had the other lobe treated on day 7 of the third or fourth cycle. CapTem was continued until progression or intolerance. Clinical and laboratory assessment was done monthly and imaging every 3 months.

Results

35/37 patients completed the prescribed regimen. Primary sites of disease were pancreas (16), lung (10), gut (7) and unknown (4). Mean duration of CapTem was 12 months (range, 4–32 months). ORR in the liver was 72% with a disease control rate of 100%. Median PFS was 36 months (95% CI, 25–45 months). Median overall survival was 41 months (95% CI, 24–87 months) from initiation of CapTemY90 therapy and 130 months (95% CI, 56–172 months) from initial diagnosis.

Conclusion

Chemoradiation with CapTem and TARE provided durable control of G2 NET liver metastases for substantially longer than expectations for embolotherapy or chemotherapy alone.

Graphical Abstract

Literature
2.
go back to reference Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The north American neuroendocrine tumor society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46:707–14.CrossRefPubMedPubMedCentral Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The north American neuroendocrine tumor society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46:707–14.CrossRefPubMedPubMedCentral
3.
go back to reference Pavel M, Baudin E, Couvelard A, et al. ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95:157–76.CrossRefPubMed Pavel M, Baudin E, Couvelard A, et al. ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95:157–76.CrossRefPubMed
4.
go back to reference Gaba RC. Chemoembolization practice patterns and technical methods among interventional radiologists: results of an online survey. AJR Am J Roentgenol. 2012;198:692–9.CrossRefPubMed Gaba RC. Chemoembolization practice patterns and technical methods among interventional radiologists: results of an online survey. AJR Am J Roentgenol. 2012;198:692–9.CrossRefPubMed
5.
go back to reference Salem R, Gilbertsen M, Butt Z, et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization compared with chemoembolization. Clin Gastroenterol Hepatol. 2013;11:1358-1365.e1.CrossRefPubMed Salem R, Gilbertsen M, Butt Z, et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization compared with chemoembolization. Clin Gastroenterol Hepatol. 2013;11:1358-1365.e1.CrossRefPubMed
6.
go back to reference Chen JX, Rose S, White SB, El-Haddad G, Fidelman N, Yarmohammadi H, Hwang W, Sze DY, Kothary N, Stashek K, Wileyto EP, Salem R, Metz DC, Soulen MC. Embolotherapy for neuroendocrine tumor liver metastases: prognostic factors for hepatic progression-free survival and overall survival. Cardiovasc Intervent Radiol. 2017;40:69–80.CrossRefPubMed Chen JX, Rose S, White SB, El-Haddad G, Fidelman N, Yarmohammadi H, Hwang W, Sze DY, Kothary N, Stashek K, Wileyto EP, Salem R, Metz DC, Soulen MC. Embolotherapy for neuroendocrine tumor liver metastases: prognostic factors for hepatic progression-free survival and overall survival. Cardiovasc Intervent Radiol. 2017;40:69–80.CrossRefPubMed
7.
go back to reference Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, Mowatt KB, Dinnen RD, Mao Y, Stevens PD, Schrope B, Allendorf J, Lee JA, Sherman WH, Cabot JA. Capecitabine and temozolomide (CAPTEM) for metastatic well-differentiated neuroendocrine cancers. Cancer Chemother Pharmacol. 2013;71:663–70.CrossRefPubMed Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, Mowatt KB, Dinnen RD, Mao Y, Stevens PD, Schrope B, Allendorf J, Lee JA, Sherman WH, Cabot JA. Capecitabine and temozolomide (CAPTEM) for metastatic well-differentiated neuroendocrine cancers. Cancer Chemother Pharmacol. 2013;71:663–70.CrossRefPubMed
8.
go back to reference Cives M, Ghayouri M, Morse B, Brelsford M, Black M, Rizzo A, Meeker A, Stroberg J. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23:759–67.CrossRefPubMed Cives M, Ghayouri M, Morse B, Brelsford M, Black M, Rizzo A, Meeker A, Stroberg J. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23:759–67.CrossRefPubMed
9.
go back to reference Kunz PL, Graham NT, Catalano PJ, Nimeiri HS, Fisher GA, Longacre TA, Suarez CJ, Martin BA, Yao JC, Kulke MH, Hendifar AE, Shanks JC, Shah MH, Zalupski MM, Schmulbach EL, Reidy-Lagunes DL, Strosberg JR, O’Dwyer PJ, Benson AB 3rd. 2022 A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol. 2023;41(7):1359–69.CrossRefPubMed Kunz PL, Graham NT, Catalano PJ, Nimeiri HS, Fisher GA, Longacre TA, Suarez CJ, Martin BA, Yao JC, Kulke MH, Hendifar AE, Shanks JC, Shah MH, Zalupski MM, Schmulbach EL, Reidy-Lagunes DL, Strosberg JR, O’Dwyer PJ, Benson AB 3rd. 2022 A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol. 2023;41(7):1359–69.CrossRefPubMed
10.
go back to reference Soulen MC, van Houten D, Teitelbaum UR, et al. Safety and feasibility of integrating Yttrium-90 radioembolization with capecitabine–temozolomide for grade 2 liver-dominant metastatic neuroendocrine tumors. Pancreas. 2018;47(8):980–4.CrossRefPubMed Soulen MC, van Houten D, Teitelbaum UR, et al. Safety and feasibility of integrating Yttrium-90 radioembolization with capecitabine–temozolomide for grade 2 liver-dominant metastatic neuroendocrine tumors. Pancreas. 2018;47(8):980–4.CrossRefPubMed
11.
go back to reference Currie BM, Hoteit M, Ben-Josef E, Nadolski GJ, Soulen MC. Radioembolization-induced chronic hepatotoxicity: a single-center cohort analysis. J Vasc Intervent Radiol. 2019;30:1915–23.CrossRef Currie BM, Hoteit M, Ben-Josef E, Nadolski GJ, Soulen MC. Radioembolization-induced chronic hepatotoxicity: a single-center cohort analysis. J Vasc Intervent Radiol. 2019;30:1915–23.CrossRef
12.
go back to reference Hickey R, Mulcahy MF, Lewandowski RJ, et al. Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 radioembolization. Int J Radiat Oncol Biol Phys. 2014;88:1025–31.CrossRefPubMed Hickey R, Mulcahy MF, Lewandowski RJ, et al. Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 radioembolization. Int J Radiat Oncol Biol Phys. 2014;88:1025–31.CrossRefPubMed
13.
go back to reference Cohen SJ, Konski AA, Putnam S, Ball DS, Meyer JE, Yu JQ, Astsaturov I, Marlow C, Dickens A, Cade DN, Merepol NJ. Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer. Br J Cancer. 2014;111:265–71.CrossRefPubMedPubMedCentral Cohen SJ, Konski AA, Putnam S, Ball DS, Meyer JE, Yu JQ, Astsaturov I, Marlow C, Dickens A, Cade DN, Merepol NJ. Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer. Br J Cancer. 2014;111:265–71.CrossRefPubMedPubMedCentral
14.
go back to reference Sharma RA, Van Hazel GA, Morgan B, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25:1099–106.CrossRefPubMed Sharma RA, Van Hazel GA, Morgan B, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25:1099–106.CrossRefPubMed
15.
go back to reference van Hazel GA, Pavlakis N, Goldstein D, et al. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J Clin Oncol. 2009;27:4089–95.CrossRefPubMed van Hazel GA, Pavlakis N, Goldstein D, et al. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J Clin Oncol. 2009;27:4089–95.CrossRefPubMed
16.
go back to reference Yang TX, Chua TC, Morris DL. Radioembolization and chemoembolization for unresectable neuroendocrine liver metastases—a systematic review. Surg Oncol. 2012;21:299–308.CrossRefPubMed Yang TX, Chua TC, Morris DL. Radioembolization and chemoembolization for unresectable neuroendocrine liver metastases—a systematic review. Surg Oncol. 2012;21:299–308.CrossRefPubMed
17.
go back to reference Schaarschmidt BM, Wildgruber M, Kloeckner R, et al. 90Y radioembolization in the treatment of neuroendocrine neoplasms: results of an international multicenter study. J Nucl Med. 2022;63:679–85.PubMed Schaarschmidt BM, Wildgruber M, Kloeckner R, et al. 90Y radioembolization in the treatment of neuroendocrine neoplasms: results of an international multicenter study. J Nucl Med. 2022;63:679–85.PubMed
18.
go back to reference Al-Toubah T, Morse B, Strosberg J. Efficacy of capecitabine and temozolomide in small bowel (midgut) neuroendocrine tumors. Curr Oncol. 2022;29:510–5.CrossRefPubMedPubMedCentral Al-Toubah T, Morse B, Strosberg J. Efficacy of capecitabine and temozolomide in small bowel (midgut) neuroendocrine tumors. Curr Oncol. 2022;29:510–5.CrossRefPubMedPubMedCentral
19.
go back to reference Arrese D, Mcnally ME, Chokshi R, Feria-Arias E, Schmidt C, Klemanski D, Gregory G, Khabiri H, Shah M, Bloomston M. Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma. Ann Surg Oncol. 2013;20:1114–20.CrossRefPubMed Arrese D, Mcnally ME, Chokshi R, Feria-Arias E, Schmidt C, Klemanski D, Gregory G, Khabiri H, Shah M, Bloomston M. Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma. Ann Surg Oncol. 2013;20:1114–20.CrossRefPubMed
20.
go back to reference Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP. Lancet Oncol. 2021;22(12):1752–63.CrossRefPubMed Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP. Lancet Oncol. 2021;22(12):1752–63.CrossRefPubMed
21.
go back to reference Ebbers SC, van Roekel C, Braat MNGJA, Barentsz MW, Lam MGEH, Braat AJAT. Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases. Eur J Nucl Med Mol Imaging. 2022;49(5):1700–10.CrossRefPubMed Ebbers SC, van Roekel C, Braat MNGJA, Barentsz MW, Lam MGEH, Braat AJAT. Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases. Eur J Nucl Med Mol Imaging. 2022;49(5):1700–10.CrossRefPubMed
22.
go back to reference Chansanti O, Jahangiri Y, Matsui Y, Adachi A, Geeratikun Y, Kaufman JA, Kolbeck KJ, Stevens JS, Farsad K. Tumor dose response in Yttrium-90 resin microsphere embolization for neuroendocrine liver metastases: a tumor-specific analysis with dose estimation using SPECT-CT. J Vasc Interv Radiol. 2017;28(11):1528–35.CrossRefPubMed Chansanti O, Jahangiri Y, Matsui Y, Adachi A, Geeratikun Y, Kaufman JA, Kolbeck KJ, Stevens JS, Farsad K. Tumor dose response in Yttrium-90 resin microsphere embolization for neuroendocrine liver metastases: a tumor-specific analysis with dose estimation using SPECT-CT. J Vasc Interv Radiol. 2017;28(11):1528–35.CrossRefPubMed
23.
go back to reference Su Y-K, Mackey RV, Riaz A, et al. Long-term hepatotoxicity of yttrium-90 radioembolization as treatment of metastatic neuroendocrine tumor to the liver. J Vasc Interv Radiol. 2017;28:1520–6.CrossRefPubMed Su Y-K, Mackey RV, Riaz A, et al. Long-term hepatotoxicity of yttrium-90 radioembolization as treatment of metastatic neuroendocrine tumor to the liver. J Vasc Interv Radiol. 2017;28:1520–6.CrossRefPubMed
24.
go back to reference Tomozawa Y, Jahangiri Y, Pathak P, et al. Long-term toxicity after transarterial radioembolization with yttrium-90 using resin microspheres for neuroendocrine tumor liver metastases. J Vasc Interv Radiol. 2018;29:858–65.CrossRefPubMed Tomozawa Y, Jahangiri Y, Pathak P, et al. Long-term toxicity after transarterial radioembolization with yttrium-90 using resin microspheres for neuroendocrine tumor liver metastases. J Vasc Interv Radiol. 2018;29:858–65.CrossRefPubMed
Metadata
Title
Integrated Capecitabine–Temozolomide with Radioembolization for Liver-Dominant G2 NETs: Long-Term Outcomes of a Single-Institution Retrospective Study
Authors
Michael C. Soulen
Ursina R. Teitelbaum
Rosemarie Mick
Jennifer Eads
Jeffrey I. Mondschein
Mandeep Dagli
Diana van Houten
Nevena Damjanov
Charles Schneider
Keith Cengel
David C. Metz
Publication date
06-12-2023
Publisher
Springer US
Published in
CardioVascular and Interventional Radiology / Issue 1/2024
Print ISSN: 0174-1551
Electronic ISSN: 1432-086X
DOI
https://doi.org/10.1007/s00270-023-03614-8

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