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Effects of CAPTEM (Capecitabine and Temozolomide) on a Corticotroph Carcinoma and an Aggressive Corticotroph Tumor

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Abstract

Corticotroph carcinomas and aggressive corticotroph tumors can be resistant to conventional therapy, including surgery, radiotherapy, and medical treatment. Recent evidence suggests that temozolomide (an oral alkylating agent) administered with capecitabine (pro-drug of 5-fluorouracil) may improve progression-free survival in patients with high-risk corticotroph tumors and carcinomas. This led to the use of capecitabine and temozolomide (CAPTEM) in two patients, one with a corticotroph carcinoma and the other with an aggressive corticotroph tumor, as well the in vitro analysis of capecitabine and 5-fluorouracil on cell growth and hormone production. Both patients had previous surgical and radiation therapy. The first patient developed leptomeningeal spread 2 years after his radiation treatment. He had 12 cycles of CAPTEM, which resulted in tumor control associated with clinical and radiological improvement. Twenty-seven months later, CAPTEM was restarted for disease recurrence with ongoing tumor response. The second patient had a rapid tumor regrowth 2 years after his third surgical resection. He was treated with 12 cycles of CAPTEM, which led to tumor shrinkage with no tumor regrowth 22 months after cessation of therapy. Experiments using mouse ACTH-producing pituitary tumor AtT20 cells demonstrated that treatment with 5-fluorouracil in combination with temozolomide had an additive effect in reducing cell viability and ACTH production in the culture medium. Our patients and experimental data in AtT20 cells support CAPTEM as a potential treatment option for aggressive corticotroph tumors and carcinomas. However, a prospective clinical trial is required to determine whether CAPTEM is superior to temozolomide in the treatment of these tumors.

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References

  1. Asa SL, Casar-Borota O, Chanson P, Delgrange E, Earls P, Ezzat S, et al (2017) From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): An international pituitary pathology club proposal. Endocr Relat Cancer 24:C5–8

    Article  CAS  Google Scholar 

  2. Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, et al (2018) European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 178:G1–24

    Article  CAS  Google Scholar 

  3. Alshaikh OM, Asa SL, Mete O, Ezzat S (2019) An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors. Endocr Pathol 30:118–27

    Article  Google Scholar 

  4. Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, et al (2017) Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur J Endocrinol 176:769–77

    Article  CAS  Google Scholar 

  5. Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, et al (2013) Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 71:663–70

    Article  CAS  Google Scholar 

  6. Thearle MS, Freda PU, Bruce JN, Isaacson SR, Lee Y, Fine RL (2011) Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor. Pituitary 14:418–24

    Article  Google Scholar 

  7. Zacharia BE, Gulati AP, Bruce JN, Carminucci AS, Wardlaw SL, Siegelin M, et al (2014) High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM). Neurosurgery 74:E447–55

    Article  Google Scholar 

  8. Donovan LE, Arnal A V, Wang S-H, Odia Y (2016) Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncol 5:203–9

    Article  CAS  Google Scholar 

  9. Joehlin-Price AS, Hardesty DA, Arnold CA, Kirschner LS, Prevedello DM, Lehman NL (2017) Case report: ACTH-secreting pituitary carcinoma metastatic to the liver in a patient with a history of atypical pituitary adenoma and Cushing’s disease. Diagn Pathol 12:34

    Article  Google Scholar 

  10. Lin AL, Jonsson P, Tabar V, Yang TJ, Cuaron J, Beal K, et al Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab. J Clin Endocrinol Metab 103:3925–30

  11. Satou M, Wang J, Nakano-Tateno T, Teramachi M, Suzuki T, Hayashi K, et al (2020) L-type amino acid transporter 1, LAT1, in growth hormone-producing pituitary tumor cells. Mol Cell Endocrinol (in press)

  12. Murakami J, Lee Y-J, Kokeguchi S, Tsujigiwa H, Asaumi J-I, Nagatsuka H, et al (2007) Depletion of O6-methylguanine-DNA methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines. Oncol Rep 17:1461–7

    CAS  PubMed  Google Scholar 

  13. Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC, et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338–45

    Article  CAS  Google Scholar 

  14. Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al (2011) First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 117:268–75

    Article  CAS  Google Scholar 

  15. Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Öberg K (2011) Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 117:4617–22

    Article  CAS  Google Scholar 

  16. Koumarianou A, Kaltsas G, Kulke MH, Oberg K, Strosberg JR, Spada F, et al (2015) Temozolomide in advanced neuroendocrine neoplasms: pharmacological and clinical aspects. Neuroendocrinology 101:274–88

    Article  CAS  Google Scholar 

  17. Papaxoinis G, Kordatou Z, McCallum L, Nasralla M, Lamarca A, Backen A, et al (2020) Capecitabine and temozolomide in patients with advanced pulmonary carcinoid tumours. Neuroendocrinology 110:413-21

    Article  CAS  Google Scholar 

  18. Al-Toubah T, Morse B, Strosberg J (2020) Capecitabine and temozolomide in advanced lung neuroendocrine neoplasms. Oncologist 25:48-52

    Article  Google Scholar 

  19. Lu Y, Zhao Z, Wang J, Lv W, Lu L, Fu W, et al (2018) Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms A meta-analysis. Medicine 97: 1–10

    Article  Google Scholar 

  20. Kunz PL, Catalano PJ, Nimeiri H et al (2018) A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN cancer research group (E2211). J Clin Oncol 36:e4004

    Article  Google Scholar 

  21. Gulati AP, Krantz B, Moss RA, Moyal WN, Tsushima DA, Mowatt KB, et al (2013) Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature. Oncology 84:127–34

    Article  Google Scholar 

  22. McCormack A, Dekkers OM, Petersenn S, Popovic V, Trouillas J, Raverot G, et al (2018) Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol 178:265-76

    Article  CAS  Google Scholar 

  23. Bengtsson D, Schrøder HD, Andersen M, Maiter D, Berinder K, Feldt Rasmussen U, et al (2015) Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J Clin Endocrinol Metab 100:1689–98

    Article  CAS  Google Scholar 

  24. Tateno T, Kato M, Tani Y, Oyama K, Yamada S, Hirata Y (2009) Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas. Endocr J 56:579–84

    Article  CAS  Google Scholar 

  25. Hayashi K, Inoshita N, Kawaguchi K, Ardisasmita AI, Suzuki H, Fukuhara N, et al (2016) The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. Eur J Endocrinol 174:213–26

    Article  CAS  Google Scholar 

  26. Murasawa S, Kageyama K, Sugiyama A, Ishigame N, Niioka K, Suda T, et al (2014) Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo. Mol Cell Endocrinol 394:37–46

    Article  CAS  Google Scholar 

  27. Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes H-P, et al (2010) SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp Clin Endocrinol Diabetes 118:760–3

    Article  CAS  Google Scholar 

  28. Ceccato F, Lombardi G, Manara R, Emanuelli E, Denaro L, Milanese L, et al (2015) Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center. J Neurooncol 122:189–96

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, 9-112 Clinical Sciences Building, Edmonton, Alberta, T6G 2G3, Canada

    Tae Nakano-Tateno, Motoyasu Satou, Toru Tateno & Constance L. Chik

  2. Department of Biochemistry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Shimotsuga District, Mibu, Tochigi, 321-0293, Japan

    Motoyasu Satou

  3. Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho Itabashi City, Tokyo, 173-0015, Japan

    Naoko Inoshita

  4. Department of Laboratory Medicine & Pathology, University of Alberta, 5B4.17 Walter Mackenzie Health Sciences Centre, 8440-112 Street, Edmonton, Alberta, T6G 2B7, Canada

    Frank K. H. van Landeghem

  5. Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta, T6G 1Z2, Canada

    Jay Easaw

  6. Division of Neurosurgery, Department of Surgery, University of Alberta, 2D, Walter Mackenzie Health Sciences Centre, 8440 -112, Edmonton, Alberta, T6G 2B7, Canada

    Vivek Mehta

Authors
  1. Tae Nakano-Tateno
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  2. Motoyasu Satou
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  7. Toru Tateno
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  8. Constance L. Chik
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Correspondence to Constance L. Chik.

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The authors declare that they have no conflict of interest. Part of this paper was presented as an abstract, number MON-406, at the 101st Annual Meeting of the Endocrine Society, March 23–26, 2019, New Orleans, LA.

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Nakano-Tateno, T., Satou, M., Inoshita, N. et al. Effects of CAPTEM (Capecitabine and Temozolomide) on a Corticotroph Carcinoma and an Aggressive Corticotroph Tumor. Endocr Pathol 32, 418–426 (2021). https://doi.org/10.1007/s12022-020-09647-w

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  • DOI: https://doi.org/10.1007/s12022-020-09647-w

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