Download PDF
Z Gastroenterol 2020; 58(02): 133-136
DOI: 10.1055/a-1042-6504
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

EpiCO (epirubicin, cyclophosphamide and vincristine) as treatment for extrapulmonary high-grade neuroendocrine neoplasms

EpiCo (Epirubicin, Cyclophosphamid und Vincristin) als Therapie für extrapulmonale high-grade neuroendokrine Neoplasien
Stefan Munker
1   Department of Medicine I, University Medical Center, Regensburg, Germany
2   Department of Medicine II, University Medical Center Großhadern, Munich, Germany
,
Martin Vogelhuber
3   Department of Medicine III, University Medical Center, Regensburg, Germany
,
Jan Bornschein
1   Department of Medicine I, University Medical Center, Regensburg, Germany
4   Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford
,
Christian Stroszczynski
5   Department of Radiology, University Medical Center, Regensburg, Germany
,
Matthias Evert
6   Department of Pathology, University of Regensburg, Regensburg, Germany
,
Hans Schlitt
7   Department of Surgery, University Medical Center, Regensburg, Germany
,
Wolfgang Herr
3   Department of Medicine III, University Medical Center, Regensburg, Germany
,
Andreas Teufel
1   Department of Medicine I, University Medical Center, Regensburg, Germany
8   Hepatology Unit, Department of Internal Medicine II, Medical Faculty Mannheim, University of Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

13 March 2019

04 November 2019

Publication Date:
02 January 2020 (online)

Also available at
    Permissions and Reprints

Abstract

High-grade neuroendocrine neoplasms (NEN) comprise a rare entity. Due to the lack of randomized controlled trials, therapy recommendations were mainly extrapolated from its pulmonary analogue, small cell lung cancer and mostly validated in small retrospective case series. The multicentric Nordic NEC Study of gastro-entero-pancreatic (GEP) and cancer of unknown primary (CUP) high-grade neuroendocrine neoplasms showed a significant disease control upon treatment with etoposide and platinum-based chemotherapies [1]. Such a combination with etoposide and a platinum (CE) compound is currently considered standard first-line treatment for high-grade GEP/CUP NEN. High-grade mixed-neuroendocrine-non-neuroendocrine neoplasms (MiNEN) formerly termed mixed adeno-neuroendocrine carcinomas (MANEC) also have a poor prognosis and are generally treated like other high-grade NEN. The CE protocol has significant activity in high-grade NEN and MiNEN, but the response is short-lived in most cases with response rates around 50–60 %. Second-line treatment alternatives are not established so far. The need for additional treatment options is evident.

Combination chemotherapy with doxorubicin, cyclophosphamide and vincristine (CAV) showed efficacy in small cell lung carcinoma (SCLC) and was considered standard first-line therapy before the era of etoposide and platinum combinations. Due to a better toxicity profile, doxorubicin was replaced by epirubicin, resulting in the combination of epirubicin, cyclophosphamide and vincristine (abbreviated as EpiCO or CEV).

In analogy to SCLC, selected patients with high-grade NEN were treated with the EpiCO regimen in second line (or in one patient first line) at our center. In this report we present the retrospective series of 5 cases with metastatic high-grade GEP/CUP NEN/MiNEN who received chemotherapy according to this protocol.

Zusammenfasung

High-grade neuroendokrine Neoplasien (NEN) sind eine seltene Entität. Bisher sind keine randomisierten kontrollierten Studien durchgeführt worden. Therapieempfehlungen sind hauptsächlich von dem pulmonalen Analog, dem kleinzelligen Bronchialkarzinom (SCLC), extrapoliert und in retrospektiven Fallserien validiert. Die multizentrische Nordic-NEC-Studie von gastroenteropathischen (GEP) und „cancer of unknown primary“ (CUP) high-grade neuroendokrinen Neoplasien zeigte ein signifikantes Therapieansprechen auf etoposid- und platinhaltige Kombinationen [1]. Diese Kombination ist Standard-Erstlinientherapie für high-grade GEP/CUP NEN. High-grade gemischtzellige neuroendokrine/nicht-neuroendokrine Neoplasien (MiNEN), früher auch als gemischtzellige adenoneuroendokrine Karzinome (MANEC) bezeichnet, zeigen ebenfalls eine schlechte Prognose und werden wie andere high-grade NEN behandelt. Das Carboplatin/Etoposide(CE)-Protokoll zeigt ein Ansprechen von 50–60 % in high-grade NEN und MiNEN, aber Remissionen sind häufig von kurzer Dauer [1]. Zweitlinientherapien sind nicht allgemein etabliert.

Eine Therapie mit Doxorubicin, Cyclophosphamid und Vincristine (CAV) zeigte Effektivität beim SCLC und galt als Standardchemotherapie vor der Ära von etoposid- und platinhaltigen Zytostatikakombinationen. Aufgrund eines besseren Toxizitätsprofils wurde Doxorubicin durch Epirubicin ersetzt, das daraus resultierende Regime mit Epirubicin, Cyclophosphamid und Vincristin wurde EpiCO oder CEV abgekürzt [4] [5] [6].

In Analogie zum SCLC wurden ausgewählte Patienten mit high-grade NEN mit EpiCO in einem Zweitliniensetting am Universitätsklinikum Regensburg behandelt. In dieser retrospektiven Arbeit berichten wir von 5 Patienten mit metastasiertem high-grade GEP/CUP NEN/MiNEN, die eine Chemotherapie nach diesem Schema erhielten.

Key words

neuroendocrine neoplasms - high-grade neuroendocrine carcinoma - mixed-neuroendocrine-non-neuroendocrine neoplasm - mixed adeno-neuroendocrine carcinoma - epirubicin - cyclophosphamide - vincristine

Schlüsselwörter

neuroendokrine Neoplasien - high-grade neuroendokrines Karzinom - gemischt-neuroendokrines-nicht-neuroendokrines Karzinom - Epirubicin - Cyclophosphamid - Vincristin
 

  • References

  • 1 Sorbye H, Welin S, Langer SW. et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24: 152-160
    PubMedSearch in Google Scholar
  • 2 Roth BJ, Johnson DH, Einhorn LH. et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 282-291
    CrossrefPubMedSearch in Google Scholar
  • 3 Einhorn LH, Crawford J, Birch R. et al. Cisplatin plus etoposide consolidation following cyclophosphamide, doxorubicin, and vincristine in limited small-cell lung cancer. J Clin Oncol 1988; 6: 451-456
    CrossrefPubMedSearch in Google Scholar
  • 4 Drings P, Bulzebruck H, Hruska D. et al. EPICO in the treatment of small cell bronchial cancer. 3. Intermediate analysis. Onkologie 1986; 9 (Suppl. 01) 14-20
    PubMedSearch in Google Scholar
  • 5 Sundstrom S, Bremnes RM, Kaasa S. et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol 2002; 20: 4665-4672
    CrossrefPubMedSearch in Google Scholar
  • 6 Sundstrom S, Bremnes RM, Kaasa S. et al. Second-line chemotherapy in recurrent small cell lung cancer. Results from a crossover schedule after primary treatment with cisplatin and etoposide (EP-regimen) or cyclophosphamide, epirubicin, and vincristin (CEV-regimen). Lung Cancer 2005; 48: 251-261
    CrossrefPubMedSearch in Google Scholar
  • 7 Rinke A, Gress TM. Neuroendocrine cancer, therapeutic strategies in G3 cancers. Digestion 2017; 95: 109-114
    CrossrefPubMedSearch in Google Scholar
  • 8 Garcia-Carbonero R, Sorbye H, Baudin E. et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 2016; 103: 186-194
    CrossrefPubMedSearch in Google Scholar
  • 9 Basturk O, Yang Z, Tang LH. et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 2015; 39: 683-690
    CrossrefPubMedSearch in Google Scholar
  • 10 Welin S, Sorbye H, Sebjornsen S. et al. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 2011; 117: 4617-4622
    CrossrefPubMedSearch in Google Scholar
  • 11 Olsen IH, Sorensen JB, Federspiel B. et al. Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas. Sci World J 2012: 170496
    PubMed
  • 12 Hentic O, Hammel P, Couvelard A. et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr Relat Cancer 2012; 19: 751-757
    CrossrefPubMedSearch in Google Scholar
  • 13 Hadoux J, Malka D, Planchard D. et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr Relat Cancer 2015; 22: 289-298
    CrossrefPubMedSearch in Google Scholar
  • 14 Koboldt DC, Steinberg KM, Larson DE. et al. The next-generation sequencing revolution and its impact on genomics. Cell 2013; 155: 27-38
    CrossrefPubMedSearch in Google Scholar
  • 15 Klempner SJ, Gershenhorn B, Tran P. et al. BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov 2016; 6: 594-600
    CrossrefPubMedSearch in Google Scholar
  • 16 Girardi DM, Silva ACB, Rego JFM. et al. Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: A systematic review. Cancer Treat Rev 2017; 56: 28-35
    CrossrefPubMedSearch in Google Scholar