Combination chemotherapy in advanced adrenocortical carcinoma

Martin Fassnacht, Massimo Terzolo, Bruno Allolio, Eric Baudin, Harm Haak, Alfredo Berruti, Staffan Welin, Carmen Schade-Brittinger, André Lacroix, Barbara Jarzab, Halfdan Sorbye, David J Torpy, Vinzenz Stepan, David E Schteingart, Wiebke Arlt, Matthias Kroiss, Sophie Leboulleux, Paola Sperone, Anders Sundin, Ilse HermsenStefanie Hahner, Holger S Willenberg, Antoine Tabarin, Marcus Quinkler, Christelle de la Fouchardière, Martin Schlumberger, Franco Mantero, Dirk Weismann, Felix Beuschlein, Hans Gelderblom, Hanneke Wilmink, Monica Sender, Maureen Edgerly, Werner Kenn, Tito Fojo, Hans-Helge Müller, Britt Skogseid, FIRM-ACT Study Group

Research output: Contribution to journalArticlepeer-review

444 Citations (Scopus)


BACKGROUND: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment.

METHODS: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival.

RESULTS: For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.

CONCLUSIONS: Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT number, NCT00094497.).

Original languageEnglish
Pages (from-to)2189-97
Number of pages9
JournalThe New England Journal of Medicine
Issue number23
Publication statusPublished - 7 Jun 2012


  • Adrenal Cortex Neoplasms
  • Adrenocortical Carcinoma
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • Cisplatin
  • Disease-Free Survival
  • Doxorubicin
  • Etoposide
  • Female
  • Humans
  • Intention to Treat Analysis
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mitotane
  • Quality of Life
  • Streptozocin
  • Young Adult


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