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CORRESPONDENCE

Adjuvant Therapy in Patients With Adrenocortical Carcinoma: A Position of an International Panel

TO THE EDITOR: Adrenocortical carcinoma (ACC) is a rare and aggressive disease. Although surgery is the mainstay of therapy and represents the only chance of cure, the majority of patients treated with radical resection (up to 80% in some series)1 are still destined to experience relapse, often with metastases. On the basis of this scenario, there is a strong rationale for administering adjuvant therapy in ACC.

In their recently published review, Veytsman et al2 correctly point out that evidence on the efficacy of adjuvant mitotane in patients with ACC is based only on retrospective studies. Most informative is a recent multi-institutional study in Italy and Germany that concluded that the outcome of patients cared for in four Italian tertiary centers that systematically prescribed adjuvant mitotane after radical surgery was significantly better than that observed in patients cared for in four comparable Italian centers that did not offer any adjuvant strategy to their patients during the study period. Using multivariate analysis after adjustment for major prognostic parameters, mitotane-treated patients showed improvement in both time to disease progression and survival. Italian patients who were treated with mitotane also had a better outcome than 75 German patients with ACC in the control arm who were added as a second comparator.3

Of course the results of this explorative study are correlative or hypothesis generating and do not provide high-grade prospective evidence that adjuvant mitotane is efficacious. Because of the rarity of ACC, no randomized prospective trials have so far been published, and no data from randomized clinical trials on adjuvant treatment in ACC will be available in the near future.

So what should be done with postsurgical ACC patients who are often young and at high risk of disease relapse? Is it ethical to not take into account the available evidence provided by a large, well-designed, case-control study? Veytsman et al2 suggest that mitotane therapy should be used only in patients with a high likelihood of recurrence (ie, patients who have large tumors with elevated mitotic rate and small or questionable surgical margins). This controversial topic was discussed in 2008 at the Second Annual International Adrenal Cancer Sympo- sium: Clinical and Basic Science at the University of Michigan in Ann Arbor, Michigan, by an international panel of physicians who direct endocrine oncology programs and are specialists in the treatment of patients with ACC. The panel concluded that radical resection with no microscopic residual disease (R0 resection) and low proliferative ac- tivity (based on mitosis count or Ki67 expression) are the most impor- tant factors predicting outcome in ACC. According to data of the German ACC Registry, patientswith stage I to III ACCwith R0 disease after surgery have a 2-year risk of recurrence of less than 40% (Fig 1A) and could be classified as a low/moderate-risk group. These results notwithstanding, the panel recognized that additional data are re- quired to include patients with stage III ACC with R0 disease after

Fig 1. (A) Recurrence-free survival in 260 patients from the German Adreno- cortical Carcinoma Registry. Only patients without evidence of distant metasta- ses (European Network for the Study of Adrenal Tumors stage I to III) with detailed information (including follow-up) were included. Low/intermediate risk is defined by histologically confirmed complete resection (R0 resection) and Ki67 expression ≤ 10%. All other patients are included in the high-risk group. (B) Proposed algorithm for adjuvant therapy.

A

100

Recurrence-Free Survival (%)

Low/intermediate risk (n = 88)

High risk (n = 172)

80

60

40

20

P < . 0001

0

1

2

3

4

5

Time (years)

B

Patients with adrenocortical carcinoma after radical resection

Stage I-II (III?) R0 disease Ki67 ≤ 10%

Stage III R0? R1 disease Ki67 ≤ 10%

Individualized decision on adjuvant mitotane

Adjuvant mitotane recommended

surgery in this risk subset. On these grounds, the panel unani- mously stated that patients with potential residual disease (R1 or Rx resection) and/or Ki67 more than 10% should be offered adju- vant mitotane, whereas adjuvant therapy was not considered man- datory in patients fulfilling all of the following criteria: stage I or II disease (based on the new European Network for the Study of Adrenal Tumors TNM classification without evidence of distant metastases4 ); histologically proven R0 resection; and Ki67 ex- pressed in ≤ 10% of neoplastic cells (Fig 1B). The panel did not express a unanimous position with respect to whether or not patients with stage III ACC with R0 disease after surgery should receive adjuvant therapy in clinical routine.

For patients with low/moderate risk of relapse according to the previous definition, including patients with stage III R0 disease, a prospective multinational randomized clinical trial was designed to

test the efficacy of adjuvant mitotane therapy versus follow-up only (http://www.adiuvo-trial.org). This trial is currently open for accrual in several European centers, and some US centers will participate in the near future.

Alfredo Berruti University of Turin, Orbassano, Italy

Martin Fassnacht University Hospital, University of Würzburg, Würzburg, Germany

Eric Baudin Institut Gustave Roussy, Villejuif, France

Gary Hammer University of Michigan, Ann Arbor, MI

Harm Haak

Máxima Medisch Centrum, Eindhoven/Veldhoven, the Netherlands

Sophie Leboulleux Institut Gustave Roussy, Villejuif, France

Britt Skogseid

Uppsala University, Uppsala University Hospital, Uppsala, Sweden

Bruno Allolio University Hospital, University of Würzburg, Würzburg, Germany

Massimo Terzolo University of Turin, Orbassano, Italy

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Massimo Terzolo, HRA Pharma (U) Stock Ownership: None Honoraria: None Research Funding: Martin Fassnacht, HRA Pharma; Eric Baudin, HRA Pharma; Harm Haak, HRA Pharma; Bruno Allolio, HRA Pharma Expert Testimony: None Other Remuneration: None

REFERENCES

1. Terzolo M, Berruti A: Adjunctive treatment of adrenocortical carcinoma. Curr Opin Endocrinol Diabetes Obes 15:221-226, 2008

2. Veytsman I, Nieman L, Fojo T: Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol 27:4619-4629, 2009

3. Terzolo M, Angeli A, Fassnacht M, et al: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356:2372-2380, 2007

4. Fassnacht M, Johanssen S, Quinkler M, et al: Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocor- tical carcinoma: Proposal for a Revised TNM Classification. Cancer 115:243-250, 2009

DOI: 10.1200/JCO.2009.27.5958; published online ahead of print at www.jco.org on June 21, 2010