Correspondence
Adjuvant Mitotane in Adrenocortical Carcinoma
N Engl J Med 2007; 357:1256-1259September 20, 2007
- Article
To the Editor:
On the basis of their analysis involving 177 patients with adrenocortical cancer from 55 centers, Terzolo et al. (June 7 issue)1 suggest that adjuvant mitotane therapy prolongs disease-free survival. This finding is important considering the poor outcome of this rare cancer.2 However, variations in management (heterogeneous follow-up among centers) and in tumor biology (molecular alterations3) suggest potential bias in this retrospective, multicenter study.
We previously reported findings from a study involving 202 patients from a single center. In our study, initiation of mitotane within 3 months after surgery improved overall survival among patients with cortisol-secreting tumors.4 We have now analyzed more recent data from a cohort of 166 patients from that study (the Cochin cohort) who underwent complete tumor resection. A total of 86 patients (52%) were treated with mitotane within 3 months after surgery (group 1). Univariate analysis showed that disease-free survival was not significantly improved in these patients, as compared with the other 80 patients (group 2) (P=0.34). Multivariate analysis indicated that shorter disease-free survival was significantly associated with older age, a higher McFarlane–Sullivan stage, and cortisol secretion but not with mitotane administration, despite a tendency for benefit in the subgroup of patients with cortisol-secreting tumors (P=0.20) (Figure 1Figure 1
Kaplan–Meier Curves for Disease-free Survival among 166 Patients Who Underwent Complete Tumor Resection.). A clear answer to this question requires a prospective, randomized trial.Jérôme Bertherat, M.D., Ph.D.
INSERM Unité 567, 75014 Paris, France
jerome.bertherat@cch. aphp. fr Joël Coste, M.D.
Université Paris-Descartes, 75005 Paris, FranceXavier Bertagna, M.D.
Hôpital Cochin, 75014 Paris, FranceDr. Bertherat reports being an investigator in a clinical trial sponsored by HRA Pharma. No other potential conflict of interest relevant to this letter was reported.
4 References1
Terzolo M ,Angeli A ,Fassnacht M , et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356:2372-2380
Full Text | Web of Science | Medline2
Luton JP ,Cerdas S ,Billaud L , et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195-1201
Full Text | Web of Science | Medline3
Libe R ,Fratticci A ,Bertherat J . Adrenocortical cancer: pathophysiology and clinical management. Endocr Relat Cancer 2007;14:13-28
CrossRef | Web of Science | Medline4
Abiven G ,Coste J ,Groussin L , et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 2006;91:2650-2655
CrossRef | Web of Science | Medline
To the Editor:
Since Terzolo et al. and, in an accompanying editorial, Schteingart1 cite our previous small study,2 we think it is relevant to describe our present, much larger study involving treatment with mitotane.
We do not resect stage I tumors (<5 cm in diameter, with no metastases) unless they secrete hormones, since stage I lesions may not be carcinomas. We have not encountered any problems by following patients with stage I tumors clinically instead. Some survivors in both of the control groups (especially control group 2) in the study by Terzolo et al. may have had adenomas. Stage II lesions that are 5 to 8 cm in diameter may also include some adenomas. The higher the proportion of patients with tumors in advanced stages (III or IV), the more meaningful the results. In the study by Terzolo et al., 16% of the patients in control group 2 had such tumors, as compared with about 36% of the patients in both the mitotane group and control group 1. This may explain the better outcome in control group 2 than in control group 1, making the effects of mitotane even more impressive.
Table 1Table 1
Outcomes among Patients Who Received 1.5 to 3.0 g of Adjuvant Mitotane. shows our current results in 14 patients treated with low doses of mitotane (1.5 to 3.0 g daily). Most patients (64%) had stage III or IV disease. The tumors were larger (median size, 12.0 cm; range, 7.5 to 36.0) than those in the study by Terzolo et al. The 5-year survival rate (75%; six of eight patients survived) was similar to that in the study by Terzolo et al. In our study, all patients were metastasis-free at 5 years except those who died, although widespread metastasis developed in one patient later.We suggest that mitotane should be started immediately after surgery, or even in the period between diagnosis and surgery, since surgical procedures may spread malignant cells. Furthermore, we would resect all metastases whenever they appear. In the study by Barzon et al.,3 cited by Schteingart as showing no efficacy, high doses (up to 8 g) of mitotane were used. No patient can tolerate such doses continually.
3 ReferencesGabriel Dickstein, M.D.
Carmela Shechner, M.D.
Ofer Nativ, M.D.
Bnai Zion Medical Center, 31048 Haifa, Israel
dicksteg@netvision.net. il 1
Schteingart DE . Adjuvant mitotane therapy of adrenal cancer -- use and controversy. N Engl J Med 2007;356:2415-2418
Full Text | Web of Science | Medline2
Dickstein G ,Shechner C ,Arad E ,Best L-A ,Nativ O . Is there a role for low doses of mitotane (o,p′-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 1998;83:3100-3103
CrossRef | Web of Science | Medline3
Barzon L ,Fallo F ,Sonino N ,Danielle O ,Boscaro M . Comment -- is there a role for low doses of mitotane (o,p′-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 1999;84:1488-1489
CrossRef | Web of Science | Medline
To the Editor:
The report by Terzolo et al. must be interpreted with caution for several reasons. First, as the authors acknowledge, the retrospective nature of their study is susceptible to selection bias. In particular, the very high recurrence rate in control group 11,2 suggests that some patients had incomplete surgery. Second, inconsistency in standardized restaging among institutions over the 20 years of the study might have resulted in ascertainment or lead-time bias with regard to recurrences. Third, limited details are provided regarding mitotane treatment. How soon was mitotane started postoperatively, and how frequently were therapeutic levels achieved? Finally, no information is provided regarding crossover treatment with mitotane among patients in the control group in whom disease recurred.
The report by Terzolo et al. does not establish adjuvant mitotane as the standard of care. Mitotane treatment is complex owing to its toxicity, the need to monitor levels, and the need for corticosteroid replacement.3 Observation without the use of adjuvant mitotane remains a preferable approach for many patients, with restaging at intervals and consideration of mitotane treatment at the time of a first recurrence, when the patient has measurable disease.
3 ReferencesJeffrey E. Lee, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77025
jelee@mdanderson.org 1
Icard P ,Chapuis Y ,Andreassian B ,Bernard A ,Proye C . Adrenal cortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 1992;112:972-980
Web of Science | Medline2
Gonzalez RJ ,Shapiro S ,Sarlis N , et al. Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery 2005;138:1078-1085
CrossRef | Web of Science | Medline3
Haak HR ,Hermans J ,van de Velde CJ , et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-951
CrossRef | Web of Science | Medline
To the Editor:
In their retrospective study of data from 177 patients, Terzolo et al. found that on the basis of multivariate analysis, adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma. In the group that received adjuvant mitotane, two dose regimens of similar duration (median, 29 months) were used: 20 patients received 3 to 5 g daily, and 27 patients received 1 to 3 g daily. As expected in a cause–effect relationship, grade 3 gastrointestinal and neurologic adverse events were associated with the higher-dose of mitotane but not with the lower dose.
With regard to recurrence-free survival, the authors do not indicate whether the higher dose of mitotane (3 to 5 g) was more effective than the lower dose (1 to 3 g). We wonder whether the authors could provide that information. Evidence of such an incremental response to treatment would further strengthen the authors' suggestion of a causal association between adjuvant mitotane chemotherapy and prolonged recurrence-free survival in patients with radically resected adrenocortical carcinoma.
Andreas Machens, M.D.
Henning Dralle, M.D.
Martin Luther University Halle-Wittenberg, 06097 Halle, Germany
andreasmachens@aol.com Author/Editor Response
In contrast to our experience, Bertherat et al. did not observe a significant advantage with respect to disease-free survival among patients treated with adjuvant mitotane after complete removal of adrenocortical carcinoma. Unfortunately, Bertherat et al. do not provide the selection criteria for the use of mitotane. Since mitotane was administered to only half of the patients in the Cochin cohort, it is very likely that the treated patients were selected for unfavorable prognostic factors, and selection bias might have contributed to the lack of efficacy of adjuvant mitotane. Conversely, we recommended mitotane on the basis of the treatment policy of the center, independent of the characteristics of either the tumors or the patients. This is a major advantage as compared with other studies, the Cochin cohort included. Nevertheless, our study was not randomized; therefore, we agree with Bertherat et al. that a randomized trial is indicated to show conclusively the efficacy of adjuvant mitotane treatment.
As Dickstein et al. note, we cannot exclude the possibility that some adrenocortical adenomas may have been included among stage I adrenocortical carcinomas. However, in our series, 8 of 16 patients with stage I adrenocortical carcinoma had a recurrence during follow-up; this is a strong argument against simple observation of such patients. We agree that adjuvant mitotane treatment should be started as soon as possible.
With regard to the comments of Lee, follow-up protocols were indeed similar among the centers participating in our study, and our article provides information about treatment after recurrence for the entire cohort. Since we have defined radical resection macroscopically, not microscopically, we cannot exclude the possibility that a few patients had histologically incomplete resection. However, recurrence rates as high as those observed in control group 1 have been reported by others.1 Serum mitotane concentrations were monitored in a subgroup of 22 patients; in all these patients, maintenance mitotane concentrations higher than 14 mg per liter were reached. Mitotane treatment is complex; however, we do not agree with the conclusion that many patients should not have any adjuvant treatment.
Machens and Dralle raise an important question about the dose–effect relationship. The pharmacokinetics of mitotane, which is characterized by a long half-life, may explain why therapeutic concentrations of mitotane can also be reached with sustained low-dose treatment.2 In the present study, 16 of the 22 patients in whom serum mitotane concentrations were monitored received a daily mitotane dose that was 3 g or less. However, the small number of patients for whom mitotane blood levels were available does not permit us to conclude whether there are differences in efficacy between lower and higher doses.
2 ReferencesMassimo Terzolo, M.D.
Università di Torino, 10043 Orbassano, Italy
terzolo@usa.net Martin Fassnacht, M.D.
University of Würzburg, 97080 Würzburg, GermanyAlfredo Berruti, M.D.
Università di Torino, 10043 Orbassano, Italy1
Allolio B ,Fassnacht M . Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006;91:2027-2037
CrossRef | Web of Science | Medline2
Terzolo M ,Pia A ,Berruti A , et al. Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. J Clin Endocrinol Metab 2000;85:2234-2238
CrossRef | Web of Science | Medline
- Citing Articles (7)
Citing Articles
1
Thomas J. Giordano. (2010) Classification of adrenal cortical tumors: Promise of the ‘molecular’ approach. Best Practice & Research Clinical Endocrinology & Metabolism 24:6, 887-892
CrossRef2
Eva Kassi, Gregory Kaltsas, George Zografos, George Chrousos. (2010) Current issues in the diagnosis and management of adrenocortical carcinomas. Expert Review of Endocrinology & Metabolism 5:3, 451-466
CrossRef3
Krystallenia I. Alexandraki, Gregory A. Kaltsas, Carel W. le Roux, Martin Fassnacht, Sharon Ajodha, Mirjam Christ-Crain, Scott A. Akker, William M. Drake, Ray Edwards, Bruno Allolio, Ashley B. Grossman. (2010) Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study. Clinical Endocrinology 72:3, 305-311
CrossRef4
Elizabeth G. Grubbs, Glenda G. Callender, Yan Xing, Nancy D. Perrier, Douglas B. Evans, Alexandria T. Phan, Jeffrey E. Lee. (2010) Recurrence of Adrenal Cortical Carcinoma Following Resection: Surgery Alone Can Achieve Results Equal to Surgery Plus Mitotane. Annals of Surgical Oncology 17:1, 263-270
CrossRef5
Emil Lou, Jeremy Goodwin, David N. Howell, John Hicks, L. Brett Caram. (2009) A G-CSF-secreting adrenal carcinoma with rhabdoid-like differentiation causing leukocytosis. Nature Reviews Urology 6:7, 392-397
CrossRef6
Alfredo Berruti, Anna Ferrero, Paola Sperone, Fulvia Daffara, Giuseppe Reimondo, Mauro Papotti, Luigi Dogliotti, Alberto Angeli, Massimo Terzolo. (2008) Emerging drugs for adrenocortical carcinoma. Expert Opinion on Emerging Drugs 13:3, 497-509
CrossRef7
Massimo Terzolo, Alfredo Berruti. (2008) Adjunctive treatment of adrenocortical carcinoma. Current Opinion in Endocrinology, Diabetes and Obesity 15:3, 221-226
CrossRef
