in the group receiving eprodisate. This observa- tion raises questions about the mechanism of ac- tion of eprodisate. Does it act by means other than inhibiting the binding of glycosaminoglycan to amyloid fibrils?
The actual beneficial effect of eprodisate may be less than was calculated by Dember et al. be- cause there were some imbalances in the two groups despite randomization; patients in the eprodisate group had a significantly greater num- ber of chronic infections (presumably treatable with antibiotics) than did those in the placebo group, and there was a trend toward lower levels of C-reactive protein in the eprodisate group. Moreover, the effect on the analysis of classifying patients with no follow-up after baseline as “wors- ened status” of disease is unclear, since twice as many patients withdrew or were lost to follow-up in the placebo group as in the eprodisate group (eight vs. four patients). Ideally, data from these patients should have been censored.
Despite these concerns, this trial of eprodisate is a milestone in which hypothesis-driven, direct targeting of amyloid fibrils has shown some ben- efit. Eprodisate should be investigated as an ad- juvant to existing treatments in patients with AL amyloidosis and forms of familial amyloidosis with renal involvement. Since AA amyloidosis rare- ly involves the heart or peripheral nerves, it is not possible to comment now on the drug’s effect on forms of amyloidosis that affect these structures.
The management of amyloidosis has been frus- trating.13 Targeting the source of the precursor protein has been beneficial for selected patients, but it is inadequate. Targeting amyloid formation directly is a new direction that offers hope to pa- tients with serious organ dysfunction. Delays in diagnosis, uncertainties about the relative merits of available therapies, and difficulties in mounting large-scale clinical trials in rare disorders combine to keep amyloidosis a challenging problem.
No potential conflict of interest relevant to this article was re- ported.
From the Division of Hematology, Mayo Clinic College of Medi- cine, Rochester, MN.
1. Sipe JD, Cohen AS. Review: history of the amyloid fibril. J Struct Biol 2000;130:88-98.
2. Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammop- athy of undetermined significance, Waldenstrom macroglobu- linemia, AL amyloidosis, and related plasma cell disorders: diag- nosis and treatment. Mayo Clin Proc 2006;81:693-703. [Erratum, Mayo Clin Proc 2006;81:1509.]
3. Dember LM, Hawkins PN, Hazenberg BPC, et al. Eprosidate for the treatment of renal disease in AA amyloidosis. N Engl J Med 2007;356:2349-60.
4. Palladini G, Perfetti V, Obici L, et al. Association of melpha- lan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood 2004;103:2936-8.
5. Gertz MA, Lacy MQ, Dispenzieri A, Hayman S, Kumar S. Transplantation for amyloidosis. Curr Opin Oncol 2007;19:136- 41.
6. Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001;358:24-9.
7. Fernandez-Nebro A, Tomero E, Ortiz-Santamaria V, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antago- nists. Am J Med 2005;118:552-6. [Erratum, Am J Med 2006;119: 191.]
8. Sharma P, Perri RE, Sirven JE, et al. Outcome of liver trans- plantation for familial amyloidotic polyneuropathy. Liver Transpl 2003;9:1273-80.
9. Olofsson BO, Backman C, Karp K, Suhr OB. Progression of cardiomyopathy after liver transplantation in patients with fa- milial amyloidotic polyneuropathy, Portuguese type. Transplan- tation 2002;73:745-51.
10. Tojo K, Sekijima Y, Kelly JW, Ikeda S. Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin vari- ant tetramers in serum against dissociation required for amy- loidogenesis. Neurosci Res 2006;56:441-9.
11. Pepys MB, Herbert J, Hutchinson WL, et al. Targeted phar- macological depletion of serum amyloid P component for treat- ment of human amyloidosis. Nature 2002;417:254-9.
12. Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th Inter- national Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol 2005;79:319-28.
13. Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR. Amyloido- sis. Best Pract Res Clin Haematol 2005;18:709-27. Copyright @ 2007 Massachusetts Medical Society.
Adjuvant Mitotane Therapy of Adrenal Cancer - Use and Controversy
David E. Schteingart, M.D.
Adrenocortical carcinoma is a rare, highly malig- nant neoplasm with an incidence of 2 cases per 1 million population per year worldwide, repre- senting 0.2% of all cases of cancer. Several treat-
ment strategies in patients with advanced dis- ease have resulted in temporary or partial tumor regression, yet very few patients attain long-term survival. Assessing the effectiveness of most pub-
N ENGL J MED 356;23 WWW.NEJM.ORG JUNE 7, 2007
lished treatment protocols has been difficult, since most series have been limited by the inclusion of relatively few subjects, with tumors at various stages and grades. Several drug regimens have been used, and multiple treatments have been ad- ministered in various sequences. In addition, the definition of response has not been uniform, and the duration of response has been unclear.
In patients with apparently localized disease (stages I and II) or regional disease without dis- tant metastases (stage III), radical surgical resec- tion with curative intent offers the best chance for prolonged recurrence-free survival. But metas- tases develop even in patients who undergo radi- cal resection within 6 to 24 months after the ini- tial surgery.
The dilemma facing physicians when there is no evidence of residual disease is whether to fol- low patients without initiating treatment or to use adjuvant therapy in the form of local radiation or systemic chemotherapy. Mitotane, an adrenalytic drug with selective activity on adrenocortical cells, has been used as adjuvant therapy with variable results, and there is controversy about its efficacy. Most studies claiming efficacy have been prospective, nonrandomized, single-center trials with various numbers of patients receiving mito- tane after surgery and comparison groups receiv- ing surgery alone. Other prospective studies, how- ever, have failed to show a convincing advantage for mitotane treatment. In this issue of the Journal, Terzolo et al.1 present a retrospective analysis in- volving a large cohort of patients with adrenocor- tical carcinoma from 8 centers in Italy and 47 cen- ters in Germany who were followed for up to 10 years. Adjuvant therapy was given to 47 Italian patients after radical surgery, and recurrence- free survival in these patients (the primary out- come) was compared with that of 55 Italian and 75 German patients whose surgery was not fol- lowed by mitotane treatment. Patients receiving mitotane had recurrence-free survival that was two to three times as long as that of those not receiving the drug.
Does the study by Terzolo et al. resolve the con- troversy concerning mitotane as adjuvant therapy in adrenocortical carcinoma and provide informa- tion sufficient to recommend adjuvant mitotane therapy to all patients with localized or regional disease? The large number of patients in this study from a carefully collected database involving mul- tiple institutions, along with systematic follow-up,
well-matched control groups, and carefully con- ducted statistical analysis, makes this retrospec- tive study credible. Although bias inherent in a retrospective study may influence the conclusions, these authors have been careful to minimize and acknowledge this problem. Previous reports came from single institutions that had less clear treat- ment assignments and that used relatively high doses of mitotane with effects that were toxic enough to limit its use. Two of these studies sup- port the use of mitotane as an adjuvant,2,3 where- as others do not.4,5 In a series with 82 patients, Kasperlik-Zaluska observed increased survival when treatment with mitotane immediately fol- lowed surgery,2 and Dickstein et al. reported that 3 of 4 patients receiving low-dose mitotane (1.5 to 2.0 g per day) had some benefit.3 However, an- other study by Barzon et al. reported no efficacy.4 In a small, prospective, randomized study by Vas- silopoulou-Selin et al., there were no differences in recurrence-free survival among those who re- ceived mitotane for 2 to 12 months, received mi- totane indefinitely, or received no mitotane.4 Given the toxic effects that are associated with what had been regarded as therapeutic doses and the lack of evidence for a beneficial effect in the negative studies,4,5 the use of mitotane for adjuvant thera- py of adrenocortical carcinoma has declined in re- cent years.
An important question is why such discrepant outcomes exist among published studies. It is pos- sible that unintended selection bias involving sub- ject entry in most studies played a role. It is also possible that the response to the drug is so varia- ble among tumors that a given trial could yield either positive or negative results in apparently similar tumors.
The mechanism of action of mitotane may help explain the various responses. Mitotane effectively destroys normal adrenal glands and hyperplastic adrenal cortexes in patients with Cushing’s dis- ease. In contrast, only 23% of patients with ad- vanced adrenal cancer respond to mitotane ther- apy. Why this difference? Mitotane belongs to the class of drugs that require metabolic transforma- tion for therapeutic action. As a result, active me- tabolites causing tissue toxicity are produced, ei- ther through covalent binding to specific targets within the cells or by oxygen activation with su- peroxide formation. The concept that mitotane re- quires metabolic transformation for activity is supported by observations of its variable activity
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Mitotane is hydroxylated at the ß-carbon and transformed by dehydrochlorination into an acyl chloride. The acyl chloride either covalently binds to bionucleophiles in the target cells or is transformed to an acetic acid derivative for excretion.
in different animal species.6 The dog adrenal, which is the most responsive to mitotane, is also the most capable of metabolic transformation and covalent binding. In contrast, the human adrenal is less capable of both metabolic transformation and covalent binding and is thus less responsive.
As depicted in Figure 1, the pathway of mito- tane metabolism follows the well-known process by which chloramphenicol causes toxicity. Mito- tane is hydroxylated at the ß-carbon and quickly transformed by dehydrochlorination into an acyl chloride. The acyl chloride either covalently binds to bionucleophiles in the target cells or through loss of water is transformed into an acetic acid derivative for renal excretion. The initial hydroxyl- ation step is carried out in the mitochondria and catalyzed by a P-450 enzyme, giving adrenal se- lectivity to the action of mitotane.7 Developing cancer cells will vary in their ability to metabolize mitotane because of alterations in this metabolic process. Tumors with an ability to metabolize mi- totane respond, but those that are unable to me- tabolize the drug may not. Pineiro-Sanchez et al. published a tritium-release assay to test the abil- ity of tumors to metabolize mitotane.8 Testing tu- mors before treatment might help select those with the highest probability of response.
Although the variability of published reports on adjuvant mitotane indicates the need for well- designed and well-powered prospective, random- ized trials,9 the rarity of adrenal cancer and the time it would take to collect sufficient data would
require a lengthy, multicenter, international study. Meanwhile, we are left with well-designed, multi- center, retrospective studies such as the one con- ducted by Terzolo et al.1
A limitation of mitotane therapy has been its marked toxicity at daily doses exceeding 6 g. Dos- es sufficient to achieve “therapeutic” levels of 16 µg per milliliter are usually associated with un- desirable toxicity. An important finding in the study by Terzolo et al. is that favorable outcomes were achieved with relatively low doses of mito- tane - 1 to 3 g per day was sufficient to produce the desired effect with reduced toxic effects.
Though physicians who are treating patients with adrenocortical carcinoma may continue to request randomized clinical trials concerning ad- juvant therapy with mitotane, the study by Terzolo et al. provides the best evidence to date that ad- juvant mitotane treatment for adrenocortical car- cinoma has benefit after radical surgery, and it should make the therapeutic choice of using the drug more acceptable. The study provides a com- pelling rationale for the use of low-dose mitotane as adjuvant therapy in patients presenting with stages I, II, and III adrenocortical carcinoma whose surgical resection has been macroscopically complete.
No potential conflict of interest relevant to this article was re- ported.
From the Division of Metabolism, Endocrinology, and Diabe- tes, University of Michigan Medical Center, Ann Arbor.
1. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007; 356:2372-80.
2. Kasperlik-Zaluska AA. Clinical results of the use of mitotane for adrenocortical carcinoma. Braz J Med Biol Res 2000;33:1191- 6.
3. 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: 3100-3.
4. Barzon L, Fallo F, Sonino N, Daniele O, Boscaro M. Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 1999; 84:1488-9.
5. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al. Impact of adjuvant mitotane on the clinical course of patients with adreno- cortical cancer. Cancer 1993;71:3119-23.
6. Schteingart DE. Conventional and novel strategies in the treatment of adrenocortical cancer. Braz J Med Biol Res 2000; 33:1197-200.
7. Martz F, Straw JA. The in-vitro metabolism of 1-(o-chloro- phenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p’-DDD) by dog adrenal mitochondria and metabolite covalent binding to mito- chondrial macromolecules: a possible mechanism for the adre- nocorticolytic effect. Drug Metab Dispos 1977;5:482-6.
8. Pineiro-Sanchez ML, Vaz A, Counsell RA, Ruyan M, Schtein- gart DE, Sinsheimer JE. Synthesis of ß3H mitotane for use in a rapid assay for mitotane metabolism. J Label Compd Radiopharm 1995;36:121-7.
9. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an interna- tional consensus conference. Endocr Relat Cancer 2005;12:667- 80.
Copyright @ 2007 Massachusetts Medical Society.
COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITE
The Journal’s Web site (www.nejm.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.
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