1. Birkmeyer NJ, Weinstein JN, Tosteson AN, et al. Design of the Spine Patient Outcomes Research Trial (SPORT). Spine 2002; 27:1361-72.
2. Cummins J, Lurie JD, Tosteson TD, et al. Descriptive epide- miology and prior healthcare utilization of patients in the Spine Patient Outcomes Research Trial’s (SPORT) three observational cohorts: disc herniation, spinal stenosis, and degenerative spon- dylolisthesis. Spine 2006;31:806-14.
DR. DEYO REPLIES: Copeland describes part of the range of patient preferences that occur with back pain and sciatica. As a neurosurgeon, he had ad- vantages not readily available to most patients: immediate knowledge of a familiar diagnosis and prognosis, nearly instant access to expert care, and deep knowledge of the best local care provid- ers. He had a satisfying job and several incentives for a quick return to work. He fortunately had im- mediate, complete relief and rapid recovery from surgery.
I know other physicians with unequivocal sciatica who were more averse to surgery, chose noninvasive treatments, and had more gradual improvement, yet never missed a day of work. However, many patients do need time off from work and time to consider their options. Many prefer to experiment with conservative care. For some, the diagnosis is ambiguous. Many who undergo surgery experience either less rapid re- covery or complete pain relief. Thus, Copeland’s usual approach to his patients seems as valid as his approach to self-care. Accommodating a range of well-informed preferences should be the goal of responsive care and shared decision-making.
Richard A. Deyo, M.D., M.P.H. University of Washington Seattle, WA 98195
Adjuvant Mitotane in Adrenocortical Carcinoma
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 sug- gest that adjuvant mitotane therapy prolongs dis- ease-free survival. This finding is important con-
sidering the poor outcome of this rare cancer.2 However, variations in management (heteroge- neous follow-up among centers) and in tumor biology (molecular alterations3) suggest potential bias in this retrospective, multicenter study.
A Non-Cortisol-Secreting Tumors
B Cortisol-Secreting Tumors
100
100
Disease-free Survival (%)
75
Disease-free Survival (%)
75
Surgery only
50
50
Surgery plus mitotane
Surgery plus mitotane
25
25
Surgery only
0
0
0
5
10
15
20
0
5
10
15
20
Years
Years
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). Uni- variate 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) (Fig. 1). A clear an- swer to this question requires a prospective, ran- domized 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, France
Xavier Bertagna, M.D. Hôpital Cochin 75014 Paris, France
Dr. Bertherat reports being an investigator in a clinical trial sponsored by HRA Pharma. No other potential conflict of inter- est relevant to this letter was reported.
1. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007; 356:2372-80.
2. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adre- nocortical carcinoma, prognostic factors, and the effect of mi- totane therapy. N Engl J Med 1990;322:1195-201.
3. Libé R, Fratticci A, Bertherat J. Adrenocortical cancer: patho- physiology and clinical management. Endocr Relat Cancer 2007; 14:13-28.
4. Abiven G, Coste J, Groussin L, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor out- come of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 2006;91:2650-5.
TO THE EDITOR: Since Terzolo et al. and, in an accompanying editorial, Schteingart1 cite our pre- vious small study,2 we think it is relevant to de- scribe our present, much larger study involving treatment with mitotane.
We do not resect stage I tumors (<5 cm in di- ameter, with no metastases) unless they secrete hormones, since stage I lesions may not be car- cinomas. We have not encountered any problems by following patients with stage I tumors clini- cally instead. Some survivors in both of the con- trol 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 re- sults. 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 1 shows our current results in 14 pa- tients 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. Further- more, 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.
Gabriel 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;356:2415-8.
2. 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.
3. Barzon L, Fallo F, Sonino N, Danielle O, Boscaro M. Com-
N ENGLJ MED 357;12 WWW.NEJM.ORG SEPTEMBER 20, 2007
| Patient No. | Stage | Tumor | Secretion | Follow-up mo | Current Status | |
|---|---|---|---|---|---|---|
| Size | Weight | |||||
| cm | g | |||||
| 1 | II | 11.0 | 320 | 147 | Alive, disease-free | |
| 2 | II | 12.0 | 760 | 111 | Alive, disease-free | |
| 3 | IV | 17.5 | 1460 | Cortisol | 107 | Alive, disease-free |
| 4 | IV | 8.0 | 180 | Testosterone | 96 | Died of unrelated cause |
| 5 | III | 7.5 | 153 | Testosterone | 87 | Died of disease |
| 6 | III | 9.0 | 190 | Cortisol | 62 | Died of unrelated cause |
| 7 | II | 14.0 | 900 | 49 | Alive, disease-free | |
| 8 | III | 23.5 | 1965 | 37 | Alive, disease-free | |
| 9 | III | 12.0 | 427 | 29 | Alive, disease-free | |
| 10 | II | 11.0 | 471 | 27 | Alive, disease-free | |
| 11 | II | 9.0 | 360 | 22 | Alive, disease-free | |
| 12 | III | 23.0 | 2615 | 21 | Died of disease* | |
| 13 | III | 23.0 | 2050 | 16 | Died of disease | |
| 14 | IV | 36.0 | 7800 | 13 | Alive, with shrinkage of lung metastases | |
* This patient started treatment with mitotane after a 3-month delay after surgery.
ment - 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.
TO THE EDITOR: The report by Terzolo et al. must be interpreted with caution for several reasons. First, as the authors acknowledge, the retrospec- tive nature of their study is susceptible to selec- tion bias. In particular, the very high recurrence rate in control group 11,2 suggests that some pa- tients had incomplete surgery. Second, inconsis- tency in standardized restaging among institu- tions 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? Fi- nally, no information is provided regarding cross- over 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. Mito- tane treatment is complex owing to its toxicity, the need to monitor levels, and the need for cor-
ticosteroid replacement.3 Observation without the use of adjuvant mitotane remains a preferable ap- proach for many patients, with restaging at inter- vals and consideration of mitotane treatment at the time of a first recurrence, when the patient has measurable disease.
Jeffrey 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. Adre- nal cortical carcinoma in surgically treated patients: a retro- spective study on 156 cases by the French Association of Endo- crine Surgery. Surgery 1992;112:972-80.
2. Gonzalez RJ, Shapiro S, Sarlis N, et al. Laparoscopic resec- tion of adrenal cortical carcinoma: a cautionary note. Surgery 2005;138:1078-85.
3. Haak HR, Hermans J, van de Velde CJ, et al. Optimal treat- ment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-51.
TO THE EDITOR: In their retrospective study of data from 177 patients, Terzolo et al. found that on the basis of multivariate analysis, adjuvant mi- totane 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 re- ceived 3 to 5 g daily, and 27 patients received 1 to 3 g daily. As expected in a cause-effect relation- ship, grade 3 gastrointestinal and neurologic ad- verse 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. Evi- dence of such an incremental response to treat- ment would further strengthen the authors’ sug- gestion 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
THE AUTHORS REPLY: In contrast to our experi- ence, 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 carci- noma. Unfortunately, Bertherat et al. do not pro- vide 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 unfa- vorable prognostic factors, and selection bias might have contributed to the lack of efficacy of adju- vant mitotane. Conversely, we recommended mi- totane on the basis of the treatment policy of the center, independent of the characteristics of ei- ther 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 indi- cated to show conclusively the efficacy of adju- vant mitotane treatment.
As Dickstein et al. note, we cannot exclude the possibility that some adrenocortical adeno- mas may have been included among stage I adre- nocortical carcinomas. However, in our series,
8 of 16 patients with stage I adrenocortical car- cinoma 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 arti- cle provides information about treatment after recurrence for the entire cohort. Since we have defined radical resection macroscopically, not microscopically, we cannot exclude the possibil- ity that a few patients had histologically incom- plete resection. However, recurrence rates as high as those observed in control group 1 have been reported by others.1 Serum mitotane con- centrations were monitored in a subgroup of 22 patients; in all these patients, maintenance mi- totane concentrations higher than 14 mg per li- ter 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 ques- tion about the dose-effect relationship. The phar- macokinetics 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 pres- ent study, 16 of the 22 patients in whom serum mitotane concentrations were monitored received a daily mitotane dose that was 3 g or less. How- ever, the small number of patients for whom mito- tane blood levels were available does not permit us to conclude whether there are differences in efficacy between lower and higher doses.
Massimo Terzolo, M.D. Università di Torino 10043 Orbassano, Italy terzolo@usa.net
Martin Fassnacht, M.D. University of Würzburg 97080 Würzburg, Germany
Alfredo Berruti, M.D. Università di Torino 10043 Orbassano, Italy
1. Allolio B, Fassnacht M. Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006;91:2027-37.
2. Terzolo M, Pia A, Berruti A, et al. Low-dose monitored mito- tane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. J Clin Endo- crinol Metab 2000;85:2234-8.