2. Mr. KS, 18 y.o. male referred from NSH with
features of cushing’s syndrome
He presented with 6/12 hx of cutaneous striae,
hirsutism (excessive hair growth) truncal obesity,
puffy face, weight gain +/-30kg, fatigue
4. CT scan revealed a large lobulated and enhancing lesion originating from the
right adrenal gland with involvement of retrohepatic IVC & liver and atleast 2 lung
metasteses noted
5. Its appearance, coupled with the patient history, physical
exam, and laboratory data strongly suggested an
unresectable metastatic adrenocortical carcinoma
Patient discharged with palliative chemotherapy-
ketoconazole
6. Mrs. DW, fit 87 y. o. female presented to private with symptomatic
anaemia with unexplained bleeding in about March/ April last year.
She had 4 Gastroscopies, 2 Colonoscopies, a barium follow-through
and a nuclear scan study was suggestive of bleeding from terminal
ileum.
She then had a resection of the terminal ileum but has continued
bleeding.
7. She then had a capsule endoscopy study which was unsatisfactory but did show
some blood in the stomach. some telangiectatic spots were noted and it was
thought that these may be the cause of the bleeding.
Since then she has required regular blood transfusions every month.
She usually presents with melaena without any acute haemodynamic event.
She had a previous left adrenocortical carcinoma which was operated in 1991 in
private.
8. CT Abdomen:
revealed a 6.5 cm relatively vascular mass arising anterior to the upper pole
of the left kidney infiltrating the posterior wall of the stomach just distal to the
OG junction highly suggestive of recurrence of adrenal carcinoma.
CT Guided Biopsy: inadequate
9.
10. Estimated incidence of 0.5-2 per 106 patients per
year
Peaks of age distribution at age <10 and in the 4 th
and 5th decades
Scattered reports of gene associations, but rarity of
lesion precludes clear associations
11. 60-65% are functional and produce hormone excess related symptoms
> rapidly progressive cushing syndrome
> mixed cushing syndrome and an androgenital disorder
> 75%are locally aggressive at the time of diagnosis, median survival of 18
months following diagnosis. Tumor grade important for survival
35-40% are non functional tumors ( or asymptomatic functioning tumors)
> abdominal pain / mass, weight loss, fatigue, nausea
12. Hormonal studies can be a first diagnostic test which
confirms ectopic steroid hormone secretion, leading to an
imaging and tissue diagnosis.
13. 24 hour urinary cortisol exrection
> More than 90% of Cushinoid patients have free cortisol levels greater than
200mcg/ 24 hours. 97% of normals have levels less than 100mcg/ 24 hours
ACTH measured with serum cortisol will demonstrate
ACTH independent nature of hypercortisolism.
14. Other steroids are elevated:
androstenediol and adrosetenedione
DHEA and DHEA-S
11- deoxycortisol
urinary 17- ketosteroids
aldosterone
Many intermediate enzymes are defective or
dysregulated, leading to inefficient steroid production
and precursor buildup
15. Serum Testosterone
Serum DHEA and DHEA-S
24 hour urinary ketosteroids
Plasma estradiol and/ or estrone
Plasma aldosterone/ renin
Urinary catecholamines/ metanephrines in all
patients
16. CT detects 98% of adrenal carcinomas
MRI scanning can also provide vascular invasion/
tumor thrombosis information.
Also provides many incidentalomas
Malignant lesions tend to be > 5cm, have irregular
shapes/ blurred margins, and be heterogeneously
enhancing.
17. Stage I — Disease confined to the adrenal gland and
<5 cm in diameter (approx 20%)
Stage II — Disease confined to the adrenal gland and
>5 cm in diameter (approx 20%)
Stage III — Local invasion that does not involve
adjacent organs or regional lymph nodes(approx20%)
Stage IV — Distant metastases or invasion into adjacent
organs plus regional lymph nodes (approx 40%)
21. Unresectable tumors include those that invade the
celiac plexus/ vascular structures/ SMA/ aorta
22. In a case review of 46 patients at MSKCC, 3 histologic
factors correlated with survival:
tumor> 12cm
6 or more mitotic figures/ 10hpf
presence of histologic evidence of intratumoral
hemorrhage
5 year survivals:
▪ 0 factors: 83%
▪ 1 factor: 42%
▪ 2 factors: 33%
23. There are scattered case reports demonstrating
improved pain when palliative XRT used for
localized lesions
24. Review of the literature reveals case reports,
retrospective treatment data, and reviews.
A few phase II trials do exist from some
cooperative or national groups
No true modern- design controlled phase III trials
exist
25. 1,1- dichloro-2-(o-chlorophenyl) ethane (o,p-DDD).
Chemical relative to DDT
It produces selective adrenocortical necrosis in both the adrenal tumor and
metastases
Reported in 1960 by Bergenstal
Subsequent NCI study in 1966 in 138 patients
Noted “reduced symptoms” in about half the patients
Another study (Haak, Netherlands) retrospectively looked at a series of 96
patients treated from 1959- 92
62 patients were treated with mitotane during their course
Of the 30 who achieved serum levels >14mg/L, they had a greater survival
27. Italian series showed no
survival difference
between two groups of
completely resected
patients
Effect of adjuvant mitotane (n = 11) compared with no treatment (n = 15) on the
disease-free interval in patients with localized or regional adrenocortical carcinoma.
28. Of 19 patients treated at MD Anderson cancer center, 8
patients received it adjuvantly, 5 patients received it
transiently, 6 patients did not receive any.
Disease free interval was actually shortest in the adjuvant
group
29. Various systemic cytotoxics have been used for
advanced disease, usually for those failing
mitotane.
Most studied have been Etoposide, cisplatin,
and adriamycin.
Paclitaxel and Temozolamide have recently
demonstrated antitumor activity in vitro
30. Original studies utilized Cisplatin and Doxorubicin with
Cyclophosphamide or 5-FU. Response Rate was 20%
Cisplatin/ Etoposide reported to have an 11% response
rate
Phase II studies with varying reported efficacy exist
31.
32. Italian study
28 patients enrolled
Etoposide (100mg/ m2) d5-7; Doxorubicin (20mg/ m2) d1,8; Cisplatin
(40mg/ m2) d1,9 every 4 weeks
Concomitant mitotane up to 4g/ day
Complete Response in 2 patients
Partial Response in 13 patients
Overall response of 54%
Stable disease in 8, progessive in 5
33. Recurrences that are amenable to re- operation
may be resected for long term survival
5 year survivals compare from 57% in those
amenable to resection to 0% for those who are not
34. Italian registry: 140 resections
Recurrences in 52 (37%)
▪ Locally in 13
▪ Distant in 25
▪ Local + Distant in 14
20 patients underwent re- resection
▪ 5 yr survival of 50% in those resected
▪ 5 yr survival of 8% in those not resected
35. MSKCC: 47 patients with recurrent/ metastatic disease
Patients who had a complete second resection had a
median survival of 74 months (5-year survival, 57%),
whereas those with incomplete second resection had a
median survival of 16 months (5-year survival, 0%).
MSKCC: Memorial Sloan Kettering Cancer Centre
36. Adrenocortical carcinoma is a rare disease that often
presents late
Primary curative therapy is surgical
No role for adjuvant chemotherapy has been demonstrated
to date
Palliative therapy with mitotane may be useful; its palliative
effect may be entirely due to adrenolytic effect
37. Reoperation appears to be the only long term curative
option in recurrent cases
Cytotoxic chemotherapy in the advanced/ metastatic
setting has not been definitively demonstrated to be useful
in controlled trials
EDP-M may be useful in metastatic settings; more
evaluation is needed
Editor's Notes
Barzon L, Fallo F, Sonino N, Daniele 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 Apr;84(4):1488-9. The role of mitotane as adjuvant treatment for adrenocortical carcinoma is controversial (1, 2, 3, 4, 5, 6, 7, 8). Our experience with adjuvant mitotane (8), as that of others (3, 4, 5, 6), indicates that it is not beneficial in terms of either disease freedom or survival. We expanded our observation, and, of 59 consecutive patients (36 females, 23 males) with adrenocortical carcinoma (34 functioning and 25 nonfunctioning), 26 (44%) with localized or regional disease (median tumor size, 8.0 cm; range, 4.6–25.0 cm) underwent complete resection of the tumoral mass. Of these, 11 patients (group 1: 7 females and 4 males) received mitotane (o,p'-DDD, Lysodren, Bristol-Myers Squibb) postoperatively at doses of 4–8 g daily, whereas 15 patients (group 2: 9 females and 6 males) were given no medical treatment. The two groups were similar with regard to sex, age, tumor size, functional status, and tumor staging at diagnosis. Six patients of group 1 were free of disease at last follow-up (range: 6–82 months after surgery), and 5 developed metastases or recurrences (disease free-intervals of 4–29 months); 3 of them died of the disease 24–40 months after diagnosis. Of group 2, 6 were free of disease at last follow-up (range, 14–74 months after surgery), and 9 developed metastases (disease free-intervals of 8–60 months), 8 of them died during follow-up (survival: 15–104 months). Cumulative disease-free interval and survival rates, estimated with the Kaplan-Meyer method and compared with the log-rank test, were not significantly different between the two groups (2 = 0.26, df = 1, P NS; and 2 = 1.15, df = 1, P NS, respectively; Fig. 1). Owing to these disappointing results and the side-effects of mitotane, which significantly worsen quality of life of patients, we would not advocate mitotane as adjuvant treatment of adrenocortical carcinoma. However, prospective studies are needed to evaluate the real efficacy of this compound.
Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71 (10): 3119-23, 1993. [PUBMED Abstract] BACKGROUND. Adrenocortical carcinoma is a rare and aggressive disease with a poor prognosis. Adjuvant mitotane administration has been suggested as a strategy that might improve the outcome of patients with localized disease. METHODS. The authors analyzed the clinical outcome of patients with localized or regional adrenocortical cancer. The study included 19 patients who were registered at M.D. Anderson Cancer Center during a 3-year period and who had localized or regional disease at the time of surgery. Of these, eight patients received mitotane postoperatively and continued the drug until their last contact or recurrence (Group A, adjuvant); five patients began taking mitotane after surgery but discontinued it after 2-12 months for reasons unrelated to the disease (Group P, postoperative); and six patients did not receive mitotane (Group N, no mitotane). All patients have been followed for at least 12 months. RESULTS. The treatment groups differed significantly in their time to recurrence; the disease-free interval was shortest in Group A (P = 0.0055, by log-rank test). There was no statistical difference in survival among the groups, but the profile remained unfavorable for Group A. The 2-year survival rate was 100% for Groups N and P but only 43% for Group A. Of the potentially confounding factors, gender, age, steroid hypersecretion, and tumor size, none had any influence on recurrence or survival rates. CONCLUSIONS. These findings do not support the conclusion that adjuvant mitotane is beneficial in patients with localized or regional adrenocortical cancer. Neither the disease-free interval nor survival was improved by the drug. The authors suggest that alternative therapeutic strategies be explored for the management of these patients.
Jensen JC, Pass HI, Sindelar WF, et al.: Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch Surg 126 (4): 457-61, 1991. In a retrospective, nonrandomized comparison of patients with first recurrence of adrenocortical cancer, 18 patients were treated with chemotherapy (primarily mitotane) and 15 patients were treated with surgical resection plus similar chemotherapy. Surgical resection of recurrent adrenocortical cancer was often extensive, with morbidity in 20% of patients and no mortality. Mitotane therapy was ineffective at controlling tumor growth. Median survival from the time of diagnosis for all patients was only 23 months and no patient was cured. Disease-free interval greater than 12 months was associated with prolonged survival, but it only occurred in six patients (18%), with a similar frequency in both treatment groups. Surgical resection of recurrent disease was associated with prolonged survival from the time of first recurrence. The potential benefit of this resection was evident in the 5 patients (33%) who were able to live greater than 5 years from the time of first recurrence with improvement in symptoms and signs of hypercortisolism. Although no patient with recurrent adrenal cancer could be cured, resection of recurrent disease was associated with a slight prolongation of survival and good palliation of Cushing's syndrome.
