CLINICAL QUESTION
What is the best approach to an apparently nonmetastatic adrenocortical carcinoma?
Martin Fassnacht and Bruno Allolio
Department of Internal Medicine I, Endocrine Unit, University Hospital, University of Würzburg, Germany
Summary
In suspected nonmetastatic adrenocortical carcinoma (ACC) a careful preoperative diagnostic work up is needed including com- prehensive endocrine analysis as recommended by the European Network for the Study of Adrenal Tumors (http://www.ENSAT. org/ACC.htm). Staging prior surgery, in particular chest CT, is indispensable to exclude distant metastases. Open surgery is still the recommended approach in ACC. However, in localized non- invasive ACC with a diameter <10 cm laparoscopic adrenalectomy by an expert surgeon is probably similarly effective and safe. As many patients will suffer from tumor recurrence after seemingly complete removal of ACC, adjuvant treatment based on the indi- vidual risk status is recommended. Key factors for risk assessment are tumor stage, resection status and the proliferation marker Ki67. All patients considered at high risk for recurrence should receive adjuvant mitotane for a minimum of 2 years aiming at a drug level of 14-20 mg/l. In selected patients (e.g. R1 resection) we recom- mend additional radiotherapy of the tumor bed. Patients with a low/intermediate risk for recurrence should be included in the Adi- uvo trial comparing adjuvant mitotane with observation only (http://www.adiuvo-trial.org). In low/intermediate risk patients who cannot be included in this trial observation only can be justi- fied in cases with a tumor diameter of <8 cm and no microscopic evidence for invasion of blood vessels or tumor capsule. In all patients a structured follow-up for 10 years is strongly recom- mended.
(Received 13 July 2010; returned for revision 2 August 2010; finally revised 9 August 2010; accepted 9 August 2010)
Introduction
Adrenocortical carcinoma (ACC) is a highly malignant tumor and even in seemingly nonmetastatic disease tumor recurrence after surgery is frequent and associated with poor prognosis.1-3 Thus a
careful preoperative diagnostic work up, complete tumor resection (R0 resection) by an experienced surgeon and structured postoper- ative care are the key components for optimal patient outcome. We here describe our approach to patients with nonmetastatic ACC based on the results of recent studies and our personal experience in treating more than 350 patients within the last 10 years.
Preoperative diagnostic work-up of localized adrenocortical carcinoma
Several recent reviews have covered the diagnostic work up of adre- nal lesions2-5 and we here will only summarize some major princi- ples.
Endocrine work-up in suspected ACC
A detailed preoperative work-up for suspected ACC has been sug- gested by the European Network for the Study of Adrenal Tumors (ENSAT; www.ensat.org/ACC.htm).2,6 It comprises assessment of (i) autonomous glucocorticoid excess to prevent adrenal failure after complete resection (dexamethasone suppression test, urinary free cortisol excretion, basal cortisol+adrenocorticotropin: ACTH). (ii) mineralocorticoid excess including aldosterone/renin ratio, in patients with hypertension or hypokalemia only. (iii) sex steroids+precursors (DHEAS, 17-OH-progesterone, androstendi- one, testosterone, estradiol). Evidence of adrenocortical steroid excess indicates the adrenocortical origin of a mass located in the suprarenal region. Furthermore, the steroid pattern may be sugges- tive for an ACC (e.g. combined androgen and cortisol secretion) and can serve as tumor fingerprint during follow-up. According to our experience autonomous hormone secretion is detectable in >80% of patients with ACC. Thus in patients with large adrenal lesions and without evidence of autonomous steroid secretion there is a significant likelihood that the adrenal mass is not an ACC. In all patients a pheochromocytoma has to be excluded prior surgery (determination of metanephrines in plasma or urine).
Imaging and staging
Modern imaging provides important information on the malig- nant potential of an adrenal lesion, although in nonmetastatic dis- ease some uncertainty remains prior surgery. The median size of an
Correspondence: Martin Fassnacht, MD, Department of Internal Medicine I, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080 Würz- burg, Germany. Tel .: +49 931 201 39021; Fax: +49 931 201 61632; E-mail: Fassnacht_m@medizin.uni-wuerzburg.de
ACC is >11 cm, whereas most benign adrenal tumors have a diam- eter <5 cm. Therefore, size alone is a valuable parameter to suspect malignancy. However, tumors between 3 and 10 cm may be diag- nostically challenging. Characterizing an adrenal mass as a benign adenoma in unenhanced CT using a threshold value of ≤10 Houns- field units (HU) has a sensitivity of about 70% and a specificity of > 95%, respectively.7 However, diagnostic accuracy is even better using CT with delayed contrast media washout. Adrenal lesions with >10 HU in unenhanced CT, a washout of <50% and an abso- lute value of >35 HU 10-15 min after contrast media are highly suspicious for malignancy.8-10 In MRI ACCs typically present iso- intense to liver on T1-weighted images and show an increase in intensity in T2-weighted sequences. The diagnostic accuracy of MRI (using dynamic gadolinium-enhanced and chemical shift techniques) for differentiating benign and malignant adrenal lesions is similar to CT.10,11
In case of uncertainty after CT or MRI imaging, 18F-FDG-PET may provide important additional information. In a prospective study in 77 patients sensitivity and specificity to distinguish adeno- mas from ACCs were 1.0 (0-85-1-00) and 0-88 (0-75-0-96), respec- tively, using a cut-off value above 1-45 for adrenal to liver max SUV ratio.12 Similar findings were reported in a series from Japan.13
Furthermore, FDG-PET may detect distant metastases not apparent in CT or MRI (e.g. bone metastases). However, it can not substitute for a chest CT, as it often does not detect small lung lesions.14,15 As adrenal surgery is the treatment of choice only when a complete resection can be achieved, it is important to perform appropriate staging16 to exclude distant metastases prior surgery. Bone scans or cerebral imaging are only required, if there is clinical evidence for bone or brain metastases, because both occur rarely without concomitant metastases in liver or lung.
The surgical approach to nonmetastatic adrenocortical carcinoma
There is consensus that in localized ACC only surgery provides a chance for long-term cure.17 However, there is an ongoing debate on the best surgical approach for localized ACC. While evidence of invasive disease before surgery undoubtedly requires open adrenal- ectomy (OA), some surgeons have postulated that tumors with a diameter of <10 cm may be treated by laparoscopic adrenalectomy (LA), whereas others state that this approach is absolutely contrain- dicated.18
Only in 2010 three larger studies on this topic have been pub- lished. Miller et al. retrospectively studied 17 patients with LA and 71 with OA and found a shorter mean time to recurrence in the LA group (9-6 vs 19-2 months, P < 0.005).19 They concluded that LA is inappropriate in suspected ACC. In contrast, an Italian study found comparable recurrence-free survival (RFS) in 18 patients with LA and 25 patients with OA.20 These findings are in agreement with a study from our own group including 152 patients with tumors ≤10 cm including 35 patients who underwent LA.21 Both a matched-pairs approach and multivariate analysis revealed no dif- ference in overall and recurrence-free survival. These opposite find- ings may result from a major selection bias. In the series reporting an increased risk of capsule violation, incomplete resection and
peritoneal carcinomatosis after LA19,22,23 none of these patients had been operated at the reporting institution and most were referred to these centers only after recurrence, leading to overrepre- sentation of poor risk patients. In other words, patients without evidence of recurrence after surgery are unlikely to contact large referral centers. In our series we analyzed the disease status at the time of registration. 45% of the patients in the LA group and 61% in the OA group (P = 0-56) had documented recurrence when referred to us.21 Therefore, it is unlikely that a major selection bias has affected the results of this study.
In conclusion, LA seems to us appropriate for potentially malig- nant adrenal tumors with a diameter <10 cm and without evidence for invasive disease. However, irrespective of the surgical approach we strongly recommend to identify the best adrenal surgeon in your area for removal of a suspected ACC. As outcome depends on volume in adrenal surgery, we propose that surgery for suspected ACC should be limited to centers with >20 adrenalectomies per year.
Post-operative treatment and follow-up
Recurrence rates as high as 60%-80% after radical resection have been reported24,25 indicating a need of adjuvant treatment concepts. Three different concepts have been suggested: mitotane, mitotane plus streptozotocin, and irradiation of the tumor bed.
The best data derives from a large retrospective analysis by Terzolo et al.1 In this Italian-German multicenter study with two independent control groups the risk for recurrence and death was significantly higher in patients who did not receive adjuvant mitotane (multivariate adjusted hazard ratio for recurrence: 3.79; 95% confidence interval 2:27-6-32, and 2-93; 1.74-4-94, respectively). Although this was not a randomized trial, the fact that the decision for or against mitotane was center- and not patient-driven reduced the selection bias in this study in comparison to previous reports. A more aggres- sive approach derives from a phase II study in Sweden.26 In this non-randomized study 17 patients had been treated with streptozotocin plus mitotane and were compared with 11 patients without any adjuvant treatment. Median RFS was longer in the streptozotocin group (49 vs 12 months, P = 0-02). However, it remains uncertain whether the positive effect was related to mitotane, streptozotocin or the combina- tion of both drugs.
Local recurrence after surgical removal of a non-metastatic ACC is a frequent and troubling event. In a retrospective analysis of the German ACC Registry, 14 patients treated with adjuvant radiother- apy of the tumor bed were compared with 14 patients matched for resection status, adjuvant mitotane treatment, tumor stage, and tumor size.27 Local recurrence was observed in only 2/14 patients in the radiotherapy group compared to 11/14 controlled patients (P = 0-01) suggesting efficacy of adjuvant radiotherapy in reducing local recurrence. However, RFS and overall survival were not sig- nificantly different between the two groups.
These reports raise the key question of post-operative care after resection of non-metastatic localized ACC: Which patient should be treated by which respective therapeutic approach?
Here again it is important to bear in mind that probably all of the published series on localized ACC suffer from the above mentioned selection bias. This became impressively obvious in a recent analysis from the German ACC Registry.28 In this analysis we compared 30 stage II patients that were referred to us within 4 months after surgery with 119 stage II patients reported to our ACC Registry later than 4 months after sur- gery. The latter group had a 5-year overall survival of 55% only, which is very much in line with many published series. In contrast, the 5-year survival of the prospectively registered patients, all of whom were disease-free at the time of registra- tion, was 96% (P < 0-05), although 5-year disease free survival was only 70%. These findings suggest that prognosis of early stage ACC is probably significantly better than has been reported previously. Based on these results it is no longer obvi- ous that all patients should receive adjuvant treatment. It is, therefore, of key importance to stratify patients according their risk for recurrence.
As shown in Fig. 1, we currently divide patients in three risk groups based on tumor stage, resection status and the prolifer- ation marker Ki67. In accordance with the consensus of an
Non-metastatic ACC
Complete resection (Ro)
R/R, resection2
Ki67 ≤10%1
Ki67 >10%1
Low/intermediate risk
High risk
Consider adjuvant mitotane3
Adjuvant mitotane consider addtional therapy4
Adjuvant mitotane + radiotherapy
Follow-up every 3 months imaging and tumor markers
Tumor free
Recurrence
Consider re-surgery5
international expert panel29 we offer patients with high risk for recurrence adjuvant treatment with mitotane although we are aware that not all centers concur with this concept.30 In selected patients with very high risk we consider additional treatment options although the evidence for these concepts is much lower. Based on data from the German ACC Registry microscopic evidence of tumor invasion into blood vessels and the tumor capsule together with a Ki67 index of ≥20% indi- cates a particularly high risk for recurrence and may justify additional radiotherapy of the tumor bed. Patients with a tumor thrombus in the vena cava are at high risk of future distant metastases and, therefore, are candidates for a more aggressive adjuvant treatment (e.g. mitotane plus streptozoto- cin).
Recommendation of adjuvant treatment is more difficult in patients with a perceived low/intermediate risk of recurrence. To address this important issue a randomized trial (mitotane versus observation only) has been initiated for these patients and is cur- rently recruiting (http://www.adiuvo-trial.org). We, therefore, sug- gest that all patients with presumably low/intermediate risk are included in this ‘Adiuvo-trial’. In patients, who cannot be included, an individualized decision is needed. According to data from the German ACC registry, factors favoring observation only include a tumor diameter <8 cm and no microscopic evidence for invasion of blood vessels or tumor capsule.
Furthermore, there is first evidence that molecular markers might help to better discriminate the individual risk for recurrence in the future.31
Patients with incomplete resection or with uncertain resection status should be considered as very high-risk patients and here we recommend radiotherapy of the tumor bed in addition to mito- tane.32,33 During radiotherapy on the right side, mitotane dosage should not exceed 3 g/d to avoid major liver toxicity.
Treatment with mitotane is associated with significant toxicity and requires a careful and structured management by an experi- enced physician.3,34 Virtually all patients experience adrenal insuf- ficiency and most patients suffer from gastrointestinal symptoms. Supportive treatment including high dose hydrocortisone replace- ment therapy is invariably needed.34,35 In addition, several other potential adverse effects have to be monitored (Table 1). We prefer an approach with a rapidly increasing dosage followed by dose adjustment depending on mitotane drug level and toxicity. Although the concept of mitotane blood monitoring has been established for advanced ACC,36,37 it is reasonable to aim at a mito- tane blood level of 14-20 mg/l also in the adjuvant setting. We rec- ommend adjuvant mitotane for a minimum of 2 years. However, a longer period (e.g. 4 years) may be advisable in patients who toler- ate mitotane very well.
In all patients a strict follow-up is required, as early detection of tumor recurrence facilitates complete surgical removal of local recurrence or metastatic disease. In the first 2 years, CT or MRI of abdomen and chest as well as monitoring of initially elevated ste- roids is recommended every 3 months. Thereafter, intervals can gradually be increased (e.g. every 4 months in year 3-4, every 6 months in year 5-6, and thereafter every 12 months). Although there is first evidence that FDG-PET is of value during follow-up,14
| Therapeutics | Administration | Common adverse effects | Monitoring |
|---|---|---|---|
| Mitotane | Start with 1-5 g/d and increase dose within 4-6 days to 6 g/d* | Gastrointestinal side effects: nausea, vomiting, diarrhea, anorexia | Mitotane plasma concentration: every 4-6 weekst; target: 14-20 mg/l |
| Adapt dosage according tolerability and plasma concentration | Adrenal insufficiency | GOT, GPT, bilirubin, (gGT): initially every 4 weeks, later every 8 weeks | |
| Duration: 2-4 years | Central nervous side effects: ataxia, confusion, speech or visual problems Fatigue Primary hypogonadism in men Increased hepatic enzymes, thyroid dysfunction, hypercholesterolemia, hypertriglyceridemia | TSH, fT3, fT4, cholesterol (HDL, LDL), triglycerides, and testosterone every 3-4 months ACTH in case of suspected adrenal insufficiency Blood count every 3-4 months | |
| Streptocotozin# | Induction: day 1-5: 1 g Sz/d Afterwards 2 g/d Sz every 21 days Duration: 6-9 cycles | Nausea, vomiting, diarrhea Renal toxicity | Blood count, serum creatinin, GOT, GPT, bilirubin, albumin before every cycle |
| Radiotherapy of the tumor bed | > 40 Gy (1-8 to 2-0 Gy per fraction); limited boost volume (tumor bed) to reach 50-60 Gy | Mild nausea, loss of appetite, and fatigue | GOT, GPT, bilirubin, (gGT) every 2 weeks when combined with mitotane |
*In patients suffering from impaired health status a slower increase of dosage is recommended. During right-sided radiotherapy we do not administer >3 g/d. +In the first 3 months mitotane blood levels should be measured every 2-3 weeks and after reaching a plateau less frequent controls are needed. #should be combined with mitotane.
the exact role of this method remains to be defined. After 10 years we recommend to stop follow-up examinations in patients without evidence of disease.
Acknowledgements
This study was supported by grants of Deutsche Krebshilfe (grant # 107111 to M.F. and grant # 106 080 to B.A. and M.F.) and the Ger- man Research Foundation DFG (grant # FA 466/3-1 to M.F.).
Disclosure
M.F. and B.A. are participating as investigators in a clinical trial on the pharmacokinetics of mitotane sponsored by HRA Pharma (France).
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