Adrenal Carcinoma Treatment & Management

Because adrenocortical carcinomas (ACs) are so rare, clinical series are small and there has been only limited prospective evaluation of treatment strategies. Therefore, significant controversy over therapy exists, and very few, if any, universally accepted treatment standards have been determined. Current practices are strongly influenced by expert consensus opinion from a few medical centers that specialize in ACs.

When feasible, total resection remains the modality of choice for the definitive treatment of AC. It also remains the only potentially curative therapy.

Medical care in patients with AC, which can be supportive or adjuvant to surgical resection, encompasses the following:

• Treatment of endocrine excess syndromes
• Use of mitotane or several multiagent chemotherapy regimens
• Treatment and prevention of potential complications
• Strategies for palliative and terminal care issues, including symptom relief and management

Management of nonfunctional tumors

Virtually all authorities agree that because of the significant potential cancer risk, all nonfunctional adrenal tumors of 6 cm or greater should be removed. Authorities also generally agree that nonfunctional adrenal tumors of 3 cm or less have a very low probability of being adrenal cancer; therefore, they can be observed safely.

The management strategy for adrenal masses larger than 3 cm and less than 6 cm is disputed. Some authorities suggest lowering the threshold for surgical removal of nonfunctional masses from 6 cm to 4-5 cm. Others individualize the follow-up of these patients depending on their clinical status, CT scan characteristics, and age. Particularly important is the fact that these criteria do not apply to children, who generally have smaller ACs.

A review of the available data suggests that the incidence rate of malignancy is small (< 0.03%) in all adrenal incidentalomas that are 1.5-6 cm. However, this rate increases considerably with tumors larger than 6 cm (up to 15%). The smallest identified AC associated with metastasis reported in the literature was 3 cm in diameter.

When feasible, total resection remains the treatment of choice for the definitive management of AC. It also is still the only potentially curative therapy. Following surgery, management shoudld focus on pathologic verification of the diagnosis, evaluation of prognostic markers, and genetic evaluation to guide discussion of adjuvant therapy. ^[25]

Open versus laparoscopic surgery

While open laparotomy for adrenalectomy represents the standard of care, several reports suggest a role for laparoscopic resection if the adrenal tumor is small and there is no evidence of metastatic disease preoperatively. ^{[31, 32, 33]} The most common sites for metastases are the lungs, liver, bone, and lymph nodes. Contiguous spread to the kidney and liver (if the primary is on the right side) and tumor extension into the venous drainage system of the adrenals and the inferior vena cava are common.

A study by Agha et al suggested that laparoscopic adrenalectomy can be effectively performed even on larger tumors (> 6 cm). Data from 279 patients who underwent the minimally invasive procedure (227 with tumors of 6 cm or smaller and 52 with tumors > 6 cm) showed that although the mean duration of surgery, estimated blood loss, intraoperative bleeding rate, conversion rate, and postoperative complication rate were greater in the patients with larger tumors, the two tumor groups each had only one major complication. ^[34]

Recurrent and metastatic tumor management

Recurrent local and metastatic tumors are common in AC, even in patients who undergo a successful complete resection. In such settings, the only effective treatment is attempted reoperation. ^{[35, 36]} Case reports indicate that repeated thoracotomy can allow for more than 10 years of high-quality survival despite recurring crops of metastatic disease. Moreover, a large, retrospective series showed that pulmonary metastasectomy may be beneficial in carefully selected patients. ^[37] In that study, by Kemp et al, median overall survival was 40 months and 5-year actuarial survival was 41%, following resection of pulmonary metastasis.

A study from Memorial Sloan-Kettering Cancer center found that in patients with AC, aggressive primary surgical removal and aggressive surgical treatment of local or distant relapse led to long-term survival rates far superior to those reported in previous studies, regardless of patient age. One important feature of this study was that patients who underwent a complete second resection had a median survival of 74 months (5-y survival rate, 57%). ^[38]

Mitotane

Mitotane remains the major chemotherapeutic option for the management of AC because it is a relatively specific adrenocortical cytotoxin. It is used as primary therapy, as adjuvant therapy, and as therapy in recurrent or relapsing disease. ^[39]

Mitotane apparently causes adrenal inhibition without cellular destruction. The exact mechanism of action is unknown. It inhibits cholesterol side-chain cleavage and 11-beta-oxyhydrase reactions. It also appears to reduce the peripheral metabolism of steroids. Alteration of extra-adrenal metabolism of cortisol reduces measurable 17-hydroxy corticosteroid while stimulating the formation of 6-beta-hydroxy cortisol. Plasma levels of corticosteroids do not fall.

This drug may be considered in the treatment of inoperable adrenal cortical carcinoma (functional and nonfunctional). It controls endocrine hypersecretion in 70-75% of patients. While objective tumor responses often are cited in as many as 20-25% of patients, a study has yet to be conducted with modern imaging techniques and response criteria accepted by clinical oncologists. Tumor response has been reported to correlate with serum levels and often requires several months of continuous therapy. Assaying mitotane levels during therapy is valuable because therapeutic efficacy depends on achieving serum levels of at least 15 mcg/mL.

Approximately 40% of the drug is absorbed, and approximately 10% of the dose is recovered in the urine as a water-soluble metabolite. Active metabolite excreted in the bile varies from 1-17%. The balance apparently is stored in tissues. Autopsy data indicate that fat tissue is the primary storage site, but the active metabolite is found in most tissues. After therapy, plasma terminal half-life varies from 18-159 days.

Experience suggests that the best approach is continuous treatment with the maximum possible dosage. If the dose is tolerated and an improved clinical response appears possible, increase the dose until adverse reactions interfere. The aim is to achieve doses as high as 10-20 g/day.

Efficacy

Mitotane’s major beneficial effect is on symptoms; treatment benefits are generally short-lived, and long-term survivors on this therapy are rare. 

El Ghorayeb et al.reported a rapid and complete remission of metastatic AC with mitotane monotherapy 2 years after a right adrenalectomy for stage III nonsecreting AC. The patient remained disease-free with good quality of life on a low maintenance dose of mitotane during the subsequent 10 years. ^[40]

Postoperative/adjuvant therapy

Adjuvant therapy with mitotane remains controversial. A retrospective study by Terzolo et al examining adjuvant mitotane therapy in patients who underwent radical surgery for AC found evidence that mitotane can significantly increase recurrence-free survival. The study included 47 Italian patients who received mitotane postoperatively and control groups of 55 Italian patients and 75 German patients.

In the Italian patients, baseline features were similar in the treatment and control groups; the German patients were significantly older and had more stage I or II disease than did patients in the mitotane group. Median recurrence-free survival was 42 months in the mitotane group, as compared with 10 months in the Italian control group and 25 months in the German control group. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival. ^[41]

A meta-analysis that included 1249 patients from five studies concluded adjuvant mitotane led to significantly longer recurrence-free survival and overall survival and concluded that adjuvant mitotane is an effective postoperative strategy. ^[42] In contrast, a US Adrenocortical Carcinoma Group review of 207 patients who underwent resection of AC, 88 (43%) of whom received adjuvant mitotane, found that adjuvant mitotane was not associated with improved recurrence-free or overall survival. ^[43]

Based on data so far, adjuvant therapy can be recommended for patients with high risk for recurrence based on positive margins, ruptured capsule, large size of the primary tumor, or high mitotic rate. Adjuvant mitotane therapy can be considered after resection of AC. ^[44]  It should be noted that patients treated with mitotane usually require lifelong steroid replacement therapy, due to the adrenolytic nature of that agent. 

Chemotherapy and mitotane in metastatic disease

Typically, the choice of systemic therapy consists of mitotane alone or in combination with chemotherapy. Various agents have been combined with mitotane, including cisplatin, carboplatin, etoposide, doxorubicin, and streptozocin. Response rates reported with mitotane monotherapy is on the order of 10-30%.

The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) study of first -line therapy for AC reported that patients who received mitotane and EDP (etoposide, 100 mg/m² on days 2-4; doxorubicin, 40 mg/m² on day 1, and cisplatin, 40 mg/m² on days 3 and 4) had higher response rates and longer median progression-free survival than patients treated with mitotane plus streptozocin (5 mo vs 2.1 mo, respectively). Toxicity rates for both of the combinations were similar. Overall survival in the entire group was not significantly better; however, the study revealed that for those patients who did not receive alternative second-line therapy, overall survival was better in the EDP-mitotane group. ^[45]

Pembrolizumab was reported to produce a 23% objective response rateRR and median OS of 24.9 months. A second study showed 15% response rate.  Pembrolizumab can be utilized as a single agent or combination with mitotane ^{[46, 47]} .  Several studies are investigating combined immune checkpoint blockade with anti-CTLA4 and anti-PD-L1 agents and other novel combinations. Other targeted therapies studies include insuline like growth factor 1, VEGF, EGFR, mTOR inhibitors but no clear evidence of benefit and no firm conclusions can be drawn.

There is evidence of mitotane plasma levels and efficacy. 55-66% response rates were reported in patient with plasma levels greater than 14 mg/L.  Lower levels were associated with decreased efficacy. Adverse events are also associated with higher plasma levels. Higher-dose regimens therefore are preferred for mitotane monotherapy and a lower-dose regimen is best when used in combination with chemotherapy. ^[48]

Second-line and subsequent treatment

Despite the superiority of EDP plus mitotane (EDP-M) in first-line therapy, the overall outlook still remains poor. In patients whose AC progresses after EDP-M therapy, second-line treatments to consider include streptozocin plus mitotane and gemcitabine plus capecitabine. The response rates reported with second-line regimens tend to be low (~10%).

Ronchi et al found that, as with other types of cancer, expression of excision repair cross-complementing group 1 (ERCC1) by ACs predicts resistance to platinum-based chemotherapy. Median overall survival after platinum treatment was 8 months in patients with high ERCC1 expression, versus 24 months in those with low ERCC1 expression. ^[49]

In the future, the treatment of adrenal carcinoma may utilize novel chemotherapeutic agents, vascular growth inhibitors, and small-molecule therapy based on a better understanding of the molecular pathways involved in tumorigenesis.

Management of endocrine syndromes

In functional tumors, management of the endocrine syndromes is often important because the associated systemic effects may significantly impact patient well-being.

Therapeutic options for Cushing syndrome include mitotane, ketoconazole, metyrapone, aminoglutethimide, RU 486 (mifepristone), and intravenous etomidate, alone or in various combinations.

For hyperaldosteronism, the major therapeutic options are spironolactone, eplerenone, amiloride, triamterene, and various antihypertensives, especially long-acting dihydropyridine calcium channel blockers.

For hyperandrogenism or hyperestrogenism, several options are available if adverse effects from androgen or estrogen significantly affect patient well-being. Antiestrogens may include the following:

• Clomiphene citrate
• Tamoxifen
• Toremifene
• Danazol

Potential antiandrogens include the following:

• Flutamide
• Cyproterone acetate
• Bicalutamide (Casodex)
• Nilutamide
• Megestrol acetate

Ketoconazole, spironolactone, and cimetidine also have a significant antiandrogen effect. The various aromatase inhibitors (eg, testolactone, anastrozole, letrozole, fadrozole) have some antiandrogen effect as well; therefore, they may be used. Controlled studies have not yet been performed to assess which of these agents, either alone or in combination, achieves the best metabolic control. The choice of medication often is guided by cost, availability, patient preference, adverse effects, and tolerance.

In the rare setting of mixed carcinoma associated with pheochromocytoma components, high-dose, radiolabeled metaiodobenzylguanidine (MIBG) has a potential role.

The management of blood pressure elevation in endocrine syndrome from adrenal cancer is similar to that in pheochromocytoma, with use of long-acting alpha blockers (usually phenoxybenzamine), followed by long-acting beta blockers (eg, propranolol) and, finally, metyrosine. There is no evidence suggesting that a combination of radiotherapy with mitotane (or any other chemotherapeutic regimen, for that matter) confers any survival benefit.

Patients treated with mitotane may present with features of both glucocorticoid and aldosterone insufficiency requiring replacement therapy.

Stem cell transplantation

Autologous hematopoietic stem cell transplantation for rescue after high-dose chemotherapy is an established approach in several hematologic malignancies and certain solid tumors. A single case report describes the successful use of a combination of adrenalectomy, chemotherapy, surgical debulking of lung metastases, and autologous transplantation in a three-year-old girl with AC. ^[50]

Some experts recommend that the use of radiation therapy be restricted to palliation of local disease, such as symptomatic metastases to the bone and local luminal obstructive disease. ^[51] Percutaneous radiofrequency ablation may provide control of local symptoms related to local compression by an invasive tumor.

In contrast, a review of 865 cases of adrenocortical carcinoma concluded that medically fit patients with stage III, node-negative disease should receive adjuvant radiation after surgical resection, as this has been associated with significantly improved overall survival, compared with surgery alone. ^[52] The American Association of Clinical Endocrinology recommends considering radiation therapy or radiofrequency ablation as part of a multidisciplinary approach in patients with advanced or recurrent disease. ^[25]

A meta-analysis by Polat et al suggested that radiotherapy to the tumor bed may be considered in patients at high risk for local recurrence. These researchers recommended administering a total dose of more than 40 Gy, with single fractions of 1.8-2 Gy (including a boost volume to reach from 50-60 Gy in individual patients). ^[51]

Ambulatory follow-up should be performed every month for the first 2 years after treatment because repeat resection of locally recurring disease and resection of metastatic lung disease can substantially improve long-term survival.

Scanning of the local area in the abdomen or pelvis and of sites of metastatic disease should continue as follows:

• First 2 years: every 3 months
• Third and fourth year: every 4 months
• Fifth year: every 6 months 

Patients should be monitored for the reappearance of adrenocortical hormone hyperactivity, along with scanning, unless their history suggests that Cushing syndrome or autonomous adrenocortical hormonal production is present. If this is the case, the physician should immediately search for recurrence.

No definitive guidelines exist for all nonfunctional adrenal masses being followed serially. A suggested follow-up regimen is to perform repeat adrenal CT or MRI scans 3-6 months after the initial evaluation, then yearly (some suggest every 6 mo for the first few years) in order to detect any change in tumor size. Accompany these with periodic checks of hormonal profiles (after 1 y, then every 1-2 y thereafter).