Adrenocortical carcinoma is a rare and aggressive cancer that affects the outer layer of the adrenal glands, small organs that sit atop each kidney and produce vital hormones. Because this disease often grows quickly and can spread to other parts of the body, understanding treatment options—both those currently available and those being investigated—is crucial for patients and their families.

How Treatment Works Against Adrenocortical Cancer

The main goal when treating adrenocortical carcinoma, also known as ACC, is to remove the cancer completely, control the symptoms it causes, slow down how fast it spreads, and improve quality of life. This cancer often produces too many hormones, which can cause serious symptoms like high blood pressure, weight gain, muscle weakness, and changes in physical appearance. It can also grow large enough to press on nearby organs, causing pain and discomfort. Because every person’s cancer behaves differently, treatment decisions depend on several factors: the stage of the cancer (how large it is and whether it has spread), which hormones the tumor is producing, the patient’s overall health, and whether the tumor can be removed by surgery.^[1][4]

Healthcare teams typically include specialists from different fields—surgeons who remove tumors, medical oncologists who manage chemotherapy, endocrinologists who handle hormone problems, and radiation oncologists who deliver targeted radiation. This multidisciplinary approach means that multiple experts work together to create a personalized treatment plan for each patient. Standard treatments have been established through years of research and clinical experience, and these are recommended by medical societies worldwide. At the same time, researchers continue to investigate new therapies through clinical trials, which offer patients access to cutting-edge treatments that may not yet be widely available.^[7][17]

Standard Treatment Options for Adrenocortical Carcinoma

Surgery: The Primary Treatment

When adrenocortical carcinoma is limited to the adrenal gland or nearby tissues and can be completely removed, surgery is the first and most important treatment option. The surgical procedure, called an adrenalectomy, involves removing the entire affected adrenal gland. If the cancer has grown into surrounding tissues or organs, the surgeon may need to perform a more extensive operation called an en bloc resection, which removes the tumor along with any affected nearby structures as a single piece. For example, if the cancer has invaded a kidney, that kidney may also need to be removed. Lymph nodes near the tumor are often removed as well, especially if they appear enlarged or suspicious on imaging tests.^[4][15]

Complete surgical removal offers the best chance for long-term survival or even cure, particularly when the cancer is caught early. However, even after successful surgery, the cancer frequently comes back—a situation called recurrence. Studies show that local recurrence and spread to distant organs are unfortunately common with this aggressive disease. For patients whose cancer has already spread to other organs like the lungs, liver, or bones, surgery may still be an option if all visible tumor can be removed. In some cases, surgeons perform debulking surgery, which means removing as much of the cancer as possible even if complete removal isn’t feasible. This can help reduce symptoms caused by hormone overproduction and relieve pressure on nearby organs.^[1][16]

Mitotane: The Cornerstone Medication

Mitotane is the only medication specifically approved for treating adrenocortical carcinoma, and it has been used since 1960. This drug works in a unique way—it actually destroys cells in the adrenal cortex and reduces the production of hormones like cortisol. Doctors prescribe mitotane in two main situations: as adjuvant treatment after surgery (meaning it’s given to patients whose tumors were removed, to lower the risk that the cancer will come back), and for patients whose cancer has spread to other parts of the body and cannot be completely removed by surgery.^[12][15]

Mitotane is taken as a pill, and treatment often continues for many months or even years. The medication needs careful monitoring because the effective dose varies from person to person, and blood tests are regularly done to measure mitotane levels and make sure they’re in the right range. Mitotane can cause significant side effects, which is why patients need close medical supervision. Common side effects include digestive problems like nausea, vomiting, diarrhea, and loss of appetite. Many patients experience fatigue and general weakness. Because mitotane suppresses the adrenal glands’ ability to make hormones, patients typically need to take replacement hormones (like cortisol and sometimes other steroids) while on this treatment. Some people develop neurological symptoms such as confusion, dizziness, or difficulty with coordination. Skin rashes and changes in liver function tests are also possible.^[13][15]

Chemotherapy Combinations

When adrenocortical carcinoma has spread to distant organs (called metastatic disease) or cannot be completely removed by surgery, chemotherapy becomes an important part of treatment. The current standard chemotherapy regimen combines three drugs: etoposide, doxorubicin, and cisplatin, often abbreviated as EDP. These drugs work by damaging cancer cells’ ability to grow and divide. This combination is typically given along with mitotane, and this approach became the standard of care after a large international study called the FIRM-ACT trial showed it was more effective than other chemotherapy combinations.^[12][13]

The FIRM-ACT study found that about 23% of patients who received the EDP plus mitotane combination had significant shrinkage of their tumors. While this might seem like a modest response rate, it represents an important improvement for this difficult-to-treat cancer. The chemotherapy is given in cycles, usually as an intravenous infusion at regular intervals, allowing the body time to recover between treatments. The duration of chemotherapy depends on how well the cancer responds and how well the patient tolerates the treatment.^[12]

Chemotherapy for adrenocortical carcinoma causes side effects similar to those seen with chemotherapy for other cancers. These can include significant fatigue, increased risk of infections because the immune system becomes weakened, nausea and vomiting, hair loss, mouth sores, and neuropathy (nerve damage that causes tingling, numbness, or pain in the hands and feet). Doxorubicin can affect heart function, so doctors monitor cardiac health during treatment. Cisplatin can damage the kidneys and hearing, requiring careful monitoring of kidney function and sometimes hearing tests. Because both chemotherapy and mitotane cause demanding side effects, the medical team works closely with patients to manage these problems and maintain quality of life during treatment.^[12]

Radiation Therapy

Radiation therapy uses high-energy beams to destroy cancer cells or stop them from growing. For adrenocortical carcinoma, radiation is most commonly used as adjuvant treatment after surgery in patients who have a high risk of the cancer coming back. This risk is higher when the surgical margins (the edges of removed tissue) contained cancer cells, meaning the surgeon couldn’t remove all visible tumor, or when the cancer had grown into nearby tissues. Radiation to the tumor bed—the area where the tumor was located—can help eliminate any microscopic cancer cells that might have been left behind.^[4]

Radiation can also be used to treat areas where the cancer has spread, particularly to bones or the brain, helping to relieve pain and other symptoms. In some situations, specialized radiation techniques like stereotactic body radiation therapy (SBRT) may be used to deliver very focused, high doses of radiation to specific tumor sites while sparing surrounding healthy tissue. Side effects of radiation depend on which part of the body is being treated. Common effects include skin irritation in the treatment area, fatigue, and temporary inflammation of nearby organs. For abdominal radiation, nausea, diarrhea, and decreased appetite can occur.^[11]

Supportive Medications for Hormone Control

Because many adrenocortical tumors produce excessive amounts of hormones, managing these hormone imbalances is a crucial part of treatment. The symptoms caused by too much cortisol, aldosterone, or sex hormones can severely affect quality of life and even be dangerous. Several medications help control these hormone-related symptoms. Besides mitotane, doctors may prescribe ketoconazole, which decreases cortisol production and can help manage Cushing syndrome symptoms. Spironolactone blocks the effects of aldosterone, helping to control high blood pressure and low potassium levels. Other medications may be used to block the effects of excess sex hormones.^[15]

After surgery to remove the adrenal gland, or when medications suppress adrenal function, patients need hormone replacement therapy. This typically includes taking cortisol (hydrocortisone or prednisone) daily, and sometimes other hormones. The doses need to be carefully adjusted, and patients must increase their doses during times of physical stress like illness or surgery, because the body naturally produces more cortisol during stress. Without adequate replacement, patients can develop life-threatening adrenal insufficiency.^[15]

Innovative Treatments Being Tested in Clinical Trials

Despite the standard treatments available, outcomes for many patients with adrenocortical carcinoma remain poor, particularly when the disease has spread. This has driven researchers worldwide to investigate new therapeutic approaches through clinical trials. Clinical trials are carefully designed research studies that test whether new treatments are safe and effective. They follow strict phases: Phase I trials focus primarily on safety and determining the right dose; Phase II trials test whether the treatment shows signs of working against the cancer; and Phase III trials compare new treatments with current standard treatments to see if they’re better.^[12]

Targeted Therapies

One promising area of research involves targeted therapies—medications designed to attack specific molecular abnormalities found in cancer cells. Scientists have discovered that many adrenocortical carcinomas have changes in specific genes or proteins that help the cancer grow. One focus has been the insulin-like growth factor system (IGF). Research showed that many ACC tumors produce high levels of IGF-II, a protein that promotes cell growth. Several clinical trials tested drugs called IGF-1 receptor inhibitors, which block the signals from this growth system. Unfortunately, while these drugs appeared promising in laboratory studies, they showed limited benefit in clinical trials. Studies testing medications like linsitinib and other IGF-1 receptor inhibitors found that tumor shrinkage was rare and the drugs did not significantly extend patient survival compared to standard chemotherapy.^[13]

Other targeted approaches have examined different molecular pathways. Some trials investigated drugs targeting proteins involved in cell growth and division, such as drugs that affect the mTOR pathway or other cell signaling systems. While some patients showed temporary disease stabilization—meaning their cancer stopped growing for a period—overall response rates remained disappointing. These results highlight how difficult adrenocortical carcinoma is to treat and underscore the need for better understanding of what drives this cancer.^[13]

Immunotherapy Approaches

Immunotherapy represents one of the most exciting advances in cancer treatment over the past decade. These drugs work by helping the patient’s own immune system recognize and attack cancer cells. The most studied type is called immune checkpoint inhibitors, which block proteins that prevent the immune system from killing cancer cells. Several clinical trials have investigated whether immunotherapy could help patients with advanced adrenocortical carcinoma.^[5]

Studies have tested various checkpoint inhibitors, including drugs that target proteins called PD-1, PD-L1, and CTLA-4. Some trials used single immunotherapy agents, while others combined two different immunotherapy drugs together. Unfortunately, results have generally been disappointing. Most studies found that only a small percentage of patients—typically less than 10 to 15%—experienced tumor shrinkage with immunotherapy. The average time before the cancer started growing again (progression-free survival) was relatively short, often just a few months. Overall response rates and survival benefits were generally poor compared to what has been seen with immunotherapy in other cancer types like melanoma or lung cancer.^[5][13]

Researchers are trying to understand why immunotherapy hasn’t worked as well for ACC. Some studies are now testing combinations of immunotherapy with chemotherapy or with mitotane, hoping that multiple approaches together might be more effective. Scientists are also looking for biomarkers—biological signs that might predict which patients are more likely to benefit from immunotherapy. For example, tumors with certain genetic characteristics or higher levels of immune cell infiltration might respond better. These investigations continue in ongoing clinical trials.^[13]

Novel Drug Combinations and Approaches

Researchers continue to explore other innovative treatment strategies. Some clinical trials are testing new combinations of existing drugs to see if they work better together. Others are investigating completely new types of medications developed based on recent discoveries about how ACC develops and grows. Molecular studies have identified numerous genetic changes common in adrenocortical carcinoma, including alterations in genes like TP53, CTNNB1, and others that control cell growth. Understanding these genetic changes may lead to development of new drugs that specifically target these abnormalities.^[9][13]

Some trials are investigating whether analyzing the specific genetic profile of each patient’s tumor (called molecular profiling or genomic testing) can help identify particular treatments that might work for that individual. This approach, sometimes called precision medicine or personalized medicine, aims to match patients with therapies most likely to help them based on their tumor’s unique characteristics. Clinical trials testing these approaches are available at major cancer centers in the United States, Europe, and other regions.^[13]

Accessing Clinical Trials

Because adrenocortical carcinoma is so rare and current treatments have limitations, participating in a clinical trial is often an excellent option for patients at any stage of treatment. Clinical trials give patients access to the newest treatments before they become widely available. They also contribute to medical knowledge that helps future patients. Patients interested in clinical trials can discuss options with their oncology team. Major cancer centers often have clinical trials available, and registries exist where patients and doctors can search for open trials. Not every patient will be eligible for every trial—each study has specific requirements regarding disease stage, prior treatments, and general health status. However, for many patients, a clinical trial offers hope for better outcomes.^[7]

Most Common Treatment Methods

• Surgery
  • Adrenalectomy to remove the entire affected adrenal gland for localized cancer
  • En bloc resection removing tumor with surrounding affected tissues as one piece
  • Debulking surgery to remove as much tumor as possible when complete removal isn’t feasible
  • Surgical removal of metastases in specific organs when technically possible
• Medication therapy with mitotane
  • Adjuvant mitotane after surgery to reduce recurrence risk
  • Mitotane for metastatic disease to suppress adrenal hormone production
  • Long-term daily oral medication requiring blood level monitoring
  • Management of side effects including digestive symptoms and need for hormone replacement
• Chemotherapy
  • EDP regimen (etoposide, doxorubicin, cisplatin) combined with mitotane as standard first-line treatment for advanced disease
  • Intravenous administration in cycles allowing recovery periods between treatments
  • Response rate of approximately 23% in metastatic disease
  • Management of chemotherapy side effects including fatigue, infection risk, nausea, and organ toxicity
• Radiation therapy
  • Adjuvant radiation to tumor bed after surgery for high-risk patients
  • Palliative radiation to sites of metastatic disease, especially bone and brain
  • Stereotactic body radiation therapy for focused treatment of specific tumor sites
• Hormone control medications
  • Ketoconazole to reduce cortisol production and manage Cushing syndrome symptoms
  • Spironolactone to block aldosterone effects and control blood pressure
  • Hormone replacement therapy with cortisol and other hormones after adrenal gland removal
  • Medications to block effects of excess sex hormones
• Targeted therapy (clinical trials)
  • IGF-1 receptor inhibitors targeting insulin-like growth factor pathway
  • Drugs affecting mTOR pathway and other cell signaling systems
  • Agents targeting specific genetic mutations found in individual tumors
• Immunotherapy (clinical trials)
  • Immune checkpoint inhibitors blocking PD-1, PD-L1, or CTLA-4 proteins
  • Combination immunotherapy approaches using multiple agents
  • Combined immunotherapy with chemotherapy or mitotane