Adenoid cystic carcinoma of the salivary gland is a rare cancer that grows slowly but presents unique challenges, requiring careful treatment planning and long-term monitoring to manage its unpredictable behavior.

How Treatment Aims to Control a Rare Salivary Gland Cancer

Adenoid cystic carcinoma of the salivary gland is an uncommon cancer that develops in the glands responsible for producing saliva. Although this cancer typically grows more slowly than many other types, it has a tendency to return even after treatment, sometimes many years later. Because of this unpredictable nature, managing this disease requires a thoughtful approach that balances removing the cancer with preserving a person’s ability to speak, swallow, and maintain their quality of life.^[1]

The main goal of treatment is to remove as much of the tumor as possible and prevent it from spreading to other parts of the body. This cancer has an unusual way of spreading—it tends to creep along nerve fibers surrounding the tumor, which makes it particularly challenging to treat completely. In some cases, cancer cells can also travel through the bloodstream to reach distant organs like the lungs or liver.^[1]

Treatment decisions depend heavily on where the tumor is located, how large it has grown, and whether it has spread beyond the original site. The stage of the disease and the patient’s overall health also play important roles in determining the best treatment approach. Because adenoid cystic carcinoma is so rare—affecting only about 4.5 out of every 100,000 people—there is limited information about which treatments work best for different situations.^[2]

Medical societies and cancer treatment centers follow established guidelines for treating this disease, which typically involve a combination of surgery and radiation therapy. However, because the cancer often comes back despite aggressive treatment, researchers are actively exploring new approaches through clinical trials. These studies test innovative therapies that might offer better outcomes for patients who face recurrent or advanced disease.^[5]

Standard Approaches to Treating Adenoid Cystic Carcinoma

Surgery remains the cornerstone of treatment for adenoid cystic carcinoma of the salivary gland. The primary objective during surgery is to remove the entire tumor along with a margin of healthy tissue around it, ensuring that no cancer cells are left behind. This type of operation is called surgical resection with clean margins. The surgeon aims to extract the tumor completely while trying to preserve as many surrounding structures as possible.^[1]

However, this surgery can be quite complex, especially when the tumor is located in the head and neck region. The cancer has a characteristic tendency to spread along nerves, a process called perineural invasion. This happens at such a microscopic level that surgeons sometimes cannot see it during the operation, even with advanced imaging techniques. Because of this invisible spread, surgeons may need to remove portions of nerves, lymph nodes, or other nearby structures to ensure complete removal of the cancer.^[1]

For some patients with advanced tumors in the salivary glands, specialized surgical techniques are available. One such approach is endoscopic endonasal surgery, which involves accessing the tumor through the nostril using tiny cameras and instruments. This technique can be particularly useful for tumors that have spread to the skull base or along nerve pathways, as it allows surgeons to reach these difficult areas while causing less visible scarring and preserving vital structures.^[11]

Following surgery, most patients receive radiation therapy, which uses high-energy beams to destroy any remaining cancer cells that the surgeon could not see or remove. Radiation therapy typically begins about four to six weeks after surgery, giving the body time to heal from the operation. Treatment usually consists of daily sessions, five days a week, for approximately six weeks.^[11]

Radiation is particularly important for adenoid cystic carcinoma because of how the tumor cells spread along nerves. Even when surgery appears to have removed all visible cancer, microscopic cells may remain along nerve pathways extending to the skull base or brain. Radiation therapy targets these areas to reduce the risk of the cancer returning. For patients whose tumors cannot be completely removed due to their location or extent, radiation therapy may be used as the primary treatment, although it is generally not as effective as surgery followed by radiation.^[11]

A specialized form of radiation called fast neutron therapy has shown promise for advanced or inoperable salivary gland tumors. This type of radiation uses neutron particles instead of standard x-rays and is considered more effective for tumors that are difficult to treat. However, it is only available at specialized centers and is typically reserved for cases where standard radiation has failed or when the tumor exhibits significant residual disease after surgery.^[6]

The duration of treatment varies depending on the extent of the disease. Surgery alone may take several hours, with recovery lasting weeks to months depending on what structures were involved. When combined with radiation therapy, the entire treatment process can extend over several months. During this time, patients typically experience side effects from radiation, including fatigue, skin changes in the treated area, dry mouth, difficulty swallowing, and changes in taste.^[5]

These side effects can be challenging to manage, but medical teams provide supportive care to help patients cope. For example, medications can help stimulate saliva production for those experiencing dry mouth, and nutritional counseling can assist patients who have difficulty eating due to mouth soreness or swallowing problems. Physical therapy may be recommended for patients who experience stiffness or weakness in the jaw, neck, or shoulder area following surgery or radiation.^[11]

Emerging Treatments Being Studied in Clinical Trials

Because standard treatments do not always prevent adenoid cystic carcinoma from returning or spreading, researchers are actively investigating new therapies through clinical trials. These studies explore different approaches to fighting the cancer, including drugs that target specific molecular pathways involved in tumor growth and spread.^[7]

One promising area of research focuses on blocking the formation of new blood vessels that tumors need to grow, a process called angiogenesis. Tumors cannot grow beyond a tiny size without developing their own blood supply, so drugs that prevent this blood vessel formation can slow or stop tumor growth. Several medications targeting the vascular endothelial growth factor receptor (VEGFR) have been tested in clinical trials for adenoid cystic carcinoma.^[7]

Among these anti-angiogenesis drugs, lenvatinib has shown encouraging results. In clinical studies, lenvatinib demonstrated an objective response rate of 11 to 16 percent, meaning that between 11 and 16 out of every 100 patients experienced measurable tumor shrinkage. This drug works by blocking multiple receptors involved in blood vessel formation, including VEGFR. Patients typically take lenvatinib as an oral medication, and while it does not cure the disease, it may help control tumor growth for a period of time.^[7]

Another VEGFR inhibitor called axitinib has also been studied in clinical trials for adenoid cystic carcinoma. This drug showed an objective response rate of 9 to 17 percent in various studies. Like lenvatinib, axitinib is taken by mouth and works by preventing the formation of new blood vessels that feed the tumor. These drugs represent a different approach from traditional chemotherapy—rather than trying to kill cancer cells directly, they aim to starve the tumor by cutting off its blood supply.^[7]

Traditional chemotherapy drugs have also been tested for adenoid cystic carcinoma, but with limited success. Chemotherapy uses powerful medications to kill rapidly dividing cells, including cancer cells. However, adenoid cystic carcinoma grows slowly compared to many other cancers, which makes it less responsive to standard chemotherapy. Single-drug chemotherapy regimens with agents like cisplatin, 5-FU, gemcitabine, paclitaxel, vinorelbine, epirubicin, or mitoxantrone have shown objective response rates of only about 5 to 10 percent.^[7]

Researchers have explored combining multiple chemotherapy drugs to improve effectiveness. The most studied combination regimen is called CAP, which includes cyclophosphamide, doxorubicin, and cisplatin. This three-drug combination showed objective response rates of 18 to 31 percent in clinical trials—better than single drugs alone, but still modest. Another combination being studied pairs cisplatin with vinorelbine, which has shown similar response rates.^[7]

These chemotherapy regimens are typically reserved for patients whose cancer has spread to distant organs or who cannot undergo surgery or radiation. The medications are usually given through an intravenous line in cycles, with treatment periods followed by rest periods to allow the body to recover. Side effects can include nausea, hair loss, fatigue, increased infection risk due to low white blood cell counts, and damage to various organs depending on the specific drugs used.^[7]

One of the most exciting areas of current research involves targeting the MYB gene, which plays a central role in adenoid cystic carcinoma. Scientists have discovered that most cases of this cancer involve abnormal activation of the MYB gene, often through a gene fusion where MYB becomes joined to another gene called NFIB. This genetic alteration drives the cancer cells to multiply and survive. For many years, researchers thought MYB would be difficult to target with drugs because it acts as a transcription factor—a type of protein that controls gene activity inside the cell nucleus.^[6]

However, recent advances have made MYB an increasingly attractive target. Researchers have developed experimental drugs that can interfere with MYB activity, and at least one clinical trial is testing a cancer vaccine designed to train the immune system to recognize and attack cells with abnormal MYB. This vaccine approach, if successful, would represent a completely new way of treating adenoid cystic carcinoma.^[7]

Another promising target is PRMT5, an enzyme involved in epigenetic regulation—the process by which cells control which genes are turned on or off without changing the DNA sequence itself. Researchers at the University of Chicago used artificial intelligence to analyze gene expression patterns in adenoid cystic carcinoma tumors and identified PRMT5 as a potential therapeutic target. A drug called PRT543, which blocks PRMT5 activity, showed the ability to shrink tumors in laboratory models including cell cultures, three-dimensional tumor models called organoids, and mice carrying human tumors.^[13]

The PRMT5 inhibitor works by interfering with key genes involved in adenoid cystic carcinoma, including MYB and another gene called MYC. Early research suggests that combining a PRMT5 inhibitor with lenvatinib might be even more effective than either drug alone, potentially offering a new treatment strategy for patients with specific molecular characteristics in their tumors. This research is still in the preclinical phase, meaning it has not yet been tested in human patients, but it represents an important step forward.^[13]

Scientists are also exploring treatments that target cancer stem cells, which are thought to be responsible for treatment resistance and cancer recurrence. Cancer stem cells are a small population of cells within the tumor that have the ability to generate new tumors and survive treatments that kill most other cancer cells. These cells can be targeted through several pathways, including the MYB gene, a signaling pathway called Notch1, the tumor suppressor protein p53, and various epigenetic mechanisms.^[7]

Clinical trials for adenoid cystic carcinoma are conducted in phases. Phase I trials focus primarily on safety, determining what dose of a new drug can be given without causing severe side effects. Phase II trials evaluate whether the drug shows signs of effectiveness against the cancer while continuing to monitor safety. Phase III trials compare the new treatment to the current standard of care to determine if it offers better outcomes. Most of the innovative therapies for adenoid cystic carcinoma are currently being tested in Phase I or Phase II trials.^[7]

Clinical trials for this rare cancer are being conducted at specialized cancer centers in various locations, including the United States, Europe, and other regions. Because adenoid cystic carcinoma is so rare, each trial typically enrolls a limited number of patients. Eligibility requirements vary by study but generally include factors such as the stage of disease, previous treatments received, overall health status, and specific molecular characteristics of the tumor.^[7]

Most common treatment methods

• Surgery
  • Surgical removal of the tumor with clean margins is the primary treatment approach for adenoid cystic carcinoma
  • Endoscopic endonasal surgery through the nostril may be used for tumors in difficult-to-reach locations
  • Surgery may require removal of portions of nerves, lymph nodes, or nearby structures to ensure complete tumor removal
• Radiation therapy
  • High-energy radiation is typically given after surgery to destroy remaining cancer cells
  • Treatment usually consists of daily sessions five days per week for approximately six weeks
  • Fast neutron therapy, a specialized form of radiation, may be used for advanced or inoperable tumors
  • Radiation can be used as primary treatment when surgery is not possible, though it is less effective alone
• Targeted therapy
  • Lenvatinib, a VEGFR inhibitor, has shown 11-16% objective response rates in clinical trials
  • Axitinib, another VEGFR inhibitor, demonstrated 9-17% objective response rates
  • These drugs work by blocking formation of blood vessels that feed the tumor
  • PRMT5 inhibitors like PRT543 are being studied in preclinical research
  • MYB-targeted therapies including cancer vaccines are under investigation in clinical trials
• Chemotherapy
  • Single-agent chemotherapy with cisplatin, 5-FU, gemcitabine, paclitaxel, vinorelbine, epirubicin, or mitoxantrone shows response rates of approximately 5-10%
  • CAP regimen (cyclophosphamide, doxorubicin, and cisplatin) shows 18-31% objective response rates
  • Cisplatin-vinorelbine combination therapy has shown similar response rates to CAP
  • Chemotherapy is typically reserved for metastatic disease or when surgery and radiation are not options