Malignant pheochromocytoma and sympathetic paraganglioma affect only about 100–200 people per year in the United States, but those who do develop these neuroendocrine cancers have only a 60% 5-year overall survival rate and limited options for effective treatment. Researchers at The University of Texas MD Anderson Cancer Center are conducting clinical trials of new treatments and studying the survival benefits of surgery to improve outcomes for patients with malignant pheochromocytoma and sympathetic paraganglioma.
Historically, response rates to standard treatment with chemotherapy or radiopharmaceuticals have been around 30% in patients with these cancers. Surgery is another treatment for these patients; but it is not always feasible, and its impact on survival was unclear until recently.
Unfortunately, the small number of patients affected by these cancers has hindered progress. “We are the only institution that currently has multiple clinical trials devoted exclusively to patients with malignant pheochromocytoma and paraganglioma,” said Camilo Jimenez, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders. Dr. Jimenez and his colleagues hope their efforts will improve the outlook for patients with these rare neuroendocrine tumors.
Ultratrace iobenguane I 131
Introduced into clinical practice 30 years ago, the targeted radiopharmaceutical agent iobenguane I 131 enters cancer cells via the cell membrane norepinephrine transporter and has been used to both visualize and treat pheochromocytoma and paraganglioma. As an imaging aid, iobenguane I 131 shows where the cancer is and whether the cancer is taking up the agent. Patients whose tumors are iobenguane avid on imaging may be given a higher, therapeutic dose to kill the cancer cells.
However, the original version of iobenguane I 131 is limited by the absence of radioactivity in most of its molecules. “Conventional iobenguane has an abundance of carrier molecules that are not radioactive but are bioactive, meaning they will cause side effects,” said Aaron Jessop, M.D., until recently an assistant professor in the Department of Nuclear Medicine at MD Anderson and now at another institution. “We want to make sure we’re treating the patient as aggressively as we can but without causing undue collateral damage.”
Ultratrace iobenguane I 131 overcomes the inefficiency of the original agent through a production process that minimizes the number of molecules without radioactivity. “Compared with conventional iobenguane, this version is highly specific,” Dr. Jimenez said. “Therefore, the delivery of radioactivity to the tumor per dose is much higher.”
Dr. Jimenez is the principal investigator of a phase II trial of Ultratrace in patients with iobenguane-avid metastatic or recurrent pheochromocytoma or paraganglioma. So far, Ultratrace has been well tolerated by patients and has demonstrated significant activity, as measured by tumor shrinkage and reduced need for antihypertensive drugs.
These promising preliminary results led to the opening of an expanded access trial (No. 2009-0210) of Ultratrace in patients with malignant relapsed or refractory pheochromocytoma or paraganglioma. This trial is ongoing at MD Anderson and other institutions and will provide access to the radiopharmaceutical prior to its anticipated approval by the U.S. Food and Drug Administration (FDA).
Another phase II trial at MD Anderson (No. 2014-0081) for patients with malignant pheochromocytoma and paraganglioma is testing cabozantinib, a tyrosine kinase inhibitor that has been approved by the FDA for the treatment of medullary thyroid cancer and kidney cancer. “This drug blocks the cMET receptor, which is important for the spread, growth, and survival of tumors and is upregulated when the tumors become resistant to other medications,” said Dr. Jimenez, the trial’s principal investigator. “So this is a drug that could be used to prevent resistance.”
The trial is enrolling patients with unresectable metastatic pheochromocytoma or paraganglioma. Because cabozantinib also may benefit bone health, the trial includes an exploratory cohort of patients whose metastases are solely or predominantly in the bone—a group excluded from many trials.
So far, about 90% of patients treated in the trial have experienced a decrease in tumor size. Symptomatic improvement has been observed as well. Dr. Jimenez said, “It’s a drug that we believe can make a difference for many of these patients.”
A third approach being studied for this disease is immunotherapy. A phase II trial (No. 2015-0948) of the PD-1 (programmed cell death protein 1) inhibitor pembrolizumab is currently open to patients with any of several rare, advanced tumors, including malignant pheochromocytoma and paraganglioma.
“This study will add crucial information about the efficacy of pembrolizumab in patients with malignant pheochromocytoma and paraganglioma,” said Mouhammed Habra, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders. “The results could establish the foundations for future immunotherapy-based trials in these diseases.”
Expanding the use of surgery
Although novel drug treatments are not yet widely available, surgery may be used for treating malignant pheochromocytoma and paraganglioma in appropriately selected patients. As with other cancers, the use of surgery for these tumors depends on the extent of the disease. For patients whose disease is localized, Dr. Habra said, “Surgery is often our best hope for long-term survival.”
However, “If a patient has distant disease on initial evaluation or if the tumor is locally very invasive or aggressive, surgical resection may not be a viable option,” said Paul Graham, M.D., an assistant professor in the Department of Surgical Oncology’s Section of Surgical Endocrinology. In these cases where the disease burden precludes surgery, medical treatment may be given first in hopes of stabilizing or shrinking the disease for future surgical consideration. In patients with metastatic disease, resection of the primary tumor may be used to palliate symptoms of catecholamine overproduction.
To determine the effect of surgery on survival in patients with metastatic pheochromocytoma and paraganglioma, Drs. Habra and Jimenez and their colleagues compared overall survival in patients who underwent primary tumor resection and those who did not. In the retrospective analysis, resection of the primary tumor was associated with longer overall survival (see graph, above) and, in patients with hormonally active tumors, improvement of symptoms of catecholamine excess. These findings indicate that surgery may be beneficial in an expanded subset of patients. However, prospective studies will be needed to determine the full benefit of primary tumor resection for patients with metastatic disease.
As a result of the ongoing research and mounting expertise on malignant pheochromocytoma and paraganglioma at MD Anderson and partner institutions, new paths of care for patients with these little-seen diseases are opening up. “For the first time, we have options that seem to be less toxic than traditional chemotherapy,” Dr. Jimenez said. “Having these options, I suspect, will help extend the survival of these patients while preserving an acceptable quality of life.”
The current trials also will help determine which patients should receive which of these new treatments. “If you can see certain predictors of who is going to respond to a treatment, then you can include or exclude certain patients from studies of that drug or that class of drugs,” Dr. Habra said. “And we’ll take the patients who do not respond and look for more effective treatment options for them.”
Roman-Gonzalez A, Jimenez C. Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials. Curr Opin Endocrinol Diabetes Obes. 2017;24: 174–183.
Roman-Gonzalez A, Zhou S, Ayala Ramirez M, et al. Impact of surgical resection of the primary tumor on overall survival in patients with metastatic pheochromocytoma or sympathetic paraganglioma. Ann Surg. 2017. doi: 10.1097/SLA.0000000000002195. [Epub ahead of print]
For more information, contact Dr. Paul Graham at 936-446-5246 or firstname.lastname@example.org, Dr. Mouhammed Habra at 713-792-2841 or email@example.com, or Dr. Camilo Jimenez at 713-792-2841 or firstname.lastname@example.org. To learn more about the ongoing clinical trials for patients with pheochromocytoma or paraganglioma, visit www.clinicaltrials.org and select study No. 2009-0210, 2014-0081, or 2015-0948.
OncoLog, August 2017, Volume 62, Issue 8
An important consideration in the management of malignant or benign pheochromocytoma and sympathetic paraganglioma is their genetic basis. “Genetic counseling and consideration of genetic testing are indicated for all patients with pheochromocytoma or paraganglioma regardless of their family history, personal history, age, or disease characteristics because 30%–40% of these patients have an underlying hereditary predisposition,” said Samuel Hyde, M.M.Sc., a genetic counselor in the Department of Clinical Cancer Genetics.
If a patient with pheochromocytoma or paraganglioma tests positive for a hereditary condition associated with his or her disease, the patient’s long-term surveillance becomes more intensive because the patient could be at risk for other tumors. “Patients with these hereditary conditions need to come back and see us more often,” Mr. Hyde said. “They need to be screened for tumors in other parts of their body and have other blood tests.” The presence of such a hereditary condition also means that family members should be tested for the same mutations.
The number of patients with pheochromocytoma, paraganglioma, and other neuroendocrine tumors seen at MD Anderson has enabled Mr. Hyde to build expertise in genetic testing for these patients while keeping up with advances in the field. “There are often subtleties to family histories or personal histories that can make us more suspicious of one condition over another,” he said.
Hereditary conditions associated with pheochromocytoma and paraganglioma include mutations in SDHB, SDHC, SDHD, and SDHAF2, each of which predisposes patients to a distinct disease phenotype. These and other mutations associated with pheochromocytoma and paraganglioma are becoming better understood, and the tools for detecting them are becoming capable of evaluating more genes at once.
Patients seeking genetic counseling or testing at MD Anderson can fill out a self-referral form at https://my.mdanderson.org/RequestAppointment or call the Clinical Cancer Genetics Program at 855-711-9908.