Malignant tumors of the anterior skull base occur in a delicate area but often need aggressive treatment. Determining the best course of therapy for patients with these tumors takes a multidisciplinary effort.
“These patients require comprehensive, coordinated treatment,” said Franco DeMonte, M.D., a professor in the Department of Neurosurgery at The University of Texas MD Anderson Cancer Center. “There are so many nuances in pathology and imaging and so many complexities in deciding which surgical approach to use, how to target the radiation therapy, which form of radiation to use, and whether to give chemotherapy before or after surgery—no single person is a repository of all that information.”
“At MD Anderson, we have everybody involved up front,” said Renata Ferrarotto, M.D., an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology. “These patients are always seen by surgeons, medical oncologists, and radiation oncologists; and we discuss their cases as a team.”
Malignant tumors of the anterior skull base are rare but include a wide range of cancers, including those originating in or at the skull base (e.g., chordoma and chondrosarcoma) and those originating elsewhere and invading the skull base (e.g., adenoid cystic carcinoma, esthesioneuroblastoma, and nasopharyngeal carcinoma). Because this variation lends itself to a high incidence of incorrect or inconclusive diagnoses, experienced pathologists are essential to correctly identify the disease.
In most patients, a tumor sample is obtained via endoscopy; image-guided fine-needle aspiration also can be used to obtain a biopsy specimen. Additional diagnostic information, most importantly the extent of the tumor, is obtained by computed tomography and/or magnetic resonance imaging. The histologic type and the extent of the tumor help determine the types of therapies used.
The vast majority of malignant skull base tumors are treated with definitive surgery.
“The first question is whether the tumor is resectable with acceptable morbidity,” Dr. DeMonte said. “Determining this involves a neurosurgeon and a head and neck surgeon primarily. Input from a plastic surgeon is crucial if large amounts of tissue are to be removed.” If the tumor is considered to be resectable, Dr. DeMonte said, the next question is whether neoadjuvant chemotherapy should be given. If the tumor is small, is compartmentalized, and appears to be resectable, the patient may undergo surgery first. But if the tumor is extensive—invading the orbit, for example—neoadjuvant chemotherapy may be given with the goal of shrinking the tumor to make it more amenable to resection.
Whether neoadjuvant chemotherapy is given also depends on the tumor pathology. “Some of these tumors—like high-grade neuroendocrine carcinomas, sinonasal undifferentiated carcinomas, or squamous cell carcinomas—are very sensitive to chemotherapy,” Dr. Ferrarotto said. “But others, like adenoid cystic carcinomas and chondrosarcomas, are resistant; so we rarely use chemotherapy for those types of tumors because the chance of response is very small.”
When neoadjuvant chemotherapy is used, the tumor’s response can determine the treatment course. Patients with a complete response do not need to undergo surgery; they may receive radiation therapy instead. Patients with a partial response usually undergo resection of the residual tumor followed by radiation therapy. Patients with no response, depending on the situation, may need surgery or definitive chemoradiation.
Five goals of surgery
According to Ehab Hanna, M.D., a professor in the Department of Head and Neck Surgery, surgery for a malignant tumor of the anterior skull base has five main goals. The first goal, complete oncologic resection of the tumor, is by far the most important because it has a direct correlation with survival. The second goal is to protect critical structures.
“This area is replete with what we call high-stakes real estate,” Dr. Hanna said. “There’s the optic nerve, the carotid artery, the spinal cord, and cranial nerves that control speaking, swallowing, and breathing—essentially a lot of nerves and vessels that have very critical functions. Preserving these neurovascular structures is important because doing so directly translates into functional preservation and better quality of life.”
The third goal of surgery is to minimize manipulation of the brain. Excessive retraction of brain tissue can cause brain swelling, which in turn delays recovery and affects some of the subtleties of emotion, memory, and personality.
The fourth goal is meticulous reconstruction of the anterior skull base and dura, which serve as a wall between the intra- and extracranial components of the head. “The dura and skull base need to be watertight,” Dr. Hanna said. “Spinal fluid leakage from the intracranial component can allow bacteria to invade and cause meningitis, and that complicates the postoperative course significantly.”
The final goal is optimal aesthetic outcome, for which the endoscopic approach is superior when indicated (see “Choosing an Open or Endoscopic Approach,” p. 3). “But when an open approach is needed, we mobilize all of our teams—the head and neck team, the neurosurgical team, the maxillofacial dental team, the plastic and reconstructive team—we want these patients to be able to walk down the street without anyone knowing from looking at them that they’ve had a skull base resection,” Dr. Hanna said.
The length of surgery tends to vary according to the number of services involved. Surgeries involving only head and neck surgery or neurosurgery can last 2 or 3 hours; those involving both services can last 5 or 6. When reconstructive surgery is added, the surgery can last a dozen hours or more. Whether the tumor involves the intracranial, the extracranial, or both compartments determines which services are involved. Intracranial tumors are removed by a neurosurgeon, whereas extracranial tumors are removed by a head and neck surgeon. The two surgical teams work together to remove tumors transgressing from the intracranial to the extracranial compartment or vice versa.
“The sequence in which the two teams work to remove the transgressing tumor isn’t important, but the concept is the same. By compartment, you need a bidirectional view; you need to look from the bottom, and you need to look from the top,” Dr. Hanna said. “It’s only when you have both sides of the exposure that you can safely cut out the tumor without injuring the critical structures nearby.”
Radiation therapy delivery
Like surgery, radiation therapy is used for local disease control in patients with malignant tumors of the anterior skull base. Radiation can be given alone to treat unresectable tumors that are highly unlikely to respond to neoadjuvant chemotherapy, or it can be given with or without concurrent chemotherapy to treat unresectable tumors or as an adjuvant to surgery for highly aggressive tumors.
Several approaches—including conventional external-beam, stereotactic, and intensity-modulated radiation therapy—can be used in the skull base area. Each approach is employed with the intent of eradicating as much of the cancer as possible while avoiding brain necrosis, which can give rise to cognitive dysfunction, and sparing structures essential to hearing, vision, smell, and taste.
“When we’re considering which radiation therapy approach we want to use in one of these patients, we’re looking at the tumor histology, we’re looking at the surrounding normal tissues, and we’re looking at how much of a radiation dose is required to eliminate the cancer,” said Steven Frank, M.D., an associate professor in the Department of Radiation Oncology. “And then we’re trying to piece that information together to determine the best tool that will allow us to achieve a high level of cure with minimal side effects.”
Both photon and proton radiation therapy can be used to treat these tumors. Whether one or the other is selected usually depends on the effective radiation dose that must be safely delivered to the tumor. In general, the higher the radiation dose needed, the greater the risk to surrounding healthy tissue and the more precise the radiation delivery must be. Unlike photons, which continue to pass through the body after they have hit the targeted tumor, protons can be made to stop within the targeted tumor, thereby reducing damage to surrounding healthy tissues and enabling higher doses of radiation to the tumor.
“If we need to give a high radiation dose to achieve disease cure without compromising the surrounding tissue, we would consider proton therapy,” Dr. Frank said. “Normal brain tissue might not tolerate a high dose given with photon therapy, which could cause brain necrosis or other problems.”
Indeed, the role of proton therapy in the treatment of malignant skull base tumors is increasing, due in large part to the work of Dr. Frank and his colleagues at MD Anderson’s Proton Therapy Center. One exciting development in this vein is the use of intensity-modulated proton therapy, a form of scanning beam radiation therapy that can be used to precisely deliver large doses of radiation to tumors embedded among critical structures.
“Just as we’ve advanced the delivery of photon therapy in a number of ways, now we’re advancing the delivery of proton therapy, defining its role not only in the skull base and other areas of the head and neck but in other areas of the body as well,” Dr. Frank said. “The rapid advancement of this technology is occurring before our very eyes.”
Chemotherapy and targeted therapy
In the treatment of patients with malignant tumors of the anterior skull base, the role of cytotoxic chemotherapy is largely limited to the neoadjuvant and concurrent treatment settings. “Sometimes we’ll give chemotherapy up front to shrink the tumor, and after surgery, we might give chemotherapy concurrently with radiation,” Dr. Ferrarotto said. “For unresectable tumors, definitive concurrent chemoradiation is a frequently used approach.”
Given the rarity of malignant anterior skull base tumors, Dr. Ferrarotto said, it’s largely infeasible to do clinical trials to test the efficacy of new agents or hone the delivery of existing agents, and this has hindered the expansion of medical therapy for these tumors. However, some promising preclinical data suggest that targeted therapies may soon have a role. For example, Dr. Ferrarotto and her colleagues found that 13% of adenoid cystic carcinomas, which arise in the secretory glands but can involve the skull base, have Notch-1 activating mutations. “Typical adenoid cystic carcinoma tends to be a very indolent disease, but the Notch-1 mutants are different—patients usually present with advanced-stage disease, they have a propensity to develop liver and bone metastasis, and they have a much worse prognosis,” Dr. Ferrarotto said. “It might be that this group would benefit from targeted systemic therapy, particularly Notch-1 inhibitors.”
Dr. Ferrarotto’s group is now looking into whether other skull base tumors have Notch-1 mutations. Other therapeutic targets are also being investigated.
For example, Dr. Ferrarotto said, poly(ADP-ribose) polymerase (PARP) inhibitors are being studied in neuroendocrine tumors that occur in the skull base. She said these preclinical studies are based on research by Lauren Byers, M.D., an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology, showing that PARP can be a target in small cell lung cancer, which is a neuroendocrine carcinoma. Immune checkpoint inhibitors, which have shown benefit against a variety of malignancies, might also benefit a subset of patients with skull base carcinomas.
New tools, new horizons
In addition to identifying novel treatment approaches, MD Anderson researchers are developing a range of tools to begin probing the biology of malignant skull base tumors.
“We are fighting a biology that frankly we do not entirely understand,” Dr. DeMonte said. “Improvements in our ability to cure these tumors will only be realized when we can unravel the biology of specific tumor cells.”
Chief among these developments is a sinonasal undifferentiated carcinoma cell line—the first line of skull base tumor cells to be isolated, grown, cultured, and maintained.
“The cell line is important because we can start screening drugs and see which ones impair the cancer cells’ viability. We can also inject the cells in mice and learn about the biology of the tumor,” Dr. Ferrarotto said. “And if we can generate solid preclinical data and identify promising therapeutic agents, we will have more leverage to propose clinical trials for this rare disease subgroup and have a greater potential to improve patients’ outcomes.”
Researchers have also developed a mouse model for skull base tumors, which can be used to study various aspects of these tumors in vivo. In addition, comprehensive gene analyses have characterized the genomic profiles of some sinus cancers. Additional analyses may unlock the codes of these tumors’ aggressive behavior and identify targets for therapy.
“It’s a pretty exciting time,” Dr. Hanna said. “We have a cell line, we have an animal model, and we have genomic data. We’re about to enter a whole other dimension of how to get a handle on these tumors.”
For more information, contact Dr. Franco DeMonte at 713-563-8706, Dr. Renata Ferrarotto at 713-745-6774, Dr. Steven Frank at 713-563-8489, or Dr. Ehab Hanna at 713-745-1815.
OncoLog, November-December 2015, Volume 60, Issue 11-12
Choosing an Open or Endoscopic Approach
Owing to recent advances in instrumentation and surgical field visualization, endoscopic surgery is becoming an increasingly viable alternative to traditional open craniofacial surgery in patients with malignant tumors of the anterior skull base. Endoscopic surgery has, for example, almost completely eliminated the need for facial incisions for the removal of malignant tumors of the clivus, and its value in the treatment of sinonasal malignancies has been shown in research done at MD Anderson. Endoscopic surgery is not appropriate for every patient, however.
“It might be considered in vogue to do the minimal access surgery, but if it doesn’t take the tumor out completely, then it’s the wrong thing—it’s potentially lethal, in fact,” Dr. Hanna said.
Tumors that have significant brain or orbit involvement and those that have invaded structures whose resection is necessary to achieve negative margins—e.g., the facial skeleton, skin, and/or soft tissues of the face—are not amenable to endoscopic surgery and must be resected using an open approach.
Tumors that extend beyond the inner third of the orbit and those immediately behind the nasal bone, which cannot be adequately visualized or manipulated endoscopically, must also be resected via an open approach.
“One would think that having a slender tube slid up your nose is better than having an incision, but not necessarily,” Dr. DeMonte said. “The risk profiles of these approaches are different. For example, endoscopic surgery carries a significantly increased risk of spinal fluid leakage and infection after surgery compared with the open cranial operation.”
According to Drs. DeMonte and Hanna, the key to the successful surgical treatment of patients with malignant tumors of the anterior skull base is knowing both when and how to pursue either approach.
“The real strength of our program is that we are not wedded to one surgical approach or technique,” Dr. Hanna said. “We can pick and choose the right approach for the right patient for the specific tumor they have.”