Anterior Subfrontal Approach - Tumor Removal Treatment & Management

Updated: Sep 22, 2021
  • Author: Ricardo L Carrau, MD, FACS; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Medical Therapy

Generally, chemotherapy is recommended for palliation of unresectable tumors or as part of combination therapy with radiation therapy (as a radiosensitizer), or as induction therapy of rapidly growing tumors, such as sinonasal undifferentiated carcinomas (SNUC) or poorly differentiated esthesioneuroblastomas or neuroendocrine carcinomas.

Combination therapy, including surgery and radiation, commonly is used because of the extent of the tumors at presentation and the impossibility of resection with true wide margins. The issue of whether preoperative external irradiation is better than postoperative external irradiation remains controversial. Most surgeons prefer to refer the patient for radiation therapy postoperatively (3-6 wk after surgery) because the cure rate offered by either regimen seems similar but increased technical difficulty and potentially greater morbidity are associated with surgery of irradiated tissues.


Surgical Therapy

Surgical planning aims to facilitate a complete resection of the tumor and an adequate reconstruction with minimal morbidity and sequelae. A surgical approach is chosen based on surgeon or patient preferences and on tumor extent, vascularity, and relationship to neurovascular structures. The extirpative phase usually begins with exposure of the tumor. An adequate exposure facilitates a complete resection, preserving normal tissue and protecting important neurovascular structures such as the brain, carotid artery, and cranial nerves.

Finally, the reconstruction should restore the separation of the cranial cavity and the upper aerodigestive tract and provide an adequate cosmetic and functional rehabilitation.

A subfrontal approach facilitates exposure and resection of the cephalic boundary of the tumor with less brain retraction than a transcranial approach (bifrontal craniotomy). It also facilitates the reconstruction of the skull base and preserves the cosmetic profile of the craniofacial region, thus meeting most of the previously mentioned surgical criteria. Endoscopic approaches are associated with less brain manipulation and no brain retraction; and in very select patients, the endoscopic approach offers the possibility of preserving olfaction. Nonetheless, not all tumors are amenable to an endoscopic resection.


Preoperative Details

Perioperative prophylactic antibiotics for 48 hours, sequential compression stockings (ie, prevention of pulmonary embolism), and a secure airway are critical components of the perioperative management of patients requiring an anterior skull base resection for tumors. In general, patients undergoing an anterior skull base resection do not require a tracheotomy. The authors prefer an airway provided by an endotracheal tube wired to a premolar or molar tooth at the beginning of the surgery. The patient usually is extubated at the end of the surgery. However, a tracheotomy is recommended if the patient requires a microvascular free flap reconstruction. Ultimately, the decision to perform a tracheotomy should take into consideration the available personnel and facilities in each institution and the experience of the surgical team.


Intraoperative Details

An anterior subfrontal approach usually involves a combination of incisions used to expose the intracranial and extracranial components of the tumor. A bicoronal incision provides access to the upper face and cranium, and the resultant scar is hidden inside the hairline, as depicted in the 1st image below. A lateral rhinotomy, degloving gingivobuccal incisions, or endoscopy-guided intranasal incisions (endoscopic assisted) are used to complement the cranial exposure, as depicted in the last two images below. In selected patients, such as those presenting with tumors that invade the skin, the incisions can be performed directly at the margins of the tumor.

Markings for a bicoronal incision. Markings for a bicoronal incision.
Markings for a lateral rhinotomy incision. Markings for a lateral rhinotomy incision.
Intraoperative demonstration of a degloving approa Intraoperative demonstration of a degloving approach.

Intraoperative navigational devices may improve the precision of incisions, craniotomies, and facial osteotomies, limiting the need for wide exposure of important anatomic structures around the tumor. During intraoperative navigation, the surgeon uses a virtual rendering of the tumor and its surrounding anatomy to guide removal, eliminating the need for conspicuous and lengthy incisions or extensive dissection of normal tissues.

The bicoronal incision divides the scalp at the level of the vertex, following a true bicoronal plane extending from the top of one auricle to the top of the other, as depicted in the 1st image above. When the surgical exposure should extend below the level of the glabella, the surgeon may increase the arc of rotation of the bicoronal scalp flap by extending the incision inferiorly, following the preauricular crease down to a level corresponding to the tragal cartilage. Carry the incision through the subcutaneous tissue, galea, and superficial temporal fascia laterally and through the pericranium centrally (ie, between the temporalis muscles). Then, elevate the scalp in a subpericranial plane transecting the pericranium at its junction with the deep temporal fascia, around the superior border of the temporalis muscle (ie, temporal line).

Once the supraorbital rims have been exposed, the supraorbital neurovascular bundle is dissected from the supraorbital notches, as depicted in the image below. When a true supraorbital foramen is present, it may be opened inferiorly using a 3 to 6mm osteotome and mallet. This maneuver allows mobilization and inferior retraction of the supraorbital neurovascular bundles and dissection of the periorbita from the superior or medial orbital walls. Thus, the bicoronal approach exposes the superior cranium and frontal area, glabella, nasal bones, temporalis muscles and temporal fossae, and the superior two thirds of the orbits.

Exposure of the superior orbital rims and glabella Exposure of the superior orbital rims and glabella. The supraorbital neurovascular bundles have been freed from their canal and are being retracted to facilitate the exposure.

Plan a craniotomy according to the extent of the lesion as a bifrontal craniotomy, a transfrontal sinus craniotomy, or a craniotomy that follows the margins of the tumor (ie, when the frontal bone has been invaded) as depicted in, as depicted in the 1st two images below. The craniotomy cuts also can be extended laterally for tumors that extend into the orbit or infratemporal fossa or inferiorly to include the orbital rims (ie, subfrontal approach as a monobloc bone graft). Alternatively, the supraorbital block is removed separately from the craniotomy, as depicted in the last three images below. This facilitates inclusion of the posterior orbital roofs in the supraorbital block bone graft.

Craniotomy bone graft including the orbital rims a Craniotomy bone graft including the orbital rims and glabella as a monobloc.
Surgical specimen after en bloc resection of anter Surgical specimen after en bloc resection of anterior cranium, ethmoids, septum, and cribriform plate (posterior view).
Craniotomy and supraorbital block removed as separ Craniotomy and supraorbital block removed as separate bone grafts.
Neurosurgical view after bifrontal craniotomy. The Neurosurgical view after bifrontal craniotomy. The osteotomies to remove the supraorbital block have been performed, but the rims are still in place.
Neurosurgical view after the supraorbital rims and Neurosurgical view after the supraorbital rims and glabella have been removed, enhancing access to the cribriform plate area.

A lateral rhinotomy may be used to expose the medial maxilla, providing ample exposure for the resection of tumors that extend into the ethmoid sinuses and lateral nasal wall. During the opening of the lateral rhinotomy, the medial attachment of the nasal ala is preserved to prevent subsequent ala retraction and deformity. The subcutaneous tissue and muscles deep to the ala also are preserved. This preserves the alar soft tissue support and enhances the postoperative cosmesis, preventing contraction. The perialar extension of the lateral rhinotomy is not necessary for tumors that are located in the superior sinonasal tract, such as ethmoid or nasal vault tumors.

Gingivobuccal degloving incisions can be used in combination with the bicoronal incision to avoid facial incisions. However, in general, approaching the ethmoid sinuses through a degloving approach is somewhat cumbersome because the cheek flaps are tethered by the infraorbital neurovascular bundles. All the intranasal incisions and osteotomies can be performed using endoscopic guidance, avoiding any type of facial or intraoral incision. The most common osteotomies for the en bloc resection of these tumors correspond to those used for a medial maxillectomy, combined with resection of the cribriform plate and upper septum.

Endoscopic resection

In the late 1990s, we stopped using a lateral rhinotomy, as most tumors amenable to this approach are also amenable to an endoscopic or endoscopic-assisted approach. The cranial extent may be removed using a traditional subfrontal approach (endoscopic assisted) or a completely endoscopic endonasal approach.

During a pure endoscopic approach, the tumor is debulked and then removed following a sequential layered resection. The middle turbinates are removed and then bilateral maxillary windows, bilateral sphenoidotomies, and a Draf III frontal sinusotomy are completed. These steps expose the tumor origin completely and help to identify the position of the lamina papyracea and the skull base. Removal of the lamina papyracea allows the control of the ethmoidal arteries, enhancing hemostasis and tumor devascularization, and serves as an additional resection margin. The tumor origin is then removed in layers sequentially: first the tumor and mucoperiosteum, then the bone, and then the dura and intradural tumor. Adequacy of the resection of each layer is corroborated by frozen-section analysis.

Contraindications to a pure endoscopic approach include dural involvement that extends lateral to the level of the midorbital roof, intraorbital extension, involvement of the anterior table or lateral recess of the frontal sinus, and tumor extension into facial or orbital soft tissues. Relative contraindications include gross brain parenchyma involvement and tumor extension to the lateral wall of the maxillary sinus and infratemporal fossa.

Nicolai et al reported on patients with malignant tumors of the sinonasal tract and anterior skull base treated with a pure endoscopic approach (n=134) or cranio-endoscopic technique (n=50). The authors concluded that patients with (1) minimal dural involvement and (2) tumor not involving the orbit, nasolacrimal duct, anterior wall of the maxillary sinus, and without massive intracranial extension or dural extension lateral to the orbit are candidates for an endoscopic endonasal approach. They also reported a statistically significant difference in the 5-year disease-specific survival between patients treated with pure endoscopic surgery versus combined cranio-endoscopic surgery (91.4% vs 58.8%). [6]

Due to the rarity of sinonasal tumors, no prospective studies comparing the results of endoscopic surgery versus craniofacial resection are available. Eloy at al compared retrospectively the results of endoscopic approach (n=18) versus open anterior craniofacial resection (n=48). [7] Because the difference in overall survival between the 2 groups was not statistically significant, the authors concluded that early- and intermediate-stage anterior skull base malignancies are safely and successfully treated with an endoscopic approach using proper oncologic principles.

Hanna et al reported on 120 patients treated for sinonasal cancer with endoscopic surgery alone or in combination with frontal craniotomy. The authors conclude that in well-selected patients and with proper use of adjuvant therapy, endoscopic resection results in acceptable oncologic outcomes. [8]

Carrau et al published a series of 20 patients with malignant tumors of the sinonasal cavity involving the skull base. In this cohort, 19 patients were alive without evidence of disease at a median follow-up of 22 months (range, 11-46 mo). [9]

Reports on individual histologic tumors are focused on esthesioneuroblastomas. Folbe et al reported on a multicenter study of 23 patients with esthesioneuroblastoma. In this cohort, 26.3% of the patients were Kadish stage C. The authors conclude that Kadish stage C tumors can be effectively treated using pure endoscopic techniques followed by radiation without sacrificing local control. [10] Results from a meta-analysis on 361 patients with a diagnosis of esthesioneuroblastoma by Devaiah et al suggest that endoscopic surgery is a valid approach, with survival rates comparable to open surgery. [11]

When analyzing the literature, one should consider that all available studies are retrospective; thus, they reflect the surgeons’ biases regarding the selection of the surgical approach. In general, endoscopic series comprise patients with less extensive tumors; thus, the groups are not comparable. Nonetheless, one can conclude that endoscopic and endoscopic-assisted surgeries are as effective in treating well-selected tumors of the anterior skull base as a traditional craniofacial approach.


A pericranial flap is the most common technique to restore the separation of the cranial cavity from the upper aerodigestive tract following a subfrontal approach (as depicted in the images below). Elevate the pericranium as a vascularized flap based on the supraorbital vessels. Ensure that the flap created can adequately cover defects that include the cribriform plate, fovea ethmoidalis, and planum sphenoidale (and occasionally the medial orbit).

Defect after resection of the cribriform plate. Defect after resection of the cribriform plate.
Elevation of a pericranial flap. Elevation of a pericranial flap.

The authors prefer to elevate the pericranial flap after completion of the extirpative phase of the surgery to avoid desiccation of the flap or accidental tearing or avulsion during resection of the tumor. Following repair of any dural defect, place the pericranial flap beneath the brain and supraorbital and craniotomy bone grafts. Stabilize the craniotomy and orbital bone grafts with titanium alloy adaptation plates, as depicted in the images below. Titanium alloy plates are preferred to wires or sutures because of their superior stability. However, cost and availability may dictate the use of wires and/or sutures.

Fixation of the cranial bone grafts with titanium Fixation of the cranial bone grafts with titanium adaptation plates. Titanium mesh is used to cover bone gaps caused by the loss of bone associated with the craniotomy.
Reconstruction of the glabellar area using titaniu Reconstruction of the glabellar area using titanium mesh.

Reconstruction after endoscopic resection

Patients who undergo an endoscopic resection are most often reconstructed with the Hadad-Bassagaisteguy flap (pedicled nasoseptal flap). The entire mucoperiosteum of one side of the nasal septum is harvested pedicled on the posterior septal arteries. Two parallel incisions are made, one 1-2 cm below the olfactory sulcus and the other at the junction of the floor of the nose and the nasal septum. These incisions can be modified and performed lower and more lateral, respectively, in deference to oncologic margins. The inferior incision is extended to follow the free edge of the posterior septum and to follow the posterior choanae toward the lateral nasal wall. The superior incision crosses the rostrum of the sphenoid sinus at the level of its natural ostium. [12]

Kassam et al reported on 75 patients who underwent endoscopic extended approaches who were reconstructed with the pedicle nasoseptal flap. The authors report a decreased rate of cerebrospinal fluid (CSF) leak from 33% to 4% with the use of the pedicle nasoseptal flap. [13] Zanation et al prospectively studied the use of the nasoseptal flap for reconstruction of skull base defects associated with high-flow leaks. The authors report a 94% success rate. [14]

Other pedicle flaps have been described as alternatives for skull base reconstruction when the pedicled nasoseptal flap is not available. These flaps include transfrontal pericranial flap, in which a pericranial flap may be harvested (endoscopic assistance or via bicoronal incision) and transposed to the defect through an osteotomy at the nasion. Others include the transpterygoid temporoparietal fascia flap, [15, 16] inferior turbinate flap, [17] middle turbinate flap, [18] and palatal flap. [19, 20] A systematic review of endoscopic repair of large skull base defects revealed that vascularized flaps had a lower CSF leak rate than free grafts (6.6 vs 15.6%, respectively), and, therefore, the wide armamentarium of pedicled flaps should be used for endoscopic repair of skull base defects. [21]


Postoperative Details

Transfer the patient to a neurosurgical intensive care unit (NICU) for continuous cardiac, respiratory, and neurologic monitoring. Stay at the NICU varies but usually extends for 48 hours.

Patients undergo a CT scan with contrast within 24 hours of surgery to detect intracranial complications, such as hematoma, tension pneumocephalus, or brain contusion. Other monitoring is discussed in Complications.



For oncologic follow-up care, the authors advise the patient to return to the outpatient office for clinical examination every 6-8 weeks for the first year, every 8-12 weeks for the second year, every 12-18 weeks for the third year, every 6 months for the fourth and fifth years, and yearly thereafter. Patients may also require debridement of intra nasal crusting that forms until the nasal epithelium regenerates. Imaging of the skull base and brain is an integral part of follow-up care for areas not amenable to clinical examination. The authors prefer to use MRI 3, 6, 12, and 18 months after the surgery and then yearly. Yearly chest radiographs also are advised. This follow-up regimen is adjusted to the nature and aggressiveness of the tumor, use of adjunctive radiation and/or chemotherapy, and patient characteristics such as compliance, reliability, and distance of residence from the hospital/office.




Scalp necrosis

Necrosis of the scalp flap is rare. Patients who have been irradiated preoperatively and who also undergo a galeal flap or galeopericranial flap procedure are at risk for this complication because elevation of the flap superficial to the galea compromises the blood supply to the remaining scalp. Prolonged use of hemostatic clamps at the scalp (eg, Raney clamps) also can result in necrosis. Debridement and reconstruction using posteriorly based scalp flaps often are required to close the resultant defect.

Wound infection

Infection of the bone and/or soft tissue is most commonly the result of faulty technique (with inadequate separation of the cranial or orbital bone grafts from the sinonasal tract) or a noncompliant patient. Necrosis of the scalp exposing the bone grafts, although rare, also can lead to a wound infection. Correction of the primary problem (eg, communication with the sinonasal tract, loss of flap), debridement (usually requiring the removal of the bone flaps), and prolonged antibiotics for osteomyelitis (45 d, guided by culture and sensitivities) are the treatments of choice.

Postoperative bleeding

Postoperative bleeding is usually self-limited or easy to control with the use of topical vasoconstrictors and/or packing with hemostatic materials or self-expanding sponges. Significant postoperative bleeding most commonly arises from a branch of the internal maxillary or anterior ethmoidal arteries. If easily identifiable, the vessel may be clipped under endoscopic assistance. Angiography with embolization is reserved for patients in whom the bleeding site is not readily apparent, such as patients who underwent a reconstruction using a microvascular free flap.

Postoperative bleeding from branches of the internal carotid artery (eg, ethmoidal, ophthalmic) is not usually amenable to embolization and may lead to intracranial hematomas, requiring surgical exploration.


Tension pneumocephalus

Intracranial air under pressure acts as a space-occupying lesion that compresses the brain parenchyma, causing neurologic deficits, such as lethargy, disorientation, slow mentation, or hemiparesis. A CT scan without contrast can help confirm the diagnosis, as depicted in the image below. Initial treatment consists of aspiration of the air using a needle placed through a burr hole or osteotomy gap. In rapidly deteriorating or unstable patients, this measure can be lifesaving. Recurrent tension pneumocephalus is rare and is usually associated with inadequate cranionasal separation (ie, loss of the reconstructive flap) or a noncompliant patient who repeatedly blows the nose. Recurrent pneumocephalus may require bypassing the airway (ie, tracheotomy, intubation) and/or surgical exploration to close any communication between the cranial cavity and the sinonasal tract.

CT scan axial view demonstrating a tension pneumoc CT scan axial view demonstrating a tension pneumocephalus. In the author's experience, this is the most common major complication after an anterior craniofacial resection.

Cerebrospinal fluid leak

Postoperative cerebrospinal fluid (CSF) leaks after traditional techniques are initially managed conservatively with bed rest, stool softeners, and a lumbar drain (50 mL q6-8h). Persistence of the leak beyond 1 week indicates need for surgical repair. However, surgical exploration may be indicated as an initial therapy if loss of the reconstructive flap or dehiscence of the dural repair is suspected.

Patients with postoperative CSF leaks after endoscopic approaches are taken back to the operating room immediately. Usually, the leak is limited to a small area in which the graft failed to take or was displaced by the pulsation of the brain.


Meningitis, like pneumocephalus, CSF leak, and osteomyelitis, is usually the result of inadequate separation of the cranial cavity from the sinonasal tract. However, meningitis can occur in the absence of a CSF leak, and its presentation may be atypical due to use of perioperative prophylactic antibiotics. A CT scan followed by a lumbar puncture can help confirm the diagnosis. The treatment of choice is intravenous antibiotic therapy with adequate CSF penetration. Persistent communication between the cranial cavity and the upper aerodigestive tract should be closed as soon as the patient is stable enough to tolerate the surgery.

Management of intracranial/cerebral abscesses is similar to treatment of meningitis. However, abscesses usually require drainage. Epidural abscesses usually require the removal of contaminated free bone grafts. This creates a deformity that can be corrected in a secondary surgery.

Cerebral edema/contusion

This complication usually occurs as a result of overenthusiastic brain retraction, as depicted in the image below. Systemic corticosteroids, correction of hemodynamic problems, and electrolyte/fluid balance are essential to avoid further brain injury brought by the parenchymal swelling and subsequent increased intracranial pressure. Consider medical prophylaxis for seizures in the presence of a contusion of the brain parenchyma or if brain had to be removed as part of the oncologic surgery.



A dacryocystorhinostomy (DCR) diminishes the incidence of epiphora after resection of the medial maxilla. DCR is performed by marsupializing the lacrimal sac upon its transection from the lacrimal duct. Occasionally, a DCR closes, requiring lacrimal stenting (eg, Crawford tubes) or even a revision DCR. Another cause of epiphora is failure to restore the medial canthus, causing laxity and failure of the lacrimal pump mechanism. Similarly, a lax lower eyelid caused by paralysis of the facial nerve or failure to fix the lateral canthus may lead to lagophthalmos and epiphora. Tarsal strip surgery and lateral canthopexy are indicated to resolve this problem.

Extraocular muscle limitation

Diplopia caused by dissection of the trochlea, postoperative edema, or removal of the orbital walls occurs in most patients but is self-limited, lasting fewer than 4 weeks. However, physicians should consider other causes for diplopia.

Reconstructive grafts over the orbital walls may entrap the medial, lateral, or inferior rectus muscles, resulting in restriction of the range of motion and leading to diplopia. Intraorbital dissection, such as that required when the periorbita is resected, or surgery of the cavernous sinus may injure the motor innervation of these muscles. A forced duction test helps to differentiate these problems.


Enophthalmos is the result of expansion of the volume of the orbital cavity due to resection of the orbital walls and is more pronounced if the periorbita is injured or resected. Preventing this complication by reconstructing the orbital walls with autogenous bone or titanium mesh (ie, rigid reconstruction), which is depicted in the image below, is best.

CT scan axial view of a frontal lobe contusion aft CT scan axial view of a frontal lobe contusion after an anterior craniofacial resection. A subfrontal approach was not used, resulting in the need for brain retraction with the subsequent trauma.


Unexpected blindness after an anterior craniofacial resection is the result of injury to the optic nerve or its blood supply. High-dose steroids and immediate optic nerve decompression are indicated.

Endocrine/electrolyte abnormalities

Endocrine abnormalities

Hyponatremia (serum sodium < 130 mg/dL) can be produced by excessive fluid replacement or by the syndrome of inappropriate antidiuretic hormone (SIADH), which usually is caused by cerebral edema. SIADH is usually self-limited and may be treated by fluid restriction. Neurologic symptoms, such as disorientation, irritability, changes in consciousness or mentation, and seizures, require administration of hypertonic (3%) sodium chloride solution.

Conversely, ischemia or traction injury to the hypothalamus may lead to diabetes insipidus (DI), which is caused by insufficient production of the antidiuretic hormone. DI is manifested by the inability to concentrate urine, leading to the voiding of large volumes, hypernatremia, and hypovolemia. Serum sodium greater than 145 mg/dL and a urine specific gravity greater than 1.020 mg/dL confirm the diagnosis. Aggressive fluid replacement and aqueous vasopressin (2.5 U q4h) is the initial treatment.

Closely monitor patients with diabetes mellitus, especially if corticosteroids are being administered. Regular insulin, administered following a sliding scale, is commonly required to control the glycemia.

Electrolyte deficits

Other electrolyte disorders, such as hypocalcemia, hypomagnesemia, and hypophosphatemia, may be encountered in patients who require extensive skull base surgery. Replacement of these electrolytes should be immediate, using calcium gluconate 10% (10 mL at < 1 mL/min), phosphate solution (10-15 mmol of sodium phosphate in 250 mL of 5% dextrose solution over 6 h), and magnesium sulphate (2-4 g in 100 mL of isotonic sodium chloride solution over 30 min). Because of the length of some cranial base surgeries, these electrolyte deficiencies may develop intraoperatively or during the immediate postoperative period. This is especially true in patients requiring transfusion of more than 5 units of PRBC.


Outcome and Prognosis

The prognosis of lesions that require a subfrontal approach for their resection mostly depends on histologic diagnosis and the completeness of the resection. On one side of the spectrum, high-grade sarcomas and melanomas have a dismal prognosis because of their propensity for early metastasis (ie, < 10% of patients alive and without disease at 5 y). Conversely, adenocarcinomas have an excellent prognosis (ie, >75% of patients alive and without evidence of disease at 5 y). Patients with SCCA have a 5-year survival rate of 60%. Adenoid cystic carcinoma of the skull base is somewhat unpredictable but behaves more aggressively than adenoid cystic carcinomas in other parts of the head and neck (eg, salivary gland).


Future and Controversies

Use of endoscopic techniques to complement or replace traditional approaches is rapidly expanding. Intraoperative navigational devices (computer-assisted surgery) and high-definition monitors and cameras, customized instruments, and new endovascular neurosurgery techniques that allow intraoperative control of the intracranial vasculature will contribute to the advancement of these techniques. Recent advances include combining expanded endonasal approaches with a transoral robotic assisted approach for extensive skull base tumors. [22] Furthermore progress in imaging has lead to the development of virtual surgical planning as well as augmented reality, where a three-dimensional image of critical structures is superimposed onto the endoscopic surgical view. [23]

Adjunctive techniques, such as brachytherapy, radiosurgery, intra-arterial chemotherapy, and chemotherapy combined with radiation, may have a role in treatment of these lesions. However, the role of these treatments remains undefined. Reports are mainly anecdotal, and their use should be limited to controlled protocols, palliative cases, or poor surgical candidates for whom conventional therapy has failed.