Cancer of the temporal bone

History of the treatment of temporal bone malignancies

Literature credits Wilde and his associates with first describing this disease around the year 1775( Peele and Hauser 1941)
However it was approximately 200 hundred years later in the twentieth century that reports appeared in literature recording attempts at treatment. Malignant disease of the temporal bone was first treated by piece by piece surgical removal with the inevitable poor results. With the emergence of radiotherapy as a treatment modality this expectedly came to be thought of as the principal treatment of choice. Surgical treatment of this disease was associated with dismal outcomes and since radiotherapy was considered noninvasive, radiation soon became the popular treatment modality of choice for the treatment of this condition. Lewis and Page using a combination of radiation followed by surgery (mastoidectomy) reported an 8% survival rate in their patients. Campbell and colleagues were the first to describe total removal of the temporal bone. Later Parsons and Lewis reported an en bloc subtotal resection of the temporal bone in 1954.
Subsequently Conley and Novack in 1960 describe a surgery that entailed removal of the external auditory canal en bloc with preservation of the facial nerve. This surgery was done for a malignancy that was restricted to the external auditory canal. This was considered to be a major refinement in the successful treatment of cancer of the temporal bone. Crabtree and colleagues further refined the operative procedure described by Conley. .Hilding and Selker further enlarged the scope of total removal of the temporal bone by successfully freeing it from the carotid artery and the jugular bulb without any major morbidity or mortality.

Introduction.

Cancer of the temporal bones is indeed a rare, highly malignant, aggressive disease in a difficult to access anatomical site and is well known to have a very poor prognosis The reported incidence is 0.05% of head and neck cancers. (Arena 1988). The rarity of these tumors prevent any one center from accumulating large amounts of patient data for comprehensive analysis thus leading to an incomplete understanding of this disease and how to successfully treat it. Many physicians mistake this disease for otitis media or external otitis of infectious origin. .Thus when the disease is finally recognized as a malignancy the disease has by then become too advanced for treatment. Formulating a treatment protocol is difficult because of a lack of standardization of protocols involving diagnosis, evaluation and treatment. The obvious difficulty makes itself apparent when comparing one series with another to determine the results of treatment.(Kuhel et al 1996) Since 1970, there have been several advances in imaging, instrumentation and operative techniques which have helped cranial base surgery to progress. Improved operative techniques along with modern anesthesia and improved surgical reconstruction of wound defects have all reduced morbidity and mortality involved in the treatment of cancer of the temporal bone.
Imaging modalities like Computerized scanning (CT Scan) and Magnetic resonance imaging(MRI) have all helped accurately to visualize the extent of disease, the involvement of vital structures and determine whether the disease has spread beyond the confines of the temporal bone. All of which has been extremely helpful when planning treatment.

Incidence of temporal bone malignancies

Temporal bone cancers, including cancers involving the external auditory canal, is reported to be about 0.01% of all cancers. Ninety percent represent primary cancers of the temporal bone while 10% are metastatic cancers (metastatic disease from other sites like the prostate, salivary gland).. The female to male ratio varies from 1: 1 to 15:1 with age ranging from 40 to 75 years (Chen and Dephner 1978). Squamous cell carcinomas form the majority of cancers of the temporal bone with approximately 20% being adenoid cystic carcinomas or adenocarcinomas (Conley and Schuller 1976).
Primary basal cell carcinomas and malignant melanomas arising in the external auditory canal are rare. There is a bimodal distribution of tumor incidence with one peak occurring in childhood while the other occurs in the fifth and sixth decade. Rhabdomyosarcomas are very common in the pediatric age group while squamous cell carcinoma commonly affect adults (Curran et al 1998).
A study published from England and Wales revealed that the age adjusted incidence remained relatively stable at about 1/ 1,000,000 per year for women and 0.8/ 1,000,000 for men from 1968 to 1977 (Morton et al 1984). Data published from the national cancer institute USA shows a similar incidence for the period 1973 to1984 (Arena and Keen 1988). Estimates of the frequency of temporal bone cancer as a fraction of all ear diseases ranges from 1:4000 to 1:20,000 (Lewis 1960). The pinna formed the commonest site of occurrence (60% to 70%) while 20% to 30% arose from the external auditory canal and 10% from the middle ear and mastoid (Conley and Schuller 1976)

Demographical data

Cancers of the temporal bone occur in adulthood (5th to 6th decade of life) and are usually squamous cell carcinoma and these were often located in the external auditory canal. It is not clear at this time if it occurs more commonly in males or female There are very rare instances of patients as young as 15 years of age who develop squamous cell carcinomas. Squamous cell carcinoma is the commonest cancer of the temporal bone that occurs in adults while rhabdomyosarcomas are the commonest cancer of the temporal bone found in children (Cunningham and Myers1988).

Etiology

Many factors have been implicated in the cause of squamous cell carcinoma of the temporal bone. Ultraviolet radiation has` been proposed as a causative agent. This is well documented with regards to the pinna. Chronic inflammatory conditions such as otitis externa are thought to be the cause of squamous cell carcinoma. Pollitzer (Curran et al 1998) first described the association of malignancy of the temporal bone with chronic ear discharge. It was postulated that chronic inflammation had likely changed the immunologic behaviour of the middle ear cleft. This predisposed the tissue to a malignant change. Aflatoxins a well known carcinogen produced by the fungus Aspergillus is thought to be a factor in malignant transformation of the lining of the middle ear. Chromate burns from repeated matchstick abuse and accidental exposure to radium paint are also well known carcinogens (Ruben et al 1977). Rarely is carcinoma associated with an intact tympanic membrane or without a history of otorrhea.
Conventional external beam radiotherapy for cancers of other sites of head and neck cancers and therapeutic radium implants are also thought to cause cancer in the temporal bone (Applebaum 1979). A high prevalence of human papilloma virus (HPV) types 16 and 18 has been found in the middle ear squamous cell carcinoma. Eighty nine percent of the carcinomas from the ear studied by Jin and colleagues (1997) contained HPV DNA. The possible mechanism of infection of the middle ear could likely be transferred from the respiratory tract via the Eustachian tube.
Chronic otitis media has for a long time thought to be an etiological factor in the pathogenesis of SCC of the temporal bone. However till date no definitive correlation has been proved (Morton et al 1984)

Clinical features

There are no pathognomonic symptoms or signs that are typical of cancer of the temporal bone. Only if the treating physician is aware of the possibility of a cancer can an early diagnosis be made. It is very rare for carcinoma of the temporal bone to be diagnosed early. Malignancies usually first arise in the external auditory canal. Very often patients discovered to be suffering from malignancies of the temporal bone are subjected to prolonged medical therapy for non specific symptoms such as otorrhea and itching. It is only when pain, blood stained otorrhea and facial palsy occur does the physician realize that the patient does not have chronic otitis media and that the diagnosis could be a lot more sinister. It is usually at this stage that the possibility of the presence of cancer presents itself.
Persistent deep boring bony pain is typical and signifies extensive involvement of bone and dura. The duration of symptoms varies from a couple of months to approximately a year. Frequently the patient will have undergone mastoidectomy because the surgeon has mistaken the diagnosis for chronic otitis media. Histopathology of the material removed following mastoidectomy reveals the true nature of the disease.
Physical examination findings are usually an ulcerative granulations or polypoid growth in the external ear canal. A serosanguinous discharge is also present. This is no different from that seen in otitis media or external otitis. A hearing loss is often present. This could either be a conductive or sensorineural. The presence of trismus indicates that the disease has spread beyond the temporal bone and has invaded the temperomandibular joint or the infratemporal fossa.
Cranial nerves 7, 9, 10 and 11 involvement indicate advanced disease and is associated with a poor prognosis and usually precludes treatment.

Diagnosis and Evaluation

Confirmation that the disease is indeed malignant is imperative if appropriate treatment is to be started. A biopsy of the lesion is a simple procedure and can be done under local anesthesia. This will reveal the histological type of cancer which will then decide the type of treatment. A comprehensive head and neck examination including an examination of the contralateral ear is absolutely necessary. The neck is carefully examined for lymph node involvement. If present they are assessed to determine if they involved by malignancy. All the cranial nerves are assessed and audiological tests are performed to detect the presence of hearing loss. The rest of the systems are assessed to detect the presence of metastatic disease.
CT scanning and MRI are the imaging modalities of choice (Moffat et al 2000) for evaluating cancers of the temporal bone. CT scanning is the imaging modality of choice for evaluation of the spread of the cancer within the temporal bone itself. MR imaging is useful to evaluate involvement of the soft tissues like dura, brain and the surrounding soft tissues. CT scanning is of paramount importance (Fig1a and 1b, 1c and 1d). and it should be taken in the axial and coronal planes with contrast. CT scanning helps localize the extent of disease and is very important when planning surgery. An accuracy of 98% was reported (Arriaga et al 1990) when preoperative assessment of tumor extent was checked against operative data and histologic findings. CT scanning has a very high specificity with a low incidence of false negative findings.
MRI helps determine if the cancer has spread beyond the confines of the temporal bone into the surrounding soft tissue. This is important for staging and will decide the modality/ modalities of treatments to be offered to the patient suffering from cancer of the temporal bone. MRI complements the data provided by CT scanning. The use of gadolinium DTPA has further enhanced the usefulness of MR imaging. Furthermore MR imaging provides important data concerning involvement of the internal carotid artery and sigmoid sinus by disease and will also demonstrate the patency of the great vessels of the temporal bone. CT scanning and MR now complement each other and provide a `wealth of information to the treating surgeon. This in turn helps the treating physician determine the stage of disease and the treatment modalities that can be offered to the patient.

Staging systems of cancer of the temporal bone

Neither the American Joint Committee on Cancer (AJC) or the Union Internationale Contre le Cancer (UICC) have accepted any universally agreed on staging systems.
Thus statistical analysis of disease, treatment modalities, etc becomes impossible. The criticism leveled against most staging systems has been directed at the small numbers of patients, all of them offering an assortment of differing histological types, metastatic lesions and differing anatomic sites etc.
The University Of Pittsburgh (Austin et al 1994) present a staging system as do Arriaga and colleagues (1991) (Table 1). However the main limitation of these systems is the fact that they assess only the external canal and not those that originate from the middle ear or mastoid.

Treatment

Surgical therapy for tumors of the external auditory include removal of the external auditory canal (EAC), the tympanic membrane and the ossicles (ME).

Two types of surgery are available for removal of malignancies of the EAC .

External auditory canal (including the bone and skin of the EAC) resection with removal of the tympanic annulus, tympanic membrane, the malleus and the incus. This also known as sleeve resection.
Complete temporal bone resection which includes the bony structures of the entire petrous temporal bone, including the tegmen superiorly., the bone over the lateral dural venous sinus and the posterior fossa dura. Structures that are also removed include the stylomastoid foramen, the facial nerve, the styloid process, the carotid jugular spine, the entire cochlea, the labyrinth including the structures of the internal auditory canal.

External auditory canal resection
EAC resection is reserved for tumors limited only to the canal in which the tympanic membrane and annulus are intact. In this operation the external auditory canal is removed en bloc. Synonyms for this procedure are lateral temporal bone resection, sleeve resection and resection of the EAC.

Under anesthesia a cortical mastoidectomy is performed.
The facial recess (posterior tympanotomy)approach is then carried out.
The facial nerve is skeletonized and further as an extended facial nerve recess approach is carried out.
The incus is disarticulated from the stapes and the malleus. In the attic the malleus head is excised and the tendon of the tensor tympani is cut. The external auditory canal is then removed from the rest of the mastoid superiorly andinferiorly.
The bone is then shaved it off the temperomandibular joint.
The EAC is the then removed from the middle ear and mastoid.
The EAC margins are evaluated by frozen section todetermine if the margins are free from disease.
Once it has been determined that the margins are free from disease the external auditory canal is sealed and closed using a flap of fascia to seal it completely.
A drain is placed in the cavity and the incision is closed in layers.

Total / subtotal temporal bone resection.

Subtotal temporal bone resection involves removal of the EAC, Middle ear and its contents, the 7th cranial nerve, the mastoid and the cochlear. The internal carotid artery is spared. This procedure is reserved for those malignancies that have extended beyond the tympanic membrane into the middle ear but have not yet gone beyond the middle ear.
Total temporal bone removal involves the entire removal of the temporal bone with sacrifice of the internal carotid artery, jugular bulb and the 9th, 10th and 11th cranial nerves.Total temporal bone removal is a very major procedure and is accompanied by high incidence of morbidity and mortality. These procedures are usually reserved for patients who are young, in reasonably good health and are able to withstand the morbidity that accompanies such a rocedure.

Management of the neck

If malignant disease has involved the local lymph nodes then the prognosis is thought to be very poor. Several reports in literatire quote cervical metastases in the range of 10% to 20% (Curran et al 1998). For the N0 neck an ipsilateral supraomohyoid neck dissection is recommended. For N1 disease an ipsilateral modified radical neck dissection is preferred (American Head and Neck Society 1996)

Reconstruction

Reconstructive modalities have improved significantly and a wide array of choices are available.. Pedicled myocutaneous flaps such as the pectoralis major flap is the workhorse of the head and neck and is very suitable for closing defects of the temporal bone. Reconstruction requires muscle bulk and skin coverage. The trapezius myocutaneous flap is another useful pedicled flap when reconstructing extensive defects that following temporal bone resection. Free tissue transfer is also an adequate method for the reconstruction of temporal bone defects. Complications like CSF leaks are rare since the introduction of vascularized myocutaneous flaps for the closure of temporal bone defects (Ariyan and Sasaki 1982).

Complications

Intraoperative hemorrhage,cerbrovascular accidents and CSF leaks are common complications encountered following formal temporal bone resections.Hemorrhage during surgery usually occurs from the jugular bulb or the sigmoid sinus. These are low pressure bleeds and simple pressure, a muscle plug or bone wax if often adequate to stop these bleeds. Infrequently these vessels may need to be ligated..
CSF leaks may result whenever the subarachnoid space is inadvertently opened. Complete obliteration of the middle ear space, suturing dural tears, sealing dead space with vascularized tissue helps minimize this complication.
Internal carotid artery bleeds are life threatening. Whenever the internal carotid artery is involved by disease and internal carotid artery sacrifice is considered likely then patient should be evaluated to see if they can safely withstand such a procedure. Reducing complications as a result of sacrificing the internal carotid completely can be to an extent reduced by bypass grafts. These can get blocked or may not function optimally which can then bring on a stroke and other complications.

Cranial nerve rehabilitation

Facial nerve injury
Facial nerve pareisis / palsy may be a likely consequence of surgery. Rehabilitation focuses on corneal protection. If the facial nerve has been intentionally sacrificed then measures to restore facial function can be considered. Primary surgery of facial nerve to hypoglossal nerve anastomosis may be considered. Facial to accessory or cross facial sural nerve interposition is an attractive viable alternative. The surgeon has the choice of doing the rehabilitative procedures immediately after primary surgery or can be staged and performed six months later. Procedures like upper eyelid gold weights and springs may be considered when facial paralysis results. They are preferred in situations where the facial nerve has not been sacrificed and facial nerve function is expected to return. In the event of the facial nerve returning to normal they can be removed. When facial nerve function is not expected to recover a combination of dynamic and static procedures can be carried out. Inputs from an experienced plastic and facial reconstructive surgeon are invaluable. Each procedure should be carried out after they’ve been individually tailored to suit the patient and the defect.

Radiotherapy and its role in the treatment of cancer of the temporal bone

At this time the role radiotherapy in the treatment of cancer of the temporal bone is not defined. Prasad and Janecka 1994 in their report indicated that the addition of radiotherapy therapy to patients with disease confined to the EAC does not improve survival as compared to surgery alone. Many surgeons are unclear as to whether radiation should be given following surgery especially if the surgery has involved total temporal bone removal. Radiation therapy as the only modality for the treatment of cancer of the temporal bone is rare. Postoperative radiation therapy may help in improving local control rates in resectable disease, but has not been found to affect recurrence and survival rates if the surgical margins are involved with residual tumor. Guidelines from the American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons are available for postoperative radiation therapy include situations when resection margins are close (less than 5mm), or when proximity of tumor to important structures such as the internal carotid artery preclude wide margins. Radiation therapy is indicated if there are multiple histologically positive nodes or evidence of extracapsular spread. In addition radiation therapy is indicated for most adenoid cystic carcinomas.
Five year survival rates from radiation therapy alone are 11% in contrast to 34% when radiation therapy is used in combination with surgery. In theory suspected micrometastases in the neck, parotid may be sterilized by a course of radiotherapy. Typically two wedged cobal 60 fields are applied at right angles, producing a circumscribed high dose volume.
Complications of radiotherapy include osteoradionecrosis, stenosis of the EAC and sensorineural hearing loss.

What are the issues still facing surgeons treating cancer of the temporal bone?

Should radiotherapy be preferred over surgery?. It is now generally accepted that primary radiotherapy has a very limited role in the management of these neoplasms because of poor bony penetration., the initiation of osteoradionecrosis and variable outcomes from different centers using similar protocols. The 5 year cure rate with radiotherapy alone is 0% to 22% (Goodwin and Jesse 1986). Usually the total dose given is 60 to 70 Gy. This is given to the primary site as well as to the neck.
Should the surgeon subject the patient through the an extremely morbid procedure such as an total temporal bone en bloc resection?

En bloc resections as proposed by Lewis (1983) and Arena (1974) appear to follow the principles of oncologic surgery. However Kinney and Wood (1987)state that total temporal bone removal did not really accomplish en bloc removal especially in the situation where the malignancy is squamous cell carcinoma. A number of authorities have questioned the effectiveness of attempting to perform a total en bloc removal of the temporal bone. Thus Kinney and Wood (1987) suggest approaching tumors that have involved the middle ear and mastoid in the following manner; en bloc resection of the EAC and tympanic membrane with further resection of residual tumor in a piecemeal fashion.

Their arguments are as follows

Extent of tumor is very often underestimated preoperatively and s usually much more than anticipated. Therefore piece meal removal becomes necessary
Since Subtotal and total bone resection are very high risk procedures accompanied by unacceptable high morbidity perhaps a less morbid approach would give the same results.

The drawback of the piece meal removal approach is that this procedure is that it is not oncologically sound and goes against the principles of oncologic surgery as it goes through the tumor rather than removing it with wide margins that are free from disease. Kinney and Wood (1987) reported on 30 patients treated in this fashion during an 8 year period. Twenty four of these had Squamous cell carcinoma with the remainder having a variety of other pathologies. Twenty five had tumors that developed in the EAC while 5 had parotid tumors that extended into the EAC. The patients in this series were followed for an average of 2.5 years with a range of 6 months to 8 years. The results were difficult to interpret because specific information regarding histology, use of radiation therapy and duration of follow up was not given for individual patients or for each of the three subgroups.. .
Arriaga and colleagues (1989, 1990, 1991)oppose the hypotheses that preoperative staging is inherently inaccurate. They believe that before abandoning the concept of en bloc tumor resection in favor of piece meal resection, the treatment results should be compared for similarly staged patients.
Spector(1991) in his study was the first to apply a prospective protocol. He first retrospectively staged 17 previously treated patients and analysed their outcomes. He then developed a prospective protocol utilizing surgery and postoperative radiotherapy with which he treated 34 subsequent patients. Survival data for the patients treated using the prospective protocol with at least 36 months follow up show that better results were seen for the patients in the group with the prospective protocol.
Spector’s (1991) included lesions in the facial skin, conchal skin, preauricular and postauricular skin as well as parotid in his protocol. He excluded metastatic lesions. His prospective series include only those with lesions within the EAC and the confines of the temporal bone.
Spector (1991) defines sleeve resection as en bloc resection of the bony and cartilagenous EAC including the tympanic membrane, malleus and bony annulus. For partial temporal bone resection the medial border of the resection was the cochlea, stapes, tegmen and the posterior fossa bony plate with preservation of the facial nerve. Spector enlarged the scope of surgery and his current policy is to perform a partial (subtotal) temporal bone resection in lieu of a lateral (sleeve) resection. This resection usually includes a superficial parotidectomy, resection of the mandibular condyle and resection of the root of the zygoma. Spector would resect the facial nerve if it was surrounded by tumor. If the disease had spread beyond the temporal bone but remained outside the intracranial cavity he would use the infratemporal fossa approach. Reconstruction of the defect would be accomplished by a variety if pedicled vascularized myocutaneous flaps. Radiation ports were enlarged to include the postauricular and parotid regions as well as the ipsilateral neck. All patients were treated with 6000 cGy which were given in fractions of 180 to 200cGy per day.

Results

It has been difficult to analyze world literature on cancer of the temporal bone precise because of the following factors

Cancer of the temporal bone is a rare disease.
There is no universally accepted staging system
Most reports use different parameters, varying protocols and mulitple staging systems.

Many use different terms for surgical procedures. All these elements have caused a lack of unity which has resulted in confusion. This in turn has lead to difficulty in proper analysis of patient data. In a report in 1994 Prasad and Janecka have reviewed all English language publications addressing the treatment of SCC of the temporal bone. Unsurprisingly no randomized or nonrandomized studies were identified. Of the 96 publications they identified only 26 containing information on 144 patients for detailed analysis. To facilitate this metaanalysis Prasad and Janecka defined 4 types of operations. They were

mastoidectomy , which referred to all types of modified and radical mastoidectomy.
Lateral TBR, which included the removal of the EAC, malleus and incus.
Subtotal TBR, which included the additional removal of the otic capsule.
Total removal which included the removal of the petrous apex.

Since many publications did not included data as to whether resection was achieved en bloc or piecemeal, the impact of this parameter on the clinical outcome was not analyzed.In addition to surgery, many patients were treated with adjuvant therapy. Details regarding radiation dosage and fractionation were not well documented making analysis impossible.. The results reported by Prasad and Janecka which are updated by Moffat et al ((2000)are reported in table 2. Meaningful conclusions could not be drawn as there was no randomization. Nonetheless general observations included the following

Patients who present with SCC limited to the EAC, survival is about 50%.
Survival rate was about 25% for those patients who presented with disease involving the middle ear.
As was expected poor outcomes were seen in those who had advanced disease.

The literature review by Prasad and Janecka and also by Moffat encompasses experience recorded as long ago as 1915. Modern skull base surgeons will likely have improved on those results. Moffat and associates(1999) analyzed 15 patients with temporal bone carcinomas ho underwent salvage surgery for recurrences in radical mastoidectomy cavities. Extended temporal bone resection with suprahyoid block dissection was performed with dural grafting along with a scalp rotation. They report a 47% 5 year survival rate which is indeed a step in the right direction and 29% of the survivors also underwent partial excision of the temporal lobe of the brain. Based on this experience Moffat and colleagues suggest that radical surgery along with radiotherapy may result in better 5 year survival figures than the conventional limited mastoidectomy and radiotherapy. Bohrer and colleagues (1995) find no statistical significance in 1 and 3 years survival rates in patients with or without dural involvement. They conclude that dural and cerebral invasion should not be a contraindication to surgical intervention. Most authors do not view the involvement of the internal carotid artery or cavernous sinus as an absolute contraindication to surgical resection The use of internal carotid artery balloon occlusion test in combination with xenon SPECT scans has helped select patients who may be candidates for internal carotid artery sacrifice. A saphenous vein graft should be placed immediately in an attempt to restore blood flow.

Conclusions

Cancer of the temporal bone is a rare entity. There is a profound need to formulate a good universally accepted staging system.
The role of radiotherapy is still undecided. Radiotherapy as the sole modality of treatment is currently controversial.
Treatment protocols also need to be formulated and common terms need to be devised so that commonality and universality will help bring about better understanding of how to recognize the disease early and so improve outcomes.
Patients with advanced disease face a poor prognosis and it is this set of patients who pose a real challenge to modern skull base surgeons. The controversy regarding en bloc removal versus step wise (piece meal removal) has not been resolved.

References.

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Table 1 : Clinical staging system

T1: -Tumor limited to the EAC without bony erosion or evidence of soft tissue erosion.
T2:- Tumor with limited erosion (not full thickness) or radiological findings consistent with limited (< 0.5cm) soft tissue involvement.
T3:- Tumor eroding the osseous EAC (full thickness) with limited (< 0.5cm) soft tissue involvement, or involvement of middle ear/mastoid or causing facial nerve palsy at presentation.
T4:- Tumor eroding the cochlea, petrous apex, medial wall of the middle ear, carotid canal, jugular foramen or dura or with extensive (0.5cm) soft tissue involvement.

Table 2 : Treatment outcome and survival

No.	Author	Year	Number	Treatment	Five year survival(%)
1	Conley	1974	36	Subtotal TB resection(TBR)	27%
2	Lewis	1975	86	subtotal TBR	25%
1	Keith	1976	89	Radiotherapy(RT)	28%
1	Lewis	1983	28	Total TBR	27%
1	Lewis	1983	11	Total TBR+ RT	35%
1	Kenyon	1985	21	radical mastoidectomy+ radiotherapy	18%
1	Arriaga	1989	35	Partial, subtotal, total TBR+RT	34%
1	Spector	1991	17	Total + subtotal TBR	65%- 75%
1	Birzgalis	1992	56	RT	32%
1	Moffat	1997	15	Extended TBR	47%