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Submitted Article:

Jeffery Williams, M.D. "Fractionated Stereotactic Radiotherapy for Acoustic Neuromas"

Submitted, International J. Radiation Oncology, Biol., Physics





Fractionated Stereotactic Radiotherapy

For Acoustic Neuromas

 

 

 

 

Jeffery A. Williams, M.D.

Department of Neurosurgery and

Department of Oncology

The Johns Hopkins University School of Medicine

 

 

Running Title: Radiotherapy for Acoustic Neuromas

Contact Information for Author:

Jeffery A. Williams, M.D.

Department of Neurosurgery

Harvey 811

The Johns Hopkins Hospital

600 North Wolfe Street

Baltimore, MD 21205-8811

Phone: 410-614-2886

FAX: 410-614-2982

Email: jw@jhu.edu

 

Abstract

When compared to radiosurgery, fractionated stereotactic radiotherapy (FSR) for acoustic neuroma (AN) offers escalation of tumor dose (Gy) and potential sparing of auditory and facial nerve functions. Over the past 7 years 249 consecutive patients have received FSR for AN. One hundred twenty-five patients have follow up greater than 1 year and comprise this report. Non-invasive, repeat-fixation mask allowed simulation via spiral CT. Differential collimation and beam weighting achieved conformality. Two distinct schedules for total dose and fractionation were used. For AN <3.0 cm diameter (mean volume 1.4 + 0.18 cc) vs. >3.0 cm (mean volume 8.1 + 1.17 cc) doses of 5 Gy given in 5 consecutive daily fractions (25 Gy total) (111 pts) vs. 10 fractions of 3 Gy (30 Gy total) (14 pts) were given. All treatments were prescribed to the 80% isodose and given via the dedicated 10 MeV accelerator. Results: The percentage decreases in tumor size were 12 + 2 (range: 0 - 100) vs. 13 + 3 (range 0 - 38) for the 25 Gy vs. 30 Gy regimens, respectively. No patient had growth of AN or developed facial weakness. Two patients developed transient decrease in facial sensation. For 37 patients who had audiograms before vs. after FSR, the speech reception threshold was 42.0 + 4.9 vs. 48.7 + 4.2 (NS), the speech discrimination (%) was 82. 0 + 3.3 vs. 64.8 + 6. (NS), and the pure tone average (dB) was 54.7 + 4.1 vs. 60.5 + 3.4 (NS). Fractionated stereotactic radiotherapy may preserve normal function and control both small and large acoustic neuromas.

Key words: acoustic neuroma, radiotherapy, radiosurgery, fractionation

 

 

 

 

 

 

Introduction:

The roles of microsurgery vs. stereotactic radiosurgery (SRS) for the treatment of acoustic neuromas continue to evolve . Many regard surgery the standard of treatment . Although surgery offers both immediacy and low rates of recurrence, the potential loss of facial and auditory cranial nerve functions during resection remains a challenge . The size of the resected acoustic neuroma may predict the risk for loss of normal cranial nerve functions .

Stereotactic radiosurgery (SRS) provides a non-invasive, single-dose treatment that results in both high rates of control and elimination of the operative morbidity for the treatment of acoustic neuromas . For SRS, however, the risks for decreased facial and auditory functions remain a concern . Similar to surgery, the risk for loss of cranial nerve functions following SRS may be proportionate to the size of the treated tumor . Risk is also proportionate to the marginal dose (Gy) .

Fractionation is the basis for the radiotherapy of many brain tumors to provide simultaneous differential sparing of normal tissues and killing of tumors . Fractionated stereotactic radiotherapy (FSR) utilizes the most advantageous features of both conventional radiotherapy and SRS. When compared to radiotherapy, FSR treats the volume of irradiation more precisely . When compared to SRS, FSR allows fractionation that may result in both the differential sparing of normal cranial nerves when compared to tumor and potential escalation of the total dose (Gy) . For the acoustic neuroma these factors are especially critical because the facial and auditory nerves are immediately adjacent to, or within the treated tumor . This report examines FSR for both large and small acoustic neuromas via two prospective schedules of fractionation. The principal endpoints for analysis include the initial control of tumors and preservation of the auditory and facial cranial nerve functions.

Methods:

Over the past 7 years 249 consecutive patients have received FSR for acoustic neuroma. One hundred twenty-five (125) patients (71 M; 54 F) have had follow up greater than 1 year and comprise this report. The mean follow-up is 2.14 + 0.09 years. The range for the follow-up is 1.01 - 5.7 years (95% confidence interval 1.96 - 2.32 years). The age (years) at the time of treatment was 55.0 + 1.1. The range in ages was 22.1 - 81.0.

Four patients had initial surgery for the acoustic neuroma and had FSR for recurrence. The intervals (years) until recurrence were 1.2 and 6.6 for one patient who had two surgical procedures for the same acoustic neuroma, and 9.2, 9.4 and 18.4 years in the remaining 3 patients. One patient was diagnosed with neurofibromatosis Type 2 (NF2). This patient was deaf in the contralateral ear as a consequence of surgical resection. The patient characteristics are summarized in Table 1.

Tumors were evaluated before and after treatment using gadolinium-enhanced T1-weighted (slice thickness 2-5 mm) MRI of the acoustic neuroma including the internal auditory canal. The maximal transverse dimension of the acoustic neuroma was recorded.

Simulation: The system for simulation was purchased (BrainLabÒ ). The patient's head was supported by the rigid, curved headrest that was attached to the base frame (BrainLabÒ ). For immobilization during simulation the synthetic, thermoplastic mask was custom fitted for each patient. Thus, the plastic strips were heated in a water bath. The plastic sheets, in specified dimensions and sequences of application, were applied over the forehead and maxillary regions. The plastic mask, rigid when cooled, was attached to the metal base frame using plastic clamps. The Brown-Roberts-Wells (BRW) localizing ring was attached to the base frame. Following intravenous contrast administration, the Picker AcQSimÒ CT provided contrast-enhanced images (2-mm slice thickness) through the entire cranium.

Treatment Planning: The CT image files were transferred to the computer workstation for dose planning (BrainLabÒ v. 2.0). This system allows automated external contouring of each CT slice and manual contouring of the target volume. For the target volume, the isocenter is manually positioned. All tumors were treated using a single isocenter. For each separate arc of rotation, the table angle, start and stop angles, weighting and the diameter of the collimator were selected. The prescription isodose was manually optimized to approximate the surface of the acoustic neuroma. The BRW co-ordinates for the isocenter were defined. Using the Picker AcQSim and the selection of windowing to show bone density, the digitally reconstructed radiograph (DRR) was created to show orthogonal (anterior-posterior (AP) and lateral) virtual skull radiographs. Using a transformation system that was developed in-house, the BRW co-ordinates were transformed to allow display within the orthogonal, virtual skull DRR images.

Treatment: On the day of the first fractional dose, the patient was positioned on the treatment table of the linear accelerator (Varian Clinac 18: nominal 10 MeV photons). The head frame, mask, and the patient's head were positioned identically to that used for the simulation. Using the linear accelerator's beam, orthogonal (AP and lateral) radiographs were taken in an orientation that was identical to that obtained for the DRR images as described above. Thus, via a double exposure technique, the skull was imaged via the larger, open field and the isocenter was imaged using the second, smaller field that was shaped by the selected collimator. In this manner, the comparison of the AP and lateral DRR images with these actual AP and lateral images allowed confirmation of the correct positioning prior to the start of treatment. This procedure was repeated prior to each daily fraction.

Patients received one fraction per day and were treated on consecutive weekdays. To achieve potential sparing of the facial and auditory nerves for the larger acoustic neuromas, the regimens for fractionation of treatments were prospectively determined. The regimens were based upon maximal size in the transverse dimension and the capacity to spare the path of the facial nerve during the antecedent treatment planning.

Prospective dose selection sought preservation of normal cranial nerve function via greater fractionation for the larger AN. Thus, for AN less than 3.0 cm diameter (mean volume 1.4 + 0.18 cc) vs. >3.0 cm (mean volume 8.1 + 1.17 cc) schedules of 5 consecutive daily fractions of 5 Gy (25 Gy total) (111 pts) vs. 10 fractions of 3 Gy (30 Gy total) (14 pts) were given. All treatments were prescribed to the 80% isodose and given via the dedicated 10 MeV accelerator. The dimensions of the treated tumors are shown in Table 2.

Patient Follow Up: Clinical and radiographic assessments were performed every three months after FSR for the first year, every 6 months for the second year, and annually thereafter. Radiographic assessment included cranial MRI, both gadolinium enhanced and unenhanced. Maximal transverse tumor measurements from the follow up MRI studies were made. The percentage change in size vs. time was recorded. Audiometric testing was requested every 6 months for the first two years and annually thereafter. Audiometric testing measured the pure tone average, the speech reception threshold and the speech discrimination. The percentage change for each was recorded vs. time after FSR.

Statistics: Measurements of age, tumor dimensions, speech reception threshold (dB), presentation loudness (dB) for speech discrimination, and speech discrimination (%) are the means +/- SEM. Analysis of variance was used for comparisons of the treatment groups.

Results:

The tumors responded similarly regardless of size. The percentage decreases in size of the treated tumors were 12 + 2 (range: 0 - 100; 95%CI: 9 - 15) vs. 13 + 3 (range 0 - 38; 95%CI: 5.9 - 20.2) for the 25 Gy (< 3.0 cm maximal diameter) vs. 30 Gy (> 3.0 cm), regimens, respectively.

Prior to FSR patients had diminished ipsilateral hearing. For 62 patients who had audiograms prior to the FSR, the speech discrimination (SD) (%) was 67.1 + 3.7 for the treated side vs. 97.8 + 0.9 for the contralateral side (p < 0.05). Measurements of hearing after FSR showed preservation. Thirty-seven patients had audiograms both before and after FSR. The mean audiometric follow up was 1.7 + 0.11 years (range 1.01 - 3.34 years). For all patients who had audiograms before vs. after FSR, the speech reception threshold (dB) was 42.0 + 4.9 before vs. 48.7 + 4.2 after FSR (NS). The speech discrimination (%) was 82. 0 + 3.3 before vs. 64.8 + 6.3 after FSR (NS). The pure tone average (PTA) (dB) was 54.7 + 4.1 before vs. 60.5 + 3.4 after FSR (NS). Based upon the results of these audiograms, the Gardner-Robinson classification for hearing was unchanged in 21 of 37 measured patients, showed decrease in 10 patients and increase in 6 patients. The rate of retention of useful hearing (Gardner-Robinson I-II) was 16 of 22 patients (72%). Three patients without useful hearing improved to Gardner-Robinson grade II.

Facial function: No patient developed facial weakness. For trigeminal function, two patients had temporary, moderate decrease in facial sensation consistent with trigeminal effect. The distribution for both patients was the ipsilateral second and third trigeminal distributions, observed 3 and 24 months after FSR, respectively. These findings resolved completely in both patients 14 and 31 months after treatment, respectively.

Discussion:

For both surgery and SRS, the relationships among the size of the treated acoustic neuroma, tumor control and the risk to normal cranial nerves have been described. For surgery, the risk for facial nerve dysfunction is proportionate to the size of the resected acoustic neuroma . Wiet et. al. noted significant increases in facial paralysis vs. size of the resected acoustic neuroma in a study of 484 patients . Sampath et. al. noted that when facial nerve outcome was examined with respect to tumor size, there was clearly an increased incidence of facial nerve palsy seen in the immediate postoperative period in cases of larger tumors: 60.8% of patients with tumors smaller than 2.5 cm had normal facial nerve function, whereas only 37.5% of patients with tumors larger than 4 cm had normal function . In a review of 58 patients and a correlation of tumor size to the outcome, Are et. al. noted that the overall rate of preservation for the facial nerve was 81%, for which 20/21 had acoustic neuromas less than 2 cm in size, 23/30 had tumors greater than 2 cm but less than 4 cm in size, and 4/7 patients had tumors greater than 4 cm in size . In a report of the long-term (1 year or greater) outcome for facial nerve function in 129 patients who had surgical removal of their acoustic neuromas with the aid of intraoperative neurophysiologic monitoring between 1986 and 1990, Lalwani et. al. noted that long-term facial function inversely correlated with the size of tumor. In a prospective study having 2-year follow-up of 35 patients undergoing acoustic neuroma surgery with facial nerve monitoring, tumor size was again a strong predictor of both immediate and long-term facial nerve function . Similarly, in a series of 276 patients with a unilateral vestibular schwannoma Gray et. al. noted that increased tumor size was associated with a worse postoperative facial nerve function . These results confirm the importance of size of the surgically removed acoustic neuroma in the prediction of facial dysfunction.

For hearing preservation, the size of the resected tumor correlates so well with the outcome that candidates for post-surgical preservation of hearing are selected according to the preoperative size of the acoustic neuroma . In a study of hearing preservation using size of the tumor as the clinical prognosticator in 60 consecutive patients, Hecht et. al. noted that removal of a tumor of 1.5 cm or less in size had a 50% chance of hearing preservation. In the group of patients with tumors larger than 1.5 cm there was only a 16% chance of preservation . Several other studies have confirmed the relationship of size to postoperative preservation of hearing .

For cranial nerve preservation after SRS, the risks to facial, trigeminal and auditory functions may be proportionate to size of the treated acoustic neuroma as well . In that study, the risks of both trigeminal and facial neuropathy following SRS were proportionate to the irradiated length of the facial and trigeminal nerves. Similarly, Mendenhall et. al. noted complications including facial and/or trigeminal cranial nerves in 13 patients (23%) after SRS. The risk for cranial nerve dysfunction was proportionate to the treatment volume. omplications were three (13%) of 23 patients for 12.5 Gy given to all volumes; two (9%) of 23 patients for 15 to 17.5 Gy given to 5.5 cm3 or less; five (71%) of seven patients for 15 to 17.5 Gy given to more than 5.5 cm3 and three (100%) of three patients for 20 to 22.5 Gy to all volumes. To reduce toxicity, the doses for SRS treatments have been reduced. Facial neuropathy decreased from 38% to 8% in one study of dose reduction but treatment failure rose to 4% . In a second study of dose reduction to 13 Gy, rates of facial neuropathy decreased to only 1% but tumor control decreased to 91% . For hearing loss after SRS, initial long-term results showed a 49% rate of decreased hearing using doses of approximately 16 Gy . Studies of dose reduction showed higher rates of preservation of speech discrimination following reduction of the dose to approximately 13 Gy . The rate of hearing preservation (same or better Gardner-Robertson class) improved from 51% to 71% after reduction of dose . The authors observed that longer follow-up may be required to know the eventual rates of tumor control after these reductions in dose .

The described results of the FSR show that cranial nerve functions may be preserved regardless of the size of the treated acoustic neuroma. The prospective schedules for fractionation versus size of tumors were associated with preservation of tumor control, facial and auditory functions. It is unknown whether one schedule (25 Gy in 5 fractions or 30 Gy in 10 fractions) would have resulted in the same percentage decreases in size and preservations of function for the treatment. However, the increase in fractionation (larger number of smaller fractions) versus size is reasonable . For larger tumors, both the volume of normal tissue immediately adjacent to the tumor and the length of normal cranial nerves within or immediately adjacent to the tumor are larger. The risk of injury for single treatments (SRS) increases exponentially with volume . Therapeutic gain is defined as the ratio of tumor biological effective doses (BED) for fractionated vs. single treatment regimens. The therapeutic gain for fractionated treatment increases with the number of fractions . Fractionation may result in sparing of the increased lengths of normal cranial nerves that reside within or adjacent to the treated acoustic neuroma.

When a fractionated regimen is used, the total dose must be larger than that given in a single fraction in order to achieve the same magnitude of killing of tumor cells and hence the same probability of tumor control. If the total dose delivered in a fractionated regimen is determined such that tumor cell kill is equivalent to that with a given single dose, normal tissue cell kill will be reduced . The alpha/beta ratio is a radiobiological parameter that represents the ratio of single-hit killing (alpha) to killing with double-hit kinetics (beta) . For comparison to the decreased dosage regimen employed recently in the SRS for acoustic neuroma, and assuming an alpha/beta ratio of 2.5 for the tumor the regimen of 25 Gy in 5 fractions has a similar biological equivalent dose (BED (Gy)) (75 Gy) when compared to the single dose of 13 Gy (BED 80.6 Gy) . For a normal tissue alpha/beta ratio of 2.0, the regimen 25 Gy in 5 fractions results in a BED of 87.5 Gy vs. 97.5 Gy for the 13 Gy single dose. For an alpha/beta ratio of 5 for acoustic neuroma, the same FSR regimen again has a similar biologically equivalent dose (50 Gy for FSR vs. 47 Gy for 13 Gy SRS). For values of the alpha/beta ratio for normal tissue (e.g. facial or auditory nerves) that are less than the alpha/beta ratio for the tumor, the FSR will result in diminished BED (Gy) for normal tissues when compared to the single dose regimen. For normal neural tissue this may in turn result in increased preservation for any given level of tumor killing.

The described results suggest that the current regimen for FSR for acoustic neuroma may result in both control of the treated tumor and preservation of the normal cranial nerve functions. Longer follow up, however, is required to determine the durability of both tumor control and preservation of normal cranial nerve function beyond the studied intervals.

Table 1

Patient Characteristics

Number

125

Age (years)

55.0 + 1.1

(range: 22.1 - 81.0) (95% C.I. 52.3 - 57.1)

Gender

71 M

54 F

Maximal Transverse Dimension (cm)

< 3 cm: 111

>3 cm: 14

Volume (cm3)

1.395 + 0.175 (111)

8.096 + 1.173 (14)

NFII (patients)

1

Prior Surgery (patients)

4

Follow Up (y)

Mean: 2.14 + 0.09 y; Range 1.01 - 5.7 y; (95% CI 1.96 - 2.32 y)

 

 

 

 

 

 

Table 2

Treatment Characteristics

Treatment Regimen1

Patients

(Number)

Size 2 (cm3)

Decrease (%)

After FSR

25 Gy / 5 fractions

111

1.395 + 0.175 (111)

12 + 2

30 Gy / 10 fractions

14

8.096 + 1.173 (14)

13 + 3

 

1 Treatment Regimen: Patients received either 25 Gy in 5 fractions or 30 Gy in 10 daily fractions. Treatments were given on consecutive weekdays.

2 Size: Dimension (cm3) of treated acoustic neuromas.

 

Table 3

Results of Audiometry

 

Before FSR 1

After FSR 2

PTA (dB)

54.7 + 4.1

60.5 + 3.4

SRT 3 (dB)

42.0 + 4.9

48.7 + 4.2 (NS)

SD 4 (%)

82. 0 + 3.3

64.8 + 6.3 (NS)

HL 5 (dB)

54.7 + 4.1

60.5 + 3.4 (NS)

1 Before FSR: Results of hearing tests obtained prior to FSR.

2 After FSR: Results after FSR until the most recent audiogram.

The audiometric follow up was 1.7 + 0.11 years (1.01 - 3.34 years)

3 SRT: speech reception threshold in decibels.

4 SD: speech discrimination.

5 HL: Hearing level in decibels for study of SD: speech discrimination