Keywords
case mix - Gamma Knife - intracranial disorders - stereotactic radiosurgery
Introduction
Stereotactic radiosurgery (SRS) is a term used to describe stereotactically-guided
high-precision conformal irradiation of a target volume in a single session as against
the multisession (fractions) dose delivery in conventional radiotherapy. The main
attributes of a SRS technique are high geometric accuracy, high conformality, and
sharp dose fall-off beyond the target volume. The disorders that are suitable for
SRS should be small and have well-defined margins on three-dimensional imaging modalities
such as computed tomography and magnetic resonance imaging (MRI). Many types of intracranial
lesions, benign as well as malignant ones, meet the criteria of suitability for SRS.
There are many technologies available for delivering SRS, but the longest experience
has been with the Gamma Knife system. The first clinical prototype Gamma Knife system
for research developed by the famous Swedish neurosurgeon Lars Leksell along with
his physics colleague B Larsson was ready in the year 1967.[1] Over 300 Leksell Gamma Knife (LGK) units have been installed worldwide in the past
15 years (till 2018) for treating various types of intracranial conditions. More than
88,000 indications were treated in 2018 and over 1.2 million patients have been treated
through 2018 by Gamma Knife alone.[2]
The Gamma Knife-based SRS (GKRS) technology has evolved considerably since its inception
in 1968. Its collimator design, patient positioning system, and the computer-based
treatment planning system have all undergone significant changes leading to improved
treatment delivery accuracy, dose conformality, shorter treatment time, and ease of
operations. It is interesting to note that even with the emergence of many linear
accelerator- based robotic SRS technologies, GKRS system is still considered as a
“gold standard” for cranial SRS in terms of accuracy and simplicity of operations.
The accuracy achievable in physical dose delivery is within 0.5 mm with GKRS.[3]
There have been studies from many Gamma Knife centers around the world revealing the
variations in application of GKRS in treating various intracranial disorders.[2]
[4]
[5]
[6] The variations became larger if one compared centers from different countries or
continents. The factors that most likely influence the composition of indications
treated with GKRS at a center are (i) expertise available in the hospital not only
in the neurosurgery domain but also in the other closely connected fields such as
interventional radiology, oncology and medical physics; (ii) disease profile of the
population being served by the hospital; (iii) reputation of the center for GKRS expertise;
and (iv) perceived relevance of Gamma Knife system for SRS among the referring physicians
as well as the patient population.
Ours is a government-funded tertiary care hospital with a team of well-trained experts
at the GKRS center. The hospital also has well-developed specialties in the closely
connected disciplines, and a structured referral system from hospitals spread across
the country. We performed a retrospective analysis of the first 1,000 cases treated
at our center in terms of diagnosis, tumor size, and other related details. We believe
that this study would provide a reasonably good idea of the relevance of the GKRS
system for cranial SRS in the fast-changing technological scenario in India. This
study would also show if GKRS was the first choice or a last resort kind of option
for the patients. However, our study is neither about the incidence rate of various
intracranial disorders nor about determination of appropriateness of GKRS for these
disorders in India.
Materials and Methods
Gamma Knife System and Procedure
The LGK model 4C (Elekta, Sweden) used in this study had a distinctive addition over
the earlier LGK models namely the automatic positioning system (APS). The APS obviated
the need of manual co-ordinate setting (trunnion system) for each isocenter (shot)
to execute a treatment delivery. The APS moved the patient head from one shot to another
within one helmet size (run) without the need for the operator to enter the treatment
room for manual change of shot coordinates, as was the practice with the earlier trunnion-based
systems. The main advantages of the APS included speeding up of the treatment delivery,
less chances of human error in setting up the coordinates manually, and a possible
reduction in manpower requirement. However, another less appreciated advantage was
the fact that a treatment planner could afford to use a larger number of shots to
improve conformality of a treatment plan, if needed. The LGK 4C had four collimator
helmet sizes of 4, 8, 14, and 18 mm like the earlier LGK models. A brief description
of the evolution of LGK machines since 1967 is provided at the end of this section
for the ready refence of the readers.
After fixation of the stereotactic frame (Leksell G-frame) on the patient head, which
was MRI compatible, all patients underwent MRI scans either on a 1.0 Tesla Magnetom
Harmony or 1.5 Tesla Magnetom Avanto (Siemens Healthcare, Erlangen, Germany) with
the MR localizer. The patients being treated for arteriovenous malformations (AVM)
underwent additional imaging in the form of a planar digital subtraction angiography
on Axiom Artis BA machine (Siemens, Germany) with the G-frame and special angiography
localizer.
The images were then exported to the Leksell Gamma Plan (LGP) for treatment planning.
The LGP version 5.34 and later 10.0 (Elekta, Sweden) were used for treatment planning.
While preparing a plan, dose conformity and radiation tolerance of adjacent organs
at risk (OAR) or normal brain tissue were our primary optimization objectives.
The first clinical LGK machine for research developed by the famous Swedish neurosurgeon
Lars Leksell along with his physics colleague B Larsson was ready in the year 1967.
Following its success, commercial models starting from LGK model U (1987), Model B(1988),
Model C/4C(1999), Model Perfexion (2006), and Model Icon (2016) were launched. Each
came with improved accuracy and efficiency in treatment delivery. Till LGK 4C, 201
Co-60 sources were distributed in a hemispherical geometry in five rings. The first
major change in terms of automation in treatment delivery was a feature called APS
provided with LGK 4C which obviated the need of manual trunnion-based coordinate setting.
The significant next step was a complete redesigning of the collimator system for
Perfexion. The four external helmets/collimators (4mm, 8mm, 14mm, and 18mm) were replaced
with automatically changing three internal collimators (4mm, 8 mm, and 16 mm). The
number of sources was now 192 distributed on a conical surface in five rings. In addition,
the introduction of a highly accurate couch-based patient positioning system (PPS)
made the limited movement APS redundant. Further, there was more space within the
internal collimator system and hence accessibility of peripheral tumors improved considerably.
Overall, Perfexion improved the treatment delivery efficiency with the introduction
of automatic treatment delivery without compromising the accuracy. Icon system added
on-board cone-beam computed tomography to the Perfexion. This has opened new avenues
for mask based fractionated SRS.
Patients
The patient population treated with GKRS at our center mainly comprised of patients
referred from across the country. From the referring hospitals, generally, either
the neurosurgeons or a team comprising of radiation oncologists and head-and-neck
surgeons referred the patients to our center for GKRS. The patients were then reassessed
at our center by the GKRS specialist team as per our institutional policy. The policy
adopted by us was in line with international practice—patients with benign lesions/metastases
having volumes less than approximately 13 cc were considered suitable for GKRS. Such
cases when found inoperable or on patients' preference were taken up for GKRS. Occasionally,
a primary cranial malignancy was also chosen for GKRS. In some cases, larger volumes
were also considered for want of any other safer treatment modality. Large AVMs fell
in this category. Volume-staged GKRS with a gap of 4 to 6 months between the two GKRS
sessions was performed in such cases. An interventional radiologist was mandatorily
part of the GKRS team in the case of AVM. Most of the cases treated with volume-staged
GKRS were treated in two stages,[7] and a few rare ones in three stages. The part of the volume containing either the
main nidus or the part that was close to any critical structure was considered for
the first session of GKRS. The volume division was based on certain anatomical landmarks
to ensure easy identification for dose matching later with the remaining part of the
volume to be considered for second session of GKRS. The second session of GKRS was
delivered after 4 to 6 months of the first session. The dose in the second session
was usually approximately 2 Gy less than the first GKRS session. Deliberate efforts
were made to avoid or minimize dose spills between the two parts of the AVM volume.
In large AVMs where volume-staged GKS was either ruled out due to patient's preference
or was considered risky due to potentially high-dose region overlap between the volumes,
an unconventionally low dose covering the entire AVM volume was delivered as a last
option of treatment. The patient was kept on follow-up to assess for reduction in
nidus volume. If the nidus volume shrank noticeably between 6 and 12 months or even
later post-GKRS, then another GKRS session with still lower dose was planned.
Occasionally, a medical physicist connected with the GKRS facility was also consulted
on technical feasibility in situations such as extremely peripheral location of the
tumor or presence of a critical OAR in close vicinity of the tumor. During case selection
for GKRS, we realized early on that there was a learning curve for the entire team.
The first most important learning was that due to space constraints within the helmet
system of LGK 4C, frame fixation was critical for feasibility of treatment execution
for tumors/targets that were located at extreme periphery of the skull. It warranted
positioning of the frame in such a way to keep the tumor well inside the four sides
and well above (at least ∼20 mm) the top edge of the G-frame. To facilitate the fixation
of the frame at the appropriate position, we decided to keep MRI scans of the patient
on display in all three major planes in the cubicle where the frame was being fixed
by the neurosurgeon. We also realized that the frame once fixed needed to be tested
to ensure that the pins holding frame to the scalp were tight enough to prevent their
movement/slippage afterwards. Any movement/slippage of the pins from their position
after the imaging meant repetition of the entire process all over again either on
the same day or on the next available GKRS slot. In the case of multiple tumors, the
team identified, in advance, the tumors that could be irradiated in one session and
accordingly positioned the frame fixation on the skull to avoid potential collisions
with the helmets during treatment execution.
. All patients, right from the first case till the 1000th case, were included in the
study. Diagnosis for benign tumors was clinical and image based if prior surgery or
biopsy was not performed.
Results and Discussion
The various types of intra cranial disorders treated with GKRS at our center are summarized
in [Table 1]. It is observed that acoustic schwannoma (AS) formed the largest group of patients
(27%) followed by meningioma (21%), AVM (18%), pituitary adenoma (PA; 16%), metastasis
(5.3%), trigeminal neuralgia (3%), cavernoma (2.4%), glomus jugulare (1.8%), craniopharyngioma
(1.1%), and “Others”(5%). The “Others” category clubbed all the less frequent cases
treated at our center for broad categorization purposes. It included all cases of
malignant tumors, except metastases, and other less frequent benign conditions. Of
the 50 disorders in this category, 39 were benign tumors such as paraganglioma, schwannomas
other than AS, and neurofibromatosis type 2. The malignancies in this category were
mainly recurrent type that included low- and high-grade astrocytomas, hemangiopericytoma,
medulloblastoma, adenocystic carcinoma orbit, pineal papillary carcinoma, and carcinoma
maxilla.
Table 1
Summary break-up of 1,000 cases treated with Gamma Knife at our center
|
Sr no.
|
Diagnosis
|
Total no. of cases
|
Male
|
Female
|
Age in years
Median (range)
|
Lesion volume (cc) Median (range)
|
Primary[a]
|
Dose (Gy)
Median (range)
|
|
1
|
Acoustic schwannoma
|
271
|
148
|
123
|
48(12–75)
|
2.33(0.07–36.2)
|
181
|
12(11–13)
|
|
2
|
Meningioma
|
208
|
75
|
133
|
52(11–88)
|
4.22(0.29–17.1)
|
114
|
13.9(10–16)
|
|
3
|
Arteriovenous malformation
|
177
|
118
|
59
|
30(6–75)
|
3.6(0.05–18.8)
|
151
|
20 (12–25)
|
|
4
|
Pituitary Adenoma
|
161
|
89
|
72
|
41.5(13–81)
|
3.7(0.09–16.1)
|
14
|
19(11–25)
|
|
5
|
Metastasis
|
53
|
25
|
28
|
53(33–74)
|
0.77(0.11–4.8)
|
52
|
18(15–23)
|
|
6
|
Trigeminal neuralgia
|
27
|
17
|
10
|
58.5(44–80)
|
NA
|
26
|
80 (70–80)
|
|
7
|
Cavernoma
|
24
|
15
|
9
|
34(3–57)
|
1.5(0.2–8.4)
|
24
|
16(11.5–22)
|
|
8
|
Glomus Jugulare
|
18
|
5
|
13
|
41(29–76)
|
3.55(1,1–11)
|
7
|
18(13–20)
|
|
9
|
Craniopharyngioma
|
11
|
10
|
1
|
28(14–50)
|
4.6(0.8–5.3)
|
2
|
12(10–14)
|
|
10
|
Others
|
50
|
28
|
23
|
NR
|
NR
|
NR
|
NR
|
Abbreviations: NA, not applicable; NR, not relevant.
a Primary: Gamma Knife radiosurgery as primary treatment.
For ease of analysis and comparison with other centers, we divided the 1,000 cases
in four broad categories namely benign tumors, vascular disorders, malignant tumors
(including metastases), and functional disorders. The proportion of cases in these
categories was 70.8, 20.1, 6.4, and 2.7% in that order. Thus, the benign disorders
formed the largest proportion of all the indications treated at our center. The overall
Indian data between 1997 and 2018 shows the proportion of these categories at 67.3,
21.6, 6.5, and 4.6% in that order, which is close to our data.[2] The Indian case mix for the year 2018 is close to the overall case mix between 1997
and 2018. Our present data shows similar pattern. The situation is somewhat similar
to the one prevailing in North America during early 1990s when the vascular and benign
tumors formed the largest proportion of all the cases treated with GKRS. But the present
trend in North America is very different. In 2018, 63% of the cases treated with GKRS
were in the malignant category followed by benign tumors (23.2%), functional disorders
(10.1%), and a minor proportion of vascular/ocular disorders.[2] The GKRS case mix of Asia for 2018 is also different from our data. The malignant
tumors formed the largest group (48.5%) followed by benign tumors (38%) and vascular
disorders (9.5%) in Asia. Japan has a very unique statistic for GKRS. In the year
2018 the case mix revealed predominantly malignant tumors (74.1%) being treated with
GKRS followed by benign tumors (19.5%) in Japan. Interestingly, the data from Middle
East and Africa for 2018 is similar to our data with benign tumors (67.7%) followed
by vascular disorders (13.2%), malignant tumors (12.5%) and functional disorders,
and others (6.6%).[2]
As shown in [Table 1], 181 out of 270 patients, that is,67% of AS cases, GKRS was the primary treatment.
These patients either had small tumor volumes or were considered as risk for open
surgery due to their associated medical condition/age or they opted for GKRS in place
of surgery. Hearing status was assessed by pure tone audiometry before the GKRS. Sixty-eight
of two-hundred seventy-one patients had either complete hearing loss or no functional
hearing in the affected side before GKRS. The institutional protocol for dose prescription
was 12 Gy at the tumor margin. However, proximity of critical structures such as brain
stem and cochlea around the tumor sometime did not allow the 12 Gy prescriptions.
At times tumor coverage was compromised to spare the OARs. Patient's informed consent
was taken on such occasions.
Among the top four disorders treated at our center with GKRS, PA tumors were the ones
with minimum percentage (9.9%) for which GKRS was a primary treatment. Probably, less
invasiveness of the transnasal trans-sphenoidal procedure for PA was the reason for
this. In the case of functional PA, which constituted 46% (67/145) of all PAs, quicker
symptom relief expected from surgery could be another reason for choosing it over
GKRS. Also, 51/145 PA cases had diminished vision. Most of these patients were nonfunctional
PAs who needed faster interventions to stop further deterioration of vision/improvement
in vision. In the case of cavernoma, GKRS was the primary treatment for all the cases.
About 50% of all the cavernoma cases were pontine cavernoma. In the case of AVMs,
18/177 cases were treated in two stages and one in three stages due to large volumes
of the nidus. Of the 53 cases of metastasis treated, 28 cases of single metastasis,
23 cases of two metastatic tumors, and 02 cases of three tumors were treated in single
sessions.
As for reirradiation, four cases of PA, three cases each of AS and AVM, and one case
each of meningioma and trigeminal neuralgia (TN) were reirradiated. The GKRS reirradiation
interval average was 3 years. In the case of PA, the reirradiation was after external
beam radiation therapy for all the four cases.
A retrospective review of first 1,017 radiosurgery treatments for intracranial lesions
by Bir et al[5] at Louisiana State University Health- Shreveport, Los Angeles, United States, between
2000 and 2013 revealed the following statistics: AS(82), meningioma (136), metastatic
brain tumors (298), astrocytoma (49), PA (92), AVMs (85), and TNs (169). The University
of Pittsburgh, United States treated a total of 13,500 cases with GKRS from 1987 to
2015. The composition of the cases was 44% malignant tumors, 34% benign, 13% vascular,
and 9% functional.[8] Our data differs from this statistic. One major difference is in the proportion
of metastatic brain tumors. At our center, it is the fifth largest number (53) as
compared with being the largest in the two quoted studies. The worldwide statistics
(2018) is also in line with the quoted studies for metastatic tumors. Similarly, share
of benign tumors is over 60% in our case as compared with 36.9% of the worldwide data
of 2017. As for functional disorders, in our case the share is 2.7% as against 16.9%
of Bir et al.[5] The worldwide share of functional disorders in 2018 was 6.1%. The reasons for these
variations could be many. As mentioned in the introduction section of this article,
incidence rate, preferences of the treating experts as well as that of patients, reputation
of a center, and even local sociocultural factors could be responsible for the variations.
Hamilton et al[4] in their worldwide survey on potential utilization of GKRS showed that the role
of GKRS for meningiomas, metastatic tumors, and AVMs had the highest consensus among
centers worldwide. In contrast there were considerable differences among centers with
regard to the management of pituitary tumors and craniopharyngiomas. In North America,
among the 33,718 cases of benign conditions treated in 2018, the most common ones
were meningiomas (42.4%), followed by AS (24.6%), and PA(14%).[2] At our center, 42% of the benign tumors were AS, 32.6% were meningioma, and 25.2%
were PA. In a study by Boari et al,[7] 72.5% of the AS tumors underwent GKRS as primary treatment that is comparable to
our practice of 69.5%.
A perspective on the usage of GKRS and differences and similarities of our data with
the overall worldwide data can be formed from the latest report (2019) of the Leksell
Gamma Knife Society.[2] The report showed that more than 1.2 million patients had been treated with GKRS
from 1968 till 2018. As per the report, of the approximately 7,000 total indications
treated worldwide in the year 1991, the share of malignant tumors was far less than
benign tumors and vascular disorders. The situation in 2018 became quite different
though. Of the total of over 84,000 indications treated in 2018 the share of malignant
tumors went up substantially (47.4%) as compared with benign tumors (37.9%). At the
same time, the share of vascular disorders decreased from over 50% in 1991 to approximately
8.3% in 2018. Another trend visible worldwide was the increasing share of functional
disorders being treated with GKRS from about nil till 1993 to 6.1% in 2018.
Conclusion
We have presented the profile of first 1,000 cases treated at our center with GKRS.
The case mix at our center is similar to the overall Indian case mix. However, it
is quite different from the international data of most of the regions/countries except
for the Middle East and Africa. Any country or region has its own established practice
borne out of years of experience and hence the treating and referring doctors, and
also the clientele develop bias for certain treatment modality. The bias may have
scientific logic but the best technological solution may not always be chosen due
to this bias. For example, Japan has the highest density of GKRS units per capita
in the world. Also, their case mix is quite unique with an overwhelming proportion
of cases treated with GKRS being malignant tumors. Among the various categories of
cranial disorders treated by us, PA tumors had minimum (8.6%) and cavernoma tumors
had maximum (100%) proportion of cases managed with GKRS as primary treatment modality.
Availability of GKRS has indeed helped the neurosurgeons optimize surgery to mitigate
the risks of surgical morbidity. For example, in the cases of AS, meningiomas, or
PAs, if complete resection is fraught with potential morbidity, then a part of the
tumor can be left behind to be later tackled with GKRS. With more awareness about
GKRS in the peripheral referring hospitals and emphasis on quality of life, we too
expect more cases of brain metastases being treated with GKRS in place of whole brain
radiotherapy. A well-trained and motivated team comprising of neurosurgeons, radiation
oncologists, and medical physicists is a must for safe and effective GKRS. In addition,
interventional radiologists for AVM and other vascular lesions and head and neck surgeons
for AS also need to be involved for optimum case selection. Close and cordial coordination
with radiological imaging center of the hospital, especially with the MRI facility,
helps a great deal in creating smooth workflow and optimal imaging sequences. The
clinical outcome study based on long-term follow-up for the first 1,000 cases is currently
being analyzed systematically. However, a preliminary assessment of the data indicated
that our results are broadly in line with the published studies world over. For example,
at a minimum of 2 years follow-up, the tumor control rates for AS and meningioma are
over 90% with less than 5% major adverse radiation reactions such as tumor swelling
or edema requiring surgical intervention.[9]
