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Current Status and Optimal Use of Radiosurgery

Current Status and Optimal Use of Radiosurgery

ABSTRACT: The field of stereotactic radiosurgery is rapidly advancing as a result of both improvements in radiosurgical equipment and better physician understanding of the clinical applications of stereotactic radiosurgery. This article will review recent developments in the field of radiosurgery, including advances in our understanding of the treatment of brain metastases and arteriovenous malformations, as well as the use of stereotactic radiosurgery as a boost following conventional radiation for nasopharyngeal carcinoma to minimize the rate of local recurrence. In addition, improved understanding of the radiobiology of normal neurologic structures adjacent to tumors undergoing radiosurgery has led to the use of fractionated stereotactic radiosurgery for the treatment of acoustic neuromas and tumors bordering the anterior visual pathways. Finally, a breakthrough in radiosurgery involving the development and use of frameless, image-guided stereotactic radiosurgery has allowed for both dose homogeneity and treatment of intracranial lesions based on nonisocentric treatment algorithms that result in improved target conformality. This same frameless radiosurgical system has also expanded the scope of radiosurgery to include the treatment of extracranial lesions throughout the body. [ONCOLOGY 15(2):209-221, 2001]

Introduction

Radiosurgery combines stereotactic techniques (to achieve
precise three-dimensional localization) with highly focused high-energy radiation
treatments. This procedure makes it possible to deliver a very large dose of
radiation to a small target while minimizing the dose outside the target volume.
A previous report surveyed the clinical results and complications associated
with radiosurgery for the treatment of metastatic tumor, primary glioma,
arteriovenous malformation (AVM), and benign conditions including pituitary
tumor, acoustic neuroma, and meningioma.[1]

Over the past several years, however, radiosurgery has advanced
rapidly. Physicians now have a better understanding of the use of radiosurgery
in the treatment of brain metastases, including whether or not the addition of
whole-brain irradiation provides any advantage over stereotactic radiosurgery
alone. Large AVMs, previously considered difficult to treat, are now routinely
treated with radiosurgery either through staged treatments or as part of a
multimodality regimen. Radiosurgery has also evolved as a potential therapy
following standard radiation for nasopharyngeal carcinoma. Improved local
control and survival rates have been reported for this common cancer.

Advances in both technique and radiosurgery equipment have led
to the use of hypofractionated radiosurgery in selected cases (which is believed
to reduce patient morbidity) and frameless image-guided radiosurgery (which has
resulted in both increased flexibility of treatment, as well as treatment of
lesions outside the head). The following discussion focuses on our experience
with these radiosurgical advances at Stanford University.

Advances in the Treatment
of Brain Metastasis

Stereotactic Radiosurgery

Stereotactic radiosurgery has emerged as a treatment for
patients with brain metastasis, either with or without whole-brain radiation
therapy (WBRT), with an 85% to 95% control rate.[2-7] Median survival after
radiosurgery (6.4 to 10 months)[3,4,6-12] is comparable to survival rates
that have been reported with surgical resection followed by conventional
fractionated radiotherapy (4 to 13 months),[13,14] with good local
control.[3,4,6-8,10-12,15,16] Recent studies have shown that patients treated
with radiosurgery for either one or two brain metastases have a prolonged
survival similar to that achieved with surgical resection.[2,5,9]

The success of stereotactic radiosurgical treatment of brain
metastases has raised the issue of whether WBRT in conjunction with radiosurgery
represents a treatment advantage over radiosurgery or WBRT alone. Reporting a
series of 105 patients treated from 1991 to 1997, Sneed et al observed that
response rates with radiosurgery alone were not statistically different from
those achieved with radiosurgery plus WBRT, with respect to freedom from
progression (71% vs 79%) and median survival (11.3 vs 11.1 months).[17] In
contrast, Fuller et al reported a series of 27 patients with 41 metastatic
tumors and noted that radiosurgery plus WBRT achieved statistically superior
disease control (P = .0007), compared with radiosurgery alone.[18]

In a review of 97 patients who had been treated for two to four
brain metastases, Schoeggl et al concluded that stereotactic radiosurgery
provided an equivalent rate of survival, compared to the historic experience of
patients treated with WBRT.[19] However, their review did not compare a subset
of patients treated with radiosurgery alone to those treated with radiosurgery
plus WBRT.

Kondziolka et al reported a randomized trial of WBRT vs
radiosurgery plus WBRT, which showed that WBRT combined with radiosurgery in
patients with two to four brain metastases significantly improved the control of
brain disease.[20] The 1-year rate of local failure was 8% for radiosurgery and
WBRT combined, compared to 100% for WBRT alone. The median survival with WBRT
alone was 7.5 months, compared to 11 months for WBRT plus radiosurgery. While
the median time to local failure and time to any brain failure were
statistically significant (P =  .0005 and .002, respectively), median
survival was not statistically different, perhaps because of the relatively
small number of patients (N = 27) in the study.

Stanford Treatment Algorithm

Based on our own experience and that of other institutions, a
fairly well-established algorithm for treating patients with multiple brain
metastases is followed at Stanford.[21] Whole-brain irradiation is the preferred
treatment for patients with progressive systemic disease, poor performance
status, or more than four lesions. Patients with multiple lesions who undergo
WBRT and have a subsequent reduction in the radiographic number of metastases
may be candidates for a stereotactic radiosurgical boost to the residual tumors
if there are four or fewer lesions.[3,22]

Patients with stable systemic disease and a good performance
status but who have mass effect from one or more tumors are candidates for
surgical resection of their symptomatic lesions, with radiosurgery or radiation
therapy used for the remaining smaller tumors. Patients with stable systemic
disease, a good performance status, and no mass effect from their brain
metastases (four or fewer tumors) are optimal candidates for stereotactic
radiosurgery.[22] A 91% tumor control rate has been observed in this
population.[3]

At our institution, most patients undergoing radiosurgery for
multiple brain metastases are treated with WBRT and radiosurgery, whereas
patients with a single brain metastasis are often treated with radiosurgery
alone. Whole-brain irradiation is reserved for tumor recurrence/progression and
new brain tumors associated with a poor performance status or progressive
systemic disease. Unlike conventional brain irradiation, radiosurgery can be
repeated for metachronous lesions months to years after initial treatment.

Multimodality Treatment
of AVMs

Stereotactic radiosurgery is an excellent treatment for small to
moderately sized AVMs, particularly those located in surgically inaccessible
regions or in patients who are poor candidates for surgery.[23-26] Such
obliteration typically takes place over 2 to 3 years. Arteriovenous
malformations less than 4 cm in diameter treated with 20 to 25 Gy have a 3-year
obliteration rate of 76% to 95%, with low morbidity (2.5% to 4.5% of patients
develop permanent neurologic deficits; 2.5% to 4.5%, transient deficits).[23-30]

Although radiosurgical treatment of smaller AVMs is routine,
larger AVMs often present a greater challenge. Arteriovenous malformations
greater than 4 cm in diameter have only a 33% to 50% rate of obliteration
at 3 years after radiosurgery but a 20% to 30% complication rate following
treatment at doses of 15 to 20 Gy.[23,25,26] The rate of obliteration increases
for larger AVMs with the use of higher doses (25 to 45 Gy), but the risk of
radiation-induced complications also increases.

Overall treatment morbidity for large to giant AVMs can be
reduced with multimodality therapy—ie, combinations of embolization,
stereotactic radiosurgery, and microsurgery.[31,32] Our previous experience with
large and complex AVMs has shown that such multimodality therapy can reduce
patient morbidity and mortality.[31]

Embolization obviously reduces the nidus volume requiring
resection, but having had stereotactic radiosurgery several years prior to
surgical resection also produces a benefit. In some patients, partial AVM
thrombosis significantly reduced the volume of residual AVM.[31]

Some authors have recommended staged stereotactic radiosurgery
when treating large AVMs.[33] In these cases, multiple radiosurgery treatments
are delivered to different portions of the AVM at various time intervals to
avoid delivering treatment to a single large target, thereby theoretically
reducing the risk of radiation necrosis. This option has been applied in
selected patients.[31,34] The disadvantages of such an approach are the second
latency period of 1 to 3 years before obliteration occurs, the possibility that
a second radiosurgery treatment may still not obliterate the AVM, and the risk
of radiation-induced injury, which may
be higher with a second radiosurgery treatment.

Stereotactic Radiosurgery Boost
for Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma arises in the mucosa or submucosa of
the nasopharynx, and frequently spreads to the skull base. Given the
radiosensitivity of the tumor, radiotherapy is the primary treatment. However,
there is a significant incidence of local failure (26% to 100%) in more advanced
cases after treatment with conventional radiotherapy.[35-37] Although higher
radiation doses or brachytherapy boosts increase local control,[35,37-40] the
possibility of normal tissue injury and/or the inability to effectively treat
tumor extension to the skull base limit the usefulness of these techniques.
Because of the historically high local failure rate, we developed a protocol to
deliver a planned stereotactic radiosurgical boost following conventional
radiotherapy in patients with nasopharyngeal carcinoma.

From October 1992 to December 1998, 23 patients at Stanford
University Medical Center underwent radiotherapy followed by planned
radiosurgery as initial management of a newly diagnosed, biopsy-proven
nasopharyngeal carcinoma. The total dose of radiotherapy to the nasopharynx was
66 Gy, divided into daily treatments of 200 cGy. Elective neck irradiation to a
dose of 50 Gy was also used; involved lymph nodes received radiation boosts
to a total dose of 66 Gy. In addition to the radiotherapy, 15 patients received
cisplatinum-based chemotherapy.

Within 4 weeks of completing radiotherapy, patients were treated
with radiosurgery. Treatment was administered with one to four isocenters,
depending on tumor volume and shape. The prescribed dose of radiation was
delivered to the periphery of the original lesion, corresponding to the 80% to
85% isodose contour. The median dose was 12 Gy (range: 7 to 15 Gy). Mean
follow-up was 27 months (range: 8 to 72 months), with 12 patients followed for
more than 2 years, and 7 patients followed for more than 3 years.

Stanford Study Results

Throughout the course of follow-up, there were no local
recurrences among the 23 patients treated with radiosurgery (Figure 1). Cervical
lymph node recurrences developed in two patients, and seven patients developed
distant metastases including liver (1), lung (2), and bone (4). Of these seven
patients, four expired as a result of their metastases.

Simultaneous cisplatin (Platinol)-based chemotherapy and
radiotherapy followed by radiosurgery was administered to 15 patients. No
significant difference in relapse-free survival was observed, but a trend
favored the chemotherapy group: Actuarial relapse-free survival at 3 years was
59% among patients receiving chemotherapy and radiotherapy followed by
radiosurgery, compared to 37.5% in the patients who were treated with
radiotherapy or radiosurgery alone. No patient developed either acute or late
complications following radiosurgery.

Study Conclusions

Our preliminary experience showed that a high rate of local
control can be achieved with stereotactic radiosurgery even in patients with
advanced-staged nasopharyngeal carcinoma. We believe that radiosurgery is more
effective than brachytherapy in such cases because of the ability of
radiosurgery to effectively treat the base of skull. Although intracavitary
brachytherapy in the nasopharynx is likely to be effective in treating tumors
confined to the mucosa or submucosa, it is unlikely to eradicate a larger mass
that extends several centimeters beneath the mucosal surface. Radiosurgery not
only provides the same benefits as brachytherapy (ie, relative sparing of normal
tissues and the ability to safely boost regions of involvement to high doses),
but it can also deliver a high radiation dose to sites that are remote from the
nasopharynx.

Although longer follow-up is needed, radiosurgery following
radiation has resulted in 100% local control of nasopharyngeal carcinoma in a
small group of patients. Based on this experience, patients with advanced
nasopharyngeal carcinoma treated at Stanford receive a 66-Gy dose of radiation
with concurrent cisplatin chemotherapy, followed by 12-Gy radiosurgery to the
primary site, after which three more cycles of cisplatin/fluorouracil
chemotherapy are administered. Despite the benefits of this approach, it is
obvious that more effective chemotherapy is needed to decrease the incidence of
late systemic recurrence in this patient population.

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