6.0 RADIATION THERAPY
6.1 Whole Brain Radiation Therapy
6.1.1 Total Dose: Whole brain radiation therapy (WBRT) must begin within one week of
randomization. One treatment of 2.5 Gy will be given daily 5 days a week for a total of
37.5 Gy. Both portals shall be treated during each treatment session. The WBRT regimen
will be identical for both arms.
6.1.2 Physical factors: Treatment will be delivered using megavoltage machines with
photon beams ranging from 4 to 8 MV. The minimum dose rate at the midplane in the brain on
the central axis must be 0.50 Gy/minute. Electron, particle, or implant therapy is not
permissible.
6.1.3 Simulation, Immobilization, Localization: The patient will be treated in the
supine position. Adequate immobilization and reproducibility of position must be ensured.
The target volume will cover the brain and the meninges to the foramen magnum.
6.1.4 Treatment Planning: Treatments must be delivered through parallel opposed fields
that cover the entire cranial contents. There should be beam fall_off of at least 1 cm.
The eyes will be excluded from the beam either by field arrangement or shielding.
6.1.5 Dose Specification: Doses will be specified at the central axis at midplane on
the brain. For the following portal arrangments, the target dose shall be specified as
follows:
6.1.5.1 For two opposed coaxial equally weighted beams: On the central ray at
mid_separation of beams.
6.2 Radiosurgery (3/17/98)
6.2.1 Timing: Radiosurgery must be delivered within seven days of
completion of whole brain radiation in Arm 1. Only those patients assigned to Arm 1
are eligible to receive SRS as a component of initial therapy. It is possible that at the
time of radiosurgery, one of these scenarios occur:
An identified metastasis at the time of enrollment now exceeds the acceptable upper
limit diameter (4.0 cm for a solitary metastasis, or 3.0 cm for multiple metastases). If
any one metastasis exceeds the limit at the time of radiosurgery, the lesion should not be
treated.
If a lesion disappears after the course of conventional radiation this lesion should
not be targeted for radiosurgery.
If more than three lesions exist at the time of radiosurgery, radiosurgery should be
delivered to the three largest treatable lesions that meet the eligibility criteria. The
physicians submitting the films should circle and number (1-3) with wax pencil,
each lesion so each lesion can be uniformly identified and teh response to treatment can
be evaluated for each corresponding lesion.
6.2.2 Total Dose Determination: The total dose is dependent on
the size of the metastastic lesion(s) as follows:
|
Maximum Tumor Diameter
2.0 cm
2.1-3.0 cm
3.1-4.0 cm |
Assigned Dose
24 Gy
18 Gy
15 Gy |
6.2.4 Target Volume Determination:
6.2.4.1 Target volume and isocenter determination will be based on a contrast enhanced
CT scan with the patient's head in a stereotactic frame. The imaging study used to deliver
the radiosurgical treatment must be the same as used to determine size of the metastatic
lesion(s).
6.2.4.2 Stereotactic CT or MRI slice thickness may not exceed 3 mm.
6.2.4.3 The target volume will include the enhancing portion of
the metastatic lesion. Surrounding areas of edema will not be considered part of the
target volume.
6.2.5 Dose Prescription and Dosimetry Requirements
6.2.5.1 The dose will be prescribed to the isodose surface (50-90% [maximum = 100%])
which encompasses the margin of the metastasis, as defined by the imaging studies. The
100% (maximum) dose will be recorded for each patient. The prescription dose shall be
delivered to the 50-90% (maximum = 100%) isodose surface, and is defined as the minimum
dose to the target volume. The minimum dose shall be established by an examination of the
dose distribution on each axial level on which the target volume has been defined, and/or
by the target dose_volume histogram.
6.2.5.2
For patients with one, two, or three brain metastase(i)s, each lesion will be
assigned to a SRS dose level according to its maximal diameter. If any two lesions are
within 0.8 to 2 cm cm of each other, the intervening midplane dose will not exceed 13.0
Gy. This dose may represent a dose to each respective target that will be less than the
dose prescription listed in Section 6.2.2. A second stipulation will involve size. If one
lesion is > 3.0 cm the remaining two metastases may not exceed 3.0 cm each in diameter.
This stipulation is designed to minimize toxicity in patients with larger volume multiple
metastases. A review of patient and tumor criteria among patients entered into RTOG 91-04,
a phase III trial for patients with unresected brain metastase(i)s, would suggest
that the majority would meet the entry criteria of this trial.
BACKGROUND INFO: Metastases to
the cranium and intracranial contents are the most common malignancy affecting the brain.6, 8,33 Of these, parenchymal brain metastases
are the most common symptomatic lesions. Autopsy series have shown that as many as 25% of
patients who die of cancer will have intracranial metastases, involving brain substance in
about 15%.33 The
majority of patients with intraparenchymal metastases have only one or two metastases, 49%
and 21%, respectively, and the remaining 30% three or more. Approximently 80% of
brain metastases are located supratentorially.11
Standard treatment for brain metastasis(es) include glucocorticoids and external beam
whole brain irradiation (WBRT) which effectively relieve symptoms and restore neurological
function in most patients.34
Untreated patients have a median survival time (MST) of less than 7 weeks.7 Three prospective randomized trials involving
more than 1800 patients conducted by the Radiation Therapy Oncology Group (RTOG) evaluated
9 different radiation doses and schedules.5 All doses up to 50 Gray (Gy) were equivalent with respect to toxicity,
neurological improvement, and survival. Higher doses resulted in greater neurologic
toxicity. MST of all patient subgroups were three to six months. Little difference was
found between patients who received 20 Gy administered over one week and 40 Gy
administered over four weeks. Furthermore, radiation boost treatment to the metastatic
site did not improve on WBRT.17 Currently, 30 Gy of WBRT delivered in 10 fractions is considered standard
treatment in the United States.
The most common cancers to metastasize to brain are lung and breast, 34 and 30%,
respectively. Of the approximately 200,000 patients with these malignancies who will die
each year, 124,000 will have brain metastases.6 The cause of death in almost 50% is persistence of lesions
or recurrence following WBRT; however, 10 to 15% of patients will survive at least one
year.4, 10, 29 These data, along
with the fact that brain metastases are so frequently single, provide the rationale for
the development of treatment modalities that exceed current palliative measures to
actually improve patient survival.
Surgical resection of brain metastases is increasingly
performed on patients with favorable prognostic factors, accessible lesion(s), and/or
metastatic lesions from relatively radio_insensitive tumors such as renal cell carcinoma
and melanoma.14, 17, 28, 34, 38 Since metastases are usually well demarcated from surrounding brain,
complete removal with a minimum of morbidity and mortality is often possible. Relief
of symptoms of intracranial hypertension and focal brain dysfunction has been
demonstrated. Patient survival is also dependent on the extent of extracranial disease.
For patients who have undergone removal of solitary brain metastases, the addition of WBRT
has been shown to result in a lower incidence of brain recurrence.34 Intergroup #0124 was testing whether there is a major benefit with the addition
of WBRT; however, this study closed due to poor accrual. Two prospective randomized trials
in which surgical excision followed by radiation therapy compared to radiation therapy
alone in patients with single metastases have been done.29, 39 Patchell and colleagues randomized patients with single metastases to either
surgical excision followed by WBRT (25 pts) or biopsy followed by WBRT (23 pts). The MST
of patients who underwent surgical resection rather than biopsy were 40 and 21 weeks,
respectively; functional independent survival times were 38 and 8 weeks, respectively, and
the intracranial recurrence rates 20 and 52%, respectively These results confirmed those
of earlier uncontrolled studies showing the benefits of surgical resection.14, 29, 31 Vecht et al. randomized 63 patients
to the same regimens with similar results. Bindal et al., in a retrospective analysis of
56 patients with multiple resected metastases, 50% of whom received WBRT, reported a MST
equivalent to that of patients with a single resected metastasis but longer than that of
patients who had one or more lesions remaining after surgery.4 Based on these reports, surgical removal in patients with a solitary accessible
lesion followed by WBRT appears superior to WBRT alone for selected patients.
The post-operative delivery of WBRT for such patients is considered
beneficial to sterilize residual disease in the tumor bed or other sites of occult disease
in the brain. There are several retrospective studies involving relatively small numbers
of patients in which surgery followed by WBRT has been compared to surgery alone.35,16,12 Smalley and colleagues demonstrated a
statistically significant difference in survival and fewer recurrences in 85 patients who
received WBRT following surgery.35
In a second retrospective analysis by the same investigators, the MST among 229 patients
was 15 months for those who underwent surgery followed by adjuvant WBRT as compared to 8
months for patients who underwent surgery but did not receive WBRT.36 On the other hand, Hagan et al. found no advantage to WBRT following surgery in
patients with melanoma, a radioresistant tumor.16 Likewise, Dorsoretz et al. found no survival advantage to low dose WBRT among 33
patients with resected solitary lesions and no active systemic cancer.12
Recent reports have suggested a role for stereotactic radiosurgery (SRS)
in the treatment of metastatic brain tumor.The recent development of linear accelerators
modified to deliver focused irradiation has expanded the availability of SRS.Advantages of
SRS are ease of administration from the patient's viewpoint (one_day treatment), the
ability to treat metastases located in areas of the brain not amenable to complete
surgical resection, and the potential to decrease neurosurgery and radiation related
morbidity and mortality.SRS allows delivery of a high dose of focal irradiation in a
single fraction to the tumor from multiple geometric positions