Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 4, pp. 1128–1133, 2011Copyright � 2011 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/$–see front matter

jrobp.2010.03.047

doi:10.1016/j.i

CLINICAL INVESTIGATION Brain

PHASE I TRIAL OF SIMULTANEOUS IN-FIELD BOOST WITH HELICALTOMOTHERAPY FOR PATIENTS WITH ONE TO THREE BRAIN METASTASES

GEORGE RODRIGUES, M.D., M.SC.,* SLAV YARTSEV, PH.D.,* BRIAN YAREMKO, M.D.,*

FRANCISCO PERERA, M.D.,* A. RASHID DAR, M.D.,* ALEX HAMMOND, M.D.,* MICHAEL LOCK, M.D.,*

EDWARD YU, M.D.,* ROBERT ASH, M.D.,* JEAN-MICHELLE CAUDRELIER, M.D.,yDEEPAK KHUNTIA, M.D.,z

LAURA BAILEY, C.C.R.P.,* AND GLENN BAUMAN, M.D.*

*Department of Oncology, University of Western Ontario and London Regional Cancer Program, London Health Sciences Centre,London, ON, Canada; yDepartment of Radiation Oncology, University of Ottawa, Ottawa, ON, Canada; zDepartment of Human

Oncology, University of Wisconsin, Madison, WI

ReprinRegionalCommiss685-8500rodrigues@

Purpose: Stereotactic radiosurgery is an alternative to surgical resection for selected intracranial lesions. Inte-grated image-guided intensity-modulated-capable radiotherapy platforms such as helical tomotherapy (HT) couldpotentially replace traditional radiosurgery apparatus. The present study’s objective was to determine the max-imally tolerated dose of a simultaneous in-field boost integrated with whole brain radiotherapy for palliative treat-ment of patients with one to three brain metastases using HT.Methods and Materials: The inclusion/exclusion criteria and endpoints were consistent with the Radiation Ther-apy Oncology Group 9508 radiosurgery trial. The cohorts were constructed with a 3 + 3 design; however, addi-tional patients were enrolled in the lower dose tolerable cohorts during the toxicity assessment periods. Wholebrain radiotherapy (30 Gy in 10 fractions) was delivered with a 5–30-Gy (total lesion dose of 35–60 Gy in 10 frac-tions) simultaneous in-field boost delivered to the brain metastases. The maximally tolerated dose was determinedby the frequency of neurologic Grade 3-5 National Cancer Institute Common Toxicity Criteria, version 3.0, dose-limiting toxicity events within each Phase I cohort.Results: A total of 48 patients received treatment in the 35-Gy (n = 3), 40-Gy (n = 16), 50-Gy (n = 15), 55-Gy (n = 8),and 60-Gy (n = 6) cohorts. No patients experienced dose-limiting toxicity events in any of the trial cohorts. The3-month RECIST assessments available for 32 of the 48 patients demonstrated a complete response in 2, a partialresponse in 16, stable disease in 6, and progressive disease in 8 patients.Conclusion: The delivery of 60 Gy in 10 fractions to one to three brain metastases synchronously with 30 Gy wholebrain radiotherapy was achieved without dose-limiting central nervous system toxicity as assessed 3 months aftertreatment. This approach is being tested in a Phase II efficacy trial. � 2011 Elsevier Inc.

Radiosurgery, Brain metastases, Helical tomotherapy, Phase I, Clinical trial.

INTRODUCTION

Brain metastases are a common cancer problem and the pa-

tient outcome with the currently available therapies remains

poor. Most patients with brain metastases undergo whole

brain radiotherapy (WBRT). Clinical trials have suggested

that selected subgroups of patients (i.e., younger age, good

performance status, extracranial metastases absent or con-

trolled, and/or a single brain metastatic site [1, 2]) might

benefit from more aggressive local treatment of their

intracranial disease with surgery or radiosurgery, often in

combination with WBRT (3, 4).

t requests to: George Rodrigues, M.D., M.Sc., LondonCancer Program, London Health Sciences Centre, 790

ioners Rd. E., London, ON N6A 4L6 Canada. Tel: (519), ext. 52833; Fax: (519)-685-8627; E-mail: george.

lhsc.on.ca

1128

Helical tomotherapy (HT) combines intensity-modulated

fan-beam RT delivery with megavoltage computed tomogra-

phy (MVCT) imaging for integrated patient positioning and

treatment delivery (5, 6). Such a combination provides

a potential alternative to conventional (7) stereotactic frame

systems for precision RT. Dosimetric comparisons of serial

tomotherapy or HT delivery for primary and metastatic brain

tumors have suggested comparable normal tissue sparing and

target coverage compared with other precision RT techniques

(8–12). HT (and other forms of intensity-modulated RT de-

livery) lends itself to synchronous boost strategies, because

multiple targets can be easily treated to different dose (and

dose per fraction) levels in the course of intensity-

Conflict of interest: none.Acknowledgments—The authors wish to thank Anne O’Connell andFrancis Whiston for clinical trial and data management support.

Received Jan 27, 2010, and in revised form March 30, 2010.Accepted for publication March 31, 2010.

SIB with HT for brain metastases d G. RODRIGUES et al. 1129

modulated RT delivery. Therefore, HT could potentially al-

low for radiosurgery-type boosts to be given synchronously

with the standard WBRT component; thus, the system could

be used to efficiently provide a boost to multiple brain metas-

tases without the need for separate stereotactic procedures.

We have previously reported the dosimetric feasibility of

using HT to deliver a boost synchronous with WBRT to

achieve intralesional biologically effective doses similar to

single-fraction stereotactic radiosurgery (12). Also, others

have recently reported the use of volumetric arc therapy

(13, 14). In the present report, we describe the results of

a Phase I dose-escalation trial of HT for one to three brain me-

tastases using WBRT with a simultaneous in-field boost tech-

nique (HT-SIB).

METHODS AND MATERIALS

Clinical trialThe institutional review boards at the participating institution ap-

proved the Phase I trial, which was registered (Ontario Clinical Tri-

als Registry OCT 1145 TOMO-B) according to the Consolidated

Standards of Reporting Trials (CONSORT) guidelines. Patient eligibil-

ity for the trial was as follows: histologically proven cancer; imaging

findings and clinical presentation consistent with brain metastases;

one to three brain metastases on pretreatment contrast-enhanced

CT or magnetic resonance imaging; lesion size of $5 mm and #3

cm in diameter; lesion >5 mm from the brainstem optic or optic ap-

paratus; Karnofsky performance status of $70; extracranial disease

absent, controlled, or planned to be treated (in the case of synchro-

nous presentation); anticipated survival >3 months; and no previous

cranial RT. The patients were allowed to have undergone previous

craniotomy provided residual tumor or additional unresected lesions

were present on postoperative imaging. The trial was designed ac-

cording to the typical Phase I dose escalation rules with five dose

levels for the SIB boost: 35, 45, 50, 55, and 60 Gy. The original trial

was designed to accrue 3 patients at each dose level, with a subse-

quent escalation if no dose-limiting toxicity (DLT) was seen at 3

months, with an additional 3 patients enrolled if 1 patient experi-

enced a DLT. DLT was as defined according to the National Cancer

Institute Common Toxicity Criteria, version 3.0, as Grade 3-5 cen-

tral nervous system (CNS) toxicity, including necrosis (symptom-

atic and interfering with activities of daily living, life-threatening

requiring intervention, or fatal). Once the trial began, it became ev-

ident that a considerable loss of patients had occurred to intercurrent

illness and systemic disease progression (despite the eligibility cri-

teria) before the 3-month assessment. Thus, the trial was modified

to allow 6 patients to be accrued at each dose level to ensure ade-

quate numbers of patients available for the 3-month assessment to

ensure timely completion of the trial. During the

3-month waiting period for the dose level under assessment, we

allowed enrollment at the previously evaluated dose level one step

below the current dose level. Patients were excluded from the

DLT analysis if the 3-month assessments for toxicity were unavail-

able, if patients had refused treatment after enrollment, or if they did

not complete all RT sessions as planned. The status of the patients

who were not evaluable at 3 months was confirmed by the primary

care physicians to assess the reason for the lack of the 3-month as-

sessment. This follow-up protocol was used to ensure that early

treatment-related toxicity was not responsible for the nonevaluable

status. The use of anticonvulsants and steroids was at the discretion

of the attending oncologist.

Toxicity was monitored weekly during treatment, every month

for 3 months after treatment, and then every 3 months for 1 year.

The response at 3 months after treatment was assessed from the im-

aging findings. Patients were accrued at 3–6 patients/dose level. Es-

calation to the next dose level occurred if no limiting (Grade 3 or

greater) toxicity was observed in >1 of 3 or >2 of 6 patients by 3

months after treatment. This endpoint was designed to be similar

to the Radiation Therapy Oncology Group 9005 radiosurgery

dose-finding study (15). The patients were also monitored for

long-term toxicity, understanding that the treatment paradigm being

explored was novel and that important CNS toxicity endpoints, such

as radionecrosis, might manifest after the initial 3-month observa-

tion point. In the case of patients who were not able to attend for im-

aging and/or clinical assessment at the 3-month follow-up because

of physical decline or death, the primary care physicians were inter-

viewed and the medical records (hospital admission notes, death

summaries, and laboratory and imaging reports) were obtained to as-

certain whether the reason for the early decline could have been

treatment-related toxicity. The attending radiation oncologist was

consulted and reviewed the information. Also, the available infor-

mation was reviewed independently by one of the study principle in-

vestigators (G.S.B.) for determination of possible treatment-related

toxicity.

Selection of optimization criteriaThe selection of the dose and fractionation prescription for the

trial was determined by previously reported experience with

single-fraction radiosurgery alone or combined with WBRT for pa-

tients with oligometastatic disease to the brain. Using the synchro-

nous boost technique, we calculated that a total intralesion dose of

60 Gy in 10 fractions delivered with a surrounding whole brain

dose of 30 Gy in 10 fractions would provide a similar biologically

effective dose to a radiosurgery boost of 18 Gy in one fraction com-

bined with WBRT to 30 Gy in 10 fractions (16, 17). Thus, we set

60 Gy in 10 fractions as the target maximal SIB dose level with

an interim SIB dose level of 35, 45, 50, and 55 Gy for this Phase

I trial. A maximal dose (D1) of 35 Gy in 10 fractions to the

brainstem and chiasm in the SIB treatment was estimated,

assuming a tolerance of 50 Gy in 25 fractions. This dose was used

as a dose constraint for these critical structures during inverse

planning.

Treatment planning and deliveryAll patients had a custom head-and-neck thermoplastic shell

(S-frame, CIVCO Medical Solutions, Kalona, IA) constructed for

simulation and treatment. A planning CT scan (Phillips Healthcare,

Andover, MA) through the whole head and upper neck was obtained

with a 3-mm slice thickness. Patients without a recent (<3 weeks)

contrast-enhanced diagnostic CT scan or magnetic resonance imag-

ing scan underwent contrast-enhanced CT scanning at simulation;

otherwise, the diagnostic CT scan was fused with the planning CT

scan for treatment planning purposes. The individual contrast-

enhancing lesions only were contoured as the SIB targets without

a margin, and the whole cranial contents with a 3-mm three-

dimensional margin was contoured as the target for the whole brain

treatment.

The planning parameters (18) used for the HT plans were a fan

beam thickness of 2.5 or 5.0 cm, pitch of 0.287–0.43, modulation

factor of 3.0, and a normal calculation grid (1.8 � 1.8 � 3 mm3).

Plans were generated for the dose level under evaluation, as well

as the next greater dose level to provide a running assessment of

the feasibility of proceeding to the next level. The treatment

Table. Helical tomotherapy planning constraints

Variable Type Importance Dmax (Gy)Dmaxpenalty

DVHvolume (%)

DVHdose (Gy)

DVHpenalty Dmin (Gy)

Dminpenalty

PTV Tumor 10 (d+1) 95 d NA d 100Brain Tumor 10 31 1 95 30 NA 30 100Optic chiasm OAR 100 30 200 2 30 10 NA NABrainstem OAR 10 30 100 2 30 50 NA NALeft eye OAR 10 30 1 78 5 33 NA NARight eye OAR 10 30 1 78 5 10 NA NALeft ON OAR 10 30 1 10 20 1 NA NARight ON OAR 10 30 1 10 20 1 NA NA

Abbreviations: Dmax = maximal dose constraint for structure; Dmax penalty = penalty weighting for violating Dmax dose constraint; DVHvolume = dose–volume histogram volume objective for structure; DVH dose = dose–volume histogram dose objective for structure; DVH pen-alty = penalty weighting for violating DVH dose constraint for structure; Dmin: minimal dose constraint for structure; Dmin penalty = penaltyweighting for violating minimal dose constraint for structure; PTV = planning target volume; d+1= phase I total dose plus 1 (in Gy); d+1 = phaseI total dose plus 1 (in Gy); NA = not applicable; OAR = organ at risk; ON = optic nerve.

1130 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 4, 2011

planning constraints specified for the inversely planned HT SIB

technique are outlined in Table 1 and have been previously reported

(12). An example of the isodose curves and dose–volume histo-

grams for a 60-Gy/10-fraction SIB case is illustrated in Figs. 1

and 2, respectively. For optimization and reporting purposes, the

maximal doses to organs were specified as the maximal dose to

a minimal, but still clinically significant, volume. For example,

the maximal dose to whole brain was specified as the maximal

dose to a minimal volume of 1% of the total brain volume (D1).

By specifying a minimal volume, spurious results owing to isolated

dose peaks within clinically insignificant volumes (e.g., a single cal-

culation voxel) were avoided.

All plans were verified in-phantom on the HT unit before treatment

began. The patients were treated using the thermoplastic immobiliza-

tion mask used for simulation, with positioning determined by co-

registration of the simulation kilovoltage CT scan with an MVCT

scan acquired on the HT unit immediately before treatment. The ini-

tial automated MVCT co-registration using the bone and soft tissue

setting on the HT unit was used with manual refinements by the ther-

apists before treatment. An attending radiation oncologist verified all

MVCT co-registrations on Day 1 of treatment.

RESULTS

Patient populationA total of 60 patients were registered for potential treat-

ment in the Phase I trial. Of the 60 patients, 12 (20%) were

Fig. 1. Sample of simultaneous in-field boost treat

excluded from the present analysis because of treatment re-

fusal by 6, ineligibility to receive treatment owing to a decline

in performance status from progressive disease in 4, and sub-

sequent loss to follow-up after treatment for 2. Both patients

lost to follow-up had been treated at the second dose level (40

Gy/10 intralesional boost). Therefore, 48 treated patients

(80%) were included in the present report. The mean age of

the patients receiving the protocol was 65.0 years (range,

39–90). Of the 48 patients, 30 (63%) were men. The median

Karnofsky performance status was 80 (range, 70–100). Of

the 48 patients, 34 (71%) had systemic disease at brain RT.

A total of 24 patients (50%) had been diagnosed with

a lung primary (23 with non–small-cell lung cancer, 1 with

small cell lung cancer). The other cancers included kidney

cancer in 7, breast cancer in 4, rectal cancer in 3, bladder can-

cer in 2, thyroid cancer in 2, sarcoma in 2, and other in 4. A

total of 70 lesions were treated, with 3 patients having 3, 16

having 2, and 29 having solitary lesions. The brain lesions

were found in the frontal lobes in 22, parietal lobes in 15, cer-

ebellum in 8, occipital lobes in 6, temporal lobes in 6, and

other locations in 13 patients. Lateralized tumors were right

sided in 31 and left sided in 18 lesions. The median lesion

size was 1.38 cm (range, 0.5–3).

Of the 48 patients, 32 (66%) were evaluable with imaging

findings at 3 months after treatment. Of the 48 patients, 29

ment of 60 Gy in 10 fractions isodose curve.

Fig. 2. Sample of dose–volume histogram dosimetry for simulta-neous in-field boost of 60 Gy in 10 fractions. ON = optic nerve;Lt = left; Rt = right; GTV = gross tumor volume.

SIB with HT for brain metastases d G. RODRIGUES et al. 1131

(60%) had also undergone their planned 3-month clinical

visit. Of the 16 nonevaluable patients (33%), 14 had clinical

documentation of decline or death from progressive systemic

cancer or complications of cancer (i.e., pneumonia or pulmo-

nary embolism); 4 of these 14 patients had undergone imag-

ing at the time of deterioration that confirmed stable or

improved intracranial disease. The remaining 2 of the 16

patients were not evaluable at 3 months because of early in-

tracranial recurrence (1 had progression at the site of the

boosted lesion and 1 had new intracranial metastases outside

the boosted lesion). Of the 3 patients with imaging but no

clinical follow-up at 3 months, the reasons for the lack of

clinical follow-up included 2 patients with physical decline

owing to documented extracranial progression and 1 patient

with combined intracranial/extracranial progression. Regard-

ing the dose level and availability for evaluation, all 3 pa-

tients at Level 1 (35 Gy) were evaluable by imaging at 3

months; 5 (31%) of 16 patients at Level 2 (40 Gy), 4

(27%) of 15 patients at Level 3 (50 Gy), 4 (50%) of 8 patients

at Level 4 (55 Gy), and 1 (17%) of 6 patients at Level 5 (60

Gy) were not evaluable by imaging at 3 months after treat-

ment. No statistically significant association was found be-

tween the dose level and the nonevaluation rate in this

patient population (chi-square p = .60). A similar proportion

of patients were not evaluable at each dose level, decreasing

the probability that an underestimation of DLT had occurred

because of a difference in early patient attrition at the dose

levels examined. Two of the 4 treated at the highest dose level

(Level 5, total lesion dose, 60 Gy) who were not evaluable at

3 months. One patient did undergo a follow-up magnetic res-

onance imaging scan before the 3-month mark that had dem-

onstrated progressive CNS disease, accounting for his death

before the 3-month clinical follow-up visit. The other patient

had documented progressive extracranial metastatic disease

before death with no neurologic signs or symptoms to sug-

gest treatment-related toxicity.

No cases of Grade 3–5 DLT were found to be possibly,

probably, or definitely attributable to the protocol treatment

in any of the study cohort levels. Therefore, the maximally

tolerated dose was not reached. The following Grade 1 and

2 toxicities likely related to RT were frequently (>5% of

the patient population) reported by the patients during their

follow-up: fatigue (22 of 48), alopecia (8 of 48), headache

(12 of 48), taste alteration (6 of 48), skin reaction (3 of 48),

anorexia (3 of 48), and vision changes (3 of 48). The median

survival of all patients was 5.29 months (range, 0.49–31.2).

Seven patients were still alive at data analysis. The median

follow-up of all living patients was 7.72 months (range,

3.4–24.2). Of the 32 patients radiologically assessed at 3

months, 2 experienced a complete response, 16 had a partial

response, 6 had stable disease, and 8 had progressive disease,

for a crude rate of stable or responding disease of 75% (24 of

32). Of the 8 patients with progression, 4 had local progres-

sion in the SIB-treated lesions, 2 had intracranial but nonlocal

CNS progression (i.e., outside the SIB-treated lesions), and 2

had both local and CNS progression on the 3-month imaging

scan.

Technical parametersThe median value of D1 (maximal dose) to the metastatic

lesions was 51.47 Gy (range, 35.5–64.8); the prescription

dose was 50 Gy (range, 35–60). The median maximal (D1)

doses were calculated for the brain (51.6 Gy), eye (17.9

Gy), brainstem (32.61 Gy), and spinal cord (29.1 Gy). The

average image-guidance shifts were 0.87 mm (range,

�2.43 to 4.46; standard deviation, 0.60) in the lateral direc-

tion, �1.27 mm (range, �6.15 to 4.56; standard deviation,

1.26) in the superoinferior direction, and 3.00 mm (range,

�3.60 to 8.83; standard deviation, 0.77) in the anteroposte-

rior direction.

DISCUSSION

Traditionally, the treatment of patients with metastatic dis-

ease has been palliative WBRT alone (19). During the past 10

years, the introduction of focal treatments (e.g., surgery or ra-

diosurgery) for selected patients with metastatic disease has

been explored in clinical trials and institutional series. The

treatment of patients with metastatic disease to the brain

can now include one or more of the following interventions:

best supportive care, palliative WBRT, radiosurgery, and/or

surgical resection with the goals of effective palliation of

symptoms, preventing intracranial progression, preserving

neurologic function, and preserving quality of life. Typically,

patients who are suitable for more aggressive, multimodality

therapies are those with oligometastatic disease (one to three

metastases), controlled extracranial disease, and good perfor-

mance status (2, 20). Randomized studies have demonstrated

local control and neurologic progression-free survival bene-

fits for surgery or radiosurgery added to WBRT in this

population compared with WBRT alone, radiosurgery, or

surgery (3, 4).

Radiosurgery delivered as a single fraction to individual

intracranial lesions has been established as a safe alternative

to surgical resection (21). The Radiation Therapy Oncology

Group 9502 trial established radiosurgery dose

1132 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 4, 2011

recommendations of 15–24 Gy for individual lesions #4 cm

according to the observed CNS toxicity at 3 months after

treatment (15). This approach has subsequently been shown

to be safe and effective in numerous single-institution and

multi-institution reports and trials (4). Logistically, radiosur-

gery requires separate localization and treatment procedures,

which adds some inconvenience and cost to the patients, pro-

viders, and caregivers. Depending on the radiosurgery

system used, invasive immobilization devices can be neces-

sary, increasing patient discomfort (7). Single-fraction treat-

ments do not permit the exploitation of the potential

radiobiologic benefits of reassortment and reoxygenation

that can occur with a fractionated RT course. Hall and Bren-

ner (17) have argued that fractionated stereotactic RT might

be more efficacious in the treatment of neoplastic disease

compared with single-fraction radiosurgery. Tumor cell repo-

pulation or sublethal damage repair might occur if a signifi-

cant break occurs between the radiosurgery and WBRT

sessions. Finally, depending on the radiosurgery system

used, treatment of more than three metastases might involve

prohibitively long treatments, requiring multiple sessions or

omission of radiosurgery entirely.

From a dosimetric standpoint, the ability to incorporate

boost contributions to larger field lower dose volumes as

a part of the optimization process is an advantage of the

simultaneous boost strategy (22) compared with radiosur-

gery. The radiosurgery dose is added to the previously de-

livered whole brain dose without an opportunity for

optimization of these two components, resulting in an

unintended increased dose to the brain. In the case of the

treatment of brain metastases using the SIB technique,

the lower isodose ‘‘spill’’ from the SIB can be incorporated

as a component contributing to the whole brain radiation

dose, thus, allowing the simultaneous optimization of

both components and improved dosimetry compared with

sequential whole brain and radiosurgery boosts (12, 13).

Finally, although our strategy has been to exploit the

ability to simultaneously boost brain lesions, conformal

avoidance with intensity-modulated RT techniques is

equally feasible. This strategy has been proposed as

a method to reduce the potential morbidity of WBRT by

the avoidance of sensitive structures such as the hippocam-

pus and other critical tissues (14, 23).

We sought to investigate whether a hypofractionated ste-

reotactic SIB approach using noninvasive stereotactic locali-

zation with on-board image guidance would be a safe

alternative to sequential whole brain and single-fraction

stereotactic radiosurgery. We have previously reported our

development and early treatment experience using this

form of SIB treatment with HT (HT-SIB) (5). Since our initial

report, others have reported on modeling our early clinical

experience using an SIB technique (13). In our Phase I trial,

we were able to achieve our target dose of 30 Gy WBRT with

a simultaneous boost of individual lesions #60 Gy, both de-

livered in 10 fractions. Treatment planning and treatment

delivery of this approach was feasible. No DLT was noted

at the 3-month assessment for any of the dose levels. Also,

among the subset of patients living >3 months, no

treatment-related late toxicity was noted. A number of pa-

tients enrolled in our trial were unable to complete the

follow-up (owing to a lack of the imaging or clinical assess-

ment) at the 3-month point primarily because of extracranial

or intracranial progression or intercurrent disease. In all

cases, it was determined, to the best of our ability, that this

early deterioration was not a results of treatment-related tox-

icity. Most of the patients in our trial had single brain metas-

tasis and patients with lesions >3 cm in size or in close

proximity to the brainstem were excluded. Thus, it is possible

that our Phase I study might have underestimated the poten-

tial toxicity of this approach in patients with multiple metas-

tases. Offsetting this somewhat was that patients with

multiple metastases were represented at all dose levels. Spe-

cifically, at the greatest dose level, 2 of 6 patients had multi-

ple metastases treated (2 and 3 metastases, respectively). A

similar proportion of patients with multiple metastatic lesions

versus single metastatic lesions were treated at the lower dose

levels.

In terms of patient outcome, partial responses were seen at

all dose levels, without a clear increase in the response rate

with an increasing SIB dose. Overall, our intracranial control

rate was inferior to that noted in prospective trials of WBRT

with a radiosurgery boost (24, 25). The numbers of patients

treated per cohort were small, and only 6 patients were

treated at the greatest dose level. Thus, it is difficult to

draw any firm conclusions regarding the relative efficacy of

the fractionated SIB technique at the greatest tolerated dose

as delivered in the present Phase I dose-escalation study.

One limitation of our study was the high early patient attrition

due to intercurrent illness and systemic disease progression

and the limited number of patients studied at the greatest

dose level. In addition, patients with imaging evidence of lo-

cal intracranial progression were not routinely investigated

with functional imaging (i.e., thallium single positron emis-

sion tomography or magnetic resonance spectroscopy) to

rule out necrosis vs. local tumor progression; thus, we might

have underestimated the true incidence of treatment-related

toxicity. In addition, outcomes such as overall survival and

late neurocognitive effects could not be fully assessed in con-

junction with a Phase I safety/feasibility study; thus, our ob-

servations in this regard must be viewed as preliminary only.

A multi-institutional Phase II trial powered to permit an as-

sessment of this approach in terms of noninferiority for intra-

cranial control compared with traditional radiosurgery

techniques is underway and includes the secondary endpoints

of survival and quality of life.

CONCLUSIONS

We have confirmed the feasibility and safety of using the

SIB approach in the present Phase I clinical trial using 30

Gy WBRT with intralesional boosts to 60 Gy within 10 frac-

tions. We plan to evaluate this approach in a larger multi-

institutional cohort of patients to evaluate the efficacy of this

treatment with the primary endpoints of overall survival,

SIB with HT for brain metastases d G. RODRIGUES et al. 1133

intracranial and local lesion control, and toxicity. Other re-

search directions could also include investigations of alternate

fractionation schemes (13), incorporation of additional avoid-

ance structures (14, 23), the treatment of patients with more

than three brain metastases who otherwise meet the criteria

for aggressive management (controlled systemic disease and

good Karnofsky performance status) (26), and the use of other

platforms (i.e., linear accelerator with volumetric arc or multi-

ple static intensity-modulated RT fields combined with on-

board imaging) (13, 14). Ultimately, randomized trials or

carefully constructed cohort comparisons will be necessary

to determine the relative efficacy of the fractionated SIB

approach compared with conventional approaches using

radiosurgery or surgery for oligometastatic disease.

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