Trial Title:
Phase II Trial of Conventional Versus IMRT Whole Brain Radiotherapy for Brain Metastases
NCT ID:
NCT01890278
Condition:
Metastatic Brain Cancer
Conditions: Official terms:
Brain Neoplasms
Conditions: Keywords:
Brain Cancer
Metastatic Brain Cancer
IMRT
Study type:
Interventional
Study phase:
N/A
Overall status:
Unknown status
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Whole Brain IMRT
Arm group label:
Whole Brain IMRT
Intervention type:
Radiation
Intervention name:
Conventional Whole Brain RT
Arm group label:
Conventional whole brain RT
Summary:
In this study the patient will receive either whole brain radiation therapy given by
intensity modulated radiation therapy (IMRT) or standard conventional radiation. In IMRT
therapy radiation dose to the parts of the brain that do not contain tumors is reduced.
This study will look to see if this approach results in less hair loss or fewer memory
Problems, as compared to the standard technique. The study will also look at the
effectiveness of both techniques in controlling the growth of the tumor.
Detailed description:
SCHEMA For Patients with MRI Evidence of Brain Metastasis within 1 Month Prior to
Registration
Prior to Treatment Start Confirmation of patient's insurance coverage prior to receiving
study-related procedures to e ensure that treatment with IMRT will not be denied.
Radiation Therapy
1. MRI with Fused CT Simulation
2. Neurocognitive Function Testing
3. Quality of Life Assessment
Arm 1 Whole brain radiation therapy delivered via IMRT (37.5 Gy to the brain tumors, 30
Gy to the uninvolved brain in 15 fractions), mean dose of less than 18 Gy to the scalp
Arm 2 Conventional whole brain radiation therapy (37.5 Gy to the brain tumors and
uninvolved brain in 15 fractions)
Patient Population: (See Section 3.0 for Eligibility) At least one radiologically
diagnosed brain metastasis associated with a histologically proven diagnosis of a
nonhematopoietic malignancy. Patients must be classified as RTOG RPA class I or RPA class
II
1.0 INTRODUCTION
1.1 Adverse Effects of Whole-Brain Radiotherapy (WBRT)
Whole brain radiotherapy (WBRT) remains the standard treatment approach for patients with
multiple brain metastases. WBRT has been shown to achieve rapid palliation of
neurological symptoms and improves overall survival compared to corticosteroids alone for
patients with multiple brain metastases 1. Additionally, adjuvant WBRT has been shown to
improve local control and time to neurocognitive function decline in patients with
limited (1 to 4) brain metastases that are treated with surgery or stereotactic
radiosurgery 2-4. Despite significant technical advances in radiation delivery and
increased survival in tumors that demonstrate sensitivity to systemic therapies,
conventional WBRT has not materially changed in the past 50 years 5. Conventional WBRT is
generally well tolerated, save for alopecia, fatigue and short-term neurocognitive
decline in patients with a short life expectancy (≤ 6 months) 6-8. In a recent randomized
trial at MD Anderson, WBRT after SRS increased the risk of neurocognitive decline ≥ 5
points as assessed by the Hopkins Verbal Learning Test at 4 months after treatment
compared to SRS alone (49% vs. 23%, p<0.05) 9. In other studies, development of
subsequent brain metastases are a significant contributor to cognitive decline 2, 10-11.
In long term survivors (≥ 12 months), irreversible neurocognitive decline has been
reported in up to 11% of patients treated with conventional WBRT, although this study
utilized daily radiation doses ≥3 Gy per day that are no longer in common use 12. The
decline in cognitive function assessed by mini mental status examination may take up to 3
years to manifest 2.
Extensive research has investigated methods of improving the efficacy of WBRT. This
included increasing the radiation dose, hyperfractionated radiation schedules and
combining WBRT with drug therapy 13-16. Currently, the standard WBRT radiation dose
schedule is 30 to 37.5 Gy in 10 to 15 fractions. One promising approach to improve local
control and survival has been combining WBRT with stereotactic radiosurgery for patients
with 1 to 4 metastases 6, 17. An emerging strategy to reduce the toxicity of WBRT is to
administer surgery or SRS alone for patients with limited brain metastases 4, 9. Although
this results in a higher risk of brain relapse, some of these recurrences can be salvaged
with repeat SRS and/or WBRT. For the majority of patients with brain metastases who
require WBRT, little research has focused on improving the therapeutic ratio of WBRT by
reducing its toxicity 18.
1.2 Rationale for selective targeting of brain metastases in WBRT
In general, radiation oncologists approach patients by selectively targeting the gross
tumor plus margin for microscopic extension and setup uncertainty to the prescription
dose while administering a lower dose to areas of subclinical risk 19. This strategy is
extensively utilized in brain, head and neck, lung, gastrointestinal, breast,
gynecologic, hematologic and genitourinary tumors. In many centers, over half of the
patients are treated with IMRT to improve dose distributions to increase efficacy and/or
reduce toxicity. Despite the critical physiological role played by the uninvolved brain,
the reason this paradigm has not been extended to WBRT likely relates to the general poor
prognosis of patients with brain metastases with a median survival of 4 months 20.
Selectively targeting brain metastases requires more physician, physicist and radiation
therapist effort and the investment of increased resources and cost of treatment for this
patient population may be unjustified unless the improved dose distribution translates
into significant clinical benefit. In the era of accountable care, determining the cost
effectiveness of IMRT vs. conventional WBRT is necessary.
The recent identification of long-term survivors of metastatic cancer treated with more
effective local and systemic therapies is slowly changing these attitudes 21-22. There
are distinct subgroups of patients with brain metastases with a more reasonable
prognosis. For instance RTOG recursive partitioning analysis (RPA) group 1 patients have
a median survival of 7 months 20. Patients with single brain metastases undergoing
surgery followed by WBRT have a median survival of 10 months 4. A recent study from Japan
further classified RTOG RPA class II to Class IIa, IIb and IIc based on the presence of
favorable factors including performance status, number of brain tumors, primary tumor
controlled or active and extracranial metastases 23. Survival for patients with RPA class
IIa, IIb and IIc was 16 to 20 months, 8 months and 4 to 5 months respectively with
long-term survivors in each subgroup.
There have been preliminary efforts to apply IMRT to improve whole brain radiation. This
concept was first proposed by Kao, et al in 2005 24. Two avenues of research were
proposed. One approach is to selectively spare parts of the brain that are critical for
neurocognitive function, such as the hippocampal stem cells in the subgranular zone 25.
This approach has been extensively tested by investigators at the University of
Wisconsin. The risk of brain metastases in the hippocampal avoidance zone is less than 5%
26-27. RTOG 0933 is an ongoing phase II trial testing IMRT WBRT to a total dose of 30 Gy
in 10 fractions while limiting the mean hippocampal avoidance zone dose to less than 10
Gy 25. The major criticism of this approach is that the hippocampal avoidance zone is
only one of several regions of the brain are involved with memory processing and
retention 28. Using the RTOG 0933 technique, potentially functional brain tissue
including the limbic circuit and neural stem cell region will receive the full
prescription dose even if clinically uninvolved with metastases. Pending further study,
this approach remains experimental and should not be performed outside the context of
controlled clinical trials.
A second strategy is to selectively boost areas of gross disease while simultaneously
treating the uninvolved brain with standard radiation doses 24. This strategy is
currently being tested in countries with socialized health systems such as the United
Kingdom and Canada as a cost-effective alternative to stereotactic radiosurgery boost. A
published report from England reported the feasibility of treating gross tumors to 40 Gy
in 10 fractions while treating the uninvolved brain to 30 Gy in 10 fractions 29.
A third application of whole brain radiation is selective sparing of the scalp 30. The
clinical target is the whole brain but unintended radiation to the scalp can result in
temporary or permanent alopecia. Due to the dose distribution of conventional WBRT, the
vertex of the scalp receives a particularly high dose. Preliminary work suggests that
IMRT can limit the mean scalp dose to 16 to 18 Gy and these reduced doses may shorten the
duration of temporary alopecia and possibly reduce the risk of permanent alopecia 30-32.
A final strategy has not yet been explored. Rather than increasing the dose of radiation
to the identified brain tumors, we can reduce the dose to the uninvolved brain to reduce
acute and long term side effects. In the setting of prophylactic WBRT for small cell and
non-small cell lung cancer, lower radiation doses of 25 to 30 Gy in 10 to 15 fractions
are considered standard treatment 33-35. In a randomized trial of prophylactic cranial
irradiation for small cell lung cancer, there was no evidence of improved disease control
with 36 Gy vs. 25 Gy 34. With the exception of a single report demonstrating subtle
effects on neurocognitive function as assessed by Hopkins Verbal Learning Test, there is
little evidence that WBRT to 25 to 30 Gy in 10 to 15 fractions results in neurocognitive
decline with prophylactic WBRT vs. observation in multiple randomized controlled trials
35-36. Higher doses of WBRT have been shown to reduce verbal memory function 37.
Additionally, there are robust data from randomized trials reproducibly demonstrating a
significant reduction in the incidence of subsequent brain metastases in regions of the
brain with no dominant mass appreciable on MRI prior to treatment 33, 35, 38. A
theoretical disadvantage of limiting WBRT to 30 Gy in 15 fractions is that this dose may
be inadequate to prevent relapse in relatively radioresistant tumors. However, as
discussed earlier, some investigators are now administering 0 Gy to uninvolved sites by
deferring WBRT due to concerns of toxicity 11.
1.3 Feasibility of Selective Avoidance of Uninvolved Brain and Scalp during IMRT
Based on this body of published evidence, we started utilizing IMRT for selected patients
with brain metastases in June 2012. Our planning objectives are to deliver 37.5 Gy in 15
fractions to the gross tumor(s) + 5 mm margin while limiting radiation dose to 30 Gy. A
secondary goal is to limit the mean scalp dose to 16 to 18 Gy. No effort was made to
achieve additional sparing of the hippocampal stem cells since definitive data
demonstrating a benefit has not yet been published. Based on the feasibility and
promising preliminary experience, we propose a prospective randomized trial to determine
whether there are significant benefits for WBRT delivered via IMRT.
1.4 Neurocognitive Function and Quality of Life Assessment
Although more extensive and sensitive neurocognitive tests such as the Hopkins Verbal
Learning Test are available, in the context of resources available to a high-quality
community hospital program, we will limit our neurocognitive function assessment to
serial mini-mental status examinations. Mini-mental status examination (MMSE) is the most
widely used global mental status measure in medical settings and requires less than 10
minutes to complete. This assessment tool has been extensively validated in nearly 2,000
patients with brain tumors treated on RTOG protocols 39.
Quality of life will be assessed using the EORTC QLQ - BN20, which is an extensively
validated one page patient-reported survey of 20 questions. The EORTC-QLQ-BN20 is
designed for use with patients undergoing chemotherapy or radiotherapy, and is composed
of 20 questions assessing visual disorders, motor dysfunction, communication deficit,
various disease symptoms (eg, headaches and seizures), treatment toxicities (eg, hair
loss), and future uncertainty. The EORTC QLQ - BN20 has robust psychometric properties
resulting from rigorous testing, development, and external validity 40.
Within 2 weeks prior to WBRT, all patients will undergo a baseline quality of life
assessment.
After completion WBRT, all patients will undergo quality of life assessments every 3
months for 6 months and then every 4 months after whole brain radiotherapy. Quality of
life assessments will be scored by a blinded reviewer to avoid potential bias.
1.5 Summary
In summary, preclinical and clinical evidence suggests that radiation dose received by
uninvolved portions of the brain during WBRT plays a critical role in causing
radiation-induced alopecia and neurocognitive decline without improving survival.
Extensive data from randomized trials suggests a benefit in reduced brain relapse from
elective treatment of uninvolved brain. Although other approaches are being pursued,
reducing the radiation dose to levels utilized for prophylactic cranial irradiation is an
attractive alternative to conventional WBRT that non-specifically irradiates the entire
brain or eliminating WBRT entirely. We hypothesize that IMRT-WBRT will reduce the
incidence and duration of alopecia while reducing the incidence of neurocognitive deficit
to the acceptable levels observed in prophylactic cranial irradiation.
Criteria for eligibility:
Criteria:
ELIGIBILITY CHECKLIST
Inclusion Criteria:
- Evidence of at least one brain metastasis on a gadolinium contrast-enhanced MRI
- Pathologic/histological/cytologic proof of a diagnosis of a non-hematopoietic
malignancy within 5 years of study entry.
- Patient ≥18 years of age?
- Fall into RTOG Recursive Partition Analysis (RPA) class I or II.
- Karnofsky Performance Score ≥70. (See Appendix III)
- Biopsy done at least 1 week prior to registration. (This requirement does not apply
to stereotactic biopsies.)
Exclusion Criteria:
- Contraindication to MR imaging such as implanted metal devices or foreign bodies,
severe claustrophobia.
- Creatinine level > 1.4 mg/dl drawn ≤30 days prior to study entry.
- Severe, active co-morbitities.
- Unstable angina, and/or congestive heart failure requiring hospitalization within
the last 6 months.
- Transmural myocardial infarction within the last 6 months
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
- Uncontrolled, clinically significant cardiac arrhythmias
- Pregnancy
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Good Samaritan Hospital Medical Center
Address:
City:
West Islip
Zip:
11795
Country:
United States
Status:
Recruiting
Contact:
Last name:
Johnny Kao, MD
Phone:
631-376-4047
Email:
johnny.kao@chsli.org
Investigator:
Last name:
Johnny Kao, MD
Email:
Principal Investigator
Start date:
June 2013
Completion date:
March 2017
Lead sponsor:
Agency:
Good Samaritan Hospital Medical Center, New York
Agency class:
Other
Source:
Good Samaritan Hospital Medical Center, New York
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01890278
