Phase I Trial of Stereotactic Radiosurgery Following Surgical Resection of Brain Metastases

Neoplasm Clinical Trial

Official title:

Phase I Trial of Stereotactic Radiosurgery Following Surgical Resection of Intra-axial Brain Metastases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01395407
• Other study ID #: IRB00049695
• Secondary ID: RADONC1962-11
• Status: Completed
• Phase: Phase 1
• First received: July 14, 2011
• Last updated: December 2, 2015
• Start date: July 2011
• Est. completion date: October 2015

Study information

• Verified date: December 2015
• Source: Emory University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Data and Safety Monitoring Board
• Study type: Interventional

Clinical Trial Summary

Brain metastases are the most common adult intracranial tumor, occurring in approximately 10% to 30% of adult cancer patients, and represent an important cause of morbidity and mortality in this population. The standard of care for solitary brain metastasis is surgery followed by whole brain radiation therapy (WBRT). Without WBRT, there are unacceptably high levels of local failure that occur. Local recurrence rates ranged from approximately 45% at 1 year to 60% at 2 years after resection alone. However, aside from improvements in intra-cranial control, it is well documented that WBRT is associated with serious long term side effects, including significant decline in short term recall by as early as 4 months after treatment.

Many centers are now offering patients stereotactic radiosurgery (SRS) to the cavity after resection alone to improve local control while avoiding the negative effects of WBRT. There have been several retrospective studies on the use of SRS to the resection cavity alone, from which the 1 year actuarial local control rates range from 35% - 82%. The high rate of in-field local failure suggests that the current dosing regimen used may not be high enough for adequate local control. Currently, the highest local control rates are approximately 80%, but there may be room for improvement with increased dose without significantly increasing the risk of side effects.

The investigators propose a trial for patients after surgical resection of solitary brain metastases. The purpose of this trial will be to determine the maximum tolerated dose for single fraction SRS to the resection cavity. There will be three groups based on the resection cavity size. Dose escalation enrollment will be done sequentially within each cohort. You will know which cohort and which specific dose level you are randomized to. After treatment, which will take one day, regardless of cohort, you will be followed closely for treatment outcome and possible side effects. You will be asked to complete three quick surveys at each follow-up appointment regarding quality of life and memory in addition to standard of care surveillance brain MRI and physical exam.

Description:

Brain metastases are the most common adult intracranial tumor, occurring in approximately 10% to 30% of adult cancer patients, and represent an important cause of morbidity and mortality in this population. The risk of developing brain metastases differs with different primary tumor histologies, with lung cancer accounting for approximately one half of all brain metastases. The prognosis of patients with brain metastases is poor. The median survival time of untreated patients is approximately 1 month. With treatment, the overall median survival time after diagnosis is approximately 4 months. The Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) describes three prognostic classes, defined by age, Karnofsky Performance Score (KPS), and disease status. The most widely used treatment for patients with multiple brain metastases is whole brain radiation therapy (WBRT). The appropriate use of WBRT can provide rapid attenuation of many neurological symptoms, improve quality of life, extend median survival, and be especially beneficial in patients whose brain metastases are surgically inaccessible or when other medical considerations preclude surgery. The use of adjuvant WBRT after resection or stereotactic radiosurgery (SRS) has been proven to be effective in terms of improving local control of brain metastases, and thus, the likelihood of neurological death is decreased.

The standard of care for solitary brain metastasis is surgery followed by WBRT. In a study by Patchell et al. for solitary brain metastases status post resection, the addition of whole brain radiation significantly reduced local recurrence from approximately 45% to 10% after resection. Although it does not prolong survival or functional independence, this treatment regimen was shown to result in significantly improved loco-regional control. A more recent study from the European Organization for Research and Treatment of Cancer (EORTC) randomized patients who underwent gross total resection (GTR) of up to 3 brain metastases to adjuvant WBRT versus observation. Adjuvant WBRT resulted in significantly reduced intracranial failure and neurologic death, however again both overall survival and functionally independent survival were not different. Among the major findings of both of these studies are the unacceptably high levels of local failure that occur after GTR alone. Local recurrence rates ranged from approximately 45% at 1 year to 60% at 2 years after resection.

However, aside from improvements in intra-cranial control, it is well documented that WBRT is associated with serious long term side effects, including significant neurocognitive decline. A randomized study conducted by Chang et al of SRS versus SRS + WBRT for 1 - 3 brain metastases found that addition of WBRT was associated with significantly worse memory recall as early as 4 months. A conclusion of this study was that a regimen of close surveillance and SRS as necessary is preferred over SRS + WBRT because the neurocognitive effects of WBRT may actually be worse than that caused by intracranial disease recurrence.

Many centers are now offering patients SRS to the cavity after resection alone to improve local control while avoiding the negative effects of WBRT. There have been several retrospective studies on the use of SRS to the resection cavity alone, from which the 1 year actuarial local control rates range from 35% - 82%. The radiation necrosis rates from these same studies range from 2% - 6%. In currently unpublished data from Emory University reviewing 63 patients with 65 cavities treated between 01/2007 and 08/2010, the 1 year actuarial local control rate was 78%. Of the 10 local failures, 70% were in-field only, 10% were marginal only, and 20% were both. The high rate of in-field failure suggests that the current dosing regimen used may be insufficient for optimal local control. The current SRS dose constraints used are derived from the phase I trial RTOG 90-05. This study determined the maximum tolerated dose for SRS in previously irradiated patients with unresected brain metastases based on lesion size. The maximum doses currently used may be artificially low for resected patients for several reasons. First, the patient population studied had been previously irradiated which most likely lowered the maximum tolerated dose versus a non-irradiated population. Secondly, the typical planning target volume (PTV) of the resection bed is the cavity with a 1 - 2mm margin. This means that the vast majority of the irradiated PTV is not brain parenchyma, but actually cerebrospinal fluid (CSF), which should result in a lower radiation necrosis rate for the same dose/volume. Currently, the highest local control rates are approximately 80%, but there may be room for improvement with increased dose without significantly increasing the risk of radiation necrosis.

The investigators propose a prospective phase I trial for patients status post surgical resection of solitary brain metastases. The purpose of this trial will be to determine the maximum tolerated dose for single fraction SRS to the resection cavity. The investigators believe that the current SRS dosing constraints may be too low, and that a larger therapeutic window exists for this patient population. Results from this trial may form the basis of future trials directly comparing WBRT with SRS to the cavity alone following resection of solitary brain metastases. This phase III study would answer the question about as to whether local irradiation is adequate treatment for patients following surgery for metastatic brain disease. Also it is anticipated that QOL measures would be built into the study in an attempt to confirm the data reported by Chang that WBRT is associated with a significant decline in QOL at even early endpoints.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologic proven diagnosis of solid tumor malignancy

• Age = 18

• RPA class I or class II

• Mini Mental Status Exam (MMSE) = 18 prior to study entry

• Karnofsky Performance Status = 70%

• Single brain metastasis status post surgical resection with = 1 cc of residual enhancing tumor

• Up to 2 additional intact brain metastases to be treated with stereotactic radiosurgery (SRS) alone

• Resection cavity volume on planning scan of = 35 cc

• First presentation of brain metastases

• Post-operative MRI within 72 hours of surgical resection

Exclusion Criteria:

• Previous brain radiotherapy (SRS or WBRT)

• RPA class III

• Resection cavity volume > 35 cc

• Radiosensitive or non-solid (eg. small cell lung carcinomas, germ cell tumors, leukemias, or lymphomas) or unknown tumor histologies

• Concurrent chemotherapy (no chemotherapy starting 14 days before start of radiation to 14 days after completion of radiation)

• Evidence of leptomeningeal disease by MRI and/or CSF cytology

• Current pregnancy

• More than 8 weeks between resection and radiosurgical procedure

• No metastases to brain stem, midbrain, pons, or medulla or within 7 mm of the optic apparatus (optic nerves and chiasm)

• Inability to undergo MRI evaluation for treatment planning and follow-up

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Metastasis
• Brain Neoplasms
• Neoplasm
• Neoplasm Metastasis

Intervention

Radiation:
• Radiosurgery dose escalation
Cohort A: resection cavity volume up to 4.2 cc (corresponds to 0 - 2 cm diameter). Cohort B: resection cavity volume > 4.2 cc and = 14.1 cc (2 - 3 cm diameter) Cohort C: resection cavity volume > 14.1 cc and = 35 cc (3 - 4 cm diameter) Dose level Cohort A (Gy) Cohort B (Gy) Cohort C (Gy) 21 18 15 23 20 17 25 22 19

Locations

Country	Name	City	State
United States	Emory University Hospital	Atlanta	Georgia
United States	The Emory Clinic	Atlanta	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Emory University

Country where clinical trial is conducted

United States, 

References & Publications (13)

Arbit E, Wronski M, Burt M, Galicich JH. The treatment of patients with recurrent brain metastases. A retrospective analysis of 109 patients with nonsmall cell lung cancer. Cancer. 1995 Sep 1;76(5):765-73. — View Citation

Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009 Nov;10(11):1037-44. doi: 10.1016/S1470-2045(09)70263-3. Epub 2009 Oct 2. — View Citation

CHAO JH, PHILLIPS R, NICKSON JJ. Roentgen-ray therapy of cerebral metastases. Cancer. 1954 Jul;7(4):682-9. — View Citation

Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):745-51. — View Citation

Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Collette S, Collette L, Mueller RP. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011 Jan 10;29(2):134-41. doi: 10.1200/JCO.2010.30.1655. Epub 2010 Nov 1. — View Citation

Mathieu D, Kondziolka D, Flickinger JC, Fortin D, Kenny B, Michaud K, Mongia S, Niranjan A, Lunsford LD. Tumor bed radiosurgery after resection of cerebral metastases. Neurosurgery. 2008 Apr;62(4):817-23; discussion 823-4. doi: 10.1227/01.neu.0000316899.55501.8b. — View Citation

Patchell RA, Regine WF. The rationale for adjuvant whole brain radiation therapy with radiosurgery in the treatment of single brain metastases. Technol Cancer Res Treat. 2003 Apr;2(2):111-5. Review. — View Citation

Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery WR, Foon KA, Young B. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998 Nov 4;280(17):1485-9. — View Citation

Roberge D, Souhami L. Tumor bed radiosurgery following resection of brain metastases: a review. Technol Cancer Res Treat. 2010 Dec;9(6):597-602. Review. — View Citation

Soltys SG, Adler JR, Lipani JD, Jackson PS, Choi CY, Puataweepong P, White S, Gibbs IC, Chang SD. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):187-93. Epub 2007 Sep 19. — View Citation

Sundström JT, Minn H, Lertola KK, Nordman E. Prognosis of patients treated for intracranial metastases with whole-brain irradiation. Ann Med. 1998 Jun;30(3):296-9. — View Citation

Wen PY, Loeffler JS. Management of brain metastases. Oncology (Williston Park). 1999 Jul;13(7):941-54, 957-61; discussion 961-2, 9. Review. — View Citation

Zimm S, Wampler GL, Stablein D, Hazra T, Young HF. Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer. 1981 Jul 15;48(2):384-94. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose	To assess whether treating a brain resection cavity with this stereotactic radiosurgery is safe and tolerable and to determine the maximum-tolerated radiation dose for SRS to the resection cavity alone with 4-month toxicity as assessed by the RTOG central nervous system (CNS) toxicity scale	4 months after intervention	Yes
Secondary	Local Control	Defined as lack of progression of disease in resection cavity as assessed by period MRI scans for up to 2 years after intervention.	up to 2 years after intervention	No
Secondary	Distant Control	Defined as lack of progression of disease in surrounding brain as assessed by period MRI scans for up to 2 years after intervention	up to 2 years after intervention	No
Secondary	Neurocognitive Outcomes	Neurocognitive assessment using the Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam (MMSE) and Cognitive Functioning Subscale of the Medical Outcomes Scale (MOS), administered to the patient periodically for up to 2 years after intervention.	up to 2 years after intervention	No
Secondary	Quality of Life	Quality of life (QOL) outcomes: using the quality of life questionnaire for the Functional Assessment of Cancer Therapy-Brain (FACT-Br) administered periodically for up to 2 years.	up to 2 years after intervention	No