Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases

Brain Metastases Clinical Trial

— ENCEPHALON  

Official title:

Whole Brain Radiation Therapy (WBRT) Alone Versus Radiosurgery (SRS) for Patients With 1-10 Brain Metastases From Small Cell Lung Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03297788
• Other study ID #: ENCEPHALON
• Status: Completed
• Phase: N/A
• Start date: December 1, 2017
• Est. completion date: December 1, 2023

Study information

• Verified date: January 2024
• Source: University Hospital Heidelberg
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients suffering from small cell lung cancer (SCLC) are at high risk for developing brain metastases (BM). To prevent a clinical manifestation of preexisting microscopic brain dissemination, prophylactic cranial irradiation (PCI) is offered to both limited and extensive disease patients, if they respond to first line regime, thus being at risk or at chance to develop clinical brain metastases. However, up to 10-15% of patients present with BM at initial diagnosis. If MRI is used as a diagnostic tool for initial staging the number even increases up to 15-20%. Additionally, between 40 - 50% of patients develop BM until time of death and the risk of developing BM further increases with prolonged survival. Treatment options are usually limited to WBRT and palliative chemotherapy but the actual effect of therapeutic WBRT has mainly been studied in small retrospective and nonrandomized studies. WBRT has been established as the treatment standard in patients with cerebral metastases from SCLC, however, it has only modest efficacy. Results might be improved by additional dose escalation. A SRS to cerebral metastases may be indicated in patients with intracranial disease, and the current protocol is aimed at exploring the neurocognition and efficacy of SCLC in patients with brain metastases treated with SRS or WBRT.

The present trial aims to exploratory investigate the treatment response to ´conventional whole brain radiotherapy´ (WBRT) and ´stereotactic radiotherapy´(SRS) in SCLC patients.

Description:

Scientific Background: Patients suffering from BM from SCLC have a poor prognosis with a median survival ranging between 2-14 months. Treatment options for BM in SCLC are usually limited to WBRT, steroids or palliative chemotherapy. SCLC patients demonstrate an exception in the treatment of BM, because treatment options for a limited number of BM from other solid tumors commonly include surgery or SRS with or without WBRT. Even though SCLC is a radiosensitive tumor, higher doses are commonly not applied. Locally ablative treatments like SRS or surgery are less frequently used in patients with BM from SCLC as compared to other types of cancer due to the high incidence of brain metastases in SCLC and the increased likelihood of a diffuse failure pattern. It is of general belief that BM from SCLC are rarely solitary and usually occur at multiple sites. The investigators could not confirm these findings from this analysis as they found 1-5 BM in 39 % of their patients. WBRT, with a treatment time of about two weeks, is commonly the technique of choice for SCLC patients with any number of BM. In a recent Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with early disease (ED) SCLC. PCI is therefore no longer recommended for patients with ED SCLC when patients receive regularly MRI examinations during follow-up.

Though, the initial response to cranial irradiation is good, especially in the synchronous setting, SCLC patients are at high risk of developing intracranial recurrence. In the investigators´ retrospective analysis median Overall survival (OS) after re-WBRT was only 2 months and the median OS after SRS was 6 months. These results are similar as compared to results for re-irradiation after PCI. In a recent analysis the investigators reported a prolonged survival for patients treated with SRS in the recurrent setting after previous PCI with a median survival of 5 months.

Therefore, the number of patients with oligometastatic cerebral disease might rise. Based on recursive partitioning Analysis (RPA) classification, the investigators found a median survival after WBRT of 17 months in RPA class I, 7 months in class II and 3 months in class III (p<0.0001), which is comparable to previous analyses using graded prognostic assessment (GPA) scoring. This is further of special interest as patients in RPA class I had a comparable or even better outcome than patients with non-cerebral disease treated with PCI. On the other hand, patients with RPA class III should be carefully selected for WBRT and treatment should be weighed against supportive therapy with steroids alone. This implicates that patient selection is mandatory, even in SCLC, and that the general paradigm of WBRT needs to be reevaluated.

Trial Objectives: The purpose of this trial is to explore the neurocognitive response in patients with brain metastases from SCLC treated with WBRT or SRS. The investigators proposed that patients treated with SRS would have inferior neurocognitive function based on the Hopkins Verbal Learning Test-Revised (HVLT-R) compared with patients treated with SRS alone.

Patients Selection: Patients with a diagnosis of brain metastases from SCLC will be evaluated and screened based on the protocol. All patients fulfilling the inclusion and exclusion criteria will be informed about the possibility to participate in the study. Registration for the study must be performed prior to beginning of RT. 56 patients will be enrolled in this exploratory clinical trial.

Trial Design: This pilot trial will be conducted as a single-center prospective, randomized, two-arm Phase II study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: December 1, 2023
• Est. primary completion date: October 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• histologically confirmed small cell lung cancer (SCLC)

• Magentic resonance (MR)-imaging confirmed cerebral metastases (no resection, max. number of 10)

• age = 18 years of Age

• For women with childbearing potential, (and men) adequate contraception.

• Ability of subject to understand character and individual consequences of the clinical trial

• Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

refusal of the patients to take part in the study

• previous radiotherapy of the brain

• Patients who have not yet recovered from acute high-grade toxicities of prior therapies

• Known carcinoma < 5 years ago (excluding Carcinoma in situ of the cervix, basal cell carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment interfering with study therapy

• Pregnant or lactating women

• Participation in another competing clinical study or observation period of competing trials, respectively

• MRI contraindication (i.e. cardiac pacemaker, implanted defibrillator, certain cardiac valve replacements, certain metal implants)

• Karnofsky score (KPS) <60

• Simultaneous cytotoxic chemotherapy

• Last application of chemotherapy/immunotherapy/targeted therapy <1 week before cerebral radiotherapy

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• Neoplasm Metastasis
• SCLC

Intervention

Radiation:
• SRS
For SRS the dose prescription to the PTV will be as follows: 20 Gy to the 70%-isodose (lesions < 2 cm max. diameter) 18 Gy to the 70%-isodose (lesions 2 - 3 cm max. diameter) 6 x 5 Gy to the conformally surrounding isodose (lesions > 3 cm max. diameter)
• WBRT
WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.

Locations

Country	Name	City	State
Germany	University Hospital of Heidelberg, Department of Radiation Oncology	Heidelberg

Sponsors (2)

Lead Sponsor	Collaborator
Juergen Debus	Heidelberg University

Country where clinical trial is conducted

Germany, 

References & Publications (37)

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* Note: There are 37 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neurocognition	Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)	3 month after treatment
Secondary	Intracranial progression	number of new cerebral metastases	up to 12 month after treatment
Secondary	Intracranial progression	Change in tumor size	up to 12 month after treatment
Secondary	Overall survival (OS)	Duration of survival defined as the interval between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first.	12 month OS
Secondary	Death due to brain metastases	Death which directly connects to existing brain metastases	up to 12 month after treatment
Secondary	Locally progression-free survival	12 month Progression-fee survival referring to local tumour progression	up to 12 month after treatment
Secondary	Progression-free survival (PFS)	12 month Progression-free survival	12 month PFS
Secondary	Changes in other cognitive performance measures	HVLT_R	up to 12 month after treatment
Secondary	Quality of life	BN20 QoL Questionaire	up to 12 month after treatment
Secondary	Quality of life	EORTC QoL Questionaire PAL (palliative)	up to 12 month after treatment
Secondary	Changes in other cognitive performance measures	CANTAB Test	up to 12 month after treatment