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

January 4, 2024 updated by: Juergen Debus

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

56

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Heidelberg, Germany, 69120
        • University Hospital of Heidelberg, Department of Radiation Oncology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A: SRS
Patient receive stereotactic radiosurgery (SRS), dose prescription according to the size of radiated brain metastases
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)
Active Comparator: Arm B: WBRT
Patients receive whole brain radiotherapy (WBRT)
Radiation: WBRT
WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurocognition
Time Frame: 3 month after treatment
Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)
3 month after treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intracranial progression
Time Frame: up to 12 month after treatment
number of new cerebral metastases
up to 12 month after treatment
Intracranial progression
Time Frame: up to 12 month after treatment
Change in tumor size
up to 12 month after treatment
Overall survival (OS)
Time Frame: 12 month 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
Death due to brain metastases
Time Frame: up to 12 month after treatment
Death which directly connects to existing brain metastases
up to 12 month after treatment
Locally progression-free survival
Time Frame: up to 12 month after treatment
12 month Progression-fee survival referring to local tumour progression
up to 12 month after treatment
Progression-free survival (PFS)
Time Frame: 12 month PFS
12 month Progression-free survival
12 month PFS
Changes in other cognitive performance measures
Time Frame: up to 12 month after treatment
HVLT_R
up to 12 month after treatment
Quality of life
Time Frame: up to 12 month after treatment
BN20 QoL Questionaire
up to 12 month after treatment
Quality of life
Time Frame: up to 12 month after treatment
EORTC QoL Questionaire PAL (palliative)
up to 12 month after treatment
Changes in other cognitive performance measures
Time Frame: up to 12 month after treatment
CANTAB Test
up to 12 month after treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Juergen Debus

Collaborators

Heidelberg University

Investigators

  • Principal Investigator: Stefan Rieken, PD.Dr., chief senior physician in the department of Radiation Oncology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2017

Primary Completion (Actual)

October 1, 2023

Study Completion (Actual)

December 1, 2023

Study Registration Dates

First Submitted

September 19, 2017

First Submitted That Met QC Criteria

September 26, 2017

First Posted (Actual)

September 29, 2017

Study Record Updates

Last Update Posted (Actual)

January 5, 2024

Last Update Submitted That Met QC Criteria

January 4, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ENCEPHALON

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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