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Supportive Care With or Without Repeated Whole Brain Radiotherapy in Patients With Recurrent Brain Metastases (RECARE)

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ClinicalTrials.gov Identifier: NCT04084431
Recruitment Status : Suspended (organizational reasons)
First Posted : September 10, 2019
Last Update Posted : October 6, 2021
Sponsor:
Information provided by (Responsible Party):
Juergen Debus, University Hospital Heidelberg

Brief Summary:

Patients with solid cancers may develop cerebral metastases, requiring whole brain radiotherapy (WBRT). Furthermore, in several cases, a secondary course of WBRT might be required due to intracerebral recurrence and limited options for alternative treatments, besides optimal supportive care (OSC). There have been few reports on re-irradiation of the whole brain, but further evaluation especially of the optimal dose concept is warranted. Especially, the efficacy compared to OSC has to date not been evaluated.

The present trial aims at evaluating the efficacy of a repeated WBRT with a total dose of 20 Gy in 10 fractions compared to OSC.

Primary endpoint is time to WHO performance status (PS) deterioration to more than 3 (duration of functional independence).

Secondary endpoints are quality of life, overall survival, radiation-induced toxicity and functional independence assessed by the Barthel Index of Activities of Daily Living (ADL)1.


Condition or disease Intervention/treatment Phase
Brain Metastases Radiation: Radiation Other: OSC Not Applicable

Detailed Description:

According to Nussbaum et al., 24-45% of cancer patients develop cerebral metastases during their disease. Brain metastases are generally associated with a poor prognosis and high morbidity2. Published median survival rates after WBRT are between 2 and 7 months3. Standard of care in multiple BM is WBRT delivered as total dose of 30 Gy in 10 fractions, leading to modest palliation with a median survival of 3 to 5 months 4-6. Prognostic factors include the RPA-classification, performance status, response to steroids and evidence of systemic disease3,6.

Unfortunately, intracerebral recurrence happens 7-9. For example, in the cohort of Meyners et al. (2010) on WBRT in relatively radio-resistant tumours, median time to recurrence was 4.5 months and the local control rates at 6 and 12 months after radiotherapy were 37% and 15%, respectively10. Furthermore, the treatment of intracerebral recurrence after previous WBRT is challenging. In case of ≤ 3 recurrent BM, surgery or stereotactic radiosurgery (SRS) are options. One other option, especially in case of >3 recurrent BM is repeated WBRT. In this setting, one of the first reports on repeated WBRT was published by Cooper et al. in 199011. The authors reported on repeated WBRT (n=52) consisting of a total dose of 25 Gy in 10 fractions. Response to re-irradiation was seen in about 40% of the patients. Furthermore, the patients improved by at least one level in their neurologic function status. Survival after second therapy averaged 5 months. In the report by Wong et al. (1996) median dose of retreatment (n=86) was 20 Gy12. Resolution of symptoms was achieved in 27% of patients, partial improvement in 43% and no improvement or worsening of symptoms was seen in 29% of patients. The majority of patients had no significant toxicity in consequence of re-irradiation. Five patients had radiographic abnormalities of their brain consistent with radiation-related changes. One patient had symptoms of dementia that was thought to be caused by radiotherapy. Sadikov et al. (2007) reported on 72 patients who underwent repeated WBRT for recurrent or progressive BM13. The median survival after re-irradiation was 4.1 months. One patient was reported having memory impairment and pituitary insufficiency after 5 months of progression-free survival.

In the report by Mayer et al. on re-irradiation tolerance of the human brain (this analysis was focused on recurrent glioma), the authors concluded that radiation-induced brain tissue necrosis is likely to occur at normalized tolerance doses of cumulative > 100 Gy14.

The recent QUARTZ trial investigated the efficacy of WBRT vs. OSC in patients with non-small cell lung cancer and low performance status. The results suggest that WBRT, even in the primary situation, offers no substantial benefit to most patients with brain metastases from NSCLC in terms of improved survival, overall quality of life, or reduction of steroid use in this cohort15.

In the present trial, the primary endpoint (time to WHO PS deterioration to more than 3) as well as the secondary endpoints QoL, overall survival, radiation-induced toxicity and functional independence assessed by the Barthel Index of Activities of Daily Living (ADL) in patients previously treated with WBRT requiring repeated WBRT for intracerebral tumour progression will be evaluated.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, randomized 2-armed Phase II Pilot-Trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Supportive Care With or Without Repeated Whole Brain Radiotherapy in Patients With Recurrent Brain Metastases Unsuitable for Resection or Stereotactic Radiotherapy.
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : July 1, 2024
Estimated Study Completion Date : July 1, 2025

Arm Intervention/treatment
Active Comparator: WBRT (10 x 2 Gy) + OSC
Whole brain radiotherapy will be applied with a total dose of 20 Gy in 10 fractions (single dose of 2 Gy). OSC as needed.
Radiation: Radiation
WBRT will be applied in 10 fractions with single doses of 2 Gy (Arm 1) to the whole brain

Experimental: Optimal Supportive Care (OSC) alone
Symptomatic treatment including steroids, pain medication, nutritional support, etc
Other: OSC
optimal supportive Care (OSC) alone




Primary Outcome Measures :
  1. Time to WHO PS to more than 3 [ Time Frame: up to 4 years or from date of randomization unitl the date of documented date of death from any cause ]
    WHO Performance status


Secondary Outcome Measures :
  1. OS [ Time Frame: up to 4 years or from date of randomization unitl the date of documented date of death from any cause ]
    Overall survival



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • histologically confirmed malignancy
  • previous WBRT or prophylactic whole brain irradiation (PCI)
  • MR- or CT-imaging confirmed recurrent cerebral metastases (>10)
  • Or: MR- or CT-imaging confirmed recurrent cerebral metastases (1-10) and inability to perform SRS or surgery (e.g. meningeal carcinomatosis), concluded by interdisciplinary conference
  • age ≥ 18 years
  • Time between initial WBRT/PCI and recurrent WBRT >3 months
  • WHO performance score ≤3
  • 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 to take part in the study

    • Pregnant or lactating women
    • Participation in another competing clinical study or observation period of competing trials, respectively
    • Ability to perform SRS or surgery on brain metastases as a treatment alternative
    • Systemic anticancer treatment <4 weeks for chemotherapy and <1 week for TKIs and targeted therapies before randomisation.
    • Persons who are in a relationship of dependence/employment with the investigators
    • Cerebral lymphomas, metastases of germ cell tumours

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04084431


Locations
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Germany
University Hospital
Heidelberg, Germany, 69120
Sponsors and Collaborators
University Hospital Heidelberg
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Responsible Party: Juergen Debus, Principal Investigator, University Hospital Heidelberg
ClinicalTrials.gov Identifier: NCT04084431    
Other Study ID Numbers: RECARE Trial Version 1.1
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: October 6, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Juergen Debus, University Hospital Heidelberg:
repeated whole brain radiation therapy
Additional relevant MeSH terms:
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Neoplasm Metastasis
Brain Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases