Early Hippocampal Avoidance Prophylactic Cranial Irradiation in Patients With LD SCLC

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ClinicalTrials.gov Identifier: NCT02058056

Recruitment Status : Completed

First Posted : February 7, 2014

Last Update Posted : January 29, 2020

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Swiss Group for Clinical Cancer Research

Study Description

Brief Summary:

The main objective of this trial is to assess NCF after early HA-PCI concomitant to the second cycle of CHT and to tRT for patients with LD SCLC.

Condition or disease	Intervention/treatment	Phase
Small-Cell Lung Cancer	Radiation: Irradiation: HA-PCI	Not Applicable

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Detailed Description:

About 15% of all lung cancers are small cell lung cancer (SCLC). SCLC is a high-grade, neuroendocrine carcinoma of the lung. Limited disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port. About 30% of all SCLC are LD at diagnosis. The median overall survival (OS) in LD SCLC is approximately 20 months, with an expected 5-year survival of less than 15%.

SCLC is characterized by rapid growth and early dissemination. The standard treatment of LD SCLC involves multimodality therapy with concurrent thoracic radiotherapy (tRT) and chemotherapy (CHT) with cisplatin and etoposide.

Recurrence in the brain is usually the primary site of treatment failure in SCLC and is associated with significant morbidity; and consequently often the cause of death. Occult early dissemination of SCLC has frequently occurred prior to the time of diagnosis. In patients with brain metastasis two randomized trials showed an overall 5-year rate of brain metastasis of 59% without prophylactic cranial irradiation (PCI) compared to 43% with PCI. However the rate of brain metastasis with PCI is still very high.

About 50% of patients with SCLC will develop brain metastases some time during the course of their disease. Therefore PCI is recommended in case of good response to CHT and tRT. PCI has shown to improve overall survival in patients with LD who have achieved a complete or partial remission after initial chemoradiotherapy. CHT might achieve insufficient drug levels in the brain. Therefore, an up-front PCI could treat occult brain metastases at a preclinical state and may increase the permeability of the blood-brain barrier for CHT products.

When evaluating PCI it is important to weigh the reduced incidence of brain metastases against the potential risk of deficits resulting from the treatment itself, including deteriorations in neurocognitive functions (NCF) or quality of life (QoL).

A possibility to reduce long-term neurocognitive effects due to PCI is the sparing of the hippocampus. Recent technological advancements in radiation oncology delivery enable the avoidance of the hippocampus. A PCI with hippocampus avoidance (HA-PCI) can reduce memory loss due to radiation.

Prospective neurocognitive testing has been increasingly used in trials for patients with CNS tumors and in patients with brain metastases in order to determine the risks versus benefits of different treatment approaches. For this trial, the choice for NCF assessments follows the recommendation provided by Meyers and Brown (2006). This neurocognitive battery for the use in multinational drug trials with neurocognitive endpoints consists of four standardized psychometric instruments, i.e. the Hopkins Verbal Learning Test, the Controlled Oral Word Association Test (COWAT) and the Trail Making Part A and Part B (TMT A/B). These tests have been shown to be sensitive to the neurotoxic effects of cancer treatment in clinical trials and cover several cognitive functions (memory, verbal fluency, visual-motor speed, executive function). In addition, published normative data are available that take into account age, and where appropriate, education and sex. To minimize the effects of repeated administration alternate forms can be used and test administration is highly standardized. The same battery of tests has been used in trials conducted by the Radiation Therapy Oncology Group (RTOG) (e.g. Wolfson 2011), and one or several of these three tests were applied in most of the studies mentioned above. Using the same tests across trials is important in order to be able to compare results of different trials. It has been shown that performing a cognitive test battery consisting of five cognitive tests (and a QoL assessment) in a multi-site trial and cooperative group setting (i.e. a RTOG trial) in patients with brain metastases is feasible.

NCF can be affected by a number of factors such as the volume of brain metastases, disease progression, other treatments (e.g. surgery, chemo- or endocrine therapy), medications and psychological factors such as anxiety and distress. These factors should be considered when evaluating the actual neurocognitive effect of concomitant CHT, tRT and PCI.

Rationale for performing the trial PCI is part of the standard treatment of LD SCLC as the rate of developing brain metastases is very high and PCI has shown to increase overall survival. PCI is given to patients presenting a good response to CHT and tRT. However the overall 5-year rate of brain metastasis with PCI is still very high.

As long as safety data are lacking on PCI administered concurrently with CHT and tRT, PCI is given after the end of CHT in the clinical practice. Therefore the aim of this phase II trial is to evaluate to what extent early HA-PCI given concomitant to CHT and tRT impairs NCF and whether this neurotoxicity can be considered acceptable to evaluate this question in a phase III trial.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	44 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Early Prophylactic Cranial Irradiation With Hippocampal Avoidance in Patients With Limited Disease Small-cell Lung Cancer. A Multicenter Phase II Trial
Actual Study Start Date :	July 11, 2014
Actual Primary Completion Date :	June 7, 2018
Actual Study Completion Date :	December 3, 2018

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Lung cancer

Genetic and Rare Diseases Information Center resources: Small Cell Lung Cancer

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental: HA-PCI treatment Irradiation HA-PCI concomitant to the second cycle of CHT and to tRT for patients with LD SCLC	Radiation: Irradiation: HA-PCI 25 Gy in 10 daily factions, five times a week

Outcome Measures

Primary Outcome Measures :

Neurocognitive functioning (NCF) [ Time Frame: at 6 months ]
NCF at 6 months after end of HA-PCI treatment measured by Hopkins Verbal Learning Test Revised (HVLT-R), Controlled Oral Word Association (COWAT) and Trail Making Test Part A and B (TMT A/B). A neurocognitive decline is defined as a decrease of one standard error of measurement (SEM) in any of the four NCF tests.

Secondary Outcome Measures :

Brain metastasis free survival (BMFS) [ Time Frame: At 6 months and 12 months. ]
Adverse events according to NCI CTCAE version 4.0 [ Time Frame: Until 1 year after the end of HA-PCI treatment. ]
Neurotoxicity [ Time Frame: Until 1 year after HA-PCI treatment. ]
Neurotoxicity according to NCI CTCAE version 4.0
Individual tests for each cognitive domain (memory, verbal fluency, visual motor speed, executive function). [ Time Frame: At 6 weeks, 6 and 12 months after the end of HA-PCI treatment. ]
Overall survival (OS) [ Time Frame: From time of registration (expected average of 20 months) ]
Quality of Life (QoL) measured by functional assessment of cancer therapy-brain (FACT-Br) and general health questionnaire (GHQ-12) [ Time Frame: At 6 weeks, 6 and 12 months after the end of HA-PCI treatment. ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Newly diagnosed cytologically or histologically confirmed diagnosis of SCLC within 6 weeks before registration.
Proven LD SCLC (CT thorax, abdomen, and bone scan (or PET/CT only) and brain MRI within 6 weeks before registration) according to the TNM classification version 7 that can be encompassed within a radical radiation port
Only patients assessed by an interdisciplinary tumor board should be declared eligible taking into account eligibility for curative tRT and CHT according to NCCN Guidelines version 2.2014
Karnofsky Index ≥ 60%
Age at registration 18 to 75 years
Normal bone marrow function: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
Calculated creatinine clearance ≥ 60 mL/min is required if chemotherapy with cisplatin is scheduled. If cisplatin has to be replaced by carboplatin a creatinine clearance ≥ 50 mL/min is required
Normal liver function: bilirubin ≤ 1 x ULN, AST and ALT ≤1.5 x ULN
Fluency in either German, French or Italian
Women are not breastfeeding. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 6 months thereafter. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential. Men agree not to father a child during participation in the trial and during 6 months thereafter.
Baseline QoL questionnaires FACT-Br and GHQ-12 have been completed within 14 days before registration
Baseline NCF assessments have been completed within 14 days before registration:
- HVLT-R
- COWAT
- TMT A
- TMT B
Patient must give written informed consent before registration

Exclusion Criteria:

Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
History of CNS metastases
Prior brain RT
History of RT to the thorax
Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling out QoL forms, participating in assessing NCF testing or interfering with compliance for oral drug intake.
Concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to trial entry.
Any serious underlying medical condition (at the judgment of the investigator) which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes).
Any concomitant drugs contraindicated for use with the treatment drugs according to the approved product information.
History of cerebrovascular disease or epilepsy requiring continuous treatment
Symptomatic cardiac disease or a history of myocardial infarction within the previous 3 months
Any psychological, familial or sociological/geographical conditions potentially hampering compliance with the study protocol and follow-up schedule
Legal incapacity or limited legal capacity

Contacts and Locations

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): NCT02058056

Locations

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Switzerland
Universitätsspital Basel
Basel, Switzerland, CH-4031
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
Bellinzona, Switzerland, 6500
Inselspital Bern
Bern, Switzerland, CH-3010
Kantonsspital Graubuenden
Chur, Switzerland, 7000
Hopital Fribourgeois
Fribourg, Switzerland, 1708
Hopitaux Universitaires de Geneve
Genève 14, Switzerland, 1211
Kantonsspital - St. Gallen
St. Gallen, Switzerland, CH-9007
Kantonsspital Winterthur
Winterthur, Switzerland, CH-8400

Sponsors and Collaborators

Swiss Group for Clinical Cancer Research

Investigators

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Study Chair:	Francesca Caparrotti, MD	Hôpitaux Universitaires de Genève, Genève

More Information

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Responsible Party:	Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier:	NCT02058056
Other Study ID Numbers:	SAKK 15/12
First Posted:	February 7, 2014 Key Record Dates
Last Update Posted:	January 29, 2020
Last Verified:	January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Swiss Group for Clinical Cancer Research:


Early prophylactic cranial irradiation hippocampal avoidance limited disease small-cell lung cancer

Additional relevant MeSH terms:

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Lung Neoplasms Small Cell Lung Carcinoma Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site	Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms

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