NCT00096265

Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer

Terminated Phase 3 Results posted Last updated 9 March 2018

What this trial tests

Phase 3 trial testing 3-Dimensional Conformal Radiation Therapy in Metastatic Malignant Neoplasm in the Brain in 126 participants. Terminated before completion.

Timeline

6 October 2004

Primary endpoint
14 June 2011

1 April 2012

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	126
Start date	6 October 2004
Primary completion	14 June 2011
Estimated completion	1 April 2012
Sites	83 locations across Canada, United States

Drugs / interventions tested

• 3-Dimensional Conformal Radiation Therapy
• Erlotinib Hydrochloride — full drug profile →
• Stereotactic Radiosurgery
• Temozolomide (temozolomide) — full drug profile →

Conditions studied

• Metastatic Malignant Neoplasm in the Brain — all drugs for Metastatic Malignant Neoplasm in the Brain →
• Recurrent Non-Small Cell Lung Carcinoma — all drugs for Recurrent Non-Small Cell Lung Carcinoma →
• Stage IV Non-Small Cell Lung Cancer AJCC v7 — all drugs for Stage IV Non-Small Cell Lung Cancer AJCC v7 →

Sponsor

National Cancer Institute (NCI)

Who can join

18 and older, any sex, with Metastatic Malignant Neoplasm in the Brain or Recurrent Non-Small Cell Lung Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Survival Primary · From randomization to date of death or last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Survival time is defined as time from randomization to date of death from any cause and estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact.

Group	Value	95% CI
WBRT + SRS	13.4	6.5 – 20.8
Temozolomide + WBRT + SRS	6.3	3.4 – 10.1
Erlotinib + WBRT + SRS	6.1	3.6 – 12.1

Rate of CNS Progression (One Year) Secondary · From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

CNS progression is defined as any increase in perpendicular bi-dimensional tumor area for any of the 1-3 tracked brain metastases, by any amount, or the appearance of any new brain metastasis on a follow-up MRI (SRS planning scan will not be used to evaluate CNS progression). For lesions smaller than 1 cm in maximum diameter, a maximum increase of 50% in perpendicular bi-dimensional treatment area is necessary to score as progression. This caveat is included to account for potential variability in measurement, which is most susceptible to proportionate errors at smaller sizes. For greater than

Group	Value	95% CI
WBRT + SRS	34.1	19.8 – 48.4
Temozolomide + WBRT + SRS	47.4	31.0 – 63.8
Erlotinib + WBRT + SRS	27.4	13.2 – 41.5

Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument Secondary · From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Quality-adjusted life years (QALY) incorporate the societal-based utilities of health states into expected life years for a health condition. The QALY model is QALY(h,y) where h is a health state and y is the years of life. Higher quality-adjusted life year values represent a better outcome. A patient's health state will be determined from the index score of the EQ-5D-5L patient questionnaire.The EQ-5D-5L is a 2-part self-assessment questionnaire, a 5-item index score and a visual analogue scale, but only the index score is used for quality-adjusted survival. The index score has 5 items (mobil

Group	Value	95% CI
WBRT + SRS	16.9	± 9.6
Temozolomide + WBRT + SRS	15.9	± 12.0
Erlotinib + WBRT + SRS	14.4	± 12.5

Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months Secondary · From randomization to three months.

The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score, which ranges from 0 to 76. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-Br including the FACT-G must be greater th

Deterioration/Decrease

Group	Value	95% CI
WBRT + SRS	12
Temozolomide + WBRT + SRS	10
Erlotinib + WBRT + SRS	11

Stable

Group	Value	95% CI
WBRT + SRS	8
Temozolomide + WBRT + SRS	2
Erlotinib + WBRT + SRS	6

Improvement/Increase

Group	Value	95% CI
WBRT + SRS	6
Temozolomide + WBRT + SRS	4
Erlotinib + WBRT + SRS	1

Change in Performance Status at Six Months Secondary · From randomization to six months.

Compared between two treatment arms using a two-group chi-squared test. Zubrod score will be collected at baseline and follow-up. The Zubrod performance score runs from 0 to 5, with 0 denoting perfect health and 5 death. Change from baseline is calculated as 6-month value - baseline value. Patients with a baseline score who have died by six months will be included in the analysis with a score of 5 at six months.

Improvement (decrease)

Group	Value	95% CI
WBRT + SRS	0
Temozolomide + WBRT + SRS	1
Erlotinib + WBRT + SRS	3

Stable (no change)

Group	Value	95% CI
WBRT + SRS	19
Temozolomide + WBRT + SRS	4
Erlotinib + WBRT + SRS	2

Deterioration (increase)

Group	Value	95% CI
WBRT + SRS	21
Temozolomide + WBRT + SRS	30
Erlotinib + WBRT + SRS	30

Change in Steroid Dependence at Six Months Secondary · From randomization to six months.

Daily steroid dose will be collected at baseline and follow-up, as one of the following: 0-4 mg, \>4 to ≤ 8 mg, \>8 to ≤12 mg, and \>12 mg. Change from baseline at six months will be evaluated to have decreased, remained stable, or increased, based on these categories.

Decrease

Group	Value	95% CI
WBRT + SRS	12
Temozolomide + WBRT + SRS	10
Erlotinib + WBRT + SRS	10

Stable

Group	Value	95% CI
WBRT + SRS	10
Temozolomide + WBRT + SRS	4
Erlotinib + WBRT + SRS	6

Increase

Group	Value	95% CI
WBRT + SRS	4
Temozolomide + WBRT + SRS	4
Erlotinib + WBRT + SRS	1

Cause of Death (Neurologic vs Other) Secondary · From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Patients were considered to have died neurologic deaths (coded as "Brain Metastases") if they had stable systemic disease and progressive neurologic disease consisting of expanding intracranial masses, CNS hemorrhages, hydrocephalus resulting in herniation or fulminant meningeal carcinomatosis.

Group	Value	95% CI
WBRT + SRS	6
Temozolomide + WBRT + SRS	5
Erlotinib + WBRT + SRS	7
WBRT + SRS	29
Temozolomide + WBRT + SRS	29
Erlotinib + WBRT + SRS	29

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

WBRT+SRS

Serious: 10/44 (23%)

Deaths: —

Temozolomide+WBRT+SRS

Serious: 22/39 (56%)

Deaths: —

Erlotinib+WBRT+SRS

Serious: 12/41 (29%)

Deaths: —

Serious adverse events (68 terms)

Reaction	System	WBRT+SRS	Temozolomide+WBRT+SRS	Erlotinib+WBRT+SRS
Anemia	Blood and lymphatic system disorders	—	—	—
Platelet count decreased	Investigations	—	—	—
Death NOS	General disorders	—	—	—
Peripheral motor neuropathy	Nervous system disorders	—	—	—
Thromboembolic event	Vascular disorders	—	—	—
Cardiac disorders - Other	Cardiac disorders	—	—	—
Fatigue	General disorders	—	—	—
Infections and infestations - Other	Infections and infestations	—	—	—
Dermatitis radiation	Injury, poisoning and procedural complications	—	—	—
Weight loss	Investigations	—	—	—
White blood cell decreased	Investigations	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—
Dysphasia	Nervous system disorders	—	—	—
Seizure	Nervous system disorders	—	—	—
Renal and urinary disorders - Other	Renal and urinary disorders	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—
Respiratory, thoracic and mediastinal disorders - Other	Respiratory, thoracic and mediastinal disorders	—	—	—
Blood and lymphatic system disorders - Other	Blood and lymphatic system disorders	—	—	—
Hemolysis	Blood and lymphatic system disorders	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Lower gastrointestinal hemorrhage	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—

Other adverse events (182 terms — click to expand)

Reaction	System	WBRT+SRS	Temozolomide+WBRT+SRS	Erlotinib+WBRT+SRS
Fatigue	General disorders	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—
Rash acneiform	Skin and subcutaneous tissue disorders	—	—	—
Weight loss	Investigations	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Dermatitis radiation	Injury, poisoning and procedural complications	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—
Dysgeusia	Nervous system disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Platelet count decreased	Investigations	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Memory impairment	Nervous system disorders	—	—	—
Peripheral motor neuropathy	Nervous system disorders	—	—	—
Confusion	Psychiatric disorders	—	—	—
Edema limbs	General disorders	—	—	—
Non-cardiac chest pain	General disorders	—	—	—
Infections and infestations - Other	Infections and infestations	—	—	—
Neutrophil count decreased	Investigations	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—

Most-reported serious reactions: Anemia, Platelet count decreased, Death NOS, Peripheral motor neuropathy, Thromboembolic event, Cardiac disorders - Other, Fatigue, Infections and infestations - Other.

Data from ClinicalTrials.gov NCT00096265 adverse events section.

Sponsor's own description

This randomized phase III trial is studying whole-brain radiation therapy and stereotactic radiosurgery with or without temozolomide or erlotinib to see how well they work compared to whole-brain radiation therapy and stereotactic radiosurgery in treating patients with brain metastases secondary to non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by blocking blood flow to the tumor. It is not yet known whether radiation therapy and stereotactic radiosurgery are more effective with or without temozolomide or erlotinib in treating brain metastases.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.
   Mehta MP, Paleologos NA, Mikkelsen T, Robinson PD, et al · · 2010 · cited 107× · PMID 19960229 · DOI 10.1007/s11060-009-0062-7
2. The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics.
   Olson JJ, Paleologos NA, Gaspar LE, Robinson PD, et al · · 2010 · cited 26× · PMID 19957013 · DOI 10.1007/s11060-009-0058-3
3. Radiotherapy and erlotinib combined: review of the preclinical and clinical evidence.
   Mehta VK. · · 2012 · cited 20× · PMID 22645717 · DOI 10.3389/fonc.2012.00031
4. Effect of chemotherapy on survival after whole brain radiation therapy for brain metastases: a single-center retrospective analysis.
   Mayahara H, Sumi M, Ito Y, Sekii S, et al · · 2012 · cited 7× · PMID 22441932 · DOI 10.1007/s00432-012-1198-y
5. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis.
   Zhang C, Zhou W, Zhang D, Ma S, et al · · 2023 · cited 2× · PMID 36820064 · DOI 10.1515/med-2022-0574