Mitigation of Radiation Pneumonitis and Fibrosis
Condition: Lung Cancer; Radiation Pneumonitis
MeSH terms: Pneumonia; Radiation Pneumonitis
Study type: Interventional
Phase: Phase 2

Summary: 
      This project will test the effect of enalapril to mitigate the lung damage that can occur as
      a side effect of radiation therapy for lung cancer or other intrathoracic cancers. Thousands
      of Veterans develop lung cancer every year, and are treated by radiation therapy. Studies of
      lung radiation injury in laboratory animals show that with enalapril, investigators can
      significantly reduce the severity of radiation injury to the lung. Enalapril is FDA approved
      and in common use for treatment of hypertension, kidney disease, and heart failure. These
      studies will advance that work to human use. Successful mitigation of lung radiation damage
      will improve the quality of life in Veterans and non-Veterans who are treated for lung cancer
      by radiation, and may also improve cure rates of radiation therapy for lung cancer.
    

Detailed description: 
      Aim 1: To test the benefit of enalapril, an angiotensin-converting-enzyme-inhibitor, to
      mitigate radiation pneumonitis and fibrosis in humans.

      Subjects

      Men and women undergoing radiation therapy for lung cancer or other intrathoracic cancers at
      the Baltimore the Milwaukee or Ann Arbor Veterans Affairs Hospital are eligible. Subjects
      will be recruited to this phase 2 trial after their diagnosis of cancer and after referral to
      Radiation Oncology for treatment. The existence of this study will be posted in the Radiation
      Oncology clinics. Dr Cohen, Dr Beth Gore, and Dr Michelle Mierzwa (co-investigators) and our
      study coordinators will ensure recruitment. The informed consent process will be done by Dr
      Cohen or Gore or Dr Mierzwa or the study coordinators. Subjects who require radiation therapy
      to attempt to cure or to palliate their disease will be eligible for this study. Subjects
      eligible for surgical resection and who do not need radiation therapy will not be eligible
      for this study. Subjects on ACE inhibitors, angiotensin blockers, or renin antagonists will
      be excluded. Use of other antihypertensives is not an exclusion criterion. There will be no
      inclusion or exclusion by race or ethnic origin. Women and minorities are eligible. Children
      are not eligible because children do not develop lung cancer. Previous surgery and past or
      current use of chemotherapy are not exclusions. Subjects will have a Karnofsky performance
      status >/=70, absolute neutrophils > 1000/mm^3, platelets > 75,000/mm^3, and hematocrit >
      25%. Liver and kidney function tests will be within normal range and baseline blood pressure
      will be systolic > 110 mmHg sitting. Pregnant or nursing subjects are excluded and fertile
      patients will use contraception. Lung function tests including spirometry, lung volumes and
      diffusing capacity will be obtained as part of standard of care for patients prior to
      radiotherapy, but indices from lung function tests will not be a cause for exclusion.

      The mean lung dose will be >/= 18 Gy and/or V20 >20%. Radiation will be delivered with
      standard fractionation schedule of 1.8 to 2 Gy per day, 5 days per week, without planned
      treatment breaks.

      Experimental design

      Radiation treatment starts at time 0, and is given to completion, as indicated. Enalapril or
      placebo are started after the first radiation treatment fraction and continued thereafter.
      The renin-angiotensin system is tested at time 0, at three weeks, and at the completion of
      radiation treatment. CT scanning is done at time 0 and every three months thereafter for the
      first two years. Median survival is expected to be 18 months.

      Subjects will undergo therapeutic irradiation as indicated for clinical care. They will be
      enrolled to this masked, phase 2 trial at the start of radiation therapy (RT), stratified for
      cancer stage, then randomized to enalapril or identical-appearing placebo. Randomization will
      be done by the Department of Biostatistics, Medical College of Wisconsin, using random number
      tables; the center pharmacies will be notified of the assignment to enalapril or placebo.
      There will be no stratification by age, gender, lung cancer histology, or use of chemotherapy
      since these do not have a consistent relation with the occurrence of RP . Use of enalapril or
      placebo will not be known to the patients or their physicians during the time of study. The
      medical center pharmacy will stock and provide the study drug. Study drug, enalapril or
      placebo, will be started after the first fraction of the RT, at 2.5 mg by mouth once a day
      and increased to 10 mg/day in weekly increments as tolerated. Routine clinical care during
      the course of irradiation includes weekly or more frequent clinical assessment and vital
      signs. Blood testing for kidney function and potassium will occur within ten days after start
      of study drug. Additional patient visits will not occur for this study alone. Additional
      blood testing will occur in usual clinical care and will also be recorded. Routine care,
      independent of this study, includes CT scan chest imaging every three months for the first
      two years of follow-up. The study drug will be continued for life.

      Endpoints for injury

      The primary endpoint is symptomatic grade 2 or higher radiation pneumonitis, as defined by
      the established criteria, within the first 4 months of irradiation. The NCI Common
      Terminology Criteria Adverse Event (CTCAE) version 4.0 will be used to grade pulmonary
      toxicity. CTCAE is a worldwide standard for reporting adverse events from all modalities on
      cancer clinical trials. Pneumonitis is a new-onset and persistent cough requiring
      anti-tussive agents and or dyspnea with effort that is unexplained by other pulmonary
      illness. It may last for days to weeks. Severe cases may evolve to respiratory failure. Use
      of such patient-reported symptoms is strongly recommended for cancer-related clinical trials.
      Radiographic changes of RP occur in over half of subjects undergoing therapeutic thoracic
      irradiation; radiographic RP will be a secondary endpoint. Classic radiographic
      manifestations of RP are increased lung density within the radiation field within the first
      six months after radiation therapy that is not explained by infection or cancer. radiographic
      pneumonitis will be recorded by two investigators (Drs Gore and Antonescu-Turcu, EG, AAT),
      using the scale reported by Guckenberger. Investigators expect a radiographic rate of RP of
      50%.

      Investigators expect almost all surviving subjects to have fibrosis by CT scanning at 6 and
      12 months, and will test this as another major endpoint. Radiation fibrosis in the lung is
      evident as scarring with volume loss and bronchiectasis within the radiation field at six
      months or more after radiation therapy, not explained by infection or cancer. radiographic
      fibrosis will be recorded and quantified by two investigators (EG, AAT). Reduction in
      diffusion capacity for carbon monoxide (DLCO) correlates with pulmonary radiation fibrosis.
      DLCO is obtained in all survivors at the 12 month time point, and will be compared to
      baseline values as an additional secondary endpoint. The occurrence of clinical grade 2 or
      higher RP, of radiographic RP and fibrosis as dichotomous variables, will be compared for the
      subjects on enalapril compared to those on placebo. For RP, any image showing RP will assign
      a subject to the RP group. For fibrosis, the last CT scan will be used.

      Investigators will test quality of life as a secondary endpoint. The Functional Assessment of
      Cancer Therapy -lung (FACT-L version 4) will be used to assess Quality of Life (QoL). FACT-L
      contains four general (physical, social/family, emotional, and functional well being) and one
      lung cancer specific subscale. QoL will be assessed pretreatment, and at 12 months post
      treatment. Use of patient-reported data is strongly recommended for cancer-related clinical
      trials.

      Aim 2: To test the mechanism of mitigation by enalapril

      Subjects These are the same subjects as in aim 1.

      Experimental design Investigators will test the major components of the renin-angiotensin
      system; angiotensinogen, plasma renin activity, and angiotensin II (ang II). These will be
      measured at baseline, at three weeks after the start of irradiation, and at the completion of
      irradiation. Investigators will test their mechanistic involvement by their change with use
      of enalapril, in particular whether the benefit of enalapril is correlated with its effect to
      lower the plasma ang II levels. Other components of the RAS, including angiotensin (1-7),
      aldosterone, AcSDKP, and bradykinin will not be tested because experimental studies have not
      shown them to be relevant to mitigation of normal tissue radiation injury.

      Baseline elevation of one or more of these RAS components, compared to known levels in the
      normal population, may correlate with development of RP and or fibrosis in the control,
      placebo group. This may permit better focused use of mitigators in the future, in only those
      at risk.

      Enalapril, by inhibition of ACE, will reduce plasma ang II and lead to a feedback elevation
      of PRA. This will confirm adherence to drug therapy and may also correlate with its benefit.
      Elevation of PRA in subjects on enalapril, but without mitigation benefit, will show that it
      is ineffective, despite its adequate bioavailability.

      Aim 3: To confirm that enalapril does not adversely affect cancer treatment outcomes.

      Subjects These are the same subjects as in aim 1.

      Experimental design Investigators will compare cancer recurrence and cancer-related survival
      in subjects on enalapril versus placebo. Cancer recurrence will be assessed clinically, as
      confirmed by CT imaging and or histology. The RECIST criteria will be used. Recurrence rates
      and survival will be assessed by interim safety analyses during the study, and finally at its
      completion. In the statistical analysis, investigators will account for the effects of
      interim sampling for the safety analyses, and will adjust for patient and disease
      characteristics as well as missing data. A benefit of enalapril on RP may enhance patient
      survival. An adverse effect of enalapril on survival will stop this study. But a cohort of
      162 Veterans showed no difference in patient survival for those on ACE inhibitor compared to
      those not on ACE inhibitor. Thus, investigators do not expect adverse changes in recurrence
      rates or patient survival.

      Expected results, potential problems, and long-term impact

      Investigators expect that subjects on enalapril will have significantly less clinical and
      radiographic RP and fibrosis, compared to those on placebo. Investigators expect that
      subjects on placebo who develop RP and or fibrosis may have baseline elevation of AGT and PRA
      compared to those who don't develop RP and or fibrosis, and that the mitigation benefit of
      enalapril will correlate with its effect to increase the PRA and reduce the plasma ang II
      levels. Investigators expect that enalapril will not increase cancer-related mortality, and
      may even enhance overall patient survival through mitigation of radiation lung injury.
    

Intervention name(s): Enalapril; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Enalapril once a day, orally, as 2.5 , 5, or 10 mg tablets to be given in escalating doses, to subjects undergoing radiotherapy for lung cancer; Placebo, once a day, orally, as 2.5 , 5, or 10 mg tablets to be given in escalating doses, to subjects undergoing radiotherapy for lung cancer
Intervention MeSH terms: Enalapril
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Prevention
Keywords: lung cancer; radiation pneumonitis; mitigation; enalapril; placebo