Lung Cancer, Interstitial Lung Disease
Conditions
Keywords
Pulmonary Irradiation, Radiation Therapy, N-Acetyl Cysteine, Dexamethasone, Radiation Pneumonitis
Brief summary
In this double-blind phase II randomized controlled trial, patients with lung cancer or ≤2 oligometastatic pulmonary lesions and a concomitant diagnosis of ILD who are planned for radical Radiation Therapy (RT) will be randomized using a 2 x 2 factorial design to oral N-acetylcysteine (NAC) versus placebo, and also to short course corticosteroids versus placebo.
Detailed description
Radiation pneumonitis (RP) is the most common and main dose-limiting toxicity after thoracic RT. RP is characterized histologically by diffuse alveolar damage and acute vascular permeability induced by direct cytotoxic effect and oxidative stress, leading to the production of proinflammatory, profibrogenic and proangiogenic cytokines. Patients with Interstitial Lung Disease (ILD) are at increased risk of developing lung cancer compared to the general population. Management of patients with lung cancer in the setting of a concomitant ILD is complex, as these patients are usually not good candidates for surgery or immunotherapy. In addition, patients with ILD, particularly fibrotic ILD, are also reportedly at increased risk of treatment-related toxicity from RT. In the present study, investigators will test the following hypotheses: 1. The use of NAC with RT in patients with underlying ILD will lead to a clinically meaningful reduction in grade 2-5 dyspnea (as per Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0). 2. The use of corticosteroids with RT in patients with underlying ILD will lead to a clinically meaningful reduction in grade 2-5 dyspnea (as per CTCAE version 5.0).
Interventions
DIETARY_SUPPLEMENTN-Acetyl cysteine
NAC capsules
DRUGDexamethasone Oral
Dexamethasone tablets
DIETARY_SUPPLEMENTN-Acetyl cysteine Placebo
Matching placebo for NAC capsules
Matching placebo for dexamethasone tablets
RADIATIONRadiation Therapy
All participants will receive radical pulmonary radiation therapy. Conventional techniques or stereotactic ablative radiotherapy will be used.
Sponsors
David Palma
London Health Sciences Centre
Centre Hospitalier de l'Universite de Montreal (CHUM)
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
double-blinded, placebo controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Lung cancer or 1-2 oligometastatic pulmonary lesions planned for radical intent radiotherapy \[minimal Biologically Effective Does (BED) of 48 Gy10 (Gray) or biological equivalent\]. * Pathologically (histologically or cytologically) proven diagnosis of cancer is not required, but strongly recommended. * If the risk of biopsy is unacceptable, pathologic confirmation is not required providing there is growth over time on Computed Tomography (CT) imaging and/or Fluorodeoxyglucose (FDG) avidity that is strongly suggestive of malignancy. * Fibrotic Interstitial Lung Disease (ILD) of any subtype, as diagnosed by a respirologist and confirmed by central review * Eastern Cooperative Oncology Group (ECOG) performance status 0-3 * Age ≥ 18 * Life expectancy \> 6 months * Patients are allowed to receive anti-fibrotic agents used in the treatment of Idiopathic Pulmonary Fibrosis (IPF) or non-IPF fibrotic ILD (e.g. nintedanib, pirfenidone) and/or corticosteroids, if those are part of their current ILD treatment regimen. Other immunosuppressive drugs such as mycophenolate, azathioprine, cyclophosphamide, and rituximab must be stopped for 2 weeks prior and 2 weeks after Radiation Therapy (RT). * Concurrent standard chemotherapy is allowed where indicated. All other systemic therapies, including biologic targeted agents or immunotherapy, or any drugs with known radiosensitive effects, must be stopped for 2 weeks prior and 2 weeks after treatment.
Exclusion criteria
* Prior lung radiotherapy * Current use of oral or intravenous corticosteroids * Plans for the patient to receive other local therapy to the target lesion(s) while on this study, except at disease progression * Any medical condition that could, in the opinion of the investigator, preclude radiotherapy or prevent follow-up after radiotherapy * Pregnancy * If not pregnant, use of effective contraception methods for women of childbearing age is required which can include: * hormonal methods (e.g. oral, injected, implanted), * placement of an intrauterine device, * barrier methods (i.e. condoms), * sterilization of the partner (e.g. previous vasectomy) * abstinence * Women who become pregnant should stop taking NAC and/or dexamethasone and inform their study doctor. * Male participants should use adequate forms of birth control with their partners. * Currently breastfeeding * Current or recent use of NAC * Contraindications to dexamethasone or N-Acetyl Cysteine (NAC). These include: * Previous intolerance or allergy to dexamethasone or NAC * Scleroderma * Active infection * Glaucoma * Psychiatric disorder that could be exacerbated by dexamethasone * Cystinuria * Any other condition that the treating physician believes to be a contraindication to dexamethasone or NAC
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rate of Grade 2-5 Dyspnea within 6 Months Post Radiation Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5 | Up to 6 months post radiation therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Scored Dyspnea Measured by Visual Analogue Scale (VAS) | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | Dyspnea (shortness of breath) severity will be reported by participants via a scale, where a score of 100 is no shortness of breath and a score of 0 is the worst shortness of breath ever. |
| Patient Scored Cough Measured by Visual Analogue Scale (VAS) | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | Cough severity will be reported by participants via a scale, where a score of 100 is no cough and a score of 0 is the worst cough ever. |
| Quality of Life Measured by FACIT.org Functional Assessment of Cancer Therapy - Lung (FACT-L) Questionnaire | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | The Functional Assessment of Cancer Therapy - Lung (FACT-L ) is a standardized questionnaire used to measure quality of life. The questionnaire consists of 5 scales measuring 37 items in total. Categories of the 5 scales are: physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns related to symptoms, cognitive function, and regret of smoking. The score for each item in the scale ranges from 0 to 4, where 0 is not at all and 4 is very much. The scores from each scale are added up, and can be combined to provide a total score. |
| Quality of Life Measured by EuroQOL Group EQ-5D-5L Questionnaire | 6 weeks, 3, 6, 9, 12,18, 24, 36, 48, and 60 months post radiation therapy | The EQ-5D-5L is a standardized questionnaire used to measure quality of life and health. The first section includes 5 categories: mobility, self-care, usual activities (e.g. work, family), pain/discomfort, and anxiety/depression. Each category contains 5 statements ranging from no problems to extreme problems, where no problems is assigned a code of 1 and extreme problems is assigned a code of 5. Participants are asked to select the statement that best describes their health that day. No score is generated, rather a 5 digit code is generated based on the response provided, which can then be combined into a data set and interpreted in a variety of ways. The second section includes a 20 cm analogue scale from 0 to 100, where 100 is the best health ever imagined and 0 is the worst health imagined. The participant will mark a score on the scale representing the state of their health on that day. |
| Local Control as Determined by Radiographic Evidence | 9 years | Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 will be used to measure tumors in the lung (by size), on imaging, to determine how tumors are responding to treatment. |
| Progression Free Survival | 9 years | Time from enrollment to death from any cause or any progression of disease (local, regional, or distant). |
| Overall Survival | 9 years | Time from enrollment to death from any cause . |
| Cancer Specific Survival | 9 years | Time from enrollment to death from lung cancer, censored at last follow-up or death from other causes. |
| Rates of Radiation Treatment Completion | 50 months | — |
| Rates of Study Drug Completion Rates | 50 months | — |
| Rates of Participant Unblinding Related to Adverse Events Development | 50 months | — |
Countries
Canada
Contacts
CONTACTDavid Palma, MD
CONTACTHouda Bahig, MD
STUDY_CHAIRDavid Palma, MD
London Health Sciences Centre, Lawson Health Research Institute
STUDY_CHAIRHouda Bahig, MD
Centre Hospitalier de l'Universite de Montreal
Outcome results
None listed