Trial of Image-Guided Adaptive Conformal Photon vs Proton Therapy, With Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Treatment Related Pneumonitis and Locoregional Recurrence

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if, compared with regular x-ray radiation, proton radiation reduces the risk of developing, treatment-related pneumonitis (TRP) or tumor recurrence (the tumor coming back in the irradiated area after treatment) in patients with lung cancer.

Detailed Description
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There are 2 types of radiation treatment being used in this study. One type of treatment is proton therapy. Proton therapy is a type of radiation therapy that uses a beam of proton particles (similar to getting an x-ray) to send radiation inside the body to the tumor. The other type of treatment is Image-Guided Adaptive Photon Therapy (IGAPT). IGAPT is a therapy that uses images to help guide the delivery of photon therapy to the tumor. Both of these types of radiation treatment are believed to help doctors to give a full dose of radiation treatment to the tumor while not damaging as much of the healthy tissue around it. Study Groups If you are found to be eligible to take part in this study, you will go through the standard radiation treatment planning procedure, called the marking session. After the marking session, a standard photon therapy plan (called Intensity Modulated Radiation Therapy, or IMRT) and a proton plan will be developed. If the radiation oncologist thinks that both the photon and proton plans are acceptable, you will then be randomly assigned to 1 of 2 groups. Participants in Group 1 will receive photon therapy. Participants in Group 2 will receive proton therapy. The first 20 participants will have an equal chance to be assigned to either group. After at least 20 participants have been enrolled and there has been at least 1 occurrence of pneumonitis and/or tumor recurrence in each treatment Group, the risk of pneumonitis and/or tumor recurrence in all previous participants will be evaluated for each treatment Group, and that information will be used to calculate the chances of being assigned to either Group 1 or Group 2. This calculation will be updated after each occurrence of pneumonitis and/or tumor recurrence and after each participant returns for a follow-up visit. Once these calculations are begun, everyone who joins the study from that point on will be more likely to be assigned to the treatment Group that appears to be better in terms of pneumonitis and/or tumor recurrence. If the tumor is too large and the standard radiation treatment plan created during the marking session is found not to be acceptable, and the radiation oncologist thinks radiation treatment it is necessary, you will still remain on study and be assigned to a third group. If you are assigned to Group 3, you will receive proton or photon treatment at a lower dose level and/or reduced length of radiation. If you are assigned to Group 2 and your insurance provider denies reimbursement, you may chose not to receive proton therapy and receive photon therapy instead. If you chose to receive photon therapy, you will be in Group 4. Radiation Therapy Administration Both radiation therapy treatments (photon and proton) are given through a radiation machine called an accelerator. The radiation therapy administration process is very similar to the way that a CT scan is performed. You will lay on a table and the treatment machine rotates around you without touching your body. Each daily treatment should take about 20-30 minutes to complete. Most of this time is used to position you correctly before the machine is turned on. The actual time used to give the radiation should take about 3-5 minutes each day. While you are on this study and if you are in Groups 1 or 2, you will receive a total of 37 radiation treatments. Radiation is given 5 days a week for about 7 1/2 weeks. If you are in Group 1, you will receive photon radiation treatment in the main hospital. If you are in Group 2, you will receive proton therapy in the proton treatment center (PTC). If you are in Group 3, you will receive either photon or proton therapy, whichever your doctor decides is better for you, for 6-7 1/2 weeks. If your doctor decides that photon therapy is better you will receive your treatment in the main hospital. If your doctor decides that proton therapy is better you will receive your treatment in the Proton Therapy Center. If you are in Group 4, you will receive Photon radiation treatment in the main hospital. Chemotherapy You will receive carboplatin and paclitaxel chemotherapy 1 time a week over 7 weeks. Each treatment will last 3-4 hours. Paclitaxel will be given by vein over 1 hour and carboplatin will be given by vein over 30 minutes. You will receive this chemotherapy combination with radiation therapy, as part of your treatment on this study. Your chemotherapy may also be decided by your treating medical oncologist as long as the therapy is allowed by the study. Study Visits During Chemoradiation At least 1 time each week for all study participants, you will have study tests performed. During this weekly study visit, the following tests and procedures will be performed: You will have a physical exam. You will be asked about any side effects you may have experienced. Blood (about 2 teaspoons) will be drawn for routine tests. If the study doctor thinks it is needed, you will have a PET/CT scan performed to check the status of the disease during Week 4 or 5 of treatment. Length of Study You will remain on study as long you are benefiting. You will be taken off study early if the disease gets worse, you experience intolerable side effects, or your doctor thinks that it is no longer in your best interest to receive the study treatment. Follow-Up Visits After you have completed chemoradiation, the study staff or study nurse will contact you 1 time each month to ask you about any symptoms you may have until 6 months after chemoradiation. Each phone call should last about 10 minutes. You will have your first follow-up visit 4-8 weeks after you have completed chemoradiation. You will have additional follow-up visits every 3-4 months for 3 years, every 6 months for the next 2 years, and then 1 time every year after that. At the first and second follow-up visit the following tests and procedures will be performed: You will have positron emission tomography (PET)/computed tomography (CT) scans and single proton emission tomography (SPECT) scans to check the status of your lungs and heart if the radiation or medical oncologist thinks it is necessary. Blood (about 1 teaspoon) will be drawn for routine tests. If the radiation oncologist or medical oncologist thinks it is needed, at the follow-up visits, you will have breathing function tests performed to check your lung function for up to 1 year after the study treatment is complete. For this test, the radiation oncologist, medical oncologist or study nurse will have you breathe into a special machine. The radiation oncologist or medical oncologist will decide how many tests are to be performed each time. PET/CT and SPECT scans will be performed again at any time the radiation oncologist or medical oncologist thinks they are needed. Other tests may be performed if the study doctor (radiation oncologist, medical oncologist, surgeon or pulmonologist) thinks they are needed. This is an investigational study. Both proton radiotherapy and IGAPT are FDA approved for the treatment of lung cancer. Up to 250 patients will take part in this multi-center research study. Up to 205 will be enrolled at M. D. Anderson.

Official Title
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A Bayesian Randomized Trial of Image-Guided Adaptive Conformal Photon vs Proton Therapy, With Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Treatment Related Pneumonitis and Locoregional Recurrence

Conditions
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Non-Small-Cell Lung Carcinoma

Intervention / Treatment
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* Radiation: Photon Therapy
* Radiation: Proton Therapy
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically proven, unresected, locoregionally advanced NSCLC without evidence of hematogenous metastases (stage II-IIIB disease according to the 7th edition of the AJCC Staging Manual) with exception as defined by inclusion #2). Patients with solitary brain metastasis without sign of progression in the brain at the time of registration will be eligible for this trial if there is clinical indication for concurrent chemoradiation to the primary disease in the lung. Suitability for concurrent chemoradiation therapy per treating radiation oncologists or treating medical oncologist's: A) Karnofsky performance score of >/= 70, or ECOG 0-1 B) Unintentional weight loss </= 10% during the 3 months before study entry. Receipt of induction chemotherapy followed by referral for concurrent chemoradiation is allowed for this protocol. Measurable disease on chest x-ray, contrast-enhanced CT, or PET scan. Locoregional recurrence after surgical resection, if suitable for definitive concurrent chemoradiation is allowed for this protocol. Forced expiratory volume in the first second (FEV1) >/= 1 liters. Fluorodeoxyglucose (FDG) -PET scan within 3 months before registration. The pretreatment (diagnostic) PET/CT should, whenever possible, be performed together with the 4-D CT simulation. PET images acquired either at the time of simulation or acquired separately should be registered with the planning CT to assist in tumor delineation. Standard pretreatment evaluations (as decided by treating radiation oncologist, medical oncologist, surgeons or pulmonologist), to include MRI or CT scan of the brain, contrast CT scan of the thorax and upper abdomen, Whole-body PET/CT, pulmonary function tests, lung and cardiac single proton emission computed tomography (SPECT), liver function tests (LFT), blood chemistry, renal function tests, and complete blood count. Age >/= 18 years but </= 85 years. A signed specific informed consent form before study entry. Exclusion Criteria: Small cell histology. Prior thoracic radiotherapy to regions that would result in overlap of radiation therapy fields. Pregnancy (female patients of childbearing potential must practice appropriate contraception). Enrollment in a clinical trial that specifically excludes IGAPT treatment. Body weight exceeds the weight limit of the treatment couch. Oxygen dependent due to preexistent lung disease (COPD, emphysema, lung fibrosis).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Group 1: Photon Therapy - 74 Gy 37 radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete. Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks. Carboplatin AUC 2 by vein 1 time each week for 7 weeks. | Radiation: Photon Therapy<br>* Group 1: 74 Gy 37 radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.<br>Drug: Paclitaxel<br>* 50 mg/m2 by vein 1 time each week for 7 weeks.<br>* Other names: Taxol;Drug: Carboplatin<br>* AUC 2 by vein 1 time each week for 7 weeks.<br>* Other names: Paraplatin;|
| Experimental: Group 2<br>Group 2: Proton Therapy - 74 Gy in 2 CGE per fraction given 5 days a week for about 7 1/2 weeks. Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks. Carboplatin AUC 2 by vein 1 time each week for 7 weeks. | Radiation: Proton Therapy<br>* Group 2: 74 Gy in 2 CGE per fraction given 5 days a week for about 7 1/2 weeks. Group 3: 66 Gy with conventional fractionation given 5 days a week for about 6-7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.<br>Drug: Paclitaxel<br>* 50 mg/m2 by vein 1 time each week for 7 weeks.<br>* Other names: Taxol;Drug: Carboplatin<br>* AUC 2 by vein 1 time each week for 7 weeks.<br>* Other names: Paraplatin;|
| Experimental: Group 3<br>Group 3: Receives either photon or proton therapy, whichever participant's doctor decides is better, for for 6-7 1/2 weeks. Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks. Carboplatin AUC 2 by vein 1 time each week for 7 weeks. | Radiation: Photon Therapy<br>* Group 1: 74 Gy 37 radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.<br>Radiation: Proton Therapy<br>* Group 2: 74 Gy in 2 CGE per fraction given 5 days a week for about 7 1/2 weeks. Group 3: 66 Gy with conventional fractionation given 5 days a week for about 6-7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.<br>Drug: Paclitaxel<br>* 50 mg/m2 by vein 1 time each week for 7 weeks.<br>* Other names: Taxol;Drug: Carboplatin<br>* AUC 2 by vein 1 time each week for 7 weeks.<br>* Other names: Paraplatin;|
| Experimental: Group 4<br>Photon Therapy - Highest practical dose (74 CGE, 66 CGE) radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete. Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks. Carboplatin AUC 2 by vein 1 time each week for 7 weeks. | Radiation: Photon Therapy<br>* Group 1: 74 Gy 37 radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.<br>Drug: Paclitaxel<br>* 50 mg/m2 by vein 1 time each week for 7 weeks.<br>* Other names: Taxol;Drug: Carboplatin<br>* AUC 2 by vein 1 time each week for 7 weeks.<br>* Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence and Time to Development of Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) Grade > 3 Treatment-related Pneumonitis (TRP) | The Primary Objective is assess and compare the incidence and time to development of CTCAE v3.0 grade > 3 TRP, among IMRT-Group 1 or PSPT-Group 2 using Bayesian randomization. TRP will be diagnosed clinically by the treating investigator. Any questions regarding the diagnosis or grade of TRP will be resolved by the Protocol PI or by his/her designee(s). The outcomes review committee will meet to discuss each and every patient reported to have developed symptomatic TRP. The final grading of TRP will be decided by the outcomes review committee. Diagnosis of TRP included receipt of radiation that included a certain volume of normal lung, radiographic changes that suggested inflammation consistent with the radiation dose distribution within 12 months after starting chemoradiation, and symptoms attributable to TRP. Final TRP outcomes also were reviewed and approved by independent external experts. | From date of protocol registration until the date of first documented development of CTCAE v3.0 grade > 3 TRP or local failure, whichever occurs first, in both treatment groups, assessed up to 6 years. | 
| The Incidence and Time to Development of Local Failure (LF) | The Primary Objective is assess and compare the incidence and time to development of local failure, among IMRT-Group 1 or PSPT-Group 2 using Bayesian randomization. Local failure was defined as treatment failure within the planning target volume plus a # 1-cm margin. Images used to report Local failure were registered with radiation dose distribution to accurately assess the location of the failure. Biopsy to confirm Local failure was strongly recommended (Data Supplement). An internal outcomes review committee reviewed each event to ensure objectivity and consistency in reporting Local failure. Final RP outcomes also were reviewed and approved by independent external experts. Tumor recurrence after achieving complete response, Residual tumor enlargement of 20% or more on CT according to RECIST criteria, Recurrence of PET FDG Avidity after achieving complete metabolic response, Increase in FDG avidity in residual tumor, Pathologically proven recurrence | From date of protocol registration until the date of first documented development of CTCAE v3.0 grade > 3 TRP or local failure, whichever occurs first, in both treatment groups, assessed up to 6 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally-advanced non-small-cell lung carcinoma, NSCLC, Lung Cancer, Image-Guided Adaptive Conformal Photon, Proton Therapy, Chemotherapy, Treatment Related Pneumonitis