Platinum Doublet Chemotherapy and Proton Beam Radiation Therapy in Treating Patients With Stage II-III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVE:

I. To compare the 1-year progression-free survival rates of 72 gray (Gy) and 60 Gy conventionally fractionated proton beam therapy (PBT) (as part of concurrent combined modality therapy).

SECONDARY OBJECTIVE:

I. To assess the adverse events, survival, quality of life, and patterns of failure (local regional, distant metastatic) associated with two dose levels of conventionally fractionated PBT (as part of concurrent combined modality therapy).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo lower dose proton beam radiation therapy daily for a total of 60 Gy for up to 30 weekdays in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo higher dose proton beam radiation therapy daily for a total of 72 Gy for up to 36 weekdays in the absence of disease progression or unacceptable toxicity.

All patients undergo computed tomography (CT) throughout the study, magnetic resonance imaging (MRI) or CT, and positron emission tomography (PET)/CT during screening.

After completion of study treatment, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.

• Carboplatin (Drug), also known as Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo: Chemotherapy
• Cisplatin (Drug), also known as Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin: Chemotherapy
• Etoposide (Drug), also known as Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16: Chemotherapy
• Paclitaxel (Drug), also known as Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat: Chemotherapy
• Pemetrexed (Drug), also known as MTA, Multitargeted Antifolate, Pemfexy: Chemotherapy
• Proton Beam Radiation Therapy (Radiation), also known as PBRT, Proton, Proton EBRT, Proton External Beam Radiotherapy, Proton Radiation Therapy, Radiation, Proton Beam: Undergo PBT
• Quality-of-Life Assessment (Other), also known as Quality of Life Assessment: Ancillary studies
• Questionnaire Administration (Other): Ancillary studies

Primary outcomes

• Proportion of Participants With Progression Free Survival (PFS) [From randomization to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years]: A Cox proportional hazards model stratified by stratification factors will be used to model PFS as a function of dose to test for an overall dose effect (a one-sided p-value < 0.10 will be considered as significant evidence of a dose effect). Subsequently, separate Cox models stratified by stratification factors will compare PFS between 72 Gy and 60 Gy (for each, a one-sided p-value < 0.10 will be considered as significant evidence of superiority). Kaplan Meier estimates and curves by dose level will also be generated

Secondary outcomes

• Overall Survival (OS) [From randomization to death due to any cause, assessed up to 5 years]: Will be modeled using Cox models. Kaplan-Meier estimates and curves by dose level will also be generated. OS will again be analyzed as exploratory analysis after 50 deaths per primary pairwise comparison have occurred or after all patients have completed follow-up (whichever occurs first).
• Number of Participants With Adverse Events [Up to 5 years]: Graded by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events are graded on a scale of 0-5 with 5 being worst. The number of participants with Grade 2 or higher adverse events will be reported.
• Proportion of Participants With Local-regional Failure [Up to 5 years]: Defined as the proportion of participants with documentation of local recurrence. The cumulative incidence of local failure will be estimated using Gray's methodology and compared across dose levels using Fine-Gray quadratic regression (with death as a competing risk).
• Proportion of Participants With Distant Metastasis [Up to 5 years]: Defined as the proportion of participants with documentation of distant metastasis. The cumulative incidence of distant metastasis will be estimated using Gray's methodology and compared across dose levels using Fine-Gray quadratic regression (with death as a competing risk).

Other outcomes

• Quality of Life Post Treatment [Up to 5 years]: Measured using the single item Linear Analogue Self-Assessment scale. Descriptive statistics by dose level at each time point will include means, standard deviations, medians, and ranges for each scale. Descriptive graphical techniques will include mean plots by dose over time for each scale. Mixed models will be used to compare each scale across dose levels at each post-baseline time point while adjusting for the baseline value of scale. Will graphically explore patterns of missing data and will employ pattern mixture models for longitudinal analyses. The lowest number measuring worst and higher number measuring best outcome.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age >= 18 years
* Histological confirmation of non-small cell lung cancer
* Forced expiratory volume in 1 second (FEV1) > 1.0 L
* Unresectable or medically inoperable stage 2-3 non-small cell lung cancer (based on computed tomography/positron emission tomography \[CT/PET\], magnetic resonance imaging \[MRI\] or CT of brain, and physical exam);

  * Eligible if recurrence after surgery and now has the equivalent stage 2-3 non-small cell lung cancer (NSCLC) OR had sub totally resected stage 2-3 NSCLC
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
* Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
* White blood cell (WBC) >= 3.0 x 10\^9/L
* Absolute neutrophil count (ANC) >= 1.5 x 10\^9/L
* Hemoglobin (Hgb) >= 9 g/dl
* Platelets (plts) > 100 x 10\^9/L
* Serum creatinine < 1.5 x upper limits of normal (ULN)
* Serum bilirubin < 1.5 x ULN
* Provide informed written consent
* Willing to return to enrolling institution for follow-up for a minimum of 1 year
* Ability to undergo potentially curative chemotherapy plus radiotherapy

Exclusion Criteria:

* Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

  * Pregnant women
  * Nursing women
  * Men or women of childbearing potential who are unwilling to employ adequate contraception
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Weight loss of > 10% in the past 3 months
* Distant metastases (M1 disease)
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, lupus, usual interstitial pneumonitis (UIP), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Receiving any investigational agent, that would be considered as a treatment for the primary neoplasm
* Active second malignancy
* History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* Received chemotherapy for lung cancer within 6 months of registration
* Previous chest radiotherapy that would overlap with the proton field

Participant flow

Outcome results

• Proportion of Participants With Progression Free Survival (PFS) (Primary), Number, proportion of participants: Arm A (Platinum Doublet Chemotherapy, Lower Dose PBT) 0.6 (0.362 to 0.995); Arm C (Platinum Doublet Chemotherapy, Higher Dose PBT) 0.429 (0.182 to 1.00)
• Overall Survival (OS) (Secondary), Count of participants, Participants: Arm A (Platinum Doublet Chemotherapy, Lower Dose PBT) 4; Arm C (Platinum Doublet Chemotherapy, Higher Dose PBT) 2
• Number of Participants With Adverse Events (Secondary), Count of participants, Participants: Arm A (Platinum Doublet Chemotherapy, Lower Dose PBT) 9; Arm C (Platinum Doublet Chemotherapy, Higher Dose PBT) 6
• Proportion of Participants With Local-regional Failure (Secondary), Number, proportion of participants: Arm A (Platinum Doublet Chemotherapy, Lower Dose PBT) 0.2 (0.057 to 0.51); Arm C (Platinum Doublet Chemotherapy, Higher Dose PBT) 0.14 (0.026 to 0.51)
• Proportion of Participants With Distant Metastasis (Secondary), Number, proportion of participants: Arm A (Platinum Doublet Chemotherapy, Lower Dose PBT) 0.1 (0.018 to 0.40); Arm C (Platinum Doublet Chemotherapy, Higher Dose PBT) 0.29 (0.08 to 0.64)
• Quality of Life Post Treatment (Other pre specified)

Adverse events

Time frame: Up to 5 years

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2019-12-13)
• Informed Consent Form (PDF, 2023-09-01)

• Terence T. Sio, M.D., M.S., Principal investigator, Mayo Clinic