(4) Radiation Therapy Oncology Group (RTOG) A Phase III Comparison of Prophylactic Cranial Irradiation versus Observation in Patients with Locally Advanced Non-Small Cell Lung Cancer (RTOG 0214): How to Improve Accrual to an Important Prospective Randomized Study A. Sun (1), A. Bezjak (1), D. Payne (1), G. Kane (1), J. Waldron (1), J. Cho (1), F. Shepherd (2), S. Keshavjee (3), E. Gore (4), H. Choy (4).   (1) Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada (2) Department of Medical Oncology, Princess Margaret Hospital, Toronto, Canada (3) Department of Surgical Oncology, Princess Margaret Hospital, Toronto, Canada (4) Radiation Therapy Oncology Group (RTOG) Radiation Therapy Oncology Group

Background Currently there is an ongoing prospective randomized trial (RTOG 0214) addressing the issue of prophylactic cranial irradiation (PCI) in locally advanced non-small cell lung cancer (LA-NSCLC) It is widely agreed that this issue and the trial is a very important one and is a high priority On the surface, it addresses a very simple question with relatively simple treatment in the experimental arm It was felt by most investigators that this trial would be relatively easy to accrue patients to, however, this has not proven to be the case so far

Objective The objective of this study is to attempt to identify reasons for this lack of accrual in order to enhance accrual in the future

Methods Since opening this trial at Princess Margaret Hospital in March 2003, we have kept a log of all patients approached for inclusion into this study As of December 2004, a total of 34 patients were approached and only 6 (18%) were entered onto the trial Screening log captures info in real time

Results The screening log indicated that for the 28 patients not entered onto the study, the reasons given were as follows: 9 not eligible - disease progression/brain mets 4 initial brain relapse 2 lymph node progression 1 lung mets, subsequent brain mets 1 bone mets 1 pt died, CVA? unrelated?

Results 6 financial reasons/too far to travel 1 too far to travel for financial reasons and SARS 5 declined as "had gone through enough" 5 side effects listed of PCI 2 “did not want brain irradiated” 1 concerned about long term toxicity 2 family decision to decline 1 stated family felt not in the best interest to participate 1 not interested in receiving “experimental” treatment “guinea pig”

Results We also examined the timing of when we initially approached the patient to see if introducing it “earlier” made any difference Of the 19 patients who declined, 13 (68%) approached during treatment, remaining 6 (32%) after completion of all treatment No differences were found in the 6 pts who agreed to study However, of the patients approached during treatment all were in the last week of RT or during their adjuvant CT (after RT) In addition, none of these patients were approached at the initial consultation, prior to any treatment or “early” on in their RT the only patient that was approached at the initial consultation agreed to the study but unfortunately was found to have brain mets at restaging.

Initial Conclusions This seemingly simple study for patient accrual has turned out to be much more difficult than anticipated A significant number of potential patients (9/34, 26%) became ineligible due to disease progression prior to study entry Of the remaining patients, 19 out of 25 (76%) declined the study Only 6/25 patients (24%) agreed to the study

Initial Conclusions Changes to the protocol may not be the solution: more centers participating and accruing to study more patients being approached more patients being informed of the study by all disciplines (ie. Med Onc and Surg Onc) Data like this can help guide interventions to achieve the accrual goal for this important study

How to Improve Accrual? Too far to travel – problem in Canada where RT is centralized Timing - approach patients upfront at initial consultation, prior to any treatment or early on during RT (when patients are still feeling relatively well) Side Effects -full discussion by MD, not just by CRA to alleviate concerns of patients after reading consent form - emphasize known benefits of PCI (reduced risk of brain mets, associated morbidity) - high risk of brain mets – up to 1 in 3 pts, 1st site of failure and up to 1 in 2 pts overall

How to Improve Accrual? “guinea pig” - discuss in relation to SCLC where evidence more clear cut and toxicity, for the most part is acceptable Potential benefit of observation arm: (Canada only? US?) regularly scheduled screening MRI of brain (not usually done in Canada, US?) potential benefit of early detection of brain mets and aggressive management may lead to better outcomes? our previous study found - among LA-NSCLC pts who failed first in the brain, those who had surgical resection + WBRT had a median survival of 26.3 months compared with 3.3 months for those treated with palliative WBRT alone. Carolan, Sun et al., Does the incidence and outcome of brain metastases in LA-NSCLC justify PCI or early detection? Lung Cancer, Vol 49(1), p. 109-115, July, 2005.

2005-since initial review as of July, 2005 (additional 6 months) - consented a further 8 out of 16 patients (50%)

2005-since initial review The screening log indicated that for the 8 patients not entered onto the study, the reasons given were as follows: 3 not eligible - disease progression/brain mets 2 initial brain relapse 1 lung mets 1 not eligible - developed complications from surgery > 16 weeks post treatment for randomization 2 declined as "had gone through enough" 1 side effects listed of PCI 1 concerned about screening MRI brain, claustrophobic

2005-since initial review Timing: Of the 4 patients who declined, 2 (50%) approached during treatment, and 2 (50%) after completion of all treatment However, of the 8 patients who agreed to the study, 7(88%) were approached during treatment while only 1(12%) was after

2005-since initial review omitting the 4 patients not eligible – accrual rate becomes 8 out of 12 (67%) now only 4 out of 12 (33%) declined almost reverses the initial percentages

Overall accrual 14/50 (28%) – 14 pts overall, currently leading accruer to RTOG 0214 study omitting the 13 ineligible patients – 14/37 (38%) accrual overall

Final Conclusions Our initial study helped to identify interventions to improve accrual by employing these interventions, we have more than doubled our accrual in ¼ of the time

Final Conclusions this has been accomplished by: identifying and approaching more pts encouraging Med/Surg Oncs participation timing: approaching pts earlier and more often detailed discussion of potential side effects by MD emphasize known benefits of PCI (reduces brain mets) high risk of brain mets – up to 1 in 3 pts, 1st site of failure, up to 1 in 2 pts overall potential benefit of screening MRI in observation arm (ie. potential “win-win” situation regardless of randomization)

RTOG 0214 A Phase III Comparison of Prophylactic Cranial Irradiation in Patients with Locally Advanced Non-Small Cell Lung Cancer RTOG (Coordinating Group) PI - Elizabeth Gore NCIC-CTG Alexander Sun ECOG James Bonner NCCTG Steven Schild SWOG Laurie Gaspar CALGB Jeffrey Bogart CTSU

SCHEMA ARM 1: PCI: 2 Gy/Fraction 15 Daily Fractions for a total dose of 30 Gy STRATIFY 1. Stage R ANDOM I Z E CR, PR, or stable disease after completing definitive therapy for stage IIIA or IIIB NSCLC 2. Histology 3. Therapy ARM 2: Observation Stratification Stage: IIIA vs IIIB Histology: Squamous vs Non Squamous Therapy: Surgery vs no surgery