I have searched for means to improve clinical outcome of patients with lung cancer. For this goal, I have divided my effort into two parts:
(A). Bioimaging in Radiotherapy for Lung Cancer: I have searched for molecular biomarkers that are surrogates for tumor response to radiotherapy (RT) or chemo-radiotherapy (CRT) in lung cancer. Fluoro-2-deoxyglucose (FDG) is glucose analog. Thus, 18F-FDG PET can measure FDG uptake representing glucose metabolism in vivo noninvasively.
To determine molecular bioimaging biomarkers that are capable for identifying patients with residual cancer after standard dose of RT or CRT and for guiding supplementary dose of RT or salvage surgery, I have conducted a prospective study, Bioimaging in Radiotherapy for Lung Cancer (Partners Protocol 03-282) to measure metabolic response parameters (MRPs) with which novel strategy, individualized RT can be developed. This was supported by NIH/NIBIB grant R01 EB002907. Specific aims of this study were:
(1). Investigate the time-course of metabolic response, measured with 18F-FDG PET, to RT or CRT in lung cancer and determine the earliest time point where the nadir of FDG uptake representing the maximum metabolic response (MRglc-MMR) is attainable.
(2). Determine correlation between the nadir value of residual FDG uptake representing MMR (MRglc-MMR) after RT or CRT and subsequent complete tumor control at 12 months.
(3). Determine the values of MRglc-MMR that correspond to tumor control probability (TCP) ≥95%, 90%, 75% and 50% at 12 months.
(4). Determine the optimum cutoff value of MRglc-MMR based on its predicted TCP, sensitivity (having residual cancer) and specificity (having no residual cancer).
The update of this study showed the following: (1). MRglc-MMR is attainable 10 days (S2) after completion of standard dose of RT or CRT, (2). Residual MRglc at S2 is strongly correlated with tumor control probability (TCP) at 12 months (m). Their values corresponding to TCP 95%, 90% and 50% are 0.70, 0.91, and 1.95 of maximum standard uptake value (SUVmax) and 0.036, 0.050 and 0.134 μmol/min/gm of simplified kinetic method (SKM), respectively, and (3). The optimum cutoff value at S2 is SUVmax ≤1.45 or MRglc ≤0.071 μmol/min/gm (SKM) with corresponding predicted TCP 80%, sensitivity 100% and specificity 63%. This means that this cutoff value will identify all patients with residual cancer for supplementary therapy while it still includes 37% of patients who already attained complete tumor control for additional therapy. To minimize the magnitude of false positive group, we tested 3’-deoxy-3’-[18F]-fluorothymidine (18FFLT) PET in a cohort of patients with increased MRglc at 10 days through 6 m months after RT suggesting either local recurrence or inflammation, and 18F-FLT PET was able to distinguish local recurrence from inflammation correctly with a sensitivity of 83% and a specificity of 89%. Therefore, 18F-FLT PET might be useful in supplementing 18F-FDG PET in this subgroup of patients. We will continue to refine MRPs including the cutoff values.
(B). Proton Therapy for Lung Cancer: I have collaborated with MD Anderson Cancer Center as MGH principal investigator for two proton protocols in lung cancer. They are: (1): Partners Protocol 09-247 (Phase II Bayesian randomized trial of image-guided adaptive conformal photon vs proton therapy, with concurrent chemotherapy, for locally advanced non-small cell lung carcinoma with study endpoints of treatment related pneumonitis and locoregional recurrence; (2) Partners Protocol 09-266 (Phase II escalated/accelerated proton radiotherapy for inoperable stage I (T1-T2, N0, M0) and selected stage II (T3N0M0) non-small cell lung cancer. I am also co-study chair for RTOG (NRG) protocol 1308 (Partners protocol 14-268), a phase III randomized trial comparing overall survival after photon versus proton radiotherapy and concurrent chemotherapy for inoperable stage II-IIIB NSCLC.