Objective
Immunotherapy improves survival after chemoradiotherapy in non-small-cell lung cancer (NSCLC). Effective immunotherapy requires functioning adaptive immunity, but radiotherapy ablates bone marrow, potentially reducing immunotherapy’s efficacy. 3'-deoxy-3'-(18)F-fluorothymidine (FLT)-PET can sensitively image bone marrow proliferation. We analysed serial FLT scans obtained before and during chemoradiotherapy in a prospective clinical trial.
Material/methods
Sixty patients with stage IIIB/IIIC NSCLC were recruited to an observational trial of serial FLT-PET scans during radical chemoradiotherapy (60Gy 3DCRT with concurrent cisplatin/etoposide or carboplatin/taxol). PET datasets were available for 28 patients. Baseline, week 2, and week 4 FLT-PET scans were retrospectively analysed. Isodose lines from 0Gy to >5.0Gy were used to determine volumes of interest (VOIs). Maximum standardised uptake values (SUVmax) values were calculated in each VOI. Visual analysis was used to assess the dose at which bone marrow uptake was unapparent, representing the lowest radiation dose resulting in ablation for each patient at each timepoint. Unirradiated marrow in a vertebral body represented normal uptake. SUVmax values were normalised to the visual ablative dose, negating blood-pool effects and isolated voxels with high SUVmax. Data was normalised to represent 0-100% of baseline marrow proliferation.
Results
Dose-response curves were produced between radiation dose and FLT SUVmax, estimating bone marrow function at weeks 2 and 4 of chemoradiotherapy. Radiation dose and bone marrow proliferation were negatively correlated from baseline to weeks 2 and 4 (p<0.001). There was steeper decline in marrow function from baseline to week 2 compared to baseline to week 4. This likely reflected the smaller dose per fraction at each isodose. Transformed curves were produced using visual estimates of marrow ablation doses, also showing negative correlations between dose and marrow proliferation at weeks 2 and 4 of chemoradiotherapy (p<0.001). At doses ≥3-4Gy, marrow proliferation was absent at week 2 in 27 out of the 28 patients.
Conclusion
In NSCLC patients, bone marrow proliferation decreased steeply with radiation dose in weeks 2 and 4 of chemoradiotherapy. Marrow was visually ablated at doses ≥3-4Gy for most patients at week 2. This data demonstrates the exquisite sensitivity of bone marrow to low-dose radiation, with implications for efficacy of subsequent immunotherapy.