This study confirmed our prior findings that concurrent chemotherapy and high-dose proton therapy yielded local control rates in excess of 80% at 2 years and a median OS time of about 29 months for patients with inoperable stage III NSCLC . DM remains the dominant pattern of failure at about 40%. Nodal recurrence outside the PTV (i.e., elective nodal failure) occurred in <10% of patients, but isolated elective nodal failure in only 2%. Our findings suggest that further escalation of the biological effective dose, perhaps as hypofractionated radiotherapy, may be needed in some cases to improve local control; they further suggest that more effective chemotherapy will be crucial for reducing DM. The question at this time is how one might select patients for further dose escalation beyond 74 Gy or for more potent chemotherapy . Our finding that an SUV2 in excess of 3.6 could predict LRFS (p = 0.017) suggests that PET/CT imaging during or toward the end of treatment could be helpful for deciding whether additional dose escalation is needed and would allow adequate time to design a boost treatment without requiring a break in therapy.
Our finding that KPS predicted survival was hardly surprising. Interestingly, however, both SUV1 and SUV2 were independent prognostic factors for DMFS, PFS, and OS (p < 0.05). A high SUV1 could be an indicator for higher dose or novel chemotherapy, given that a high SUV1 predicted DMFS and OS. This finding is important, because SUV1 was obtained before the treatment began.
Previously, FDG accumulation before preoperative chemoradiotherapy was not associated with pathologic outcome, but FDG uptake by residual tumor masses 2 weeks after induction chemoradiotherapy predicted pathologic response with 88% sensitivity when an SUV cutoff of 3.0 was used; specificity was only 67% because of treatment-related inflammation . This finding is consistent with our own. However, the predictive value of SUV1 remains uncertain. 18 F-FDG SUV in the primary tumor before chemoradiotherapy has been shown to predict local-regional failure in NSCLC and a high SUV value within the target volume to correlate with local recurrence [12, 19, 20]. However, the radiation dose in those studies was <70 Gy (median, 63 Gy). In the present study, all patients received 74 Gy(RBE) proton therapy with chemotherapy, which may have affected the predictive value of SUV1 before therapy. The p value for SUV1 and LRFS (p = 0.052) was sufficiently close that inclusion of additional patients may demonstrate statistical significance; nevertheless, SUV1 did predict disease progression and DM. Perhaps high-dose proton therapy with concurrent chemotherapy kills most of the cancer cells in the target volume but leaves viable, resistant residual cells that may eventually grow and lead to recurrence. We speculate that a higher PET SUV2 value may indicate the regrowth of such cancer cells. Also, close review of image patterns with respect to the radiotherapy field can be crucial for distinguishing local recurrence from radiation-induced inflammation. Although biopsy can be used to confirm local-regional recurrence, serial images are often obtained as a less-invasive alternative. Prospective studies are needed to clarify the value of SUV2 for predicting LRFS, particularly SUV measurements obtained during or toward the end of proton therapy.
We further found that SUV before and after induction chemotherapy did not predict LRFS, DMFS, PFS, or OS. This finding could result from the small number of such patients in our study. However, SUV2 still predicted LRFS, and SUV1 and SUV2 were still associated with DMFS, PFS, and OS in the patients who received concurrent chemotherapy and proton therapy without induction chemotherapy.
We did not find an association between ΔSUV or ΔSUV/SUV1 and survival, although others have shown such an association among patients with stage III/IV NSCLC treated with chemotherapy [21, 22]. Our study was limited by its retrospective nature and the relatively broad interval between completion of therapy and obtainment of the second set of PET/CT images (median 4.2 months, range 0.8–6.0 months). Prospective studies with PET/CT scans obtained at set times, particularly during treatment, are needed to validate our observations and guide further dose escalation.