In this study of NSCLC diagnosed during routine clinical care, tumor volumetric measurements increased remarkably in a short interval. In contrast, tumor metabolic activity (NSUVmean and NSUVmax) remained relatively stable during the same period of time. VDT of early stage lung cancer has been widely studied based on X-ray and CT evaluations of pulmonary nodules and has a strikingly broad range [3
]. One study found that the mean VDT of pulmonary nodule was approximately 150 days on chest radiographs and 480 days on CT in screening studies, compared to a VDT of 135 days for those detected during routine medical care [14
]. Using direct volume measurement on the non-contrast CT portion from the PET/CT imaging, we found a median VDT of 139 days. The distribution of CT-VDT in our study was consistent with a recent report based on routine CT detection, in which each VDT category (<100, 100–249 and ≥250 days) accounted for approximate one third of the overall study cohort [15
Metabolic tumor volume (PET-MTV) on PET/CT is being increasingly studied as a characteristic of tumor biological behavior. At present PET-MTV does not have a consistent definition [16
]. To our knowledge, there have been only two studies exploring the changes in PET-MTV in untreated lung cancer [11
]. One reported a 32% mean relative increase in PET-MTV with a median interval of 24 days between scans and an expected DT of 66 days [11
]. Another study of 11 NSCLC patients found a 51% average increase in PET-MTV with a median interval of 33 days between PET scans, with 4 patients demonstrating a DT less than 45 days [20
]. In our study of PET-MTV, we observed a 55% mean increase with a median interval of 43 days and an estimated median DT of 124 days in 34 patients. Interestingly, the DT of PET-MTV did not significantly differ from the median CT-GTV derived DT based on the near-simultaneously acquired CT imaging. Interval PET-MTV shrinkage was observed in our study, including two patients with very small regression (<10 cc) in the primary tumor, and two with regression in hilar nodes. These findings are similar to the first study above mentioned who found 24% of their patients underwent a PET-MTV remission at the second PET/CT scan. Decreases in tumor volume without treatment intervention has also been reported on numerous CT based studies [6
] and may be attributable to multiple factors such as measuring variation, respiratory motion, misregistration, proximity to the mediastinum, re-expansion of adjacent consolidated lung tissue, and tumor necrosis due to insufficient blood and nutrition supply.
The natural history of metabolic activity in lung cancer remains poorly understood and currently we are aware of only one published study investigating the NSCLC SUV change prior to treatment [11
]. In this study, a significant increase in SUV measurements was observed within a median interval of 24 days, including 19% enhancement in maximum SUV and 15.6% in average SUV. Notably, 24% of patients underwent interim reduction in maximum SUV. In our study, the observed change in metabolic activity was less significant. Within the median interval of 43 days, NSUVmean achieved a marginally increase while NSUVmax was relatively stable. Nearly one third of our patients displayed interval reduction in metabolic activity. It should be noted that different methods of SUV measurements were used; absolute SUV in the above-mentioned published study and internally normalized SUV in our study. In addition, it is important to note that maximum SUV measurements are more susceptible to noise, which may exacerbate observed percentage changes between scans [21
We found metabolic evidence for pre-treatment disease progression in 21% patients and TNM upstaging in 18% after a relatively short median inter-scan interval of 43 days. Longer intervals before start of treatment appear to have higher risk of pre-treatment progression, lending credence to the notion that excessive delay before treatment may lead to worsened patient-outcomes. Using criteria for pre-treatment disease progression similar to that in our study, one study found disease progression prior to treatment occurred in 13%, 31% and 46% of patients at 4 weeks, 8 weeks and 16 weeks after initial clinical detection with upstaging in 13% of patients at 8 weeks, and 21% at 16 weeks [1
]. Another study reported an even greater chance of tumor progression within a median interval of 28 days, with upstaging in TNM scores in 39% of patients, and changes in treatment intent from curative to palliative in 29% of patients [11
]. Given these findings of significant pre-treatment disease progression, repeated staging appears justified after certain delays in treatment initiation. One study recommended complete restaging after 4–8 weeks of treatment initiation delay [1
]. In our study, longer inter-scan interval (ISI) was found significantly correlated with higher risk of interval disease progression prior to treatment. Based on the estimation of progression probability, we suggest that restaging of PET-CT should be performed for NSCLC patients with longer than 2 months (58 days) waiting after the initial PET/CT examination.
Studies investigating the effects of delays to treatment on patient-outcomes have found that local control rates decreased with increasing TTT, raising the possibility that these increased rates of local recurrence might in turn translate into worse survival [22
]. In our study, no significant difference was detected between TTT and OS or PFS. Furthermore, we did not find that DT significantly affected OS or PFS, which was counter-intuitive. These negative findings may be explained by our small sample size, heterogeneity of tumor parameters, and the lack of multivariate modeling of additional prognostic factors. The active intervention of salvage treatment and supporting care may also offset the detrimental effect of longer TTT and shorter DT on outcome. Despite this, in view of the findings of pre-treatment disease progression within a 2 month period, it seems prudent to follow recommendations by the Joint Council for Clinical Oncology that potentially curative treatment should ideally start within 2 weeks and no longer than 4 weeks after decision of treat [26
We acknowledge several limitations in our study. Firstly, the estimation of the doubling times was based on only two pre-treatment PET/CT images rather than multiple serial scans, therefore the calculations would be more susceptible variation due to technical factors in volumetric and metabolic measurements. Another limitation was that CT-GTV in our study was delineated on the CT portion of integrated PET/CT rather than IV-contrast enhanced CT, which could lead to substantial uncertainty for target identification, though our protocol did not allow for an IV-contrast CT in addition to the PET/CT for our patient. Further investigations on a larger number of patients with multiple serial measurements would be required to better understand the natural growth of lung cancer, however due to ethical considerations this would not be acceptable as a clinical study design.