This work demonstrated that the early assessment of response to TKIs using a combination of FDG uptake and tumor size could predict not only the PFS but also the OS of patients with advanced RCC. To our knowledge, it is the first to address this issue. The benefit of assessment by FDG uptake as well as is the ability to evaluate the biological dormancy induced by the treatments. Although the prognosis of advanced RCC was dramatically improved with the development of TKIs such as sunitinib or sorafenib, the best responses were usually found in stable diseases according to RECIST. Indeed, treatment by sunitinib is associated with 31% overall response rate and that by sorafenib was only 2% in clinical trials [6
]. Some RCCs treated with TKIs do not decrease in tumor volume but maintain long-term dormancy without enlargement of volume or novel metastasis. But there have been no clinical answers to the question of whether an individual case treated with TKIs whose tumors did not decrease in size should continue the treatment or change to other therapeutic options including other TKIs and mammalian target of rapamycin (mTOR) inhibitors, which have been reported to benefit patients with advanced RCC [16
]. This was primarily because there has been no biological marker to evaluate the biological activity of RCCs, especially the dormancy induced by TKIs. In this regard, FDG PET/CT is a useful tool to evaluate glucose metabolic status, which can be the index of biological activity of cancer; a decrease of FDG accumulation can express the biological dormancy of RCC induced by TKI treatment. Indeed, a patient with only 7% decrease in tumor diameter sum and 20% decrease in SUVmax maintained an SD status for 887
days (Figure ) and another with only 3% decrease in the tumor diameter sum and 20% decrease in SUVmax achieved 458
days of SD in our series.
Figure 4 A patient demonstrating long tumor dormancy. 57 y.o. female with mediastinal lymph node metastasis. CT images at (A) pretreatment state and (B) post-treatment state, PET images at (C) pretreatment state and (D) post-treatment state, fused PET/CT images (more ...)
There have been trials to evaluate the tumor dormancy other than by tumor volume. Krajewski KM et al. previously reported that tumor attenuation in contrast-enhanced CT (CECT) predicts the outcome of RCC patients treated with sunitinib [18
]. In our study, most patients whose tumors demonstrated attenuation had a decrease in SUVmax and their prognoses proved to be good. However, we experienced one case in which tumors showed apparent attenuation of contrast-enhancement but a decrease of only 5% in FDG uptake, and his prognosis was poor (Figure ). It was speculated that some RCCs continue to progress against the inhibition of angiogenesis, and that attenuation was not a sufficient condition to reflect tumor dormancy. Additionally, the renal function of most patients with advanced RCC is deteriorated due to nephrectomy or the existence of the original tumor, and CETC entails a risk of worsening kidney function. So, we think that the evaluation by FDG PET/CT is more precise and safer than that by CECT.
Figure 5 A patient demonstrating rapid progression. 59 y.o. male with thoracic vertebral metastasis. CT images at (A) pretreatment state and (B) post-treatment state, PET images at (C) pretreatment state and (D) post-treatment state, fused PET/CT images at (E) (more ...)
However, it was not sufficient to assess the response to TKIs of RCCs by FDG uptake alone because there were some RCC cases with decreased SUVmax but increased tumor volume, and their prognoses were poor as shown Figure . In our series, 3 patients demonstrated a decrease in SUVmax
20% but an increase in tumor size after 1
month, and their PFSs were very short: 28, 28, and 146
days, respectively. Additionally, the classification of our series by EORTC criteria, which assess the response by FDG uptake, was not statistically associated with prognosis. Kayani et al. previously reported that the assessment of patients with RCC treated with sunitinib by FDG uptake alone after 4
weeks failed to predict the disease course [20
]. These results suggested the existence of RCCs that progress independently of glucose uptake, and emphasize the need for a combination assessment of both tumor size and FDG uptake.
Some questions remain. We defined metabolic response as a ≥20% reduction of SUVmax in the novel criteria we advocated. The EORTC proposed a SUV diminution of 15-25% for a partial response after the first cycle. Kayani et al. the defined cut-off point as 20% when they evaluated the response to sunitinib in metastatic RCC and succeeded in predicting the disease course by assessment after 16
weeks. Lyrdal et al. reported that responders with a decrease of ≥20% FDG accumulation to sorafenib had a long OS. A further study expanding the number of patients is necessary to verify this cut-off point.