Cryoablation increases the clinical efficacy of treatment with the oral multi-target antitumour drug sorafenib for advanced renal cell carcinoma (RCC), a new study published in the International Journal of Hyperthermia has found. Joint first authors Changfu Liu and Fei Cao (both Department for Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China) conclude that combining cryoablation with sorafenib can reduce tumour load, improve anti-tumour immunosuppressive status, increase survival, and maintain quality of life in patients with RCC that cannot be surgically resected.
This is the first publication investigating the safety and efficacy of cryoablation combined with sorafenib for the treatment of this disease, but previous work has shown the combined treatment to be better at prolonging survival than sorafenib alone in patients with hepatocellular carcinoma (HCC).
The present study is observational, and followed 156 patients with advanced RCC who were unsuitable candidates for surgical resection. Participants received cryoablation and sorafenib (n=67), or sorafenib only (n=89), and all patients were followed up to at least seven months, with a mean follow-up time of 28.8 months (and a maximum of 67 months).
Of the 156 patients enrolled in the study, 87 were men (56%), and the median age was 65 years (with an age range of 48–84 years). A total of 184 tumours were recorded, with diameters ranging from 3.8cm–14cm, and were classified as clear cell carcinoma (92.95%), papillary carcinoma (5.13%), or chromophobe RCC (1.92%). All patients presented with stage III or IV tumours. There were no statistically meaningful differences between the two treatment groups at baseline.
Improved survival with cryoablation and sorafenib compared to sorafenib alone
“The combined therapy had a clear advantage in terms of efficacy,” the study authors write.
Both progression-free survival and overall survival were statistically significantly higher (p<0.05) in the group treated with a combination of cryoablation and sorafenib than the cohort treated with sorafenib alone, indicating that cryoablation and sorafenib together can more significantly prolong these survival metrics than sorafenib alone can. Progression-free survival was 20 months in the combined group, versus 12 months in the sorafenib only group, and overall survival was 36 months in the former cohort compared to 29 months with just sorafenib.
Additionally, Liu and Cao et al report a higher progression-free survival and overall survival in patients who underwent complete cryoablation (n=25, 38.81% of the patients treated with cryoablation) than the patients who only had a partial cryoablation. Stratification analysis revealed a progression-free survival of 23 months for those patients who had a complete cryoablation; progression-free survival was 17 months for those participants with a particle cryoablation. This trend was the same for overall survival: 41 months in complete cryoablation recipients, versus 32 months in partial cryoablation recipients.
Based off these results, Liu and Cao et al recommend complete cryoablation for advanced RCC with relatively small tumour diameters, and further cryoablation treatments for tumours with larger diameters to achieve complete ablation.
Cryoablation and sorafenib together lower the proportion of patients with disease progression
The combined treatment group had a higher proportion of complete response and stable disease than the group treated with sorafenib alone. The study authors used these metrics to calculate the overall response rate and disease control rate. These measures provide further clarity when assessing the efficacy of the different treatment options for RCC.
The overall response rate was higher for patients treated with cryoablation and sorafenib than sorafenib alone (p<0.05). The overall response rate is calculated by adding the number of patients with a complete response following treatment and the number who exhibited a partial response, and dividing the sum by the total number of patients. In the combined cryoablation and sorafenib arm, a complete response was observed in five patients, and a partial response in 43. In comparison, a complete response was seen in just one patient the sorafenib only group, and a partial response in 16. This yields an overall response rate of 71.64% in the combined cohort, and 19.10% in the sorafenib group.
The researchers also calculated the disease control rate: the total sum of the number of patients with a complete response to treatment, a partial response to treatment, and a stable disease condition after treatment, divided by the overall number of patients. The number of patients with a stable disease condition following treatment was 12 (17.91%) in the combined arm, and 58 (65.17%) in the sorafenib only arm. A progressive disease condition was reported in seven patients (10.45%) in the combined treatment group, and fourteen patients (15.73%) in the single treatment group.
Therefore, the disease control rate was significantly higher when both cryoablation and sorafenib were used together, at 89.55%, than when sorafenib was used alone, 84.27% (p<0.05).
The significantly higher survival rates in the cryoablation and sorafenib group could be explained by a couple of different concepts, Liu, Cao and colleagues suggest. They first propose that cryoablation can effectively reduce tumour load within a short time, thereby increasing overall response rate and disease control rate, and effectively controlling tumour progression in patients with advanced RCC. Secondly, they explain how cryoablation results in the necrosis of a large number of tumour cells in the target area, and “may increase the permeability of tumours and surrounding tissues, thus increasing the sensitivity of residual tumour cells to target drugs.” They continue: “Hyperthermia has been shown to enhance drug delivery, so the changes induced by cryotherapy may improve the uptake of sorafenib, although this association requires further investigation.”
A third reason given by the study authors for the improved disease control rate and survival scores is predicated on the knowledge that the kidney is an immunogenic organ. Liu and Cao et al speculate that “cryoablation may influence the immunogenicity and drug resistance of residual tumour cells, thereby changing or prolonging the effective time of targeted drug therapy.”
In terms of safety, the authors note that cryoablation did not increase the risk of side effects of targeted drugs; there was no significant difference between side effects experienced by patients in either arm of the study.
Enhanced antitumour immunity: A new treatment strategy for advanced RCC
Liu, Cao and colleagues report that the combined therapy of cryoablation and sorafenib “may enhance the body’s antitumour immunity, and effectively prolong progression-free survival and overall survival without compromising patient quality of life, thus representing a new treatment strategy for advanced RCC.”
The antitumour immunity is particularly important, as the authors note that, “similar to other targeted drugs for tumour treatment, […] patients develop resistance to sorafenib, leading to disease progression and death.”
The study investigators therefore analysed serum indicators related to immune function in both the combined treatment group and the sorafenib only group. In the combined treatment arm, the proportion of Treg cells was significantly decreased, and the proportions of several T lymphocytes were significantly increased after treatment compared to before treatment. This was not the case in the sorafenib only group: in this cohort, no significant difference in Treg cells or T lymphocytes was observed before and after treatment.
Explaining this finding, Liu, Cao and colleagues write that these data “suggest that cryoablation enhanced tumour immunity more than sorafenib alone.”
The authors summarise: “As a potential new treatment strategy for advanced RCC, cryoablation combined with sorafenib, therefore, requires further investigation in future randomised controlled trials.”
