The prognosis of untreated patients who present with RCC and IVC tumor thrombi is dismal4. Although surgical extirpation was performed, long-term survival of patients remains reduced compared to localized disease. Five-year OS rate of 35% to 70% has been reported2,7,11. In our study, 2-year OS of 80% for the entire cohort was observed; however, OS was significantly reduced in patients with IVC thrombus level IV (p=0.025). Radical nephrectomy with IVC thrombectomy is surgically challenging especially in large renal mass and high tumor thrombus level. The surgical technique depends on the cranial extent of IVC thrombus2,3,8,10. An infrahepatic IVC thrombus (level I-II) can be safely removed via abdominal isolation of the IVC. On the other hand, thrombus extending to right atrium requires mandatory of large thoracoabdominal access with CPB. Controversy exists in the management of a thrombus extending to retrohepatic and/or supradiaphragmatic IVC (level III-IV) because of complex anatomical region. Liver mobilization technique has been developed for the IVC control and prevention of emboli from tumor thrombi. We retrospectively reviewed our 18-year experience in surgical management of RCC patients with IVC thrombi focusing on surgical outcomes and survival benefits in Thai (Southeast Asian) population.
Mortality and morbidity of radical nephrectomy and IVC thrombectomy were considered high; 1.5-10% and 15-80% for mortality and morbidity, respectively2,3,12. Previous study from IRCC-VTC, a total of 2147 patients from 22 institutions in the US and Europe, demonstrated 34% postoperative complications; 13% were classified as Clavien grade 3-5. Mortality rate was 2% within 30 days and high level of tumor thrombus was associated with increased complication rate particularly high-grade complications (p=0.03)1. In our study, perioperative morbidity and mortality were unsurprisingly high especially in supradiaphragmatic thrombus patients. As a result, operative time, blood loss and transfusion, and ICU stay were significantly greater in these patients (p<0.01). Furthermore, 80% of major complications were observed in patients with thrombus level III-IV. Recent study of 62 patients with tumor-thrombus level III-IV from four tertiary centers in the US reported that preoperative limited performance status and reduced serum albumin were associated with increased postoperative ninety-day mortality12.
The role of preoperative renal arterial embolization (RAE) to reduce intraoperative blood loss and perioperative complications has been debating1-3. RAE, generally performed on the operation day, could cut off blood supply to renal mass and thus reduce blood loss and complications. Previous study from Cleveland Clinic demonstrated significant risk of perioperative mortality in patients with preoperative embolization (OR 5.5, p=0.03) as well as postoperative complications13. Recent study from Tang and colleagues, however, supported reduced blood loss and transfusion in patients receiving perioperative embolization(p<0.03)14. Notably, patients from Cleveland Clinic cohort had higher thrombus level when compared to Tang’s study. No preoperative RAE was performed in our series.
Level of IVC thrombus on patients’ survival has been controversial5,6,11,15. Our study showed that tumor size and histology, supradiaphragmatic tumor thrombus and positive surgical margin were associated with OS on univariate analysis. However, tumor thrombus level was not an independent factor for OS on multivariate analysis. A study of 1192 pT3b and pT3c patients from 13 European institutions also demonstrated similar results15. IVC thrombus level was not a predictor for OS after radical surgery. Nevertheless, subsequent study based on a pooled analysis of 11 international centers (IRCC-VTC), the level of IVC thrombus was shown to be an independent factor of survival; HR 2.1(1.53-3.0)6. Our study also demonstrated that sarcomatoid dedifferentiation was associated with reduced overall survival. Similar results were reported from the recent study, including 125 RCC with IVC tumor thrombus patients (14% sarcomatoid histology). Sarcomatoid dedifferentiation was s significant factor associated with progression-free and cancer-specific survival (CSS)16.
The greater risk of cancer recurrence after tumor thrombectomy is observed. Residual tumor may be entrapped in the vessel intima and 40-50% of patients will develop disease-recurrence within 3 years17. Sanli and colleagues showed that microscopic venous invasion was associated with tumor recurrence and reduced CSS18. In non-metastatic RCC patients with IVC tumor thrombi, seven risk factors were found associated with tumor recurrence – BMI, preoperative hemoglobin, tumor size, non-clear cell histology, IVC thrombus height, nuclear grade and perinephric fat invasion19. In our study, median follow-up time was 15(5-41) months, none of patients with IVC thrombus level IV experienced disease free beyond 12 months postoperatively. In pN0M0 cohort, DFS was reported 42.8%.
Neoadjuvant systemic treatment to reduce tumor thrombus and then facilitate surgery has been discussed20-23. A previous retrospective study of 14 patients received neoadjuvant sunitinib or sorafenib for 2 cycles demonstrated limited results. Eighty-five percentage of patients had stable disease while one patient had an upstage. Only one tumor decreased in this report21. Contrarily, a recent multicenter comparison study of 53 RCC patients with IVC tumor thrombi demonstrated survival advantages of neoadjuvant sunitinib20. High risk patients due to either surgical or medical cause received preoperative sunitinib. IVC thrombus significantly decreased by 1.3 cm and 40% percent of patients had reduced tumor-thrombus level in neoadjuvant cohort. Also, neoadjuvant sunitinib was an independent factor of improved CSS (p=0.02). Currently, immune checkpoint inhibitors play an important role in RCC field. Labbate and colleagues reported a complete response of level IV tumor thrombus after neoadjuvant nivolumab and ipilimumab23. The patient had disease-free after surgery up to last follow-up of a year.
Metastatic renal cell carcinoma with IVC tumor thrombus has been reported 30-50% and the role of cytoreductive nephrectomy has been disputed15,17,24-27. Radical nephrectomy and complete removal of tumor thrombus is the key to prolong survival and provide better quality of life17. However, only RCC patients with tumor thrombus below diaphragm had advantages from such surgery26,27. Abel and colleagues proposed preoperative factors associated with reduced overall survival after cytoreductive nephrectomy of metastatic RCC with IVC thrombus patients – high serum lactase dehydrogenase, systemic symptoms, supradiaphragmatic tumor thrombi and sarcomatoid features. These could be considered for preoperative counselling and neoadjuvant therapy. In our study, 21% of patients had distant metastases before surgery which was comparable to the prevalence in Asian studies7. The advantages of surgery in metastatic patients were found in our study with 2-year OS rate of 67% and no significant difference when compared to non-metastatic group(p=0.12). Additionally, one patient after thrombectomy and lung metastatectomy has been alive with stable disease at 110 months follow-up time.
Retrospective design with single center is the limitation of this study. Regarding to tertiary center, some patients were loss to follow-up and OS was utilized as our primary outcome instead of CSS. Nevertheless, our study provides medium to long term experience with the number of patients with RCC and IVC thrombi in Thailand and represents Southeast Asian population. Limited number of the patients in this study is another limitation regarding to low incidence of disease in our area and some were not fit for surgery. No prior study has ever been addressed this clinical information of such patients in the Southeast Asian region. Even though, multicenter study from this area would be required.