Twenty patients enrolled in the study. A historic control group was used for comparison of surgical parameters. Patient characteristics are summarized in . In the study group, 4 patients had radiographic evidence of metastatic disease at presentation. Study patients who underwent laparoscopic partial nephrectomy had significantly larger tumors when compared to historic controls undergoing the same procedure. The tumor size in is measured from the pretreatment CT and does not reflect tumor shrinkage from sunitinib treatment.
Patient demographics by surgical type.
The most common sunitinib-toxicities were GI symptoms (nausea, abdominal pain, dyspepsia, indigestion, vomiting, flatulence, diarrhea, abdominal cramps, and constipation) and hematologic (leukopenia and thrombocytopenia), occurring in 13 (65%) and 11 (55%)patients, respectively (Supplemental Tables 1 and 2
, online). Other side effects were fatigue in 9 patients (45%), hand-and-foot syndrome in 3 patients (15%), and hypertension in 5 patients (25%). Grade 3 toxicities were rare and included 2 patients (10%) with neutropenia, 2 patients (10%) with hand-and-foot syndrome and 3 patient (15%) with pancreatitis. The only grade 4 toxicity was an episode of hyponatremia that resolved with fluid restriction. Twelve patients (60%) completed the full 90 day-treatment of oral sunitinib at the full dose. Dose interruptions were required for 5 patients (25%) and dose reductions were required in 2 patients (10%). No patient required a delay in surgery due to toxicities.
Surgical outcomes are summarized in . No intra-operative or postoperative complications were attributable to administration of sunitinib. There was one nonemergent conversion from laparoscopic to open partial nephrectomy in a patient with a 5.5 cm central tumor in a solitary kidney. This patient’s estimated creatinine clearances before and after surgery were 179 and 161, respectively. One patient undergoing laparoscopic partial nephrectomy was reported to have negative margins on intraoperative frozen-section; however the final pathology review of the same margin tissue was determined to be focally positive. Tumor size for the study group was larger than for controls as protocol eligibility required a primary tumor size of 4 cm or greater. There was no significant difference for any surgical parameter between study patients and historic controls with the exception of warm ischemia time (p<0.001).
Surgical and pathologic outcomes of study patients.
Surgical complications were typical for patients undergoing nephrectomy. In patients undergoing radical nephrectomy, complications included pneumothorax(1), urinary retention(1), bile leak from the liver that spontaneously resolved(1), and deep venous thrombosis(1). In patients undergoing partial nephrectomy, complications included conversion to open surgery(1), AV fistula requiring selective embolization(1), and ventral hernia(1).
All study patients undergoing radical nephrectomy had formal retroperitoneal lymph node dissection; one patient with clinically enlarged nodes (cN2) had pathologically proven lymph node metastases (pN2). A second patient with clinically normal nodes also had pathologically proven nodal disease (pN2). Long-term follow-up for oncologic efficacy was not a primary endpoint of this study. Both the mean and median postoperative follow-up was 6.5 months. At last follow-up, all patients were alive. One patient treated for clinically localized disease recurred in the lung 9 months following surgery, and another recurred in the psoas muscle 12 months after surgery.
Seventeen of 20 patients (85%) had a decrease in tumor size on 2 month follow-up CT ( and Supplemental Table 3
, online,). The mean change in tumor diameter was −11.8% (range −27 to 11%), with negative number indicating a decrease in size; one patient had a formal partial response and all others had stable disease as defined by the RECIST criteria. The mean change in tumor cross-sectional area was −27.9% (range −43% to 23%); two patients had a formal partial response as defined by the WHO criteria. In 2 patients (5%), the tumor grew while on sunitinib. Fifteen patients exhibited a decrease in CT density, with a mean percent change in HU of −22% (range −74% to 29%). The average cross-sectional area that was necrotic was 58.8% (range 0%-94%).
Figure 1 A) Waterfall plot of the response of the primary tumor to sunitinib determined from baseline CT and CT after at least 2 months of therapy. Response was determined using the RECIST and WHO criteria. B) Comparison of primary tumor response determined using (more ...)
There was a range of correlations between the differing CT scan response criteria (RECIST, WHO, and Hounsfield unit changes) applied to the primary tumors. The percent change in tumor diameter (RECIST) correlated highly with the percent change in cross-sectional area (WHO) (R2 0.9105, p<0.001, ). However, neither the percent change in tumor diameter nor cross-sectional area correlated significantly with percent decrease in CT scan density (R2 0.4074, p=0.0746 and R2 0.3005, p=0.1980; respectively). There was a statistically significant correlation between the final, contrast-enhanced CT density and histologic necrosis (R2 0.2408, p=0.0280).