Neoadjuvant Sunitinib Research Articles

P2-09-09: Dynamic FDG PET and DCE-MRI To Assess Tumor Metabolism and Blood Flow in Response to Neoadjuvant Sunitinib and Paclitaxel Followed by AC + G-CSF in Patients with Locally-Advanced (LABC) and/or Inflammatory Breast Cancer (IBC).

Abstract Background Kinetic analysis of FDG PET and DCE-MRI can identify patterns of breast tumor metabolism and perfusion that predict pathologic response, relapse, and survival in patients (pts) receiving neoadjuvant chemotherapy (NC). We are enrolling pts with LABC or IBC on a phase II trial of neoadjuvant sunitinib and metronomic chemotherapy. The addition of sunitinib, a tyrosine kinase inhibitor of VEGFR1-3, PDGFR, c-KIT, to NC is hypothesized to increase rate of pathologic complete response (pCR). Assessment of FDG PET measures of glucose metabolism (Ki), glucose delivery (K1) which approximates blood flow, and MRI measures of blood flow and vascularity (peak enhancement (PE), signal enhancement ratio (SER), and volume) during NC offers the opportunity to evaluate the in vivo pharmacodynamics of sunitinib. Methods: Pts with HER2−negative LABC or IBC participated in a companion imaging trial with [18F]-FDG PET and DCE-MRI before NC (T0), after a 1 wk run-in of sunitinib 25 mg po daily (T1), after 12 wks of paclitaxel 80 mg/m2 IV Qwk and sunitinib 25 mg po daily (T2), and prior to breast surgery (T3) after 15 wks of doxorubicin 24 mg/m2 IV Qwk, cyclophosphamide 60 mg/m2 po daily with G-CSF 5 mcg/kg SC days 2–6 each wk. FDG metabolic rate (Ki), glucose delivery (K1), and MR indices (PE, SER, volume) were assessed. Imaging parameters were compared for groups defined by NC pathologic complete response (pCR) vs. non-pCR using a two-sample t-test. Results: The imaging trial included 14 pts. Median age was 50 years (43-79). All had HER2−negative LABC (n=13, 93%) or IBC (n=1, 7%). Most tumors were ductal (n=12, 86%) and high grade (n=9, 64%). Seven (50%) tumors were ER negative. pCR was observed in 4/14 (29%) pts in this cohort. Changes in Ki, K1, and MRI volume were observed between baseline (T0) and the sunitinib run-in (T1). For example, 8/14 (57%) had a decrease in K1 of >20%, and 3 (21%) had an increase of ≥20%. These 1 week changes did not predict subsequent response to NC. However, declines in Ki and K1 between baseline (T0) and following sunitinib and paclitaxel (T2) did predict pCR. The average change in glucose metabolism (Ki) was a 95% decline with pCR and a 68% decline otherwise (p= 0.007). The average T0-T2 K1 change was 83% decline for pts with pCR and 47% decline otherwise (p= 0.029). In contrast to our previous studies in LABC pts treated with NC where decline in K1 was predictive of response, decline in Ki appears to be the more robust predictor of response in this cohort. Of 11 pts with PET scans at T2 and T3, 5 showed marked increase (>20%) in Ki and 6 showed marked increase in K1 after withdrawal of sunitinib. Conclusion: Changes in breast tumor glucose metabolism (Ki), glucose delivery (K1), and blood flow (MR PE, SER, volume) can be detected after 1 wk of sunitinib, but are not predictive of response to NC. In the setting of anti-vascular therapy, measures of tumor glucose metabolism (Ki) are predictive and perhaps, more predictive of outcome than measures of glucose delivery (K1) which may be altered by sunitinib. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-09.

P3-16-15: Phase I Study with Biomarker Evaluation of Neoadjuvant Sunitinib in Combination with Exemestane in Post-Menopausal Women with Hormone-Sensitive, Her-2 Negative Primary Breast Cancer.

Abstract Background In preclinical models, oestrogen causes a rapid induction of VEGF in mammary tumours leading to tumour angiogenesis, tumor growth and cell migration whereas aromatase inhibitors (AI) have the opposite effect. Exemestane (E) is an AI, effective in metastatic hormone-dependent breast cancer, as well as in the adjuvant and neoadjuvant settings. Sunitinib (S) is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic activities via inhibition of VEGFR, PDGFR, KIT, RET, CSF-1R and FLT-3, and direct antitumor activity shown in heavily pretreated subjects with advanced breast cancer. The use of antiangiogenic agents at initial stages of the disease, when fewer proangiogenic factors are present, may result in significantly greater efficacy than using these agents at a later stage. Safety profiles of both agents indicate only modest toxicity and do not overlap. We hypothesize that since antiangiogenic and hormonal agents use different mechanisms of action, combination will have additive activity. Regarding (S), continuous dosing (CD) at low doses might result in improved efficacy while maintaining good tolerability. Methods: This is a phase I study to evaluate the safety of (S) in combination with (E) administered for 24 weeks (1cycle=4weeks) as neoadjuvant therapy for post-menopausal women with newly diagnosed hormone-sensitive, Her-2 negative primary breast cancer. We report the results of the first dose escalation part of the study intended to determine a safe dose level of (S) that can be combined with (E) at conventional fixed dose of 25mg/d. Preliminary efficacy data in terms of objective clinical response by WHO criteria will also be reported. Results: 18 postmenopausal women with ER-positive invasive breast cancer, adequate organ function and ECOG 0–1 were enrolled in the study (median age 74, range 57–84) to be treated at two dose levels: 25 mg of (E) with either 25mg or 37.5mg of (S) CD. Two DLTs were identified: grade 3 mucositis at level 25mg of (S) and grade 3 asthenia at level 37.5mg of (S). Main toxicities were asthenia, leucopenia, mucositis, diarrhea and HBP. 78% of patients had grade 2 toxicities; 22% had grade 3. There were no serious adverse events reported. Median time on treatment with the combination was 23 weeks (range 2–24). 16% of patients needed one dose reduction of (S), 16% needed two or more and 28% suspended (S) administration due to toxicity. 50% of patients completed 24 weeks of treatment. None of the patients at 37.5mg (S) level could tolerate full doses for the entire treatment period, therefore in our study the recommended dosage of (S) that can be safely combined with (E) is 25mg. Concerning efficacy, 11 out of 18 patients had partial response (61%), 6 out of 18 had SD (33%) and only one patient had PD (5%) as best response. Conclusion: Safety profile of the combination seems to be manageable in most patients. Toxicities were observed mainly within the two first cycles. Response rates were similar than those previously observed with (E) as monotherapy in the neoadjuvant setting. Biomarkers information will be provided. This study was supported by an Independent Investigator Research grant from Pfizer, Inc. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-15.

Commentary on “Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery.” Silberstein JL, Millard F, Mehrazin R, Kopp R, Bazzi W, DiBlasio CJ, Patterson AL, Downs TM, Yunus F, Kane CJ, Derweesh IH, Division of Urology, Department of Surgery, University of California San Diego, School of Medicine San Diego, CA: BJU Int 2010;106:1270–6

Commentary on “Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery.” Silberstein JL, Millard F, Mehrazin R, Kopp R, Bazzi W, DiBlasio CJ, Patterson AL, Downs TM, Yunus F, Kane CJ, Derweesh IH, Division of Urology, Department of Surgery, University of California San Diego, School of Medicine San Diego, CA: BJU Int 2010;106:1270–6

Dramatic Reduction in Tumor Burden With Neoadjuvant Sunitinib Prior to Bilateral Nephron-sparing Surgery

Neoadjuvant sunitinib has recently been described for the management of renal cell carcinoma. We present the pre and posttreatment images of a 49-year-old male with bilateral biopsy-proven clear cell renal cell carcinoma who underwent treatment with sunitinib prior to nephron-sparing surgery. After four four-week cycles of daily 50 mg sunitinib, the patient demonstrated a dramatic reduction in tumor burden allowing for successful bilateral partial nephrectomy.

Contrast enhanced CT (CE-CT) changes and nephrometry down-scoring of unresectable primary renal cell carcinoma (RCC) tumors in patients (Pts) treated with neoadjuvant sunitinib.

299 Background: The impact of neoadjuvant sunitinib on CE-CT parameters and nephrometry score of primary RCC tumors remains unknown. Methods: Retrospective review of baseline and prenephrectomy CE-CT from a prospective phase II trial of neoadjuvant sunitinib (50 mg sunitinib continuous dosing) in unresectable primary RCC tumors with or without metastatic disease. CE-CT parameters and R.E.N.A.L. nephrometry score for each lesion were determined in pts who underwent subsequent surgery. RECIST and MASS criteria were used to assess primary tumor radiographic response. CT changes were analyzed using the sign test and Wilcoxon signed rank test. Results: Twenty nine pts were enrolled, of which 13 pts (85%M; median age 63y) underwent post-sunitinib resection of 16 primary tumors (3 pts had multifocal RCC). Post-therapy, 88% of tumors had decreased long diameter (median 32% decrease, p<0.001 vs. baseline), 88% decreased attenuation (median 30 HU reduction, p=0.006) and 69% increased necrosis (p=0.001). 56% of tumors had a decrease in nephrometry score (median 1 point decrease; 10 to 9, p=004). At baseline, 81% of tumors were highly complex by nephrometry score; following therapy 46% of the highly complex tumors became moderately complex. At baseline 13 tumors abutted renal hilar vital structures, whereas following treatment 4 tumors demonstrated abutment. Adenopathy decreased (range, 23%-83%) in 4/4 patients with enlarged baseline lymph nodes, with complete resolution in 1 patient. RECIST objective response was seen in 38% and SD in 56% of primary tumors; 1 tumor had PD based on size despite > 95% necrosis. MASS criteria response was favorable 38%, intermediate 62%. Two of four pts had reduction in extent of venous thrombus (1 pt from level 0 to resolved and 1 pt from level IV to II). Conclusions: Neoadjuvant sunitinib resulted in decreased size/attenuation, increased necrosis of the primary tumor and reduction in lymphadenopathy and venous thrombus in pts who underwent subsequent surgery. Sunitinib reduced the RENAL nephrometry score and facilitated nephrectomy, notably due to impact on tumor proximity to vital structures in the renal hilum. [Table: see text]

Surgical outcomes and complications associated with presurgical tyrosine kinase inhibition for advanced renal cell carcinoma (RCC)

BackgroundTyrosine kinase inhibitors (TKI) have dramatically changed the management paradigm of advanced renal cell carcinoma (RCC) and are increasingly being used preoperatively to achieve cytoreduction. ObjectiveTo review our case series of post-TKI surgical procedures to add to the current perioperative efficacy and complication profile. Materials and methodsBetween October 2006 and February 2010, 14 cytoreductive nephrectomies, radical nephrectomies, and metastectomies were performed after neoadjuvant sunitinib or sorafenib for advanced RCC. During the same time frame, a control group of 73 consecutive patients underwent radical nephrectomy, cytoreductive nephrectomy, or metastectomy in the absence of prior systemic therapy. We compared the incidence of perioperative complications and outcomes after surgical procedures between the two cohorts. ResultsMedian preoperative renal mass size was 11 cm (6.7–24.2 cm). Primary tumor shrinkage was seen in 57%; median shrinkage was 18% (8%–25%). The median treatment period was 17 weeks, and the median time from TKI discontinuation was 2 weeks. Compared with a control group and after adjusting for confounding covariates, presurgical TKI use was not associated with a significant increase in perioperative complications (50% vs. 40%, P = 0.25) or perioperative bleeding (36% vs. 34%, P = 0.97) but was associated with increased incidence and grade of intraoperative adhesions (86% vs. 58%, P = 0.001; grade 3 vs. 1, P = 0.002). ConclusionsCompared with the published reports, we observed less hemorrhagic and wound healing issues but a significant increase in incidence and severity of intraoperative adhesions, which can present a formidable technical challenge. Potential reasons for our lower complication rate could be increased time from TKI discontinuation to surgery, longer time to postoperative TKI re-initiation, increased use of preoperative angioembolization, and the lack of preoperative bevacizumab administration. Presurgical TKI therapy can permit effective surgical cytoreduction with a safety and complication profile equivalent to that of non-TKI-nephrectomy; however safety data continue to evolve, and preoperative TKI use requires further prospective investigation.

A Comparison of Open Radical Nephrectomy Complication Rates in Patients Treated with Neoadjuvant Sunitinib for Metastatic Renal Cell Carcinoma versus Non-Metastatic Renal Cell Carcinoma

A Comparison of Open Radical Nephrectomy Complication Rates in Patients Treated with Neoadjuvant Sunitinib for Metastatic Renal Cell Carcinoma versus Non-Metastatic Renal Cell Carcinoma

Progression of intramedullary metastasis during perioperative cessation of sunitinib

A 57-year-old woman presented with metastatic renal cell carcinoma (RCC). She was enrolled in a clinical study, in which she received two cycles of neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy. Her primary tumor and rib metastasis showed a good response to neoadjuvant therapy; however, after surgery, the patient developed neurologic symptoms, including flaccid paraparesis with paresthesia and hypoesthesia. MRI of the brain and spine revealed a leptomeningeal lesion at the T12-L1 space, which was presumed to have progressed during the 3-week treatment-free perioperative period. The patient underwent radiation therapy for the intramedullary lesion 1 month later, and sunitinib therapy was subsequently reinstated. After 6 months, her extracranial lesions remained stable and the intramedullary lesion was undetectable on MRI. CT of the chest and abdomen, bone scan, kidney and liver function tests, measurement of serum levels of calcium, electrolytes and lactate dehydrogenase, CBC, MRI of the brain and spine. Progression of a central nervous system metastasis linked to the interruption of neoadjuvant sunitinib therapy. Neoadjuvant sunitinib therapy followed by cytoreductive nephrectomy for the primary RCC; radiation therapy for the intramedullary lesion, followed by reinstatement of sunitinib therapy owing to a good clinical response observed in the extracranial lesions.

Prospective Clinical Trial of Preoperative Sunitinib in Patients With Renal Cell Carcinoma

Sunitinib is an approved treatment for metastatic renal cell carcinoma. We performed a prospective clinical trial to evaluate the safety and clinical response to sunitinib administered before nephrectomy in patients with localized or metastatic clear cell renal cell carcinoma. Patients with biopsy proven clear cell renal cell carcinoma were enrolled in the study and treated with 37.5 mg sunitinib malate daily for 3 months before nephrectomy. The primary end point was safety. In an 18-month period 20 patients were enrolled. The most common toxicities were gastrointestinal symptoms and hematological effects. Grade 3 toxicity developed in 6 patients (30%). No surgical complications were attributable to sunitinib treatment. Of the 20 patients 17 (85%) experienced reduced tumor diameter (mean change -11.8%, range -27% to 11%) and cross-sectional area (mean change -27.9%, range -43% to 23%). Enhancement on contrast enhanced computerized tomography decreased in 15 patients (mean HU change -22%, range -74% to 29%). After tumor reduction 8 patients with cT1b disease underwent laparoscopic partial nephrectomy. Surgical parameters, such as blood loss, transfusion rate, operative time and complications, were similar to those in patients who underwent surgery during the study period and were not enrolled in the trial. Preoperative treatment with sunitinib is safe. Sunitinib decreased the size of primary renal cell carcinoma in 17 of 20 patients. Future trials can be considered to evaluate neoadjuvant sunitinib to maximize nephron sparing and decrease the recurrence of high risk, localized renal cell carcinoma.

Feasibility and efficacy of neoadjuvant sunitinib before nephron‐sparing surgery

To investigate efficacy of neoadjuvant tyrosine kinase-inhibitor therapy (TKI) before imperative nephron-sparing surgery (NSS), as NSS in patients with large locally advanced or centrally located tumours can be challenging, and TKI therapy might result in a reduction of primary tumour burden and increase the feasibility of NSS. This was a multicentre retrospective review and prospective pilot study of patients undergoing neoadjuvant sunitinib before planned NSS from February 2006 to February 2009. All patients underwent confirmatory biopsy for clear cell renal cell carcinoma. Patients received two 28-day cycles of sunitinib before NSS. Demographics/tumour characteristics, tumour response (by the Response Evaluation Criteria In Solid Tumors), outcomes and complications were analysed. Twelve patients (seven men and five women; mean age 60.1 years, tumours on 14 renal units) were given TKI before NSS for imperative indications. The mean pretreatment tumour diameter was 7.1 cm; all patients had a decrease in size of the primary tumour after TKI, with a mean reduction in maximum diameter of 1.5 cm (21.1%). Four of 14 and 10 of 14 primary tumours had a partial response and stable disease after TKI. NSS was achievable in all 14 kidneys. Four patients had a concurrent metastasectomy. The mean warm ischaemia time was 22.5 min; postoperative dialysis was not required in any patients. Final pathology revealed negative tumour margins in all 14 tumours. The mean creatinine and estimated glomerular filtration rate (before/after NSS) were 1.34/1.40 mg/dL (P = 0.431) and 57.7/53.4 mL/min/1.73 m(2) (P = 0.475), respectively. At a mean follow-up of 23.9 months, 10 of the 12 patients were alive, one died from metastatic RCC and none required dialysis. Three of the 14 renal units developed delayed urinary leaks, all in patients who also received postoperative sunitinib. All leaks resolved with conservative measures. Neoadjuvant TKI followed by NSS is safe and feasible, with all patients achieving a reduction in maximum tumour diameter, and with NSS being achievable with negative margins and with no requirement for postoperative dialysis. Further investigation is required.

1477 PROSPECTIVE CLINICAL TRIAL OF PREOPERATIVE SUNITINIB IN PATIENTS WITH RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Localized V1 Apr 20101477 PROSPECTIVE CLINICAL TRIAL OF PREOPERATIVE SUNITINIB IN PATIENTS WITH RENAL CELL CARCINOMA Nicholas Hellenthal, Willie Underwood, Remedios Penetrante, Alan Litwin, Shaozeng Zhang, Bin Teh, and Hyung Kim Nicholas HellenthalNicholas Hellenthal Buffalo, NY More articles by this author , Willie UnderwoodWillie Underwood Buffalo, NY More articles by this author , Remedios PenetranteRemedios Penetrante Buffalo, NY More articles by this author , Alan LitwinAlan Litwin Buffalo, NY More articles by this author , Shaozeng ZhangShaozeng Zhang Buffalo, NY More articles by this author , Bin TehBin Teh Grand Rapids, MI More articles by this author , and Hyung KimHyung Kim Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1193AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sunitinib is an approved treatment for metastatic renal cell carcinoma (RCC). A prospective clinical trial was conducted to evaluate the safety and clinical response to sunitinib administered prior to nephrectomy in patients with localized or metastatic clear cell RCC. METHODS Patients with biopsy-proven clear cell RCC were enrolled and treated with sunitinib malate, 37.5 mg daily, for 3 months prior to nephrectomy. A baseline CT scan was obtained prior to starting treatment and repeated after 2 months of therapy. In the first 5 patients, sunitinib was discontinued 5 days before surgery. In the final 15 patients, sunitinib was continued to the day before surgery. The primary endpoints were safety and the clinical response of the primary tumor to preoperative sunitinib. RESULTS Twenty patients were enrolled during an 18 month period. The most common toxicities were GI symptoms and fatigue. Grade 3 toxicities occurred in 5 patients (25%). No surgical complications were attributable to treatment with sunitinib. Seventeen of the 20 patients (85%) experienced a decrease in tumor diameter (mean -11.8%, range -27% to 11%) and cross-sectional area (mean -27.9%, range -43 to 23%). Enhancement on contrast-enhanced CT decreased in 15 patients, with a mean change in Hounsfield units of -22% (range -74% to 29%). Following a decrease in tumor size, 8 patients presenting with cT1b tumors underwent laparoscopic partial nephrectomy. Surgical parameters such as blood loss, transfusion rate, operative time, and complications were similar to those who underwent nephrectomy during the study period and were not enrolled on the trial. CONCLUSIONS Preoperative treatment with sunitinib in patients undergoing nephrectomy is safe. Sunitinib decreased the size of primary RCC in 17 of 20 patients, and future trials can be considered to evaluate the use of neoadjuvant sunitinib to maximize nephron-sparing and decrease recurrence risk for high-risk, localized RCC. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e569 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicholas Hellenthal Buffalo, NY More articles by this author Willie Underwood Buffalo, NY More articles by this author Remedios Penetrante Buffalo, NY More articles by this author Alan Litwin Buffalo, NY More articles by this author Shaozeng Zhang Buffalo, NY More articles by this author Bin Teh Grand Rapids, MI More articles by this author Hyung Kim Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Commentary on Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma: Thomas AA, Rini BI, Lane BR, Garcia J, Dreicer R, Klein EA, Novick AC, Campbell SC, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH

We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection. A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks-on and followed by 2 weeks-off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated. Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patient experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease, and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease, and 10 (53%) with disease progression. At a median follow-up of 6 months (range 1–15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3–4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity. Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection.

Neoadjuvant Sunitinib Facilitates Nephron-Sparing Surgery and Avoids Long-Term Dialysis in a Patient With Metachronous Contralateral Renal Cell Carcinoma

Bilateral Renal Cell Carcinoma (RCC) is an uncommon clinical entity, affecting 3%-6% of patients with localized RCC. Sunitinib has proven efficacy in the management of metastatic RCC (mRCC), however, there is very limited evidence of primary tumor response. With the changing treatment paradigm, the role of sunitinib should be extended to the neoadjuvant setting, to downstage locally advanced primary renal tumors, to facilitate nephron-sparing surgery (NSS), and to select responding patients with mRCC for continuation of treatment after cytoreductive nephrectomy. The role of sunitinib in downstaging primary renal tumors to facilitate curative NSS has not been previously reported. We report the case of recurrent renal tumors in a solitary kidney, where neoadjuvant sunitinib downstaged the tumors enough to allow NSS.

Laparoscopic radical nephrectomy after shrinkage of a caval tumor thrombus with sunitinib

A 57-year-old woman presented to the emergency department at a community hospital with a 2-month history of fatigue and right-sided flank and abdominal pain. Noncontrast CT of the abdomen and pelvis revealed a 9.1 cm right renal mass. Contrast CT of the chest, abdomen and pelvis, MRI of the abdomen and pelvis with gadolinium, radionuclide bone scan, lung nodule biopsy, complete blood count, comprehensive metabolic profile, and measurement of serum lactate dehydrogenase. Stage IV, T3bN0M1 clear cell renal cell carcinoma, with an associated tumor thrombus extending into the vena cava. The patient was treated with neoadjuvant sunitinib, which resulted in a marked response in the primary tumor and metastatic lesions as well as regression of the tumor thrombus well into the renal vein. Thus, laparoscopic radical nephrectomy was feasible and was achieved without hemorrhagic or wound healing complications. One month after surgery, she had evidence of disease progression in the lung and a periaortic lymph node. She was restarted on sunitinib with resultant disease stabilization, but discontinued the drug owing to toxicity. Eight months after cessation of sunitinib, she received a dendritic cell vaccine. She remains alive without evidence of disease progression 2 years after her diagnosis.

Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with downsizing to reconsider cytoreductive surgery

To evaluate neoadjuvant sunitinib in patients with synchronous metastatic renal cell cancer (mRCC) to downsize surgically complex tumours and reconsider cytoreductive surgery. Retrospective analysis of ten consecutive mRCC patients treated with sunitinib in an expanded access program who presented with surgically complex primary tumours or bulky locoregional metastases. Surgery-limiting tumour sites (SLTSs) were defined as primary or retroperitoneal lesions with direct invasion of adjacent organs or encasement of vital structures on imaging. Patients received sunitinib 50 mg/day for 4 weeks on and 2 weeks off to be followed by cytoreductive surgery after downsizing and individual reassessment. Response was measured according to Response Evaluation Criteria in Solid Tumours (RECIST). Six out of ten SLTSs revealed a reduction of tumour size with a median of 14% according to RECIST. None of the ten SLTSs had a partial response (PR), whilst at distant metastatic sites one complete remission and two PRs occurred. Downsizing of SLTSs appeared most prominent in the first 2-4 months, which resulted in reconsidering cytoreductive nephrectomy in three patients. These three tumours invaded the liver on imaging and were reduced by 11, 18 and 20%. In this patient group with mRCC and surgically complex primary tumours or locoregional metastases, downsizing of SLTSs by neoadjuvant sunitinib was limited. Cytoreductive surgery was reconsidered in three patients. Given the overall reduction in tumour burden by sunitinib alone, further investigation to define the role of cytoreductive surgery is warranted.

DCE-MRI and dynamic FDG PET to monitor breast cancer response to neoadjuvant sunitinib in patients with locally-advanced breast cancer.

Abstract Abstract #6006 Background: We are enrolling patients with locally-advanced (LABC) or inflammatory breast cancer on a phase II trial of neoadjuvant sunitinib and metronomic chemotherapy. The addition of sunitinib is hypothesized to increase rate of pathologic complete response (pCR) via its effect on tumor vasculature. Measurement of FDG PET and MRI parameters of metabolism and blood flow (BF) after a one week run-in of sunitinib alone provides an opportunity to evaluate in vivo pharmacodynamics of sunitinib which may be predictive of response and provide insight into mechanism of sunitinib activity. Materials and Methods: Patients with HER2 negative LABC participated in an imaging trial with pre-therapy [18F]-FDG PET and DCE-MRI (T0) followed by a one-week run-in of sunitinib 37.5 mg orally daily with a second PET and MRI on day 7 (T1). FDG metabolic rate (MRFDG), transport (FDG K1) and MR indices of tumor perfusion (peak enhancement (PE), signal enhancement ratio (SER), and washout volume(WV)) were assessed. Results: Metabolism and perfusion parameters are available for the first 3 patients treated on this trial. All patients presented with grade 3, HER2 negative LABC. DCI-MRI (left) and PET images (right) pre-therapy (T0, top) and after one week sunitinib (T1, bottom) are illustrated in Figure 1. DCE-MRI studies show gray-scale images with color-coded regional perfusion (SER) superimposed; red indicates high levels of perfusion and blue lower levels. Three different responses were observed and expressed as percent change T0 to T1: patient 1 had no significant change in metabolism (MRFDG) or perfusion (K1,SER, PE); patient 2 showed a decline in perfusion with decreases in K1 (-55%), SER (-19%), PE (-10%), and WV (-56%), but minimal change in MRFDG (+ 5.9%); while patient 3 had marked declines in perfusion K1 (-41%), SER (-25%), WV (-78%) and MRFDG (-59%). Discussion: These early data demonstrate the ability to measure changes in tumor metabolism and blood flow by PET and MRI and illustrate heterogeneity in tumor response to sunitinib. As patients complete neoadjuvant chemotherapy (NC), metabolism and perfusion parameters from mid-therapy (T2) and end-therapy (T3) imaging will be evaluated in the context of pCR versus other with the goal of exploiting functional imaging parameters to predict response to NC and elucidate mechanism of response to sunitinib and metronomic chemotherapy. Supported by grant from NCCN, SI11.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6006.

Complete Histologic Remission after Sunitinib Neoadjuvant Therapy in T3b Renal Cell Carcinoma

The authors present the first case report of complete histologic remission after neoadjuvant sunitinib treatment on primary renal tumour and vena cava thrombus. A 78-yr-old woman with an Eastern Cooperative Oncology Group (ECOG) score of 0 presented with a T3b renal tumour. She refused surgical treatment but agreed to percutaneous biopsy and medical treatment. A Fuhrman III renal cell carcinoma was histologically confirmed on percutaneous biopsy, and sunitinib treatment was administered over 6 mo. A significant objective response was observed for tumour size and thrombus. The patient finally accepted surgical treatment. Pathologic examination concluded with a complete response of primary tumour and thrombus.

Response of the Primary Tumor to Neoadjuvant Sunitinib in Patients With Advanced Renal Cell Carcinoma

We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection. A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks on followed by 2 weeks off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated. Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patients experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease and 10 (53%) with disease progression. At a median followup of 6 months (range 1 to 15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3-4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity. Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection.