Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

PURPOSE: We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. EXPERIMENTAL DESIGN: Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2). RESULTS: Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. CONCLUSIONS: The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.

High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Long-acting sandostatin (S-LAR; octreotide acetate) is well tolerated and effective for symptom control and possibly disease control in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We undertook a retrospective analysis to study the efficacy and tolerability of higher doses (more than 20-30 mg/month) of S-LAR in GEP-NETs. PATIENTS AND METHODS: With IRB approval, charts of all patients with GEP-NET who received S-LAR between June 2002 to September 2007 at Roswell Park Cancer Institute were reviewed and their data analyzed. RESULTS: Fifty-four patients with GEP-NET received S-LAR; thirty required dose escalation. Patients received a median of 5 doses of S-LAR at conventional dose followed by up-titration of the dose for symptom control (20) and radiological progression (17). Median high dose of S-LAR was 40 mg (range: 40-90 mg) with a median of 8.5 high doses received. No treatment related toxicities were seen. The estimated 1-year survival for patients on conventional dose alone was 0.77 (95% CI of 0.50 to 0.91) and those on high-dose was 0.88 (95% CI of 0.68 to 0.96) (p=0.4777) while median time to any other intervention was 2.9 months versus 17.7 months (p=0.12). CONCLUSION: Dose escalation of S-LAR is well tolerated and may provide longer disease control.

Effective endovascular stenting of malignant portal vein obstruction in pancreatic cancer.

We report herein the case of a patient successfully treated by transhepatic portal venous stent placement for malignant portal vein obstruction with associated gastric and small bowel varices and repeated gastrointestinal bleeding. CT angiography and portography showed severe portal vein obstruction from recurrent pancreatic cancer 15 months following pancreaticoduodenectomy with tumor encasement and dilated collateral veins throughout the gastric and proximal small bowel wall as the suspected cause of the GI bleeding. Successful transhepatic endovascular stent placement of the splenic vein at the portal vein confluence followed by balloon dilation was performed with immediate decompression of the gastric and small bowel varices and relief of GI hemorrhage in this patient until his death four months later. The treatment for patients with this dilemma can prove to be difficult, but as we have shown endovascular stenting of the portal system is an effective treatment option.

Metastatic pancreatic adenocarcinoma and renal cell carcinoma treated with gemcitabine and sunitinib malate. A case report.

CONTEXT: Pancreatic adenocarcinoma and renal cell carcinoma are relatively frequent cancers that have been rarely reported as synchronous primary malignancies. When present simultaneously, they pose a therapeutic challenge given the many available targeted agents with reported efficacy in renal cell cancer and limited options for metastatic pancreatic cancer. CASE REPORT: We report the case of a 43-year-old Caucasian gentleman diagnosed simultaneously with metastatic pancreatic adenocarcinoma and localized renal cell carcinoma treated with combination chemotherapy, consisting of gemcitabine and sunitinib. Patient had a radiographic response and prolonged progression free survival of twenty six weeks; side effects were manageable and included grade 3 neutropenia and grade 2 hypertension. CONCLUSION: This encouraging response, safety profile and progression free survival response suggest that we should further examine this and other such regimens to improve clinical outcomes for maximum efficacy with minimal side-effects.

Surgical resection after TNFerade therapy for locally advanced pancreatic cancer.

CONTEXT: Treatment of pancreatic cancer remains a major oncological challenge and survival is dismal. Most patients, present with advanced disease at diagnosis and are not candidates for curative resection. Preoperative chemoradiation may downstage and improve survival in locally advanced pancreatic cancer. This has prompted investigators to look for novel neoadjuvant therapies. Gene therapy for pancreatic cancer is a novel investigational approach that may have promise. TNFerade is a replication deficient adenovirus vector carrying the human tumor necrosis factor (TNF)-alpha gene regulated under control of a radiation-inducible gene promoter. Transfection of tumor cells with TNFerade maximizes the antitumor effect of TNF-alpha under influence of radiation leading to synergistic effects in preclinical studies. CASE REPORT: We describe a case of locally advanced unresectable pancreatic cancer treated with a novel multimodal approach utilizing gene therapy with TNFerade and concurrent chemoradiation that was followed by successful surgical resection. CONCLUSION: Neoadjuvant TNFerade based chemoradiation therapy may be a useful adjunct to treatment of locally advanced pancreatic cancer.

A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patients with refractory colorectal cancer.

PURPOSE: We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX). EXPERIMENTAL DESIGN: Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied. RESULTS: Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) on day 5 compared with day 1. The median C(max) of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR. CONCLUSIONS: The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.

Adjuvant FOLFOX chemotherapy and splenomegaly in patients with stages II-III colorectal cancer.

BACKGROUND: The impact of adjuvant chemotherapy on hepatic function and portal hypertension in patients with stages II-III colon cancer has not been previously described. We conducted a retrospective study to assess the effects of adjuvant FOLFOX chemotherapy on the splenic index (SI) as a surrogate marker for portal hypertension. METHODS: Stage II-III colorectal cancer patients treated with adjuvant FOLFOX or fluorouracil/leucovorin (5-FU/LV) at Roswell Park Cancer Institute between 2002 and 2006 were identified. Computerizedt omography (CT) scans obtained prior to and at completion of chemotherapy, and every 6 months thereafter were reviewed. Splenic size was evaluated using the SI (SI = length x width x height of the spleen). RESULTS: 40 patients were identified in the FOLFOX group and 23 in the 5-FU/LV group. After 6 months of adjuvant chemotherapy, the mean increase in SI was 45.7 and 16.3% in the FOLFOX and 5-FU/LV groups, respectively (p = 0.0069). SI increased by >100% in 6 patients (15%) in the FOLFOX group versus none in the 5-FU/LV group (p = 0.16). The mean SI at completion of adjuvant chemotherapy was significantly higher in the FOLFOX group than in the 5-FU/LV group (p = 0.007). The mean SI decreased steadily over a period of 2 years after discontinuation of FOLFOX, suggesting potential reversibility of oxaliplatin-induced hepatic injury in this setting. CONCLUSIONS: Adjuvant FOLFOX significantly increases the SI in patients with resected colorectal cancer in comparison to adjuvant 5-FU/LV. The increase in SI may be a marker of oxaliplatin-induced hepatic injury and should be investigated further in prospective longitudinal studies of oxaliplatin-based adjuvant chemotherapy.

A dramatic, objective antiandrogen withdrawal response: case report and review of the literature.

Antiandrogen withdrawal response is an increasingly recognized entity in patients with metastatic prostate cancer. To our knowledge, there have been no reports describing a durable radiologic improvement along with prostate-specific antigen (PSA) with discontinuation of the antiandrogen agent bicalutamide. We report a case in which a dramatic decline of serum PSA levels associated with a dramatic improvement in radiologic disease was achieved with bicalutamide discontinuation.

Qualitative radiology assessment of tumor response: does it measure up?

Our purpose was to assess whether a simpler qualitative evaluation of tumor response by computed tomography is as reproducible and predictive of clinical outcome as the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) methods. This study was a two-reader retrospective evaluation in which qualitative assessment resulted in agreement in 21 of 23 patients with metastatic colorectal carcinoma (91.3%, kappa=0.78; 95% CI, 0.51-1.00). Hepatic metastases were classified as increased, decreased, or unchanged, compared with agreement in 20 of 23 patients (87.0%) for RECIST (kappa=0.62; 95% CI, 0.23-1.00) and WHO (kappa=0.67; 95% CI, 0.34-1.00) methods. Patients were placed into partial response, stable disease, and disease progression categories. Time to progression of disease was better predicted qualitatively than by RECIST or WHO. Our pilot data suggest that our qualitative scoring system is more reproducible and predictive of patient clinical outcome than the RECIST and WHO methods.

Hyperostosis in an orbital defect with craniofacial implants and open-field magnets: a clinical report.

An orbital facial prosthesis wearer was found to have significant hyperostosis in an exenterated orbit exposed to long-term, open field, rare earth magnets attached to craniofacial implants. Localized exophytic osseous formation was found in multiple areas around the exenterated orbit. The overall thickness of the walls of the exenterated orbit was approximately double that of the unaffected side. Magnetic field effect on bone formation and recommended treatment are discussed.

Reversible grade 4 hyperbilirubinemia in a patient with UGT1A1 7/7 genotype treated with irinotecan and cetuximab.

Irinotecan-induced gastrointestinal toxicities are common and typically present in the form of diarrhea or nausea and vomiting. However, severe hyperbilirubinemia (grade 3/4) has not been previously reported in association with this chemotherapeutic agent. We report a case of prolonged grade 4 hyperbilirubinemia after a single dose of irinotecan at 125 mg/m(2). This severe toxicity was attributed to a UGT1A1 7/7 genotype and resolved to grade 2 after 8 weeks of supportive care. This case outlines the possibility of severe hepatic toxicity with moderate doses of irinotecan in patients with a UGT1A1 7/7 genotype. Despite the severity and prolonged duration of the associated irinotecan-induced hepatic toxicity, the management of similar cases should focus on intensive supportive measures because the toxicity is likely to resolve eventually.

Cystic pancreatic tumors (CPT): predictors of malignant behavior.

BACKGROUND AND OBJECTIVES: Due to widespread use of imaging studies, increasing cystic pancreatic tumor (CPT) cases are being detected. The diagnosis of malignancy in CPT cases requires pancreatectomy. Clinical and laboratory characteristics of CPT may predict underlying malignancy. METHODS: CPT cases treated between 1994 and 2004 at our institution were included. Pseudocysts were excluded. Serous cystadenoma (SCA), mucinous cystadenoma (MCA), intrapapillary mucinous tumor, cystic endocrine tumor, and lymphoepithelial cysts were classified as benign or pre-malignant. Serous cystadenocarcinoma (SCACA), mucinous cystadenocarcinoma (MCACA), and adenocarcinoma (ACA) were classified as malignant. RESULTS: Thirty-five patients had histological confirmation. Median age was 65 years. Male/female ratio was higher in malignant group (P = 0.0284). Weight loss and abdominal mass were more prevalent in malignant group (P = 0.042 and 0.028, respectively). Malignant lesions were larger, associated with local invasion (superior mesenteric artery (SMA), superior mesenteric vein (SMV), portal vein (PV) complex or celiac encasement) and CA 19-9 elevation. On univariate analyses, local invasion (P = 0.0029), negative surgical intervention (P = 0.0010), presence of ACA (P = 0.0044), or malignant CPT (P = 0.0018) were associated with shorter survival. On a multivariate analysis, local invasion was associated with shorter survival [Hazard ratio (HR) = 4.322, P = 0.0218], while surgical intervention was associated with improved survival (HR = 0.179, P = 0.0124). CONCLUSION: Male sex, abdominal mass, weight loss, larger tumor size, local invasion, and elevated CA 19-9 were associated with malignant CPT.

Diagnosing regenerative nodular hyperplasia, the "great masquerader" of liver tumors.

Distinguishing benign tumors and pseudotumors of the liver from malignant tumors is a common clinical problem. Regenerative nodular hyperplasia (RNH) represents one of the more challenging pseudotumors to diagnose, because they can appear clinically indistinguishable from either a primary or a secondary liver malignancy. Even after comprehensive radiologic evaluation and image-guided percutaneous biopsy, the diagnosis of RNH can remain elusive. We reviewed the pathophysiology of RNH and present five cases illustrating the limitations of percutaneous biopsy and the utility of laparoscopic wedge biopsy in establishing the diagnosis. All patients underwent a complete workup that included percutaneous biopsy. Patients with a nondiagnostic percutaneous biopsy underwent a laparoscopic wedge biopsy or anatomical resection. H&E, vimentin, trichrome, and reticulin staining as well as CD34 immunostaining were performed. Five patients were diagnosed with RNH between May 2002 and April 2004. Three had focal nodular disease, whereas the other two had a diffuse multinodular presentation. Percutaneous biopsy definitively made the diagnosis in only one out of the five cases. Laparoscopic wedge biopsy was necessary to accurately make the diagnosis in three cases, whereas the fifth diagnosis was established after an anatomical resection. RNH is a unique pseudotumor of the liver that can present either as a solitary nodule or as a multinodular process. Percutaneous biopsy is associated with limitations in diagnosing RNH, and a more definitive surgical biopsy may be required. When RNH is considered, laparoscopic wedge biopsy is a safe and efficient way to obtain enough tissue to preserve the hepatic architecture required for diagnosis, while avoiding the morbidity of an unnecessary open resection.

Gadolinium-enhanced computed tomographic angiography: current status.

This article reviews the research to date, as well as our clinical experience from two institutions, on gadolinium-enhanced computed tomographic angiography (gCTA) for imaging the body. gCTA may be an appropriate examination for the small percentage of patients who would benefit from noninvasive vascular imaging, but who have contraindications to both iodinated contrast and magnetic resonance imaging. gCTA is more expensive than CTA with iodinated contrast, due to the dose of gadolinium administered, and gCTA has limitations compared with CTA with iodinated contrast, in that parenchymal organs are not optimally enhanced at doses of 0.5 mmol/kg or lower. However, in our experience, gCTA has been a very useful problem-solving examination in carefully selected patients. With the advent of 16-64 detector CT, in combination with bolus tracking, we believe that the overall dose of gadolinium needed for diagnostic CTA examinations, while relatively high, can be safely administered.

Bronchogenic cyst presenting as a symptomatic neck mass in an adult: case report and review of the literature.

We report the unusual clinical manifestation and subsequent management of a symptomatic congenital bronchogenic cyst that connected to the trachea and presented in the neck of an adult. The embryology, clinical presentation, diagnostic evaluation, and management options of this rare aberration are discussed.

Contemporary management of benign liver tumors.

Benign lesions of the liver represent diagnostic dilemmas, clinically and radiographically; however, certain clues can help the extensive differential diagnosis of both benign and malignant processes. Hemangiomas and simple cysts have very distinct and very specific radiographic characteristics, and if diagnosed, no further work-up is necessary. The remaining benign lesions have significant overlap, even though there are some more common characteristics to each of the entities. Still, differentiation of any particular lesion outside simple cysts or hemangioma may be difficult. It is reasonable and relatively simple, with minimal invasiveness, to perform US- or CT-guided, percutaneous core-needle biopsies. It is recommended that core biopsies be performed, because many of the benign entities have some overlapping histologic features, and if fine-needle aspirations are performed, a definitive diagnosis may be difficult to obtain. A definitive pathological diagnosis still cannot be made in some cases, even after needle biopsy. Therefore, a surgical resection or wedge resection may be necessary if a benign process cannot be definitively ruled out.