Piotr Czaykowski

Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206

PURPOSE Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted. PATIENTS AND METHODS Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%). CONCLUSION Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.

Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206

PURPOSE Bevacizumab is an antibody that binds vascular endothelial growth factor and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN-alpha) is the historic standard initial treatment for RCC. A prospective, randomized, phase III trial of bevacizumab plus IFN-alpha versus IFN-alpha monotherapy was conducted. PATIENTS AND METHODS Patients with previously untreated, metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN-alpha (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN-alpha monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety. RESULTS Seven hundred thirty-two patients were enrolled. The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-alpha and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-alpha monotherapy (unstratified log-rank P = .097). Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = .069) favoring bevacizumab plus IFN-alpha. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-alpha. Patients who developed HTN on bevacizumab plus IFN-alpha had a significantly improved PFS and OS versus patients without HTN. CONCLUSION OS favored the bevacizumab plus IFN-alpha arm but did not meet the predefined criteria for significance. HTN may be a biomarker of outcome with bevacizumab plus IFN-alpha.

Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB 90206

LBA5019 Background: Bevacizumab (BEV) plus interferon alpha (IFN) demonstrated a superior objective response rate and progression-free survival (PFS) versus IFN monotherapy in renal cell carcinoma (RCC) patients in 2 phase III trials. The primary objective of CALGB 90206 was to compare overall survival (OS) for advanced RCC patients receiving BEV plus IFN or IFN alone. METHODS Patients with previously-untreated, metastatic RCC with a clear cell component and Karnofsky performance status of ≥ 70% were eligible. Patients were prospectively randomized to receive BEV (10 mg/kg intravenously every 2 weeks) plus IFN (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN as monotherapy. Randomization was stratified by nephrectomy status and number of MSKCC adverse features. The primary endpoint was OS, defined as the time from randomization to death due to any cause. The trial was designed with 86% power to detect a hazard ratio (HR) of 0.76, assuming a two-sided type I error of 0.05. The primary analysis was an intent-to-treat approach using the stratified log-rank statistic, and the present analysis was based on the target number of 588 deaths. RESULTS Between October 2003 and July 2005, 732 patients were enrolled; 369 pts to BEV plus IFN and 363 pts to IFN monotherapy. The median duration of follow up among censored patients was 46.2 months (IQR=45.2-48.2). The median OS was 18.3 months (95% CI; 16.5-22.5) for BEV plus IFN and 17.4 months (95% CI; 14.4-20.0, unstratified log rank p = 0.097) for IFN monotherapy. The stratified HR was 0.86 (95% CI; 0.73-1.01) for BEV plus IFN compared to IFN (stratified log-rank p = 0.069). The median OS for BEV plus IFN versus IFN was 32.5 vs. 33.5 months (p = 0.524) for MSKCC good risk, 17.7 vs. 16.1 months (p = 0.174) for intermediate risk and 6.6 vs. 5.7 months (p = 0.245) for poor risk patients. The median PFS was 8.4 months vs. 4.9 months (p<0.0001). Fifty-three percent of patients received subsequent systemic therapy. CONCLUSIONS The addition of BEV to IFN significantly improves the objective response rate and PFS versus IFN monotherapy. Overall survival favored the BEV plus IFN arm, not meeting pre-defined criteria for significance. [Table: see text].

Adjuvant chemotherapy for stage III colon cancer: does timing matter?

BACKGROUND: Clinical trials commonly mandate that adjuvant chemotherapy for colon cancer should commence within 8 weeks (56 days) of surgery. OBJECTIVE: We investigated the consequences of the timing of adjuvant chemotherapy for stage III colon cancer. PATIENTS AND METHODS: This is a retrospective review of all patients with newly diagnosed stage III colon cancer who received adjuvant chemotherapy in 2 provincial centers in 1999 and 2000. The impact of time to adjuvant chemotherapy on overall survival and relapse-free survival was analyzed by the use of univariate and multivariate Cox modeling, adjusting for prognostic factors. RESULTS: Three hundred forty-five subjects were included. Median time to adjuvant chemotherapy was 50 days (range, 20–242 days); in 111 (32.2%) patients, it was beyond 56 days. On univariate analysis, time >56 days was nonsignificantly associated with a hazard ratio of death of 1.31 (P = .12). Similar results were seen for relapse-free survival. Planned exploratory analysis suggests that the commencement of adjuvant chemotherapy up to 10 weeks postsurgery still confers a benefit. CONCLUSIONS: Delaying adjuvant chemotherapy in stage III colon cancer beyond 8 to 10 weeks postsurgery appears to be associated with diminished benefit.

Concordance With ASCO Guidelines for Surveillance After Colorectal Cancer Treatment: A Population-Based Analysis

PURPOSE Intensive surveillance after curative treatment of colorectal cancer (CRC) is associated with improved overall survival. This study examined concordance with the 2005 ASCO surveillance guidelines at the population level. METHODS A cohort of 250 patients diagnosed with stage II or III CRC in 2004 and alive 42 months after diagnosis was identified from health administrative data in Manitoba, Canada. Colonoscopy, liver imaging, and carcinoembryonic antigen (CEA) testing were assessed over 3 years. Guidelines were met if patients had at least one colonoscopy in 3 years and at least one liver imaging test and three CEA tests annually. Multivariate logistic regression assessed the effect of patient and physician characteristics and disease and treatment factors on guideline concordance. RESULTS Guidelines for colonoscopy, liver imaging, and CEA were met by 80.4%, 47.2%, and 22% of patients, respectively. Guideline concordance for colonoscopy was predicted by annual contact with a surgeon, higher income, and the diagnosis of colon (rather than rectal) cancer. Adherence was lower in those older than 70 years and with higher comorbidity. For liver imaging, significant predictors were annual contact with an oncologist, receipt of chemotherapy, and diagnosis of colon cancer. Concordance with CEA guidelines was higher with annual contact with an oncologist and high levels of family physician contact, and lower in urban residents, in those older than 70, and in those with stage II disease. CONCLUSION Completion of recommended liver imaging and CEA testing fall well below guidelines in Manitoba, whereas colonoscopy is better provided. Addressing this gap should improve outcomes for CRC survivors.

Risk of Colorectal Cancer After Diagnosis of Endometrial Cancer: A Population-Based Study

PURPOSE Site-specific risk of colorectal cancer (CRC) among survivors of endometrial cancer (EC) is not known. The objective of the present study was to assess the risk of CRC (overall and subsite specific) among EC survivors. METHODS A historical cohort study was performed by linking the Manitoba Cancer Registry and the Manitoba Health administrative databases. Each subject diagnosed with EC as her first cancer between 1987 and 2008 was age matched with up to five women with no history of invasive cancer on the index date (date of EC diagnosis). All subjects were followed up to the date of diagnosis of CRC or another cancer, death, migration, or study end point (December 31, 2009). Competing-risk proportional hazards models were used to compare the CRC incidence rates with adjustment for age, history of lower gastrointestinal endoscopy, and socioeconomic status. There were three mutually exclusive (and competing) outcomes: CRC, another primary cancer, and death. RESULTS A total of 3,115 women with EC and 15,084 without EC were followed up for a total of 145,502 person-years. Women diagnosed with EC at age ≤ 50 years had an increased risk of being diagnosed with CRC (all CRC: hazard ratio [HR] = 4.41; 95% CI, 1.47 to 13.26; right-sided CRC: HR = 7.48; 95% CI, 1.29 to 43.28). There was no increased risk of all CRC among women 51 to 65 years of age or those older than 65 years at the time of EC diagnosis. However, women 51 to 65 years of age at EC diagnosis had an increased risk of right-sided CRC (HR = 2.30; 95% CI, 1.05 to 5.01). CONCLUSION This study suggests young women (age ≤ 50 years) with EC are at increased risk of CRC; risk of right-sided CRC is also increased in women 51 to 65 years old at EC diagnosis.

Geographical disparities of rectal cancer local recurrence and outcomes: a population-based analysis.

BACKGROUND: Challenges exist in providing high-quality cancer treatments to populations spread over large geographical areas. Local recurrence of rectal cancer is a complicated clinical problem associated with high morbidity and mortality. OBJECTIVES: The objectives of this study were to evaluate population-based rates and predictors of local recurrence of rectal cancer in the Province of Manitoba, Canada, with emphasis on the effects of geography. DESIGN: This was a population-based retrospective analysis. Administrative data from the Manitoba Cancer Registry and individual patient charts were reviewed. SETTINGS: Patients with stages I to III rectal cancer who underwent surgery with curative intent in Manitoba between 2004 and 2006 were included. MAIN OUTCOME MEASURES: The primary outcome was the development of local recurrence after surgical resection. RESULTS: Three hundred seventy patients with a mean age of 67 years were identified. The 5-year local recurrence rate was 17.4%. In multivariate analysis, relative to Winnipeg residents, rural residents, regardless of where they underwent surgery, had an increased risk of local recurrence (HR, 3.47; 95% CI, 1.74–6.92 for surgery in Winnipeg; HR, 2.98; 95% CI, 1.59–5.57 for surgery in rural Manitoba). The absence of both neoadjuvant radiotherapy and adjuvant chemotherapy was associated with a higher risk of local recurrence. Higher risk of mortality was noted for rural patients (HR, 1.90; 95% CI, 1.24–2.89) and for those who developed local recurrence (HR, 2.01; 95% CI, 1.27–3.19). CONCLUSION: Local recurrence rates for rectal cancer are high in Manitoba. Geography is an important variable, because rural status is associated with higher local recurrence rates and decreased survival. The use of neoadjuvant radiotherapy was an important predictor of lower local recurrence rates. Further initiatives are imperative to identify why rural patients experience differences in outcomes in Manitoba.

Metastatic signet ring cell adenocarcinoma of the bladder: responsive to treatment?

Signet ring cell variant of mucinous adenocarcinoma of the urinary bladder is an exceptionally rare urologic malignancy, generally felt to be resistant to chemotherapy and radiotherapy. We describe a case of this malignancy with unusual sites of metastasis and an unexpectedly good response to treatment.

Tumor-to-Tumor Metastasis: Report of a Case of Renal Cell Carcinoma Metastasizing to a Pancreatic Endocrine Neoplasm

Case Report A 53-year-old healthy man presented to the clinic with painless hematuria. An ultrasound and computed tomography (CT) scan showed a 10-cm mass within the left kidney. He subsequently proceeded to left radical nephrectomy and adrenalectomy. The pathology report described a Fuhrman grade 2 clear-cell carcinoma with involvement of the renal pelvis. The renal vein and left adrenal gland were free of disease. Two years later on routine follow-up CT imaging, the patient was found to have a solitary lesion in the distal pancreas. The patient was asymptomatic. The first attempt at resection of the mass failed because of difficult anatomy. The mass did not exhibit [F]fluorodeoxyglucose avidity on positron emission tomography scanning. It was observed with serial CT imaging and 2 years later had enlarged (Fig 1, arrow); a second attempt at a distal pancreatectomy and splenectomy was successful. On gross pathologic examination, the specimen received in formalin consisted of pancreas measuring 9 4 3 cm. A wellcircumscribed red and yellow variegated lesion measuring 2 cm in greatest dimension was present on a background of grossly unremarkable pancreatic parenchyma. The lymph nodes identified separately were free of cancer, and the spleen was unremarkable. Histology of the pancreatic lesion was considered quite noteworthy. As seen in Figure 2, eosinophilic trabeculae of neoplastic pancreatic endocrine neoplasm (PEN; upper left side of image) contrast with renal cell carcinoma (RCC) composed of lobules of clear cells separated by delicate branching vessels ( 200 hematoxylin and eosin). Immunohistochemistry confirms the histologic picture with CD10 immunoperoxidase showing staining of RCC with no uptake of stain by PEN (Fig 3A, 600) and synaptophysin immunoperoxidase of an adjacentsectiondemonstratingstainingofPENonly(Fig3B, 600).Thiswas felt to be entirely consistent with a pancreatic endocrine neoplasm surrounding a well-defined nodule of metastatic RCC, representing an unusual case of RCC metastatic to a pancreatic endocrine neoplasm.

Does geography influence the treatment and outcomes of colorectal cancer? A population-based analysis.

BackgroundThe Canadian province of Manitoba covers a large geographical area but only has one major urban center, Winnipeg. We sought to determine if regional differences existed in the quality of colorectal cancer care in a publicly funded health care system.MethodsThis was a population-based historical cohort analysis of the treatment and outcomes of Manitobans diagnosed with colorectal cancer between 2004 and 2006. Administrative databases were utilized to assess quality of care using published quality indicators.ResultsA total of 2,086 patients were diagnosed with stage I to IV colorectal cancer and 42.2% lived outside of Winnipeg. Patients from North Manitoba had a lower odds of undergoing major surgery after controlling for other confounders (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.26 to 0.90). No geographic differences existed in the quality measures of 30-day operative mortality, consultations with oncologists, surveillance colonoscopy, and 5-year survival. However, there was a trend towards lower survival in North Manitoba.ConclusionWe found minimal differences by geography. However, overall compliance with quality measures is low and there are concerning trends in North Manitoba. This study is one of the few to evaluate population-based benchmarks for colorectal cancer therapy in Canada.