Bernhard C. Pestalozzi

Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

PURPOSE This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer. PATIENTS AND METHODS Patients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent. RESULTS A total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms. CONCLUSION GemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

Positron emission tomography/computed tomography influences on the management of resectable pancreatic cancer and its cost-effectiveness.

Objective:We sought to determine the impact of positron emission tomography/computed tomography (PET/CT) on the management of presumed resectable pancreatic cancer and to assess the cost of this new staging procedure. Summary Background Data:PET using 18F-fluorodeoxyglucose (FDG) is increasingly used for the staging of pancreatic cancer, but anatomic information is limited. Integrated PET/CT enables optimal anatomic delineation of PET findings and identification of FDG-negative lesions on computed tomography (CT) images and might improve preoperative staging. Material and Methods:Patients with suspected pancreatic cancer who had a PET/CT between June 2001 to April 2004 were entered into a prospective database. Routine staging included abdominal CT, chest x-ray, and CA 19-9 measurement. FDG-PET/CT was conducted according to a standardized protocol, and findings were confirmed by histology. Cost benefit analysis was performed based on charged cost of PET/CT and pancreatic resection and included the time frame of staging and surgery. Results:Fifty-nine patients with a median age of 61 years (range, 40–80 years) were included in this analysis. Fifty-one patients had lesions in the head and 8 in the tail of the pancreas. The positive and negative predictive values for pancreatic cancer were 91% and 64%, respectively. PET/CT detected additional distant metastases in 5 and synchronous rectal cancer in 2 patients. PET/CT findings changed the management in 16% of patients with pancreatic cancer deemed resectable after routine staging (P = 0.031) and was cost saving. Conclusions:PET/CT represents an important staging procedure prior to pancreatic resection for cancer, since it significantly improvespatient selection and is cost-effective.

Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced Head and Neck Cancers Treated With Hyperfractionated Radiotherapy

PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone. PATIENTS AND METHODS From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity. RESULTS There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease-free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups. CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.

Distinct Clinical and Prognostic Features of Infiltrating Lobular Carcinoma of the Breast: Combined Results of 15 International Breast Cancer Study Group Clinical Trials

PURPOSE To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local treatment, and patterns of recurrence. PATIENTS AND METHODS Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types. RESULTS Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)-positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01). CONCLUSION ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.

The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate

PurposeGastrointestinal stromal tumours (GIST) are mesenchymal neoplasms of the gastrointestinal tract that are unresponsive to standard sarcoma chemotherapy. Imaging of GIST patients is done with structural and functional methods such as contrast-enhanced helical computed tomography (ceCT) and positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG). The aim of this study was to compare the prognostic power of PET and ceCT and to evaluate the clinical role of PET/CT imaging.MethodsAll patients with GIST undergoing PET or PET/CT examinations were prospectively included in this study, and the median overall survival, time to progression and treatment duration were documented. The prognostic significance of PET and ceCT criteria of treatment response was assessed and PET/CT was compared with PET and ceCT imaging. Data for 34 patients (19 male, 15 female, 21–76 years) undergoing PET or PET/CT for staging or restaging were analysed.ResultsIn 28 patients, PET/CT and ceCT were available after introduction of treatment with the tyrosine kinase inhibitor imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). Patients without FDG uptake after the start of treatment had a better prognosis than patients with residual activity. In contrast, ceCT criteria provided insufficient prognostic power. However, more lesions were found on ceCT images than on PET images, and FDG uptake was sometimes very variable. PET/CT delineated active lesions better than did the combination of PET and ceCT imaging.ConclusionBoth PET and PET/CT provide important prognostic information and have an impact on clinical decision-making in GIST patients. PET/CT precisely delineates lesions and thus allows for the correct planning of surgical interventions.

Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial

Objective:To evaluate the morbidity of pancreaticoduodenectomy after neoadjuvant chemotherapy for resectable pancreatic cancer and to assess its histologic and metabolic response. Background:Adjuvant chemotherapy improves the outcome of pancreatic cancer, but 25% of patients remain unfit after surgery. Neoadjuvant chemotherapy can be offered to all patients in a multimodality approach, but its efficacy and surgical morbidity are unknown. Methods:Patients with resectable, cytologically proven adenocarcinoma of the pancreatic head received 4 bi-weekly cycles of gemcitabine (1000 mg/m2) and cisplatin (50 mg/m2) in this prospective phase II trial. Staging and restaging included chest x-ray, abdominal computed tomography (CT), positron emission tomography (PET)/CT, endoscopic ultrasound, and laparoscopy. Fluorodeoxyglucose uptake was quantified by the standard-uptake value (SUV) on baseline and restaging PET/CT. Immunohistochemistry for GLUT-1 and Ki-67 was performed. The histologic response, cytopathic effects, and surgical complications were graded by respective scores. Results:Twenty-four of 28 patients had resection for histologically confirmed adenocarcinoma. The surgical morbidity was low without perioperative death and one pancreatic fistula. Histologic response was documented in 54% and cytopathic effects in 83% of the patients. A significant SUV decrease occurred during chemotherapy (P = 0.031), which correlated with the baseline SUV (P = 0.001), Ki-67 expression (P = 0.016), and histologic response (P = 0.01). Neither the metabolic nor the histologic response was predictive of the median disease-free (9.2 months) or overall survival (26.5 months). Conclusion:Neoadjuvant chemotherapy induced a significant metabolic and histologic response, which was best predicted by PET. Most importantly, surgery after neoadjuvant chemotherapy for pancreatic cancer was safe.

Cediranib Plus FOLFOX/CAPOX Versus Placebo Plus FOLFOX/CAPOX in Patients With Previously Untreated Metastatic Colorectal Cancer: A Randomized, Double-Blind, Phase III Study (HORIZON II)

PURPOSE Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points. RESULTS In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSION Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.

Prospective Phase II Trial of Neoadjuvant Chemotherapy With Gemcitabine and Cisplatin for Resectable Adenocarcinoma of the Pancreatic Head

PURPOSE To test the safety of neoadjuvant chemotherapy for resectable pancreatic cancer. PATIENTS AND METHODS Patients with cytologically proven resectable adenocarcinoma of the pancreatic head were eligible for this prospective phase II trial. After confirmation of resectability by contrast-enhanced computed tomography (ceCT), positron emission tomography/CT, laparoscopy, and endoscopic ultrasound, patients received four biweekly cycles of gemcitabine 1,000 mg/m(2) and cisplatin 50 mg/m(2). Thereafter, staging was repeated and patients underwent surgery. Quality of life (QoL) and prealbumin serum levels were determined pre- and postchemotherapy. Follow-up included 3-month CA 19-9 measurements and ceCT after 6, 12, 18, and 24 months. Histologic tumor response was assessed by two scoring systems. RESULTS Twenty-eight patients entered this study. Adverse effects were mainly gastrointestinal and hematologic, most often mild, and never of grade 4. Twenty-six patients (93%) had resectable cancer on restaging examinations, and the R0 resection rate was 80%. Histologic tumor response and cytopathic effects were documented in 54% and 83% of patients, respectively. On intention-to-treat analysis, disease-free and overall survival were 9.2 months (95% CI, 5.6 to 12.9 months) and 26.5 months (95% CI, 11.4 to 41.5 months) and 9 months (95% CI, 6.99 to 10.1 months) and 19.1 months (95% CI, 15 to 23.1 months) for ductal adenocarcinoma, respectively. QoL improved in two items and was unchanged in all other items. Moreover, prealbumin serum levels significantly improved during chemotherapy (P = .008). CONCLUSION Neoadjuvant chemotherapy with gemcitabine and cisplatin is well tolerated and does not impair resectability of pancreatic cancer. Furthermore, it improves the QoL and the nutritional status of affected patients with favorable overall and disease-free survival.

Contrast-Enhanced 18F-FDG PET/CT: 1-Stop-Shop Imaging for Assessing the Resectability of Pancreatic Cancer

Patients with pancreatic cancer continue to have a poor prognosis, with a 5-y survival rate of less than 5%. Surgery is the only treatment that offers a potential cure. Determining resectability is the principal goal of staging in pancreatic cancer patients. Our objective was to evaluate the value of combined contrast-enhanced 18F-FDG PET/CT in assessing the resectability of pancreatic cancer and to compare enhanced PET/CT with the performance of PET alone and unenhanced PET/CT. Methods: Fifty patients (25 women and 25 men; mean age, 64.3 y; range, 39–84 y) with biopsy-proven pancreatic adenocarcinoma underwent enhanced 18F-FDG PET/CT for the evaluation of resectability. Criteria for unresectability were distant metastases, peritoneal carcinomatosis, arterial infiltration, or invasion of neighboring organs other than the duodenum. The performance of enhanced PET/CT regarding resectability was compared with that of PET alone and unenhanced PET/CT. Histology, intraoperative findings, and follow-up CT with clinical investigations were used as the reference standard. Results: According to the reference standard, 27 patients had disease that was not resectable because of distant metastases (n = 17), peritoneal carcinomatosis (n = 5), or local infiltration (n = 5). In the assessment of resectability, PET alone had a sensitivity of 100%, specificity of 44%, accuracy of 70%, positive predictive value of 61%, and negative predictive value of 100%; unenhanced PET/CT had respective values of 100%, 56%, 76%, 66%, and 100%; and enhanced PET/CT, 96%, 82%, 88%, 82%, and 96%. In 5 patients, unresectability was missed by all imaging methods and was diagnosed intraoperatively. Enhanced PET/CT was significantly superior to PET alone (P = 0.035), and there was a trend for enhanced PET/CT to be superior to unenhanced PET/CT (P = 0.070). Conclusion: The use of enhanced PET/CT as a 1-stop-shop imaging protocol for assessing the resectability of pancreatic cancer is feasible and accurate. Enhanced PET/CT is significantly superior to PET alone.

Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its value as a serum marker in hepatocellular carcinomas.

Hepatocellular carcinomas (HCCs) and bile duct carcinomas (BDCs) have a poor prognosis. Therefore, surveillance strategies including sensitive and specific serum markers for early detection are needed. Recently, Golgi Phosphoprotein 2 (GOLPH2) has been proposed as a serum marker for HCC, but GOLPH2 expression data in liver tissues was not available. Using tissue microarrays and immunohistochemistry, we semiquantitatively analyzed GOLPH2 protein expression in patients with HCC (n = 170), benign liver tumors (n = 22), BDC (n = 114) and normal liver tissue (n = 105). A newly designed sandwich enzyme‐linked immunoassay (ELISA) was used to analyze GOLPH2 levels in the sera of patients with HCC (n = 62), hepatitis C virus (HCV) (n = 29), BDC (n = 10), and healthy control persons (n = 12). By immunohistochemistry 121/170 (71%) of HCC showed strong GOLPH2 expression, which was significantly associated with a higher tumor grade (P = 0.01). A total of 97/114 (85%) BDCs showed a strong GOLPH2 expression which proved to be an independent prognostic factor for overall survival (P < 0.05). Serum levels of GOLPH2 measured by ELISA were significantly elevated in patients with HCC with underlying HCV infection (median 18 mg/L, P < 0.05) and patients with BDC (median = 14.5 mg/L, P < 0.01) in comparison to healthy controls (median 4 mg/L). Conclusion: GOLPH2 protein is highly expressed in tissues of HCC and BDC. GOLPH2 protein levels are detectable and quantifiable in sera by ELISA. In patients with hepatitis C, serial ELISA measurements in the course of the disease appear to be a promising complementary serum marker in the surveillance of HCC. GOLPH2 should be further evaluated as a serum tumor marker in BDC on a larger scale. (HEPATOLOGY 2009.)