E. Van Cutsem

Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer

PURPOSE To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

Utility of Positron Emission Tomography for the Staging of Patients With Potentially Operable Esophageal Carcinoma

PURPOSE A prospective study of preoperative tumor-node-metastasis staging of patients with esophageal cancer (EC) was designed to compare the accuracy of 18-F-fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET) with conventional noninvasive modalities. PATIENTS AND METHODS Seventy-four patients with carcinomas of the esophagus (n = 43) or gastroesophageal junction (n = 31) were studied. All patients underwent attenuation-corrected FDG-PET imaging, a spiral computed tomography (CT) scan, and an endoscopic ultrasound (EUS). RESULTS FDG-PET demonstrated increased activity in the primary tumor in 70 of 74 patients (sensitivity: 95%). False-negative PET images were found in four patients with T1 lesions. Thirty-four patients (46%) had stage IV disease. FDG-PET had a higher accuracy for diagnosing stage IV disease compared with the combination of CT and EUS (82% v 64%, respectively; P: =.004). FDG-PET had additional diagnostic value in 16 (22%) of 74 patients by upstaging 11 (15%) and downstaging five (7%) patients. Thirty-nine (53%) of the 74 patients underwent a 2- or 3-field lymphadenectomy in conjunction with primary curative esophagectomy. In these patients, tumoral involvement was found in 21 local and 35 regional or distant lymph nodes (LN). For local LN, the sensitivity of FDG-PET was lower than EUS (33% v 81%, respectively; P: =.027), but the specificity may have been higher (89% v 67%, respectively; P: = not significant [NS]). For the assessment of regional and distant LN involvement, compared with the combined use of CT and EUS, FDG-PET had a higher specificity (90% v 98%, respectively; P: =. 025) and a similar sensitivity (46% v 43%, respectively; P: = NS). CONCLUSION PET significantly improves the detection of stage IV disease in EC compared with the conventional staging modalities. PET improves diagnostic specificity for LN staging.

Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study

BACKGROUND Bevacizumab significantly improves survival when added to chemotherapy for metastatic colorectal cancer (mCRC). The Bevacizumab Expanded Access Trial (BEAT) evaluated the safety and efficacy of bevacizumab plus first-line chemotherapy in a general cohort of patients with mCRC. PATIENTS AND METHODS Patients with unresectable mCRC received chemotherapy (physicians choice) plus bevacizumab [5 mg/kg every 2 weeks (5-fluorouracil regimens) or 7.5 mg/kg every 3 weeks (capecitabine regimens)]. The primary end point was safety, including prospective data collection in patients receiving unanticipated surgery during the study. Secondary objectives were progression-free survival (PFS) and overall survival (OS). RESULTS The final analysis comprised 1914 assessable patients (male 58%; median age 59 years). Chemotherapy included 5-fluorouracil/leucovorin (5-FU/LV) + oxaliplatin (29%), irinotecan plus 5-FU/LV (26%), capecitabine plus oxaliplatin (18%) and monotherapy (16%). Serious/grade 3-5 adverse events of interest for bevacizumab included bleeding (3%), gastrointestinal perforation (2%), arterial thromboembolism (1%), hypertension (5.3%), proteinuria (1%) and wound-healing complications (1%). Sixty-day mortality was 3%. Median PFS was 10.8 months [95% confidence interval (CI) 10.4-11.3 months] and median OS reached 22.7 months (95% CI 21.7-23.8 months). CONCLUSIONS The BEAT study shows that the efficacy and safety profile of bevacizumab in routine clinical practice is consistent with results observed in prospective randomised clinical trials and another large observational study in the United States (BRiTE study).

Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

E. Van Cutsem1, A. Cervantes2, B. Nordlinger3 & D. Arnold4, on behalf of the ESMO Guidelines Working Group* Digestive Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Department of General Surgery and Surgical Oncology, Hopital Ambroise Pare, Assistance Publique – Hopitaux de Paris, Paris, France; Klinik fur Tumorbiologie, Freiburg, Germany

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m−2 twice daily, days 1−14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885–1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84–1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.

Phase III Study of Weekly High-Dose Infusional Fluorouracil Plus Folinic Acid With or Without Irinotecan in Patients With Metastatic Colorectal Cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986

PURPOSE To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel

The past 5 years have seen the clear recognition that the administration of chemotherapy to patients with initially unresectable colorectal liver metastases can increase the number of patients who can undergo potentially curative secondary liver resection. Coupled with this, recent data have emerged that show that perioperative chemotherapy confers a disease-free survival advantage over surgery alone in colorectal cancer (CRC) patients with initially resectable liver disease. The purpose of this paper is to build on the existing knowledge and review the issues surrounding the use of chemotherapy +/- targeted agents combined with surgery in the treatment of CRC patients with liver metastases, with a view to providing clinical recommendations. An international panel of 21 experts in colorectal oncology comprising liver surgeons and medical oncologists reviewed the available evidence. In a major change to clinical practice, the panels recommendation was that the majority of patients with CRC liver metastases should be treated up front with chemotherapy, irrespective of the initial resectability status of their metastases.

Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment

Clinical or biochemical suspicion of metastatic disease should always be confirmed by adequate radiological imaging [usually a computed tomography (CT) scan or alternatively magnetic resonance imaging (MRI) or ultrasonography]. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan can be useful in determining the malignant characteristics of tumoral lesions, especially when combined with CT scan. FDGPET scan is especially useful to characterize the extent of metastatic disease when the metastases are potentially resectable. Histology of the primary tumour or metastases is always needed before chemotherapy is started. For metachronous metastases histopathological or cytological confirmation of metastases should be obtained, if the clinical or radiological presentation is atypical or very late after the initial diagnosis of the primary tumour. Resectable metastases do not need histological or cytological confirmation before resection because of a low chance of seeding. Evaluation of the general condition, organ function and concomitant non-malignant diseases determines the therapeutic strategy for patients with metastatic CRC. determination of the treatment strategy

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first‐line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium‐177 (177Lu)–Dotatate in patients with advanced, progressive, somatostatin‐receptor–positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well‐differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu‐Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long‐acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu‐Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression‐free survival. Secondary end points included the objective response rate, overall survival, safety, and the side‐effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data‐cutoff date for the primary analysis, the estimated rate of progression‐free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu‐Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu‐Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu‐Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu‐Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu‐Dotatate resulted in markedly longer progression‐free survival and a significantly higher response rate than high‐dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu‐Dotatate group. (Funded by Advanced Accelerator Applications; NETTER‐1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011‐005049‐11.)