Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial.

BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).

Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer.

BACKGROUND: This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC). METHODS: Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m(-2), folinic acid 400 mg m(-2), and 5-fluorouracil (400 mg m(-2) bolus then 2400 mg m(-2) over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate. RESULTS: Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8-77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0-16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0-30.0) and 10.0 months (7.0-12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0-NA); median PFS 12.0 (8.0-20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0-37.0); median PFS 7.0 (4.0-18.0)). The most common grade ⩾3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%). CONCLUSION: First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted.

Adenocarcinoma arising in gastric heterotopic pancreas. Case report and review of the literature.

A sixty years-old patient was admitted with a gastric tumor corresponding to an adenocarcinoma developed in ectopic pancreatic tissue. Hundred cases of gastric heterotopic pancreas are shown in literature. This entity may remain asymptomatic. Symptoms such abdominal pain are described as the result of tumour growth. Carcinogenesis of ectopic pancreas (EPa) is however rare. Diagnosis is rarely pre-operative because modern imaging depicts a gastric tumour with no more information. The only treatment is surgery, with a best interest in frozen sections to direct the procedure, in this case a total gastrectomy with D2 lymphadenectomy. Based on this case report, an analysis of the literature focusing on diagnosis and treatment is presented.

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology.

BACKGROUND: Cholangiocarcinomas are uncommon tumours with a poor prognosis, that frequently present epidermal growth factor receptor overexpression. METHODS: In a multi-centre phase II trial, patients with unresectable cholangiocarcinoma, naïve to chemotherapy, received Cetuximab (400 mg/m(2) at week 1, then 250 mg/m(2)/week) and Gemcitabine (1 g/m(2) on day 1, 8 and 15 every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Moreover, we assessed the impact of KRAS status and skin toxic effect on efficacy. RESULTS: Forty-four patients (41% locally advanced/59% metastatic) were enrolled. Median age was 61.5 years; ECOG PS was 0 (68%) or 1. Six months PFS reached 47%. Median OS was 13.5 months [95% confidence interval (CI) 9.8-31.8 months]. Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were haematological (52.2%), skin rash (13.6%) and fatigue (11.4%). KRAS mutations were found in 7 of 27 patients and had no influence on PFS. Skin toxic effect ≥grade 2 was associated with increased PFS (P = 0.05). CONCLUSION(S): Our study met its primary end point, suggesting that Gemcitabine-Cetuximab has activity in cholangiocarcinoma. KRAS status was not associated with PFS, unlike skin toxic effect, which could be used as a surrogate marker for efficacy. ClinicalTrials.gov Identifier: NCT00747097.

Splenic metastasis from gastrointestinal neoplasms: a review.

Spleen metastases from solid tumours are rather exceptional, especially for those located in the digestive tract. Although these lesions are usually associated with multivisceral disease at terminal stage, several cases of isolated lesions have also been described in the literature. Diagnosis of spleen lesions associated with multivisceral disease rarely influences patient's outcome. On the other hand, isolated, only-splenic lesions could be curatively treated, allowing physicians to obtain better patient's survival. The aim of this article is therefore to review and summarize a systematic search of all the literature in English based on a Medline search (Pubmed) carried out from January 2000 to February 2011, focusing on only-spleen lesions secondary to digestive tract cancers, and pointing out diagnostic and treatment challenges medical oncologists have to face in their clinical practice.

Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.

BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.

Feasibility of percutaneous radiofrequency ablation for pulmonary malignancies in the hands of the surgeon.

AIM: To assess the feasibility of percutaneous pulmonary radiofrequency ablation (RFA) executed by a single surgeon. MATERIALS AND METHODS: Between 2007 and 2010, 15 procedures were performed in 11 patients during 13 sessions. Sex, age, pulmonary localisation and tumor diameter are discussed. Metastatic lesions as well as pulmonary primitive malignancies were treated. For metastatic lesions, the primitive tumor was considered as completely treated. Surgery was refused because of impaired pulmonary function or due to patient's refusal. All interventions were carried out by a single thoracic surgeon under CT-guidance in the department of radiology. RESULTS: RFA was completed in all patients without perprocedural complications. There was no significant perioperative morbidity. Pneumothorax was the most frequent complication but none of the patients needed thoracic drainage. Hospital stay decreased progressively since the start of this series. Follow-up was complete. Most lesions were stable or diminishing in size. CONCLUSION: These early results show that pulmonary RFA is a safe and feasible technique in the hands of the surgeon. Longer follow-up and larger series will be welcome to confirm the results and position of this procedure which might become an important tool for the surgeon and not only for radiologists.

Diagnostic pitfalls in digestive neuroendocrine tumours.

Gastro-entero-pancreatic neuroendocrine tumours (GEP NET) represent a rare and highly heterogeneous entity that often is revealed by vague and non-specific symptoms, leading to a delayed diagnosis. Here we will review some of the most regularly observed false positive and false negative cases and provide clues to recognize and manage them properly. Particularly, the value of chromogranin-A as a serum tumour marker and Somatostatin receptor scintigraphy as an imaging test, are reviewed. Indeed, chromogranin-A and other hormones, such as gastrin, as well as urinary 5-hydroxy-indolic acetic acid (5-HIAA) are often tested to diagnose NET without appraising the clinical situation, leading to extensive work-up on false bases. On the other hand, some tests are performed in situations where they do not add additional information (e.g. 5-HIAA in pancreatic or rectal NET) because invariably negative. Somatostatin receptor scintigraphy is an expensive examination, still not reimbursed in Belgium, for which indications must be carefully assessed, knowing its specificity and sensitivity.

Carcinoid heart disease--a hidden complication of neuroendocrine tumours.

Carcinoid heart disease (CHD) develops in serotonin-producing neuroendocrine tumours (NET) due to fibrotic endocardial plaques with associated valve dysfunction leading most often to right-sided heart failure. The classical carcinoid syndrome usually occurs when serotonin-producing NET metastasize to the liver. Up to 50% of those patients will exhibit carcinoid heart disease. The pathophysiological process is not yet completely understood: serotonin is considered to be a major initiator of the fibrotic process, but other tumour secreted factors may contribute to the pathogenesis. Histopathology reveals intact valvular cusps with superimposed fibrotic plaques, leading to thickening and retraction of the valves, causing valvular dysfunction. A high index of clinical suspicion to diagnose CHD is needed since symptoms can be rather non-specific. Transthoracic echocardiography is the gold standard for diagnosis and should probably be performed at the time of diagnosing serotonin-producing NET and then repeated annually. On the other hand, when diagnosing right-heart failure, the presence of CHD and underlying serotonin-producing NET should be taken into account. Therapeutic options include pharmacotherapy for heart failure, control of the systemic carcinoid disease and in selected individuals cardiac valve replacement. The elucidation of the pathologic process is necessary to develop targeted antifibrotic therapeutic agents since CHD seems to be irreversible and associated with poor prognosis.

Locoregional and radioisotopic targeted treatment of neuroendocrine tumours.

Gastro-entero-pancreatic neuroendocrine tumours (GEP NET) are a heterogeneous group of proliferative disorders whose management dramatically relies on tumour biology. For well-differentiated, low-proliferative index tumours, locoregional treatment and targeted radioisotopic therapies offer an attractive and seemingly efficient alternative to palliative surgical resections. Lack of well-designed, prospective, randomized multicentric studies hinders a balanced evaluation of available locoregional treatment methods: embolization, chemo-embolization, radio-embolization. According to available datas, all techniques achieve a 50-60% radiological response rate and almost 80% of symptomatic relieve for the patients, while their impact on progression-free and overall survival remains not assessable. Same conclusions can be drawn for radiolabeled targeted therapies like MetaiodoBenzylGuanidine (MIBG) and Peptide Receptor Radionuclide Therapy (PRRT), which, provided that their target is expressed by tumour cells, can deliver therapeutic doses of radiation to neoplastic tissues. 131I-MIBG has been associated with a 50% symptomatic response rate and mainly haematological toxicities. PRRT with 111In-DiethyleneTriamineentaacetic Acid-Octreotide, [90Y-DOTA0-Tyr3]-Octreotide, or [177Lu-DOTA0-Tyr3]-Octreotate seem to alleviate symptoms in 50% of patients and obtain a radiological response in 30-38%. Renal toxicity, partially preventable, is more frequent than previously thought and result in an annual decrease in glomerular function by 4 to 8% per year. Forthcoming research in GEP NET should by a majority be designed in randomized, prospective and multicentric fashion. Locoregional disease trials must focus on clinical outcome differences between embolization techniques (embolization, chemoembolization and radioembolization) and surgery. In disseminated disease, studies should assess radiolabeled targeted therapies efficiency when administered along with and compared to new biological and older chemotherapeutic agents.

The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours.

Somatostatin analogs (SSAs) have an important role in the management of patients with neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP NETs). These compounds can control the symptoms induced by the production of hormones and peptides. The antiproliferative effects of SSAs and especially tumour shrinkage are less obvious in patients with GEP NETs than in those with acromegaly. However, based upon phase II experience there is a strong suggestion of a disease stabilizing effect of SSAs in selected patients. Those patients with a progressive, non-functional GEP NET, positive octreotide scintigraphy, a low proliferation index and in the absence of surgical options may benefit from a first-line medical therapy with SSAs. The exploration of the mechanisms of this effect are unclear and hampered by the lack of suitable preclinical models. The better understanding of the tumour biology of GEP NETs, together with the development of new SSAs with better affinity on all somatostatin receptors, represent an unmet medical need.

The potential role of targeted therapies in the management of neuroendocrine tumours.

The management of gastro-entero-pancreatic neuroendocrine tumours is evolving thanks to new TNM-classification, diagnostic and staging procedures and new therapeutic options. Targeting new pathways, mostly angiogenesis, development of novel agents is under way and opens new perspectives in controlling the evolution of these tumours and possibly changing their management. In parallel, new functional imaging techniques and biomolecular markers will be developed to provide adequate tools for the assessment of tumor response according to therapeutic intervention on angiogenesis, proliferation and apoptosis. This paper reviews the potential role of new investigational targeted agents which will likely become the backbone of future therapy of neuroendocrine tumors.

Role of chemotherapy in gastro-entero-pancreatic neuroendocrine tumors: the end of a story?

Gastroenteropancreatic Neuroendocrine Tumours (GEP NET) are heterogeneous and rare malignancies although their prevalence is increasing. Multiple therapeutic approaches are available to date for their management, including surgery, hormonal and immune radionucleide therapies and chemotherapy. The purpose of this review is to collect, examine, and analyze data available regarding contemporary chemotherapeutic management of GEP NET in order to determine whether or not chemotherapy still takes place in the therapeutic arsenal of GEP NET. We therefore performed a systematic search of all the English-spoken literature regarding GEP NET. Anthracyclins, 5-fluorouracil (5-FU), DTIC and streptozotocin are amongst the most commonly used chemotherapeutic agents, usually prescribed in combination. Their efficiency in reducing tumor burden is not always associated with better survival, perhaps due to severe toxicity. Chemotherapy in GEP NET is mainly devoted to poorly differentiated tumours, but also in well differentiated carcinomas either not eligible or resistant to other therapies. Chemotherapy remains therefore useful in specific cases of GEP NET management. However, a new era of antitumoral agents, such as targeted therapies, could eventually replace these old recipes in the near future.

The role of surgery and transplantation in neuroendocrine tumours.

Surgery represents the only chance of cure for a patient with a neuroendocrine tumour (NET). The main indications for surgery lie in the risk of developing metastatic disease with increasing tumour diameter and for a functioning NET also in control of the hormonal syndrome. However, only a small minority of patients presents with a potentially resectable primary NET without metastatic disease. An R0-resection is mandatory, which may be achieved in selected cases by tissue sparing surgical techniques. Most patients unfortunately present with a locally advanced or metastatic disease. For patients with an advanced functioning NET, control of the hormonal syndrome may also represent a surgical indication. Various cytoreductive techniques or, in highly selected cases, liver transplantation can be applied. For locally advanced non-functioning tumours, there is an indication for surgery in large tumours which tend to create local complications because of bleeding or bowel obstruction. Especially in ileal NETs aggressive surgical therapy is recommended because of prevention of long-term complications, which may improve survival.

Upper gastrointestinal bleeding: what has changed during the last 20 years?

AIM OF THE STUDY: The purpose of this study was to assess the clinical, epidemiological, therapeutic and prognostic changes observed in patients with upper gastrointestinal bleeding (UGIB) during the last two decades. METHODS: Two cohorts of 200 patients with UGIB consecutively recruited during the period 1984-1987 (cohort A) then during the period 2004-2006 (cohort B) were compared. RESULTS: Median age was 61.5 years in the cohort A and 67 years in the cohort B. The main etiologies remained variceal bleeding and peptic ulcer, but esophagitis and Mallory-Weiss syndrome were more frequently observed recently. The intake of gastrotoxic drugs did not decreased despite the widely acknowledged harmful effects of these drugs. Regarding management practices, a therapeutic intervention during the first endoscopy was performed in 36% of the cases in the cohort B but only in 2% of the cases 20 years ago. The frequency and the volume of blood transfusion dramatically decreased during the last two decades. Regarding the outcome, the requirement for surgery and the rate of recurrent bleeding decreased by half, but mortality remained unchanged. CONCLUSION: The main changes observed in patients admitted for UGIB 20 years apart concerned epidemiological features, treatment and prognosis.

Colorectal cancer (CRC) screening using sigmoidoscopy followed by colonoscopy: a feasibility and efficacy study on a cancer institute based population.

BACKGROUND: Advanced distal neoplasia found at sigmoidoscopy could be the marker for more proximal lesions. PATIENTS AND METHODS: In the setting of a screening clinic, subjects underwent flexible sigmoidoscopy. If no significant lesion was found, sigmoidoscopy was planned after 5 years. If an advanced neoplasia was found, colonoscopy was performed just after the first sigmoidoscopy and at 1, 3 and 5 years. If a non-advanced neoplasia was found, sigmoidoscopy was performed at 1, 3 and 5 years and followed by colonoscopy if advanced lesion was found. RESULTS: At first screening 1704/1912 (88%) subjects had a negative sigmoidoscopy, 104 (5.4%) had an advanced neoplasia, 96 (6%) had a non-advanced neoplasia and eight (0.4%) had invasive colorectal cancer (CRC). At follow-up examinations at 1, 3 and 5 years, among 170 subjects with advanced and non-advanced neoplasia, one developed invasive CRC and 47 (31.6%), advanced neoplasia. At 5 years, among 718 first negative sigmoidoscopies, 572 (80%) were confirmed negative and 97 (14%) had advanced neoplasia. Colorectal cancer status at 5 years could be checked for interval cancers in 97% of subjects and no CRC was diagnosed in subjects who did not attend sigmoidoscopy at 5 years. Comparison of the incidence of invasive CRC to the data of registries of the Netherlands and Luxembourg suggested that the incidence of CRC was decreased by 36%-46%. Seven of the nine CRCs were Duke's A and the two others were Duke's B and C. CONCLUSIONS: Screening with sigmoidoscopy followed by colonoscopy in case of positive sigmoidoscopy leads to substantial decreases in the incidence of CRC. Most CRCs found are at an early, curable stage of their development.

[Treatment of peritoneal carcinomatosis from colorectal and appendiceal cancer by extensive cytoreductive surgery combined with hyperthermic intraoperative intraperitoneal chemotherapy]. / Traitement a visée curative des carcinoses péritonéales d'origine colorectale et appendiculaire par chirurgie maximaliste et chimiothérapie hyperthermique intrapéritonéale peropératoire.

Peritoneal carcinomatosis (PC) from colorectal cancer is a dreadful situation characterized by a rapid and mortal evolution (median survival of 5 to 7 months amongst the series published in the literature). The classical treatment includes systemic chemotherapy whether or not associated with palliative surgery. Since the early nineties, locoregional treatments combining extensive cytoreductive surgery with intraperitoneal hyperthermic chemotherapy have been developed, affording some patients a cure and yealding a 5-year survival as high as 30 to 40% in some series. However, it is associated with high morbidity and mortality rates.

Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741.

BACKGROUND: Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. PATIENTS AND METHODS: Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n = 264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n = 267) and (G) oxaliplatin/irinotecan (IROX, n = 265) were reviewed. TTP and median OS were calculated. RESULTS: Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free. CONCLUSIONS: Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.

Treatment of advanced digestive non-colon cancer with a weekly 24-h infusion of high-dose 5-fluorouracil modulated by folinic acid and cisplatin: an easy-to-use and well-tolerated combination.

The combination of 5-fluorouracil (5-FU) modulated by folinic acid (FA) and cisplatin is commonly used in advanced digestive non-colon cancers (ADNCC). In order to simplify treatment administration by avoiding cisplatin-related hydration, we investigated a weekly regimen of 5-FU/FA/cisplatin. Patients with ADNCC were treated with 5-FU 2.0 g/m2, FA 500 mg/m2 and cisplatin 25 mg/m2 day 1, for 6 weeks with a 2-week rest, and were assessed for toxicity, tumor response and disease-free survival. Forty-three patients with measurable ADNCC were treated with this weekly regimen. Primary tumor sites were mainly esophagus (n = 17), stomach (n = 12) and pancreas (n = 9). Results were as follows. Toxicity was mostly hematological, with 16% grade 3/4 neutropenia (seven of 43) and 4% febrile neutropenia (two of 43). Objective response (OR) was observed in 19 of 43 (44%) patients including four complete responses (9%) and 15 partial responses (35%). Another 18 patients (42%) experienced stable disease. Time to progression was 6.5 months. The median response and stable disease durations were 4.3 (range 3-34) and 5 (range 2-16) months, respectively. We conclude that weekly administration of 5-FU/FA/cisplatin is an active and well-tolerated regimen. Toxicity is manageable and allows chemotherapy on an outpatient basis without hydration program as required when cisplatin is used at the dose of 50 mg/m2.