[Show abstract][Hide abstract] ABSTRACT: Background:
The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab.
In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609.
Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group).
Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.
RochePharma AG and AIO Studien gGmbH.
The Lancet Oncology 09/2015; DOI:10.1016/S1470-2045(15)00042-X · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Complete mesocolic excision (CME) and central vascular ligation (CVL) for right-sided colon cancer may be superior to standard hemicolectomy in terms of oncological results. This hypothesis is currently being investigated in a large multicentre trial conducted by the authors of this paper (Resektatstudie). Because CVL in right-sided hemicolectomy is technically rather demanding the incidence of central node involvement is of special interest. Therefore, during the single centre pilot phase of our multicentre trial we have analysed the incidence of central lymph node metastasis in CME specimens.
In 51 patients with right-sided colon adenocarcinoma (cT1-3, cM0) an open CME with CVL was performed. In the fresh specimen the central four centimetres of the ileocolic vessels that would have been presumably left in place during a standard hemicolectomy were marked with a suture. The lymph nodes in this segment were separately analysed.
In the CME specimen the mean lymph node count was 52.6 (range: 27-171). 35.0 % (range: 13.1-65.6 %) of the nodes were located in the central 4 cm segment. The proportion of patients with positive nodes was 25.5 % (13/51). Of all nodes 1.97 % (53/2686) were metastatic. In 3/51 (5.8 %) patients the central nodes were involved. In one patient the central nodes were the only metastatic site. UICC stage was influenced in two of the three patients who had central involvement (stage migration: UICC IIB to IIIB, UICC IIIB to IIIC).
CME with CVL in right-sided colon adenocarcinoma increases the probability of complete removal of the local lymph node drainage and thus local metastatic lymph nodes. Considering this result an improvement of long-term survival by the CME procedure seems conceivable but needs to be confirmed by the current multicentre trial.
[Show abstract][Hide abstract] ABSTRACT: Current evidence suggests that complete mesocolic excision (CME) for right-sided colon cancer could be beneficial in terms of long-term survival. However, CME is a considerably more complex operation than standard right hemicolectomy; this is especially true for the laparoscopic approach. Consequently, we have explored a new laparoscopic approach that provides surgical radicality at the mesenteric root on the one hand and maximum safety on the other hand.
The key feature of the uncinate process first approach (UFA) is the commencement of the dissection at the fourth part of the duodenum using a medial to lateral approach, thus mobilizing the whole mesenteric root posteriorly before the central parts of the mesenteric vessels are accessed. Twenty-eight selected patients with right-sided colon cancer underwent surgery using the UFA and were compared with 51 patients who underwent an open CME procedure (CON). In 11/28 and 51/51 patients in the UFA and CON groups, respectively, a planimetric assessment of the specimen was performed.
Surgical time was longer (144.8 vs. 202.5 min; p < 0.000) and postoperative stay shorter (8.0 vs. 10.5 days; p < 0.01) for the laparoscopic approach. The area of the resected mesentery (UFA, 15,097 mm(2); CON, 15,788 mm(2); p = 0.47) and the lymph node count (UFA, 59.0; CON, 51.0; p = 0.09) was not significantly different; additionally, no difference was observed regarding anastomotic leakage (both n = 0) and postoperative mortality (UFA, 0/28; CON, 1/51; p = 1.0).
Laparoscopic right hemicolectomy with CME using the UFA provides adequate radicality according to the CME principles and seems feasible and as safe as an open technique. However, future trails will have to demonstrate whether the theoretical advantages of the UFA, with a higher degree of mobility and accessibility of the mesenteric root, translate into a significant clinical benefit, especially relative to the other laparoscopic techniques.
[Show abstract][Hide abstract] ABSTRACT: In 2013, a 68-year-old male had a pancreaticoduodenectomy for pancreatic cancer. The pancreaticojejunostomy was sealed with cyanoacrylate (Dermabond) to prevent postoperative pancreatic fistula. Local recurrence of malignancy at the anastomosis was suspected 18 months later in PET/CT. Surgical revision was performed and anastomosis resected. However, histology showed no tumor recurrence, but strong inflammation and foreign-body reaction towards Dermabond. The sealant caused false-positive PET/CT findings, so its use in oncologic surgery should be abandoned.
Journal of Gastrointestinal Surgery 03/2015; 19(5). DOI:10.1007/s11605-015-2780-9 · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HintergrundDas Management von „kleinen Polypen“ im distalen Kolon und Rektum ist in den Fokus der Kosten-Nutzen-Analyse der Vorsorgekoloskopie geraten. So wird insbesondere im angloamerikanischen Sprachraum aktuell diskutiert, winzige (Die Amerikanische Gesellschaft für Gastroenterologische Endoskopie (ASGE) hat im Rahmen ihrer sog. Innovationsdiskussion („Preservation and Incorporation of Valuable Endoscopic Innovations [PIVI]“) diskutiert, Polypen unter 0,5 cm Durchmesser zwar zu entfernen, nicht jedoch histopathologisch zu untersuchen - um angeblich Kosten zu sparen (www. http://www.asge.org/publications/). In Computermodellrechnungen wurde ermittelt, dass durch das „Entfernen und Verwerfen“ pro Vorsorgekoloskopie 25 US-Dollar gespart werden könnten [1, 2].Nicht nur aus berufspolitischen Gründen wird die Diskussion auch in Deutschland geführt - und von einigen be ...
Der Pathologe 03/2015; 36(2). DOI:10.1007/s00292-015-0003-5 · 0.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: IgG4-associated autoimmune diseases are systemic diseases affecting multiple organs of the body. Autoimmune pancreatitis, with a prevalence of 2.2 per 100 000 people, is one such disease. Because these multi-organ diseases present in highly variable ways, they were long thought just to affect individual organ systems. This only underscores the importance of familiarity with these diseases for routine clinical practice. Methods: This review is based on pertinent articles retrieved by a selective search in PubMed, and on the published conclusions of international consensus conferences. Results: The current scientific understanding of this group of diseases is based largely on case reports and small case series; there have not been any randomized controlled trials (RCTs) to date. Any organ system can be affected, including (for example) the biliary pathways, salivary glands, kidneys, lymph nodes, thyroid gland, and blood vessels. Macroscopically, these diseases cause diffuse organ swelling and the formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with IgG4-positive plasma cells, which leads via an autoimmune mechanism to the typical histologic findings-storiform fibrosis ("storiform" = whorled, like a straw mat) and obliterative, i.e., vessel-occluding, phlebitis. A mixed Th1 and Th2 immune response seems to play an important role in pathogenesis, while the role of IgG4 antibodies, which are not pathogenic in themselves, is still unclear. Glucocorticoid treatment leads to remission in 98% of cases and is usually continued for 12 months as maintenance therapy. Most patients undergo remission even if untreated. Steroid-resistant disease can be treated with immune modulators. Conclusion: IgG4-associated autoimmune diseases are becoming more common, but adequate, systematically obtained data are now available only from certain Asian countries. Interdisciplinary collaboration is a prerequisite to proper diagnosis and treatment. Treatment algorithms and RCTs are needed to point the way to organ-specific treatment in the future.
Deutsches Ärzteblatt International 02/2015; 112(8):128-+. DOI:10.3238/arztebl.2015.0128 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Ductal adenocarcinoma of the pancreas is the fourth most common cause of death from cancer in men and women in Germany: about 15 000 persons die of this disease each year. Methods: The S3 guideline on exocrine pancreatic carcinoma was updated with the aid of systematic literature reviews on the surgical, neoadjuvant, and adjuvant treatment of ductal pancreatic carcinoma, and on treatment in the metastatic stage. These reviews covered the periods 2002 to February 2012 (for radiotherapy) and 2006 to August 2011 (for all other topics). Results: The criteria for borderline resectable pancreatic tumors are the same as those of the guidelines of the National Comprehensive Cancer Network. Preoperative biliary drainage with a stent is recommended only if cholangitis is present or if a planned operation cannot be performed soon after the diagnosis is made. When a pancreatic carcinoma is resected, at least 10 regional lymph nodes should be excised, and the ratio of affected to excised nodes should be documented in the pathology report. Gemcitabine and 5-fluorouracil are recommended for adjuvant therapy. Neither of these drugs is preferred over the other; if the one initially given is poorly tolerated, the other one should be given instead. When gemcitabine and erlotinib are given for palliative treatment, erlotinib should be given for no longer than 8 weeks if no skin rash develops. In selected patients, the folfirinox protocol yields markedly better results than gemcitabin. Moreover, the new combination of nab-paclitaxel and gemcitabine can be used as first-line treatment. In the event of disease progression under first-line treatment, second-line treatment should be initiated. Conclusion: In recent years, new chemotherapeutic protocols have brought about marked improvement in palliative care. Further trials are needed to determine whether the perioperative or adjuvant use of these protocols might also improve the outcome of surgical treatment with curative intent.
Deutsches Ärzteblatt International 01/2015; 112(4):60-60. DOI:10.3238/arztebl.2015.0060b · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity.
We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material.
Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype.
These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Gut 01/2015; DOI:10.1136/gutjnl-2014-307616 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The TNM classification is used to assess cancers of the oral cavity, and advancements in imaging techniques have revealed clear variations in tumor volume at presentation. This study therefore aimed to clarify whether preoperative imaging, with exact measurements of the tumor, could affect post-surgery survival after controlling for demographic, clinical, and tumor characteristics.
We included 437 patients with histologically confirmed, stage T1-4, N1-3, M0, invasive squamous cell carcinoma of the tongue. Participants were assessed for recurrence every 3 months for the first 2 years, every 6 months for another 2 years, and annually thereafter; routine computed tomography was performed annually. Associations were determined using the Kaplan-Meier estimator, univariate log-rank test, and Cox proportional hazards regression models.
The mean survival of all patients was 68.1 ± 48.2 months. The 2- and 5-year overall survival rates were 82.2 and 66.7 %, respectively. The mean primary tumor volume was 7.14 cm(3) with a range of 1.3-24.21 cm(3). The ROC curve and Youden Index analysis revealed that the optimal cutoff volume was between ≤5.9 and ≤18.3 cm(3) for three different volume groups (p < 0.0001). Large tumor volume was associated with a significantly poorer overall survival (p < 0.0001).
Tumor volume was significantly associated with the overall survival of patients. This has both prognostic and reconstructive implications that will affect health-related quality of life. In addition, this will inform surgical planning and the allocation of resources.
Journal of Cancer Research and Clinical Oncology 11/2014; 141(6). DOI:10.1007/s00432-014-1881-2 · 3.08 Impact Factor