Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer.

BACKGROUND: Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve cancer treatment. Nevertheless, responsiveness to these treatments is often correlated with the extent of T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor T cell infiltration and, therefore, does not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy has profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immune checkpoint inhibition was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immune checkpoint inhibition have never been tested in these tumors. METHODS: Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5 Gy × 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed three weeks after the last pembrolizumab injection. Our clinical trial includes an extensive translational research program involving the transcriptomic and proteomic analysis of tumor and blood samples throughout the course of the treatment. DISCUSSION: Our study is the first clinical trial to combine short-course radiotherapy and immune checkpoint inhibition in rectal cancer, which could potentially result in a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer insights into immunological changes within the tumor and blood and their correlation with patient outcome. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients. TRIAL REGISTRATION: This study was registered with www. CLINICALTRIAL: gov : NCT04109755 . Registration date: June, 2020.

Where Are We Now and Where Might We Be Headed in Understanding and Managing Brain Metastases in Colorectal Cancer Patients?

OPINION STATEMENT: Compared to liver and lung metastases, brain metastases (BMs) from colorectal cancer (CRC) are rare and remain poorly investigated despite the anticipated rise in their incidence. CRC patients bearing BM have a dismal prognosis with a median survival of 3-6 months, significantly lower than that of patients with BM from other primary tumors, and of those with metastatic CRC manifesting extracranially. While liver and lung metastases from CRC have more codified treatment strategies, there is no consensus regarding the treatment of BM in CRC, and their management follows the approaches of BM from other solid tumors. Therapeutic strategies are driven by the number and localisation of the lesion, consisting in local treatments such as surgery, stereotactic radiosurgery, or whole-brain radiotherapy. Novel treatment modalities are slowly finding their way into this shy unconsented armatorium including immunotherapy, monoclonal antibodies, tyrosine kinase inhibitors, or a combination of those, among others.This article reviews the pioneering strategies aiming at understanding, diagnosing, and managing this disease, and discusses future directions, challenges, and potential innovations in each of these domains. HIGHLIGHTS: • With the increasing survival in CRC, brain and other rare/late-onset metastases are rising. • Distal colon/rectal primary location, long-standing progressive lung metastases, and longer survival are risk factors for BM development in CRC. • Late diagnosis and lack of consensus treatment strategies make BM-CRC diagnosis very dismal. • Liquid biopsies using circulating tumor cells might offer excellent opportunities in the early diagnosis of BM-CRC and the search for therapeutic options. • Multi-modality treatment including surgical metastatic resection, postoperative SRS with/without WBRT, and chemotherapy is the best current treatment option. • Recent mid-sized clinical trials, case reports, and preclinical models show the potential of unconventional therapeutic approaches as monoclonal antibodies, targeted therapies, and immunotherapy. Graphical abstract.

Long-term outcome of dasatinib first-line treatment in gastrointestinal stromal tumor: A multicenter, 2-stage phase 2 trial (Swiss Group for Clinical Cancer Research 56/07).

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS: This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS: Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS: Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54. © 2018 American Cancer Society.

[VIPoma : a rare etiology of diarrhea with hypokalemia]. / VIPome : étiologie rare d'une diarrhée hypokaliémiante.

VIPoma or Verner Morrison syndrome is a very rare disease with an incidence rate of 1 case per 10 000 000 person-years. It is a neuroendocrine tumor issue from ß-pancreatic islets leading to profuse diarrhea, hypokalemia and gastric achlorydria due to secretion of vasoactive intestinal polypeptide (VIP) hormone. Diagnosis is based on histology of tumor and the dosage of VIP in a blood sample. Somatostatin analog is a simple and efficient treatment for diarrhea. Curative treatment with surgery could be proposed for a localized disease. For disseminated disease, there are different treatments and a multimodal assessment that should be discussed in a multidisciplinary team might be curative.

Le VIPome ou syndrome de Verner Morrison est une maladie très rare, avec une incidence annuelle estimée à 1/10 000 000 habitants. Il s'agit d'une tumeur neuroendocrine issue des îlots ß pancréatiques qui sécrète une hormone appelée vasoactive intestinal polypeptide (VIP), à l'origine d'une achlorhydrie gastrique et de diarrhées profuses entraînant une hypokaliémie. Le diagnostic est posé à partir d'une analyse anatomopathologique de la tumeur et du dosage du VIP sanguin. Le traitement symptomatique par les analogues de la somatostatine est efficace sur la diarrhée. Un traitement curatif par la chirurgie peut être proposé pour une maladie tumorale localisée. Pour les maladies disséminées, différentes modalités thérapeutiques existent et dans certains cas une approche multimodale discutée dans un colloque spécialisé peut être curative.

Reversibility of chemotherapy-related liver injury.

BACKGROUND & AIMS: Chemotherapy-associated liver injury (CALI) increases the risk of liver resection and may prejudice further surgery and chemotherapy. The reversibility of CALI is therefore important; however, no data concerning this are available. This study aimed to retrospectively analyze the reversibility of CALI in patients undergoing liver resection for colorectal metastases. METHODS: All resections of colorectal liver metastases after oxaliplatin and/or irinotecan-based chemotherapy were included. First, liver resections were stratified by time between end of chemotherapy and hepatectomy and several possible cut-off values tested. CALI prevalence in various groups was compared. Second, CALI in the two specimens from each patient who had undergone repeat liver resections without interval chemotherapy were compared. RESULTS: Overall, 524 liver resections in 429 patients were analyzed. The median interval chemotherapy-surgery was 56days (15-1264). CALI prevalence did not differ significantly between groups with a chemotherapy-surgery interval <270days. Grade 2-3 sinusoidal dilatation (SOS, 19.4% vs. 40.0%, p=0.022) and nodular regenerative hyperplasia (NRH, 6.5% vs. 20.1%, p=0.063) occurred less frequently in patients with an interval >270days (n=31); prevalence of steatosis and steatohepatitis was similar in all groups. A chemotherapy-surgery interval >270days was an independent protector against Grade 2-3 SOS (p=0.009). Forty-seven patients had repeat liver resection without interval chemotherapy. CALI differed between surgeries only for a chemotherapy-surgery interval >270days (n=15), Grade 2-3 SOS having regressed in 4/5 patients and NRH in 7/8; whereas steatosis and steatohepatitis had persisted. CONCLUSIONS: CALI persists for a long time after chemotherapy. SOS and NRH regress only after nine months without chemotherapy, whereas steatosis and steatohepatitis persist. LAY SUMMARY: The patients affected by colorectal liver metastases often receive chemotherapy before liver resection, but chemotherapy causes liver injuries that may increase operative risks and reduce tolerance to further chemotherapy. The authors analyzed the reversibility of the liver injuries after the chemotherapy interruption. Liver injuries persist for a long time after chemotherapy. Sinusoidal dilatation and nodular regenerative hyperplasia regress only nine months after the end of chemotherapy, whereas steatosis and steatohepatitis persist even after this long interval.

Chemotherapy-induced Takotsubo cardiomyopathy, a case report and review of the literature.

BACKGROUND: Several chemotherapy molecules, monoclonal antibodies and tyrosine kinase inhibitors, have been linked to Takotsubo cardiomyopathy (TC). CASE PRESENTATION: In this article, we describe the case of a 45-year-old woman who developed TC after receiving an intra-arterial and intra-venous polychemotherapy for locally advanced epidermoid carcinoma of the anal canal. This is the first described case of TC associated with intra-arterial chemotherapy. CONCLUSIONS: A review of the literature points to 5-fluorouracil as the most common molecule associated with TC and highlights the potential risk associated with rechallenging patient with the same drug.

[Multidisciplinary management of localized rectal cancer]. / Prise en charge multidisciplinaire du cancer localisé du rectum.

Rectal cancer remains a frequent pathology, with a good prognosis, according to a proper management. During the last decades, we have been confronted with important improvements, notably regarding the diagnosis and the treatment. In the era of highly specialized medicine, it is clear that the management must be multidisciplinary, incorporating not only the surgeon, the oncologist and the radiation oncologist, but also the radiologist, the gastroenterologist, and the pathologist. We aim to review the recent concepts and the future developments in the management of rectal cancer.

Le cancer du rectum demeure une pathologie fréquente, dont le pronostic est heureusement bon. Ces dernières décennies, nous avons été confrontés à plusieurs avancées importantes, que ce soit au niveau du diagnostic ou du traitement. Sa prise en charge fait partie intégrante de la médecine hautement spécialisée, et il est devenu clair que l'approche se doit d'être multidisciplinaire, incorporant aussi bien le chirurgien, l'oncologue et le radio-oncologue, que le radiologue, le gastroentérologue et le pathologue. Dans cet article, les concepts récents ainsi que les perspectives futures sont analysés.

Mutational analysis of anal cancers demonstrates frequent PIK3CA mutations associated with poor outcome after salvage abdominoperineal resection.

BACKGROUND: A better understanding of the molecular profile of anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment. METHODS: We retrospectively analysed tumours from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, TP53 and FBXW7 genes by HRM and Sanger sequencing analysis. RESULTS: Specimens from 148 patients were analysed: 96 treatment-naive tumours and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes were present in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumours (4.7%), respectively. The distribution of the mutations was similar between treatment-naive tumours and recurrences, except for TP53 mutations being more frequent in recurrences (P=0.0005). In patients treated with abdominoperineal resection (APR) after relapse (n=38, median follow-up of 18.2 years), overall survival (OS) was significantly correlated with HPV16 status (P=0.048), gender (P=0.045) and PIK3CA mutation (P=0.037). The PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (P=0.025). CONCLUSIONS: Our study identified PIK3CA mutation as an independent prognostic factor in patients who underwent APR for ASCC recurrence, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PIK3CA-mutated patients.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

[Epidemiology, treatment and follow-up of colorectal polyps]. / Epidémiologie, prise en charge et suivi des polypes colorectaux.

Colorectal polyps are frequent in the general population. The diagnostic is made by endoscopy. Polyp's characteristics determine the technic to be used to remove them. Transanal endoscopic microsurgery offers an alternative to radical surgery for large rectal polyps or rectal tumors with low risk of node invasion. One peace resection is necessary to evaluate the resection margins. Lymphatic invasion, ≥ 1 mm submucosae invasion, tumor budding and poorly differentiated tumor are the four main risk factors for node invasion. In case of high risk of lymph node invasion a radical surgery is recommended. Surveillance must be adapted to the polyp type, their number, size, presence of a carcinomatous component as well as age and clinical status of the patient.

[Management of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. / Prise en charge de la carcinose péritonéale par chirurgie cytoréductive et chimiothérapie hyperthermique intrapéritonéale.

In 2016, peritoneal carcinomatosis can be considered as a chronic disease that can be treated and sometimes cured. Hyperthermic Intra PEritoneal Chemotherapy (HIPEC) is a procedure developed in the eighties. Combined with CytoReductive (CR) surgery, this protocol underwent a considerable expansion in Washington Cancer Institute. CR combined with HIPEC was demonstrated to be the only curative treatment for PseudoMyxoma Peritonei syndrome (PMP). It is actually approved in the management of peritoneal carcinomatosis of ovarian, colorectal, or peritoneal primitive (mesothelioma) origin but is still studied for gastric cancer. CR/HIPEC is associated with an important mortality and morbidity. This article takes stock of indications to CR/HIPEC.

Rectal outcomes after a liver-first treatment of patients with stage IV rectal cancer.

BACKGROUND: The treatment of patients with metastatic rectal cancer remains controversial. We developed a reverse strategy, the liver-first approach, to optimize the chance of a curative resection. The aim of this study was to assess rectal outcomes after reverse treatment of patients with metastatic rectal cancer. METHODS: From May 2000 to November 2013, a total of 34 consecutive selected patients with histology-proven adenocarcinoma of the rectum and liver metastases were prospectively entered into a dedicated computerized database. All patients were treated via our reverse strategy. Rectal and overall survival outcomes were analyzed. RESULTS: Most patients presented with advanced disease (median Fong clinical risk score of 3; range 2-5). One patient failed to complete the whole treatment (3%). Rectal surgery was performed after a median of 3.9 months (range 0.4-17.8 months). A total of 73.3% patients received preoperative radiotherapy. Perioperative mortality and morbidity rates were 0 and 27.3% after rectal surgery. Severe complications were reported in two patients (6.1%): one anastomotic leak and one systemic inflammatory response syndrome. The median hospital stay was 11 days (range 5-23 days). Complete local pathological response was observed in three patients (9.1%). The median number of lymph nodes collected was 14. The R0 rate was 93.9%. There was no positive circumferential margin. After a mean follow-up of 36 months after rectal surgery, 5-year overall survival was 52.5%. Five patients experienced pelvic recurrence. CONCLUSIONS: In our cohort of selected patients with stage IV rectal cancer, the reverse strategy was not only safe and effective, but also oncologically promising, with a low morbidity rate and high long-term survival.

Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.

The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026.

Complete pathological response (ypT0N0M0) after preoperative chemotherapy alone for stage IV rectal cancer.

BACKGROUND: Complete pathological response occurs in 10-20% of patients with rectal cancer who are treated with neoadjuvant chemoradiation therapy prior to pelvic surgery. The possibility that complete pathological response of rectal cancer can also occur with neoadjuvant chemotherapy alone (without radiation) is an intriguing hypothesis. CASE PRESENTATION: A 66-year old man presented an adenocarcinoma of the rectum with nine liver metastases (T3N1M1). He was included in a reverse treatment, aiming at first downsizing the liver metastases by chemotherapy, and subsequently performing the liver surgery prior to the rectum resection. The neoadjuvant chemotherapy consisted in a combination of oxaliplatin, 5-FU, irinotecan, leucovorin and bevacizumab (OCFL-B). After a right portal embolization, an extended right liver lobectomy was performed. On the final histopathological analysis, all lesions were fibrotic, devoid of any viable cancer cells. One month after liver surgery, the rectoscopic examination showed a near-total response of the primary rectal adenocarcinoma, which convinced the colorectal surgeon to perform the low anterior resection without preoperative radiation therapy. Macroscopically, a fibrous scar was observed at the level of the previously documented tumour, and the histological examination of the surgical specimen did not reveal any malignant cells in the rectal wall as well as in the mesorectum. All 15 resected lymph nodes were free of tumour, and the final tumour stage was ypT0N0M0. Clinical outcome was excellent, and the patient is currently alive 5 years after the first surgery without evidence of recurrence. CONCLUSION: The presented patient with stage IV rectal cancer and liver metastases was in a unique situation linked to its inclusion in a reversed treatment and the use of neoadjuvant chemotherapy alone. The observed achievement of a complete pathological response after chemotherapy should promote the design of prospective randomized studies to evaluate the benefits of chemotherapy alone in patients with stages II-III rectal adenocarcinoma (without metastasis).

[Opening of the Geneva University Hospital Prostate Cancer Center]. / Création du Centre du cancer de la prostate des HUG.

In 2014, Geneva University Hospital has opened the first certified prostate cancer Center of western Switzerland. It incorporates 29 entities implicated in the diagnosis and treatment of this disease, thereby assuring that all available ressources are made available to patients, regardless of the division to which they were initially referred. The main strength of the Center lies in the synergy generated by its multidisciplinary tumor board. Furthermore, regular conferences, staff meetings, propectively held registers and the yearly re-certification audit support its constant quality improvement.

Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer.

BACKGROUND: The mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in colorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for overall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We investigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the patient population. METHODS: We retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3 clinical trial (N = 1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations defined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site, tumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by log rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance level was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical significance was set at 0.05 for unadjusted p-values. The significance of the interactions was tested by Wald test, with significance level of 0.05. RESULTS: In stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in subpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole population. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We found that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that KRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show evidence of heterogeneity in survival of patients with BRAF V600E mutation. CONCLUSIONS: The BRAF mutation represents an additional risk factor only in some subpopulations of colorectal cancers, in others having limited prognostic value. However, in the subpopulations where it is prognostic, it represents a marker of much higher risk than previously considered. KRAS mutation status does not seem to represent a strong prognostic variable.

A survival analysis of the liver-first reversed management of advanced simultaneous colorectal liver metastases: a LiverMetSurvey-based study.

BACKGROUND: Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. METHODS: The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. RESULTS: A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). CONCLUSIONS: Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.

Survival after lung metastasectomy in colorectal cancer patients with previously resected liver metastases.

BACKGROUND: Resection of hepatic metastases is indicated in selected stage IV colorectal cancer (CRC) patients. A minority will eventually develop pulmonary metastases and may undergo lung surgery with curative intent. The aims of the present study were to assess clinical outcome and identify parameters predicting survival after pulmonary metastasectomy in patients who underwent prior resection of hepatic CRC metastases. METHODS: We performed a retrospective analysis of 27 consecutive patients (median age 62 years; range: 33-75 years) who underwent resection of pulmonary metastases after previous hepatic metastasectomy from CRC in two institutions from 1996 to 2009. All patients underwent complete resection (R0) for both colorectal and hepatic metastases. RESULTS: Median follow-up was 32 months (range: 3-69 months) after resection of lung metastases and 65 months (range: 19-146 months) after resection of primary CRC. Three- and 5-year overall survival rates after lung surgery were 56 and 39%, respectively, and median survival was 46 months (95% CI 35-57). Median disease-free survival after pulmonary metastasectomy was 13 months (95% CI 5-21). At the time of last follow-up, seven patients (26%) had no evidence of recurrent disease and 6 of these 7 patients presented initially with a single lung metastasis. CONCLUSIONS: Resection of lung metastases from CRC patients may result in prolonged survival, even after previous hepatic metastasectomy. Yet, prolonged disease-free survival remains the exception, and seems to occur only in patients with a single lung lesion.

Adjuvant radio-chemotherapy for extrahepatic biliary tract cancers.

BACKGROUND: Extrahepatic biliary duct cancers (EBDC) are uncommon malignancies characterized by a poor prognosis with high rate of loco-regional recurrence. The purpose of the present study is to assess the feasibility and the potential impact of adjuvant radiotherapy (RT) in a series of patients treated in one institution. METHODS: Twenty three patients with non-metastatic bile duct cancer treated surgically with curative intent (4 gallbladder, 7 ampullary and 12 cholangiocarcinoma) received 3D conformal external beam RT to a median total dose of 50.4 Gy. Concurrent chemotherapy based on 5-FU was delivered to 21 patients (91%). Surgical margins were negative in 11 patients (48%), narrow in 2 (9%), and microscopically involved in 8 (35%). Eleven patients (55%) had metastatic nodal involvement. The average follow-up time for all patients was 30 months (ranging from 3-98). RESULTS: Acute gastrointestinal grade 2 toxicity (RTOG scale) was recorded in 2 patients (9%). Nausea or vomiting grade 1 and 2 was observed in 8 (35%) and 2 patients (9%) respectively. Only one patient developed a major late radiation-induced toxicity. The main pattern of recurrence was both loco-regional and distant (liver, peritoneum and/or lung). No difference was observed in loco-regional control according to the tumor location. The 5-year actuarial loco-regional control rate was 48.3% (67% and 30% for patients operated on with negative and positive/narrow/unknown margins respectively, p=0.04). The 5-year actuarial overall survival was of 35.9% for the entire group (61.4% in case of negative margins and 16.7% in case of positive/narrow/unknown margins, p=0.07). CONCLUSIONS: Postoperative RT with 50-60 Gy is feasible with acceptable acute and late toxicities. The potential benefit observed in our series may support the use of adjuvant RT in patients with locally advanced disease. Prospective randomized trials are warranted to confirm definitively the role of RT in this tumor location.

Successful closure of anal cancer-related fistulas with upfront intra-arterial chemotherapy: a report of 8 cases.

BACKGROUND: Fistulas arising from the perforation of anal cancer into adjacent organs are a debilitating complication in the course of the disease. OBJECTIVE: We studied intra-arterial chemotherapy as a strategy to close such fistulas before the initiation of standard chemoradiation. DESIGN: This study was based on a retrospective chart review. SETTING: The investigation was conducted at Geneva University Hospital. PATIENTS: Eight patients with anal cancer-related fistulas were included in the study. INTERVENTION: Patients were treated at our institution from 2002 to 2009 with upfront chemotherapy consisting of 1 to 4 cycles of intra-arterial cisplatin, 5-fluorouracil, methotrexate, and mitomycin C, and intravenous bleomycin. Intra-arterial chemotherapy was followed by standard chemoradiation. MAIN OUTCOME MEASURE: Fistula closure was assessed by an expert proctologist. RESULTS: Complete closure of fistulas was documented in 7 of 8 patients. Toxicity was manageable and consisted mainly of thrombocytopenia, neutropenia, and febrile neutropenia as well as fatigue. LIMITATIONS: This is a retrospective, uncontrolled review of only 8 patients and thus a meaningful comparison with standard chemoradiation is not feasible. CONCLUSION: Upfront intra-arterial chemotherapy is a promising strategy to close anal cancer-related fistulas before initiating chemoradiation, potentially obviating the need for hazardous reconstructive surgery after radiotherapy.