Ravit Geva

The role and limitations of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and computerized tomography (CT) in restaging patients with hepatic colorectal metastases following neoadjuvant chemotherapy: comparison with operative and pathological findings.

BackgroundRecent data confirmed the importance of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the selection of patients with colorectal hepatic metastases for surgery. Neoadjuvant chemotherapy before hepatic resection in selected cases may improve outcome. The influence of chemotherapy on the sensitivity of FDG-PET and CT in detecting liver metastases is not known.MethodsPatients were assigned to either neoadjuvant treatment or immediate hepatic resection according to resectability, risk of recurrence, extrahepatic disease, and patient preference. Two-thirds of them underwent FDG-PET/CT before chemotherapy; all underwent preoperative contrast-enhanced CT and FDG-PET/CT. Those without extensive extrahepatic disease underwent open exploration and resection of all the metastases according to original imaging findings. Operative and pathological findings were compared to imaging results.ResultsTwenty-seven patients (33 lesions) underwent immediate hepatic resection (group 1), and 48 patients (122 lesions) received preoperative neoadjuvant chemotherapy (group 2). Sensitivity of FDG-PET and CT in detecting colorectal (CR) metastases was significantly higher in group 1 than in group 2 (FDG-PET: 93.3 vs 49%, Pu2009<u20090.0001; CT: 87.5 vs 65.3, Pu2009=u20090.038). CT had a higher sensitivity than FDG-PET in detecting CR metastases following neoadjuvant therapy (65.3 vs 49%, Pu2009<u20090.0001). Sensitivity of FDG-PET, but not of CT, was lower in group 2 patients whose chemotherapy included bevacizumab compared to patients who did not receive bevacizumab (39 vs 59%, Pu2009=u20090.068).ConclusionsFDG-PET/CT sensitivity is lowered by neoadjuvant chemotherapy. CT is more sensitive than FDG-PET in detecting CR metastases following neoadjuvant therapy. Surgical decision-making requires information from multiple imaging modalities and pretreatment findings. Baseline FDG-PET and CT before neoadjuvant therapy are mandatory.

Is there a role for adjuvant chemotherapy in pathological complete response rectal cancer tumors following neoadjuvant chemoradiotherapy

PurposeTo investigate the contribution of neoadjuvant chemotherapy in rectal cancer patients with pathological complete response (pCR).MethodsData were collected on all consecutive locally advanced rectal cancer patients treated with neoadjuvant chemotherapy and later resected in our institution between 2001 and 2013. Surgery was performed by a single proctology team, and tumor specimens were evaluated by the hospital pathologists.ResultsThe medical records of 260 patients were analyzed, and 54 patients of those patients were found to have achieved pCR (20.8xa0%). Two of those patients were lost to follow-up. Thirty-five of the 54 pCR patients received adjuvant chemotherapy (Group A) and 17 did not (Group B). With the sole exception of the Group A patients being younger than the Group B patients (60.9xa0±xa011.9 vs. 68.7xa0±xa010.8xa0years, respectively, pxa0=xa00.0272), all other evaluated parameters were identical between the two groups. There was no advantage for the administration of adjuvant chemotherapy for disease-free survival (DFS) and overall survival (OS).ConclusionsAdjuvant chemotherapy played no part in disease-free survival and OS of patients with rectal cancer who had been treated with neoadjuvant chemotherapy and achieved pCR. Our findings indicate a tendency for adjuvant chemotherapy to be administered to younger rectal cancer patients. A randomized trial should be conducted to resolve the question of whether they derive any benefit from it.

Perioperative Complications After Neoadjuvant Chemotherapy With and Without Bevacizumab for Colorectal Liver Metastases

PurposeBevacizumab has been shown to increase progression free and overall survival in patients with metastatic colorectal cancer. Neoadjuvant bevacizumab is commonly used in patients undergoing liver resection. Our purpose was to evaluate whether bevacizumab is associated with increased rate of perioperative complications in patients undergoing hepatic resection for colorectal liver metastases (CRLM).MethodsRetrospective analysis of patients undergoing hepatic resection for CRLM who received chemotherapy and bevacizumab (group 1, nu2009=u2009134), or chemotherapy alone (group 2, nu2009=u200957). We compared demographics, surgical characteristics, and perioperative course.ResultsPerioperative complications developed in 35xa0% of patients in group 1, and 47xa0% in group 2 (pu2009=u20090.11). Of those complications, 15 (11.2xa0%) in group 1, and 5 (8.8xa0%) in group 2 were considered major (pu2009=u20090.617). Four patients, all of whom received preoperative bevacizumab, developed enteric leaks following combined liver and bowel resection. The rate of anastomotic leak in group 1 was 10xa0%, compared with 0 in group 2, pu2009=u20090.56.ConclusionNeoadjuvant chemotherapy along with bevacizumab was not associated with an increased risk of postoperative complications after hepatic resection. Possible association of increased morbidity with simultaneous bowel and liver resections following bevacizumab administration was found and we recommend avoiding such treatment combination.

The impact of overall radiotherapy treatment time and delay in initiation of radiotherapy on local control and distant metastases in gastric cancer

ObjectivesTo study the impact of time factors on local and distant metastases in stomach cancer.Methods67 patients with gastric cancer who received adjuvant treatment were reviewed for the time to initiation of radiotherapy, overall duration of RT and the events of first local recurrence or distant metastasis.ResultsThe risk probability of local recurrence is increased by 10% (HRu2009=u20091.1, pu2009=u20090.0009) in association with each additional day of radiotherapy and by 3.8% (HRu2009=u20091.038, pu2009=u20090.13) per increased day of waiting time before the initiation of RT. The risk probability of distant recurrence was associated with an increase of 7.4% (HRu2009=u20091.074 pu2009=u20090.0031) with each additional day of RT time and by 2.3% (HRu2009=u20091.023, pu2009=u20090.0598) following the increase of a day of waiting time. Each day of prolongation of RT beyond 36xa0days was associated with an increased risk of local recurrence by 10% (ORu2009=u20091.1, pu2009=u20090.015). Prolongation of waiting time prior to initiation of irradiation retained significance in multivariate analysis.ConclusionThere is an association between total treatment time and, to some extent, the time between the surgery and the initiation of radiation on local control and distant metastases.

Unusually long-term responses to vemurafenib in BRAF V600E mutated colon and thyroid cancers followed by the development of rare RAS activating mutations

ABSTRACT Introduction: V600E BRAF mutation is an established driver mutation in a variety of tumors. Vemurafenib is a selective inhibitor of the BRAF V600E kinase, known to be highly effective in BRAF V600E-positive metastatic melanoma. As a single agent, vemurafenib is relatively ineffective in other V600E-positive malignancies. Case 1: A 72 year old man with metastatic CRC who failed several previous lines of chemotherapy. Genetic analysis of 315 cancer-related genes (Foundation Medicine, FMI) revealed a BRAF V600E mutation. The patient was treated with vemurafenib resulting in a partial response of 18 months. Genetic analysis following development of resistance revealed a new mutation in KRAS-G12R. Case 2: V600E mutation was identified in a 59 year old woman with metastatic PTC refractory to radioiodine therapy. The patient was treated with vemurafenib resulting in a partial response lasting 43 months. Genetic analysis following development of resistance revealed a new mutation in NRAS-Q61K. The presented cases demonstrated the development of rare RAS mutations as a genetic mechanism of acquired BRAF inhibitor resistance. This observation is strongly supported by the analysis of a large database consisting of 712 BRAF V600E-positive melanoma samples showing higher rates of BRAF V600E and RAS mutations co-occurrence in metastatic lesions compared to local tumors (OR = 3.8, p = 0.035). This enrichment is likely a result of the development of RAS mutations following treatment with BRAF inhibitors. Discussion: We report two cases showing extreme response to vemurafenib, which could not be predicted prior to treatment commencement. Genetic testing demonstrated a resistant mechanism not previously reported in CRC or PTC patients, namely an acquired mutation of RAS. This is supported by an analysis of a large cohort of BRAF V600E-positive melanomas. Further studies are needed in order to identify predictive markers for response to vemurafenib and to explore novel strategies to overcome RAS-mediated resistance.

Determining the role of radiotherapy in the adjuvant management of gastric cancer: an ocean apart

Springer-Verlag 2010 Although the incidence of gastric cancer may be leveling off as of late, mortality rates––especially among those with locally advanced disease––are quite formidable [1]. The cornerstone of therapy for locally advanced disease continues to be surgical extirpation but a consensus has emerged that resection should be supplemented with adjuvant therapies which must continually be improved in order to optimize the percentage of patients who achieve cure. The agents that should comprise such adjuvant programs have been debated for well over a decade. At present, clinicians who counsel patients diagnosed with locally advanced gastric adenocarcinoma are ironically left with two standards of care; neither of which is associated with cure in the majority of cases. The first option is to follow the schema of Intergroup Study 0116 where chemoradiation (fluorouracil and leucovorin plus 45 Gy delivered to the surgical bed and draining lymph nodes) favorably influenced disease-free survival and overall survival [2]. The second alternative is to invoke the results published by Cunningham and colleagues [3] who observed that peri-operative chemotherapy significantly improved progression-free and overall survival among patients with operable disease. This experience, often referred to as the MAGIC study, involved administration of epirubicin, cisplatin and fluorouracil (Three pre-operative cycles; three post-operative cycles of ECF) and begged the question of radiotherapy by excluding the latter modality

LY2495655, an antimyostatin antibody, in pancreatic cancer: a randomized, phase 2 trial: LY2495655 in patients with stage II-IV pancreatic cancer

Cachexia is a formidable clinical challenge in pancreatic cancer. We assessed LY2495655 (antimyostatin antibody) plus standard‐of‐care chemotherapy in pancreatic cancer using cachexia status as a stratifier.

Neoadjuvant FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer: An intention to treat analysis

OBJECTIVEnTo assess clinical and pathologic efficacy of neoadjuvant FOLFIRINOX for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).nnnMETHODSnPatients receiving neoadjuvant FOLFIRINOX for LAPC and BRPC treated between 2014 and 2017 were identified. Post-treatment patients achieving resectability were referred for surgery, whereas unresectable patients continued chemotherapy. Clinical and pathological data were retrospectively compared with control group consisting of 47 consecutive patients with BRPC undergoing pancreatic and portal vein resection between 2008 and 2017.nnnRESULTSnThirty LAPC and 23 BRPC patients were identified. Reasons for unresectability included disease progression (70%), locally unresectable disease (18%), and poor performance status (11%). Three patients (10%) with LAPC, and 20 (87%) with BRPC underwent curative surgery. Compared with control group, perioperative complication rate (4.3% versus 28.9%, pxa0=xa00.016), and pancreatic fistula rate (0 versus 14.8%, pxa0=xa00.08) were lower. Peripancreatic fat invasion (52.2% vs 97.8%, pxa0=xa00.001), lymph node involvement (22% vs 54.3%, pxa0=xa00.01), and surgical margin involvement (0 vs 17.4%, pxa0=xa00.04) were higher in the control group. Median survival was 34.3 months in BRPC patients operated after FOLFIRINOX and 26.1 months in the control group (pxa0=xa00.07). Three patients (13%) with complete pathological response are disease-free after mean follow-up of 19 months.nnnCONCLUSIONSnWhereas neoadjuvant FOLFIRINOX rarely achieves resectability in patients with LAPC (10%), most BRPC undergo resection (87%). Neoadjuvant FOLFIRINOX leads to complete pathological response in 13% of cases, tumor downstaging, and a trend towards improved survival compared with patients undergoing up-front surgery.

Does residual microscopic disease after chemoradiotherapy for locally advanced rectal cancer translate into good clinical outcome

This study aimed to assess the progression‐free and overall survival of patients with residual microscopic disease following neoadjuvant chemoradiotherapy and rectal resection for locally advanced rectal cancer.

The Role of Primary Tumor Resection (PTR) in Metastatic Colorectal Cancer

Patients with unresectable metastatic colorectal cancer can either receive systemic chemotherapy as first treatment or have a palliative resection of the primary tumor or endoscopic placement of a self-expanding metallic stent if they present with colonic obstruction. The ongoing dilemma is whether resection of the primary tumor in asymptomatic patients is beneficial. The effectiveness of current systemic treatment regimens on the primary tumor as well as the survival benefit of primary tumor resection in the era of new chemotherapy agents, biologics, and targeted therapy is underreported. No prospective randomized studies have yet been published; nevertheless, based on the available literature, it seems that primary tumor (PTR) can possibly improve short- and long-term outcome in highly selected patients with favorable characteristics, specifically low tumor burden and good performance status.