Diane Reidy-Lagunes

Neoadjuvant Chemotherapy Without Routine Use of Radiation Therapy for Patients With Locally Advanced Rectal Cancer: A Pilot Trial

PURPOSE Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy. PATIENTS AND METHODS Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate. RESULTS Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%). CONCLUSION For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.

Consensus guidelines for the management and treatment of neuroendocrine tumors.

Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.

Neuroendocrine tumors of the gynecologic tract: A Society of Gynecologic Oncology (SGO) clinical document

OBJECTIVE Neuroendocrine tumors of the gynecologic tract are rare, and pose a significant clinical challenge because of the tumor heterogeneity and lack of standardized guidelines for treatment. This manuscript summarizes the available literature concerning these tumors in an effort to provide the clinician a framework from which to guide patient management. METHODS MEDLINE was searched for all research articles published in English between January 1, 1966 and March 1, 2011 in which the studied population included women diagnosed with neuroendocrine tumors of the gynecologic tract. Although preference was given to prospective studies, studies were not limited by design or by numbers of subjects given the limited availability of reports. RESULTS Most, but not all, neuroendocrine tumors of the gynecologic tract have an aggressive clinical course and those of the cervix histologically and clinically share similarities with small cell lung cancer. Cumulative data supports a multi-modality therapeutic strategy. A proposed management algorithm for neuroendocrine carcinomas of the cervix is outlined. For less frequent disease sites including the adnexa, uterus, vagina and vulva, as well as well differentiated carcinoid tumors, surgical resection is appropriate in selected cases. Etoposide/platinum based chemotherapy is used for neuroendocrine carcinomas but not for well differentiated carcinoid tumors. Well differentiated carcinoid and atypical carcinoid tumors should be managed similar to gastroenteropancreatic NETs (GEP-NETs). CONCLUSIONS Most neuroendocrine tumors of the gynecologic tract require a multi-modality therapeutic approach, determined by extent of disease and primary organ of involvement. Pathologic diagnosis is critical to guide therapy.

Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels

PURPOSE Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. METHODS We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. RESULTS Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0). CONCLUSION A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.

Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors

PURPOSE There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. PATIENTS AND METHODS We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. RESULTS A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). CONCLUSION The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuroendocrine tumors†

Neuroendocrine tumor (NET) cell lines frequently express both insulin‐like growth factor (IGF) ligand and the cognate IGF‐1 receptor (IGF‐1R) and, as such, potentially depend on the activation of IGF‐1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF‐1‐dependent signaling, suggesting that IGF‐1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK‐0646, a fully human monoclonal antibody (MoAb) that binds to the IGF‐1R, as monotherapy in patients with metastatic, well‐differentiated NETs.

Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs.

The Management of Extrapulmonary Poorly Differentiated (High-Grade) Neuroendocrine Carcinomas

Extrapulmonary high-grade neuroendocrine carcinomas (HGNECs) are rare but aggressive tumors that can be found throughout the body but are most commonly located in the gastrointestinal (GI) and the genitourinary tracts. They also have been described in the thymus, breast, oropharynx, and other organs. Due to the rarity of these tumors, publications are limited to small series and, as a result, treatment regimens are extrapolated from more robust data published on pulmonary HGNECs. For metastatic disease, platinum-based chemotherapy is the backbone of treatment. For localized disease, there are currently no standard treatment algorithms. Surgical resection with low morbidity is a reasonable treatment option, particularly in lesions where the possibility of obstruction is high. However, given the very high risk of disease recurrence, a multimodality approach with either neoadjuvant or adjuvant therapy is warranted. For locally advanced disease, chemoradiation should be considered, incorporating a platinum-based regimen when possible. Chemoradiation also should be considered when primary resection would lead to significant morbidity, such as with rectal, pancreas, and esophageal HGNECs.

Clinical and histopathologic characteristics of rash in cancer patients treated with mammalian target of rapamycin inhibitors

Dermatologic adverse events stemming from anticancer therapies have become an increasingly frequent clinical problem. Inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, have been associated with a high rate of skin eruptions, but their clinical and histopathologic characteristics have not been explored.

Outcomes of Patients Undergoing Percutaneous Biliary Drainage to Reduce Bilirubin for Administration of Chemotherapy

PURPOSE To describe outcomes in patients undergoing percutaneous biliary drainage to reduce total serum bilirubin level for administration of chemotherapy. MATERIALS AND METHODS A total of 647 consecutive patients underwent percutaneous biliary drainage between September 2001 and December 2008. In 168, the indication for biliary drainage was to decrease total serum bilirubin level to permit administration of chemotherapy. Of these, 20 were excluded because they had hepatic arterial infusion pumps, leaving 148 patients as the study group. The primary diagnoses for these patients were gallbladder cancer (n = 23), cholangiocarcinoma (n = 21), pancreatic cancer (n = 36), and other metastatic cancers (n = 68). Medical records and imaging studies were reviewed for demographic data, procedural information, pre- and postdrainage total serum bilirubin level levels, 30-day complications, and subsequent biliary procedures. RESULTS The probability of attaining a total serum bilirubin level of 1 mg/dL or lower by 100 days was 31% (95% CI, 23%-39%). Predrainage total serum bilirubin level of 9 mg/dL or lower (hazard ratio [HR], 3.27; 95% CI, 1.86-5.75; P < .001), 100% liver drainage (HR 2.73, 95% CI, 1.56-4.78; P <.001), and lower predrainage International Normalized Ratio (INR; HR, 0.80; 95% CI, 0.70-0.92; P = .002) were associated with an increased likelihood of attaining a total serum bilirubin level of 1 mg/dL or lower. The most common indication for follow-up was pericatheter leakage, which occurred in nearly one third of cases. During follow-up, patients required three visits per 100 catheter-days, or approximately one per month. Median overall survival in this population was approximately 3.5 months. CONCLUSIONS Only 31% of patients attained a normal serum bilirubin level by 100 days, and median overall survival was 107 days. Careful patient selection is warranted before biliary drainage for this indication. Maximal biliary drainage, a preprocedure total serum bilirubin of less than 9 mg/dL, and a lower INR were factors associated with serum bilirubin normalization in this cohort.