Gaurav Goel

Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future.

Despite a few breakthroughs in therapy for advanced disease in the recent years, pancreatic ductal adenocarcinoma continues to remain one of the most challenging human malignancies to treat. The overall prognosis for the majority of patients with pancreatic cancer is rather dismal, and therefore, more effective treatment options are being desperately sought. The practical goals of management are to improve the cure rates for patients with resectable disease, achieve a higher conversion rate of locally advanced tumor into potentially resectable disease, and finally, prolong the overall survival for those who develop metastatic disease. Our understanding of the complex genetic alterations, the implicated molecular pathways, and the role of desmoplastic stroma in pancreatic cancer tumorigenesis has increased several folds in the recent years. This has facilitated the development of novel therapeutic strategies against pancreatic cancer, some of which are currently under evaluation in ongoing preclinical and clinical studies. This review will summarize the existing treatment approaches for this devastating disease and also discuss the promising therapeutic approaches that are currently in different stages of clinical development.

Advances in the management of gastrointestinal cancers—an upcoming role of immune checkpoint blockade

Gastrointestinal cancers are a group of highly aggressive malignancies, and novel therapeutic strategies with higher clinical efficacy are being actively sought. ‘Immunotherapy’ is now emerging as one such promising strategy for the treatment of these tumors. This article briefly reviews the recent advances that utilize targeting of immune checkpoint pathways, in the management of gastrointestinal malignancies.

Role of modern immunotherapy in gastrointestinal malignancies: a review of current clinical progress

Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms. Immune checkpoint blockade with antibodies directed against these pathways has already shown clinical efficacy that has led to their FDA approval in the treatment of several solid tumors including melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancer. This review will summarize the current clinical progress of modern immunotherapy in the field of GI tumors, with a special focus on immune checkpoint blockade.

Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma

BACKGROUND AND OBJECTIVES At present, there is no standard regimen for the treatment of gastroesophageal cancer. Docetaxel, cisplatin and fluorouracil (DCF) has been shown to be an effective regimen; however, toxicity is an area of concern in the palliative case setting. Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin, respectively. To reduce the toxicity of DCF while maintaining efficacy, we conducted this study to evaluate the efficacy of docetaxel, oxaliplatin and capecitabine (DOX) combination in advanced gastroesophageal cancer. METHODS Patients with histologically confirmed metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction received docetaxel 25 mg/m2 and oxaliplatin 50 mg/m2 on days 1 and 8 with capecitabine 625 mg/m2 twice daily from day 1-14, in 21-day cycles. The primary endpoint was overall response rate (ORR). RESULTS Of 21 patients, there were 16 males and 5 females with a median age of 57 years, range 37-80 years. The primary tumor was located at the gastroesophageal junction in 7 patients and in other parts of the stomach in the remaining 14 patients. One patient had locally advanced tumor without distant metastases and 20 patients presented with metastatic disease. Grade 3/4 toxicities included diarrhea (24%), hand-foot syndrome (5%) and febrile neutropenia (5%). The ORR was 29%. The median survival was 8.4 months. At the time of analysis, 5 of the 21 patients (24%) were alive. CONCLUSIONS The DOX combination is tolerable, active and a promising day-care regimen for advanced gastroesophageal cancer.

Ramucirumab, another anti-angiogenic agent for metastatic colorectal cancer in second-line setting—its impact on clinical practice

The recent FDA approval of ramucirumab (RAISE trial) has added a third agent to our existing armamentarium of angiogenesis inhibitors (bevacizumab and ziv-aflibercept) for the second-line treatment of metastatic colorectal cancer, which may have some impacts in the current clinic practice.

Evolving Role of Gene Expression Signatures as Biomarkers in Early-Stage Colon Cancer

PurposeColorectal cancer (CRC) is a major health problem in the USA and worldwide. At the time of initial presentation, approximately 26 % of CRC patients will have stage II disease while another 30 % will present with stage III disease. Although surgical resection plays a critical role in the management of patients who have early-stage disease, it is usually not curative by itself. As a result, adjuvant chemotherapy is generally administered to eradicate clinically occult micrometastatic disease. It is now being increasingly realized that not all patients with stage II and III disease derive significant benefit from adjuvant chemotherapy. Moreover, due to a growing concern for long-term chemotherapy-associated adverse effects, its utility in unselected stage II/III patients is now being questioned.Methodology and ResultsSignificant efforts have been made in recent years to identify potential biomarkers that would help to define the subset of stage II and III colon cancer patients expected to derive significant benefit from adjuvant chemotherapy, especially in those with borderline indications. Oncotype DX Colon Cancer Assay and ColoPrint are gene expression profiling-based recurrence score (RS) assays that have been developed with this intent. The greatest utility of RS assay has been conventionally believed to be for identifying recurrence risk in stage II patients. Recent data now suggests that stage III patients similar to stage II patients, vary in their tumor recurrence risk and that there might be a role for a more selective approach in treating these patients, based on the results of RS assays.ConclusionIn such an evolving landscape, this article aims to review the current role of gene expression signatures such as Oncotype DX and ColoPrint in the management of early-stage colon cancer.

Incidence, Etiology and Risk Factors Associated with Neonatal Healthcare-Associated Conjunctivitis: A Prospective Study from a Tertiary Care Hospital in India.

INTRODUCTION Healthcare-associated conjunctivitis (HAC) can lead to serious sequelae including blindness. We conducted a one-year prospective study to determine the epidemiology of neonatal HAC at a tertiary-care hospital in India. METHODS From the neonates fulfilling a set of predefined inclusion criteria, cases of HAC were diagnosed based on CDC guidelines. Conjunctival swabs, obtained from neonates with suggestive clinical signs, were processed using standard protocols. Twenty-eight potential risk factors were analyzed. RESULTS We detected 24 cases of HAC among 591 enrolled neonates, with Escherichia coli being the most frequently isolated microorganism. On multivariate analysis, intubation at birth (p = 0.046) and orogastric feeding (p = 0.029) had a statistically significant association with neonatal HAC. Average hospitalization increased from 9.6 to 20.8 days for neonates diagnosed with HAC. CONCLUSION A standardized case-definition and physician awareness of potential serious sequelae would help improve detection rates and timely institution of therapy. Hand hygiene could help control the menace of neonatal HAC.

Pharmacokinetically Guided Dose Adjustment of 5-FU—A Critical Element Toward Personalized Medicine

Colorectal cancer (CRC) is one of the leading causes of cancer mortality in the United States and worldwide. Systemic chemotherapy has been the mainstay treatment approach for patients with metastatic disease and in the adjuvant setting after curative resection of early-stage CRC. Since the 1950s, 5-fluorouracil (5-FU) has been the backbone of systemic combination chemotherapy for the treatment of CRC. The dosing of 5-FU, as is the case for nearly all cytotoxic agents, has traditionally been based on body surface area (BSA). There is now growing evidence that BSA-based 5-FU dosing has several limitations, perhaps the most important being significant interpatient and intrapatient variability in 5-FU drug levels when dosing is based on BSA. 1,2 The situation is further complicated by a narrow therapeutic window leading to dose-limiting toxicity of 5-FU. Several studies have shown that BSA-based dosing results in, at most, 20% to 30% of patients being in the appropriate dose range of 5-FU. 3 Approximately 40% to 60% patients are underdosed, whereas a smaller fraction of patients in the range of 10% to 20% are overdosed. 3 It is now widely accepted that BSA dosing is not accurate for extremes of body size and does not account for important sources of variability such as age, sex, a decrease in 5-FU clearance during the course of chemotherapy, drug interactions, and pharmacogenomic differences. 4 There is a clearly defined relationship between 5-FU plasma concentration and biological effects, including toxicity and efficacy. 5,6 Several studies, including a large multicenter randomized trial in France, have shown that pharmacokinetically guided dose adjustment of 5-FU in patients with metastatic CRC allows individualized dose adjustment and results in improved clinical efficacy and reduced risk of toxicity. 7,8 Pharmokinetically guided dose adjustment of 5-FU in the United States has only been facilitated during the past few years with the recent development of a fast, simple, and relatively inexpensive immunoassay that is now available for clinical use. This test is highly specific for 5-FU, and studies by Beumer et al have shown that this test has a high correlation with validated liquid chromatographyemass spectrometry and high-performance liquid chromatography. 9 In this issue of Clinical Colorectal Cancer, Kline et al have evaluated the impact of pharmacokinetically guided dose adjustment of 5-FU in both patients with early-stage and those with advanced-stage CRC who received infusional 5-FU as part of FOLFOX (5-fluorouracil, leucovorin [folinic acid], oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin [folinic acid], irinotecan) chemotherapy. This study was conducted at a single institution between 2010 and 2013. 10 A total of 84 patients were evaluated, and of this group, 35 patients had stage II/III disease, whereas 49 patients had stage IV disease. Among the 84 patients, 46 patients received 5-FU based on BSA and 38 patients received 5-FU dose adjustment based on pharmacokinetic (PK) monitoring using the 5-FU immunoassay. For patients in the PK dosing arm, the first 5-FU dose was determined using the traditional BSA method, and subsequent dosing was based on 5-FU PK test results targeting the

Ramucirumab: a Novel Anti-Angiogenic Agent in the Treatment of Metastatic Colorectal Cancer

Angiogenesis is a multistep process that plays a key role in cancer growth and metastases. It is mediated through multiple vascular endothelial growth factor receptors (VEGFRs) and their ligands. The expression of VEGFR-2 is upregulated in tumor endothelial cells, and it is considered to be the primary receptor driving malignant angiogenesis. Ramucirumab (IMC-1121B, LY3009806) is a fully human monoclonal antibody that directly binds to VEGFR-2 with high affinity and specificity. It is also the most recent addition to our armamentarium of anti-angiogenic drugs approved for the treatment of metastatic colorectal cancer (CRC). The aim of this review is to summarize the pre-clinical and clinical development of ramucirumab and discuss its place in the current treatment paradigm for metastatic CRC.

NeoadjuvantNab-paclitaxel and Gemcitabine in Borderline Resectable or Locally Advanced Unresectable Pancreatic Adenocarcinoma in Patients Who Are Ineligible for FOLFIRINOX

Background/Aim: Combination nab-paclitaxel/gemcitabine (AG) is superior to gemcitabine in patients with metastatic pancreatic cancer (PC). There are limited data for AG in borderline resectable (BR) or locally advanced pancreatic cancer (LAPC). Herein, we report our experience with neoadjuvant AG for BR/LAPC in patients ineligible for FOLFIRINOX. Patients and Methods: This retrospective series, included patients with BR/LAPC who received AG as neoadjuvant therapy for 3-4 months followed by radiation, then re-evaluation for surgery. Results: Between 10/2013-2/2018, 32 patients (22 BR, 10 LAPC) were treated with this approach. Median age was 70 years. Nine patients were converted to resectability by imaging; six had R0 resections (19%), five (16%) achieved a partial response and 24 (75%) had stable disease. Conclusion: In this small series, the R0 resection rate and response rate were 19% and 16% respectively. These data suggest that neoadjuvant AG may be an alternate option for patients ineligible for FOLFIRINOX.