Lakshmi Rajdev

Treatment Options for Surgically Resectable Gastric Cancer

Opinion statementSurgery is the only curative therapy for gastric cancer. The standard recommendations for resectable gastric adenocarcinoma are free-margin surgery with at least D1 resection and the removal of a minimum of 15 lymph nodes. The overall 5-year survival rate for resected gastric patients remains poor due to locoregional recurrence. The results of a large North American study (Gastrointestinal Cancer Intergroup Trial INT 0116) reported that postoperative chemoradiotherapy conferred a survival advantage compared with surgery alone, which led to the regimen being adopted as a standard of care. More recently the MAGIC/UK Medical Research Council (MRC) trial demonstrated that perioperative chemotherapy resulted in an improvement in overall survival and progression free survival. Thus, two successful strategies are available to improve outcomes in patients with localized gastric cancer. This article reviews data on adjuvant and perioperative treatment modalities for gastric cancer. The article discusses ongoing randomized adjuvant and perioperative trials that are designed to optimize chemotherapy regimens and also investigate combinations of chemotherapy and biologic agents. It is important to understand the mechanisms or pathways involved in gastric cancer development and metastasis. Identification of novel molecules pivotal to tumor biology may lead to new therapeutic approaches for this malignancy.

Targeted Therapy in Biliary Tract Cancers.

Opinion statementA paradigm shift towards molecular-based, personalized cancer therapeutics has occurred in recent years and a number of targeted drugs have emerged. Various targeted therapies like erlotinib, trastuzumab, and cetuximab have been approved in lung, breast, and colon cancers, respectively. Numerous clinical trials involving targeted drugs in biliary tract cancers are currently in progress, though none have been approved for this disease. Biliary tract cancers are divided into separate entities both anatomically and in terms of pathogenesis but are grouped together in most trials given their rarity. Combination chemotherapy involving cisplatin and gemcitabine is the current standard of care in the metastatic setting. In this review, we will discuss the various molecular pathways implicated in biliary tract cancers and potential therapeutic targets.

A phase I trial of gemcitabine administered as a 96-h continuous intravenous infusion in patients with advanced carcinoma and lymphoma

Background and objectivePreclinical data suggest gemcitabine may have schedule-dependent activity fovoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h.Patients and methodsGemcitabine was initially given at 1 mg/m2/d for 48, then, 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m2/d. Dose levels of 7, 8, 9 mg/m2/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule. we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk.ResultsThirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1–10 cycles). The RPTD, was 8 mg/m2/d every 3 wk, and 6 mg/m2/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (>- grade 2) included fever (n=14), dyspnea (n=7). mucositis (n=6), hypotension (n=6), nausea/vomiting (n=6), and fatigue (n=5). Neutropeni and/or thrombocytopenia were uncommon.ConclusionA dministration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m2/d (32 mg/m2/course) when given every 3 wk, or 6 mg/m2/d (24 mg/m2/course) when given every 2 wk.

Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer

PURPOSEnToxa0obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer.nnnPATIENTS AND METHODSnEligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4xa0cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0xa0Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1xa0×xa0109xa0colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation.nnnRESULTSnTen patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (nxa0=xa02), back pain (nxa0=xa01), and hyponatremia (nxa0=xa01). All ADXS11-001 toxicities occurred within 24xa0hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42xa0months.nnnCONCLUSIONSnPreliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted.

Immunotherapeutic Approaches to Biliary Cancer.

Opinion statementBiliary tract cancers (BTCs) are rare aggressive neoplasms with a poor prognosis and a median survival of less than 1xa0year in the locally advanced or metastatic setting. Among the few patients who undergo curative resection the recurrence rates are high. About 90% of patients are detected at advanced stages, and systemic chemotherapy is the mainstay of their treatment. The treatment options for these patients are limited and multiple modalities of therapy from targeted therapy to immunotherapy and combination therapies (immunotherapy, targeted therapy, and chemotherapy) have been tested in this disease. Targeted therapies have failed to show a survival benefit. The deregulation of the immune system plays a significant role in the pathogenesis of BTCs. Therefore, immunotherapy, especially, immune checkpoint inhibitors hold great promise for this group of cancers. Numerous trials of immunotherapy in BTC are currently ongoing. In this review, we will discuss the available data and evidence for immunotherapy in BTC.

Taxane-Based Therapy for Breast Cancer: Combination or Sequential Therapy?

In this issue, Cohen et al. describe the results of a phase I trial of weekly paclitaxel plus vinorelbine in patients with advanced cancer. This study joins a growing list of phase I and phase I1 trials investigating this combination in patients with a variety of tumor types, especially breast and lung cancer. This study and others investigating taxane-based combinations raise several important questions, especially regarding the treatment of breast cancer.

Evolving Paradigms in HIV Malignancies: Review of Ongoing Clinical Trials

This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non-AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy-naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.