Emer O. Hanrahan

Non-Hodgkin lymphoma: an update

Non-Hodgkin lymphoma (NHL) causes many deaths worldwide, and its incidence is increasing. Although some cases are associated with immunodeficiency, autoimmunity, or viral infections, in most cases the causes of NHL are not understood. However, there have been some important advances in our understanding of the development of healthy lymphocytes and the pathogenesis of NHL over the past 10 years. These advances have been accompanied by an improvement in treatment for NHL. Before the late 1990s, the only treatment option available was cytotoxic chemotherapy. In the past 10 years, however, high-dose chemotherapy and autologous stem-cell reconstitution have become established parts of treatment for aggressive lymphoma. Furthermore, monoclonal antibodies have become another therapeutic option. Rituximab (an anti-CD20 monoclonal antibody) is the most advanced monoclonal antibody in clinical trials and has become part of standard treatment for some lymphomas. Rituximab, and many other monoclonal antibodies, continue to be assessed in clinical studies. Monoclonal antibodies can be used alone or in combination with standard-dose or high-dose chemotherapy, and they can also be conjugated to radionuclides to enhance cytotoxicity. Here, we review advances in the treatment of NHL that have occurred over the past 10 years.

Distinct Patterns of Cytokine and Angiogenic Factor Modulation and Markers of Benefit for Vandetanib and/or Chemotherapy in Patients With Non–Small-Cell Lung Cancer

PURPOSE There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. METHODS Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. RESULTS VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk. CONCLUSION Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.

Prognosis and Management of Patients With Node-Negative Invasive Breast Carcinoma That Is 1 cm or Smaller in Size (stage 1; T1a,bN0M0): A Review of the Literature

PURPOSE Mammographic screening has led to an increase in the number of small, node-negative breast cancers being diagnosed. Node-negative breast cancers that are < or = 1 cm are stage T1a,bN0M0. Controversy surrounds the prognosis of these patients with locoregional therapy only and the need for adjuvant systemic therapy. METHODS We performed a comprehensive review of the literature describing outcome and prognostic factors in stage T1a,bN0M0 breast cancer. We also reviewed current guidelines for systemic therapy in these patients. RESULTS Early studies reported 10-year relapse-free survival (RFS) rates higher than 90% without adjuvant systemic therapy, but some more recent data suggest inferior outcomes. High tumor grade is the most consistent factor associated with poor prognosis. Other adverse prognostic factors are younger age, lymphovascular invasion (LVI), high Ki-67, and larger tumors within the T1a,b subgroup. Patients with high-grade tumors and/or LVI may have 10-year RFS rates of less than 75% in the absence of systemic therapy. The prognostic significance of hormone receptor status is unclear. Current guidelines for the systemic management of early-stage breast cancer differ when applied to stage T1a,bN0M0, reflecting the controversial nature of the issue. CONCLUSION Adjuvant systemic therapy is advisable for most patients with stage T1a,bN0M0 breast cancer who have grade 3 tumors and/or LVI. Other T1a,bN0M0 cases should be considered for systemic therapy based on clinicopathologic factors with known prognostic significance and assessment of the risk-benefit ratio. More reliable tools are needed to assess the prognosis of patients with stage T1a,bN0M0 breast cancer and their potential to benefit from specific therapeutic agents.

Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer

Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: vandetanib versus gefitinib (study 3), docetaxel ± vandetanib (study 6), and carboplatin-paclitaxel and/or vandetanib (study 7). In study 7, vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving vandetanib versus gefitinib or vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either vandetanib monotherapy or carboplatin-paclitaxel.

Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vandetanib (ZD6474)and AZD2171 in Lung Cancer

Vascular endothelial growth factor (VEGF) is a rational target for advanced non–small cell lung cancer (NSCLC), a hypothesis validated by the recent Eastern Cooperative Oncology Group E4599 trial showing that the addition of the VEGF monoclonal antibody bevacizumab to chemotherapy prolongs overall survival. Several new tyrosine kinase inhibitors targeting the VEGF pathway are currently in advanced clinical development for NSCLC and offer several possible advantages compared with monoclonal antibodies, including oral administration, more flexible dosing, a broader spectrum of target inhibition, and different toxicity profiles. Among these agents, vandetanib (ZD6474), an inhibitor of the VEGF receptor (VEGFR)-2 and epidermal growth factor receptor tyrosine kinase, has been the most extensively studied. In a randomized phase II study of patients with platinum-refractory NSCLC, including squamous histology, vandetanib prolonged progression-free survival compared with gefitinib. In another phase II trial, an improvement in progression-free survival was observed for vandetanib in combination with docetaxel compared with docetaxel alone. AZD2171 is an inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 and other tyrosine kinases that has shown clinical activity in NSCLC in combination with carboplatin and paclitaxel. Several phase III trials are under way testing these agents either as monotherapy or in combination with chemotherapy in patients with lung cancer. Early results with these agents, and others being tested, raise the possibility that there will eventually be multiple VEGF-targeted therapies available in the clinic that can potentially benefit a broader range of patients with advanced-stage NSCLC.

Neoadjuvant systemic therapy for breast cancer: an overview and review of recent clinical trials

Neoadjuvant chemotherapy (NAC) is long established as part of the multi-modality management of locally advanced breast cancer or inflammatory breast cancer, leading to significantly improved outcome. Numerous recent studies have compared the use of anthracycline-based NAC with adjuvant chemotherapy in earlier-stage disease, and have shown equivalent disease-free and overall survival rates with increased breast conservation rates. These studies have also shown that a pathological complete response after NAC is associated with improved long-term outcome. More recently, the taxanes have been introduced into clinical trials of NAC with increased overall and pCR rates. However, there is no evidence that the addition of taxanes to neoadjuvant anthracycline-based chemotherapy significantly improves long-term disease free survival or overall survival. This paper reviews these trials, as well as trials of dose-dense and trastuzumab-containing NAC regimens. The review discusses the potential for NAC to replace prolonged adjuvant trials in the assessment of new therapeutic agents (using pathological complete response as a surrogate for long-term outcome), to be used as an in vivo chemosensitivity assay to guide further treatment, and to identify molecular markers that correlate with tumour sensitivity or resistance to chemotherapeutic agents so that the treatment of patients can be individualised.

A phase II study of lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck

Objective:Treatment options for recurrent squamous cell carcinoma of the head and neck (SCCHN) following platinum-based therapy are limited. Lonafarnib is a potent, specific inhibitor of farnesyl transferase that demonstrated marked antitumor activity as monotherapy in treatment-naive SCCHN in a phase Ib study. A phase II study of lonafarnib was conducted to determine its efficacy and safety in patients with recurrent, platinum-refractory SCCHN. Methods:This was an open-label, phase II, single-center study in patients with recurrent SCCHN after platinum-based therapy. A Simon 2-stage design was used, with a plan to close the study to further accrual if <2 of the first 15 patients had objective responses. Patients were treated with lonafarnib 200 mg twice daily (b.i.d.) by mouth continuously in 4-week cycles. Results:Fifteen patients with baseline Eastern Cooperative Oncology Group PS 0–1 and median age 57 years were enrolled. Twelve patients had received at least 2 previous chemotherapy regimens. Median duration of treatment with lonafarnib was 61 days. No objective response was observed. Seven (47%) patients maintained stable disease through ≥3 cycles of therapy. Median time to progression and survival time were 2.04 and 9.17 months, respectively. Most treatment-related toxicities were grade 1–2, and there were no treatment-related deaths. Conclusions:Lonafarnib at a dose of 200 mg b.i.d. was well-tolerated. However, there were no objective responses observed in the first 15 patients enrolled in this study, and the study was closed to further accrual, as per predefined criteria. Further evaluation of lonafarnib in platinum-refractory SCCHN is not planned.

The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer

Purpose: Resistance to VEGFR inhibitors is a major obstacle in the treatment of non–small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors. Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes. Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In patients with cancer receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. Clin Cancer Res; 23(18); 5489–501. ©2017 AACR.

Small Cell Carcinoma of the Lung

Small cell lung cancer (SCLC) is a malignant epithelial tumor that occurs almost exclusively in smokers. It accounts for approximately 13% of lung cancer diagnoses in the United States annually. For treatment planning, SCLC is divided into either limited stage disease (LS-SCLC- that is, disease is confined to the chest and can be encompassed within a tolerable radiation field)- or extensive stage disease (ES-SCLC). Approximately 60-70% of patients with SCLC have extensive stage disease (ES-SCLC) at diagnosis. With treatment, the median survival times are about 18-30 months in LS-SCLC and 8-12 months in ES-SCLC.

Neoadjuvant therapy of breast cancer: Current status

Primary systemic therapy is defined as the first systemic treatment a patient receives after cancer is diagnosed, and indicates that subsequent therapies are intended. It is also known as preoperative, induction, or neoadjuvant systemic therapy. Because of high tumor regression rates, primary systemic chemotherapy has become part of the standard of multidisciplinary care for patients with locally advanced and inflammatory breast cancer.An expert panel has reviewed all large randomized clinical trials of primary systemic chemotherapy versus adjuvant systemic therapy in operable breast cancer and concluded that both result in equivalent disease-free, local recurrence-free, and overall survival rates when compared head to head. However, the rate of successful breast-conserving surgery is statistically significantly increased in patients who receive primary chemotherapy; thus, primary systemic therapy is a reasonable alternative for patients with operable breast cancer who are deemed to be appropriate candidates for mastectomy but who desire breast-conserving surgery, or for those patients who desire less extensive breast-conserving surgery. The addition of taxanes or trastuzumab to primary systemic chemotherapy results in a significant increase in the overall and complete clinical response rates and in pathologic complete response (pCR) rates.A poor response to primary systemic chemotherapy is a predictor of poor prognosis and of a high risk of recurrence, irrespective of the type of surgery performed. In contrast, a pCR of the tumor or of cytologically documented axillary lymph node disease correlates strongly with both prolonged disease-free survival and overall survival, and occurs in 6–31% of patients, depending on the breast cancer subtype, the particular chemotherapy regimen used, and on the definition of what constitutes a pCR that is used by the particular group. Thus, pCR may be regarded as one major goal of primary systemic chemotherapy. Emerging data suggest that the achievement of pCR is associated with an excellent long-term outcome, regardless of the therapy regimen that results in pCR.If this association of pCR with outcome, regardless of the therapy regimen resulting in pCR, is confirmed, the application of newer gene- or protein-based technologies to predict at diagnosis which patients will achieve pCR in response to various biologic therapies and chemotherapies will have important clinical implications. In addition, the ability of pCR to predict an excellent long-term outcome may, with further study, become routinely applicable to the study of novel anticancer agents in the adjuvant setting, perhaps ultimately allowing us to avoid the need to perform large expensive trials with many years of follow-up.