Gail Walker

Neoadjuvant Treatment for Resectable Cancer of the Esophagus and the Gastroesophageal Junction: A Meta-Analysis of Randomized Clinical Trials

Background: There is no general agreement on the effect of neoadjuvant treatment for esophageal cancer on patient survival.Methods: A meta-analysis was performed to determine the effect of preoperative treatment on survival of patients with resectable esophageal cancer and the effect of preoperative treatment on patient mortality. A standard variance-based method was used to derive summary estimates of the absolute difference in both 2-year survival and treatment-related mortality.Results: Eleven randomized trials involving 2311 patients were analyzed. Preoperative chemotherapy improved 2-year survival compared with surgery alone: the absolute difference was 4.4% (95% confidence interval [CI], .3%–8.5%). Marginal evidence of heterogeneity was eliminated by restricting attention to the four most recent studies, which increased the estimate to 6.3% (95% CI, 1.8%–10.7%). For combined chemoradiotherapy, the increase was 6.4% (nonsignificant; 95% CI, −1.2%–14.0%). Treatment-related mortality increased by 1.7% with neoadjuvant chemotherapy (95% CI, −.9%—4.3%) and by 3.4% with chemoradiotherapy (95% CI, −.1%–7.3%), compared with surgery alone.Conclusions: There seems to be a modest survival advantage for patients who receive neoadjuvant chemotherapy followed by surgery, as compared with surgery alone. There is an apparent increase in treatment-related mortality, mainly for patients who receive neoadjuvant chemoradiotherapy.

Randomized Trial of Hypofractionated External-Beam Radiotherapy for Prostate Cancer

PURPOSE To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and/or clinical disease failure (BCDF) in men treated primarily for prostate cancer. PATIENTS AND METHODS Between June 2002 and May 2006, men with favorable- to high-risk prostate cancer were randomly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional fractionation intensity-modulated radiation therapy [CIMRT]) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated IMRT [HIMRT]); the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions. High-risk patients received long-term androgen deprivation therapy (ADT), and some intermediate-risk patients received short-term ADT. The primary end point was the cumulative incidence of BCDF. Secondarily, toxicity was assessed. RESULTS There were 303 assessable patients with a median follow-up of 68.4 months. No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related (ADT use and length) factors. The 5-year rates of BCDF were 21.4% (95% CI, 14.8% to 28.7%) for CIMRT and 23.3% (95% CI, 16.4% to 31.0%) for HIMRT (P = .745). There were no statistically significant differences in late toxicity between the arms; however, in subgroup analysis, patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT. CONCLUSION The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks. Men with compromised urinary function before treatment may not be ideal candidates for this approach.

Immunohistochemical expression of estrogen receptor in adenocarcinomas of the lung: the antibody factor.

BackgroundImmunohistochemistry for estrogen receptor may be used to distinguish metastatic breast cancers from adenocarcinomas of other sites, including those of the lung. The estrogen receptor exists as 2 subtypes, α and β. Estrogen receptor α is the predominant subtype expressed by more than two-thirds of human breast cancers. Adenocarcinomas of lung origin may also express estrogen receptor, primarily the β subtype. Human estrogen receptor α is highly homologous to estrogen receptor β and consequently, antibodies used to detect estrogen receptor α in breast carcinomas may detect estrogen receptor β in pulmonary adenocarcinomas. We investigated the immunohistochemical expression of estrogen receptor in proven primary lung adenocarcinomas using 3 anti-estrogen receptor α antibodies: mouse monoclonal 1D5, 6F11, and rabbit monoclonal SP1. DesignNinety-two pulmonary adenocarcinomas (53 women and 39 men) confirmed by clinical presentation and positive immunohistochemistry for thyroid transcription factor-1 (TTF-1) were included in this study. There were 19 incisional biopsies and 73 excisional specimens. Immunohistochemistry for estrogen receptor using antibodies 1D5, 6F11, and SP1 was performed on formalin-fixed, paraffin-embedded tissue following antigen retrieval. Any nuclear reactivity for estrogen receptor was considered a positive result. ResultFocal positive nuclear reaction for estrogen receptor was detected in 7 (7.6%) cases of primary pulmonary adenocarcinoma using antibody 1D5, 13 (14.1%) using 6F11, and 25 (27.2%) using SP1. The differences in reactivity for estrogen receptor in pulmonary adenocarcinomas between SP1 and 1D5, and between SP1 and 6F11 were statistically significant (P<0.001). Positive cases showed only a focal pattern of staining with each of the 3 antibodies. There was no significant difference in reactivity for estrogen receptor in pulmonary adenocarcinomas of men and women. Positive staining was highest in nonmucinous bronchioloalveolar adenocarcinomas for all of the antibodies, and for SP1, variation by histologic subtype was significant (P<0.001). ConclusionsSP1 has a significantly higher detection rate for the expression of estrogen receptor in pulmonary adenocarcinomas when compared with either 1D5 or 6F11. Caution should therefore be exercised in the use of this antibody alone in distinguishing a metastatic breast from a primary pulmonary adenocarcinoma.

Is adjuvant 5-FU-based chemoradiotherapy for resectable pancreatic adenocarcinoma beneficial? A meta-analysis of an unanswered question

The objective of this study was to determine the effect, if any, on survival of adjuvant 5-FU-based chemoradiotherapy following pancreaticoduodenectomy for pancreatic carcinoma. A systematic review of the published literature was undertaken. Survival estimates were derived from published reports. Five prospective studies (4 level I, 1 level II) with a total of 607 (229 surgery only; 378 surgery- adjuvant) patients followed for survival met selection criteria. Two-year survival ranged from 15%–37% in the surgery only group and 37%–43% in the surgery and adjuvant groups. The survival advantage (absolute difference) ranged from 3%–27% and no individual study achieved statistical significance (5%). Although clinical heterogeneity existed in surgery-alone control groups with regard to trial date, no statistical heterogeneity was detected (P = 0.459, χ2 test), allowing pooling of survival data. Using a fixed effects model, the summary estimate showed an absolute 2-year survival benefit with adjuvant therapy of 12% (95% CI, 3%–21%, P = 0.011). Trials after 1997 (n = 3) indicated a survival benefit of 8% to patients receiving adjuvant therapy (95 % CI, −3–18 %, P = 0.145). The result was not statistically significant, and there was no evidence of heterogeneity (P = 0.626, χ2 test). Summary estimates were unchanged when the analysis was performed with a random effects model. 5-FU based chemotherapy with radiotherapy given after resection imparts a small overall survival benefit of 2 years. The benefit of 5FU-based adjuvant therapy, however, has declined in recent years, and its significance remains unproven in the context of current diagnostic and surgical practice.

Oncogenic IRFs Provide a Survival Advantage for Epstein-Barr Virus- or Human T-Cell Leukemia Virus Type 1-Transformed Cells through Induction of BIC Expression

ABSTRACT miR-155, processed from the B-cell integration cluster (BIC), is one of the few well-studied microRNAs (miRNAs) and is involved in both innate immunity and tumorigenesis. BIC/miR-155 is induced by distinct signaling pathways, but little is known about the underlying mechanisms. We have identified two conserved potential interferon (IFN) regulatory factor (IRF)-binding/interferon-stimulated response element motifs in the Bic gene promoter. Two oncogenic IRFs, IRF4 and -7, in addition to some other members of the family, bind to and significantly transactivate the Bic promoter. Correspondingly, the endogenous levels of IRF4 and -7 are correlated with that of the BIC transcript in Epstein-Barr virus (EBV)-transformed cells. However, RNA interference studies have shown that depletion of IRF4, rather than of IRF7, dramatically decreases the endogenous level of BIC by up to 70% in EBV- or human T-cell leukemia virus type 1 (HTLV1)-transformed cell lines and results in apoptosis and reduction of proliferation rates that are restored by transient expression of miR-155. Moreover, the endogenous levels of the miR-155 target, SHIP1, are consistently elevated in EBV- and HTLV1-transformed cell lines stably expressing shIRF4. In contrast, transient expression of IRF4 decreases the SHIP1 level in EBV-negative B cells. Furthermore, the level of IRF4 mRNA is significantly correlated with that of BIC in adult T-cell lymphoma/leukemia (ATLL) tumors. These results show that IRF4 plays an important role in the regulation of BIC in the context of EBV and HTLV1 infection. Our findings have identified Bic as the first miRNA-encoding gene for IRFs and provide evidence for a novel molecular mechanism underlying the IRF/BIC pathway in viral oncogenesis.

P63 differentiates subtypes of nonsmall cell carcinomas of lung in cytologic samples: implications in treatment selection.

Bevacizumab in combination with carboplatin and paclitaxel improves overall response and survival in patients with advanced or recurrent nonsmall cell lung carcinoma. However, this drug is not recommended in patients with squamous cell carcinoma or neoplasms with a dominant squamous component. Therefore, identification of squamous cell differentiation has therapeutic implications. In many instances, cytology is the diagnostic tool of choice; however, routine cytomorphology is limited in classification of nonsmall cell carcinomas into squamous and nonsquamous subtypes. The aim of this study was to identify the value of p63 immunocytochemical analysis in this distinction.

Adoptively Transferred Tumor-Specific T Cells Stimulated Ex vivo Using Herpes Simplex Virus Amplicons Encoding 4-1BBL Persist in the Host and Show Antitumor Activity In vivo

4-1BB is a T-cell costimulatory receptor which binds its ligand 4-1BBL, resulting in prolonged T cell survival. We studied the antitumor effects of adoptively transferred tumor-specific T cells expanded ex vivo using tumors transduced with herpes simplex virus (HSV) amplicons expressing 4-1BBL as a direct source of antigen and costimulation. We constructed HSV amplicons encoding either the 4-1BBL (HSV.4-1BBL) or B7.1 (HSV.B7.1) costimulatory ligands. Lewis lung carcinoma cells expressing ovalbumin (LLC/OVA) were transduced with HSV.4-1BBL, HSV.B7.1, or control HSV amplicons and used to stimulate GFP+ OVA-specific CD8+ T cells (OT-1/GFP) ex vivo. Naive or ex vivo stimulated OT-1/GFP cells were adoptively transferred into LLC/OVA tumor-bearing mice. Higher percentages of OT-1/GFP cells were seen in the peripheral blood, spleen, and tumor bed of the HSV.4-1BBL-stimulated OT-1/GFP group compared with all other experimental groups. OT-1 cells identified within the tumor bed and draining lymph nodes of the HSV.4-1BBL-stimulated OT-1 group showed enhanced bromodeoxyuridine (BrdUrd) incorporation, suggesting ongoing expansion in vivo. Mice receiving HSV.4-1BBL-stimulated OT-1/GFP had significantly decreased tumor volumes compared with untreated mice (P<0.001) or to mice receiving naive OT-1/GFP (P<0.001). Transfer of HSV.B7.1-stimulated OT-1/GFP did not protect mice from tumor. Mice that received HSV.4-1BBL-stimulated OT-1/GFP exhibited increased cytolytic activity against LLC/OVA and higher percentages of Ly-6C+ OT-1/GFP in the spleen and tumor bed compared with controls. Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44+Ly-6C+CD62L- effector memory T cells.

Efficacy and Toxicity of Chemoradiotherapy with Carboplatin and Irinotecan Followed by Consolidation Docetaxel for Unresectable Stage III Non-small Cell Lung Cancer

Introduction: In 2003, consolidation docetaxel was a promising concept for unresectable stage IIIA/B nonsmall cell lung cancer (NSCLC). To test the hypothesis that chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel would be feasible and clinically active, we conducted a phase II study. Methods: Thirty-two patients with unresectable stage IIIA/B NSCLC received irinotecan (30 mg/m2) and carboplatin dosed to a target area under the concentration curve of 2, each administered weekly for 7 weeks. Concurrent radiotherapy was administered more than 7 weeks to a total dose of 63 Gy in 35 fractions. Consolidation docetaxel (75 mg/m2) was administered every 3 weeks for 3 doses 4 weeks after chemoradiotherapy. The primary end point was objective response rate by RECIST. Results: Complete responses occurred in 4 patients and partial responses occurred in 14, for an objective response rate of 56.3% (95% confidence interval [CI], 37.7-73.6%). Median progression-free survival was 6.5 months (95% CI, 4.6-13.5); median duration of survival was 14.8 months (95% CI, 6.9-27.3). The most common hematologic toxicity was leukopenia, which were grade 3 or 4 in 16 patients (50%). Radiation pneumonitis (grade ≥2) occurred in 13 of 31 treated patients (42%). Conclusions: These findings suggested that concurrent chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel is clinically active based on median survival in patients with unresectable stage III NSCLC; however, the 42% incidence of clinical radiation pneumonitis was unexpected and warrants further investigation to determine the mechanism and preventive strategies.

Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

PURPOSE Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). METHODS AND MATERIALS Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV46 and CTV60, respectively). MTVCho and MTVNAA were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. RESULTS The MRSI coverage of the brain was between 70% and 76%. The MTVNAA were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTVCho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV46 and CTV60. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTVCho for these patients were outside of CTV60. CONCLUSIONS This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information.

P63 differentiates subtypes of nonsmall cell carcinomas of lung in cytologic samples

Bevacizumab in combination with carboplatin and paclitaxel improves overall response and survival in patients with advanced or recurrent nonsmall cell lung carcinoma. However, this drug is not recommended in patients with squamous cell carcinoma or neoplasms with a dominant squamous component. Therefore, identification of squamous cell differentiation has therapeutic implications. In many instances, cytology is the diagnostic tool of choice; however, routine cytomorphology is limited in classification of nonsmall cell carcinomas into squamous and nonsquamous subtypes. The aim of this study was to identify the value of p63 immunocytochemical analysis in this distinction.