Prior Chemoradiation Research Articles

Germline single-nucleotide polymorphisms (SNPs) associated with response of urothelial carcinoma (UC) to platinum-based therapy: The role of the host.

236 Background: Platinum-based therapy improves outcome in neoadjuvant and metastatic UC. Since cell-line and human subject studies in other cancers show germline associations with platinum response, we hypothesized that germline variation also identifies genes that determine UC response to platinum-based therapy. Methods: Saliva or blood was prospectively collected from 651 UC patients (pts) diagnosed between 1984 and 2010. SNPs (n=80) were selected based on previously reported associations with UC and/or platinum response and genotyped using Sequenom MassArray iPLEX system. Samples and SNPs were filtered for genotyping rate (<0.8), minor allele frequency (<0.05) and departures from Hardy-Weinberg equilibrium (<1E-03). Clinical data were ascertained and linked with the genomic data in an anonymized manner. This analysis focused on 199 pts who received cisplatin or carboplatin and were eligible for response assessment (RES=partial response or complete response, n=90). Associations between SNPs and RES were tested using one and two degree of freedom tests. Results: Sixty-nine pts received neoadjuvant therapy (RES=54%), 126 chemo-naive pts received first-line metastatic treatment (RES=37%) and 4 received systemic treatment after prior chemoradiotherapy (RES=25%). We expected 4 associations due to chance alone at p < 0.05. However, on univariate analysis using a 2 degree of freedom test, 9 SNPs were associated (p < 0.05) with RES. Individual odds ratios (ORs) ranged from 0.32 to 3.29 with p-values ranging from 0.006 to 0.05. In analysis of rs9344 (CCND1) in all treated pts, 75/148 (51%) responded with AG/GG compared to 12/44 (27%) with AA [p=0.005312, OR 2.74 (CI 1.34, 5.92)]. In neoadjuvant pts treated with cisplatin, rs9344 analysis showed 29/48 (60%) responses in AG/GG pts compared to 5/17 (29%) with AA [p=0.026, OR 3.66 (CI 1.16, 13.1)]. Conclusions: We identified associations between 9 SNPs and response of UC to platinum-based therapy that are biologically and clinically relevant. A larger study will be required to independently validate these findings. Additional investigation of associations with time to metastasis and overall survival is ongoing. [Table: see text]

Challenging cases encountered in colorectal cancer screening for Lynch syndrome reveal novel findings: nucleolar MSH6 staining and impact of prior chemoradiation therapy

Many pathology laboratories have developed specific screening protocols to detect patients with Lynch syndrome. With recent recommendations to test all patients with newly diagnosed colorectal cancer for Lynch syndrome, the volume of testing will increase, and the most economic and reliable screening test will prevail. Although the detection of microsatellite instability by polymerase chain reaction and the detection of loss of the mismatch repair proteins by immunohistochemistry can each be used as a screening tool, each methodology has its strengths and weaknesses. During the time of our study, we used both polymerase chain reaction and immunohistochemistry to screen for Lynch syndrome in colorectal cancer specimens. We encountered 21 cases that posed significant interpretive challenges. A previously unpublished pattern of nucleolar MSH6 staining and potential spurious results induced by chemoradiation therapy are described. We feel that it is important to report these cases so that potential pitfalls in screening for Lynch syndrome can be avoided.

Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response observed in adenocarcinoma.

41 Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial combining sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We are studying single agent sorafenib in a phase II trial with the primary endpoint to assess progression free survival (PFS). Secondary endpoints include response and therapy tolerance. Methods: Patients (pts) with measurable metastatic E and GEJ cancer with no more than 3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Sixteen of 35 pts have been accrued and 14 are currently evaluable. 13 male, 3 female, median KPS 80%, age 58, GEJ 7, E 9, squamous 2, adenocarcinoma (AC)14. An ongoing complete response (11+ months) was observed in a pt with biopsy proven metastatic neck lymphadenopathy (E primary AC, recurrence after prior chemoradiotherapy and surgery). A second pt (GEJ AC) had protracted stable disease in bulky celiac node disease (15+ months). Grade 3 toxicity was limited to skin rash (1 pt), hand foot reaction (1 pt), and fatigue (1 pt). Only 3 of 14 pts (21%) had early disease progression at 2 months or less. Median PFS 4 mos, 4 patients (29%) continue on therapy for more than 7 months. The majority of tumors tested positive for phospho-erk by immunohistochemistry (11/14, 79%). Conclusions: The observation of a durable complete response and protracted stable disease to sorafenib in E cancer is remarkable. Further accrual continues to define PFS. Supported by a grant from Bayer. [Table: see text]

Does Prosthesis Diameter Matter?

To assess the impact of tracheoesophageal voice prosthesis diameter and treatment status on prosthesis-related complications. Historical cohort study. Single academic medical institution. Patients who underwent total laryngectomy (TL) between 1996 and 2008 were divided into 2 subgroups according to prosthesis diameter: 16F (n = 19) and 20/22F (n = 71). Each patient only used 1 diameter of prosthesis. Time to leakage through the prosthesis, number of episodes of leakage around the prosthesis, number of prosthesis dislodgements, and length changes after the first 6 months were chosen as outcomes of interest. Analysis included 90 patients. Analysis of selected complications by prosthesis diameter revealed no significant differences for time to leakage through the prosthesis, number of leaks around the prosthesis, or dislodgement. Larger diameter prosthesis use was associated with a greater number of length changes (P = .008). Multivariable regression analysis did not find any significant association between prosthesis-specific complications and prosthesis diameter when controlling for other variables. Prior radiation was associated with an increased number of size changes (β = 2.0, P = .004) and a decrease in time to leakage through the prosthesis (β = -4.4, P = .048), after controlling for other variables. Prosthesis diameter is not associated with an increased prevalence of certain voice prosthesis complications in laryngectomy patients, regardless of initial treatment modality, whereas prior radiation or chemoradiation is associated with complications. These data suggest that factors affecting tissue health, rather than prosthesis size, may be more responsible for prosthesis complications.

A Phase II Study of Imatinib in Patients with Advanced Anaplastic Thyroid Cancer

Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.

Prognostic Factors for Survival in Patients With Recurrent Cervical Cancer Previously Treated With Radiotherapy

The aim of this study was to identify the prognostic factors and to establish a model for the prediction of life expectancy in patients with recurrent cervical cancer that had previously been treated with radiotherapy. The records of consecutive women with recurrent cervical cancer after radiotherapy were retrospectively reviewed. Primary disease, follow-up, and recurrence data were collected. Univariate and multivariate analyses of prognostic factors of survival were performed. A total of 162 patients were included in our database. The median survival after recurrence was 15 months. Multivariate analysis revealed that symptom status, the site of relapse, prior chemoradiotherapy, and treatment modality were significant prognostic factors in terms of survival after recurrence. Patient survival was inversely correlated with the number of these prognostic factors. When the patients were divided into 3 prognostic groups, (low risk: patients with no poor prognostic factors; intermediate: patients with one poor prognostic factor; and high-risk: patients with more than 2 poor prognostic factors), the patients in the high-risk group had a significantly shorter survival (median, 10 months) than those with one risk factor (median, 20 months) or no risk factors (median, 36 months). Symptom status, the site of relapse, prior chemoradiotherapy, and treatment modality are significant prognostic factors in patients with recurrent cervical cancer that had previously been treated with radiotherapy. Our prognostic model, composed of 4 clinical variables, may enable physicians to predict survival more accurately.

Breast density and calculated breast cancer risk.

1556 Background: Breast density is an independent risk factor for breast cancer; associated with an OR ≥ 4 for very dense breast tissue. Given the prevalence of breast density, the attributable risk may be as high as 33%. The majority of density is determined by heredity however, many factors influence density. Several techniques to quantify density have been described. Here, we evaluate density using the visual analog scale and correlate density with calculated breast cancer risk in a population of women at increased risk for breast cancer. Methods: The High Risk Breast Program database, for women with strong family history, BRCA mutations, high risk pathology or prior chemoradiotherapy for lymphoma, was initiated in 2003 and contains 450+ women. A subset of 37 women ranging in age from 28-63 with a mean lifetime Gail Risk of 22% is the subject of this analysis. Data collected included: mammograms, a medical and dietary history, and BMI. Breast density was interpreted (at baseline and 2 years) from mammograms using a visual analogue scale and reliability was evaluated. Multivariate analyses were performed, using Pearson correlations. Results: Intra-rater variability for density determination at 0 (r = 0.866) and 2 (r = 0.912) year time points was comparable to published studies. Of the variables analyzed, BMI and weight had the most significant influence upon density, with an inversely proportional relationship at both time points (each p = 0.001). Percent density had a significant inversely proportional relationship to short-term (5 year) Gail Risk at both 0 (r = -0.396; p = 0.034) and 2 year (r = -0.359; p = 0.043) time points. Conclusions: Our early results demonstrate the reliability of the visual analogue scale (with high intra-rater variability and correlation with known influences). The negative correlation with risk (also noted by Cuzick et. al 2009) bears further exploration. Breast density may not be an important predictor of risk in high-risk populations. Study accrual is ongoing, and further analysis will clarify this trend. Future studies will need to evaluate the influence of breast density in high and average risk populations. No significant financial relationships to disclose.

Clinical Outcomes of Using a Conservative Approach of Late Esophageal Stent Placement in Palliation of Malignant Dysphagia

Esophageal stents have been used as first-line treatment for palliation of malignant dysphagia, but this is associated with significant complications. The present study evaluated clinical outcomes and survival in patients with malignant dysphagia with esophageal stent placement who did not respond to prior chemoradiation or endoscopic modalities. Patients with esophageal cancer, who had esophageal stents, were retrospectively reviewed from the electronic medical records. The patient demographics, type of stent placed, dysphagia scores, stent-related complications, and survival were recorded. Thirty-five patients with esophageal cancer received a total of 41 stents. There were 25 males and 10 females with mean age of 69.8 years. Twenty-two patients had esophageal adenocarcinoma, ten patients had squamous cell carcinoma, and three had poorly differentiated tumor. Esophageal malignancy was early stage (I, II) in 10 patients and advanced (III, IV) in 24 patients. Three patients had upper esophageal involvement, eight patients had mid-esophageal involvement; distal esophageal malignancy was present in 24 patients with 10 patients having gastroesophageal junction involvement. Six patients presented with tracheoesophageal fistula. Nine patients had prior esophagectomy. Thirty-three patients had chemoradiation, and 32 patients had other endoscopic therapies previously. Twelve of the 35 (33%) patients developed stent-related complications; nine patients had dysphagia due to various causes; one patient each developed aspiration, intractable hiccups, and intractable vomiting after stent placement, respectively. Nine patients underwent a repeat esophagogastroduodenoscopy. Development of stent-related complications was not significantly associated with poor survival. The clinical outcomes for patients with esophageal stent placement for malignant dysphagia after chemoradiation and other endoscopic treatments is not worse than that reported in patients where esophageal stent placement was used as first-line treatment.

Immortalization of Human Carcinoma-Associated Fibroblasts from Primary Colorectal Carcinomas

Introduction: Reciprocal interplay bewteen epithelial and stromal cells contributes to the initiation, progression and metastasis of colorectal cancer. The importance of carcinoma-associated fibroblasts (CAFs) in tumor develoment is highlighted by the observation that nontumorigenic prostate epithelial cells can form tumors in nude mice when co-implanted with CAF, but not when co-implanted with fibroblasts from benign prostatic hypertrophy. The precise role of colorectal CAFs in tumor-stroma interactions has been difficult to study, in part because of the difficulty of obtaining primary CAFs in sufficient quantity for experiments. Once isolated, the CAFs can be passaged for a limited number of times before they undergo senescence. Further characterization of human colorectal CAFs would provide the basis for stromal-specific therapeutic targeting in colorectal cancers. The purpose of this study was two-fold: 1) immortalize human CAFs derived from colorectal cancers in order to begin to investigate their influence on human colorectal cancer cells and 2) document gene-specific changes attributable to the immortalization process. Methods: Freshly dissected and dissociated cells were cultured from a resected colon cancer specimen under an IRB-approved protocol. The patient had not received prior chemoradiotherapy. The cells were cultured on collagen I and the purity of the fibroblast culture was verified by immunohistochemistry. Fibroblasts are positive for vimentin and/or α-smooth muscle actin, but negative for cytokeratin. CAFs were infected with lentiviral vectors containing a CMV promotor upstream of SV40 Large T antigen and human telomerase. Total RNA was extracted using RNAqueous (Ambion) from triplicate cultures of transformed (t)CAFs and parental (p)CAFs. The purity and concentration of the RNA samples were determined using Agilent 2100 Bioanalyzer. Samples were hybridized to Affymetrix Gene Chips (HGU133 Plus 2.0). Analyses using the Partek Genomics Suite included routine quality controls, raw data background subtraction and normalization. Differentially expressed candidate genes were identified using the Benjamani-Hochberg multiple hypothesis comparisons (ANOVA, p<0.01 and p<0.005) to decrease the false discovery rate. Ingenuity Pathways analyses were performed to identify differences between the t- and p-CAFs. Results: ANOVA identified 2779 and 648 genes that were significant at the p≤0.01 and 0.005 level, respectively. The major pathways representing the genes differentially expressed bewteen the t- and p-CAFs include: 1) the transcriptional regulator TP53 2) growth factor TGFB1, 3) mitogen-activated protein kinase pathways (p38 and p-extracellularly regulated kinase), and 4) the transcriptional regulator nuclear factor-κB. As expected, one canonical pathway that was altered by the transformation, were genes involved in cell cycle and G1/S checkpoint regulation. Conclusions: The immortalization and subsequent careful characterization of human colorectal CAFs provides an invaluable tool for further study of stromal-epithelial interactions in colorectal carcinogenesis and metastasis. Although genes related to the cell cycle has been significantly altered, future studies are required to verify that the t-CAFs alone are non-tumorigenic in nude mice, similar to the p-CAFs. Additionally, immortalized normal fibroblasts derived from the normal a colonic mucosa will need to be generated as an important control.

Independent histological risk factors for lymph node metastasis of superficial esophageal squamous cell carcinoma; implication of claudin-5 immunohistochemistry for expanding the indications of endoscopic resection

Endoscopic resection is curative for superficial esophageal squamous cell carcinoma (ESCC) limited to the lamina propria. Endoscopic resection is not recommended for superficial ESCC invading muscularis mucosa or submucosa, however, because of the high frequency of lymph node metastasis (LNM) in such patients. Methods to more accurately predict LNM by analysis of endoscopically resected specimens are needed. Patients with superficial ESCC who underwent surgery without prior chemoradiotherapy (n= 110) were retrospectively examined to determine whether LNM correlated with immunohistochemical parameters and conventional histological parameters, including depth of invasion and vascular permeation. Cancer cell expression of claudins-1, 5, and 7, E-cadherin, beta-catenin, and matrix metalloproteinase 7 was evaluated. Univariate analysis revealed that LNM correlated with claudin-5 expression, but not any other immunohistochemical parameter examined. Multivariate analysis revealed three independent risk factors for LNM: aberrant claudin-5 expression in cancer cells (odds ratio; OR [95% confidence interval]= 4.61[1.44-14.77]), depth of submucosal invasion greater than 200 microm (3.55 [1.02-13.17]), and positive lymphatic permeation (3.34 [1.22-9.15]). LNM was found in one of 29 (3.4%) patients with none of these three risk factors, and in 32 of 81 (39.5%) patients with one or more of these risk factors. In superficial ESCC, routine analysis of claudin-5 expression in cancer cells together with depth of invasion and lymphatic permeation may be useful for predicting LNM and thereby reducing the number of patients undergoing additional surgery after successful endoscopic resection.

A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial IND.184

Objective Vascular endothethial growth factor (VEGF) and stem cell factor (c-KIT) signaling may play a role in the development and progression of cervical carcinoma. Sunitinib malate is an oral, multi-targeted tyrosine kinase inhibitor that inhibits receptors for VEGF, c-Kit and platelet-derived growth factor. This multi-centre phase II study was performed to evaluate the activity of sunitinib in women with locally advanced or metastatic cervical carcinoma who had received up to one prior line of chemotherapy for advanced disease. Methods Sunitinib, 50 mg/day, was administered in 6-week cycles (4 weeks on followed by 2 weeks off treatment). The primary endpoint was the objective response rate. Results Sixteen (84%) of 19 patients enrolled had stable disease (median duration 4.4 months, 2.3–17 months), but no objective response was observed. Median time to progression was 3.5 months (range, 2.7–7.0 months). Four patients had fistulae develop on study treatment and an additional patient developed a fistula 3.5 months after discontinuation of therapy. All five patients had received either prior chemoradiation or radiation. Conclusions A higher rate of fistula formation (26.3%) was observed than would be expected and is of concern. Sunitinib has insufficient activity as a single agent in cervical cancer to warrant further investigation.

Phase II trial evaluating imatinib (I) in patients (pts) with anaplastic thyroid carcinoma (ATC)

6057 Background: There is no standard treatment for ATC. Response to doxorubicin ranges between 5–22%; median survival ranges between 3–6 months. Affymetrix gene chip showed PDGFR overexpression in ATC. In p53 mutated/deficient ATC cell lines, c-Abl is overexpressed, and selective inhibition of c-Abl resulted in cytostatic effect. (I) inhibits tyrosine kinase activity of Bcr-Abl and PDGF. We hypothesize that ATC that overexpress PDGFR or Abl will respond to (I). Methods: Pts ≥ 18 years old with histologically confirmed ATC, overexpressing PDGFR or c-Abl by immunohistochemistry who had measurable disease were eligible. Pts must have Zubrod performance status ≤ 1, and adequate hepatic and renal function. Prior chemotherapy, chemoradiation, radiation therapy, or surgery must have been completed at least 28 days prior to registration. (I) was administered at 400mg orally twice daily without drug holiday. Response to treatment was assessed after every 8 weeks. Pts with complete response (CR)/partial responses (PR)/stable disease (SD) were treated until disease progression. The study was terminated early due to poor accrual. Results: From February 2004 to May 2007, eleven pts from our institution were enrolled and were started on (I) (6 men; 5 women) with a median age of 63 years (ranges 53–80). At baseline, 4/11 pts (36%) had locoregional disease, 5/11 pts (45%) had distant metastases, and 2/11 pts (18%) had both. Nine pts had prior chemoradiation, and 7 pts had thyroidectomy. Out of 11 pts, 8 were evaluable for response; 3 were excluded for lack of follow up radiological evaluation. The overall responses at 8 weeks were CR 0/8; PR 2/8 (25%); SD 4/8 (50%); and PD 2/8 (25%). The median time to follow up was 26 months (ranges 23–30 months). The estimate of 6-month progression free survival was 27% (95% CI, 7–54%). The estimate of 6-month overall survival was 46% (95% CI, 17–71%). The most common G3 toxicity was lymphopenia in 45%; other G3 toxicities included edema (27%), anemia (18%), and hyponatremia (18%). There was no G4 or higher or treatment related death. Conclusions: (I) appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing pts with a rare malignancy at a single institution, investigation of (I) in ATC may be warranted in a multi-institution setting. No significant financial relationships to disclose.

Cetuximab (C) and bevacizumab (B) in patients with recurrent or metastatic head and neck squamous cell carcinoma: An updated report

6049 Background: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) represent important therapeutic targets in SCCHN. Cetuximab (C), an IgG1 monoclonal antibody against EGFR, has single agent activity in SCCHN. Upregulation of VEGF has been associated with C resistance, thus, combined targeting may enhance anti-tumor activity. We designed a phase II trial of bevacizumab (B), an anti-VEGF humanized monoclonal antibody, with C to evaluate this hypothesis. Methods: Eligible patients have recurrent or metastatic SCCHN, measurable disease (RESIST), ECOG performance status (PS) 0–2, and no history of bleeding or thrombosis. Up to 1 regimen (without an EGFR inhibitor) for recurrent or metastatic disease and prior chemoradiotherapy with curative intent are allowed. Treatment consists of weekly cetuximab, 250 mg/m2 (after a loading dose 400 mg/m2) and bevacizumab, 15 mg/kg given intravenously every 21 days, until disease progression. The primary endpoint is the objective response rate. Sample size is 45 eligible patients. Specific biomarkers relating to EGFR and VEGFR signaling will be evaluated in tumor tissues and blood samples. Results: 28 patients enrolled (27 eligible). Median age 60 years (range 33–92); male 19; PS 0 (7 pts), PS 1 (18), PS 2 (2). All had prior RT, and 26 had chemotherapy. A median of 4 cycles were given (range, 1–12). Best response in 25 evaluable patients: 5 (20%) PR (1 was uncomfirmed), 14 (56%) SD, and 6 (24%) PD. Progression-free survival was 2.8 months and median overall survival was 8.1 months. Grade (G) 3 adverse events included: hemorrhage (from a benign neck ulcer), 1; hypertension, 2; infection, 2; rash, 2; dysphagia, 4; hypophosphatemia, 1; and fatigue, 1. G 4 AEs: proteinuria, 1. One pt died of aspiration pneumonia, with possible cardiac ischemia of uncertain relationship to study drugs. Conclusions: Preliminary results show that cetuximab and bevacizumab is an active regimen in SCCHN with rare serious toxicities. In particular, our results establish the safety of this bevacizumab-based regimen in regards to bleeding complications in SCCHN. Study accrual continues and biomarker analysis is planned. (Supported by U01 CA099168–01 and P50 CA097190) No significant financial relationships to disclose.

Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas

The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma. Seventy-seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty-five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine-based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure. The median follow-up was 6 months (range, 3-31 months) and, among surviving patients, it was 12 months (range, 3-31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6- and 12-month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12-month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression-free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade > or = 2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade > or = 3 late toxicity. At 6 months and 12 months, the rates of grade > or = 2 late toxicity were 11% and 25%, respectively. SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease-related mortality.

Concomitant Presentation of Acute Myeloid Leukemia (AML) and Lung Cancer

Smoking is associated with AML and lung cancer, suggesting a common carcinogenic origin and raising the question of how to treat patients with concomitant cancer presentations. The Roswell Park Cancer Institute Tumor Registry was searched for patients with both diagnoses, followed by medical record review. Among 775 AML cases and 5225 lung cancer cases presented to Roswell Park Cancer Institute between January 1992 and May 2008 we identified twelve patients with both AML and lung cancer (1.5% of AML cases; 0.2% of lung cancer cases). Of these, seven cases had metachronous and five cases had synchronous presentation. Eleven of the twelve (92%) patients had a known smoking history; five (42%) of them were males. The median age at the respective diagnoses was 65 (range 58–85) years for AML and 66 (range 53–79) years for lung cancer. Five of the twelve (42%) patients had a complex karyotype.Metachronous group: Lung cancer preceded AML in six patients by a median interval of eight (range five-14) years, while AML preceded the diagnosis of lung cancer in one patient by three years. For their lung cancer, five patients had surgical resection. Two had definitive chemoradiation, one patient had adjuvant chemotherapy and one patient had adjuvant radiation suggesting that their subsequent AML was secondary. Two patients had preceding MDS even though they underwent only surgical resection for their lung cancer. For their AML, five of the seven patients were treated with cytarabine and anthracycline-containing regimens; two achieved complete remission, two had primary refractory disease and one patient died during induction. One patient with primary refractory disease underwent sibling matched allogeneic transplantation and is still alive in remission. The median survival for lung cancer was 65 (range 22–120) months. The median survival since AML diagnosis was less than one (range <1–105) month. Five of the seven patients died from AML complications, one patient died of an unrelated cause and one patient is alive in remission.Synchronous group: All five patients were treated initially for AML with cytarabine and anthracycline-containing regimens; two achieved complete remission, two had refractory disease and one patient had prolonged cytopenia. Two patients underwent surgical resection for their lung cancer after treatment for AML and one had palliative radiation. The median survival was five (range three-21) months and four of the five patients died of AML related causes.Conclusions: Less than 2% of AML patients present with lung cancer. Prior chemoradiation for non small cell lung cancer may be a risk factor for secondary AML but does not explain development of AML in the majority of patients, suggesting a potential role of prior tobacco use as a common carcinogenic risk factor. Although AML and lung cancers both carry poor prognoses, our data imply that AML has a more aggressive course than lung cancer and is the main cause of mortality in these patients. This miniseries highlights again the need for enforcing smoking cessation.

Nonoperable Patients With Superficial Esophageal Cancer Treated by Photodynamic Therapy After Chemoradiotherapy Have More Severe Complications Than Patients Treated in Primary Intent

Photodynamic therapy (PDT) is a therapeutic option in patients with a superficial esophageal cancer. Recently, PDT was shown to be effective as a salvage therapy for a local recurrence after chemoradiotherapy (CRT). To compare retrospectively the results and the complications rate of PDT between consecutive patients treated in primary intent for a superficial esophageal cancer versus patients treated by PDT for a local recurrence after CRT. Between 1999 and 2007 in a single center, 40 consecutive patients were treated by PDT for a superficial esophageal cancer, 25 (group 1) in primary intent and 15 (group 2) for a local recurrence after CRT. Two days after intravenous (IV) Photofrin (2 mg/kg), the phototherapy was performed with a dye laser. The treatment response and severe complications, defined as perforation and stricture requiring endoscopic dilation, were compared between the two groups. The patient and tumor characteristics were not different between the two groups. In group 1, 19 out of 25 patients (76%) were successfully treated versus 8 out of 15 patients (53%) in group 2 (P= 0.17). Severe complications occurred more frequently in patients with a prior CRT (8%vs 46.7%, P= 0.008) and included two perforations and five strictures requiring endoscopic dilation, while only two strictures occurred in group 1. A prior CRT was an independent risk factor of severe complications (odds ratio [OR] 8.05; 95% confidence interval [CI]1.22-43.0). Severe complications were significantly more frequent in patients treated after a prior CRT. PDT as a salvage therapy in patients with a local recurrence after CRT for esophageal cancer tended to be less efficient than in first-line treatment.

Lymph node involvement in advanced gastroesophageal junction adenocarcinoma

The prognosis of gastroesophageal junction adenocarcinoma is unquestionably related to the extent of nodal involvement; nonetheless, few studies deal with the pattern of lymph node spread and specifically analyze the prognostic value of the site of metastasis. The present study was aimed at evaluating these key aspects in advanced gastroesophageal junction adenocarcinoma. Of 219 patients consecutively operated on for gastroesophageal junction adenocarcinoma at the Department of General Surgery and Surgical Oncology, University of Siena, and at the Department of General Surgery, University of Verona, 143 pT2-4 tumors not submitted to prior chemoradiation were analyzed according to the Japanese Gastric Cancer Association pN staging system. The majority of patients were given diagnoses of nodal metastases (77.6%). The mean number (P = .076) and the percentage of patients with pN+ disease (P = .022) progressively increased from Siewert type I to type III tumors. Abdominal nodes were involved in all but 1 of the patients with pN+ disease; conversely, nodal metastases into the chest were 46.2% for type I, 29.5% for type II, and 9.3% for type III tumors. Survival analysis showed virtually no chance of recovery for patients with more than 6 metastatic nodes or lymph nodes located beyond the first tier. In advanced gastroesophageal junction adenocarcinoma, the high frequency of nodal metastases and the related unfavorable long-term outcome achieved by means of surgical intervention alone are indicative of the need for aggressive multimodal treatment along with surgical intervention to improve long-term results.

SCOTCERV: A phase II trial of docetaxel and gemcitabine as second-line chemotherapy in cervical cancer

5548 Background: Concurrent Cisplatin chemotherapy along with radiotherapy is standard therapy for locally advanced cervical cancer. There is no established second line regimen. Taxanes and Gemcitabine are not thought to share drug resistance with Cisplatin. In combination they are reasonably tolerated; myelosuppression is the dose limiting toxicity. Response is more likely in recurrences outside the irradiated area. Methods: This was a multi-centre phase II trial of Docetaxel (75mg/m2 d1) and Gemcitabine (1,000 mg/m2 d1,d8) in relapsed patients (pts) after treatment with cisplatin alone or in combination (excluding with taxanes) and/or radiotherapy. A Gehan two-stage design was used (minimum response rate requirement 25%). Pts had to have disease assessable by RECIST outside the irradiated pelvis and adequate organ function. After 12 pts the Docetaxel dose was reduced to 60 mg/m2. Results: 26 eligible pts were recruited to the study; information is available currently for 24. The median age is 43 years (range 30–62) and the median time from prior treatment is 12 months (1–55). 23 pts had prior chemoradiotherapy. Performance status: 0 (15) or 1 (9). Histology: squamous 17, adenoCa (6) mixed (1). Major metastatic sites were lung (11) and para-aortic nodes (11). The principal toxicity was neutropenia (gd 3 (8), gd 4 (8)) with 4 pts experiencing grade 3 febrile neutropenia. Dose reductions occurred in 29% of pts (Docetaxel) and 25% of pts (Gemcitabine), primarily for neutropenic fever. Haematological toxicity resulted in d8 Gemcitabine being omitted in 41% of cycles. 1 patient had gd3 SOB and 1 patient gd 3 diarrhoea. Reduction of Docetaxel dose did not reduce haematological toxicity. 5 pts have not, as yet, had response reported. In 19 pts (16 completed therapy) there was 1 CR, 4 PR, 6 stable disease, 7 progressions and 1 unevaluable. The overall response rate is 26% (95% ci 9%-51%). Conclusions: This preliminary data shows this combination has activity against platinum resistant metastatic cervical cancer, although the ability to deliver d8 Gemcitabine is compromised. Final results will be available for the meeting. [Table: see text]

A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients &gt;60 years old

7012 Background: Overexpression of Bcl-2, an inhibitor of apoptosis, may render AML cells resistant to chemotherapy and has been associated with unfavorable outcome. Genasense is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2. In a phase I study of older (≥60 yrs) AML patients (pts) treated with Genasense in combination with cytarabine (Ara-C) and daunorubicin (DNR) induction and with high-dose cytarabine (HiDAC) consolidation, no antisense-related toxicity was reported. Furthermore, overexpression of Bcl-2 at diagnosis and down-regulation of the Bcl-2 target after antisense treatment was shown in pts achieving complete remission (CR). Methods: A phase III trial (CALGB 10201) randomized untreated older AML pts to induction treatment with Ara-C (100 mg/m2/d by CIVI on days 4–10) and DNR (60 mg/m2/d on days 4–6) followed by consolidation therapy with HiDAC (2 g/m2/d on days 4–8) with (Arm A) or without (Arm B) Genasense (7 mg/m2/d CIVI on days 1–10 for induction and days 1–8 for consolidation). The study was powered to identify a survival advantage for pts receiving Genasense. Results: 503 pts enrolled between 12/03 and 10/06; 76 had prior MDS and 24 prior chemoradiotherapy for unrelated cancers. The arms were balanced for age, sex, race, and performance status. No differences in toxicities were observed between the 2 arms. An interim futility analysis performed at 34 months from initiation of the study showed no differences in CR rates (48% vs 52%; p=0.75) or overall survival (OS; p=0.83) between the 2 arms. Estimated OS at 1 yr was 36% for Arm A and 40% for Arm B. Similarly, there were no differences in disease-free survival from date of CR (DFS; p=0.78) or event-free survival (EFS; p=0.77). DFS and EFS rates at 1 yr were 40% and 25% for Arm A, and 43% and 7% for Arm B, respectively. Conclusions: Addition of Genasense to induction and consolidation chemotherapy failed to improve the outcome of older AML pts. Pretreatment levels and post-antisense treatment changes in Bcl-2 expression are now being measured and correlated with outcome. No significant financial relationships to disclose.

Chemotherapy for recurrent, metastatic, or persistent cervical cancer: a systematic review

To determine the front-line chemotherapeutic options for women with recurrent, metastatic, or persistent cervical cancer. The Medline, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing chemotherapy regimens for patients with recurrent, metastatic, or persistent cervical cancer. Studies were included if response rate, survival, toxicity, or quality of life data were reported. Fifteen RCTs were identified. The proportion of patients with prior chemoradiotherapy ranged from 0% to 57%. Four of the 15 RCTs detected significant improvements in overall response with combination cisplatin-based chemotherapy when compared with single-agent cisplatin. One of the 15 RCTs reported a significant median survival advantage with topotecan and cisplatin when compared with single-agent cisplatin (9.4 vs 6.5 months, P = 0.017); 57% of patients in this trial had previous chemoradiotherapy. Significant increases in grade 3 and 4 adverse events, especially severe hematologic toxicities, were detected among patients treated with that combination of chemotherapy. Thus, we conclude that cisplatin and topotecan should be discussed as a reasonable treatment option for appropriate patients who may wish to maximize the response and survival benefits associated with combination chemotherapy. Patients should understand that prior chemoradiotherapy with cisplatin may moderate the benefits observed, and that the relative benefits in response and survival outcomes come at the expense of increased toxicity. The improvement in median survival of 2.9 months represents a novel survival benefit in this difficult-to-treat patient population. Further randomized trials are needed to inform the role of single-agent or combination chemotherapy regimens, particularly in patients with prior chemoradiotherapy.