bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of combination therapy with docetaxel, cisplatin, and S-1 (DCS) for advanced gastric cancer: (KDOG 0601)
Authors: Nakayama N. , Koizumi W. , Sasaki T. , Tanabe S. , Nishimura K. , Higuchi K. , Takagi S. , Katada C. , Azuma M. , Saigenji K.
Published: August 2020

4555

Background: Our previous phase I study (Oncology 2008, 75:1–7) provided evidence that combination chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is effective and well tolerated in patients with advanced gastric cancer. The present multicenter phase II study was conducted to confirm the efficacy and toxicity of DCS in advanced gastric cancer. Methods: Eligibility criteria included a histologically proved diagnosis of gastric adenocarcinoma with at least one measurable metastatic lesion, no previous treatment for gastric cancer except for surgery, an ECOG performance status of 0 to 2, and adequate organ function. Docetaxel (40 mg/m2) and cisplatin (70–60 mg/m2) were given intravenously on day 1, and S-1 was given orally at a dose of 40 mg/m2 twice daily from days 1 to day 14 of a 28-day cycle. Patients received a maximum of 6 cycles. Subsequently, patients were given repeated cycles of S-1 plus docetaxel (DS). The primary endpoint was the objective response rate. Results: 59 patients (47 men, 12 women) were enrolled. The median age was 62 (range: 35–75) years. PS 0/1/2 was 40/18/1. The median number of treatment cycles was 7 (DCS 6+DS 1: range, 1–20). Because myeloid suppression and renal dysfunction developed during the study, we lowered the recommended dose of cisplatin from 70 mg/m2 to 60 mg/m2. The dose of cisplatin was 70 mg/m2 in 19 patients and 60 mg/m2 in 40. The overall response rate was 81.3% (48/59; 95% CI, 80.7–91.2). The response rates with cisplatin 70 mg/m2 and 60 mg/m2 were 78.9% (95% CI, 60.5–97.2) and 82.5% (95% CI, 70.7–94.2), respectively. Tumor down-staging was achieved in 9 (18.7%) of the 48 patients who responded to treatment. The median survival time and median progression-free survival were not reached. Grade 3 or 4 major toxicity comprised leukopenia (44.0%), neutropenia (72.8%), anemia (15.2%), febrile neutropenia (13.5%), anorexia (6.7%), nausea (5.1%), vomiting (5.1%), fatigue (1.6%), and diarrhea (5.1%). There was one treatment-related death caused by the perforation of the primary tumor. This patient refused surgery. Conclusions: DCS was a well-tolerated regimen with a high response rate in patients with advanced gastric cancer. Cisplatin at a dose of 60 mg/m2 was considered adequately effective.

No significant financial relationships to disclose.
Prognostic significance of the endoluminal ultrasound defined lymph node metastasis count in esophageal cancer
Authors: Twine C. , Rawlinson C. , Escofet X. , Blackshaw G. , Crosby T. , Roberts A. , Lewis W.
Published: August 2020

4558

Background: TNM histopathological staging system for esophageal cancer is controversial, and will soon be revised to account for the relative burden of the number of lymph node metastases. The aim of this study was to assess the prognostic significance of endoluminal ultrasound (EUS) defined lymph node metastasis count (eLNMC) in patients with esophageal cancer. Methods: Two hundred and sixty-seven consecutive patients (median age 63 yr, 187 m) underwent EUS followed by stage directed multidisciplinary treatment [183 esophagectomy (92 neoadjuvant chemotherapy), 79 definitive chemoradiotherapy, and 5 palliative therapy]. The eLMNC was subdivided into four groups (0, 1, 2 to 4, >4) and the primary measure of outcome was survival. Results: Survival was related to EUS T stage (p<0.0001), EUS N stage (p<0.0001), EUS tumour length (p<0.0001), and the eLNMC (p<0.0001). Multivariable analysis revealed EUS tumour length (HR 1.071, 95% CI 1.008 to 1.138, p=0.027) and eLNMC (HR 1.302, 95% CI 1.133 to 1.496, p<0.0001) to be significantly and independently associated with survival. Median and 2 year survival for patients with 0, 1, 2 to 4, and >4 lymph node metastases were: 44 months and 71%; 36 months and 59%; 24 months and 50%; and 17 months and 32% respectively. Conclusions: The eLNMC was an important and significant prognostic indicator in patients with esophageal cancer, which should in future be reported and used to revise the perceived radiological stage, in order to inform stage directed multimodal therapy.

No significant financial relationships to disclose.
Helicobacter pylori infection as an independent prognostic factor for locally advanced gastric cancer with curative resection
Authors: Kang S. , Hwang Y. , Lee H. , Jeong S. , Choi J. , Jo Y. , Han S. , Kim J. , Han J.
Published: August 2020

4562

Background: A few studies reported the association between helicobacter pylori (HP) infection and better overall survival (OS) in resected gastric cancer patients (pts). Methods: We investigated the HP infection status and its association with clinicopathologic characteristics in 210 locally advanced gastric cancer patients (stage IB: 18, II: 61, IIIA: 62, IIIB: 31, IV: 38) who underwent adjuvant chemotherapy (CTX) after curative resection (≥D2 dissection). HP infection status in hematoxlin and eosin stained peritumoral tissue was graded according to the updated Sydney System and categorized as HP(-) (normal or mild infection) and HP(+) (moderate or marked infection) (Am J Surg Pathol 20:1161, 1996). Twenty-two pts received 5-FU, doxorubicin (DOX) CTX (5- FU 500 mg/m2 weekly for 36 wks, DOX 40 mg/m2 q 3 weeks x 12) with or without OK432, while 188 pts underwent 5-FU, mitomycin-C (MMC), and polysaccharide-K (PSK) CTX (5-FU 500 mg/m2 weekly for 24 wks, MMC 8 mg/m2 q 6 wks x 4, PSK 3 g/day for 16 wks) (Br J Cancer 84:186, 2001, Hepatogastroenterol 54:290, 2007). Results: The median follow-up duration of survivors was 125 (107–155) months. HP (-) was significantly correlated with Bormann type IV, larger tumor size (>5.5cm),and stage IIIB. In univariate analysis, patients with HP(-) (104 pts) demonstrated significantly poor 10-year OS compared with those with HP (+) (106 pts) (15.9% vs. 87.7%, p<0.0001). HP(-) was associated with poor outcome in all stages except stage IB (p=0.075). In multivariate analysis, HP(-) was the most significant independent prognostic factor of poor OS (hazard ratio 9.646, 95% CI 5.407–17.206, p<0.0001) followed by advanced stage (p=0.032), Bormann type IV (p=0.037) and old age (p=0.015). Conclusions: HP infection status seems to have strong prognostic significance in locally advanced gastric cancer. HP (-) pts may need intensified adjuvant treatment and careful follow-up.

No significant financial relationships to disclose.
Polymorphism of nucleotide excision repair genes as predictors for clinical outcome in advanced gastric cancer patients treated with oxaliplatin-based chemotherapy
Authors: Hur H. , Song K. , Park C. , Hong Y. , Chun H. , Jeon H.
Published: August 2020

4565

Background: The individual variations in treatment response and the toxicity of combination regimen of oxaliplatin and 5-fluorouracil with leucovorin (FOLFOX) for advanced gastric cancer patients have been reported. The aim of this study is to evaluate the influence of polymorphism of nucleotide excision repair genes that are involved in the metabolism of cisplatin on the clinical outcomes of gastric cancer patients treated with modified FOLFOX-6 chemotherapy. Methods: From March 2006 to December 2007, eighty-two patients with advanced gastric cancer were treated with modified FOLFOX-6 as the primary chemotherapy in our institution. Of these patients, 55 patients who were available for peripheral blood sampling before starting chemotherapy were enrolled in this study. Genomic DNA was extracted from mononuclear cells of patients’ blood. Four polymorphisms were investigated in three genes, ERCC, GSTP and XRCC. Results: The overall response rate (RR) was 40.0%. Median time to progression (TTP) and overall survival (OS) was 6 months (C.I.: 5.0 - 7.0 months) and 15.0 months (C.I.: 9.7 - 20.3 months). Grade 3 or 4 hematologic toxicities were presented in 17 patients (30.9%), gastrointestinal toxicities in 5 patients (9.1%), peripheral neuropathy in 5 patients (9.1%) and hepato-toxicity in 4 patients (7.3%). Most common types of polymorphism were G/G (67.3%) in XRCC1 Arg399Gln, A/A (74.5%) in GSTP1 Ile105Val, C/C (60.0%) in ERCC1 Asn118Asn and C/A (49.1%) in ERCC1 C8092A. The RR was significantly lower in patients with C/C type in ERCC1 C8092A gene than those with other type (25.0% vs 51.6%, p=0.046). However, there were no differences of TTP and OS among the polymorphisms in three genes. The rate of grade 3 or 4 hematologic toxicity was higher in patients with C/T or T/T in ERCC1 codon 118 gene than those with C/C type (45.5% vs 21.2%, p=0.057). Conclusions: We demonstrated that modified FOLFOX-6 chemotherapy was effective and tolerable. The polymorphism of C/C type in ERCC1 C8092A gene was found to be a predictive marker of the poor response and C/C type in ERCC1 Asn118Asn gene was to be a predictive marker of the hematologic toxicity.

No significant financial relationships to disclose.
The prognostic impact of hypoxia-inducible factor-1α and VEGF, IGF-2, p21, p53 expression in gastric adenocarcinoma
Authors: Kakeji Y. , Mizokami K. , Sumiyoshi Y. , Yoshinaga K. , Saeki H. , Tokunaga E. , Endo K. , Morita M. , Kitao H. , Emi Y. , Maehara Y.
Published: August 2020

4571

Background: Hypoxia caused by either radiation or chemotherapy induces various intracellular adaptive responses, which contribute to tumor progression. The clinicopathological characteristics of human gastric cancer and the clinical outcomes were analyzed to investigate the effects of the expression of hypoxia-inducible factor1α (HIF-1α) and some related proteins, such as, vascular endothelial growth factor (VEGF), insulin-like growth factor-2 (IGF-2), p21, and p53 on the prognosis of human gastric cancer. Methods: The expressions of HIF-1α, VEGF, IGF-2, p21, and p53 proteins were determined by immunohistochemistry in 216 specimens of primary gastric cancer. Results: Of all 216 patients, 85 (39.4%) showed a positive expression of HIF-1α. In addition, the HIF-1α expression positively correlated with the tumor size and depth of invasion, while it was also more frequent in tumors with lymphatic invasion and undifferentiated adenocarcinomas. Though the VEGF expression significantly correlated with the HIF-1α expression, the expressions of IGF-2, p21 and p53 did not show any correlation. HIF-1α-positive/p21-negative tumors had a lower apoptotic index, and the patients with such tumors also had a significantly poorer prognosis. Similarly, HIF-1α-positive/p53-positive tumors had a significantly poorer prognosis. A multivariate Cox regression analysis showed the depth of invasion, lymph node metastasis, and HIF-1α positivity to all be independent prognostic factors in patients with gastric cancer. Conclusions: Based on the above findings, HIF-1α is therefore considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1α protein overexpression with the loss of p21 expression or nonfunctional p53 thus tends to indicate a dismal prognosis. Controlling hypoxia, especially in the HIF-1α pathways, may therefore hold the key to a greater individualization of therapy and also lead to the development of new treatments for patients with gastric cancer.

No significant financial relationships to disclose.
Predictors of treatment outcomes in early stage hepatocellular carcinoma (HCC) detected in a surveillance program
Authors: Chan S. L. , Mo F. K. , Koh J. , Hui E. P. , Yu S. C. , Lai P. B. , Chan H. L. , Chan V. T. , Chan A. T. , Yeo W. , Mok T.
Published: August 2020

4584

Background: Surveillance for HCC in hepatitis B virus (HBV) carriers aims to improve survival by detection of early resectable tumor. In 2005, our group reported low surgical resection rates despite detection of small sized tumors in a prospective surveillance cohort of 1018 HBV carriers (Mok TS et al. J Clin Oncol 05). In current study, we aim to identify predictive factors for treatment outcomes in HCC detected from our surveillance program. Methods: The prospective cohort was recruited at the Prince of Wales Hospital between Oct 1997 and Nov 2000. We updated the database in Dec 2008 and performed univariate and multivariate analysis on clinical (age, sex, cirrhosis, ascites, anti-viral therapy, bilirubin, ALT, albumin, INR), tumorous (size, number, resection) and virologic factors (HBV DNA, Genotype) for prediction of outcome in HCC patients (pts). Results: In the prospective cohort, total 923 HBV carriers were updated (95 lost to follow-up). After median follow-up of 9.95 years, we confirmed diagnosis of 105 HCC. Median age = 51 (range: 40–69); M:F = 82:23; Child's A and B cirrhosis = 38:67. Fifty seven pts (54.3%) had solitary tumor but only 34 (32.4%) are amenable to resection. Absence of cirrhosis (p=0.0072) and normal albumin level (p=0.0379) are predictors of surgical resection while tumor size and number are not. The median survival of all HCC pts was 2.26 years. Anti-viral therapy during the surveillance period is a strong predictor of survival (3.74 vs. 1.63 years; p=0.0115). In multivariate analysis, both anti- viral therapy (HR=0.35; 95%CI: 0.19–0.73; p=0.0041) and normal bilirubin level (HR=0.30; 95% CI: 0.25–0.80; p=0.0069) were predictive of improved survival in pts with HCC. The benefits of anti-viral therapy applied to both surgical and non-surgical candidates (p=0.17). Conclusions: Anti-viral therapy is a potent predictor of survival of HBV related HCC. Liver function is more important than tumor characteristics in determining the outcome of HCC detected in the surveillance program.

No significant financial relationships to disclose.
A phase II study of bevacizumab (B) and erlotinib (E) in combination for Asian patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC): An interim safety report
Authors: Hsu C. , Kang Y. , Yang T. , Su W. , Sandoval-Tan J. , Chiou T. , Jin K. , Button P. , Hsu C. , Cheng A.
Published: August 2020

4585

Background: Asian pts with advanced HCC have a poor prognosis, and a median survival of 2–4 months with best supportive care (ph III). As HCCs are highly vascular tumors, dual inhibition of VEGF and EGFR with B plus E is an attractive combination strategy. B has demonstrated promising phase II results in 34 HCC patients, with 75% non-progression at 16 weeks (wks) (65% in Caucasians) (Thomas et al., 2007). However, 6–11% of pts had variceal bleeding, some cases of which were fatal. This study was initiated to investigate the safety and efficacy of B+E in Asian HCC pts. Methods: Screening esophagogastroduodenoscopy (EGD) was used to exclude pts with high risk of variceal bleeding. Asian pts with advanced/metastatic, measurable HCC who were unsuitable for surgery or other loco-regional therapies received B 5mg/kg q2w i.v. and E 150mg/day orally. The primary endpoint was PFS at 16 wks. Responses were evaluated using RECIST. Tumor tissue samples were collected for biomarker analysis. Results: Baseline characteristics of the 51 pts enrolled between March and October 2008 were median age: 58 years (range 26–84); male/female: 44/7; ECOG PS 0/1/2: 30/20/1; Child-Pugh A/B: 50/1; BCLC stage C n=44 (88%); hepatitis B/C/B+C/nonB+nonC: 42/4/3/2; grade I/II varices n=16 (none with red sign). Pts received a median 8 wks of study treatment. No variceal bleeding was observed; 3 pts had upper GI bleeding (grade 1/2; 2 peptic ulcer, 1 gastritis). See table for most common toxicities. 7/10 deaths were due to disease progression, none were due to study treatment. At the time of analysis, 2 pts had a confirmed partial response (PR; duration 24+ and 8+ wks). 1 pt with an unconfirmed PR continued on treatment. Data for the primary analysis were immature. Conclusions: Bevacizumab plus erlotinib was well tolerated. Screening EGD was feasible and reduced the risk of variceal bleeding. Follow-up is ongoing.

[Table: see text]

[Table: see text]
Circulating tumor cells (CTCs) as a surrogate marker for determining response to chemotherapy in advanced gastric cancer (AGC)
Authors: Matsusaka S. , Chin K. , Mizunuma N. , Ogura M. , Suenaga M. , Shinozaki E. , Terui Y. , Hatake K.
Published: August 2020

4600

Background: The purpose of this study was to quantitate circulating tumor cells (CTCs) in advanced gastric cancer (AGC) patients and to demonstrate the role of CTCs in cancer therapy. This study investigates the hypothesis that CTC levels can predict clinical outcomes in patients with AGC. Methods: Eligibility criteria: PS (ECOG) of 0 to 2; histopathology of adenocarcinoma; adequate major organ functions. Chemotherapy regimen was S-1 based regimen (S-1 with or without cisplatin) or paclitaxel. Treatment was continued unless disease progression was observed. CTCs of whole blood in baseline, 2 week and 4 week after initiation of chemotherapy were isolated and enumerated using immunomagnetics. Results: From November 2007 to September 2008, thirty patients with unresectable or recurrent gastric cancer were enrolled onto a prospective study. Pts characteristics were as follows: median age: 60 years (range 24–78), PS 0/1/2: 21/8/1, primary tumor ±: 21/9 and regimen S-1/S-1with cisplatin/paclitaxel: 3/15/12. Among 30 pts, best response rates were 36.7% (CR/PR/SD/PD: 0/11/8/11). Patients with ≥4 CTCs at 2 week points and 4 week points had the shorter median progression-free survival (PFS) (1.4, 1.4 months, respectively), than the median PFS of <4 CTCs (6.3, 6.3 months, respectively) (logrank test; p=0.0008, p=8.78E-07, respectively). A finding of <4, CTCs of 2 week and 4 week after initiation of chemotherapy was associated with significantly longer overall survival (OS) as compared with these patients with ≥4 CTCs (p=0.016702, p=0.027788 respectively). Conclusions: These data demonstrate that CTC measurement may be useful as a surrogate marker for determining response to S1 based regimen or paclitaxel regimen in AGC.

No significant financial relationships to disclose.
A randomized phase II trial of adjuvant chemotherapy with cisplatin, epirubicin, 5-fluorouracil, gemcitabine (PEFG regimen) or gemcitabine alone after curative resection for pancreatic cancer
Authors: Reni M. , Cereda S. , Aprile G. , Tronconi M. C. , Milandri C. , Passoni P. , Rognone A. , Balzano G. , Di Carlo V. , Villa E.
Published: August 2020

4608

Background: The PEFG regimen yielded a statistically relevant outcome advantage as compared with gemcitabine (G) in patients with advanced pancreatic adenocarcinoma (PA). The current trial assessed the impact upon disease control of PEFG regimen and single agent G after curative resection for PA. At time of trial design, both arms were experimental since the role of adjuvant therapy in PA was debated. Methods: After R0 or R1 resection for PA, patients with stage IB-III disease, aged 18–70 years, Karnofsky performance status (PS) >60 were randomized within 8 weeks from surgery to receive either G 1 g/m2/weekly Q3 every 4 weeks (Arm A), or PEFG (cisplatin and epirubicin at 40 mg/m2 each on day one, gemcitabine at 600 mg/m2 on days 1 and 8 and 5-FU at 200 mg/m2/day on days 1 to 28) every 4 weeks (Arm B). In both treatment arms chemotherapy was administered for 3 months and followed by radiotherapy (54–60 Gy in 27–30 fractions) with concurrent 5-FU 250 mg/m2/day. A CT scan was performed every three months. The primary endpoint was the probability of being disease-free at 1 year (DFS1y) from surgery. The Fleming design was used to calculate the sample size. Assuming P0=35% and P1=55%, α .05 and β.10, the study was to enroll 51 patients per arm. The treatment arm had to be considered of interest with > 23 patients being DFS1y. Results: Between August 2003 and August 2008, 102 patients were enrolled, stratified by center and resection margin and randomized (51 per arm). All patients were eligible. One patient in arm A and 2 in arm B refused the assigned treatment. An intent-to-treat analysis was performed. Patients’ characteristics were (A/B): median age 61/60, median PS 90/90, stage IIA 19/12%; stage IIB 73/81%; stage III 8/7%; grade 3 30/46; R1 36/30; pre- and post-surgery surgery CA19.9 > upper limit of laboratory normal 68/80% and 29/33%, tumor size > 2.9 cm 41/43%. To date, 41 patients per arm are assessable for the primary endpoint: 19 (46%) and 28 (68%) patients were DFS1. Main G3–4 toxicity was: neutropenia in 21/85% and thrombocytopenia in 0/23% of patients. Conclusions: With a mature follow-up for 80% of patients, PEFG reached the primary endpoint of the trial and warrants further study while G not yet.

No significant financial relationships to disclose.
Detection of early-stage pancreatic carcinoma
Authors: Gold D. , Modrak D. E. , Newsome G. , Karanjawala Z. , Hruban R. , Goggins M. , Goldenberg D. M.
Published: August 2020

4613

Background: Invasive pancreatic carcinoma is a virtually lethal disease, mostly because of the failure to detect it at a sufficiently early timepoint for successful treatment. Our laboratory has identified a unique biomarker detected by MAb PAM4 that shows high specificity for a mucin glycoprotein expressed by pancreatic carcinoma (PC). While identified in almost 90% of PC and its precursor lesions, the antigen is not detectable in normal pancreas. We are investigating this biomarker for the early detection of PC. Methods: Both immunohistochemical (IHC) and enzyme immunoassay (EIA) were employed for detection and/or quantitation of PAM4-mucin in tissue and sera, respectively. Results: We have extended our prior IHC results with precursor lesions (Clin Cancer Res 2007;13:7380–7); PAM4 gave an intense, diffuse labeling pattern in 81% of mucinous cystic neoplasms (MCN), with an additional 11% showing a focal pattern (n=27). Thus, a total of 92% of MCN showed evidence of PAM4-antigen expression. Of interest, a difference in the labeling pattern was observed in association with the grade of dysplasia, providing easy identification of MCN with high- grade dysplasia. We previously reported use of an EIA for quantitation of PAM4-antigen in sera. The assay demonstrated a sensitivity and specificity of 77% and 95%, respectively, for identification of PC (J Clin Oncol, 2006;24:252–8). We have now confirmed these results in a set of serum specimens (n= 49 PC, 13 normal) for which staging information was available. Overall specificity and sensitivity were 82% and 85%, respectively, calculated by ROC curve analysis (AUC=0.878±0.045; 95% CI=0.769–0.947). Although only a small number of specimens were from patients with stage I disease (n=12), 92% of these were above the cutoff value for positive response. A correlation was observed for average concentration of antigen in the circulation with stage of disease (R2=0.988). Conclusions: IHC and EIA results indicate that PAM4 identifies a biomarker for PC that is present at the earliest stages of neoplastic transformation, thus warranting controlled analyses of larger specimen numbers. (Supported in part by USPHS grant CA096924 from the NIH.)

[Table: see text]
Multicenter study of radiosensitizing gemcitabine combined with fractionated radioimmunotherapy for repeated treatment cycles in advanced pancreatic cancer
Authors: Pennington K. , Guarino M. J. , Serafini A. N. , Rocha-Lima C. , Suppiah K. , Schneider C. J. , Gold D. V. , Sharkey R. M. , Wegener W. A. , Goldenberg D. M.
Published: August 2020

4620

Background: In a phase I study, a single dose of 90Y-labeled anti-mucin humanized antibody, hPAM4 (90Y-hPAM4), led to several transient reductions or stabilization of lesions in advanced pancreatic cancer, with bone marrow toxicity limiting the maximum tolerated dose to 20 mCi/m2. Preclinical studies showed gemcitabine enhanced radioimmunotherapy, so a phase Ib study was undertaken to evaluate repeated treatment cycles of 90Y-hPAM4 plus gemcitabine. Methods: Patients (pts) with previously untreated, locally advanced or metastatic, pancreatic cancer were treated in 4-week cycles (200 mg/m2 gemcitabine once-weekly; 111In-hPAM4 the 1st wk for imaging, biodistribution, and dosimetry; 90Y-hPAM4 once-weekly the last 3 wks), which could be repeated in the absence of progression or unacceptable toxicity. The 90Y-dose was escalated by patient cohort following a 3+3 design, with tumor responses assessed by CT and FDG/PET imaging, and by CA19.9 serum levels. Results: Eight pts (3F/5M, 56–72 years old, 7 with metastatic disease) have now been treated at the first 2 dose levels (6.5 and 9.0 mCi/m2 90Y-hPAM4 x 3) with hematologic toxicity all transient Grade 1–2 (NCI CTC v3). 111In-hPAM4 imaging showed normal biodistribution, evidence of tumor targeting and acceptable dosimetry estimates to normal organs per treatment cycle. Two pts had tumor responses to initial treatment with significant decreases in FDG metabolic activity on PET imaging, regression of lesion sizes on CT, and CA19.9 decreases. Both pts continue in excellent performance status now at 9 and 11 months after study entry, after receiving a total of 3 and 4 treatment cycles, respectively, without additional toxicity. A 3rd pt with a stable response by PET and CT 4 weeks after initial treatment and decreases in CA19.9 levels is now undergoing a 2nd treatment cycle. Four other pts had early progression of disease by or before post-treatment week-4 evaluation, and the remaining pt is still being evaluated. Conclusions: Dose escalation is continuing after fractionated radioimmunotherapy with 90Y-hPAM4 plus low-dose gemcitabine demonstrated therapeutic activity at the first two 90Y dose levels, with minimal hematologic toxicity, even after 4 treatment cycles.

[Table: see text]
E4201: Randomized phase II study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with locally advanced, unresectable, pancreatic cancer (LAPC): Quality-of-life (QOL) analysis
Authors: Cardenes H. R. , Powell M. , Loehrer P. J. , Wagner L. I. , Cella D. F. , Brell J. , Ramanathan R. K. , Crane C. H. , Alberts S. R. , Benson A. B.
Published: August 2020

4627

Background: E4201 compared radiation and gemcitabine (RT+Gem) versus Gem alone in LAPC. The primary endpoint was overall survival; secondary objectives included: objective response rate (RR), progression-free survival (PFS), toxicity and QOL. We previously reported that RT+Gem was associated with improved overall survival compared with Gem alone [median survival time, 11 months and 9.2 months, respectively; p=0.034], without impact in RR or PFS. (ASCO 2008, abstract # 4506). We now report on QOL as measured by the Hep subscale from the FACT-Hepatobiliary [FACT-Hep] between both arms. Methods: Eligible patients had LAPC adenocarcinoma, PS <2, without prior therapy. They were randomized to Arm A: Gem alone (1,000 mg/m2/week x 3, every 4 weeks, 7 cycles), or Arm B: RT (50.4Gy/28 fractions) plus Gem (600 mg/m2/weekly x 6) followed by 5 cycles of Gem alone (1,000 mg/m2/weekly x 3 every 4 wks). The FACT-Hep was administered at baseline (before starting induction), 6 weeks (immediately after completing induction), week 16 (Arm A) or week 15 (Arm B) mid-consolidation, and at 9 months. Results: From April, 2003 to December, 2005, 74 patients were enrolled, 71 were eligible [37 Arm A; 34 Arm B]. Grade ≥3 was reported in 80% and 82.4% in ARM A and B, respectively (p=1.00). Grade IV toxicities, mainly gastrointestinal and hematologic, were more common in ARM B (41.2% vs 5.7%, p=<0.0001). QOL compliance declined over time, most commonly attributable to either patients or staff choosing not to complete or administer the instrument due to declining health (96%, 69%, 60%, and 40% at baseline, week 6, 15/16 weeks and 9 months, respectively). Within Arm B, QoL scores dropped significantly from baseline to 6 weeks. By week 15, QoL scores for patients on Arm B rebounded to levels similar to baseline. Two-sided Wilcoxon rank sum tests failed to suggest differences in median FACT-Hep subscale score between treatment arms at any of the four time-points (alpha = 0.10). Conclusions: RT+Gem is associated with an overall survival benefit without apparent long term adverse impact on QOL when compared with Gem alone.

No significant financial relationships to disclose.
Phase I study of intravenous Seneca Valley virus (NTX-010), a replication competent oncolytic virus, in patients with neuroendocrine (NE) cancers
Authors: Rudin C. M. , Senzer N. , Stephenson J. , Loesch D. , Burroughs K. , Police S. R. , Hallenbeck P.
Published: August 2020

4629

Background: NTX-010 is a naturally occurring replication competent picornavirus with potent and selective tropism for human NE tumors, including small cell cancers and carcinoid. NTX-010 elicts rapid cytolysis in vitro and durable responses following IV dosing in multiple xenograft models. Methods: A first-in-human phase I study of IV NTX-010 was conducted across 5 log-increment dose cohorts from 107 vp/kg to 1011 vp/kg, in patients with NE cancers. Study endpoints included toxicity assessment, response assessment, evaluation of viral titers and clearance in blood, sputum, nasal swabs, urine, and stool, and assessment of neutralizing antibody (Ab) development. Results: 30 patients were treated (6 small cell, 24 carcinoid-type). All small cell patients were heavily pretreated (> third line) and received 107 vp/kg. In these patients, median PFS was 1.2 months and median OS was 4.1 months, including 1 long term (16 month +) survivor with prolonged SD after progressing through prior therapies. Carcinoid patients in cohorts 1–4 have 70% SD rate and median PFS of 5.4 months (95% CI 3.6 to NE); median OS has not been reached. Cohort 5, a 12 patient expansion cohort at 1011 vp/kg restricted to carcinoid, is still being monitored and shows promising antitumor activity including improvement in carcinoid syndrome symptoms, decline in 5HIAA and other serum markers, minor responses by CT scan, and an objective PET response (>50% decrease in SUV). There were no DLTs in any cohort. Evidence of intratumoral viral replication includes delayed kinetics in serum viral titer, post-infusion serum titers greater then the dose administered and positive immunohistochemistry and/or RT-PCR signal for viral antigens in tumor mass despite Ab production. Viral clearance was documented in all subjects and correlated temporally with development of antiviral Ab. Conclusions: NTX-010 is the first picornavirus to be evaluated as an anticancer therapeutic. A single IV dose of 1011 vp/kg of NTX-010 is safe, has predictable viral kinetics, and shows promising activity against NE tumors. Phase II testing of this novel agent either as a single agent or in combination with standard cytotoxic therapies is warranted.

[Table: see text]
Phase II presurgical study of bevacizumab plus erlotinib in untreated patients with metastatic renal cell carcinoma
Authors: Jonasch E. , Tsavachdidou D. , Wood C. G. , Matin S. F. , Corn P. G. , Tamboli P. , Wang X. , Tannir N.
Published: August 2020

5004

Background: The safety and efficacy of presurgical bevacizumab in patients with metastatic renal cell carcinoma (mRCC) is not known. The current study was designed to answer these clinical questions, and to define predictive tissue biomarkers using nephrectomy specimens from patients on trial. Methods: Patients with newly diagnosed clear cell mRCC whose primary tumor was considered resectable were enrolled. In this single arm phase II trial, patients received bevacizumab plus erlotinib or bevacizumab alone for 8 weeks, followed by restaging. Primary endpoint was progression free survival (PFS). If patients demonstrated progressive disease and had a declining performance status after eight weeks, nephrectomy was deferred. Postoperatively, patients continued on study drug(s) if disease stabilization or regression had occurred. Reverse phase protein arrays (RPPAs) were generated from nephrectomy specimens. Results: Between March 2005 and March 2008, 52 patients were enrolled on the study, and 50 were included in the analysis. By the Memorial Sloan-Kettering Cancer Center criteria, 82% of patients had intermediate-risk, and 18% had poor-risk features. Twenty-three patients received bevacizumab plus erlotinib, and 27 received bevacizumab alone. Forty-two patients underwent nephrectomy. Median progression-free survival was 11.0 months (95% CI: 5.5, 15.6 months). Median overall survival was 25.4 months (95% CI 11.4, not estimable). Two perioperative deaths occurred, and neither was attributable to study drug. Wound dehiscence resulted in treatment discontinuation for three patients. RPPA analysis demonstrated a clear separation of better versus worse responding patients. Conclusions: Presurgical treatment with bevacizumab therapy is relatively safe and yields clinical outcomes comparable to post surgical treatment with antivascular therapy in patients with mRCC. Prospective randomized trials testing the use of presurgical therapy to select appropriate patients for cytoreductive nephrectomy are warranted.

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Southwest Oncology Group S9921: Prolonged event-free survival in high-risk prostate cancer (PC) patients receiving adjuvant androgen deprivation
Authors: Glode L. M. , Tangen C. M. , Hussain M. H. , Wood D. P. , Swanson G. P. , Quinn D. I. , Dawson N. , Balzer-Haas N. , Crawford E. D. , Thompson I. M.
Published: August 2020

5009

Background: Patients with adverse pathologic risk factors after radical prostatectomy are at high risk for biochemical relapse and eventual death from disease. Adjuvant hormonal therapy with or without chemotherapy may prolong event free survival. Methods: SWOG 9921 randomized 859 eligible high risk PC patients to receive 2 years of adjuvant combined androgen blockade (CAB) (goserelin + bicalutamide) with (433) or without (426) chemotherapy (mitoxantrone + prednisone). The primary endpoint is survival. The DSMC has approved this analysis. PSA was to be assessed every 3 mo for 5 yrs and then every 6 mo for 10 more yrs. PSA relapse was defined as 3 consecutive measurements > 0.2 ng/ml. Death w/o relapse is censored. The CAB only eligible group is being reported (n=426). Risk groups based on eligibility criteria are as follows: Risk Group 1= positive margins or extraprostatic extension only with Gleason 7; elevated PSA (pre-op > 15 ng/ml), or had a pre-op PSA > 10 ng/ml and a biopsy Gleason 7(N=113); Risk Group 2 = seminal vesicle invasion or Gleason >/= 8, but no positive nodes (N=240), Risk Group 3 =positive nodes (N=69), 397 patients from both arms who completed 2 years of CAB were assessed for time to testosterone (T) recovery. T was assessed every 6 mo until it reached the institutional lower limit of normal. The median follow-up time from randomization is 3.8 years. Results: See Table . The estimated median time to T recovery (> 50ng/ml) is 11.7 mo from the end of CAB (95% CI 11.3, 11.9 months). The 6 and 18 mo recovery rates were 16% and 89%. Of 17 deaths (including ineligibles), 7 were from prostate cancer; 4 from other cancers, one cardiovascular disease, and 5 from miscellaneous causes. Conclusions: These data indicate a markedly low PSA relapse and death rates in high risk PC patients who received CAB. This likely is the result of stage migration, patient selection and/or the effects of CAB itself.

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A multicenter phase II study of cisplatin (C), gemcitabine (G), and bevacizumab (B) as first-line chemotherapy for metastatic urothelial carcinoma (UC): Hoosier Oncology Group GU-0475
Authors: Hahn N. M. , Stadler W. M. , Zon R. T. , Waterhouse D. M. , Picus J. , Nattam S. R. , Johnson C. S. , Perkins S. M. , Waddell M. J. , Sweeney C. J.
Published: August 2020

5018

Background: Despite CG therapy, most metastatic UC patients die from their disease. Novel approaches are needed. Combining anti-angiogenic therapy with chemotherapy has improved outcomes in other malignancies, offering hope for similar improvements in UC patients. Methods: Metastatic or unresectable chemonaive UC patients (pts) with an ECOG performance status of 0–1 received C 70 mg/m2 iv d1, G 1,000–1,250 mg/m2 iv d1, 8, and B 15 mg/kg iv d1 on a q21d cycle for up to 8 cycles. Gemcitabine was reduced to 1,000 mg/m2 iv d1, 8 for all subsequent pts after 7 thromboembolic events were noted in the first 17 pts. The primary endpoint was progression free survival (PFS). The trial was designed to detect a 33% improvement in PFS from 7.5 months with traditional CG therapy to 11.25 months with CGB. Results: By December 2008, 45 pts were enrolled, with 43 evaluable for toxicity, 36 for response. Demographics include: 33 (77%) male, 10 (23%) female; median age 66 (Range: 41 - 78); 26 (60%) and 17 (40%) ECOG 0/1; 19 (44%) and 24 (56%) lymph node only / visceral metastases. PFS will be evaluated in May 2009 when all pts will have more than 6 month follow-up data. 14 (33%) and 6 (14%) pts experienced grade 3 or 4 hematologic toxicity (4 pts - thrombocytopenia, 2 pts - neutropenic fever). Grade 3 or 4 nonhematologic toxicity was observed in 24 (56%) and 9 (21%) pts (DVT/PE - 9 pts, CNS hemorrhage/proteinuria/hypertension - 1 pt each) Best RECIST response was: complete response 6 pts (17%, 95% CI 6–33%), partial response 18 pts (50%, 95% CI 33–67%); with overall response rate of 67% (95% CI 51–82%). Stable disease lasting at least 12 weeks was observed in 10 pts (28%, 95% CI 14–45%) and progressive disease in 2 pts (5%, 95% CI 1–19%). Conclusions: CGB demonstrates significant clinical activity in the first-line treatment of metastatic UC patients at the expense of considerable toxicity. The durability of disease control will be determined by assessment of PFS. A phase III trial to further define the toxicity risk vs. clinical benefit of bevacizumab addition to platinum-based doublets is planned in this population.

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BC2001: A multicenter phase III randomized trial of standard versus reduced volume radiotherapy for muscle invasive bladder cancer (ISCRTN:68324339)
Authors: Huddart R. A. , James N. D. , Adab F. , Syndikus I. , Jenkins P. , Rawlings C. , Hendron C. , Lewis R. , Rogers S. , Hall E. ,   on behalf of the BC2001 Investigators
Published: August 2020

5022

Background: Radiotherapy (RT) is an alternative to radical cystectomy in the management of muscle invasive bladder cancer. Limitations are probability of attaining and maintaining local tumour control and risk of late bladder toxicity. BC2001 tests whether concomitant chemotherapy (CT) improves loco-regional control and whether RT volume modification reduces late toxicity without detriment to tumour control. Methods: Pts were randomized in a 2x2 factorial design to (i) RT vs RT + concomitant CT (5FU 500mg/m2 d1–5 wks 1 & 4 + mitomycin C 12mg/m2 d1) and/or (ii) standard RT to tumour and whole bladder with 1.5cm margin (sRT) vs reduced volume RT (rvRT) where tumour + 1.5cm margin was treated to 100(±5)% target dose and remaining bladder received 80% target dose. RT dose was 55Gy/20F or 64Gy/32F according to local practice. RT volume comparison results (primary endpoint RTOG toxicity at 1 yr) are reported. Target sample size was 480 pts but the RT randomisation closed early due to slow recruitment. Estimated power is 73% (two-sided α = 0.05) to detect a 20% difference in G3/4 toxicity. Results: 219 pts were recruited (108 sRT; 111 rvRT); 49 received neoadjuvant CT; 31 sRT and 33 rvRT were randomised to concomitant CT. Median age was 74 yrs. Median follow up is 36 mths. There was no difference in loco-regional disease-free survival (LRDFS: HR = 1.06, 95% CI: 0.62–1.84) nor overall survival (HR = 0.99, (0.61 - 1.35)) between randomised RT groups. 2yr LRDFS is 71% in both RT groups. 27 (16) sRT vs 32 (15) rvRT pts have had local (invasive) recurrences (p = 0.09); 32 pts have undergone salvage cystectomy. No difference was seen in CTC G3/4 acute toxicity (26% sRT vs 21% rvRT, p = 0.35), RTOG G3/4 toxicity at 12 mths (8% sRT vs 4% rvRT, p = 0.27) nor Lent Som G3/4 toxicity at 12 mths (45% sRT vs 34% rvRT, p = 0.21). Bladder capacity fell significantly in sRT group (mean reduction at 12 mths: 59mls, 95%CI: 47–118mls, p = 0.02) but not in rvRT group. Conclusions: RT in the modern era can attain local control in most patients with T2-T3 bladder cancer. Acute and late toxicity was less than anticipated in both treatment groups. Modifying standard RT volumes had minimal effect on local control and toxicity in this trial. 2 yr toxicity and quality of life data will be presented.

No significant financial relationships to disclose.
Paclitaxel (T) plus ifosfamide (I) followed by high-dose carboplatin (C) and etoposide (E) with autologous stem cell support for patients (pts) with previously treated germ cell tumors (GCT): TI-CE results and prognostic factor analysis in 107 pts
Authors: Feldman D. R. , Sheinfeld J. , Bajorin D. F. , Fischer P. , Turkula S. , Ishill N. , Patil S. , Bains M. , Bosl G. J. , Motzer R. J.
Published: August 2020

5027

Background: Pts with incomplete response (IR) to first-line chemotherapy or relapsed primary mediastinal non-seminomatous GCT (NSGCT) have <10% 3-year (yr) survival with conventional-dose salvage regimens (Cancer. 67:1305). The doses, schedule, and safety of TI-CE in this population were previously reported (J Clin Oncol. 25: 85). Efficacy and prognostic factor analysis are now presented. Methods: Phase I/II trial of TI-CE conducted in GCT pts with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, IR to first-line therapy, or relapse/IR to ifosfamide/cisplatin-based conventional-dose salvage). Univariate and multivariate analyses of prognostic factors were performed. Einhorn (N Eng J Med. 357:340) and Beyer (J Clin Oncol. 14: 263) prognostic models were also assessed. Results: Of 107 pts, primary site was testis in 72, mediastinum (all NSGCT) in 21, and other in 14. 81 had 1 prior line of therapy and 26 had ≥2. 79 were platinum-refractory and 7 had late relapses. A complete response was achieved in 54 (50%) and partial response with negative markers in 8 (8%). 5-yr disease-free survival (DFS) was 47% and overall survival 52% with a median follow-up of 61 months (m). No relapses occurred after 2 yrs. 5/21 (24%) primary mediastinal NSGCT and 2/7 late relapses are continuously disease-free. On multivariate analysis, primary mediastinal site (p = 0.0002), ≥2 lines of prior therapy (p = 0.0005), baseline HCG >1000 (p = 0.01), and lung metastases (p = 0.02) significantly predicted adverse DFS. By Beyer model, 79% were intermediate and 21% poor risk (0 good risk). DFS was better for intermediate than poor risk pts (p < 0.002), with 2-year rates of 54% and 23%, respectively. By Einhorn model, 15% pts were good, 38% intermediate, and 47% poor risk; good/intermediate risk pts had superior DFS compared to poor risk pts (p < 0.05) with DFS at 2 yrs of 69% vs. 44%. Conclusions: TI-CE is effective salvage therapy for GCT pts with poor prognostic features. Mediastinal primary site and ≥2 lines of prior therapy were most predictive of adverse DFS. Beyer & Einhorn models can assist in predicting outcome.

No significant financial relationships to disclose.
Tumor endothelial interaction, CD44+/CD24- stem cell signature, and prognosis in early-stage breast cancer
Authors: Buess M. , Rajski M. , Vogel B. , Herrmann R. , Rochlitz C.
Published: August 2020

503

Background: The effects of tumor-endothelial interaction on global gene expression in breast cancer are not yet well characterized. We hypothesized that gene expression signatures induced by tumor-endothelial interaction might be of clinical relevance. Methods: To this aim we set up an ex vivo co-culture model with human benign and a panel of 6 malignant breast epithelial cells in combination with human venous and microvascular endothelial cells and determined associated gene expression changes with cDNA microarrays. Pretreatment gene expression profiles of 295 early stage breast cancers from the Netherlands Cancer Institute with a median follow up of 12.6 years allowed evaluating in vitro effects in vivo. Results: The most prominent response to co-culture was the induction of a set of “M-phase cell cycle” genes in a subset of breast cancer co-cultures, which were absent in co-cultures with normal breast epithelial cells. While in monoculture tumor cells containing the stem cell like CD44+/CD24- signature showed a lower expression of the “M-phase cell cycle” genes than the CD44-/CD24+ cells, in the co-cultures with CD44+/CD24- cells these genes were induced. Interestingly, these tumor cells co- expressed a set of angiogenic factors such as VEGF, PTN, and FGF12 mRNA at significantly higher levels. In vivo, the expression of the gene set derived from the co-culture was remarkably coherent providing a basis for segregation of tumors into two groups. In a univariate analysis, early stage tumors with high expression levels (n= 137) of “M-phase cell cycle” genes had a significantly lower distant metastasis-free survival (p=1.8e-5) (50 % at 10 years) and overall survival rate (p= 5e-9) (52 % at 10 years) than tumors with low expression levels (n= 158) (metastasis-free survival: 73 %; overall survival: 84 % at 10 years). Conclusions: Our results suggest that the interaction of tumor cells expressing the CD44+/CD24- stem cell like signature, implicating a low proliferative potential, with endothelial cells might explain the unexpected and paradoxical association of the CD44+/CD24- signature with highly proliferative tumors with an unfavorable prognosis. Multiple co-expressed angiogenic factors represent potentially interesting additional therapeutic targets.

No significant financial relationships to disclose.
Phase II trial of ABT-869 in advanced renal cell cancer (RCC) after sunitinib failure: Efficacy and safety results
Authors: Tannir N. , Wong Y. , Kollmannsberger C. , Ernstoff M. S. , Perry D. J. , Appleman L. J. , Posadas E. , Qian J. , Ricker J. L. , Michaelson D. M.
Published: August 2020

5036

Background: ABT-869 is a novel, orally active and potent inhibitor of all VEGF and PDGF receptor tyrosine kinases. Results from a phase I study suggested antitumor activity in advanced solid tumors including RCC. The recommended dose for phase II investigation was 0.25 mg/kg (maximum 25 mg) daily. Methods: We conducted an open-label, multicenter phase II trial of oral ABT-869 in advanced RCC. Eligibility criteria included progressive disease (PD) within 100 days of enrollment after at least 2 cycles of sunitinib, prior nephrectomy, and adequate organ function. The primary endpoint was objective response rate (ORR) per RECIST by central imaging. Secondary endpoints were best response, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Safety was assessed by NCI-CTCAE, v3.0. Results: 53 patients (pts, median age, 61 y [range, 40–80]; clear-cell histology [41 pts]; median number of prior therapies, 2 [range, 1–4]) were enrolled from 8/07 to 10/08. All pts were previously treated with sunitinib, and additional prior treatments included cytokine (19%), sorafenib (15%), temsirolimus (4%), and bevacizumab (4%). Preliminary efficacy data are shown in the Table below. Median TTP was 4.9 mos [95% CI: 3.5–6.8] per central imaging. Median OS is not estimable. The most common adverse events (AEs) were diarrhea (78%), fatigue (67%), hypertension (53%), nausea (51%) and vomiting (39%). AEs ≥ grade 3 included hypertension (24%), fatigue (18%), diarrhea (14%) and hand-foot syndrome (14%). 39 pts required dose reductions. Of the 20 pts who have discontinued therapy at the time of this analysis, 16 were due to PD, 3 due to AEs (1 hemoptysis, 1 fatigue, 1 fatigue/hypertension) and 1 withdrew consent. The remaining 33 pts continue protocol treatment, and updated results will be presented. Conclusions: ABT-869 has activity in RCC after sunitinib failure. The dose will be optimized for future studies.

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