bluuebunny/crossref_metadata_2025 huggingface dataset:
Superiority of trimodality therapy to surgery alone in esophageal cancer: Results of CALGB 9781
Authors: Tepper J. E. , Krasna M. , Niedzwiecki D. , Hollis D. , Reed C. , Goldberg R. , Rich T. , Kiel K. , Mayer R.
Published: March 2020

4012

Background: CALGB 9781 was a prospective randomized Intergroup trial of trimodality therapy versus surgery alone for the treatment of stages 1–3 esophageal cancer. Methods: Five-hundred patients were targeted for enrollment with three years of follow-up planned. The primary endpoint was overall survival. All patents had EGD with biopsy, barium esophagogram and CT. Additional staging by EUS and/or thoracoscopy/laparoscopy was recommended. Patients were randomized to treatment with either surgery alone or cisplatin (100mg/m2) and 5FU (1000 mg/m2/d × 4d) weeks 1 and 5 concurrent with radiation therapy (50.4 Gy- 1.8 Gy/fx over 5.6 weeks) followed by esophagectomy with lymph node dissection. Results: A total of 56 patients were entered on study between October 1997 and March 2000 when the trial was closed due to poor accrual. Thirty patients were randomized to trimodality therapy and 26 to surgery alone. Patient characteristics were similar between groups. Surgical staging was conducted in just over 50% of patients in both groups. The primary toxicities of Gr 3 or greater with preoperative therapy were hematopoietic (54%), and esophagitis/dysphagia (40%). There were 14 and 17 patients with surgical complications on the trimodality and surgery alone arms, respectively, with 2 post-surgical deaths (within 30 days), both on the surgery alone arm. Postoperative hospital stays were 11.5 and 10 days, respectively. Median follow-up is 6 years. An intent- to- treat analysis showed a median survival of 4.5 yrs vs 1.8 yrs in favor of trimodality therapy (log-rank p=0.02). A log rank test with stratifications by N stage, staging approach and histology demonstrated a p-value of 0.005. 5-year survival was 39% (95% CI [21%, 57%]) vs 16% (95% CI [5%, 33%]) in favor of trimodality therapy. Analysis of progression-free survival is underway. Conclusions: This randomized study demonstrates a long-term survival advantage with the use of chemoradiation therapy followed by surgery in the treatment of esophageal cancer. Although accrual was well below that planned, the observed survival difference is statistically significant and suggests that trimodality therapy is an appropriate standard of care for patients with this disease.

No significant financial relationships to disclose.
Irinotecan/capecitabine versus cisplatin/capecitabine in advanced adenocarcinoma of the stomach or gastroesophageal junction: Interim analysis of a randomized German AIO phase II study
Authors: Moehler M. , Kanzler S. , Geissler M. , Raedle J. , Ebert M. , Scherubl H. , Flieger D. , Seufferlein T. , Galle P. R. , Hoehler T.
Published: March 2020

4032

Background: Irinotecan with 5-FU is highly effective in advanced gastric cancer. In addition, capecitabine seems to be as effective as 5-FU, with its advantage of oral administration. Thus, we compared efficacy and toxicity of irinotecan/capecitabine versus cisplatin/capecitabine in this prospective multicentric, open trail. Methods: Patients (pts) with previously untreated locally advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction and Karnofsky Performance status (KPS) of ≥ 60%, at least one measurable lesion and adequate organ functions were eligible. Pts were randomized to 3-weekly cycles of irinotecan 250 mg/m2, day 1 (arm A) or to cisplatin 80 mg/m2, day 1 (arm B). Capecitabine was administered at a 1000 mg/m2 twice daily for 14 days followed by a 7-day rest in both arms. Primary endpoint was remission rate, treatment was continued until disease progression. Results: At time of abstract submission, 91 of 120 pts (planned sample size) were randomized to arm A (45 pts) or B (46 pts). Interim data were available on 76 patients included into intent to treat analysis (34 pts arm A, 42 pts arm B). Baseline characteristics (arm A vs. B) were median age: 60 vs. 64 years, gender (female/male) 23%/77% vs. 30%/70%, KPS (≥80%) 97% vs. 93%, tumor distribution of gastric origin and gastroesophageal junction 85%/15% vs. 63%/37%. Grade 3 toxicities in A/B (% of pts) were anemia 3/9, neutropenia 17/19, diarrhoea 17/5, nausea 14/21, vomiting 3/14, hand-foot syndrome 6/2, respectively. Grade 4 toxicity occured only for neutropenia with 3% vs.5% in A/B, respectively. In 59 evaluable pts (28/31 in A/B), overall remission rate (CR + PR) and tumor control rate (CR + PR + SD) were 39% vs. 42% and 64% vs. 74%, respectively. Despite being only very descriptive, median progression-free and overall survival (arm A vs B) were 5.2 vs. 5.0 and 8.9 vs. 9.4 months, respectively. Conclusions: In patients with locally advanced or metastatic gastric and gastroesophageal cancer, both regimen irinotecan/capecitabine or cisplatin/capecitabine are effective, well tolerated and can be administered safely on an out-patient basis. Currently, both treatment arms are comparable. Accrual continues.

No significant financial relationships to disclose.
Pancreatectomy for neoplasm: National outcomes in mortality
Authors: McPhee J. T. , Zayaruzny M. , Whalen G. F. , Litwin D. E. , Sullivan M. E. , Anderson F. A. , Tseng J. F.
Published: March 2020

4035

Background: Pancreatic resection remains the only potentially curative intervention for pancreatic cancer. The goal of this study was to evaluate factors affecting outcomes after pancreatectomy for neoplasm using a large national database. Methods: This is a retrospective analysis of 6,091patients (pts) undergoing pancreatic resection for non-endocrine neoplastic disease obtained from the National Inpatient Sample 1998–2003 (≈ 30,241 pts nationally by weighted analysis). Crude primary outcome measures of in-hospital mortality and postoperative disposition were analyzed by chi-square. A proportional hazards model was then constructed to adjust outcomes for age, sex, hospital teaching status, hospital surgical volume and selected co-morbid conditions. Results: 42,380 patient discharges (≈209,016 nationally) occurred with a primary diagnosis of pancreatic neoplasm. 6,091 (14%) pts underwent resection during that hospitalization. In-hospital mortality was 5.8% with a significant decrease of 7.7% - 4.4% from 1998–2003 (p=.016, regression coefficient .0042). In the univariate analysis pts treated at a non-teaching hospital had higher mortality rates (9.4% vs. 4.4% p<.0001). However, when adjusted for covariates including hospital surgical volume [low (<4 resections/year), medium (4–13/year), high (>13/year)] teaching status became insignificant in predicting mortality. Resections done at low and medium volume centers were predictive of higher mortality compared to high volume centers (OR 4.1 [2.7, 6.1] and OR 2.4 [1.6, 3.6]). Female gender was predictive of lower mortality (OR 0.58 [0.46, 0.74]). Younger pts (40–69) had lower mortality than pts 70 years or older. Overall, median post-operative length of stay (LOS) was 11 days (SD 23.9). LOS was shorter for female patients (median 10 days vs. ll days) and for resections done at high volume centers (median 10 days vs. ll days). Conclusions: This large observational study demonstrates an improvement in operative mortality for patients undergoing pancreatectomy for neoplastic disease 1998–2003. Furthermore, it demonstrates superior adjusted outcomes in terms of mortality, and LOS, for females, younger patients, and those treated at high volume surgical centers in the United States.

No significant financial relationships to disclose.
Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3
Authors: Bello C. , Deprimo S. E. , Friece C. , Smeraglia J. , Sherman L. , Tye L. , Baum C. , Meropol N. J. , Lenz H. , Kulke M. H.
Published: March 2020

4045

Background: Sunitinib malate (SU11248) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity that specifically inhibits VEGFR, PDGFR, KIT, RET, and FLT3. In a phase II trial of 109 patients with metastatic neuroendocrine tumors (NET), sunitinib treatment was associated with ORR and high rates of SD in patients with carcinoid and pancreatic islet cell tumors (Kulke et al, ASCO 2005). To characterize potential biomarkers of biological response to sunitinib, we analyzed plasma levels of a panel of soluble proteins from patients in this trial. Methods: Patients received sunitinib in 6-week cycles comprised of 50 mg/day for 4 weeks followed by 2 weeks off treatment. Pre-dose plasma samples from 106 patients were obtained on days 1 and 28 of multiple cycles. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), interleukin-8 (IL-8), and a novel biomarker, sVEGFR-3, were measured via ELISA analysis. Results: Plasma levels of each protein were frequently modulated during the course of treatment. At the end of cycle 1, VEGF levels were increased more than 3-fold over baseline in ∼50% of all patients. Average baseline VEGF levels were higher in the islet cell group (62 vs. 40 pg/ml, P = 0.06). In cycle 1, sVEGFR-2 and sVEGFR-3 levels were significantly decreased by ≥30% in ∼60% and 70% of all patients, respectively (P < 0.0001). Levels tended to return to near-baseline after 2 weeks off treatment. The reduction in sVEGFR-3 levels in cycle 1 was, on average, greater in the subset of patients with PR (n=11) compared to others (45% vs. 38%). Overall, there was a 2.2-fold average increase in IL-8 levels by the end of cycle 1, and a larger proportional increase in IL-8 levels in patients exhibiting decreases in tumor size, patients who also tended to have lower baseline IL-8 levels. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: Our results suggest that this panel of circulating proteins may be of utility as pharmacodynamic biomarkers of sunitinib activity in patients with advanced NET. sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib in NET, and IL-8 may be of particular interest as a potential predictor of response.

[Table: see text]
Clinical effects of esophagectomy for patients 80 years of age and older with thoracic esophageal cancer
Authors: Morita M. , Nishida K. , Koga T. , Egashira A. , Tokunaga E. , Oki E. , Sadanaga N. , Kakeji Y. , Maehara Y.
Published: March 2020

4049

Background: Esophageal cancer tends to mainly occur in elderly patients. Although a radical operation is the most effective existing therapy, the associated operative morbidity is still high. As a result, the indications for an esophagectomy in elderly patients (especially for patients over 80 years of age) remain controversial. Methods: A total of 599 patients with thoracic esophageal cancer who underwent an esophagectomy by the transthoracic approach since 1986 were evaluated. They were divided into 3 groups depending on age, namely groups I (<69 y.o., n = 441), II (70–79 y.o., n = 143) and III (≥80 y.o., n = 15). No significant differences were observed in the location of the tumor, histological type or stage. A distal esophagectomy with a left thoracotomy was performed for 40, 46, and 47% of the patients, respectively, while the others underwent a subtotal esophagectomy with a right thoracotomy. In group III, surgery was only done for cases with PS 0 or 1 as well as a normal cardiac and pulmonary function (ejection fraction ≥65 %, vital capacity ≥80 %, FEV 1.0% > 70%). Results: Postoperative complications occurred in 31 % of group I and 39 % of group II patients, and the incidence of pulmonary complication was 9 and 18 %, respectively (P < 0.01). In group III, the operative morbidity and mortality were 27 and 0 %, respectively, and pulmonary complications only occurred in one patient (7%). No significant difference was observed in the disease-free survival (DFS: 50, 46 and 58 % for 3yrs, 44, 40 and 33 % for 5 yrs), while the overall survival rates were worse in the older groups as a result of death due to causes other than recurrence (45, 34 and 34 % for 3yrs and 38, 26 and 9 % for 5 yrs in groups I, II and III, respectively. P < 0.01 group I v.s. II). Conclusions: An esophagectomy is considered to be a viable treatment alternative in patients over 80 years of age without increasing morbidity, when the indications for surgery are strictly determined. Furthermore, the DFS in these patients was similar to that observed in younger patients although the incidence of death due to causes other than cancer was found to be higher. An esophagectomy should therefore be considered as an effective treatment strategy even in elderly patients over 80 years of age.

No significant financial relationships to disclose.
A phase II study of capecitabine plus oxaliplatin (XELOX) as first-line therapy for patients with advanced gastric cancer
Authors: Park Y. , Lee J. , Ryoo B. , Ryu M. , Yang S. , Kim B. , Shin D. , Chang H. , Kim T. , Kang Y.
Published: March 2020

4079

Background: The combination chemotherapy of capecitabine and cisplatin showed considerable activity and good feasibility in patients with advanced gastric cancer. Oxaliplatin has a more favorable toxicity profile compared to cisplatin. The purpose of the study is to evaluate the efficacy and toxicity of capecitabine plus oxaliplatin combination chemotherapy in previously untreated patients with advanced gastric carcinoma. Methods: Patients received intravenous oxaliplatin 130 mg/m2 over 2 hours on day 1 plus oral capecitabine 1000 mg/m2 twice daily on days 1–14, every 3 weeks. Treatment was continued until progression of disease or intolerable toxicities with a maximum of 8 cycles. All the measurability and response evaluations were reviewed and confirmed by one investigator. Results: Total 54 patients were enrolled (37 men, 17 women). The median age was 57 years (range 29–70). Among these 54 patients, fifty-two patients were evaluable. A total 311 cycles of chemotherapy were delivered. The overall response rate was 63% (95% CI, 50–76%), with complete response in 2 patient and partial responses in 32 patients. After a median follow-up of 13 months, median progression-free survival was 5.8 months (95% CI, 4.4–7.2 months); median overall survival was 11.9 months (95% CI, 8.8–15.1 months). The treatment was generally well tolerated. The most common haematological adverse event was anaemia (70% of patients). Grade 3- 4 neutropenia was observed in 4 patients and neutropenic fever was experienced in only 1 patient. Four patients had G3 thrombocytopenia, which was accompanied by G3 gastrointestinal bleeding. The most common non-haematological toxicities were neuropathy (70%), vomiting (50%), diarrohea (33%), and hand-foot syndrome (39%). But, G3–4 toxicities were rare. There was one treatment related death which was associated with grade IV neutropenic sepsis. Conclusion: XELOX was active and well tolerated as a first-line therapy for advanced gastric carcinoma.

No significant financial relationships to disclose.
Extended safety and efficacy data on S-1 plus cisplatin in patients with advanced gastric carcinoma in a multi-center phase II study
Authors: Lenz H. , Lee F. C. , Haller D. G. , Singh D. , Benson A. B. , Strumberg D. , Yanagihara R. H. , Yao J. C. , Phan A. T. , Ajani J. A.
Published: March 2020

4083

Background: We obtained additional phase II safety and efficacy data in a multi-center setting on an active regimen of S-1 plus cisplatin; the experimental arm of the global phase III First-Line Advanced Gastric cancer Study (FLAGS). Methods: Eligible patients had untreated advanced gastric cancer (AGC), histologic proof, KPS ≥70%, adequate organ function, and gave written consent. Patients received S-1 (25mg/m2 p.o. bid on days 1–21) plus cisplatin (75mg/m2 i.v. on day 1) every 28 days. All reported confirmed overall response rate (C-ORR), response durations, and time-to-progression (TTP) are externally reviewed. Results: All 72 patients were assessed for safety and 64 for efficacy. The median age was 56 years and median KPS was 90%. Median no. of cycles was 4. C-ORR was 50% (95% CI, 37%-63%). Median duration of response is >6 months. At 6 months, only 35% of patients have had cancer progression. Median survival (n=72) is 10.5 months (95% CI, 9.3 to NR). At least one SAE occurred in 43% of patients. The frequent grade 3 or 4 adverse events (occurring in >10% of patients) included: fatigue/asthenia (26%), vomiting (21%), nausea (18%), diarrhea (17%), neutropenia (18%), anorexia (11%), and dehydration (11%). Febrile neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. Conclusions: These extended data confirm that S-1 plus cisplatin has a very desirable safety profile and impressive efficacy data in AGC. FLAGS will complete accrual of >700 patients by March of 2007. (Supported by Taiho Pharma-USA).

[Table: see text]
Evaluation of significance of endoscopic mucosal resection (EMR) in early esophageal cancer
Authors: Yoshii T. , Tamai S. , Motohashi O. , Yonemitsu K. , Kiyohashi A. , Takagi S. , Nakayama N. , Murata Y.
Published: March 2020

4088

Background: Radical surgery for esophageal cancer is very invasive. Endoscopic mucosal resection (EMR), which conserves the esophagus, is a minimally invasive and attractive therapeutic modality for early stage esophageal cancer. However, when the tumor reaches the deep mucosal or submucosal layer (“T1b” according to TNM classification), the incidence of lymph node metastasis (LNM) increases up to 10–50%. Therefore, the indications of EMR have to be clarified. Methods: Retrospective analysis was performed regarding the clinical course of 41 patients who were diagnosed as having cT1bN0M0 esophageal cancer and underwent EMR between 1994 and 2004 at our hospital. Statistical analysis was performed by the log-rank and Kaplan-Meier methods. Results: Thirty nine patients were selected and followed up without any additional therapy after obtaining written informed consent. Twenty patients (51%) had multiple primary cancers, 10 died, and 29 are still alive. MST of the dead patients was 22 months, and 7 of them (70%) died of advanced multiple primary cancers, while death was cause specific in only one case (due to LNM). The survival curves showed no significant differences between the patients with early multiple primary cancers and those without multiple cancers patients (MST = 72 months, p < 0.7784). In most of the dead patients and 23 of the surviving patients, the local lesion was well controlled without any recurrence. Conclusions: Many patients with early esophageal cancer who underwent EMR tended to die of multiple primary cancers. When the patient had early multiple primary cancers, the prognosis was not different from those without such cancer and the local lesion was well controlled. We concluded that EMR is a very useful therapeutic modality for local control as it is minimally invasive, especially in patients with multiple primary cancers.

No significant financial relationships to disclose.
Surgical resection for pancreatic cancer: Correlates of margin positivity
Authors: Ashraf S. , Andrews C. , Kuvshinoff B. , Pande A. , Javle M. , Gibbs J. F.
Published: March 2020

4097

Background: Positive surgical margins (PSMs) occur in 20–40% of pancreatic cancer cases treated surgically. PSMs are associated with local recurrence and poor survival. Objectives: Correlate clinicopathological parameters with PSMs in pancreatic cancer patients (pts) undergoing surgical resection. Methods: Clinicopathological data for 71 pts who underwent surgical resection for pancreatic cancer from 1999–2005 were obtained. Data including location, AJCC stage, tumor size, type of resection, use of neoadjuvant therapy, grade, morphology, perineural and angiolymphatic invasion were correlated with PSMs and survival using logistic regression, Fisher-exact test and log-rank test. Results: There were 29 males; median age was 65 years and median follow-up 14 months. Histologies were: adenocarcinoma (n = 67), sarcomatoid (n = 2), adenosquamous (n = 1) and mucinous cystadenocarcinoma (n = 1). Sites of disease were: head only (n = 56), head/uncinate (n = 7) and body/tail (n = 8). Surgical treatments included Whipple (n = 43), pylorus preserving Whipple (n = 18) distal pancreatectomy (n = 8) and total pancreatectomy (n = 2). Pathological AJCC stages were: ΙA (n = 4), ΙB (n = 2), ΙΙA (n = 14), ΙΙB (n = 48), and ΙΙΙ (n = 3). Neoadjuvant chemoradiation (CRT) was administered in 10 cases; 38 other pts received postoperative adjuvant therapy including CRT (n = 36)/chemotherapy only (n = 2). Overall median survival was 30 months and disease free survival 18.6 months. Nineteen cases (27%) had PSMs. PSMs were pancreatic transection line (n = 11), retroperitoneal margin (n = 9), bile duct (n = 1) and peripancreatic soft tissue (n = 2). On univariate analysis, PSM was associated with advanced AJCC stage (p = 0.02) and tumor location other than pancreatic head (p = 0.02). PSM rate was 10% (1/10) and 31% (18/61) for pts with/without neoadjuvant therapy, respectively (p = 0.27). On multivariate analysis, PSM correlated with AJCC stage (p = 0.04) and tumor location (p = 0.05). PSMs were not significantly related to survival or recurrence (p = 0.09). Conclusions: Advanced AJCC stage and tumor in pancreatic body/tail or uncinate are associated with PSMs following pancreatic cancer resection. Strategies to “downstage” with novel therapies prior to surgery should be investigated to facilitate a complete surgical resection.

[Table: see text]
The PACT trial: Interim results of a randomized trial of TNFerade biologic plus chemoradiation (CRT) compared to CRT alone in locally advanced pancreatic cancer (LAPC)
Authors: Senzer N. , Rosemurgy A. , Javle M. , Reid T. , Posner M. C. , Chang K. J. , Owens M. , Shirinian M. , Stephenson J. , Hecht J. R.
Published: March 2020

4102

Background: TNFerade is a second-generation replication-deficient adenovector, carrying the transgene encoding human TNF-α, regulated by the stress-inducible promoter Egr-1. In a phase I trial of TNFerade + radiation in 36 patients with advanced or refractory solid tumors, a 47% objective tumor response rate was observed, including 100% complete responses in 3 stage 4 melanoma patients, with 2/3 disease-free at >3.5 years. Methods: This controlled phase II trial randomizes 74 patients with newly diagnosed unresectable LAPC to 5-wks of TNFerade (4 × 1011 pu via weekly intratumoral injection) + CRT (5-FU [200 mg/m2/day CIV × 5 days/wk] and 50.4 Gy radiation) or CRT alone. All patients receive maintenance gemcitabine. Endpoints: Progression-free survival, safety, radiographic tumor response, CA 19–9 and survival. Results: In dose escalation (n=50) dose-limiting toxicities occurred in 3 patients at 1 × 1012 pu (pancreatitis in 2 and biliary obstruction), setting the MTD at 4 × 1011 pu. Compared with the first two cohorts (n=30), the MTD (n = 11) was associated with greater locoregional control and progression-free survival, a higher rate of stable or decreasing CA 19–9, improved overall survival (median = 11.2), and a high (45%) resection rate. Accrual continues in the randomized phase of the study at 20+ centers. The most frequent adverse events in the first 16 enrolled patients have been nausea (75%), abdominal pain (63%), constipation (50%), anemia (38%), diarrhea (38%), vomiting (38%), and weight loss (38%), with no significant difference in severity or frequency between the TNFerade + CRT and CRT groups. No thromboembolic events have been reported. Serum TNF-alpha levels have remained low (peak = 45.3 pg/mL, in a CRT patient). CA 19–9 has been stable (no change > 100 U/mL) or decreased in all but one CRT patient. Conclusions: These initial data indicate that TNFerade plus CRT, given as weekly intratumoral injections to patients with LAPC, is feasible and tolerable compared to CRT alone. With continued accrual, comparative tumor response and toxicity data will be available and updated.

No significant financial relationships to disclose.
Phase I trial of gefitinib with concurrent radiotherapy and fixed dose-rate gemcitabine infusion, in locally advanced pancreatic cancer
Authors: Maurel J. , Martin-Richard M. , Conill C. , Sanchez M. , Petriz L. , Ginés A. , Gallego R. , Cajal R. , Navarro S. , Fernandez-Cruz L.
Published: March 2020

4105

Background: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor (EGFR) is over-expressed in pancreatic cancer and in vitro studies have shown that EGFR inhibitors can overcome radio- and chemo-resistance. The aim of the study was to determine the maximally tolerated dose of gefitinib, in combination with RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC). Methods: Eighteen patients with pathological proven LAPC, due to major vascular invasion based on helical computed tomography and endoscopic ultrasound, were entered. The targeted irradiated volume included the tumor and 2 cm-margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cc of planned tumor volume (PTV) were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150 and 200 mg/m2/day of gemcitabine in a 2 hour infusion over weeks 1,2,3,4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers (VEGF and IL-8) was also performed. Results: Mean PTV was 293cc (range 137–462 cc). There were no dose-limiting toxicities on study. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. One patient showed a partial response of 13 months in duration, and 7 patients showed disease stabilization. Median progression free survival (PFS) was 3.7 months and median overall survival (OS) was 7.5 months. No patients have a reduction in VEGF levels >50%. Reduction in VEGF serum levels >25% and IL-8 levels >50% had no impact on PFS and OS. Conclusion: Our results support thatthe combination of gefitinib, RT and gemcitabine showed an acceptable toxicity but with modest activity in LAPC.

[Table: see text]
Use of pre-trial EBV titres as a measure of immune status: Further support for independence from health status of immunological response to G17DT in gemcitabine—G17DT combination pancreatic cancer trial patients
Authors: Broome P. , Mudde G. , Kircheis R. , Takhar A. , Watson S. A.
Published: March 2020

4108

Background: In a Phase III pancreatic cancer trial combining G17DT with gemcitabine (Gem) vs Gem alone [ASCO 2005, Abstract 4012], a significant survival effect, independent of baseline KPS, was seen in patients with gastrin antibody response (Placebo + Gem 178 days vs 264 for antibody responders > 16U, p = 0.03). A consistent criticism of such analyses of vaccine trials in cancer patients is that the immuno-responders reflect a fitter sub-population. To show that response to G17DT was at least partially independent of health status, pre-trial EBV titres, which can be considered as a marker of immunological status, were shown to be predictive of survival in the placebo group. However, in the G17DT treated group, antibody responders and non-responders had similar distributions of anti EBV titres. Methods: Baseline PC4 patient sera from both Gem alone (placebo) and Gem + G17DT groups were examined for antibodies against EBV by ELISA. The placebo patients were assigned high or low EBV status if they were respectively above or below the mean titre. Kaplan-Meier curves for these sub-populations were compared using the log rank statistic. G17DT-treated patients were grouped into high, low and non-responders. Mean EBV titres of the G17DT subgroups were compared with each other and with the placebo group using the t-test. Results: HighEBV titre was shown to predict improved survival in the placebo arm of the Phase III trial (Gem treatment only, p = 0.049). However, mean EBV titres were similar in high G17DT antibody responders cf non-responders (EBV titre 125 vs 159, p = 0.13) and in placebo patients cf non-responders (160 vs 159, p = 0.98). Conclusions: Pre-trial EBV titre, found to be predictive of survival in pancreatic cancer patients treated with gemcitabine, was similar between G17DT responders and non-responders, adding further weight to the hypothesis that G17DT response is substantially independent of health status.

[Table: see text]
A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy (PROSPECT - CONKO 004)
Authors: Pelzer U. , Hilbig A. , Stieler J. , Roll L. , Stauch M. , Opitz B. , Scholten T. , Hahnfeld S. , Dörken B. , Riess H. , Oettle H.
Published: March 2020

4110

Background: Approximately 20% of patients (pts) diagnosed with pancreatic adenocarcinoma (PA) develop venous thromboembolism, which may contribute to the dismal prognosis of PA. A small phase II trial suggested an improved survival by the addition of low molecular weight heparin (LMWH) to chemotherapy (Icli et al., ASCO 2003). We conducted a small pilot study which indicated that the addition of enoxaparin to chemotherapy GFFC chemotherapy (see below) is safe and feasible in pts with advanced PA. Furthermore, results of several phase III studies suggest that pts in good performance status may benefit from more intensive chemotherapy regimen (Riess et al; Heinemann et al; ASCO 2005). Based on these considerations we started the multicenter phase III study CONKO 004. Methods: 540 patients are to be recruited into this study. Primary stratification takes place according to Karnowsky performance status and kidney function. Patients with KPS > 80% and normal kidney function receive GFFC ± LMWH (gemcitabine 1 g/m2 (30 min), cisplatin 30 mg/m2 (90 min), 5-fluorouracil 750 mg/m2 (24 h), folinic acid 200 mg/m2 (30 min), d1, 8; q3w ± Enoxaparin 1mg/kg daily s.c.). Pts with KPS < 80 % and increased creatinin plasma levels (>1.3 mg/dl) receive the current standard therapy (gemcitabine 1 g/m2 (30 min), d1, 8, 15; q4w) ± LMWM ± Enoxaparin 1mg/kg daily s.c. After 12 weeks of initial chemotherapy all patients who have not progressed received the standard therapy (gemcitabine 1 g/m2 (30 min), d1, 8, 15; q4w) ± Enoxaparin 40mg daily s.c. Results: From April 2004 to Dezember 2005 140 pts have been recruited in this study. Until now no unexpected serious adverse events concerning severe bleedings were observed in the enoxaparin treatment group. No heparin induced thrombocytopenia (HIT II) was documented. The first interim analysis per protocol is planned after 12 pts. with deep vein thrombosis or thromboembolic events. This interim analysis is expected to be completed in May 2006. Conclusions: Our observations indicate that the addition of enoxaparin—given the dosage mentioned above—to GEM/GFFC is safe, does not change toxicity and maintains activity of chemotherapy in pts with advanced PA. This study is open to recruitment.

No significant financial relationships to disclose.
A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer
Authors: Morizane C. , Okusaka T. , Furuse J. , Ishii H. , Ueno H. , Ikeda M. , Najima M. , Hirokawa S. , Nakachi K. , Ogura T.
Published: March 2020

4115

Background: Gemcitabine (Gem) monotherapy or Gem-containing chemotherapy is the standard first line therapy for advanced pancreatic cancer. After disease progression, there is no standard regimen available. In a previous phase II trial (J. Furuse et al, Proc ASCO 2005: # 4104), S-1 has been reported to show considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. This study evaluated the efficacy and toxicity of S-1 in patients with Gem-refractory metastatic pancreatic cancer. Methods: Eligibility criteria were pathologically-proven pancreatic cancer with confirmation of progressive disease while receiving Gem-based chemotherapy, Karnofsky performance status 80 to 100%, age 20 to 74 years, with measurable metastatic lesions, adequate hematological, renal and liver functions, and written informed consent. S-1 was administered orally at 40 mg/m2 twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. The primary study end point was objective response, secondary end points included toxicity, progression-free survival (PFS) and overall survival, as well as clinical benefit response in symptomatic patients. Results: Forty patients (pts) from two institutions were enrolled between September 2004 and November 2005. Thirty-three pts are currently evaluable for response in this ongoing trial. There have been 5 confirmed partial responses (12.5%), and 14 pts (35%) with stable disease. Median survival has not been reached. Median PFS was 2.1 months. Toxicity data were available for 28 patients. Grade 3 and 4 toxicities were anemia (1 pts), appetite loss (2 pts), and fatigue (2 pts). Conclusions: Preliminary results demonstrated the safety and activity of S-1 in Gem-refractory metastatic pancreatic cancer. Efficacy and toxicity analysis are ongoing. Final results will be presented at the meeting.

No significant financial relationships to disclose.
Proposal of a new staging system for hepatocellular carcinoma based on the treatment strategy: An analysis of 1,084 patients
Authors: Ishii H. , Furuse J. , Kinoshita T. , Nakachi K. , Suzuki E. , Yoshino M. , Konishi M. , Nakagohri T. , Takahashi S. , Gotohda N.
Published: March 2020

4137

Background: Although several prognostic models have been proposed for hepatocellular carcinoma (HCC), they are not useful for conducting treatment strategy. Methods: Between July 1992 and May 2005, consecutive 1084 patients (pts) with naïve HCC were treated in our hospital. Based on our treatment strategy, we set our own HCC stage as follows: stage 1; Child-Pugh A or B, N0M0, solitary tumor without vascular invasion (VI), stage 2; Child-Pugh A or B, N0M0, multiple tumors without VI, stage 3; Child-Pugh A or B, N0M0, solitary tumor with VI, stage 4A; Child-Pugh A or B, N0M0, multiple tumors with VI, stage 4B; Child-Pugh A or B, N1 or M1, any T, stage 4C; Child-Pugh C, any TNM. Generally, treatments for stage 4C, 4B, & 4A were observation, chemotherapy trials or aggressive local therapies in selected pts, & hepatic arterial infusion chemotherapy. For the pts with stage 1–3, the priority of treatment options was hepatectomy first, percutaneous ablation (PA) second, and transcatheter arterial chemoembolization third. PA was indicated for 3 or fewer HCC nodules without VI, of which the largest diameter were smaller than 3 cm. Treatment outcomes were retrospectively analyzed according to the above staging system. Results: The overall survival rate was 50% at 3 yrs, 33% at 5 yrs, 24% at 7 yrs & 13% at 10 yrs. The median survival in stage 1, 2, 3, 4A, 4B & 4C was 5.5 yrs (N = 444), 2.9 yrs (N = 397), 0.8 yr (N = 36), 0.5 yr (N = 109), 0.3 yr (N = 76) & 0.2 yr (N = 22), respectively. Most of the definitive local therapy (91% of 371 hepatectomies with curative intent & 99% of 191 PAs) were classified in stage 1 or 2. The prognosis was also well predicted by the other 6 staging systems (Okuda, AJCC, CLIP, JIS, Tokyo and BCLC). However, hepatectomy with curative intent & PA were distributed into a CLIP score of 0–5 & 0–3, respectively, & into a JIS score of 0–4 & 0–3, respectively. Conclusions: The present staging system was simple & predicted prognosis well. Although other scoring systems caused various heterogeneities (hepatic reserve & tumor status) in each score, our staging system consisted of homogenous hepatic reserve & simple tumor status, so it might be useful for conducting treatment plan. Validation study is warranted in other population.

No significant financial relationships to disclose.
Molecular analysis for new kinase mutations in imatinib resistant gastrointestinal stromal tumor patients
Authors: Ling K. , Liu C. , Tsen C. , Hsieh R. , Huang M.
Published: March 2020

4155

Background: Gastrointestinal stromal tumors (GISTs) are characterized by expression of activated mutation of KIT or platelet-derived growth factor receptor alpha (PDGFRA). Imatinib had now been widespread used for treatment of unresectable or metastatic GISTs. However, most patients developed resistant to imatinib in a period of 1∼2 years. We have recently found the resistance to imatinib in GIST might be related to additional mutations in the kinase domain and we intend to identify the secondary mutation in imatinib resistant GISTs in Taiwanese patients. Patients and Methods: From April 2001 to November 2005, 20 advanced GIST patients were treated in Taipei MMH. Within 32 months, 10 patients with initial near-complete response to imatinib developed disease progression and resistant to imatinib. Nine harbored mutations in KIT exon 11, and one harbored mutation in KIT exon 9 before imatinib treatment. Five patients expired and the other (residual) five patients received excision or biopsy of progression lesions. Genomic DNA extracted from paraffin-embedded specimens from alive patients, were analyzed by sequencing for KIT (exon 9, 11, 13, 17) and PDGFRA (exon 10, 12 14, 18) gene mutation. Results: Molecular analysis revealed two patients harbored KIT exon 13 mutation Val654Ala substitution in their progression lesion. The other three patients harbored KIT exon 17 mutation Asn822Lys substitution. Conclusion: The novel missense mutation of KIT exon 17 N822K has never been reported before. The finding of an association between new mutation and disease progression is very impressive. The relationship between secondary mutation in these kinases and clinical response to imatinib will require further investigation.

No significant financial relationships to disclose.
Long-term non-cancer mortality among 39,657 one-year testicular cancer survivors (TCSs)
Authors: Fosså S. D. , Chen J. , Dores G. M. , McGlynn K. A. , Schonfeld S. J. , Travis L. B.
Published: March 2020

4508

Background: Multiple reports address the incidence of second cancer (SC) and long-term morbidity in TCSs, yet few data analyze the impact of non-malignant late sequelae on mortality. Methods: 39,657 one-year TCSs were identified in 14 population-based cancer registries in North America and Europe, with 17,856, 13,084 and 6,298 men followed for 10, 20 and 30 years, respectively. Standardized mortality ratios (SMRs), comparing TCSs to the general population, were calculated for deaths due to all non-cancer causes (n = 2,942) and specific sites. Further, absolute mortality due to TC, non-TC SC and all non-cancer disorders was estimated. Results: The SMR for all non-malignant diseases combined was 0.99 (95% CI: 0.95–1.02), with a significant reduction of deaths due to circulatory diseases (SMR: 0.92, n = 1,117). However, following initial treatment with chemotherapy and radiotherapy, the SMR for circulatory diseases was significantly elevated (SMR: 1.76), with a non-significant 29% excess after chemotherapy alone. Mortality due to digestive diseases was significantly increased (SMR: 1.32, n = 222), including gastric and duodenal ulcers (SMR = 1.52; excess deaths were observed between 10 and 25 years after initial radiotherapy). For the first 20 years after TC diagnosis, deaths due to infection were significantly elevated (SMR: 1.52, n=211). Absolute mortality due to non-cancer disorders always exceeded that due to SC, and was 15% after 30 years in a TCS diagnosed at age 35 compared with about 11% for SC. Conclusions: Compared with the general population, the overall risk of mortality due to all non-cancer causes combined does not appear to be increased in TCSs. However, they experience excess non-cancer deaths due to infection and digestive diseases, but not circulatory diseases. Additional analytic studies with detailed data on treatment and co-morbidities are required to further evaluate associations with specific causes of death.

No significant financial relationships to disclose.
A phase II study of sunitinib administered in a continuous daily regimen in patients with cytokine-refractory metastatic renal cell carcinoma (mRCC)
Authors: De Mulder P. H. , Roigas J. , Gillessen S. , Srinivas S. , Pisa P. , Vogelzang N. , Fountzilas G. , Peschel C. , Baum C. , Escudier B.
Published: March 2020

4529

Background: Renal cell carcinomas are known for their vascularity and production of high levels of VEGF. Sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor of multiple receptors including VEGFR, PDGFR, KIT, RET, and FLT3, has previously demonstrated significant efficacy in 168 patients (pts) with mRCC, with a 42% objective response rate (ORR) at 50 mg/day in 6-week (wk) cycles of 4 wks on treatment followed by 2 wks off. This study sought to determine the efficacy and safety of single-agent sunitinib in mRCC when administered in a continuous 37.5 mg/day regimen. Methods: Pts with histologically proven mRCC, refractory to a cytokine-based regimen, were enrolled in this open-label, multicenter, phase II study. Eligibility criteria included measurable disease, ECOG PS 0/1, and adequate organ function. Pts were randomized to receive sunitinib in the morning (AM) or in the evening (PM) at a dose of 37.5 mg/day, with individual doses subsequently titrated based on tolerability. The primary endpoint was RECIST-defined ORR. Secondary endpoints includedprogression-free survival, adverse events (AEs) and quality of life measures. Results: A total of 88/100 planned pts have been randomized to date: AM (43) and PM (45), and enrollment will be completed by end January 2006. 44 pts have been on continuous sunitinib treatment at 37.5 mg/day for >16 wks (3), >12 wks (9), >8 wks (12), and >4 wks (20). 2 pts (2.3%) discontinued (colon perforation and renal insufficiency) and 9 (10.2%) dose reduced to 25 mg/day due to grade 2/3 AEs: mucositis (2), hand-foot syndrome (2), thrombocytopenia (2), asthenia (1), nausea/diarrhea (1), and neutropenia (1). Preliminary efficacy data show some tumor shrinkage in the majority of patients evaluated at 4 wks, with 3 initial partial responses. There has been no significant difference between pts who received AM or PM doses. The most commonly reported AEs were mucositis, fatigue, hair/skin discoloration, and hand-foot syndrome. Conclusions: Sunitinib administered at a continuous dose of 37.5 mg/day was generally well tolerated; only a few patients required treatment breaks and/or dose reduction. Preliminary efficacy data are encouraging. Mature data will be presented.

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CD8+ tumor-infiltrating lymphocytes as a statistically significant marker of disease recurrence and survival in transitional cell carcinoma patients
Authors: Sharma P. , Sato E. , Bajorin D. , Shen Y. , Wen S. , Reuter V. , Jungbluth A. , Gnjatic S. , Old L.
Published: March 2020

4544

Background: Superficial transitional cell carcinoma (TCC) is an immune-responsive tumor evidenced by immunotherapy trials with BCG demonstrating improved survival. In contrast, more advanced muscle-invasive TCC is not considered an immunologically active tumor. Yet, host immune functions that may have a clinical impact on the biologic activity of these more invasive tumors have not been systemically evaluated. CD8+ T-cells are responsible for cytotoxicity and potential tumor eradication by interaction with antigen plus human leukocyte antigens (HLA). A clear association between intratumoral CD8+ T-cells and clinical outcome has not been established in TCC. Methods: We performed pathological, immunohistochemical and RT-PCR analyses of 69 TCC patient samples that were obtained with appropriate informed consent on an Institutional Review Board (IRB)-approved protocol. The samples were studied for pathological stage, tumor-associated antigen expression, class I HLA expression, and CD8+ intratumoral T-cells. Systemic CD8+ T-cells from one patient with positive CD8+ intratumoral T-cells were studied by tetramer analyses for reactivity against the NY-ESO-1 tumor antigen expressed on the patient’s tumor. Results: In a subset analysis, advanced TCC (pT2, pT3 and pT4) patients who had higher numbers of CD8+ tumor infiltrating lymphocytes (TILs) had a greater disease-free survival (p = 0.0002) and overall survival (p = 0.011) than similarly staged TCC patients with lower numbers of CD8+ TILs. In the multivariate analyses, CD8+ TILs (p = 0.04) and tumor stage (p < 0.001) were significant risk factors to predict overall survival. Furthermore, a CD8+ T-cell clone derived from one patient demonstrated strong recognition of the tumor antigen NY-ESO-1. Conclusions: This is the first report, to our knowledge, that CD8+ TILs is an important prognostic indicator for patients with advanced TCC. Investigational immunotherapy strategies to evoke CD8+ T-cell responses are warranted in patients with advanced TCC.

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Toremifene citrate increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer
Authors: Smith M. R. , Chu F. , Forrest J. , Malkowicz S. B. , Price D. , Sieber P. , Barnette K. G. , Segal S. , Steiner M. S.
Published: March 2020

4553

Background: In men with prostate cancer, androgen deprivation therapy by either surgical orchiectomy or treatment with a gonadotropin releasing hormone agonist decreases bone mineral density (BMD) and increases clinical fracture risk. In postmenopausal women, selective estrogen receptor modulators (SERMs) increase BMD and decrease fracture incidence. We conducted a multicenter randomized controlled trial to evaluate the efficacy of the SERM toremifene citrate in men with prostate cancer. Methods: In a 24-month prospective study, 1392 men with prostate cancer who have been treated with ADT for at least 6 months and are at increased risk of fracture based on either being older than 70 years of age or having evidence of osteopenia by baseline dual energy X-ray absorptiometry (DEXA) scan were assigned randomly (1:1) to receive either toremifene citrate 80mg or placebo (by mouth daily). The primary study endpoint is proportion of men with one or more fracture at 24 months. Secondary endpoints include changes in BMD of the hip and spine. Here we report the results of a planned interim analysis of 12-month changes in BMD for the first 200 subjects. Results: As summarized in the table below, toremifene citrate significantly increased BMD of the lumbar spine, total hip, and femoral neck compared to placebo. Conclusions: In men receiving ADT for prostate cancer, toremifene citrate significantly increased BMD of the hip and spine. In randomized controlled trials of SERMs in postmenopausal women, similar BMD improvements translated into statistically and clinically significant decreases in fractures risk. These interim results of BMD effects suggest toremifene citrate has the potential to provide a fracture reduction benefit in men with prostate cancer, the hypothesis being tested in the ongoing study.

[Table: see text]

[Table: see text]