bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors (PF) in advanced hepatocellular carcinoma (AHCC): Multivariate analysis and comparison between staging systems (SS) in patients (pts) treated at Memorial Sloan-Kettering Cancer Center (MSKCC)
Authors: Huitzil F. D. , Capanu M. , Jacobs G. , Smith W. , O’Reilly E. , Shah M. , Schwartz G. K. , Saltz L. B. , Kelsen D. P. , Abou-Alfa G. K.
Published: March 2020

4601

Background: Several SS have been proposed in hepatocellular carcinoma. These include TNM, Okuda, Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI), and Barcelona Clinic Liver Cancer (BCLC). There is no consensus as to what constitutes the best SS for use by oncologists for pts with AHCC with no locoregional therapy options. We propose to define the PF and compare SS in this patient population. SS may help select pts for systemic therapy, predict outcome, and help in clinical trial design for AHCC. Methods: We retrospectively identified pts with AHCC treated at MSKCC between 2001 and 2006. Clinical, laboratory, tumor characteristics and all four SS were recorded. Survival (S) was measured from the date of development of AHCC to the date of death. S was estimated using Kaplan-Meier’s method, differences in S were tested using the log rank test. A Cox regression model was used for the multivariate analysis. A second Cox regression was done to compare SS and was expressed using the Akaike information (AI) criterion. AI helps determine which SS is the most informative of S. A low AI is favorable. Results: We identified 280 pts. Data on the first 101 pts analyzed are presented. Median age 61 years; 71% males, 29% females; 60% Caucasians, 9% Black, 24% Asians and 5% Hispanics. Etiologies included HCV 24%, HBV 38%, and alcohol 22%. Child Pugh score: A in 65% and B in 29% of pts. Multivariate analysis independent PF for S were albumin (p=0.0358), alkaline phosphatase (ALP) (p=0.001), identified etiology (p=0.008), abdominal pain (p=0.001) and liver tumor extent (more or less than 50% of the liver) (p=0.0043). AI ranked SS as follows: TNM 6th (588.991), TNM 5th (591.373), BCLC (541.095), Okuda (540.490), CLIP (537.8), and CUPI (526.483). CUPI S was 19.47 months (m) for low, 5.89 m for medium, and 1.36 m for high risk pts. Conclusions: Pts with AHCC who are treated by oncologists in this US-based population have distinct PF. CUPI provided the best prognostic information for our patient population. CUPI may be suggested as the SS to use clinically for AHCC. These results need prospective validation.

No significant financial relationships to disclose.
Preliminary results of a phase I/II study in pancreatic carcinoma, malignant melanoma, and colorectal carcinoma with the TGF- β2 inhibitor AP 12009
Authors: Oettle H. , Seufferlein T. , Schmid R. , Luger T. , Ludwig S. , Schmaus S. , Wuerth G. , Heinrichs H. , Schlingensiepen K.
Published: March 2020

4607

Background: TGF-β2 plays a pivotal role in tumor progression as it regulates key mechanisms, namely immunosuppression, metastasis, angiogenesis, and proliferation. The TGF-β2 inhibitor AP 12009 has shown clinical efficacy including complete and long-lasting remissions in patients with high-grade glioma. Methods: The currently ongoing clinical phase I/II study AP 12009-P001 is an open-label, multicenter, dose-escalation study. AP 12009 is being administered intravenously in adult patients with pancreatic carcinoma (PC, stage IVA/IVB), metastatic melanoma (MM, stage III/IV), or advanced colorectal carcinoma (CRC, stage III/IV). Primary endpoint is determination of the maximum tolerated dose (MTD). 3 to 6 patients per cohort (dose group) were enrolled into this dose escalation study. Results: So far, 17 patients have been treated in four dose groups, 11 patients with PC, 2 with MM, and 4 with CRC. Per cycle, AP 12009 was applied as a continuous i.v. infusion at weekly intervals in an out-patient setting. The 17 patients received one to ten cycles of AP 12009 (mean: 2.8). At the current stage, no (possibly) drug related serious adverse event (SAE), and only 17 (possibly) drug related adverse events (AEs) in eight patients have been observed. The 17 patients received one to ten cycles of AP 12009. Three dose-limiting toxicities (DLTs) occurred in the 4th dose group (exanthema grade 3 in one patient, thrombocytopenia grade 3 in two patients) and consequently, the MTD was determined as being 160 mg/m2/day with the current administration schedule. One patient suffering from MM stage IV is still alive 64 weeks after start of treatment. Moreover, one PC patient (stage IV) from the 2nd cohort is still after 72 weeks, having experienced a complete response. Further dose escalation studies in PC, MM, and CRC patients using a modified schedule are currently in preparation. Conclusions: In conclusion, encouraging case reports from the phase I/II study along with a good safety profile form a rational basis for the use of the TGF-β2 inhibitor AP 12009 as targeted therapy for advanced solid tumors such as PC, MM and CRC.

No significant financial relationships to disclose.
Phase I/II trial of docetaxel plus oxaliplatin and 5-fluorouracil (D-FOX) in patients with untreated, advanced gastric or gastroesophageal cancer
Authors: Ajani J. A. , Phan A. , Ho L. , Tetzlaff E. D. , Baker J. , Wei Q.
Published: March 2020

4612

Background: Docetaxel combined with cisplatin/5-fluouracil resulted in significantly longer time-to-progression and survival but also 30% rate of complicated neutropenia (JCO 2006; 24:4991). To improve the safety profile of docetaxel-based therapy, we studied docetaxel with oxaliplatin/5-fluorouracil (D-FOX) to establish the first-cycle MTD (phase II trial to follow). Methods: Patients with histologic proof of gastric or gastroesophageal adenocarcinoma with untreated stage IV cancer were eligible. ECOG PS of <2, near-normal organ function, and written consent were other eligibility criteria. The initial doses of oxaliplatin (85mg/m2) and 5-fluorouracil (2.2g/m2 as 48-hour infusion), given every 2 weeks, were kept constant. Docetaxel was started at 20mg/m2 (Level 1) every 2 weeks in a typical 3x3 phase I design. Subsequent levels (+5mg/m2 every 4 weeks) were added. Fatigue, incompletely treated nausea, and oxaliplatin/5-flurouracil-related toxicities were excluded to determine the MTD. Results: A total of 36 patients have been treated. Currently, docetaxel dose is 47.5mg/m2 every 2 weeks (Level 11). MTD was not reached at Level 10. Overall, grade 3 or 4 first-cycle toxicities have occurred in <5% of patients and without complicated neutropenia. Fifteen of 34 patients have had a confirmed partial response, 13 had stability, and 6 patients had progression. Conclusions: The MTD of D-FOX has not yet been established but its safety profile (D-FOX with 45mg/m2 of docetaxel every 2 weeks) is excellent and the regimen is quite active against untreated gastric or gastoresophageal cancer. Translation studies and additional clinical data will be presented. Supported in part by sanofi-aventis pharma.

[Table: see text]
Association between high tumor CCL2 expression and poor survival in patients with resectable pancreatic cancer
Authors: Yan L. , Hu Y. , D’Andrea M. R. , Towers M. A. , Wang Y. , Kesavan P. , DeWitte M. , Nakada M. T. , Ahrendt S.
Published: March 2020

4618

Background: CCL2 (MCP-1) is a chemoattractant protein highly expressed in a variety of cancer types. The expression level of CCL2 has been linked to aggressive disease progression, early dissemination, and poor survival in certain cancers. Therefore, we assessed the potential association between CCL2 expression and patient prognosis in pancreatic cancer. Methods: Cylindrical tissue cores from a large retrospective, nonrandomized series covering 133 patients with resected pancreatic cancer were used to build a tissue microarray. CCL2 expression was determined using immunohistochemistry. Results: High intratumoral CCL2 expression and low intratumoral CCL2 expression were present in 44 (33%) and 89 (67%) tumors, respectively. Kaplan-Meier median survival among patients with low intratumoral CCL2 expression (19.1 months) was longer than that among those with high CCL2 expression (12.1 months). In multivariate analysis, more advanced pathological stage [risk ratio (RR) = 1.57; P = 0.038], poorly differentiated histology (RR = 1.68; P = 0.019), and high CCL2 expression [RR = 1.62; 95% confidence interval (CI) = 1.05–2.49; P = 0.028] were independent predictors of mortality. Conclusions: High CCL2 expression is a marker of poor prognosis in resected pancreatic cancer.

[Table: see text]
Initial findings from the Memorial Sloan-Kettering Early Onset and Familial Gastric Cancer Registry (EOFGCR)
Authors: Harlan M. , Sheehy E. , Randazzo J. , Schrag D. , Kemeny M. M. , Kelsen D. P. , Shah M. A.
Published: March 2020

4619

Background: Hereditary Diffuse Gastric Cancer(HDGC) is an autosomal dominant cancer susceptibility syndrome defined as having 2 or more diffuse GC(one of which diagnosed before the age of 50) or 3 or more diffuse GC in 1st or 2nd degree relatives. A germline mutation in E-Cadherin(CDH1) is found in 20–30% of HDGC families. HDGC is responsible for 30% of all hereditable GC. The genetic cause for the remaining 70% of hereditable GC is unknown. We created a registry for early onset and familial gastric cancer to capture epidemiologic and family history data matched with DNA and tissue to characterize various phenotypic and risk factor profiles and their associations with HDGC and other non-HDGC hereditable GC. Methods: Patients with a family history(patients with one first degree relative or 2 second degree relatives with GC) or who developed GC at an early age(age < 50) were eligible for registry participation. Participants complete a GC risk factor questionnaire, family history, provide blood and tissue for repository, and meet with a genetics counselor to consider germline CDH1 mutation testing. Results: 57 patients have enrolled since January 2006: 36 patients with early onset, 21 with familial GC. Eleven patients have a family history meeting HDGC criteria, two with known CDH1 mutations. Three of the 11 HDGC families are from Ecuador. GC risk factor questionnaires are available from 46 patients(81%), see table . Although no novel CDH1 mutations were found in 13 fully sequenced patients, 4 patients(31%) were found to have uncommon genotypes, including two with early onset of disease diagnosis (ages 22 and 34) with multiple variants in CDH1. Conclusions: HDGC patients tend to have more high risk features including smoking history, use of salt, and H. pylori infection. We have identified a cluster of patients with HDGC of Ecuadorian descent. Genetic variation in CDH1 suggests that novel haplotypes may be associated early onset GC risk.(Supported by the DeGregorio Family Foundation)

[Table: see text]

No significant financial relationships to disclose.
Clinical and molecular determinants of survival in pancreatic cancer patients treated with second line chemotherapy: results of an Italian/Swiss multicenter survey
Authors: Mancuso A. , Sacchetta S. , Saletti P. , Tronconi C. , Milesi L. , Garassino M. , Martelli O. , Labianca R. , Cavalli F. , Sternberg C. N.
Published: March 2020

4622

Background: The impact on survival of palliative second-line therapy in pancreatic cancer has not been clarified and clinical/molecular predictive factors are needed in order to decide which therapeutic regimens may be effective. Methods: Clinical records of 160 Gemcitabine resistant/refractory pancreatic cancer patients (pts) treated in 11 medical oncology departments in Italy and Switzerland were reviewed. All pts received a second line regimen from June 1997 to February 2006. There were 99 males, 61 females, median age 62 years (range 34–78) and median ECOG performance status (PS): 1 (range 0–2). 16 different salvage regimens were administered consisting of monotherapy with fluoropyrimidines in 59% of cases and combinations of platinum- salts/fluoropyrimidines in 36%. Fluoropyrimidines combinations with bevacizumab, irinotecan and mitomycin C were administered in the remaining 5%. ERCC-1 expression was examined by performing immunohistochemical staining in pts treated with platinum-salts. Results: Second line chemotherapy produced partial responses (PR) in 16 (10%) and stable disease (SD) in 40 pts (25%) by RECIST criteria. The median progression free survival (PFS) was 2.65 months. Multivariate analysis revealed that the most important prognostic factor for PFS was PS at the beginning of second line therapy (Second line PFS PS=0–1 vs PS=2: 78 days vs 48 days, p<0.05, log-rank test). Pts who had responded (PR) to first-line Gemcitabine were more likely to respond or attain stable disease after second-line treatment, with a PFS of 2.6 vs 1.6 months (p<0.05, log-rank test). The overall survival (OS) for all evaluable pts was 11.5 months and 1-year survival was 45%. Among 57 pts treated with platinum-containing doublets, a low ERCC1 level (28/57 pts) was highly predictive of longer survival (11.9 versus 9.9 months, p<0.05 log-rank test). Conclusions: These results suggest that fluoropyrimidine-based salvage regimens have marginal activity and should be considered only in pts with a good PS who have responded to first line chemotherapy. ERCC-1 expression should be further evaluated as a predictive test to select patients who may benefit from platinum/fluoropyrimidine salvage regimens.

No significant financial relationships to disclose.
Comparison of squamous cell carcinoma of the canal anal (SCCA) prognosis in patients infected or not by human immunodeficiency virus (HIV)
Authors: Mathieu N. , Aparicio T. , Roudot-Thoraval F. , Lemarchand N. , Bauer P. , Hennequin C. , Mitry E. , Romelaer C. , Abramowitz L. , Sobhani I.
Published: March 2020

4632

Background: Incidence of SCCA is increasing promoted by HIV infection. Previous small series of SCCA revealed a worst prognosis in HIV+ than in HIV- patients. Few data are available since the use of highly active antiretroviral therapy (HAART) in HIV patients. The aim of the study was to compare clinical outcome of patients recently treated for SCCA according to HIV status. Methods: Retrospective study in 6 hospitals. all consecutive patients treated for SCCA from January 1998 to October 2004 were included. Clinical outcome and pattern of care according to HIV status were compared. Results: 151 patients were included, 44 (29%) of them were HIV infected. Median follow-up was 27 (16–44) months. HIV+ patients were youngest (45 vs 62 years old, p<0.001) and only male (100% vs 27%, p<0.001). There were no significant difference in tumor stage I : 37.5 vs 25%, II : 48 vs 42.5%, IIIa : 7.5 vs 16.5%, IIIb : 12.5 vs 5% and IV : 0 vs 6% according to HIV+ or HIV- respectively. The treatments performed in HIV+ and HIV- patients were: Pelvic radiotherapy in 86 vs 91% (ns) delivering a median dose of 48 and 46 Gray. A boost in reduced fields or brachytherapy was performed in 58% vs 64% (ns). Concomitant chemotherapy (5-fluorouracile and cisplatin) was administered in 52% vs 56% (ns). Dose intensity of 5-fluorouracile and cisplatin was similar in both group. Grade 3–4 toxicity of chemoradiotherapy was observed in 11% vs 10% (ns). Complete response was obtained in 82 vs 75% (ns) and surgery (colostomy or abdominoperineal resection) was performed in 2.4% vs 7.6% of the patients (ns). During the follow-up local or metastatic recurrence occurred in 32% vs 22% of the patients (ns). The 3 years disease free survival were 77% vs 67% (ns) and 3 years overall survival were 85% and 84% (ns). Among HIV+ patients, 42/44 were on HAART, the survival was not modified by the duration of infection, viral load and CD4 count. Conclusions: The clinical outcome of HIV+ patients with SCCA is now similar to HIV- patients. The same therapeutic guidelines should be applied in both population. This improvement of prognosis is probably due to extensive use of HAART in HIV+ patients.

No significant financial relationships to disclose.
Circulating tumor cells detected in patients with gastrointestinal cancers associate with tumor stage and response to chemotherapy
Authors: Hiraiwa K. , Takeuchi H. , Kitagawa Y. , Hasegawa H. , Saikawa Y. , Ando T. , Irino T. , Yoshikawa T. , Ishii S. , Kitajima M.
Published: March 2020

4635

Background: Circulating tumor cells (CTCs) in metastatic breast cancer has been reported to correlate with shorter overall survival. The purpose of this study was to clarify the clinical significance of CTCs in gastrointestinal cancers. Methods: CTCs of 108 patients with stage III or IV gastrointestinal cancers and 38 healthy volunteers were measured by use of the CellSearch system. Correlation between CTC counts and clinicopathologic variables was examined. Results: The number of CTCs in stage IV patients (23.0 ± 109.1) was significantly larger than that in healthy donors (0.1 ± 0.2) and that in stage III patients (0.4 ± 1.8) (p < 0.001). =2 CTCs were more frequently found in stage IV patients (41.6%) than in healthy donors (0%) and in stage III patients (3.2%) (p < 0.001). =2 CTCs in gastric or colorectal cancer had significant correlation with peritoneal dissemination (p = 0.029). =2 CTCs in esophageal cancer had significant correlation with pleural dissemination (p = 0.030). In 10 of 32 CTC positive (=2) patients with stage IV gastrointestinal cancers, CTC was measured before initiation of a new line of chemotherapy and more than 3 weeks after initiation of therapy. The change in CTCs correlated with disease progression and reflected chemotherapeutic effect. Conclusions: This study suggested measurement of CTCs in gastrointestinal cancer patients shows promise as a tool for judging advanced tumor stage, predicting peritoneal or pleural dissemination and monitoring response to chemotherapy.

No significant financial relationships to disclose.
Transarterial infusion chemotherapy alone versus transarterial chemoembolization for the treatment of hepatocellular carcinoma: Results of a multicenter randomized phase III trial
Authors: Okusaka T. , Sato T. , Hinotsu S. , Shioyama Y. , Kasugai H. , Tanaka K. , Kudo M. , Saisho T. , Osaki Y. , Sata M. , Fujiyama S.
Published: March 2020

4643

Background: Transarterial chemoembolization (TAE) is widely used for patients (pts) with hepatocellular carcinoma (HCC) although evidence of a survival benefit remains controversial. A multicenter phase III trial was designed to compare the effects of TAE and transarterial infusion chemotherapy alone (TAI) on overall survival. Methods: Pts with newly diagnosed unresectable HCC were randomly assigned to either the TAE or the TAI group, stratified according to center and the serum alpha-fetoprotein level. Zinostatin stimalamer (SMANCS), up to a maximum of 6 mg, plus lipiodol emulsion with or without gelatin sponge was injected into the hepatic artery. Treatment was repeated when a follow-up computed tomography examination showed the appearance of new lesions in the liver or the regrowth of the treated tumors. Based on our previous phase II studies, reporting a 2-year survival rate of 80% in pts treated with TAE and of 60% in pts treated with TAI, 80 pts were needed in each group to achieve a level of statistical significance of 5% (2-sided) and a power of 80%. Results: From October 1999 to June 2003, 79 pts were assigned to the TAE group and 82 pts to the TAI group. The two groups were well balanced with regard to their baseline characteristics. The total number of treatment courses was 170 with a mean of 2.2 courses per patient (range, 1–9 courses) in the TAE group and 193 with a mean of 2.4 courses (range, 1–6 courses) in the TAI group. As of June 2005, 51 pts in the TAE group and 58 pts in the TAI group had died. The median overall survival time was 646 days in the TAE group and 679 days in the TAI group. No significant difference in survival was seen between the two groups (p=0.383). The mortality rate reduction for overall survival was 15.8% (95% CI, -24.1% to 42.9%) for the TAE relative to the TAI alone. Conclusions: This study suggests that treatment intensification as a result of embolization did not increase survival, compared with SMANCS transarterial chemotherapy alone, in pts with HCC.

No significant financial relationships to disclose.
Imaging and therapy for Epstein-Barr virus-associated gastric cancer
Authors: Fu D. , Chong J. , Foss C. , Fox J. , Wang S. , Green G. , Chen J. , Lemas M. V. , Pomper M. , Ambinder R.
Published: March 2020

4644

Background: Epstein-Barr virus (EBV) has been identified in a wide variety of malignancies, including gastric carcinomas. The virus encodes kinases that phosphorylate nucleoside analogs such as 2’-deoxy-2’-fluoro-5-iodo-1-beta-D- arabinofuranosyluracil (FIAU). We hypothesized that it might be possible to use the viral enzyme to specifically concentrate [125I]FIAU or [131I] FIAU in tumor cells harboring virus and thus deliver imaging and therapeutic radiation. Bortezomib is a potent stimulator of viral kinase expression in EBV tumor cell lines. Methods: We imaged lytic induction in vivo and evaluated the effect of [131I] FIAU on human cancer xenografts in SCID mice. These include a tumor line engineered to constitutively express the EBV thymide kinase (EBVTK), and a control engineered with a sham vector (SHAM), as well one EBV-associated human gastric tumor (KT tumor). Mice were treated with buffer, bortezomib (2μg/g), or radiolabeled FIAU or radiolabeled FIAU and bortezomib in combination. For imaging, mice, [125I]-FIAU and SPECT/CT were used. For therapy, 131I-FIAU was used and tumor dimensions were monitored with calipers. Results: SPECT/CT imaging with [125I]-FIAU of tumor-bearing SCID mice showed selective concentration of radiotracer in tumor tissue in EBVTK (3/3) and in EBV-associated KT tumors (3/3) when animals were pretreated with bortezomib. Treatment with buffer had no effect on 3 EBVTK tumors and 3 SHAM tumors all of which increased in volume. Treatment with 1.6 mCi of [131I]-FIAU alone led to tumor response in 3/3 mice with EBVTK tumors and 0/3 mice with SHAM tumors. Treatment with [131I]-FIAU alone had no effect on EBV KT tumor xenografts (0/3) and all tumors increased in volume. Treatment with bortezomib induced modest responses in all KT tumors. However, treatment with bortezomib and [131I]-FIAU led to marked tumor regression (>80%) in EBV-associated KT tumors (3/3). Conclusions: Treatment with bortezomib leads to selective concentration of radiolabeled FIAU in the EBV-associated tumor xenografts. In combination with [131I]-FIAU it leads to tumor regression.

No significant financial relationships to disclose.
Gene expression levels of HER2 and IL-8 and polymorphism in IL-8 associated with clinical outcome in advanced or metastatic gastric cancer treated with lapatinib in SWOG 0413 trial
Authors: Chang H. , Azuma M. , Goldman B. , Nagashima F. , Iqbal S. , Danenberg K. , Benedetti J. , Zhang W. , Blanke C. , Lenz H.
Published: March 2020

4647

Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of EGFR and HER2. In SWOG0413 trial, advanced or metastatic gastric cancer patients were treated with lapatinib. In this study, we investigated whether gene expressions and polymorphisms of EGF and angiogenesis pathway genes were associated with clinical outcome in the patients enrolled in SWOG0413 trial. Methods: A total of 46 patients were enrolled in SWOG0413 trial and treated with lapatinib. Blood and tissue samples were available from 42 and 37 patients, respectively. RT-PCR was performed for intratumoral gene expression levels of EGFR, HER2, VEGF, IL-8, COX2 and cyclin D1 genes. We also analyzed 8 polymorphisms in the EGF, EGFR, HER2, VEGF, IL-8, COX2 and cyclin D1 genes by PCR-RFLP. Results: Patients who have lower IL-8 [median overall survival (OS), 6 vs 3 months, p=0.03] and higher HER2 (6 vs 3 months, p=0.005) gene expression levels showed better OS. According to gene polymorphisms, patients who have A allele of IL-8 T251A polymorphism showed improved OS (A/A, 10 months vs T/A, 5 months vs T/T 3 months, p=0.04). And patients with A allele of IL-8 T251A and T allele of VEGF C936T polymorphisms showed better response rates (p<0.01, p<0.01, respectively). All other polymorphisms and gene expressions did not show significant association with clinical outcome. Conclusions: Our results suggest that intratumoral gene expression levels of HER2 and IL-8 and polymorphism in IL-8 are potential molecular predictors for survival in patients with advanced or metastatic gastric cancer treated with lapatinib. And polymorphisms in IL-8 and VEGF genes may be potential markers in predicting response in this population. A larger prospective study is needed to validate and confirm these preliminary findings.

[Table: see text]
Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC)
Authors: Duffy A. , Capanu M. , Abou-Alfa G. K. , Huitzel D. , Williams P. , Jarnagin W. , Fong Y. , Kelsen D. P. , O’Reilly E. M.
Published: March 2020

4648

Background: The incidence of GBC in the US is 1.2/ 100,000. Given the dearth of phase III data on the use of adjuvant therapy, institutional review can provide a justification for future studies. This report examines the patterns of presentation, treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. Methods: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between 1/1995 and 12/ 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Univariate analysis of survival times and log rank test were employed. Results: 435 GBC cases were identified. 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28–100). Pathology: 88% adeno, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy (LC). 136 of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections, 8 received adjuvant chemotherapy, 2 adjuvant radiotherapy and 17 combined chemoradiation. Median OS for the cohort was 9.11 months(m). The median survival(MS) for those presenting with stage IV disease was 4.5 m (95% CI 3.8–6.1) compared to 12.9 m (95% CI 11.7–15.8 m) for those with stage IA-III disease. MS was better for those discovered incidentally at LC (15.7 m,p<.001). For those who underwent re-exploration, MS was 13.9 m if residual disease was present, and 68 m if no residual disease. The MS for those who received adjuvant therapy was 23.4 m. Conclusions: GBC is commonly diagnosed incidentally (47%) at LC. Re- exploration reveals a high incidence of residual disesase (74%). MS is better for patients diagnosed incidentally and those without evidence of disease on re-exploration. Overall prognosis is poor. Although the number of patients was small, adjuvant therapy appeared to confer a survival benefit. Prospective randomized trials of adjuvant therapy are needed in this disease.

No significant financial relationships to disclose.
Concurrent and adjuvant docetaxel with three dimensional conformal radiation therapy (3-D CRT) for poor-risk localized prostate cancer: A phase II trial
Authors: FERRERO J. , Bolla M. , Maingon P. , Buffet-Miny J. , Bougnoux A. , Bauer J. , Descotes J. , Conil M. , Colonna M.
Published: March 2020

5003

Background: Docetaxel increases survival in hormone refractory prostate cancer. The objective of this trial is to evaluate the feasibility of concomitant weekly docetaxel with 3-D CRT and adjuvant docetaxel in unfavorable localized or locally advanced prostate carcinoma. Methods: Sixteen patients with poor risk localized carcinoma (T1c-2b N0M0) and 34 with locally advanced tumors (T3N0- 1M0) according to the 1997 UICC classification, underwent 3-D CRT (72Gy/36 fractions); docetaxel 20mg/m2 iv was delivered concurrently on weeks 1–2-3–5-6–7; adjuvant docetaxel 60mg/m2 q3w started 4 weeks after the completion of radiotherapy for 3 cycles. The patients had to receive LHRH agonist, 6 months to 3 years, according to the number of poor prognostic factors. Acute toxicity was assessed with the NCI CTC v:2.0. Results: From November 2003 to November 2005, 50 patients were included (438 cycles) from six institutions. Median age was 50 years (48–76), median PSA 17.7 ng/ml (3.4–260) and median follow-up 17 months (9–38). Forty six patients completed the chemoradiation regimen (423 cycles), with full dose of docetaxel, 4 patients did not, due to: 1 grade 4 GI toxicity during the cycle 3, 1 grade 3 dysuria after cycle 6, 1 grade 4 myocardial infarction after cycle 6, 1 grade 4 anal fistula between two cycles of adjuvant docetaxel; these patients were excluded. The percentage of grade 3 acute toxicity was 10.8% (5/46): 1 grade 3 neutropenia, 1 grade 3 rectal bleeding, 2 grades 3 diarrhea, 1 grade 3 dysuria. Grade 2 toxicity (nausea, diarrhea and rectitis) were observed, in a percentage of 26%; no grade 2–3 toxicity occurred as regard hypotension, venous thrombosis, peripheral neuropathy, respiratory morbidity, oedemas. Twelve months after the end of the treatment, 44 patients were in complete remission (clinical and biological) and two patients suffer from distant metastases. Conclusion: The feasibility of this combined chemo-radiation regimen deserves to be followed by a phase III trial.

No significant financial relationships to disclose.
A phase II trial of rapid androgen cycling and docetaxel (Doc) in prostate cancer patients with a rising prostate-specific antigen (PSA) in the noncastrate state
Authors: Rathkopf D. E. , Carducci M. A. , Slovin S. , Morris M. J. , Kelsen M. , Pili R. , Denmeade S. R. , Eisenberger M. , Scher H. I.
Published: March 2020

5004

Introduction: Prostate cancer patients in the noncastrate state with a rapidly rising PSA are at high-risk for cancer-specific mortality. Since hormonal therapy alone is not curative, we have explored the use of rapid androgen cycling with Doc to recruit proliferating cells into successive waves of apoptosis, thereby shifting the treatment outcome for these patients from palliation to cure. Methods: Patients with noncastrate levels of testosterone (T), a rising PSA ± metastases, and = 6 months of prior hormones were eligible. Cohort 1: Six 4- week cycles of monthly leuprolide and Doc (75 mg/m2), with 7 days of topical T repletion (AndroGel 1% 5G) prior to each treatment. Cohort 2: Nine 3-week cycles of Doc (70 mg/m2), with 3 days of T repletion per cycle and 3-month depot leuprolide on day 1 of cycles 1, 5, and 9. The primary endpoint was the proportion of patients with a treatment-specific undetectable PSA at 6 and 18 months defined as: = 0.05 after surgery, = 0.5 after radiation, or = 2.0ng/ml with untreated disease. This is based on the premise that an undetectable PSA is a prerequisite to, but no guarantee of cure. Results: There were no increases in sequential PSA peaks or troughs and 100 out of 102 patients completed the planned 6 months of chemohormonal treatment. Twenty three of 62 (37%) patients in cohort 1, and 25 of 38 (66%) patients in cohort 2 achieved the primary endpoint of a treatment-specific undetectable PSA at 6 months. At 12 months, no patient in cohort 1 had maintained an undetectable PSA in the setting of a noncastrate T level; whereas, 8 of 15 (53%) patients in cohort 2 have achieved the endpoint at 12 months. Toxicities were similar to those observed with Doc and hormonal therapy administered separately. Conclusions: Rapid androgen cycling with docetaxel is feasible, and can induce successive declines in PSA peaks and troughs. The more dose-dense cohort 2 schedule of 21-day Doc administration for 9 cycles, along with reduced exposure to androgen repletion from 7 to 3 days, has resulted in a higher proportion of undetectable PSA outcomes at both 6 (66% vs. 37%) and 12 (53% vs. 0%) months. Complete PSA outcomes for cohort 2 at 12 and 18 months are still pending. Supported by Sanofi-Aventis, CA-05816, and PepsiCo.

No significant financial relationships to disclose.
The prognostic value of PSA derivatives in favourable risk localised prostate cancer
Authors: van As N. J. , Ng M. K. , Norman A. R. , Huddart R. , Dearnaley D. , Horwich A. , Thompson A. , Woode-Amissah R. , Khoo V. , Parker C.
Published: March 2020

5008

Introduction: Risk stratification in localized prostate cancer is based on PSA level, Gleason score and T stage. PSA derivatives may be of additional prognostic value. We have assessed the use of PSA derivatives in the prediction of histologic disease progression on repeat biopsy in patients on active surveillance. Methods: In a prospective cohort study of active surveillance, men with untreated, low- and intermediate-risk, clinically localized prostate cancer (T1/2a, PSA < 15 ng/ml, Gleason score ≤ 3 + 4, and % positive cores ≤ 50%) had repeat octant prostate biopsies 18–24 months after diagnosis. Histologic progression was defined as primary Gleason pattern ≥ 4, or % positive cores > 50 %, or an increase in Gleason score from ≤ 6 to ≥ 7. Standard clinical variables and PSA derivatives were analysed with respect to histologic progression. Multivariate analysis was performed including all standard variables both with each PSA derivative individually, and with all PSA derivatives. Results: 175 men had repeat biopsy. Median age was 67 yrs and median initial PSA, 6.5 ng/ml. Histologic disease progression was seen in 50 (29%) cases. Factors associated with histologic progression on univariate analysis were PSA velocity (p=0.0001), PSA density (p=0.0002), free-total PSA ratio (p=0.002), maximal % core involvement (p=0.009), age (p=0.003), and initial PSA level (p=0.02). On multivariate analysis, each PSA derivative was significant, independent of standard clinical variables. On combined multivariate analysis, free-total PSA ratio (p=0.0027), PSA velocity (p=0.009), age (p=0.0057) and maximal % core involvement (p=0.011) were significant determinants of histologic progression. Conclusions: Free-total PSA ratio and PSA velocity may be useful in the subclassification of favourable-risk localized disease. Larger validation studies in active surveillance patients are warranted.

No significant financial relationships to disclose.
Multi-center study evaluating circulating tumor cells (CTCs) as a surrogate for survival in men treated for castration refractory prostate cancer (CRPC)
Authors: Moreno J. , DeBono J. S. , Shaffer D. , Montgomery B. , Miller M. C. , Tissing H. , Doyle G. , Terstappen L. W. , Pienta K. J. , Raghavan D.
Published: March 2020

5016

Background: Monitoring CTCs in patients undergoing therapy for metastatic breast cancer is an effective means to predict outcome and monitor treatment. The primary endpoint of this prospective multi-center study was to demonstrate a significant relation between the presence of CTCs and survival in men treated for CRPC. Methods: 276 patients with diagnosed CRPC, PSA progression, and an ECOG score of 0–2 about to begin initial or salvage chemo and/or combination therapy were enrolled. CTCs were enumerated with the CellSearch System in blood drawn pre-treatment and monthly thereafter for up to 18 months. Patient data were collected and maintained by an independent CRO. Median overall survival (OS) was determined for patients with =5 CTC /7.5mL at baseline and specified intervals. Results: Of 240 evaluable patients, 142 (59%) are alive - mean follow-up 11.4 ± 4.4 months. Median OS (in months) and significance between the two groups (logrank p-value) at different time points after the initiation of therapy are indicated in the table . Median OS for 40 (19%) patients with a reduction of CTCs below 5 CTCs 2–5 weeks after initiation of therapy was significantly longer as compared to those 78 (38%) patients that remained above 5 CTCs (>20 vs. 9.3mth, p=0.0000) and was not significantly different from the 83 (40%) patients with 20 vs. >20mth, p=0.2725). In multivariate analyses, which included stage at diagnosis, age, ECOG, Gleason score, LDH, Alkaline Phosphotase, and PSA, CTCs remained the most significant independent predictor of outcome. Conclusions: CTC levels in CRPC patients are a strong predictor of OS. The persistence of CTCs after initiation of therapy suggests that the patients are deriving less than optimal benefit from their current therapy. CTC levels may be a valid surrogate end-point in monitoring response to chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
Use of a tissue biomarker panel to predict which men with a rising PSA post-definitive prostate cancer therapy will have systemic progression
Authors: Jenkins R. B. , Nakagawa T. , Kollmeyer T. , Morlan B. , Bergstrahl E. , Davis B. , Klee G. , Ballman K. V.
Published: March 2020

5017

Background: The majority of men with prostate cancer are diagnosed with cancers with low mortality. Such men are treated with radical prostatectomy, external beam radiotherapy, or brachytherapy and followed by serum PSA evaluations. Some men with a rising PSA therapy will have local recurrence or metastasis, but many will have no other evidence of recurrent disease other than a rising PSA. The PSA doubling time has been used to determine which of these men deserve adjuvant hormonal ablation, radiation therapy, or observation. We hypothesize that additional biomarkers will predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Methods: We designed a custom array containing 526 RNA targets whose expression has been reported to be altered in association with prostate cancer progression. We included targets from Mayo Clinic prostate cancer research. Together with a second commercial array, 530 genes implicated in prostate cancer progression and 420 other cancer-related genes were evaluated. A case-control design was used to test the association of the expression results with outcome. Cases were men post-radical prostatectomy who developed systemic progression within 5 years after PSA recurrence (N=213). Controls were matched men post-radical prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years (N=213). Results: Of 426 eligible patients, paraffin blocks were available on 418 (98.1%). RNA was prepared from all 418 blocks, and both arrays were both successful on 405 (96.9%) RNAs. Upon univariate analysis, 40 genes were highly significantly over- or under-expressed in the cases versus controls (1x10-22 < p < 1x10-7). Recursive partitioning (RP) selected 4 genes (TPX2, FAM13C1, TOPO2A and TSP2) that distinguished cases from controls. Random Forest analysis selected 24 genes (including 3 of the RP 4). A multivariable ROC analysis using these 24 genes generated an AUC of 0.80 (95% CI: 0.75–0.84). Conclusions: A specific gene expression pattern was significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence.

No significant financial relationships to disclose.
Initial versus recent outcomes with a non–risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT)
Authors: Duran I. , Sturgeon J. F. , Jewett M. A. , Anson-Cartwright L. , Berthold D. R. , Kakiashvili D. , Warde P. R. , Alison R. E. , Pond G. R. , Moore M. J.
Published: March 2020

5021

Background: Since 1981 the Princess Margaret Hospital testicular cancer group has used surveillance as the preferred management option for all patients (pts) with clinical stage I NSGCT. In a report of the first 105 pts [Sturgeon et al. J Clin Oncol, 1992] the relapse rate was 35% and the disease specific 5-year survival 99%. Improvements in imaging technique over time could cause stage migration with an overall lower relapse rate in this patient population. We compare our experience with surveillance over different time points. Methods: Three-hundred and five pts with stage I NS-GCT were placed on an active surveillance protocol between 1981–2004. They were not stratified by risk and only received treatment on the event of a relapse. Recurrence rates, time to relapse, risk factors predictive for recurrence, disease specific and overall survival were determined. For the analysis by time period, pts were divided in two groups based on diagnosis date. (Initial=1981–1992 [N=141] and Recent=1993–2004 [N=164]). Results: With a median follow-up of 6.3 years, 77/305 pts (25%) relapsed; 46/141 pts (32.6%) in the initial group and 31/164 (18.9%) in the recent. All but 3 (4%) relapses occurred within 2 years after orchiectomy with a median time to relapse of 7 months. A multivariate analysis established lympho-vascular invasion (p<0.01) and pure embryonal carcinoma (p= 0.03) as independent predictors of recurrence. Overall 104/305 (34.1%) pts were designated as ‘high- risk’ based on the presence of at least one of these factors. In the initial group 60/141 (42.6%) pts were high risk and 32/60 (53%) relapsed versus 14/81 (17.3%) low-risk (p=0.047). In the recent group 44/164 (26.8%) pts were high-risk and 17/44 (38.6%) recurred, versus 14/120 (11.7%) low-risk (p<0.001). There were 2 (0.7%) deaths due to testis cancer. The estimated 5-year disease specific survival was 98.9% in the initial group and 100% in the recent one. Conclusions: Surveillance is an effective strategy for the management of all stage I NSGCT. A risk-adapted policy would result in more than 50% of the patients being unnecessarily treated. The relapse rate has reduced over time, likely due to improvements in imaging causing stage migration.

No significant financial relationships to disclose.
Sequential use of sorafenib and sunitinib in renal cancer: Retrospective analysis in 90 patients
Authors: Sablin M. P. , Bouaita L. , Balleyguier C. , Gautier J. , Celier C. , Balcaceres J. L. , Oudard S. , Ravaud A. , Négrier S. , Escudier B.
Published: March 2020

5038

Background: Sorafenib (So) and sunitinib (Su) have been recently approved for the treatment of advanced renal cell carcinoma (RCC). Following this approval, sequential use of both drugs is often proposed, although very few data are available to support it. Material and Methods: We reviewed all patients (pts) who received sequentially So-Su or Su-So in the last 3 years from 4 sites in France. All pts had been enrolled in clinical studies or in the extended access programs. In all patients demography, prognostic factors (MSKCC score), number of metastatic sites, best response (BR) and PFS with each treatment were recorded. Some patients are still too early for response and PFS assessment under the second treatment. Results: 68 pts first received So while 22 pts received Su first (continuous dosing in 12, intermittent in 10). Results under the first treatments were as follows: median PFS 26.1 wks, mean duration of treatment 33.2 wks; and median PFS was 22 wks, mean duration of treatment 26.9 wks for So and Su respectively. BR in terms of partial response (PR), stable disease (SD), progressive disease (PD) is given in the table . 2 pts stopped So because of toxicity and response is not available (NA), and 22 pts (NE) are too early in the course of the second treatment. Overall, PR rate was 17.6% for So and 22.7% for Su. PR or SD was observed as best response in the second treatment in both sequences. Only 6 pts had PD with both drugs: all of them had 3 or more metastatic sites and were in intermediate or poor MSKCC risk groups. Conversely, 4 pts had PR with both drugs, and were in good (n=2) or intermediate (n=2) risk groups. 11 pts only have died so far. Conclusions: these results suggest the lack of cross resistance between So and Su, and support the sequential use of So and Su in RCC. Updated data will be presented at ASCO.

[Table: see text]

No significant financial relationships to disclose.
Phase I study of PTK787/ZK222584 (PTK/ZK) and RAD001 for patients with advanced solid tumors and dose expansion in renal cell carcinoma patients
Authors: Speca J. C. , Mears A. L. , Creel P. A. , Yenser S. E. , Bendell J. C. , Morse M. A. , Hurwitz H. I. , Armstrong A. J. , George D. J.
Published: March 2020

5039

Background: PTK/ZK is an orally active tyrosine kinase inhibitor that blocks all known VEGF receptors. RAD001 is an orally active macrolide which selectively inhibits mTOR. Combination therapy with VEGFR and mTOR inhibition may have additive efficacy in several tumor types, particularly renal cell carcinoma (RCC). Materials and Methods: A phase I/II study of PTK/ZK and RAD001 was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety and tolerability. Patients were given escalating daily doses of PTK/ZK in combination with RAD001 (see table ) in 28-day cycles. Patients were assessed for adverse events every 2 weeks and tumor response every 2 cycles. A dose expansion cohort of 20 patients with metastatic RCC is ongoing to further evaluate safety and preliminary efficacy. Results: To date, 27 patients have received a total of 136 cycles. The dose escalation phase included 14 patients and 3 dose levels; dose-limiting toxicities included grade 3 diarrhea and hypertriglyceridemia (14%); asthenia, fatigue and mucositis (7%). Pharmacokinetic studies are pending. A MTD of PTK/ZK 1,000 mg and RAD001 5 mg daily was determined and studied in an expanded cohort of RCC patients. Prior therapy with a VEGF inhibitor was allowed. To date, 13 evaluable RCC patients demonstrate 2 (15%) partial responses and 8 (62%) with stable disease > 3 months; median TTP is 6 months. Conclusions: PTK/ZK and RAD001 combination is well-tolerated and demonstrates clinical activity in patients with RCC despite prior exposure to VEGF inhibition. An MTD of 1,000 mg daily of PTK/ZK and 5 mg daily of RAD001 is the recommended dose for Phase II/III testing.

[Table: see text]

No significant financial relationships to disclose.