tbuckley/cabot-search huggingface dataset:
A randomized phase II factorial design trial of CPT-11 versus PTX versus each combination with S-1 in patients with advanced gastric cancer refractory to S-1: Final results of OGSG0701.
Authors: Kazuhiro Nishikawa, Hiroshi Imamura, Tomono Kawase, Masahiro Gotoh, Yutaka Kimura, Shugo Ueda, Jin Matsuyama, Junji Kawada, Naotoshi Sugimoto, Junya Fujita, Takao Tamura, Norimasa Fukushima, Daisuke Sakai, Toshio Shimokawa, Yukinori Kurokawa, Taroh Satoh, Toshimasa Tsujinaka, Hiroshi Furukawa
Journal: Journal of Clinical Oncology (2015)

117 Background: S1 + platinum (SP) is recognized as standard first-line chemotherapy for advanced gastric cancer(AGC), and S1 monotherapy is suggested for frail AGC patients or adjuvant setting in Japan. However, taxane or CPT-11 were often employed as second-line treatment for the patients who were resistant to S1-containing regimen. A retrospective analysis has reported that S1 combination chemotherapy extended overall survival as second-line treatment for AGC. Methods: Patients with AGC who confirmed disease progression by imaging after the first-line therapy with S1 or SP were randomized in four groups; CPT-11 150 mg/m2, day1, q2w (Group A), PTX 80 mg/m2, day1, 8,15, q4w (Group B), CPT-11 80 mg/m2, day1, 15, S-1 80 mg/m2, day1-21, q5w (Group C1), PTX 50 mg/m2,day1, 8, S1 80 mg/m2, day1-14, q3w (Group C2). Primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), overall response rate (ORR) and safety. Sample size was set at 100 to 120 to achieve 2 months improvement of OS by using CPT-11 or by adding S1 with approximately 80% probability of the correct selection. Results: From July 2008 to March 2012, 127 patients were enrolled. The OS was 11.3/11.3/14.6/10.5 months(M) (Group A/B/C1/C2), 11.8M in Group A+C1 and 11.1M in Group B+C2 (p=0.922, HR: 0.981 [0.679-1.419]), 11.3M in Group A+B and 11.1M in Group C1+C2 (p=0.808, HR: 0.952 [0.643-1.412]), respectively. The PFS was 3.0/4.4/3.8/3.5M (Group A/B/C1/C2), 3.6M in Group A+C1 and 4.1M in Group B+C2 (p=0.035, HR:0.674 [0.468-0.972]) 3.7M in Group A+B and 3.7M in Group C1+C2 (p=0.931, HR: 1.017 [0.643-1.412]). The ORR was 7.1/16.3/4.5/5.0% (Group A/B/C1/C2), 4.7%[1.7-15.2] in Group A+C1 and 12.7%[5.6-23.5] in Group B+C2 (p=0.241), 11.8%[5.8-20.6] in Group A+B and 4.6%[0.6-16.2] in Group C1+C2 (p=0.572).Major Grade 3/4 toxicity (Group A/B/C1/C2, %), was leukopenia (12/7/5/0), neutropenia (29/16/24/24), nausea (7/2/10/5), diarrhea (5/0/10/0), and fatigue (5/2/10/5). Conclusions: From our results, we do not recommend consecutive use of S1 but CPT-11 or PTX monotherapy as second-line treatment in AGC refractory to S1 or SP. Clinical trial information: 000000677.
Expression relationships among EGFR family members and c-MET in esophagogastric adenocarcinoma.
Authors: Ellie Chan, Thomas J. George, Ahmad Alkhasawneh, Lizette Vila Duckworth, Tania Zuluaga Toro, Xiaomin Lu, Steven J. Hughes
Journal: Journal of Clinical Oncology (2014)

e15014 Background: The incidence of esophagogastric adenocarcinoma is on the rise. The only targeted therapy that improves patient outcomes is the anti-HER2 antibody trastuzumab; however, benefit is limited to cases with HER2 overexpression. Inhibition of EGFR in EGA is unsuccessful. cMet overexpression is a proposed resistance pathway for EGFR family inhibition. We sought to characterize the co-expression relationships among the EGFR family and cMet to identify potential dual therapeutic targets. Methods: This study included all sequential patients (pts) with adenocarcinoma of the esophagus and GEJ who underwent primary resection between 2001 to 2011 without neoadjuvant therapy or HER2 inhibition. Demographics, risk factors, tumor features, and outcome data were analyzed. Central blinded immunohistochemistry (IHC) was performed on FFPE tumor specimens with EGFR, HER2, HER3, HER4 and cMet expression scored as low/negative or high/positive expression. Descriptive statistics, Exact chi square test and Cox regression model were used for statistical analyses. Results: 48 pts (39 M/9 F) were eligible (median age 66yr; 37-83). Most (63%) were stage I (T1N0) and 93% had underlying Barrett’s esophagus. High expression of EGFR, HER2, HER3, HER4 and cMet were present in 70%, 43%, 77%, 38% and 56% of tumors respectively. HER3 and HER4 were commonly co-expressed (p=0.003) and moderately differentiated tumors had high expression of HER3 (p=0.01). Stage was the only variable that correlated significantly with survival (p=0.007). Conclusions: This study demonstrated that static baseline cMET expression levels are not associated with EGFR family expression profiles, although HER3/HER4 co-expression is common. No receptors demonstrated prognostic value. Further investigation into dynamic cMET expression changes related to active EGFR inhibition including prognostic and predictive value is warranted.
Phase I study of apoptosis gene modulation with oblimersen within preoperative chemotherapy in patients with primary breast cancer
Authors: J. Rom, G. von Minckwitz, F. Marme, M. Sievert, D. Kozian, F. Schuetz, A. Scharf, M. Kaufmann, C. Sohn, A. Schneeweiss
Journal: Journal of Clinical Oncology (2009)

e11576 Background: The expression of the Bcl-2 protein confers resistance to chemotherapy mediated apoptotic signals in patients with breast cancer. The development of chemo sensitizing drugs may result in new treatment options. We investigated the effects of Bcl-2 down-regulation by the Bcl-2 antisense oligodeoxynucleotide oblimersen in breast tumor biopsies. Oblimersen targets Bcl-2 mRNA, thereby down regulates Bcl-2 protein translation, and enhances the antitumor effects of sub therapeutic doses of docetaxel. Methods: Within a phase I trial we administered escalating doses of oblimersen (3/5/7mg/kg/day) as continuous infusion on day 1–7 in combination with standard dosed docetaxel, doxorubicin, cyclophosphamide (TAC) on day 5 as preoperative chemotherapy in 28 patients with T2–4 breast cancers. Effects of oblimersen were evaluated in tumor biopsies and peripheral blood mononuclear cells (PBMCs) 4 days after start of oblimersen continuous infusion and before TAC treatment by quantitative microfluidic real-time polymerase chain reaction (RT-PCR). Read-outs consisted in measurement of Bcl-2 mRNA modulations and of 18 other putative predictive markers. Results: Two out of 13 patients showed a diminution of Bcl-2 transcripts after 4 days of treatment with oblimersen 5 mg/kg/day. PBMCs could not be evaluated as a surrogate tissue, because no qualified RNA could be isolated. Conclusions: Nevertheless, we demonstrated the feasibility to process clinical samples and to obtain good quality RNA from tumor biopsies, and indicated the potential of oblimersen to lower Bcl-2 mRNA in breast cancer. No significant financial relationships to disclose.
NEOHX study: Perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER-2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—18 m DFS analysis.
Authors: Fernando Rivera, Paula Jiménez-Fonseca, Pilar Garcia Alfonso, Javier Gallego, M. Luisa Limon, Maria Alsina, Luis Lopez-Gomez, MaCarmen Galan, Esther Falco, Jose Luis Manzano, Encarnación González, Enrique Aranda, Eva Fernandez, Monica Jorge
Journal: Journal of Clinical Oncology (2015)

107 Background: Perioperative chemotherapy has demonstrated better OS and DFS than surgery alone in resectable stomach or EGJ adenocarcinoma. Trastuzumab has improved OS when added to chemotherapy in pts with HER-2 + metastatic gastric cancer and is interesting to explore its role in the perioperative setting. Methods: A Spanish, multicenter, open-label phase II study evaluated the efficacy and toxicity profile of perioperative XELOX-T (Capecitabine 1000 mg/m2/12h po days 1-14, oxaliplatin 130 mg/m2 day 1, trastuzumab 8 mg/kgà6 mg/kg day 1, q3w ; 3 preoperative cycles and 3 postsurgery cycles followed by 12 cycles of trastuzumab monotherapy) in patients with T1-2N+M0 or T3-4NxM0 resectable stomach or EGJ adenocarcinoma, HER-2+ ( IHQ3+ or IHQ2+/FISH+). The primary endpoint was 18 months DFS, secondary endpoint included pCR, R0 resection rate, ORR, toxicity of preoperative treatment (NCI CTC v3.0 criteria) and biomarker analysis. Results: From June 2010 to March 2012, 36 pts were included: median age 65 (39-85); ECOG 0/1/2: 16/19/1 pts; localization: stomach 21 pts, EGJ 15 pts; histologic type: intestinal: 23 pts, diffuse: 4 pts, mixed: 1pt, not specified 8 pts; TNM: T 4: 7 pts; N+: 31 pts. Preoperative XELOX-T: Response: PR: 14 pts (39%), SD: 18 pts, PD: 0 pts, NE: 4 pts. Surgery was performed in 31 pts: R0: 28 pts (78%, 95% CI: 61-90%), R1: 1 pt, R2: 2 pts (1 had peritoneal carcinomatosis); pCR was observed in 3 pts (8.3 %; 95% CI: 2-22%). Two pts died due to surgical complications. After R0/R1 resection, postoperative XELOX-T was administered to 24 patients, 22 of whom underwent T monotherapy. G3-4 toxicity (&gt;5% of pts): diarrhea 33%, nauseas and vomiting 8% and pneumonia, anemia, neutropenia, anorexia, asthenia and pleural effusion with pneumothorax: 5.5%. With a median follow up of 24.1 months, 18m DFS is 71% (95% CI: 53-83%), 24 m DFS is 60% and median DFS and OS has not been reached. Conclusions: These data suggest that perioperative XELOX+T in HER-2 positive resectable stomach or esophagogastric junction adenocarcinoma is feasible and has promising activity. Clinical trial information: NCT01130337.
Molecular profiling in gastric cancer: Examining potential targets for chemotherapy.
Authors: John Thomas Miura, Thejus T. Jayakrishnan, Daniel Eastwood, Fabian McCartney Johnston, Susan Tsai, Kathleen K. Christians, Kiran Turaga, T. Clark Gamblin
Journal: Journal of Clinical Oncology (2014)

131 Background: Current NCCN guidelines recommend perioperative epirubicin (E), cisplatin (C), and 5-fluorouracil (F) along with other triple agent derivations as first line therapeutic approaches for operable gastric adenocarcinoma (GC). In this study, we utilized molecular profiling to evaluate expression of chemotherapy targeted biomarkers associated with ECF therapy for GC. Methods: Surgically obtained GC specimens were analyzed by immunohistochemistry for TOP2A, ERCC1, and TS expression (Caris Life Sciences, Phoenix) from 2009-2012. Actionable gene targets were analyzed for mutually exclusive or simultaneous expression. Results: A total of 230 GC specimens were analyzed. The median age of patients was 61 (IQR: 50-72) years with the majority being male (n= 139, 60%). IHC actionable targets included: 60% (n=138) high TOP2A, 55% (n=127) negative ERCC1, and 63% (n=145) negative TS, indicating potential benefit from E, C and F respectively. When analyzing for simultaneous expression profiles of the three genes, only 24 % (n=55) of patients had gene expression levels that suggested sensitivity to all three agents (ECF). Moreover, biomarker results of 6.5% (n=15) of patients demonstrated a potential complete lack of sensitivity to first line ECF therapy. Overall, 61% (n=140) of patients had molecular profiles that indicated sensitivity to two or more agents. Conclusions: Biomarker analysis of GC suggests that there is potential for TOP2A, ERCC1and TS to define patients who have the greatest likelihood of deriving benefit from ECF therapy. 93.5% of patients had the biomarker profile that predicted sensitivity to at least one of these agents. Prospective controlled studies are required to validate the role of TOP2A, TS and ERCC1 in routine management of GC patients.
Polymorphisms in EGF a+61G, GSTP1 Ile105Val, and MTHFR A1298C to predict response and survival in a phase II study for patients with metastatic or unresectable gastric (G) or gastroesophageal junction (GEJ) cancer treated with capecitabine, oxaliplatin (XELOX), and cetuximab.
Authors: S. Iqbal, M. J. Labonte, D. Yang, W. Zhang, P. O. Bohanes, Y. Ning, L. Benhaim, R. El-Khoueiry, P. M. Wilson, A. Gerger, A. B. El-Khoueiry, H. Lenz
Journal: Journal of Clinical Oncology (2011)

4121 Background: Advanced gastric cancer (AGC) remains the second leading cause of cancer death worldwide. We performed a phase II study to evaluate cetuximab combined with XELOX as first-line treatment of metastatic unresectable G or GEJ adenocarcinoma. The aim of this study was to identify molecular predictors of response/survival to XELOX+cetuximab by evaluating germline single nucleotide polymorphisms (SNPs) in genes involved in 5-FU (TYMS, MTHFR) and oxaliplatin (ERCC1, XPD, GSTP1) metabolism and human epidermal receptor signaling (EGF, HER2, COX2, FCgR2A, FCgR3A) to identify patients (pts) that benefit from this regimen. Methods: DNA was extracted from whole blood in 59 of 72 pts (14 XELOX; 58 XELOX+cetuximab). One more evaluable pt needed for complete accrual. The median progression-free survival (PFS) and overall survival (OS) among 68 pts with a minimum of 1-month follow-up were 5.3 and 13.3 months, respectively. SNPs were analyzed by PCR-based protocols and their association with response rate (RR) and OS were analyzed using Fisher’s exact test, Kaplan-Meier curves, and log-rank tests, as appropriate. Results: There was a statistically significant association between the SNPs EGF A+61G rs4444903 and GSTP1 Ile105Val rs1695 and RR: 40 patients with EGF+61 G allele had a 62.5% RR, whereas the 11 patients with the AA genotype had a 27.3% RR (p=0.0477). 22 patients with the Ile genotype of the GSTP1 was 72.7% RR, whereas the 31 patients with Val (AG or GG) had a 38.7% RR (p=0.0248). In addition, there was a statistically significant association been MTHFR A1298C rs1801131 and OS (p=0.044). Pts carrying MTHFR 1298 AA had a longer OS (21.3 months) compared with pts carrying AC or CC (8.7 months). No other significant associations between SNPs and RR or OS were observed. Conclusions: This analysis suggests that the EGF A+16G and GSTP1 SNPs may be predictive markers for RR and MTHFR A1298C may be predictive of OS for pts with G and GEJ adenocarcinoma treated with XELOX+cetuximab. Further evaluation is warranted.
Optimizing endocrine therapy in postmenopausal women with early stage breast cancer: A decision analysis for biological subsets of tumors
Authors: H. J. Burstein, E. P. Winer, K. M. Kuntz, J. C. Weeks, R. S. Punglia
Journal: Journal of Clinical Oncology (2005)

529 Background: Choices for adjuvant endocrine therapy in postmenopausal breast cancer patients include sequential treatment with tamoxifen and then aromatase inhibitors, or upfront therapy with an aromatase inhibitor. Available data do not define which strategy would be optimal. Previously we modeled these strategies and found that sequential therapy with tamoxifen followed by crossover to an aromatase inhibitor at 2.5 years yielded superior 10-year disease-free survival (DFS) than treatment with either tamoxifen or aromatase inhibitor treatment, alone (SABCS 2004). Based on emerging data, we sought to analyze whether the optimal treatment strategy would differ for ER+PgR+ and ER+PgR- tumors. Methods: We developed a Markov model to simulate 10-year DFS among a cohort of postmenopausal women with hormone-receptor positive breast cancer. Treatment strategies analyzed were aromatase inhibitor alone, tamoxifen alone, or tamoxifen followed by crossover to an aromatase inhibitor at 2 years. Risk estimates were derived from reports of randomized clinical trials. Results: The optimal treatment strategy differed based on the biological features of the tumor. The 10-year DFS estimates are shown in the Table. Two-way sensitivity analyses suggest these findings are robust across the range of hazard ratios reported inthe ATAC, ARNO/ABCSG, and IES trials, and provide a framework for evaluating future data from related trials. Conclusions: Modeling estimates suggest that the optimal adjuvant endocrine strategy in postmenopausal patients may differ based on the biological features of the tumor. Sequential tamoxifen then aromatase inhibitor treatment after 2 years appears superior for ER+PgR+ tumors, but upfront treatment with an aromatase inhibitor may yield superior outcomes for ER+PgR- tumors. Clinicians and patients may find this information useful while awaiting results from prospective randomized trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis AstraZeneca
Primary bone lymphoma: Single institution experience
Authors: G. Korpanty, D. G. Power, A. Treacy, G. P. McVey, C. O’Keane, D. N. Carney
Journal: Journal of Clinical Oncology (2008)

19515 Background: Primary bone lymphoma (PBL) is a rare condition and accounts for less than 2% of all adult lymphomas and 3% of all primary bone malignancies. Presentation is usually in the fifth or sixth decade with limited stage disease. Due to the rarity of this disease there is a lack of prospective randomized clinical trials and hence optimal treatment is unceratin. Methods: Using our hospital database, we identified all patients with PBL, their international prognostic index (IPI) score, treatment, and long-term follow-up. All patients had a bone marrow aspirate and biopsy remote from the primary tumor. Results: From January 1989 to July 2007 we identified 12 patients with PBL. Male to female ratio was 1:1, and median age was 36.5years (range,20–68years). Diffuse large b-cell type (DLBCL) was the most common histology (11 pts). Long extremity bones were the most common presenting sites (femur=4, tibia=1, humerus=1). Multifocal disease was present in three cases and one of these presented with spinal cord compression. Nine patients had stage 1E disease. Pathological fracture was a presenting feature of 5 pts, of which 3 needed surgery first. Treatment modalities included surgery, chemotherapy, and radiotherapy. Chemotherapy was given first in 8 patients and the most common regimen was CHOP (8 pts) with Rituximab added after 2002. Median follow-up is 8 years (range,0.5–18.5 years), and overall and disease free survival is 100%. Conclusions: PBL has a better prognosis than nodal DLBCL and other extranodal lympohomas. Combined modality therapy (CMT), i.e. chemotherapy followed by radiotherapy is the prefered treatment option, despite the lack of prospective randomized clinical trials, unless adverse neurology or an unstable fracture presents first. PET scanning should be used to assess response to treatment. The pathogenesis of bone lesions in PBL is unclear and the use of bisphosphonates and periodic checking of calcium levels should be further explored. Pathological fractures and spinal cord compression, as well as multifocal disease do not confer a worse prognosis. No significant financial relationships to disclose.
A phase II study of weekly docetaxel (T), estramustine (E), and celecoxib (C) in patients with hormone refractory prostate cancer (HRPC)
Authors: B. Mellado, A. Font, J. Carles, G. Catalán, J. L. González Larriba, E. Gallardo, L. A. Fernández, M. Nogué, P. Lianes, A. González Del Alba
Journal: Journal of Clinical Oncology (2005)

4725 Background: T/E is an active chemotherapy treatment for HRPC. COX-2 inhibitors could also delay disease progression in these patients. The purpose of this study is to evaluate the response to treatment with T, E, and C in patients with HRPC. Methods: Patients with progressive HRPC, age ≥ 18 years, Karnofsky Index (KI) ≥ 60%, and adequate bone marrow, renal and hepatic function were eligible. No prior chemotherapy was allowed. Antiandrogen therapy should be stopped 4 to 8 weeks prior to study entry and hormone blockade with LHRH analogs was continued. Treatment: T 35 mg/m2 iv on days 2, 9 and 16; E 280 mg po bid on days 1–3, 8–10, and 15–17; and C at 400 mg po bid, each day, as 28-day cycles for at least 6 cycles. RECIST and PSA levels were used to evaluate response. Results: Thirty-three patients were included. Median age was 66 years (range, 47–76). Tumor staging at diagnosis was 22% stage II, 16% stage III and 62% stage IV. KI ≤ 70% in 8 pts and KI > 70% in 25 pts. Metastatic sites were bone (80%), lymph nodes (37%), and liver (10%). A total of 91 cycles (median: 4; range: 1–6) were administered. Median RDI was 98% for T and 99% for E. Efficacy: Seven patients were not evaluable for response (2 left the study after the first cycle, 1 withdrew due to investigator criteria, and 4 were still undergoing treatment). Of 11 patients with measurable disease, 1 achieved CR, 2 PR, 4 SD, 1 PD, and 3 too early resulting in an ORR of 27%. PSA level reduction >50% from baseline was found in 70% of patients. Median OS was not reached. All patients were evaluable for toxicity. The most frequent G 3–4 toxicities per patient were asthenia (15%), anorexia (11%), nausea (7%), and stomatitis (7%). There was one toxic death due to a gastric perforation associated with C. Conclusions: Preliminary results show that the combination of T, E, and C appears to be a very promising regimen with an acceptable toxicity profile. Further data will be presented at the meeting. No significant financial relationships to disclose.
Bone loss and vitamin D deficiency post gastrectomy for gastro-esophageal malignancy.
Authors: Kiran Virik, Robert Wilson
Journal: Journal of Clinical Oncology (2016)

165 Background: Metabolic bone disease is a known but incompletely understood consequence of gastrectomy. Post gastrectomy osteoporosis (OP) is multifactorial. Evidence suggests that patients who undergo this surgery require long term bone health assessment and nutritional support. Methods: 30 post gastrectomy patients (2000-2008) from a single centre in Australia were evaluated re bone health post surgery and post nutritional supplementation. Exploratory analysis included: age, gender, pathology, type of surgery, 25 OH-vitamin D, calcium, parathyroid hormone (PTH), bone mineral density (BMD), vertebral XRs, urinary calcium and N telopeptides of type I collagen. Other risk factors evaluated were: smoking, corticosteroid use, alcohol intake, hyperthyroidism, menopausal status, hyperparathyroidism (hPTH), pre-existing bone disease. Results: The median age of the cohort was 67.5 (range 53-83) of whom 22 (73%) were male. Histology showed 16 (53%) gastric adenocarcinoma, 6 (20%) esophageal adenocarcinoma, 2 (7%) GISTs, 5 (17%) gastric/duodenal lymphoma and 1 other category. Similar numbers of patients underwent total (12) and partial/distal gastrectomy (12), with 6 having a subtotal gastrectomy. 22 (73%) had a Roux-en-Y or BR II reconstruction and 8 had a BRI/other. Median time from surgery to first BMD was 54.5 months (range 12-360) with median correlative calcium level 2.24 (range 1.97-2.49), median vitamin D level 43 (range 11-82) and median PTH 6.4 (range 1.8-13.8). Osteoporosis was diagnosed in 14 (47%) of patients, osteopenia in 14 and 2 (7%) patients had a normal BMD. Low vitamin D was seen in 23 (77%) patients, low calcium levels in 5 (17%) and secondary hPTH in 12 (41%). Post nutritional supplementation preliminary results showed 2/23 (9%) had a low vitamin D level, 3/11 (27%) had secondary hPTH, 5/19 (26%) had osteoporosis, 12/19 (63%) had osteopenia and 2/19 had a normal BMD. Analysis of other risk factors is to follow. Conclusions: Poor bone health and vitamin D deficiency is a clinically significant problem post gastrectomy. Patients should undergo long term nutritional and bone health surveillance in addition to their oncological follow up post resection.