tbuckley/cabot-search huggingface dataset:
Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX).
Authors: David Cunningham, Istvan Lang, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Niko Alexander Andre, Daniel Waterkamp, Mark P. Saunders
Journal: Journal of Clinical Oncology (2013)

337 Background: Elderly patients (pts) comprise the majority of pts diagnosed with mCRC, although they are in general underrepresented in clinical trials. AVEX, an open-label phase III trial, evaluated the efficacy and safety of cape ± bev in elderly pts with previously untreated mCRC. Methods: Pts ≥70 years with mCRC, for whom single-agent chemotherapy was deemed appropriate, were randomized 1:1 to receive first-line cape (1000 mg/m 2 bid days 1–14) as monotherapy or in combination with bev (7.5 mg/kg) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), and safety. The study was powered to show a difference in PFS, but not OS, between treatment arms. PFS and OS estimates were calculated using Kaplan-Meier methods. Results: 280 pts across 10 countries were randomized to cape + bev (n=140) and cape alone (n=140). Median age at enrollment was 76 years (range, 70–87), and 91.1% of pts had an ECOG performance status of 0–1. Baseline pt and disease characteristics were well balanced between arms. Bev + cape was associated with significantly prolonged PFS compared with cape alone (median of 9.1 vs 5.1 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p&lt;0.001). The ORR was also significantly improved in the bev + cape arm (19.3% vs 10.0%; p=0.042). OS was longer in pts treated with bev + cape vs cape alone, although this difference did not reach statistical significance (median of 20.7 vs 16.8 months; HR, 0.79; 95% CI, 0.57–1.09; p=0.182). Grade ≥3 adverse events occurred in 59.0% vs 44.1% of pts in the bev + cape and cape arm, respectively. Treatment was in general well tolerated and the safety profile consistent with previously reported data for bev + cape. Conclusions: This is the first randomized study prospectively evaluating bev specifically in elderly pts with mCRC. Based on the efficacy and safety results, bev plus cape might be an optimal treatment approach to improve outcomes in elderly pts. Clinical trial information: NCT00484939.
Significant impact of HLA class I allele expression on outcome in melanoma patients treated with an allogeneic melanoma cell lysate vaccine. Final analysis of SWOG-9035
Authors: V. K. Sondak, J. Sosman, J. M. Unger, P. Y. Liu, J. Thompson, R. Tuthill, R. Kempf, L. Flaherty
Journal: Journal of Clinical Oncology (2004)

7501 Background: SWOG-9035 compared 2 years of an allogeneic melanoma lysate (Melacine™) to observation in patients (pts) with stage II melanoma 1.5–4.0 mm thick. We also analyzed the effects of expression of certain HLA antigens (≥2 of HLA-A2, A28, B44, B45, C3 - called M5 - or either HLA-A2 and or C3). Now we report the mature overall survival (OS) analysis as planned. Methods: Primary analyses were conducted on the eligible pt population (intent to treat, ITT) using a Cox model adjusted for stratification and recognized prognostic factors. HLA analyses were \(\underline{\mathrm{prospective}}\), involved all typed pts and were adjusted for stratification and prognostic factors. Results: In total, 689 pts were entered over 4.5 years (598 eligible). Median follow-up time is 7.8 years (maximum 10.9 years). Ninety-one patients are ineligible, mostly (n=75) by pathology (tumor too thin or too thick). For the ITT analysis, the 5-year OS for the observation arm is 77% and for the vaccine arm is 81% (p=.98). For all randomized pts, the 5-year OS for the observation arm is 76% and for the vaccine arm is 82% (p=.49). We HLA typed 553 of the total 689 pts enrolled (80% of the total). There was a significant interaction of M5 status (≥2 vs 0–1) and treatment (p=.02). Among pts with 2 or more of the M5, 5-year OS for vaccine pts is 93% and for observation pts is 74% (p=.009). Among patients with 0–1 of the M5, 5-year OS for vaccine pts is 83% and for observation pts is 82% (p=.68). The interaction remained significant when only HLA A2/C3 status was considered (A2+ and/or C3+ vs A2- and C3-, p=.004). In the A2+ and/or C3+ group, 5-year OS for vaccine pts is 90% and for observation pts is 76% (p=.007). In the A2- and C3- group, 5-year OS for vaccine pts is 80% and for observation pts is 84% (p=.16). Conclusion: There was no significant benefit of vaccine therapy overall, but this prospective analysis indicates significant survival benefit of vaccine therapy among early-stage melanoma pts expressing ≥2 of the M5 alleles. HLA-A2 and C3 were the predominant alleles contributing to this effect. A prospective confirmatory trial in pts expressing HLA-A2 and/or HLA-C3 is planned. No significant financial relationships to disclose.
A phase II study of capecitabine and oxaliplatin (CAPOX) in metastatic adenocarcinoma of the small bowel (SBA) or ampulla of Vater
Authors: M. J. Overman, S. Chedid, J. Morris, S. Waldrum, R. A. Wolff
Journal: Journal of Clinical Oncology (2006)

14025 Background: Metastatic SBA and ampullary adenocarcinoma (AAC) are incurable, aggressive malignancies. Limited data exists regarding the role of systemic chemotherapy in these diseases. Given the marked activity of CAPOX in other cancers of the gastrointestinal tract, we have investigated the activity of this combination in these two tumor types. Methods: Patients (pts) with either metastatic or unresectable SBA and AAC who had adequate organ function, ECOG performance status (PS) ≤2 and measurable disease per modified RECIST criteria were enrolled. Prior use of 5-FU or capecitabine as adjuvant therapy, neoadjuvant therapy, or with radiation was allowed. CAPOX was administered as a 21 day cycle with oxaliplatin 130mg/m 2 IV on day 1 and capecitabine 750mg/m 2 PO BID days 1–14. Up to 30 pts will be enrolled. The primary endpoint is overall response rate (ORR). Results: Eleven pts have been enrolled from 11/04 to 12/05 (6 with AAC and 5 with SBA). Ten pts have received ≥2 cycles and are evaluable for response. All pts had metastatic disease and none had received prior chemotherapy. Patient (pt) characteristics: median age 59 (49–76); M/F (4/7); 91% PS 0–1. Grade 3/4 toxicities included fatigue (5), neuropathy (1), anorexia (1), thrombocytopenia (1), hypokalemia (1), hyponatremia (1), and musculoskeletal (1). Common grade 1/2 toxicities included neuropathy (8), nausea (8), diarrhea (6), and fatigue (5). Four pts required dose reduction and 1 pt discontinued due to toxicity (grade 3 fatigue). Six pts, 3 AAC and 3 SBA, responded with an ORR of 60% (95% CI 31 to 83%). Five responses have been confirmed and 1 AAC pt obtained a complete response after 5 cycles of treatment. Median time to progression was 6.8m (95% CI 4.4 to 9.3+m). Conclusions: The combination of CAPOX is both well-tolerated and highly active. The ORR of 60% is one of the highest yet reported in the literature for the treatment of adenocarcinoma of the small bowel and ampulla of Vater. Enrollment continues on this trial. (Supported by a research grant from Sanofi-Aventis). [Table: see text]
Arsenic trioxide induces apoptosis in MDS cell line MUTZ-1 cells via caspase-dependent pathways and down regulation of hTERT
Authors: J. Jin, W. Xu, H. Meng, W. Qian
Journal: Journal of Clinical Oncology (2005)

3208 Myelodysplastic syndrome(MDS) is a group of monoclonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral blood cytopenias. The clinical course of the disease and response to therapy vary considerably among individuals, therefore no single agent is expected to benefit all MDS patients universally. Recently arsenic trioxide (As2O3) was used to treat patients with MDS. To determine the effection of arsenic trioxide on MDS, MUTZ-1 cell line which was isolated from the peripheral blood of a MDS-RAEB patient, was treated by 0.5–8μmol/l As2O3. The inhibition of cell growth was detected by MTT assay. Apoptosis was assessed by morphology, DNA ladder, and the apoptotic peak before G1 phase cells by flow cytometry. The results revealed that As2O3 inhibited MUTZ-1 cell growth with IC50 of 5.7μmol/l, 1.87μmol/l, 0.91μmol/l when treated after 24h,48h and 72h respectively. As2O3 induces apoptosis in MUTZ-1 cells in a dose- and time-dependent manner. 2.0μmol/l is an effective concentration in the action of As2O3 induces apoptosis in MUTZ-1cells. Caspase protease family is a group of key apoptosis regulatory molecule that becomes activated during the early stages of apoptosis. We demonstrated that in the process of apoptosis of MUTZ-1 cells induced by As2O3, some members of the caspase protease family include caspase-8, caspase-3 and its substrate PARP were activated. It means that the activation of caspase protease is an important way in the apoptosis of MUTZ-1 cells induced by As2O3. In addition to the activation of caspase protease, we detected the expression of hTERT mRNA by RT-PCR meanwhile. We found that the expression of hTERT mRNA was down regulated by 2–8μmol/l As2O3 in MUTZ-1cells. We concluded that As2O3 should be an effective agent in the treatment of MDS. It induces apoptosis in MDS cell line MUTZ-1 cells in vitro via the activation of caspases and down-regulation of hTERT mRNA expression. No significant financial relationships to disclose.
Predisposing factors of blood brain barrier penetration from docetaxel during lung cancer treatment: Preliminary study
Authors: K. Zarogoulidis, A. Chatzopoulou, T. Kontakiotis, G. Theodoridis, P. Pousinis, D. Patakas
Journal: Journal of Clinical Oncology (2006)

17102 Background: Patients with lung cancer account for approximately 50% of brain metastasis cases. On the other hand the majority of active cytotoxic agents (like taxanes) in lung cancer treatment, are unable to penetrate blood brain barrier (BBB) so the role of chemotherapy in management of brain metastasis from lung cancer remain controversial. To investigate predisposing factors (if any) of penetration of BBB from cytotoxic agents we measured concentation levels of Docetaxel in serum and cerebrospinal fluid (CSF) during first line chemotherapy. Methods: Twelve lung cancer patients receiving chemotherapy consisted of Docetaxel (100 mg/m 2 ) and Carboplatin AUC 6 were included in this study. CSF and plasma samples were withdrawn half an hour after termination of chemotherapy infusion. Measurements were performed with high performance liquid chromatography and UV detection was at 227 nm. Results: Mean levels of docetaxel in blood was 2,5530 ± 0,53 mg/l and in CSF 0,7397 ± 0,22 mg/l. Three out of twelve patient had SCLC (2 with ED and 1 with LD) and 9 with NSCLC (2 stage IIIB and 7 stage IV). In three patients without metastasis no detectible level of docetaxel was measured. We were also unable to detect Docetaxel in CSF of the patient with NSCLC and metastasis in the ipsilateral lung. On the other hand in 9 patients with metastatic disease (4 brain metastasis 2 with bone metastasis 1 with metastasis in liver and adrenal and 2 with liver and bone metastasis) had detectable levels of docetaxel in CSF. There was not statistically significant correlation of docetaxel in plasma and CSF. Only one patient without any evidence of metastasis had a detectable level of Docetaxel in CSF (0,33229) but in 6 weeks a brain metastasis was apparent in brain MRI. Conclusions: Metastasis development seems to be associated with a modification of BBB penetration. If Docetaxel penetrates BBB (especially in the presence of brain metastasis) it would be probable to accelerate radiotherapy sensitivity of brain metastasis. No significant financial relationships to disclose.
HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: Results of a phase 1 and PK study
Authors: L. Q. Chow, S. G. Eckhardt, D. L. Gustafson, C. O’Bryant, S. Hariharan, S. Diab, N. L. Fox, A. Corey, K. Padavic, M. Brown, R. B. Cohen
Journal: Journal of Clinical Oncology (2006)

2515 Background: HGS-ETR1 (mapatumumab) is a fully-human monoclonal antibody agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1, DR4). Activation of TRAIL-R1 by HGS-ETR1 initiates a caspase cascade leading to apoptosis. HGS-ETR1 in combination with platinum or taxanes results in at least additive activity in preclinical models. Phase 1 and 2 trials have demonstrated that single agent HGS-ETR1 is well tolerated. Methods: This Phase 1 study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of HGS-ETR1 in combination with standard doses of paclitaxel and carboplatin. Patients received 3, 10 or 20 mg/kg HGS-ETR1 with paclitaxel (200 mg/m 2 ) and carboplatin (AUC 6) every 21 days for up to 6 cycles in the absence of disease progression. Results: Enrollment is complete; 28 patients have received 106 cycles of HGS-ETR1, including 12 patients in each of the 10 mg/kg and 20 mg/kg cohorts. Fourteen of 28 pts received at least 3 cycles (median = 2.5, range 1–12). Dose-limiting toxicity has been neutropenic fever (attributed to chemotherapy) and hypersensitivity (attributed to HGS-ETR1). Other non-dose limiting adverse events at least possibly related to HGS-ETR1 include fatigue, myalgia, transaminitis, anorexia and arthralgia. Preliminary analyses reveal that carboplatin and paclitaxel PK are not affected by HGS-ETR1. Similarly, the PK profile of HGS-ETR1 is not affected by paclitaxel and carboplatin, with plasma HGS-ETR1 concentrations consistent with those observed in the Phase 1 single agent trials. Three patients with NSCLC and 1 with adenocarcinoma of an unknown primary have experienced a confirmed partial response. Conclusions: HGS-ETR1 can be safely administered with carboplatin and paclitaxel. Evaluation of HGS-ETR1 in combination with other chemotherapeutic regimens is warranted. [Table: see text]
The von Hippel Lindau (VHL) gene status is not always identical in paired primary (P) and metastatic (M) lesion in patients with clear cell renal cell carcinoma (CCRCC)
Authors: S. A. Vaziri, A. R. Golshayan, B. I. Rini, H. Aydin, M. Zhou, L. Sercia, L. Wood, M. K. Ganapathi, R. M. Bukowski, R. Ganapathi
Journal: Journal of Clinical Oncology (2008)

16049 Background: In sporadic CCRCC, the VHL gene is often inactivated by mutation or methylation in >50% of P tumors. Due to differing effects of wild-type (WT) and mutant (MT) VHL gene on downstream signaling pathways regulating angiogenesis, targeted therapy based on VHL gene status could impact clinical outcome. In CCRCC genetic differences between paired P and M tumors has been reported (Bissig et al, Am J Path 1999, 155:267). We thus sequenced the VHL gene in paired tumor specimens to determine a possible clonal relationship between P tumor and M lesions in patients with CCRCC. Methods: Using paraffin embedded specimens, genomic DNA from microdissected samples (>95% tumor) of paired P tumor and M lesion from 12 patients, as well as adjacent normal tissue to the P tumor in 3 patients was analyzed in this study. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GeneBank Accession No. AF010238) to identify the occurence of mutations. Methylation status of the VHL gene was determined using VHL methylation- specific PCR primers after DNA bisulfite modification. Results: In 6/12 (50%) patients the VHL gene status differed between the P tumor and the M lesion (Table 1). Interestingly, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, the VHL gene in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. Conclusion: These results demonstrate for the first time that the VHL gene status is significantly different between paired primary and metastatic tissue in patients with CCRCC. These findings emphasize that therapy based on VHL gene status of the P tumor should consider VHL gene status and gene expression of the M lesion for outcome following therapy targeted against VHL pathway elements. Table 1: VHL gene status in P tumor and M lesion Metastatic Lesion wild-type VHL mutated/methylated VHL Primary Tumor wild-type VHL 2 2 mutated/methylated VHL 4 4 No significant financial relationships to disclose.
Administration of tegafur/uracil after transcatheter arterial embolization inhibit plasma vascular endothelial growth factor level and local recurrence of hepatocellular carcinoma
Authors: H. Ueda, H. Tanaka, Y. Kida, H. Hamagami, M. Ichinose
Journal: Journal of Clinical Oncology (2005)

4153 Background: Transcatheter arterial embolization (TAE) of the hepatic artery has been accepted as an effective treatment for advanced hepatocellular carcinoma (HCC). However, it is difficult to achieve complete tumor necrosis by TAE alone, and embolized vessel recanalization and collateral circulation formation are the main factors of HCC growth and recurrence after TAE. On the other hand, recent studies have shown that Uracil/Tegafur (UFT) inhibits tumor angiogenesis. In the present study, therefore, we examined whether administration of UFT after TAE inhibit of plasma Vascular Endothelial Growth Factor (VEGF) level and prevent recurrence of HCC or not. Methods: Twenty patients with advanced HCC, who had been repeated only TAE therapy more than two times, were enrolled. After obtaining informed concent, UFT (300mg/day) was randomly administrated to ten patients (UFT group) on the 3day after TAE, and not administrated to ten patients (control group). Peripheral blood samples were taken from all patients before and 1, 3, 7 and 14days after TAE. Plasma VEGF level was measured with ELISA. And period of local recurrence were compared between UFT group and control group. Results: Plasma VEGF levels in the control group significantly increased and reached the peak value on the 7 to 14day after TAE(p<0.01). In contrast, there were no significant increases of plasma VEGF levels in the UFT group. On the other hand, the period of recurrence in the control group was 69 days on average. In the UFT group, the average period of recurrence was significantly extended(127days, p<0.05), and there were three patients in the UFT group without local recurrence during the follow-up period. Conclusions: These data suggest that UFT administration after TAE improve local recurrence of HCC by inhibition tumor angiogenesis. No significant financial relationships to disclose.
PhaseI/II clinical trial of dose escalation using daily on-line cone beam CT guided radiotherapy combined with active breath control after transcatheter arterial chemoembolization for hepatocellular carcinoma
Authors: J. Yue, J. Yu, S. LI, Y. Yin, T. Liu, J. Zhu, J. Lu
Journal: Journal of Clinical Oncology (2009)

e15654 Background: The radiation dose is the key factor to improve survival of patients with hepatocellular carcinoma (HCC). The optimal way to increase radiation dose is to reduce uncertainties of target mainly due to respiratory motion and setup error in radiotherapy. Our previous study demonstrated that lipiodol can be a reliable surrogate of direct tumor targeting in Kv- cone beam CT(CBCT) for patients with good lipiodol embolization. Relying on lipiodol,the daily on-line CBCT guidance with ABC is feasible. By reducing geometric position uncertainty, as well as liver movement, the technique of ABC combined with on-line CBCT guidance can permit CTV(clinical target volume)-PTV(planning target volume) margin reduction and dose escalation. The purpose of the study is to apply the new technique for clinical application and investigate the dose escalation, toxicities and response of liver tumors with the technique combined with chemoembolization(TACE). Methods: 20 HCC patients with Child-Pugh A liver function score were treated by daily on-line CBCT guided radiotherapy relying on lipiodol combined with ABC after TACE. After current doses of 45Gy/ 9 fractions,3 fractions/weeks were delivered,the scheduled dose escalation ranged from 5 to 20Gy. Each mean liver dose not reached 23G y, V30 ( the percentage of normal liver volume with radiation dose≥30 Gy) less than 28%. Results: The planned dose escalation was finished in all subgroups. None of these patients developed Grade 2 or greater liver toxicity except two patients developed Grade 2 gastrointestinal complications and one had grade 1 acute liver toxicity.The overall immediate tumor response rate was 76.3%. 1-year overall survival rate was 80.5%. Conclusions: The technique of daily on-line CBCT guided radiotherapy combined with ABC after TACE is a safe and effective treatment which can reduce CTV-PTV margin significantly and increase target precision greatly. With the technique combined with TACE, the total irradiation dose above 65Gy is feasible in daily fraction of 5Gy. No significant financial relationships to disclose.
Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma.
Authors: C I Falkson, G Falkson, H C Falkson
Journal: Journal of Clinical Oncology (1991)

Sixty-four patients with histologically confirmed metastatic malignant melanoma were entered on a prospectively controlled randomized trial. Patients received dacarbazine (DTIC) alone or DTIC plus interferon (IFN) alfa-2b. Patients were reasonably balanced with respect to age, sex, performance status (PS), site of metastases, and number of metastatic sites. Objective response (complete plus partial remission [CR + PR]) was documented in six patients on DTIC and in 16 patients on DTIC plus IFN alfa-2b. Median time to treatment failure (TTF) and median survival are significantly better on the combination arm, with some long-term CRs observed. More toxicity was encountered in the combination arm, which was acceptable except in three patients where treatment was discontinued because of IFN toxicity.