tbuckley/cabot-search huggingface dataset:
FAC followed by paclitaxel in breast cancer (BC) patients (pts)with high risk for recurrence
Authors: R. Gerson, A. Serrano, F. Flores, A. Vilallobos
Journal: Journal of Clinical Oncology (2004)

874 Background: BC is the second most frequent cancer in women. Several prognostic factor have been identified in early clinical stages. Most important of these is axillary lymph nodes (ALN) status. Various treatment strategies have been attempted in high risk pts. Objective: To determine recurrence free time and overall survival in stage II, premenopausal BC pts with 4 or more positive ALN. Patients: Premenopausal pts, less than 50 years old, with histologically confirmed BC, stages IIA and IIB with 4 or more positive ALN. After breast surgery they received FAC (500–50-500 mg/m2) every 21 days for 4 cycles, then paclitaxel 175 mg/m2 every 21 days for 4 cycles, followed by radiotherapy and hormonal therapy according to hormonal receptors status. We determine age, clinic and pathologic stage, disease free and overall survival. Results: From 09/98 to 04/03 13 pts were enrolled, mean age 41.1 yrs, range 32 –49. T1 five pts were enrolled, T2 8 pts; mean tumor size 2.5 cm, mean cut positive ALN 13.1 range 4 –35. Stage IIA 5 pts, IIB 8. All pts were menstruating at the time of chemotherapy; 6 stopped menstruating during chemotherapy and did not regain menses. Radical mastectomy 11 pts, conservative 2. RE+/RP+ 9/9 pts, negative RE/RP 2/2, unknown RE/RP 2/2. HER2-neu + 2 pts, negative 7, unknown 4; P53+ 5 pts, negative 3, unknown 5. Mean follow-up time 20.2 mos, range 3 –57. All pts completed chemotherapy and radiotherapy, 10 pts received hormonotherapy after chemo. We detected 2 recurrences, 1 local which was treated with radical mastectomy and 1 to lung and pleura which was treated with chemotherapy. 2 deaths were registered, 1 tumor related, and 1 because sudden death which was unrelated to tumor activity. No correlation was observed between chemo scheme and prognostic factors. Conclusions: In this study, FAC followed by paclitaxel appears to reduce the incidence of recurrence in high risk patients. We do not observe a relation between chemotherapy effect and prognostic factors. These findings need to be confirmed with a longer follow-up time and larger population; therefore this will continue to be an ongoing study. No significant financial relationships to disclose.
Paclitaxel/carboplatin (PC) plus bevacizumab/erlotinib as first-line treatment for patients (pts) with carcinoma of unknown primary (CUP) site
Authors: F. A. Greco, H. A. Burris, D. R. Spigel, D. S. Thompson, D. M. Waterhouse, S. Hanson, E. R. Vazquez, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2008)

4607 Background: Empiric chemotherapy with PC is a common approach in the first-line treatment of pts with CUP. The combination of bevacizumab/erlotinib recently showed substantial activity as a second-line treatment in CUP patients (JCO 25:1747, 2007). In this multicenter, community-based phase II trial, we evaluated PC in combination with bevacizumab/erlotinib. Methods: Pts with CUP (adenocarcinoma, poorly differentiated carcinoma, poorly differentiated squamous carcinoma) and no previous treatment were eligible. Well recognized treatable CUP syndromes were excluded. Additional eligibility criteria: ECOG PS 0, 1; measurable disease; adequate organ function; no active brain metastases; standard bevacizumab exclusions; informed consent. All pts received paclitaxel 175mg/m2, IV D1; carboplatin AUC 6.0 IV D1; bevacizumab 15mg/kg IV D1; erlotinib 150mg PO daily; cycles repeated every 21 days. Responding/stable pts after 2 cycles continued PC for a total of 4 cycles, and then received bevacizumab/erlotinib until progression. Pts were monitored for response rate (RECIST criteria), PFS, OS, and toxicity. Results: Between 4/06 and 11/07, 51 pts entered this clinical trial. Pt characteristics: median age 62 years (range 23 - 81 years); > 1 metastatic site, 69%; adenocarcinoma, 65%. 36 pts were reevaluated after 2 cycles of treatment; 4 pts were removed with early progression; 11 pts not yet reevaluated. 34 pts have completed 4 cycles; 31 then received bevacizumab/erlotinib maintenance. 19 of 40 pts (48%) had major responses (CR2, PR17); 16 pts (40%) were stable. Median PFS and OS for all pts are 7 months and 11.3 months, respectively. During chemotherapy, myelosuppression was the major toxicity, consistent with the well known side effects of PC (grade 3/4 neutropenia 19%; thrombocytopenia 9%). Grade 3/4 toxicity attributed to bevacizumab and/or erlotinib: skin rash, 16%; diarrhea, 12%; colon perforation, 2%. Conclusions: PC + bevacizumab/erlotinib was active and well tolerated as first-line treatment for pts with CUP. In this preliminary analysis, response rate, PFS, and OS compare favorably with other regimens. Further evaluation of this regimen is indicated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Genentech Genentech Bristol-Myers Squibb, Eli Lilly and Company, Genentech, GlaxoSmithKline, GPC Biotech, sanofi-aventis
Proliferation and lymphangiogenesis markers, and risk of lymph-nodal metastasis in early cervical cancer.
Authors: S. Bogliolo, A. Buenerd, P. Mathevet, F. Lecuru
Journal: Journal of Clinical Oncology (2010)

5099 Background: Lymph Vascular Space Involvement (LVSI) and lymph nodal metastasis are significant risk factors in early-stage cervical cancer. The association between LVSI and nodal metastasis has been described. But, it is not known if the lymphatic dissemination is related to the direct potential of dissemination of the tumoral cells and/or to creation of new lymphatic vessels (lymphangiogenesis) by the tumor. The goal of this study was to evaluate the lymphangiogenesis in relation with LVSI and sentinel node metastasis in early cervical cancer. Methods: A multicenter prospective study of 75 early cervical carcinomas diagnosed and surgically treated in seven French hospitals was performed. The inclusion criteria were: patients with cervical cancer FIGO stage IA2 or IB1, histologic diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma. All patients were treated with radical hysterectomy or trachelectomy and pelvic lymph node dissection with identification of the sentinel nodes. All the resected nodes were evaluated for micrometastasis and tumoral cells embolism with serial sections and immunohistochemistery.The cervical tumors were evaluated with the following markers: Ki67, D2-40 (lymphatic marker), CD31 (marker of blood and lymphatic vessels) and VEGF-C (marker of vascular proliferation). Also the cervical specimens were evaluated for the presence of LVSI. Results: A nodal metastasis was detected in 23 nodes from 14 (19%) patients. LVSI was evidenced in 45 (60%) cases. The correlation between LVSI and nodal metastasis was highly significant (p = 0.007). Evaluation of cell proliferation with Ki67 staining showed a statistically significant increase in case of adenocarcinoma. There were no correlation between CD31, D2-40, VEGF-C staining, and LVSI and nodal metastasis. Conclusions: This study showed that the only predictive factor of nodal metastasis (including micrometastasis and tumoral cells embolism) was LVSI. None of the proliferation and angiogenesis markers studied can predict the lymph nodal status. So, lymph node dissection (with ultrastaging of the sentinel nodes) remains an important step of the management of early cervical cancers. No significant financial relationships to disclose.
Cxcr4 expression and risk of bone metastasis in patients with early breast cancer
Authors: R. Conforti, W. Xia, T. Boulet, S. Michiels, S. Delaloge, M. Spielmann, G. N. Hortobagyi, L. Pustzai, F. Andre, M. Cristofanilli
Journal: Journal of Clinical Oncology (2007)

10610 Background: CXCR4, a receptor for SDF1, has been reported to be involved in early metastatic process. This study aimed at evaluating i. prognostic value of CXCR4, ii. correlation between CXCR4 expression in primary tumors and occurrence of metastases in SDF1- expressing organs. Patients and Methods: CXCR4 expression in the primary tumor was analyzed by immunohistochemistry (Human CXCR4 MAb 170, R&amp; D System, MN, USA) in 823 patients included in two randomized trials evaluating efficacy of anthracyclines-based chemotherapy over a no-chemotherapy arm. The prognostic value of CXCR4 expression was assessed by the Cox regression model adjusted for tumour grade, stage, estrogen-receptor (ER) status and age. Distant metastasis rates for a specific site (either as first event or as subsequent metastases) were calculated by time untill occurrence of metastasis or death. We predefined 4 recurrence sites of interest: liver, brain, lung and bone that are organs expressing SDF1. Results: CXCR4 was expressed in 92 of 794 assessable primary tumors (12%). There was no significant association between CXCR4 expression and clinical characteristics, except a trend for a higher rate of ER- positive disease in CXCR4+ tumors (p=0.05). CXCR4 was not prognostic for neither overall survival (Hazard Ratio (HR) = 1.03 CI 95% =[0.63 - 1.67], p=0.90), disease-free survival (HR = 0.93 CI 95% =[0.63 - 1.37] , p=0.93), nor incidence of overall metastases (HR= 1.36 CI 95% =[0.87–2.12], p=0.17). We next assessed the incidence of metastases in SDF1-producing organs according to CXCR4 staining. While CXCR4 was not associated with an increased risk of liver (HR=0.67 [0.27–1.70] p=0.40), lung (HR=0.89 [0.20–3.87] p=0.87) or brain metastases (HR=1.04 [0.40–2.70] p=0.94), CXCR4+ tumors presented a higher risk of bone metastases (HR=2.17 [1.30–3.65] p&lt;0.01). The 10 year incidence of bone metastases were 23% [14–33%] and 12% (10–15%] in CXCR4+ and CXCR4- tumors respectively. Conclusions: This study suggests that expression of CXCR4 in breast cancer is associated with higher rate of bone metastases, a finding concordant with data from mouse models (Kang et al, Cancer Cell). This finding might lead to further development of adjuvant strategies using bone-targeting agents (e.g. biphosphonates, CXCR4 inhibitors). No significant financial relationships to disclose.
Phase II trial of sunitinib as maintenance therapy after stereotactic radiosurgery in patients with one to three newly diagnosed brain metastases.
Authors: D. Peereboom, C. Brewer, J. H. Suh, S. T. Chao, B. I. Rini, M. Parsons, P. Elson, G. Barnett
Journal: Journal of Clinical Oncology (2010)

TPS148 Background: For patients with 1-3 brain metastases, standard therapy after stereotactic radiosurgery (SRS) is whole brain radiotherapy (WBRT). SRS without WBRT leads to a significantly higher rate of relapse in the brain and local site (Aoyama, JAMA, 2006). Due to concerns about neurologic sequelae of WBRT, however, a substantial number of patients and physicians opt to delay WBRT until the time of CNS progression. This trial offers chemotherapy as an alternative treatment to WBRT for this patient subgroup. Sunitinib targets VEGFR and therefore vasculature. Because this target lies on the abluminal side of the blood brain barrier (BBB), sunitinib should not need to cross the BBB. Sunitinib might be effective in preventing growth of microscopic brain metastases. This trial uses sunitinib after SRS with the goal of preventing recurrent disease in the brain and at the site of SRS and preserving neurocognitive function (NCF). The hypothesis is that sunitinib will provide an effective alternative to WBRT for the prevention of recurrent brain metastases. Methods: The primary endpoint of the study is the rate of CNS progression at 6 months (PFS6) following SRS. Secondary endpoints include NCF over time, time to systemic progression, toxicity, and rates of brain and local failure. Eligible patients will have pathologically proven carcinoma with 1-3 newly diagnosed brain metastases, KPS ≥ 70, (RTOG RPA I or II). Enrollment, neuropsychiatric testing (NP), and the start of therapy must occur no later than 1 month following SRS. Patients with controlled systemic disease may continue chemotherapy provided the combined regimen (therapy + sunitinib) has been reported as safe. A list of such regimens is included in the protocol. Patients receive sunitinib 37.5 mg/d days 1-28 every 42 days and may increase to 50 mg/d if well tolerated. Patients receive drug until disease progression. NP and MRIs are obtained every 2 cycles. Based on a historical PFS6 of 50% with SRS alone for 1-3 brain metastases, this trial will attempt to achieve a PFS6 of 65%. To achieve a 2 sided p = 0.05, 52 evaluable patients will be required. A positive result will lead to a phase III trial of WBRT vs. chemotherapy as post-SRS therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
Predictive factors of response to docetaxel (DOC) rechallenge (ReC) in castration-resistant prostate cancer (CRPC) patients (pts).
Authors: A. Veccia, O. Caffo, S. Brugnara, A. Caldara, M. C. di Pasquale, A. Ferro, M. Frisinghelli, V. Murgia, B. Soini, F. Valduga, G. L. Pappagallo, E. Galligioni
Journal: Journal of Clinical Oncology (2011)

e15126 Background: ReC with DOC is an option for CRPC pts, who have responded to first-line DOC and have stopped the treatment without progression. The possibility of obtaining a new response by a DOC ReC is usually considered on the basis of the response to the previous treatment. We attempt to identify if there are additional factors able to predict ReC response. Methods: From March, 2002 to December, 2010, a consecutive series of 45 CRPC pts received at least one ReC after first-line DOC, for a total of 91 ReC courses (median 2, range 1-7). ReCs consisted of 4-6 DOC cycles and were proposed until the appearance of a true resistance to DOC: we consider as DOC-resistant pts showing a clinical and/or biochemical progression during DOC treatment. For each ReC course, we recorded the following parameters: treatment schedule (3 wks vs weekly), estramustine use (yes vs no), PSA response (↓ > 50%) at the previous DOC course, baseline parameters (hemoglobin, alkaline phosphatase, pain presence, ECOG), number of previous DOC courses, PSA parameters (slope LOG, doubling time, velocity) during both previous DOC course and treatment holiday, duration of treatment holiday before ReC. A binary logistic regression analysis was applied. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: In 67% of 91 ReCs we observed a PSA reduction > 50%. After a median follow-up of 25 mos, the median survival is 32 mos and the projected 2-years overall survival is 77.5%. ReC was well tolerated with no more than grade 1-2 hematological and non-hematological toxicities. Having an interval log-PSA equal to or more than 0.62 [(exp(beta) 8.965; p= 0.020], an interval from the previous cycle equal to or more than 23 weeks [(exp(beta) 8.212; p= 0.002], a response to the previous cycle [(exp(beta) 7.658; p= 0.014], resulted to be independently predictive of a response to ReC. Conclusions: In our experience, for CRPC pts sensitive to DOC, ReC appears to be a good option to obtain further response. Response to the previous cycle, interval log-PSA and interval from the previous cycle are factors able to identify the pts having more probabilities to respond to ReC.
A double-blind, randomized, placebo-controlled phase III intergroup study of gefitinib (G) in patients (pts) with advanced NSCLC, non-progressing after first-line platinum-based chemotherapy (EORTC 08021-ILCP 01/03).
Authors: R. M. Gaafar, V. Surmont, G. Scagliotti, R. Van Klaveren, D. Papamichael, J. Welch, B. Hasan, V. Torri, J. P. Van Meerbeeck
Journal: Journal of Clinical Oncology (2010)

7518 Background: Based on the results of the 2 INTACT trials, EORTC trial 08021 evaluated the role of G, an oral TKI inhibitor, administered following standard first-line chemotherapy (CT) in pts with advanced NSCLC. Methods: Pts with advanced NSCLC not-progressing after 4 cycles of platinum-based CT were randomized to receive either G 250 mg/d or matched placebo (P) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and toxicity. 598 pts had to be randomized and 514 deaths observed in order to detect a 28% increase in OS from a median of 11 to 14.1 months (HR = 0.78). Results: After inclusion of 173 pts, the trial was prematurely closed to entry due to low accrual. Baseline characteristics for G (n = 86) and P (n = 87) arms: median age 61/62 y; % male: 78 and 76; % adeno+ bronchoalveolar cell carcinoma/squamous-cell/other: 56/16/28 and 43/20/38; % stage IIIB: 19 and 15; % WHO PS 0/1/2: 36/57/7 and 35/61/5; % prior chemotherapy response (PCR) CR-PR/SD: 40/60 and 40/60; % current/former/never smoker: 29/49/21 and 26/48/23. 149/173 patients (86%) died. The difference in OS in the G and P groups was not statistically significant (medians 10.9 and 9.4 months, HR 0.83 [95% CI 0.60-1.15]; p = 0.2, adjusted by PCR, stage, PS). The difference in PFS was significant (medians 4.1 and 2.9 months, HR = 0.61, [95% CI 0.45,0.83]), p = 0.0015 favouring G. The majority of treatment-related adverse events (AEs) with G were grade 1/2. 19% of pts receiving G had a treatment-related SAE. 8%/5% pts in G/P withdrew due to a treatment-related AE. AEs reported in ≥ 10% of all pts were rash (47% with G versus 13% with P) and diarrhea (34% with G versus 13% with P). Conclusions: The continuous administration of G following platinum-based chemotherapy in pts with advanced NSCLC is well tolerated. Based on 149 of the required 514 deaths, no difference in OS could be detected, however G significantly prolongs PFS. Supported by AstraZeneca NCT00091156. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, AstraZeneca, Lilly, sanofi-aventis AstraZeneca, Lilly, Roche, sanofi-aventis Lilly
A phase II study of neoadjuvant irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) for resectable liver metastases from colorectal cancer
Authors: O. F. Bathe, S. Ernst, F. Sutherland, E. Dixon, J. Koppel, C. Butts, D. Bigam, D. Ruether, B. Walley, S. Dowden
Journal: Journal of Clinical Oncology (2005)

3662 Background: Perioperative chemotherapy may potentially improve survival in patients undergoing resection of colorectal liver metastases. Neoadjuvant chemotherapy has several potential advantages: it provides in vivo chemosensitivity data; it may help select patients with occult extrahepatic disease (averting unnecessary metastasectomy); and it expedites systemic therapy for micrometastases. Methods: We have initiated a phase II trial in which patients with resectable liver metastases receive CPT-11 (180 mg/m2, on day 1) with 5-FU (400 mg/m2 bolus + 600 mg/m2 by 22 hour infusion) and LV (200 mg/m2) on days 1 and 2, every two weeks for 6 cycles. Hepatic metastasectomy was performed unless extrahepatic disease appeared. Postoperatively, patients with stable or responsive disease receive the same regimen for 12 cycles. Patients with progressive disease receive either second-line chemotherapy or best supportive care. The primary endpoint is survival; secondary endpoints include response, safety, feasibility and quality of life. Results: Since January 2002, 29 patients have been accrued. Median age is 57 years (range 44 - 69); median number of metastases is 2 (range 1 - 10); 16 patients (55%) presented with synchronous metastases. The neoadjuvant phase has been completed in 27 patients. The preoperative response rates are: 1 CR (4%), 10 PR (37%), 10 SD (37%), and 5 PD (19%). During preoperative chemotherapy, 6 patients (22%) had grade 3/4 toxicities. Resection was not possible in 5 patients, due to the appearance of extrahepatic disease (3), clinical deterioration (1), or refusal (1). One patient died of arrhythmia following surgery, and 1 patient had liver failure. Postoperative CPT-11, 5-FU and LV has been given to 13 patients so far. During this treatment phase, 5 patients (38%) had grade 3/4 toxicities; 9 patients (69%) received all prescribed cycles. Conclusions: A 3 month course of chemotherapy prior to hepatic metastasectomy is safe and well tolerated. Response can consequently be assessed and postoperative treatment can be directed. Further accrual and follow-up will be necessary to assess the overall safety of this regimen, as well as impact on survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Canada Pfizer Canada
A tool for assessing adverse events in phase I/II oncology clinical trials
Authors: M. Coombes, S. Mukherjee, B. Kowaleski, M. Levine, J. Cosby, A. Arnold
Journal: Journal of Clinical Oncology (2007)

6518 Background: RECIST and NCI's Common Terminology Criteria are accepted systems that have standardized the reporting of oncology clinical trial outcomes. A standard system for attributing causality to Serious Adverse Events (SAEs) is lacking which can impact drug development and patient safety. The objectives of this study were to: 1) understand the clinical reasoning behind causality assessment during phase I/II oncology clinical trials; and, 2) use this information to develop a causality assessment tool for oncology. Methods: In-depth interviews were conducted with oncologists and trial coordinators at 6 Canadian academic cancer centres. Five main conceptual categories were explored: clinical reasoning; information resources; tools; challenges and concerns; and education. Interviews were recorded and transcribed verbatim. Individual interview content analysis was followed by thematic analysis across the interview set. A new causality assessment tool was developed based upon the qualitative findings and an analysis of existing generic tools. Results: Thirty-two interviews were conducted between May and August 2006 (65% participation). Half of participants were female, 66% were oncologists and 42% had more than 10 years of clinical trial experience. Data showed that participants use a common strategy to assess causality: they gather information, eliminate alternative explanations, and consider the study drug as the cause of the SAE. Over half cited the quality of information resources as a major factor contributing to uncertainty when assessing causality. Participants expressed the need for a standardized approach to causality assessment in oncology clinical trials. The tool developed in this study guides users to consider 5 statements related to potential alternative etiologies and 4 related to other factors that support a drug-SAE connection. The user is asked for their overall impression using a continuous probability rating scale. Conclusions: Attributing causality to SAEs is complex and uncertain. Clinicians describe using a logical system of reasoning, but have encountered barriers which must be addressed. We have developed and are validating a new tool to assist cancer clinicians in providing higher quality safety data about new cancer drugs early in development. [Table: see text]