tbuckley/cabot-search huggingface dataset:
Weekly versus 3-weekly docetaxel (D2) plus doxorubicin (D4) for first-line treatment of metastatic breast cancer (MBC)
Authors: H. Stemmler, N. Harbeck, I. Groell der Rivera, U. Vehling-Kaiser, G. Rauthe, W. Abenhardt, H. Sommer, H. Meerpohl, M. Kiechle, V. Heinemann
Journal: Journal of Clinical Oncology (2009)

1101 Background: We investigated the toxicity and efficacy of weekly applied docetaxel compared to its standard 3-weekly application in pts previously untreated with chemotherapy for MBC. Methods: In the D2 trial (&gt;60 yrs or KPS 60–80%), pts were randomized to receive docetaxel either on a 3-weekly (75 mg/m 2 q3w) or on a weekly schedule (30 mg/m 2 d1, 8, 15 q4w). In the D4 study (&lt;65 yrs or KPS 70–100%), pts received doxorubicin (50 mg/m 2 , d 1) in addition to docetaxel given either at q3w dose of 75 mg/m 2 or at as 35 mg/m 2 (days 1, 8, 15, q4w). Results: The primary endpoint (toxicity) was achieved in D2 and failed in D4. Both studies were terminated prematurely (D2 n = 102/162 D4 n = 85/242 pts). In the D2 study, leucopenia ≥grade 3 was significantly less frequent in the weekly arm (4.2% q1w versus 51.9% q3w, p &lt; 0.0001). In the weekly versus 3-weekly arm ORR was 26.8% versus 46.9% (p = 0.08), TTP was 5.4 versus 6.3 months (p = 0.91), and OS was 22.7 versus 15.8 months (p = 0.24). In the D4 study, an unexpectedly low rate of leucopenia ≥grade 3 was observed in the 3-weekly arm (29.7% q3w versus 35.7% q1w, p = 0.21). In the weekly versus 3-weekly arm, ORR was 50.0% versus 55.0% (p = 0.82), TTP was 6.2 versus 10.3 months (p = 0.36), and OS was 20.5 versus 28.9 months (p = 0.98). Non-hematological toxicity ≥grade 3 was generally mild and comparable within the two schedules. Conclusions: The present data support the feasibility of both, the weekly and the 3-weekly regimen of docetaxel application either as a single-agent or in combination with doxorubicin. As expected, leucopenia seems avoidable in the weekly scheduled of single-agent docetaxel (D2), whereas a combined weekly schedule of docetaxel/doxorubicin as given in the D4 study failed to confirm an expected lower rate of leucopenia. [Table: see text]
A comprehensive panel of mutation scanning assays detects mutations in the APC, TP53, KRAS, BRAF genes and hypermethylated APC and MLH1 DNA in plasma of patients with various stages of colorectal cancer: Utility for early detection, prognosis, and disease monitoring
Authors: S. L. Lilleberg, J. Durocher, C. Zhi, B. Walters, C. Sanders
Journal: Journal of Clinical Oncology (2004)

3765 Background: Tumor-associated DNA has been detected in plasma of colorectal cancer (CRC) patients, including DNA with mutations in APC, TP53, K-RAS, BRAF genes and hypermethylation in APC and MLH1 promoter regions. However, a comprehensive study assessing these markers in the plasma of CRC patients at various stages of neoplasia has not been reported. Methods: Plasma DNAs isolated from 120 CRC patients were scanned for mutations in APC, TP53, K-RAS, and BRAF, and alteratons of methylation status in APC and MLH1 without regard to the molecular or pathological analyses of the matched primary tumors. We chose mutation and methylation scanning technology and these targets to develop a comprehensive screen for somatic and epigenetic alterations known to be associated with sporadic CRC. Alterations in these targets were identified with a denaturing high-performance liquid chromatography (DHPLC) platform that uses post-separation fluorescence technology. This scanning technology enables the detection of variants that represent < 0.1% of the total analyzed DNA. Results: Using this combined-scanning approach, we were able to identify at least one somatic event in 120/120 (100%) CRC patients. In no case was a mutation found in the primary tumor that was not also present in the plasma. Thus, the six markers together detected 100% of patients with CRC at various stages, all of which had at least one alteration. Stastistical analysis of these alterations shows a significant correlation with the type of alterations, Dukes' staging, and prognosis. Conclusions: The results emphasis the heterogenous pattern of tumor mutations and methylation status and that scanning provides an attractive approach to comprehensive CRC genetic and epigenetic screening. The thoroughness of approach may have important implications for CRC screening and staging, and disease monitoring during and following therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Transgenomic Transgenomic Transgenomic
PAN1: A randomized phase II study evaluating potential predictive biomarkers in the treatment of metastatic pancreatic cancer.
Authors: Yu Jo Chua, Christos Stelios Karapetis, Craig Underhill, Louise M. Nott, David Goldstein, Michelle F. Cronk, Val Gebski, Nicole Wong, Katrin Marie Sjoquist, Andrew Victor Biankin
Journal: Journal of Clinical Oncology (2012)

TPS4137 Background: Biomarker-based selection of cancer treatments has already entered routine clinical practice in some cancer types. Recent retrospective data suggests the human equilibrative nucleoside transporter 1 (hENT1) to be promising predictive marker for benefit from gemcitabine in pancreatic cancer, at least in resected disease. Methods: 80 patients will be randomised to receive either gemcitabine or FOLFOX chemotherapy (folinic acid (FOL) fluorouracil (F) and oxalipatin (OX)) with stratification based on hENT1 status. All patients will be required to have tumour samples tested for hENT1 prior to randomisation, with both hENT1 positive and negative patients eligible for inclusion. Patients will continue their assigned treatment until progression, or unacceptable toxicity. Primary endpoint: Progression free survival in each chemotherapy arm (FOLFOX/gemcitabine). Secondary endpoints: efficacy/activity of gemcitabine and FOLFOX as assessed by OS (overall survival), TTP (time to progression), RR (response rate according to RECIST v1.1), CA19.9 response; Percentage of eligible patients able to be randomised within 14 days of screening; PFS in each biomarker-selected cohort (hENT1 positive/negative); Treatment related toxicity in each chemotherapy group (CTCAE v4.0) and in biomarker cohorts (hENT1 positive/negative); establishment of a tissue bank from patients treated with and without gemcitabine for further biomarker studies. Eligibility: Adult patients with radiologically and histologically confirmed metastatic pancreatic adenocarcinoma who have not previously received treatment for metastatic disease, and who have tumour tissue available for hENT1 testing are eligible for the study. Patients who do not have tumour tissue available will be required to undergo core biopsy to obtain tissue for hENT1 testing. Status: Opened to accrual July 2011.
Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803)
Authors: L. B. Saltz, D. Niedzwiecki, D. Hollis, R. M. Goldberg, A. Hantel, J. P. Thomas, A. L. A. Fields, G. Carver, R. J. Mayer
Journal: Journal of Clinical Oncology (2004)

3500 Background: Irinotecan prolongs survival in second line 5FU-refractory metastatic colorectal cancer (MCRC). First line irinotecan, weekly bolus 5FU, and leucovorin (IFL) was superior to daily x 5 bolus 5FU and leucovorin alone (FL) in a phase III trial in MCRC in terms of response rate, progression free survival and overall survival (OS). We conducted a phase III randomized study to evaluate whether IFL was also superior to weekly bolus FL after curative resection for stage III colon cancer. Methods: Eligible patients had TxN1–2M0 disease, Zubrod 0–2, and no prior chemotherapy. Patients (pts) received either IFL (irinotecan 125mg/m2 over 90 minutes followed by leucovorin 20 mg/m2 IV bolus and then 5FU 500mg/m2 IV bolus, given 4 weeks on, 2 weeks off, x 5 cycles (30 weeks total)) or the Roswell Park schedule of FL (leucovorin 500mg/m2 IV over 2 hours plus 5FU 500 mg/m2 at 1 hour after start of leucovorin, given 6 weeks on, two weeks off, x 4 cycles (32 weeks total)). Pts were stratified for N1 vs. N2 disease, high vs. low grade histology, and preoperative CEA of < 5 ng/ml, ≥ 5ng/ml, or unknown. Results: 1264 pts were randomized between April, 1999 and April, 2001. Median follow up is 2.6 years, and 67% of total expected deaths and 85% of total expected failures have occurred. Median OS and failure-free survival (FFS) have not yet been reached. IFL shows no improvement over FL in terms of either OS (p=0.88) or FFS (p=0.84) Futility boundaries for both of these endpoints have been exceeded. Toxicities are shown in the table. 18 deaths occurred on the IFL arm during treatment vs. 6 deaths on the FL arm (p=0.008). Conclusions: In stage III colon cancer, IFL, as compared to FL, is associated with a greater degree of neutropenia, neutropenic fever, and death on treatment, with no associated clinical benefit. Weekly bolus IFL should not be used in the management of stage III colon cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pfizer Pfizer; Roche
Phase I study of gefitinib in combination with oxaliplatin and weekly 5-FU/FA (FUFOX) for second-/third-line treatment in patients (pts) with metastatic colorectal cancer (CRC)
Authors: J. T. Hartmann, H. Kroening, C. Bokemeyer, M. Holtmann, H.-J. Schmoll, L. Kanz, C. G. Gahlemann, T. Hoehler
Journal: Journal of Clinical Oncology (2005)

3154 Background: Gefitinib (IRESSA) is an orally active epidermal growth factor receptor tyrosine kinase inhibitor with antitumor activity approved for the treatment of advanced NSCLC. This dose-finding phase I study investigated the safety and tolerability of gefitinib in combination with weekly FUFOX (5-fluorouracil [5-FU], folinic acid [FA; 500 mg/m2], and oxaliplatin [50 mg/m2]) in pts with metastatic CRC who had previously received CPT-11and 5-FU/FA. Methods: 4 dose levels (L) were tested: L1 and L2, gefitinib 250 mg/day and FUFOX with 5-FU at 1.6 and 2 g/m2, respectively; L3 and L4, gefitinib 500 mg/day and FUFOX with 5-FU at 1.6 and 2 g/m2, respectively. Each cycle lasted 5 weeks: gefitinib was applied daily and FUFOX on day 1, 8, 15, and 22; cycles were repeated on day 36. Predefined dose-limiting toxicity (DLT) was determined in pts who had completed at least one full cycle. Tumor assessment was performed every 3 cycles using RECIST. Results: 18 pts were enrolled: median age, 65 years (range, 45–77); m/f, 13/5; 1 pt was excluded due to screening failure. No DLTs were observed at L1-L3. At L4 (n=7), diarrhea was the major DLT requiring treatment interruption in 3 pts; diarrhea resolved in 1 pt following treatment and was not considered a DLT. Numbers of pts experiencing adverse events (NCI-CTC) during the first treatment cycle are listed below. Clinical benefit was seen in 9/17 pts (53%; 4 partial response [24%], 5 stable disease [29%]). Median time to progression was 413 days (range, 63–446), and survival was not reached; 1-yr survival rate was 67% (CI 95% [35–98]). Conclusion: Gefitinib in a dose of 250 mg daily in combination with weekly 5-FU at 2 g/m2 and oxaliplatin (50 mg/m2) has an acceptable safety profile and appears to be an actice regimen in metastatic CRC. IRESSA is a trademark of the AstraZeneca group of companies. No significant financial relationships to disclose.
166. OncoVEX: A Family of Oncolytic Herpes Simplex Viruses Optimised for Therapeutic Use
Authors: Robert S. Coffin, Binlei Liu, Han Ziqun, Magdalena Assenberg, Suzanne Thomas, Jennifer Hu, Guy Simpson
Journal: Molecular Therapy (2006)

HSV in which the neurovirulence factor ICP34.5 is inactivated directs tumour selective cell lysis and has proven safe in the Phase I clinical studies conducted so far. To produce oncolytic HSV with enhanced anti-tumour properties, we have deleted ICP34.5 from a clinical isolate of HSV-1, which enhances the tumour cell killing capabilities of the virus, and also deleted ICP47 (which blocks antigen presentation in HSV infected cells) and inserted the gene encoding GM-CSF. This aimed to maximize anti-tumour immune responses following intra-tumoural injection and provide an in situ, patient- specific, anti-tumour vaccine, combined with oncolysis. In vivo, both injected and non-injected tumours could be cured with this virus and animals were then protected against further tumour cell challenge. Following this promising data a Phase I clinical trial with the virus (OncoVEXGM-CSF) was conducted including patients with cutaneous or sub-cutaneous deposits of a number of tumour types (Lead Investigator: Professor Charles Coombes, Hammersmith Hospital, London). This demonstrated the virus to have a good safety profile, the main side effects observed being 'flu-like symptoms, similar to those which have previously been observed with other oncolytic products and cancer vaccines, combined with evidence of biological activity including virus replication and GM- CSF expression. In addition inflammation, tumour flattening and necrosis was observed in injected lesions which was in some cases considerable and which was also in some cases observed in lesions which had not themselves been injected. In all cases where necrosis was observed in biopsy material, this correlated with areas of staining for HSV, suggesting the virus had caused the effect. Following this promising data, preparation for Phase II studies is underway. In addition to OncoVEXGM-CSF, further versions of the OncoVEX virus expressing other active genes have been constructed and tested in pre-clinical models. These include a virus expressing TNF∝, intended to be synergistic with radiotherapy, and versions of the virus expressing a pro-drug activating gene combined with the delivery of a fusogenic glycoprotein designed to maximize the properties of the virus for local tumour control. Each of these have shown promising results in pre-clinical tumour models, including in combination with chemotherapy and radiotherapy where benefits which are at least additive have been demonstrated.
Progression-free and overall survival analysis in patients with metastatic melanoma undergoing first- versus second-line therapy
Authors: J. B. Allred, V. Suman
Journal: Journal of Clinical Oncology (2009)

9078 Background: A frequently discussed topic at meetings of oncologists is the question of expected clinical outcomes for patients with metastatic melanoma undergoing 1 st vs 2 nd line systemic therapy. Differing outcomes in these two patient populations could affect interpretation of non-randomized clinical trials involving both patient populations. Some have suggested superior clinical outcome in patients undergoing 2 nd line therapy. As there is little data addressing this issue, we sought to answer the question by comparing the clinical outcomes of patients with metastatic melanoma treated on 1 st vs 2 nd line therapy across clinical trials conducted at our institution. Methods: Data were collected from 10 phase II clinical trials for patients with stage IV melanoma for which Mayo Clinic was the data center. The 10 trials included three categories of treatments: cytotoxic chemotherapy (4), cancer vaccines (4), and biologic agents (2). In all studies, eligibility criteria required: stage IV melanoma, life expectancy &gt;3 months, reasonable hematology and serum chemistry laboratory results, and an ECOG performance status of ≤2. Cox proportional hazards models were fit to assess the relationship between patients' “therapy” status (1 st vs 2 nd line) and time to events, both overall survival (OS) and progression free survival (PFS), for each treatment category. Results: We identified 318 unique eligible patients across 10 trials. Removed from the analysis were 55 patients (ocular melanoma and/or metastases involving the central nervous system) leaving 263. Cox proportional hazards results demonstrated no differences in PFS or OS for 1 st vs 2 nd line patients for either “chemotherapy” or “vaccine” treatment regimens. However, patient treated on “biologic” trials as 1 st line therapy appeared to demonstrate a PFS advantage over 2 nd line treatments (HR=1.98, p-value=0.02). There was a suggestion of an OS benefit for 1 st line patients in this category, however, the relationship was not significant (HR=1.77, p=0.07). Conclusions: The presented data suggest that there is no PFS/OS difference in stage IV melanoma patients receiving 1st vs 2nd line therapy (no PFS/OS advantage to patients treated in 2 nd line vs. 1 st line). No significant financial relationships to disclose.
Do ACE-I protect against the development of doxorubicin cardiac toxicity?
Authors: A. Blaes, B. A. Peterson, D. Yee, B. Virnig
Journal: Journal of Clinical Oncology (2009)

6623 Background: Doxorubicin (DOX), an anthracycline, has been associated with irreversible cardiotoxicity. Recently, newer agents such as angiotensin converting enzyme (ACE-I) inhibitors have been used in small trials to prevent cardiac toxicity in patients receiving DOX. This retrospective study analyzes whether ACE-I and other medications are protective in the development of DOX cardiomyopathy. Methods: Patients receiving DOX chemotherapy at the University of Minnesota Cancer Center who had two or more multigated blood pool imaging (MUGA) scan or echocardiograms performed were identified and reviewed. Patients who had at least a 10% drop in their ejection fraction (EF) to below the lower limits of normal (50%) or had an absolute decrease in EF of 15% or greater were identified and compared with those that did not have a decline in EF. Patient variables and the use of concurrent medications were compared between these two groups using logistic regression. Results: 350 patients received DOX chemotherapy between November 2004 and 2007. Of 142 patients who had two or more MUGA scans performed during the course of their therapy, 22 (15%) had a significant drop in EF. Median age was 52 years old (range 7–88). 85 (60%) were female. Cancer diagnosis was breast (n = 26), lymphoma (n = 92), and other (n = 25). The median baseline EF of all patients was similar (62% versus 63%). A stepwise variable selection retained two predictors significant at alpha = 0.1 in a logistic regression model: Age and ACE-I (p = 0.0252 and p = 0.0940, respectively). Adjusting for Age, the odds ratio for ACE-I is 0.267, suggesting that ACE-I has a protective effect, as it reduces the probability of a drop in EF. Cumulative DOX dose, obesity, hypertension, and history of tobacco use did not appear to be associated with a decline in ejection fraction. The use of beta-blockers, aspirin or statins did not appear to be associated with a decline in ejection fraction. Conclusions: DOX chemotherapy has been associated with the development of cardiomyopathies. While this is an observational study that is limited by its retrospective nature, the study supports our hypothesis that the use of ACE-I is possibly protective when given with DOX chemotherapy and warrants further investigation. No significant financial relationships to disclose.
Epidemiology of lung cancer in India: Is there a change in trends here too?
Authors: V. Noronha, N. V. Raut, K. Prabhash, J. Agarwal, C. Pramesh, R. Dikshit, G. Karimundackal, A. Munshi, N. Purandare, R. Singh
Journal: Journal of Clinical Oncology (2010)

e12028 Background: The worldwide resurgence of interest in the epidemiology of lung cancer is due to the changing histological spectrum, global increase in non smokers, females and the introduction of targeted therapy. We set to study the epidemiological patterns of lung cancer in India and attempt to identify risk factors contributing to it. Methods: All patients presenting to the department of thoracic oncology were interviewed with the help of a carefully designed questionnaire and data entered in SPSS. Results: Of 489 patients there were 255 smokers and 234 smokers. The median age was 56 years. The male is to female ratio was 3.5:1..133 patients had consumed smokeless tobacco with same frequency of use in both the sexes.90 patients had co morbidities of which diabetes (9.2%), hypertension (6.3%) and heart disease (1.4%) were most common. 54 patients (11%)had been treated for tuberculosis in the past while 69 patients (14.1%) were on antitubercular treatment which delayed the diagnosis of lung cancer by 4 months. The most common histology was adenocarcinoma (38.4%) followed by squamous cell carcinoma (22.9%), small cell ca (7.6%), and large cell ca (1.8%).Our hypothesis that the place of residence would influence the smoking patterns and hence the location of the primary tumour was proven to be false. Most patients (43%) were in stage III at presentation and the least were in stage I /II. Lung followed by bone was by far the most common site of metastasis. Majority (almost half) received chemotherapy with palliative intent .Among definitive therapy concurrent chemo radiation (11-15%) was more offered than surgery (6%).There were 10% patients who received neoadjuvant chemotherapy. 2.3% were offered symptomatic care. Conclusions: The global trend of rise in adenocarcinoma is paralleled in India however the increase of lung cancer in non-smokers is alarming. Non-tobacco-related risk factors need further investigation .The changing epidemiological trends warrant special attention especially when viewed in relation to the amount of funding dedicated to the therapy of lung cancer. No significant financial relationships to disclose.
Primary endocrine therapy for advanced breast cancer: To start with tamoxifen or with medroxyprogesterone acetate?
Authors: M. Castiglione-Gertsch, S. Pampallona, M. Varini, F. Cavalli, K. Brunner, H.J. Senn, A. Goldhirsch, U. Metzger
Journal: Annals of Oncology (1993)