tbuckley/cabot-search huggingface dataset:
Impact of relative dose intensity and G-CSF use in the adjuvant treatment of resected colon cancer.
Authors: Daniel Adam Breadner, Frances Whiston, Larry Stitt, Stephen Welch
Journal: Journal of Clinical Oncology (2016)

752 Background: The benefits of adjuvant chemotherapy in stage III colon cancer (CC) are well established. However, the consequences of dose delays and modifications are not well established. Relative dose intensity (RDI) and dose scheduling have been shown to have prognostic significance in a number of cancers. We examine the effect of RDI, dose intensity (DI) and dose delays on disease free survival (DFS) and overall survival (OS) in stage III CC. Furthermore, we investigate the role of G-CSF in CC and its role in preserving RDI, and its effect on outcomes. Methods: A retrospective review was conducted for patients with stage III CC seen at a Canadian academic cancer center between 2006 and 2011. Patients who received at least three cycles of FOLFOX or at least two cycles capecitabine were included in the analysis. The RDI and DI were calculated and examined for correlation with DFS and OS. The influence of G-CSF on RDI and DI was also investigated. Results: FOLFOX was used more commonly than capecitabine, 64% vs. 36%. Within the FOLFOX regimen median RDI for oxaliplatin was 76.3%, and 83.5% for 5-FU. Median capecitabine RDI was 73.8%. Median DI were similar at 75.4%, 86.5%, and 69.1%, respectively. 60% of patients receiving FOLFOX got over 80% of their intended dose, while only 29% of patients receiving capecitabine achieved this DI. 3-year DFS was higher when RDI or DI was &gt; 80%, compared to ≤ 80%, for each chemotherapeutic, however the differences did not reach significance. 3-year OS trended towards being higher in patients with an RDI and DI &gt; than 80%, however there were limited events in these groups. Over half of patients on FOLFOX experienced a dose delay, 56.9%, most of whom then received G-CSF, 64.9%. Patients who received G-CSF had a higher DI than those who did not, 74.9% and 87.4% versus 66.5% and 76.8%, for the oxaliplatin and 5-FU components, respectively. 3-year DFS and OS was higher in patients who received G-CSF versus those who did not, 78.3% and 97.5% vs. 69.8% and 91.5%, respectively. Conclusions: In patients with stage III colon cancer an RDI or DI is associated with improved 3-year DFS and OS, although the difference did not reach significance in our review. G-CSF as secondary prophylaxis improves RDI, DI, DFS and OS.
The phase II study of efficacy and safety of oxaliplatin with doxorubicin in recurrent ovarian cancer (OC).
Authors: I. Pokataev, G. M. Manikhas, V. Borisov, M. Stenina, A. Tjulandina, S. Tjulandin
Journal: Journal of Clinical Oncology (2011)

5087 Background: There is no current standard of salvage chemotherapy in recurrent OC. Oxaliplatin is an effective third generation platinum compound which has no complete cross-resistance with carboplatin or cisplatin in OC. The purpose of our study was to assess efficacy and tolerability of combination of oxaliplatin and doxorubicin in second-line chemotherapy of OC. Methods: In case of disease progression following first-line chemotherapy pts received second-line chemotherapy with oxaliplatin 130 mg/m2 and doxorubicin 50 mg/m2 q3w. Time to progression (TTP) was chosen as the primary end-point. Three investigator centers participated in the study. Results: Totally 29 pts were included in this study. Tumors were platinum-sensitive (PFI>12 m) in 5 (17.2%), partially platinum-sensitive (PFI>6 m) in 12 (41.4%), platinum-resistant (PFI<6 m) in 11 (38.0%) cases, in 1 (3.4%) case sensitivity of tumor to platinum was not known. Objective response rate was 55.1% (24.1% complete remissions and 31.0% partial remissions). The median TTP was 10.7 m. With the median f.-up of 14.8 m the median overall survival was not reached. 1-year overall survival was 89%. There were no statistically significant differences in response rate and TTP between platinum-sensitive and platinum-resistant cancers (p>0.05). The median number of cycles was 5 (range 2-6). Toxicity grade 3-4 per cycle included neutropenia 14.6%, febrile neutropenia 0.7%, thrombocytopenia 5.1%. Sensory neuropathy grade 1-2 and 3 was observed in 8 (27.6%) and 2 (1.4%) cases respectively. There were 5 cases of oxaliplatin dose reductions and 10 cases of doxorubicin dose reductions; 10 cycles of chemotherapy were delayed due to toxicity. Conclusions: The combination of oxaliplatin and doxorubicin showed promising efficacy in either platinum-sensitive or platinum-resistant recurrent OC. Tolerability of this regimen was acceptable.
Neoadjuvant interferon-based chemoradiation for locally advanced pancreas cancer: A phase II pilot study.
Authors: Eric Hans Jensen, Leonard Armstrong, Todd M. Tuttle, Selwyn M. Vickers, Timothy D. Sielaff, Edward Greeno
Journal: Journal of Clinical Oncology (2012)

266 Background: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with locally advanced pancreas cancer. We evaluated the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. Methods: We performed a phase II pilot study treating patients with locally advanced pancreas cancer, including borderline resectable and initially non-resectable cases. Patients with evidence of metastases, previous chemotherapy, ECOG performance status &gt;1, or inadequate hematologic, renal or hepatic function were excluded. Results: We enrolled 23 patients between 1/2005 and 10/2010. Mean age at enrollment was 58.6 years. Males made up 73.4% of the cohort. Of 23 patients, 7 (30.4%) completed all treatments. The remaining 16 (69.6%) patients did not receive all scheduled treatments due to severe side effects (n=7, 30.4%), progressive disease (n=3, 13%), alternative treatment (n=3, 13%), patient withdrawal (n=1, 4.3%), other disease (n=1, 4.3%), and death on study (n=1, 4.3%). Hospitalization was required due to toxicity for 47.8% (n=11) of patients. The most commonly reported grade 3 or 4 toxicities were leucopenia/cytopenia (n=19, 82.6%) and gastrointestinal (n=19, 82.6%). Other toxicities were much less common (fatigue, weight loss, pain, skin rash, all n&lt;3). Tumor regression was not seen in any patient. Surgical resection was ultimately successful in 7 (30.4%) cases. Surgical margins were negative in 6 of 7 cases (85.7%). The mean lymph node count was 11. Positive lymph nodes were identified in 3 of 7 cases (42.8%). Overall survival for all patients was 11.5 months. Surgical resection provided significantly improved survival (22.6 months) compared to CRT alone (8.8 months). Disease free survival in resected patients was 17.2 months. Conclusions: Aggressive neoadjuvant CRT with immunotherapy may allow for resection of initially non-resectable, locally advanced pancreas cancer, but with significant toxicity. Overall survival was similar to other, less toxic regimens. In the absence of surgical resection, survival remains dismal.
Evaluation of esophageal carcinoma for a radioresistant subpopulation with cancer stem cell characteristics.
Authors: J. K. Smit, M. Niemantsverdriet, R. P. van Os, H. Hollema, J. T. Plukker, R. P. Coppes
Journal: Journal of Clinical Oncology (2011)

36 Background: Neo-adjuvant chemoradiation is considered as standard treatment in esophageal cancer (EC). However, a significant proportion of these tumors do not respond well to radiotherapy. Here, we investigated the presence of radioresistant cells in EC with cancer stem cell characteristics. Methods: EC OE-33 adenotype and OE-21 squamous cell carcinoma cell-lines and fresh tumor material of EC patients were analyzed for common CSC-markers with Fluorecence Activated Cell Sorting (FACS) and immunohistochemistry. Subpopulations were tested for clonogenic survival to determine radioresistance. Non-adherent 3D sphere-cultures and xenograft tumors generated in NOD/SCID mice were performed to investigate stem cell properties. Results: Both cell lines lacked expression of CD133 and CD90, whereas the expression of EpCam overlapped with CD44 in OE-33. In sub-confluent cultures the expression of CD44+/CD24- was 5.6% SD ± 2.3 and 35.1% SD ± 1.3 in OE-33 and OE-21, respectively. In a clonogenic survival assay the CD44+/CD24- cells showed up to a 2-fold lower radiosensitivity compared to CD44+/CD24+ cells in both the OE-33 (p = 0.02) and the OE-21 cell line (p = 0.01). The CD44+/CD24- subpopulation had a 2.2-fold higher sphere-forming capacity compared to the CD44+/CD24+ subset (p = 0.01) in OE-33. Analysis of the spheres showed an enrichment in the CD44+/CD24- phenotype from 5.6% to 56.4% (p = 0.01) after 4 days of culturing as measured by FACS, but differentiated to a higher percentage of CD44+/CD24+ in time. Furthermore, CD44+/CD24- cells exhibited a greater in vivo tumor initiating capacity, shorter latency time and faster growth speed compared with unsorted or CD44+/CD24+ cells. Importantly, a clear CD44+/CD24- population could be identified in fresh EC biopsies of patients. Conclusions: EC appear to contain a radioresistant CD44+/CD24- subpopulation. This phenotype displays some CSC characteristics in vitro and in vivo and is present in human EC tumors. This marker could be used in future trials to predict tumor response. No significant financial relationships to disclose.
External beam radiotherapy and concurrent gemcitabine for muscle-invasive bladder cancer: Toxicities and early outcomes.
Authors: Elana Nack, Jonathan E. Rosenberg, Bernard H. Bochner, Guido Dalbagni, Michael J. Zelefsky, Marisa Kollmeier
Journal: Journal of Clinical Oncology (2016)

443 Background: To report toxicities and early outcomes of external beam radiotherapy (EBRT) with concurrent gemcitabine for muscle-invasive bladder cancer (MIBC) Methods: Between 9/04 - 4/15, 85 patients (median age 77) with MIBC (cT2-T4, Nx-3) underwent transurethral resection (TUR) (39 complete, 43 incomplete, 2 unknown) followed by EBRT (median dose 64.8Gy) with concurrent gemcitabine (20-27 mg/m 2 ) twice weekly. 25 patients (29%) received neoadjuvant chemotherapy. Patients were followed q3 months with imaging, cystoscopy and/or cytology. Early ( &lt; 90 days) and late ( &gt; 90 days) toxicities were graded according to the Common Terminology Criteria for Adverse Events (v4.0). Median followup was 19.5 months; 74 (87%) had &gt; 3 month followup. Kaplan-Meier and Cox regression were used for survival and multivariate analyses. Results: Acute grade ≥ 3 hematologic, gastrointestinal or genitourinary toxicity occurred in 18%, 1.5% and 1.3% of patients, respectively. 73/85 (86%) patients received full EBRT course without interruption. 78/85 (92%) received &gt; 50% of the prescribed gemcitabine. The most common reason for a gemcitabine interruption/dose reduction was hematologic (80%). Late grade 3 toxicity included hematuria (n = 5), urinary obstruction (n = 4) and cystitis (n = 1). The 2-year freedom from in-bladder recurrence and bladder-intact survival was 53% and 60%, respectively. The 2-year distant metastasis-free, disease-specific and overall survivals were 66%, 69% and 62%, respectively. A complete TUR was associated with improvements in 2 year bladder-intact (73% vs 51%, p = 0.01), disease-specific (87% vs 54%, p = 0.001), distant metastasis-free (83% vs 52%, p &lt; 0.0001) and overall survival (78% vs 50%, p = 0.003) compared with incomplete TUR. Neoadjuvant chemotherapy and nodal status had no significant impact on survival outcomes. Conclusions: EBRT with concurrent gemcitabine is well-tolerated for MIBC, even in an elderly population. Hematologic (acute) and genitourinary (late) toxicities are most common. Survival outcomes in this unselected population are comparable to prior trials, although longer followup is needed. A complete TUR prior to chemoradiation is strongly recommended.
Patient identification and tracking for chemotherapy delivery: Use of RFID or barcode technologies for automated self check-in.
Authors: Matthew C. Cheung, Maureen E. Trudeau, Ben De Mendonca, Kathy Beattie, Philomena Sousa, Simron Singh
Journal: Journal of Clinical Oncology (2012)

316 Background: The Odette Cancer Centre (OCC) is the sixth largest cancer institution in North America and manages over 24,000 chemotherapy patient visits/year. We initiated an automated kiosk system whereby patients can “actively” self-check-in to the chemotherapy unit as part of a quality initiative to improve one of the most complex processes in patient care. Methods: From January-May 2012, consecutive patients receiving &gt;2 cycles of chemotherapy were randomly assigned to either radio-frequency identification (RFID) or barcode technologies to facilitate self check-in and time-in-motion studies. In parallel, the former manual check-in system (with OCC staff) continued. The primary outcome was the proportion of patients with more 3 or more scheduled appointments who used the self-check system at least 2 times. Patient satisfaction was attained with baseline and post-study surveys. Results: The study accrued 81 patients (43 patients using RFID and 38 patients using barcodes). Mean age was 59 (20-81 years). Of 48 patients who completed baseline surveys, most had regular access to a computer (87.5%) and used the internet at least &gt;1 hour/day (50%). However, 21% at baseline felt a person-to-person check-in was preferable to an automated option. With implementation of the study, 24 of 81 patients (29%) have used the kiosk only once. Of individuals with multiple scheduled appointments (at least 3), 50% assigned to the RFID group and 52.6% assigned to the barcode group used the kiosk at least 2 times (p=0.827; Fisher’s exact). In follow-up, 96.7% of patients agreed or strongly agreed that the kiosks were easy to use although only one-third (33.3%) of patients felt the new system improved the efficiency of care. Conclusions: An automated check-in process is feasible for a diverse population of patients receiving chemotherapy. Multiple uses of the kiosk technology suggest appropriate uptake and retention of the technology. Continued use of the system was not different between RFID and barcode technologies. Patient satisfaction was high despite the lack of improvement in efficiency. The next phase will incorporate patient tracking and real-time status updates to address these concerns.
Effects of cytochrome P450 polymorphisms on tamoxifen metabolism
Authors: M. B. Sawyer, S. Damaraju, E. Pituskin, S. J. Carter, J. Dufour, D. Carandang, J. Hanson, J. R. Mackey
Journal: Journal of Clinical Oncology (2005)

2055 Background: Tamoxifen (TAM) is a cornerstone of the hormonal adjuvant treatment of breast cancer. TAM is metabolized by cytochromes (CYP) P450 to inactive and active metabolites. The CYP P450 that metabolize TAM are polymorphic, and we hypothesized that single nucleotide polymorphisms (SNPs) in the CYPs could predict levels of TAM and its metabolites. Methods: We studied the effects of polymorphisms in CYPs 3A4, 3A5, 2D6, and 2C9 on the concentrations of TAM and its metabolites. 65 pts were genotyped and the concentrations of TAM, 4-hydroxyTAM (4HOTAM), 4-hydroxy N-desmethylTAM (4HODMTAM), N-desmethylTAM (DMTAM) and N-didesmethylTAM (DDMTAM). All patients received TAM 20 mg/day for at least 3 mths to ensure that drug levels had reached steady state. All patients were female and the median age was 55 (39–93). 10 pts were stage I, 42 pts stage II, 5 pts were stage III, and 10 stage IV. Results: The median (range) concentrations of TAM and its metabolites were: TAM 1.95 ug/ml(0.5–5.53), 4-hydroxyTAM .05 ug/ml (0.0–0.15), N-desmethylTAM 2.52 ug/ml (0.91–11.27), 4-hydroxy N-desmethylTAM 0.22 ug/ml(0.05–0.86), and N-didesmethylTAM 0.19 ug/ml(0.05–1.03). For CYP 3A4, pts who were homozygotes for CYP 3A4 1A had higher median concentrations of TAM than pts heterozygotes for CYP 3A4 1B (p=0.05). Pts homozygous for CYP 3A5 1* had higher TAM concentrations than heterozygotes or wild type CYP 3A5 (p=0.02). CYP2D6*4 homozygotes had lower concentrations of N-didesmethylTAM than heterozygotes or wild type (p=0.04) and there was a trend for homozygotes to have lower concentrations of N-desmethylTAM (p=0.07) and 4-hydroxyTAM (p=0.07). Conclusions: CYP 2D6, CYP 3A4 and CYP 3A5 polymorphisms predict concentrations of TAM and its metabolites. The CYP2D6*4 allele warrants study as a genotypic marker of tamoxifen resistance because of its association with low concentrations of the active metabolites N-didesmethylTAM and possibly 4-hydroxyTAM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Concordance between substance P levels and antiemetic guidelines
Authors: G. M. Higa, M. L. Auber, R. Altaha, G. Hobbs
Journal: Journal of Clinical Oncology (2008)

9552 Background: While serotonin is believed to be the major mediator acute emesis, recent evidence suggests substance P (SP) is also involved in the pathogenesis of chemotherapy-induced vomiting. Research data accumulated over 18 months were used to analyze the degree of concordance between SP levels and the current antiemetic practice guidelines which incorporate the use of an NK1 receptor antagonist (RA). Methods: Levels of SP were measured in five blood samples obtained over 72 hours from 17 patients who received cisplatin-based chemotherapy regimens. Cisplatin doses ranged between 20–120 mg/m2. Each patient received a serotonin antagonist plus glucocorticoid; 15 patients also received an NK1 RA. Results: Analyses of the SP data were performed by: 1) phase of emesis; 2) cisplatin dose classified as Hesketh level 5 vs 4; and 3) cisplatin dose criterion utilized in the NK1 clinical trials. The mean change in SP (from baseline) in the acute and delayed phases was +9.1% and +31.5%, respectively. The trend of SP changes over 72 hours was similar regardless if the data were grouped by cisplatin dosages partitioned at 50 mg/m2 or 70 mg/m2. The least square mean changes in SP during the delayed phase were −28% and −25.8%, in patients receiving cisplatin dosages of <50 mg/m2 and <70 mg/m2, respectively. However, the absolute mean change between the acute and delayed phases was two-fold greater with data partitioned at < or ≥70 mg/m2 compared to < or ≥50 mg/m2. Clinically, 15 of the 17 patients had complete control of vomiting. None of the five patients who received <70 mg/m2, including two patients who did not receive the NK1 RA, experienced emesis during the entire study period. Conclusions: Measured levels of substance P: 1) support current practice guidelines related to the addition of an NK1 RA in patients receiving Hesketh level 5 cisplatin-containing regimens; 2) suggest that the likelihood of SP-mediated delayed emesis occurring is low with cisplatin dosages <70 mg/m2; and 3) provide biochemical justification for the cisplatin dosage criterion in clinical trials of the NK1 RA. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck
Reporting of cancer clinical trial adverse drug events: A RADAR report.
Authors: S. M. Belknap, C. H. Georgopoulos, S. A. Weitzman, L. Qualkenbush, A. T. Samaras, J. M. McKoy, B. J. Edwards, S. T. Rosen, D. P. West
Journal: Journal of Clinical Oncology (2011)

6090 Background: The timely identification of unknown toxicities of cancer drugs is an important, unsolved problem. Because of their cytotoxic effects, distinguishing cancer drug toxicity from disease progression or comorbidity can be difficult. Also, because of the need for novel cancer therapies, regulatory approval is typically based on fewer than 3000 patients. The adverse event detection failure rate during cancer clinical trials has not previously been determined and there has been relatively little evaluation of the utility of applying validated methods for ADE abstraction in this setting. Here, we compare routine adverse event reporting to structured case abstraction (SCA) of the research record and medical record. Outcomes of interest included detection, description, severity grading, and causality attribution. Methods: We obtained all adverse event data (2001-2008) reported to the Northwestern University Institutional Review Board (IRB) for all six clinical trials involving bevacizumab or oxaliplatin. We compared routine IRB reports to SCA for ability to detect an adverse event and for utility of assessing causality attribution with the 10-item Naranjo Scale. Results: Of the 205 adverse events found in the research record and medical record, 182 events (75%) were not reported; six of the 30 (20%) events with a severity grade of “severe,” “life-threatening,” or “fatal” and a causality assessment of “possible”, “probable”, or “definite” were unreported. The mean number of Naranjo items for which there was useful information was higher with SCA than with the standard IRB report (6.0 vs. 2.4 items, p<0.0001). Conclusions: One-fifth of “reportable” adverse events were unreported to the IRB via routine adverse event reporting. SCA also provided more useful information as to whether the adverse event was caused by the cancer drug exposure. Our results suggest that SCA has potential to improve adverse event detection and to improve the accuracy of causality attribution during cancer drug clinical trials. Use of SCA may reduce delays in recognition of novel cancer drug safety signals. There is an urgent need to prospectively evaluate use of structured case abstraction during cancer drug clinical trials.
Phase 3 clinical Trial Evaluating <sup>90</sup>y glass microspheres in patients with metastatic colorectal carcinoma of the liver who have failed first-line chemotherapy.
Authors: Maria Angela Karpf
Journal: Journal of Clinical Oncology (2015)

474 Background: Colorectal cancer (CRC) is the third most common cancer in the US. Half of pts diagnosed with CRC develop liver disease. Unresectable liver metastases are responsible for morbidity/mortality. Typically, pts with metastatic CRC receive an oxaliplatin- or irinotecan-based regimen as first -line chemotherapy, +/- bevacizumab. On progression, pts are treated with the regimen they did not receive during first -line chemo. A study to evaluate yttrium 90 glass microspheres (TheraSphere; 90 Y) in pts with unresectable mCRC of the liver showed that pts with good performance status, no extrahepatic metastases, and ≤ 25% tumor may benefit most from 90 Y. 90 Y glass microspheres are approved by FDA under a Humanitarian Device Exemption (HDE). This study will evaluate outcomes in this patient subset when 90 Y is added to second- line SOC chemo. The objective is to evaluate efficacy/safety of 90 Y in patients with liver mCRC that has progressed after first -line chemo. Methods: Open-label, multi-center, randomized study to evaluate 90 Y treatment in ~340 eligible pts, in whom SOC 2 nd -line chemo with either an oxaliplatin or irinotecan-based regimen is planned. Eligible pts will be randomized 1:1 to control or treatment. Treatment pts will receive a first cycle of second-line chemo within 21 days of randomization and at least 14 days after the last dose of first-line agents including VEGF inhibitors. 90 Y will be administered in place of the second chemotherapy cycle. Control pts will receive planned SOC second-line chemo. Primary endpoint is progression-free survival. Secondary: overall survival, hepatic progression-free survival, time to symptomatic progression, tumor response rate, and adverse events. Pts will have regular study visits as long as they participate, at which time safety/efficacy data will be collected and recorded. Results: NA Conclusions: Given the potential benefit to mCRC pts, this Phase 3 study will evaluate 90 Y in the second-line setting in patients who have progressed following SOC first-line chemotherapy. Clinical trial information: NCT01483027.