tbuckley/cabot-search huggingface dataset:
Impact of 1<sup>st</sup> and subsequent cycle pegfilgrastim on neutropenic events in patients receiving myelosuppressive chemotherapy: Preliminary results of FIRST, a prospective community-based study
Authors: H. Ozer, B. Mirtsching, M. Rader, B. Ding, R. Dansey
Journal: Journal of Clinical Oncology (2005)

8118 Background: Most alterations to chemotherapy (CT) dose and schedule are due to neutropenic events, which mostly occur in the 1st cycle. The ANC registry study has prospectively documented 1st cycle febrile neutropenia (FN) of 8% in patients (pts) receiving CT with usual community CSF support. In addition to FN, dose reductions and delays may be prevented with 1st cycle use of pegfilgrastim (Neulasta). A large, prospective study has been initiated in cancer pts receiving myelosuppressive CT to evaluate the impact of 1st and subsequent cycle pegfilgrastim on neutropenic events. Methods: This open-label, single-arm study is being conducted at 387 sites, with an expected enrollment of ∼2300 pts by Dec 2004. Pts ≥18 yrs with cancers other than leukemia or MDS are eligible, including pts with major co-morbid illnesses who are not generally eligible for clinical trials. Key exclusions are weekly CT and concurrent radiotherapy (RT). Pts receive pegfilgrastim 6 mg ∼24 hours post-CT in each cycle. Endpoints include neutropenic complications and CT dose reductions and delays. Point estimates and 95% CL are provided. Results: 1st cycle data from 200 pts at 77 sites are shown. 80.5% of pts were women and most had breast cancer (60.5%) followed by lymphoma (12%), lung (9.5%), and other malignancies (18%). The mean (SD) age was 57.8 (12.0). 51% of pts had early stage (I-II) disease, 22% received prior CT, 14% received prior RT, and 19% had significant co-morbidities. Reported serious adverse events were consistent with those observed in pts receiving myelosuppressive CT. Conclusions: Pts treated in community practice receiving pegfilgrastim in first and subsequent cycles of myelosuppressive CT experience a low incidence of neutropenic complications and alterations in CT dose and schedule. Data on an additional 700 pts will be available. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen, Aventis, Bristol-Myers Squibb, Genentech Amgen, Antigenics, AstraZeneca, Bristol-Myers Squibb, EXAMIAS, Genentech, Genta, GlaxoSmithKline, Novartis, Telik, Threshold, Wyeth
Axitinib versus sorafenib as first‑line therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Thomas E. Hutson, Jorge Gallardo, Vladmir Lesovoy, Salman Al-Shukri, Viktor Stus, A. H. Bair, Brad Rosbrook, Paul W. Bycott, Jamal Christo Tarazi, Sinil Kim, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2013)

LBA348 Background: In the phase III AXIS trial, second-line therapy with axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib for mRCC. We conducted a multicenter, randomized, open-label, phase III trial to compare PFS of axitinib vs sorafenib as first-line therapy. Methods: Patients with untreated, measurable (RECIST v1.0), clear‑cell mRCC and Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomized 2:1 to axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. Randomization was stratified by PS. Primary endpoint was PFS per independent radiology committee. The study had 90% power to detect a 78% PFS improvement from 5.5 mo with sorafenib to 9.8 mo with axitinib, corresponding to a hazard ratio (HR) of 0.561 (overall 1-sided α=0.025). Results: Patients (N=288) were mainly from Eastern Europe (51%), Asia (25%), North America (14%), or South America (10%).Patient baseline characteristics for axitinib (n=192) vs sorafenib (n=96) included: median age, 58y vs 58y; male, 70% vs 77%; white, 71% vs 69%; favorable risk, 49% vs 55%; PS 0, 57% vs 57%; nephrectomy, 85% vs 90%. Median (m) PFS was 10.1 vs 6.5 mo with axitinib vs sorafenib (HR adjusted for PS, 0.767; 95% confidence interval [CI], 0.559–1.053; 1‑sided P=0.0377). In patients with PS 0 and 1, respectively, mPFS with axitinib vs sorafenib was 13.7 vs 6.6 mo (HR, 0.644; 95% CI, 0.419–0.991; 1‑sided P=0.022) and 6.5 vs 6.4 mo (HR, 0.931; 95% CI, 0.585–1.482; 1‑sided P=0.38). Objective response rates (ORRs) with axitinib vs sorafenib were 32.3% vs 14.6% (1‑sided P=0.0006 adjusted for PS). Overall survival data were not mature. All-grade all‑causality adverse events (≥20%) with axitinib vs sorafenib were diarrhea (50% vs 40%), hypertension (49% vs 29%), weight decreased (37% vs 24%), fatigue (33% vs 26%), decreased appetite (29% vs 19%), palmar-plantar erythrodysesthesia (26% vs 39%), dysphonia (23% vs 10%), asthenia (21% vs 16%), and hypothyroidism (21% vs 7%). Conclusions: The study did not achieve its primary endpoint statistically, but axitinib demonstrated numerically longer mPFS and significantly higher ORR vs sorafenib, with an acceptable safety profile, as first-line therapy for mRCC. Clinical trial information: NCT00920816.
Comprehensive analysis of potential predictive biomarkers for insulin-like growth factor type-1 receptor (IGF-1R) targeted therapy in pancreatic cancer.
Authors: R. T. Shroff, M. M. Javle, D. Li, R. A. Wolff, D. J. Mauro, G. Naumov, M. Nebozhyn, T. Zhang, Y. Li, S. Sathyanarayanan
Journal: Journal of Clinical Oncology (2011)

4052 Background: IGF-1R pathway activation is associated with an adverse prognosis in GI cancers. Preliminary data from a phase I/II study of the IGF-1R antibody, MK-0646 with gemcitabine and erlotinib for advanced pancreatic cancer (APC) indicate sustained responses in a subset of patients (pts). The identification of predictive markers will allow treatment personalization with IGF-1R inhibitors for APC pts. Methods: Study A - Preclinical: gene expression profiling using Affymetrix microarray for IGF-1R pathway genes was conducted in 242 resected pancreatic cancers. Sensitivity to anti-IGF-1R therapy was assessed in a panel of 20 pancreatic cancer cell lines. Xenografts were performed using BxPC3 cells implanted subcutaneously and treated with MK-0646. Study A - Clinical: in the phase I/II study of 58 pts with APC treated with MK-0646, the following biomarker analyses were performed:i) DNA was extracted from blood samples of 35 pts with APC treated with MK-0646 and analyzed for 5 IGF-1R-related single nucleotide polymorphisms (SNPs) previously described by our group via the Sequenom method. ii) IGF-1R protein expression was measured by IHC (Novus Biologicals, Littleton, CO) in tissue from 23 pts. Scoring was based on intensity of staining and extent of cells stained. A positive score was > 3. Results: Study A: IGF-1 and IGF-2 overexpression was seen in 30% of resected tumors; IGF-1 and IGFBP5 were co-expressed. IGF-1R level was associated with increased sensitivity to anti-IGF-1R therapy in vitro. Xenograft studies confirmed the activity of MK-0646 in an IGF-1R expressing pancreatic tumor model. Study B: Analyses from the study with MK-0646 in APC: i) SNP analysis showed that 15% of pts treated with MK-0646 had an IRS1 gene variation, most of whom (66.7%) progressed (p=0.253). ii) 70% of available tumors were positive for IGF-1R tissue expression. Of this group, 80% of pts with disease control (PR+SD) were positive for IGF-1R expression. In comparison, 50% of pts with PD had IGF-1R positivity (p=0.182). Conclusions: Preliminary data suggest promising predictive biomarkers for IGF-1R-targeted therapy in APC. These need to be confirmed in a larger population.
Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.
Authors: Toni K. Choueiri, Youjin Je, Guru Sonpavde, Matt D. Galsky, Marina Kaymakcalan, Paul Linh Nguyen, Fabio Schutz, Daniel Yick Chin Heng, Christopher J. Richards
Journal: Journal of Clinical Oncology (2013)

347 Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.
An exploratory analysis of cisplatin-induced nephrotoxicity and ototoxicity in cancer patients with solid tumors.
Authors: S. Subongkot
Journal: Journal of Clinical Oncology (2010)

e19683 Background: Cancer is a major health-related problem for many worldwide. From 1999 to 2009, the incidence of mortality by cancer has been increasing in Thailand. At present, cisplatin is one of the most widely used chemotherapeutic agents for the treatment of numerous malignancies. The efficacy of cisplatin is dose dependent, but the significant risk of toxicities frequently put off the use of higher doses. Several reports have demonstrated that most patients receiving cisplatin for prolonged treatment or on high doses will develop nephrotoxicity and ototoxicty. Methods: A retrospective design exploratory study aiming to determine the incidence, cumulative dose and onset of cisplatin induced nephrotoxicity and ototoxicity. The data was collected from cancer patients who received cisplatin at ward 5E in Srinagarind hospital, Thailand during 2003-2006. Data was validated by utilizing a standard collecting form and standard operating procedure for data collection was created. Common toxicity criteria (CTC) version 2.0 for assessing toxicity was used to categorize toxicities and naranjo's algorithm was used to assess the possibility of toxicity caused by cisplatin. Results: 131 eligible patients were recruited. The results showed that the incidence of nephrotoxicity and ototoxicity were 6.9% and 4.6% respectively. Cumulative dose was 420.9 mg/m2 and 211.4 mg/m2 respectively. The onsets of both toxicities were seen within 179.2 and 72.3 days after initiation of cisplatin therapy respectively. Conclusions: The information abstracted from this analysis will provide critical evidence to optimal therapeutic effect cisplatin while minimizing cisplatin-induced toxicities by actively monitoring the cumulative doses and onset of such adverse effects. No significant financial relationships to disclose.
Pathological heterogeneity after trastuzumab and combination chemotherapy in HER2+ gastroesophageal adenocarcinoma xenograft.
Authors: Connie Yip, Amanda Weeks, Gary J. R. Cook, Karen Shaw, Muhammad Siddique, David B. Landau, Vicky Goh
Journal: Journal of Clinical Oncology (2016)

42 Background: Trastuzumab (T) is the standard of care in advanced HER2+ gastroesophageal (GE) adenocarcinoma with response in 47% of patients. We evaluated its pathological effects in a HER2+ OE19 xenograft model aiming to improve future treatment intensification/response assessment. Methods: SCID mice (n = 23) bearing subcutaneous OE19 tumors were treated with intraperitoneal saline (control), Cisplatin 4mg/kg once a week (C), Trastuzumab 20mg/kg twice a week (T) or Cisplatin and Trastuzumab (CT) for 2 weeks. Volumetric tumor response was measured by MRI. Excised tumors were stained for IHC markers of hypoxia (Pimonidazole), proliferation (Ki-67) and angiogenesis (CD34). Hypoxic (HF) and proliferative fractions (PF) were defined as the ratios of tumor area positively stained for Pimonidazole/Ki-67 to area of whole tumor section. Microvessel density (MVD) was defined as the average number of blood vessels/endothelial cells identified within 0.01cm 2 field at x100 magnification. Pathological assessment was performed for whole tumor, centre and rim. Mean±SD are presented. Kruskal-Wallis test was used to compare HF, PR, MVD and volumetric change between groups; significance at &lt; 0.05. Results: Tumor growth was reduced in CT (+83% from baseline MRI) compared to control (+600%), C (+275%) and T (+129%) groups (p= 0.015). Monotherapy treated tumors had lower HF (C 0.08±0.03, T 0.09±0.07) compared to CT (0.16±0.06) and control (0.15±0.04) (p= 0.039). T and CT treated animals had higher MVD (T 23.5±12.7, CT 37.3±10.3) compared to control (18.1±10.4) and C (18.1±7.5) (p= 0.014). Whole tumor PF was lower in the monotherapy groups but this was not significant (p =0.123). PF and MVD were higher in tumor centre compared to rim in T and CT groups compared to control but there was no spatial difference in hypoxia distribution. Conclusions: Tumor control was improved with combination treatment but no synergistic pathological effect was seen; CT treated tumors were more hypoxic/angiogenic compared to monotherapy with greater cellular density/angiogenesis within tumor centre. This could be due to predominant early cytostatic effect and ongoing angiogenic normalisation with CT therapy at 2 weeks.
Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: Final overall survival analysis of phase II study.
Authors: Lucjan Wyrwicz, Dobromila Tyc-Szczepaniak, Magdalena Mydlowska, Lucyna Pietrzak, Andrzej Rutkowski, Krzysztof Bujko, Wojciech Michalski, Marta Olszyna-Serementa, Jakub Palucki
Journal: Journal of Clinical Oncology (2016)

726 Background: A palliative surgery and chemotherapy is the standard of care in stage IV rectal cancer patients with pelvic symptoms. Recently we published primary results of the single-arm phase II study on combination of short-course radiation (5x5 Gy) with an oxaliplatin-based chemotherapy started after one-week rest (NCT01157806). The study met its primary end-point with only 17.5% (95% CI 13% to 22%) of patients (pts) who needed stoma throughout the observation and 67% (95% CI 58% to 76%) of pts having significant resolution of pelvic symptoms. Here we provide the long-term follow up data after median 60 months of observation. Methods: 40 consecutive patients with symptomatic rectal cancer with unresectable distant metastases were enrolled from September 2009 to February 2011. The time of treatment failure on chemotherapy (TTF3) was measured from the start of radiation to disease progression on fluoropiridine, oxaliplatin and irinotecan. All eligible patients were assessed for KRAS/NRAS status. Due to limitations in access to targeted agents none of patients were treated with anti-angiogenic agents and anti-EGFR treatment was restricted to third line. Results: Total 40 pts were assessed for pelvic symptoms, chemotherapy response and overall survival. In the group of patients with survival reaching over 2 years we have not observed any additional local complications which were treated surgically. The patients with total symptoms’ resolution after one month had significantly longer time-to-treatment failure (TTF3) than non-responders (median 22.5 vs 5 months, p &lt; 0.05), while patients with minor local response had intermediate TTF3. The subgroup of patients who experienced clinical complete response of rectal tumor had a median TTF3 and overall survival reaching median 40 months. Conclusions: In the palliative setting short-course radiotherapy and early chemotherapy allowed for acceptable and durable local control. Metastatic rectal cancer patients with early symptomatic response of primary tumor had significantly better prognosis. Clinical trial information: NCT01157806.
DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma (NSLA).
Authors: J. Han, K. Yoon, Y. Lee, G. Lee, S. Yoon, K. Hwang, T. Yun, H. Kim, J. Lee
Journal: Journal of Clinical Oncology (2010)

7621 Background: DNA repair gene polymorphisms are thought to modulate DNA repair capacity and may affect response and prognosis. We investigated the impact of DNA repair gene polymorphisms on clinical outcome of a first-line study of gefitinib versus gemcitabine plus cisplatin (GP) in NSLA. Methods: Genomic DNA was obtained from 158 patients among 313 NSLA who were randomized to receive gefitinib or GP. RRM1 (2455A>G, 2464G>A, -524C>T, - 37C>A), ERCC1 (8092C>A, 19007T>C), and XRCC1 Arg399Gln were genotyped. Immunohistochemistry for ERCC1 and direct sequencing of EGFR exon 19 and 21 were performed using available tumor samples (n = 38 and 42, respectively). Results: In gefitinib arm (n = 81), higher response rate (RR) was observed in patients with EGFR mutations compared to those with wild type (87% v 11%, p < 0.0001). Patients with XRCC1 Arg399Arg also showed higher RR to gefitinib (71% v 36%, p = 0.002) and were more likely to have EGFR mutations (82% v 29%, p = 0.001) than those with Gln allele. In GP arm (n = 77), higher RR was observed only in patients with ERCC1 negative compared to those with positive (83% v 13%, p = 0.026). When comparing gefitinib versus GP, significantly longer progression-free survival (PFS) was observed with gefitinib than with GP among patients with XRCC1 399 Arg/Arg (7.5 v 6.6 months, p = 0.013), RRM1 2464GG (11.5 v 6.0 months, p = 0.004), and ERCC1 8092CA (7.5 v 6.4 months, p = 0.024). When comparing combinations of variant alleles across these three polymorphisms, significantly longer PFS was observed with gefitinib than with GP among patients with more than two variants (8.1 v 6.4 months, p = 0.009). Whereas, patients without any of them showed a trend for longer PFS with GP compared with gefitinib (6.3 v 2.0 months, p = 0.06). In a multivariate Cox regression model, the presence of more than two variants independently predicted improved overall survival irrespective of treatment (HR = 0.5; 95% CI, 0.3- 0.8; p = 0.006). ERCC1 expression and EGFR mutations were not predictive of survival. Conclusions: Patients harboring XRCC1 399 Arg/Arg, RRM1 2464GG, and ERCC1 8092CA did benefit from gefitinib. The presence of greater number of these variants was found to be an independent favorable prognostic marker for NSLA. No significant financial relationships to disclose.
Assessing changes in tumor size with CT scans in lung cancer: are volumetric measurements better than unidimensional (1D) and bidimensional (2D) assessments?
Authors: M. Pietanza, L. P. James, L. H. Schwartz, M. S. Ginsberg, B. Zhao, C. S. Moskowitz, J. Zheng, N. A. Rizvi, M. G. Kris
Journal: Journal of Clinical Oncology (2008)

14562 Background: Tumor volume measurements may allow a more accurate evaluation of response than conventional 1D (RECIST) or 2D (WHO) methods. We prospectively compared 1D, 2D and volumetric measurements in patients enrolled in two Phase II trials at our institution. Methods: 71 patients received a targeted agent for up to 3 weeks. Lung lesions were assessed with baseline and follow-up standard CT scans. 1D, 2D and volumetric measurements were obtained for primary lesions. Tumor volume calculations were made using a semiautomated algorithm that we developed (Zhao, Radiology 2006). The percentage change of tumor size by 1D, 2D and volume were compared directly. A change cutoff of 20% was selected based on RECIST criteria. McNemar’s test was applied to analyze differences in the percentage change calculated. Results: 45 of 71 (63%) patients had an absolute change in tumor volume of ≥ 20%. Significantly fewer patients had a change in 1D [n=14 (20%), p<0.0001] and 2D [n=28 (39%), p=0.001] measurements of ≥ 20%, when compared to measured volumes. Conclusions: Tumor size changes of ≥ 20% were identified in more patients when volumetric measurements were used rather than RECIST or WHO criteria, indicating that volumetric measurements detect smaller changes in tumor burden than 1D and 2D measurements. Volumetric measurements provide a quicker and likely more accurate assessment of tumor burden and response to therapy, which is needed to improve care and the development of new agents for the treatment of lung cancer. No significant financial relationships to disclose.
Prognostic factors for metastatic colorectal cancer with and without bevacizumab therapy.
Authors: Ikenna Osuorji, Greg Dyson, Durga Yerasuri, Philip Agop Philip, Anthony Frank Shields, Minsig Choi
Journal: Journal of Clinical Oncology (2012)

e14163 Background: Metastatic colorectal disease is generally incurable and treatment is palliative with the intent to balance toxicity with quality of life. Coin 3 trial showed that pre-chemotherapy platelet counts &gt; 400,000 per μL were associated with poor survival when intermittent chemotherapy was used, whereas patients with lower platelet counts did not have any significant difference between the intermittent and continuous chemotherapy arms. Methods: We reviewed retrospectively 775 stage IV colorectal cancer patients at Karmanos Cancer Center over a 10 year period to see if high platelet count was associated with a poor outcome irrespective of treatment. Our analysis included 480 patients with adenocarcinoma who had not received chemotherapy prior to referral, and where information on the baseline platelet count, race, and age was available. We also analyzed the impact of race, age and bevacizumab use. We used Cox regression model for analysis. Results: Among the patients 48.3% were African American (AA) and 51.7% were Caucasians (C). 34.4 % had had PLT &gt; 400,000 per μL. For those with lower platelet counts the median survival was 26.2 months in the C and 14.1 months in the AA groups respectively. Patients with platelet above 400,000 had a median survival of 15.2 months for C and 12.6 months for AA. Cox regression analysis, showed hazard ratios for outcome of death were; 1.16(1.07-1.26) p&lt;0.001 for age (per 10 yrs), 1.60(1.31-1.94) [AA versus C(ref)] p&lt; 0.001 for race and 1.35(1.10-1.65)[&gt;400 versus &lt;] p&lt;0.004 for platelet count. In subset analysis, 296(61.7%) patients who received chemotherapy had data regarding use of bevacizumab (B). Among the 31.7% who received B, the median survival was 25.6 months compared to14.1 months in the no B arm. A Cox regression model using B as a stratification variable showed that the impact of race {hazard ratio = 1.32 (1.02-1.69) p =0.03} and platelet count {hazard ratio = 1.27(0.97-1.65) p =0.08} were much less. Conclusions: Pre-chemotherapy Platelet count&lt; 400,000, C race and younger age are associated with improved survival. Use of bevacizumab may mitigate the impact of these factors.