tbuckley/cabot-search huggingface dataset:
Cisplastin (C) and ifosfamide (I) chemotherapy with vaginal cuff brachytherapy (VCBT) for treatment of uterine carcinosarcoma.
Authors: H. Wang, K. Y. Lin, M. Merl, S. A. Higgins, D. Silasi, A. Santin, M. Azodi, T. Rutherford, P. E. Schwartz, M. M. Abu-Khalaf
Journal: Journal of Clinical Oncology (2010)

5123 Background: Uterine carcinosarcoma is an uncommon and aggressive type of uterine cancer with a poor prognosis. The purpose of this retrospective study is to report the efficacy and tolerability of C and I chemotherapy with VCBT in the treatment of uterine carcinosarcoma at Yale-New Haven Hospital (YNHH). Methods: Patients (pts) diagnosed with uterine carcinosarcoma in years 1996-2008 were identified through the Tumor Board Registry of YNHH. Demographic and clinical data including stage, histology, grade, dose, cycles, need for dose reduction, toxicities, comorbidities, progression-free (PFS) and overall survival (OS) were obtained. Pts received C 40 mg/m2 on day 1 and I 1.2 mg/m2 daily on days 1 to 4 with Mesna every 4 weeks for 6 cycles. High-dose rate intracavitary VCBT was delivered with a vaginal cylinder. A total of 14 Gy was delivered in 2 fractions of 7 Gy each prescribed to a depth of 0.5 cm. The two fractions were administered 2 weeks apart in cycle 1 and 2. Results: A total of 29 pts treated with C and I were identified, and 23 of 29 pts received VCBT. Median age of pts is 65 (range 40-82). Sixteen pts (54.8%) with stage I/II, 8 (27.6%) stage III, and 5 (17.2%) with stage IV disease. Eighteen (62%) pts completed C and I without a dose reduction, 6 required a dose reduction, while 5 required early termination (3 of 5 pts completed < 5 cycles). At median follow up of 19 month (range 6-73), disease progression occurred in 9 pts (31%) and death occurred in 7 pts. With VCBT, no isolated vaginal failures were identified. Documented grade 3 toxicities included neutropenia (17%), anemia (14%), thrombocytopenia (3%), neurotoxicity (7%), fatigue (7%), nausea/vomiting (3%), hematuria (3%), cardiac toxicity (3%) and dyspnea (3%). Two pts (7%) had grade 4 neutropenia. Conclusions: C and I chemotherapy with VCBT represents a well tolerated regimen with promising activity for uterine carcinosarcoma. The addition of VCBT results in excellent local response. No significant financial relationships to disclose.
Influence of concomitant medications on toxicity from chemotherapy in elderly patients. Focus on cytochrome P-450 inhibition and protein binding effects
Authors: K. J. Wallace, A. Cantor, J. Overcash, J. Yoder, P. Vranas, M. Extermann
Journal: Journal of Clinical Oncology (2005)

8025 Background: Of the elderly taking 3 or more chronic medications, 33% are rehospitalized within 6 months from hospital discharge, 20% of them due to medication-related problems. Drug interactions are also relevant to toxicity from chemotherapy. For example, ketoconazole and irinotecan, via p450 inhibition, or oxaliplatin and warfarin, possibly via competition for protein binding. Methods: To assess the impact of polymedication on toxicity from chemotherapy, we analyzed patients 70 and older treated at Moffitt Cancer Center with P450 metabolized chemotherapy. A first analysis using unweighted assessment of p450 interactions did lead to some results approaching significance, and highlighted albumin level as a predictor of non-hematologic toxicity (Extermann et al. Abstr 27. 8th Internat Conf Geriatr Oncol, Rome, Italy, 2003.). We refined our analysis by introducing weighted P450 inhibition/induction effects and assessing the impact of competition for protein binding. We focused on strongly bound drugs, defined as >=50%, 75% or 90%. Two alternate models considered chemotherapy either as a block (B), or as the sum of the individual drugs (S) in it for protein binding. Logistic regression was used to assess correlation with G4 hematologic or G3–4 non-hematologic toxicity. Results: Our present cohort consists of 260 patients. In univariate analysis tumor stage (p=0.045) and albumin level (p=0.005) correlated with non-hematologic toxicity, whereas bone marrow invasion was borderline (p=0.087). In multivariate analysis, only albumin remained significant (p=0.006). For hematologic toxicity, the MAX2 score (p=0.009), and protein interactions at the 50% threshold (S) were significant (p=0.028) in univariate analysis, whereas female sex (p=0.091) and protein interactions at the 75% threshold (S) (p=0.067) were borderline. In multivariate analysis, only the MAX2 score correlated (p=0.011), whereas sex was borderline (p=0.056). Conclusions: Drug distribution factors appear to play an important role in chemotherapy toxicity in the elderly. The role of protein binding in the pharmacokinetics/dynamics of chemotherapy drugs should be further explored. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Genomic alterations of <i>KIT</i> in acral and mucosal melanomas
Authors: M. C. Heinrich, C. Beadling, B. P. Rubin, S. Muller, F. S. Hodi, C. L. Corless
Journal: Journal of Clinical Oncology (2008)

9016 Background: KIT gene mutations have recently been reported in mucosal and acral melanomas. While the KIT inhibitor imatinib is ineffective in the treatment of cutaneous melanoma, we observed a dramatic clinical response in a patient with a rectal melanoma harboring a KIT mutation. We therefore surveyed a series of melanoma subtypes for genomic alterations in KIT, BRAF and NRAS to determine what fraction of tumors might be amenable to kinase inhibitor therapy. Design: DNA from archival melanomas was amplified by PCR and the products were screened by denaturing HPLC for mutations in KIT exons 11, 13, 17; BRAF exon 15; and NRAS exons 1 & 2. Mutations were confirmed by direct sequencing. Immunohistochemistry for CD117 was performed on a subset of cases. KIT copy number was assessed by quantitative PCR assay in some cases. Results: KIT mutations included substitutions in exons 11 (W557R, K558N, V559A/D, L576P) or 17 (Y823D), and size-altering mutations in exon 11 (del 554–559; ins PYDHKWE at E583). Notably, all of these mutations occur in GI stromal tumors and nearly all (except Y823D) are sensitive to imatinib. Among mucosal melanomas, KIT mutations were more common in anorectal/vaginal melanomas (4/8; 50%) than in tumors of the head & neck (3/36; 8.3%). KIT mutations were rare in conjunctival and cutaneous tumors, and absent in choroidal tumors. There was no correlation between CD117 staining and KIT mutation status. There was a trend for KIT-mutant melanomas to have increased copy number (4/8; 50%) compared with KIT wild-type tumors (8/39; 20.5%). Conclusion: Our findings confirm that KIT mutations of the type known to be sensitive to imatinib occur in mucosal and acral melanomas. In addition, a substantial minority of these tumors have increased KIT copy number. NRAS mutations are also common in these tumors and would be predicted to be unresponsive to KIT inhibitor therapy. BRAF mutations are found in acral but not in mucosal melanomas. Genotyping can play an important role in the clinical management of these rare melanomas. Genomic Abnormalities in Melanoma Subtypes KIT mutations BRAF mutations NRAS mutations KIT copy number increase Acral 23% (3/13) 16.7% (2/12) 11.1% (1/9) 27.3% (3/11) Mucosal 15.2% (7/46) 0% (0/47) 26.3% (10/38) 25.0% (10/40) Cutaneous 1.8% (1/57) 30.3% (20/66) 10% (6/60) 9.1% (2/22) Conjunctival 7.7% (1/13) 26.7% (4/15) 0% (0/11) Not done Choroidal 0% (0/60) 0% (0/60) 0% (0/60) 0% (0/5) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Pfizer MolecularMD Novartis, Pfizer Novartis, Pfizer
A prospective phase II study of induction carboplatin and vinorelbine followed by concomitant topotecan and accelerated radiotherapy (RT) in locally advanced non-small cell lung cancer (NSCLC)
Authors: S. H. Patel, M. Ajlouni, R. Chapman, M. Lu, J. Kim, B. Movsas
Journal: Journal of Clinical Oncology (2006)

7146 Background: The key limiting factor in combining chemotherapy with accelerated RT is excessive esophagitis. We investigated the toxicity, response rate, and overall survival (OS) with induction carboplatin and vinorelbine followed by concomitant topotecan and accelerated RT in patients (pts) with locally advanced/unresectable NSCLC. Methods: This was a phase II trial using a two stage study design with a planned sample size of forty pts. Stage IIIA or IIIB NSCLC pts with a KPS &gt; 50 were eligible. Initially, pts received induction carboplatin (AUC 5.5) on days 1, 22 and vinorelbine 25 mg/m 2 on days 1, 8, 22, and 29. During the concurrent chemoRT, pts received IV topotecan 0.5 mg/m 2 on days 43–47, days 57–61, and days 71–75 prior to the morning RT fraction (fx). RT was given in an accelerated fashion at 2 Gy per fx, bid for 5 consecutive days, every other week to a cumulative dose of 60 Gy over a five week period. Results: Thirty-seven pts were accrued of which thirty-five were evaluable. Overall response rate was 71% (14% CR, 57% PR). Six of 35 (17%) pts had stable disease. Four (11%) pts progressed during treatment. At a median f/u of 17.4 months (3–74 mo), the median survival based on Kaplan-Meier estimates, was 18 months. OS at 1, 2, and 3 yrs was 62%, 41%, and 33%, respectively. Actuarial 5-yr OS was 21%. The median time to relapse was 12.2 months (9.1–24.7 mo). Acute RTOG grade 3 or 4 neutropenia, anemia, and thrombocytopenia were 77%, 49%, and 6%, respectively. There were no cases of grade 3 or 4 esophagitis; RTOG grade 3 or 4 pneumonitis occurred in two pts (6%). Conclusions: This combined modality regimen yielded encouraging OS rates with no grade 3/4 esophagitis. Using 4D RT treatment planning, we plan to further evaluate altered fractionation RT and chemotherapy for this group of pts. [Table: see text]
Correlation between thymidylate synthase (TS) genotype, clinical outcome, and TS mRNA expression in subjects treated with oxaliplatin (OX) and capecitabine (Cape)
Authors: J. L. Grem, D. Nguyen, K. Uchida, D. Salonga, K. D. Danenberg, P. V. Danenberg
Journal: Journal of Clinical Oncology (2006)

13073 Background: TS mRNA has a unique tandemly repeated 28-base pair sequence in the 5’ UTR &amp; is polymorphic in the number of this repeat (2 or 3). Homozygosity for the 3-repeat sequence has been associated with increased TS protein content in tumor samples, &amp; decreased likelihood of clinical benefit with TS-directed therapy. This study assessed the possible association of TS genotype with clinical outcome in subjects receiving OX &amp;Cape in an IRB-approved Phase I clinical trial. Methods: Pre-therapy genomic DNA was isolated from peripheral blood mononuclear cells in 88 subjects treated with OX 130 mg/m 2 day 1 &amp; Cape 600–1500 mg/m 2 twice daily days 1–5 &amp; 8–12 every 3-weeks. The number of tandem repeats was determined by the size of the PCR-amplified DNA fragments by staining after 3% agarose gel electrophoresis. The genotype was also compared to TS mRNA expression that was previously determined by quantiitative real-time PCR in microdissected specimens of metastatic tumor tissue. Results: The majority of subjects participating in this trial had colorectal cancer, &amp; most had prior 5-FU &amp; irinotecan (median of 2 prior chemotherapies). The distribution of TS genotypes among 84 informative samples was 2/2, 12%; 2/3, 70%; 3/3, 18%. The objective response rate (CR + PR) according to genotype was 22% (2/2), 21% (2/3) &amp; 13% (3/3). No appreciable difference was seen in the median time to treatment failure (150 vs 156 vs 156 days) or median survival (379 vs 323 vs 332 days) among the 2/2, 2/3 or 3/3 genotype cohorts. There was no significant difference in the distribution of TS intratumoral gene expression according to TS genotype: median (25 th &amp; 75 th percentiles): 2/2, 3.96 (2.93, 5.3); 2/3, 4.11 (2.52, 6.62); &amp; 3/3, 2.66 (1.73, 5.23). Conclusions: In this study involving mostly pre-treated subjects with colorectal cancer receiving OX/Cape, those homozygous for 3-tandem repeats in the 5’ UTR of TS did not experience a significantly worse clinical outcome. There was no relation between TS genotype in genomic DNA &amp; TS mRNA expression in tumor tissue; this observation is consistent with information suggesting that the 3-repeat sequence of TS mRNA increases translational efficiency. [Table: see text]
Comparative efficacy and safety analysis of sorafenib in patients with advanced hepatocellular cancer (HCC) with varying liver dysfunction: A south Texas institutional analysis.
Authors: Raed Moh'd Taiseer Al-Rajabi, Norma Ketchum, Nicole A. Dierschke, Ting Wei Lu, Brad H. Pollock, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2013)

e15171 Background: Sorafenib (SOR) is the first systemic therapy to improve survival in patients (pts) with advanced (HCC), mainly amongst pts with Child-Pugh (CP) A cirrhosis. In the US however, HCC pts often present with ECOG status ≥ 1 and CP B cirrhosis. The GIDEON study reported variation in disease characteristics and treatment patterns for US pts compared to rest of the world. Our aim was to further assess clinical efficacy and safety of SOR at our institution’s minority rich South Texas HCC population. Methods: We reviewed medical records of HCC pts who received SOR from 2008-2011. The association between demographic, clinical and laboratory variables with overall survival (OS) and progression free survival (PFS) were assessed by comparison of Kaplan-Meier curves. Groups were statistically compared by the log rank test and the magnitude of association with outcome was summarized as the hazards ratio with 95% confidence interval (CI). Results: A total of 67 pts were included. Median age 55 (range 41-93), males 83%, Hispanic 76%, CP A 59% vs B 39%. The median OS (mOS) was 10.0 months (mo) (95% CI: 7.2-18.3) and median PFS (mPFS) was 4.9 mo (95% CI: 3.1-7.1); both comparable to reported efficacy of the SHARP trial. In subgroup analysis, mOS was 12.8 (95% CI: 7.7–18.3) vs 7.2 mo (95% CI: 2.6–24.4) for CP A and B (HR 0.72, 95% CI: 0.37–1.38, p = 0.32), respectively. CP A pts had a mPFS of 5.9 (95% CI: 1.6–10.0) vs 3.6 mo (95% CI: 4.4–7.6) with CP B pts (HR 0.77, 95% CI: 0.45–1.34, p = 0.36). Pts on SOR daily dose of 800 mg had a better mOS at 12.8 (95% CI: 6.9–24.4) vs 8.7 mo (95% CI: 2.0–15.8) compared to those on 400 mg (HR 0.58, 95% CI: 0.29–1.15, p = 0.11). Although no significant difference in efficacy was noted between ethnicities, pts ≥ 60 years had an improved mOS at 15.9 (95% CI: 6.9–24.4) vs 7.9 mo (95% CI: 2.0–15.8) amongst pts &lt; 60 (HR 0.56, 95% CI: 0.28-1.12, p = 0.10). There was no difference in toxicity observed. Conclusions: SOR was well tolerated in both CP A and B groups. Efficacy analysis showed a trend towards improved survival among pts with CP A treated with a daily dose of 800mg. The improved efficacy of SOR among pts ≥ 60 may be related to a more indolent HCC in this age group.
Acute gastrointestinal complications in patients with histologically aggressive primary gastric lymphoma treated with doxorubicin-containing regimens
Authors: N. Haim, K. Drumea, Y. Ben-Arieh, M. Ben-Shachar, E. Rosenblatt, A. Kuten, R. Epelbaum
Journal: Journal of Clinical Oncology (2005)

6645 Introduction: Non-surgical treatment of primary gastric non-Hodgkin’s lymphoma [PGL] can be complicated by gastrointestinal [GI] bleeding or perforation. The exact risk of these complications is unknown. In our department, patients with histologically aggressive PGL are treated without surgery and according to the guidelines for other presentations of non-Hodgkin’s lymphoma. Patients and Methods: PGL patients were those who presented with GI symptoms proven by endoscopy to be caused by the gastric involvement. Treatment consisted of primary doxorubicin-containing chemotherapy, followed by involved-field radiotherapy in patients with limited disease. All patients were hospitalized for 10–14 days after the onset of the first cycle of chemotherapy and watched for possible bleeding or perforation. Results: Of 94 consecutive patients [median age, 62 years; range, 19–86 years] with histologically aggressive PGL, 80 [85%] were treated according to the above-noted policy. The most common histology was diffuse large cell B [73 (91%) patients]; 49 [61%] patients had Musshoff’s stage I or III. Chemotherapy was followed by radiotherapy in 38 [48%] patients. Hematemesis and/or melena was observed in 11 [14%] patients on days 3–18 of the first cycle of chemotherapy. GI bleeding required surgery in one of these patients who was treated with gastric devascularization, without gastrectomy. Perforation was not observed during chemo- or radio-therapy in any patient. Risk of GI bleeding was associated with bulky abdominal disease [7/11 in patients who developed bleeding vs 10/69 in patients without bleeding, p<0.005], palpable abdominal mass [6/11 vs 8/69, p<0.005], and lack of complete resolution on first-line therapy [4/9 vs 54/64, p<0.006]. Conclusions: The risk of life-threatening GI complications in this series of non-selected PGL patients was minimal. However, GI bleeding during the first cycle requires close follow-up. No significant financial relationships to disclose.
Concomitant chemoradiation plus induction (I) or consolidation (C) chemotherapy (CT) with docetaxel (D) and gemcitabine (G) for unresectable stage III non-small cell lung cancer (NSCLC) patients (p). Results of the randomized SLCG 0008 phase II trial
Authors: P. Garrido, T. Massutí, T. Morán, F. Cardenal, O. Juan, M. Dómine, M. Cobo, R. García, I. Maestu, D. Isla
Journal: Journal of Clinical Oncology (2007)

7620 Background: Neither the optimal sequence of treatment nor the best combination CT is yet well-defined in p receiving concomitant therapy Methods: P with unresectable stage III NSCLC with IK ≥ 70 and weight loss &lt; 5% were initially randomized to sequential treatment (arm A), concurrent CT/TRT followed by consolidation CT (arm B) or induction CT followed by CT/TRT (arm C). Based on RTOG 9410 results, arm A was closed and the study continues with two concomitant arms (B, C). All p receive 2 cycles of D 40 mg/m 2 d1, 8 plus G 1,200 mg/m 2 d1, 8 as I or C therapy. Concomitant treatment includes D 20 mg/m 2 and carboplatin (Cb) AUC 2 weekly plus 60 Gy TRT. Results: From May 01 to Jun 06, 151 p were included (A: 19, B: 66, C: 66). Due to the early closing of arm A, only data of evaluable arms B and C p are shown: toxicity 127 p (B: 63, C: 64) and response 110 p (B: 53, C: 57). All groups are well-matched for baseline disease characteristics. Toxicity grade 3–4 by CTC and RTOG criteria was: esophagitis 19.5% (arm B) and 14.2% (arm C); pneumonitis 8.8 % (arm B) and 10% (arm C). Neutropenia during I or C therapy: 22% (B) and 6.2% (C). Thrombocytopenia 8% (B) and 3% (C). Neutropenia during concomitant therapy: 6.3% (B) and 6% (C). No thrombocytopenia or severe anemia was found during CT/TRT. The reduction CT rate was superior in consolidation (35%) than in induction (15%) and in arm C during concomitant therapy (22.4% C, 6.5% B). Delay of CT dose was similar in B and C arms during I or C (22% B, 20% C) but superior in arm C during concurrent treatment (19.6% B, 30.6% C). The final response rates were 57% (B) and 56.9% (C). A trend for longer time to progression (TTP) was found (B: 7.6 months (m) and C: 9.2 m; p= 0.12) but with similar overall survival (B: 14.3 m and C: 14.7 m; p=0.38). Conclusions: Non- platinum CT plus concomitant chemoradiation offer similar response rate and a favorable hematological toxicity profile in unresectable stage III NSCLC p. No differences in OS but a trend for longer TTP in the arm C (I followed by concurrent approach) has been found. Final data are pending in order to select the best sequence for further studies. No significant financial relationships to disclose.
Efficacy report of a multicenter phase II trial testing a biologic-only combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer (BC): A Phase II Consortium (P2C) study
Authors: K. D. Holen, M. R. Mahoney, N. K. LoConte, D. W. Szydlo, J. Picus, W. J. Maples, G. P. Kim, H. C. Pitot, P. A. Philip, J. P. Thomas, C. E. Erlichman
Journal: Journal of Clinical Oncology (2008)

4522 Background: Unresectable BCs, though uncommon, have a high mortality rate due to few effective available chemotherapies. BCs are known to express EGFR and increased angiogenesis in BC tumors has correlated with poor outcome. Bevacizumab (B), a VEGF inhibitor, and erlotinib (E), an EGFR tyrosine kinase inhibitor, have individually shown modest activity in BC (Philip et al, JCO 2006 and Clark et al, JCO 2007). The combination of B and E has demonstrated tolerability and modest efficacy in solid tumors (Hainsworth, et al, JCO 2005). Methods: Eligible patients have had no prior systemic treatment for metastatic or unresectable BC. Patients were treated with B 5 mg/kg IV d1,15 and E 150 mg PO QD d1–28, repeated every 28 days. The primary endpoint was confirmed response rate (RR). Two confirmed responses in 20 patients were required to complete enrollment of 50 patients, with 4 needed to declare efficacy (Fleming design). Secondary endpoints included tissue analysis for EGFR and signalling pathway member expresssion, EGFR mutation status, VEGF levels, and VEGFR-1 and -2 expression. Results: 34 eligible patients have been enrolled (13 male, 16/17/1 ECOG PS 0/1/2, 6 gallbladder, 27 cholangiocarcinoma). A median of 2 cycles have been administered (range 0–12), with 18 pts still on active treatment. 30 pts are evaluable for toxicity. One pt had grade 4 cerebral ischemia possibly related to treatment. Observed grade 3 events related to treatment included rash/desquamation (3), fatigue (1), hypokalemia (1), and hyponatremia (1). 1 pt died on day 21 of a CVA considered unrelated to treatment. 9 pts have progressed. Four partial responses have been observed in the first 20 evaluable pts (RR 20%, 95% 7–29%), lasting 3, 4, 6, and 9 mos. Seven patients had stable disease greater than 4 months duration. Conclusions: B and E is a tolerable regimen for BC. The RR observed warrants larger studies with greater than half the patients achieving a response or stable disease. Accrual continues to gain precision regarding study endpoints. Supported by the P2C Contract (NCI N01 CM62205). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech Genentech