tbuckley/cabot-search huggingface dataset:
Use of Statins in Adults Older Than 75 Years—Reply
Authors: Jerry H. Gurwitz, Alan S. Go, Stephen P. Fortmann
Journal: JAMA (2017)

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Small cell carcinoma of the female genital tract: A single institution experience.
Authors: Faraj El-Gehani, Julia Sun, Muna Kamal, Danielle Pertschy, Kurian Joseph, Katia Tonkin, Sunita Ghosh, Nadeem Pervez
Journal: Journal of Clinical Oncology (2012)

e15540 Background: Small cell carcinomas (SCC) of the female genital tract (FGT) are rare and there is no standard treatment strategy for managing these patients (pts). The objectives of this study are to report the clinical experience and management of pts with SCC of the FGT, treated at the Cross Cancer Institute, Edmonton, AB, Canada from 1982 to 2009. Methods: A retrospective chart review of all pts diagnosed with SCC of the FGT between 1982 and 2009 was undertaken. Data was collected on demographics, clinical and pathological characteristics, and patient outcomes. Results: Twenty-seven pts were identified with primary sites as follows: cervix 16 (59%), endometrium 7 (26%), ovary 3 (11%) and vagina 1 (4%). Median age at diagnosis was 53 years. Seventy-eight percent (21/27) had pure SCC; the rest had mixed histology. Seventy percent (19/27) were positive for at least one neuroendocrine marker. Overall, thirty percent (8/27) had limited stage (LS) disease; Seventy percent (19/27) had extensive disease (ES). Treatment of limited stage pts was 3/8 (38%) concurrent chemotherapy with radiation, 3/8 (38%) surgery, 1/8 (12%) chemotherapy alone and 1/8 (12%) radiation alone. For extensive stage pts, 6/19 (31%) treated with surgery with or without adjuvant chemotherapy, 4/19 (21%) concurrent chemotherapy with radiation, 2/19 (11%) palliative chemotherapy and 7/19 (37%) supportive care only. For relapsing pts brain was the site of first distant recurrence in three pts. Median survival for the entire cohort was 7.4 months (25.9 months for limited stage disease and 4.8 months for extensive; p &lt; .0001). Conclusions: SCC of the FGT tract is aggressive with an overall poor prognosis. There is no standard of care for these pts and they are often treated according to local protocols based on data extrapolated from SCC lung cancer. Incidence of brain metastasis as the site of first relapse is relatively lower in FGT SCC, suggesting unclear benefit to prophylactic cranial irradiation.
Axitinib in refractory colorectal metastatic cancer: A phase II study of increasing doses with dynamic contrast-enhanced ultrasonography monitory of the response.
Authors: Michel Ducreux, Valerie Boige, Laura Faivre, David Malka, Pascal Burtin, Antoine Hollebecque, Anne-Laure Villing, Serge Koscielny, Baya Benatsou, Benedicte Coiffier, Agnes Laplanche, Nathalie Lassau
Journal: Journal of Clinical Oncology (2014)

3638 Background: Anti-angiogenic therapy plays a role in the treatment of colorectal cancer (CRC). We used monotherapy axitinib every other week given in refractory patients to evaluate the efficacy of this drug given at increasing doses and the role of Dynamic Contrast enhanced ultrasonography (DCE-US) to predict and measure its efficacy. Methods: Patients (pts) should have refractory metastatic CRC with at least one measurable lesion into the liver with DCE-US. They were given axitinib 5mg bid for one week followed by one week rest (Cycle 1) and then in case of good tolerance 7 mg bid for one week followed by one week rest (Cycle 2) and then 10 mg bid for one week followed by one week rest (Cycle 3). After 6 weeks of treatment a new CT-scan was performed to evaluate the efficacy of the treatment following RECIST criteria. If at least a stable disease was observed axitinib alone was continued at the same dose, if not addition of chemotherapy (CT) (Folfiri regimen) was allowed. DCE-US was performed on one liver metastasis at baseline D2, 7, 15, 21, 29, 35, 43. AUC, corresponding to the blood volume was calculated at each time point. Results: 25 pts (W: 10, M: 15; median age 60) are evaluable. Kras status: mutant 11, wild-type 9, unknown 5. 84% of the pts received more than 2 lines of CT before entry in the study. ECOG PS was 0 in 24% of the pts, 1 in 60%, 2 in 12% and 3 in 4%. Cycles received: 25 pts cycle 1, 24 pts cycle 2, 21 pts cycle 3. The only grade 3 toxicity frequently observed was hypertension (28%, 25%, 15% in cycle 1, 2, 3, respectively). No objective response was observed, stable disease was seen in 32% of the cases. Median overall survival was 5.8 months [IC 95%: 5.1 – 9.9], median overall progression free-survival was 1.5 months [IC 95%: 1.3 – 3.0]. A total of 169 DCE-US were analyzed. The median of AUC decreases by 55% from baseline to D43. AUC decreases by 53%, 1 % and 10 % after the first, second and third cycle, respectively. Conclusions: This study has shown that heavily pretreated patients patients who received axitinib monotherapy given every other week had a median overall survival of 5.8 months. DCE-US monitoring could help to detect the patients who get the greater benefit of the treatment. Clinical trial information: NCT01486251.
Dose adherence and baseline exposure analysis of the ibrutinib 420 mg dose administered to patients with previously treated chronic lymphocytic leukemia (CLL).
Authors: Paul M. Barr, Jennifer R. Brown, Peter Hillmen, Susan O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, Stephen P. Mulligan, Ulrich Jäger, Richard R. Furman, Florence Cymbalista, Marco Montillo, Claire Dearden, Tadeusz Robak, Carol Moreno, John Pagel, Jan Andreas Burger, Samuel Suzuki, Danelle Frances James, John C. Byrd
Journal: Journal of Clinical Oncology (2015)

7012 Background: Ibrutinib (ibr), a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), is rapidly eliminated from plasma after oral administration (Advani, JCO 2013). Complete or near complete BTK active site occupancy (median > 90%) is achieved at 4 hours and maintained at 24 hours with ibr 420 mg once-daily (O'Brien, Lancet Oncology 2013). At 140 or 280 mg doses, fewer patients (pts) attained complete BTK occupancy (Poggesi, AACR 2014). This analysis evaluated the effect of the ibr 420 mg once-daily dose on IRC-assessed progression-free survival (PFS) in pts with previously treated CLLfrom thephase 3 RESONATE trial. Methods: Dose intensity (DI) was defined as the proportion of actually administered vs planned doses of 420 mg. DI was also defined in first 8 weeks to compare statistically with post-week 8 PFS. Steady-state AUC/Cmax was estimated per NONMEM modeling using 2 timepoint samples (weeks 1 and 4). Missed doses had to be consecutive. Results: Ibr-treated pts (n = 195) had a mean DI of 95% (median 100%) with 8.3 months of treatment. The majority of dose interruptions restarted at 420 mg; 3.6% of pts had 1 and 0.5% had 2 dose reductions due to AEs. Pts with higher DI experienced longer PFS (median NR) compared to lower DI (11 months). Using an adjusted mean DI of 96% in first 8 weeks and post week-8 PFS, this trend was confirmed with HR = 0.4 (P= 0.0127). Pts with higher DI had a lower rate of progression regardless of del17p, p53 mutation, or del11q CLL. In 179 pts receiving ibr 420 mg with PK assessment at weeks 1 and 4, no difference was seen in median PFS with lower vs higher ibr exposure (AUC or Cmax). There were fewer PFS events in pts not missing (n = 136) vs those missing (n = 59) ibr doses for ≥ 8 consecutive days (13% vs 31%, respectively), with median PFS of NR vs 11 months, respectively. The mean duration of these missed doses was 26 days. Conclusions: A higher mean dose intensity of ibr is associated with improved PFS, with patients missing more than 1 week of treatment experiencing more PFS events. These results, and the established clinical profile, support the clinical utility of sustained adherence to the once-daily 420 mg dose of ibr in patients with previously treated CLL. Clinical trial information: NCT01578707.
Kent experience of radical chemoradiotherapy for muscle invasive bladder cancer.
Authors: Jessica Gough, Mathini Sridharan, Ruochen Li, Rakesh Raman, Albert Edwards, Amanda Clarke, Sharon Beesley, Henry J. H. Taylor, Kathryn Lees
Journal: Journal of Clinical Oncology (2017)

373 Background: The BC2001 trial in 2012 showed concurrent chemoradiotherapy to be the new standard of care for bladder preserving treatment of muscle invasive bladder cancer. Addition of concurrent MMC and infusional 5FU showed a relative risk reduction of 33% in locoregional recurrence (James ND, Hussain S, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–88.). This audit evaluates the experience across Kent in six hospitals adopting this protocol. Methods: 116 patients treated with radical radiotherapy for bladder cancer between January 2013 and December 2015 were retrospectively reviewed. 64 patients received radiotherapy alone due to contraindications to chemotherapy, performance status and patient choice. 52 patients received concurrent chemotherapy, the majority with 5FU/MMC and a subset with oral Capecitabine in place of infusional 5FU. Kaplan Meier and Log-Rank analysis of overall survival, local recurrence free survival and metastasis free survival were performed using SPSS. Results: Local recurrence free survival in the chemoradiotherapy group was 73% (95% CI 59-87%) compared to the radiotherapy group 61% (45-77) (p=0.27). There was a trend for greater metastasis free survival at 2 years, 63% (47-79) in the chemoradiotherapy group compared to 52% (38-66) in the radiotherapy group (p=0.21). Similarly, overall 2 year survival was 74% (60-88) and 59% (43-75) respectively (p=0.21). Conclusions: Our results showed a trend towards improved local control, distant control and increased overall survival in patients treated with concurrent chemoradiotherapy compared to radiotherapy alone. The differences did not meet statistical significance; however this was a small retrospective series with a relatively short median followup of 17.5 months. Treatment was well tolerated in our patient group. Overall, our data is in keeping with the results of the BC2001 trial (James ND, Hussain S, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–88.)
The pharmacokinetic driver of thrombocytopenia and its implications for clinical dose schedule optimization.
Authors: Mayank Patel, Munjal Patel, Ekta Kadakia, Jing-Tao Wu, Wen Chyi Shyu, Arijit Chakravarty
Journal: Journal of Clinical Oncology (2015)

e20726 Background: Therapeutic intervention in oncology often results in thrombocytopenia. Clinical schedule modification may be used to mitigate thrombocytopenia in patients. Prior knowledge of the pharmacokinetic (PK) driver of toxicity provides useful insights for effectively managing thrombocytopenia. In this work, we propose that scheduling effects for toxicities resulting from myelosupression such as thrombocytopenia are a function of the biological system and thus independent of the compound. Using data from published clinical models, we have identified a PK correlate of thrombocytopenia toxicity. Methods: Clinical platelet time-profile resulting from different schedules was simulated for Abexinostat, Carboplatin and Linezolid using published PK/PD models. Platelet nadir, probability of grade-4 thrombocytopenia and probability of grade-4 thrombocytopenia > 7 days were correlated with AUC and Cmax. In a previous publication we had identified a novel PK parameter, the maximum moving average concentration over 15 days (AUW-15) and demonstrated its correlation with neutropenia severity. Here, we have used a similar approach to test the correlation of thrombocytopenia severity and AUW over different time frames. Results: Thrombocytopenia severity failed to correlate with AUC or Cmax. However, we found that the maximum moving average concentration over 11 days predicted thrombocytopenia severity for all the three compounds. Conclusions: This work identifies a practical correlate of thrombocytopenia that can be used in clinical decision-making. Notably, the identified PK correlate suggests that lower, more frequent doses, coupled with short rest breaks provide better management of thrombocytopenia than highly infrequent doses (which, for the same total dose, would lead to higher peak doses and higher peak AUW-11). Though empirical in nature, the duration of moving average concentrations may be interpreted as the induction and recovery time associated with thrombocytopenia toxicity. Leveraging the information obtained from this work, clinicians may prospectively select schedules associated with lowest AUW-11 to mitigate the risk of developing thrombocytopenia.
Using low sensitivity of direct sequencing to detect K-ras mutations? A new method for improving diagnostic accuracy.
Authors: Chi-Kuan Chen
Journal: Journal of Clinical Oncology (2013)

e22100 Background: Identifying K-ras mutation has became a standard procedure in cancer treatment. Colorectal cancer patients with K-ras mutation are likely to poorly respond to cetuximab. Therefore, detecting K-ras gene mutations should be suggested before the selection of personalized treatment in colorectal cancer. To date, general molecular biology techniques contain HRM, PCR-RFLP, TaqMan PCR and CE-IVD-validated Cobas 4800 KRAS (Roche Diagnostics) are used for K-ras mutation detection in molecular diagnosis, but the sensitivity limitation of these method is approximately 1%. Methods: Therefore, we used a new approach, a universal genetic detecting method (FemtoPath), which improves sensitivity of K-ras mutation detection and the limitation of sensitivity is closed to 0.1% of mutation type. Results: We compared the sensitivity between FemtoPath/direct sequencing test and Cobas KRAS real-time PCR. Cobas real-time PCR identifies mutations in 21 (40.38%) of the 52 tumors. Surprisingly, the FemtoPath/direct sequencing test identified mutations in 40 (76.92%) of the 52 tumors. Our data showed that the FemtoPath/direct sequencing test can identify 19 additional mutation samples. In addition, the FemtoPath/direct sequencing test can identify more unknown K-ras mutations adjacent to codon 12 and 13. Conclusions: Ensure the most timely and appropriate therapy for cancer patients is the first priority of clinical application. FemtoPath/direct sequencing test is more sensitive, accurate and inexpensive and needs fewer sample amount than Cobas real-time PCR.
Neoadjuvant accelerated MVAC (AMVAC) in patients with muscle invasive bladder cancer: Results of a multicenter phase II study.
Authors: Elizabeth R. Plimack, Jean H. Hoffman-Censits, Rosalia Viterbo, Richard Evan Greenberg, David Chen, Costas D. Lallas, Edouard John Trabulsi, Yu-Ning Wong, Alexander Kutikov, Jianqing Lin, Gail Duncan, Beth Adair, Charlotte Cione, Conor O'Sullivan, Deborah Kilpatrick, Eric A Ross, Stephen A. Boorjian, Robert G. Uzzo, William Kevin Kelly, Gary R. Hudes
Journal: Journal of Clinical Oncology (2012)

4526 Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) demonstrates a survival benefit in the neoadjuvant setting for patients (pts) with muscle invasive bladder cancer (MIBC). Compared with standard MVAC, AMVAC yielded higher response rates with less toxicity in the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with CrCl &gt;=50 and adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m 2 , vinblastine 3 mg/m 2 , doxorubicin 30 mg/m 2 , cisplatin 70mg/m 2 ) on day 1, with pegfilgrastim 6 mg day 2 or 3, every 2 weeks. Pts with CrCl &lt; 60 could receive cisplatin split over 2 days. Radical cystectomy (RC) with lymph node dissection was performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month period. Median age 64 (range 45-83). Three withdrew from study early and are not evaluable for response (2 physician discretion, 1 withdrawal of consent). An additional 8 are currently receiving treatment on study with toxicity and response data pending. Of the 33 evaluable pts for whom final data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts received &lt; 3 cycles due to grade 3 fatigue (1), low platelets (1), and disease progression precluding RC (1). 32/33 pts underwent RC, all within 8 weeks of last chemotherapy. Median time from start of chemotherapy to RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI, 22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non muscle invasive disease. For the intent to treat cohort (n=36) 8 pts had grade 3-4 AMVAC related adverse events, the most common being anemia (3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95% CI, 20.4-51.8%). All pts will have completed study treatment by April 2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is well tolerated and preliminary results show a pCR rate similar to that reported for standard 12-week MVAC, suggesting that AMVAC for three cycles (6 weeks) is a safe and efficient alternative.
Phase I combination of pazopanib and everolimus in <i>PIK3CA</i> mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy.
Authors: Heloisa Veasey Rodrigues, JoAnn Lim, Bettzy Stephen, Filip Janku, Apostolia Maria Tsimberidou, Sarina Anne Piha-Paul, Siqing Fu, Aung Naing, Vivek Subbiah, Gerald Steven Falchook, Razelle Kurzrock, Jennifer J. Wheler
Journal: Journal of Clinical Oncology (2015)

2588 Background: Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors. Methods: Patients with refractory solid tumors were enrolled in a modified 3+3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway. Results: Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600mg every other day (QOD) alternating with everolimus 10mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27% (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥ 6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27% (7/26) versus 26% (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive. Conclusions: Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted. Clinical trial information: NCT01430572.
Efficacy and safety of first-line palbociclib plus letrozole compared with letrozole alone in patients aged ≥ 65 years with estrogen receptor-positive, HER2-negative advanced breast cancer: A subgroup analysis by age of the PALOMA-1/TRIO-18 trial.
Authors: John Crown, Richard S. Finn, Johannes Ettl, Katalin Boer, Ravi Patel, Anu Thummala, Sophia Randolph, Sindy Kim, Xin Huang, Sashi Nadanaciva, Patrick Schnell, Cynthia Huang Bartlett, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2015)

571 Background: Of the estimated 232,670 new cases of breast cancer (BC) diagnosed in the U.S. in 2014, 40% will have occurred in women ≥ 65 years. In this population, the most common type of BC is estrogen receptor-positive (ER+), HER2-negative (HER2-) for which endocrine treatment (ET) is currently the treatment of choice. When tumors become refractory to ET, chemotherapy is often initiated; palliative measures might also be suitable. Palbociclib (P) is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). In a randomized phase 2 trial (PALOMA-1/TRIO-18; NCT00721409), first-line P plus letrozole (L) showed median progression-free survival (PFS) benefit that was double that shown by L alone in patients (pts) with ER+ and HER2- advanced BC (Finn et al, Lancet Oncol, 2015; 16: 25-35). In the present subgroup analysis, we evaluated the effect of P + L versus L alone in pts aged ≥ 65 years. Methods: Postmenopausal women (N = 165) with advanced ER+, HER2- BC were randomized 1:1 to receive P (125 mg/day for 3 weeks, 1 week off) plus L (2.5 mg/day) or L alone (2.5 mg/day). Of the 76 pts aged ≥ 65 years, 37 were assigned to P + L and 39 were assigned L alone. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: In pts ≥ 65 years, the median PFS was 26.6 months (95% CI 12.6 – NR) for the P + L arm and 7.7 months (95% CI 3.7 – 10.9) for the L arm (HR 0.505, 95% CI 0.269 – 0.948; one-sided p = 0.0155). In pts eligible for safety analysis, grade 3-4 neutropenia was reported in 56.8% in the P+L arm vs 2.7% in the L arm, leucopenia in 29.7% vs none, and fatigue in 10.8% vs none. In general, neutropenia associated with P+L was short-lived and did not require management with hematopoietic growth factors. Conclusions: The median PFS was > 3 times longer in the P+L arm than in the L alone arm for the subgroup of pts ≥ 65 years. The toxicity profile was consistent with that of entire study population. A phase III study evaluating P+L is ongoing; P+L is an important treatment option for elderly, as well as non-elderly, patients with ER+, HER2- advanced BC. Clinical trial information: NCT00721409.
Erratum: Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia
Authors: V Madan, P Shyamsunder, L Han, A Mayakonda, Y Nagata, J Sundaresan, D Kanojia, K Yoshida, S Ganesan, N Hattori, N Fulton, K T Tan, T Alpermann, M C Kuo, S Rostami, J Matthews, M Sanada, L-Z Liu, Y Shiraishi, S Miyano, E Chendamarai, H A Hou, G Malnassy, T Ma, M Garg, L W Ding, Q Y Sun, W Chien, T Ikezoe, M Lill, A Biondi, R A Larson, B L Powell, M Lübbert, W J Chng, H F Tien, M Heuser, A Ganser, M Koren-Michowitz, S M Kornblau, H M Kantarjian, D Nowak, W K Hofmann, H Yang, W Stock, A Ghavamzadeh, K Alimoghaddam, T Haferlach, S Ogawa, L Y Shih, V Mathews, H P Koeffler
Journal: Leukemia (2016)