tbuckley/cabot-search huggingface dataset:
A phase 0 microdosing trial of an in vivo assay for predicting chemoresistance to platinum.
Authors: C. Pan, S. Wang, R. deVere White, D. R. Gandara, P. Lara, T. Li, P. Mack, A. Rodriguez-Fahrni, J. S. Lee, M. Malfatti, K. Turteltaub, P. T. Henderson
Journal: Journal of Clinical Oncology (2011)

2578^ Background: As alkylating agents, platinum (Pt) analogs kill cancer cells mainly through induction of DNA damage. We hypothesize that low Pt-induced DNA damage is predictive of chemoresistance. We have developed a supersensitive accelerator mass spectrometry (AMS) method, with a sensitivity of 10-18~21 mole. AMS can detect carboplatin (carbo)-induced DNA damage in tissues after patients receive one subtoxic microdose (1/100th the therapeutic dose) of 14C-labeled carbo, and further allows mechanistic analysis of chemoresistance. Methods: A 2-stage accrual design was employed. In the first stage, a dose escalation/de-escalation strategy was used to determine toxicity and recommended Phase II dose (RP2D) of 14C-Carbo. Stage II was designed to determine if DNA damage levels induced by microdosing carbo correlate with chemoresistance, and to determine underlying resistance mechanisms. Patients with advanced non-small cell lung cancer or bladder cancer planning to receive Pt-based therapy are eligible. Primary endpoint is to determine and compare DNA damage levels induced by microdosing and therapeutic carbo. Secondary endpoints: pharmacokinetics (PK) of microdosing and therapeutic carbo, levels of tumoral DNA damage, and tumor response. Results: Stage I of the Phase 0 trial has been completed with an accrual of 5 patients. The Dose Level I of 107 dpm/kg of body weight is RP2D of 14C-carbo, which results in a desirable 14C signal-to-noise of 10~100 times background. This 14C level could be easily detected by AMS, but with minimal radiation exposure to patients (less than 1% that of an abdominal CT scan.). No acute toxicity was observed. Serum half life of carbo ranged from 1.30 to 1.58 hours—well within the reported range for the therapeutic carbo. DNA damage levels positively correlated with carbo half-life. Comparisons of the microdosing and therapeutic carbo PK, correlation of DNA damage and tumor response to subsequent chemotherapy, and the results of Stage II trial will be reported. Conclusions: A Phase 0 trial as a platform to study Pt resistance can be feasibly conducted with one non-toxic microdose of 14C-labeled carbo using supersensitive AMS-based technology and has implications for personalized therapy.
Effect of dose modification on the efficacy of capecitabine: Data from six randomized, phase III trials in patients with colorectal or breast cancer.
Authors: J. Cassidy, J. O'Shaughnessy, H. Schmoll, C. Twelves, T. H. Cartwright, A. Buzdar, E. McKenna, F. Gilberg, N. Scotto, D. G. Haller
Journal: Journal of Clinical Oncology (2011)

3627 Background: Capecitabine has established efficacy and tolerability profiles in the treatment of colorectal and breast cancer. Dose modification is recommended upon the occurrence of grade 2–4 adverse events (AEs). The effect of dose modification on efficacy was analyzed using data from 6 large, randomized phase III trials of pts treated with capecitabine monotherapy or in combination with oxaliplatin or docetaxel. Methods: Data regarding appropriate modification, interruption or delay of capecitabine dose were prospectively captured during 6 clinical trials (breast cancer: NO17629, NO16853; colorectal cancer: NO16966, NO16967, NO16968 and M66001). Uniform prespecified criteria for dose modification were used across trials. Data were analysed using descriptive statistics. KM curves for DFS (NO16968, M66001 and NO17629) or PFS (NO16966, NO16967 and NO16853) were constructed to assess the effects on pt outcomes. Results: Data from each study show that capecitabine dose reduction for AE management has no detrimental effect on DFS/PFS. Findings were similar across trials, indications and settings (adjuvant/metastatic). Outcomes were numerically worse in pts with no capecitabine dose modifications; a trend observed across indications/settings. The difference was more pronounced in pts receiving combination therapy. Across all studies 57-67% pts had cycle interruptions, delays or capecitabine doses reduced. Median delivered capecitabine dose intensities ranged from 0.67–0.94 across trials. Dose modification reduced the occurrence of subsequent AEs in the only capecitabine monotherapy trial (M66001 [X-ACT]), a trend less apparent in combination regimen trials where initial capecitabine doses were lower. Conclusions: Data from 6 phase III trials show that AEs associated with capecitabine treatment are manageable by appropriately planned dose modification or cycle delay without detrimental effects on efficacy, across indications/settings. Observed reduced performance among pts with no dose modifications in the mCRC setting may suggest underdosing as data indicate treatment may have been stopped due to disease progression rather than AEs.
The integration of palliative care into treatment of oncology patients at the Istituto Oncologico Veneto (IOV): The interdisciplinary clinic of simultaneous care.
Authors: Antonella Galiano, Stefania Schiavon, Antonella Brunello, Michela Michielotto, Irene Guglieri, Maria Teresa Nardi, Evelina Lamberti, Annalisa Stablum, Eleonora Capovilla, Leonardo Trentin, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2016)

150 Background: WHO defines palliative care as an approach that improves the quality of life of patients (pts) and their families facing problems associated with life threatening illnesses. This occurs by means of early identification, assessment and treatment of pain and other problems physical, psychosocial, and spiritual. Recently, palliative care has been incorporated into the treatment of oncology pts earlier in the course of their disease. We aimed to explore this approach at our institution. Methods: We established an interdisciplinary clinic at IOV with the goal of promoting pts’ comprehensive support by integrating palliative care into active oncology treatments. Our primary objectives were to: optimize the quality of life of pts at every stage of their disease, ensure continuity of care through proper coordination of available services and avoid a sense of abandonment at the end of life. Pts included were those with advanced disease who had a life expectancy of less than one year, pts who had symptomatic disease regardless of prognosis, and pts who were considered frail, because of clinical, social, psychological, spiritual, logistical, and economical criteria. The multidisciplinary team consisted of a medical oncologist, a palliative care physician, a psychologist, a nurse and a nutritionist. Results: Between March 2014 and March 2016, 337 pts were visited, with different types of cancer. Median age was 69 (range: 34-93), 44% were men, median PS (ECOG) was 1.5, 47% were undergoing anti-cancer treatment. Reasons for referral included: physical complaints (71%), psychosocial issues (30.3%), nutritional problems (38%) and social problems (7%). For the 46% of patients, domiciliary health care was activated directly by the Local Health Department or through the General Practitioner; specific action have been made in relations to the problems encountered. Conclusions: The Interdisciplinary Clinic of Simultaneous Care carried out at IOV represents a successful pilot experience that proposes an organizational model for early integration of palliative care as an integral part of treating the oncology patient.
The topoisomerase I inhibitor gimatecan exhibits synergistic antitumor activity in combination with imatinib mesylate and everolimus against malignant glioma xenografts
Authors: G. Vassal, N. Hamelin, P. Opolon, R. Versace, B. Geoerger
Journal: Journal of Clinical Oncology (2008)

2073 Background: The novel oral lipophilic camptotecan gimatecan (ST1481; NVP-LBQ707) has shown antitumor activity against malignant glioma xenografts and synergistic effects with temozolomide (Vassal et al. Proceedings ASCO 2007). The present work evaluated gimatecan with tyrosine kinase inhibitor imatinib mesylate and mTOR inhibitor everolimus in glioma. Methods: In vivo antitumor activity was evaluated against subcutaneous advanced stage IGRG121 and IGRG93 xenografts derived from primary malignant gliomas. Gimatecan 0.19 or 0.05 mg/kg/d was administered orally q5d/w x 4 weeks, imatinib 150 mg/kg/d q5d/w x 4 weeks, everolimus 5 mg/kg/d q3d/w. Results: In IGRG121, gimatecan 0.19 mg/kg resulted in 2 PR and 2 CR of 8 tumors, significant tumor growth delay (TGD) in median time to reach 5 times initial tumor volume of 46.6 days compared to controls (p<0.01; Kruskal-Wallis test) and a tumor log cell kill (LCK) of 5.8. Imatinib and everolimus were inactive with 1.4 and 3.3 days TGDs (p=ns). Imatinib and gimatecan achieved 100% tumor regressions (6 PR and 2 CR of 8 tumors), a TGD of 49.6 days (p<0.001) and a LCK of 6.2. The observed/estimated TGD ratio of 1.30 suggests the combination being synergistic. In contrast, gimatecan and everolimus resulted in 1 PR out of 6 tumors, TGD of 42.6 days (p<0.001), and LCK of 5.2, which was not superior to gimatecan alone. IGRG93 had been proven highly sensitive to gimatecan which at 0.05 mg/kg resulted in 5 PR and 2 CR out of 10 tumors, TGD of 32.5 days compared to controls (p<0.001) and LCK of 2.5. Although imatinib activity was limited in this PDGFRA gene amplified glioma (TGD 9.2 days (p=ns); LCK 0.1), its combination with gimatecan resulted in 8 CR of 8 tumors, TGD of >66.0 days (p<0.001), and LCK 5.4. The observed/estimated TGD ratio of 1.75 suggested the combination being highly synergistic. Similarly everolimus was inactive (TGD 6.6 days (p=ns); LCK 0.2), but administration with gimatecan resulted in 7 CR and 2 PR of 9 tumors, TGD of 57.8 days (p<0.001), LCK of 4.9 and an observed/estimated TGD ratio of 1.31. Conclusions: Imatinib and everolimus potentiated antitumor activity of gimatecan against glioma xenografts suggesting their combination for the treatment of malignant glioma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
A randomized phase II study of ixabepilone (Ix) or mitoxantrone and prednisone (MP) in patients with taxane (T)-resistant hormone refractory prostate cancer (HRPC)
Authors: J. E. Rosenberg, W. K. Kelly, M. D. Michaelson, G. Wilding, M. Hussain, M. Gross, E. J. Small
Journal: Journal of Clinical Oncology (2005)

4566 Background: No standard of care exists for T-resistant HRPC, although MP is frequently used. Ix is an epothilone B analogue with activity against T-resistant cell lines. We therefore tested the activity of Ix or MP in T-resistant HRPC pts. Methods: HRPC pts with progression during or within 60 days of stopping T chemotherapy are randomized to M 14 mg/m2 IV q3wks and P 5 mg PO BID, or Ix 35 mg/m2 IV q3wks, with crossover (3rd-line) allowed for progression or toxicity. This non-comparative study will accrue 40 pts to each arm to detect the primary endpoint of a ≥50% PSA reduction by Consensus Criteria in at least 25% of 2nd-line pts (H0=10%, α=0.04, β= 0.82 for each arm). Results: Safety data is reported for the first 51 2nd-line pts enrolled as of 12/6/2004, and 23 3rd-line patients. To date, median follow-up is 2.7 months (range: 0.1–9.8), and the median number of cycles administered to each 2nd-line arm is 3 (range Ix: 1–7, MP: 1–5). Hematologic toxicities included grade 3/4 neutropenia in 6 Ix 2nd-line (26%), 2 Ix 3rd-line (13%), 11 MP 2nd-line (39%), and 6 MP 3rd-line pts (75%). 1 2nd-line Ix pt experienced grade 3 anemia. 2 Ix pts experienced grade 3 febrile neutropenia; 1 MP pt each experienced grade 3 febrile neutropenia and grade 3 nausea. 1 grade 5 neutropenic sepsis was observed with Ix. 5 grade 1–2 and 1 grade 3 sensory neuropathies were observed with Ix. 7 MP pts experienced grade 1–2 sensory neuropathy. Overall, 6 MP and 8 Ix pts experienced grade 3–4 non-hematologic toxicity related to therapy. Conclusions: In 51 pts with available toxicity data, despite significant neutropenia, Ix and MP appear to have acceptable toxicity profiles as 2nd- and 3rd line HRPC chemotherapy. No conclusions about activity can be made at this time. PSA response data will be reported on the entire group. No significant financial relationships to disclose.
Is sorafenib effective in colorectal cancer? Definition of resistance indicators and impact of potential comedications.
Authors: C. C. Schimanski, P. R. Galle, M. H. Moehler
Journal: Journal of Clinical Oncology (2011)

e14126 Background: We initiated this study in order to analyse the value of sorafenib in colorectal cancer and to define potential combination chemotherapeutics and resistance indicators. Methods: The expression of diverse targeted tyrosine kinases was analysed in 103 colorectal cancer samples and correlated with clinico-pathologic parameters. The effect of increasing sorafenib doses on proliferation, apoptosis, migration, invasion and activation of signal cascades was analysed in vitro. In addition, the efficacy of a sorafenib monotherapy and different combination therapies was analysed in vitro (sorafenib +/- 5-FU, irinotecan or oxalipaltin) and in vivo (sorafenib +/- 5-FU). Results: The expression of VEGFR3 and PDGFRα correlated with lymphatic metastatic disease (P=0.06 and P=0.01, respectively) and with distant metastases (VEGFR3; P=0.06). In vitro, SW480 and HT29 cell lines were sorafenib sensitive, whereas Caco2 and SW620 cell lines were resistant, independent of the mutation status of K-ras, Raf, PTEN or PI3K. The effect on migration and invasion was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib+5-FU; irinotecan) and disadvantageous in others (sorafenib+oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. In vivo, the combination of sorafenib + 5-FU was not superior to the respective monotherapy. Sensitive cell lines revealed a down-regulation of AKT and had a hint expression-level of GADD45ß. In resistant cell lines, pp53 and GADD45ß levels decreased upon sorafenib exposure. Conclusions: Sensitivity to sorafenib and combination-therapies exists in certain settings and definition of resistance indicators such as GADD45ß might help to select patients for future studies.
Phase II study of carboplatin (CBDCA) and irinotecan (CPT-11) for patients with cancer of unknown primary (CUP)
Authors: M. Ando, K. Yonemori, M. Yunokawa, E. Nakano, T. Kouno, C. Shimizu, N. Katsumata, K. Tamura, H. Arioka, Y. Fujiwara
Journal: Journal of Clinical Oncology (2008)

13514 Background: Optimal chemotherapeutic-regimen for CUP without favorable prognostic- factors is uncertain. Platinum containing regimens are widely used for those patients. Methods: To evaluate the efficacy and toxicity of the combination of CPT-11 and CBDCA in patients with CUP. Patients who had been histologically confirmed metastatic carcinoma were eligible for this study, if the systemic surveys had not revealed any primary sites. The eligible pts had PS (0 –2), age (20 –75 yrs), no prior chemotherapy, adequate organ functions. Some patient subgroups of CUP known to have good prognosis were excluded. Patients received CPT-11 at the dose of 60 mg/m(2) on days 1, 8 and 15, and CBDCA at the dose of AUC 5 on day 1 every 4 weeks up to six cycles. The tumor response was evaluated by the RECIST criteria. Results: Between May 2003 and August 2007, forty-three patients entered into this study (median age 59 yrs (36 - 78), M/F: 23/20, and median number of disease sites 2 (1 - 7)). The following histrogies were included; well or moderately differentiated (W/M) adenocarcinoma 19 patients, poorly differentiated adenocarcinoma or carcinoma 13, squamous cell carcinoma 7, and others 4. The median cycles was 4 (1 - 6). The objective response rate was 40% (95%CI: 25.7- 54.3%). 8 of 19 patients (42%) with W/M adenocarcinoma showed response. Median time to progression was 4.8 months and median survival was 11.4 months (95%CI: 7.1–20.9). The most frequent grade > or =3 adverse events were neutropenia (33%), thrombocytopenia (16%) and anemia (22%). Conclusions: The combination of CPT-11 and CBDCA is active regimen for CUP without favorable prognostic-factors and may be active for patients with W/M adenocarcinoma. No significant financial relationships to disclose.
Agreement between physician and patient performance status ratings in an outpatient setting.
Authors: Gordana Popovic, Ashley Pope, Thana Harhara, Nadia Swami, Lisa Le, Camilla Zimmermann
Journal: Journal of Clinical Oncology (2015)

66 Background: Performance status (PS) scores are generally completed by physicians, although patient PS measures are increasingly available. The objective of this study was to assess agreement between physician-recorded Eastern Cooperative Oncology Group (ECOG) PS and a patient-rated measure of performance status based on the ECOG measure in an outpatient oncology palliative care clinic. Methods: Physicians recorded ECOG PS for every patient as part of routine clinical practice. Patients recorded their PS using a measure based on the ECOG, where 0 = normal with no limitations; 1 = not my normal self, but able to be up and about with fairly normal activities; 2 = not feeling up to most things, but in bed or chair less than half the day; 3 = able to do little activity and spend most of the day in bed or chair; and 4 = pretty much bedridden, rarely out of bed. Patients also completed the ESAS-CS measure. Medical and demographic data were abstracted from the patients’ charts. We examined correlation between physician and patient PS measures as well as factors associated with a difference in patient versus physician measures for 949 patients with a visit between August 1, 2013 and December 31, 2014. Results: Weighted Kappa statistics indicated moderate inter-rater agreement at 0.32 (95%CI: 0.28-0.36). On average, patients rated their ECOG higher by 0.31 (95%CI: 0.25-0.37, p &lt; 0.0001); 40.7% of patients rated their PS worse, 41.9% the same, and 17.3% better than did physicians. Worst agreement was for ECOG 0 (5 of 25 patients rated 0 by physicians also rated 0 themselves, 20% agreement); the highest agreement was in those with physician-rated ECOG 3 (87/136 patients, 64% agreement). Older patients reported better PS than physicians (p = 0.002) while those with worse ESAS distress scores reported worse ECOG than physicians (p &lt; .0001). Conclusions: Patients tend to rate their PS as worse than rated by physicians, particularly those with greater symptom burden. However, older patients tend to rate their PS as better. This could be due to age bias of physicians or due to older patients assessing their PS optimistically. Future research will assess the survival data of participants to assess correlation of PS assessments of each group with prognosis.
Effect of a communication skills intervention on resident comfort and knowledge of discussing goals of care and advance care planning.
Authors: Rushil Virendra Patel, Elizabeth Golding, Aaron Lampkin, Mary Walker Larach, Lawrence Klima
Journal: Journal of Clinical Oncology (2016)

50 Background: Inpatient providers are sometimes challenged with advanced care planning for their patients. At a teaching hospital, resident physicians find themselves tasked with this responsibility for inpatients they may have only just met, as well as in their assigned outpatient panel. Education on communication skills though has been shown to improve resident comfort level and knowledge of discussing goals of care and advance care planning. Methods: Internal medicine categorical residents (n = 15) and preliminary (n = 3) residents at a university-affiliated, community hospital learned the fundamentals of discussing goals of care and advance care planning using selected modules from the Center for Advancing Palliative Care’s (CAPC) online curriculum in communication skills during their outpatient clinic rotation from February through June 2016. Residents then discussed a patient encounter from their experience with their colleagues along with a member from the inpatient palliative care team and a clinical psychologist in weekly 1-hour afternoon sessions. A pre- and post-intervention survey was administered and recoded by a numerical identifier to assess the change in each resident's comfort level and knowledge level with conducting these discussions with their patients. Sessions were also audiorecorded to identify recurrent themes and insights for future follow-up projects. Results: Preliminary analysis (n = 11) demonstrates a statistically significant improvement in the median difference between overall resident comfort level (p = 0.007) and knowledge (p = 0.027) of discussing goals of care and advance care planning. Several participants also expressed desires for additional opportunities to practice these skills under supervision by experienced providers. Conclusions: Residents value developing skills requisite to facilitate goals of care discussions and advance care planning. Further opportunities for practice and feedback should be identified.
Total Lymphocyte and Natural Killer (NK) Cell Count Day 30 Post-Transplant Strongly Predict Transplant Outcome after T Cell Depleted Allogeneic Stem Cell Transplantation.
Authors: Bipin N. Savani, Stephan Mielke, Katayoun Rezvani, Agnes Yong, Nancy Hensel, Elizabeth J. Read, Richard Childs, A. John Barrett
Journal: Blood (2006)
Pelvic exenteration in patients with nonmetastatic, locally advanced castration-resistant prostate cancer.
Authors: Timothy F. Donahue, Michael J. Morris, William M. Hilton, Howard I. Scher, Bernard H. Bochner
Journal: Journal of Clinical Oncology (2014)

168 Background: A subset of patients who present with localized prostate cancer (PCa) do not develop metastatic disease and recur locally after definitive primary therapy, local salvage therapy, hormones, and systemic intervention. We report our experience in patients with non-metastatic, locally advanced castration resistant prostate cancer (CRPC) treated with radical cystectomy or pelvic exenteration (RC/PEx). Methods: Institutional review board (IRB) approved retrospective review of all patients undergoing RC/PEx for non-metastatic, locally recurrent CRPC after definitive and salvage therapies. Patients were excluded if RC/PEx was for complications of definitive therapy alone. Results: Of 31 patients who had RC/PEx for PCa, 20 met inclusion criteria. Initial therapy was RP (4), XRT (6), brachytherapy (4), brachy/XRT (3), ADT/chemo (2), and ADT alone (1). Five patients had salvage XRT. All received ADT at relapse and 11 had chemotherapy prior to RC/PEx. RC/PEx was performed a median of 8.16 years (0.7 to 24.5) after PCa diagnosis. Patients had pT2b (1), pT3 (5), and pT4 (14) disease at surgery. Lymph nodes were clinically negative in all patients but pathologically positive in six, negative in nine, and not resected in five. Concurrent resections included rectum (12), pelvic wall (6), pubis (1), and iliac vein (1). Eighty five percent of patients had symptoms attributable to locally progressive PCa at RC/PEx including pain, genitourinary or gastrointestinal obstruction and bleeding. All symptomatic patients had relief of disease-related symptoms until recurrence. After a median follow-up of 3.12 years (0.7 to 13.4), nine patients are alive (four have no evidence of disease, five alive with disease), nine dead of disease, and two dead of other causes. Median time to death after RC/PEx was 2.8 years (0.8 to 5.9). For 14 patients who relapsed, metastases developed a median of 398 days (110 to 1,679) after RC/PEx. Ten patients received chemotherapy and 16 had androgen-deprivation therapy after surgery for local recurrence or distant metastases. Median time to chemotherapy after RC/PEx was 346 days (96 to 1,709). Conclusions: For patients with non-metastatic, locally advanced CRPC, RC/PEx to resect symptomatic disease is feasible and appears clinically beneficial. In addition to local control, it may confer significant disease free intervals and relief of symptoms. Even after relapse, performance status was sufficient to undergo systemic therapy.