tbuckley/cabot-search huggingface dataset:
Cost comparison and economic implications of commonly used originator and generic chemotherapy drugs in India.
Authors: Gilberto Lopes, Hrishikesh Kulkarni, Vivek Bele
Journal: Journal of Clinical Oncology (2013)

e17505 Background: Generic substitution may lead to increased access to cancer drugs. Little data have been published on cost savings in emerging markets. Methods: Estimate of cost and savings per cycle, per patient, and for India with generic drugs. Cost of paclitaxel, docetaxel, gemcitabine, irinotecan and oxaliplatin was obtained for originator branded and generic versions from a distributor in India. Costs are depicted in 2012 Rupees. Utilization was based on a BSA of 1.7, standard doses, expected lenght of treatment for common oncology indications and incidence data from GLOBOCAN. Results: Generic drugs cost from 8.9% to 36% of their equivalent branded originator drug, resulting in cost-savings of approximately INR 11,000 to 90,000 [US$ 200-1,600] per each drug per cycle; and approximately INR 50,000 to 240,000 [US$ 900-4,300] per patient treated. Overall, potential yearly savings for health systems in India were nearly INR 47 billion [US$ 843 million]. Conclusions: Generic substitution for commonly used chemotherapy agents has an enormous potential to generate significant cost-savings and increase access to cancer treatments in India and other low and middle income countries. [Table: see text]
An evaluation of phase I clinical trial designs of chemotherapeutic agents tested on solid tumors and approved in last 10 years.
Authors: Chetan Dilip Deshmukh, Ganesh Divekar, Shailesh Arjun Bondarde, Minish Mahendra Jain, Kumar Prabhash
Journal: Journal of Clinical Oncology (2012)

e13127 Background: Phase I trials are performed with the aim of finding the maximum tolerated dose and often start with a very low dose that is subsequently escalated based on the toxicity seen. As a result patients treated on these trials often receive doses of chemotherapeutic agents that are frequently either below or above the biologically active level, thus reducing their chances for therapeutic benefit or increasing chances for toxicity. This evaluation was undertaken to determine how phase I trials are currently conducted and to correlate phase I doses tested with MTD and marketed doses. Methods: Published phase I trials of 16 chemotherapeutic agents tested on solid tumors and approved in last 10-years were identified by searching the Medline database and reviewed to determine methodology employed, cohorts taken to complete the trial, definition of dose limiting toxicity (DLT), number of cohorts treated below MTD, relation between MTD and marketed dose and DLT (dose limiting toxicity). Results: Twenty-three published trials involving 891 patients were identified. These trialsused the standard method of enrolling cohorts of patients at increasing dose levels and observing toxic effects to determine next dose.. Of these 15 used traditional dose escalation, 6 used accelerated titration, 2 used continual reassessment method. Six trials that used accelerated titration method of dose escalation, 2 were used to test cytotoxic agent (5 trials) while 1 tested targeted therapy. Sixty five cohorts were treated below MTD. Average number of cohorts required to complete trial were 6.2. Nineteen trials defined MTD as a dose below DLT dose while 4 trials defined MTD being DLT. Five of 23 trials were completed with-out reaching MTD. Marketed dose for these 16 chemotherapeutic agents was 0 to 50% lower than MTD. DLT reported was myelosupression, fatigue, rash, hypertension or diarrhea. Conclusions: These results show the need for methods to reduce cohorts to reduce number of patients recruited at doses significantly lower than MTD and complete the trials rapidly so that effective agents can be marketed sooner.
Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.
Authors: Richard J. Lee, M. Dror Michaelson, Philip James Saylor, Carol Ann Gurski, Stephen M. Rothenberg, David Tomoaki Miyamoto, Shyamala Maheswaran, Daniel A. Haber, Jonathan G. Goldin, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2012)

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. &lt;8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to &lt;5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.
Morphoproteomics of mTORC2 pathway as resistance signature and activated ERK and STAT3 prosurvival/antiapoptotic pathways in metastatic renal cell carcinoma (mRCC) progressing on rapalogs.
Authors: Swetha Siddappa Yadav, Jamie Buryanek, Robert E Brown, Fangqian Ouyang, Robert J. Amato
Journal: Journal of Clinical Oncology (2013)

e15548 Background: Resistance to rapalog therapies (rapamycin, temsirolimus or everolimus) in mRCC may be due to adaptive switching from mammalian target of rapamycin complex (mTORC)1 to mTORC2. A preclinical study using an agent targeting both complexes demonstrated the combination is more effective than temsirolimus in vitro but not in xenograft models (Zhang 2013 PLos One). Methods: Morphoproteomic analysis of mRCC biopsies showed progression while the patients were treated with everolimus or temsirolimus at the time of biopsy. Constitutive activation evidenced by expression (≤3) of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment coupled with concomitant expression of p-Akt (Ser 473) favors mTORC2 and constitutive activation by p-extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) and p-signal transducer and activator of transcription (STAT)3 (Tyr705) in the nuclear compartments (≤3) indicates convergent signaling through prosurvival/antiapoptotic pathways. Results: Overexpression of mTORC2 with strong expression of p-ERK1/2 and p-STAT3 indicates adaptive switch from mTORC1 to mTORC2 pathway and constitutive activation of prosurvival/antiapoptotic pathways (Table). Overexpression of mTORC1 with strong expression of p-ERK 1/2 and p-STAT3 indicates adaptive resistance to everolimus. Equal expression of mTORC 1 and 2 with concomitant strong expression of p-ERK1/2 and p-STAT3 indicates resistance to everolimus and constitutive activation of the adaptive prosurvival/antiapoptotic pathways. Conclusions: Morphoproteomics confirms mTORC2 as resistance signature to rapalog therapy and uncovers constitutive activation of the prosurvial ERK and STAT3 pathways as additional adaptive mechanisms to such treatment, indicating the need for a combinatorial therapeutic approach in mRCC progressing on rapalogs. [Table: see text]
Screening for Pancreatic Cancer—Is There Hope?
Authors: Anne Marie Lennon, Ralph H. Hruban, Alison P. Klein
Journal: JAMA Internal Medicine (2019)

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A retrospective analysis of early CA19-9 progression in salvage-chemotherapy for refractory pancreatic cancer.
Authors: Yousuke Nakai, Hiroyuki Isayama, Takashi Sasaki, Naminatsu Takahara, Hirofumi Kogure, Natsuyo Yamamoto, Kenji Hirano, Hideaki Ijichi, Keisuke Tateishi, Minoru Tada, Kazuhiko Koike
Journal: Journal of Clinical Oncology (2013)

e15146 Background: Early response assessment is important to differentiate patients (pts) who will benefit from salvage chemotherapy (sCx) for refractory pancreatic cancer (PaC), given its palliative nature. CA19-9 has been reported as a prognostic factor in the first-line treatment, but little data is available in sCx. Methods: Pts receiving sCx for refractory PaC at the University of Tokyo Hospital were retrospectively studied. Serum CA19-9 was measured prior to the initiation of each course. Cumulative progression-free (PFS) and overall survival (OS) were calculated by Kaplan-Meier analysis and compared by log-rank test. Prognostic value of CA19-9 change prior to 2 nd course was evaluated using a landmark method. Finally, multivariate analyses by the Cox proportional hazard model were performed for PFS and OS. Possible prognostic factors were age, gender, PS, disease status, metastatic site, pretreatment albumin, LDH, CRP, CA19-9, CA19-9 change prior to 2 nd course, prior PFS, treatment line (2 nd line or beyond) and sCx agents. Results: A total of 167 pts (a median age of 65, 95 males, 21 recurrent and a median previous PFS of 5.8 Mo) received 239 regimens as sCx including S-1(n=87), CPT-11 (n=53), GEM+oxaliplatin(Ox) (n=20), S-1+Ox(n=29), GEM (n=14) and S-1+paclitaxel iv+ip (n=12). Median PFS and OS were 2.7 (95%CI, 2.4-3.1) and 6.1 (95%CI, 5.3-7.2) Mo, respectively. Early CA19-9 progression was defined as CA19-9 increase &gt;17.8%, a median value of CA19-9 change prior to 2 nd course in this study population. Median PFS and OS were 2.6 vs. 1.0 Mo and 7.5 vs. 3.6 Mo (p&lt;0.001) after landmark CA19-9 measurement in pts with and without CA19-9 response. Multivariate analyses demonstrated early CA19-9 progression was a negative prognostic factor of both PFS and OS (HR 1.75 and 2.04, p&lt;0.001). Pretreatment serum markers (albumin, LDH, CRP and CA19-9) were prognostic of OS, but not PFS. Conclusions: Early CA19-9 progression was a negative prognostic factor of both PFS and OS in S-Cx for refractory PaC. Early termination should be considered in these patients who would less likely benefit from sCx.
Platinum-based combinations as first-line chemotherapy in advanced, persistent, or recurrent cervical cancer.
Authors: Svetlana Vladimirovna Limareva, Svetlana Victorovna Khokhlova, Anastasiya Sergeevna Odintsova, Marina Valerievna Cherkasova, Liliya Igorevna Vinogradova, Vera A. Gorbunova
Journal: Journal of Clinical Oncology (2012)

e15543 Background: Platinum compounds are the most active agents in cervical carcinoma. The aim of this study was to evaluate the activity and toxicity of platinum-based chemotherapy as first line treatment in patients with advanced/recurrent cervical cancer. Methods: Since 2005 to 2011years 68 pts were include in the pilot study. Patients with histological proven primary carcinoma, measurable tumors, age ≥ 18, PS of 0-1, adequate bone marrow, renal and hepatic functions were eligible for this trial. Prior chemotherapy was allowed only in the context of radiosensitization. Treatment consisted of 2 modes: PC - paclitaxel 175 mg/m2 3-h I.v. + cisplatin 75 mg/m2 or carboplatin AUC-6 ( 6 pts)- d1x 21d; IC – irinotecan 65 ìg/m2 + cisplatin 40 mg/m2 on d 1 and 8 x 21 d. Responses were assessed using RESIST. Results: 68 pts were identified. There were no differences between the groups in terms prior radiation or radiochemotherapy. Group PC: 28 pts were included. Efficacy and toxicity was available for 27. Two pts continue treatment. Median age 43,5 years (range 28-69). The ORR was 55.5% (CR - 5(18.5%) and PR -10(37.0%)). 8 pts (29.6%) SD and 4 (14.8%) PD. The median TTP was 7 months. Overall, 148 cycles were administered with a median of 5 (range 2-8) cycles. Major toxicities were as follows: GIII and GIV neutropenia in 22.2% and 11.1% pts; GIII anemia - in 2 pts; GI-II neuropathy in 45.9% pts. G III nausea/vomiting were in 3 pts (11.1%). Group IC: 40 pts were included, 38 were available for efficacy. Median age 49,8 years (range 25-67). The ORR was 47.3% (5 CR(13.2%) and 13 PR (34.2%)). 13 (34.2%) pts had SD and 7 (18.4%) - PD. The median TTP was 6 months. All 40 pts receved 254 cycles ( median 6.3 (range 1-11) cycles. GIII and IV neutropenia were in 40% and 10% pts; GIII anemia in 20% pts. G I-II neuropathy and G I-II diarrhea in 15% pts and 30%pts. G IV of diarrhea observed in 1 pt. GIII-IV nausea and vomiting were in 20% and 15%pts. There were no statistical differences in clinical outcome (OR(p= 0,69) and TTP(p=0,65)) between these 2 platinum-based regimes. Conclusions: Our data indicate that both regimes had high efficacy and well tolerated as first line treatment in patients with advanced/recurrent cervical cancer. The randomized study is necessary.
A phase II trial of concurrent chemoradiaiton with paclitaxel/carboplatin in high-risk cervical cancer patients after radical hysterectomy: A multicenter prospective Korean study
Authors: T. Lee, S. Kang, Y. Kim, B. Park, Y. Kim, J. Lee, S. Kim, Y. Kim, J. Kim, K. Kim
Journal: Journal of Clinical Oncology (2007)

5598 Background: In 1999, five randomized studies demonstrated that cisplatin based chemoradiation had a benefit over radiotherapy in cervical cancer. However, paclitaxel has been known to be safe and effective as a radiosensitizer, and carboplatin to be less toxic than cisplatin with simpler administration. Therefore, the object of this study was to evaluate the 2 year disease free survival and toxicity of high risk cervical cancer patients who received chemoradiation with paclitaxel/carboplatin. Methods: Seventy-one patients with at least one high risk factor after radical hysterectomy (metastasis to pelvic lymph nodes (LNs), invasion of parametrial tissue (PMs), positive vaginal resection margin) were administered 135 mg/m 2 of paclitaxel, carboplatin (AUC = 5) every 3 weeks for 3 cycles as an adjuvant treatment. Radiotherapy was concomitantly administered to the whole pelvic region in 28 fractions totaling 4.5∼5.4Gy. Results: Median age was 49 (range: 26–80). Seven women were dropped from the study due to noncompliance and two patients did not complete treatment due to anaphylactic shock and prolonged infection. In total, sixty-two patients completed the protocol treatment. Of 211 chemotherapy cycles administered, grade 3 or 4 neutropenia occurred in 85 (40.3%) and the majority were transient. Dose reductions were in 7 cycles due to prolonged (over 4 days) neutropenia (6), and elevated liver enzyme (1). Febrile neutropenia occurred in only two patients. 14 patients experienced grade 3 or 4 non-hematologic toxicities: 1 sensory neurotoxicity, 2 fatigue, 4 diarrhea, 3 allergic reaction, 2 genitourinary, 2 hepatic, with no treatment related deaths. With a median follow-up of 20.1 (16–28) months, 8 patients experienced recurrences, 2 distant lung metastasis and 6 pelvic side wall or paraaortic recurrences (DFS: 87.1%, 95CI:78.8∼95.4). Conclusions: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and appears effective in early stage high risk cervical cancer patients. Considering the advantages of lower toxicity and shorter treatment schedule, this regimen shows promise and should be further tested on a larger number of patients with a prolonged follow-up. No significant financial relationships to disclose.
Abstract O.67: Carotid Intima-media Thickness In Patients With A History Of Kawasaki Disease
Authors: Sanne Dietz, Carline Tacke, Johan Gort, Irene Kuipers, Eric de Groot, Albert Wiegman, Barbara Hutten, Taco Kuijpers
Journal: Circulation (2015)

Aims: Kawasaki disease (KD) is an acute pediatric vasculitis with the development of coronary artery aneurysms (CAA) being recognized as a serious clinical complication of KD. It has been suggested that KD predisposes to premature cardiovascular disease (CVD) later in life, however, conflicting results have been reported. We therefore assessed the risk of CVD in patients with a history of KD. Methods and results: Carotid B-mode ultrasound scans and measurements of carotid intima-media thickness (cIMT), a validated marker of CVD risk, were performed in 161 KD patients (119 with CAA, 42 without CAA based on worst-ever z-score; age range: 7-20 years). CIMT measurements were also performed in 82 unaffected family controls in the same age range. Differences in cIMT between patients and controls were evaluated by linear regression analyses while correcting for confounders by stepwise backward elimination. Mean cIMT (±SD) was increased in patients with KD (0.378 ± 0.030 mm versus 0.360 ± 0.027 mm; P adjusted &lt; 0.0001). If the difference in cIMT between patients and controls was plotted against age, in patients without CAA, increased cIMT was only apparent at young age, whereas in patients with CAA increased cIMT was observed over the entire age range. Conclusion: Our findings in KD patients show significant arterial wall changes in patients with a history of KD, in particular in those with CAA. In contrast to the cIMT findings at young age - irrespective of the absence or presence of CAA, the data demonstrate that - with age - the cIMT in KD patients without CAA became indistinguishable from controls but remained increased in the patients with CAA. The age-dependency of cIMT values could in part explain the variable and conflicting results of previous reports in KD. Furthermore, these explicit differences in cIMT between CAA-negative and CAA-positive patients may suggest that the pathophysiology of the arterial wall changes in KD differ from atherosclerosis. Finally, our results indicate that follow-up in patients with KD seems justified in patients with CAA, but may not be necessary in children without CAA.
How liquid biopsies can change clinical practice in oncology
Authors: G. Siravegna, B. Mussolin, T. Venesio, S. Marsoni, J. Seoane, C. Dive, N. Papadopoulos, S. Kopetz, R.B. Corcoran, L.L. Siu, A. Bardelli
Journal: Annals of Oncology (2019)

Cell-free DNA fragments are shed into the bloodstream by tumor cells. The analysis of circulating tumor DNA (ctDNA), commonly known as liquid biopsy, can be exploited for a variety of clinical applications. ctDNA is being used to genotype solid cancers non-invasively, to track tumor dynamics and to detect the emergence of drug resistance. In a few settings, liquid biopsies have already entered clinical practice. For example, ctDNA is used to guide treatment in a subset of lung cancers. In this review, we discuss how recent improvements in the sensitivity and accuracy of ctDNA analyses have led to unprecedented advances in this research field. We further consider what is required for the routine deployment of liquid biopsies in the clinical diagnostic space. We pinpoint technical hurdles that liquid biopsies have yet to overcome, including preanalytical and analytical challenges. We foresee how liquid biopsies will transform clinical practice: by complementing (or replacing) imaging to monitor treatment response and by detecting minimal residual disease after surgery with curative intent.
The association of human epidermal growth factor receptor-2 (HER-2) expression with clinicopathologic findings in patients with colorectal cancer receiving adjuvant therapy.
Authors: Halit Karaca, Veli Berk, Mevlude Inanc, Kemal Deniz, Metin Ozkan
Journal: Journal of Clinical Oncology (2012)

e14089 Background: Colorectal cancers (CRC) are the third frequent cancer worldwide. Like in other cancers; factors which might be associated with prognosis and treatment of the disease are investigated in molecular basis. In this study, it was aimed to determine the levels of HER-2 expression and it’s association with clinicopathological findings in patients with CRC receiving adjuvant therapy. Methods: A total of 80 patients (48 female, 32 male) whom were diagnosed with CRC and received adjuvant FOLFOX-4 from March 2006 to September 2010 were included in the study. The parameters; age, gender, histopathological diagnosis, tumor localization, presence of obsruction-perforation-bleeding history, grades, presence of perineural-lymphovascular invasion, pathological TNM staging at time of diagnosis, findings of relapse-metastasis, history of surgery and radiotherapy, the chemotherapy regimens received in adjuvant and metastatic stages, follow up intervals and survival data were analyzed. HER-2 receptors were stained immunohistochemically. FISH was performed for samples which were stained (++) or (+++). Statistical analysis was performed for the data. Results: Median follow up was found 24 months (min-max: 1-67) and median age was 59 (min-max: 33-84). Thirteen patients (16%) died and 17 patients relapsed (21%) during follow-up. The median disease-free survival was found 55 months (95% CI: 42.84-55.95). Themedian overall survival was not reached yet.In immunohistochemical stainings; (+++) staining was found in 2 patients (2.5%) while (++) was in 13 (16%) patients. All of 15 patients were performed FISH for HER-2; samples which were (+++) showed positivity but the ones with (++) were negative for FISH. No significant correlation was found between HER-2 expression and clinicopathological findings (p&gt;0.05). Also, no statistical significance was found between HER-2 expression and survival (p&gt;0.05). Conclusions: To current data; prognostic and predictive value of HER-2 overexpression for CRC seems to be poor. Larger, prospective and long-lasting studies are required to clarify this controversial topic.
Elipsis: A Longitudinal Study of Electronic Patient-Reported Outcomes, Actigraphy and Biomarkers to Identify and Assess at-Home Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease
Authors: Michael U. Callaghan, Patrick C. Hines, Debra D Pittman, David Beidler, Denis Rybin, Ahmar Urooj Zaidi, Jennell White, Ke Liu, Bryan Hannan, Xiufeng Gao, Andreas M Pleil, Alexandra Barsdorf, Martin David, Melanie Simmons, Andrew L Frelinger, Alan D Michelson, Nick Clarke, Robert J Charnigo
Journal: Blood (2017)