tbuckley/cabot-search huggingface dataset:
SAMIT: Preliminary safety data from a 2x2 factorial randomized phase III trial to investigate weekly paclitaxel (PTX) followed by oral fluoropyrimidines (FPs) versus FPs alone as adjuvant chemotherapy in patients (pts) with gastric cancer.
Authors: A. Tsuburaya, K. Yoshida, M. Kobayashi, S. Yoshino, Y. Miyashita, S. Morita, K. Oba, M. E. Buyse, J. S. Macdonald, J. Sakamoto
Journal: Journal of Clinical Oncology (2011)

4017 Background: Recently, S1 has become a standard adjuvant chemotherapy for localized gastric cancer in Japan with no comparison among FPs so far. PTX is one of key drugs in gastric cancer especially for those with peritoneal metastases, for which serosal invasion is a major risk. SAMIT is an ongoing randomised phase III trial of adjuvant FPs (S1 or UFT) ± PTX in pts with SE or SI gastric adenocarcinoma. Methods: Pts received either A: UFT 267 mg/m2/day for 4w, every 4w x6; B: S1 80 mg/m2/day for 2w, every 3w x 8; C: paclitaxel 80 mg/m2 Day 1, 8 for the first 3w x1, Day 1, 8, 15 every 4w x2, followed by UFT 267 mg/m2/day for 4w, every 4w x3; or D: paclitaxel as in C, followed by S1 80 mg/m2/day for 2w, every 3w x4. The duration of treatment was amended from 24w to 48w by prolonging the part of FPs according to the results of ACTS-GC in 2007. Primary endpoint is disease-free survival and total number of patients was calculated to be 1480 where 90% power for superiority of C+D group and non-inferiority of UFT with 88% power in the upper equivalence margin of 1.25. The Independent Data Monitoring Committee undertook a review of the first 976 pts at the first interim analysis, and we present the preliminary safety data. Results: Between August 2004 and September 2009, 1,538 pts were accrued from 232 institutes, and 1495 pts were randomized. The pts who required dose reduction or skip between the first to third courses were 32%, 33%, 22%, and 27%; in the fourth to sixth courses were 18%, 20%, 18%, and 28% for A, B, C, and D, respectively. The compliance of UFT or S1 between the fourth to sixth courses were 76%, 86%, 81%, and 85% for A, B, C, and D, respectively. Grade 3/4 hematological toxicities were 0.8%, 0.4%, 1.6%, and 3.4%; grade 3/4 non-hematological toxicities were 7.3%, 7.2%, 2.4%, and 8.9% for A, B, C, and D, respectively. There was no treatment-related death. Conclusions: Preliminary safety data indicate comparable compliance; different but acceptable rates of complications in the 4 arms. The second interim analysis is currently undertaken and the final results will be formally assessed in 2012.
Phase I report from a multicenter trial of perifosine (PERI) + sunitinib (SUT) in patients with advanced cancers including renal cell carcinoma (RCC)
Authors: J. P. Allerton, B. Ebrahimi, M. T. Schreeder, P. Kaiser, S. P. Chawla, P. Sportelli, L. Gardner, R. Birch, I. C. Henderson
Journal: Journal of Clinical Oncology (2008)

14565 Background: PERI is an oral alkylphosphocholine that affects multiple signaling pathways, most importantly Akt, and is active in multiple tumor types including sarcoma and RCC. In a phase II trial, 6/9 (66%) RCC patients (pts) derived clinical benefit from PERI: 3 PR’s, 3 SD ≥ 6 mo’s (ASCO 2007 Abstract 15622). Pre-clinical data suggests the combination of PERI with other signal transduction inhibitors results in significantly more apoptosis. This potential synergism along with encouraging RCC results with both PERI and suninitib (SUT), led to a phase 1 trial to determine the MTD combining PERI with SUT. Methods: The trial was designed for 4 cohorts of 3 - 6 pts. The PERI dose was escalated from 50mg qd to 50mg tid and SUT from 25mg to 50mg qd for 4 weeks out of 6. NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade (G) 3 non-hematologic toxicity or G4 hematologic toxicity. The MTD is the dose cohort below that in which 2 DLT’s are observed. Response assessed by RECIST criteria was a secondary endpoint. Results: 14 pts (8 m / 6 f, median age 62 y, range 28 - 81) had been enrolled by 12/31/07. Disease type was as follows: RCC (3), Sarcoma (3), Other (8). 13/14 pts are evaluable for toxicity with most common related AE’s as follows: One DLT has been reported in cohort 4. 6 pts are evaluable for response with best response to PERI + SUT after ≥ 2 cycles as follows: PR - 1 pt, SD - 3 pts and PD in 2 pts. 3/3 RCC patients are evaluable for response with 1 PR, 1 SD and 1 PD. Conclusions: Pts to date have tolerated PERI + SUT well with no unexpected toxicities and clinical activity has been noted within the first 3 cohorts with 4 of 6 (67%) evaluable pts with advanced cancer achieving at least SD (≥ 6 mo’s). 1 PR has been seen. Accrual is in the last cohort and final results in this phase I will be updated at the meeting. Adverse Event Cohort 1 N=3 Cohort 2 N=3 Cohort 3 N=6 Cohort 4 N=2 PERI Dose (mg) 50 50 100 150 SUT Dose (mg) 25 50 50 50 Nausea 3 G1 2 G1 4 G1 1 G1, 1G2 Vomiting 1 G1 2 G1 1 G1, 1 G2 1 G3 Diarrhea 1 G1 3 G1, 1 G1 Fatigue 1 G1, 1 G2 1 G1, 1 G2 2 G2 2 G3 Hand/foot Syndrome 1 G1 1 G1 Rash 1 G1 1 G1 Hypertension 1 G3 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Keryx Biopharmaceuticals Keryx Biopharmaceuticals Keryx Biopharmaceuticals Keryx Biopharmaceuticals
Clinical and Technical Aspects of Genomic Diagnostics for Precision Oncology
Authors: Yuri Sheikine, Frank C. Kuo, Neal I. Lindeman
Journal: Journal of Clinical Oncology (2017)

The emergence of precision medicine has been predicated on significant recent advances in diagnostic technology, particularly the advent of next-generation sequencing (NGS). Although the chemical technology underlying NGS is complex, and the computational biology expertise required to build systems to facilely interpret the results is highly specialized, the variables involved in designing and deploying a genomic testing program for cancer can be readily understood and applied by understanding several basic considerations. In this review, we present key strategic decisions required to optimize a genomic testing program and summarize the technical aspects of different technologies that render those methods more or less suitable for different types of programs.
Efficacy of continuous venous infusion of fluorouracil and consecutive low-dose cisplatin as adjuvant treatment in resectable colorectal cancer: a prospectively randomized trial
Authors: F. Hata, K. Hirata, K. Sasaki, T. Tsuruma, T. Furuhata, H. Nishimori, T. Honma, T. Yasoshima
Journal: Journal of Clinical Oncology (2005)

3696 Background: Low-dose cisplatin (CDDP) is used as an efficient modulator of fluorouracil (5-FU), as is leucovorin. On the other hand, in Japan, adjuvant therapy using oral fluoropyrimidines after curative resection of a colorectal tumor has been achieved since the 1980s. For many years, oral fluoropyrimidines have been frequently used in the adjuvant setting for curatively resected colorectal cancer. We performed a randomized trial to compare the efficacy and toxicity of a continuous venous infusion of 5-FU plus low-dose CDDP (low-dose FP) treatment followed by oral 5-FU with those of oral 5-FU alone in Dukes’ B and C colorectal cancer in the adjuvant setting. Methods: One hundred and eighty-two patients were enrolled. Patients were randomly assigned to receive a treatment of low-dose FP (5-FU; 320 mg/m2, days 1–21, CDDP; 3.5 mg/m2 daily for 21 days) followed by oral 5-FU (200 mg/day daily for 2 years) or an oral 5-FU treatment (200 mg/day daily for 2 years) exclusively. Results: The 5-year disease-free survival (DFS) and the 5-year overall survival (OS) indicated no significant difference between the two groups. By stratified analysis, in the colon cancer patients, the DFS in patients receiving low-dose FP treatment was significantly increased: 93.5% in the FP treatment group as compared with 76.9% in the oral 5-FU group (p=0.024). However, in the rectal cancer patients, there was no difference between the oral 5-FU group and the low-dose FP treatment group (5-year DFS; 60.0% vs. 59.4%, p=0.887). After covariate adjustment, the low-dose FP treatment improved the hazard risk of relapse in the colon cancer patients (HR=0.301, 95%CI. 0.081–1.115, p=0.072). Grade 3–4 toxicities were low in the two groups. Conclusions: In the overall analysis, this study failed to show improvement in DFS or in OS. However, the subgroup with colon tumors treated with low-dose FP followed by oral 5-FU seemed to have a DFS advantage in comparison with the oral 5-FU treatment. Low-dose FP has mild toxicities and is a tolerable regimen. These data suggest that low-dose FP followed by oral 5-FU is a feasible regimen for cancer patients with a resected colon cancer patients. No significant financial relationships to disclose.
Attempt to improve the safety of development studies with a new design for phase I combination trials of targeted therapies: The PARASOL trial.
Authors: S. Negrier, D. Pérol, J. Soria, S. Chabaud, S. Metzger, B. Escudier
Journal: Journal of Clinical Oncology (2010)

TPS165 Background: The combination of 2 agents is an important way to improve treatment efficacy. Phase I trials are required to determine the maximum tolerated doses (MTD) defined by the occurrence of limiting acute toxicities. This produces very limited data and does not preclude from long exposure subacute toxicities often observed with targeted therapies. These results do not predict the feasibility of combinations in subsequent efficacy trials. A phase I trial of bevacizumab (Bev) and sunitinib (Feldman et al, J Clin Oncol 2009) in patients (pts) with metastatic renal cell carcinoma (mRCC) detected subacute or chronic toxicities that were not identified from the MTD endpoint. Similar results were observed in a randomized phase II trial (SABRE-R, AVF 4167g: clinicaltrials.gov). Of note, the same combination used in a solid tumour population gave different conclusions and seemed feasible (Rini et al, Clin Cancer Res 2009). Based on these experiences, we aimed at building a specific phase I design in order to reinforce the safety and feasibility of targeted therapy combination regimens. Methods: We designed a new phase I trial concept, the PARASOL trial, using a novel endpoint:the Optimal Long Exposure Dose (OLED). Bev will be combined to pazopanib (Paz), a new selective oral multityrosine kinase inhibitor just approved in mRCC by the FDA, in pts with mRCC and other advanced refractory tumors. The primary endpoint is the OLED of Paz with Bev. The OLED represents the dose level, less than or equal to the MTD, where <= 2/7-8 or <= 3/9 pts experience definitive treatment discontinuations of any cause but disease progression, observed between 4 to 24 weeks of treatment. The secondary endpoint is the MTD defined in a 3+3+3 escalation design, as the dose level below the DLT observed in at least 2/3, 3/6 pts or finally in ≥ 3/9 pts, during the first 2 cycles (i.e. 56 days). The starting doses are Bev: 7.5mg/kg q2w in combination with Paz: 400 mg od continuously. Conclusions: Combination phase I trials using OLED will identify of subacute toxicities and should improve the safety and feasibility of further developments. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO, GlaxoSmithKline, Novartis, Pfizer, Roche Bayer, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth GlaxoSmithKline, Roche
Mutations of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC)
Authors: M. Sonobe, H. Katakura, T. Adachi, H. Wada, F. Tanaka
Journal: Journal of Clinical Oncology (2005)

7070 Background: Mutations within tyrosine kinase domain of the EGFR gene have been identified as a potential predictor of EGFR inhibitor treatment for NSCLC patients. Detailed characteristics of EGFR gene mutations in NSCLC patients should be clarified, especially in correlation with their clinical and other genetic characteristics as well as EGFR-downstream signaling alternation. Methods: Mutations of EGFR, p53 and k-ras genes as well as hypermethylation of p16, RASSF1A and APC1A gene were examined on surgical specimens obtained from 230 NSCLC patients. Expression of p-AKT and p-MAPK was evaluated immunohistochemically. Results: Among all 230 cases, 82 cases (35.6%, 81 adenocarcinoma [Ad] cases and 1 large cell carcinoma [La] case) showed EGFR mutations (deletion mutations within the exon 19 in 51 and point mutations within the exon 21 in 31 cases). As EGFR mutations were observed exclusively in Ad or La cases (n=181), subsequent analyses were performed in these cases. Incidence of EGFR mutations was significantly higher in female than in male (66.7% vs. 28.0%, P<0.001), in non-smoker than in smoker (73.3% vs. 25.5%, P<0.001), and in well-to-moderately differentiated tumors than in poorly differentiated tumors (56.0% vs. 7.7%, P<0.001). The incidence of k-ras mutations within codon-12 was 6.8%, and no k-ras-mutated tumor showed EGFR mutation. EGFR mutation status was not correlated with p53 gene mutation status or hypermethylation status of any gene. There was no significant difference in expression status of p-AKT or p-MAPK according to the status of EGFR mutations. Conclusions: EGFR mutations were frequently observed in Ad patients without smoking history. EGFR mutations may play a key role in development of smoking-independent Ad. No significant financial relationships to disclose.
Incorporating comparative effectiveness research study endpoints into the treatment for positive-node, endocrine-responsive breast cancer (RxPONDER) study.
Authors: S. D. Ramsey, W. E. Barlow, C. Moinpour, A. M. Gonzalez-Angulo, G. N. Hortobagyi, D. L. Veenstra, L. P. Garrison, S. R. Tunis, L. H. Baker
Journal: Journal of Clinical Oncology (2011)

TPS101 Background: The Center for Comparative Effectiveness Research in Cancer Genomics (CANCERGEN RC2 CA148570) is an NCI-funded “Grand Opportunity” grant designed to integrate comparative effectiveness research (CER) into prospective SWOG trials. In collaboration with SWOG investigators CANCERGEN assisted in the design of the RxPONDER Study. This prospective randomized trial is evaluating the role of Oncotype DX-guided therapy vs. usual care among women with lymph node-positive, endocrine-responsive breast cancer. Methods: Process: CANCERGEN created an external stakeholder advisory group (ESAG)—comprised of health insurers, pharmaceutical and device industry representatives, clinicians, and patient advocates—to work with SWOG clinical trials developers to incorporate CER perspectives and endpoints into the clinical trial. ESAG members met in person and on conference calls with SWOG representatives. Design: Women with endocrine-responsive HER2-negative breast cancer involving 1-3 lymph nodes are invited to enroll and receive a test based on the 21 gene assay. Those with RS score ≤ 25 are randomized to chemotherapy followed by endocrine therapy or endocrine therapy alone. The primary outcome is to determine whether disease-free survival (DFS) for patients treated with chemotherapy compared to no chemotherapy depends directly on the RS score. CER modifications: After consultation with the ESAG, CER-related endpoints were added, including those related to the decision process following RS results (Anxiety, decision conflict, perceptions of testing), PROMIS measures of fatigue and cognitive function, general health status and preference for health states (EuroQol-5D), health utilization, and costs. In addition, economic modeling and trial data will be used to assess the cost effectiveness of management using RS vs. usual care. One thousand women will complete the patient-reported outcome (PRO) measures before and after RS testing; 500 will be assessed in the clinical trial. Size/Timing: 9,400 women will be tested to recruit 4,000 patients over 6 years; the study was activated in January 2011 with clinical trial registry: NCT01272037.
Neuroendocrine tumors (NETs) of unknown primary: Is early surgical exploration and aggressive debulking justifiable?
Authors: Yi-Zarn Wang, Jeffery Rau, Anne E. Diebold, Adwoa Opoku-Boateng, J Philip Boudreaux, Eugene Woltering
Journal: Journal of Clinical Oncology (2013)

166 Background: Neuroendocrine Tumors (NETs) are rare tumors that often present with vague symptoms. Identification and localization of the primary NET can be challenging and up to 10% of patients are classified as having an unknown primary. These patients have been thought to have a poor prognosis compared to those patients with a known primary. Treatments for patients with unknown primaries are directed towards symptom control and/or cytoreduction of metastatic disease. We hypothesized that early surgical exploration and discovery of a previously unknown primary will increase long-term survival. Methods: The charts for all 342 surgical patients, seen in our clinic between 1/2009-9/2012 were retrospectively reviewed to determine which patients had a pre-operative diagnosis of a “NET with unknown primary”. Twenty-six patients were identified. For these patients, the rate of successful surgical exploration in which a primary site was identified were recorded. Clinical outcomes for these “unknown primary” patients were compared to historical survival data for patients with unknown primaries that did not undergo a surgical exploration in search of a primary. Results: Twenty-six (26/354, 7%) NET patients with a pre-operative diagnosis of an unknown primary were explored and cytoreduced. The primary tumor site was identified in all 26 patients (100%). The primary sites identified for these patients were 23 ileal (88.4%) and 3 pancreatic (11.6%). All twenty-six patients were still alive as of 9/2012 therefore, a survival curve could not be generated. Conclusions: Unknown primary NETs are not associated with a poor prognosis should timely surgical exploration and debulking result in an identification of the primary and a maximum cytoreduction. Early surgical exploration with aggressive debulking is indicated for the treatment of these patients.
Off-label prescribing of antidepressants
Authors: Daniel R Morales, Bruce Guthrie
Journal: BMJ (2017)

Strength of evidence matters more than presence or absence of a specific licence 

In most countries, medicines have a product licence that describes how they should be used. Licensing is intended to ensure that medicines meet acceptable standards of efficacy, safety, and quality for a particular indication in a particular group of patients.1 “Off-label” use occurs when a drug is prescribed for an unlicensed indication, to an unlicensed patient group (such as children), and/or as an unlicensed dosage or formulation. In their paper (doi:10.1136/bmj.j603), Wong and colleagues found that almost a third of antidepressants were prescribed for off-label indications, most commonly pain, insomnia, and migraine.2

Clinicians can legally prescribe off-label, and professional licensing agencies recognise that off-label use is necessary if licensed medicines are ineffective, if they are associated with adverse effects, or if the licensed dose or formulation does not meet the patient’s needs. Professional responsibility in these circumstances is fundamentally the same as for on-label prescribing. As the UK medical regulator says, “We …
Treatment-related microangiopathic glomerulopathy and severe chronic kidney disease (CKD) in recurrent epithelial ovarian cancer (rEOC): A possible relationship with pegylated liposomal doxorubicin (PLD).
Authors: M. Kwa, R. A. Baumgartner, L. Shavit, I. Barash, J. Michael, I. Puzanov, J. Kopolovic, O. Rosengarten, A. Hung, H. Jones, A. Gabizon, F. Muggia
Journal: Journal of Clinical Oncology (2011)

e15551 Background: Treatment-related CKD and hypertension (HTN) are emerging as problems in patients receiving multiple treatments for recurrent epithelial ovarian cancer (rEOC). Methods: 8 patients (pts) treated for rEOC with PLD for >1y manifested stage 4/5 CKD and HTN prompting retrospective analysis of pts in studies and practice of the senior authors. Results: See table. #1&2 (SZMC) were among 73 patients on PLD for rEOC; none of 40 on PLD for breast cancer and sarcoma had CKD; #3-8 (NYU) were among 56 consecutive rEOC pts on PLD. All received carboplatin (C)/paclitaxel (T) induction (#3&4 also had cisplatin) and upon recurrence received C and PLD >1y until noting ↑creatinine (Cr) and HTN; some also had bevacizumab (B) and gemcitabine (G). Three had microangiopathy on kidney biopsy. Hemodialysis (HD) was planned in 6, but ↓Cr allowed delaying HD in 4. Progressive disease (PD) prompted more chemotherapy in 7, leading to death in 3. Conclusions: CKD after PLD may reflect a cumulative damage of PLD manifesting only after prolonged treatment of rEOC. However, findings suggest that platinum-induced subclinical renal damage predisposes to CKD and HTN upon exposure to PLD, B, and G. This leads to questioning routine use of 6 cycles of platinums for rEOC and type and duration of maintenance therapy. Prophylactic measures (adapted from anthracycline-related murine models of CKD) need study. Patient Age at diagnosis (y) Drugs for recurrence (cumulative dose, mg/m2) CKD diagnosis (peak Cr) Outcome 1 34 PLD (1,445) Stage V (5.5), renal biopsy: thrombotic microangiopathy, HD <1y, stable to improved Cr PD: on T 2 56 C, PLD (1,140) Stage IV (2.8), stable to improved Cr PD: on T 3 58 C, PLD (1,730) Stage V (5.0), HD x 2y DOD (age 67) 4 61 C, PLD (905), B, G Stage V (5.2), renal biopsy: thrombotic microangiopathy, stable to improved Cr PD: on T 5 64 C, PLD (2070) Stage V (5.1) DOD (age 69) 6 60 C, PLD (960), B Stage IV (2.6) DOD (age 61) 7 64 C, PLD (1120) Stage V (4.9), refused HD NED, died of CHF and ESRD (age 65) 8 58 C, PLD (880), G Stage V (5.0), renal biopsy: thrombotic microangiopathy, stable to improved Cr PD: on T Abbreviations: DOD, dead of disease; NED; no evidence of rEOC.