tbuckley/cabot-search huggingface dataset:
Meta-analysis of outcomes of VEGF and EGFR targeted biologic therapy in relapsed metastatic colorectal cancer (mCRC).
Authors: David Chan, Eva Segelov, Jeremy David Shapiro, Timothy Jay Price, Christos Stelios Karapetis, Niall C. Tebbutt, Nick Pavlakis
Journal: Journal of Clinical Oncology (2014)

534 Background: Biologic therapies used in treatment of mCRC are expensive and there is debate about their value. We examined the impact of biologic therapy on overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3/4 toxicity for patients beyond first-line treatment. Methods: MEDLINE, EMBASE, and Cochrane libraries were searched for randomized studies in relapsed mCRC comparing treatment containing targeted therapy to the same treatment without targeted therapy. Biologic agents were classed as: EGFR-inhibitors (EGFR-I), VEGF antibody/trap and VEGFR tyrosine kinase inhibitors (TKI). Only KRAS wild-type patients were included for EGFR-I analysis. Results were aggregated according to standard meta-analytic techniques. Results: 10 studies evaluating 5,847 patients were identified. Considering subgroups and lines, OS and PFS benefit was demonstrated in all groups across all lines except for OS in 2nd line EGFR-I use (which may be due to subsequent crossover). A benefit to ORR was seen with EGFR-I 2nd line (Pooled ORR benefit +24%, Odds Ratio (OR) 4.44, 95% CI 3.20-6.18), EGFR-I 3rd line and beyond (Pooled ORR benefit +16%), VEGF antibody/trap (Pooled ORR benefit +7.2%, OR 2.00, 95% CI 1.57-2.54) and VEGFR TKI (Pooled ORR benefit +1.9%, OR 2.05, 95% CI 1.27-3.30). The risk of grade 3/4 toxicity was greater with the addition of all targeted agents. Conclusions: The use of VEGF and EGFR targeted biologic agents beyond first-line setting in mCRC results in a benefit to OS, PFS and ORR for all agents except for OS benefit with second-line EGFR-I. This benefit comes at the cost of increased toxicity. [Table: see text]
Focus on the assessment of physical activity level of patients with cancer cachexia enrolled in a randomized phase III clinical trial.
Authors: G. Mantovani, A. Macciò, C. Madeddu, M. Dessì, R. Serpe, G. Antoni, E. Massa, G. Astara, F. Panzone
Journal: Journal of Clinical Oncology (2010)

9164 Background: Physical activity is an important component of the physical and social domains of quality of life (QL); therefore any restoration of physical activity level (PAL) towards a normal level may translate into an improvement in QL of cachectic cancer patients. Purpose: We carried out a phase III randomized study to establish which was the most effective and safest treatment to improve the primary endpoints of cancer cachexia and among them we have selected as the most relevant PAL. Patient total daily PAL and associated energy expenditure was assessed with an electronic device (SenseWear PRO2 Armband), shown in some validation studies to be able to assess appropriately the total energy expenditure (TEE) and its specific components, resting energy expenditure (REE) and active energy expenditure (AEE). AEE was recorded at an intensity ≥ 3.0 metabolic equivalents corresponding to a moderate physical activity. The armband is able to identify the specific type of patient physical activity in such a way to attribute to it a “functional quality.” Methods: Seventy out of 332 patients with cancer cachexia enrolled in the study were assessed for total daily PAL before and after treatment. The study design planned to randomly assign eligible patients to 1 of 5 arms of treatment: 1) medroxyprogesterone 500 mg/d or megestrol acetate 320 mg/d; 2) oral supplementation with 2 g EPA; 3) L-carnitine 4 g/d; 4) thalidomide 200 mg/d; 5) a combination of the above. Treatment duration: 4 months. Results: Total daily PAL showed that TEE and AEE increased significantly in arm 5 (TEE from 1291 kcal/die to 1649 kcal/die, p=0.04 and AEE from 93.8 kcal/die to 155 kcal/die, p=0.032) with a concomitant significant decrease of REE (from 1227 ± 439 to 1067 ± 181 kcal/die, p=0.044). The primary endpoints LBM (by DEXA) and fatigue improved significantly in arm 5. Toxicity was substantially negligible, comparable between treatment arms. Conclusions: The present study showed that the combination regimen was the only effective treatment in improving patient total daily PAL. Our trial shows that PAL monitoring provides a new dimension in the assessment of the comprehensive quality of life of cachectic cancer patients. No significant financial relationships to disclose.
Low Frequency of Molecular Alterations of H3.3-Atrx-Daxx Chromatin Remodeling Component Genes in Myelodysplastic Syndromes (MDS)
Authors: Youmna Attieh, Yue Wei, Hui Yang, Yu Jia, Hong Zheng, Zhihong Fang, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2012)
Phase I dose finding and pharmacokinetic study of NKTR-102 (PEGylated irinotecan): Early evidence of anti-tumor activity
Authors: M. J. Borad, J. T. Hamm, L. S. Rosen, G. S. Jameson, J. Utz, M. Mulay, M. Eldon, S. Dhar, L. Acosta, D. D. Von Hoff
Journal: Journal of Clinical Oncology (2008)

13518 Background: NKTR-102 is a novel PEGylated form of irinotecan with superior efficacy against a range of xenografts compared with irinotecan. Sustained tumor inhibition is associated with increased SN38 exposure. A phase I trial of NKTR-102 was conducted to establish the maximum tolerated dose (MTD) and to characterize safety and pharmacokinetics (pk) in patients (pts) with refractory solid tumors. Methods: NKTR-102 was infused over 90 minutes weekly for 3 weeks every 4 weeks. Cohorts of 3 to 12 pts were treated. Serial plasma samples were analyzed for NKTR-102, irinotecan, SN38 and SN38-glucuronide using LC-MS/MS. Results: As of 12/6/07, 27 pts were enrolled [colorectal (6), NSCLC (5), esophageal (4)]. Patients received a median of 2 cycles/pt (range 0.3 to 6) over 5 dose cohorts (58 mg/m2: 3 pts, 115 mg/m2: 4 pts, 173 mg/m2: 14 pts, 230 mg/m2: 3 pts, 144 mg/m2: 3 pts, cohort still open). No CTC Grade 4 (G4) toxicity was observed. G3 diarrhea was dose limiting (8 pts; 3 pts at 230 mg/m2, 5 pts at 173 mg/m2). Other toxicities included transient uncomplicated G3 neutropenia (1 pt at 230 mg/m2, 1 pt at 173 mg/m2) and transient infusion related visual disturbance (6 pts). PK data are available for 12 pts (dose levels: 58 –173 mg/m2, cycles/pt: 0.3 –6.8). Cumulative SN38 exposures were 1.2 –6.5 fold higher AUC(0-tlast) (mean 3.1, SD 1.6) than those predicted for irinotecan at equivalent doses and treatment schedules. Two partial responses were observed in pts with advanced cervical cancer and SCLC. Anti-tumor activity was seen in 4 other pts; ovarian: CA125 decreased from 2557 to 518, Hodgkin’s disease: 28% radiologic improvement with symptomatic benefit, adrenocortical: cortisol levels normalized, metabolic response by PET, esophageal: CEA decreased from 35.5 to 13.6, metabolic response by PET. Conclusions: NKTR-102 shows early evidence of activity in a wide spectrum of tumors. Cumulative SN38 exposure is 1.2 to 6.5 fold higher than that predicted for irinotecan. Toxicity is manageable; diarrhea (not neutropenia) is dose limiting. The likely MTD in this ongoing study is 144 mg/m2. Data support further evaluation of NKTR-102 to include alternative schedules, combination therapies and PK/PD relationships. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nektar Therapeutics Nektar Therapeutics Nektar Therapeutics Nektar Therapeutics
Secondary cancers after breast-conserving therapy in Tokyo database.
Authors: Kenshiro Shiraishi, Keiichi Nakagawa, Jiro Kawamori, Kenji Ibukuro, Atsushi Fukuuchi, Tsunehiro Nishi, Tomohiro Shinozaki
Journal: Journal of Clinical Oncology (2013)

139 Background: The more patients overcome early breast cancer and become cancer survivors as a result of modern sophisticated approach, the more secondary cancers inevitably arise. The second malignancies after breast conserving therapy (BCT) are well-known sticky dilemma because of additional anxiety and need for medical care for longer-time. However, it is unclear whether secondary cancers negatively affect prognosis of breast cancer survivors. Methods: We performed a retrospective study of long-term cancer survivors after BCT for locoregional invasive or noninvasive breast cancer diagnosed between 1982 and mid-2012. Actuarial rates of overall (OS) and cause-specific survival (CSS) were calculated by using the Kaplan-Meier method. We compared between-group differences using the log-rank test. Results: Eight hundred sixty patients (32%) were followed-up for more than 10 years. At a median follow-up of 90 months, 146 patients had developed a second malignancy. The greatest increases in risk were for leukemia (Standardized incidence ratio (SIR): 4.24 (1.52–8.31)), ovarian cancer (SIR: 4.12 (2.40–6.31)), reno-ureteral cancer (SIR: 3.18 (1.14–6.23)), endometrial cancer (SIR: 2.48 (1.27–4.08)), and pancreatic cancer (SIR: 2.32 (1.11–3.99)). No increased risk was observed for other gastrointestinal and genitourinary cancer, malignant melanoma, lymphoma, thyroid or head and neck cancer. Overall 10-year cumulative incidence of OS without secondary cancer was 93.3%, and 10-year cumulative incidence of OS with secondary cancer was 81.5%. (p&lt;0.001)Overall 10-year cumulative incidence of CSS without secondary cancer was 94.2%, and 10-year cumulative incidence of CSS with secondary cancer was 92.8%. (p=0.749). This likelihood of survival disadvantage is similar to that with ipsilateral breast tumor recurrecnce. Conclusions: Secondary cancers after BCT negatively impact on OS. Given the life-threatening nature to cancer survivors, lifetime caution such as smoking cessation, alcohol intake abstention, weight control, physical activity, and other healthy lifestyle must be paid.
Characterizing tumor responses from RAINBOW, a randomized phase III trial of ramucirumab (RAM) plus paclitaxel (PAC) vs placebo (PBO) plus PAC in patients (pts) with previously treated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Gyorgy Bodoky, Marian Gil-Delgado, Stefano Cascinu, Oleg N. Lipatov, David Cunningham, Eric Van Cutsem, Kei Muro, Kumari Chandrawansa, Astra M. Liepa, Roberto Carlesi, Atsushi Ohtsu, Hansjochen Wilke
Journal: Journal of Clinical Oncology (2016)

45 Background: In RAINBOW, OS and PFS were improved for pts with previously treated gastric/GEJ adenocarcinoma in the RAM + PAC arm. Objective response rate was also significantly improved: 28% (92/330) RAM + PAC vs 16% (54/335) PBO + PAC (P =.0001). Timing and duration of responses and quality of life (QoL) are described. Methods: Patients were randomized 1:1 to RAM 8 mg/kg or PBO on days 1 and 15 + PAC 80 mg/m 2 on days 1, 8, and 15 (28-day cycle). Radiographic assessment of disease per RECIST v1.1 and assessment of QoL with the EORTC QLQ-C30 were done at baseline and 6-wk intervals following the first dose of study therapy. Time to response (TTR) was the time from randomization to first tumor response (complete or partial). Duration of response (DoR) was the time from first tumor response to disease progression. A swimmer plot of DoR, survival, and status at study end was developed. Time-to-event curves were generated using the Kaplan-Meier method. Hazard ratio (HR) for DoR was generated from a stratified Cox model. QoL scores were classified as improved or worsened if change from baseline was ≥ 10 points (100-point scale), otherwise considered stable. Results: Median TTR was 6.7 wks (range 4.3-33.3) for RAM + PAC pts and 6.6 wks (5.1-37.1) for PBO + PAC pts. A detailed swimmer plot confirms a majority of RAM + PAC pts (58% [53/92]) and PBO + PAC pts (61% [33/54]) responded by the first 6-wk assessment. Of these responders, 11% (6/53) and 6% (2/33) were still responding at 12 mos. Median DoR was 4.4 mos (95% CI 4.1, 5.5) in the RAM + PAC arm and 2.8 mos (95% CI 2.1, 4.2) in the PBO + PAC arm (HR = 0.66, 95% CI 0.45, 0.97; P =.0332). At 6 wks, rates of improved/stable QoL scores among responders were similar between treatment arms and higher among the responders (73% RAM + PAC vs 74% PBO + PAC) than in the intent-to-treat population (53% vs 50%). Conclusions: Patients with advanced gastric/GEJ cancer not only showed an improved response rate with RAM + PAC, but responses were also more durable. For the majority of pts, response occurred within the first 6 wks of therapy and was associated with QoL benefit. Clinical trial information: NCT01170663.
High-intensity interval training: how much pain to get a gain?
Authors: George P Nassis
Journal: British Journal of Sports Medicine (2017)

High intensity interval training (HIIT) can produce similar if not greater improvements in cardiorespiratory fitness, an independent protective factor against premature death, and some health-related parameters compared to conventional, moderate intensity continuous training (MICT). HIIT takes substantially less time to complete and this enhances its potential in public health promotion given that lack of time is one of the barriers to long-term adherence to physical activity and exercise training. HIIT describes exercise bouts of 10 s to 4 min with ‘all-out’ maximal effort or intensities of 85–95% of maximum heart rate (HRmax) interspersed by periods of low activity or rest (30 s to 4 min). MICT describes prolonged continuous exercise at 60–80% HRmax.

Despite the accumulated evidence, very little improvement has been made in terms of HIIT implementation in real life settings given that most studies lack the required level of ecological validity (most are of healthy volunteers training under research-based conditions—this is far from …
Malignant tumours on the radiation-induced trail in the Altai territory
Authors: Y. N. Shoikhet, A. F. Lazarev, V. D. Petrova, S. A. Terekhova, V. P. Tcivkina
Journal: Journal of Clinical Oncology (2008)

22036 Background: The Altai territory is situated close to Semipalatinsk Nuclear testing area. It is known that radiation-induced trails of 48 test explosions spread to the Altai territory. The doses of radiation and trajectories of most powerful explosions were reconstructed. The areas of the Altai territory where population suffered from radiation more than otherwhere were reported (Model area). Methods: This epidemiological study of thyroid, lung, skin, colon cancers and malignant lymphomas was conducted to reveal the difference in the incidence of these malignancies in 1995–2000 and 2001–2006, between Model area and the areas of the Altai territory that did not suffer from radiation. At the basis of the study were the data of the Altai territory cancer registry (more than 150 000 cases of cancer) and The State Program “Semipalatinsk Nuclear Testing Area - Altai”. Results: It was found out that the incidence of studied sites of cancer was related directly to the radiation dose: in the areas with max dose (100 cSv and more) in the period of 1995–2000 the incidence was twice higher than in the Altai territory in the whole and 2.6 times higher than in the control areas. Since the radiation effect had ceased (1989) in the period of 2000–2005 the incidence in Model area decreased and approximated to the average in the Altai territory. Conclusion: This study showed significant direct relation between radiation and the incidence of thyroid, lung, skin, colon cancers and malignant lymphomas on the radiation-induced trail. As the effect of radiation discontinued and rehabilitation measures were taken, the incidence of those malignancies among the population of the areas suffered from radiation decreased. No significant financial relationships to disclose.
A randomized placebo-controlled trial of daily high-dose oral risedronate in men with metastatic prostate cancer commencing androgen deprivation therapy (ADT).
Authors: C. Sweeney, W. M. Dugan, R. Dreicer, F. Chu, G. Parks, K. Baker, D. Reed, K. Jansz, J. Zadra, C. T. Yiannoutsos
Journal: Journal of Clinical Oncology (2010)

e15000 Background: High-dose bisphosphonate therapy delays skeletal-related events (SRE) in men with castration resistant prostate cancer (CRPC). Methods: Randomized double-blind, placebo-controlled trial in prostate cancer pts with bone metastases commencing ADT within 30 days of randomization. Primary objective: Assess the ability of 30 mg oral daily risedronate to prevent SRE in patients starting ADT. Secondary objectives: Assessments of time to CRPC and markers of bone turnover. Both arms received at least 500 mg/day oral calcium carbonate and 400 IU of vitamin D. Time-to-event data were analyzed using Kaplan-Meier curves. All statistical tests were two-sided. Results: From 12/03 and 8/05, 63 of 360 planned patients were enrolled. Study was closed due to slow accrual and analysed as a randomized phase II trial. All had ECOG PS 0 or 1 and adequate organ function. Baseline PS, extent of metastases, comorbidity indices and markers of bone turnover were balanced. Median follow- up was 39.7 months. Endpoints are presented in the Table. Median OS was not reached in either arm. Markers of bone turnover were suppressed in both arms but to a significantly greater degree in patients on combined therapy. Conclusions: High-dose oral risedronate plus ADT suppresses bone turnover to a greater degree than that that associated with disease regression from ADT alone. Ongoing phase III trials will definitively define the clinical benefit of early versus late high-dose bisphosphonate therapy. Placebo N=31 Risedronate N=32 P value Median time (months) to: SRE 41.5 (95% CI: 23-N/A) 44.2 (95% CI: 35.1-N/A) 0.598 Castration-resistant disease 17.4 (95% CI: 8.8- 28.3) 32.2 (95% CI: 13.8-42.1) 0.154 Serological progression 14.2 (95% CI: 11.2-32.7) 23.4 (95% CI: 14.7-35.7) 0.416 Pts with PSA nadir < 0.2 ng/mL 9 (29%) 16 (50%) 0.123 % AE ≥ grade 3 at 12 months 37.3 (95% CI: 41.7-78.0) 10.9 (95% CI: 70.0-96.4%) 0.163 24 wk median: Urine total DPD (nmol/mmol Creat) 12.62 (N=22) 6.91 (N=22) p<0.001 Urine NTX (nmol BCE/mmol creat) 62.95 (N=19) 20.63 (N=20) p<0.001 Serum bone alkaline phosphatase (ng/mL) 13.16 (N=17) 9.5 (N=19) p=0.01 Serum osteocalcin (μg/L) 27.35 (N=18) 11.88 (N=19) p<0.001 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis sanofi-aventis
Surgeon influence on patient appraisal of ASCO breast cancer quality indicators.
Authors: S. T. Hawley, A. S. Hamilton, J. Graff, S. J. Katz
Journal: Journal of Clinical Oncology (2010)

6016 Background: There has been no research evaluating provider level variation in patient appraisal of 3 key indicators of quality breast cancer care defined by ASCO: timely access, care coordination, and decision satisfaction. Methods: 3,133 women with nonmetastatic breast cancer diagnosed from 6/05-2/07 and reported to the Detroit and Los Angeles SEER registries were identified and surveyed after diagnosis. Latina and African American (AA) women were oversampled (N=2,268, response rate 72.4%). Patient survey and SEER data were merged with surveys of attending surgeons (N=311). Three multi-item patient-reported scales were adapted from ASCO's national initiative on cancer care quality: 1) timely access to care; 2) perceived care coordination; 3) decision satisfaction. Each continuous outcome (range 1 to 5) was analyzed using hierarchical regression to determine the amount of total variation explained by surgeons. Subsequent stepwise models controlled for patient factors (clinical and demographic), surgeon characteristics (specialization, gender, age), and two novel surgeon practice process measures (multidisciplinary communication scale, patient decision support scale). Results: Mean scores for the 3 outcomes were 4.2, 3.9 and 4.1 for access, coordination, and decision satisfaction. Individual surgeons explained a very small amount of the total variation in patient-reported timely access (4.7%), care coordination (3.8%), and decision satisfaction (1.3%) after controlling for patient factors. Adding surgeon characteristics and practice process measures to the models did not substantially affect between-surgeon variation in any of the outcomes (Table). Conclusions: Patients' appraisals of ASCO-based quality indicators for breast cancer were generally high. There was little surgeon influence on total variation in quality scores after controlling for patient factors. Surgeon practice processes appear to contribute minimally to patient perceptions of these quality measures. Amount of total variation in quality indicators explained by surgeons (%) Controlling for: Access Coordination Decision satisfaction Patient factors 4.7 3.8 1.3 Surgeon characteristics 4.3 2.1 0.6 Practice process measures 4.1 2.4 0.2 No significant financial relationships to disclose.
A phase I/II trial of the multipeptide cancer vaccine IMA910 in patients with advanced colorectal cancer (CRC).
Authors: Frank Mayer, Andrea Mayer-Mokler, Elzbieta Nowara, Laszlo Torday, Joerg Ludwig, Sabrina Kuttruff, Toni Weinschenk, Steffen Walter, Harpreet Singh, Carsten Reinhardt
Journal: Journal of Clinical Oncology (2012)

555 Background: Treatment interruption after 12 weeks of oxaliplatin-based therapy followed by re-introduction upon signs of progression results in better overall tolerability and quality of life compared to continuous therapy while survival rates are only modestly impaired. Specific immunotherapy may provide a safe and tolerable intervention to prolong time to re-introduction and eventually overall survival. IMA910 is a novel peptide-based cancer vaccine consisting of 13 tumor-associated peptides (TUMAPs), which are naturally presented on MHC molecules of colorectal tumors. Methods: HLA-A*02 + advanced CRC patients being at least clinically stable after 12 weeks of first-line oxaliplatin-based therapy were enrolled. After immunomodulation with a single low dose of cyclophosphamide (300 mg/m2), patients were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF (cohort 1; n=66) or IMA910 with GM-CSF plus topically applied imiquimod (cohort 2; n=26). T-cell responses to individual IMA910 peptides were analyzed by HLA-multimer and intra-cellular cytokine assay. Analysis of disease control rates (DCR) and progression-free survival (PFS) was based on RECIST-centrally reviewed CT/ MRI scans. Results: IMA910 was overall well tolerated with most AEs being mild and transient local site reactions. Three patients presented with systemic hypersensitivity reactions, all of which were observed after ≥10 vaccinations and were confirmed to have an in vitro reaction against GM-CSF in all cases. IMA910 induced immune responses in 71% and 72% of patients in the two cohorts, respectively. Interestingly, patients developing CD8 T-cell responses against multiple TUMAPs had a better clinical outcome compared to others, in terms of DCR (18% vs. 2% at 6 months; p=0.012) and PFS (HR: 0.652; p=0.039). OS data will be shown at the meeting. Conclusions: Vaccination with IMA910 is safe, well tolerated, and immunogenic. Significantly better clinical outcome of multi-TUMAP responders in comparison to patients with one/no TUMAP response indicates clinical activity of IMA910 in 1 st line advanced CRC patients.