bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequence-dependent cytoxicity of docetaxel and erlotinib in head and neck squamous cell carcinoma (HNSCC)
Authors: Glisson B. S. , Saigal B. , Xu Y. , Johnson F. M.
Published: March 2020

6084

More effective systemic treatment is needed for HNSCC. The taxoids are the most efficacious single agents identified. Epidermal growth factor receptor (EGFR) is almost universally expressed by HNSCC tumors but inhibitors have only modest activity as single agents in clinical studies. However, the combination of the taxoids with EGFR inhibition has additive anti-tumor effects in HNSCC in vitro and in animals. Despite similar pre-clinical data in lung cancer, clinical trials showed no benefit when EGFR inhibitors were added to chemotherapy. In vitro studies in lung, breast and colon cancer cell lines demonstrate that the separation of EGFR TKI from chemotherapy and the order in which these agents are administered influences efficacy. We sought to determine if a similar sequence-dependent effect exists in HNSCC in order to help design future clinical trials with these agents. We chose three human HNSCC cell lines with diverse levels of basal EGFR expression and activation. None had EGFR mutations, which are very rare in HNSCC. Cells were treated with single agent docetaxel or erlotinib or combinations for 72 h and cytotoxicity was measured with an MTT assay. Concurrent treatment with docetaxel and erlotinib resulted in more cytotoxicity than single agents and calculated combination indices demonstrated additive effects. When erlotinib was added 4 to 24 h prior to docetaxel, the efficacy was similar to or less than that of concurrent therapy regardless of whether the erlotinib was washed off prior to the docetaxel or left in the cell medium. In contrast, when docetaxel was added ≥ 10 h prior to erlotinib, cytotoxicity was enhanced as compared to concurrent therapy. The most efficacious combination was docetaxel treatment for 24 h followed by erlotinib for 48 h. This combination was chosen for further analysis. Consistent with previously published studies in other cell types, erlotinib resulted in G1 cell cycle arrest and docetaxel in G2-M arrest. On-going studies to investigate the mechanism for the sequence-dependent cytotoxicity include examination of the effects of the sequence on cell cycle and apoptosis, tubulin expression, and cell signaling molecules that mediate pro-survival signals from EGFR.

[Table: see text]
Intraoperative identification of sentinel lymph node guided by near-infrared fluorescence imaging for breast cancer patients
Authors: Tagaya N.
Published: March 2020

615

Background: Recently, radioactive tracer, a vital dye, or a combination of both has been applied intraoperatively to detect sentinel lymph nodes (SLN) for patients with early breast cancers. We present a novel method of SLN identification using near-infrared fluorescence imaging that provides with high detection and low false-negative rates. Materials and Methods: This study enrolled 52 patients with a tumor less than 3 cm in diameter. Their mean age was 54.7 years. Preoperative TNM stage was I in 35 cases, IIa in 12, and IIb in 5, respectively. Initially the combination dye of indocyanine green and indigocarmine was injected subdermally in the areola. Fluorescence imaging (photodynamic eye: Hamamatsu Photonics Co.) was obtained using a charge coupled device camera with a cut filter as the detector, and light emitting diodes at 760 nm as the light source. Subcutaneous lymphatic channels draining from the areola to the axilla or other directions were visible by fluorescence imagings immediately. After incising the axillary skin 1 cm cranial side from the disappeared point of fluorescence image, SLN was then dissected under the guidance of fluorescence. Results: In all but one patient, lymphatic channels and SLN were successfully visualized (identification rate: 98.1%). SLN was observed before skin incision in two patients. The number of fluorescence SLN ranged from 0 to 11 (mean: 4.7) and blue dyed SLN ranged from o to 6 (mean: 2.0). SLN was not identified in one patient in the former and 7 patients in the latter. Twelve patients had lymph node metastases pathologically. All of them were recognized by fluorescence imaging, however, three patients with metastatic LN were not identified by a vital dye. Conclusions: This method is feasible and safe to detect SLN intraoperatively with less invasive, real-time observation and no requirement of training. We are convinced that this method will provide with high detection and low false-negative rates in SLN navigation surgery.

No significant financial relationships to disclose.
A randomized trial of computer and pamphlet-based versions of the Decision Board (DB)
Authors: Whelan T. J. , Gafni A. , Julian J. , Sebaldt R. J. , Tozer R. , Heller B. , Ellis P. , Hodgson N. , Mukherjee S. , Levine M. N.
Published: March 2020

6508

Background: Many women with breast cancer want to be involved in treatment decision making. The DB is a visual aid poster board which sequentially presents written and graphical information from clinical trials regarding treatment options for early breast cancer. The physician presents the DB to the patient during the consultation. Randomized trials have demonstrated that the standard version of the DB improves patient comprehension, satisfaction and comfort with decision making. The standard DB is cumbersome to use and hard to update. Computer based instruments are attractive as they provide more flexibility in presenting information, and can be easily updated and accessed via the Internet. On the other hand pamphlet based versions may be easier to use. We developed computer versions of the DB for breast cancer surgery and adjuvant chemotherapy options using a Windows type format. Pamphlet versions were also developed. The objective of this study was to compare the computer and pamphlet versions of the DB to the proven standard version. Methods: 309 women were randomized to the physician consultation plus the standard (105), computer (103) or pamphlet (101) versions of the DB. Patients were stratified according to type of decision: surgical treatment or adjuvant chemotherapy. Patients were evaluated following the consultation for their knowledge about the breast cancer treatments offered, decisional conflict, and satisfaction with preparation for decision making using established validated instruments. Usefulness of the instrument for the patient and physician was also assessed. Results: Study outcomes were similar between the three versions of the DB ( Table ). Usefulness of the instrument for the patient and physician was also similar for the different versions. Conclusions: The different versions of the DB appeared equally effective in facilitating shared decision making. Physicians and patients now have the option of choosing which instrument best suits their needs. Such versatility may encourage wider use of the DB.

No significant financial relationships to disclose.

[Table: see text]
The transition from phase II to phase III studies
Authors: Tannock I. , Gulamhusein A. , Berthold D. R.
Published: March 2020

6514

Background: Phase II trials are performed to detect potential anti-tumor effects of a new treatment and should be used to decide whether to proceed to a phase 3 trial or not. However, many phase 2 trials never lead to a phase 3 trial despite encouraging results. Here we sought to determine how often (i) positive phase 2 trials have led to phase 3 trials, and (ii) how often phase 2 trials were designed to lead to a phase 3 trial. Methods: We reviewed 200 phase 2 trials, presented at ASCO meetings in 1995–1996, and 2006, selecting randomly 20 abstracts with encouraging results for 5 cancer sites (breast, lung, GI, GU, Gyn) in each time period. For those presented in 1995–1996, we searched systematically for subsequent randomized studies where one treatment arm was similar to that in the phase 2 study. For those presented in 2006, a questionnaire was sent to authors asking whether they recommend evaluating the regimen in a phase 3 trial, whether a phase 3 trial is planned and whether resources (budget, patients, drugs) are available to conduct a phase 3 trial. Results: Ten years after presenting phase 2 trials with positive results, only 13 regimens have been evaluated in a phase 3 trial. Of 100 investigators who presented a phase 2 trial in 2006, 42 returned the questionnaire, 36 confirmed that the results met criteria of efficacy and 25 thought the regimen should be evaluated in a phase 3 trial. Only 10 investigators plan to undertake a phase 3 trial, and 8 stated they had resources to do so. Reasons for not planning a phase 3 study included insufficient efficacy (7), insufficient access to patients (5) or financial support (5), lack of interest from colleagues (6), and lack of support from the company (8). Conclusions: Few (∼13%) phase 2 trials with promising activity are followed by phase 3 trials and this is not increasing with time. Reasons include lack of resources such as money, drugs and patients. Many of these limitations are known when planning the phase 2 study, implying that many phase 2 trials are not planned as precursors of phase 3 trials. Resources spent on such trials would be better applied to practice-changing phase 3 trials.

No significant financial relationships to disclose.
A regression model for predicting conditional survival for head and neck cancer patients: A SEER analysis
Authors: Wang S. J. , Fuller C. D. , Sittig D. F. , Holland J. M. , Thomas C. R.
Published: March 2020

6527

Background: Survival probability changes as patients survive longer periods of time after diagnosis, and estimates of prognosis at diagnosis are no longer valid. Conditional survival (CS) accounts for the changing hazard rate over time and is a more accurate estimate of survival probability for these cancer survivors. The specific aim of this project was to build a statistical model and web-based tool to predict conditional survival for an individual head & neck cancer patient based on tumor and patient characteristics. Methods: Using 27,825 patients diagnosed with head & neck cancer between 1988–97 from the Surveillance, Epidemiology, and End Results 17 (SEER) database, we built a multivariate Cox proportional hazards regression prediction model. Patient and tumor characteristics included as covariates were age, sex, race, tumor site, stage, and grade. The primary endpoint was conditional overall survival. The model was validated for discrimination using the concordance index and a calibration plot was constructed. Bootstrapping was used to correct for optimistic bias. We also built a web-browser software tool to allow a user to enter patient information into the model and calculate conditional survival probability. Results: The regression model showed very good calibration and discrimination with a bootstrap-corrected C-index of 0.71. For a 65-yr old white male with a moderately-differentiated tonsil cancer with regional lymph nodes, the model predicted that the 5-yr conditional overall survival would increase from 50% at the time of diagnosis to 63% at 3 years after diagnosis. For a 75-yr old black male with a well-differentiated localized lip cancer, 5-yr conditional survival would improve from 58% at diagnosis to 70% by 3 years from diagnosis. Conclusions: Our regression model can accurately predict conditional survival for head & neck cancer patients based upon specific patient and tumor characteristics. This tool allows the calculation of more specific prognosis predictions for individual cancer patients who have already survived a period of time after diagnosis and treatment.

No significant financial relationships to disclose.
Quality of psychosocial care in oncology: A national survey of oncologists
Authors: Pirl W. F. , Muriel A. , Hwang V. , Greer J. , Kornblith A. , Greenberg D. B. , Donelan K. , Temel J. , Schapira L.
Published: March 2020

6561

Background: Little is known about the quantity and quality of psychosocial care being delivered by oncologists in the United States. This study surveyed oncologists about their management of psychosocial distress, using the National Comprehensive Cancer Network (NCCN) guidelines for psychosocial distress as a standard. Availability of mental health services and routine screening for distress were used as measures of quality care. Methods: A random sample of 1,000 oncologists in the United States belonging to ASCO were surveyed with an anonymous e-mail and mail-based questionnaire between 9/05 and 7/06. Initial univariate analyses were used to test differences in frequencies among groups using Chi-square for categorical variables, and t-tests and ANOVA for continuous variables. Variables that were associated with reported routine screening at the .05 significance level in the univariate analyses were entered into a logistic regression model to determine independent predictors of screening. Results: Forty-six percent (448/965) of oncologists responded. Almost two-thirds (63.6%, 285/448) practiced in community settings, 27.2% (122/448) at cancer centers, and 6.9% (31/448) in hospitals. Only half (50.3%, 95% CI 45.7–54.9%; 225/448) reported having any mental health services affiliated with their practice. Availability differed by practice setting, with cancer centers having the most and community having the least (P<.001). Only one-third (32.3%, 144/445) reported being at least somewhat familiar with the NCCN guidelines. Two-thirds (65.0%, 95% CI 60.6–69.4%; 290/446) reported routinely screening for distress, but only 14.3% (64/447) use a screening instrument. Availability of mental health services, knowledge of NCCN guidelines, experience, time, certainty about identifying distress and being female were independent predictors of reported screening. Conclusion: Only 36.4% (95% CI 34.1–38.7%; 162/445) reported both of our measures of quality care, available mental health services and routine screening for distress. While the majority report routinely screening for distress, only a small percentage follow NCCN guidelines by using a screening instrument, and only half report having mental health services available.

No significant financial relationships to disclose.
Incidence of minimally invasive colorectal cancer (CRC) surgery in patients treated at NCCN institutions
Authors: Weiser M. , Romanus D. , terVeer A. , Rajput A. , Skibber J. , Earle C. , Shibata S. , Martin E. , Engstrom P. , Schrag D.
Published: March 2020

6575

Background: In May 2004 the Clinical Outcomes of Surgical Therapy Study Group published the results of the North American randomized trial demonstrating that oncologic outcome is similar for laparoscopic assisted and open surgery for CRC. This and other studies have shown quicker recovery with laparoscopic CRC surgery including earlier resolution of postoperative ileus, less discomfort, and earlier discharge from the hospital. The extent to which surgeons have adopted the minimally invasive surgical (MIS) approach in CRC is unknown. Methods: Using the NCCN Colon/Rectal Cancer Outcomes Project Database, 715 patients were identified who underwent CRC resection in 2005–6. The distribution of lesions included right colon (39%), left colon (31%), and rectum (30%). The incidence of MIS for CRC and clinicopathologic features associated with this approach were analyzed by logistic regression; results are reported as odd ratio (OR) with 95% confidence intervals (CI), and significance defined at p<0.05 level. Results: A total of 167 (23%) patients underwent MIS colorectal surgery (laparoscopy in 98% and robotic in 2%). Conversion to open surgery was noted in 33 cases (20%). Surgery was performed in outside institutions in 21% of cases prior to patients presenting to NCCN institutions for further treatment. The MIS approach was more common in colon than rectal cancer (30% vs.12%, OR 2.96, CI 1.94–4.51, p<0.0001). Within the colon cancer cohort, right sided lesions were more likely to be approached with MIS techniques rather than left sided lesions (32% vs. 25%; OR 1.42, CI 1.96–2.21, p<0.0001). Stage I tumors were also more likely to be managed with the less invasive approach: Stage I-41%; II-20%; III-21%; IV-19% (Stage I vs. IV, OR=3.00, CI 1.74–5.16 p<0.0001). No differences in surgical approach were noted based on age, gender, race, Charlson comorbidity score, insurance type, or location of surgery (NCCN vs outside facility). Conclusion: The majority of CRC surgery for patients presenting to NCCN institutions is performed by open techniques. Right sided and early stage CRCs were more likely treated with MIS, possibly related to the less demanding nature of the procedure. The adoption of MIS is expected to rise as surgeons become trained in MIS techniques for CRC.

No significant financial relationships to disclose.
DNR patterns in cancer patients (pts) 16 years after the Patient Self Determination Act (PSDA)
Authors: Helft P. R. , Qi R. , Brown B. P. , Drabiak K. , Morrell E. D.
Published: March 2020

6582

Background: In 1991, the PSDA required institutions receiving federal funding to inform pts about the right to refuse life prolonging treatments such as CPR. Studies conducted around 1991 suggest that most DNR orders are written by oncologists less than 3 days prior to death in hospitalized pts, raising ethical concerns. 16 years later, are oncology clinicians writing DNR orders earlier in cancer pts’ hospital course compared to non-cancer pts? Methods: We conducted a chart review of 284 of the 296 total adult deaths during 2005 at Indiana University Hospital. Demographic, diagnostic, and attending service info was collected from hospital billing records. Pts’ DNR status, timing of DNR orders, and presence of a written advanced directive (AD) were assessed through chart review. Results: 76 of 284 (26.8%) patients had cancer diagnoses. Of these, 59 had documented DNR orders. There was no difference in presence or absence of DNR orders at the time of death for cancer vs. non-cancer pts (77.6 vs 72.7%, p=0.35). Mean time from writing of the DNR order to death was 3.51 ± 4.61 days for cancer pts compared to 3.26 ±3.81 days for non-cancer pts (p=0.40), however, the majority of DNR orders written by oncologists were written less than 2 days prior to death. We calculated a ratio of the time between DNR order writing and death to the overall length of stay for cancer and non-cancer pts, excluding pts with very short lengths of stay ( = 5 days). In univariate analyses, this ratio trended toward statistical significance (p=0.08). In multivariate analyses, cancer pts had a higher ratio of the time between DNR order and death to LOS (0.30 vs 0.21, p=0.05). Existence of an AD had no significant impact on this ratio. Surgical specialists wrote DNR orders less frequently (64.2 vs 77.3%, p=0.02) and later than non-surgical specialists (mean 21 vs 10 days from admission, p=0.0008). Conclusions: In this study, DNR ordering patterns among hospitalized cancer and non-cancer pts have changed little since the PSDA. Although cancer pts on average had DNR orders written relatively earlier in their terminal hospital stay than non-cancer pts, the timing varied little from pts in prior studies. Although the majority of hospitalized pts in this sample died with DNR orders, these orders were written very late in their hospital stay.

No significant financial relationships to disclose.
Impact of timeliness of breast radiotherapy on health outcomes in early breast cancer
Authors: Gold H. T. , Do H. T.
Published: March 2020

6591

Background: The objective of this study is to understand the impact of timely radiotherapy on disease-free survival (DFS) in early breast cancer patients ages 65 and above. Methods: The study population is women diagnosed from 1991–1999 in the linked SEER-Medicare database who underwent breast-conserving surgery and radiotherapy within 6 months of diagnosis. Median followup varies from 4 years for ductal carcinoma in situ (DCIS)(n=1,185) to 5 years for Stage 1 disease (n=7,481), and ranges from 0–11 years. Descriptive and proportional hazards analysis of this longitudinal cohort were conducted. Covariates include age, race, poverty, marital status, comorbidity, rurality, radiation completion and delay, elapsed time since diagnosis, comedo necrosis histology (DCIS only), and chemotherapy receipt (Stage 1 only). Subjects were censored at end of followup (including enrolling in Medicare managed care from Medicare fee-for-service) or death. Treatment delay is defined as radiotherapy beginning 8+ weeks post-surgery without chemotherapy or 4+ weeks after chemotherapy ends; other definitions also were explored. Radiotherapy is considered complete if the patient received greater than 16/22 of expected treatments, based on scientific literature. Results: DFS is negatively associated with radiation delay (OR=1.24, p=0.003 for Stage 1; OR=1.40, p=0.054 for DCIS) and Klabunde's inpatient comorbidity index (OR=1.32, p=0.004 for Stage 1; OR=1.66, p=0.065 for DCIS). Additional analyses suggest that a longer delay of 12+ weeks post-surgery (16+ weeks post-chemotherapy) further reduces DFS (OR=4.66, p<0.0001 for Stage 1; OR=12.4, p<0.0001 for DCIS). Non-white women with Stage 1 disease are more likely to delay radiotherapy (p<0.0001), but are not more likely to have worse outcomes (p>0.3). Conclusions: Delayed initiation of radiation therapy is associated with decreased DFS following radiotherapy for early breast cancer and DCIS. Non-white race is associated with delay, but not reduced DFS. Programs targeting referring physicians and patients should be developed to promote timely receipt of radiotherapy by early breast cancer patients, thereby reducing the risk of adverse health outcomes.

No significant financial relationships to disclose.
Economic value of zoledronic acid compared with placebo in the treatment of skeletal metastases in patients with solid tumors: The case of the United Kingdom (UK)
Authors: Marfatia A. A. , Botteman M. F. , Foley I. , Brandman J. , Langer C. J.
Published: March 2020

6603

Background: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in patients with solid tumors (i.e., renal cell carcinoma, thyroid, head and neck, small cell lung, or others cancers, excluding breast, prostate and non small cell lung [NSCLC] cancers) and bone metastases. This analysis assessed, from the perspective of the UK National Health Service, the economic impact of ZA in this patient population. Methods: A literature-based decision-analytic model was developed to compare the direct costs and quality adjusted life years (QALY) of patients with bone metastases secondary to solid tumors receiving ZA or placebo. Survival, SRE incidence, and number of infusions administered were obtained from a clinical trial comparing patients randomized to 4 mg ZA or placebo for up to 21 months. Drug acquisition and administration costs and SRE costs were estimated using published sources and national fee schedules (e.g., NHS reference costs, British National Formulary). The impact of SREs on quality of life was estimated using the literature. Consistent with previous economic analyses of bisphosphonates in cancers (e.g., Hillner et al, 2000), patients were assumed to experience quality of life improvements lasting 1 month for each SRE avoided. Results: The average remaining life expectancy was conservatively assumed equal in both groups and was 9.54 months (median, 6.61 months). Patients receiving placebo were projected to experience 2.64 SREs on average v. 1.64 SREs among ZA patients. QALYs were estimated at 0.3917 per patient (pp) and 0.3728 pp in the ZA and placebo groups, respectively. ZA drug- related costs were estimated at £1,386 pp, based on an average of 5.52 infusions pp. The use of ZA was associated with a reduction of £1,830 pp in SRE costs. Overall, ZA saved costs and increased QALYs v. no therapy, by £445 pp and 0.0189 QALYs pp, respectively. In sensitivity analyses, ZA cost £25,000 or less per QALY under a wide range of assumptions. Conclusions: The use of ZA leads to fewer SREs, better estimated quality of life, and lower costs relative to placebo in UK patients with bone metastases secondary to solid tumors other than breast, prostate or NSCLC cancer. ZA appears therefore highly cost effective in this population.

No significant financial relationships to disclose.
Economic value of zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer: The case of the United Kingdom (UK)
Authors: Botteman M. F. , Foley I. , Marfatia A. A. , Brandman J. , Langer C. J.
Published: March 2020

6617

Objectives: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in lung cancer patients with bone metastases and may improve survival among those patients with high levels of bone metabolism. This analysis assessed, from the UK National Health Service's perspective, the economic impact of ZA therapy in patients with bone metastases secondary to lung cancer. Methods: A literature-based decision analytic model was developed to compare the direct costs and quality adjusted life years (QALY) experienced by lung cancer patients with bone metastases receiving placebo or ZA. Survival, SRE incidence, and number of infusions administered were obtained from a randomized clinical trial comparing 4 mg ZA with placebo. Drug acquisition and administration costs and SRE costs were estimated using published sources and national fee schedules (i.e., NHS reference costs, British National Formulary, Personal Social Services Research Unit reference costs). The impact of SREs on quality of life was estimated using the literature. Consistent with previous economic analyses of bisphosphonates in cancers (e.g., Hillner et al, 2000), patients avoiding SREs were assumed to experience quality of life improvements for 1 month. Results: The average remaining life expectancy was conservatively assumed equal in both groups and was 8.50 months (median, 5.89 months). During those months, patients receiving placebo were projected to experience 2.07 SREs on average compared to 1.32 SREs among ZA patients. QALYs were estimated at 0.3523 per patient (pp) and 0.3350 pp in the ZA and placebo groups, respectively. ZA drug-related costs were estimated at £1,473 pp, based on 5.87 infusions pp and a cost of £251.01 per infusion. The use of ZA was associated with a reduction of £1,562 pp in SRE costs. Overall, ZA saved costs and increased QALYs compared to no therapy, by £89 pp and 0.0173 QALYs pp, respectively. In sensitivity analyses, ZA cost £25,000 or less per QALY under a wide range of assumptions. Conclusions: The use of ZA leads to fewer SREs, better estimated quality of life, and lower costs relative to placebo in UK lung cancer patients with bone metastases. The use of ZA in this population therefore appears highly cost effective.

No significant financial relationships to disclose.
Palliative chemotherapy and cancer-related fatigue in advanced NSCLC patients
Authors: Cleeland C. S. , Shi Q. , Lu C. , Johenson V. , Mendoza T. , Palos L. , Mobley G. , Wang X.
Published: March 2020

6622

Background: Cancer-related fatigue is one the most severe and prevalent symptoms in patients with advanced-stage non- small cell lung cancer (NSCLC). Whether palliative chemotherapy causes additional fatigue, beyond that which is caused by the disease itself, is unknown. Methods: Study subjects were 88 patients with advanced NSCLC who were treated with platinum-based chemotherapy at The University of Texas M. D. Anderson Cancer Center. Fatigue severity and other symptoms were measured weekly using the 0–10 rating scales of the M. D. Anderson Symptom Inventory (MDASI). Using mixed-effect modeling, we assessed fatigue severity over time of receiving chemotherapy. Results: Over the time of this longitudinal symptom assessment study, fatigue severity was overwhelmingly higher than all other symptoms. We observed no significant impact on fatigue severity by age, sex, or race/ethnicity variation; however, there was a significant difference in fatigue severity using longitudinal analysis between patients who discontinued chemotherapy within 0–6 week vs beyond 12 weeks (P<.05), and within 6–12 weeks vs beyond 12 weeks (P<0.01). By each cycle of chemotherapy, the fatigue pattern showed a consistent trend of reduced severity at day 0–3, a fatigue peak on day 5–6 (P<.05), then unchanged during days 7–21. Fatigue was most severe during the first cycle. Discussion: Cancer-related fatigue was the most severe symptom in the study sample, especially for patients only able to receive 2–4 cycles of chemotherapy. However, patients who received over 4 cycles of chemotherapy had a stable level of fatigue, which indicates that continued chemotherapy does not increase fatigue. Additional analysis demonstrated that fatigue was at it's lowest immediately following chemotherapy, possibly related to the use of steroids in conjunction with chemotherapy administration.

No significant financial relationships to disclose.
Evaluating a new income source for medical oncologists: Market research
Authors: Hoffman K. R.
Published: March 2020

6629

Background: Recently market research has become a ‘booming business‘ serving pharmaceutical and biotechnology firms and financial institutions. From internet studies and focus groups to consultations with Wall Street analysts, medical oncologists are getting increasing involved in providing their expertise in non-patient matters. Payment is usually of a greater amount that what one would earn from direct patient care. Potentially, this may be the source of significant income. Methods: 47 private practice-based medical oncologists agreed to anonymously complete questionaires on this subject. 32 were returned (68% response rate). 17 academic hematologists and oncologists were approached. 7 returned completed questionaires (41% response rate). While group comparisons could not be made, some interesting points were found. Results: Each week an average of 6 Internet and 1 phone-based invitations week were received by the private practitioners. Most physicians received 2–3’ ‘focus group’ or ‘in-person’ invitations/month and attended the majority of them. Like in- person interviews, Internet-based marketing participation was based on the amount of money being offered and not on ‘interesting topic.‘ The majority of studies with an honorarium averaging $150/hour were completed. Academicians were much less likely to participate in Internet research. 4 of the 7 responded that they did not even open them. All participated in interviews, particularly if invited as a ‘key opinion leader‘ (KOL). With respect to interviews, the 3 major differences between the private practitioners and academicians were: in the number of requests received (1 vs 3/week); type and timing of interview requests (KOL received the majority of their interview requests from financial analyists and were inundated at or just around major oncology meetings); and the amount of reimbursement for an hour of interview time (Individual interviews for privates were in the $200–300 range. KOL interviews were reimbursed in the $500 to $5,000 range with $1,000–1,500 being the norm.) Conclusion: Clearly, market research is playing an increasing important role in the financial health of many physicians. Much more planned research needs to be done to see how this interaction affects individual physicians, patient care and society.

No significant financial relationships to disclose.
Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One-year results of CA180034
Authors: Shah N. P. , Kim D. W. , Kantarjian H. M. , Rousselot P. , Dorlhiac-Llacer P. E. , Milone J. H. , Bleickardt E. , Francis S. , Hochhaus A.
Published: March 2020

7004

Background: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented.

[Table: see text] [Table: see text]
Seventy percent of complete responders remain in continuous remission: Five-year follow-up of 300 patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy of CLL
Authors: Tam C. S. , O'Brien S. , Wierda W. , Lerner S. , Kantarjian H. , Keating M. J.
Published: March 2020

7008

Background: The early results of 224 CLL patients receiving the FCR regimen were previously reported (JCO 23:4079). Mature follow-up data (median 62 months for survivors) is now available for the complete cohort of 300 patients. Methods: Eligible patients were =16 years old with previously untreated CLL requiring therapy. Median age was 57 years (31%=60 years, 14% =70 years), and 61% & 36% were in modified Rai intermediate & high risk categories respectively. Prognostic factors: B2m >2x normal 42% (n=295), CD38 positive 28% (n=253), abnormal metaphase cytogenetics 29% (n=221), IgVH unmutated 66% (n=94), ZAP-70 positive 49% (n=88). The planned six cycles of therapy were completed in 74% patients. Results: Responses were: 72% CR, 11% nodular PR (PRn) & 12% PR. On multivariate analysis, CR rates were inferior in patients with B2m >2N (p=0.001) and white cell count >150 × 109/L (p=0.01). Rai stage, CD38 positivity, IGVH mutational status and ZAP-70 positivity were not associated with inferior CR. Median Times to Progression (TTP) were 80 months for CR (n=216), 80 months for PRn (n=32) & 27 months for PR (n=36), with 77%, 65% and 28% projected to be progression-free at five years; projected 5 yr survival were 90%, 81% and 37% respectively. Restricting the analysis to 190 patients with at least five years followup, actual 5 yr TTP and 5yr survival were 70% & 88% respectively in complete responders. Five cases of Richter transformation and eight cases of MDS/AML occurred during remission, with projected 5 yr risk of 2% & 3% respectively. When compared with a historical cohort of patients receiving fludarabine (n=190) or fludarabine and cyclophosphamide/mitoxantrone (n=140) in multivariate analysis, FCR was independently associated with superior TTP (p<0.001) and survival (p<0.001). Conclusion: FCR is the most effective CLL frontline regimen reported to date. 70% of complete responders remain progression-free at five years.

No significant financial relationships to disclose.
Identification of a new subgroup of adult acute T-lymphoblastic leukemia (T-ALL) with a very favorable outcome using low ERG and BAALC expression
Authors: Baldus C. D. , Martus P. , Burmeister T. , Schwartz S. , Goekbuget N. , Bloomfield C. D. , Hoelzer D. , Hofmann W. K. , Thiel E.
Published: March 2020

7014

Background: High expression of the oncogenic ETS transcription factor ERG is an independent adverse prognostic factor in T-ALL and acute myeloid leukemia (AML). The gene BAALC similarly shows high expression in hematopoietic progenitors, downregulation with onset of differentiation, and prognostic significance in AML. Therefore, we assessed whether combined expression of ERG and BAALC would better predict outcome in T-ALL. Methods: ERG and BAALC mRNA expression was determined by realtime RT-PCR in pretherapy bone marrow of 152 adults with newly diagnosed T-ALL treated on German ALL protocols (05/93, 06/99). Patients (pts) were designated low (n=76) or high (n=76) ERG expressers based on median ERG expression and as low (n=111) or high (n=37) BAALC grouping the lower quartiles 1–3 vs. quartile 4. HOX11 and HOX11L2 expression was determined and immunophenotyping differentiated 3 T-ALL groups (early, thymic, mature). Results: High BAALC expression correlated with immature T-ALL with a higher frequency of early T-ALL (P<0.0001), CD34 positivity (P<0.0001), co-expression of myeloid markers (CD13 and/or CD33; P=0.03), and high ERG expression (P=0.02). Pts with high BAALC had fewer complete remissions (73% vs. 89%, P=0.03) and a higher relapse rate (67% vs. 32%, P=0.01) than low BAALC pts. Excluding 33 pts that had received stem cell transplantation (SCT), high expression of ERG (P=0.002) and of BAALC (P=0.0004) was associated with inferior relapse-free survival (RFS) and overall survival (OS, ERG: P=0.004; BAALC: P=0.0001) compared to low expression of ERG and BAALC, respectively. In contrast, pts with low expression of both ERG and BAALC had the most favorable outcome (5y-RFS: low ERG/low BAALC 81% vs. high ERG and/or high BAALC 33%, P<0.0001; 5y-OS: low ERG/low BAALC 69% vs. high ERG and/or high BAALC 26%, P=0.0001). On multivariable analysis low ERG/low BAALC expression was of independent favorable prognostic significance (RFS, HR: 0.18, P=0.0003; OS, HR: 0.3, P=0.001); the only other prognostic factor was the immunophenotype. Conclusions: Low expression of both ERG and BAALC identifies T-ALL pts with a distinctly favorable long term outcome, thus detecting pts that may not benefit from further treatment intensification including SCT.

No significant financial relationships to disclose.
A unique microRNA signature associated with nucleophosmin mutations in normal karyotype acute myeloid leukemia
Authors: Garzon R. , Volinia S. , Falini B. , Croce C. M.
Published: March 2020

7015

Background: Nucleophosmin (NPM) mutations are present in about 30 to 50 % of the patients with normal karyotype acute myeloid leukemia (NK-AML). The mutant NPM protein shows aberrant cytoplasmic location and is frequently associated with FLT3 mutations. Little is know, however how NPM mutants promote leukemia. To obtain insights about the biology of NPM+ AML we investigated the expression of microRNAs in NK-AML patients characterized for NPM mutations. Methods: We studied 85 adult NK-AML patients characterized for NPM, FLT3 ITD and FLT3 D835 mutations using a miRNA microarray platform containing 345 mature and precursors miRNAs. Mutation analysis for NPM, FLT3 ITD and FLT3 D835 were carried out in most of the patients as previously described (Falini, Blood 2006). The distribution of the mutations were as follows: NPMc+ (54 patients), NPMc- (31), FLT3 ITD+ (27), FLT3 ITD-(51) and FLT3 D835+ (21) and FLT3 D835-(26). Data were analyzed after background subtraction and normalization with a set of housekeeping genes using Significance Analysis of Microarrays and Predictive Analysis of microarrays. The results were validated using miRNA q-RT-PCR. Results: We identified a strong miRNA signature that distinguishes NPMc+ cases with high accuracy and includes the up-regulation of miR-10a, miR-10b and several let-7 family members. Many of the down-regulated miRNAs including miR-134, miR-194, miR-204, miR-526 and miR-28 are predicted to target many HOX genes suggesting that NPM mutants may induce HOX genes through the down-modulation of miRNA regulators of these genes. The signatures associated with FLT3 mutations were not accurate to predict this abnormality. However, when we analyzed the subgroup of NPMc+ FLT3 ITD + cases a distinctive signature was found with respect to other NPMc+ FLT3 negative cases. Conclusions: A unique miRNA signature is associated with NPMc+ mutations in AML. FLT3 ITD and FLT3 D835 are not clearly associated to any characteristic miRNA signature when analyzed individually. However the subgroup of NPMc+ FLT3 ITD has a distinctive miRNA signature. This data provide with new insights about the pathogenesis of NPMc+ AML that could be exploited to generate novel therapeutic strategies for one of the most common mutations in AML.

No significant financial relationships to disclose.
Decitabine in older patients with acute myelogenous leukemia (AML)
Authors: Issa J. , Saba H. I. , Garcia-Manero G. , Shan J. , Kantarjian H. M.
Published: March 2020

7021

Background: Advanced myelodysplasia and AML are age-related diseases with known poor prognosis in patients over age 60. AML is defined by World Health Organization (WHO) criteria as patients with =20% blasts in the bone marrow. SEER database analysis has indicated that 64% of AML patients over age 65 go untreated, other than with supportive care. Their median survival is 1.7 months. The main reason for this reluctance to treat is perceived toxicity of chemotherapy in this age group. Decitabine is a hypomethylating agent that provides a low-intensity alternative for patients with myeloid malignancies. Methods: We reviewed patients with =20% blasts in the bone marrow treated on a randomized study of decitabine vs. supportive care in myelodysplastic syndromes, and similar patients enrolled on two consecutive studies of decitabine alone or in combination with valproic acid, conducted at MD Anderson Cancer Center. Response to decitabine was analyzed by International Working Group criteria. Results: Overall, there were 33 patients with the WHO criteria of AML that were treated with decitabine alone (23 patients) or in combination with valproic acid (10 patients) as first-line therapy. There were 20 men (61%) and their median age was 72, range 39 to 85. Median bone marrow blasts at study entry was 26%, and 14 (42%) had >30% blasts. There were three different schedules of decitabine IV, which gave a total of 100–150 mg/m2/course over 3–10 days. Of the 33 patients treated, there were 8 CRs (24%) and 9 marrow CR/PR/Hematologic improvement (27%) for a total response rate of 17 (52%). Overall mortality at 4 weeks and 8 weeks was 3% and 15%, respectively. At a median follow-up of 20 months, median survival of the entire group was 12.6 months (95% CI: 6.5–23.0), and 2-year survival was 25% (95% CI: 13–48), which compares favorably to reported AML survival in this age group in the United States. Conclusions: We conclude that decitabine is an effective and less toxic treatment in this AML age group and may prolong survival compared with supportive care.

No significant financial relationships to disclose.
A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP)
Authors: le Coutre P. , Gattermann N. , Hochhaus A. , Larson R. , Weitzman A. , Haque A. , Giles F. , O′Brien S. G. , Kantarjian H. M.
Published: March 2020

7026

Background: CML-AP is often associated with imatinib-resistance and the occurrence of BCR-ABL mutations. This phase II open-label study was designed to evaluate the safety and efficacy of Nilotinib, a potent novel tyrosine kinase inhibitor, in imatinib-resistant or - intolerant CML-AP pts. Methods: Imatinib-resistance and -intolerance were defined using standard criteria, and all resistant pts failed imatinib >/= 600mg/day. Primary endpoint was a confirmed hematologic response (HR) determined by conventional ITT analysis. Nilotinib was started at 400mg BID and escalated to 600mg BID for inadequate responses. Results: Safety and efficacy are reported for first 64 consecutively enrolled pts completing >/= 8 mos treatment. 52 (81%) were imatinib-resistant; 12 (19%) -intolerant. Median duration of CML was 74 mos; median duration of prior imatinib use was 28 mos. Median duration of nilotinib exposure was 208 days; median average dose intensity (mg/days) was 787. Median cumulative duration of dose interruption was 23 days. Treatment is ongoing for 27 (42%) pts; 37 (58%) have discontinued (9 for AEs; 17 for disease progression). HR occurred in 38 (59%) pts, of which 15 (23%) were complete, 8 (13%) were marrow responses, and 15 (23%) returned to chronic phase. MCyR occurred in 23 (36%) pts; 14 (22%) were complete and 9 (14%) were partial. 6 (9%) pts did not respond; 5 (8%) pts had disease progression. Median time to HR was 1.0 (1–3) mos and to MCyR was 2.0 (1–8) mos. Estimated 1-yr survival rate was 69% and median duration of HR has not been reached. The most common Grade 3/4 AEs included neutropenia (45%), thrombocytopenia (40%), asymptomatic lipase elevations (17%), and anemia (16%) pts. No pts experienced Grade 3/4 peripheral edema, or pleural/pericardial effusions; 2 pts had pulmonary edema. Conclusion: In pts with CML-AP, nilotinib is an effective therapeutic option in CML-AP pts with imatinib-resistance or -intolerance and is generally well tolerated with acceptable rates of myelosuppression and minimal non- hematologic toxicities.

No significant financial relationships to disclose.
TG101348, a potent, highly selective JAK2 inhibitor, inhibits colony formation in stem cells from polycythemia vera patients and prevents JAK2V617F-mediated splenomegaly and death in a mouse model
Authors: Hood J. , Doukas J. , Martin M. , Noronha G. , Jamieson C. , Soll R.
Published: March 2020

7031

Background: The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia has been strongly linked to an activating mutation of JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino acid residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Methods: In order to address this unmet clinical need we designed, synthesized and performed preclinical evaluations on a series of structurally novel compounds optimized for JAK2 inhibition. Results: TG101348, a compound which potently inhibits JAK2V617F enzymatically and in human cells, was selected as a clinical development candidate from this medicinal chemistry campaign. TG101348 displays remarkable kinase specificity as shown by 83X selectivity versus JAK3 and potent inhibition of <2% of the kinases evaluated in a commercial, phylogenetically diverse panel of 212 kinases. TG101348 potently inhibits erythroid colony formation in patient-derived cells from polycythemia patients at doses 2–3X lower than in normal control patients. Consistent with this observation TG101348 inhibits JAK2-driven STAT5 phosphorylation, cell proliferation and cell survival in JAK2V617F-expressing cell lines. In vivo, TG101348 exhibits promising pharmacokinetic profiles in species ranging from mouse to monkey including oral availabilities >20%, and half-lives consistent with once or twice daily dosing. TG101348 reduces the number of circulating mutant JAK2 cells, inhibited splenomegaly and improved survival without significantly impacting normal hematocrit in an aggressive JAK2-driven circulating cell model of disease in rodents. Conclusion: TG101348 has considerable potential for the treatment of JAK2- driven myeloproliferative disorders based on its promising preclinical potency, selectivity and pharmaceutical properties.

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