bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone health practices in men on androgen deprivation therapy (ADT): A population-based analysis of 25,802 patients
Authors: Alibhai S. M. , Duong-Hua M. , Sutradhar R. , Cheung A. M. , Fleshner N. E. , Warde P. , Paszat L.
Published: August 2020

9631

Background: ADT is used in up to 1 in 2 men with prostate cancer. Osteoporosis and fragility fractures are important side effects of ADT. Guidelines recommend 2 important bone health practices for men on ADT - measurement of bone mineral density with dual x-ray absorptiometry (DEXA) and use of bisphosphonates in men at risk of osteoporosis. The implementation of these guidelines in practice is not well known. Methods: Using linked administrative databases, we identified 25,802 men (mean age 75.9 y, range 66–100 y) with prostate cancer who were treated with at least 6 months of ADT or who underwent bilateral orchiectomy in Ontario, Canada between 1995 and 2005. Performance of DEXA and prescription of bisphosphonates were captured using specific procedure codes and drug identification numbers, respectively. Prior use of DEXA and bisphosphonates, as well as prior diagnoses of osteoporosis and fragility fracture, were captured with specific diagnostic codes and a 3 y look-back period. Annual rates per 100 person-years were determined for both outcomes. Results: Among 25,802 men, 3.09% had a DEXA more than one year prior to starting ADT, and 3.14% had a prior diagnosis of osteoporosis. Within 2 years of starting ADT, the rate of undergoing DEXA rose from 0.50 per 100 person-years in 1995 to 19.47 in 2005. Rates of DEXA testing were higher among those with a prior diagnosis of osteoporosis, prior DEXA test, or prior fragility fracture but did not reach rates above 50 per 100 person-years in any of these groups. Bisphosphonate use increased from 0.27 per 100 person-years in 1995 to 3.18 in 2005 among prior non-users. More men on ADT were started on a bisphosphonate in the third year after starting ADT as compared to the second year, and rates were higher in year 2 than year 1. Less than one-third of men starting a bisphosphonate underwent any DEXA testing within 12 months of bisphosphonate initiation. Conclusions: Rates of DEXA testing and bisphosphonate use have increased over time among older men starting ADT, but significant gaps and delays remain in the quality of bone health care in this population.

No significant financial relationships to disclose.
Cytokine-mediated changes associated with improvements in cancer-related fatigue induced by exercise: Results from a randomized pilot study of cancer patients receiving radiotherapy
Authors: Mustian K. M. , Fisher S. , Adams J. , Janelsins M. , Palesh O. , Darling T. , Peppone L. , Heckler C. , Williams J. , Morrow G.
Published: August 2020

9632

Background: Radiation therapy (RTH) results in dysregulated inflammatory profiles which increase cancer-related fatigue (CRF). Research suggests physical exercise can have a positive influence on CRF during RTH. Exercise may mediate improvements in CRF through a self-regulating inflammatory exercise response involving cytokines and myokines (muscle contraction-induced cytokines known as exercise factors that mediate exercise benefits in other tissues) which help the body adapt to inflammation. We explored the influence of a home-based exercise intervention (HBEX), including resistance and aerobic training, on mediators of inflammation, as well as the association between changes in these mediators and CRF. Methods: Breast and prostate cancer patients (N=38; mean age=57; 71% breast/female), beginning at least 28 sessions of RTH, were randomized to a 4wk HBEX (7 days/wk) or standard care (SC; RTH with no exercise). Cytokines (IL-8, TNFα, TNFαr1, IL-8, IL-1β and IFNγ) and the myokine IL-6 were measured by enzyme-linked immunoassays and CRF was assessed via valid self-report questionnaires pre- and post-intervention. Results: ANCOVAs, controlling for baseline, revealed significant differences between groups in mean levels of IFNγ and IL-6 (p=<0.05) and a trend toward differences in IL-8 and TNFαr1 (p<0.10) with significant baseline interactions for IFNγ, IL-6 and IL-8 (p<0.05) post-intervention. ANCOVAs revealed no significant differences between groups in mean levels of TNFα and IL-1β. Pearson correlations revealed a significant inverse association between changes in IL-8 (p<0.05;r=-0.64) and CRF and a trend toward an inverse association between changes in IL-6 (p=0.10;r=-0.44) and CRF in the HBEX condition but not in the SC condition. Conclusions: These data suggest that exercise-induced changes in IL-8 and IL-6 may mediate improvements in CRF. Future phase III randomized controlled trials are needed with larger samples to fully investigate these relationships. Funded by NCI grant 1R25CA102618.

No significant financial relationships to disclose.
A randomized pilot study comparing aprepitant to olanzapine for treatment of chemotherapy-induced nausea and vomiting
Authors: Shumway N. M. , Terrazzino S. E. , Jones C. B.
Published: August 2020

9633

Background: Chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC) is prevalent. The NK1antagonist, aprepitant (APR), has been shown to decrease CINV and with increased use, cost of supportive care is rising. Recent studies have shown that olanzapine (OLN) is safe and effective for CINV when used in combination with dexamethasone and palonosetron. We conducted a randomized, double-blind, placebo controlled pilot study to evaluate the use of OLN compared to APR for prevention of CINV in patients receiving HEC. Methods: Chemotherapy naïve patients receiving HEC were randomized to an APR containing arm or an OLN containing arm [see Table ] for the first 2 cycles of treatment. Patients recorded episodes of emesis and use of rescue meds using a daily diary and symptoms using the M.D. Anderson Symptom Inventory(MDASI). 18 patients consented to the protocol and 17/18 (OLN=8, APR=9) patients were evaluable (1 lost daily diary) with a median age 60 (range 24–71) 11/18 were females. Results: Chemo regimens for OLN group included (AC=50%, cisplatin=25%, ABVD=25%, and ifos=25%) and for APR (AC=55%, cisplatin=33%, and ABVD=11%) For both cycles (C1+C2) the complete response (CR=no emesis, no rescue) during the anticipatory period (D-2, D-1) was 87.5% in the OLN group compared to 77.8% in the APR group. Acute period (D1) CR rates were 75% in OLN vs. 44% in the APR group. Delayed (D2–4) CR rates were 62.5% in OLN vs. 55.6% in the APR group. Rates of nausea (score ≥ 1 on scale of 0–10, MDASI) were 25% OLN vs. 22.2% APR for anticipatory period, 62.5% OLN vs. 44.4% APR for acute period, and 62.5% OLN vs. 66.7% APR for delayed period. There were no grade 3 /4 toxicities. Conclusions: OLN containing antiemetic regimens were well tolerated and offered similar efficacy as APR containing regimens in preventing CINV in patients receiving HEC. Larger studies are needed to evaluate non-inferiority and potential cost savings of OLN containing regimens. [Table: see text]

No significant financial relationships to disclose.
Is there a preferred dose of palonosetron? Results of an abstracted data (AD) meta-analysis (MA) of all eight randomized double-blind (RDB) studies and the impact on guideline considerations
Authors: Raftopoulos H. , Bria E. , Gralla R. , Lesser M. , Napolitano B. , Giannarelli D.
Published: August 2020

9636

Background: Controversy continues whether there should be a guideline-preferred 5-HT3 antagonist. Large trials with palonosetron (palo) 0.25 mg demonstrated advantages over earlier 5-HT3 agents in preventing emesis with chemotherapy (chemo). Guideline groups have not consistently adopted palo as the preferred 5HT3 agent since these trials omitted the recommended addition of dexamethasone (dex). A recent 1100 patient RDB trial (Yoshizawa, ESMO 2008) found superiority for palo 0.75 mg + dex versus granisetron 3 mg + dex. Both palo and granisetron are approved at varying doses in different countries. This abstracted-data MA was conducted to see if this palo dosing yields differences. If not, results from randomized trials at either dose can aid practice and guideline committees in 5-HT3 agent selection. Methods: A literature search and colleague inquiry identified RDB trials that included treatment arms with 0.25 mg and 0.75 mg of palo. MA primary endpoint: Complete Response (CR - no vomiting, no rescue) over days 1–5 after chemo. Secondary endpoints: 1)Acute CR (day 1), 2)Delayed CR (days 2 - 5), 3) Grade 3–4 toxicities. Data were abstracted and checked by at least 2 reviewers. CMA software v2 (Biostat, NJ) was used to calculate relative risk ratios (palo 0.75 vs palo 0.25) with 95% confidence intervals (CI). Results: 8 trials with 1926 patients included all RDB studies with these palo doses - 4 with HEC and 4 with MEC (6 with IV and 2 with oral palo). The Cochrane Q test indicated no heterogeneity (het) for overall and delayed CR; het seen in the acute setting was accounted for by the 2 smaller dose-finding studies. No significant toxicity differences were found. Conclusions: Palo doses of 0.25 mg or 0.75 mg yield very similar efficacy and safety with both HEC and MEC in this literature-based MA. Results with either dose can aid in practice and guideline considerations for all chemo groups studied. [Table: see text]

[Table: see text]
Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial
Authors: Aschele C. , Pinto C. , Cordio S. , Rosati G. , Tagliagambe A. , Artale S. , Rosetti P. , Lonardi S. , Boni L. , Cionini L. ,   on behalf of STAR Network Investigators
Published: August 2020

CRA4008

The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology.

No significant financial relationships to disclose.
Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment
Authors: Poultsides G. A. , Servais E. L. , Saltz L. B. , Patil S. , Kemeny N. E. , Guillem J. G. , Weiser M. , Temple L. K. , Wong W. , Paty P. B.
Published: August 2020

CRA4030

The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology.

[Table: see text]
Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC)
Authors: Belani C. P. , Brodowicz T. , Ciuleanu T. , Kim J. H. , Krzakowski M. , Laack E. , Wu Y. L. , Peterson P. , Krejcy K. , Zielinski C.
Published: August 2020

CRA8000

The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology.

[Table: see text]
Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC)
Authors: Herbst R. S. , Sun Y. , Korfee S. , Germonpré P. , Saijo N. , Zhou C. , Wang J. , Langmuir P. , Kennedy S. J. , Johnson B. E.
Published: August 2020

CRA8003

The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology.

[Table: see text]
An economic analysis of arthralgia/myalgia (A/M) versus recurrence in women with hormone receptor-positive (HR+) breast cancer (BC) on aromatase inhibitors (AIs)
Authors: Hadji P.
Published: August 2020

e11601

Background: The symptoms of A/M are associated with estrogen suppression and are more common with AIs relative to tamoxifen (TAM). AIs have demonstrated superior efficacy when compared with TAM. In BIG 1–98, letrozole (LET) treatment provides a significant reduction in the risk of distant metastasis (DM); the updated 76 month BIG 1–98 analysis now suggests that early reduction in DM ultimately leads to overall survival (OS) benefit, 40 fewer deaths with LET compared with TAM. [Mouridsen, 2008] It has been reported that women reporting new joint symptoms at 3 months after initiating an AI have a significantly lower risk for recurrence compared with women not reporting these symptoms [Cuzick, 2008]. Methods: Data from the Henry Ford Health System (1995–2005) were used to identify postmenopausal HR+ early BC patients with at least 1 year of AI therapy follow-up after surgery. Total health care costs of managing A/M associated with hormone therapy as well as BC recurrences were estimated from charges incurred during health care encounters for these conditions. Results: In the 834 patients eligible, the treated A/M incidence was 21% and the total health care cost ∼ $429 per symptomatic patient/yr. The average annual cost of any BC recurrence was previously reported at ∼$131,000/yr, with greatest cost seen with DM at ∼ $265,783/yr [Weiderkehr, 2008]. Conclusions: The economic costs of treating A/M are nominal, particularly in light of the superior efficacy of AIs and the economic burden of BC recurrences. DM is the most costly of the recurrences, and in BIG 1–98, reducing early DM appears to impact OS. Discontinuation of AIs, or switching to less effective therapies in an effort to manage A/M, should be weighed against the benefit of AI therapy in reducing BC recurrences, particularly DM, as well as the high costs associated the managing these recurrences.

No significant financial relationships to disclose.
Triple detection method for sentinel lymph node detection
Authors: Lee S. , Yang J. , Nam S. , Lee J. , Kim W. , Choi J. , Kim G. , Kim G.
Published: August 2020

e11605

Background: Sentinel lymph node biopsy is widely accepted method to determine nodal stage of breast cancer. There are several reported method for detecting sentinel lymph node. The aim of this study was to show the new detection method of sentinel lymph node and show the effectiveness of this method. Methods: We did prospective study and enrolled 25 patients who underwent partial mastectomy and sentinel lymph node biopsy. We injected indigocyanine green (green dye) at peritumoral lesion, indigocarmine dye (blue dye) in subareolar area and radioisotope (Tc-99m) injection. Sentinel lymph nodes are identified by color change or radioisotope uptake, and classified by each color (blue or green) and radioisotope uptake. We compared the detection rate from our study with that from the previous studies. Results: Sentinel lymph nodes were detected in all patients (25/25). Green color stained sentinel lymph nodes were identified in 18 patients (18/25), blue color stained sentinel lymph nodes were identified in 15 patients (15/25) and radioactive lymph nodes were identified in 19 patients (19/25). Conclusions: The triple mapping method showed higher detection rate than the previous studies and this method is recommendable to detect sentinel lymph node.

No significant financial relationships to disclose.
Male breast cancer retrospective institution review of a 17-year period
Authors: Rodriguez Franco C. , Aguiar Bujanda D. , Saura Grau S. , Bohn Sarmiento U. , Aguiar Morales J.
Published: August 2020

e11638

Background: Male breast cancer (MBC) is a very uncommon illness relative to female breast cancer (FBC) The are some differences between both that could influence the management, like gene expression, hormonal enviroment and anatomy of the gland. Methods: Retrospective review of patients diagnosed in a seventeen year period (1990–2007). Results: There were 22 male patients diagnosed in our institution with a median age of 62.4 years (range 34 to 83 years) during the period. One had bilateral breast cancer. Stage of disease was I-II in 13 patients (59%), III in 8 patients (36%), and IV in 1 patient (5%). Five patients (22.7%) had familiar history of breast cancer and 3 patients (13%) had familiar history of other kind of neoplasias. Hormonal receptor were positive in thirteen patiens (59%) and 5 were unknown (23%). Ductal carcinoma was the predominant histologic subtype with 17 patients (77%). Other types were pleomorfic, mucoid and papilar carcinoma (one each type) and 3 patients with intrapapilar carcinoma with microinfiltration. Eleven of 20 patologic available axilla had node positive (55%). Grade were I in 3 patients (13%), II in 4 patients (18%), III in 8 (37%) and undefined in in 7 (32%). Surgery was the initial treatment in 18 patients (81%), just 2 of them performing tumorectomy and the other 16 radical mastectomy. 3 patients receive neoadyuvant chemotherapy with 1 complete response and one partial response. 13 patients (59%) received adjuvant radiotherapy (RT) and 17 (77%) adjuvant hormonal therapy (HT) mostly of them with tamoxifen (14/17) and the others 3 patients with aromatase inhibitors. Adjuvant chemotherapy was used in 9 (41%) patients with an antracycline regimen. With a median follow-up of 78 months (range 7–125), overall survival was 77 % with 3 patients died with progression disease and two patients died because of intercurrent illness without evidence of cancer progression. Regarding to our population area we had an incidence of 0.96/100.000 inhabitants during this 17 year period. Conclusions: MBC in our area are in the upper limit of occidental countries incidence. Most cases can be treated with radical intention with surgery (mostly radical) and adjuvant treatment with a good survival percentage. We manage MBC like we do FBC because of absence of clinical randomized trial specific for MBC.

No significant financial relationships to disclose.
Peritoneal metastases in breast cancer patients: Differences in survival depending on histological subtype
Authors: Atassi Z. , Varga D. , Plotzki K. , Kurzeder C. , Kreienberg R.
Published: August 2020

e12024

Background: Distant spread from breast cancer is commonly found in bones, lungs, liver, and central nervous system. Metastatic involvement of peritoneum and retroperitoneum is unusual and unexpected. The aim of the study was to perform a comprehensive analysis of breast cancer patients with peritoneal metastases and to compare survivals depending on biological subtypes. Methods: 44 breast cancer pts with peritoneal metastases were detected out of a database of 2,500 breast cancer patients treated in one institution between 1995 and 2005. Clinical characteristics such as estrogen receptor and progesterone receptor as well as survivals were analized based on breast cancer subtypes. Results: Mean patient age was 54 years, 25 patients (56%) had ductal invasive carcinoma while 19 (44%) were diagnosed lobular invasive carcinoma. 30 (68%) patients had endocrine responsive tumors. A HER-2 percentage is not provided due to the lack of data before the year 2000. Median survival calculated from peritoneal metastases in histologic subgroups was as follows: Median progression free survival was 36.5 months for ductal invasive carcinoma, and 23.5 months for lobular invasive breast cancer. Median overall survival was 46 (Std 38.5) months for ductal invasive breast cancer and 32 (Std 54.5) months for lobular invasive breast cancer. Conclusions: Patients with peritoneal metastases are a heterogenous group with a different outcome. The histologic subtype seems to be an important predictive factor as lobular invasive breast cancer is associated with worsened progression free an overall survival rates.

No significant financial relationships to disclose.
Isolated tumor cells versus micro-metastasis in sentinel lymph node biopsy for T1, T2 breast cancer compared to macro-metastasis: Significance after complete axillary dissection
Authors: Alabdulkarim Y. A. , Nassif E.
Published: August 2020

e12028

Background: Evaluating the axillary lymph nodes is extremely important in the management of breast cancer, with the recent improvement in histopathology techniques detection of micro-metastasis and even isolated cancer cells (ITC) in a setting of sentinel lymph node examination is feasible. In this study we aim to compare the outcome and significance of; positive SLN for macro versus Micro-metastasis, and ITCs. Methods: We reviewed all the patients who had SLN for breast cancer of stage T 1–2 between April 2006 and November 2008. Identifying all those who had positive macro-metastasis, micro-metastasis, or isolated tumor cells, pathology results of the full axillary LN dissection was evaluated for each type. Results: 350 patients had SLN of these 226 had a disease of T1–2, thirty seven patients (16.3%) had full axillary dissection, of these 27/37 had positive SLN for macro-metastasis, six had micro-metastasis and 3/37 had only ITCs. The presence of other LN metastasis was detected in 8 cases (21.6%); all of them were in the macro-metastasis group. No metastasis was found in either the micro-metastasis or the ITC groups. The ITC was only detected with DCIS; while micro-metastasis was present in DCIS or IDC. No relation was identified between the histopathology grade with ITC or micro-metastasis. Conclusions: Our findings did not show any presence of lymphatic metastasis after full axillary dissection, in case of positive micro-metastasis or ITCs in SLN, compared to the group of macro-metastasis.

No significant financial relationships to disclose.
Investigation of cognitive screening measures in patients with brain tumors: Diagnostic accuracy and correlation with quality of life
Authors: Olson R. A. , Iverson G. , Parkinson M. , Carolan H. , Ellwood A. , McKenzie M.
Published: August 2020

e13000

Background: Brief cognitive screening measures are often selected by clinicians and researchers for brain tumor patients, primarily because of their ease of use. Currently, the Mini Mental State Examination (MMSE) is the most commonly chosen, despite a reported low sensitivity. The primary objective of this study was to compare the sensitivity of the MMSE with the Montreal Cognitive Assessment (MoCA). Methods: 44 patients with brain tumors were prospectively accrued and administered the MMSE and MoCA by blinded investigators, 75% of who completed a 4-hour “gold standard” neuropsychological assessment (NPA). Quality of life and community integration were measured with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) and Community Integration Questionnaire (CIQ), respectively. McNemar's test was used to compare sensitivity and specificity at pre-defined cutoff scores and receiver operating characteristic curve analyses were used to examine outcomes across all cutoffs. Correlations were assessed with Spearman's rank correlation coefficient. Results: 55% of patients met criteria for the DSM-IV diagnosis of Cognitive Disorder NOS on the NPA. Using pre-defined cutoffs, the MoCA was significantly more sensitive than the MMSE (55.5% versus 16.6%; p = 0.016), although specificity of the MoCA was poor (60.0%). MMSE scores below 27 were 100% specific; however, this applied to only three subjects. Furthermore, 39% of cognitively impaired subjects scored perfectly on MMSE. A MoCA cutoff of 22 had 28% sensitivity and 93% specificity, and a cutoff of 28 had 94% sensitivity and 20% specificity. The MoCA was correlated with both the FACT-Br (r = 0.319, p = 0.04) and CIQ (r = 0.427, p = 0.005), while MMSE scores did not correlate with either (p > 0.2). Conclusions: The MoCA is more sensitive than the MMSE, though at no cutoff is it both sensitive and specific. Despite its limitations, the MoCA may offer cost saving in the oncology clinic as a cognitive screen: individuals with MoCA scores a) below 22 are likely cognitively impaired, b) above 27 are likely cognitively normal, and c) 22–27 would likely benefit most from NPA. Furthermore, the MoCA is better able to detect cognitive impairment that is related to functional limitations and quality of life.

[Table: see text]
Phase I trial combining SCH 66336 to temozolomide (TMZ) for patients with grade 3 or 4 malignant gliomas (MG)
Authors: Desjardins A. , Reardon D. A. , Gururangan S. , Peters K. , Threatt S. , Friedman A. , Friedman H. , Vredenburgh J.
Published: August 2020

e13004

Background: Ras plays a crucial role in the control of cellular proliferation and differentiation. Farnesylation is an essential step in the post-translational processing of Ras. SCH 66336 inhibits farnesyl transferase, the crucial enzyme in this process. We report a phase I trial of TMZ and SCH 66336. Methods: Eligibility included: adult patients with stable or recurrent MG (GBM, anaplastic astrocytoma [AA], anaplastic oligodendroglioma [AO]) previously treated with radiation therapy (RT) and with or without chemotherapy; interval of at least two weeks between prior RT, or four weeks between prior chemotherapy; Karnofsky ≥ 60%; and adequate hematologic, renal and liver function. Patients were divided in two strata: those receiving enzyme-inducing antiepileptic drugs (EIAED) and those not receiving EIAED. Each patient was treated with TMZ for five days every 28 days, first cycle dosed at 150 mg/m2 and subsequent cycles at 200 mg/m2. SCH 66336 was dosed orally daily and was dose escalated. Responses were assessed after two cycles (8 weeks). The primary endpoints of this study were to determine the maximum tolerated dose (MTD) of SCH 66336 when administered with TMZ, and the toxicity of this combination. Results: Thirty-six patients were enrolled (25 GBM, 6 AA, 3 AO). Fifteen patients have been accrued to the EIAED stratum at SCH 66336 doses of 125, 175, and 250 mg orally BID. Twenty-one patients have been accrued to the non-EIAED stratum at SCH 66336 doses of 75, 100, 150, and 200 mg orally BID. Dose-limiting toxicities were: deep venous thrombosis (1 grade 3); nausea and vomiting (1 grade 3); diarrhea (1 grade 3); elevated ALT (1 grade 3); elevated creatinine (1 grade 3); and fatigue (1 grade 3). Radiographic evaluation reported: 2 partial responses, 14 stable disease for at least 4 cycles, and 11 disease progression after either the first or second cycle. Sixteen patients have completed at least six cycles. One patient is still on treatment, completing cycle 12. The MTD of this combination for the EIAED stratum is 175 mg BID and the non-EIAED stratum is 150 mg BID. Conclusions: SCH 66336 in combination with TMZ is well-tolerated and shows promising response when administered to patient when stable on TMZ alone or after RT and TMZ.

No significant financial relationships to disclose.
Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma
Authors: Kirkpatrick J. P. , Vredenburgh J. J. , Desjardins A. , Gururangan S. , Peters K. B. , Boulton S. T. , Friedman A. H. , Friedman H. S. , Reardon D. A.
Published: August 2020

e13007

Background: Malignant glioma (MG), an incurable primary CNS tumor, is characterized by frequent aberrant activation of EGFR, VEGFR, and PDGFR. This study will determine the MTD and DLT of vandetanib (V), a once-daily, oral selective inhibitor of VEGFR and EGFR when combined with imatinib mesylate (IM), an inhibitor of multiple tyrosine kinases including PDGFR and hydroxyurea (H). Methods: Adult recurrent MG patients with ≤ 3 prior recurrences, KPS ≥ 60% and adequate organ function were stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC). Both strata were independently escalated using a “3+3” design. H is administered at 500 mg BID while IM is administered at 500 mg BID for patients on EIAC and 400 mg QD for those not on EIAC. V is increased by 100 mg in successive cohorts beginning at 100 mg and 200 mg for patients not on and on EIAC, respectively. Evaluations were after every other 28-day cycle. Pharmacokinetics of V and IM were obtained on days 1 and 28 of cycle 1. Results: Twenty-six patients (grade 4 MG, n = 20; grade 3 MG, n = 6) have enrolled. Only 1 DLT (reversible grade 4 transaminase elevation; dose level 1) occurred among 22 non-EIAC patients and enrollment to this stratum is planned to continue at dose level 4. The MTD of V for patients on EIAC is 200 mg/day due to 2 of 3 patients developing grade 3 thrombocytopenia at the 300 mg/day dose level. Evidence of therapeutic benefit to date includes 1 partial response and 15 patients (58%) with stable disease for at least 4 weeks, including 4 patients for ≥4 months. Conclusions: Combination of V, IM, and H is well-tolerated in recurrent MG patients. Further accrual is ongoing and an update of outcome, toxicity, and pharmacokinetic analyses will be presented.

No significant financial relationships to disclose.
Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas
Authors: Herndon J. , Vredenburgh J. , Reardon D. , Desjardins A. , Peters K. , Gururangan S. , Norfleet J. , Friedman A. , Bigner D. , Friedman H. S.
Published: August 2020

e13016

Background: Recurrent malignant gliomas have a poor prognosis, with a median survival of 6–15 months, with grade 4 glioblastomas more aggressive than grade 3 anaplastic astrocytomas or oligodendrogliomas. Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are critically important in glioma biology. Vandetanib is a multi-kinase inhibitor, predominantly of VEGF and EGF. We report a phase I trial of vandetanib in combination with oral etoposide for recurrent malignant glioma. Methods: Patients with histologically documented recurrent grade 3 or grade 4 malignant glioma were eligible. Patients were treated with daily oral vandetanib and oral etoposide. The trial design was a modified 3 + 3 Phase I design, with the dose levels outlined below. Results: Eighteen patients have been accrued. There was more hematologic toxicity than expected, with 3/6 of the patients enrolled at dose level 1 developing grade 4 neutropenia. There were no DLT's at the -1 dose level. The protocol was amended to decrease the dose of etoposide to 50 mg daily for 21 days, then 7 days off and dose escalation of vandetanib started again at 100 mg daily. Six patients had no dose limiting toxicity at the new dose level 1 of vandetanib 100 mg daily and etoposide 50 mg daily. Dose escalation continues. There has been clinical activity, with patients remaining stable on study for multiple cycles. Conclusions: Vandetanib and oral etoposide appear to interact to produce more marrow toxicity than expected. A phase II trial is planned when the MTD of vandetanib with reduced dose etoposide is determined.

[Table: see text]

No significant financial relationships to disclose.
Very late relapses in glioblastoma long-term survivors
Authors: Baehr O. , Herrlinger U. , Weller M. , Steinbach J. P.
Published: August 2020

e13017

Background: Long-term survival of patients with histologically confirmed glioblastoma is a rare event with figures in the range of 2–3% for 5-year survival. Prognosis and further clinical course of these patients beyond 5 years after diagnosis are in essence unknown with only anecdotal reports of patients surviving for 10 years or more. Methods: We here report on the extended follow-up (mean, 139.4 months) of a cohort of 10 glioblastoma long-term survivors. Retrospective central histology, clinical monitoring, and regular magnetic resonance imaging were done. Results: A total of 5 patients of the 9 patients alive at a previous analysis have died during the extended follow-up. Four of these patients died from recurrent tumor. One patient died from leukoencephalopathy-associated complications without evidence of tumor progression. Details concerning the occurrence of relapses and their treatment are displayed in table 1. Notably, very late relapses occurred in three patients after 118, 124, and 126 months of progression-free survival. Thus, from the original cohort of 10 patients only 3 remain free from recurrence after the extended follow up of more than 10 years. Conclusions: Very late relapses pose a serious threat for glioblastoma long-term survivors and call for continuous vigilance. The maintenance of a tight control schedule even in patients surviving for more than 10 years should be considered.

[Table: see text]

No significant financial relationships to disclose.
Efficacy of protracted dose-dense temozolomide (TMZ) in patients with progressive high-grade glioma
Authors: Abacioglu M. U. , Caglar H. B. , Yumuk P. F. , Akgun Z. , Atasoy B. M. , Sengoz M.
Published: August 2020

e13018

Background: The study was aimed to evaluate the efficacy of TMZ on a protracted dose-dense schedule after standard 5-day TMZ regimen in patients with progressive high-grade glioma. Methods: In this phase II prospective study, patients who had progression on standard 5-day TMZ for recurrence (group 1) or recurrence after concurrent radiotherapy+TMZ and ≥ 2 cycles of adjuvant TMZ (group 2) for high-grade glioma received TMZ 100 mg/m2× 21 q28 days until progression according to MacDonald's criteria. Patients were included in the study after ethical committee approval and written informed consent. The primary end-point was 6 months PFS. Secondary end-points were OS and toxicity. Results: Between October 2006 and October 2008, 25 patients were included in the study. Nine of the patients were group 1 and 16 of them were group 2. Male/female ratio was 18/7. The median age was 50 (range, 18–70) and median KPS score was 80 (range, 50–100). The histopathology was glioblastoma in 18 and grade 3 glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma or anaplastic oligodendroglioma) in 7. The median cycles of 5-day TMZ received before study entry was 6 (range, 2–18) in group 1 and 6 (2–7) in group 2. With a median follow up of 6 months (1–14 months) the median number of 21-day TMZ cycles received was 2 (range, 1–8). Radiological evaluation could not be performed in 5 patients because of early clinical progression. The best response during treatment was partial response in 2 (8%), stable disease in 9 (36%), and progression in 9 (36%) out of 20 patients assessed. The median time to progression was 2 months (1–8 months) and 6 months PFS rate was 11%. The median OS time was 8 months and 1 year OS rate was 38%. Out of 80 cycles received there was no anemia; 5 (6%) grade 1, 8 (10%) grade 2, 2 (3%) grade 3 leucopenia; 1 (1%) grade 1, 2 (3%) grade 2, 1 (1%) grade 3, 1 (1%) grade 4 thrombocytopenia; 9 (11%) grade 1, 7 (9%) grade 2, 32 (40%) grade 3, and 11 (14%) grade 4 lymphopenia. Study was terminated in 2 patients (one with grade 4 thrombocytopenia and the other with grade 4 hepatic toxicity). There was no dose reduction in the study drug due to toxicity. Conclusions: Protracted dose-dense TMZ after 5-day schedule for recurrent or progressive disease has modest efficacy with tolerable toxicity.

No significant financial relationships to disclose.
Expression and prognostic significance of differentiation markers in primary CNS lymphoma (PCNSL)
Authors: Momota H. , Narita Y. , Miyakita Y. , Shinomiya A. , Maeshima A. , Maruyama T. , Muragaki Y. , Shibui S.
Published: August 2020

e13028

Background: BCL-6 expression has been reported to be associated with a better prognosis in PCNSL. However, significant differences of B-cell lymphoma subtypes exist in different geographic regions. The objectives of this study were to characterize the immunophenotypes of PCNSL in Japan and to determine their utility in predicting clinical outcomes. Methods: Immunostaining for CD5, CD10, BCL-6, and MUM-1 was done to determine the profile of diffuse large B-cell lymphoma of PCNSL from 27 immunocompetent patients in Japan. Then, the authors evaluated whether clinical and immunophenotypic markers were associated with progression-free or overall survival. Results: Germinal center B-cell (GCB) marker CD10 was positive in 22% of PCNSL samples, while another GCB marker BCL-6 was positive in 48% of samples. Post-GCB marker MUM-1 was positive in 81% of samples. Poor prognostic marker of systemic B-cell lymphoma CD5 was expressed in 15% of samples. In univariate analyses, only BCL-6 expression had a significant effect on progression-free survival (median, 6.1 months in BCL-6-positive patients versus 15.6 months in BCL-6-negative patients; p = 0.037). Patients with BCL-6 expression had a trend towards longer overall survival but nonsignificant. GCB subgroup (CD10-positive or CD10-negative/BCL-6-positive/MUM-1-negative) was not significantly associated with favorable survival. Conclusions: BCL-6 expression is associated with a poor prognosis in patients with PCNSL. The discrepancy between the reports from other groups and our results is potentially due to the racial, geographic or immunophenotypic differences of PCNSL.

No significant financial relationships to disclose.
Primary central nervous system lymphoma: An Irish clinical experience
Authors: Forde P. , Grant C. , Smith E. , Farrell M. , Brett F. , Bolger C. , Grogan L. , Breathnach O.
Published: August 2020

e13032

Background: North American studies have demonstrated an increase in incidence of primary CNS lymphoma in recent decades. To our knowledge there have been no studies analyzing primary CNS lymphoma in the Irish setting. This prompted a review of cases diagnosed at our institution, the larger of two national neurosurgical/neuro-oncology referral centers. Methods: The records of 78 patients diagnosed with primary CNS lymphoma at our institution between January 1999 and October 2008 were reviewed. Patient's age, sex, and time to diagnosis were noted. Histology and radiology was reviewed for cell of origin, CD20 status, and sites of involvement. HIV serology results were available for 23 patients. Results: The median age was 60 (4–78). There was a slight female preponderance (1.1:1]). Median time from hospital presentation to histological diagnosis was 17 days (4–790). 92% (74) of primary CNS lymphomas were B cell and CD20 positive with 8% (4) being T cell. One-third of patients had multifocal brain involvement by lymphoma. 2 of 23 patients tested were HIV positive. Conclusions: In comparison with international published series primary CNS lymphoma in Ireland is diagnosed at an older median age, has a more even sex distribution and a relatively higher incidence of T cell origin. Multifocal tumor involvement was also more frequent than in other series possibly indicating later clinical presentations. There was a much lower incidence of HIV infection in patients who were tested than in similar North American studies. The wide range in time to diagnosis indicates the difficulties associated with diagnosing this uncommon condition.

No significant financial relationships to disclose.
A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC)
Authors: Leal T. B. , Schelman W. , Traynor A. , Kolesar J. , Marnosha R. , Eickhoff J. , Alberti D. , Wilding G.
Published: August 2020

e13502

Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally-administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mc1–1, Bcl-W, and through upregulation of the proapoptotic proteins Noxa and Puma. Bcl- 2 is over-expressed in >80% of SCLC. In vitro study using SCLC cells showed that treatment with EP had synergistic cytotoxic effects in suppression of Bcl-2. This is a phase I dose-escalation study of AT in combination with EP with an expanded cohort of patients with ES-SCLC. This study is being conducted to determine the maximum tolerated dose (MTD), pharmacokinetics and activity of AT with EP ± pegfilgrastim (F) in patients with advanced, refractory solid tumors and/or ES-SCLC. Methods: This study used standard eligibility criteria except patients must not have received prior therapy that inhibits the Bcl-2 family. At dose level 1, patients received P 60 mg/m2 on day 1 and E 100 mg/m2 on days 1, 2, and 3 every 21 days. AT was administered 30 mg orally BID on days 1, 2 and 3 of each cycle. Results: 10 patients have been enrolled; 7 men, 3 women. Tumor types: 6 lung; 2 prostate; 1 head & neck; 1 unknown primary. 2 of 5 patients enrolled at dose level 1 experienced a DLT of neutropenic fever in cycle 1. Three subsequent patients were enrolled to dose level -1 (20 mg BID x 3 days, d1–3) which was well tolerated. Additional patients are being enrolled at dose level 1a (EP+AT with F). Grade 3/4 toxicities related to AT without F at dose level 1 and -1 were as follows: ANC (8), leucopenia (7), febrile neutropenia (2), low hemoglobin (1), thrombocytopenia (1), elevated AST (1), cardiac ischemia/MI (1), diarrhea (1). There were no reported grade 3/4 toxicities in two patients at level 1a. Four patients had stable disease; two progressive disease and four patients were unevaluable. Conclusions: The MTD without F was established at AT 20mg orally BID, P 60 mg/m2 on day 1, and E 100 mg/m2 on days 1, 2, and 3 every 21 days. The MTD with F has not yet been established. Accrual continues at dose level 1a. Subjective and objective evidence of clinical activity has been observed in patients with refractory solid tumors. This study was supported by NCI, UO1 CA062491, SAIC 25XS097 and 1ULRR025011.

No significant financial relationships to disclose.
Dose-finding study of NKTR-102 in combination with cetuximab
Authors: Hamm J. T. , Richards D. , Ramanathan R. K. , Becerra C. , Jameson G. , Walling J. , Gribben D. , Dhar S. , Eldon M. , Von Hoff D.
Published: August 2020

e13503

Background: NKTR-102 is an advanced polymer conjugate of irinotecan with broad single agent activity and a unique pharmacokinetic (pk) profile. The apparent half-life of the active metabolite SN-38 in patients (pts) administered NKTR-102 is approximately 50 days. NKTR-102 in combination with cetuximab was evaluated in pts with refractory solid tumors to define the maximum tolerated dose (MTD). Methods: NKTR-102 was infused over 90 minutes every 3 weeks per cycle. Cetuximab was infused over 2 hours at 400mg/m2 on day 1 followed by a weekly 1 hour infusion at 250mg/m2. Cohorts of 3 -12 pts were treated with escalating doses of NKTR- 102. MTD was established based on the dose limiting toxicities observed in cycle 1 and safety data from subsequent cycles. Serial plasma samples were collected throughout the study for PK analysis. Results: Eighteen pts were enrolled: main tumor types include colon (5), pancreas (4), rectal (2), breast (2), gastric (1), other (4). Pts received 100 mg/m2 (12) or 125 mg/m2 (6) of NKTR-102 for a median of 2.5 cycles (range 1 to 11+). At 125 mg/m2, 3 pts had G3 diarrhea, 1 in cycle 1; 2 in cycle 2. At 100mg/m2, 1 pt had G3 diarrhea in cycle 1 and a further pt had G4 fatigue in cycle 2. Other G3 toxicities for all patients in both dose groups include nausea (3), vomiting (3) and neutropenia (2). No G3 rash was reported. Partial responses (PR) were observed in 3 pts at 100 mg/m2: confirmed (rectal, colorectal) and unconfirmed (gastric). Another pt with pancreatic cancer had a decrease in CA19–9 from 2000 at baseline to 157 U/ml with associated symptomatic benefit. NKTR-102 resulted in sustained exposure to SN-38 with no evidence of PK drug interactions between NKTR-102 and cetuximab. Conclusions: NKTR-102 shows evidence of clinical antitumor activity in combination with cetuximab. Toxicity is manageable; diarrhea and neutropenia are dose limiting. The recommended dose of NKTR-102 with cetuximab is 100mg/m2 every three weeks. Data support further evaluation of this combination in appropriate tumor types.

[Table: see text]
A phase I study dose escalation clinical study of hepatic intraarterial cisplatin, combination systemic intravenous liposomal doxorubicin in patients advanced cancer dominant liver involvement
Authors: Vaklavas C. , Tsimberidou A. M. , Moulder S. , Ng C. , Naing A. , Daring S. , Bedikian A. , Uehara C. , Kurzrock R.
Published: August 2020

e13512

Background: Patients with liver metastases treated on phase I clinical trials have a median survival of 7.5 months (range, 6.0–9.5). We conducted a phase I study of hepatic arterial infusion (HAI) and intravenous (IV) chemotherapy in patients with advanced cancer and dominant liver involvement. Patients: Patients were treated with HAI cisplatin 100–200 mg/m2 intraarterially D1+ 3000 IU heparin intraarterially on D1; followed by liposomal doxorubicin 20–35 mg/m2 IV D1 every 4 wks using a conventional “3 + 3” design. Results: Thirty patients were treated (median age, 56 y; range, 15–76; 5 men, 25 women). Diagnoses were breast cancer (n=11), colorectal cancer (n= 8), ocular melanoma (n=4), and other (n=7). The median number of prior therapies was 5 (range, 1–13). Enrollment was: HAI cisplatin (mg/m2)/IV doxil (mg/m2): 100/20 (n=3); 100/25 (n=4); 100/30 (n=3); 100/35 (n=16) and 125/35 (n=4) and the maximum tolerated dose (MTD) was 100/35. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (1 of 4 patients). Among 30 patients who completed cycle 1, 7 (23%) patients had no toxicity >Grade 1. Overall, 77 cycles were administered (median per patient, 4; range, 1–6). The most common toxicities were nausea/vomiting (n=23), fatigue (n=15), and constipation (n=13). Twenty-one patients were evaluable for response. Treatment resulted in a partial response (PR)(n=4) or stable disease (SD)(n=6) by RECIST in 10 (48%) patients and lasted for ≥4 months (tumor reduction by 5% to 44%). Four (19%) patients achieved a PR (tumor reduction by 38%, 42%, 44% and 51%, for 4, 4, 6, and 4 months, respectively). Of the 11 patients with breast cancer, 3 had a PR and 4 had SD. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD. One patient with hepatocellular carcinoma had SD. Of 11 evaluable patients treated at the MTD, 3 (27%) had a PR and 4 (36%) had SD. Conclusions: The MTD of HAI cisplatin 100 mg/m2 and systemic liposomal doxorubicin 35 mg/m2 demonstrated antitumor activity in this patient subset.

No significant financial relationships to disclose.
Safety and early efficacy results from a phase I study of volociximab (V) in combination with carboplatin (C) and paclitaxel (P) in patients (pts) with advanced non small cell lung cancer (NSCLC)
Authors: Besse B. , Almokadem S. , Planchard D. , Chico I. , Tsao C. L. , Ringeisen F. , Soria J. , Belani C. P.
Published: August 2020

e13513

Background: Volociximab is a chimeric monoclonal antibody that blocks fibronectin binding to α5β1 and induces apoptosis in proliferating endothelial cells. Its anti-angiogenic actions are independent of the VEGF pathway. This is the first clinical study of voloxicimab in patients with advanced NSCLC. Methods: This phase 1b multi-center open-label, dose-escalation study was designed to determine the maximum tolerated dose of V in combination with full doses of C (AUC=6mg/ml.min) P (200mg/m2) with cycles repeated every 3 wks for a maximum of 6 cycles followed by a maintenance treatment with V alone. Eligible pts had histologically confirmed untreated stage IIIb or IV NSCLC. In cohorts 1 and 2, pts received V at 10 mg/kg and 20mg/kg IV, respectively, on days 1 and 8, of the first 21 day cycle then every 21 days. In cohort 3, pts received V 30 mg/kg IV every 21 days from day 1. We present here the interim safety analysis and RECIST response data of the combination therapy. Results: A total of 22 patients (9, 6 and 7 in cohorts 1, 2 and 3 respectively) who received at least one dose of treatment constitute the safety population. Reported salient adverse events (any grade) were constipation (68%), asthenia (64%), nausea (59%), arthralgia (55%) and paresthesia (46%). Grade 3 bowel obstruction in one patient was considered a DLT in cohort 2. No DLT's were observed in cohort 3. Seven pts reported at least one serious adverse event (all Grade 3) including deep vein thrombosis (1), peripheral arterial occlusion (1), proteinuria (1), pneumonitis (1), small intestinal obstruction (1), pleural effusion (1), hypoxia (1), dehydration (1) and orthostatic hypotension (1). Partial response was seen in 6 pts and stable disease in 12 out of 18 pts who were evaluable for response by RECIST. Conclusions: The highest dose of V tested (30 mg/kg q3w) in combination with CP appears well tolerated and the regimen has promising clinical activity in advanced NSCLC.

[Table: see text]