bluuebunny/crossref_metadata_2025 huggingface dataset:
Success rate and myeloid toxicity of carboplatin desensitization protocol in low grade glioma patients
Authors: Berrak S. , Beker D. B. , Canpolat C. , Cakir F. B.
Published: March 2020

20012

The effectiveness of carboplatin and vincristine chemotherapy in the treatment of low grade glial tumors is well established. This study was retrospectively designed to investigate the success rate and myeloid toxicity of carboplatin desensitization in a group of patients with carboplatin allergy. A total of 45 patients followed between October 1998-January 2007 with low grade glial tumors were included into study. Patients with severe hypersensitivity reactions (including anaphylaxis) were given 6-step desensitization protocol with gradual increase in concentration of carboplatin over 6 hours. Weekly absolute neutrophil count (ANC) and number of febrile neutropenia episodes of each patient during treatment period were collected from patient files. Among 45 patients, eight were switched to desensitization protocol. They had received a median of 6 courses (range 1–29) of carboplatin before developing their first allergic reaction. A median number of 15 courses of desensitizations (range 3–40) were given to these patients. Desensitization was successful in 6 patients. Age, gender, diagnosis were found to be similar in patients with and without carboplatin allergy. Regarding myeloid toxicity, mean percentage of follow-up weeks with ANC values below 1,500/mm3 in patients with and without desensitization were 0.42±0.04 and 0.21±0.02, respectively (p=0.009). Mean percentage of weeks with ANC values below 500/mm3 were not significant between two groups (p=0.28). However, desensitization protocol was not found to have an impact on number and presence of febrile neutropenia episodes. In conclusion, desensitization protocol might be an alternative to complete scheduled treatment in low grade glioma patients with hypersensitivity to carboplatin. Although, the percentage of low ANC weeks seemed to be statistically higher, insignificance of febrile neutopenia episodes in our patients demonstrated safety of desensitization protocol in terms of myeloid toxicity.

No significant financial relationships to disclose.
Exercise intervention for pediatric cancer survivors: Feasibility and preliminary efficacy
Authors: Collett B. , Acosta A. , Whitsett S. , McTiernan A. , Friedman D.
Published: March 2020

20013

Background: Obesity and diminished physical activity are known sequelae of cancer and its treatment. In medical oncology, data support the efficacy of exercise interventions. We therefore evaluated such an intervention for overweight/inactive adolescent cancer survivors. Methods: Participants were randomized to an exercise or control condition. The intervention group attended exercise sessions for 12-weeks with an exercise physiologist, during which they developed an individualized program emphasizing cardiovascular fitness. Controls received written exercise and nutrition materials. Outcome measures included self-reported health-related quality of life (HRQOL), physical activity, and fatigue; and lab measures of body mass index (BMI) and VO2max. Results: Among the 36 participants (mean age = 18.0 yrs, mean = 12.0 yrs post-diagnosis), at baseline both groups had diminished HRQOL, elevated BMIs, low physical activity, decreased V02max and high levels of fatigue. Post-treatment, there was little change in BMI, while physical activity and fatigue slightly increased in both groups. Study participation among survivors was limited due to the commute and time commitment for center-based sessions. Table 1 . a7-Day Physical Activity Recall; minutes/week of moderate-intense physical activity bMultidimensional Fatigue Questionnaire; lower scores = increased fatigue Conclusions: Survivors of childhood cancer are at risk for impaired HRQOL, high BMI, decreased physical activity, and fatigue, even 10+ years after diagnosis. Preliminary data are discouraging with respect to the immediate benefits of intervention, but analyses are ongoing to assess other outcomes as well as the impact 3 months following study completion. Feasibility issues of conducting such a study in a tertiary cancer center served by a broad catchment area have been identified. Continued research is required, which includes novel approaches to overcome concerns of time commitment, which limited study participation.

[Table: see text]

No significant financial relationships to disclose.
Delayed cognitive, behavioral, and radiological changes related to canial irradiation for pediatric brain tumors
Authors: Wahab M. M. Abdel , Hussien H. , Maher K. M.
Published: March 2020

20023

Purpose: To evaluate the delayed adverse changes in neuro-cognitive functions as well as white matter damage in radiated survivors of pediatric brain tumors. Methods: Forty two children (22 males) with primary brain tumors who were only treated with cranial radiation, were recruited. 28 patients were treated for low risk medulloblastoma, 10 patients for low grade astrocytoma, 3 patients for low grade ependymoma, and 1 patient for craniopharyngioma. Their ages ranged from 3 to 18 years (mean 10.3±3.98 years).They were subjected, initially just before radiotherapy and at follow-up 1–2 year after completion of cranial radiation, to serial clinical and neuropsychological assessments including Wechseler Intelligence Scale for Children, Vineland social maturity test, Benton Visual Memory Test, and Revised Behavior Problem Checklist. Magnetic resonance scans were also performed to detect the presence of white matter damage before radiotherapy and at follow up. Results: Initially, after surgery and before radiation, intelligence test scores were below normal scores for age and this was of high statistical significance (Total IQ: t= -3.02, P= 0.006). Visual memory test showed evidence of organicity in all cases. Social maturity showed a statistically significant decline as well (t= -2.11, P= 0.04). Follow-up after radiotherapy showed further decline with high statistical significance (Total IQ t= 3.228, P=0.003; visual memory t= 4.08, P= 0.001); An attentional problem has emerged (t= -6.12, P= 0.00). Both radiation dose and volume of radiation showed negative and statistically significant correlation with IQ. Age at diagnosis correlated positively and significantly with IQ ( r= 0.601, P=0.001). Multiple linear regression showed impaired neurocognitive function which was correlated with the degree of white matter damage. (standardized B= -0.577, P= 0.001) and young age at diagnosis (standardized B= -0.427, P= 0.014). Conclusions: Cranial radiation in pediatric brain tumors is associated with a decline in multiple neurocognitive functions including total IQ, visual memory, and attention; which are related to the toxic effect of cranial radiation on white matter of the brain especially in young age of childhood with high dose and whole cranial radiation.

No significant financial relationships to disclose.
PRODIGE: A phase III randomized placebo-controlled trial of thromboprophylaxis using dalteparin low molecular weight heparin (LMWH) in patients with newly diagnosed malignant glioma
Authors: Perry J. R. , Rogers L. , Laperriere N. , Julian J. , Geerts W. , Agnelli G. , Malkin M. , Sawaya R. , Baker R. , Levine M.
Published: March 2020

2011

Background: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We have conducted an RCT testing the efficacy and safety of long-term dalteparin for the prevention of VTE in newly diagnosed malignant glioma. Methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5,000 anti-Xa units or placebo, both subcutaneously daily for 6 months starting within the first month after surgery. Patients were allowed to continue study medication for up to 12 months. Because of the poor prognosis of malignant glioma it was determined apriori that the primary outcome was 6-month VTE-free survival. In order to detect a 60% VTE hazard reduction with LMWH with 80% power, 512 patients were required. Results: Recruitment began October 2002 and was closed in May 2006 because of expiration of study medication and no further re-supply. Of the 563 patients screened at 15 centers, 174 were excluded. Of the 389 eligible patients approached for consent, 186 were randomized: 99 to LMWH, 87 to placebo. Twenty-one patients developed objectively confirmed VTE during the first 6 months: 9 on LMWH and 12 on placebo (11% and 17% respectively; HR=0.7, 95% CI: 0.37–1.5, p=0.3). Over the 12 months there were 5 (5.1%) major bleeds with LMWH and 1 (1.2%) with placebo (HR=4.0, 95%CI: 0.5–34, p=0.2). All major bleeds were intracranial. Twelve-month mortality was 48% for LMWH and 45% for placebo (HR=1.2, 95%CI: 0.7–1.9, p=0.5). Conclusions: Although there was a trend in favor of the LMWH reducing VTE this was not statistically significant, likely as a result of low power. There was also a trend for increased intracranial bleeding with LMWH. Our study confirms the high incidence of thromboembolism in these patients; however, the role of long-term anticoagulant thromboprophylaxis remains unclear. Supported in part by a grant in aid from Pfizer Inc. and the Ontario Cancer Research Network. The PRODIGE steering committee thanks Terri Finch for superb administrative support.

Pfizer
Blood brain barrier disruption (BBBD) and intra-arterial methotrexate based therapy for newly diagnosed primary CNS lymphoma: The BBBD Consortium Experience
Authors: Angelov L. , Doolittle N. D. , Siegal T. , Kraemer D. F. , Peereboom D. , Jahnke K. , Ference S. , Barnett G. , McGregor J. , Neuwelt E. A.
Published: March 2020

2014

Background: Primary central nervous system lymphoma (PCNSL) incidence in immunocompetent patients has been increasing and now represents 4% of intracranial neoplasms. Similar to systemic lymphoma, PCNSL can display considerable chemosensitivity. Most chemotherapy regimens for PCNSL use intravenous methotrexate, often in combination with whole brain radiation. We present our multi- institutional experience in the treatment of PCNSL using BBBD in conjunction with Intra-arterial methotrexate (IA MTX)-based chemotherapy. Methods: A retrospective IRB approved analysis was performed on 177 newly diagnosed PCNSL patients treated monthly with osmotic BBBD in conjunction with an IA MTX-based chemotherapy regimen (n= 2,469 procedures) at 4 institutions from 1982–2005. No patient had received prior irradiation. Descriptive summaries and Kaplan-Meier survival summaries were estimated. Results: Among 177 patients, median age at diagnosis was 59.1 years (range 5.7 to 82.7 years). 101 patients (57%) achieved a complete response and 41 (23%) achieved a partial response (overall response rate 80.2%). 67 patients (37%) are currently alive (57 [32%] with no evidence of disease). Median overall survival (OS) was 3.1 years (25% estimated survival at 11.3 years). Median progression free survival (PFS) was 1.6 years with 40% progression-free at 5 years. Evaluation of the subgroup of patients < 60 years (n= 100), demonstrated an OS of 5.2 years with a 40% survival plateau after about 8 years, suggesting that some of these patients may be cured. The procedures were generally well tolerated with the most frequently encountered complication being procedure related seizures (9.5%) without long-term sequelae. Conclusions: This large multi-center series demonstrates that BBBD/IA MTX is a generally well tolerated and effective treatment for patients with newly diagnosed PCNSL. Further, it allows for the deferral of radiation and its associated cognitive compromise in these patients. These results are comparable or superior to other published chemotherapy (± radiation) treatment regimens suggesting that BBBD/IA MTX is an excellent treatment option for PCNSL patients and can result in successful and durable tumor control.

No significant financial relationships to disclose.
Metastatic neuroblastoma (NB) to the central nervous system (CNS): Improved outcome with combined modality including 131-I-8H9 or 131-I-3F8 radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF)
Authors: Kramer K. , Modak S. , Kushner B. H. , Souweidane M. , Wolden S. , Humm J. , Zanzonico P. , Smith-Jones P. , Larson S. , Cheung N.
Published: March 2020

2022

Background: NB metastatic to the CNS (NB-CNS) is difficult to control. We describe a salvage regimen incorporating intra- Ommaya RIT delivered to the CSF. Methods: 37 patients (pts) with NB-CNS (parenchymal masses and/or leptomeningeal [LM] carcinomatosis) treated at MSKCC from 1988 through 2006 were reviewed. Nine (group #1) of 37 pts developed NB-CNS metastasis (median age 3.8 years) and were treated with a salvage regimen: resection of parenchymal masses, 2160 cGy craniospinal irradiation (CSI), intravenous irinotecan and oral temozolomide, and RIT with 131I-8H9 and or 131I-3F8 targeting tumor associated antigens on phase I/II studies. Immunotherapy (intravenous anti-GD2 monoclonal antibody 3F8 plus subcutaneous GM-CSF) was also given for systemic control. Survival was compared to the other 28 (group #2) pts who developed NB-CNS (median age 4.2 years) treated with combinations of surgery, chemotherapy, and radiation but without CSI + RIT. Results: All 37 pts had high risk disease at initial diagnosis of NB. 9 of 9 group #1 pts had marrow and/or bony involvement; 6 of 9 had MYCN amplification and 5 of 9 had serum LDH >1500 U/ml. All had intensive chemotherapy and radiotherapy prior to CNS relapse. Despite this, the CNS salvage regimen was well-tolerated. Myelosuppression following CSI and chemotherapy was common; 2 pts received stem cell support. All 9 pts in the RIT group are alive and well, disease-free at 3+, 11+, 15+, 18+, 18+, 20+, 22+, 31+, 42+ months since CNS relapse. In contrast, pts in group #2 had a median time to death of 5.5 months, (p<0.0001) for survival by Kaplan-Meier analysis. Conclusion: Similar to CNS metastases in most other solid tumors, conventional therapies have been ineffective for NB-CNS. The addition of RIT using 131I-3F8 or 131I-8H9 is well-tolerated and improves the prognosis for these high risk patients.

No significant financial relationships to disclose.
Phase II study of combination carboplatin and erlotinib in patients with recurrent glioblastoma multiforme
Authors: Groot J. F. De , Gilbert M. R. , Hess K. R. , Hanna T. , Groves M. , Conrad C. , Aldape K. , Colman H. , Puduvalli V. , Yung W. A.
Published: March 2020

2024

Background: Targeting the epidermal growth factor receptor (EGFR) in glioblastoma is effective in a subset of patients whose tumors express the phosphatase and tensin homolog (PTEN) tumor suppressor gene and overexpress the EGF variant vIII receptor. Therefore, this study was designed to assess the clinical activity of the EGFR inhibitor erlotinib when combined with carboplatin and to determine molecular predictors of response. The primary endpoint is progression-free survival (PFS). To be eligible for the study, patients had to have recurrent, histologically confirmed glioblastoma or gliosarcoma, no more than two prior relapses, a KPS = 60, and no enzyme-inducing anticonvulsants. Methods: In this ongoing phase II study, patients are given carboplatin intravenously on day 1 of every 28-day cycle to achieve a target AUC of 6 (mg x ml/min) based on creatinine clearance. Erlotinib is administered orally once daily throughout the 28-day cycle at 150 mg/day with dose escalation to 200 mg/day, as tolerated. Patients undergo clinical and MRI assessment every 4 weeks. The primary endpoint is median PFS using a Bayesian time-to-event design. To determine histologic correlates of response, tumor tissue is undergoing immunohistochemical evaluation for known markers of response to EGFR inhibitors, including PI3K/AKT and PTEN status. Results: Of the first 20 patients enrolled, 17 were evaluable and all had failed temozolomide-based therapy. The median age is 56 years, and the median KPS is 80. The median time to progression is 15.2 weeks with a 95% credible interval of 8.0 to 28.4 weeks. These results compare favorably with historical data (median of 9.0 weeks, 95% CI of 8.1 to 10.1 weeks). Bayesian analysis using computer-based simulations indicate a high probability (69%) that the median PFS in our study is at least 3 weeks longer than the historical median PFS. Grade 3 and 4 toxicities included fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. Conclusions: The results from this ongoing study suggest that the combination of carboplatin and erlotinib has promising activity in patients with recurrent glioblastoma who have failed temozolomide-based therapy. Tumor tissue is being analyzed to determine molecular markers of response.

[Table: see text]
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluation in glioblastoma (GBM) patients treated with bevacizumab (BEV) and irinotecan (CPT-11)
Authors: Desjardins A. , Barboriak D. P. , Herndon J. E. , Reardon D. A. , Quinn J. A. , Rich J. N. , Sathornsumetee S. , Gururangan S. , Friedman H. S. , Vredenburgh J. J.
Published: March 2020

2029

Background: Significant responses seen in GBM patients treated with BEV and CPT-11 generated the need to develop ways to predict clinical benefit. DCE-MRI can be used to evaluate the microvasculature within tumors. DCE-MRI uses Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space, to determine vascular permeability. A 50% reduction in Ktrans is clinically meaningful. We report a phase II trial to determine the correlation between vascular permeability and radiographic response in GBM patients treated with the combination. Methods: Eligibility included patients with recurrent GBM. Both agents were given every 14 days. All patients received BEV at 10 mg/kg IV. CPT-11 was dosed at 340 mg/m2 for patients on enzyme inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAED. Radiographic responses were assessed every 6 weeks. DCE-MRIs were performed before administration of chemotherapy, one day after treatment and after the first cycle. The primary endpoint was to examine the effect of BEV and CPT-11 treatment on vascular permeability as measured by percent change from baseline in Ktrans. Results: Twenty patients were enrolled, with a median age of 49.5 years. Fifteen patients are assessable for response. Best responses include one patient with complete response, 8 with partial response (response rate=60%), six patients with stable disease, and one with disease progression. Ktrans values are available for 13 patients; data are not available for seven patients (too early: 4, technical difficulty: 3). A reduction in Ktrans by 50% was observed in 6 patients one day after treatment and in 12 patients at the end of cycle 1. Changes in Ktrans value were highly correlated with the percentage decline in tumor volume from baseline to end of cycle one (Pearson correlation = 0.82; p=0.0006). Fifteen patients are still on study. Five patients came off due to disease progression. Conclusions: The utilization of DCE-MRI to determine a reduction in vascular permeability following a combination of BEV and CPT-11 is feasible and correlates significantly with the degree of tumor volume decrease.

No significant financial relationships to disclose.
A randomized phase II trial of concurrent temozolomide (TMZ) and radiotherapy (RT) followed by dose dense compared to metronomic TMZ and maintenance cis-retinoic acid for patients with newly diagnosed glioblastoma multiforme (GBM)
Authors: Sul J. , Panageas K. S. , Lassman A. B. , Hormigo A. , Nolan C. , Gavrilovic I. T. , Grimm S. A. , DeAngelis L. M. , Abrey L. E.
Published: March 2020

2031

Background: Metronomic and dose dense scheduling are alternatives to conventional TMZ regimens to overcome drug resistance in part by depleting O-6 methylguanine-DNA methyltransferase (MGMT). Furthermore, metronomic TMZ may inhibit endothelial recovery and act as an anti-angiogenic therapy; dose dense TMZ increases the intensity of drug delivery. Objective: To determine the overall (OS) and progression free survival (PFS) of patients with newly diagnosed GBM treated with concurrent TMZ and RT followed by dose dense or metronomic TMZ and maintenance cis-retinoic acid. Methods: Patients with newly diagnosed, histologically confirmed GBM underwent standard RT with TMZ. Upon completion of this treatment, patients were randomized to receive dose-dense TMZ (150mg/m2, days 1–7 and 15–21 of a 28 day cycle) or metronomic TMZ (50mg/m2 daily in 28 day cycles), for 6 cycles. Maintenance cis-retinoic acid was prescribed following the 6 cycles of adjuvant TMZ. OS and PFS were calculated from date of diagnosis. Prospective correlative tissue analysis of MGMT status is planned. A Simon minimax 2-stage design was used for each cohort. If either group has 70% survival probability at 1 year, further evaluation in a phase III trial will be recommended. Results: 51 patients were randomized: 24 to metronomic, and 27 to dose dense. Median age is 57, and median KPS 90. 26 patients have progression of disease (POD), with a median follow up of 5 months. Grade 3/4 hematologic toxicity occurred in 7 patients (14%), 3 in the metronomic and 4 in the dose dense arm. Conclusions: Our patient population is comparable to that of other upfront GBM treatment trials. Metronomic and dose dense TMZ appear to be well tolerated with equivalent toxicities. Early analysis suggests that patients on the dose dense regimen may have better PFS than those on the metronomic arm.

[Table: see text]

No significant financial relationships to disclose.
Osteosarcoma pulmonary metastasis: Prognostic factors of 88 patients submitted to surgical resection
Authors: Schutz F. A. , Younes R. N. , Borges J. A. , Gross J. L.
Published: March 2020

20502

Background: Pulmonary metastasis from Osteosarcoma occurs in 30% to 40% of cases. Chemotherapy and surgical resection are the current preferred options for these patients, although overall outcome remains poor, with few patients achieving long term overall survival. Prognostic factors for better selecting these patients are needed. Methods: We reviewed the survival and the prognostic factors from 88 consecutive patients with pulmonary metastasis from osteosarcoma, submitted to metastasectomy at a single institution. Clinical and demographic variables, related to the primary tumor as well as to the pulmonary metastases and treatment procedures were registered. Univariate ( Log-rank and Breslow tests) and multivariate analysis (Cox-regression) were performed to identify significant prognostic factors related to overall survival. Results: Median follow-up time was 34 months, and 12.5% were alive without disease, 14.8% were alive with disease, 58% were dead of disease, 1,1% were dead from other causes, and 14.8% were lost to follow-up. The overall 5- year survival was 19%. Disease free interval (DFI), number of thoracotomies and complete resection at last thoracotomy were significant prognostic factors at univariate analysis. Median survival from first thoracotomy for patients with DFI = 12 months was 24.6 months, compared to 9.6 months for DFI < 12 months (p= 0.0014). Complete resection at last thoracotomy significantly improved median overall survival (19.1 versus 9.6 months) (p=0.0117). Cox-regression analysis showed only disease free interval more than 12 months (p=0.014) and complete resection at last thoracotomy (p=0.003) to be independent significant prognostic factors. Sex, age, site and stage of primary tumor, number of lung nodules, bilateral nodules, and chemotherapy treatment for lung metastases did not significantly impact on survival. Conclusion: Disease free interval and complete resection at last thoracotomy are significant prognostic factors for patients with resected pulmonary metastasis from osteosarcoma.

No significant financial relationships to disclose.
Combination of pegylated-liposomal doxorubicin (PLD) and bevacizumab (B) (PLD-B) in sarcoma (SAR)
Authors: Skubitz K. M. , Haddad P. A.
Published: March 2020

20506

Background: Vascular endothelial growth factor (VEGF) plays an important role in many tumors including SAR. Because of the known efficacy of PLD in SAR and the presumed importance of VEGF in SAR, we have treated SAR patients with PLD-B. It is possible that the addition of B to PLD might alter the toxicity profile. The toxicities of this combination are not well described. Methods: To better define the toxicity of the combination of PLD-B in SAR, we reviewed our experience with PLD-B in patients treated between 2004 and 2006. Results: We identified 20 patients with SAR treated with PLD-B at our institution. There were 9 men and 11 women, with a median age of 47.5 years (range 23–77). Ten patients initiated therapy with PLD q28 days at a median dose of 45 mg/m2 (range 45–50), and 10 q14 days at a median dose of 21.2 mg/m2 (range 20–25), in combination with B at 5 mg/kg q14 days. A median of 5 cycles was given (range 1–15). Dose delay was required in 3 patients for the second cycle, and dose reduction was required in 9 patients by cycle 3. Of the 10 patients starting with monthly PLD, 7 were changed to q14 day PLD by cycle 4. Mucositis and skin toxicity were the dose limiting toxicities (DLT) in 14/20 patients, and myelosuppression was the DLT in 1/20 patients. Nine patients were felt to have clinical benefit; 3 had a PR and 6 had SD. Notably, 2/4 recurrent Ewing sarcoma patients had symptomatic improvement and at least SD for 10 and 11 months, respectively, with minor toxicity allowing a good quality of life. Conclusions: This report describes the toxicity profile of PLD-B in 20 patients with SAR. The toxicities observed were similar to those seen with PLD alone, however, these toxicities appeared more pronounced with the addition of B. Since VEGF is important for wound healing, the known effects of B on this process may contribute to more skin and mucosal toxicity of PLD at a given dose. Future studies of PLD-B should consider the potential of increased mucosal and skin toxicity. The use of q14 day PLD to allow more control over toxicity is suggested; a maximal starting dose of 20 mg/m2 is reasonable, although dose reduction will be common due to skin or mucosal toxicity. This combination can be given with limited toxicity, and meaningful responses were observed in recurrent sarcomas, including 2/4 Ewing sarcomas.

No significant financial relationships to disclose.
Non-methotrexate based triple drug combination chemotherapy for untreated osteosarcoma
Authors: Hingmire S. S. , Pai S. K. , Bakshi A. V. , Bharath R. , Agarwal M. , Puri A. , Dangi U. , Mandhaniya S. , Maksud T. , Parikh P. M.
Published: March 2020

20512

Background: Considering the high cost of intensive high-dose methotrexate based chemotherapy, a non-methotrexate based chemotherapy regimen was evaluated in newly diagnosed osteosarcoma patients Methods: A total of 54 patients of newly diagnosed osteosarcoma (2000 to 2005) were included in the study. Chemotherapy protocol included 3 drugs viz. Doxorubicin (20 mg/m2 on Day1 to Day3), Cisplatin (100 mg/m2 on Day 1) and Ifosfamide (2000 mg/m2 on Day1 to Day 5) in combination as A1 cycle - Ifosfamide + Doxorubicin, B1 cycle - Doxorubicin + Cisplatin, C1 cycle - Cisplatin + Ifosfamide. The sequence was repeated as A2, B2 and C2 (total 6 cycles). Surgical excision of primary tumor was done after 3 cycles of chemotherapy Results: The median age at diagnosis was 15.5 years with a slight male preponderance (n=38, 70.4 %). Axial skeleton (maxillary) was affected only in one patient. Lower end of femur was the most common appendicular skeletal site for the primary tumor (n=27, 50 %). Forty two out of 54 (77.8 %) patients had nonmetastatic disease at diagnosis. Lung was the most common site of distant metastasis at diagnosis (11 out of 12 patients). Fifty patients received all 6 chemotherapy cycles as planned. Limb salvage with reconstruction surgery was performed in 35 (64.8 %) patients. Complete (100%) tumor necrosis was seen in 18 (33.3 %) patients. The median duration of follow-up was 16 months. The actuarial disease free and overall survival at 3 years would be 41.4 % and 43.6 % respectively. The incidence of febrile neutropenia was 11.85 % and of grade III/IV thrombocytopenia was 10 % of all chemotherapy cycles. Easily controllable emesis was the commnoest non-hematological toxicity, experienced by 31.5 % of patients. Two patients died due to post chemotherapy neutropenic sepsis. With univariate analysis, complete histological response (100 % tumor necrosis) alone could be identified as independent favorable prognostic factor (3 year OS of 73.6 %, P=0.003). The overall survival outcome was not statistically different in subgroups of sex, age group and pathological tumor size. Conclusions: Non-methotrexate based triple drug combination chemotherapy is an effective treatment option for patients with newly diagnosed osteosarcoma in developing countries like India.

No significant financial relationships to disclose.
ET 743 is an effective agent against sarcoma
Authors: Boyle H. , Favier B. , Lurkin A. , Ray-Coquard I. , Ranchère D. , Decouvelaere A. , Blay J. , Fayette J.
Published: March 2020

20516

Background: ET-743 has shown clinical activity in soft tissue sarcoma after failure of anthracyclines and ifosfamide. We propose to assess these results in our institution. Methods: We reviewed the patients treated (in phase II studies or on a compassionate basis) until June 2006 Results: Median age of the 99 patients was 53 years (18–82, with 20% leiomyosarcomas, 18% other spindle cell sarcomas, 12% liposarcomas, 9% osteosarcomas and 4% Ewing's sarcomas. The initial tumor was in the lower limbs in 31% of cases, and 70% had lung metastases. Patients had received anthracyclines (72%) or ifosfamide (61%), but 12% received ET-743 as their 1st chemotherapy. Most patients received ET-743 as a single agent, but 7 received it in combination with doxorubicin. After a median of 4 cycles (1–25), 50% of patients responded: 0 CR, 12 patients with PR, 4 MR (minor response), 34 SD and 49 progressed. Median time to progression for patients with a clinical benefit (PR+MR+SD) was 7 months (1.5 to 66 months). Among the 29 patients who didn't progress in the first six months, 10 had leiomyosarcomas and 8 spindle cell sarcomas. Grade3/4 toxicity, mainly hematological (42% neutropenia, 16% anemia, 11% thrombocytopenia) and hepatic (33%), was noted in 69 patients (28 needed a dose reduction). Main cause of treatment discontinuation was progression (70%) but 7 patients had to stop treatment because of toxicity. Conclusions: ET- 743 can benefit some patients with sarcomas, especially leiomyosarcomas, even pretreated. Some patients have long lasting responses. Grade ¾ toxicity is frequent but rarely leads to treatment discontinuation

No significant financial relationships to disclose.
Phase 2 dose multi-center, open-label study of ARQ 501, a checkpoint activator, in adult patients with persistent, recurrent or metastatic leiomyosarcoma (LMS)
Authors: Hartner L. P. , Rosen L. , Hensley M. , Mendelson D. , Staddon A. P. , Chow W. , Kovalyov O. , Ruka W. , Skladowski K. , Jagiello-Gruszfeld A. , Byakhov M.
Published: March 2020

20521

Background: ARQ 501 selectively induces apoptosis in cancer cells by inducing a rapid and sustained increase of the pro- apoptotic protein E2F-1. ARQ 501 has been studied in three phase 1 studies, demonstrating acceptable toxicity and encouraging signs of efficacy. A 54 y/o female with metastatic LMS who failed 7 previous therapies achieved a prolonged PR on ARQ 501 monotherapy. This was consistent with preclinical data, where induction of E2F-1 and corresponding efficacy in human leiomyosarcoma xenografts was observed. Methods: A phase 2 study in adult LMS patients (>3 prior systemic therapies) was initiated to assess ORR, TTP and further characterize the safety of ARQ 501. ORR included CR, PR and SD=4 mo. Four week cycles (ARQ 501 450mg/m2) were repeated until progression, unacceptable toxicity, or another discontinuation criterion. Results: 49 patients were enrolled and 45 received ARQ 501. Data is available for 43 patients (4M/39F, median age, 54). Of the 43, 10 did not reach a protocol defined tumor assessment (4 deaths, 5 PD and 1 lost to follow-up prior to week 8), 19 have been assessed for response per RECIST at eight weeks (7 SD of 8–28+ weeks, 1 PR, 11 PD) and 14 active patients yet to reach first tumor assessment. The most common AEs were: anemia (68%, 21%=G3), hyperbilirubinemia (35%, 6%=G3), fatigue (35%, 0%=G3), nausea (30%, 0%=G3), constipation (24%), hemolysis (21%, 6%=G3), dyspnea (21%), and vomiting (21%). One treatment related death was reported in a 47 y/o Asian male with severe hemolysis following a single infusion of ARQ 501 at 450 mg/m2. The pt was hospitalized, but severe hemolysis led to acute renal failure and the patient expired after 4 days. Conclusions: ARQ 501 was administered to 45 patients with advanced, recurrent or persistent leiomyosarcoma. Several patients have achieved some clinical benefit (1 PR, 3 prolonged SD), further analysis of efficacy data is warranted prior to additional clinical investigation.

No significant financial relationships to disclose.
Tumours associated with gastrointestinal stromal tumors (GIST): A case report
Authors: Fayaz S. , George T. , Mohammad M. , Samir S.
Published: March 2020

20529

Background: Much progress has been made in the diagnosis and treatment of GIST but the rarity of second neoplasms in association with gastro intestinal tumours (GIST) have rarely been reported. Methods: We present three case reports of breast cancer, Hodgkin's disease and thyroid cancer associated with GIST Results: The first pt, aged 50 underwent left lumpectomy and axillary clearance for infiltrating ductal carcinoma. Estrogen and Progesterone receptors were positive. Adjuvant chemotherapy , radiotherapy and tamoxifen was administered .Three years later patent was operated for a sub mucous nodule in the stomach which was reported as GIST, CD117+ve,CD34 positive and the patient was followed up. The second pt, male aged 50 was operated for a large intrabdominal GIST tumour (16x16cm) arising from the stomach and later on referral found to have a Rt Supraclavicular node with a nodule in the thyroid. He under went total thyroidectomy with functional node dissection for papillary carcinoma. This was followed Radioactive iodine ablation and eltroxin. Three months later he presented with thoraco abdominal metastasis and treatment with Imatnib was begun, but he soon progressed and succumbed to his disease. The third pt, female, with a history of Hodgkin's disease treated with chemotherapy on follow up. Twelve years later the pt was subjected to extensive debulking for pelvic GIST (16cmx15cm).CD117 positve.She was kept on follow up. A ct chest abdomen and pelvis eight months following surgery was unremarkable. Conclusions: Very few cases have been reported in literature regarding association of second tumours with GIST .And no correlation can be made to generate a hypothesis regarding these associations.

No significant financial relationships to disclose.
Phase I study of gadolinium texaphyrin in newly diagnosed glioblastoma
Authors: Shaw E. G. , Grossman S. A. , Carson K. A. , Fisher J. D. , Kleinberg L.
Published: March 2020

2064

Background: Gadolinium texaphyrin (Gad Tex) is a putative radiosensitizer which inhibits cellular respiration resulting in the production of reactive oxygen species and induces apoptosis (Drugs R D. 2004; 5(1):52–7). Methods: The New Approaches to Brain Tumor Therapy (NABTT) consortium conducted a prospective phase I dose-escalation trial to determine the maximum tolerated dose of Gad Tex along with brain radiation therapy (RT) in newly diagnosed glioblastoma multiforme with KPS > 60. RT was 60 Gy in 30 fractions, 5 days per week over 6 weeks, to localized treatment fields. Two different dosing regimens of Gad Tex were utilized. In regimen A, the initial dose was 2.5 mg/kg with each daily fraction of RT whereas in regimen B it was 5.5 mg/kg with every fraction of RT. Gad Tex was administered 2–5 hours before each radiation treatment. Results: The initial dose in both regimen A and B was found not to be tolerable. Of three patients treated at 2.5 mg/kg/dose on regimen A (daily dosing), one completed planned therapy (30 doses of Gad Tex), one had treatment stopped after 16 doses of Gad Tex when diffuse pulmonary infiltrates with shortness of breath developed and returned after rechallenge with an additional dose of Gad Tex, and one patient developed an allergic reaction after 15 doses of Gad Tex which returned on rechallenge. Of three patients treated at 5.5 mg/kg/dose (qod dosing) on regimen B, one completed planned therapy (15 doses of Gad Tex) after a dose reduction related for skin blisters, and the other two patients discontinued treatment after 9 doses of Gad Tex for debilitating skin blisters. Conclusions: Gad Tex was poorly tolerated as administered in this small phase I study as 4 of 6 patients experienced dose limiting toxicities. As such, NABTT elected not to pursue this drug in subsequent clinical trials. However, similar or more intensive regimens utilizing Gad Tex in combination with brain RT have been successfully administered in patients with newly diagnosed glioblastoma and brain metastases.

No significant financial relationships to disclose.
Retrospective analysis of glioblastoma multiforme (GBM) patients treated initially with BCNU compared to temozolomide (TMZ) with concomitant radiation therapy
Authors: Vinjamuri M. , Adumala R. , Altaha R. , Hobbs J. , Crowell E.
Published: March 2020

2071

Background: TMZ and radiation as initial treatment has become the standard of care for GBM. There are no randomized studies comparing TMZ to BCNU in GBM. Methods: We did a retrospective analysis of all 100 GBM patients (pts) diagnosed by our pathology department in the last 10 years. 20 pts were excluded, in 12 pts no chemotherapy was given and there was no data available for 8 pts. BCNU treatment was given in earlier years than TMZ generally. Overall survival (OS), progression free survival (PFS) and four prognostic factors were compared between BCNU and TMZ treated groups. Results: Results show that there is no significant difference in OS and PFS between the two groups. Survival curves were superimposable. This is despite the fact that tumor size and ECOG performance status were worse, though not significantly so in the BCNU group. Age was the only variable that correlated with survival. After correcting for age there was still no difference in PFS and OS between the BCNU and TMZ group. Conclusions: Our study fails to shows superiority of TMZ over BCNU despite the fact that the BCNU group had worse prognostic factors. A randomized comparison of these two agents seems justifiable.

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No significant financial relationships to disclose.
The topoisomerase I inhibitor gimatecan exhibits anti-tumor activity against malignant glioma xenografts as single agent and in combination
Authors: Vassal G. , Hamelin N. , Opolon P. , Versace R. , Geoerger B.
Published: March 2020

2081

Background: Gimatecan, a novel oral lipohilic camptotecan (ST1481; NVP-LBQ707), has shown to irinotecan and topotecan superior anti-tumor activity against several cell lines and human xenografts. We evaluated gimatecan in microemulsion in vivo alone and in combination with temozolomide and the EGFR and VEGF tyrosine kinase inhibitor AEE788 against subcutaneous malignant glioma xenografts derived from primary tumors. Results: Gimatecan exhibited dose-dependent activity against all three advanced tumor stage glioma models with IGRG93 being the most sensitive: 0.10 to 0.25 mg/kg gimatecan daily orally in a protracted schedule 5 days/week during 4 weeks resulted in 100% partial and complete tumor regressions, significant tumor growth delays (TGD; 48 to >100 days), log cell kills of 4.3 to 9.1, and were thus considered as ++++ highly active according to the SRI activity criteria. Anti-tumor activity in the TP53 wild-type IGRG93 correlated with significant induction of apoptotic cell death, as measured by TUNEL and cell cycle analysis, and lack of induction of p21. Moreover, combination of gimatecan and temozolomide resulted in synergistic activity against the TP53 wild-type IGRG121 glioblastoma and gimatecan at the MTD could be combined with temozolomide without enhanced toxicity. Gimatecan 0.19 mg/kg q5/wx4w combined with AEE788 50 mg/kg q3/wx4w was evaluated against the TP53 mutant, EGFR gene amplified IGRG88 glioma. Both agents were highly active resulting in 100% tumor regression. Gimatecan treated tumors started to grow 2–3 weeks after treatment end, while tumors treated with AEE788 regrew directly after treatment stop resulting in less significant TGD. Gimatecan and AEE788 given simultaneously during 4 weeks yielded less significant TGD compared to gimatecan alone, thus antagonistic effects. AEE788 induced G1 cell growth arrest which may reduce sensitivity to gimatecan, necessitating S-phase to be most efficient. An alternative schedule with gimatecan followed by AEE788 may be more appropriate. Conclusions: Gimatecan is highly active against malignant glioma xenografts and has synergistic activity with temozolomide suggesting this new topoisomerase I inhibitor for the treatment of malignant glioma.

No significant financial relationships to disclose.
Estrogen receptor (ER) status of disseminated tumor cells in the bone marrow of breast cancer patients
Authors: Tanja F. N. , Krawczyk N. , Wallwiener D. , Becker S. , Solomayer E.
Published: March 2020

21013

Background: The presence of disseminated tumor cells (DTC) in bone marrow (BM) of primary breast cancer patients is associated with poor prognosis. These patients may benefit from adjuvant endocrine therapy since cytotoxic agents are not able to completely eliminate DTCs as previously shown. Only patients with hormone receptor positive breast cancer are eligible for hormonal treatment. The ERa status is routinely defined in primary tumor tissue. However, the ERa status of DTC may differ compared to the primary tumor. Therefore, the aims of this study were (1) to determine the ERa status of DTC in BM of breast cancer patients, (2) and to compare the ERa status of DTC and corresponding primary tumors. Methods: BM aspirates from 251 primary breast cancer patients were included into the study. A double immunofluorescence staining procedure was established for the identification of cytokeratin-positive (CK)/ERa positive cells. ERa status of the primary tumor was immunohistochemically assessed using the same antibody against ERa. Results: In 105 of 251 (42%) breast cancer patients CK-positive cells could be detected in BM. The number of detected cells ranged between 1 and 13 / cells per 2*106 mononuclear cells. Disseminated tumor cells demonstrated ERa positivity in 13 (12%) of these 105 patients. The ERa expression on DTC was heterogeneous in 10 of 13 (79%) patients. Concordance rate of ERa status between primary tumor and DTC was 27%. Only 11 of 83 patients with ER a positive tumors had also ERa positives DTC. Conclusions: (1)The hormone receptor status between primary tumor and corresponding DTC is disconcordant. (2)This discrepancy may explain the rate of non-responders to adjuvant endocrine therapy despite ER-positive primary tumors. (3)These patients may benefit from adjuvant therapy regimens based on antibody strategies or bisphosphonates.

No significant financial relationships to disclose.
Critical role of FoxO3a transcription factor in response to therapy with EGFR inhibitors, gefitinib and lapatinib, in breast cancer
Authors: Krol J. , Lam E. , Coombes C.
Published: March 2020

21018

Background: Inhibition of the EGF-receptor is a potential therapeutic strategy for breast cancer. The PI3-K/PKB signalling pathway plays an important role in cell proliferation, survival and malignant transformation. The Forkhead box group O transcriptional factor, FoxO3a, is a direct downstream target of PKB. Here we studied the role of the FoxO3a in response to the EGFR inhibitors Gefitinib and Lapatinib. Methods: Response of breast cancer cell lines to treatment with Gefitinib and Lapatinib was evaluated by proliferation assay and FACS analysis. Expression of FoxO3a and its downstream targets was analysed using Western blotting. Sub-cellular localisation of FoxO3a was analysed by confocal microscopy. FoxO3a mRNA level was measured by RTq-PCR. siRNA transfections were performed using Oligofectamine reagent. Immunohistological staining was performed on patient samples to validate our findings. Results: Treatment of a panel of breast cancer cell lines with both inhibitors resulted in decreased proliferation due to G1-arrest and apoptosis in two sensitive cell-lines, BT474 and SKBR3. Western blot analysis revealed that response to the treatment was associated with a decrease in PKB and FoxO3a phosphorylation and thus the nuclear relocalisation of FoxO3a. Confocal microscopy confirmed that treatment induced nuclear translocation of FoxO3a only in sensitive but not resistant cells. This relocation of FoxO3a was accompanied by an induction of FoxO3a mRNA and its principal targets, p27kip1 and Bim. Transfection of the sensitive BT474 cells with FoxO3a specific siRNA resulted in a significant reduction in FoxO3a protein expression and Gefitinib-induced cell death. Comparison of immunohistochemical staining of biopsies from breast cancer patients before and after Gefitinib treatment revealed that therapy resulted in a significant increase in nuclear FoxO3a staining. Conclusion: Our results demonstrate for the first time that the EGFR-family inhibitors, Gefitinib and Lapatinib, specifically target FoxO3a to induce cell cycle arrest and apoptosis. This finding helps to define the mechanism of action of Gefitinib and Lapatinib and may provide novel insights into the molecular basis for resistance to these inhibitors.

No significant financial relationships to disclose.