bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric phase 1 study of pemetrexed: A report from the Children’s Oncology Group
Authors: Nicholson H. S. , Blaney S. M. , Ingle A. M. , Krailo M. , Stork L. C. , Ames M. M. , Adamson P. C.
Published: March 2020

9019

Background: Pemetrexed is a new multi-targeted antifol that inhibits enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Methods: A phase 1 dose escalation and pharmacokinetic study (PK) was performed in children with refractory solid tumors to define the dose limiting toxicities (DLTs) and a recommended phase 2 dose. Pemetrexed was administered as a 10 min iv infusion every 21 days. All patients received folic acid (400 mcg/day po), vitamin B12 (500–1000 mcg every 3rd course IM) and dexamethasone (0.1 mg/kg/dose bid × 3 days each course) . Cohorts of 3 to 6 children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910 and 2,480 mg/m2. DLT was defined as any Gr. 3 or 4 non-hematological toxicity (except nausea/vomiting, alopecia, or AST/ALT elevation that returns to Gr. 1), Gr. 4 neutropenia or Gr. 4 thrombocytopenia ≥ 7 days. Results: 33 subjects (31 fully evaluable for toxicity), median age of 12 yrs (range, 1–21), with diagnoses including osteosarcoma (12), Ewing’s sarcoma (3), hepatoblastoma (2), renal cell carcinoma (2), brainstem glioma (3), glioma (3), and other (n=8) were enrolled. DLT occurred in 1/6 patients at 1,470 mg/m2 (Gr. 3 AST and ALT), and in 2/4 at 2,480 mg/m2 (Gr. 3 ANC and Gr. 3 rash in both). Other DLTs at 2,480 mg/m2 that occurred in 1 patient included Gr. 3 diarrhea and rectal hemorrhage, and Gr. 4 thrombocytopenia, lipase, GGT, hypophosphatemia, hypokalemia and hyponatremia. At 1,910 mg/m2, 0/6 patients had DLT. The median number of courses administered was 1 (range 1 to 17). No CRs or PRs have been observed. Results of PK and other correlative studies will be presented. Conclusions: The recommended phase 2 dose of pemetrexed for children and adolescents with recurrent solid tumors is 1,910 mg/m2 administered q21 days with dexamethasone, folic acid and B12 supplementation. A phase II COG study is planned.

No significant financial relationships to disclose.
Outcome of adolescents with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols, 1991–2000
Authors: Barry E. , Levy D. E. , Goldwasser M. A. , Loh M. L. , Deangelo D. J. , Sallan S. E. , Silverman L. B.
Published: March 2020

9023

Background: Historically, adolescents with ALL have had inferior outcomes compared with younger pediatric patients (pts). Recent studies suggest that older adolescents treated on pediatric protocols have better outcomes than similarly aged pts treated on adult protocols. We report the outcome of adolescents enrolled on two consecutive DFCI ALL Consortium protocols conducted between 1991–2000. Methods: Pts aged 1–18 years (yrs) with newly diagnosed ALL were enrolled on two consecutive protocols, 91–01 (1991–1995) and 95–01(1995–2000). All adolescent pts received 20–30 weeks asparaginase (post-remission consolidation), 18 Gy cranial radiation and doxorubicin (cumulative dose 300 mg/m2). Results: 847 pts were enrolled. Median follow-up was 6.5 yrs. Presenting characteristics and outcome of pts according to age are displayed in the table below. Older pts (age ≥ 10 yrs) were more likely to experience pancreatitis (p=0.007) and thromboembolic complications (p<0.001) from asparaginase, but had similar rates of asparaginase-related allergic events (p=0.21) compared to younger pts. Conclusions: Older adolescents (aged 15–18 yrs) with ALL are more likely to present with T-cell phenotype and TEL/AML1-negative disease than younger children. Despite these biologic differences, older adolescents (aged 15–18 yrs) fared relatively well on DFCI ALL Consortium protocols, with a 5-year EFS of 75 ± 6%. This EFS rate compares favorably to published outcomes for older adolescents treated on other childhood ALL protocols. Although adolescents had an increased risk of asparaginase-related toxicity, this therapy was well-tolerated overall. Based on this experience, we are currently piloting our treatment regimen in adults aged 18–50 yrs.

[Table: see text]

No significant financial relationships to disclose.
Effect of prophylactic cranial irradiation dose on CNS relapse, late cognitive decline and learning disabilities in children treated for acute lymphoblastic leukemia
Authors: Meshref M. M. , Elshazly N. , Nasr M. , Abdelhai R.
Published: March 2020

9032

Background: Prophylactic cranial irradiation is still standard in treatment of high risk childhood acute lymphoblastic leukemia. In this study we assessed the effect of cranial irradiation dose of 1,800 cGy and 1200 cGy on CNS relapse as well as the late cognitive decline and learning disabilities in both groups versus a control group using neurophysiologic and psychometric studies. Methods: 42 patients treated from acute lymphoblastic leukemia and categorized to be at high risk of relapse were assessed in this study. 28 patients received prophylactic cranial irradiation at a dose of 1,800 cGy and 14 received a dose of 1,200 cGy. A control group of 42 age and sex matched normal children was also assessed. Visual and auditory P300 studies were carried out to assess high visual and auditory processing functions. Several selected subscales of Wechsler Intelligence scale for children were applied to both subgroups as well as the control group. Results: Mean age at receiving irradiation was 5.7 years. Mean testing age was 10 years. Mean follow up period was 4.6 years.There was one CNS relapse in the group who received 1,800 cGy (3.5%) and one in the group who received 1,200 cGy (7%). As compared to the control group the group of patient who received 1,800 cGy showed a high statistically significant delay in the latency and significant reduction in the amplitude of the Visual P300 (p <0.001, =0.01 respectively). The Auditory P300 showed a significant delay in latency (p=0.01). In the group receiving 1,200 cGy only the latency of the visual P300 was significantly affected(p=0.01). The other parameters in the 1,200 cGy subgroup were not significantly affected. As for the psychometric studies there were significant differences in several subscales between controls and 1,800 cGy subgroup namely in similarities, total performance and picture compilation which were not found between controls and 1,200 cGy subgroup. Conclusions: These findings reflects that there is impairment in the intellectual abilities as well as visual and auditory processing functions in the subgroup receiving 1,800 cGy compared to the controls which was much less in the subgroup receiving 1,200 cGy at no significant increased protection from CNS relapse.

No significant financial relationships to disclose.
The use of IV pentamidine as second line prophylaxis for pneumocystis pneumonia
Authors: Chuk M. K. , Dabb A. A. , Kim S. Y. , Glenn D. J. , Loeb D. M.
Published: March 2020

9043

Background: Pneumocystis jirovecii, formerly carinii, pneumonia (PCP) poses a serious risk to pediatric oncology patients. The use of trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis greatly reduces the risk of infection, however many children cannot take TMP-SMZ because of bone marrow suppression, drug allergy or patient noncompliance in taking oral medication. Inhaled pentamidine has been used successfully as second line prophylaxis, with a breakthrough PCP rate of 2.7%. However, many centers are unable to administer this specialized respiratory treatment to pediatric patients and in very young children, there are concerns about the effectiveness of the drug delivered in this manner. We performed a retrospective analysis of the use of intravenous pentamidine to assess its efficacy as second line prophylaxis. Methods: We conducted a retrospective review of all pediatric oncology patients at our institution who received at least one dose of pentamidine in the year 2005. The total number of doses dispensed allowed us to calculate the patient-months of pentamidine used. The charts of these patients were reviewed for the justification for the change from TMP-SMZ to pentamidine. Children who developed symptoms of pneumonia underwent diagnostic bronchoscopy, allowing us to calculate the breakthrough rate. Results: A total of 100 patients received 506 doses of pentamidine (4 mg/kg) administered monthly over a twelve month period. The main reasons for discontinuing TMP-SMZ were bone marrow suppression and drug allergy. Two children developed PCP, resulting in a breakthrough rate of 2% (or 0.4% per patient-months of treatment). Conclusions: The use of IV pentamidine once a month as second line prophylaxis against PCP results in a breakthrough rate of 2%. These results are similar to the breakthrough rate observed with inhaled pentamidine. When possible, we encourage the use of TMP-SMZ prophylaxis, however, when needed, the use of IV pentamidine is effective as second line prophylaxis.

No significant financial relationships to disclose.
Central venous access in the pediatric cancer patient—Problems unique to developing countries: 5-year experience at a regional cancer center in Western India
Authors: Pandey R. , Patel A. A. , Shah S. A. , Patel K. M. , Shah P. M. , Shukla S. N. , Parikh B. J. , Anand A. S. , Talati S. S. , Panchal H. P.
Published: March 2020

9049

Background: Central venous catheter (CVC) is required in the pediatric cancer patient for chemotherapy administration and supportive care. This study was carried out to review our experience with CVC, with special reference to issues unique to developing countries. Methods: 178 children who underwent 181 CVC insertions at our institute between January 2001 and October 2005 were retrospectively analysed for demographics, diagnosis, type of CVC, infective and non infective complications. Continuous data were assessed using the t test or the Wilcoxon rank sum test and categorical data by the chi square test or the Fisher’s exact test. Results: Median age was 6.5 years (0.6–13 yr). Commonest diagnosis was acute lymphoid leukemia (ALL) (n=60). CVC used were Hickman (n=162), subcutaneous ports (n=9) and peripherally inserted central catheters (n=10). Patients with hickman catheters had 164 insertions for 162 patients with a total of 14,090 catheter days, an average of 86.9 days/catheter. There were 5.36 culture positive infections /1000 catheter days. The commonest isolate was Coagulase negative S. Aureus (CNS) (44/80 cases). CVC infection with CNS was associated with higher risk of recurrent infections (OR=3.5 {95%CI=2.12–8.23} p=0.01). Patients having recurrent CVC infections received antibiotics for a median of 9.4 days as against a median of 10 days for those with non-recurrent infections (p=0.01, Wilcoxon rank sum). In 58 ALL patients, early (within 15 days of induction) insertion of CVC was associated with increased risk of culture positive infection as against late (after 15 days of induction) insertion (OR=2.3, 95%CI=1.0–5.2, p=0.05). Other complications were thrombosis (n=3), exit-site infection (n=5), tunnel infection (n=3), catheter fracture (n=1) and dislodgement (n=3). Conclusions: As most patients do not afford port, Hickman is the most preferred CVC in pediatric oncology in a developing country. Most patients are of low literacy and poor socioeconomic status. This is reflected in significantly high rates of CVC infection. Communication between the inserting doctor, nursing staff and proper counseling of the patient is the key to reduce complications

No significant financial relationships to disclose.
Preliminary data of a phase I-II clinical and pharmacokinetic study of plitidepsin in children with malignant tumors. On behalf of the European ITCC (Innovative Therapies for Children with Cancer) Consortium
Authors: Geoerger B. , Doz F. , Estlin E. , Kearns P. , Lopez-Martin J. , Vassal G. , Bezares S. , Ruiz M.
Published: March 2020

9060

Background: Plitidepsin (Aplidin) is a cyclic depsipeptide isolated from the tunicate Aplidium albicans, nowadays manufactured by synthesis. It is a rapid and potent inductor of apoptosis. Phase I trials in adults explored 5 different schedules. Muscle and liver toxicities were dose-limiting; hematological toxicity was not observed at the recommended dose (RD). Methods: This is a multicentre, open-label, non-randomized phase I-II study with a dose finding stage in children with solid tumors, and two expanded cohorts in leukemia and solid tumors at the RD. Plitidepsin was administered as a 3 h iv infusion every 2 weeks (=1 cycle). The initial dose level was 4 mg/m2 (80% of the RD in adults), with a classical escalation to 5 and 6 mg/m2. Results: 16 patients have been entered to date with median age 7.5 years (range 2–17). 54 cycles in 15 patients were evaluable for toxicity. 8 patients were treated at 4 mg/m2, five at 5 mg/m2 and three at 6 mg/m2. One patient presented dose-limiting G2 myalgia lasting more than 2 weeks at 4mg/m2. The Maximum Tolerated Dose (MTD) has not been reached at 6 mg/m2. Non-hematological toxicities included G1-G2 muscle side effects: (myalgia, CPK elevation, muscle weakness), G1–2 fatigue, G3 vomiting. One G3 hypersensitivity reaction was observed without prophylactic treatment. Pharmacokinetic data are similar to those reported in adult (extensive tissue distribution, a long half-life); if any, clearance was slightly higher and half-life shorter. Partial response was observed in a pancreatoblastoma and disease stabilization in a progressive medulloblastoma. Conclusions: Plitidepsin was well tolerated in children, with muscular side effects being the most relevant toxicity observed. The MTD for the pediatric population has not yet been achieved at a dose 1.2 fold above the RD in adults.

[Table: see text]
Solid-pseudopapillary tumor of the pancreas and pancreatoblastoma in children: Experience over 18 years at a Pediatric Oncology Center
Authors: Rizzatti M. , Gatti E. , Brandalise S. R. , Oliveira Filho A. G. , Cardinalli I. A. , Aguiar S. D.
Published: March 2020

9062

Background: Malignant pancreatic tumor is a rare disease in the pediatric population. Guidelines for treatment, including management in advanced disease are controversial until this moment (REBHANDL, 2001). Regarding to the pathology findings, pancreatoblastoma and solid-pseudopapillary tumor of the pancreas (Frantz’s tumor) are the more frequent pancreatic tumors in childhood. The aim of this study was a retrospective analysis of all malignant pancreatic tumors diagnosed at Boldrini’s Children Cancer Center during a period of 18 years. Methods: A retrospective analysis of eight cases of malignant pancreatic tumors, admitted at the Boldrini’s Children Cancer Center, from January 1987 to April 2005. All the data concerning age, sex, clinical presentation, stage, treatment and follow-up were collected. Results: The patient’s population refers to 8 children. There were 4 boys and 4 girls. Age ranged from 1 month to 15 years old (median age of 14 years). Main symptom was the increase of abdominal volume. None of them had metastatic disease at diagnosis. Regarding to pathology, 4 patients had pancreatoblastoma and 4 Frantz’s tumor. One patient (who had pancreatoblastoma) received chemotherapy before surgery, with a partial response, and then had a complete tumor ressection. All others (7 patients) had complete surgery as first treatment. Only one patient with Frantz’s tumor had pancreatic injury during tumor ressection and is now receiving enzimatic reposition. All the patients are alive, free of disease, from 6 months to 11 years (median follow-up of 2 years). Table I . Conclusions: Total pancreatectomy is the most important treatment in pancreatoblastoma and Frantz’s tumor. Neoadjuvant chemotherapy may be an important tool in unresectable tumors, increasing the disease-free survival.

[Table: see text]

No significant financial relationships to disclose.
Spontaneous pneumothorax in children with osteosarcoma
Authors: Kebudi R. , Fayda M. , Ayan I. , Görgün Ö. , Dizdar Y. , Aksu G. , Gün F.
Published: March 2020

9070

Background: Spontaneous pneumothorax (SPx) is an emergency situation and early diagnosis and management is very important. SPx may sometimes be seen as a complication of malignancy or its treatment. SPx have been reported in some osteosarcoma patients, mostly in adults. The incidence of SPx in children with osteosarcoma is not well documented. The aim of this paper is to investigate the incidence, treatment and outcome of children with osteosarcoma in a single institution and to review the literature. Methods: Files of all children with osteosarcoma diagnosed and treated in a single institute during September 1989 and December 2002 and followed up until September 2005 were investigated retrospectively for the development of SPx and its outcome. Results: Three of the 81 children (3.7%) developed pneumothorax during their follow-up. Two cases had lung metastases and one case had a broncho-pleural fistula but no metastatic foci at the time pneumotorax was detected. He subsequently developed lung metastasis. Retrospectively, it was suspected that the bronchopleural fistula might have been a manifestation of an undetected micrometastasis. The incidence of developing spontaneous pneumotorax in children with osteosarcoma was 3.7% (3/81) in this single institution survey. We have also reviewed the 45 osteosarcoma cases with pneumothorax in the literature. Including the three cases reported in this paper, 39 of the 48 (81%) were metastatic. Conclusions: Although spontaneous pneumothorax is a rare event in the cancer patient, it should be kept in mind if there is worsening of pulmonary symptoms or shoulder pain. SPx is encountered mostly in metastatic patients, although it may occur in non-metastatic cases.

No significant financial relationships to disclose.
Imatinib for the treatment of aggressive fibromatosis (desmoid tumors) failing local treatment. A phase II trial of the French Sarcoma Group
Authors: Penel N. , Le Cesne A. , Bui B. , Tubiana-Hulin M. , Guillemet C. , Cupissol D. , Berthaud P. , Mahier C. , Pérol D. , Blay J.
Published: March 2020

9516

Background: Background: Aggressive fibromatosis/desmoid tumors (AF/DT) are rare tumors with loco regional spreading. Few options are available when local treatments have failed. Although cytotoxic agents, hormonal treatment have been reported to induced responses and tumor control in some patients, only few prospective phase II trials have been reported in the literature. Recently, antitumor activity of imatinib in AF/DT was reported. We report a phase II trial of imatinib in AF/DT after failure of local treatment options. Methods: Pts ≥ 18 years with advanced AF/DT from all sites in whom neither surgery nor radiotherapy was possible were eligible. The principal inclusion criterias were: disease not amenable to surgery and/or radiation with curative intent, systemic pre-treatments allowed and presence of a measurable lesion with evidence of progression. Imatinib was given at the dose of 400 mg/d and increased to 800 mg/d if progression. Primary endpoint was the rate of progression free at 3 months. A two stages Simon‘s optimal design was used with p0=10%, p1=30%, α=0.05 and 90% power. 18 pts were scheduled to be recruited in the first stage for a total of 35 evaluable pts. Results: Between 09/2004 and 10/2005, 40 pts were included in 15 centers. The median age was 40 years (range 20–72) with 26% males. Primary sites were extra abdominal, mesenteric, abdominal wall in 79, 15, and 6% respectively. 15% patients had not been operated previously and 17% undergone radiotherapy. Prior systemic treatments were: NSAID, hormonal therapy or chemotherapy in 34, 46 and 23%, respectively. Median treatment duration was 4 months (range 0–12). No G4 toxicity was reported. Toxicities (G1–3) were notified for 30 pts including asthenias (70%), nauseas (53%), diarrheas, oedema (40%). G3 toxicities were abdominal pain (10%), rash, nausea, vomiting and asthenia (7%). At 3 months, 22 pts (55%) were evaluable with 1 CR, 17 SD and 4PD. As of December 2005, 7 of the 40 pts had progressed. After progression, dose was stopped in 2 pts and increased to 800mg in 5 pts with 2 tumor control following dose-escalation. Conclusions: Imatinib induces prolonged disease stabilization in the majority of evaluable patients with AF/DT in whom no local treatment option was available.

[Table: see text]
A multicentric prospective study of intensive induction chemotherapy (API-AI) in localized osteosarcoma patients: Results of a phase II trial coordinated by the French Sarcoma Group (FSG) and the FNCLCC BECT
Authors: Piperno-Neumann S. , Bui B. , Blay J. , Roché H. , Pichon F. , Peny A. , Duclos B. , Jimenez M. , Perol D. , Le Cesne A.
Published: March 2020

9521

Background: Based on the severe toxicity of high dose methotrexate (MTX) in adult patients, an alternative intensive chemotherapy (CT) was designed, associating doxorubicin, cisplatinum and ifosfamide in API-AI regimen. Promising results in 32 patients in a single institution study (Le Cesne ASCO 2004) led to a national multicenter phase II trial coordinated by the FSG of FNCLCC. Methods: Patients with a localized operable osteosarcoma were eligible. API-AI regimen consisted in 2 cycles every 28 days of doxorubicin 60 mg/m2 d1 and d15, cisplatinum 100 mg/m2 d1 and ifosfamide 5g/m2 d2 and d15, with equivalent dose of mesna and lenograstim after each course for 7 days. Good responders ≥95% necrosis (GR) received 2 postoperative API courses, and poor responders <95% necrosis (PR) a salvage regimen of 3 cycles of etoposide 100 mg/m2 d1 to d3 and ifosfamide 4 g/m2 d1 to d3. Results: From March 2001 to January 2004, 43 patients (male/female 28/15) with a median age of 23 years (range 17–50), were included. The median tumor size was 88 mm (13–280). All 43 patients received the preoperative API-AI regimen, with a dose intensity of ≥ 89% of the planned protocol. Toxicity was mainly haematological, with grade 3–4 sepsis, grade 4 neutropenia and thrombocytopenia observed in 12%, 79% and 49% of patients respectively. There was no severe renal and cardiac toxicity. All but 5 patients had a limb sparing surgery performed 77 days (median) after the first cycle (range 56–114 days). Intent to treat analysis showed 16/43 GR (37%). With a median follow-up of 36 months (25–48), the 2 year event-free and overall survival were 74% and 86% respectively. Conclusions: Despite the haematological toxicities, these results compare favorably with other previous induction CT schedules containing MTX in adults. A longer follow-up is required to evaluate the impact of this regimen on overall survival.

No significant financial relationships to disclose.
DNA repair functionality modulates the clinical outcome of patients with advanced sarcoma treated with trabectedin (ET-743)
Authors: Schöffski P. , Casali P. G. , Taron M. , Van Oosterom A. T. , Judson I. R. , Grosso F. , Blay J. Y. , Maki R. G. , Tercero J. C. , Jimeno J. M. , Rosell R.
Published: March 2020

9522

Background and Methods: The sensitivity to trabectedin (Yondelis, ET-743) in experimental cancer models correlates with functional transcription-coupled nucleotide excision repair (TC-NER) and with deficient homologous recombination repair (HRR) activity. In order to assess the clinical relevance of this observation we have characterized the mRNA expression levels of ERCC1, XPD, BRCA1 and BRCA2 by RT-PCR in historical tumor samples from 92 sarcoma patients (pts) treated with the agent. Results: The overall objective response (CR+PR) rate to Yondelis in this group was 9%, which confirms the previous clinical experience with the compound in unselected, pre-treated patients with sarcoma. The Kaplan-Meier estimates for progression-free survival at 6 months (PFS6) was 23% and for median survival 8 months (mo). 26% of pts were alive at 24 mo. Correlative Study: Pts with high expression levels (> median) of ERCC1 had better PFS6 (32% vs 15%, p = 0.07) and better median survival (12 vs 7 mo) as compared to pts with low expression ( ≤ to median). Pts with low expression levels of BRCA1 had better PFS6 (33 vs 11%, p = 0.02) and superior median survival (15 vs 5 mo, p = 0.0003) than pts with high expression. Expression levels of XPD and BRCA2 (58 pts) had no significant impact on PFS and survival. The analysis of co-expression of ERCC1-BRCA1 identified a highly sensitive group of pts, characterized by high ERCC1 and low BRCA1 expression levels, with a PFS6 of 50% (p=0.0003) and median survival of 20.4 mo (p = 0.0005). A Cox regression analysis demonstrated that ERCC1 (HR=0.52, p = 0.02) and BRCA1 (HR=2.73, p = 0.0006) are independent variables for PFS, while BRCA1 (HR= 2.57, p = 0.0005) is also an independent variable for survival. Conclusion: This exploratory retrospective study supports the hypothesis that the sensitivity to Yondelis in pts with sarcoma correlates with a functional TC-NER and with deficient HRR. Prospective studies in sarcoma and other potentially sensitive tumor types are required to confirm and validate these findings.

[Table: see text]
Pharmacodynamic case study of sunitinib/SU11248 in a gastrointestinal stromal tumor patient: Evidence toward a mechanism of effect
Authors: Seandel M. , Shia J. , Linkov I. , Maki R. G. , Antonescu C. , Dupont J.
Published: March 2020

9526

Background: Despite abundant pre-clinical data, the mechanisms of action in humans of multi-targeted small molecule tyrosine kinase inhibitors against sarcomas remain unclear. Herein, we sought evidence from pre- and post-treatment biospies to suggest whether the primary mechanism of action of sunitinib/SU11248 is anti-angiogenic or rather a direct anti-tumor cell effect. Methods: We report data regarding a 59 year old woman with imatinib-resistant GIST who demonstrated a marked tumor response to sunitinib treatment. Her gastric primary GIST tumor was previously resected, followed by recurrence one year later. A complete remission lasting 24 months was then attained on imatinib therapy. After progression of disease, sunitinib was started at 50 mg orally per day. A major clinico-radiographic response was seen after 12 months of therapy, followed by resection. To assess the pharmacodynamic effects of sunitinib, we undertook immunohistochemical analysis of formalin-fixed tissue sampled immediately prior to treatment and just after completing sunitinib, using anti-CD117, anti-CD34, or anti-CD31 antibodies, respectively. Results: We found a dramatic effect of sunitinib on the tumor parenchyma. Whereas the pretreatment biopsy revealed viable, mitotically active, CD117+ and CD34+ tumor cells, the post-treatment specimen was >90% sclerotic and necrotic. The CD31+ blood vessels appeared robust both pre- and post-treatment. Vessel counts did not differ significantly before and after treatment by CD31 staining (3.3±2.0 per field vs. 1.8±1.3, p= 0.09). Thus, the tumor cells were largely eliminated with sunitinib treatment, while blood vessels were still present after 12 months of therapy. Conclusions: This observation supports the assertion that the mechanism of sunitinib in GIST is predominantly cytotoxic against the tumor by directly targeting KIT and that an anti-angiogenic effect, either through the VEGF-R2 in endothelium or through the PDGF-R in pericytes, may be secondary.

[Table: see text]
Percutaneous tissue debulking and cement augmentation for advanced malignant vertebral compression fractures
Authors: Georgy B. , Wong W.
Published: March 2020

9535

Background: Percutaneous cement injection procedures (eg vertebroplasty, kyphoplasty) are used successfully to palliate patients with painful osteoporotic vertebral compression fractures (VCFs). When VCFs occur because of malignant lesions however, treatment can be challenging; often by the time symptoms occur, the tumor has extended into the epidural tissue and is associated with posterior cortical disruption. As a result, patients have a higher likelihood of cement extravasation outside the vertebral body, thought to be associated with increased complication risk. This study was to investigate clinical viability and effectiveness of a technique designed to improve control of bone cement placement over standard methods when treating patients with symptomatic VCFs caused by malignancy. Methods: All patients had intractable pain determined to be associated with VCFs caused by metastasized malignancy. The procedure involved using a plasma-mediated radiofrequency-based device to debulk tissue and etch a void within the affected vertebral body and then filling the void and adjacent interstices with bone cement to stabilize the vertebral body and relieve pain. Results: 28 patients (36 vertebral bodies) with various types of metastatic lesions were treated. No evidence of cement extravasation outside the vertebral boundary was detected in 34/36 (94%) cases, even in cases with severe posterior cortical compromise and prominent epidural involvement pre-operatively. In the 2 observed cases, cement extravasation was clinically inconsequential. All treated patients reported marked pain relief. No patients were prevented from continuing other oncologic treatments. Conclusions: Tissue removal to create a void before injecting bone cement into a vertebral body compromised by malignancy may reduce the complication rate observed when injecting cement. This technique may redirect cement away from the spinal canal, notably in cases with posterior cortical defect and epidural extension, while also improving interdigitation of cement and decreasing risk of metastatic embolization. The resulting palliation potentially improves functionality and quality of life during and does not appear to affect the effectiveness of continued oncologic treatment.

[Table: see text]
Pattern of progression and its impact on outcome in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: A retrospective multicenter long-term follow-up study
Authors: Hartmann J. T. , Heidel F. , Stoehlmacher J. , Duex M. , Izbicki J. R. , Elsaid A. , Wardelmann E. , Fischer T. , Jaeger E. , Al-Batran S.
Published: March 2020

9541

Background: To investigate the clinical impact of the different types of disease progression (focal v extensive) in patients (pts) with metastatic gastrointestinal stromal tumors (GIST) after initial response to imatinib. Methods: Pts who received imatinib for metastatic GIST at three Cancer Centers and who have been followed up for at least 2.5 years were eligible for the study. Disease progression was classified as focal or extensive as defined by protocol. Responses were evaluated according to WHO criteria. Progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier-method. In three pts with focal progressions, serial biopsies were obtained for mutation analysis. Results: Thirty-eight patients (21 men; mean age 58.4 years; range, 37–73 years) were included in the analysis. After a median follow-up of 31.8 mos, 25 of 38 (65.8%) patients had progressed. Nine of 25 progressions were classified as focal and 16 as extensive. Salvage therapies included dose escalation of imatinib with or without surgical resection. Median and 6- and 12-mos PFS were 11.3 mos, 89%, and 40% in pts with focal progression, and 2.5 mos, 39%, and 32%, in patients with extensive progression, respectively. The median OS was 22.8 mos in pts with extensive progression, and was not reached in pts with focal progression. Two subsequent focal progressions in one pt were associated with 2 different secondary KIT-mutations, whereas non-progressive disease harbored the original KIT-mutation alone. Conclusions: Imatinib resistance seems to be partial in a subset of progressing GIST pts. These pts may benefit from local treatment and imatinib continuation and further investigation of imatinib combinations with other compounds appears warranted. Extensive progression is associated with a dismal survival.

No significant financial relationships to disclose.
A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)
Authors: Reichardt P. , Casali P. G. , Blay J. , Von Mehren M. , Schoffski P. , Hosseinzadeh S. , Tanaka C. , Gsponer T. , Veronese M. L. , Demetri G. D.
Published: March 2020

9545

Background: Although imatinib induces durable clinical benefit in pts with metastatic GIST, resistance may emerge. AMN107 is a novel agent rationally designed to inhibit the PDGFR, KIT and Bcr-Abl tyrosine kinases. It has been shown to inhibit the proliferation of both imatinib-sensitive and imatinib-resistant GIST cells in vitro. Methods: Cohorts of imatinib-resistant GIST pts with radiological progressive disease (PD) were treated with AMN107 alone (400 mg p.o. bid) or with escalating doses of AMN107 (200 mg qd, 400 mg qd, or 400 mg bid) in combination with imatinib (400 mg p.o. bid). Pharmacokinetic (PK) analyses were performed for both AMN107 and imatinib. Serial tumor assessments included CT and 18FDG-PET scans. Results: As of 30 November 2005, 30 pts (13 women and 17 men), median age 51 yr (range 24–83) received AMN107 alone (n=18) or in combination up to 400 mg qd with imatinib (n=12) for 7 to 98 days (median 49 days). This study continues to accrue. Serious adverse events (SAE’s) reported in four patients deemed related to disease included abdominal pain, peritonitis and anemia. Grade 1/2 drug-related adverse events included hyperbilirubinemia, myalgias, peripheral edema and skin rash. Dose-limiting toxicity (Grade 3 elevated bilirubin) was reported in one pt on AMN107 alone. Efficacy data available for 18 patients show that three patients experienced progressive disease and 15 patients had stable disease, although the duration of follow-up was short. PK results in a limited number of patients showed that the effect of imatinib co-administration on AMN107 PK appears to be minimal, while AMN107 increases imatinib exposure on the average by 50%. Conclusions: AMN107 alone or in combination with imatinib has acceptable tolerability in patients with imatinib-resistant GIST. These initial data suggest there may be relevant activity of AMN107 alone and in combination with imatinib in imatinib-resistant metastatic GIST patients.

[Table: see text]
Real-time reverse transcription-polymerase chain reaction for detection of SYT-SSX translocation in synovial sarcoma
Authors: Liu J. , Qu K. , Chai C. , Li H. , Sferruzza A. , Bender R. A.
Published: March 2020

9553

Background: Synovial sarcoma is the most common non-rhabdomyosarcomatous soft tissue sarcoma in children and adolescents. A specific translocation, t(X;18), induces fusion of the SYT gene on chromosome 18 to an SSX gene on chromosome X. The resulting fusion gene consists of at least 2 subtypes with different breakpoints: SYT-SSX1(X;18)(p11.23;q11.2) and SYT-SSX2 (X;18)(p11.21;q11.2). Because t(X;18) transcripts occur in >90% of synovial sarcoma subtypes, this marker may be useful for diagnosis. We evaluated the accuracy of a multiplex real-time reverse transcription-polymerase chain reaction (RT-PCR) assay for detection of the primary SYT-SSX fusion transcript types in formalin-fixed, paraffin-embedded (FFPE) tissues and frozen tissues. Methods: 17 tumors (7 synovial sarcomas, 4 Ewing’s sarcomas, 5 rhabdomyosarcomas, 1 small round blue-cell tumor), 4 normal tissues, and 4 control samples were tested for SYT-SSX translocations using real-time RT-PCR. Results were compared to those obtained with gel electrophoresis detection of amplified transcripts; discrepant results were confirmed by sequencing. Results: Concordance between real time RT-PCR and gel electrophoresis was 100% (25/25) for internal control genes and SYT-SSX1, and 92% (23/25) for SYT-SSX2. Of the 2 samples with discordant SYT-SSX2 results, 1 was positive by real-time RT-PCR but not gel electrophoresis and 1 was positive by electrophoresis but not real-time RT-PCR; in both cases, DNA sequencing confirmed the real-time RT-PCR results. The minimum percentage of tumor to normal cells required for detection of SYT-SSX fusion transcripts by real-time RT-PCR was 6.25%. Conclusions: This real-time RT-PCR assay appears to provide greater accuracy than gel electrophoresis for identification of SYT-SSX translocation and fusion types.

No significant financial relationships to disclose.
The HIV protease inhibitor ritonavir and the proteasome inhibitor bortezomib induce synergistic cytotoxicity on soft tissue sarcoma cells in vitro
Authors: Driessen C. , Kraus M. , Müller H. , Gogel J. , Kanz L. , Simon-Klingenstein K. , Koscielniak E. , Hartmann J. T.
Published: March 2020

9566

Background: HIV-protease inhibitors like Ritonavir produces regressions in HIV-associated Kaposi‘s sarcoma, reportedly due to proteasome inhibition. We have here assessed the effect of Ritonavir and the proteasome inhibitor Bortezomib on the viability and proteasome activity of the soft tissue sarcoma cell lines RD (rhabdomyosarcoma) and A-673 (ewing‘s sarcoma) in vitro. Methods: Cytotoxixity was assessed by MTS-test. To directly dissect proteasome activity in viable sarcoma cells, we used a recently developed cell-permeable affinity label that for the first time allows to assess the individual activity profile of the different catalytically active proteasomal subunits in living cells (Berkers et al., Nature Methods, May 2005). Results: Both types of cells were resistant towards Bortezomib and Ritonavir monotherapy at therapeutic concentrations (20 nM for Bortezomib, 20μM for Ritonavir). Ritonavir induced cytotoxicity in sarcoma cell lines with an IC50 of 40μM. The combination of clinically meaningful concentrations of Ritonavir (20μM) with Bortezomib (10–20 nM) induced robust synergistic cytotoxicity in both sarcoma cell lines. Using affinity labelling of proteasome activity, we directly demonstrate that a) Botezomib abrogates beta5, but also beta1-proteosomal activity in sarcoma cells and b) that Ritonavir at 20μM does not affect proteasom activity. Conclusions: We here present the first analysis of active proteasomal subunits in living human sarcoma cell lines. Ritonavir and Velcade induce synergistic cytotoxicity at clinically meaningful concentrations in vitro, which is not mediated through a direct effect of Ritonavir on proteasome activity. Based on our data, the synergistic combination of Ritonavir and Bortezomib might warrant further clinical testing in soft tissue sarcoma in vivo.

No significant financial relationships to disclose.
Semi-physiological pharmacokinetic/pharmacodynamic (PKPD) model for trabectedin-induced neutropenia
Authors: Hing J. , Perez Ruixo J. , Stuyckens K. , Zannikos P. , Soto-Matos A. , Lopez-Lazaro L. , Izquierdo M. A. , Pico C. , Yver A. , Chow A.
Published: March 2020

9575

Background: Neutropenia was the trabectedin (T) dose limiting toxicity in phase I studies. The objective of the present study was to develop a semi-physiological PKPD model that describes the time course of the absolute neutrophil counts (ANC) in cancer subjects receiving trabectedin. Methods: A total of 704 subjects receiving intravenous T as monotherapy (dose range: 0.024 - 1.8 mg/m2) as a 1, 3 or 24 hr infusion every 21 days; 1 or 3 hr infusion on day 1, 8, 15 every 28 days; or a 1 hr infusion daily for 5 consecutive days every 21 days were used to develop (N=405, ANC=7253) and validate (N=299, ANC=4977) the model. The model comprised of a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (ANC0), mean transit time in bone marrow (MTT), and a feedback parameter. T concentrations at the effect compartment were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to a sigmoid-EMax function. Model evaluation was examined using goodness of fit plots, relative error measurements, and posterior predictive checks. Computer simulations were undertaken to evaluate the neutropenia schedule dependency. Results: The mean (between subject variability, %) of the ANC0, MTT, T potency were estimated to be 4.4 × 109/L (39%), 3.99 days (40%), and 15.6 μg/L (58%), respectively. The feedback parameter, EMax and Hill coefficient were estimated to be 0.198, 154 and 1.48. Model validation procedure evidenced accurate prediction of the incidence of grade 3/4 neutropenia. Simulations indicated that T dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model predicted time course of the ANC confirmed that neutropenia is reversible, short-lasting, and non-cumulative. Conclusions: The extent and time course of neutropenia following five different dosing regimens of T were well predicted by the semi-physiological PKPD model.

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Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201)
Authors: Poplin E. , Levy D. E. , Berlin J. , Rothenberg M. L. , O’Dwyer P. J. , Cella D. , Mitchell E. , Alberts S. , Benson A.
Published: March 2020

LBA4004

Background: Gemcitabine (GEM) is the cornerstone of treatment of metastatic pancreatic cancer (PANCA). FDR GEM or GEMOX are promising, but have yet to convincingly demonstrate a survival advantage over GEM alone. E6201 compares overall survival (OS) of standard GEM 1000 mg/m2/30 min wkly ×7 over 56 days then wkly ×3 q28 d (ARM A) vs. FDR GEM 1500 mg/m2/150 min wkly ×3 q28 days (ARM B) or GEM 1000 mg/m2/100-min/d1 + oxaliplatin 100 mg/m2/d2 q14d (ARM C). Secondary endpoints are the comparison of the experimental regimens, toxicity, response, patterns of failure, progression-free survival and quality-of-life. Methods: This multi-institutional trial included patients (pts) with measurable and non-measurable advanced, unresectable PAN CA, normal organ function and PS 0–2. Pts were chemonaive, although prior adjuvant radiosensitizing 5FU was permitted. Pts were stratified by PS 0–1 vs 2 and locally advanced vs metastatic disease The study was designed to detect a 33% difference in median survival (hazard ratio 1.33) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons, assuming exponential failure and median survival of 6 mo for Arm A and 8 mo for Arm B and C (N = 750 eligible). Results: Accrual started in 3/03 and completed in 3/05. Median follow up is 5.8 mo. 833 pts (53% men; 88% PS 0–1; 88% metastatic), were randomized with 280, 277 and 276 pts in Arms A, B and C. The third interim analysis was conducted with 89.5% information on 3/2006. The predominant toxicity, available for 758 pts, was grade 3/4 myelosuppression and fatigue. Two deaths from ARDS and infection occurred. Median OS for ARMS A, B, and C are 4.96, 6.01 and 6.47 months, respectively. Hazard ratio A vs B is 1.21 with stratified log rank of 0.053 and for A vs C is 1.22 with stratified log rank of 0.045, neither statistically significant. Conclusion: E6201 final OS results will be available in June, 2006.

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Randomized phase III trial of standard D2 versus D2 + para-aortic lymph node (PAN) dissection (D) for clinically M0 advanced gastric cancer: JCOG9501
Authors: Sasako M. , Sano T. , Yamamoto S. , Nashimoto A. , Kurita A. , Furukawa H. , Tsujinaka T. , Kinoshita T. , Arai K.
Published: March 2020

LBA4015

Background: The INT-0116 study proved the efficacy of radiochemotherapy after R0 resection for gastric cancer and thus the importance of the local control and the insufficiency of D0/1 surgery. Recently D2 surgery was for the first time proven to improve the survival compared with D1 in a Taiwanese RCT (Lancet Oncol 2006). In our study, D2+PAND was compared with D2 in a RCT. Low operative mortality has been reported (Sano et al. J Clin Oncol 2004) and we now present the survival results. Methods: Eligibility criteria included; histologically proven adenocarcinoma, cT2b-T4, cM0, no macroscopic metastasis to the PAN, negative lavage cytology, adequate organ function, and age <76. Linitis plastica was excluded. Eligible pts were randomly assigned to D2 with or without PAND during surgery. All patients were followed without adjuvant therapy until recurrence. The primary endpoint was overall survival (OS) to be compared by stratified log-rank test. Assuming 256 eligible pts in each arm, the study had 75% power to detect 0.73 hazard ratio for D2+PAND to D2 in OS at 0.05 one-sided alpha. Results: Between 07/1995 and 04/2001, 523 pts were randomized (263 to D2 and 260 to D2+PAND). Baseline characteristics were well balanced between the arms. At the time of the final analysis on 23/03/06, 191 (96 and 95, in D2 and D2+PAND, respectively) had died. The 3- and 5-year OS were 76% and 69% in D2 and 76% and 70% in D2+PAND, respectively (p = 0.57, Hazard ratio was 1.03 (95% CI: 0.77–1.37)). Disease free survival did not show any difference between the groups as well. Median operation time was 63 minutes longer and median blood loss was 230 ml larger in D2+PAND than in D2. There was no difference in the incidence of major surgical complications and hospital mortality (0.8% in both arms). Conclusions: D2 or D2+PAND could be carried out safely and showed excellent survival for advanced gastric cancer treated with curative intent. PAND could not improve the survival achieved by D2. General use of PAND should be avoided.

No significant financial relationships to disclose.
First mature analysis of the Intergroup Exemestane Study
Authors: Coombes R. C. , Paridaens R. , Jassem J. , Van de Velde C. J. , Delozier T. , Jones S. E. , Hall E. , Kilburn L. S. , Snowdon C. F. , Bliss J. M.
Published: March 2020

LBA527

Background: We have previously shown that switching to exemestane (E) after 2–3 years tamoxifen (T) improves disease free survival (DFS) in postmenopausal (PM) women with early breast cancer (BC). We report results with 95% of patients (pts) having ≥3 years follow-up. Methods: 4724 PM pts (2352 E vs 2372 T) with ER +ve/unknown unilateral BC, disease-free after 2–3 years T, were randomized to continue T or switch to E to complete a total of 5 years adjuvant endocrine therapy. 122 pts (56 E vs 66 T) originally reported as ER unknown were later found to be ER −ve. In addition to intention to treat (ITT), we repeated analyses excluding ER −ve pts. Adverse events (pre relapse) by treatment received were analysed on treatment (TRT) and also including follow-up (TRTFU). In safety analyses P < 0.01 was taken as significant due to multiple testing. Results: With median follow up of 58 months there were 808 first events (disease relapse, contralateral breast cancer (CLBC), intercurrent death) and 483 deaths. See table for unadjusted hazard ratios (HR). In ER +ve/unknown pts, adjusting for pre-specified prognostic factors of nodal status, chemo use, HRT use, gave HR for DFS of 0.74 (0.64, 0.85); p < 0.0001 and for overall survival (OS) of 0.83 (0.69, 0.99); P = 0.04. There were 145 intercurrent deaths (65 E vs 80 T), including deaths from cardiac (14 E vs 13 T), vascular (17 E vs 11 T) and other cancers (20 E vs 35 T). No statistically significant differences in myocardial infarctions, angina, or cerebrovascular accidents were observed. In T pts there were more thromboembolic (TRT p = 0.006, TRTFU p = NS) and serious gynaecologic events (TRT p < 0.001, TRTFU p < 0.001) and less fractures (TRT p = NS, TRTFU p = 0.003). Conclusions: Switching to E following 2–3 years of T significantly improves DFS, reducing chance of first event, CLBC and distant recurrence. In ER +ve/unknown pts, the switching strategy with E significantly reduces the risk of dying.

[Table: see text] [Table: see text]