bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas
Authors: Goli K. J. , Desjardins A. , Herndon J. E. , Rich J. N. , Reardon D. A. , Quinn J. A. , Sathornsumetee S. , Bota D. A. , Friedman H. S. , Vredenburgh J. J.
Published: March 2020

2003

Background: Recurrent malignant gliomas have low response rates to current treatments. Malignant gliomas have high concentrations of VEGF receptors which are poor prognostic indicators. Bevacizumab is a humanized IgG1 monoclonal antibody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor with modest activity against recurrent malignant gliomas. Methods: We report the mature data for our FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. We enrolled 68 patients (35 with grade IV tumors and 33 with grade III tumors.) All patients had progressive disease and received prior radiation therapy and temozolomide. The first 32 patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m2 (non EIAED) or 340 mg/m2 (EIAED). The last 36 patients were treated with irinotecan 125 mg/m2 (non EIAED) or 350 mg/m2 (EIAED) on days 1, 8, 22, and 29 and bevacizumab 15 mg/kg on days 1 and 22. Results: The regimen was well tolerated. Only 1 CNS hemorrhage occurred after 10 cycles of treatment. Eight patients were taken off study for thrombotic complications (four PE, two DVT, one TTP, one thrombotic stroke) and 2 of these patients died (one with PE and one with thrombotic stroke). Two patients were discontinued secondary to grade 2 proteinuria and 3 were discontinued because they required non-neurosurgical surgery. The response rate was 59% (38 PRs and 2 CRs). In Grade IV, the median PFS was 23 weeks (95% confidence intervals 17–34). The 6 month PFS was 43% (95% confidence intervals 29%-63%), the median overall survival was 40 weeks (95% confidence intervals 34–50). In grade III patients the median PFS was 42 weeks, the 6 month PFS was 61% (95% confidence intervals 46%-80%), the medial overall survival was 60 weeks (95% confidence intervals 37%-73%). The follow-up for the second cohort is short with similar efficacy and more toxicity. Conclusion: The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas.

[Table: see text]
M1 medulloblastoma should be considered high risk at any age
Authors: Sanders R. P. , Onar A. , Boyett J. M. , Broniscer A. , Fouladi M. , Boop F. A. , Sanford R. A. , Kun L. E. , Merchant T. M. , Gajjar A.
Published: March 2020

2016

Background: Metastatic (M) stage is an important prognostic marker in medulloblastoma. With current therapy including higher-dose craniospinal irradiation and dose intensive chemotherapy, older children with metastatic medulloblastoma have had improved survival. Some investigators have suggested that older children with M1 medulloblastoma be treated as average-risk patients. Additionally, the prognostic value of M1 disease in very young children has not been documented. Methods: We retrospectively reviewed the records of all newly diagnosed medulloblastoma patients treated at St. Jude Children’s Research Hospital from 1984 to 2006. Treatment generally included resection and chemotherapy. Older children received post-operative craniospinal and tumor bed irradiation; radiotherapy for younger children depended on treatment era and physician/family preference. We compared event-free and overall survival for patients with M1 disease to that of patients with M0 and M2/M3 disease for both age groups using the Kaplan-Meier method. Results: 286 patients were included. 56 were <3 years old at diagnosis and 230 were =3 years old. Event-free (EFS) and overall survival (OS) by age and M-stage are reported below. Within the younger group, a significant difference in 5-year EFS was detected among M-stage groups (p<0.002 by Mantel-Haenszel test); 5-year EFS for M0 (n=33), M1 (n=5), and M2/M3 (n=18) patients was 67%, 20%, and 22%, respectively. The difference in 5-year EFS by M-stage was also significant for older patients (p<0.0001); 5-year EFS for 154 M0, 13 M1, and 63 M2/M3 patients was 82%, 59%, and 42%, respectively. Results were similar for OS; differences in OS were significant for older (p<0.0001), but not younger (p=0.21) children. Conclusions: Children <3 years old with M1 medulloblastoma fared poorly in our small series. Survival for older children with M1 disease treated with higher-dose CSI was better than that of M2/M3 patients, but still less than optimal; our findings do not support reduction in therapy for either cohort.

[Table: see text]

No significant financial relationships to disclose.
A phase IIb actively controlled study with the TGF-beta-2 inhibitor AP 12009 for recurrent or refractory anaplastic astrocytoma
Authors: Bogdahn U. , Mahapatra A. , Olyushin V. E. , Mouli C. , Parfenov V. E. , Stockhammer G. , Ludwig S. , Wuerth G. , Heinrichs H. , Schlingensiepen K.
Published: March 2020

2025

Background: The TGF-β2 antisense phosphorothioate oligonucleotide inhibitor AP 12009 is a targeted anti-tumor therapy for TGF-β2 overexpressing tumors. In three Phase I/II dose escalation studies complete and long-lasting responses were observed in patients with recurrent or refractory anaplastic astrocytoma. Methods: The Phase IIb actively controlled dose finding study G004 is an open-label, randomized trial in adult patients with recurrent or refractory high-grade glioma (HGG) confirmed by central histopathology. 145 patients were randomized into three groups: Low dose AP 12009 (10 μM), high dose AP 12009 (80 μM), or standard chemotherapy, i.e. TMZ (or PCV if TMZ had already failed). Study objective was to compare the efficacy and safety of the three treatment groups. AP 12009 was applied locoregionally by convection- enhanced delivery (CED) with up to 11 treatment cycles (7-day-on, 7-day-off / per cycle). Results: Here we report on patients with recurrent anaplastic astrocytoma (AA, Grade III; GBM patients see separate abstract). 39 AA patients were treated, 12 pts received AP 12009 10 μM (AP-10), 15 pts 80 μM (AP-80), and 12 pts standard chemotherapy (10 pts TMZ, 2 pts PCV). Preliminary safety data reveal no SAEs related to the study drug in the AP-10 and AP-80 groups vs. one in the control group. Survival rates were higher in both AP 12009 groups compared to the chemotherapy group (see table ). In both AP 12009 groups mOS has not yet been reached. Overall survival at present is 28.6 months for the AP-10 group, 24.2 months for the AP-80 group, and 20.2 months for the control group. Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table ). Conclusion: AP 12009 revealed a positive benefit-risk profile and demonstrated excellent potential as monotherapy for the treatment of recurrent or refractory AA patients, especially for the AP 12009 10 μM group.

[Table: see text]

[Table: see text]
A pilot study of bevacizumab and stereotactic intensity modulated re-irradiation for recurrent high grade gliomas
Authors: Mohile N. A. , Abrey L. E. , Lymberis S. C. , Karimi S. , Hou B. L. , Gutin P. H.
Published: March 2020

2028

Background: Bevacizumab is a humanized monoclonal antibody directed at vascular endothelial growth factor A (VEGF-A). Preclinical studies suggest that inhibition of VEGF-A improves glioma response to radiotherapy. The concurrent use of bevacizumab and cranial radiotherapy has not been investigated. The objective of this study is to determine the safety of this combination. Methods: Patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytomas (AA) less than 3.5 cm received bevacizumab (10 mg/kg IV) every 2 weeks. MRI after cycle 1 (28 days) was done to reassess response and for RT planning. Patients then received stereotactic intensity modulated radiation therapy (IMRT): 30Gy in 5 fractions over 15 days. Bevacizumab treatment, given every 2 weeks, was administered during radiotherapy and continued until tumor progression. Brain MRI to assess response was performed after odd cycles. MR T1 and T2* perfusion were performed at baseline and after cycle 1. Results: 12 patients (10 GBM, 2 AA) with median age 53 (range, 30–61) and median KPS 90 (range, 80–100) received a median of 5.5 cycles of bevacizumab. In 1 patient, stereotactic IMRT could not be delivered safely to tumor. Grade III events occurred in 10 patients including hypertension, headache, seizures, neutropenia, hyponatremia and hypophosphatemia. There were no grade IV or V events, no dose limiting toxicities and no intracranial hemorrhage. 7/12 patients had objective responses (3 CR and 4 PR). In 5, SD was the best reported response. At last follow up, ten patients remain on study; 2 have come off for PD. Estimated 6 month PFS is 76%. MR perfusion imaging demonstrated a decrease in mean perfusion values after 1 cycle of bevacizumab. Conclusions: Bevacizumab in combination with RT is safe and well tolerated. Imaging responses and duration of disease control suggest that this regimen is active in this subset of recurrent glioma patients. Further investigations to determine efficacy and possible synergy of bevacizumab with radiotherapy are warranted.

[Table: see text]
Potentiation of proteasome inhibitor-induced apoptosis in glioma cells by histone deacetylase inhibitors
Authors: Friday B. , Yu C. , Yang L. , Wigle D. , Sarkaria J.
Published: March 2020

2038

The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Co-exposure of LBH589 (LBH) and botezomib (btzmb) results in a striking induction of apoptosis, at minimally toxic doses of either drug alone, in established U251, U87, and D37 GBM cell lines, as well as in GBM8 (G-8), GBM10 (G-10), GBM12 (G-12), GBM14 (G-14), and GBM56 (G-56) cells, which have been developed from the Mayo xenograft GBM panel and maintained in short-term cultures. Synergism of apoptosis induction was also observed in U251 cells when co-exposing other HDAC inhibitors, including LAQ824 (LAQ) and trichostatin A (TSA), with another proteasome inhibitor MG132, demonstarting a class effect. In U251 cells, btzmb alone or in combination with LBH decreased Raf-1 levels and inactivated Akt and Erk. Either LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly increased JNK activation. In addition, cell death after exposure to LBH589 and bortezomib is associated with cytochrome c release, Bax translocation, as well as caspase and PARP cleavage. Bax translocation may contribute to the synergistic cytotoxicity of the combination of LBH and btzmb in glioma cells since Bax translocation to mitochondria is known to precede cytochrome c release and apoptosis, but other pathways are likely to be involved. This combination regimen warrants further preclinical and possible clinical study for glioma patients.

No significant financial relationships to disclose.
Hypofractionated radiotherapy versus conventional fractionated radiotherapy in elderly patients with glioblastoma multiforme
Authors: El-Shenshawy H. M. , El-Razek A. Abd , Bader H.
Published: March 2020

2042

Background: To evaluate efficacy of short- course radiotherapy(RT) in elderly (>60 years) patients with glioblastoma multiforme (GBM), and compare this biological similar short -course radiotherapy with a standard radiotherapy. Methods: Forty-four elderly patients with GBM were randomly assigned after surgery to receive either a short-course of radiotherapy (45 Gy in 15 fractions over 3 weeks) or standard radiotherapy (60 Gy in 30 fractions over 6 weeks) to a target volume described as tumor visible on CT scan and a 2 cm margin. The primary end point was overall survival. Results: The overall response rate and median duration of response were 60% and 8.5 months in short-course RT versus 65% and 8 months in standard RT. Improvement in pretreatment performance status and increase in post-treatment corticosteroid dosage were observed in 50% and 25% in short-course RT versus 40% and 50% in standard RT (P=0.09, P=0.031) respectively. Median survival time was 5.9 months in short-course RT versus 5.6 months in standard RT. Six months, 1-year survival and progression-free survival rates were 40%, 15% and 30% ,10% in short-course RT versus 45%, 10% and 35%, 5% in standard RT, respectively. In both treatment groups, females did significantly better than males, patients with KPS 60–70 did significantly better than those with KPS 50, patients having tumors 4–5 cm did significantly better than those with tumors 6–8 cm as well as did those with more radical surgery when compared to those with biopsy only. On multivariate analysis, only tumor size and extent of surgery were found to independently influence survival. Acute toxicity was generally assessed as mild in the two treatment groups. While RT-induced brain necrosis appeared only in one patient received short- course RT, but this patient died from tumor recurrence. Conclusions: Hypofractionated RT is feasible and safe treatment for elderly patients with GBM.

No significant financial relationships to disclose.
Phase I clinical pharmacokinetics of RTA 744: A blood brain barrier penetrating anthracycline active against high-grade glioma
Authors: Kazerooni R. , Conrad C. , Baud C. , Johansen M. , Thapar N. , Meyer C. , Priebe W. , Madden T.
Published: March 2020

2045

Background: Preclinical studies demonstrated that RTA 744, a 4’-O benzyl anthracycline designed to circumvent P-gp and MRP1-mediated efflux, effectively crosses the BBB, is retained in brain & brain tumor tissue for >24 hrs, and has demonstrated in vivo activity against glioblastoma multiforme (GBM) in an orthotopic model. Methods: We designed a multicenter, phase I dose- escalation study of RTA 744 administered as a short intravenous infusion for 3 consecutive days, every 3 weeks. Patients enrolled in the study were adult patients with recurrent or refractory GBM, anaplastic astrocytoma, or other primary brain tumors. Peripheral blood samples for PK analysis were collected prior to and at selected timepoints from 5 min to 96 hrs after drug administration, and quantified by LC/MS/MS. PK parameters describing RTA 744 disposition were determined by fitting compartmental models to individual patient plasma concentration-time data. Results: Twenty patients have been enrolled at daily doses ranging from 1.2 to 9.6 mg/m2. Mean (range) population terminal half-life was 34.6 (20.5–89.2) hrs, plasma drug clearance was 45.0 (27.4–86.9) L/hr/m2, and Vss was 1942 (684.9–4721.7) L/m2; population PK values reported for doxorubicin are 20–32 hrs, 24–35 L/hr/m2, and 700–1100 L/m2, respectively. Regimen related toxicity has been minimal with the most common adverse event being myelosuppression. Percentage of unchanged parent drug renally eliminated was 2.4% (0.42–6.03%). Several partial responses and one complete response have been noted, even at dose levels below the observed MTD of 7.5 mg/m2/day. Conclusions: These results are similar to what we have observed in our preclinical studies, demonstrating increased lipophillicity and enhanced biodistribution of RTA 744 when compared to doxorubicin. Direct confirmation of drug penetration into the CNS has not been determined in this study, however this is the focus of an ongoing trial in patients with leptomenigeal malignancies.

No significant financial relationships to disclose.
Different types of mutations in GISTs: Different clinical implications?
Authors: Braconi C. , Bearzi I. , Bianchi F. , Bracci R. , Costagliola A. , Arduini F. , Mandolesi A. , Cellerino R.
Published: March 2020

20505

Background: Mutations of KIT or PDGFRa are associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of these mutations is still controversial. Methods: We examined 125 patients diagnosed with GISTs. Genomic DNA was extracted from paraffin-embedded tumor tissues and analysed for the presence of KIT exon 9 and 11 mutations and PDGFRa exon 12 and 18 mutations. DFS (Disease Free Survival) was analysed in 92 radically resected patients. The relation between mutations and clinico-pathological factors was analysed using Fisher's exact test and Kaplan-Meyer analysis. Results: KIT mutations occurred in exon 9 in 15 cases and in exon 11 in 78 cases. PDGFRa mutations have been detected mainly in exon 18 (10 cases) and less frequently in exon 12 (3 cases). Exon 11 mutations were as follows: deletions in 58%, point mutations in 30%, insertions and duplications respectively in 4 and 5 cases. Although type of mutations within exon 11 KIT didn't correlate with DFS, a better trend was evident for duplicated and point mutated GISTs. Exon 9 KIT mutated GISTs were associated with intestinal location and higher grade. There was significant association between PDGFRa mutations, gastric location and lower mitotic index. Moreover, PDGFRa mutated and wild type GISTs seemed to have a better outcome. Conclusions: Point mutations and duplications in exon 11 KIT were associated with a better clinical trend in DFS. Exon 9 KIT mutations significantly correlated with intestinal location and higher mitotic count. PDGFRa mutated GISTs were localized in the stomach and seemed to have a favorable clinical behavior.

No significant financial relationships to disclose.
Radiation-induced sarcoma: A single center experience with 36 cases
Authors: Mayer F. , Kopp H. G. , Classen J. , Kluba T. , Koenigsrainer A. , Horger M. , Bamberg M. , Hartmann J. T.
Published: March 2020

20525

Background: Radiation-induced sarcoma (RIS) is a rare complication of radiation therapy for any cause. With increasing numbers of patients receiving radiotherapy, data concerning the incidence and treatment outcome of RIS are urgently needed. Methods: We screened our local sarcoma registry for patients with RIS. 36 cases of RIS that had developed after radiation for malignant disease were identified and analyzed retrospectively over a 12 year period (1994–2006). Results: All patients had received radiation therapy between 1968 and 2002. The most frequent primary tumors were breast cancer (n = 19) and lymphoma (including Hodgkin`s and non-Hodgkin`s lymphoma, n = 9). The remainder received radiation therapy for tumors of the female reproductive organs (n = 2), head and neck cancer (n = 4), neuroblastoma (n = 1), and seminoma (n = 1).The median of delivered total radiation dose per patient was 50 Gy (35 to 72 Gray). Sources of irradiation were photons (n = 9), cobalt (n = 6), electrons (n = 2), and unknown in 19 cases. The median time interval from the start of irradiation the detection of the sarcoma was 11 years (1 - 35 years). The tumors arose within the radiation field in 29 cases, on the border of the field in 6 cases, and out of field in 1 case. The histology of RIS was angiosarcoma in most cases (n = 12), followed by pleomorphic sarcomas (n = 11), leiomyosarcoma (n = 4), fibrosarcoma (n = 2), osteosarcoma (n = 2), and others (n =5). Most cases were detected in a localized stage of disease (n = 33), and therefore, complete surgical removal was achieved in almost 50% (n = 17). However, this did not translate into long term survival within the overall study population. Only 11 patients remain free of disease during a mean follow-up period of 29 months (range, 0 - 51). Conclusions: Angiosarcomas within or on the border of the radiation field are the most common histological subentity of RIS. Therefore, follow-up of previously irradiated patients should include examination of irradiated regions with a high level of suspicion if cutaneous atypical vascular lesions are found. However, the clinician should be aware of the fact that RIS also occurs out of field and can be of non-angiogenic subtype as well. As far as treatment is concerned, RIS is treated the same as non-radiation induced sarcoma.

No significant financial relationships to disclose.
The prognostic analysis of gastrointestinal stromal tumor
Authors: Shi Y. , Du C. , Fu H. , Zhao G. , Zhou y.
Published: March 2020

20534

Objective: To investigate the prognostic factor of gastrointestinal stromal tumor. Methods: The clinicopathological data of 103 patients with gastrointestinal stromal tumors were analyzed restrospectively. Life table, kaplan-meier survival rate and cox regression model were used to evaluate the prognostic factors. Results: The 1 year ,3 years and 5 years total survival rate of these 103 gastrointestinal stromal tumors was 86.3%, 51.7%, 42.8%. Tumor size, mitotic rate, primary organ of tumor and radical surgical excision or not were analyzed respectively, the difference is statistical significance (P<0.05). No significiant difference between the group of sex, age, immunohistochemistry expression and multi-organ resection or not. Conclusion: Flechers’ classification is rational, scientific, simple and feasible. Radical surgical excision is the best therapy to the primary gastrointestinal stomal tumor.

No significant financial relationships to disclose.
Phase I trial of VNP40101M in children with recurrent brain tumors—A Pediatric Brain Tumor Consortium (PBTC) study
Authors: Gururangan S. , Turner C. , Stewart C. F. , Kocak M. , Poussaint T. Y. , Boyett J. M. , Kun L. E. , Karsten V. , Gerson S. L. , Friedman H. S.
Published: March 2020

2059

Background: VNP40101M, a novel DNA alkylating agent and a potent inhibitor of alkylguanine alkyl transferase (AGT) in pre- clinical studies, was evaluated in a phase I study in children with recurrent brain tumors. Methods: VNP40101M was given intravenously (i.v) daily for 5 days q 6 weeks up to 8 cycles. Using the continual reassessment method, dose escalation was performed independently in pts stratified based on intensity of prior therapy (stratum I-less-heavily pre-treated; stratum II- heavily pre-treated). Dose limiting toxicities (DLTs) and responses were assessed at the end of the first and 2nd cycles of treatment, respectively. Correlative studies included pharmacokinetics and measurement of AGT activity in peripheral blood mononuclear cells (PBMC) before and after treatment. Results: 41 eligible pts (stratum I- 19, stratum II- 22; median age 9.3 yrs, range 0.9 to 21.5) were enrolled on this study. Dose levels (in mg/m2/day) evaluated in Stratum I were 45, 60, and 78 mg; In Stratum II 20, 30, 45, and 60 mg. DLT in evaluable pts was myelosuppression (grade IV neutropenia for > 7 days or any grade IV thrombocytopenia) and occurred in 4/16 pts in stratum I [45 mg (n=1/12), 60 mg (n=1/2), 78 mg (n= 2/2)] and 3/19 pts in stratum II [45 mg (n= 3/4), 60 mg (n=0/1), 30 mg (n= 0/12), and 20 mg (n= 0/2)] respectively. Other significant toxicities post first course included renal failure (n=2), pulmonary (n=2), and fatal infection (n=1). PK studies showed median (range) terminal half-life of 62 mins (7.3 to 522 min). The MTDs in stratum I and II were 45 mg/m2/day and 30 mg/m2/day daily for 5 days q 6 weeks, respectively. Objective responses were observed in one pt each with brain stem glioma and medulloblastoma respectively. PBMC AGT levels did not decrease following VNP40101M treatment. Conclusions: The recommended pediatric phase II dose of VNP40101M given i.v daily for 5 days q 6 weeks is 45 mg/m2/day in less-heavily treated and 30 mg/m2/day in heavily treated pts.

[Table: see text]
Phase I dose escalation of temozolomide with thiotepa and carboplatin with autologous hematopoietic cell reinfusion in patients with recurrent/refractory malignant brain tumors
Authors: Gardner S. , Fisher M. , Belasco J. , Phillips P. , Finlay J.
Published: March 2020

2060

Background: The prognosis for most patients with recurrent malignant brain tumors is dismal. Treatment options are limited especially for patients who have already received irradiation. TMZ is an oral alkylating agent which is approved for use in patients with high grade glioma and has also been shown to have activity in patients with recurrent medulloblastoma. It’s primary dose-limiting toxicity is non- cumulative bone marrow suppression. In the present study, TMZ is given in a dose escalation fashion with fixed doses of high dose thiotepa and carboplatin with AHCR in the treatment of patients with recurrent or refractory malignant brain tumors. Methods: Treatment consisted of TMZ twice daily on days -10 to -6 followed by thiotepa 300 mg/m2/day and carboplatin AUC=7/day on days -5 to -3 with AHCR on day 0. Filgrastim was given day +1 and continued until engraftment. Results: 27 patients (18M; 9F) ages 3–46 years were treated from 11/00 until 10/04. Diagnoses included high grade glioma (n=12); medulloblastoma/PNET (n=9); CNS germ cell tumor (GCT) (n=4); and 1 each ependymoma and spinal cord PNET. TMZ doses ranged from 50 mg/m2 twice daily (100 mg/m2/day) to 200 mg/m2 twice daily (400 mg/m2/day) for 5 days. One patient had dose limiting toxicity consisting of reversible veno-occlusive disease at dose level 3 (TMZ 100 mg/m2 twice daily). Two patients had dose limiting toxicity at dose level 7 (TMZ 200 mg/m2 twice daily) consisting of transient encephalopathy (n=1) and severe mucositis (n=1). Additional toxicities included bacteremia (n=11), C. difficile enteritis (n=6) and grade 4 elevation of bilirubin and/or liver transaminases (n=2). There were no toxic deaths. Survival included 3 patients with glioma (38–48 months); two of whom had relapsed following standard dose TMZ; 3 patients with PNET/MB (48–72 months) and 3 patients with CNS GCT (26–71 months). Conclusions: Increased doses of TMZ are feasible when given with AHCR. There is presently a phase II study underway through the Pediatric Blood and Marrow Transplant Consortium evaluating the efficacy of TMZ at a dose of 175 mg/m2/day twice daily for 5 days with high dose thiotepa and carboplatin and AHCR.

No significant financial relationships to disclose.
Phase II study of ifosfamide, carboplatin and etoposide (ICE) in recurrent glioblastoma
Authors: Aoki T. , Nojima K. , Mizutani T. , Ishikawa M. , Takasu A. , Hashimoto N.
Published: March 2020

2066

Background: To evaluate the efficacy and tolerability of ifosfamide, carboplatin and etoposide ( ICE ) in patients with recurrent glioblastoma. Methods: This was an open-label, single-center phase II trial. Forty-two patients with first recurrent glioblastoma after surgery, standard radiotherapy and a first-line temozolomide-based or ACNU-based chemotherapy, were enrolled.The primary endpoint was progression-free survival at 6 months ( PFS-6 ), and secondary endpoints were response rate, toxicity, and survival. Chemotherapy consisted of Ifosfamide ( 700 mg / m2 on day 1, 2 and 3 ), carbopaltin ( 100 mg / m2 on day 1 ), etoposide ( 70 mg / m2 on day 1, 2, and 3 ), every 6 weeks. Results: PFS-6 was 37 %. The median PFS was 17 weeks. Response rate was 27 %. Adverse events were generally mild ( grade 1 or 2 ) and consisted mainly of alopecia. Conclusions: This regimen is well tolerated and has activity in patients with recurrent glioblastoma.

No significant financial relationships to disclose.
Radiation and concurrent temozolomide followed by rotational multi-agent chemotherapy for glioblastoma (GBM) patients
Authors: Affronti M. L. , Day J. M. , Herndon J. E. , Rich J. N. , Quinn J. A. , Reardon D. A. , Vredenburgh J. J. , Desjardins A. , McLendon R. E. , Friedman H. S.
Published: March 2020

2068

Background: GBM is the most lethal type of brain tumor with a 1 yr median survival. We hypothesized that GBM patients who receive adjuvant rotational multi-agent chemotherapy (temozolomide, CCNU, and CPT-11) have improved overall survival when compared to patients receiving single agent adjuvant regimens (carmustine, temozolomide). Methods: We conducted an IRB-approved retrospective data analysis of 80 primary GBM patients who received radiation therapy and concurrent temozolomide followed by 12 mos of adjuvant rotational multi-agent chemotherapy. All patients with the intent to treat were included in the analysis. The survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA). These data were compared to the recently published Stupp RPA analysis (JCO 2006) and the RTOG trial (radiation alone). Results: 73% were male. Mean age was 52 yrs (range 21–76 yrs); 39 % were < 50 yrs.. 82% were white. WHO performance status was: 0, 14%; 1, 62%; 2, 20%; and 3, 4%. Overall survival was 59% (95% CI: 49%, 71%) at 1 yr and 31% (23%, 43%) at 2 yrs. Median survival was 65.1 wks (49.7, 78.9) with median follow-up of 122.1 wks.. No difference in the 2-yr overall survival rate in RPA classes III-IV was detected between the Duke and Stupp regimens (p>0.4733), but 66% (33, 77) of the Duke rotational therapy GBM patients are living longer than the RTOG patients (p > 0.0086). Univariate Cox Hazard ratio of 1.27 (0.522, 3.08) did not correlate MGMT status with survival (p > 0.60). Conclusions: (1) Concurrent Temozolomide and radiation followed by rotational chemotherapy is an effective therapy compared to recent published gold standard adjuvant regimens. (2) Concurrent Temozolomide and radiation followed by rotational chemotherapy resulted in a statistically significant survival benefit compared to RTOG trial. (3) Lack of correlation between MGMT and overall survival suggests that agents whose damage is not repaired by MGMT may be an important therapeutic approach. (4) Future prospective randomized trials with concurrent Temozolomide and radiation must compare post radiation multi-modality regimens.

No significant financial relationships to disclose.
Overall survival of primary glioblastoma (GBM) patients (pts) receiving carmustine (BCNU) wafers followed by radiation (RT) and concurrent temozolomide (TMZ) plus rotational multi-agent chemotherapy
Authors: Rich J. N. , Affronti M. L. , Day J. M. , Herndon J. E. , Quinn J. A. , Reardon D. A. , Vredenburgh J. J. , Desjardins A. , Friedman H. S.
Published: March 2020

2070

Background: Treatment of pts with primary GBM using BCNU wafer implantation at initial surgery (Westphal, 2003) as well as the administration of TMZ concurrently and after RT (Stupp, 2005) have each been shown to increase survival. Thus, we hypothesize that the use of the combination of BCNU wafer followed by RT and concurrent (TMZ) plus rotational multi-agent chemotherapy (CCNU, TMZ, CPT-11) will increase survival compared to pts that do not receive BCNU wafers. Methods: Retrospective IRB-approved analysis was conducted on 85 eligible GBM pts who received surgery with (36 pts) and without (49 pts) BCNU wafer insertion followed by RT and concurrent (TMZ) plus adjuvant rotational multi-agent chemotherapy. Survival was estimated within treatment groups using the Kaplan-Meier method. Cox regression was used to evaluate the effect of BCNU wafers on survival after controlling for covariates such as RPA (Recursive Partition Analysis) class, race, and gender. Results: Within the non-BCNU wafer cohort, 39% of patients were younger than 50 and 89% had KPS>70%. Within the BCNU cohort, 31% of patients were younger than 50 and 94% had KPS>70. Overall 1- and 2-year survival for the non-BCNU wafer cohort was 67% (95% CI: 55%, 82%) and 27% (95% CI: 17%, 42%), respectively, with a median survival of 72.7 wks (median follow-up: 123.9; range 14.3–198). Overall 1-year survival for the BCNU wafer cohort was 78% (95% CI: 65%, 93%) with a median survival of 89.6 wks (median follow-up: 118.6; range 26.7–192.1). Given the trends towards significance (p=0.092) between the two groups using a log-rank test, a Cox regression model to control for known prognostic factors was examined: Conclusions: After controlling for the effects due to RPA class, a significant difference in survival is found between treatment groups (p = 0.0325) and patients receiving BCNU wafers have a lower risk of death (HR = 0.548) than patients not receiving BCNU wafers.

[Table: see text]

No significant financial relationships to disclose.
Joint NABTC + NCCTG prognostic factors analysis for high grade recurrent glioma
Authors: Lamborn K. , Wu W. , Prados M. , Jaeckle K. , Chang S. , Novotny P. , Buckner J.
Published: March 2020

2075

Background: Multiple variables may impact endpoints used to assess therapeutic efficacy for patients with recurrent gliomas. To identify prognostic factors for each of 3 outcome variables, a master analysis file was constructed by pooling datasets summarizing key baseline factors and outcomes obtained in 15 North Central Cancer Treatment Group (NCCTG) trials (n=583, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n=596, 1998–2002). Methods: In addition to traditional variables (gender, age, performance score (PS), race, extent of primary resection, year of study entry, last known histology, time since initial diagnosis, baseline steroid use, prior chemotherapy (Y/N), prior nitrosoureas, baseline anticonvulsant use), we investigated prior t (TMZ), number of relapses, academic vs. community site and low grade at initial diagnosis. Outcome variables were: (1) overall survival (OS), (2) progression free survival (PFS) and (3) PFS6 = proportion of patients alive and progression-free 6 months after start of treatment. For all 3 endpoints, Classification and Regression Tree (CART) models and bootstrap samples were used to identify prognostic variables and to look for evidence of interactions among the independent variables affecting outcome. Results: For all outcomes the initial CART analysis selected last known grade (4 vs. 3) as the most important variable. Additional factors selected as predicting poor prognosis differed with grade and outcome measure and included prior TMZ, longer time since primary diagnosis, older age and poor PS. Community vs. academic was not a strong predictor in any of the models nor was low grade at initial diagnosis. Additional analyses are planned to better describe the impact of all the variables on outcome, including use of Cox models and logistic models considering all baseline variables with backwards selection. Conclusions: The results from analyses to date are consistent with current thinking that last known histology (grade) is an important factor. Time since initial diagnosis is likely a surrogate for number of relapses. More definitive conclusions await the completion of ongoing analyses.

No significant financial relationships to disclose.
Bevacizumab and irinotecan in patients (pts) with recurrent glioblastoma multiforme (GBM)
Authors: Raval S. , Hwang S. , Dorsett L.
Published: March 2020

2078

Background: Primary GBM exhibits overexpression or amplification of the epidermal growth factor gene. The effectiveness of bevacizumab and irinotecan in pts with relapsed GBM was first reported in 2005 (Stark-Vance, et al, Neuro-Oncol, 2005). In this report, we assess the effects of combination of bevacizumab and irinotecan on overall responses, toxicity, cognitive function and functional status in recurrent GBM pts. Methods: From August 2005 to December 2006, 22 consecutive GBM pts failed > 1 prior chemotherapy with measurable disease on MRI were included. Each patient received bevacizumab 5mg/kg IV and irinotecan 125mg/m2 IV infusion every 2 weeks until disease progression or developed unacceptable toxicity. The response was determined by MRI every 2 cycles. Cognitive function was assessed by Blessed Orientation-Memory-Concentration Test (BOMC) and functional status was assessed by Karnofsky performance status (KPS), Barthel Index (BI) and Instrumental Activities of Daily Living (IADL) prior to each cycle of treatment. Descriptive statistics analysis was used. Results: All pts failed temozolomide and radiation therapy; 1 pt had prior BCNU and 2 pts had prior irinotecan treatment. The median (M) age was 55 years (37-77) with pre treatment M KPS 80 (40–80), BOMC 7 (0–28), BI 85 (10–100) and IADL 6 (0–17); 12 pts exhibited mild (3 pts), moderate (7 pts) to severe (2 pts) cognitive impairment. The M number of cycles received was 8 (2–27); 21 pts are evaluable for MRI responses with 95.2% response rate (2CR’s + 14PR’s + 4 minimal responses). Seven pts have expired; the M length of survival was 4.6 months (range 1.1–15.4+) and the M time to progression was 3 months (0.5–13.8+). There were only two grade 3 thrombocytopenia and one grade 3 neutropenia. Improvement in BOMC score was seen in 15 pts (62%) with M improvement of 7 point. Improvement in functional status was seen in 18 pts (85.7%) with M improvement in KPS by 10 point, BI by 8 points and IADL by 2 point. Conclusions: The combination of bevacizumab and irinotecan is well tolerated and safe. The overall response rate was 95.2% and significant improvements in cognitive functional and functional status were demonstrated. The longer follow up will determine the impact of this most active combination.

No significant financial relationships to disclose.
COM-1 is over-expressed in human colorectal carcinomas
Authors: Davies M. L. , Watkins G. , Torkington J. , Fodstad O. , Jiang W. G.
Published: March 2020

21001

Background: COM-1, candidate of metastasis-1, is a primarily nuclear protein thought to play a role in the development and maintenance of metastatic tumours and to have some mitogenic activity. However subsequent investigations have demonstrated a much more diverse role in cancer and cell growth. Here we have investigated the expression and sub-cellular distribution patterns of COM-1 in human colorectal carcinomas. Methods: Carcinoma and normal matched tissues were collected following surgery and frozen for future analysis. Sections of tissue underwent immuno-histochemistry (IHC) staining for COM-1 to determine degree of staining and changes in cellular distribution of the proteins within the tissue. Furthermore, quantitative analysis (quantitative polymerase chain reaction - qPCR) of mRNA levels of COM-1 transcripts was performed to compare levels in normal tissue with those in carcinoma tissues. Statistical analysis was by the Mann-Whitney test. Results: IHC -Normal tissue demonstrated strong nuclear staining for COM-1 protein with little or no cytoplasmic staining. In carcinoma tissue the level of overall staining was found to be much greater, with a greater degree of cytoplasmic staining and little evidence of nuclear staining. qPCR- COM-1 mRNA expression within cells was significantly higher within tumour tissue when compared to normal tissue (Mean 36.7 v 26.5, p=0.003). Moreover, there was a trend in increasing levels of expression and significance of difference between normal tissue and carcinoma tissue with increasing Dukes stage (A p=.52, B p=0.03, C p=0.03) , T-Stage (1 p=1.0, 2 p=0.69, 3 p=0.04, 4 p=0.03), Nodal status (−ve p=0.07, +ve p=0.04 and tumour differentiation (well diff p=0.91, Mod. Diff p= 0.06, Poor. Diff. p= 0.026). Conclusions: COM-1 expression is increased in colorectal tumour tissues when compared to normal mucosa. This is reflected at both the protein and mRNA levels within the cells. In addition there is evidence of dislocated expression and redistribution of COM-1 protein with normal protein expression remaining intra-nuclear however, in tumours COM-1 then becomes cytoplasmic. Aberant over-expression of COM-1 has been identified in other human carcinoma types and has been linked with advanced disease, here we have demonstrated a similar pattern in colorectal carcinomas.

No significant financial relationships to disclose.
Validation of an RT-PCR multi-gene prognostic signature for distant metastasis in node negative (N-), ER positive (ER+) breast cancer patients using FFPE sections
Authors: Tutt A. , Wang A. , Springall R. , Lau K. , Ryder K. , Kam Morgan L. , Broder S. , Esserman L. , Gillett C. , Sninsky J.
Published: March 2020

21009

Background: We sought to validate a previously developed 14-gene prognostic signature and a metastasis score (MS) that predicted distant metastasis in N-, ER+ breast cancer patients in an independent sample set of patients without systemic treatment. The genes consisted primarily of proliferation genes involved in p53 and TNF signaling pathways. Methods: : A cohort of 294 N-, ER+ breast cancer patients from Guy's Hospitals, London, UK without systemic therapy were tested. The cohort had a mean age of 55.5 yrs with 49% > 55 yrs, mean tumor size of 1.93 (max. 3) cm, and a median follow up of 14.3 yrs. The primary endpoint was distant metastasis free survival. RT-PCR was carried out on fixed sections. The MS was calculated. Results: The mean MS (SD) was 0.44 (0.59) with a range of -1.31 to 2.0. Hazard of distant metastasis increased 3.02 fold (95% CI 1.91–4.76, p <0.0001) per unit increase in MS from Cox model. The pre-determined cut point of zero was used to stratify patients into low- and high-risk groups. The 5-yr distant-metastasis-free survival rate (DMFSR) for low- and high-risk groups were 1 and 0.86 (SE 0.024); the 10-yr DMFSR were 0.97 (0.021) and 0.77 (0.030), respectively. Univariate Cox regression analyses indicated that MS (hazard ratio (HR) 5.65, 95% CI 2.05–15.56, p=0.008), tumor size (HR 1.62, p=0.0047) and tumor grade (HR 2.52, p=0.036) were significant but age was not. Multivariate Cox regression indicated that the signature had independent prognostic value with a HR of 4.71 (1.42–15.61, p=0.011) after adjusting for age, tumor size and grade. AUC of MS at 5-and 10-yr were 0.78 (0.71–0.85, p<0.001) and 0.73 (0.66–0.80, p<0.001) with sensitivities of 1 and 0.96 and specificities of 0.31 and 0.31 at zero cut point, respectively. The differential risk between the median MS scores of the lowest and highest deciles was 8-fold. Conclusions: A previously defined RT-PCR prognostic signature for N-, ER+ patients has been confirmed. A metastasis score that quantifies distant metastasis risk, not confounded with treatment effect can complement treatment response predictors. Insight on natural history of tumors is critical for evaluating impact of therapy.

No significant financial relationships to disclose.
Identification of epigenetic aberrant promoter methylation of RASSF1A in serum DNA and its clinicopathological significance in lung cancer
Authors: Chen L. , Wang Y. , Yu Z.
Published: March 2020

21014

Objective: To detect the hypermethylation status of RASSF1A promoter in serum DNA of lung cancer patients and to analyze its correlation with clinicopathological features. Methods: Serum DNA was extracted from peripheral blood from 80 primary lung cancer patients, 35 benign pulmonary disease patients and 15 healthy donors. The methylation status of RASSF1A promoter was determined using methylation-specific PCR technique, and the correlation between methylation profiles and clinicopathological parameters was statistically analyzed. Results: Aberrant methylation of RASSF1A was detected in 27 of the 80 (33.8%) patients with lung cancer but no benign pulmonary disease patients or healthy donors (p<0.001). RASSF1A was preferentially observed in small cell lung cancer (p=0.042), while no statistical difference was found among methylation frequencies of different subtypes of non-small cell lung cancer. The methylation status was also found to be associated with relative poor differentiation (p=0.009) and late stage (p=0.013), but not with gender, age or treatment. Conclusion: RASSF1A promoter is frequently hypermethylated in serum DNA of primary lung cancer patients, and RASSF1A is a promising novel biomarker for lung cancer diagnosis.

No significant financial relationships to disclose.
Lymph node metastasis in breast cancer: The role of tumor markers
Authors: Lund M. J. , Graham S. M. , Liff J. M. , Coates R. J. , Flagg E. W. , Yuan X. , Lin M. G. , Eley J. W. , Porter P. L.
Published: March 2020

21019

Background: Women diagnosed with lymph node positive breast cancer have a greater chance of recurrence and death than women with lymph node negative disease. Tumor markers are becoming increasingly important to understanding breast cancer progression, yet little is known about their relationship with lymph node status. The purpose of this study is to examine whether prognostic and novel cell-cycle tumor markers are associated with lymph node status in black and white women with invasive breast cancer. Methods: This study included 202 lymph node positive and 292 node negative women, ages 20–54 years, diagnosed with invasive breast cancer between 1990 and 1992, and previously enrolled in a population-based study in Atlanta, Georgia. Tumor specimens were centrally reviewed and evaluated for lymphovascular invasion (LVI) and Nottingham tumor grade. Expression of estrogen and progesterone receptors (ER and PR), c-ErbB-2, Ki-67, pRb, p16, p21, p27, p130/Rb2, p53, cyclin E, and cyclin D1 were centrally assayed by immunohistochemistry. Relationships between each tumor marker and lymph node status were assessed by logistic regression, after adjusting for prognostic and socio-demographic factors. Results: Several tumor markers were associated with lymph node status, but differed by tumor size. Among women with smaller tumors (≤2.0 cm), p130 (OR=0.6, 95% CI 0.4–1.0), Bcl-2 (OR=0.4, 95% CI 0.2–0.8), and cyclin D1 (OR=1.7, 95% CI 1.0–2.8) were significant predictors of positive lymph node status. Among women with tumors > 2.0 cm, p53 (OR=0.5, 95% CI 0.3–0.8), and cyclin E (OR=0.4, 95% CI 0.2–0.9), and pRb (OR=1.6, (95% CI 1.0–2.6) were significant predictors. Black women with smaller tumors were 50% more likely to have lymph node metastasis. LVI and high grade remained the strongest predictors of lymph node metastasis in all regression models. Conclusions: Our findings suggest that there may be a different mechanism for lymph node spread in aggressive smaller tumors compared to larger tumors. Identifying markers for aggressive tumors could lead to the benefit of more effective treatment, particularly among black women for whom race may be a surrogate for other markers not accounted for in our study.

No significant financial relationships to disclose.