bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in the distribution of methotrexate into high grade gliomas following intravenous administration, as monitored by microdialysis, are associated with blood brain barrier integrity
Authors: Olson J. J. , Blakeley J. O. , Grossman S. A. , Weingart J. , Rashid A. , Supko J.
Published: March 2020

1548

Background: Microdialysis (MD) is an accepted technique to monitor neurochemicals in pts with traumatic brain injury. This study was conducted to evaluate the use of MD to define the time course of intratumoral drug concentrations in pts with high grade gliomas (HGG) receiving systemic chemotherapy. Methods: MD catheters were placed in residual HGG following tumor debulking and infused with Ringer’s solution at 1 μL/min. MD probe location and integrity of the blood brain barrier (BBB) in adjacent tissue were determined by fused MRI/CT. Highdose (12g/m2) methotrexate (MTX), was given as a 4 h iv infusion the next day. MTX was measured in plasma and dialysate samples, collected at 30 min intervals from 1 h before to 24 h after dosing, with an LC/MS assay. Results: Six pts have been enrolled without any adverse events attributed to the MD catheter. Adequate pharmacokinetics (PK) were obtained in 4/6pts. MTX plasma pharmacokinetics (PK) were very consistent between the 4 evaluable pts and similar to published data. Time courses of the uncorrected MTX concentration in extracellular fluid (CECF) exhibited two distinctly different kinetic profiles. For 2pts in whom the MD probe resided within contrast enhancing tumor, CECF increased and decreased in parallel with drug levels in plasma, with a peak CECF of 189 ± 6 μM, an apparent elimination half-life in ECF of 4.44 ± 0.07 h, and an ECF/plasma AUCratio of 0.13 ± 0.01. The other 2pts had a much lower peak CECF (10.4 ± 0.4 μM) and AUC ratio (0.028 ± 0.020), with a more prolonged ECF half-life (11.4 ± 4.5 h). Fused images from 2 of these pts showed that the MD probe was located in nonenhancing tissue. Conclusions: MD is a clinically practical technique to monitor the distribution of systemically administered drugs to brain tumors in pts. It has the capability to elucidate variations in kinetic behavior that are consistent with regional differences in BBB integrity. Appropriate interpretation of data from MD studies to evaluate the distribution of investigational new drugs into brain tumors necessarily requires radiographic determination of the region of the tumor into which the probe has been placed.

No significant financial relationships to disclose.
Toxicity and efficacy profiles of intrathecal injection of I-131 NaI via intraventricular (IVent) or intralumbar (Ilumb) route for leptomeningeal metastases (LM) therapy
Authors: Wong F. C. , Groves M. , Papadopoulos N. , Kim S. , Conrad C. , Meyers C. , Hsu S. , Kumar A. , Tummala S. , Kim E.
Published: March 2020

1549

Background: LM is a fatal complication occurring in up to 30% of cancer patients. Intrathecal chemotherapy of LM is limited by diffusion while external beam irradiation is limited by neurotoxicity. Radioiodine I-131 may serve as a ablating agent because of its radiations transverse the meningeal thinkness but spare distant underlying nervous tissues. Two phase I studies are designed to determine MTD and to evaluate potential toxicity and efficacy of intrathecal I-131 sodium iodide (NaI) injected via IVent or the ILumb route. Methods: The IVent or Ilumb protocols each accured 5 groups of patients with cytology-confirmed LM from solid tumors. An injection of 15, 30, 60, 90 or 120 mCi of I-131 NaI was performed after thyroid blockade (Lugol solution and perchlorate), via an Ommaya reservoir (IVent) or lumbar puncture (ILumb). Patients underwent whole-body scintigraphy for biodistribution and radiation dosimetry. Follow-up studies consisted of serial CSF cytology, neuropsychology, ophthalmology, and serum tests (TSH and CBC) to 6 months. Results: The IVent and Ilumb studies accured 16 and 15 patients respectively with LM from melanoma, lung, breast and other tumors (13, 8, 6 and 4 of 31 patients). Because of re-entry into the protocols, one patient received a total of 407 mCi; the maximum radiation absorbed doses were estimated at 3716 cGy in the ventricular CSF and 54 cGy in the red marrow. No treatment-related NCI-Grade II/III/IV neurologic, hematologic or thyroid toxicity is noted. Transient improvements up to 6 weeks are noted in neuropsychologic tests (5/16 and 5/15), ophthalomologic test (3/16 and 1/15) and CSF cytology conversion (to negative) in 5/16 and 4/15 patients, respectively. Electrophysiology tests of 2 patients demonstrated normalization of P37 waves measured by somatosensory evoked potentials along with neuropsychologic test improvements. Conclusions: The MTD has not been reached up to 120 mCi on either the IVent or Ilumb protocol. Intrathecal I-131 NaI is likely to be efficacious to eradicate tumors in the CSF for LM therapy. Because of the low toxicity and likely efficacy, a phase II study with higher dosages is needed to fully explore therapeutic potentials of intrathecal I-131 NaI.

No significant financial relationships to disclose.
Phase-2 study of imatinib in metastasized medullary thyroid carcinoma
Authors: Zonnenberg B. A. , Links T. , Quarles van Uffort P. , Lips C. , De Groot J. , Voest E.
Published: March 2020

15500

Background: Medullary thyroid carcinoma (MTC) is a relatively rare tumor that metastasizes to regional lymph nodes, lung, liver and bone. When surgery is no longer a curative treatment option, no effective systemic therapy is currently available. In most cases a (somatic or germline) mutation in the RET (REarranged during Transfection) gene is considered to be an essential step in the pathogenesis of MTC. Imatinib is an oral inhibitor of several protein-tyrosine kinases including RET kinase. It has shown to be an effective drug in chronic myeloid leukemia and gastrointestinal stromal tumors. Methods: A two-step open label phase-2 study was initiated using 600 mg imatinib daily with a scheduled dose increase to 800 mg in case of minimal toxicity. Standard RECIST criteria were used for response evaluation using CT/MRI scans every 2 months. The two-step design allowed no further inclusion in the absence of objective responses in 15 patients. Results: 15 patients with metastasized MTC were included. No objective responses were observed but long term stable disease over 18 months was noted in 4 patients. However, toxicity was considerable. Emergency tracheotomy had to be performed in 2 cases due to mucosal swelling in patients with laryngeal nerve palsy and a narrow vocal cleft. In 3 cases the dose of Imatinib had to be decreased because of unacceptable toxicity (malaise, mucosal swelling (2) and fatigue). In 7 patients with a history of a thyreoidectomy, the dose of thyroxine had to be increased considerably to avoid serious hypothyroidism due to an incompletely understood interaction. Conclusion: Treatment with Imatinib yielded no objective responses and considerable toxicity in patients with MTC. Long-term stabilization of the disease was observed in only a minority of the patients. Patients with hypothyroidism and with laryngeal nerve palsy are at risk for serious adverse events and need special attention when treated with Imatinib.

No significant financial relationships to disclose.
Phase II clinical trial preliminary report: Cetuximab, gemcitabine and simultaneous radiotherapy for locally advanced head and neck cancer: Preliminary report
Authors: De La Garza J. G. , Granados M. , Aguilar J. L. , Lavin J. , Cabrera G. , Maldonado F. , Moran A. , Cruz J. , Luna K. , Segura B. , Olvera G.
Published: March 2020

15502

Background: Previous studies with cetuximab in SCCHN demonstrate to be clinically beneficial. In the present study we wished to evaluate the efficacy and safety of a chemotherapeutic scheme using gemcitabine, radiotherapy and cetuximab for SCCHN. Preliminary report of 20 of 40 enrolled patients into a phase II clinical trial. Methods: inclusion criteria; histological confirmation of epidermoid carcinoma, ages 18 to 70, K > 70%, normal renal, hepatic and haematologic functions, without previous treatment, surgically inoperable disease, or patients with operable disease that did not consent to surgery. All patients signed an informed consent form. Radiotherapy: 200 cGy/d/5/w until 70Gy were completed. Cetuximab: an initial dose of 400 mg/m2 one week prior to initiation of radiotherapy, followed by 250 mg/m2 weekly until completion of radiotherapy. Gemcitabine: 50 mg /m2 weeks 1–2, 4–5 and 7. Results: 20 patients were enrolled (16m/4f) from november of 2004 to november of 2005, (5 oral cavity, 5 oropharynx, 8 larynx, 1 hypopharynx and 1 paranasal sinus). Mean age 56 yrs (33–75). Tumor staging: 7/III, 8/IVa and 5/IVb. One female was excluded, 19 completed the study and were evaluated. GR 17/19 (89.5%), CR 13/17 (76.5%) and PR 4/17 (23.5%). 2/19 NR (10.5%). CR of the 1ary tumor 15/19 patients (78.9%); CR 6/11 patients with lymphatic disease at diagnosis (54.5%), PR 3/19 (27.3%). Toxicity: mucositis g/III-IV 8/19 patients; rash g/III 4 patients. 2/19 did not complete treatment with chemotherapy due to mucositis but did with radiotherapy. No relationship was found between clinical response and the severity of the rash. One patient developed leukopenia g/III. 4 patients developed disphagia g/II, one has not resolved after 8 month follow up. Xerostomia g/II was 7/19 patients. Dermatological toxicity resolved by the end of the treatment. Mean follow up: 6 months, 1 patient which did not respond died and 1 patient with a PR recurred. Conclusions: The scheme is safe and effective with tolerable toxicity. In our previously reported experience, the addition of cetuximab to gemcitabine and radiotherapy does not increment local toxicity, statistical validation of these findings require the completion of the 40 patient study.

No significant financial relationships to disclose.
The effect of induction therapy with carboplatin-paclitaxel and low dose radiotherapy followed by hyperfractionated radiotherapy and intraarterial chemotherapy on advanced cancers of the head and neck
Authors: Warren G. W. , Arnold S. M. , Curtis G. , Valentino J. , Brill Y. , Regine W. F. , Spring P. M. , Mohiuddin M. , St. Clair W. H. , Kudrimoti M. R.
Published: March 2020

15517

Background: The purpose of this study is to evaluate the potential benefits of induction therapy followed by intraarterial cisplatin and hyperfractionated radiation (HYPERRADPLAT) on patients with advanced head and neck tumors. Methods: 20 patients with Stage III-IV squamous cell carcinoma of the head and neck were treated with induction therapy consisting of 2 cycles of carboplatin (AUC 6) and paclitaxel (225 mg/m2) and 0.8 Gy BID on the day of and the day following chemotherapy. Induction therapy was given over 2 cycles separated by 3 weeks (previously described in ASCO 2002 abstract # 921 and 2004 abstract # 5593). Patients were then treated with the HYPERRADPLAT regimen consisting of external beam radiotherapy (74.4–81.6 Gy) delivered in 1.2 Gy BID fractions with intraarterial cisplatin (150 mg/m2) administered when patients had reached 60 Gy. Tumor response, disease free survival, overall survival, and toxicity were assessed for all patients according to NCI CTCAE criteria. Results: Of 20 patients, 9 had tumors of the oropharynx, 9-supralaryngeal, and 2-hypopharyngeal. Fifty percent of patients had T4 tumors and 35% had T3 tumors. Complete tumor response was observed in 80% of patients and 20% had a partial response. Three-year disease free survival was 75% and overall survival was 75%. Locoregional recurrence was noted in 25% of patients and 15% had distant failure. Overall recurrence was noted in 40% of patients with a median time to recurrence of 12 months (range 6–55 months). Median weight loss during treatment was 10% of initial body weight and 13 patients required a feeding tube within 6 months of starting treatment. Grade 3 mucositis was noted in 65% of patients and no patients developed Grade 4 toxicity. Conclusions: Two cycles of carboplatin-paclitaxel induction therapy followed by intraarterial cisplatin and hyperfractionated radiotherapy produces excellent tumor response and reduces distant failure. These results compare favorably with historical controls and produce tolerable toxicity profiles.

[Table: see text]
Tumour thickness as a predictor of neck node metastasis at presentation in early T stage squamous cell carcinoma of oral tongue
Authors: Jamshed A. , Hussain R. , Azam M. , Hameed S. , Shah M. A. , Bilal M. , Khurram S. , Faruqui Z.
Published: March 2020

15518

Background: Pakistan has one of the highest incidence of oral cancer in the world. Twenty to thirty percent of the patients have occult neck nodal metastasis at presentation. Elective treatment of neck in early T stage tongue cancer is controversial. The study was conducted to determine the risk of neck node metastasis in patients with T1 or T2 carcinoma tongue on the basis of pathological tumour thickness. Methods: The study group consisted of 20 patients with early T stage carcinoma oral tongue treated at Shaukat Khanum Memorial Hospital and Research Centre between December 2003 - October 2005. There were 10 males and 10 female patients. The median age for the group was 54 years. All patients underwent partial glossectomy with modified neck dissection. Histopathological reports were analysed to stage the patients according to AJCC 2002 system. The glossectomy specimen were serially sectioned to determine histological thickness. Nine patients (45%) had pT1 and 11 patients (55%) had pT2 disease. Patients were divided in to three groups based on tumour thickness; Group I (tumor < or = 3 mm), Group II (> 3 mm but < or = 9 mm) and Group III (> 9 mm). Results: In patients with pT1 lesions there were 2, 3 and 4 patients in group I, II and III respectively. Pathological neck nodal metastasis were seen in 0/2 patients in group I, 1/3 patients in group II and 1/4 in group III. With pT2 lesions there were 0, 4 and 7 patients in group I, II and III respectively. Neck nodal metastasis were found in 3/4 and 3/7 in group II and III patients. The risk of neck node metastasis in patients with tumor thickness more than 3 mm was 28% (2/7 patients) for pT1 patients and 55% (6/11 patients) for patients with pT2 disease. Conclusions: Tumor thickness more than 3 mm in patients with early T stage squamous cell carcinoma oral tongue carries a high risk of neck nodal metastasis. Elective neck treatment should be considered for this group of patients.

No significant financial relationships to disclose.
Phase II study of concurrent chemoradiation with gemcitabine (GEM) in locally advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary result
Authors: Sirisinha T. , Sirilertrakul S. , Kraiphibul P. , Dangprasert S. , Sirachainanm E. , Ativitavas T. , Ratanatarathorn V.
Published: March 2020

15519

Background: Concurrent chemoradiation is effective in the treatment of unresectable SCCHN. Cisplatin is the most frequently used agent but has significant toxicity and also requires hospitalization for hydration. Due to above limiting factors and the known radiosensitization effect of GEM, this study was initiated to evaluate the feasibility, safety and antitumor activity of low dose GEM concomitant with radiation (RT) in locally advanced (LA) SCCHN. Methods: Patients (pts) with LA SCCHN with no prior radiotherapy, adequate organ function and signed informed consent were eligible. RT was given at 65–70 Gy over 6.5–7 weeks concurrently with 7 weekly GEM at 4 dose levels (30 mg/m2, 50 mg/m2, 60 mg/m2 or 75 mg/m2) before RT. Results: Between 11/01–12/05, 26 pts (22 men, 4 women) were enrolled; median age 55 (range 33–77); 24 with primary tumors and 2 with recurrent disease following prior resection; stage III/IV: 5/19; T2–3/T4: 18/7; N 0–1/ 2–3: 9/17 and ECOG 0–1/2: 23/3. Four pts received GEM at 30 mg/m2, 3, 4 and 15 pts received 50, 60 and 75 mg/m2, respectively, with a median of 6 GEM doses (range 3–7) and a median RT of 70 Gy (range 45–75). Two pts who are currently receiving chemoradiation and one patient who died during chemoradiation from COPD exacerbation were not included in the analysis. Grade 3/4 acute toxicity were: mucositis 13/3, acute dermatitis 1/0, fatigue 1/1, neutropenia 1/0 and anemia requiring transfusion or erythropoietin use in 5 pts, 17 pts required enteral feeding during the treatment and median weight loss was 3.5 kg. RT was interrupted briefly in 12 pts, mostly due to grade 3/4 mucositis but treatment was completed in 87%. Nineteen pts (83%) responded (9CR, 10PR) with 3SD and 1PD. Eleven pts have relapsed or progressed. With the median F/U time of 16 months (range 2–31), the median overall survival was 28.3 months (95% CI 16.3, 40.2). Conclusions: Concurrent chemoradiation with GEM is feasible and effective with moderate but manageable treatment-related toxicity.

No significant financial relationships to disclose.
Neoadjuvant paclitaxel plus carboplatin followed by concomitant radiochemotherapy in stage IVb nasopharyngeal carcinoma: Preliminary results
Authors: Jouhadi H. , Tawfiq N. , Sahraoui S. , Benider A.
Published: March 2020

15521

Background: Nasopharyngeal cancer Is the first head and neck cancer in Morocco. undifferentiated carcinoma (WHO 3)is dominant. Loco regional advanced stages IVa and IVb (AJCC/UICC 1997) represents 60 to 78%. Classical treatment is neoadjuvant chemotherapy (3 courses of BEP protocol) followed by radiotherapy. Therapeutic results are characterised by a high rate of failure. For stage IVb failure is due to distant metastasis wich occur in 30 to 40% of cases needing more systemic therapy. The aim of this prospective study is to analyse for stage IVb the benefit of introducing paclitaxel associated to carboplatin as a neoadjuvante chemotherapy followed by chemoradiation in terms of reducing distant metastasis and improving local control. Tolerance of this protocol was also analysed. Methods: Between September 2003 and January 2004, a total of 33 previously untreated, histologically confirmed NPC adults, were enrolled in this study. The new protocol is based on 1-Four courses of neoadjuvant chemotherapy (1 course = paclitaxel: 175 mg/m2 day 1 + carboplatin: 300 mg/m2 day 1; 1 course every 21 days) 2-followed by a concomitant radiochemotherapy: -radiotherapy to a total dose of 65 gray -and low dose of cisplatine (30 mg/m2) delivered on a weekly schedule. Eligibility criteria were: histologically confirmed NPC, stage IVb, no prior treatment, and informed consent of patients. There were 21 male and 12 female patients and their ages ranged from 19 to 58 years. Results: The minimal follow up was 2 years. The 2 year DFS was 85% and the 2 year loco regional free survival was 91%. All patients completed radiotherapy. Neutropenia grade III-IV was observed in 6% without fever. According to NCI toxicity criteria, acute mucositis (due to radiation) grade 3 was observed in 15% and grade 2 in 24%. Xerostomia grade 1 was observed in 70%. Conclusion: This protocol is very effective with less toxicity. Radiation dose is reduced without decreasing local control rate. The 2 years DFS is increased with this protocol to 85%.

No significant financial relationships to disclose.
Nutritional and environmental risk factors of nasopharyngeal carcinoma in Morocco
Authors: Bouras N. , Tahri A. , Ammor S. , Baali A. , Tahiri F.
Published: March 2020

15535

Background: The nasopharyngeal carcinoma (NPC) has a high incidence in north Africa and in southeast Asia. The goal of this study is to analyze the implication of nutritional and environmental factors in the raise of this cancer. Methods: It is a retrospective investigation with 274 affected by the NPC and 394 witnesses. Results: The nasopharyngeal carcinoma affects mens more then womens with a sex ratio of 1.8. We observed a peak between 20 and 29 years with the women and between 40 and 49 years with the men. We noted also a high frequency of the young population touched by this disease: 10.5% less than 20 years old, which was also observed in Tunisia, Algeria and Sudan while the young patients are rarerly affected in the Asian southeast. The patients have mostly rural origin with agricultural parents, having lived during their childhood in precarious habitat and hygiene conditions and with an instruction level generally low, often without function or exercising in the primary or secondary sector. The study of nutritional and environmental risk factors showed a statistically meaningful relation between this cancer and some factors bound to the food: consumption of pickle, of smen (butter fermented), and to the environment: life in agricultural environment, practice of the farm, absence of drinkable water and contact with toxic substances. Conclusions: It seems that the exposition to environmental risk factors could increase the risk to contract this cancer, especially with the already exposed persons to nutritional risk factors. We observed a territorial variability of the exposition to the NPC risk factors that explains the gradient south north of the incidence of this cancer in Morocco. The results of this study show the complexity of factors being able to take to a cancerogenesis.

No significant financial relationships to disclose.
Safety and tolerance of multiple weekly intracavitary injections of 131I-chlorotoxin (TM-601): Preliminary results of a prospective clinical trial in patients with recurrent glioblastoma multiforme
Authors: Fiveash J. B. , Nabors L. B. , Mamelak A. N. , Avgeropoulos N. G. , Guthrie B. L. , Salomon N. W. , Portnow J. , Bucholz R. D.
Published: March 2020

1555

Background: 131I-chlorotoxin is a peptide originally derived from scorpion venom that will specifically bind to tumor cells targeting lamellipodia and produces a variety of secondary messenger effects through phosphatidyl inositol signaling. Preclinical studies suggest it is both a radiation and chemotherapy sensitizer. A previous phase I/II clinical trial defined the distribution and dosimetry of single injection intracavitary 131I-chlorotoxin and suggested clinical activity in patients with recurrent glioma. Methods: 15 patients with recurrent GBM after prior treatment (radiation therapy), were enrolled in this sequential, multiple-dose escalation study with re-resection and implantation of a ventricular access device (VAD) into the resection cavity. Dose limiting toxicity was defined as any grade 3 or greater toxicity judged probably related to study drug and occurring within 7–11 days of the last dose. Dosing cohorts of 3–5 patients were entered at each of the listed dose levels designed to maintain a constant drug specific activity. Results: One subject did not complete treatment due to thrombocytopenia possibly related to a VAD infection necessitating removal of the VAD following the initial dose of study drug. Eight serious adverse events (SAEs) were observed in 15 patients after study drug administration. These included seizure, cerebral edema, and gait disturbances. None were judged to be both unexpected and related to study drug. No dose limiting toxicity was observed. Two subjects experienced Grade 1/2 CTC 3.0 neutropenia. Conclusions: The safety profile of weekly intracavitary injections of 131I-chlorotoxin was acceptable. Dose limiting toxicity was not reached at the final planned dose level D (6 x 40 mCi/0.8 mg peptide, total 240 mCi), which is the maximum practical dose. Accrual to the randomized phase II portion of this trial comparing three vs. six weekly injections began 12/2005.

[Table: see text]

[Table: see text]
A stratified phase II study of cetuximab for the treatment of recurrent glioblastoma multiforme: Preliminary results
Authors: Sadones J. , Chaskis C. , Joosens E. J. , Dhondt L. A. , Baurain J. , In ’t Veld P. , Michotte A. , De Grève J. , Neyns B.
Published: March 2020

1558

Background: The Epidermal Growth Factor Receptor (EGFR) gene is frequently amplified and mutated in high-grade gliomas. We are investigating the activity of the EGFR-targeted monoclonal antibody cetuximab for the treatment of patients (pts) with recurrent glioblastoma multiforme (GBM) following surgery, radiotherapy and chemotherapy. Methods: Adult pts with recurrent GBM are allocated to two parallel treatment strata according to the amplification status of the EGFR gene (determined by FISH). According to a Simon two-stage phase II study design 1 response in 13 pts/stratum is required to continue recruitment and complete the second stage of pt recruitment. Cetuximab is administered at 400 mg/m2 (2 hour infusion) day 1 and 250 mg/m2 day 8 and for all subsequent weekly doses (1 hour infusion). Results: Between May and December 2005, 17 pts were recruited (10 without EGFR-ampl, 4 with EGFR-ampl and 3 under investigation); 4F/13M; median age 51 years, range 32–67). Recruitment is ongoing. Sixteen pts initiated study treatment; 1 pt withdrew consent before the initiation of therapy. Treatment related toxicity in the first 94 treatment cycles consisted of grade 1/2 folliculitis/dermitis in all treated pts. Grade 3 adverse events consisted of thrombocytopenia (n=1 pt), diminished consciousness (n=1 pt), dizziness/confusion (n=1 pt), infectious bronchopneumonia (n=1 pt), and infectious cellulitis (n=1 pt). Thirteen pts have been evaluated for response ≤ week 8 of study treatment. Eleven pts had progression of disease. Two patients had SD at 8 weeks (follow-up is ongoing). Conclusions: These preliminary data suggest that cetuximab can be safely administered to pretreated patients with recurrent GBM. Updated results regarding safety and activity as well as a correlative study of EGFR and PTEN expression and gene copy number of the GBM and response to cetuximab will be presented at the meeting.

No significant financial relationships to disclose.
Protracted administration of low doses of temozolomide (TMZ) in the treatment of relapse glioblastoma (GBM) enhances the antitumor activity of this agent
Authors: D’Amico A. , Gabbani M. , Dall’oglio S. , Cristofori L. , Turazzi S. , Sanzone E. , Maluta S.
Published: March 2020

1572

Background: The efficacy of temozolomide (TMZ) is strictly related to the possibility to reach and maintain high and prolonged cellular drug concentrations in the target tissue. Evidence exists demonstrating that the achievement of this goal and the subsequent activity of TMZ are categorically schedule dependent. Aim of the present randomized phase II study is to verify whether a treatment schedule with TMZ appropriately modified induces better response rates along with a decrease of mielotoxicity as compared to the conventional one. Methods: Twenty patients (5 F/15 M), median age of 53 years (range 35–74), median Karnofsky PS 90 (range 70–100), with GBM in progression after surgery and adjuvant RT have been treated as follows: Schedule A - TMZ for 5 days in a 28-day cycle, at the dose of 150 mg/m2/d at the first cycle and of 200 mg/m2/d thereafter, up to a total of 8 cycles. Schedule B - TMZ for 7 days alternating with 7 days of rest up to a total of 12 cycles: the starting dose of TMZ at the first cycle was 50 mg/m2/d with progressive serial dose escalations of 25 mg/m2/d in the subsequent ones until the achievement of the dose of 150 mg/m2/d at the 5th cycle, and then keeping this regimen until the 12th cycle. Results: They are summarized in the table : Severe thrombocytopenia and stomatitis have been observed only in patients treated with Schedule A. Conclusions: These preliminary results, which deserve to be confirmed in a larger sample size, indicate that the treatment with TMZ on alternate week basis is strongly interesting and promising. In spite of the modality and the small number of patients included in this study, which doesn’t allow a direct comparison between two different treatments, it should be noted that schedule B achieved a 2-year OS and PFS rate of 40% and 20% respectively, compared to 10% and 0% of schedule A.

[Table: see text]

No significant financial relationships to disclose.
MGMT expression correlates with response rate and survival in patients with inoperable glioblastoma (GBM) treated with neoadjuvant temozolomide (TMZ)
Authors: Barrie M. , Eudes N. , Metellus P. , Fuentes S. , Honore S. , Boucard C. , Dufour H. , Figarella-Branger D. , Chinot O.
Published: March 2020

1574

Background: Methylation of the promotor of O6-alkylguanine alkyltransferase (MGMT), a DNA repair gene, may enhance chemosensitivity to alkylating agents. In GBM, this methylation has been correlated to survival as well as to the benefit of adding TMZ concomitant and adjuvant to radiotherapy (RT) (Hegi, NEJM, 2005). We examine the relationship between MGMT expression and objective response rate to dose intense TMZ schedule administered as neoadjuvant treatment before RT in inoperable GBM, as previously presented (Chinot, ASCO, 2005). Methods: Thirty patients were included in this phase II trial that tested TMZ (150 mg/m2/day) on days 1 to 7 and 15 to 21 of each 28 days cycle for up to 4 cycles prior to RT. We analysed retrospectively MGMT expression by immunochemistry (streptavidin-peroxydase) after antigen retrieval using anti-MGMT antibody (Abcys, 1/100) in 25 formalin-fixed paraffin embedded samples from the study population. Results: In the eligible population (n = 28) response rates (RR) were of 25% (95% CI, 8.63% to 41.37%); SD 32%; PD 43%. Median progression free survival (PFS) and overall survival (OS) were 3.8 and 5.8 months, respectively. MGMT expression was analysed in 25 pts while material was considered as inadequate in 3 pts because of insufficient tumor material. The median percentage of cells that expressed MGMT in tumor nuclei was 35% and so was chosen as cut-off. Low MGMT expression was significantly associated with a high RR (55%) while tumor that exhibit high MGMT expression was associated to a RR of 9% (chi-2 p=0.004). MGMT was also strongly correlated to PFS (log rank p=0.009) and OS (log rank p=0.003). Conclusion: Despite limited number of patients, our study strongly supports the predictive value of MGMT expression for objective response to TMZ in addition to its prognostic value for PFS and OS in GBM. If confirmed in prospective study, MGMT expression may help to guide therapeutic decisions as well as more targeted trial design.

[Table: see text]

No significant financial relationships to disclose.
Prolonged gemcitabine infusion as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM): A phase I study
Authors: Carapella C. M. , Mirri A. M. , Felici A. , Vidiri A. , Pace A. , Carosi M. A. , Occhipinti E. M. , Arcangeli G. , Cognetti F. , Fabi A.
Published: March 2020

1581

Background: The use of cytotoxic drugs concurrent with RT represents a promising approach in the combined treatment of malignant gliomas. Gemcitabine (dFdCyd) is a drug widely explored for its potential radiomimetic activity in different tumors. The present study was aimed to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of weekly prolonged dFdCyd infusion, administered in combination with RT as first line treatment, in adult pts affected by supratentorial GBM. Methods: Within 6 weeks after surgery, in the presence of measurable residual disease and KPS >70, pts were treated with fractionated RT at a dose of 2.0 Gy/daily fractions, 5 days a week (global dose 60 Gy). From 24 to 72 hours before the first RT application, and afterwards once weekly, pts received concurrent dFdCyd, at fixed dose rate of 10 mg/m2/min, over a total period of six weeks. Planned dose levels of dFdCyd started from 200 mg/m2/weekly (level 1), with sequential steps of 25 mg/m2/w based on toxicity. Results: Ten pts were enrolled into the study: six were male, median age 55.2 years (range 44–75), with a median KPS at baseline of 85 (SD 9.71). The median time from diagnosis to the start of treatment was six weeks (range 4–7). The median RT duration was 6 weeks (range 4–7), all but one pt received the planned dose and all pts received concomitant CT. Four pts entered at Level 1; one pt was excluded from the study, due to rapid progressive disease during the treatment. Two of the three valuable pts presented a relevant neurological worsening; on this basis the dFdCyd dose was reduced to 175 mg/m2/w (Level -1). A total of six pts were entered at Level -1, and none of them reported DLT. No hematological grade 3–4 toxicity was reported. Grade 3 non-hematological toxicity was observed in one pt (transaminases increase). After a median follow-up of 13.4 months (range 3–24), the median progression-free survival was 8 months (CI 95% 1–18), and the median overall survival was 14 months (CI 95% 12–17). Conclusions: The recommended dose of prolonged infusion of dFdCyd concomitant with RT is 175 mg/m2/w. The observed activity has been considered interesting enough to support a phase II study of this concurrent CT-RT schedule as first line treatment in GBM.

[Table: see text]
The ERB family receptor dimerization in glioblastoma—An eTag assay analysis of 23 cases
Authors: Hameed M. R. , Sharer L. , Cho E. , Aisner S. , Cao L. , Tan Y. , Mukherjee A. , Chenna A. , Singh S. , Petropoulos C.
Published: March 2020

1582

Background: Glioblastoma is the most malignant astrocytic tumor and accounts for about 50–60% of all astrocytic neoplasms. Despite intensive radiation and chemotherapy, less than 2% of patients survive more than 3 years. The Erb family of signaling molecules are transmembrane receptors with intrinsic kinase activity (except ErbB3) capable of modifying tyrosine residues on the receptor itself as well as on downstream signaling molecules. Under physiological conditions a variety of ligands interact and act as driving forces in the formation of homo and heterodimeric complexes between the four receptors leading to signal amplification and downstream activities. More than one third of glioblastoma cases show gene amplification of epidermal growth factor receptor (EGFR) which can be in truncated or rearranged form. The eTag assay system (Monogram) is an antibody based fluorescent assay that has the potential to assess the activation state of the EGFR signaling pathway. Methods: Twenty three cases of glioblastoma were selected for eTag analysis. There were twelve males and eleven females with ages ranging from 20–84 years. After reviewing the histology, 10 micron sections were cut from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Specific monoclonal antibodies of the Erb family bound to a fluorescent reporter (eTag) were applied to tissue sections. After binding of specific analyte, a second monoclonal antibody is added which acts as molecular scissors resulting in cleavage of “eTags”. The released eTag molecules are separated by capillary electrophoresis and measured as relative fluorescent units. Various FFPE tumor cell lines were used as controls. Results: Nineteen out of twenty three tumors (82%) showed the presence of dimers of the Erb family signaling pathway. High levels of intra and /or extracellular EGFR homodimers (HER-1-HER-1) were detected in eight samples (35%). EGFR-HER-3 dimers and EGFR-HER-2 dimers were seen at high levels in four and six samples (17% and 26% respectively). High levels of HER-2-HER3 dimers were detected in six samples (26%). Conclusion: The EGFR signaling pathway plays a substantial role in tumorigenesis of glioblastoma. Identification of receptor homo and heterodimers may be of value during treatment planning of individual patients.

No significant financial relationships to disclose.
Palliative chemotherapy preferences and factors that influence patient choice in advanced cancer
Authors: Kim M. , Lee K. , Hyun M. , Do Y. , Song H. , Kim J. , Baek J. , Bae S. , Ryoo H. , Park K.
Published: March 2020

16010

Background: We conducted this prospective study to determine the treatment preference of patients receiving chemotherapy in a palliative setting. We investigated the survival threshold for justifying toxicity, the factors influencing individual preference for chemotherapy, and the attitude of patients towards randomized trials. Methods: 138 patients (median age, 58 years; 73% male) with advanced cancer who had received at least one cycle of palliative chemotherapy were recruited. General demographic information, patient preferences for palliative chemotherapy, and randomized trials were determined using structured patient interviews. Results: The median age was 58 years (range, 25–77 years), and the majority of the study population were male (73%). 73 patients (60.1%) answered that they had some support by dependents. Fewer than half were given information about the impact of their chemotherapy on survival (n = 64, 48.1%), and just over one third of patients (n = 53, 40.5%) were presented with an alternative to anticancer therapy, such as supportive care (p < 0.001). While 75.7% of patients agreed to receive chemotherapy with mild toxicity, only 57.9% of patients agreed to chemotherapy with severe toxicity (p = 0.002). The median survival threshold was 12 months for mild toxicity, and 21 months for severe toxicity. Patients who experienced improvement of symptoms or quality of life were more likely to judge the treatment as acceptable. 105 patients (78.4%) refused a clinical trial with randomization between a conventional chemotherapy and supportive care. There were 85 patients (62.6%) that would refuse randomization between conventional chemotherapy and investigational chemotherapy. Finally, 58.6% of patients agreed to participate in trials with investigational agents. Conclusions: In the palliative setting, a discussion of prognosis and the merits of chemotherapy is a necessary part of the treatment decision-making processes, and choosing the proper treatment for cancer patients. Individual preferences assume greater importance in this setting. Randomized trials must be carefully designed with a priori equipoise.

No significant financial relationships to disclose.
A comparison of hematology/oncology clinic attendance between insured and under-insured patients at an urban academic hospital: Identifying barriers and ways to overcome them
Authors: Youssef J. A. , Lyckholm L. J. , Smith T. J. , Shickle L. M. , Matsuyama R. K. , Parker G. L.
Published: March 2020

16015

Background: There are persistent disparities in cancer outcomes based on non-clinical factors such as race, socioeconomic status, and access to care. Successful treatment outcomes in oncology and symptom control depend heavily on patient compliance. To improve patient attendance at oncology appointments, the reasons why patients miss appointments must be understood, and then interventions must be enacted to rectify the problem. Methods: At the hematology/oncology clinics of Virginia Commonwealth University, the fellows’ clinic consists of patients that are primarily uninsured or underinsured, and the faculty clinic consists of patients that are primarily well-insured. On Mondays and Fridays from January 31–June 30, 2005, attendance of scheduled patients was recorded. Patients were then called and asked why they did not attend their appointments. Also, the patient’s sex, age, race, diagnosis, and insurance status were recorded. Results: Of the 1705 appointments scheduled in the predominantly under-insured fellows’ clinic, 223 (13.1%) of these were no shows. Of the 1614 appointments scheduled in the better-insured faculty clinic, 115 (7.1%) of these were no-shows (p < .0001). Of African-American patients in both clinics, 30.9% did not attend their appointments as compared to 19.4% of Caucasian patients (p = .0003). The no-show rate among women was 22.4% as compared to 28.6% for men in both clinics (p = .025). Of all patients under age 50, 30.1% did not show up as compared with 22.4% of all patients aged 50 or higher (p = .009). Chi-square was used to test for significance. Among both clinics, the reasons for missing appointments included: the patient did not know of the appointment (35), patient illness (24), transportation difficulties (12), family emergency (7), forgot (7), and weather (2). Conclusions: In this study, appointment knowledge and patient illness affect oncology clinic attendance most. It is our goal to implement measures, such as appointment reminders and transportation assistance, and then reassess attendance rates.

No significant financial relationships to disclose.
Epidemiological data of cancer of the only cancer center of the western Black Sea region of Turkey
Authors: Engin H. , Ozdamar S. , Gun B. , Bahadir B. , Kertis G. , Numanoglu G. , Ustundag Y. , Kuzey G.
Published: March 2020

16041

Background: 600 patients diagnosed as having cancer between years 2000–2005 at Zonguldak Karaelmas University were evaluated. Methods: All information pertaining to patient characteristics were retrieved from files of the Pathology and Medical Oncology Departments. Results: 383 (63,83%) were male and 217 (36,17%) were female. The most common malignancies among males are; prostate cancer 21,40 %, stomach cancer 14,62%, tumors of the bronchi and the lungs 12,10%, colorectal cancers 10,70%, skin tumors (non-melanoma 8,90%, melanoma 1,30%), malignancies of the lymphatic and hematopoietic system 7,83%, bladder cancer 6,52%, metastasis of unknown origin 3,40%, laryngeal cancer 2,61%, tumors of the hepatobiliary system 2,61%, brain tumors 2,00%, tumors of the bone and soft tissues 1,82%, tumors of the oral cavity and pharynx 1,31%, esophagus cancers 1,04%, thyroid cancers 1,04%, testicular cancers 0,52%, renal tumors 0,26%, tumors of the small intestine 0,26%. The most common malignancies among females are: breast cancer 22,11%, skin tumors (non-melanoma 15,60%, melanoma 0,92%), colorectal cancers 12,37%, stomach cancers 8,29%, malignancies of the lymphatic and hematopoietic system 5,99%, endometrial cancers 5,52%, ovarian cancers 3,22%, thyroid cancers 5,06%, metastatic tumors of unknown origin 4,14%, brain tumors 3,22%, tumors of the hepatobiliary system 2,76%, tumors of the bronchi and the lungs 2,30%, tumors of the bones and soft tissues 2,30%, esophagus cancers 1,38%, tumors of the oral cavity and pharynx 0.92%, tumors of the cervix uteri, vulva and vagina 0,50%, renal tumors 0,46% and tumors of the small intestine 0,46%. Conclusions: Although Turkish Health Department data demonstrates that the tumors of the bronchi and the lungs are the most common malignancies in the general Turkish population, prostate cancer was found to be the most common malignancy among our patient population. Additionally, colorectal tumors were also found to be more prevalent in our patient population than in the general Turkish population. Breast cancer was the most common malignancy among female patients in our patient population, as it is in general. While stomach and colorectal tumors among women were more prevalent than in the general population, gynecological tumors were rare.

No significant financial relationships to disclose.
Predictors of autologous stem cell transplant related mortality in older adults
Authors: Klepin H. D. , Harish V. , Lovato J. , Keung Y. , Owen J. , Hurd D.
Published: March 2020

16509

Background: Autologous stem cell transplantation (ASCT) is increasingly performed in older adults. Predictors of transplant related mortality (TRM) are not well established in this population. Our objective was to identify characteristics associated with TRM in older adults treated with ASCT. Methods: A retrospective chart review was conducted to identify all patients ≥ 60 years of age treated with ASCT at our institution between July 1990 and July 2005. We used logistic regression to investigate the effect of baseline characteristics and of transplant complications on TRM. Results: 143 patients met eligibility criteria of whom 139 were evaluable for the 100 day mortality outcome. The median age was 64.5 (range 60–76.6) years, 34% were female. Primary diagnoses included non-Hodgkin’s lymphoma (55%), multiple myeloma (29%), acute myelogenous leukemia (8%), breast cancer (5%), and Hodgkin’s lymphoma (3%). 100 day TRM was 7.9%. The mean time to engraftment (absolute neutrophil count >1000) was 12.2 ± 5.5 days. Complications included bacteremia (26.3%), cardiac events (myocardial infarction, congestive heart failure or arrhythmia) (11.5%), renal failure (7.4%), and respiratory failure (6.7%). Multivariate analysis including age, sex, diagnosis, number of comorbidities, number of medications, congestive heart failure, coronary artery disease, diabetes mellitus, hemoglobin, and creatinine at the time of transplant did not identify any baseline predictors of 100 day TRM (p > .05 for all). Development of renal failure or respiratory failure during transplantation was associated with increased TRM with an odds ratio of 11.2 (CI 2.5, 49.2) and 13.6 (CI 3.0, 62.2) respectively. Peritransplant cardiac events or bacteremia were not associated with increased TRM. Conclusions: Development of renal failure or respiratory failure is associated with increased TRM in this study. However, age and baseline comorbidities are not predictive of TRM. Future prospective studies should incorporate specific measures of functional and cognitive status which may be more reflective of decreased physiologic reserve in older adults being considered for ASCT.

No significant financial relationships to disclose.
Novel tyrosine kinase inhibitor therapy (NTKI) prior to allogeneic stem cell transplantation (ASCT) in patients (pts) with chronic myeloid leukemia (CML): No evidence for increased transplant-related toxicity
Authors: De Lima M. J. , Jabbour E. , Cortes J. E. , Kantarjian H. , Giralt S. , Andersson B. S. , Champlin R. E.
Published: March 2020

16515

Background: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 8 patients with CML (1 chronic, 4 accelerated, and 3 in blastic) who received dasatinib (n = 2) or AMN-107 (n = 6) prior to ASCT. Results: The median time on treatment was 85 days, and the median time from the end of NTKI therapy to HSCT was 37 days. Preparative regimen was ablative in 5 patients and non-ablative in 3. All patients engrafted within 13 days. There was no significant early transplant-related toxicity. Five patients achieved a molecular response after a median follow-up of 8 months; three complete and two major (Q-PCR < 0.05%). Three patients relapsed within 3 months. Two patients died of disease progression, and extensive GVHD, respectively. Conclusions: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations.

No significant financial relationships to disclose.