bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of a phase II trial of h-R3 monoclonal antibody (nimotuzumab) in the treatment of resistant or relapsed high-grade gliomas in children and adolescents
Authors: Bode U. , Buchen S. , Janssen G. , Reinhard T. , Warmuth-Metz M. , Bach F. , Fleischhack G.
Published: March 2020

1522

Background: Children and adolescents suffering from high grade gliomas (HGG) have a poor prognosis when they relapse during or after primary treatment. Thus novel therapeutic approaches as the inhibition of growth-signalling pathways are needed. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (Nimotuzumab) in the treatment of these patients. Methods: Pediatric patients with glioblastoma multiforme, anaplastic astrocytoma or intrinsic pontine glioma (PG) with radiologically proven progressive disease following primary or relapse treatment were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 Nimotuzumab for six weeks, and in case of non-PD a subsequent consolidation therapy of four infusions in a three week interval. The response was documented by MRI in week 8 and 21. Results: Between June 2004 and August 2005 34 patients aged 5.0 to 17.4 years (median 10.9 years) were enrolled in this study. According to RECIST 12 out of 34 patients showed response (PR n=1, SD n=11) in the MRI of week 8 after the induction therapy with a median change in the largest diameter of the index lesion of −5% (−39 to +16%) accompanied by clinical deterioration in four and markedly clinical improvement in two patients. Surprisingly, 9 PR/SD were seen in the 14 patients with PG. Eight patients continued with the consolidation therapy. So far 5 out of 8 Patients are evaluable for response after consolidation therapy and showed three PR, one SD and one PD in week 21. Eight patients with consolidation therapy are free of progression for a median of 7.5 months (1.2–13.2 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of Nimotuzumab is well tolerated and safe. It has cytotoxic efficacy in heavily pre-treated relapsed HGG, especially in intrinsic pontine glioma. A phase III study for patients with newly diagnosed PG is warranted.

[Table: see text]
A randomized phase III/IV study to determine benefit and safety of cytarabine liposome injection for treatment of neoplastic meningitis
Authors: Shapiro W. R. , Schmid M. , Glantz M. , Miller J. J.
Published: March 2020

1528

Background: Cytarabine liposome injection (CLI) maintains cytotoxic concentrations in the cerebral spinal fluid (CSF) for >14 days with a single 50 mg dose. This study compared patient benefit and safety of intrathecal CLI with methotrexate (MTX) or nonliposomal cytarabine (Cyt) against solid tumor neoplastic meningitis (STNM) and lymphomatous neoplastic meningitis (LNM), respectively. Methods: This multicenter, randomized, open-label, active-controlled study was powered to detect a 50% hazard ratio for progression-free survival (PFS; i.e., days from randomization to neurological progression or death) in STNM patients. STNM patients (n=103) were randomized to CLI or MTX and LNM patients (n=25) to CLI or Cyt. Patients had either histologically documented STNM or LNM confirmed by ventricular or lumbar CSF cytology or symptomatic meningeal tumor verified by magnetic resonance imaging or computed tomography. CLI treatment consisted of 6 Induction Cycles (2 weeks per cycle) and 4 Maintenance Cycles (4 weeks per cycle). Results: By per-protocol Cox regression analysis, CLI (STNM and LNM combined) was noninferior to MTX and Cyt combined (Control Group). The median PFS was 35 days and 43 days (p=0.7321), respectively; the hazard ratio (95% CI) was 0.98 (0.65, 1.46). CLI was also noninferior to MTX in the STNM group, where the hazard ratio was 0.94 (0.58; 1.53). In the LNM group, superiority of CLI over Cyt was demonstrated a hazard ratio of 0.12 (0.02, 0.77). Median PFS was 34 and 50 days, respectively. More LNM patients had complete response (clearance of tumor cells from CSF) with CLI (33.3%) than with Cyt (16.7%; p=0.3640). All patients experienced AEs; 48% and 60% of the patients in CLI and Control Group, respectively, experienced drug-related AEs. The incidence of serious AEs was 86% and 77%, respectively. Conclusions: These results demonstrate at least comparable patient benefit between CLI and control treatments for STNM and improved benefit for CLI in LNM patients. Intrathecal CLI provides patients with the added convenience of bimonthly treatment.

[Table: see text]
FDG-PET versus Thallium-201 SPECT in the evaluation of putative CNS lymphoma in AIDS patients
Authors: Vidan E. , Kostakoglu L. , Coleman M. , Jillapalli D. , Philips S. M. , Leonard J. , Goldsmith S. J.
Published: March 2020

1537

Background: The evaluation of CNS lesions in AIDS patients is challenging as both CNS lymphoma and non-neoplastic lesions can have similar clinical presentations and imaging findings. Both Tl-201 SPECT and FDG PET imaging have been used to differentiate malignancy from infection. This study investigates the accuracy of FDG PET compared to Tl-201 SPECT in the diagnosis of CNS lymphoma in patients with AIDS-associated CNS lesions. Methods: Nine patients with AIDS who were found to have rim enhancing brain lesions on MRI underwent both Tl-201 SPECT and FDG PET imaging prior to diagnosis. Diagnosis was made by stereotactic brain biopsy in 6 pts and clinical follow-up in the remaining 3. FDG PET of the brain was performed using a dedicated PET/CT instrument (GE Discovery) 1 hour after 444 MBq FDG. Brain SPECT was performed on a dual head gamma camera (GE Hawkeye) with 185 MBq Tl-201. Images were reviewed along with MRI for anatomic correlation by 2 experienced nuclear medicine physicians blinded to the diagnosis. Results: 43 MRI lesions in 9 patients were evaluated. Clinically, 5 pts (18 lesions) were diagnosed with lymphoma (4 biopsy proven, 1 with known history of lymphoma), and 4 pts (25 lesions) were diagnosed with toxoplasmosis (2 with negative biopsies for malignancy, 2 with clinical course consistent with toxoplasmosis). FDG PET had true positive results for lymphoma in 5 of 5 pts, while Tl-201 SPECT was true positive in only 2 of 5. FDG PET had true negative results in 4 of 4 pts with toxoplasmosis, while Tl-201 had false positive results in 2 of 4. FDG PET had positive and negative predictive values of 100%, while Tl-201 SPECT had PPV 50% and NPV 40%. On a lesion basis, PET showed increased uptake of FDG in 8 of 18 brain lesions in patients with lymphoma, while SPECT showed increased uptake of Tl-201 in 4 of 18 lesions. Tl-201 was positive in 2 lesions in patients diagnosed with toxoplasmosis, while FDG had no false positive lesions. Conclusion: In this limited study, FDG PET proved to be superior to Tl-201 SPECT in the differentiation of CNS lymphoma from toxoplasmosis (overall accuracy 100% vs 44%, respectively). With the increasing availability of FDG PET, this test should probably supplant Tl-201 SPECT as the study of choice following conventional imaging (CT, MRI) of CNS lesions in AIDS patients.

No significant financial relationships to disclose.
Venous thromboembolism in 9,489 patients with glioma
Authors: Semrad T. J. , O’Donnell R. , Zhou H. , Wun T. , White R.
Published: March 2020

1538

Background: Venous thromboembolic events (VTE) are a commonly reported complication of brain tumors. The objective of this study was to define the incidence, risk factors, and outcomes associated with VTE in a population-based cohort. Methods: This was a retrospective analysis of all glioma cases diagnosed in California between 1993–1995 and 1997–1999. Glioma cases in the California Cancer Registry were linked to the California Patient Discharge Database to identify incident VTE. Cox models were generated to analyze the association of pre-specified risk factors with VTE or death within one year of the cancer diagnosis. Results: There were 9489 cases: 76% were Caucasians and 56% were men. The 1-year cumulative incidence of VTE was 663 (7%) with an incidence rate during the first year of 11.1 events per 100 person-years. Sixty-six percent of all VTE diagnosed in the first year occurred within 3 months of the cancer diagnosis with a corresponding incidence rate of 21.6 events per 100 person-years. Of 663 first year VTE, 405 (61%) occurred <2 months after an invasive neurosurgical procedure. Glioblastoma multiforme (GBM) was associated with an increased risk of VTE (HR=1.6, CI: 1.3–2.0) compared to other gliomas. The risk of VTE was strongly associated with the number of chronic co-morbidities (HR=4.0, CI: 3.1–5.0 for ≥3 chronic co-morbidities). Asian race was associated with significantly lower risk of VTE (HR=0.3, CI: 0.2–0.6) and female gender conferred a modestly lower risk (HR=0.8, CI: 0.7–0.9). A VTE in the first year was associated with slightly lower risk of death (HR = 0.8; CI: 0.8–0.9), whereas increasing age (HR=6.3, CI: 5.6–7.0 for age≥75), number of co-morbidities (HR=1.9, CI: 1.7–2.0 for ≥3 chronic co-morbidities), and GBM (HR=2.2, CI: 2.0–2.4) or anaplastic astrocytoma (HR=1.5, CI: 1.3–1.7) histology were associated with a higher risk of death within 1 year. Conclusions: In this large glioma cohort, the incidence of symptomatic VTE was very high. Two-thirds of all VTE occurred early after the diagnosis of glioma, and most of these occurred within 2 months of an invasive neurosurgical procedure. The presence of chronic medical co-morbidities and GBM histology were strong predictors of VTE. A diagnosis of VTE was not associated with an increased risk of death within 1 year.

No significant financial relationships to disclose.
Temozolomide (TMZ) and radiation (XRT) for brain metastasis of solid tumors
Authors: Addeo R. , Montella L. , Guarrasi R. , Dello Russo A. , Faiola V. , Del Prete S.
Published: March 2020

1543

Background: Whole Brain Radiotherapy (WBRT) remains the mainstay of therapy for brain metastasis of solid tumours not amenable to surgical resection. Temozolomide (TMZ) is a new orally administered imidazo-tetrazine with a mechanism of action and efficacy similar to dacarbazine (DTIC). It has been already used alone or in combination with radiotherapy in the treatment of primary brain tumours is currently used in the therapy of malignant glioblastomas also as single agent. Methods: Patients with solid cancers and recurrent or progressive brain metastases (BM) were eligible. We have treated 59 consecutive patients (32 F and 27 M, mean age: 56.2 ± 23.8 yrs; median age: 58.5 yrs) affected by brain metastases from different solid tumours (21 breast adenocarcinoma, 22 non small lung cancer, 16 other primitive cancers type) with WBRT at 3 Gy/day administered over a two-week period (on wks 1–2), total dose 30 Gy, and an induction with TMZ 75 mg/m2/day during this period, following TMZ 750mg/m2 fractionated in 5 days every 28 days, for up to 6 cycles. Pts who received at least one cycle of TMZ were assessable for response. Results: All patients were subjected to the induction therapy and 154 cycles were performed, mean cycles 3,7. Fifteen grade II and ten grade I neutropenia (CTC), 2 grade II hand and foot syndrome, seven grade I and four grade II thrombocytopenia and nine grade I alopecia were recorded. Fourteen grade I nausea and vomiting were observed, moreover, liver or renal toxicity were never recorded in our series being the schedule well tolerated in all patients. Five CR, in patients with breast cancer and NSCLC, and 21 PRs were recorded in 11 patients with breast tumours, 9 patients with NSCLC and 3 in other cancers, while a clinical benefit was achieved in other 18 patients. Seventeen still alive pts. (breast, NSCLC and colorectal cancer respectively), who achieved a PR and a SD, had an OS between 17 and 8 months, respectively. At the present, in our series, overall survival was 59% at 1 year. Patients continue to be followed to evaluate long term effects of the treatment. Conclusions: The schedule was safe and well tolerated (also in old pts.) and has suggested an encouraging activity in brain metastases from breast and lung cancer.

No significant financial relationships to disclose.
Validation of the M. D. Anderson symptom inventory (MDASI-BT)
Authors: Armstrong T. S. , Mendoza T. , Gning I. , Coco C. , Gilbert M. R. , Cleeland C. , Cohen M. Z. , Eriksen L.
Published: March 2020

1546

Background: The occurrence of symptoms has been shown to predict treatment course and survival in a number of solid tumor patients. Primary brain tumor patients are unique in the neurologic symptoms that occur. Currently, no instrument exists that measures both neurologic and cancer-related symptoms. Methods: Patients diagnosed with Primary Brain Tumors (PBT) participated in this study. Data collection tools included a patient completed demographic data sheet, an investigator completed clinician checklist, and the core M.D. Anderson Symptom Inventory to which 18 neurologic symptoms were added (M.D. Anderson Symptom Inventory-Brain Tumor Module, MDASI-BT). The study evaluated the reliability and validity of the MDASI-BT in primary brain tumor patients. Results: 201 patients participated in this study. Mean symptom severity of items as well as cluster analysis was used to reduce the number of total items to 22. Regression analysis showed more than half (56%) of the variability in symptom severity was explained by the 9 remaining brain tumor items. Factor analysis was then performed to determine the underlying constructs being evaluated by the remaining items. The 22 item MDASI-BT measures six underlying constructs including affective, cognitive, focal neurologic deficit, constitutional, generalized symptom, and a gastrointestinal related factor. The internal consistency (reliability) of the sets of items comprising the six factors and also the interference scale were .87, .82, .72, .81, .69, .67 and .91 respectively). Test-retest reliability was good in a subset of 19 patients completing the instrument at two points in time. The MDASI-BT was sensitive to disease severity based on Karnofsky performance status (KPS) based on mean symptom severity (1.7 versus 3.8, p < .001) and mean symptom interference (2.2 versus 6.1, p < .001). Conclusions: The 22 item MDASI-BT demonstrated validity and reliability in patients with PBT. This instrument can be used to describe symptom occurrence throughout the disease trajectory and to evaluate interventions designed for symptom management.

[Table: see text]
Phase I study of capecitabine combined with weekly carboplatin and intensity modulated radiation therapy (IMRT) for treatment of locally advanced squamous cell carcinomas of the head and neck (HNSCC)
Authors: Thomas C. Y. , Read P. , Sheng K. , Bliesner D. , Levine P. , Reibel J.
Published: March 2020

15522

Background: Chemoradiotherapy (CRT) programs for locally advanced HNSCC that reduce toxicity but maintain efficacy are needed. Methods: A two-step phase I trial to determine the maximum tolerated dose (MTD) of capecitabine combined with fixed dose carboplatin, given prior to and during concomitant IMRT. Start dose of capecitabine =1500 mg/m2/d p.o. BID days 1–14 and 22–35 with carboplatin AUC =2 IV weekly x 6. With IMRT, the doses were adjusted to 1000 mg/m2/d and AUC =1.5, respectively. Parotid-sparing IMRT = 50 and 45 Gy/25 fractions to gross disease (GD) and low risk nodes, respectively; 3D conformal boost of 20 Gy/10 fractions to GD. Dose limiting toxicity (DLT) defined as ANC <750, ≥ grade 3/4 thrombocytopenia or selected non-hematologic toxicities. Results: 11 patients (pts) with stage III/IV (T2–4,N1–2C) HNSCCs of the oropharynx (7), oral cavity (2), both (1), or hypopharynx (1) were studied. 10/9 pts evaluable for toxicity after induction/concomitant chemotherapy, respectively; 2 pts had early disease progression (d22 and 43). During radiation, the MTD for capecitabine established as 825 mg/m2/d. At start dose, 2/3 pts developed thrombocytopenia as DLT; CRT-related toxicities = grade 3 mucositis (3), dysphagia (3), fatigue (1), anemia (1), and dermatitis (1). For induction chemotherapy, DLTs seen in 0/3 pts at capecitabine =1750 mg/m2 and 1/6 at lower doses (grade 4 diarrhea; no other Gr3/4 drug-related toxicities). Response of primary (or neck) tumors to induction: CR 3 (3), PR 6 (3), SD 1 (3), and PD 2 (2). After CRT, 8/9 pts achieved CR and are alive without disease (mean follow-up 6 months). Conclusions: Capecitabine 825 mg/ m2/d and carboplatin AUC =1.5 weekly given on the described schedule and in combination with IMRT produce moderate toxicity and a high complete response rate in stage III/IV HNSCC pts that received the same drugs as induction therapy. The latter combination was also well tolerated and had anti-tumor activity (capecitabine Y=1500–1750 mg/m2/d). Additional studies are warranted to determine if these regimens provide an effective but less toxic alternative to cisplatin or taxane-based CRT programs. Supported in part by Bristol-Myers-Squibb.

No significant financial relationships to disclose.
A phase I/II trial of induction chemotherapy followed by concomitant docetaxel with concomitant boost radiotherapy (CBR) and amifostine for advanced head and neck cancer (HNC)
Authors: Saurel C. , Meredith R. , Bonner J. A. , Peters G. , Carroll W. , Spencer S. A. , Nabell L.
Published: March 2020

15525

Background: Concomitant chemo-radiation for head and neck cancer has emerged as the optimal method of treating advanced head and neck cancers, although the acute and late toxicities can be formidable. The addition of induction chemotherapy to concomitant chemo-radiation for head and neck cancer is designed to impact the incidence of distant metastasis while delivering aggressive local treatment. This trial evaluates the tolerability and effectiveness of induction chemotherapy followed by CBR with concurrent docetaxel and subcutaneous (SC) amifostine in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods: Patients with stage III/IV nonmetastatic SCCHN received 3 cycles of primary chemotherapy with docetaxel and cisplatin, each at 75 mg/m2. Patients then received 4 weekly doses of docetaxel at 20 mg/m2 with concurrent CBR. SC amifostine was given at a dose of 500 mg in divided doses during each day of XRT. Results: The phase I component defined the MTD of concurrent docetaxel as 20 mg/m2 for 4 cycles during CBR. 18 patients are evaluated for response. No patient developed progressive disease during primary chemotherapy. Grade 3–4 mucositis was common, but all patients completed the planned concomitant docetaxel. At 6 months after treatment, 7/18 patients still used a feeding tube, though most have had them subsequently removed. Amifostine given by SC was well tolerated; 7 patients developed transient hypotension not requiring any intervention, with grade1 dermatitis and nausea reported. 2 patients discontinued amifostine due to rash or persistent hypotension. Conclusions: Response to induction chemotherapy was greater then 75% by radiological assessment, with no patient developing distant metastasis thus far. Local control has been excellent but side effects from docetaxel and CBR have necessitated prolonged use of feeding tubes for up to 6 months. SC amifostine has been well tolerated without significant side effects. This aggressive therapy is effective treatment for locally advanced SCCHN.

No significant financial relationships to disclose.
Clinical, signaling pathway, and cellular effects of epidermal growth factor receptor (EGFR) inhibition with gefitinib in combination with paclitaxel and radiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: Allen C. T. , Donovan E. A. , Chen Z. , Gius D. , Morris J. C. , Vanwaes C.
Published: March 2020

15540

Background: EGFR, overexpressed in >90% of SCCHN, activates pathways that modulate proliferation, apoptosis, and therapeutic resistance. We examined the clinical, signaling, and cellular effects of EGFR inhibition in serial tumor biopsies in patients (Pts.) with locally advanced SCCHN receiving the EGFR-inhibitor gefitinib (GEF) in combination with paclitaxel (PTX) and radiation (XRT). Methods: Phase I dose-escalation study of concurrent GEF 250 mg with weekly PTX 45mg/m2 x 6 doses and XRT to 72Gy. Eligiblity: SCCHN, Stage III-IVB, age ≥18 yr., no prior XRT or chemotherapy, ECOG ≤2, adequate organ function and informed consent. Endpoints include determination of maximum tolerated dose (MTD) and immunostaining of tumor pre- and post-treatment for expression of phospho-EGFR, Akt, Erk1/2, STAT3, NF-κB p65, Ki67, and TUNEL, and measurement of serum IL-6, IL-8, VEGF, HGF and GROα to assess the functional effects of EGFR-inhibition. Results: Four Pts., median age 63 yr. (range 41–83), 3 men, 1 woman were treated. Aspiration pneumonia and interstitial pneumonitis were each observed in 1 Pt and prolonged Grade 3/4 mucositis in all 4 Pts. Three Pts achieved a CR, with one Pt requiring neck dissection to remove a residual node. One Pt had a local CR but rapidly developed pulmonary metastasis. One Pt. exhibited decreased staining of all signaling phosphoproteins and Ki67 with increased TUNEL staining. Decrease or increase in IL-8, VEGF and HGF at one month corresponded with response or progression in two patients. Conclusions: Pulmonary complications and prolonged mucositis were dose-limiting. EGFR inhibition affects downstream signaling, cell survival and serum factors in a subset of patients.

No significant financial relationships to disclose.
Cancer information acquisition differs by patient characteristics
Authors: Gray S. W. , Romantan A. , Kelly B. , Ramirez S. , Stevens R. , Wong N. , Kim A. , Schwartz J. S. , Hornik R.
Published: March 2020

16008

Background: While cancer patients have access to multiple sources of information, including mass media, the internet and personal and professional contacts, little is known about use of these sources in decision making. Methods: 43 patients with one of three cancer types (37% breast, 28% colon and 35% prostate, 58% stage 1) randomly recruited through the Pennsylvania Cancer Registry completed semi-structured in-person interviews about cancer related information acquisition and decision making. (Median age 59 (range 40–71), 47% male, 79% white, 74% married, mean education 14.6 years (SD = 2.48). Separate analyses were performed for actively looking for information (seeking) vs. passively coming across information (scanning). The primary endpoint was patient use of information sources in cancer related decision making. Results: All cancer patients reported use of both interpersonal and mass media information sources in making cancer related decisions. Patients with more advanced cancer (stage 3 vs. stage 1 or 2), higher education, and younger age were more likely to actively seek cancer information (χ2 = 4.7, p = .095, χ2 = 10, p = .04 and χ2 = 8.6, p = .07). Breast cancer patients and women were more likely to report passively coming across information (χ2 = 9.1, p = .058 and χ2 = 5.1, p = .078). Conclusions: Cancer information acquisition varied according to patient characteristics. Seeking was reported more in younger patients and those with higher formal education, and more advanced cancer. Highly educated and younger patients may be better at navigating the information environment; patients with more advanced cancer may have increased anxiety causing them to actively seek information. Scanning was more common among breast cancer patients and women. Women may attend to general health related information more than men or information about breast cancer may be more accessible and pervasive than information on colon or prostate cancer.

No significant financial relationships to disclose.
Toward an integrated analysis of risk and benefit in clinical research
Authors: Hirschfeld S.
Published: March 2020

16012

Background: Clincial data collection can be resource intensive, and yet typically only a proportion of the data is informative to determine outcome. Outcomes are conventionally displayed as single entities or as a composite of several variables for benefit and as single entities, often categorized with regard to severity, for risk. Analysis is then collapsed to a series of analyses expressed in one or two dimensions with several probability factors, one associated with each outcome. Integrated risk-benefit assessment is generally left with individual practitioners to determine, both in consultation with patients and with colleagues as part of a formal or informal consensus process. Methods: A graphical approach assigning each variable of interest plus time a dimension in an n-dimensional space is proposed, calculating the coordinates of each patient as time progresses in that space to describe a path, and describing the sum of all paths for a patient population as bounded by a space. Results: Dispersion of outcomes can be readily determined as well as an integrated risk-benefit index using linear algebra. Comparisons between patient populations can be made on the basis of the boundaries of the space, the dispersion, the vector paths, and the average coordinates at the time of interest of the population as a whole. The number of dimensions can be restricted or expanded as required and can be collapsed into composite risk, including cost, and benefit indices to describe an integrated risk-benefit assessment. A density map can be plotted for all patients in the study space and probabilities assigned for the likelihood of any patient passing through a region of interest. Particular regions within the time-space continuum are then defined as desirable, acceptable, or unacceptable with regard to integrated outcome. Examples will be provided to illustrate the general method. Conclusions: A multidimensional graphical system has been developed to provide an integrated outcome assessment. Multiple analyses are possible including projections, density maps and transformations that may yield further insights into outcomes. Comparisons may be possible using conventional techniques, but in addition new types of comparisons using transformations and other techniques applicable to a space-time continuum may apply.

No significant financial relationships to disclose.
Inhibition of DNA repair in chronic lymphocytic leukemia: Therapeutic implications
Authors: Amrein L. , Aloyz R. , Panasci L. C.
Published: March 2020

16513

Background: Chronic lymphocytic leukemia (CLL) is an indolent leukemia in which there is an accumulation of immature malignant B-lymphocytes. While treatment with chlorambucil, a nitrogen mustard analogue or fludarabine can control the disease, eventually all patients become resistant to chlorambucil/fludarabine. Chlorambucil’s cytotoxicity is mediated by the interstrand crosslinks (ICLs) introduced into DNA. In mammalian cells, two main pathways are known to be involved in double strand break(DSB) repair: homologous recombinational repair (HRR) and nonhomologous endjoining (NHEJ). Methods: Our laboratory has demonstrated that resistance to chlorambucil involved accelerated repair of the ICLs associated with enhanced DNA repair, specifically enhanced nonhomologous endjoining (NHEJ) and homologous recombinational repair (HRR). We also recently demonstrated that gleevec inhibition of c-abl with resulting inhibition of Rad51-related HRR sensitizes CLL lymphocytes in vitro to chlorambucil. This exciting result has stimulated the development of a clinical protocol to test this combination in CLL. Furthermore, our laboratory has demonstrated that wortmannin, a nonspecific inhibitor of DNA-PK (a key component of NHEJ) sensitizes CLL lymphocytes to chlorambucil. Results: We are actually evaluating the effect of NU7026, a relatively specific DNA-PK inhibitor, in the sensitivity of CLL cells to chlorambucil. Our results indicate that in a CLL cell line (I83) and primary CLL-lymphocytes chlorambucil plus NU7026 have a synergistic cytotoxic effect. Noteworthy, the NU7026 doses used in combination with chlorambucil were not toxic to the cells when used alone. Moreover, chlorambucil treatment induced DNA-PK nuclear foci which were inhibited by NU7026 suggesting that the synergy of both drugs is mediated by Nu7026-inhibition of DNA-PK. Conclusion: NU7026 plus chlorambucil should be a useful combination to treat CLL.

No significant financial relationships to disclose.
A phase II study of DJ-927 administered orally once every three weeks as second line therapy to subjects with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of platinum-based non-taxane regimen
Authors: Szczesna A. , Milanowski E. , Juhász E. , Albert I. , Von Pawel J. , Sztancsik Z. , Oyama R. , Baas P.
Published: March 2020

17006

Background: For the treatment of NSCLC (1st and 2nd line) effective oral formulations of drugs are currently investigated. DJ-927 is a semi-synthetic novel taxane with in vitro activity against NSCLC cells lines. Phase I studies show active plasma concentrations after oral administration with hematologic dose-limiting toxicity (DLT). This multi-centre phase II study was conducted to evaluate the safety and efficacy of the DJ-927 in patients (pts) with recurrent NSCLC. Methods: Pts with locally advanced or metastatic NSCLC who have received one prior platinum (non-taxane) containing treatment regimen, performance status 0 -2, and adequate organ function were enrolled. Pts received an initial DJ-927 dose of 27 mg/m2 on day 1 of cycle 1, orally, every 3-weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at that dose level. The primary endpoint was to assess the response rate. Pts were also assessed for time to disease progression (TTP), survival and safety. Results: 36 pts were enrolled, male/female 27/9; median age of 57 years (range 33–75); ECOG 0/1/2 7/21/8; stage IIIB/IV 12/24. Histology included adenocarcinoma 5; squamous cell 16; large cell 3; undifferentiated 3; other 7; unknown 2. Thirty-four pts received DJ-927; the median number of cycles was 2 (range 1–8). The optimal dosing level was confirmed at 27 mg/m2 as no dose escalation was performed based on toxicity data from parallel studies. Response in evaluable pts (completed Course 1) included CR 1, PR 1, SD 15, PD 8; for an overall response rate of 7 % and a disease control rate (CR, PR and SD) of 61%. Toxicity, ≥ grade 3, in evaluable pts (n = 32) included neutropenia (15), anaemia (6), thrombocytopenia (2), fatigue (2), nausea (2), anorexia (2), pneumonitis (1). Conclusions: In a 3-weekly setting, an oral dose 27 mg/m2 of DJ-927 shows limited efficacy in 2nd line therapy for NSCLC with neutropenia, gastrointestinal toxicity and fatigue as major side effects.

[Table: see text]
Phase II study of induction docetaxel/cisplatin with rhG-CSF followed by concurrent pulsed docetaxel chemoradiation for stage III non-small cell lung cancer (NSCLC)
Authors: Chen Y. , Pandya K. J. , Smudzin T. , Qazi R. , Smith B. D. , Hyrien O. , Johnstone D. W. , Watson T. , Feins R. H.
Published: March 2020

17034

Background: Both local and distant failures contribute to poor outcome in chemoradiation (CRT) for stage III NSCLC. Our previous study applied pulsed low-dose paclitaxel CRT for stage III NSCLC yielded 97.6% in-field tumor control and a modest survival gain. A follow-up study was designed to target distant micrometastasis up-front by one-cycle induction (IND) chemotherapy (CT) w/o further delay of local therapy. This was followed by low-dose sensitizing docetaxel (Doc) CRT. Methods: IND CT consisted of day 1 Doc 75 mg/m2 & cisplatin 75 mg/m2, and rhG-CSF (150 mg/m2 days 2–10). CRT started 3–6 wks later. Twice-weekly Doc at 12 mg/m2 was given with daily RT of 64.8 Gy to gross dz and 45–57.6 Gy to subclinical dz. Toxicity (Tox), response and survival were assessed. Results: 22 pts enrolled with 16 evaluable. 6 did not complete due to: allergy, intercurrent dz or progressive dz prior-to/during RT. Overall response was 69%. Kaplan-Meier survival was 67%, 55%, and 55% for years 1, 2, and 3. Grade (Gd) 3 Tox of IND CT included: allergy (10%), infection/nl ANC (20%), nausea (10%), HTN (5%) hyperglycemia (5%), H/A (5%), fatigue (10%), dyspnea/gd 4 hyperglycemia/fatigue (5%). No gd 3/4 hematologic Tox. Esophagitis was the main Tox of CRT. Doc was reduced after 10th pt enrolled for high incidence of gd 3 esophagitis: 4/8 (50%) at Doc dose of 12 mg/m2. Subsequent pts received reduced Doc of 10 mg/m2 and 1/8 had gd 3 esophagitis (12.5%). Other gd 3 Tox of CRT included: fatigue (14%), appetite loss (14%), flushing (7%), chest pain (7%), diarrhea (7%), and nausea (28%). No other gd 3 or 4 Tox from CRT. Conclusion: The regimen is associated with low hematologic Tox. Despite published MTD of twice-weekly Doc/RT at 15 mg/m2, 50% treated at 12 mg/m2 had gd 3 esophagitis. This was reduced to 12.5% at 10 mg/m2. Local response was 69% and survival was much better compared with our previous study of pulsed paclitaxel/RT w/o IND CT, which yielded 2 and 3-year survival of 33% and 18% for all, and 40% and 21% for pts completed protocol (Chen et al Clin Cancer Res 9:969–975,2003). Data suggest that one-cycle IND CT followed by low-dose taxane-based CRT improves survival of stage III NSCLC pts and deserves further investigation. Study partly supported by Sanofi-Aventis.

No significant financial relationships to disclose.
Prospective randomised phase II study of gemcitabine and vinorelbine versus gemcitabine and docetaxel combination in patients with previously untreated advanced non-small cell lung cancer
Authors: Fernández Y. , Esteban E. , Villanueva N. , Fra J. , Muñiz I. , Jimenez P. , Luque M. , Vieitez J. , Estrada E. , Lacave A. , Buesa J. M.
Published: March 2020

17052

Background: Previous comparative studies have shown similar efficacy and less toxicity with either the Gemcitabine(G)/Vinorelbine(V) or Gemcitabine/Docetaxel(D) combination with respect to platinum-based chemotherapies in patients with advanced NSCLC. This trial was designed to test the efficacy and safety of both GV and GD combination in non-selected patients with advanced NSCLC. Methods: Patients (n = 39) with ≤75 years of age, KPS ≥ 60% and adequate haematological, renal and hepatic function were randomly assigned to: G 1250 mg/m2 i.v. d1 and d8 plus either V 25 mg/m2 i.v. d1 and d8 or D 35 mg/m2 i.v. d1 and d8 every 3 weeks. Prophylactic i.v. ranitidine (50 mg), diphenhydramine (25 mg) and dexamethasone (8 mg) were prescribed just prior to the administration of taxane that was given over 30 minutes immediately before gemcitabine. Results: Baseline characteristics were comparable in GV (n = 20) and GD (n = 19) arms: median age (67 years) and KPS (70%), most patients were male (79%), had metastatic disease (85%) and adenocarcinoma histology (55%). Treatment indicated objective response of 7 (35%) versus 6 (31%) patients, median time-to-treatment failure of 120 versus 90 days, and overall survival of 209 versus 177 days in GV and GD arms respectively. The most common non-haematological toxicities were (GV versus GD; No. of patients): grade 2–4 pulmonary toxicity in 1 versus 7 (37%); grade 2–3 diarrhoea in 0 versus 4 (21%) and oedemas 1 versus 3. Grade 2–4 haematological toxicities in 5 versus 2 patients. All side effects were reversible phenomena since resolution was achieved by suspending the treatment and in the case of the pulmonary toxicity, by the prescription of additional corticoids. Conclusion: The combination of Gemcitabine/Docetaxel does not have a favourable safety profile with this schedule of administration, particularly in terms of pulmonary toxicity. Further patients’ enrolment was stopped and the study has been terminated. This kind of toxicity and alternative schedules of GD combination warrant further investigation.

No significant financial relationships to disclose.
Preliminary results of G versus GViElC: A phase III trial of gemcitabine associated to vindesine or gemcitabine alone in elderly or poor performance patients with advanced non-small cell lung cancer (NSCLC)
Authors: Santo A. , Genestreti G. , Terzi A. , Azzoni P. , Caffo O. , Galligioni E. , Cipriani A. , Binato E. , Cartei G. , Cetto G.
Published: March 2020

17083

Background: Monochemotherapy with gemcitabine (GEM) or vinorelbine is considered the standard treatment in elderly or poor performance (PS) patients (pts) with advanced NSCLC. Many topics report a synergic enhancement of antitumor effect of GEM if associated to Vindesine (VDS). The aim of this study is to evaluate if GEM combined to VDS produces an advantage in terms of overall survival (OS) compared to GEM alone without enhancement of toxicity. Methods: Chemonaive pts with stage IIIB/IV NSCLC, aged ≥ 70 years with PS < 2 or aged < 70 years with PS > 2 were enrolled. Pts were randomized to receive either GEM 1200 mg/m2 day 1 and 8 every 21 days for three cycles (arm 1) or GEM 1000 mg/m2 and VDS 3 mg/m2 (max dose 5 mg) both drugs infused on day 1 and 8 every 21 days for three cycles (arm 2). Pts of both arms received other three cycles in case of responsive or stable disease. Overall survival (OS) was the primary end-point, secondary end-points were time-to-progression and toxicity. First interim analysis was planned at 120 pts enrolled. Results: From May 2002 to December 2005, 107 pts from 13 Italian institutions were enrolled. Their characteristics are: 24 stage IIIB and 83 stage IV, 79 pts with ≥ 70 years (ECOG PS 0–1) and 28 pts with < 70 years (ECOG PS > 2). In arm 1 there were enrolled 55 pts while 52 pts in arm 2: both arms were well balanced with pts characteristics. Conclusions: The enrollment of this phase III trial is ongoing: we are achieving first step for an interim analysis to assess if GEM associated to VDS produces an advantage in terms of OS compared to standard treatment as GEM in monochemotherapy without toxicity enhancement. (Supported by GIVOP: Gruppo Interdisciplinare Veronese di Oncologia Polmonare).

No significant financial relationships to disclose.
Phase II study of weekly chemotherapy with paclitaxel and gemcitabine as second-line treatment for advanced non-small cell lung cancer
Authors: Mori K. , Kamiyama Y. , Kondo T. , Kodama T.
Published: March 2020

17096

Background: Second-line chemotherapy has become almost routine in non-small cell lung cancer (NSCLC) patients (pts) with good performance status (PS). The availability of the new pharmacological agents opens up new possibilities for their use in pts who have retained a good PS following relapse or progression after first-line chemotherapy. Paclitaxel (PTX) and Gemcitabine (GEM) are among the most active new agents in NSCLC and are worth considering for second-line chemotherapy. In phase II study, we evaluated the tolerability and activity of the combination of weekly PTX and GEM in second-line treatment of NSCLC. Methods: PTX (100mg/m2) and GEM (1000 mg/m2) were administered on days 1 and 8 at every 3–4 weeks. A total of 40 pts (M/F, 27/13 pts; median age 59.3 years [33–75]; PS 0/1/2, 7/27/6 pts) were enrolled between October 2000 and July 2003. Results: The number of cycles conducted was 1 in 5 pts, 2 in 8 pts, 3 in 10 pts, and 4 in 17 pts (mean: 4). The final efficacy was PR in 13, NC in 26 and PD in 1 for a response rate of 32.5 % (95% CI: 18.0–47.0%). The median survival time was 41.7 weeks (95% CI: 28.5–54.7 weeks). The median time to progressive disease was 19 weeks. Hematologic toxicities observed included Grade 3 or 4 neutropenia in 60%, Grade 3 or 4 anemia in 20%, and Grade 3 or 4 thrombocytepenia in 10%. Non-hematologic toxicities were mild except Grade 3 diarrhea in 3 pts and Grade 3 pneumonitis in 2 pts. There were no toxic deaths. Conclusions: The combination of weekly PTX and GEM is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC.

No significant financial relationships to disclose.
Gemcitabine/docetaxel (GD) versus gemcitabine/cisplatin (GC) in stage III/IV non-small cell lung cancer (NSCLC): Preliminary results
Authors: Gamaz M. , Makhloufi T. , Taright S. , Baba-Ahmed R. , Amrane R. , Bouzid K.
Published: March 2020

17116

Background: This study was designed to compare the response rates and toxicities of the standard GC regimen versus GD, a non-platin regimen, in locally advanced and metastatic NSCLC. Methods: In both arms, gemcitabine 1250 mg/m2 was administered on days 1 and 8. In the GD arm, docetaxel 75 mg/m2 was given on day 8. In the GC arm, cisplatin 70 mg/m2 was given on day 1. Both regimens were repeated every 3 weeks. Results: From September 2004 to September 2005, 47 patients were enrolled In the GD arm (N = 25), the median age was 54.6 years (range, 45–70), and 22 (88.0%) were male. The majority of patients had either squamous cell (52.0%) or adenocarcinoma (44.0%), and stage IIIB disease (64.0%). In the GC arm (N = 22), the median age was 60.9 years (range, 42–74), and 20 (90.9%) were male. Most patients also had either squamous cell (50.0%) or adenocarcinoma (31.8%), and stage IIIB disease (59.1%). The difference in age between arms was significant (p = 0.046), but the differences in the remaining baseline characteristics and demographics were not significant. Toxicity and response results are in the table below. Conclusions: Overall response rate was numerically higher in the GC arm than the GD arm, but the difference was not significant because of the small sample size in each arm. The toxicity profile was significantly better in the GC arm for fatigue and nausea/vomiting. We think that GC regimen will remain the standard in treatment for advanced and metastatic NSCLC; however, we will confirm these findings in a randomized phase II study.

[Table: see text]

No significant financial relationships to disclose.
Simplified gemcitabine and platin regimen for NSCLC to be used in the neoadjuvant setting
Authors: Cartei G. , Binato S. , Sacco C. , Scalone S. , Ceravolo R. , Fantoni U. , Cingarlini S. , Palamidese A. , Iop A. , Colombrino E.
Published: March 2020

17155

Background: Platin (P) salts and Gemcitabine (G) are used for NSCLC. GP regimens frequently included G on day 1, 8 and 15; P on day 2; every 28 days. However, the third G dose often is omitted because of myelo-toxicity, with a consistent no respect of the intended drugs’ doses. We devised a simplified regimen, based on two Day-Hospital admissions per cycle (c), with G on day 1 and 8; P after G on day 8; every 21 days. Aim of study: a high RR within the first 3 c.s for a GP regimen for neoadjuvant therapy. Methods: This prospective, multi-centre investigation included G (1500 mg/m2) on day 1 and 8, and P (100 mg/m2) on day 8 immediately following G, on a 3-weeks-c. Eligible criteria: age 18 to 75 years, NSCLC histologically, no previous chemotherapy, KPS 50%, WBC ≥ 4.0 × 109/L, platelet ≥100 × 109/L and normal kidney-liver function. QoL evaluation: 46 out of 95 valuable patients. Restaging procedures: repeated 3 and 6 c.s. Results: Out of 105 patients, 95 had at least 3 c.s and 59 of them had further 3 c.s. Myelo-toxicity ≥ G3 was mainly neuthropoenia, easily amenable with symptomatic and GCSF therapies; PNS toxicity occurred in 17.9% of patients. QoL was ameliorated (p < 0.05). Therapy was tolerable; gave RR was 52.3% after 3 c.s (Intention-to-treat analysis) and 57.9% in 95 valuable patients after at least 3 therapy c.s. In the 95 valuable patients over the first 42 days, i.e. after 2 c.s and just before the third c., 10 c.s out of 190 were delayed by one week, with a dose intensity reduction of 5.29%. Conclusions: This two Day-Hospital admissions regimen is at least as good as more complex GP regimens, with an appreciable RR after 3c.s; it may be proponed in the neoadjuvant setting. Acknowledgments: Present work was part of studies program of, and partly supported by, AOI (Associazione Oncologia Italiana, Padova, Italy).

No significant financial relationships to disclose.
A phase II study of combination of bortezomib, liposomal doxorubin, and dexamethasone (VDD) as first line therapy for multiple myeloma
Authors: Jakubowiak A. J. , Friedman J. , Kendall T. , Al-Zoubi A. , Kaminski M. S.
Published: March 2020

17504

Background: We have recently reported that a combination of bortezomib (Velcade), liposomal doxorubicin (Doxil), and dexamethasone (VDD) is very active and well tolerated in relapsed/refractory myeloma (MM) producing 83% overall response rate and 33% of complete (CR) or near complete (nCR) response rate. In the current study, we evaluated the activity of VDD as first line therapy in newly diagnosed patients with MM. The primary objective of this study was to determine the efficacy of this regimen. Methods: This is a phase II, single institution trial which opened in July 2005 with target accrual of 30 patients. EBMT criteria were used for evaluation of responses. The regimen was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone for a total of 160 mg per cycle, initially at 40 mg on days 1–4 and then 20 mg on days of Velcade and the day after. VDD was repeated every 3 weeks for a total of 6 cycles. Results: To date, 19 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 4.7 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 58 (range 39–83), chromosome 13 deletion in 4 patients, beta2-microglobulin 4.4 (61% > 4.0). CR + nCR have been observed in 2 patients (11%), very good partial response (VGPR) in 5 patients (28%), partial response (PR) in 9 patients (50%) and minor response (MR) in 1 patients (5%) for an overall response (≥ MR) of 94%, ≥ PR of 89% and ≥ VGPR of 39%. All patients who proceeded to stem cell transplant collected without any problems. The regimen was very well tolerated. Most surprisingly, only 1 patient developed peripheral neuropathy grade 1. One patient developed pneumonia and PE and one patient grade 3 diarrhea, which was found to be secondary to cryptosporidium. Grade 3 or 4 neutropenia was observed in 6 patients and grade 3 thrombocytopenia in 1 patient. The most common grade 1 and 2 toxicities were thrombocytopenia and fatigue, both significantly less common than in relapsed patients treated with the same regimen. One patient developed grade 2 DVT and 1 grade 2 PPE. Conclusions: VDD combination shows high overall activity of 94% and ≥ 90% disease reduction of 39%. The regimen is very well tolerated and has a surprisingly low incidence of peripheral neuropathy.

[Table: see text]