bluuebunny/crossref_metadata_2025 huggingface dataset:
An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma
Authors: Sathornsumetee S. , Reardon D. A. , Quinn J. A. , Rich J. N. , Vredenburgh J. J. , Desjardins A. , Gururangan S. , Egorin M. , Salvado A. , Friedman H. S.
Published: March 2020

1560

Background: Imatinib mesylate, a kinase inhibitor of the PDGF receptor has been shown to decrease tumor interstitial pressure resulting in enhanced delivery of cytotoxic therapy. Recent phase II trial demonstrated promising anti-glioma activity of imatinib mesylate in combination with chemotherapy, hydroxyurea. Methods: The current phase I study is designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate when combined with temozolomide, a DNA methylator with established efficacy against gliomas. Eligibility criteria include: histologically confirmed malignant glioma; age of at least 18 years; KPS of at least 60%; less than grade 2 intratumoral hemorrhage; adequate hepatic, renal, and bone marrow function and lack of prior failure or significant toxicity following treatment with either imatinib mesylate or temozolomide. Temozolomide is dosed at 200 mg/m2 on days 4–8 of each 28-day cycle. Imatinib mesylate is administered on days 1–8 of each cycle and the dose is escalated in successive cohorts of 3–6 patients via a standard “3+3” dose escalation design. Patients are stratified based on concurrent use of enzyme-inducing anticonvulsants (EIAC) and both strata are independently escalated. Results: To date 47 patients have been enrolled including 40 with GBM and 7 with anaplastic gliomas. Median age is 53.9 years (range 28 to 72); 66% are male and 51% are on EIAC. The MTD has yet to be defined for either stratum. To date DLT of ALT elevation has been observed in one patient from non-EIAC stratum. Two patients discontinued therapy due to toxicities with one asymptomatic intracerebral hemorrhage and one severe hematologic toxicity. Pharmacokinetic sampling has been performed in approximately half of the patients. One patient completed the study (12 cycles) with stable disease. Eleven patients remain on study with one partial response and three patients have undergone more than 10 cycles of therapy with stable disease. Twenty-eight patients (59%) have developed progressive disease and discontinued therapy. Conclusions: Combination of imatinib mesylate and temozolomide is safe and well tolerated. Further accrual and dose escalation are ongoing.

[Table: see text]
A phase II study of temozolomide and oral VP-16 for adults with recurrent glioma—Final results
Authors: Korones D. N. , Benita-Weiss M. , Coyle T. , Bushunow P. , Mechtler L. , Friedman H. S.
Published: March 2020

1565

Background: Although temozolomide has proven activity in patients with high and low grade gliomas, many patients do not respond, and for those who do, responses are often short-lived. We therefore undertook a trial of temozolomide in combination with oral VP-16 (etoposide) for patients with recurrent glioma. Methods: Patients were eligible for the study if they had recurrence of a glioma (glioblastoma [GBM], anaplastic glioma, or low-grade glioma), were ≥ 18 years of age, had a WHO score of 0–2, and had not received prior therapy with temozolomide or oral VP-16. All patients received temozolomide, 150 mg/m2/d days 1–5 and oral VP-16, 50 mg/m2/d days 1–12 (based on the maximum tolerated dose established in a previous phase 1 study [Cancer 2003, 97 (8); 1963–68.]). Cycles were repeated every 28 days for up to 12 cycles. All patients received prophylaxis for pneumocystis. Results: Fifty-one patients were enrolled - 32 with glioblastoma, 12 with anaplastic gliomas, and 7 with low-grade glioma. Median age was 52 years (21–76), and 67% were male. Forty-one were enrolled at first and 10 at second recurrence. Fifty had had prior radiation, and 30 of these 50 patients had also received prior chemotherapy. Of the 32 subjects with GBM, 4 had a PR (12.5%), 13 (41%) SD, 13 (41%) PD, and 2 were not evaluable because of deterioration prior to imaging. The median progression-free survival (PFS) was 2 mo. (0–51+ mo), and the 6 mo. PFS was 19%. Of the 12 patients with anaplastic gliomas, 2 had a PR (16%), 7 SD (58%), 2 PD (16%) and one was not evaluable. Their median PFS was 5.5 mo, and the 6 mo. PFS was 50%. Of the seven subjects with low grade gliomas, 4 had a PR, 2 SD, and 1 PD. Their median PFS was 5 mo. (0–12) and 6 mo. PFS was 57%. Of the entire cohort, two patients developed fever and neutropenia and died of pseudomonas sepsis. Another two patients were prematurely withdrawn from the study due to toxicity (one for grade 4 neutropenia and a second for grade 2 diarrhea). Conclusions: In this population of previously treated patients with recurrent glioma, the combination of oral VP-16 and temozolomide has only modest efficacy and significant toxicity. The results of this study suggest that in this setting, the combination offers no advantage over either agent used alone.

[Table: see text]
Results of G004, a phase IIb actively controlled clinical trial with the TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma
Authors: Hau P. , Stockhammer G. , Kunst M. , Mahapatra A. , Sastry K. V. , Parfenov V. E. , Leshinsky V. G. , Jachimczak P. , Bogdahn U. , Schlingensiepen K.
Published: March 2020

1566

Background: In 3 phase I/II dose-escalation studies the TGF-β2 specific compound AP 12009 proved to be well tolerated and revealed an excellent safety profile. Furthermore, antitumor activity including complete tumor remissions was observed. Methods: G004 is an international open-label, actively controlled, dose finding phase IIb trial in adult patients with histopathologically confirmed recurrent high-grade glioma. 145 patients with recurrent anaplastic astrocytoma (AA, WHO grade III) or glioblastoma (GBM, WHO grade IV) were enrolled into the study. Objective of the current phase IIb study is to compare the efficacy and safety of two doses of AP 12009 and standard treatment. Patients were randomized to receive either one of two doses of AP 12009 (10 μM or 80 μM) or standard chemotherapy (TMZ or PCV). AP 12009 was administered intratumorally by CED. 134 patients received treatment and all of them have completed active treatment. Primary endpoint is tumor response by local and central MRI reading and survival. Results: Here we report on patients with recurrent AA (for GBM see separate Abstract). 38 patients with AA (68% male, 32% female; median age 39, range 22–60; median Karnofsky performance status: 90, range 70–100) were treated. 26 patients received AP 12009 (10 μM or 80 μM), 12 patients were treated with TMZ or PCV. Up to now, in 89 patients treated with AP 12009 (both AA and GBM patients) 6 SAEs possibly related to the study drug and 37 procedure related SAEs (92% mild or moderate) were documented. Partial and complete tumor responses were observed. Exact response rates will be determined after central MRI reading is completed. Responses in the AP 12009 groups are long lasting. The results confirm the good safety profile of AP 12009 as well as the efficacy data seen in phase I studies. The median overall survival is not yet reached. Conclusions: The long-term tumor free survival of several patients may actually hint towards a potential to cure some patients with this devastating disease. Phase III clinical trials in both AA and GBM patients are currently in preparation.

[Table: see text]
Outcomes of critically ill patients with lung cancer
Authors: Soares M. , Darmon M. , Ferreira C. G. , Salluh J. , De Miranda S. , Adda M. , Spector N. , Azoulay E.
Published: March 2020

16001

Background: Recent advances in oncology and critical care have resulted in improved survival in critically ill cancer patients. An appraisal of the prognosis of critically ill patients with lung cancer is timely. Methods: The aim of this study was to evaluate the outcomes and prognostic factors of critically ill cancer patients with lung cancer. From 2000 to 2005, patients with either small-cell (SCLC) or non-small-cell lung cancer (NSCLC) admitted at two intensive care units (ICU) in Brazil and France were included. Patients with postoperative care, ICU stay <24 h and readmissions were excluded. Demographics, clinical, cancer related and outcome variables were collected. Hospital mortality was the outcome variable of interest. Variables selected in the univariate analysis (p < 0.25) and those considered clinically relevant were entered in a multivariable logistic regression analysis [results were expressed as odds-ratios (OR), 95% confidence interval (CI)]. Results: A total of 132 patients were studied (INCA = 87, St Louis Hospital = 45). Their mean age was 61 ± 10 years and 73% were males. Twenty-five (19%) had SCLC and 107 (81%), NSCLC. The SAPS II score was 48 ± 21 points. The main reasons for ICU admission were severe sepsis (45%) and acute respiratory failure (33%). During ICU stay, 96 (73%) patients received mechanical ventilation, 76 (58%) vasopressors and 11 (8%) dialysis; 15 (11%) patients were treated with chemotherapy and 6 (5%), radiation therapy. Thirty-eight (29%) patients had end-of-life decisions. ICU and hospital mortality were 43% and 60%, respectively. Multivariable analysis identified three independent determinants of hospital mortality: airway obstruction/infiltration by cancer [OR = 2.87 (1.34–8.13), p < 0.001], number of organ failures [OR = 1.91 (1.01–2.74), p = 0.047] and performance status 3–4 before admission [OR = 2.90 (0.94–8.95), p = 0.065]. Conclusions: Improved survival in overall ICU cancer patients extends to patients with lung cancer, including those needing mechanical ventilation. Interestingly, the characteristics of the cancer are not associated with the outcome and should not be the grounds for the ICU decision making. Mortality is increased with the number of organ dysfunctions, in particular when respiratory failure is due to cancer progression.

No significant financial relationships to disclose.
Access to specialized cancer care and clinical trials for cancer patients from non-urban areas is facilitated by a Cancer Network organization
Authors: Brunet J. , Martin B. , Del Barco S. , Juez I. , García A. , Viñas G. , Hernández X. , Arnedos M. , Borràs J. M. , Colomer R.
Published: March 2020

16006

Background: In non-urban areas, there is a controversy about whether medical cancer treatments should be administered exclusively in referral cancer centers (CC) or in community hospitals (CH) (Br J Cancer 2004; 90: 1688). Limitations such as geographical distance or absence of treatment guidelines may reduce the access to specialized cancer care or clinical trials. A network organization that involves at the same time a CC and the CH from the same geographical area may provide an adequate balance between proximity, equity and quality of cancer services. Methods: We designed a cancer network in 2003 in order to consolidate all Oncology resources in an area covering a population of 700,000. A CC is placed adjacent to a general hospital in a centrally located urban area of 250,000. The remaining area is served by 6 CH. Our cancer network is based on: 1) approximately half of the Medical Oncology Dpt staff members work part-time at a CH, participating in outpatient clinic, chemotherapy treatments administration, and multidisciplinary meetings; and 2) other cancer health professionals are organized in network groups like the pharmacy group and the chemotherapy nursing group. Specialized medical cancer care included concomitant radio-chemotherapy, complex outpatient or inpatient therapies, genetic counseling and therapy for some pre-defined malignancies such as germ cell and ovarian cancers. Results: From January to December 2004, 1862 new patients were visited, 1013 (54%) at the CC (Medical Oncology Dpt.), and 849 (46%) at the CH. One-hundred ninety-three cancer patients were referred from the CH to the CC. In total, 141 of the cancer patients seen at the CC were included in clinical trials. It is remarkable that clinical trial participation was much enhanced by referrals, since 101 (72%) of patients in clinical trials came from non-urban areas. Conclusions: The establishment of a cancer network facilitates access to specialized cancer care and clinical trials for patients living in non-urban areas, therefore contributing to therapeutic equity.

No significant financial relationships to disclose.
Using qualitative data to examine disparities in cancer outcomes: Results from interviews with African American (AA) and white (W) patients regarding health beliefs and perceptions of chemotherapy
Authors: Polite B. N. , Gehlert S. , Hlubocky F. , Smith D. , Daugherty C. K.
Published: March 2020

16016

Background: Prior data indicate African Americans are less likely to receive appropriate and timely therapy for breast, colon, and lung cancers. The reasons for this may involve differences in how AA patients (pts) perceive the risks and benefits of available therapies. In general, little is known about the beliefs of pts, and about AA’s in particular, toward the risks and benefits of chemotherapy. Methods: Semi-structured qualitative interviews are being conducted on pts who have been referred to receive chemotherapy for breast, colon, and lung cancer. Results: To date, 18 patients have been interviewed: 9AA, 9W; median age 61 (range 35–77); 11 lung, 4 breast, 3 colon (11 for adjuvant therapy and 7 with metastatic disease). Pts provided their beliefs on the role of chemotherapy. Many described the advantages of chemotherapy indicating the possibility of cure or remission. Others expressed a degree of skepticism about the curative intent of chemotherapy. Many indicated an expectation of moderate to severe side effects that may have lasting effects on the body. Trust in one’s physician and the role of religion/spirituality are also emerging themes. One AA pt described that chemotherapy was a way for physicians to experiment on patients. Others believed that trust in one’s physician was implicit and essential. Many indicated a belief in God but few believed that his/her religious beliefs affected his/her approach to treatment. Conclusions: Consistent with the health beliefs’ model, perceived benefits and perceived barriers (one’s belief about the tangible and psychological costs of the advised action) shape pts’ perceptions of chemotherapy. In this ongoing analysis, the perceived benefits are tempered by a degree of skepticism. The perceived barriers include concerns about the overall impact of chemotherapy on the body and spirit rather than specific short-term side effects. Also, belief in the use of chemotherapy as an experiment is potentially consistent with some African American patients’ perceptions.

No significant financial relationships to disclose.
Health state utility and toxicities in metastatic lung cancer: A qualitative study
Authors: Nafees B. , Stafford M. , Bhalla S. , Watkins J.
Published: March 2020

16017

Background: In metastatic lung cancer, it is expected that quality of life is impacted both by the efficacy and toxicity of therapy. Previous research has reported health states either based on response to therapy or on toxicity, but not in combination. Using methodology applied in breast cancer (Narewska 2005), we developed health state descriptions for advanced non-small cell lung cancer (NSCLC) for use in cost-utility analyses. Methods: An interview discussion and content validation guide was produced based on literature review and clinical input. Response to therapy was described as responding disease, stable disease, or progressive disease. The most common toxicities were selected based on randomized clinical trials. Descriptions of health states were reviewed by clinical specialists. Final health states will be piloted and then used in a societal-based valuation study using standard gamble technique. The contributory effect of disease state and toxicity will be estimated using a mixed model analysis and compared with the data from the previous breast cancer utility study. Results: Eight toxicities were identified: alopecia and grade 3/4 neutropenia, febrile neutropenia, hand-foot syndrome, gastrointestinal (diarrhea/vomiting), rash, stomatitis and fatigue. These were combined with response to therapy to yield 19 health states: 9 responding disease (one with each toxicity plus one with no toxicity), 9 stable disease (one with each toxicity plus one with no toxicity) and one progressive disease (toxicity not included). These health states were reviewed by 6 pulmonary oncologists and 3 specialist nurses. Conclusions: Development of health states that combine both efficacy and toxicity will be useful in evaluating the relative value of therapies for advanced NSCLC and comparison with other diseases. Input by clinical experts has provided validation for the proposed health states. Evaluation of these health states by members of society will provide appropriate perspective for economic evaluations.

[Table: see text]
Involving cancer patients in clinical practice guidelines (CPGs) development in a French guidelines program: What are the key issues?
Authors: Fervers B. , Bataillard A. , Carretier J. , Kelson M.
Published: March 2020

16029

Background: The translation of clinical research knowledge into CPGs involves interpretation of the evidence and value judgments. Patients’ preferences are essential in defining optimal cancer treatment because of the uncertain outcomes and important side effects. Their perspective should therefore be integrated into the development of CPGs (one item of the AGREE instrument). The Standards & Options: Recommandations program (SOR), of the French Federation of Comprehensive Cancer Centres has developed evidence-based cancer CPGs since 1993. To improve the quality and relevance of their CPGs the SOR program decided to develop a comprehensive method to involve cancer patients in the process. Methods: We developed an approach for the French context of cancer CPGs based on 3 inputs 1) Review of the literature from relevant databases and websites. 2) Review of the experiences of the National Institute for Health and Clinical Excellence and the Scottish Intercollegiate Network. 3) Multidisciplinary scientific committee (clinicians, patients, psychologists, sociologists, methodologists and healthy volunteers). Results: The data and the work of the experts allowed to identify the key issues for building a French approach 1) “Patient” includes patients under treatment, former patients, carers, members of a patients’ association, healthy volunteers. Patients are recruited through patients’ associations, clinicians, educational groups, newspaper announcements. 2) The patient plays a significant role in defining the clinical question, particularly the outcomes to be considered as well in the drafting of the CPG. They ensure that a patient perspective complements (and sometimes challenges) the views of professional members of the working group. 3) The major method for involving patients is to have them participate in the working group. 4) To train and support the patients is essential. 5) Informing the working group on the importance of taking into account the patient in the drafting of the CPG is a major issue. 6) A preliminary study demonstrates the feasibility and acceptability of patients’ involvement. Conclusions: This process is valuable and will be implemented in the SOR program.

No significant financial relationships to disclose.
Quality measures for the diagnosis and management of colorectal cancer
Authors: Patwardhan M. B. , Samsa G. P. , Michael M. A. , Prosnitz R. G. , Fisher D. A. , Mantyh C. R. , McCrory D. C.
Published: March 2020

16031

Background: The huge burden of illness from colorectal cancer (CRC) can be reduced by improving the quality of care for CRC patients. Identifying appropriate quality measures that can assess the processes of care is the first step in this process. Therefore we conducted a comprehensive literature search to identify process measures available in the United States to assess the quality of care for diagnosing and managing patients with CRC and the extent to which they were field-ready. Methods: We conducted a standard literature search using MEDLINE and the Cochrane Database; also explored gray literature, and identified 3771 abstracts. By sequential exclusion, 74 of them were finally included. We included quality measures from traditional QI literature, and supplemented them with those included in studies where these measures were used as part of their research agenda. All measures were abstracted into evidence tables and evaluated using a set of standard criteria regarding their importance, usability, and scientific acceptability. In order to assess the extent to which they were field-ready, we devised a summary rating scale for each quality measure using three criteria: importance and usability, scientific acceptability, and extent of testing. Results: Overall, the coverage of general process measures in CRC is extensive. Process measures are available for diagnostic imaging, staging, surgical therapy, adjuvant chemotherapy, adjuvant radiation therapy, and colonoscopic surveillance. The highest rated measures were those related to chemotherapy (abstract submitted by Morse et al) and pathology reporting. There were no process measures for assessing the quality of: polyp removal, surgical management of stage IV rectal cancer, hepatic metastasis, chemotherapy for stage II colon cancer, stage IV rectal cancer, radiation for stage IV rectal cancer, and notes for endoscopy, surgery, chemotherapy and radiology - all because of lack of guidelines. Conclusions: Our evidence report suggests that we need to actively pursue the task of developing scientifically accurate quality measures for leverage points in the diagnosis and management of CRC; so we can evaluate the quality of care delivered by providers and initiate quality improvement activities, with the aim of providing better patient care.

No significant financial relationships to disclose.
Intravenous busulfan and cyclophosphamide as an autologous transplant conditioning regimen for relapsed non-Hodgkin’s lymphoma
Authors: Escalon M. P. , Pereira D. L. , Santos E. S. , Goodman M. , Byrnes J. J. , Fernandez H. F.
Published: March 2020

16508

Purpose: High-dose chemotherapy and hematopoietic stem cell transplantation has become the standard of care for chemosensitive relapsed Non-Hodgkin’s Lymphoma. Multiple conditioning regimens including CBV, BEAM, and BEAC have been used in the past with success. Limitations on the supply of carmustine have made it important to find other effective conditioning regimens. Methods: We retrospectively evaluated the use of intravenous Busulfan and Cyclophosphamide (IV Bu/Cy) as a conditioning regimen for autologous stem cell transplantation in Non-Hodgkin’s Lymphoma patients. Patients were given Busulfan 3.2 mg/kg total intravenously on days -7 to -4 (either once daily or in 2 or 4 divided doses) followed by Cyclophosphamide 120 mg/kg intravenously on days -2 and -1. Results: Forty-four patients, ages 20 to 68 years (median 50) were treated from January 2000 to April 2005. Most patients had diffuse large B-cell lymphoma (n = 29). Of the remaining patients, 8 had follicular lymphoma, 4 had mantle cell lymphoma and 3 had peripheral T-cell lymphoma. At the time of transplant, 27 patients had attained a complete response (CR or CRu) to salvage chemotherapy, 13 patients had achieved a partial response, and 4 had stable disease. The patients received a median of 3.0 × 106 CD34+ cells/kg (range 1.3–16.6 × 106). There were 4 treatment-related deaths by day 100: 1 from sepsis, 1 from pneumonia, and 2 from veno-occlusive disease (VOD). With a median follow-up of 42 months, 3-year Kaplan-Meier estimates of event free and overall survival for the entire cohort were 44% and 45%. For the patients that attained a CR or CRu prior to transplant, the EFS and OS were 42% and 53%, respectively. Conclusions: IV Bu/Cy is a safe and effective conditioning regimen. Due to the incidence of VOD, this regimen should be used with caution in patients with pre-existing hepatic dysfunction. Overall, our outcomes are comparable to that of other published regimens. Further investigation of Busulfan with Cyclophosphamide or with other chemotherapy combinations is warranted.

No significant financial relationships to disclose.
Pilot remission induction therapy with idarubicin, plus intensified dose of Ara-C and priming with granulocyte colony-stimulating factor for acute myeloid leukemia
Authors: Cho Y. , Baek J. , Sohn S. , Chae Y. , Kim D. , Kim J. , Yang D. , Kim Y. , Lee J. , Kim H.
Published: March 2020

16516

Background: The sensitization of leukemic cells with hematopoietic growth factors can enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML). Intensified remission induction (RI) therapy can also improve the treatment results for AML. Therefore, the current trial attempted to evaluate the efficacy and toxicity of granulocyte colony-stimulating factor (G-CSF) priming and a dose intensification of Ara-C in RI chemotherapy for AML. Methods: A total of 29 patients with newly diagnosed AML received G-CSF-priming RI chemotherapy consisting of idarubicin (12 mg/m2, D1–3), G-CSF (150 ug/m2, D3–8), and Ara-C (500 mg/m2, bid, D4–8), and the outcomes were compared with those for a historical group treated with a standard regimen consisting of idarubicin (12 mg/m2, D1–3) and Ara-C (100 mg/m2, D1–7). Results: There was no difference in the sex, age, subtype, and cytogenetic risk between the two groups. The complete remission (CR) rate and treatment-related mortality (TRM) were 72% and 17% for G-CSF-primed group and 71% and 10% for the historical group, respectively (p = 0.89 and p = 0.32). The time to neutrophil and platelet recovery did not differ significantly between the two groups (25 days vs. 24 days, p=0.17; 24 days vs. 23 days, p = 0.23, respectively). Similarly, the duration of fever was also not significantly different (5 days vs. 7 days, p = 0.58). Thirteen patients (45%) experienced fever and 5 patients (17%) manifested skin rashes during the G-CSF priming. After a median follow-up of 336 days, the 1-year overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) rates were 72% vs. 63% (p = 0.83), 74% vs. 56% (p = 0.059), and 53% vs. 38% (p = 0.32), respectively. Conclusion: The G-CSF-priming RI regimen with an intensified dose of Ara-C did not show a superior efficacy when compared with a standard regimen, yet did produce a slightly longer DFS. Therefore, the sensitization of leukemic cells with growth factors and dose intensification would only seem to be a clinically applicable means to enhance the efficacy of RI chemotherapy in selected patients with AML, thereby warranting further studies focusing on specific subgroups of AML patients.

No significant financial relationships to disclose.
Phase I/II study of arsenic trioxide (ATO) in combination with cytosine arabinoside (ARA-C) in patients with myelodysplastic syndromes (MDS)
Authors: Batista W. M. , Hineman L. , Seneviratne L. , Bagdasarian B. , Wada J. K. , Aboulafia D. , Malpass T. , Gota C. H.
Published: March 2020

16525

Background: MDS is a group of myeloid disorders characterized by ineffective erythropoeisis with peripheral pancytopenia. We studied the efficacy and safety of ATO with/without ARA-C. Methods: We enrolled 10 patients with biopsy proven MDS per original FAB classification. See table for treatment design. Response was as follows: for CR the blast count in the BM should be <5% with normal maturation of all cell lines without evidence of dysplasia and PB values of Hemoglobin >11 g/dL, Neutrophils ≥1500/mm3, Platelets ≥100,000/mm3 lasting 2 months without transfusion support. PR was all of CR criteria except blasts decreased by > 50% over pretreatment or a less advanced MDS FAB classification than pretreatment. SD was failure to achieve at least a PR but without evidence of progression for at least 2 months. Results: 3 of 10 patients completed the study. 7 did not complete due to: 1 death from unrelated causes, 1 death from PD, 2 subjects withdrew, 2 were withdrawn at physician’s discretion, 1 withdrawal from toxicity. Of the 3 patients who completed study, 2 had SD and 1 had PR. 1 SD patient is alive 2 years later with transfusion support and another patient lasted 6 months before requiring transfusion. PR patient succumbed to acute myelogenous leukemia 12 months post-treatment. Conclusions: ATO with ARA-C appears to be an active regimen for patients with high risk MDS. Additional studies are warranted to confirm these findings.

[Table: see text]

[Table: see text]
Variable clinical response of hypereosinophilic syndromes (HES) to current therapeutic options
Authors: Mitra S. , Murphy P. T. , O’Donnell J. R.
Published: March 2020

16527

The term Hypereosinophilic syndrome (HES) refers to a heterogeneous group of disorders characterised by marked blood (>1500/cu mm) and tissue eosinophilia resulting in end organ damage.Several visceral complications like cardiomyopathies and cerebrovascular accidents are common. Treatment of HES includes corticosteroids,chemotherapeutic agents (hydroxyurea, cyclophosphamide, vincristine), interferon-alpha. Newer treatment modalities,including tyrosine kinase inhibitors (eg Imatinib) and monoclonal anti IL5 antibodies are now available. We report a case series of patients with HES which demonstrate the variable clinical response to above therapeutic options. Case 1: A 43 year old man who presented with a right lacunar infarct had a eosinophil count of 1200/cu mm. No cause was found. He also had Mitral valve endocarditis. Following initial treatment with Methylprednisolone, the eosinophil count came down to 3500/cu mm, but the eosinophilia persisted. He was given a trial of Imatinib. In 2 months time his eosinophilia resolved. However, he was negative for FILIPI-PDGFRa. Case 2: A 37 year old lady with history of Splenectomy (due to trauma) presented with a eosinophil count of 2660/cu mm. Result of the FILIPI-PDGFRa was equivocal. There was no response to Imatinib. A trial of Prednisolone (1 mg/Kg) was ineffective. She did not respond to Interferon-alpha. However when given a combination of Prednisolone (0.5 mg/kg) and Interferon-alfa, her counts were normal in a month. Case 3: A 63 year old man with history of Atrial Fibrillation had persistent eosinophilia (>1500/cu mm). His serum Tryptase was raised but he was negative for FILIPI-PDGFRa. A trial of Imatinib failed He responded partially to high dose of Hydroxyurea. Prednisolone, Interferon-alpha or a combination of both are future options for him. Case 4: A 80 year old man with background history of Alzheimer’s Disease was found to have persistent unexplained eosinophilia. He had no complains of joint symptoms but his ANF was positive in low titres. A bone marrow showed no evidence of lymphoma or a myeloproliferative disorder. Karyotype was normal. He was given a trial of Hydroxyurea to which he responded in two weeks. Thus, response of HES patients to treatment is variable often unpredictable.

No significant financial relationships to disclose.
Arsenic trioxide as primary treatment in acute promyelocytic leukemia
Authors: Aziz S. A.
Published: March 2020

16533

Acute Promyelocytic Leukemia (APL) is a separate, distinct and biologically unique subset of Acute Myelogenous Leukemia (AML). The affordability of ATRA is detrimental for its use especially in the developing world. The use of Arsenic trioxide (As2O3) has radically changed the treatment, initially for relapsed APL and now is being used upfront as first line therapy in APL some studies. We accrued 11 cases (6 males, 5 females) of APL for the past 1 year. 2 patients of these had been already treated with ATRA + chemotherapy (Daunorubicin and Cytosine Arabanoside). These relapsed patients were switched over to Arsenic trioxide. One of these relapsed patients has completed the treatment and is in CR for the past 6 months after completing treatment. The other patient has recently completed the treatment and is in remission. 9 of our patients are newly diagnosed and could not afford ATRA and chemotherapy. All these patients were explained the treatment protocol and after obtaining a formal consent, patients were put on Arsenic trioxide. The protocol consists of Induction therapy with Arsenic trioxide given in a dose of 0.15 mg/kg/day till CR is achieved or to a maximum of 60 doses, followed by Consolidation treatment with Arsenic trioxide in the similar dose schedule but only for 28 days, and finally Maintenance therapy with Arsenic trioxide every 10 days a month for a total of 6 months with an interval of 4–6 weeks in between the cycles. Of the remaining patients (n = 7), 2 patients did not respond to Arsenic trioxide after 60 doses. The remaining patients (n = 5) are in different phases of treatment (all having completed Induction therapy) and are presently in CR (Mean duration to avhieve CR-57 days, documented by bone marrow examination). There were no major morbidities and none of our patients exhibited APL syndrome. The lower cost of treatment with Arsenic trioxide (Approx. Rs. 50–60,000) compared to ATRA + chemotherapy (Approx. Rs. 90,000–1,10,000), the magnitude of response and the least encountered adverse effects seem awesome in this treatment especially in the developing countries.

No significant financial relationships to disclose.
Topotecan—Single agent activity in a weekly intravenous (IV) schedule for first-line therapy in poor prognosis extensive stage small cell lung cancer (SCLC): A Minnie Pearl Cancer Research Network phase II trial
Authors: Murphy P. B. , Hainsworth J. D. , Spigel D. R. , Gray J. R. , Liggett W. H. , Shipley D. L. , Switzer A. , Gandhi J. G. , Dannaher C. L. , Greco F. A.
Published: March 2020

17000

Background: Topotecan IV weekly produces significantly less myelotoxicity than the standard 5-day IV schedule and appears as active in patients (pts) with relapsed ovarian cancer. Topotecan 5-day IV schedule is the standard for second-line therapy for pts with sensitive relapse SCLC. Methods: The primary endpoints were to determine the response rate and toxicity of weekly topotecan IV in pts with previously untreated extensive stage SCLC who were elderly, with poor performance status (PS), or severe coexistent medical illness. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be eligible. Results: 39 pts were enrolled: 21 men, 18 women; age range 60–90 (median 71); PS 0 = 2, 1 = 18, 2 = 19). 31 pts were evaluable by WHO criteria for response. 4 pts had partial responses (13%, 95% CI 4%-30%); 20 pts (65%) had stable disease (4 had minor responses with tumor shrinkage of 29%, 19%, 12%, and 5%); 7 pts had progressive disease (22%). 15 pts completed 12 weeks of therapy. Grade 3/4 neutropenia/thrombocytopenia was seen in 11 pts and 3 pts; grade 3 infection 4 pts; grade 3/4 fatigue 12 pts. A total of 225 weeks of therapy was administered with 32 weeks of treatment delay and 10% required dose reduction. There were no treatment-related deaths. The median and 1-year survival of PR/stable pts were 5.6 months and 24%. Conclusions: Topotecan IV weekly has activity and was relatively well tolerated as first-line therapy in this very poor prognostic group of pts with extensive stage SCLC. The therapeutic index is improved with weekly topotecan IV schedule in contrast to the 5-day IV schedule. Additional study of weekly topotecan in combination with other agents in SCLC is warranted.

[Table: see text]
A randomized phase II trial comparing carboplatin pleurodesis with cisplatin pleurodesis in patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with malignant pleural effusions (MPE)
Authors: Sasaki T. , Yasuda H. , Nakayama K. , Okinaga S. , Suzuki T. , Asada M. , Kanda A. , Shindo T. , Ohuchi Y. , Yamaya M.
Published: March 2020

17012

Background: We previously reported that carboplatin pleurodesis in patients with advanced lung adenocarcinoma with MPE, renal insufficiency, and poor performance status (PS) was an effective palliative therapy. However, the efficacy and toxicity profile of carboplatin pleurodesis in patients with NSCLC with MPE in comparison with those of cisplatin pleurodesis have not been reported. Methods: Thirty patients with stage IIIB/IV NSCLC accompanied with MPE who did not have an indication for systemic chemotherapy because of poor PS more than 2 were randomized to carboplatin pleurodesis (target area under the curve as 5 μg-min/ml using Calvert’s formula) and cisplatin pleurodesis (80 mg/m2) in a single-blind and controlled trial. Enrollment took place between Oct 2004 and Dec 2005. Primary efficacy endpoints were the best confirmed response rate, time to progression (TTP) in controlling MPE and adverse effects. Results: Fifteen of 30 patients were treated by carboplatin pleurodesis, and resting 15 of 30 patients were treated by cisplatin pleurodesis to control MPE. The response rate in carboplatin pleurodesis was not statistically different from that for patients in cisplatin pleurodesis (P = .226). The use of anticancer drugs for pleurodesis was not significantly associated with response rate in logistic regression analysis (relative risk = 14.2, 95% CI: 0.6–320.5, P = .095). Median TTP in carboplatin pleurodesis was not different from that in cisplatin pleurodesis (96 days vs 83 days). The use of carboplatin for pleurodesis (P = .016) and gender (P = .005) were associated with prolongation of TTP in the Cox regression method. Kaplan-Meier analysis showed that the progression free probability curve in carboplatin pleurodesis was not different from that in cisplatin pleurodesis (P = .275). The rate of Grade 3 thrombocytopenia in carboplatin pleurodesis (25%) was higher than that in cisplatin pleurodesis (0%), but there was no statistical significance (P = .096). Conclusions: Carboplatin pleurodesis and cisplatin pleurodesis may be feasible and acceptable toxicity profiles.

No significant financial relationships to disclose.
Second line chemotherapy with topotecan and gemcitabine in small cell lung cancer (SCLC) patients: An Alpe-Adria Thoracic Oncology Multidisciplinary group phase II study (ATOM 012)
Authors: Belvedere O. , Sacco C. , Ardizzoni A. , Rossetto C. , Follador A. , Sibau A. , Tumolo S. , Defferrari C. , Fasola G. , Grossi F.
Published: March 2020

17014

Background: Topotecan is the only single agent currently approved for the treatment of relapsed or recurrent SCLC, showing activity both in chemotherapy-refractory (RR 2–14%) and in chemotherapy-sensitive patients (RR 14–38%). The role of topotecan in combination with other active agents is still under investigation. Methods: Aim of this phase II study is to assess the activity and safety of topotecan (1mg/sqm iv d1–5) plus gemcitabine (1250 mg/sqm iv d1) in relapsed or recurrent SCLC patients. Treatment is repeated every 4 weeks, up to a maximum of 6 cycles. Eligibility criteria: histologically or cytologically confirmed SCLC; documented progressive disease after ≥ 1 chemotherapy regimen; age ≥ 18 yrs; ECOG PS 0–2; measurable disease (RECIST); no prior treatment with topotecan or gemcitabine; adequate hematologic, hepatic and renal function; brain metastases are allowed. Results: A total of 44 patients have been enrolled. Patient characteristics are as follows: median age, 64 yrs (range 35–77); male/female, 35/9; ECOG PS 0/1/2, 12/21/11 patients; 68% patients had sensitive disease (recurrence > 3 months after first-line chemotherapy) and 32% patients had refractory disease (failure ≤3 months after first-line chemotherapy). One-hundred and seventeen chemotherapy courses have been administered (median 2, range 1–6). The following preliminary results refer to 37 patients. Grade 3–4 toxicities: 54% neutropenia, 16% anemia, 46% thrombocytopenia, 13% neutropenic fever, 27% fatigue. One toxic death was observed. Objective responses have been documented in 9 patients, for an overall response rate of 24% (3% CR, 21% PR); SD was observed in 7 patients (19%), PD in 17 patients (46%). Four early deaths were reported. Median time to progression is 8.9 weeks. Median survival time is 16.3 weeks, and 1-year survival rate is 14%. Conclusions: Based on these preliminary results, the combination of topotecan plus gemcitabine shows moderate activity and an acceptable toxicity profile in previously treated SCLC patients. However, it is unlikely that the addition of gemcitabine improves the outcome compared to single agent topotecan.

No significant financial relationships to disclose.
Survival in previously treated advanced NSCLC: Pemetrexed versus best supportive care (BSC)
Authors: Fossella F. V. , Berry D. A. , Adachi S. , McAndrews P. , Peterson P.
Published: March 2020

17015

Background: Patients with advanced NSCLC who progress following initial treatment have several approved secondary treatment options including single agent intravenous chemotherapy (docetaxel or pemetrexed) and an oral EGFR tyrosine kinase inhibitor (erlotinib). Docetaxel and erlotinib were shown in randomized trials to have an overall survival (OS) advantage over BSC. On the other hand, pemetrexed was approved based on a randomized trial (JMEI) in which it showed clinically equivalent survival to docetaxel. Investigators felt that it was not ethical to compare pemetrexed to BSC because docetaxel was approved in that setting. However, indirect comparisons of pemetrexed with BSC are possible and are legitimate statistically. Methods: We used summary data from JMEI and TAX317(b) in the analysis. Studies BR21 and ISEL provide relevant data from recent trials with a BSC arm. We based comparisons on the logarithms of these HRs and their variances in proportional hazards models, accounting for interstudy variability. Results: Patients in these studies had similar prognostic characteristics. Docetaxel in TAX317(b) showed a significant survival benefit over BSC (HR = 0.56, 95% CI 0.35–0.88). In JMEI, the pemetrexed over docetaxel HR was 0.99 (95% CI 0.82–1.20). The HR of pemetrexed over BSC for survival was 0.55 (95% CI 0.33–0.90). The similarity of median OS for the placebo (or BSC) arms of studies TAX317(b), BR21 and ISEL supports the above analysis. Conclusions: In comparison with BSC pemetrexed lowers the hazard of mortality in previously treated advanced NSCLC by an estimated 45% (95% CI 10%-67%).

[Table: see text]

[Table: see text]
Neoadjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM): An Italian experience with cisplatin-based regimens
Authors: Marino A. , Pinto C. , Mutri V. , Galetta D. , Di Bisceglie M. , Bini A. , Dell’amore D. , Sacco R. , Gentile A. L. , Martoni A. A.
Published: March 2020

17022

Background: We have evaluated the feasibility and the impact on survival of two different preoperative chemotherapy regimens in potentially resectable MPM. Methods: Eligibility criteria were: histologically confirmed MPM, stage T1–3 N0–2 M0, adequate organ function, KPS ≥80. A first group of pts (group A) received cisplatin 75 mg/m2 d1 and gemcitabine 1200 mg/m2 d1,8, every 3 weeks for 4 courses, followed by EPP and by 6 courses of adjuvant chemotherapy with mitoxantrone 10 mg/m2 d1, methotrexate 35 mg/m2 d1 and mitomycin 7 mg/m2 d1, every 3 weeks with mitomycin in alternate cycles. A second group of pts (group B) received cisplatin 75 mg/m2 d1 plus pemetrexed 500 mg/m2 d1 with full vitamin supplementation for 4 cycles. In each group, only pts with metastatic lymph nodes and/or positive resection margins underwent radiotherapy after EPP. Results: Twenty-five pts were enrolled from February 2000 to August 2005 (8 in group A and 17 in group B). Pt characteristics were: 21 (84%) males and 4 (16%) females, asbestos exposure in 16 (64%) pts, median age 64 years (range, 51–72), median KPS 100 (80–100), histological subtype: 19 (76%) epithelial, 2 (8%) sarcomatous, 3 (12%) mixed, 1 (4%) unknown; IMIG stage: 6 (24%) I, 14 (56%) II, 5 (20%) III. Clinical response to neoadjuvant chemotherapy consisted of 4 (16%) CR, 2 (8%) PR, 11 (44%) SD, 5 (20%) PD; 3 (12%) pts were not evaluable. The overall response rate (CR + PR) was 24% (95% CI: 9.4 - 45.1). Toxicity was mild in each group. Fourteen (56%) pts have undergone EPP, 5 (20%) pleurectomy and 6 (24%) pts were inoperable. Three postoperative complications and two postoperative deaths (one for controlateral pneumonia and one for ARDS) occurred after EPP. The 1-year survival rate was 60%. Long-term survivors (≥18 months) included 5 pts who had undergone EPP (18, 26, 54, 57 and 63 months) and 2 pts who had undergone pleurectomy (22 and 32 months). Conclusions: These preliminary data, albeit in a small series, suggest that preoperative chemotherapy followed by EPP is a feasible approach to be investigated in larger trials in pts with MPM.

No significant financial relationships to disclose.
Role of early serial change in serum carcinoembryonic antigen levels as a predictive marker for gefitinib sensitivity in Japanese patients with non-small cell lung cancer
Authors: Hotta K. , Kiura K. , Tabata M. , Takigawa N. , Fujiwara Y. , Umemura S. , Hosokawa S. , Hisamoto A. , Ueoka H. , Tanimoto M.
Published: March 2020

17029

Background: The aim was to evaluate the utility of an early change in CEA levels for predicting subsequent gefitinib sensitivity in NSCLC patients. Methods: CEA level was measured before and after the beginning of gefitinib treatment (day1) in 110 (91%) of consecutive 121 patients. Daily decline rate of CEA was simply defined for each patient as follows: (M0−Mx)/Dx/M0*100(%), with the baseline level (M0), the level on days × (Mx), and days from day 1 to day X (Dx). Results: Patient characteristics were as follows; median age: 62, M/F: 61/39%, Ad/others: 84/16% and smoker: 66%. Objective response rate and disease control rate were 28.2% and 74.5%, respectively. Median baseline CEA level was 12.6 ng/mL. Daily decline rate of CEA level from day 1 to the date on which confirmation of objective response was performed significantly differed among the response categories; median decreases in percentages were 0.86, 0.06, and −1.52%/day in CR/PR, SD, and PD patients, respectively (p < 0.0001). This association was more evident in the 70 patients with abnormal baseline CEA level (≥5.0 ng/mL). A cutoff level of −0.58% decrease per day most accurately reflected tumor shrinkage in the 70 patients, with sensitivity, specificity, and positive and negative predictive values for disease control (CR/PR/SD) of 89.1, 73.3, 92.5 and 64.7%, respectively. Among 49 (41%) patients reassessed CEA levels within the first 2 weeks since day 1, 41 could continue the treatment without any disease progression during this period. The daily decline rate in this early phase tended to differ between the responses (median; 1.57 and −0.50% in CR/PR/SD and PD, respectively; p = 0.0975), and less exactly reflected disease control with sensitivity, specificity, and positive and negative predictive values of 82.1, 40.0, 88.5, and 28.6%, respectively when a cutoff of −0.58% was applied. Conclusion: Degree of change in CEA level from the start of gefitinib treatment to confirmation of objective response significantly correlated with tumor shrinkage. As a predictor for obtaining disease control, monitoring early change in CEA level might be useful due to high sensitivity and positive predictive value, in spite of low specificity for detection of PD patients.

No significant financial relationships to disclose.