Hari Menon

A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer

BACKGROUND This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab. PATIENTS AND METHODS Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). RESULTS ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies. CONCLUSIONS The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.

Brain metastasis-evidence based management

Advances in cancer management have resulted in a significant increase in median survival of number of diseases. Consequently we are seeing more patients living long enough to develop symptomatic brain metastases. The management of such patients will be discussed here. The most important definitive investigation is contrast enhanced MRI scan of brain. Management consists of supportive care and disease directed treatment. Surgical resection remains the gold standard for the treatment of solitary brain metastases. Whole brain radiotherapy is considered standard treatment for all patients with brain metastases. The role of chemotherapy was limited in the past. Recently several new agents have been identified as potentially useful. Preliminary results indicate that drugs like temozolomide and topotecan have antitumor activity against the brain metastases as well as the primary systemic malignancies. The goal of multimodality treatment for brain metastases is to palliate local symptoms and prevent consequences of neurological involvement.

Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors

Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952)

Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide

SummaryWe report the case of a 30-year-old woman with glioblastoma multiforme (GBM) treated with surgery followed by concomitant Temozolomide (TMZ) and external beam radiation, which she tolerated well without any interruptions. However, when she was being evaluated for adjuvant Temozolomide, she developed progressive decline in leukocyte counts and platelet counts and subsequently, febrile neutropenia with bleeding manifestations. A bone marrow aspiration and biopsy done showed a gross hypocellular bone marrow with very few erythriod and myeloid cells and no suggestion of progenitor cells, consistent with aplastic anemia.

Comparison of the efficacy and safety of Rituximab (Mabthera™) and its biosimilar (Reditux™) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: A retrospective analysis

Background: Rituximab (Mabthera™) have been in use in India since 2000. A biosimilar molecule of rituximab (Reditux™) was approved in India in 2007. This retrospective audit was done to compare the efficacy and safety of Mabthera™ with Reditux™. Materials and Methods: We reviewed the charts of 223 adult diffuse large B-cell lymphoma patients who had received cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab chemotherapy. Tumor recurrence, survival and toxicities experienced during chemotherapy were obtained from the patient charts. The survival analysis was restricted to patients who received at least 4 cycles of the same brand. Results: Of the 223 patients evaluated, 101 received Mabthera™, 72 received Reditux™. There were no differences in the infusional reaction rates, grades 3 and 4 neutropenia and oral mucositis between the two brands. Complete-remission (CR) rates were similar with Mabthera™ and Reditux™ (75% and 82%, respectively; P = 0.294). The progression free survival (PFS) rate at 5 years were 72% in Mabthera™ and 81% in Reditux™ (P = 0.382). The overall survival (OS) at 5 years were comparable in the two groups (66% in Mabthera™ and 76% in Reditux™; P = 0.264). Conclusion: We observed no significant differences in the toxicity, tumor response rates, PFS and OS between the two available brands of rituximab.

Clinicopathologic study and outcome analysis of thyroid lymphomas: Experience from a tertiary cancer center

The aim of this study was to review clinicopathologic presentations of patients diagnosed with thyroid lymphomas at a tertiary cancer center. Thyroid lymphomas represent less than 2% of all lymphomas.

Large cell neuroendocrine carcinoma of the endometrium: An extremely uncommon diagnosis, but worth the efforts

Neuroendocrine carcinomas (NEC) of the female genital tract are aggressive and uncommon tumors. They usually involve the cervix and ovary, and are seen very rarely in the endometrium. The overwhelming majority of endometrial NECs are of conventional small cell type (up to 60 cases). Only seven cases of large cell type NEC of the endometrium have been reported. We report a case of large-cell neuroendocrine carcinoma (LCNEC) of the endometrium in a 70-year-old female. The case is described for its rarity and shows that a high index of suspicion can help the pathologist to use immunohistochemistry and in turn help in selection of appropriate chemotherapy.

Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia

According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years. The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India. This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India.

Avascular necrosis of head of femur in a patient with acute promyelocytic leukemia.

Avascular necrosis (AVN) of head of the femur is associated with various pathological conditions and treatment modalities. We present a case of acute promyelocytic leukemia who was treated with all-transretinoic acid (ATRA), daunomycin, cytarabine and a short course of dex-amethasone. He developed AVN of bone after 2 years of treatment. Whether this is related to ATRA is dealt with in the discussion.

A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome TM ) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India

BACKGROUND In patients with persistent fever and netropenia, amphotericin B is administered empirically for early treatment and prevention of systemic fungal infections. Despite this treatment, there are chances of breakthrough fungal infections and drug is also toxic. MATERIALS AND METHODS A multicentric, randomized, controlled clinical trial was conducted to compare liposomal amphotericin B two doses with conventional amphotericin B as empirical antifungal therapy. RESULTS The average body weight of patients was 26.4 ± 14.8 (n=22), 32.9 ± 19.4 (n=23) and 37.9 ± 20.0 (n=20) kg in 1 mg, 3 mg Fungisome (liposomal amphotericin B) and 1 mg/kg/day conventional amphotericin B group, respectively. The mean age was 16.2 ± 13.4, 16.0 ± 10.9 and 22.7 ± 16.2 yrs in 1 and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional AMP B group, respectively. The average duration of treatment with 1 mg and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional amphotericin B was 17 ± 9.8, 16.2 ± 8.3, and 14.7 ± 10.7 days, respectively. The time to resolve fever was 13.3 ± 10.2, 10.9 ± 7.1, 10.1 ± 6.7 days, and for absolute neutrophil count (ANC) to be above 500 cells per microliter, it took 13.4 ± 9.6, 10.6 ± 7.6 and 7.3 ± 3.4 days, respectively. Liposomal formulations were well-tolerated compared to conventional amphotericin B. CONCLUSIONS This small randomized study showed that the indigenous liposomal formulation Fungisome appears to be equally efficacious and safer than conventional amphotericin B. Also, the lower dose Fungisome (1 mg/kg/day) appears to be equally efficacious and was well-tolerated as compared to higher dose Fungisome (3 mg/kg/day). Treatment cost would be a major factor for limiting use of higher dose of Fungisome.