Clinical and economic implications of the use of nanoparticle paclitaxel (Nanoxel) in India.

Paclitaxel (Taxol), one of the most commonly used chemotherapeutic agents, is poorly soluble in water and requires cremophor, which often causes infusion reactions, as a solvent. Nanoxel, a nanoparticle formulation of the taxane, has been approved by the Indian regulatory authority. In the present article, we aim to describe the experience with the use of Nanoxel in India and its clinical and economic implications. We present three retrospective series in a common practice environment and an economic model. The first series shows no reactions in 596 Nanoxel infusions; the second series shows comparable adverse events other than infusion reactions between 83 patients who received Nanoxel and 32 treated with conventional paclitaxel. The third reveals comparable clinical outcomes for 51 patients treated with Nanoxel or conventional paclitaxel for gastroesophageal tumors. Finally, we describe an economic model which estimates savings of 21 580 Indian rupees per cycle with Nanoxel vis-à-vis conventional paclitaxel in the treatment of solid tumors in India. In conclusion, in an era in which the greatest challenge we face as medical oncologists is how to conciliate hard-won and incremental--but small--improvements in survival with exponentially rising drugs costs, it is refreshing to see a potential new formulation of a commonly used drug that may actually generate cost-savings while improving clinical outcomes and patient well-being. Further studies are clearly warranted to determine the optimal dose and schedule for Nanoxel as well as its comparative effectiveness to cremophor-based paclitaxel.

Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors.

Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m² twice daily days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.

Identification of PML/RARalpha fusion gene transcripts that showed no t(15;17) with conventional karyotyping and fluorescent in situ hybridization.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation, t(15;17)(q22;q11-21), resulting in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARalpha) genes. Using conventional cytogenetic methods, these translocations are normally detected in about 70-90% of patients; most negative results are due to technical problems or cryptic variants. These masked PML/RARalpha fusions can be identified by molecular analyses, such as reverse transcriptase-polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH). Approximately 5 to 10% of all APL cases reported do not show PML/RARalpha fusion transcripts, even with dual-colored FISH. We report three of 40 diagnosed APL cases that showed morphological, cytochemical, and immunophenotypic features of hypergranular APL, but did not show a PML/RARalpha fusion signal or any of its variants, on FISH. All cases were identified by RT-PCR, which was further confirmed by cDNA sequencing. Conventional karyotyping showed other clonal aberrations in these cases, but failed to show t(15;17) or any other variants or complex translocations.

First-line management of metastatic non-small cell lung cancer: An Indian perspective.

Lung cancer has been the most common cancer in the world for several decades. The non-small cell lung cancer (NSCLC) constitutes approximately about 80% of the total cases of lung cancer. Therapeutic interventions in NSCLC have shifted to the target-based approach from histology-based approach, and this has completely changed the face of the management of NSCLC. Developing countries, such as India, have very limited data compiled about the prevalence and treatment practices of lung cancer, despite a large burden of the disease. However, in recent times, there has been a lot of data generated in this regard. This article is an attempt to collate and shine light on the available data for the first-line treatment of NSCLC in India keeping in mind the current standards of care in this area.

Fludarabine in lymphoproliferative malignancies: a single-centre experience.

BACKGROUND: Fludarabine has been reported to be an effective drug for the treatment of chronic lymphocytic leukaemia (CLL) and indolent lymphomas. However, its safety and efficacy in Indian patients has not been studied. We retrospectively analysed our experience with fludarabine in low grade lymphomas and CLL. METHODS: The records of all patients with low grade lymphoma or CLL who received fludarabine between April 1999 and November 2006 were analysed. Response evaluation was done as per the National Cancer Institute-Working Group guidelines for CLL and International Workshop criteria for non-Hodgkin lymphomas, respectively, in those patients who received at least 3 cycles of fludarabine. Toxicity was graded as per the common terminology criteria for adverse events, version 3.0. Median event-free survival was obtained using Kaplan-Meier survival analysis. RESULTS: Forty-seven patients were included in the study and 189 cycles were administered (median: 4 cycles per patient). Sixteen patients had a treatment delay, 14 due to myelosuppression. Twenty-five patients had low grade lymphoma and 22 had CLL. The response was evaluable in 22 patients with low grade lymphoma and 20 with CLL. The overall response rate for CLL was 100% in those treated upfront (n=9) and 55% in those with relapsed disease (n=11). The overall response rate for low grade lymphoma was 88% (63% complete remission) in untreated patients and 79% (43% complete remission) in those with relapsed disease. Common adverse events were myelosuppression and infection. Two patients died of sepsis and 4 due to disease progression on treatment. Median event-free survival for patients treated upfront with fludarabine was 31.4 months. CONCLUSION: In our patient population, response to fludarabine is similar to that in the published literature. Our patients had a higher frequency of haematological toxicity.

Newer therapeutic molecules for multiple myeloma.

Therapeutic management of multiple myeloma (MM) for the last several decades has mainly involved regimens based on use of glucocorticoids and cytotoxic chemotherapeutics. Despite progress in delineating the activity of such regimens, at either conventional or high doses, MM has remained an incurable disease. This has sparked major interest in the development of novel therapies that in part capitalize on recent advances in our understanding of the biology of MM, including the molecular mechanisms by which MM cell-host bone marrow (BM) interactions regulate tumor-cell growth, survival, and drug resistance in the BM milieu. Herein, we review the latest progress in the development of these novel anti-MM therapies, with major focus on therapies which have translated from preclinical evaluation to clinical application, including thalidomide and its more potent immunomodulatory derivatives (IMiD), the first-in-class proteasome inhibitor bortezomib (formerly known as PS-341). Search strategy included Medline using the terms 'Myeloma and Newer Drugs' citations relevant to treatment guidelines issued in 1999 and 2008 were screened.

Practical consensus recommendations for tumor margins and breast conservative surgery.

My suggestion: There is no difference in survival of breast cancer patients treated with either mastectomy or with breast conservation therapy combined with external beam radiotherapy. A positive margin (s) is an important factor contributing to the increased risk of local recurrence. However, in published literature, there is a lack of consensus on the definition of acceptable margin (s). As a result decision process about need for re-excision after positive margins remains uncrear.

Practical consensus recommendations for gestational breast cancer.

This manuscript provides a practical and easy to use consensus recommendation to community oncologists on how to manage gestational breast cancer.

Practical consensus recommendations on fertility preservation in patients with breast cancer.

Young women diagnosed with cancer today have a greater chance of long-term survival than ever before. Successful survivorship for this group of patients includes maintaining a high quality of life after a cancer diagnosis and treatment; however, lifesaving treatments such as chemotherapy, radiation, and surgery can impact survivors by impairing reproductive and endocrine health. Expert oncologists along with reproductive medicine specialists discuss fertility preservation options in this chapter since fertility preservation is becoming a priority for young women with breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations for the benefit of community oncologists.

Practical consensus recommendations regarding the management of sentinel lymph node issues in early breast cancer.

Axillary lymph node involvement is a very important poor prognostic factor in the clinical staging and management of breast cancer patients. Traditionally, axillary lymph node dissection (ALND) has been used for determining the status of the axillary lymph nodes. More recently the sentinel lymph node biopsy (SLNB) procedure has gained wider acceptance as the standard of care, having the advantage of being less invasivewhile providing good accuracy. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of the two different procedures and other issues in patients with early breast cancer for the benefit of community oncologists.

Practical consensus recommendations regarding the management of HER2 neu positive metastatic breast cancer.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors, including where the cancer has spread, the patient's overall health, and the levels of hormone receptors and HER2 in the tumour. Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours.[7],[8],[9],[10] This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of these agents and the management of HER2 positive MBC for the benefit of community oncologists.

Practical consensus recommendations for neo-adjuvant chemotherapy in triple negative breast cancer.

This manuscript provides a practical and easy to use consensus recommendation to community oncologists on how to use neoadjuvant chemotherapy in triple negative breast cancer patients.

Activity and toxicity of 2-CDA in Langerhans cell histiocytosis: a single institutional experience.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of immature and abnormal bone marrow derived langerhans cells. Treatment is usually multimodal. Potent anti-monocyte as well as immunomodulatory activity of 2-CDA and its proven efficacy in many lymphoproliferative disorders has made 2-CDA a rational choice in treatment of LCH. AIM: To evaluate the efficacy and toxicity profile of 2-CDA in children with relapsed or refractory LCH. SETTING AND DESIGN: This is a pilot study and we present the initial data of the first seven patients treated at our institution. MATERIALS AND METHODS: Seven patients of relapsed and refractory LCH were enrolled from July 2000 to June 2004. The cohort of seven patients included six males and one female with a median age at initiation of cladribine was 2.25 years (range, 1.67 to 7.0 years). Three patients had received one prior chemotherapy regimen while the rest were heavily pretreated. Cladribine was administered over two hours IV daily for five days and repeated every four weeks. RESULTS: After a median of six courses of cladribine (range, 2 to 9), two (33%) patients achieved PR and two (33%) patients have SD on imaging but are clinically better. None experienced grade 3 or 4 hematologic toxicity. At a median follow-up of 19 months (range, 8 to 52 months), five patients remain alive and one patient has died. CONCLUSION: Our study shows that single agent 2-CDA is active and well-tolerated in children with relapsed or refractory LCH.

In vitro chemosensitivity profile of oral squamous cell cancer and its correlation with clinical response to chemotherapy.

CONTEXT: Oral cancers represent a disparate group of tumors with diverse clinical behavior and chemosensitivity profile. Currently, it is difficult to predict whether a tumor will respond to chemotherapy and which drug(s) will achieve the maximum clinical response. AIMS: To study in vitro chemosensitivity profile of oral cancers and to correlate the in vitro chemosensitivity of oral cancer to clinical response to chemotherapy. SETTINGS AND DESIGN: Prospective study in a tertiary cancer care center. METHODS AND MATERIAL: We prospectively studied the chemosensitivity profile of 57 untreated, advanced, unresectable oral cancers to cisplatin, methotrexate, 5-fluorouracil and their combinations by using histoculture drug response assay (HDRA) and correlated them to the clinical response to chemotherapy. STATISTICAL ANALYSIS USED: Chi Square test. RESULTS: Biopsy samples were successfully histocultured in 52/57 (91%) cases. Of these 52 evaluable patients, 47 had primary gingivo-buccal cancers and five had tongue / floor of mouth cancers. Based on the assay, 27 (52%) tumors were sensitive to cisplatin, 27 (52%) to methotrexate, 24 (46%) to 5-fluorouracil, 38 (73%) to combination of cisplatin and methotrexate and 36 (69%) to combination of cisplatin and 5-fluorouracil. Of these, 31 patients with good performance status received two cycles of chemotherapy using one or more of these test drugs. There was a significant correlation (p=0.03) between the in vitro chemosensitivity and the clinical response. Negative predictive value of the test was 80%, positive predictive value-69%, sensitivity-79% and specificity -71%. The overall accuracy of the assay was 74%. CONCLUSIONS: We found HDRA to be a fairly good predictor of chemo-response of oral cancer.

Metachronous gastric diffuse large B-cell lymphoma and adenocarcinoma.

The development of gastric carcinoma in a patient with gastric lymphoma is rare. Helicobacter pylori is a common etiologic agent for both these conditions. We report a 38-year-old lady who was initially diagnosed to have gastric lymphoma and developed early gastric carcinoma on follow up. She was operated on for the carcinoma and is in complete remission since.

Successful complete regression of isolated intramedullary spinal cord metastases from epithelial ovarian carcinoma with chemotherapy and radiotherapy.

Advances in the management of ovarian cancer by use of aggressive surgery and effective platinum-based chemotherapy have prolonged survival; this may have resulted in an alteration of the metastatic pattern of the disease and spread to unusual sites (e.g, CNS) has become more common. Also, with the availability of more sensitive imaging techniques, these tumors are being diagnosed with increasing frequency. Intramedullary spinal cord metastasis is rare. We report one such case treated successfully with chemotherapy and radiotherapy with long-term survival.

Rituximab (anti-CD20 monoclonal antibody) in lymphoproliferative malignancies: Tata Memorial experience.

Rituximab has been used extensively in lymphoproliferative disorders. We evaluated the results of 64 consecutive patients treated between 2001 and 2004 at our institution. This included 54 males and 10 females. The median age was 54 years (range 17 to 85 years). One-fourth of patients were above 60 years. The histology was aggressive NHL in 35, indolent NHL in 22 and 7 cases were diagnosed as CLL. Among NHL, sixteen were in early stage (I/II) and the remaining forty-one were in advanced stage (III/IV) of disease. B symptoms were present in 47% of cases. A total of 33 were de novo cases and 31 were previously treated. Rituximab monotherapy was used in 17 cases. Rituximab was used in combination with chemotherapy in the other 47 cases. Infusional toxicity included anaphylaxis in one, hypotension in one and minor infusional reactions in four others. The patient who developed anaphylaxis required discontinuation of further Rituximab. Growth factors were used in 25 patients. Febrile neutropenia occurred in 19 patients. The overall RR (CR + PR) was 72%. One patient had stable disease and progressive disease was documented in 17 patients. A total of seven patients died, three due to progressive disease, three due to chemotherapy related toxicity and one due to an unrelated cause. We conclude that Rituximab is a valuable addition to the treatment armamentarium of lymphoproliferative disorders.

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma.

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of "Take Home Messages" at the end is a convenient tool for busy practitioners.

Outcome of acute myeloid leukaemia in adults: a retrospective analysis.

BACKGROUND: There are little data from India on the management of acute myeloid leukaemia. With better understanding of the biology of the disease, and routine use of high-dose cytarabine as post-remission therapy with or without haematopoietic blood stem cell transplantation (HSCT), the results have improved in the past two decades. We analysed our results in a cohort of recently treated patients. METHODS: A total of 166 newly diagnosed patients with AML (excluding acute promyelocytic leukaemia), 15-60 years of age were treated with daunorubicin (60 mg/m2/day x3 days) or idarubicin (12 mg/m2/day x3 days) with cytarabine (100 mg/m2/day continuous i.v. infusion x7 days) induction chemotherapy. Post-remission therapy included 2 cycles of high-dose cytarabine (15-18 g/m2) followed by monthly cycles of outpatient maintenance chemotherapy x4 cycles, consisting of daunorubicin (45 mg/m2 i.v. x1 day and cytarabine 100 mg/ m2 s.c. twice daily x5 days). Six patients in remission received sibling donor allogeneic HSCT. RESULTS: Morphological complete remission was achieved in 69.9% of the patients. Resistant disease after induction chemotherapy was seen in 14.6% and early mortality occurred in 16%. Relapse-free survival and event-free survival at a median of 36 months was 34% and 22%, respectively. Relapse occurred in 43.9%. The median duration of remission was 12 months. CONCLUSIONS: Our results conform to the published literature from larger cooperative studies from the West. Currently available cytotoxic drugs are unlikely to improve the results any further.

A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma.

The primary objective of this study was to determine the response rates of a combination of gemcitabine and cisplatin in unresectable hepatocellular carcinoma (HCC) in Indian patients. The secondary objectives were to evaluate the toxicity, time to progressive disease and overall survival for this combination. Chemonaive patients with histopathologically proven, bidimensionally measurable, stage Ill or IV unresectable HCC were enrolled into this study. All the patients were required to have a Zubrod's performance status not greater than 2, should not have undergone prior radiotherapy and were required to have adequate major organ function. Patients received gemcitabine (1250 mg/m2 intravenously over 30 to 60 min) on days 1 and 8, and cisplatin (70 mg/m2 intravenously over 2 hours) on day land every 21 days. Response assessment was done by a Computed Tomography scan after every two cycles of chemotherapy. From May to December 1999, 30 patients were enrolled in the study; they were all eligible for efficacy and toxicity analysis. Six (20%) patients achieved a partial response and 13 (43%) patients demonstrated stable disease with 11 (37%) patients showing disease progression. The median time to progression was 18 weeks (range 1 to 74 weeks) and the median duration of response was 13 weeks (range 4 to 68 weeks). The 1-year survival rate was 27% and the median overall survival was 21 weeks (95% CI: 17 to 43 weeks). WHO grade 3 and 4 anemia was seen in 11 (37%) and 2 (7%) patients, respectively. Four (13%) patients each experienced grade 3 and 4 neutropenia and grade 3 and 4 thrombocytopenia was seen in 2 (7%) patients each. Major, non-hematologic toxicities were grade 4 elevated bilirubin levels and grade 3 oral toxicity, in 1 patient (3%) each. This regimen was well tolerated and did show activity in Indian patients with advanced unresectable HCC. There is a need to further evaluate this combination in order to define its role in the treatment of HCC.