Luis Casanova

Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix

PURPOSE To determine whether addition of gemcitabine to concurrent cisplatin chemoradiotherapy and as adjuvant chemotherapy with cisplatin improves progression-free survival (PFS) at 3 years compared with current standard of care in locally advanced cervical cancer. PATIENTS AND METHODS Eligible chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease and Karnofsky performance score ≥ 70 were randomly assigned to arm A (cisplatin 40 mg/m(2) and gemcitabine 125 mg/m(2) weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m(2) on day 1, plus gemcitabine, 1,000 mg/m(2) on days 1 and 8) or to arm B (cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A). RESULTS Between May 2002 and March 2004, 515 patients were enrolled (arm A, n = 259; arm B, n = 256). PFS at 3 years was significantly improved in arm A versus arm B (74.4% v 65.0%, respectively; P = .029), as were overall PFS (log-rank P = .0227; hazard ratio [HR], 0.68; 95% CI, 0.49 to 0.95), overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49 to 0.95), and time to progressive disease (log-rank P = .0012; HR, 0.54; 95% CI, 0.37 to 0.79). Grade 3 and 4 toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A. CONCLUSION Gemcitabine plus cisplatin chemoradiotherapy followed by BCT and adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable toxicity when compared with standard treatment.

Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-Naïve chronic myeloid leukemia patients trial

PURPOSE We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. PATIENTS AND METHODS Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). RESULTS At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. CONCLUSION These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.

Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor : Identification of two age subgroups with differing hematologic toxicity

PURPOSE Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkins lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.

Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: results of a multivariate analysis.

PURPOSE It has been suggested that age is associated with chemotherapy-related death in patients with non-Hodgkins lymphoma (NHL) treated with doxorubicin-containing chemotherapy. The purpose of this study was to evaluate the relative influence of increasing age and other clinical parameters on the occurrence of treatment-related death in elderly patients with intermediate- or high-grade NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. METHODS A retrospective study of patients 60 years of age or older with intermediate- or high-grade NHL treated with CHOP chemotherapy in a single cancer center. The following variables were recorded: age (60 to 69, 70 to 79, and 80 to 94 years), histology (Working Formulation [WF] D, E, F, G, and H), Ann Arbor stage, B symptoms, extranodal involvement, bulky disease (> 7 cm), performance status (Eastern Cooperative Oncology Group [ECOG] scale), International Prognostic Index (IPI score), serum lactate dehydrogenase (LDH) level and doxorubicin relative dose-intensity (RDI). The relationship between these features and treatment-related death was assessed in univariate and multivariate logistic regression analysis. RESULTS From 1982 to 1991, 267 consecutive patients were treated. Median age was 70 years (range, 60 to 94 years). There were 35 toxic deaths. Sixty-three percent of the deaths occurred after the first cycle. Infection accounted for 82% of the toxic deaths. In the univariate analysis, the features associated with an increased risk of toxic death were ECOG performance status 2 to 4 (relative risk [RR], 7.82), B symptoms (RR, 3.38), diffuse large-cell histology (RR, 3.06), bulky disease (RR, 2.58), serum levels of LDH (RR, 2.53), and IPI score (RR, 2.46). The age groups did not show significance. In the regression model, performance status 2 to 4 was the only independent predictor of treatment-related death (RR, 3.52; 95% confidence interval [CI], 2.98 to 4.06). CONCLUSION Our results show that in elderly patients with NHL treated with doxorubicin-based chemotherapy the risk for treatment-related death is associated with poor performance status rather than with increasing chronologic age.

Extranodal NK/T-cell lymphoma, nasal type: Study of clinicopathologic and prognosis factors in a series of 78 cases from Peru

It is well known that extranodal NK/T-cell lymphoma (NK/TCL) nasal type clusters in Asian countries. A large series of 78 cases of nasal NK/TCL from Peru is analyzed in the present study. Two histologic groups 1 (monomorphic) and 2 (polymorphic), were segregated according to the proportion of large cells (above and below 30%, respectively). Catalyzed signal amplification technique was performed for enhancement of immunohistochemistry reactivities. Epstein-Barr virus (EBV) sequences and types were investigated using polymerase chain reaction. Clinical characteristics, stage, outcome, and response to treatment were evaluated in both groups. Fourteen cases (18%) and 64 cases (82%) corresponded to groups 1 and 2, respectively. Except for nasal obstruction, more common in group 2, all other symptoms were similar in both groups. Local extension and staging were also comparable. Both groups showed CD3c+CD2+CD56+CD3s−CD20− immunophenotype. All cases were positive for EBV. In this series type-2 EBV was found more frequent than type-1 EBV, contrarily to that observed in Asian series. However, about one-third of cases simultaneously harbored both viral types. Both groups received an average of 50-Gy dose of radiation therapy (RT), with or without chemotherapy. Complete therapeutic response was achieved in 89% of group 1 and in 74% of group 2, but this difference was not statistically significant. There were no significant differences between the groups regarding disease-free survival, failure-free survival, relapse, and overall survival. The overall survival, in both groups, was longer for patients treated with RT alone compared with those treated with combined RT therapy and chemotherapy. The present study has shown that dividing nasal NK/TCL in monomorphic and polymorphic variants, according to frequency of large cells, does not correlate with clinical and prognostic factors.

Addition of amifostine to the CHOP regimen in elderly patients with aggressive non-Hodgkin lymphoma: a phase II trial showing reduction in toxicity without altering long-term survival.

BACKGROUND AND OBJECTIVES We report the 8-year follow-up of 34 patients aged ≥69 years old with NHL included in a phase IIb open-label randomized parallel groups study to evaluate the effectiveness of amifostine in preventing the toxicity of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP regime) . PATIENTS AND METHODS Patients were randomized to receive classical CHOP (cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and prednisone 100 mg/day for 5 days) or CHOP plus amifostine (6 cycles of amifostine 910 mg/m(2) on day 1). Efficacy (time to progression, TTP; disease-free survival, DFS; overall survival, OS) and toxicity endpoints were evaluated. RESULTS Thirty-four patients were randomized to A-CHOP (n=18) or CHOP (n=16). Patients with A-CHOP vs CHOP had significantly lower toxicity; neutropenia grade 4 ocurred in 13/92 (13%) vs 23/85 (27%, P=0.007) cycles, febrile neutropenia in 3/92 A-CHOP (3%) vs 8/85 (10%, P=.056) CHOP cycles, hospitalization for toxicity in 4/92 (4%) A-CHOP vs 11/85 (13%, P=.05) CHOP cycles. Median hospitalization stay for toxicity was 5 days with A-CHOP vs 8 days with CHOP (P=.05). There were no significant differences at 8 years in TTP (A-CHOP, 48.9% vs CHOP, 36.3%; P=.65), DFS (A-CHOP, 72.9% vs CHOP 55.6%; P=.50) and OS (A-CHOP, 44.3% vs CHOP, 54.4%). There was no long-term toxicity of clinical interest. The only prognostic factor identified to 8 years was the International Prognostic Index (IPI low/low intermediate risk vs high intermediate/high risk; HR=2.98; CI 95%:1.01-8.77; P=.048). CONCLUSION These results show that amifostine can be added to the standard CHOP treatment schedule with less acute toxicity and without influencing the outcome.