Comparison of 60 and 80 mg/m2 of daunorubicin in induction therapy of acute myeloid leukaemia

For finding better method of acute myeloid leukaemia (AML) induction, we designed a prospective clinical trial to find a more effective regimen with least toxicity for induction therapy of AML. Hence, we examined different accepted doses of daunorubicin and their outcomes. Total of 114 patients were included in the study. Fifty‐five patients received 60 mg/m² of daunorubicin (arm 1) 1 h IV infusion for 3 days, and the remaining 59 received 80 mg/m² (arm 2) 1 h IV infusion for 3 days. Continuous infusion of 100 mg/m²/day of cytosine arabinozide IV for 24 h for 7 days was given in both groups. Complete remission rate was 77.78% in group 1 and 76.92% in group 2 (p = 0.92). One‐year overall survival was 55.85% [standard error (SE) = 8.05%] in arm 1 and 57.94% (SE = 7.32%) in arm 2. Median follow‐up time was 11.1 (SE = 1.43) and 10.28 (SE = 1.29) months, respectively. One‐year disease‐free survival was 64.41% (SE = 7.39%) in arm 1 and 54.86% (SE = 7.53%) in arm 2. Complete remission, overall survival and disease‐free survival were statistically the same in both groups (p = 0.92, 0.697, 0.31). Toxicity and safety profile were similar in two groups but need to transfusion was higher in arm 2. Febrile neutropenia, days of antibiotics consumption and invasive fungal infection prevalence did not show any difference. Mean transfused packed cells and platelets rate were higher in the group that received higher dose of daunorubicin. Considering these results, we found that 60 mg/m² of daunorubicin would be more rational and as effective with lower toxicity to 80 mg/m² in induction therapy of AML patients at least as scheduled in our trial. Copyright © 2015 John Wiley & Sons, Ltd.     

Results of a phase I/II trial adding carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing autologous stem cell transplantation.

Autologous stem cell transplantation (SCT) with high-dose melphalan (HDM, 200 mg/m2) is the most effective therapy for multiple myeloma. To determine the feasibility of combining carmustine (300 mg/m2) with HDM, we enrolled 49 patients with previously treated Durie-Salmon stage II/III myeloma (32M/17W, median age 53) on a phase I/II trial involving escalating doses of melphalan (160, 180, 200 mg/m2). The median beta2-microglobulin was 2.5 (0-9.3); marrow karyotypes were normal in 88%. The phase I dose-limiting toxicity was > or =grade 2 pulmonary toxicity 2 months post-SCT. Other endpoints were response rate and progression-free survival (PFS). HDM was safely escalated to 200 mg/m2; treatment-related mortality was 2% and > or =grade 2 pulmonary toxicity 10%. The complete (CR) and near complete (nCR) response rate was 49%. With a median post-SCT follow-up of 2.9 years, the PFS and overall survival (OS) post-SCT were 2.3 and 4.7 years. PFS for those with CR or nCR was 3.1 years while for those with stable disease (SD) it was 1.3 years (P=0.06). We conclude that carmustine can be combined with HDM for myeloma with minimal pulmonary toxicity and a high response rate.     

Toxicity of doxorubicin and cyclophosphamide (60 mg/600 mg/m2) in adjuvant chemotherapy for breast cancer

We evaluated the toxicity of 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (AC 60/600) in adjuvant chemotherapy for breast cancer. Between 1994 and 2003, 62 patients received 6 cycles of doxorubicin (40 mg/m2) and cyclophosphamide (500 mg/m2) every 3 weeks (AC 40/500), and 106 patients received AC 60/600 as adjuvant chemotherapy for breast cancer. The performance status of all patients was 0 or 1. Toxicity was determined using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) ver. 2. Grade 3/4 neutropenia was frequent in AC 60/600 (6.5% vs 24.3%, p < 0.001). However, febrile neutropenia was not significant in either group (1.6% vs 3.8%, p = 0.39). There was also no statistical difference in the toxicity greater than grade 3 of anemia, nausea, vomiting, fatigue, diarrhea and cardiotoxicity. There was no treatment-related death in both groups. The number of patients who completed chemotherapy was higher in those receiving AC 60/600 than in those receiving AC 40/500 (91.9% vs 99.1%, p = 0.026). AC 60/600 is tolerated and feasible in adjuvant chemotherapy of breast cancer in Japanese patients from the viewpoint of toxicities.     

Experience with intermediate-dose (110–120 mg/m2) epirubicin

Summary A total of 23 patients with advanced malignancies received escalating doses of epirubicin (100–120 mg/m²) i.v. at 3-week intervals; 15 had received previous chemotherapy. In all, 46 courses of chemotherapy were given. Mucositis (grade II or III) occurred in 47% of courses at 120 mg/m², but in only 15% of courses at 115 mg/m². Myelotoxicity was manifest as leucopenia, with a median white blood count nadir of 1.9 (range, 0.8–7.0)×10⁹/l. Nausea and vomiting were generally well controlled by prophylactic antiemetic therapy. Alopecia was WHO grade 0 in 2 patients, grade I in 1, grade II in 5 and grade III in 14. No renal or hepatic toxicity was noted, and there were no episodes of congestive cardiac failure. One fatal coronary thrombosis (proven at post-mortem examination) occurred 48 h after a dose of 115 mg/m². Four patients developed thrombophlebitis at the injection site that was not dose-related; it occurred at doses between 100 and 120 mg/m². Two patients who had been given chemotherapy in the past had complete responses (one penile carcinoma, one gastric carcinoma). Six patients had partial responses, including two with breast cancer, one with gastric cancer and three with sarcoma. Intermediate-dose epirubicin was well tolerated up to 120 mg/m², when mucositis became a significant clinical problem. Preliminary data suggest promising activity in gastric cancer, breast cancer and a variety of sarcomas.     

Daunorubicin 90 mg/m2 in Acute Myeloid Leukemia Induction: Increased Toxicity in Young Patients

BackgroundThe combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia for more than 3 decades. The clinical benefit of intensification of the daunorubicin dose to 90 mg/m² has been supported by randomized trials. Based on these promising results, in 2010 we changed our induction protocol of acute myeloid leukemia, increasing the dose of daunorubicin.Patients and MethodsWe retrospectively analyzed the treatment outcome of patients treated with high-dose daunorubicin (90 mg/m² on days 1-3) and cytosine arabinoside (200 mg/m²/day continuous infusion on days 1-7) compared with patients receiving 45 to 60 mg/m² of daunorubicin. Twenty-six previously untreated patients younger than 60 years of age were included. Twelve received high-dose daunorubicin (HD) and 14 the low-dose (LD). Seventeen patients were in complete remission after 1 induction cycle.ResultsThere was no overall difference in complete remission rate between HD and LD (66% vs. 64%; P = 1.0). Thirty-day induction mortality was 15.3% overall, with a nonsignificant difference between groups (25% vs. 7.1%; P = .3). Relapses were observed in 9 (53%) patients: 3 (37.5%) in the HD group and in 6 (66.6%) in the LD group (P = .34). Invasive fungal disease (41.6% vs. 0%; P = .012), creatinine elevation (P = .001), abdominal pain (33% vs. 0%; P = .033), and need for intensive care unit admission (33.3% vs. 0%; P = .033) were more frequent in the HD group. Four patients in the HD group developed neutropenic enterocolitis (P = .033).ConclusionThese data indicate that 90 mg/m² of daunorubicin increased the toxicity compared with lower doses.     

Pharmacokinetics of high-dose melphalan (200 mg/m2) in a case of total renal insufficiency

The pharmacokinetics of the alkylating agent melphalan was determined in a dialysed patient, 30 years old, who underwent unilateral orchidectomy for a malignant testicular tumor. Melphalan was included in a polychemotherapy treatment with eight 1-h infusions of 230 mg of etoposide (VP 16), then one 5-min infusion of 370 mg of melphalan (200 mg/m2) followed by autologous bone marrow grafting (ABMG). In this patient, melphalan pharmacokinetics was different from that of patients without important renal dysfunction for the area under the concentration curve (1,324 mg.l-1.min). However, with a melphalan elimination half-life of 80 min, ABMG could be performed, as usually, 24 h after melphalan administration. Plasma alpha-fetoprotein (AFP) concentrations showed that chemotherapy was efficient. Furthermore, we observed a modification of etoposide kinetics due to melphalan.     

Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer

Purpose: A phase III study was performed in patients with metastaticbreast cancer (MBC) to evaluate the effect on response rate and survival ofa doubling of the epirubicin dose intensity.Patients and methods: Four hundred fifty-six patients were randomisedto receive either epirubicin 100 mg/m² or 50mg/m² in combination with 5-FU (500 mg/m²) andcyclophosphamide (500 mg/m²) (FEC 100 vs. FEC 50) i.v., every21 days for a maximum of six cycles (eight in case of CR).Results: Of 456 patients, 390 were evaluable for efficacy. Objectiveresponse (CR + PR) was seen in 57% (FEC 100) vs. 41% (FEC 50)of the evaluable patients (P = 0.003). The CR rate was higher in the FEC100 arm (12% vs. 7%, P = 0.07). FEC 100 producedsignificantly higher response rates in patients with visceral localisation(50% vs. 34%, P = 0.011) and in patients with more thantwo metastatic organ sites (64% vs. 37%, P = 0.001).Median time to progression (7.6 vs. 7 months) and overall survival (18 monthsvs. 17 months) were similar. Myelosuppression was the principal toxic effect,with grade IV neutropenia observed in 57% of the patients treated withFEC 100 vs. 9% of those on FEC 50. Grade IV infection or febrileneutropenia were observed in 8% (FEC 100) vs. 0.4% (FEC 50), butthe incidence of septic death was the same in the two arms (two patientseach). Cardiac toxicity was similar in the two treatment groups, with5% vs. 3% of the patients taken off study due to cardiac events,primarily due to a decline in LVEF. Only three patients (two in FEC 100)experienced congestive heart failure.Conclusion: This trial shows that FEC with epirubicin at 100mg/m² can be administered for repeated cycles without bonemarrow support with increased, though acceptable, toxicity and with asignificant increase of antitumor effect (especially in visceral and/orhigh-burden disease), but no increased survival.     

Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versuspaclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): A multicenter randomized trial

Purpose:The combination of paclitaxel and carboplatin has becomea widely used regimen in NSCLC due to phase II reports of moderate toxicity,reasonable activity and easy outpatient administration. Purpose of our presentprospective study was to evaluate the dose–response relationship ofpaclitaxel. Patients and methods:Since July 1996, 198 patients withnon-operable NSCLC and measurable disease without previous chemotherapyentered the trial. Ninety nine patients (group A) were randomized to receivepaclitaxel 175 mg/m² in three-hour infusion plus carboplatin dosedto an area under the concentration–time curve of 6 every 3 weeks and 99(group B) to receive the same regimen with paclitaxel increased to 225mg/m². Eligibility criteria included WHO performance status0–2, documented inoperable stage IIIA and IIIB, IV, no brain metastasis,no prior chemotherapy and adequate renal and hepatic function. Patients inboth groups were well-matched with baseline disease characteristics. Results:In group A with 90 evaluable patients, the response ratewas 25.6%(6 CR, 17 PR) whereas in group B with 88 evaluable patients,the response rate was 31.8% (3 CR, 25 PR),P = 0.733. Mediantime to progression favored the high-dose paclitaxel (4.3 vs. 6.4 months,P = 0.044). The median survival was 9.5 months for group A versus11.4 months for group B (P = 0.16). The one-year survival was37% for group A and 44% for group B (P = 0.35). Thebest prognostic factor for one-year survival was the response rate (P< 0.0001). With a relative dose intensity of paclitaxel 0.94 in bothgroups, neurotoxicity (P = 0.025) and leucopenia (P = 0.038)were more pronounced in group B patients. No toxic death was observed. Conclusions:Higher dose paclitaxel prolongs the median time toprogression but causes more neurotoxicity and leucopenia. The better responserate, the longer overall and better one-year survival seen with the higherdose of paclitaxel are not statistically significant.     

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed,platinum-sensitive,advanced ovarian cancer

BackgroundThis randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC).Patients and methodsPatients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m² 24 h (arm A, n = 54) or 1.3 mg/m² 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute—Common Toxicity Criteria v. 2.0.ResultsORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3–8.6 months; arm A) and 6.8 months (95% CI 4.6–7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B).ConclusionsBoth every-3-weeks trabectedin regimes, 1.5 mg/m² 24 h and 1.3 mg/m² 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.     

Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m(2)).

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m(2), MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m(2), MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.     

Docetaxel 100 versus 80 mg/m2 as adjuvant treatments of early breast cancer: an exploratory analysis of a randomised trial

Docetaxel-containing regimens are widely used as adjuvant treatmentof early breast cancer, and the dose 100 mg/m² is often selectedas the starting dose. Yet the optimal starting dose is unknown,since different docetaxel doses have never been compared ina randomised trial in the adjuvant setting. In metastatic breastcancer, three doses of     

Efficacy of docetaxel 60 mg/m2 in patients with metastatic breast cancer according to the status of anthracycline resistance.

PURPOSE: To evaluate the efficacy of docetaxel 60 mg/m2 in metastatic breast cancer (MBC) according to the status of anthracycline resistance. PATIENTS AND METHODS: Ninety-nine patients with anthracycline-resistant MBC were treated with docetaxel 60 mg/m2 intravenously for a 90-minute period every 3 to 4 weeks. Anthracycline resistance was defined as primary and secondary resistance. Primary resistance was defined as progression during or within 6 months after completion of adjuvant anthracycline, and no MBC response to a first-line regimen that contained anthracycline. Secondary resistance was defined as progression after a documented clinical response to a first-line anthracycline treatment for MBC. Secondary resistance was further divided into three categories: (1) absolute resistance, or progression during treatment with anthracycline after a period of response; (2) relative resistance, or progression within 6 months after anthracycline administration ended; and (3) sensitive regrowth, or progression more than 6 months after the conclusion of anthracycline administration. RESULTS: The response rate in the 99 patients was 35.4% (95% confidence interval, 30.1% to 44.8%). The response rates according to the status of anthracycline resistance were as follows: primary resistance (n = 46), 19.6%; secondary resistance (n = 53), 49.1% (absolute resistance [n = 16], 56.3%); relative resistance (n = 17), 47.1%; and sensitive regrowth (n = 20), 45.0%. The median time to treatment failure in patients with primary resistance was 2.9 months, compared with 5.2 months in patients with secondary resistance (P = .0022). CONCLUSION: Docetaxel at a dose of 60 mg/m2 seemed to be effective in MBC with secondary resistance to anthracycline. The status of anthracycline resistance is important for the prediction of response to second-line treatment with docetaxel.     

Glomerular filtration rate prior to high-dose melphalan 200 mg/m(2) as a surrogate marker of outcome in patients with myeloma

We correlated age and body surface area corrected glomerular filtration rate (GFR) at the time of high-dose melphalan (HDM) administration with treatment-related toxicity (TT), time to disease progression and survival. Between 8/85 and 6/98, 144 newly diagnosed myeloma patients with a median age of 53 years (range, 31-72) received infusional chemotherapy with vincristine, doxorubicin and methylprednisolone, with/without cyclophosphamide or verapamil, followed by HDM 200 mg/m(2)and stem cell rescue. An additional patient received HDM at diagnosis. GFR was below normal in 38 patients (26%). At presentation, patients with low GFR at the time of HDM had higher serum creatinine, beta(2)M, stage III disease, calcium and Bence-Jones proteinuria. Toxic deaths post-HDM were similar in both groups (2/38 (5%) vs. 4/107 (4%)), though patients with low GFR had more oral mucositis (P< 0.0001), diarrhoea (P = 0.005) and infections (P = 0.04). The response and relapse rates of the 2 groups were not substantially different, but the median overall survival (OS) was significantly shorter in patients with low GFR (5.1 vs 7.5 years, P = 0.015). Multivariate analysis showed that a normal GFR and being in CR at the time of HDM were predictive of longer OS. We conclude that in context of high-dose chemotherapy for myeloma, dose of melphalan should not be modified in patients with low GFR and that early intensive treatment at relapse may improve results in patients with abnormal renal function.     

Lack of intrafollicular memory CD4 + T cells is predictive of early clinical failure in newly diagnosed follicular lymphoma

Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Cells in the microenvironment may be a key contributor to treatment failure. We used a discovery and validation study design to identify microenvironmental determinants of early failure and then integrated these results into the FLIPI. In total, 496 newly diagnosed FL grade 1–3 A patients who were prospectively enrolled into the MER cohort from 2002 to 2012 were evaluated. Tissue microarrays were stained for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRP-α, TIM3, PD-1, and PD-L1. Early failure was defined as failing to achieve event-free survival at 24 months (EFS24) in immunochemotherapy-treated patients and EFS12 in all others. CyTOF and CODEX analysis were performed to characterize intratumoral immunophenotypes. Lack of intrafollicular CD4 expression was the only predictor of early failure that replicated with a pooled OR 2.37 (95%CI 1.48–3.79). We next developed a bio-clinical risk model (BioFLIPI), where lack of CD4 intrafollicular expression moved patients up one FLIPI risk group, adding a new fourth high-risk group. Compared with BioFLIPI score of 1, patients with a score of 2 (OR 2.17; 95% CI 1.08–4.69), 3 (OR 3.53; 95% CI 1.78–7.54), and 4 (OR 8.92; 95% CI 4.00–21.1) had increasing risk of early failure. The favorable intrafollicular CD4 T cells were identified as activated central memory T cells, whose prognostic value was independent from genetic features. In conclusion, lack of intrafollicular CD4 expression predicts early failure in FL and combined with FLIPI improves identification of high-risk patients; however, independent validation is warranted.Subject terms: Cancer microenvironment, CD4-positive T cells