Frontline therapy of acute promyelocytic leukemia: Randomized comparison of ATRA and intensified chemotherapy versus ATRA and anthracyclines.

OBJECTIVES: Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). PATIENTS AND RESULTS: Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. CONCLUSIONS: The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.

Outcome of elderly patients with acute promyelocytic leukemia: results of the German Acute Myeloid Leukemia Cooperative Group.

Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high-risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide.

Application of cisplatin as intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer: analysis of pharmacokinetics and of nephrotoxicity.

UNLABELLED: The purpose of this study was to assess the extent of the systemic absorption of cisplatin during intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer. MATERIALS AND METHODS: The pharmacokinetics and nephrotoxicity of cisplatin were analyzed in patients receiving IHPL (8000 ml of Ringer's solution containing 150 mg/m2 cisplatin and 15 mg/m2 mitomycin C for one hour at 43.5 degrees C). Levels of ultrafiltrable platin were determined by flameless atomic absorption spectrometry. Nephrotoxicity was assessed by nephelometric analyses of urinary marker-proteins. The data were compared to respective analyses in patients receiving intravenous cisplatin. RESULTS: Twenty-four patients received five applications of cisplatin as IHPL (five patients) and 53 applications of intravenous cisplatin (21 patients). Platin levels within the lavage fluid declined monophasically (half-life, 0.48 +/- 10 hours; area under curve (AUC) 29,274 +/- 9075 ng/ml*h). The pharmacokinetic parameters calculated for IHPL vs. intravenous application of cisplatin were: maximum plasma levels 2392 +/- 407 vs. 1349 +/- 692 ng/ml; terminal half-lives 93 +/- 73 vs. 36 +/- 9 hours; AUC 9508 +/- 856 vs. 11,627 +/- 3372 ng/ml*h; total urinary excretion of platinum 24 +/- 6 vs. 49 +/- 13% of dose; renal clearance 127 +/- 34 vs. 145 +/- 35 ml/min. Pathologic urinary albumin excretion occurred on days 9 +/- 0 vs. 5 +/- 2 (maximum 232 +/- 179 vs. 20 +/- 20 mg/l). Plasma creatinine levels rose to 1.5 +/- 0.4 vs. 0.9 +/- 0.1 mg/dl on days 15 +/- 4 vs. 16 +/- 26. The degree of albuminuria was related to the clearance of platin from the lavage fluid (p = 0.048). CONCLUSION: A significant amount of intraperitoneally applied cisplatin is available systemically and probably adds to the nephrotoxicity of IHPL.