Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma

2016 ◽  
pp. e505-e514 ◽  
Author(s):  
Alexander C.J. van Akkooi ◽  
Michael B. Atkins ◽  
Sanjiv S. Agarwala ◽  
Paul Lorigan
Keyword(s):  
Overall Survival ◽  
Adjuvant Therapy ◽  
Sentinel Node ◽  
Trial Participation ◽  
High Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Long Term Treatment ◽  
Adjuvant Interferon

Wide local excision is considered routine therapy after initial diagnosis of primary melanoma to reduce local recurrences, but it does not impact survival. Sentinel node staging is recommended for melanomas of intermediate thickness, but it has also not demonstrated any indisputable therapeutic effect on survival. The prognostic value of sentinel node staging has been long established and is therefore considered routine, especially in light of the eligibility criteria for adjuvant therapy (trials). Whether completion lymph node dissection after a positive sentinel node biopsy improves survival is the question of current trials. The MSLT-2 study is best powered to show a potential benefit, but it has not yet reported any data. Another study, the German DECOG study, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting did not show any benefit but is criticized for the underpowered design and insufficient follow-up. There is no consensus on the use of adjuvant interferon in melanoma. This topic has been the focus of many studies with different regimens (low-, intermediate-, or high-dose and/or short- or long-term treatment). Adjuvant interferon has been shown to improve relapse-free survival but failed to improve overall survival. More recently, adjuvant ipilimumab has also demonstrated an improved relapse-free survival. Overall survival data have not yet been reported due to insufficient follow-up. Currently, studies are ongoing to analyze the use of adjuvant anti–PD-1 and molecular targeted therapies (vemurafenib, dabrafenib, and trametinib). In the absence of unambiguously positive approved agents, clinical trial participation remains a priority. This could change in the near future.

scholarly journals Low value of whole-body dual-modality [18f]fluorodeoxyglucose positron emission tomography/computed tomography in primary staging of stage I–II nasopharyngeal carcinoma: a nest case-control study

2021 ◽  
Author(s):  
Bei-Bei Xiao ◽  
Qiu-Yan Chen ◽  
Xue-Song Sun ◽  
Ji-Bin Li ◽  
Dong-hua Luo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Stage I ◽  
Relapse Free Survival ◽  
Retropharyngeal Lymph Node ◽  
Free Survival ◽  
Pet Ct ◽  
Pre Treatment

Abstract Objectives The value of using PET/CT for staging of stage I–II NPC remains unclear. Hence, we aimed to investigate the survival benefit of PET/CT for staging of early-stage NPC before radical therapy. Methods A total of 1003 patients with pathologically confirmed NPC of stages I–II were consecutively enrolled. Among them, 218 patients underwent both PET/CT and conventional workup ([CWU], head-and-neck MRI, chest radiograph, liver ultrasound, bone scintigraphy) before treatment. The remaining 785 patients only underwent CWU. The standard of truth (SOT) for lymph node metastasis was defined by the change of size according to follow-up MRI. The diagnostic efficacies were compared in 218 patients who underwent both PET/CT and CWU. After covariate adjustment using propensity scoring, a cohort of 872 patients (218 with and 654 without pre-treatment PET/CT) was included. The primary outcome was overall survival based on intention to treat. Results Retropharyngeal lymph nodes were metastatic based on follow-up MRI in 79 cases. PET/CT was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions (72.2% [62.3–82.1] vs. 91.1% [84.8–97.4], p = 0.004). Neck lymph nodes were metastatic in 89 cases and PET/CT was more sensitive than MRI (96.6% [92.8–100.0] vs. 76.4% [67.6–85.2], p < 0.001). In the survival analyses, there was no association between pre-treatment PET/CT use and improved overall survival, progression-free survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival. Conclusions This study showed PET/CT is of little value for staging of stage I–II NPC patients at initial imaging. Key Points • PET/CT was more sensitive than MRI in detecting neck lymph node lesions whereas it was significantly less sensitive than MRI in detecting retropharyngeal lymph node lesions. • No association existed between pre-treatment PET/CT use and improved survival in stage I–II NPC patients.

Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity.

1988 ◽  
Vol 6 (9) ◽  
pp. 1491-1500 ◽  
Author(s):  
A E Chang ◽  
T Kinsella ◽  
E Glatstein ◽  
A R Baker ◽  
W F Sindelar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Dose Regimen ◽  
Soft Tissue Sarcomas ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
High Dose Regimen ◽  
Disease Free

We have previously reported the results of a randomized trial that demonstrated the survival benefit of adjuvant chemotherapy in the treatment of patients with high-grade extremity sarcomas compared with no chemotherapy. This regimen included doxorubicin, cyclophosphamide, and methotrexate. This report updates and extends our experience. The median follow-up of this trial is now 7.1 years and reveals a 5-year disease-free survival of 75% and 54% for chemotherapy and no chemotherapy groups, respectively (two-sided P [P2] = .037). The 5-year overall survival for patients in this trial was 83% and 60% for the chemotherapy and no chemotherapy groups, respectively, with a trend towards improved survival in the chemotherapy arm (P2 = .124). Because of doxorubicin-induced cardiomyopathy we performed a subsequent randomized trial comparing this high-dose regimen to reduced cumulative doses of doxorubicin and cyclophosphamide without methotrexate. Eighty-eight patients were entered into this trial which has a median follow-up of 4.4 years. The 5-year disease-free and overall survival for patients treated with the reduced doses of chemotherapy was 72% and 75%, respectively, and was not significantly different from the high-dose regimen. No patients developed congestive heart failure on this study. We conclude that adjuvant chemotherapy improves disease-free survival in patients with extremity soft-tissue sarcomas. The overall survival advantage in patients receiving adjuvant chemotherapy in our initial randomized high-dose chemotherapy trial has diminished though it continues to favor the chemotherapy group. A reduced-dose chemotherapy regimen was found to be comparable to the high-dose regimen.

Rituximab (R) + Hypercvad Alternating with R-Methotrexate/Cytarabine after 9 Years: Continued High Rate of Failure-Free Survival in Untreated Mantle Cell Lymphoma (MCL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 833-833 ◽  
Author(s):  
Jorge Romaguera ◽  
Luis Fayad ◽  
Alma Rodriguez ◽  
Fb Hagemeister ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Response ◽  
Serum Lactate ◽  
High Rate ◽  
Serum Lactate Dehydrogenase ◽  
High Dose ◽  
Free Survival ◽  
Mantle Cell ◽  
Rate Of Failure

Abstract MCL has a poor outcome with current non-intense therapies. We present an update of our results utilizing an intense chemotherapy regimen comprising fractionated cyclophosphamide, doxorubicin, vincristine and dexamethasone to which rituximab has been added (R-HyperCVAD, one cycle), alternating with rituximab and high dose methotrexate/cytarabine (R-MA, one cycle) for a total of 6–8 cycles (J Clin Oncol 2006 Feb 1;24(4):724). Treatment was started at most within 2 months from the initial evaluation. Overall survival (OS) was defined as the time from start of treatment until recurrence or death from any cause. Failure-free survival (FFS) was defined as the time from start of treatment until recurrence or death from toxicity or death from treatment-related malignancy. Of 97 consecutive evaluable patients, 87% achieved a complete response (CR) or unconfirmed CR after 6 cycles and did not receive additional therapy. With a median follow up on 84 months (7 years), the overall survival and failure-free survival at 7 years was 60% and 43%, respectively. Among patients 65 years of age or younger, the 7-year OS and FFS was 68% and 52%, respectively. Important prognostic variables included age (65 yrs or less vs > 65 yrs; initial serum B2 microglobulin 3 or less mg/dL vs > 3); and initial serum lactate dehydrogenase (normal vs > normal). Further subset analysis will be presented at the meeting. Figure Figure

Predictive Value of Molecular Remissions Post Consolidation Chemotherapy in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemias – a Single Centre Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3693-3693
Author(s):  
Uday Deotare ◽  
Marwan Shaheen ◽  
Joseph M. Brandwein ◽  
Bethany Gill ◽  
Suzanne Kamel-Reid ◽  
...  
Keyword(s):  
Median Time ◽  
High Dose ◽  
Relapse Free Survival ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Post Induction ◽  
Binding Factor ◽  
High Dose Cytarabine ◽  
Time To Relapse

Abstract Background: Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). Although this group represents a favorable cytogenetic AML subgroup, 30-40% of these patients nevertheless relapse after standard intensive chemotherapy. The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered as 2-4 repetitive cycles. Here we present retrospective data from a single centre, on this favourable AML subgroup. Methods: We analyzed retrospectively the outcome of 80 sequential patients with CBF-AML (46 t(8;21), 34 inv(16)/t(16;16)) treated over a 13 year period from 2000-2012. The median age was 48 years (range 20-80) with a median white cell count of 13x109/L(range 1-426x109/L). All patients underwent induction chemotherapy consisting of daunorubicin (60 mg/m2/d x 3 days) and continuous infusion cytarabine (100 or 200 mg/m2/d x 7 days, for ages <60y and ≥60y, respectively). Patients in CR then received 3 cycles of consolidation chemotherapy which included high dose cytarabine (3 or 1.5 g/m2 on days 1, 3 and 5, for ages <60y and ≥60y, respectively) with daunorubicin 45 mg/m2 on days 1 and 3 added during cycle 1. Results: Ninety percent of patients achieved morphological complete remission (CR) post induction, but 33.3% of these remained molecularly positive by quantitative reverse transcriptase polymerase chain reaction (qR-PCR). The majority of patients (93.6%) subsequently achieved molecular negativity by qR-PCR after the 3rd consolidation cycle. With a median follow-up of 5 years, the estimated 5-year relapse free survival (RFS) was 58% and 5-year overall survival (OS) was 66%. This is in keeping with the earlier AMLSG and UK MRC studies. Only 21% of patients relapsed and the median time to relapse was 10 months. Of the 16 patients who relapsed, 7 underwent allogeneic hematopoietic cell transplantation (HCT) from HLA- matched sibling or unrelated donors, and of these, 4 remain alive and in remission with a median follow up of 8 years. While relapse occurred in 2 of the 4 patients who did not achieve a molecular CR after 3 cycles of consolidation, 13 of 16 relapsing patients had been in a molecular CR after final consolidation and one patient was not evaluated. Therefore, molecular remission post consolidation does not guarantee long term disease free survival. Further molecular analyses and the roles of additional mutations in predicting relapse will be presented. Conclusion: Sustained remissions can be achieved in patients with CBF AML after 3 cycles of high dose cytarabine consolidation, but post consolidation molecular remission does not necessarily preclude relapse. Comprehensive molecular profiling may be better in predicting relapse risk in this group of patients. Table1: Patient characteristics & response N=80 Sex 45 M : 35 F Median age, years (range) 48 (20-80) WBC at diagnosis (x106 cells/L) (range) 13 (1-426) Cytogenetics t(8;21) inv16/t(16;16) 46 (58%) 34 (42%) Response post-induction chemotherapy CR Primary refractory 72 (90%) 8 (10%) Number of consolidation cycles (range) 3 (2-4) Molecular CR post –induction Yes No Not evaluated 16 (20%) 32 (40%) 32 (40%) Molecular CR post –consolidation –cycle 3 Yes No Not evaluated 59 (74%) 4 (5%) 17 (21%) Relapse Yes No Unknown 16 (20%) 59 (74%) 5 (6%) Median time to relapse, months (range) 10 (6-17) Median time to follow up, y (range) 5 (0.5-11.5) Figure 1 : Overall and Relapse free survival in CBF-AML patients. Figure 1 :. Overall and Relapse free survival in CBF-AML patients. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Randomized trial of high-dose chemotherapy with autologous haematopoietic stem cell support vs. standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: Overall survival after 6 years of follow up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 672-672 ◽  
Author(s):  
A. R. Zander ◽  
N. Kroeger ◽  
C. Schmoor ◽  
W. Krueger ◽  
V. Moebus ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Standard Dose ◽  
Interactive Effect ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Grade Iii

672 Background: Investigation of high dose chemotherapy (HD-CT) supported by autologous hematopoietic stem cell transplantation compared with standard dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more axillary lymph nodes. Methods: Between November 1993 and September 2000 307 patients were randomized to receive the following cycles of Epirubicin (90 mg/m2), Cyclophosphamide (600 mg/m2) intervenously (every 21 days) either HD-CT of Cyclophosphamide (1500 mg/m2), Thiotepa (150 mg/m2) and Mitoxantrone (10 mg/m2) intervenously for 4 consecutive days followed by stem cell transplantation or standard dose chemotherapy SDCT in 3 cycles of Cyclophosphamide (500 mg/m2), Methotrexate (40 mg/m2) and Fluoruracil (600 mg/m2) intervenously on days 1 and 8 every 28 days. The primary end points were event-free survival and overall survival. Results: After a median follow-up of 6.1 years 166 events with respect to event-free survival (SD-CT: 91, HD-CT: 75) and 123 with respect to overall survival (SD-CT: 66 and HD-CT: 57) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0,80, p = 0,15. The hazard ratio for overall survival for high dose chemotherapy versus standard dose chemotherapy is estimated as 0,84, p = 0,33. Analysing the effect of treatment on event-free survival premenopausal patients, patients with tumor grade III and ER-positive patients had a better outcome with HD-CT with an interactive effect of 2.5 and 1.4. The significance was only shown in grade III patients in favour of HD-CT, (p = 0,049). The interactive effect of HD-CT with prognostic factors did not reach significance for overall survival. Conclusion: Even with a follow-up of 6.1 years there was only a trend in favour of high dose chemotherapy with respect to overall survival but without a statistical significance. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients which might benefit from this treatment approach. No significant financial relationships to disclose.

Nonsurgical treatments for stage 0-IA squamous esophageal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 113-113
Author(s):  
Hitoshi Ito ◽  
Satoshi Itasaka ◽  
Shinichi Miyamoto ◽  
Yasumasa Ezoe ◽  
Manabu Muto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Esophageal Cancer ◽  
Lymph Node ◽  
Treatment Option ◽  
Alternative Treatment ◽  
Initial Treatment ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Alternative Treatment Option

113 Background: Surgery has been the standard treatment for operable squamous esophageal cancer. However, radiation therapy/chemoradiotherapy (RT/CRT) or endoscopic resection (ER) could be an alternative treatment option for stage 0-IA (TNM 7th edition) squamous esophageal cancer, because these treatments are less invasive and can preserve the organ. To evaluate the efficacy of surgery, RT/CRT and EC for stage 0-1A squamous esophageal cancer in clinical practice, we reviewed our experience. Methods: From March 2007 to December 2010, 92 patients with stage 0-IA squamous esophageal cancer were treated in our institute. Overall survival, relapse-free survival, and relapse pattern were evaluated according to the initial treatment modality. Results: Of 92 patients (pts), 76 were male and 16 were women. Median age was 65.5 years old. Tis/T1a/T1b:4/36/52. Median follow up time was 29.1(4.7-55.5) months. As an initial treatment, 9 pts received surgery, 27 pts received RT/CRT and 56 pts received ER. Among the pts underwent ER, one patient underwent esophagectomy and 13 pts were received CRT based on the pathological evaluation for the risk of the lymph node metastasis. Two-year relapse free survival and overall survival of surgery, RT/CRT and ER was 77.8%/100%, 68.6%/100% and 89.8%/95.7%, respectively. After completion of initial therapy, local failures (residual or recurrent disease), regional lymph node relapse and distant metastasis and 1 undetermined relapse were observed in 6, 3 and 5 pts, respectively. Eight out of the 15 pts with recurrence could be disease free after salvage therapy. While 4 pts died during the follow up period, all pts died from other diseases and no pts died from esophageal cancer. Overall esophageal preservation rate was 89.1% (82/92). Conclusions: Although longer follow-up was needed, this study showed that non-surgical treatments (RT/CRT or ER) for stage 0-1A squamous esophageal cancer could be an alternative treatment option and could provide a chance of organ preservation. [Table: see text]

Five-Year Outcomes of a Randomized Phase III Trial Comparing Adjuvant Chemotherapy With S-1 Versus Surgery Alone in Stage II or III Gastric Cancer

2011 ◽  
Vol 29 (33) ◽  
pp. 4387-4393 ◽  
Author(s):  
Mitsuru Sasako ◽  
Shinichi Sakuramoto ◽  
Hitoshi Katai ◽  
Taira Kinoshita ◽  
Hiroshi Furukawa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Adjuvant Chemotherapy ◽  
Stage Ii ◽  
Disease Stage ◽  
Relapse Free Survival ◽  
Free Survival ◽  
End Point

Purpose The first planned interim analysis (median follow-up, 3 years) of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer confirmed that the oral fluoropyrimidine derivative S-1 significantly improved overall survival, the primary end point. The results were therefore opened at the recommendation of an independent data and safety monitoring committee. We report 5-year follow-up data on patients enrolled onto the ACTS-GC study. Patients and Methods Patients with histologically confirmed stage II or III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 after surgery or surgery only. S-1 (80 to 120 mg per day) was given for 4 weeks, followed by 2 weeks of rest. This 6-week cycle was repeated for 1 year. The primary end point was overall survival, and the secondary end points were relapse-free survival and safety. Results The overall survival rate at 5 years was 71.7% in the S-1 group and 61.1% in the surgery-only group (hazard ratio [HR], 0.669; 95% CI, 0.540 to 0.828). The relapse-free survival rate at 5 years was 65.4% in the S-1 group and 53.1% in the surgery-only group (HR, 0.653; 95% CI, 0.537 to 0.793). Subgroup analyses according to principal demographic factors such as sex, age, disease stage, and histologic type showed no interaction between treatment and any characteristic. Conclusion On the basis of 5-year follow-up data, postoperative adjuvant therapy with S-1 was confirmed to improve overall survival and relapse-free survival in patients with stage II or III gastric cancer who had undergone D2 gastrectomy.

scholarly journals Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II–III Melanoma Adjuvant Therapy

2017 ◽  
Vol 110 (1) ◽  
pp. 87-96 ◽  
Author(s):  
Stefan Suciu ◽  
Alexander M M Eggermont ◽  
Paul Lorigan ◽  
John M Kirkwood ◽  
Svetomir N Markovic ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adjuvant Therapy ◽  
Stage Ii ◽  
Relapse Free Survival ◽  
Free Survival

Timing of Second Autologous Transplantations in Multiple Myeloma: Results of a Multicenter Sequential Randomized Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 59-59 ◽  
Author(s):  
Abderrahman Abdelkefi ◽  
Saloua Ladeb ◽  
Tarek Ben Othman ◽  
Lamia Torjman ◽  
Amel Lakhal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Trial ◽  
Rank Test ◽  
Optimal Timing ◽  
High Dose ◽  
Consolidation Therapy ◽  
Event Free Survival ◽  
Free Survival ◽  
Log Rank Test

Abstract Background: Autologous stem cell transplantation (ASCT) is now considered standard therapy in young patients (<65 years) with multiple myeloma (MM). The Intergroupe Francophone du Myelome conducted a randomized trial of the treatment of MM with high-dose chemotherapy followed by either one or two successive ASCTs. The probabilities of event-free-survival and overall survival were doubled with a double transplant. However, no randomized trial has compared tandem transplant up-front with a strategy including planned second ASCT at relapse or progression. Therefore, we performed a multicenter, sequential, randomized trial designed to assess the optimal timing of a second ASCT. Methods: From May 2003 to April 2006, 140 patients with symptomatic MM (de novo) and less than 60 years of age, were randomly assigned to receive either tandem transplantation up-front (within 6 months of the first transplantation) [Arm A, n=69] or one ASCT followed by a consolidation therapy with thalidomide (day +90, 100 mg/per day during 5 months) [Arm B, n=71]. Patients included in the arm B received a second transplant in case of disease progression on consolidation therapy, or in case of relapse in responders. Clinical characteristics of each group were similar. In both arms of the study, ASCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m2) and G-CSF. Data were analyzed on an intent-to-treat basis. Results: With a median follow-up of 23 months (range: 6–34), the 2-year overall survival was 55% in the arm A and 75% in the arm B. Survival curves were not different (P=0.28, log-rank test). The 2-year event-free survival was 41% in the arm A and 60% in the arm B (P=0.4, log-rank-test). In the arm B, relapse-free survival of ≥ 16 months following the first transplantation was an important predictor of overall survival (p< 0.001). Conclusion: Data from the present study suggest that up-front single ASCT followed by a consolidation therapy with thalidomide and a second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients. Longer follow-up is needed before definite conclusions can be given concerning the optimal timing of second autologous transplantations in patients with MM.

Ten Year Follow up Analysis of the OSHO Phase III Trial (AML 96) Comparing Different Application Modes of AraC in Patients below 60 Years with Acute Myeloid Leukemia (AML): No Impact of AraCApplication Mode on Remission Rate, Toxicity, Disease-Free Survival or Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2966-2966
Author(s):  
Cornelia Becker ◽  
Rainer Krahl ◽  
Antje Schulze ◽  
Georg Maschmeyer ◽  
Christian Junghanß ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Significant Difference

Abstract Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) &gt; 109/l and median platelets (plt) &gt; 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p&lt;10−6) and for EFS (p&lt;10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (&gt;1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p&lt;10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

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