Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

1991 ◽  
Vol 9 (10) ◽  
pp. 1766-1775 ◽  
Author(s):  
G Saeter ◽  
T A Alvegård ◽  
I Elomaa ◽  
A E Stenwig ◽  
T Holmström ◽  
...  
Keyword(s):  
Preoperative Chemotherapy ◽  
Single Agent ◽  
High Dose ◽  
Preoperative Treatment ◽  
High Dose Methotrexate ◽  
Histologic Response ◽  
Dose Methotrexate ◽  
High Grade Osteosarcoma ◽  
The Individual ◽  
Grade Iii

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

scholarly journals Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

2018 ◽  
pp. 1-10 ◽  
Author(s):  
Jyoti Bajpai ◽  
Arun Chandrasekharan ◽  
Vijai Simha ◽  
Vikas Talreja ◽  
Ashay Karpe ◽  
...  
Keyword(s):  
International Standards ◽  
High Dose ◽  
The Novel ◽  
High Dose Methotrexate ◽  
Histologic Response ◽  
Term Survival ◽  
Dose Methotrexate ◽  
Metastatic Osteosarcoma ◽  
Treatment Naïve ◽  
Dose Dense

Purpose Metastatic osteosarcoma is largely treated with high-dose methotrexate (HDMTX)–based therapy, especially in the pediatric population. This mandates complex pharmacokinetic monitoring in a costly inpatient setting to mitigate unpredictable serious toxicities. Hence, a non-HDMTX–based regimen is worth exploring, especially in India and low- and middle-income countries. Materials and Methods All consecutive treatment-naïve patients with metastatic osteosarcoma were prospectively treated on the novel OGS-12 protocol consisting of sequential doublets of doxorubicin, cisplatin, and ifosfamide. Four cycles were administered as neoadjuvant therapy followed by planned curative intent surgery and metastasectomy when feasible, followed by four cycles of adjuvant chemotherapy. Baseline characteristics, histologic response, event-free survival (EFS), overall survival (OS), and toxicity data were prospectively collected. Results Three hundred seventeen patients were enrolled onto the OGS-12 protocol from 2011 to 2014, of whom 80 (25%) had metastatic disease; median age was 17 years. The majority of patients were nutritionally challenged with high-risk features. At presentation, 83% of patients (66 patients) had lung metastases. After neoadjuvant chemotherapy, 57% of patients were histologically good responders. Four-year EFS and OS rates were 24% and 27%, respectively, in the intent-to-treat population and 27% and 29%, respectively, in the per-protocol analysis. Significant grade 3 or 4 toxicities were febrile neutropenia (51%), thrombocytopenia (36%), and anemia (54%). Histologic response was an independent predictor for EFS and OS in patients who underwent surgery. Surgical intervention was found to be significant for survival in univariable analysis. Conclusion The novel, low-cost, non-HDMTX–based, dose-dense OGS-12 regimen has shown comparable outcomes to international standards in metastatic osteosarcomas and is worthy of wider clinical application. An aggressive multimodality approach may result in long-term survival in a select group of patients and, hence, is worth considering.

Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7533-7533 ◽  
Author(s):  
Christian Grommes ◽  
Jacqueline Stone ◽  
Craig Nolan ◽  
Elina Tsyvkin ◽  
Julia Wolfe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Systemic Disease ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate ◽  
Phase 1B

7533 Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.

Use of Palifermin for the Prevention of High-Dose Methotrexate-Induced Oral Mucositis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4445-4445
Author(s):  
Eva Schmidt ◽  
Nils H. Thoennissen ◽  
Annika Rudat ◽  
Ralf Bieker ◽  
Christoph Schliemann ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Oral Mucositis ◽  
Wilcoxon Test ◽  
Clinical Activity ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Who Grade ◽  
Dose Methotrexate ◽  
Grade Iii

Abstract Oral mucositis is a frequent problem in high-dose methotrexate (HD-MTX) based chemotherapy, impairing the patient’s quality of life, leading to higher rates of infections and delaying subsequent chemotherapy. Numerous substances have been used to prevent or treat oral mucositis, but none of them has proven clinical benefit. Palifermin, a recombinant human keratinocyte growth factor, can lead to a prevention of oral mucositis by different effects. Clinical activity of palifermin has been proven in a controlled randomized study with patients undergoing high-dose therapy with autologous stem cell rescue. The purpose of this report is to describe the effect of palifermin in patients treated within the GMALL-B-ALL 2002 protocol containing HD-MTX who developed a severe mucositis in cycles A1 or B1. Ten patients who were treated within this protocol developed a severe WHO grade III–IV oral mucositis in cycles A1 or B1. Before and after the subsequent similar or identical cycles A2 or B2 palifermin was given to reduce the risk of mucositis. Thus, patients serve as their own control for efficacy of palifermin. All ten patients developed a grade III–IV mucositis in cycles A1 or B1 without palifermin, whereas only 2/10 developed a grade III–IV mucositis in corresponding cycles A2 or B2 with palifermin (Mann-Whitney-Wilcoxon-test p < 0.05). Five patients were treated with a lower palifermin dose than recommended. Also these patients did not develop a higher grade mucositis. Only 4/10 patients showed infections in the cycles with palifermin compared to 10/10 patients without palifermin. The duration of mucositits in patients who aquired a higher-grade (III, IV) mucositis despite treatment with palifermin could be reduced from 12.9 days (median) without to 10.4 days with palifermin. In conclusion, palifermin can significantly reduce the incidence and severeness of oral mucositis and may influence clinical sequelae such as infection and quality of life.

scholarly journals Shortening Infusion Time for High-Dose Methotrexate Alters Antileukemic Effects: A Randomized Prospective Clinical Trial

2011 ◽  
Vol 29 (13) ◽  
pp. 1771-1778 ◽  
Author(s):  
Torben S. Mikkelsen ◽  
Alex Sparreboom ◽  
Cheng Cheng ◽  
Yinmei Zhou ◽  
James M. Boyett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
The United States ◽  
Leukemia Cells ◽  
High Dose ◽  
Infusion Time ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Infusion Duration

Purpose To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m2) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG1-7) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes. Methods From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m2) as either a 24-hour infusion or a 4-hour infusion at two pediatric hospitals in the United States. The primary outcome measures were the accumulation of MTXPG1-7 in leukemia cells and the antileukemic effects (eg, inhibition of de novo purine synthesis in bone marrow ALL cells, and decrease in circulating ALL cells). Results The 24-hour infusion resulted in significantly higher amounts of MTXPG1-7 in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/109 cells, P = .0059), and better antileukemic effects. The 24-hour infusion had the greatest effect on MTXPG1-7 accumulation in hyperdiploid ALL (median: 3,919 v 2,417 pmol/109 cells, P = .0038); T-cell ALL exhibited smaller differences in MTXPG1-7 but greater antileukemic effects with the longer infusion (median decrease in leukemia cells: 88.4% v 51.8%, P = .0075). In contrast, infusion duration had no significant impact on MTXPG1-7 accumulation or antileukemic effects in ALL with the t(12;21)/(ETV6-RUNX1) chromosomal translocation. Conclusion Shortening the infusion time of HDMTX reduces accumulation of active methotrexate in leukemia cells and decreases antileukemic effects, with differing consequences among major ALL subtypes.

Chemotherapy in malignant pleural mesothelioma. A review.

1996 ◽  
Vol 14 (3) ◽  
pp. 1007-1017 ◽  
Author(s):  
S T Ong ◽  
N J Vogelzang
Keyword(s):  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Combination Chemotherapy ◽  
Response Rate ◽  
Single Agent ◽  
High Dose ◽  
Pleural Mesothelioma ◽  
High Dose Methotrexate ◽  
Phase Ii Trials ◽  
Dose Methotrexate

PURPOSE AND DESIGN We reviewed the published literature of clinical studies in malignant pleural mesothelioma, including phase II trials of the newer antifolates and plant derivatives, as well as older single-agent and combination chemotherapy trials. We excluded trials with less than 15 patients, although we have mentioned smaller trials in the text to make a specific point, as well as ones that show promise. We have also included confidence intervals when cited in the original reports, or calculated them when absent. RESULTS No drugs have consistently induced a response greater than 20%. Higher response rates have been reported with detorubicin, high-dose methotrexate, and edatrexate at 26%, 37%, and 25%, respectively, but these have yet to be confirmed. Agents that produce response rates in 10% to 20% of patients include doxorubicin, epirubicin, mitomycin, cyclophosphamide, ifosfamide, cisplatin, and carboplatin. Combination chemotherapy trials do not demonstrate a consistently greater response rate than single-agent trials. However, the combination of doxorubicin, cisplatin, bleomycin, and mitomycin demonstrated a response rate of 44% (95% confidence interval, 27% to 63%), but this remains unconfirmed. Intrapleural therapy using interferon gamma, particularly for small-volume disease, shows promise. CONCLUSION The successful treatment of unresectable pleural mesothelioma awaits the discovery of active drugs. Recent trials of high-dose methotrexate and other antifolates are encouraging. Newer agents, including suramin, should be evaluated in phase II trials. Off-protocol combination therapy cannot be recommended over single-agent therapy, but studies that use combinations of the newer agents should be conducted.

scholarly journals Improved Pharmacy Department Workflow with New Method of Order Entry for Single-Agent, High-Dose Methotrexate

2014 ◽  
Vol 49 (11) ◽  
pp. 1039-1043
Author(s):  
Polly E. Kintzel ◽  
Thomas H. VanDyke ◽  
Paul W. Athmann ◽  
Lisa B. Mills ◽  
Michael P. Bonter ◽  
...  
Keyword(s):  
Single Agent ◽  
New Method ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Order Entry ◽  
Pharmacy Department ◽  
Dose Methotrexate

scholarly journals Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma

2021 ◽  
Author(s):  
S. Bernard ◽  
L. Hachon ◽  
J. F. Diasonama ◽  
C. Madaoui ◽  
L. Aguinaga ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Renal Toxicity ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Outpatient Basis ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Grade Iii

AbstractHigh-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin.

1998 ◽  
Vol 16 (2) ◽  
pp. 658-663 ◽  
Author(s):  
G Bacci ◽  
S Ferrari ◽  
N Delepine ◽  
F Bertoni ◽  
P Picci ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Complete Response ◽  
Primary Chemotherapy ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Histologic Response ◽  
Histologic Subtype ◽  
Dose Methotrexate ◽  
Serum Peak ◽  
Localized Disease

PURPOSE In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy. PATIENTS AND METHODS In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response. RESULTS Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). CONCLUSION Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.

scholarly journals Five decades of low intensity and low survival: adapting intensified regimens to cure pediatric Burkitt lymphoma in Africa

2020 ◽  
Vol 4 (16) ◽  
pp. 4007-4019
Author(s):  
Nmazuo W. Ozuah ◽  
Joseph Lubega ◽  
Carl E. Allen ◽  
Nader Kim El-Mallawany
Keyword(s):  
Burkitt Lymphoma ◽  
Low Dose ◽  
Single Agent ◽  
The United States ◽  
High Income ◽  
Sub Saharan Africa ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Sub Saharan

Abstract Long-term cure of childhood Burkitt lymphoma (BL) in sub-Saharan Africa after treatment with single-agent cyclophosphamide has been documented for more than half of a century. Contemporary cure rates for the highest-risk patients with BL in high-income countries exceed 90% using intensive multiagent chemotherapy. By contrast, the majority of African children with BL still die. Data spanning 5 decades in Africa have repeatedly shown that the children most likely to achieve cure with limited cyclophosphamide regimens are those with lower-stage disease isolated to the jaw. Attempts to intensify the cyclophosphamide monotherapy backbone with the addition of vincristine, low-dose methotrexate, prednisone, doxorubicin, and/or low-dose cytarabine have not yielded significant improvement. High-dose methotrexate is a critical component in the treatment of childhood BL worldwide. Although initial efforts in Africa to incorporate high-dose methotrexate resulted in high treatment-related mortality, more recent collaborative experiences from North and West Africa, as well as Central America, demonstrate that it can be administered safely and effectively, despite limitations in supportive care resources. Recognizing the unacceptable disparity in curative outcomes for BL between the United States/Europe and equatorial Africa, there is a critical need to safely adapt contemporary treatment regimens to optimize curative outcomes amid the resource limitations in regions where BL is endemic. Here, we critically review reports of BL treatment outcomes from low- and middle-income countries, in addition to data from high-income countries that predated modern intensified regimens, to identify potential strategies to improve the therapeutic approach for children suffering from BL in sub-Saharan Africa.

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