Systemic Therapy for Osteosarcoma and Ewing Sarcoma

2015 ◽  
pp. e644-e647 ◽  
Author(s):  
Paul A. Meyers
Keyword(s):  
Ewing Sarcoma ◽  
Systemic Therapy ◽  
Dose Intensity ◽  
Initial Response ◽  
Response To Therapy ◽  
High Dose ◽  
Improve Outcome ◽  
Curative Therapy ◽  
Dose Methotrexate ◽  
Multiagent Chemotherapy

Curative therapy for both osteosarcoma and Ewing sarcoma requires the combination of effective systemic therapy and local control of all macroscopic tumors. Systemic therapy for osteosarcoma consists of multiagent chemotherapy. The most common regimen uses cisplatin, doxorubicin, and high-dose methotrexate. Addition of ifosfamide and etoposide to treatment for patients with poor initial response to therapy does not improve outcome. Addition of interferon to treatment for patients with favorable initial response does not improve outcome. Addition of liposomal muramyl tripeptide to chemotherapy may improve overall survival. Systemic therapy for Ewing sarcoma consists of multiagent chemotherapy including doxorubicin, vincristine, etoposide, and cyclophosphamide and/or ifosfamide. Increased dose intensity of therapy, either by shortening the intervals between cycles of chemotherapy or by increasing doses of chemotherapy, improves outcome. Regimens such as irinotecan/temozolomide or cyclophosphamide/topotecan have shown activity in metastatic recurrent Ewing sarcoma. Trials are ongoing to evaluate the addition of these drugs to existing multiagent regimens in order to test their ability to improve outcome. High-dose systemic therapy with autologous stem cell reconstitution is being tested for patients at high risk for recurrence; definitive results await completion of a prospective randomized trial.

Long Term Outcomes of Rituximab, Temozolamide, and High-Dose Methotrexate for Lymphoma Involving the Central Nervous System

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2701-2701
Author(s):  
Sarah Jordan Nagle ◽  
Nirav N. Shah ◽  
Alex Ganetsky ◽  
Daniel J. Landsburg ◽  
Sunita Dwivedy Nasta ◽  
...  
Keyword(s):  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Initial Response ◽  
Response Assessment ◽  
Response To Therapy ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Dose Methotrexate

Abstract Background Management of patients (pts) with primary central nervous system lymphoma (PCNSL) and those with secondary CNS involvement by diffuse large B cell lymphoma (DLBCL) present a therapeutic challenge. There is no clear standard of care but traditionally initial treatment of PCNSL involves induction with intravenous high-dose methotrexate (HD-MTX) followed by consolidation including whole brain radiation therapy (WBRT), cytarabine, or autologous stem cell transplant. This approach has been associated with significant toxicities, especially the risk of cognitive dysfunction with WBRT. Treatment of secondary CNS involvement by DLBCL may depend on the extent of concomitant systemic disease, but HD-MTX is often the backbone of therapy. We report results of our institutional approach in pts with PCNSL and secondary involvement of the CNS by DLBCL using a prolonged course of rituximab, temozolamide, and HD-MTX (RTM) without consolidation. Methods We conducted a retrospective cohort study describing outcomes of pts with PCNSL or secondary CNS DLBCL who were treated on the RTM protocol. Eligible pts are treated with rituximab 375 mg/m2 on day 1 in combination with HD-MTX 8 g/m2 (days 1 and 15) and temozolamide 150 mg/m2 (days 1-5) in 28-day cycles. HD-MTX is administered with leucovorin rescue and adjusted for creatinine clearance. Initial response assessment is usually after 2 cycles with brain MRI. Once a complete response (CR) has been achieved, the day 15 HD-MTX is omitted from future cycles. Pts typically complete a total of 6-12 cycles, at the discretion of the clinician, without further planned consolidation. Descriptive and survival analyses using the Kaplan-Meier methodology were performed (STATA 13). The primary endpoints, overall survival (OS) and progression free survival (PFS) were estimated from the date of the first treatment with RTM to death, progression, or date of last follow-up. A log-rank test was utilized to compare OS/PFS between pts with PCNSL versus secondary CNS DLBCL. A Cox proportional hazard analysis was performed to evaluate the effect of patient level variables on OS. Clinical response was evaluated using International Workshop on Response Criteria for PCNSL (Abrey, J Clin Oncol 2005). Results We identified 46 pts who received RTM at our institution between 2009 and 2014. Twenty-seven (59%) pts had PCNSL and 19 (41%) pts had secondary CNS DLBCL. The median age at diagnosis was 61 years (range 21-85) with 50% males. Treatment was well tolerated. Two (4%) pts discontinued treatment prematurely and 7 (15%) pts required a dose reduction in HD-MTX due to toxicity. Toxicities included transaminitis, acute renal failure, infection, fatigue, and cytopenias. In pts with PCNSL, all received RTM as their initial treatment. Best response to therapy in this group was as follows: 19 (70%) had a CR, 3 (11%) had PR, 3 (11%) had SD and 2 (7%) had PD. The overall response rate was 81%. All patients with secondary CNS DLBCL had received prior systemic therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Best CNS response to therapy in this group was as follows: 7 (37%) had CR, 2 (11%) had PR, 1 (5%) had SD, and 9 (47%) had PD. The overall response rate was 47%. For the entire cohort, the median OS was 41 months (m) and median PFS was 8 m. Compared with secondary CNS DLBCL, patients with PCNSL had a significantly longer median OS (54 m vs. 5 m; p<0.01) (Figure 1). PFS was also significantly longer for pts with primary versus secondary CNS DLBCL (22 m vs. 2 m; p=0.02) (Figure 2). Univariate cox analysis demonstrated that sex and age did not impact OS but pts who were in a CR or PR at initial response assessment compared to SD or PD had a hazard ratio for OS of 0.12 (95% CI: 0.05 to 0.29, P<0.01). Conclusions In our cohort, pts with PCNSL had excellent outcomes using a prolonged course of the RTM regimen without the toxicities of consolidation with radiation or high dose chemotherapy. These outcomes did not translate to pts with secondary CNS DLBCL, which may be consistent with the different biology and aggressive nature of this subgroup in addition to the prior therapies received. Early response assessment is vital to assess prognosis pts as those who respond within 2 cycles of therapy have an improved OS. This data suggests that RTM without further consolidation is an acceptable alternative regimen for PCNSL. Future prospective studies are needed to validate our findings. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ganetsky: Onyx: Speakers Bureau. Dwivedy Nasta:Millenium: Research Funding; BMS: Research Funding. Mato:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy. Schuster:Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding.

A single-institution experience with the hyper-CVAD regimen in aggressive NHL.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18510-e18510
Author(s):  
Mariam Younas ◽  
Stephanie A. Gregory ◽  
Ahmad Jajeh ◽  
Melissa L. Larson ◽  
Taha Al-Rifai
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematological Malignancies ◽  
Chemotherapy Regimen ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
High Dose ◽  
Single Institution ◽  
Dose Methotrexate ◽  
40Mg Daily ◽  
Age Over 60

e18510 Background: Hyper-CVAD (± rituximab) is a chemotherapy regimen designed as a treatment for aggressive hematological malignancies. It consists of 8 cycles. Cycle 1, 3, 5, 7 (3-4 weeks/cycle) includes cyclophosphamide 300mg/m2 IV over 2 hours (hrs) every 12 hrs for 6 doses on day 1-3 + Mesna 600mg/m2 per day continuous IV on days 1-3 to start 1 hr before cyclophosphamide till 12 hrs after completion of cyclophosphamide + vincristine 2mg IV on days 4 and 11 + doxorubicin 50mg/m2 IV over 24 hrs on Day 4 + dexamethasone 40mg daily orally on days 1-4 and days 11-14. Cycle 2, 4, 6, 8 (3-4 weeks/cycle) consist of high dose methotrexate (MTX) (200mg/m2) IV over 2 hrs followed by 800mg/m2 continuous IV infusion over 22 hrs on day 1 + cytarabine 3gm/m2 (1gm/m2 for patient age over 60 years old) IV over 2 hrs every 12 hrs for doses on days 2 and 3 + leucovorin 50mg IV every 6 hrs starting 12 hrs after completion of MTX till MTX level < 0.05µM. Hyper-CVAD is a short intensified regimen given over eight months compared to known therapy for ALL and Burkitt lymphoma. Methods: Retrospective review of all cases of acute lymphoblastic leukemia/lymphoma and Burkitt’s lymphoma between 2000 and 2012 was done. It included all patients and evaluated response to therapy including Hyper-CVAD. Results: A total of 79 patients with aggressive acute lymphoblastic leukemia/lymphoma and Burkitt’s NHL were analyzed. Mean age 39 years (range 15-75 years). All patients were admitted at least twice with febrile neutropenia. Prolonged cytopenias were observed in more than 50% of patients. Conclusions: Hyper-CVAD is an intense regimen that produces high rates of clinical remission in less than 8 months of therapy compared to established regimen for aggressive hematological malignancies. [Table: see text]

Carboplatin/Ifosfamide Window Therapy for Osteosarcoma: Results of the St Jude Children’s Research Hospital OS-91 Trial

2001 ◽  
Vol 19 (1) ◽  
pp. 171-182 ◽  
Author(s):  
William H. Meyer ◽  
Charles B. Pratt ◽  
Catherine A. Poquette ◽  
Bhaskar N. Rao ◽  
David M. Parham ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Primary Tumor ◽  
Pilot Trial ◽  
Disease Rate ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Chemotherapy Protocol ◽  
Multiagent Chemotherapy

PURPOSE: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent chemotherapy protocol that eliminated cisplatin. PATIENTS AND METHODS: Sixty-nine patients with newly diagnosed, previously untreated osteosarcoma received three cycles of carboplatin (560 mg/m2 × 1) and ifosfamide (2.65 g/m2/d × 3). Assessment of response was evaluated after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant therapy comprised two additional carboplatin/ifosfamide cycles, doxorubicin, and high-dose methotrexate. Patients were stratified at enrollment: stratum A, resectable primary tumor without metastases; stratum B, unresectable primary tumor; and stratum C, metastatic disease at diagnosis. Week 6 response was compared with that of a historic group that received only ifosfamide during the initial window evaluation. RESULTS: The clinical and radiographic response rate to three cycles of carboplatin/ifosfamide was 67.7% (95% confidence interval, 55.0% to 78.8%). Compared with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide reduced the progressive disease rate at week 6 (31.9% v 9%, P = .003). For patients in stratum A, the 3-year event-free survival and survival were 72.3% ± 6.7% and 76.4% ± 6.4%, respectively. Patients who received carboplatin-based therapy had less long-term renal toxicity and ototoxicity. CONCLUSION: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.

Durable Complete Responses With High-Dose Bolus Interleukin-2 in Patients With Metastatic Melanoma Who Have Experienced Progression After Biochemotherapy

2007 ◽  
Vol 25 (25) ◽  
pp. 3802-3807 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
John M. Kirkwood ◽  
William E. Gooding ◽  
Chao Cai ◽  
Sanjiv S. Agarwala
Keyword(s):  
Survival Time ◽  
Metastatic Melanoma ◽  
Interleukin 2 ◽  
Rest Period ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Initial Response ◽  
Disease Stage ◽  
High Dose ◽  
Ajcc Stage

Purpose We conducted a phase II trial of high-dose bolus (HDB) interleukin-2 (IL-2) in patients with metastatic melanoma who had experienced progression after biochemotherapy (BCT). Patients and Methods Eligible patients had experienced progression on or after BCT (cisplatin, vinblastine, dacarbazine, IL-2 9 MU/m2/d for 4 days, and interferon alfa-2b). HDB IL-2 was administered at 600,000 U/kg per dose for a maximum of 14 doses per cycle with a 1-week rest period between cycles. Stable or responding patients were offered an additional course (two cycles) after 6 to 8 weeks. Results Twenty-six patients (12 men and 14 women), age 28 to 70 years (median, 45 years), have been treated. All but three patients received at least two cycles of HDB IL-2; 10 patients received a second course of therapy. Disease stage was American Joint Committee on Cancer (AJCC) stage M1a (n = 5), M1b (n = 5), and M1c (n = 16). Grade 3 and 4 toxicities included hyperbilirubinemia (n = 10), thrombocytopenia (n = 6), oliguria (n = 3), diarrhea (n = 1), infection (n = 2), and neurologic toxicity (n = 2). Overall response rate was 19.2% (four complete responses, lasting 4, 4, 26+, and 41+ months; and one partial response, lasting 3 months). Five patients (19%) had stable disease lasting 1 to 3 months, but all eventually experienced progression. All four complete responders had AJCC stage M1a disease. At a median follow-up time of 10 months, median survival time was 42 weeks (95% CI, 19.1 to 86.6 weeks), and median progression-free survival time was 10 weeks (95% CI, 8 to 16.1 weeks). An initial response to BCT was not found to be predictive for response to HDB IL-2. Conclusion HDB IL-2 is active therapy for patients who experience progression on BCT. This observation has implications regarding the importance of dose-intensity for IL-2 therapy.

VARIABILITY IN DOSE INTENSITY OF HIGH-DOSE METHOTREXATE FOR NONMETASTATIC OSTEOSARCOMA

2002 ◽  
Vol 19 (7) ◽  
pp. 483-489
Author(s):  
Patrick J. Leavey ◽  
Elpis Mantadakis ◽  
Gerhard Maale
Keyword(s):  
Dose Intensity ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

Effect of single agent high-dose methotrexate-related acute kidney injury on length of hospitalization and relative dose intensity in adult patients with central nervous system lymphoma

2016 ◽  
Vol 23 (7) ◽  
pp. 496-501 ◽  
Author(s):  
Jennifer S Steward ◽  
Heather M Bullard ◽  
Timothy J O’Rourke ◽  
Alan D Campbell ◽  
Brett T Brinker ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Length Of Stay ◽  
Kidney Injury ◽  
Dose Intensity ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Chemotherapy Dose ◽  
Grade 3 ◽  
Chemotherapy Dose Intensity

Purpose Grade ≥3 adverse effects prolong hospitalization and reduce chemotherapy dose intensity. The purpose of this study was to evaluate the rate and severity of high-dose methotrexate-related acute kidney injury and analyze its effect on hospital length of stay and relative chemotherapy dose intensity. Methods This was a retrospective cohort analysis. Patients receiving ≥1 dose of high-dose methotrexate were analyzed for acute kidney injury and length of stay. Patients receiving ≥6 cycles of induction therapy were included in the analysis of relative chemotherapy dose intensity. Chi squared analysis was used to determine the differences between dichotomous data; Student’s t-test for parametric data and Mann-Whitney U test for non-parametric data for continuous variables. Statistical analyses were performed with IBM SPSS Statistics (version 21). Results Twenty-six patients and 194 treatment encounters were identified. Thirteen patients were evaluated for relative chemotherapy dose intensity. Grade ≥3 acute kidney injury occurred in four patients (15% of patients; 2% of encounters). There were no grade 5 adverse events. Mean length of stay for encounters with grade ≥3 acute kidney injury was almost three times longer than for those with ≤ grade 2 acute kidney injury (p = 0.041). Mean relative chemotherapy dose intensity was reduced approximately in half for patients experiencing grade ≥3 acute kidney injury (p < 0.01). The most common adverse events were hypokalemia and nausea. Proton pump inhibitors were the most frequently co-administered medications with the potential to affect high-dose methotrexate pharmacokinetics. Conclusion At our cancer program, the rate of grade ≥3 acute kidney injury with high-dose methotrexate is similar to that reported by others. Grade ≥3 acute kidney injury following high-dose methotrexate administration significantly prolonged length of stay and reduced relative chemotherapy dose intensity.

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