Search

Purpose: The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma., Methods: Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests., Results: Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS., Conclusion: While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma., Competing Interests: Patrick J. LeaveyResearch Funding: Eleison Pharmaceuticals Nadia N. LaackResearch Funding: Bristol Myers Squib Mark D. KrailoConsulting or Advisory Role: Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Sharp & Dohme R. Lor RandallHonoraria: Daiichi Sankyo, Onkos Surgical, OncliveTravel, Accommodations, Expenses: Biomet, Daiichi Sankyo/Lilly Steven G. DuBoisResearch Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Salarius PharmaceuticalsUncompensated Relationships: Y-mAbs Therapeutics Inc Damon R. ReedConsulting or Advisory Role: Eisai, PfizerTravel, Accommodations, Expenses: Salarius Pharmaceuticals Douglas S. HawkinsResearch Funding: Loxo (Inst), Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Bayer (Inst), Lilly (Inst), Eisai (Inst), Amgen (Inst), Seattle Genetics (Inst), Incyte (Inst), Jazz Pharmaceuticals (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Bayer, AstraZeneca Helen NadelConsulting or Advisory Role: ICON Clinical Research G. Douglas LetsonEmployment: StrykerConsulting or Advisory Role: StrykerTravel, Accommodations, Expenses: Stryker Mark BernsteinResearch Funding: Merck Paul ChubaEmployment: Radiation Oncology Specialists Neyssa MarinaEmployment: Five Prime Therapeutics, Genentech/Roche (I), Synthorx, Sanofi PasteurStock and Other Ownership Interests: Five Prime Therapeutics, Genentech/Roche (I), Synthorx, Sanofi PasteurTravel, Accommodations, Expenses: Five Prime Therapeutics, SynthorxUncompensated Relationships: Stanford University School of MedicineOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1210881 Richard GorlickResearch Funding: Eisai Katherine A. JanewayHonoraria: Foundation MedicineConsulting or Advisory Role: Bayer, IpsenTravel, Accommodations, Expenses: Bayer Leo MascarenhasConsulting or Advisory Role: BayerResearch Funding: AstraZeneca/MedImmune, Lilly, Bayer, Salarius Pharmaceuticals, Turning Point Therapeutics, Pfizer, Incyte, Amgen, E.R. Squibb Sons, LLC, Jazz Pharmaceuticals, MerckTravel, Accommodations, Expenses: Bayer, Lilly, Thermo Fisher Scientific, Salarius PharmaceuticalsUncompensated Relationships: Children's Oncology Group Foundation, The Pablove Foundation, American Society of Pediatric Hematology/OncologyNo other potential conflicts of interest were reported.

Purpose: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy., Patients and Methods: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary)., Results: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model., Conclusion: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

Purpose: To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma., Patients and Methods: Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival., Results: In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96)., Conclusion: The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.

Purpose: To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS)., Patients and Methods: Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS., Results: Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%., Conclusion: The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.