Rituximab Maintenance Treatment for a Maximum of 5 Years in Follicular Lymphoma: Final Results of the Randomized Phase III Trial SAKK 35/03

Abstract Background: Follicular lymphoma is usually a disase with a prolonged course and a chemotherapy-free regimen might be a favourable treatment strategy. SAKK 35/03 investigated two different durations of rituximab maintenance (5 years vs. 6 months) in patients with follicular lymphoma after induction with 4 weekly doses of rituximab monotherapy. With a median follow-up of 6.4 years we were not able to show a benefit with long-term rituximab maintenance up to five years in event-free survival (EFS) or overall survival (OS ). Here we report the final results with a median follow-up of 10 years. Methods: 270 patients (median age 57 years: range 25-82) with untreated, relapsed, stable or chemotherapy resistant follicular lymphoma were treated with 4 doses of rituximab monotherapy in weekly intervals (375 mg/m²). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of five years or until disease progression or unacceptable toxicity). The primary endpoint was EFS . Progression-free survival (PFS), OS, and toxicity were secondary endpoints. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints. Results: 165 patients were randomly assigned to short-term (n=82) or long-term (n=83) maintenance. At a median follow-up period of 10 years, the median EFS is 3.4 years (95% CI 2.1-5.5) in the short-term arm and 5.3 years (95% CI 3.5-7.5) in the long-term arm. Using the pre-specified log-rank test this difference is statistically not significant (p=0.39 ). There is no significant difference in PFS and OS. Median OS in the short-term arm is 11.0 years (95% CI 11.0, NA ) and not reached in the long-term arm (p=0.80). The incidence of subsequent cancers increased in both arms over time, nine patients developed a subsequent cancer in the short-term maintenance arm and 10 in the long-term maintenance arm. There was no major additional toxicity with longer follow-up. Conclusions : Even with a long follow-up of 10 years we were not able to show a significant benefit of long-term compared to short-term rituximab maintenance in EFS, PFS and OS. Treatment strategies and study designs need to take these results into consideration in order to guarantee optimal medical and scientific results. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Prolonged rituximab maintenance in follicular lymphoma patients: long-term results of the SAKK 35/03 randomized trial

Blood Advances ◽

10.1182/bloodadvances.2020002858 ◽

2020 ◽

Vol 4 (23) ◽

pp. 5951-5957

Author(s):

Alden A. Moccia ◽

Christian Taverna ◽

Sämi Schär ◽

Anna Vanazzi ◽

Stéphanie Rondeau ◽

...

Keyword(s):

Follicular Lymphoma ◽

Randomized Trial ◽

Long Term Results ◽

Short Term ◽

Free Survival ◽

Long Term Treatment ◽

Significant Difference ◽

Term Maintenance

Abstract The Swiss Group for Clinical Cancer Research (SAKK) conducted the SAKK 35/03 randomized trial (NCT00227695) to investigate different rituximab monotherapy schedules in patients with follicular lymphoma (FL). Here, we report their long-term treatment outcome. Two-hundred and seventy FL patients were treated with 4 weekly doses of rituximab monotherapy (375 mg/m2); 165 of them, achieving at least a partial response, were randomly assigned to maintenance rituximab (375 mg/m2 every 2 months) on a short-term (4 administrations; n = 82) or a long-term (up to a maximum of 5 years; n = 83) schedule. The primary end point was event-free survival (EFS). At a median follow-up period of 10 years, median EFS was 3.4 years (95% confidence interval [CI], 2.1-5.5) in the short-term arm and 5.3 years (95% CI, 3.5-7.5) in the long-term arm. Using the prespecified log-rank test, this difference is not statistically significant (P = .39). There also was not a statistically significant difference in progression-free survival or overall survival (OS). Median OS was 11.0 years (95% CI, 11.0-NA) in the short-term arm and was not reached in the long-term arm (P = .80). The incidence of second cancers was similar in the 2 arms (9 patients after short-term maintenance and 10 patients after long-term maintenance). No major late toxicities emerged. No significant benefit of prolonged maintenance became evident with longer follow-up. Notably, in symptomatic patients in need of immediate treatment, the 10-year OS rate was 83% (95% CI, 73-89%). These findings indicate that single-agent rituximab may be a valid first-line option for symptomatic patients with advanced FL.

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Rituximab Maintenance Treatment For a Maximum Of 5 Years In Follicular Lymphoma: Results Of The Randomized Phase III Trial SAKK 35/03

Blood ◽

10.1182/blood.v122.21.508.508 ◽

2013 ◽

Vol 122 (21) ◽

pp. 508-508 ◽

Cited By ~ 6

Author(s):

Christian J. Taverna ◽

Giovanni Martinelli ◽

Felicitas Hitz ◽

Walter Mingrone ◽

Thomas Pabst ◽

...

Keyword(s):

Follicular Lymphoma ◽

Disease Progression ◽

Maintenance Treatment ◽

Rank Test ◽

Free Survival ◽

Rituximab Maintenance ◽

Log Rank Test ◽

Grade 3 ◽

Unacceptable Toxicity

Abstract Background Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance treatment remains unknown. Methods 270 patients (median age 57 years: range 25-82) with either untreated, relapsed, stable or chemotherapy resistant follicular lymphoma of all grades were treated with 4 weekly doses of rituximab monotherapy (375 mg/m²). Patients responding to the induction treatment (partial or complete response) received rituximab (375 mg/ m²) maintenance and were randomized either to a short maintenance consisting of four administrations every two months (arm A), or a prolonged maintenance for a maximum of five years or until disease progression or unacceptable toxicity (arm B). The primary endpoint was event-free survival (EFS) from randomization. Sample size calculation allowed detecting a median EFS increase with prolonged maintenance from 2.5 to 4.5 years with 80% power. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and objective response. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints. Results From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. 124 patients were chemotherapy-naïve. The median EFS is 3.4 years (95% CI 2.1-5.3) in arm A and 5.3 years (95% CI 3.5-NA) in arm B. Using the prespecified log-rank test this difference is statistically not significant (p=0.14). We observed an unexplained difference in disease progression and relapse during the first 8 months after randomization (3 in arm A vs. 10 in arm B) when treatment in both arms was the same which led to an early crossing of the EFS curves at 18 months. Considering only patients at risk after 8 months from randomization EFS in arm B is significantly prolonged compared to arm A (median EFS 7.1 (95% CI 4.4-NA) vs. 2.9 years (95% CI 1.8-4.8); log-rank test p=0.004). Median PFS is significantly longer in arm B (7.4 (95% CI 5.1-NA) vs. 3.5 years (95% CI 2.1-5.9); log-rank test p=0.04). There is no significant difference in OS and in the observed best response. Maintenance treatment was stopped due to unacceptable toxicity in no patient in arm A vs. 3 in arm B. Six subsequent cancers developed in arm A and 8 in arm B. One infection grade ≥3 was reported in arm A whereas seven infections grade ≥3 occurred in 5 patients in arm B. Conclusions EFS, the primary endpoint was not met which is mainly due to the early separation of the survival curves favouring arm A, at a time when the treatment in both arms was the same. However, a retrospectively defined analysis considering only EFS events from the time when treatment was different in the two arms, shows a statistically significant increase in EFS with long-term maintenance compared to the 8 months maintenance regimen. Long-term rituximab maintenance also doubles the median PFS without leading to increased undue toxicity. Disclosures: Off Label Use: Rituximab for 5 years. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open esophagectomy: long-term follow-up of a randomized clinical trial

Diseases of the Esophagus ◽

10.1093/dote/doaa079 ◽

2020 ◽

Vol 33 (Supplement_2) ◽

Author(s):

Eline M de Groot ◽

Sylvia van der Horst ◽

B Feike Kingma ◽

Lucas Goense ◽

Pieter C van der Sluis ◽

...

Keyword(s):

Overall Survival ◽

Disease Free Survival ◽

Rank Test ◽

Robot Assisted ◽

Short Term ◽

Free Survival ◽

Log Rank Test ◽

Disease Free

ABSTRACT Initial results of the ROBOT, which randomized between robot-assisted minimally invasive esophagectomy (RAMIE) and open transthoracic esophagectomy (OTE), showed significantly better short-term postoperative outcomes in favor of RAMIE. However, it is not yet clarified if RAMIE is equivalent to OTE regarding long-term outcomes. The aim of this study was to report the long-term oncological results of the ROBOT trial in terms of survival and disease-free survival. This study is a follow-up study of the ROBOT trial, which was a randomized controlled trial comparing RAMIE to OTE in 112 patients with intrathoracic esophageal cancer. Both the trial protocol and short-term results were previously published. The primary outcome of the current study was 5-year overall survival. Secondary outcomes were disease-free survival and recurrence patterns. Analysis was by intention to treat. During the recruitment period, 109 patients were included in the survival analysis (RAMIE n = 54, OTE n = 55). Majority of patients had clinical stage III or IV (RAMIE 63%, OTE 55%) and received neoadjuvant chemoradiotherapy (80%). Median follow-up was 60 months (range 31–60). The combined 5-year overall survival rates for RAMIE and OTE were 41% (95% CI 27–55) and 40% (95% CI 26–53), respectively (log rank test P = 0.827). The 5-year disease-free survival rate was 42% (95% CI 28–55) in the RAMIE group and 43% (95% CI 29–57) in the OTE group (log rank test P = 0.749). Out of 104 patients, 57 (55%) developed recurrent disease detected at a median of 10 months (range 0–56) after surgery. No statistically difference in recurrence rate nor recurrence pattern was observed between both groups. Overall survival and disease-free survival of RAMIE are comparable to OTE. These results continue to support the use of robotic surgery for esophageal cancer.

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Rituximab Maintenance Treatment for a Maximum of 5 Years In Follicular Lymphoma: Safety Analysis of the Randomized Phase III Trial SAKK 35/03

Blood ◽

10.1182/blood.v116.21.1802.1802 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1802-1802 ◽

Cited By ~ 7

Author(s):

Christian J. Taverna ◽

Simona Bassi ◽

Felicitas Hitz ◽

Walter Mingrone ◽

Thomas Pabst ◽

...

Keyword(s):

Follicular Lymphoma ◽

Safety Analysis ◽

Phase Iii ◽

Advisory Committees ◽

Phase Iii Trial ◽

Rituximab Maintenance ◽

Grade 3 ◽

Unacceptable Toxicity

Abstract Abstract 1802 Background: Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance remains unknown. Methods: We prospectively registered 270 patients with untreated, chemotherapy resistant or relapsed follicular lymphoma. All patients received rituximab induction consisting of 4 weekly doses (375 mg/m2). Responding patients (PR and CR) were randomized to a short maintenance consisting of four doses of rituximab (375 mg/m2) every two months (arm A) or prolonged maintenance consisting of rituximab every two months for a maximum of five years or until disease progression or unacceptable toxicity (arm B). Primary endpoint is event-free survival. Here we present the safety analysis results after a median long-term maintenance period of 3.3 years. Results: From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. The median follow-up time is 3.2 years for arms A and B combined. While receiving maintenance therapy a total of 899 hematological and non-hematological adverse events were observed, 28 of grade 3 and 6 of grade 4. After randomization five patients experienced subsequent cancers. Seven grade 3 and 4 infections were reported. Two grade 3 infections occurred after 2 years of maintenance. Grade 3 and 4 neutropenia occurred in 6 (3.6 %) patients, decreased levels of IgG were observed in 24 (14.6 %) patients. In arm B, maintenance was stopped due to unacceptable toxicity in 2 patients after 16 and 42 months respectively and due to subsequent breast cancer in 1 patient after 20 months. One patient died 4 months after randomization because of ileus and consecutive peritonitis, considered to be unrelated to therapy. Sixty-three patients are on maintenance for two or more years of which 48 patients are on for three or more years. Two patients have completed the 5 years of maintenance. Conclusions: Rituximab maintenance beyond two years is feasible without evidence for increased toxicity. However, close follow up of patients under prolonged rituximab maintenance is still necessary. The trial has been closed for accrual but there are still patients on treatment. Disclosures: Taverna: Roche: Membership on an entity's Board of Directors or advisory committees. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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First results of long-term rituximab maintenance treatment in follicular lymphoma: Safety analysis of the randomized phase III trial SAKK 35/03

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8534 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8534-8534

Author(s):

C. J. Taverna ◽

S. Bassi ◽

F. Hitz ◽

W. Mingrone ◽

T. Pabst ◽

...

Keyword(s):

Follicular Lymphoma ◽

Safety Analysis ◽

Phase Iii ◽

Phase Iii Trial ◽

Rituximab Maintenance ◽

First Results ◽

Grade 3 ◽

Unacceptable Toxicity

8534 Background: Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance remains unknown. Methods: We prospectively registered 270 patients with untreated, chemotherapy resistant or relapsed follicular lymphoma. All patients received rituximab induction consisting of 4 weekly doses (375 mg/m2). Responding patients (PR and CR) were randomized to a short maintenance consisting of four doses of rituximab (375 mg/m2) every two months (arm A) or prolonged maintenance consisting of rituximab every two months for a maximum of five years or until progression or unacceptable toxicity (arm B). Primary endpoint was event-free survival. Here we present the safety analysis. Results: From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. The median follow up is 22.7 months. A total of 442 hematological and non-hematological adverse events were observed, 27 of grade 3 and 6 of grade 4. Five subsequent cancers and 9 grade 3 and 4 infections were reported. Grade 3 and 4 neutropenia occurred in 5 patients, decreased levels of IgG were observed in 19 patients. Four grade 3 infections occurred after 2 years of maintenance. In arm B, maintenance was stopped due to unacceptable toxicity (fever) in 1 patient after 18 months and due to subsequent breast cancer in 1 patient after 20 months. One patient died 4 months after randomization because of ileus and consecutive peritonitis; considered to be unrelated to therapy. Twenty-nine patients are on maintenance for two or more years of which 6 patients are on for three or more years. In this analysis, median duration of the prolonged maintenance is 23.7 months. Conclusions: Rituximab maintenance beyond two years is feasible. We do not have evidence for increased toxicity after 2 years of maintenance. However, close follow up of patients under prolonged rituximab maintenance is necessary. The trial has been closed for accrual but there are still patients on treatment. [Table: see text]

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Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03

Journal of Clinical Oncology ◽

10.1200/jco.2015.61.3968 ◽

2016 ◽

Vol 34 (5) ◽

pp. 495-500 ◽

Cited By ~ 34

Author(s):

Christian Taverna ◽

Giovanni Martinelli ◽

Felicitas Hitz ◽

Walter Mingrone ◽

Thomas Pabst ◽

...

Keyword(s):

Maintenance Therapy ◽

Follicular Lymphoma ◽

Progression Free Survival ◽

Short Term ◽

End Points ◽

Free Survival ◽

Rituximab Maintenance ◽

End Point ◽

Unacceptable Toxicity

Purpose Rituximab maintenance therapy has been shown to improve progression-free survival in patients with follicular lymphoma; however, the optimal duration of maintenance treatment remains unknown. Patients and Methods Two hundred seventy patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma were treated with four doses of rituximab monotherapy in weekly intervals (375 mg/m2). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of 5 years or until disease progression or unacceptable toxicity). The primary end point was event-free survival (EFS). Progression-free survival, overall survival (OS), and toxicity were secondary end points. Comparisons between the two arms were performed using the log-rank test for survival end points. Results One hundred sixty-five patients were randomly assigned to the short-term (n = 82) or long-term (n = 83) maintenance arms. Because of the low event rate, the final analysis was performed after 95 events had occurred, which was before the targeted event number of 99 had been reached. At a median follow-up period of 6.4 years, the median EFS was 3.4 years (95% CI, 2.1 to 5.3) in the short-term arm and 5.3 years (95% CI, 3.5 to not available) in the long-term arm (P = .14). Patients in the long-term arm experienced more adverse effects than did those in the short-term arm, with 76% v 50% of patients with at least one adverse event (P < .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups. Conclusion Long-term rituximab maintenance therapy does not improve EFS, which was the primary end point of this trial, or OS, and was associated with increased toxicity.

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Re-bleeding and its predictors after capsule endoscopy in patients with obscure gastrointestinal bleeding in long-term follow-up

BMC Gastroenterology ◽

10.1186/s12876-019-1137-3 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Panu Wetwittayakhlang ◽

Jirapat Wonglhow ◽

Nisa Netinatsunton ◽

Naichaya Chamroonkul ◽

Teerha Piratvisuth

Keyword(s):

Specific Treatment ◽

Rank Test ◽

Gi Bleeding ◽

Free Survival ◽

Log Rank Test ◽

Negative Study ◽

Long Term Follow Up ◽

Bleeding Episodes

Abstract Background Capsule endoscopy (CE) is the preferred diagnostic test of choice in the investigation of obscure gastrointestinal bleeding (OGIB). Although, a conservative strategy is recommended in the short-term, for cases with a negative result from CE, the impact of CE on long-term re-bleeding still remains unclear. Hence, the aim of this study was to determine the long-term re-bleeding rate along with predictors after CE in patients with OGIB. Methods We retrospectively reviewed 216 patients with OGIB, whom had received a CE examination, so as to investigate the cause of obscure GI bleeding; between July 2008 and March 2018. The patient’s characteristics, medication use, CE finding, treatments strategy, re-bleeding episodes and follow-up information were collected from the institutional electronic medical chart and CE database. Re-bleeding free survival was evaluated using Kaplan-Meier curves with log rank test, whilst predictors associated with the re-bleeding episodes were analyzed via the use of Cox proportional hazard model. Results One hundred and thirty-three patients with OGIB, having received CE were enrolled in the analysis. The pool rate of re-bleeding was 26.3% (35/133) during a follow-up duration of 26 months after CE. Patients with positive CE study, without specific treatment, had higher rates of re-bleeding (47.6%) than those with positive study whom received specific treatment (25.7%), and negative study (20.8%) (p = 0.042). Although, the re-bleeding free survival was not significantly different among the groups (log rank test; P = 0.10). Re-bleeding events occurring within 6, 12, and 24 months after CE were 36, 64 and 92%, respectively. The high-frequency re-bleeding etiologies were the small bowel angiodysplasias and abnormal vascular lesions. Furthermore, independent predictors for re-bleeding after CE were patients with cirrhosis (hazard ratio, HR 4.06), incomplete CE visualization (HR 2.97), and a history of previous GI bleeding (HR 2.80). Conclusions The likelihood of re-bleeding after CE was higher in patients with positive CE study than those with negative study. Specific treatments, or therapeutic interventions for patients with detectable lesions reduced the probability of re-bleeding episodes in long-term follow-up. Close follow-up for recurrent bleeding is recommeded for at least 2 years after CE.

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Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study

Journal of Clinical Oncology ◽

10.1200/jco.19.01073 ◽

2019 ◽

Vol 37 (31) ◽

pp. 2815-2824 ◽

Cited By ~ 40

Author(s):

Emmanuel Bachy ◽

John F. Seymour ◽

Pierre Feugier ◽

Fritz Offner ◽

Armando López-Guillermo ◽

...

Keyword(s):

Follicular Lymphoma ◽

Progression Free Survival ◽

Hazard Ratio ◽

Long Term Results ◽

Induction Treatment ◽

Free Survival ◽

Rituximab Maintenance ◽

To Receive

PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

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Efficacy and safety assessment of prolonged maintenance with subcutaneous rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results of the Phase III MabCute study

Haematologica ◽

10.3324/haematol.2020.274803 ◽

2021 ◽

Author(s):

Simon Rule ◽

Wolney Gois Barreto ◽

Javier Briones ◽

Angelo M. Carella ◽

Olivier Casasnovas ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Progression Free Survival ◽

Standard Of Care ◽

Phase Iii ◽

Rank Test ◽

Free Survival ◽

Non Hodgkin Lymphoma ◽

Log Rank Test ◽

Chemotherapy Induction

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers long-term progression-free survival (PFS) benefit in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years’ initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed PFS in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 PFS events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log rank test; hazard ratio 0.76 [95% confidence interval: 0.37–1.53]). Median PFS was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non-Hodgkin lymphoma.

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Frontline treatment of localized osteosarcoma without methotrexate: Results of the St. Jude Children's Research Hospital OS99 trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.10036 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 10036-10036

Author(s):

N. C. Daw ◽

M. D. Neel ◽

B. N. Rao ◽

C. A. Billups ◽

J. Wu ◽

...

Keyword(s):

Rank Test ◽

High Dose ◽

Free Survival ◽

Log Rank Test ◽

Significant Toxicity ◽

Frontline Treatment ◽

Definitive Surgery ◽

Carboplatin Dose

10036 Background: Standard treatment of osteosarcoma includes cisplatin and high-dose methotrexate (HD-MTX), but both agents are associated with significant toxicity and MTX administration requires complex pharmacokinetic monitoring. In our previous OS91 trial, the combination of carboplatin and ifosfamide with doxorubicin and HD-MTX yielded outcomes comparable to those of cisplatin-based regimens with less long-term toxicity in localized osteosarcoma. Methods: Between 1999 and 2006, we conducted a multi-institutional trial (OS99) to evaluate the activity of carboplatin, ifosfamide, and doxorubicin without HD-MTX in newly-diagnosed patients with localized osteosarcoma. Treatment comprised 12 cycles of chemotherapy given every 3 weeks: 3 consecutive cycles of carboplatin (dose targeted to AUC 8 mg/ml×min on day 1) and ifosfamide (2.65 g/m2 daily for 3 days) and one cycle of doxorubicin (25 mg/m2 daily for 3 days) followed by definitive surgery (week 12) and 2 additional cycles of carboplatin/ifosfamide and 3 cycles each of ifosfamide/doxorubicin and carboplatin/doxorubicin for a total of 35 weeks. The log rank test was used to compare survival and event-free survival (EFS) distributions. Results: A total of 72 eligible patients were enrolled. The median age was 13.4 years and 41 (57%) were male. The most common tumor site was the femur (n = 46; 64%). The median follow-up for survivors was 4.4 years. Forty of the 66 (60.6%) evaluable patients had good histologic response (tumor necrosis > 90%) to preoperative chemotherapy. There was no difference in EFS or survival distributions between OS99 and OS91. Four-year estimates of EFS were 68.1 ± 6.7% for OS99 compared to 70.2 ± 6.6% for OS91 (p = 0.89). The 4-year OS was 82.4% ± 5.7% for OS99 compared to 74.5% ± 6.3 for OS91 (p = 0.25). Conclusions: OS99 produced outcomes similar to cisplatin or HD-MTX containing regimens and offers an alternative treatment regimen especially for patients with renal compromise and institutions where pharmacokinetic monitoring of MTX is not available. No significant financial relationships to disclose.

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