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Cited by 359Sarcoma Diagnosis and TreatmentBone Tumor Diagnosis and TreatmentsOvarian cancer diagnosis and treatment

A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study

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Grignani, G., Palmerini, E., Dileo, P., Asaftei, S.D., D’Ambrosio, L., Pignochino, Y., Mercuri, M., Picci, P. +4 more·2012·Annals of Oncology
DOI 10.1093/annonc/mdr151
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Abstract

Purpose After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma.Experimental design Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided.Results Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥ 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity.Conclusions Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

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  • Clinical trials involving tyrosine kinase inhibitors alone typically have median progression-free survival ranging from 4 to 6 months and are accompanied by inevitable development of secondary drug resistance.

    “Additionally, clinical trials involving TKIs alone are typically with median PFS ranging from 4 to 6 months accompanied with inevitable development of secondary drug resistance1–5.”

    From Apatinib plus ifosfamide and etoposide versus ifosfamide and etoposide in patients with advanced osteosarcomas (OAIE/PKUPH-sarcoma 11): a randomized phase II study (2025) · cites this paper as [1]

    The efficacy section reports a median PFS of 4 months in this sorafenib trial involving patients with relapsed, unresectable high-grade osteosarcoma. It does not establish that TKI-only trials typically have median PFS of 4–6 months. The original-articles discussion describes short-lived responses and suggests possible escape mechanisms, but does not show that secondary resistance is inevitable. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Although multi-targeted tyrosine kinase inhibitors can induce measurable responses, durable disease control continues to be a major challenge.

    “Although multi-targeted TKIs can induce measurable responses, durable disease control continues to be a major challenge1,4–6,13,14,18.”

    From Apatinib plus ifosfamide and etoposide versus ifosfamide and etoposide in patients with advanced osteosarcomas (OAIE/PKUPH-sarcoma 11): a randomized phase II study (2025) · cites this paper as [1]

  • Previous studies have demonstrated that multi-targeted tyrosine kinase inhibitors can induce varying degrees of objective responses and prolong progression-free survival.

    “Previous studies have demonstrated that multi-targeted tyrosine kinase inhibitor (TKIs) can induce varying degrees of objective responses and prolong progression-free survival (PFS)1–5.”

    From Apatinib plus ifosfamide and etoposide versus ifosfamide and etoposide in patients with advanced osteosarcomas (OAIE/PKUPH-sarcoma 11): a randomized phase II study (2025) · cites this paper as [1]

  • Dose interruptions and reductions of MTKIs have been frequent across these trials secondary to common toxic effects, including hand-foot rash syndrome, gastrointestinal toxic effects and hypertension.

    “Of note, dose interruptions and reductions of MTKIs have been frequent across these trials secondary to common toxic effects of this drug class, including hand-foot rash syndrome (palmar-plantar erythrodysesthesia), gastrointestinal toxic effects and hypertension 146,147,148,149,150,151 .”

    From Osteosarcoma (2022) · cites this paper as [147]

  • Four-month progression-free survival with MTKIs ranged from 35% to 70%.

    “Four-month progression-free survival (PFS) ranged from 35% to 70% 146,147,148,149,151 .”

    From Osteosarcoma (2022) · cites this paper as [147]

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Research works printed but not linked: 1

  1. Chou AJ, Kleinerman ES, Krailo MD et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma. Cancer 2009; 115: 5339-5348.

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Authors
Grignani, G., Palmerini, E., Dileo, P., Asaftei, S. D., D’Ambrosio, L., Pignochino, Y., Mercuri, M., Picci, P., Fagioli, F., Casali, P. G., Ferrari, S., & Aglietta, M.
Affiliations
  • Candiolo Cancer Institute (IT)
  • Istituto Ortopedico Rizzoli (IT)
  • Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
  • Ospedale Regina Margherita (IT)
Corresponding author
Grignani, G.
ORCID
Venue
Annals of Oncology
Publisher
Elsevier BV
Published
2012-02
Volume
23
Issue
2
Pages
508-516
ISSN
0923-7534 (ISSN-L)
DOI
10.1093/annonc/mdr151
OpenAlex
W2167348613
Cited by
359
References
48
Citations by year
2026: 8 · 2025: 16 · 2024: 25 · 2023: 28 · 2022: 34 · 2021: 40 · 2020: 43 · 2019: 21 · 2018: 18 · 2017: 21 · 2016: 23 · 2015: 19 · 2014: 17 · 2013: 24 · 2012: 16
FWCI
16.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
Keywords
sorafenib, high-grade osteosarcoma, relapsed osteosarcoma, multikinase inhibitor, targeted therapy, progression-free survival, overall survival, clinical benefit rate, mitogen-activated protein kinase, second-line therapy, FDG-PET response, drug toxicity
MeSH terms
Sorafenib, Adolescent, Adult, Antineoplastic Agents, Benzenesulfonates, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Niacinamide, Phenylurea Compounds, Pyridines, Osteosarcoma, Treatment Outcome, Treatment Failure, Young Adult

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