Hindawi Publishing CorporationSarcomaVolume 2013, Article ID 641687, 2 pageshttp://dx.doi.org/10.1155/2013/641687
EditorialOsteosarcoma: Lessons Learned and Future Avenues
Ajay Puri,1 Norman Jaffe,2 and Hans Gelderblom3
1 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai 400012, India2 Children’s Cancer Hospital, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA3Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
Correspondence should be addressed to Hans Gelderblom; [email protected]
Osteosarcoma is the most commonmalignant bone tumor inmen.The incidence peaks around puberty, with a broader andlower peak after 60 years of age. Risk factors are (pubertal)growth, genetic factors, Paget’s disease, and prior radiother-apy. More than 90% of tumors are of high grade, and theirprognosis, even without metastasis at presentation, remainsdismal in up to 30–45% of cases despite great improvementsdue to the introduction of chemotherapy some decades ago.
The contribution “Osteosarcoma: evolution of treatmentparadigms” to this osteosarcoma special issue is truly uniqueas it describes the history of systemic treatment from firsthand, as the first author N. Jaffe coauthored the first studieson the dramatic improvement of long-term survival from 10–15% to 55–70% due to addition of multiagent chemotherapy.This magnitude of improvement has never been observed inother solid tumors, with the exception of germ cell tumorsand some childhood cancers such as rhabdomyosarcomaand Ewing’s sarcoma. However, these percentages have notfurther improved over the last decades, and new therapies areneeded urgently to cure the remaining one-third of patientsand increase the chances for patients with metastatic disease.The authors describe the design of the current EURAMOSstudy. Meanwhile, the first results of the PEG interferonrandomization in the good responder arm were presented atthe 2013 annual meeting of the American Society of ClinicalOncology [1]. From the 2260 included patients, 1034 had agoodpathological response to preoperative chemotherapy.Ofthese patients 715, were randomized to either PEG interferonor observation. Only 76% of the patients randomized tointerferon started treatment, mainly due to refusal. Theevent-free survival (primary endpoint) was not statistically
improved in the interferon arm, although the results mayhave been influenced by the low randomization and hightreatment refusal rate. Definite results and results of the poorresponder randomization are pending. The study has proventhat a worldwide platform for potential practice changingrapidly accruing randomized phase III studies is feasible inthis rare disease and therefore should be used in the future.
The Birmingham experience with low-grade conven-tional osteosarcoma (LGCO), a rare (1.2%) and difficult todiagnose variant of osteosarcoma, is also part of this specialissue. The diagnosis of LGCO is challenging due to therelatively nonspecific radiological and histological findings.Since treatment of LGCO is so different compared to abenign lesion as well as to high-grade osteosarcoma, accuratediagnosis is essential. The authors therefore advise that anydifficult or nondiagnostic biopsies of solitary bone lesionsshould be referred to a specialist (bone) tumor unit for asecond opinion: a conclusion that we fully agree with andshould be part of all guidelines.
N. Federman et al. describe a novel osteosarcoma-ass-ociated cell surface antigen, ALCAM. The authors createdan anti-ALCAM-hybrid polymerized liposomal nanoparti-cle immunoconjugate (𝛼-AL-HPLN) to specifically targetosteosarcoma cells and deliver a cytotoxic agent such as dox-orubicin. If feasible in clinical practice, these 𝛼-AL-HPLNsare a promising new strategy to specifically deliver cyto-toxic agents in osteosarcoma. A similar approach recentlytook place in breast cancer where the antibody-drug con-jugate trastuzumab-DM1 (T-DM1) was designed to com-bine the biological activity of trastuzumab with the tar-geted delivery of a highly potent chemotherapeutic agent to
2 Sarcoma
HER2-overexpressing breast cancer cells. The success of theapproach in breast cancer underlines the promise of 𝛼-AL-HPLN in osteosarcoma.
Y. Suehara et al. focus on proteomics to provide proteinexpression profiles of osteosarcoma that can be used todevelop novel diagnostic and therapeutic biomarkers as wellas to understand its biology. The authors provide a briefdescription of the methodology as well as examples of therecent proteomic studies that have generated new informa-tion regarding osteosarcomas. This approach should lead theway to predictive andprognostic information aswell as neces-sary new drug targets in order to bring the necessary furtherimprovement of our therapeutic strategies in osteosarcoma.
M.M. Hagleitner et al. show us a single center experiencewith osteosarcoma patients under the age of 20. In thisretrospective series, improvement in toxicity and outcomewas observed over the past 30 years that was attributed toimproved supportive care allowing the intended full-dosechemotherapy regimen to be given. It is very well possiblethat improved experience due to centralizationmay also haveadded to this effect.
S. Piperdi et al. present a preclinical evaluation of the roleof 𝛽-catenin in osteosarcoma development thought to orig-inate from the mesenchymal stem cell. Despite fosteringosteogenic differentiation, 𝛽-catenin does not induce themalignant features and tumorigenicity conveyed by onco-genic H-RAS when introduced into partly transformed mes-enchymal stem cells. Despite this observation, C. H. Lin etal. show, using in vivo and in vitro studies, that Dickkopf-3protein (Dkk-3) transfected 143B cells inhibited tumorigen-esis and metastasis in an orthotopic xenograft model of OS.As Dkk-3 is known to inhibit the canonical Wnt/𝛽-cateninpathway and its expression has been shown to be down-regulated in osteosarcoma cell lines, we must realize that adelicate interplay of this pathway is present in osteosarcomaand requires further understanding before it can be targetedin the clinic.
In the paper by R. Muff et al., forty-eight common genesthat are differentially expressed in metastatic cell linescompared to parental cells were identified. This subset ofmetastasis relevant genes in osteoblastic osteosarcoma over-lapped only minimally with differentially expressed genesin the other four preosteoblast or nonosteoblastic cell linesystems.These studies add to themicroarray studies that wereperformed in the clinical research setting [2].
X. Mu et al. present a preclinical rationale for m-TORinhibition for the treatment and prevention of osteosarcomametastases. A phase II study including osteosarcoma patientswas promising [3]. However, the Sarcoma mUltiCenter Clin-ical Evaluation of the Efficacy of riDaforolimus (SUCCEED)trial did not lead to registration of maintenance mTOR-targeted therapy in metastatic (osteo)sarcoma as the FDArejected the application in May 2012 [4]. Maybe earlier treat-ment in nonmetastatic patients or combination treatment orpatient selection based on prospectively collected biomarkersmay lead the way to future clinical use.
In our opinion, the holy grail towards further survivalbenefit in osteosarcoma is thorough preclinical studies lead-ing to new targets and biomarkers, followed by properly
designed studies that can be performed rapidly in interna-tional collaboration of bone centers. This osteosarcoma issueof Sarcoma is just a tiny step in this process that will needperseverance.
Ajay PuriNorman Jaffe
Hans Gelderblom
References
[1] S. S. Bielack, S. Smeland, J. Whelan et al., “MAP plus mainte-nance pegylated interferon 𝛼-2b (MAPIfn) versus MAP alonein patients with resectable high-grade osteosarcoma and goodhistologic response to preoperative MAP: First results of theEURAMOS-1 “good response” randomization,” Journal of Clin-ical Oncology, vol. 31, Article ID LBA10504, 2013.
[2] A.-M. Cleton-Jansen, J. K. Anninga, I. H. Briaire-De Bruijn etal., “Profiling of high-grade central osteosarcoma and its puta-tive progenitor cells identifies tumourigenic pathways,” BritishJournal of Cancer, vol. 101, no. 11, pp. 1909–1918, 2009.
[3] S. P. Chawla, A. P. Staddon, L. H. Baker et al., “Phase II study ofthe mammalian target of rapamycin inhibitor ridaforolimus inpatients with advanced bone and soft tissue sarcomas,” Journalof Clinical Oncology, vol. 30, no. 1, pp. 78–84, 2012.
[4] G. D. Demetri, S. P. Chawla, I. Ray-Coquard et al., “Results of aninternational randomized phase III trial of the mammalian tar-get of rapamycin inhibitor ridaforolimus to control metastaticsarcoma in patients after benefit from prior chemotherapy,”Journal of Clinical Oncology, vol. 31, no. 19, pp. 2485–2492, 2013.
