30845 Suppl Giot.pdf - Giornale Italiano di Ortopedia e Traumatologia

Durable cure and reconstructive success in osteogenic sarcoma
Cura durevole e successo ricostruttivo nel sarcoma osteogenico
J.H. Healey
The lament that osteogenic sarcoma
(OGS) treatment has improved little
since work of Rosen in cytotoxic
chemotherapy and Campanacci and
Marcove in limb salvage is common,
but inaccurate 1-3 . This paper reviews
the progress in chemotherapy, highlights
basic science advances that may
change treatment, and introduces new
prosthetic measures that will make
joint reconstruction more durable.
Progress in these realms promise to
transform OGS care.
The most recent US national study
INT-133 was a factorial double randomized
trial of ifosfamide preoperatively
and liposomal Muramyl tripeptide
phosphoethanolamine (MTP-PE)
on top of conventional three drug
chemotherapy. This was an exciting
trial in that MTP-PE was the most
effective single agent in naturally
occurring dog osteogenic sarcoma 4 ,
constituting the first application of a
biologic agent as a first line adjuvant
therapy for cancer. Patients who received ifosfamide at those
doses and schedule had the worst prognosis, whereas patients
who received both ifosfamide and MTP-PE had the best prognosis
5 . Using the primary outcome measure, overall survival,
there was a dramatic reduction of recurrence by 30% and death
by 25% 5 . It is a particularly appealing since there was no overlapping
toxicity with conventional chemotherapy agents. The
agent is the focus of new protocols under development in the
Children’s Oncology Group.
Basic science investigation sought to identify more specific
targets for chemotherapy. Genes that direct the cell cycle
were investigated next for their prognostic value and potential
mechanistic significance in the development and progression of
the disease. P53 and Rb pathways are the initiating factors for
the cancer, telomere maintenance mechanisms sustain cellular
immortality, and other genetic changes contribute to disease
progression 6-9 Fig. 1.
.
Trying to integrate these disparate findings, a powerful method,
Correspondence:
healeyj@mskcc.org
G.I.O.T. 2010;36(suppl. 1):S15-S16
SAGE analysis of genetic tags from osteogenic sarcoma cell
lines, xenografts, fresh tumor samples, meshenchymal stem cells
and osteoblasts was used. Seven major participants in the Insulin
Growth Factor pathway were identified that distinguished
osteogenic sarcoma cells from mesenchymal stem cells those of
other cells in the osteogenic lineage. Most of these changes were
reductions in the expression of IGF binding proteins. This effectively
increases active free IGF, stimulating growth of the osteogenic
sarcoma. The clinical significance of this observation was
confirmed by recent tissue array analysis that showed that patient
survival correlated to IGF receptor immunohistochemistry staining
levels 10 . It confirms the importance of the IGF pathway from
several different lines of evidence. Various IGF-1R antibodies
are currently available to attack this growth factor pathway.
Much of the variation of chemotherapy effectiveness is due to the
tumor genetic profile. Using Affymatrix gene array, we identified
a chemoresistance profile of genes that correlate highly with
a poor extent of necrosis in the primary tumor after neoadjuvant
chemotherapy 11 . Lack of osteoprotogerin and the presence of
several pro-osteoclast agents (annexin 2, SMAD, PLA2G2A, and
TGFbeta1) suggest that exposure of matrix elements promote the
cancer and contribute to drug resistance. Blocking this osteo-
S15