Current Oncology Reports (2021) 23: 71

https://doi.org/10.1007/s11912-021-01053-7

ORTHOPEDIC ONCOLOGY (JA ABRAHAM, SECTION EDITOR)

Update on Osteosarcoma
Rebekah Belayneh 1 & Mitchell S. Fourman 1 & Sumail Bhogal 1 & Kurt R. Weiss 1

Accepted: 11 March 2021 / Published online: 21 April 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review Osteosarcoma (OSA) is the most common primary tumor of bone, mainly affecting children and adolescents.
Here we discuss recent advances in surgical and systemic therapies, and highlight potentially new modalities in preclinical
evaluation and prognostication.
Recent Findings The advent of neoadjuvant and adjuvant chemotherapy has markedly improved the disease-free recurrence
and overall survival of OSA. However, treatment efficacy has been stagnant since the 1980s. This plateau has prompted
preclinical and clinical research into in precision surgery, inhaled chemotherapy to increase pulmonary drug concentration
without systemic side effects, and novel immunomodulators intended to block molecular pathways associated with OSA
proliferation and metastasis.
Summary With the advent of novel surgical techniques and new forms and vectors for chemotherapy, it is hoped that OSA
treatment outcomes will exceed their currently sustained plateau in the near future.

Keywords Osteosarcoma . Metastasis . Doxorubicin . Methotrexate . Pediatric sarcoma . Limb salvage . Near-infrared imaging .
Indocyanine green . Gemcitabine . Aerosolized chemotherapy . Sorafenib . Pazopanib . GD2 inhibition . Aldehyde
dehydrogenase . Chimeric antigen receptor T-cell therapy

Introduction childhood and adolescence, with a yearly incidence of 5.6

cases per million in children under the age of 15 [2–5]. OSA
Osteosarcoma (OSA) is a mesenchymal malignancy that is is most commonly seen in the metaphysis of long bones,
characterized by the formation of immature osteoid by tu- with the three most common locations being, in order of
mor cells. It has a bimodal distribution that peaks during the frequency, distal femur, proximal tibia, and proximal hu-
second decade of life and after age 65, and is the third most merus [2].
common type of cancer among children and adolescents
between the ages of 12 and 18 after leukemia and lymphoma
[1, 2]. It is the most common primary skeletal tumor of
Historical Treatment and Outcomes
This article is part of the Topical Collection on Orthopedic Oncology
Pre-chemotherapy
* Kurt R. Weiss
weiskr@upmc.edu OSA was a surgical disease prior to the advent of chemother-
apy. Samuel Gross in 1879 [6] advocated for early amputation
Rebekah Belayneh
Belaynehr2@upmc.edu after observing that more conservative limb-sparing proce-
dures had an unacceptably high mortality rate. Despite this
Mitchell S. Fourman
aggressive strategy, the 5-year overall survival rate was only
mfourman@gmail.com
20% with surgery [7, 8], as pulmonary metastases reliably
Sumail Bhogal developed within 6 to 12 months of amputation [9, 10].
bhogalsumail@gmail.com
Such a rapid and reliable spread of disease was theorized to
1
Division of Orthopaedic Oncology, Department of Orthopaedic
be due to circulating tumor cells and micro-metastases that
Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, were already present at the time of diagnosis, supporting the
USA need for systemic therapy.
71 Page 2 of 8
Post-chemotherapy
Jaffe et al. [11] reported that high-dose methotrexate—a folic
acid antagonist used at that time in the treatment of leukemia
and lymphoma—reduced the number and size of OSA pul-
monary metastases. In 1972, the multidrug regimen of cyto-
toxin, vincristine, melphalan, and doxorubicin improved the
2-year survival of OSA to over 50% [12, 13]. Doxorubicin
was also found to delay the growth of metastatic OSA [14].
The addition of doxorubicin, cisplatin, or cyclophosphamide
to high-dose methotrexate increased disease-free survival to
up to 65% [15, 16]. A randomized prospective trial performed
by Edmonson et al. [17, 18] reported a 52% 5-year survival of
patients treated with adjuvant high-dose methotrexate
chemotherapy.
Multi-agent adjuvant chemotherapy markedly improved
OSA overall survival. Link et al. [19] demonstrated that the
use of a multidrug adjuvant chemotherapy regimen that in-
cluded cyclophosphamide, bleomycin, actinomycin-D, high-
dose methotrexate, doxorubicin, and cisplatin increased OSA
relapse-free survival from 17 to 66% over a 2-year period
following definitive surgery. Eilber et al. [20, 21] found that
at a median follow-up of 2 years after surgical excision or
amputation, patients who received adjuvant chemotherapy
with doxorubicin, high-dose methotrexate, and bleomycin/
cytoxan/actinomycin-D had greater disease-free (55%) and
overall survival (80%) rates than controls who received sur-
gery alone (20% and 48%, respectively). OSA recurrence in
the treatment arm was 43% compared with 74% in controls
[20, 22]. The results of Eilber’s study were so striking that it
was terminated prematurely after 2 years.
In 1976, Rosen et al. [23] introduced the idea of delaying
surgery for OSA until a period of chemotherapy was complet-
ed. Neoadjuvant chemotherapy was found to be both safe and
effective [24]. It also permitted the analysis of surgical mar-
gins to assess the histologic response of the OSA primary
tumor to chemotherapy, aiding in the assessment of long-
term disease prognosis [25–27]. A subsequent study by
Bielack et al. in 2002 validated that chemotherapeutic re-
sponse in patients treated with neoadjuvant systemic therapy,
particularly those sustaining preoperative tumor necrosis of
greater than 90%, had a statistically significant improvement
in long-term survival [28].
Current Management
Local and Metastatic Disease
The current standard of care for OSA remains neoadjuvant
chemotherapy, wide surgical resection, and adjuvant chemo-
therapy. Parosteal OSA can be treated with surgical resection
alone due to its negligible metastatic potential [29]. Improved
Curr Oncol Rep (2021) 23: 71
treatment principles and chemotherapy have increased the 5-
year survival of OSA from less than 30 to 70% [27].
The standard chemotherapy regimen in Europe and North
America for children and adults younger than 40 years of age
is high-dose methotrexate, doxorubicin, and cisplatin (MAP)
[27, 30–32]. No significant survival advantage has been ob-
served between doxorubicin and cisplatin versus vincristine,
methotrexate, doxorubicin, and bleomycin, or between doxo-
rubicin and cisplatin with or without the addition of metho-
trexate [33–35]. However, the benefits of methotrexate in
older patients are unclear, and it is therefore commonly omit-
ted from this patient group [21].
Surgery is essential to achieving local control in OSA.
While limb amputation was the rule rather than the exception
for OSA in decades past, approximately 90% of patients now
undergo a limb-sparing procedure. While limb-sparing sur-
gery has a slightly higher rate of local recurrence than ampu-
tation (8.2% vs 3.0%, respectively), the decision to pursue this
approach must be made carefully [28].
Even in the absence of radiographically detectable metas-
tases, it is assumed that most OSA patients harbor micro-
metastatic disease at the time of diagnosis [36], which neces-
sitates systemic therapy [37, 38]. Thoracotomy and
metastatectomy are a possibility for patients with resectable
pulmonary OSA metastases, which have improved the 5-year
survival of patients who present with metastatic OSA [4]. In
retrospective analysis of outcomes, a subgroup analysis com-
parison of patients with patients with resectable masses with
metastatectomy and patients with resectable masses who re-
ceived systemic therapy, metastatectomy patients had superior
progression-free survival (21.6 vs 3.65 months) and overall
survival (34.0 vs 12.4 months) [39]. Candidacy for
metastatectomy requires careful consideration; however, as
retrospective reviews have demonstrated that patients that
are older, have a short disease-free interval, require a thora-
cotomy or lobectomy or have synchronous disease, all have
progressively worsened outcomes when these risk factors are
combined [40].
Palliative Treatment
If the patient declines surgery, or has advanced disease requir-
ing a palliative approach, radiation can be considered. Intensity-
modulated radiotherapy is the standard of care, while proton
beam radiation can be considered in younger patients to reduce
the radiation dose to uninvolved normal tissues [41].
Otherwise, the role of radiation in OSA is quite limited.
Prognosis
OSA prognosis has largely remained stable since the mid-
1990s. Mirabello et al. examined changes in OSA survival
Curr Oncol Rep (2021) 23: 71
from 1973 to 2004, and found that the introduction of neoad-
juvant chemotherapy improved the overall survival rate sig-
nificantly between 1973–1983 and 1984–1993 [42].
However, 5-year and overall survival have plateaued since
[43].
Patients with low-grade OSA (generally parosteal or some
periosteal surface lesions) have better outcomes than higher
grade intramedullary lesions, with about a 90% 5-year surviv-
al [44–47]. However, the long-term outcomes of patients with
metastatic OSA remain dismal. The survival rates of patients
with metastases at their initial diagnosis are 10–40%, with a
30–40% rate of recurrence, and a > 70% mortality rate [48,
49]. Nearly half of all patients who do not have pulmonary
metastases at the time of OSA diagnosis will develop them
later in their disease course [4]. Additional prognostic indica-
tors of a poor outcome include advanced age, secondary OSA
(such as from Paget’s disease), elevated serum LDH, large
primary tumor size, and axial/proximal tumor location [7,
28, 50, 51]. High LDH levels correspond with relapse and
consequently a poor prognosis, while normal LDH levels
were associated with an improved 5-year disease-free survival
[38]. The degree of tumor necrosis on histologic examination
also correlates with a good prognosis. A good histologic re-
sponse to neoadjuvant chemotherapy is less than 10% viable
tumor cells at time of surgery [52], and is seen in approximate-
ly 45% of patients following neoadjuvant therapy [53].
Recent Advances in OSA
Clinical
Novel modalities for preoperative and intraoperative surgical
imaging present opportunities for immediate technical im-
provement. Near-infrared (NIR) intraoperative imaging pre-
sents an opportunity for “precision surgery” and the improved
ability for the surgeon to reliably identify and resect primary
and metastatic OSA. Indocyanine green (ICG) is an FDA-
approved NIR fluorophore that binds with plasma albumin,
and therefore remains intravascular except when there are
“leaky” blood vessels, as are found in the setting of trauma,
burns, and tumors [54, 55]. Preoperative intravenous ICG ad-
ministered 24 h preoperatively has been shown to histologi-
cally localize to experimental primary and metastatic OSA
[56••], and targeted excision of ICG-positive tissue in a mouse
model has been associated with the elimination of primary
tumor recurrence [57••]. ICG-guided primary sarcoma resec-
tion in pediatric patients is currently being examined in an
ongoing clinical trial [58]. Mao et al. [59] report that ICG-
aided metastatectomy during thoracoscopic surgery had a sen-
sitivity of 88.7% and a positive predictive value of 92.5% for
tumor nodules.
Page 3 of 8 71
Antibody-bound NIR fluorophores are more expensive
than unbound dyes but have the potential to yield more spe-
cific and detailed tumor images, permitting greater and more
precise tissue preservation during tumor resection. Pegylated
CH1055 dye has been found to rapidly localize to multiple
tumor types, and yielded high-quality OSA tumor imaging
with a clear tumor boundary 2 min after tail vein injection in
a mouse model [60]. Recombinant vesicular stomatitis virus-
bound Katusha (VSV-K) near-infrared protein infects OSA
cells, causing them to fluoresce. In preclinical trials, VSV-K
significantly reduced the tumor margins necessary to achieve
a complete resection while yielding equivalent local recur-
rence and overall survival rates [61]. Silver nanoparticle-
bound fluorophores have “theranostic” utility, providing
high-resolution tumor imaging while also delivering chemo-
therapy or antibiotics to the tumor bed [62].
Aerosolized chemotherapy seeks to permit the delivery of
high-dose lung-targeted chemotherapy that avoids first-pass
metabolism and does not result in elevated systemic toxicity
[63]. Inhaled vectors may be of particular use in the treatment
of OSA given the significant deleterious effects of pulmonary
metastatic disease. It is intellectually satisfying to maximize
the delivery of chemotherapy directly to the anatomic site of
potential metastasis. Preclinical studies by Sharma et al. [63]
in their canine trial of doxorubicin and by Koshkina et al. [64]
with liposomal-inhaled paclitaxel endorse increased local con-
centration and marginal systemic levels with aerosolized che-
motherapy vectors. Aerosolized vectors may also permit the
introduction of potentially useful immunotherapies that could
not be used systemically. For example, aerosolized IL-2 was
used to enhance the proliferation and activity of natural killer
cells injected into the lungs of nude mice with metastatic hu-
man OSA, without systemic side effects [65]. A current phase
I/II clinical trial of aerosolized gemcitabine administered twice
weekly is in progress, and may provide the first evidence of
the clinical efficacy of inhaled chemotherapy against OSA
[66••].
The reduced efficacy of traditional MAP chemotherapy
against recurrent OSA has prompted the evaluation of alter-
native treatment vectors. Sorafenib—a Raf, Mek, and Erk-
kinase inhibitor—has been effective and well-tolerated in the
treatment of multiple types of refractory solid visceral tumors
in pediatric patients [67]. Sorafenib supplemented by the
mTOR inhibitor everolimus was employed in a phase II trial
of adults with unresectable high-grade OSA. While few pa-
tients sustained significant side effects that warranted treat-
ment discontinuation (2/38, 5%), progression-free survival at
6 months was only seen in 45% of patients [68]. An additional
trial currently undergoing recruitment is a phase I/Ib trial eval-
uating maximally tolerated dosage of losartan and sunitinib in
combination therapy. Losartan, an angiotensin receptor
blocker, has demonstrated growth suppression of pulmonary
metastasis via inhibition of CCR2 signaling [69••].
71 Page 4 of 8
Pazopanib—a second-generation selective, multitargeted
tyrosine kinase inhibitor—has been shown to be effective
and well-tolerated in the treatment of metastatic bone sarco-
mas [70]. Initially approved based on the pazopanib for met-
astatic soft tissue sarcoma (PALETTE) study for metastatic
soft tissue sarcomas [70], the off-label use of pazopanib in
the treatment of metastatic OSA has shown modest results in
case series involving 6 patients with metastatic disease who
failed chemotherapy [71, 72]. A pilot trial observed a clinical
benefit—defined as stable disease or a partial response—in
9/15 patients (60%) [73]. A phase II study on pazopanib in
metastatic osteosarcoma (NC01759303) was terminated due
to low accrual [74].
A multicenter, single-arm, phase 2 clinical trial (CABONE
trial) evaluated the antitumor activity of cabozantinib, an in-
hibitor of MET and VEGFR2 kinase activity that is a gener-
ally well-tolerated and effective in patients with OSA who
have been heavily pretreated. The 6-month objective response
to cabozantinib was 11.9%, and the 6-month non-progression
rate was 33.3%. Five of 42 patients had an objective response
(all partial responses) to cabozantinib, while a third (14/42)
had 6-month non-progression [75••].
The phase II, multicenter single-arm clinical trial, ESMMO
trial, evaluated mycophenolate mofetil in patients with OSA.
Mycophenolate mofetil is an immunosuppressive agent that is
currently used for organ rejection prophylaxis has a known
acceptable safety profile due to its current use in humans,
eliminating the need for a phase I trial [76]. Mycophenolate
in vivo inhibits OSA tumor growth and lung metastasis [77••].
Results of ESMMO are pending.
Denosumab, a human monoclonal antibody against
receptor-activator of NF-KB ligand (RANKL) more common-
ly associated with the treatment of giant cell tumors, has
gained traction as a potential therapy for OSA [78, 79].
Denosumab has shown promising results in preclinical
models, demonstrating the ability to reduce proliferation and
motility of OSA cells [80, 81]. A phase II study on denosumab
treatment of osteosarcoma patients (NCT02470091) is cur-
rently active [82].
The use of bisphosphonates in the treatment of OA remains
debatable. Zoledronate has been shown to reduce the prolifer-
ation and angiogenesis of OSA cells in vitro [83]. However,
these benefits remain unproven in vivo. In a randomized mul-
ticenter phase III trial, patients with high-grade sarcoma given
chemotherapy with zoledronate had an event-free survival of
57.1% compared to 63.4% in the control group. [84]
Preclinical
Histologic and immunohistochemical evaluation of the prima-
ry OSA tumor continues to yield useful prognostic markers
that may serve as future therapeutic guides. Microscopic vas-
cular invasion (MVI) observed in OSA tumor specimens has
Curr Oncol Rep (2021) 23: 71
been identified as a predictor of poor 5-year and overall sur-
vival. Tsuda et al. [85] observed that the presence of MVI
predicted a poor response to neoadjuvant chemotherapy, a
high risk of tumor metastasis, and lower overall survival.
Anderson et al. [86] speculate that MVI may be used as justi-
fication for wider tumor margins, or to indicate the need for
compound vs. alternative chemotherapy regimens.
The GD2 tumor-associated glycolipid antigen is highly
expressed by OSA [87], and induces cell death by altering
the membrane potential of the mitochondria [88]. GD2 anti-
bodies are effective against neuroblastoma in vitro and in a
phase 2 clinical trial as part of a combined chemotherapy
regimen with irinotecan and temozolomide [89]. GD2 recep-
tor positivity persists in recurrent OSA [90], and the safety of
weekly and daily dosing of the anti-GD2 antibody
hu14.18K322A in patients with OSA has been confirmed in
a phase I clinical trial [91]. It is proposed that anti-GD2 ther-
apy may be a viable treatment for patients who have recurrent
OSA and failed conventional therapy.
Aldehyde dehydrogenase (ALDH) has been previously
linked with OSA metastatic potential and tumor viability
[92, 93]. ALDH acts in conjunction with matrix metallopro-
teinase (MMP) activity [94]. Disulfiram is an FDA-approved
drug for alcoholism that has been shown to inhibit both
ALDH and MMP-2 and MMP-9 in an in vitro invasion assay
[95]. In a randomized controlled preclinical trial using a pre-
viously validated immunocompetent orthotopic mouse model
of OSA, Crasto et al. [96] observed that disulfiram significant-
ly reduced metastatic OSA tumor burden vs. untreated con-
trols, and displayed an equivalent reduction in metastatic dis-
ease burden to doxorubicin-treated animals. A potential syn-
ergy between disulfiram, an ALDH-inhibitor that also chelates
copper, and doxorubicin in the setting of exogenous copper
has been demonstrated by Mandell et al. [97••], which is con-
sistent with the theory by Denoyer et al. [98] that exogenous
copper delivery increases the intracellular levels of copper
within the tumor, permitting augmented chelation and cyto-
toxicity activity.
Chimeric antigen receptor T-cell therapy (CAR-T) in-
volves the modification of the patient’s own T-cells to lo-
cate receptors commonly expressed on tumor cells, and sub-
sequently use cytotoxic mechanisms to kill them while si-
multaneously avoiding healthy host cells due to receptor
specificity. This technique has been used with variable suc-
cess in many cancer types, most prominently in the treat-
ment of pediatric acute lymphocytic leukemia. CAR-T was
applied in vitro against the CD166 receptor of multiple OSA
cell lines, displaying expression-dependent cytotoxicity
[99]. The efficacy, toxicity, and longevity of GD2-targeted
CAR-T cell therapy against OSA and neuroblastoma in T-
cells previously exposed to the varicella zoster virus are
being evaluated in an ongoing early-phase clinical trial
[100].
Curr Oncol Rep (2021) 23: 71
Conclusion
While our knowledge and local management of OSA con-
tinues to grow, these advances have not yet translated into
improvements in progression-free and overall survival. A bet-
ter command of the mechanisms of OSA metastatic biology is
required such that these processes can be understood and
interrupted. With the advent of fluorescence-guided resection
techniques and new forms and vectors for chemotherapy, it is
hoped that OSA treatment outcomes will exceed their current
sustained plateau in the near future.
Declarations
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Conflict of Interest The authors declare no competing interests.
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