International Journal of Clinical Medicine, 2013, 4, 357-363 Published Online August 2013 (
A Minimally Invasive Surgery for Bone Metastases Using
the Combination of Photodynamic Therapy and
Hyperthermia Treatment
Takao Matsubara1*, Katsuyuki Kusuzaki2, Akihiko Matsumine1, Kunihiro Asanuma1,
Tomoki Nakamura1, Atsumasa Uchida1, Akihiro Sudo1
1Department of Orthopaedic Surgery, Mie Graduate School of Medicine, Mie, Japan; 2Department of Orthopaedic Surgery, Kujo
Hospital, Kyoto, Japan.
Email: *
Received March 19th, 2013; revised April 20th, 2013; accepted May 21st, 2013
Copyright © 2013 Takao Matsubara et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Aims: Cancer patients with bone metastases in their extremities may require surgical intervention to prevent deteriora-
tion in their quality of life due to a pathological fracture or severe bone pain. However, curative surgical interventions
sometimes have severe complications due to the status of the original cancers. To avoid the decreased quality of life
caused by bone metastasis, minimally invasive surgery that avoids additional surgical morbidity is required. We have
established two therapeutic treatments for bone metastasis, a photodynamic acridine orange treatment (AOT) and an
electronic magnetic hyperthermia treatment (EMHT). The present study investigated the clinical outcomes of combina-
tion therapy with EMHT and AOT for patients with bone metastases in their extremities. Methods: The study included
6 patients with 7 bone cancer metastasis locations. For bone metastases, all patients received intraregional tumor exci-
sion supported by AOT, in which photodynamic and radiodynamic therapy kills tumor cells during surgery with mini-
mal damage to normal tissues. After the curettage, bone reconstruction was performed by using magnetic materials with
calcium phosphate cement. EMHT was repeatedly performed after surgery. In EMHT, tumor cells are killed with an
electric magnetic field generator, and bony union is promoted by electronic stimulation. Results: The mean duration of
follow-up was 14 months. During the follow-up period, only one patient experienced a local recurrence, and this recur-
rence occurred 14 months after surgery. Bony union occurred in 4 of 5 cases (80%), and the pain score was significantly
reduced after surgery. Conclusions: In the present study, AOT reduced the invasiveness of surgery. EMHT reduced the
tumor growth without major complications and promoted bone formation after surgery. Our clinical results confirmed
that EMHT and AOT combination therapy for bone metastasis can preserve limb function without local recurrence or
bone absorption.
Keywords: Photodynamic Therapy; Minimal Invasive Surgery; Hyperthermia Treatment; Acridine Orange; Bone
1. Introduction
Patients with bone metastases in their extremities some-
times require surgical intervention to prevent a deteriora-
tion in quality of life due to a pathological fracture or
severe bone pain [1-6]. Localized radiotherapy with sur-
gical reinforcement has been a standard treatment for
bone metastases. However, radiotherapy can cause bone
absorption due to tumor regrowth or the lack of bone
metabolism [7,8]. If a new adjuvant therapy could reduce
the surgical invasiveness and surgical margin without an
increased incidence of local recurrence, excellent limb
function and better quality of life could be maintained
after surgery. We have focused on photodynamic therapy
(PDT) with photosensitizers as a neoadjuvant therapy.
We employed acridine orange (AO) as a photosensitizer
to establish AO photodynamic therapy [9-17]. With this
technique, tumor cells labeled with AO are visualized
under a fluorescence microscope to allow curettage to be
easily performed with minimal damage to normal tissue
[18-21]. Labeled tumor cells are killed not only by illu-
*Corresponding author.
Copyright © 2013 SciRes. IJCM
A Minimally Invasive Surgery for Bone Metastases Using the Combination of
Photodynamic Therapy and Hyperthermia Treatment
mination but also by a low-dose (5 Gy) radiation beam
after surgery [22]. AO therapy eliminates tumor cells
without invasiveness and has the potential to reduce this
complication by conventional radiation therapy.
Radiation toxicity is another problem associated with
conventional radiotherapy for bone metastasis. Compli-
cations caused by irradiation, such as fibrosis, skin ne-
crosis, and nerve palsy, can prevent the repeated use of
radiotherapy even if a local recurrence occurs.
Our hyperthermia treatment that uses an electronic
magnetic generator (EMHT: electronic magnetic hyper-
thermia treatment using magnetic materials) reduces lo-
cal recurrence by thermal heating and promotes bone
formation after surgery [23,24]. EMHT can be repeatedly
performed because there are no complications from the
thermal heat or electric stimulation.
We established a clinical regimen consisting of photo-
dynamic surgery with AO-labeled tumor cells (AO-PDS);
photodynamic therapy with AO (AO-PDT); radiodyna-
mic treatment, in which labeled cells were treated with
X-rays (AO-RDT); and EMHT after surgery. The present
study examined the clinical outcomes of this regimen in
patients with bone metastases.
2. Patients and Methods
Between 2003 and 2009, 6 patients with bone metastasis
in their extremities were treated with a combination of
EMHT and AO treatment (AOT). We selected the pa-
tients who required surgical intervention by curettage or
marginal resection because AO therapy can be performed
during such surgeries. Bone metastases that require cu-
rettage are commonly located in the epiphysis. Metasta-
ses that extend into extra-osseous lesions can cause mas-
sive bone defects. Severe bone defects carry a risk of pa-
thological fracture and sometimes require mass volume
reduction by curettage or tumor resection.
2.1. AO Therapy
All patients first received intraregional tumor excision
with minimal damage to normal tissues, which is similar
to conventional tumor excision for benign bone tumors.
Photodynamic surgery was performed with AO-labeled
tumor cells (AO-PDS) by using an ultrasonic surgical
knife (Olympus, Tokyo, Japan) and a fluorescence surgi-
cal microscope (Carl Zeiss, Oberkochen, Germany). Tu-
mor fluorovisualization was performed after local ad-
ministration of 1 μg/ml of AO solution (A8097: Sigma
Aldrich Co., St. Louis, MO) for 5 min, followed by wash-
ing out the excess AO solution with saline and excitation
with blue light, which most effectively excites AO to
emit green fluorescence [25]. Microscopic curettage was
repeated until the green fluorescence (tumor cells) had
disappeared. After AO-PDS, AO-PDT was performed
[13-18]. AO-PDT was applied to the area of tumor cu-
rettage under illumination with >100,000 lx of unfiltered
light (visible light) from a xenon lamp for 10 min, again
using fluorescence surgical microscopy. After the curet-
tage, bone reconstruction was performed by using mag-
netic materials (Fe3O4 powder with calcium phosphate
cement) for EMHT [23,24]. Finally, radiodynamic treat-
ment, in which labeled cells were treated with low dose
X-rays (AO-RDT) was performed after closure of the
surgical wound without washing out the AO solution. In
the radiotherapy room, a single session of X-ray irradia-
tion was applied to the resected area to achieve a strong
cytocidal effect of AO excited by low-dose X-rays [22].
Tumor cells labeled with AO can be killed by low-dose
2.2. Hyperthermia Treatment with an Electronic
Magnetic Generator (EMHT)
The concept of EMHT is that the thermal heating of the
magnetic material by the electronic generator kills the
tumor cells and that the electronic stimulation by the
magnetic field induces bone formation [23,24]. For the
clinical application of EMHT, magnetic materials are
used. Magnetic material hyperthermia was postopera-
tively applied by inserting the affected limb into a cylin-
drical coil of the electromagnetic field generator. EMHT
was performed postoperatively on days 8, 10, 12, 15, 17,
19, 22, 24, 26 and 29 for 30 minutes.
2.3. Patient Distribution
Six patients with bone metastasis (7 locations) in their
extremities were treated with AO therapy and EMHT
combination therapy. The patient distribution is shown in
Table 1. The average patient age was 62 years old (range:
56 - 70 years). The cancer types were renal cancer (n = 2),
bladder cancer (n = 1), lung cancer (n = 1), and multiple
myeloma (n = 1). The location of bone metastasis was
distal humerus (n = 4), distal femur (n = 1), proximal
tibia (n = 1), and distal tibia (n = 1).
3. Results
Curettage to remove the tumor was performed in all cases.
Six patients received bone reconstruction with Fe3O4
powder and calcium phosphate or bone cement, and 1 pa-
tient with a distal femur metastasis received reconstruc-
tion with a distal femur tumor prosthesis (Table 1).
All study patients died during the study period. None
of the deaths were related to the combination procedure.
The mean postoperative survival time was 13 months
(range, 6 - 33 months). There were no deaths during the
immediate postoperative period. All patients received
Copyright © 2013 SciRes. IJCM
A Minimally Invasive Surgery for Bone Metastases Using the Combination of
Photodynamic Therapy and Hyperthermia Treatment
Copyright © 2013 SciRes. IJCM
Table 1. Patient distribution, sur g ic al procedures and clinical outcome.
No. Age
(years) Diagnosis Metastasis site Pattern of excisionReconstruction
up Local
recurrence Outcome Bony
1 56 Bladder
cancer Dis-Humerus Curettage FeO4 + Hap* 8 () DOD +
2 63 Lung
cancer Dis-Humerus Curettage FeO4 + Hap* 21 13 months DOD +
3 68 Renal
cancer Dis-Humerus Curettage FeO4 + Hap* 6 () DOD moderate
4 70 Liver
cancer Dis-Humerus Curettage FeO4 + Hap* 28 () DOD +
5 57
myeloma Prox-Tibia Curettage
FeO4 + Hap*
+ Nail 33 () DOD +
6 61 Renal
Shaft of Femur
Marginal resection/
prosthesis 10 () DOD /
“ “ Dis-Tibia Curettage FeO4 + PMMA 8 () “ /
Dis-, distal; Prox-, proximal; FeO4, metal powder of FeO4; *Hap, Hydroxyapatite paste; PMMA, polymethyl methacrylate; DOD, death of disease.
combination therapy with an air tourniquet and then
showed minimal operative blood loss (mean, 80 ml;
(range, 40 - 300 ml). In the follow-up period, only one
patient experienced a local recurrence, and this recur-
rence occurred 13 months after surgery. EMHT was re-
peatedly performed for the recurrence case, and tumor re-
progression was suppressed until the end of the patient’s
Bony union occurred in 4 of 5 patients (80%), and the
limb function of all patients 2 months after surgery was
assessed as excellent or good by the Enneking limb func-
tional score.
The relief of pain was successful in all patients at an
early postoperative period. At two weeks after surgery,
all patients reported minimal or no pain. The range of
motion (ROM) in adjacent joints showed no limitations,
except for one case in which reconstruction was per-
formed with a distal femur prosthesis.
There were no surgical complications. There were no
neurological injuries, vascular injuries, or infections from
this combination therapy.
Figure 1. X-ray images of a multiple myeloma metastasis at
the proximal tibia that destroyed part of the cortex (A).
Two months after surgery, bone formation was identified
(B; white arrow). No osteolytic change was identified (C)
for 34 months. Limb function was preserved, and the pa-
tient was able to walk without pain until the time of de ath.
3.1. Case Presentation 1
Case 1 was a 57-year-old man who had multiple mye-
loma at the proximal tibia (Figure 1(A)). The patient had
severer lower leg pain and could no longer walk. The os-
teolytic lesion extended outside the cortex, and there was
a risk of pathological fracture. The osteolytic lesion at
the tibia was treated with curettage following AOT with
an ultrasonic knife. After curettage, reconstruction with
Fe3O4 powder, calcium phosphate cement, and an intra-
medullary nail was performed (Figure 1(B)). Two months
after undergoing EMHT, new bone formation was visi-
ble, and the patient walked smoothly without any pain.
Local tumor regrowth was not seen during the follow-up
period. The patient died of multiple myeloma 33 months
after surgery (Figure 1(C )).
3.2. Case Presentation 2
Case 2 was a 68-year-old man who had distal humerus
bone metastasis with renal cancer (Figure 2(A)). The
A Minimally Invasive Surgery for Bone Metastases Using the Combination of
Photodynamic Therapy and Hyperthermia Treatment
bone metastasis extended from the distal humerus into
the bone marrow around the middle of the humerus. Cu-
rettage following AOT with an ultrasonic knife was per-
formed through the window of the distal cortex. Tumor
labeled with AO can be visible with green fluorescence
(Figures 3(A) and (B)). After curettage, reconstruction
with the Fe3O4 powder with calcium phosphate cement
was performed (Figure 2(B)). Three months after un-
dergoing EMHT, new bone formation had become visi-
ble, and limb function was preserved, although the other
metastasis progressed, and the patient died 6 months after
surgery (Figure 2(C)).
4. Discussion
Bone metastases occur in the advanced stages of cancers
such as lung, renal, and breast cancers. Pathological frac-
tures caused by bone metastasis are associated with lim-
ited life expectancy, and the pathological fracture itself is
a negative risk factor for prognosis [26]. Multiple metas-
tases indicate poor prognosis. The goals of surgical in-
tervention for bone metastases are pain relief and mobil-
Figure 2. X-ray image for AO-RDT before surgery (A). The
tumor extended into the middle of the humerus. The area
was curettaged and packed with hydroxyapatite paste and
FeO4 powder (B). X-ray image 6 months after surgery. A
callus appeared on the X-ray, and there was no local recur-
rence for the remainder of the patient’s life (C).
Figure 3. The microscopic views in the surgical fields
through the optical light (A) and fluoresce nce with Acridine
Orange (B). Tumor labeled with AO can be visible with
green fluorescence.
ity preservation.
Therapeutic treatments for bone metastases to extremi-
ties include intramedullary nails, plates combined with
bone cement and tumor prosthesis [1-7]. Rigid intrame-
dullary nailing for bone metastasis is a convenient and
effective method of stabilization [4]. In cases of bone
metastasis at the diaphysis, we achieved good local con-
trol of bone metastasis by using intramedullary fixation
before EMHT [23,24].
On the other hand, bone metastasis at the epiphysis
sometimes requires surgical intervention without an in-
tramedullary nail. The cortex at the epiphysis is thinner
than at the diaphysis, and it is difficult to use an intra-
medullary nail. Around the epiphysis lesion, tumor cu-
rettage or resection is performed, and plates or pros-the-
ses are used. However, the use of a tumor prosthesis is
costly and more invasive than curettage with plates or
bone cement, which is commonly performed [27]. Local
adjuvants most commonly used for improving the effect
of curettage in local cancer surgery may exert their ef-
fects either chemically or physically. In orthopaedic on-
cology, the most commonly used adjuvants are phenol,
liquid nitrogen, and laser [27]. Liquid nitrogen some-
times causes bone fracture or skin erosion; the effect of
laser treatment is limited to the bone surface; and phenol
has toxicity. Epiphysial bone metastasis is an adequate
indication for AO therapy, because the effect of AO the-
rapy reaches deep areas and has fewer surgical complica-
We reported that AO accumulates in malignant tumors
with low extracellular pH [28]. Cancer bone metastases
in clinical specimens have a low extracellular pH (5.9 -
6.8) and high fluorescence intensity for AO. Thus, cancer
bone metastasis is an adequate application for AO ther-
AO therapy includes AO radiodynamic therapy with
low-dose (5 Gy) radiation. Regardless of whether the
course of treatment for metastatic bone lesions is nonop-
erative or operative, conventional radiation therapy is
mandatory for local tumor control and effective pain re-
Copyright © 2013 SciRes. IJCM
A Minimally Invasive Surgery for Bone Metastases Using the Combination of
Photodynamic Therapy and Hyperthermia Treatment
lief. Disease progression occurs in approximately 15% to
20% of patients with only surgery at the humerus [29].
Evidence indicating the best radiation dose fraction sche-
dule is lacking. Higher doses may promote local control,
but also increase complications due to radiation toxicity.
AO-RDT uses the dose of only 5 Gy, because AO in-
creases radiation sensitivity of the tumor cells. AO-RDT
accelerates the effect of radiation therapy without the in-
creased complications of conventional high-dose radia-
tion therapy.
Radiation therapy for bone metastasis without surgical
intervention is a risk for pathological fracture [7,8]. Fur-
thermore, radiation therapy cannot repeatedly be per-
formed, due to the development of tolerance.
EMHT has the advantage of reducing complications of
radiotherapy. Radiation therapy inhibits bone formation,
due to the death of osteoblasts. On the other hand, hyper-
thermia by EMHT kills the tumor cells, EMHT can re-
peatedly be performed without increased complications
(unlike conventional radiation therapy), and EMHT has
the potential to promote bone formation by electronic sti-
mulation [30-33]. We previously reported the efficacy of
hyperthermia treatment for bone metastasis compared
with the surgical treatment in combination with or with-
out radiotherapy [23]. The 8 patients who underwent only
palliative operation without radiotherapy showed poor
local control, and the radiographic assessment showed the
significant difference between palliative operation alone
and the EMHT alone. The palliative operation group
showed 38% bony union, in contrast with 80% bony un-
ion in this study [23]. Thus, EMHT can reduce the com-
plications of radiation therapy and has the potential to
promote bone union for the cancer bone metastasis.
Furthermore, hyperthermia promotes the chemother-
apy effect of thermal heating [34-36]. EMHT can be per-
formed without interrupting post-surgical chemotherapy
and has the potential to promote the effect of chemo-
therapy on bone metastasis lesions.
Clinical results of our combined therapy showed that
only one patient experienced local recurrence; this recur-
rence occurred 13 months after surgery. Thus, the local
recurrence was controlled by EMHT. Complete bony
union occurred in 80% of cases, and excellent local con-
trol was achieved even though all cases had a positive
surgical margin. Because the surrounding normal tissue
was preserved, the limb function after surgery was as-
sessed as excellent in 5 of 6 cases.
For patients with multiple bone metastases, a reduction
surgical procedure is generally performed, because can-
cer is a systemic disease, and local treatment of bone
metastasis can preserve the patients’ quality of life.
Cancers often become tolerant to chemotherapy or ra-
diation therapy, and this tolerance allows the disease
stage to progress. In many cases of local recurrence of
bone metastases, additional surgery cannot be performed
due to the patient’s deteriorating condition caused by
advanced disease. For these patients, EMHT would serve
as a repeatable and noninvasive treatment suitable for
bone metastasis.
There are several additional advantages of AO therapy
combined with EMHT: 1) Tumors can be visualized by
fluorescent microscopy during surgery; 2) Visible cells
can be removed without damage to healthy tissues; and 3)
Residual AO-labelled tumor cells seated in deep areas
are killed by low-dose radiation after surgery. Because of
these advantages, the combination of AO therapy and
EMHT has the potential to replace conventional tumor
surgery and radiotherapy in some cases.
In conclusion, minimally invasive treatment of patients
with bone metastasis with AO therapy and EMHT com-
bination therapy is an effective and safe procedure. This
surgical method is associated with a low rate of compli-
cations. Our goal of preserving excellent limb function
with low risk of local tumor recurrence in bone metasta-
sis was mostly achieved. However, we studied only a
small number of patients. A future study with a large
number of patients is needed to confirm the clinical util-
ity of AO therapy combined with EMHT in cancer treat-
5. Acknowledgements
We thank Dr. Haruhiko Satonaka (Ise Municipal General
Hospital, Ise City, Mie, Japan) for technical and basic
research assistance.
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