2011.hyperthermia in Cancer Treatment

Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2011;1(2):1-48.
Hyperthermia in Cancer Treatment

Erik Cabuy
1. Abstract ................................................................................................................................ 3
2. What is it? ............................................................................................................................ 4

2.1 Introduction................................................................................................................. 4
2.2 Principles of hyperthermia .......................................................................................... 4
2.3 Mechanisms of heating ............................................................................................... 6
2.3.1 Thermal conduction ............................................................................................ 6
2.3.2 Electromagnetic power deposition .....................................................................6
2.3.2.1 Radiative hyperthermia ...............................................................................6
2.3.2.2 Magnetic induction hyperthermia............................................................... 7
2.3.3 Ultrasound power deposition .............................................................................7
2.4 Modes of application ..................................................................................................7
2.4.1 Local hyperthermia ..................................................................................................8
2.4.1.1 External local hyperthermia ........................................................................8
2.4.1.2 Intraluminal or endocavitary local hyperthermia .......................................9
2.4.1.3 Interstitial local hyperthermia .....................................................................9
2.4.2 Regional hyperthermia............................................................................................. 9
2.4.2.1 Deep regional hyperthermia .......................................................................9
2.4.2.2 Regional perfusion hyperthermia ................................................................ 9
2.4.3 Whole-body hyperthermia....................................................................................... 10
2.4.4 Nanoparticle-mediated hyperthermia .....................................................................11
2.5 Thermal dose, monitoring and treatment planning ................................................... 11
2.5.1 Thermal dose definition ...................................................................................... 11
2.5.2 Temperature monitoring ..................................................................................... 12
2.5.3 Hyperthermia treatment planning ......................................................................12
2.6 Mechanisms of synergies: hyperthermia in combination with other therapies ........13
2.6.1 Hyperthermia alone ............................................................................................ 13
2.6.2 Hyperthermia and radiotherapy .........................................................................13
2.6.3 Hyperthermia and chemotherapy .......................................................................14
2.6.4 Hyperthermia and radiochemotherapy .............................................................. 15
2.6.5 Integration of hyperthermia with therapies under development ...................... 15
2.6.5.1 Immunotherapy and hyperthermia ............................................................. 15
2.6.5.2 Gene therapy and hyperthermia .................................................................16
3. Does it work? ....................................................................................................................... 16

3.1 Introduction ................................................................................................................ 16
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3.2 Evidence-based results for using hyperthermia per anatomical location ................. 17
3.2.1 Bladder cancer .....................................................................................................17
3.2.2 Breast cancer and chest wall recurrences ........................................................... 18
3.2.3 Esophageal cancer ............................................................................................... 19
3.2.4 Gynecological cancers ......................................................................................... 20
3.2.4.1 Cervical cancer ............................................................................................. 20
3.2.4.2 Ovarian cancer ............................................................................................. 22
3.2.4.3 Vaginal cancer .............................................................................................. 22
3.2.5 Head and neck cancers ........................................................................................ 23
3.2.6 Mesothelioma .....................................................................................................23
3.2.7 Non-small cell lung cancer .................................................................................. 24
3.2.8 Prostate cancer ....................................................................................................24
3.2.9 Rectal and colorectal cancers ..............................................................................25
3.2.9.1 Rectal cancer................................................................................................ 25
3.2.9.2 Colorectal cancer ......................................................................................... 26
3.2.10 Skin cancer and skin metastases of various primary tumors ............................ 27
3.2.11 Soft tissue sarcomas .......................................................................................... 27
4. Is it safe? ............................................................................................................................. 29
4.1 Does hyperthermia have any complications or side effects? .....................................29
4.2 Hyperthermia and metastasis ..................................................................................... 30
4.3 Risks involved in combining hyperthermia with other therapies ............................... 30
4.4 Exclusion criteria for using hyperthermia ...................................................................31
5. Concluding remarks .............................................................................................................31
6. References ........................................................................................................................... 33
6.1 Scientific publications .................................................................................................33
6.2 Books ........................................................................................................................... 46
6.3 Professional Societies/Organizations ..........................................................................46
7. Table .....................................................................................................................................46
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1. Abstract
Hyperthermia is a therapeutic procedure used to raise the body or local tissue temperature
to about 41-43°C through the application of electromagnetic or ultrasound energy for a
defined period of time to sensitize cells for additional therapies. It was introduced into
clinical oncology practice several decades ago. Positive clinical results, mostly obtained in
single institutions, resulted in clinical implementation albeit in a limited number of cancer
centers worldwide. Hyperthermia is almost always used with other forms of cancer
therapies as it provides a possibility for synergy with different actions of conventional
therapies. Hyperthermia in combination with radiotherapy and/or chemotherapy results in
higher response rates, accompanied by improved local tumor control rates, better palliative
effects and/or better overall survival rates in selected cases of tumor types. Significant
improvement in clinical outcome has been demonstrated for tumors of the bladder, breast,
cervix, head and neck, and soft tissue sarcomas. In this article, background information on
the biological rationale for the application of hyperthermia to human cancer treatment, an
overview of technologies and a summary of clinical outcomes published since 2005 are
provided.
Keywords: chemohyperthermia, continuous hyperthermic peritoneal perfusion,

electromagnetic therapy, heated intraoperative intraperitoneal chemotherapy,
hyperthermia, hyperthermic intraperitoneal chemotherapy, HIPEC, isolated limb infusion,
thermal therapy, thermotherapy
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2. What is it?
2.1 Introduction
The tumoricidal properties of hyperthermia have been recognized since ancient times
(Breasted, 1930). The first paper on hyperthermia was published by W. Bush in 1886. At the
end of the 19th century William B. Coley used infections with bacteria and/or injections of
bacterial extracts to induce fever for treating patients with cancer, now referred to as the
Coley Toxin. Increased interest in the use of hyperthermia for the treatment of cancer
developed in the 1960s, and various devices to produce either systemic hyperthermia or
hyperthermia in selected parts of the body were developed. In the past 15 years new
developments and technologies have transformed hyperthermia into a valuable therapy for
certain tumor cases. However, today hyperthermia is not widely used and the three
conventional therapeutic modalities (surgery, radio- and chemotherapy) dominate cancer
treatments. What are the reasons for this, given its long history and evidence of promising
results over the last decade? Initially, hyperthermia in oncology had many controversial
results and as a consequence, ambivalence in the medical community. In addition, the
incorrect use especially during the emergence of hyperthermia some 10 years ago or
inadequate techniques to allow treatments to be reproduced in clinics may be responsible
for its current limited acceptance. Technical challenges in treatment delivery, including
difficulty achieving therapeutic temperatures for deep-seated tumors, have hindered the
widespread use of hyperthermia (Hurwitz et al., 2011). The challenges for hyperthermia lie
also in its relatively complicated practice as, despite its simple principle, the required
permanent and intensive care from medical personnel takes a relatively long time in
comparison to the radio- or chemotherapies. Hyperthermia today also lacks adequate
treatment experience and long-range, comprehensive statistics. At this moment, most
advances are being made on improving heating technology, thermometry, the development
of hyperthermia treatment planning models and, most recently, drug targeting using
thermosensitive drug-carriers such as nanoparticles (Cherukuri et al., 2010) and liposomes
(Landon et al., 2011). The understanding of the biological effects involved is growing, i.e.
heat-shock proteins, anti-cancer immune responses and the role of hyperthermia in
hormone gene therapy. The positive results of most of the recent studies may explain the
renewed enthusiasm for hyperthermia, which is reflected in the growing number of
institutes interested in the application of hyperthermia. Currently, hyperthermia is available
in clinical research centers and private clinics mainly in Austria, China, Germany, Italy, Japan,
North America, Switzerland and The Netherlands.
2.2 Principles of hyperthermia
Various forms of thermal therapies are being used in the treatment of cancer. They are
divided into hyperthermia, thermal ablation and cryoablation in accordance with the
temperature range being used. Hyperthermia, also often called thermal therapy or
thermotherapy, is a cancer treatment in which cancer tissue or the whole body is exposed to
temperatures between 41-43°C through the application of electromagnetic energy for a
defined period of time to damage and kill cancer cells. Above this temperature, heat has a
direct cytotoxic effect on both normal and tumor cells and is referred to as thermal ablation.
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Thermal ablation is using much higher temperatures of >45°C and will be reviewed
elsewhere. Cryoablation or cryosurgery, using temperatures below minus 50°C is also
defined within the category of thermal therapies even though it is part of a surgical
intervention.
Hyperthermia causes numerous subtle changes in tissue physiology. An increase in

temperature due to hyperthermia changes the microcirculation of the tumor and hence the
oxygenation (Franckena and van der Zee, 2010). The oxygenation of the tissue is tightly
connected to vascular permeability which is modified by hyperthermia (Song et al., 2001;
Thrall et al., 2006). Also, increased temperature may slow down or even block DNA
replication (Xu et al., 2007) or inhibits cellular repair mechanisms (Krawczyk et al., 2011),
denature proteins, and inhibit angiogenesis (Dahl et al., 2008). Hyperthermia has been
shown to induce heat-shock proteins (Ciocca et al., 2010; Jolescha et al., 2011) and stimulate
the immune system (Calderwood et al., 2005; Dieing et al., 2007; Peer et al., 2010) with
observed increases in natural killer cell activity (Dayanc et al., 2008). Lymphocytes, which are
encountered in large numbers both in the blood as well as between the body cells, would be
more reactive due to the increased temperature. Another potential harmful effect of
hyperthermia is the triggering of programmed cell death or apoptosis in tumor cells (O’Neill
et al., 1998; Arya et al., 2007). The effects of hyperthermia on cancer are thus pleiotropic
and complex. All of these events can significantly disrupt a tumor cell’s capacity to divide,
ultimately leading to shrinkage of tumors. The tissue injury caused by hyperthermia occurs in
two distinct phases. The initial phase is direct heat injury that is predominantly determined
by the total energy applied to the tumor, tumor biology, and tumor microenvironment
(Nikfarjam et al., 2005a). The second phase is indirect injury after focal hyperthermia
application, which produces a progression in tissue damage. This progressive injury may
involve a balance of several factors including microvascular damage, ischemia reperfusion
injury, induction of apoptosis, Kupffer cell activation, altered cytokine expression, and
modulation of the immune response (Nikfarjam et al., 2005b; Torigoe et al., 2009). The
effects of heat depend on tissue temperatures attained, determined by the total thermal
energy applied, rate of removal of heat, and the specific thermal sensitivity of the tissue. In
addition, the form, type and size of tissue and the homogeneity of temperature distribution
can affect the denaturation of cellular and subcellular elements.
Hyperthermia can be applied using several methods. The most common method is to apply
hyperthermia locally using electromagnetic energy to heat the tumors which may be located
in various parts of the body. Local hyperthermia has been used extensively for superficial
lymph nodes, prostate, and cutaneous or subcutaneous melanoma metastasis. Regional
hyperthermia has been used primarily for recurrent or advanced breast cancer, advanced
pelvic tumors and for sarcomas of the trunk or extremities. In general, hyperthermia can be
used with all stages of cancer, although its current main use is with advanced solid tumors
that are hardly operable or inoperable, as well as with recurrent tumors and metastases.
Also where conventional therapy approaches (surgery, chemotherapy, radiation therapy) are
not very likely to be successful, or have proven to be inadequate, hyperthermia has already
been successfully used with some tumors including their metastases in different organs (see
3.2).
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Today, hyperthermia is almost always used with other forms of cancer therapies as it
provides a possibility for synergy with different actions of conventional therapies. The
scientific basis for the use of hyperthermia as an adjunct for the treatment of cancer rests on
several observations. Tumor cells that make deoxyribonucleic acid (DNA) in preparation for
division and those that are acidic and poorly oxygenated tend to be resistant to radiation
(Dewhirst et al., 2005). As a consequence, hyperthermia may make cancer cells more
sensitive to radiation or harm other cancer cells that radiation cannot damage. The
combination of chemotherapeutic agents and hyperthermia produces additive and
synergetic killing effects on tumor cells as well (Ponce et al., 2006; Issels, 2008). These
effects appear more dramatic at low pH. Heat can also potentiate the cytotoxic effect of a
variety of chemotherapeutic agents.
2.3 Mechanisms of heating
Laboratory and clinical studies have documented multiple mechanisms of action for
hyperthermia. A large number of different methods exist to apply active hyperthermia. To
deliver the heat three fundamental processes exist: (1) thermal conduction of heat away
from a source at higher temperature; (2) a combination of resistive and dielectric losses in
tissue from an applied electromagnetic (EM) field; or (3) mechanical losses from molecular
oscillations caused by an ultrasonic pressure wave.
2.3.1 Thermal conduction
In the simplest form of hyperthermia, tissue may be heated by circulating externally pre-
heated blood through the tissue, by placing a heated surface (e.g. a water bolus pad) on the
skin or in the body cavities, or by interstitially implanting hot sources in wires, needles, or
catheters into the target tissue. It is generally not possible to heat well perfused, normal
tissue more than 3 to 5 millimeters from a hot surface. Today, this technique is rarely used.
2.3.2 Electromagnetic power deposition
The electric properties of human tissues vary considerably. The primary mechanism of EM
heating of tissue also varies with frequency. In the radiofrequency (RF) range (hundreds of
kilohertz to a few megahertz), the alternating field induces a net movement of free
electrons, and power deposition results from resistive (ohmic) losses caused by the electric
currents in lossy tissue. At microwave (MW) frequencies (hundreds of megahertz to
approximately ten gigahertz), the dielectric losses in tissue predominate and heating results
primarily from friction caused by interactions between polar water molecules that rotate
and oscillate to maintain alignment with the time-varying EM field. At higher frequencies,
power is deposited more superficially, whereas lower frequencies provide deeper
penetration. Lower RF frequencies penetrate well but affect large regions of the body,
whereas higher MW frequencies may be localized effectively in tumor-sized tissue volumes.
Despite the large numbers of heating methods, presently the electromagnetic methods
dominate in the field of oncological hyperthermia. The different electromagnetic heat
delivery methods are described hereafter.
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2.3.2.1 Radiative hyperthermia
Radiative hyperthermia for heat generation uses the lower frequency waves (RF, MW, far IR
and near IR) of the EM spectrum. Among the radiation treatment modalities, RF has the
longest wavelength and the largest penetration possibility. To heat large tumors at depth, RF
fields in the range of 10–120 MHz are generally used with wavelengths that are long
compared to body dimensions and, thus, deposit energy over a sizeable region (Stauffer,
2005). Radiative hyperthermia creates an alternating electric field within the tumor tissue of
the patient causing agitation of the ions. This ionic agitation creates frictional heating within
the body, which can be tightly controlled through modulation of the amount of RF energy
deposited (Habash et al., 2006). Microwave hyperthermia has generally utilized single
waveguide microwave antennas working at 434, 915, and 2450 MHz. A widely used method
for electromagnetic energy delivery is antenna-array coupling. The body is ringed by the
antenna array which delivers a chosen field intensity with controlled phase and frequency.
Radiative hyperthermia has an ablative solution also (see review on Thermal ablation).
Water-filtered infrared-A hyperthermia is used in regional or whole body hyperthermia (see
2.4.2 and 2.4.3).
2.3.2.2 Magnetic induction hyperthermia
Inductive heating by coupled energy transfer from a coil carrying alternating current (AC)
surrounding a biological object through air is used to achieve deeper hyperthermia (for
example, more than 5 cm). Magnetic fields in RF induction heating can penetrate tissues,
such as subcutaneous fat, without excessive heating. Such magnetic fields induce eddy
currents inside the tissues. Since the induced electric fields are parallel to the tissue
interface, heating is maximized in muscle rather than in fat. However, the heating pattern is
generally toroidal in shape, with a null at the center of the coil. These applicators are usually
operated at frequencies of 13.56, 27.12, and 40 MHz, with the depth of penetration typically
being a few centimeters (Habash et al., 2006). In order to improve the magnetic energy
absorption within the target tissue, magnetic materials, such as microparticles and ferrite
rods, may be injected into the targeted area (see paragraph 2.4.4). There is an emerging field
of application of magnetic treatments using magnetic suspensions and other magnetic
liquids (Laurent et al., 2011).
2.3.3 Ultrasound power deposition
Ultrasound waves involve the propagation of sound waves at frequencies of 2-20 MHz
through soft tissues. Unlike EM radiation, ultrasound energy propagates through tissue as
travelling pressure waves. Variations in pressure from the alternating compressive and
expansive forces cause tissue molecules to vibrate and collide, producing heat from
mechanical friction within the molecular structure. Ultrasound delivered hyperthermia may
be carried out with external transducers, appropriately coupled to the surface of the body.
Ultrasound is significantly more penetrating in fat than in muscle tissue. For example, at 1
MHz the penetration depths are 4.4 cm in muscle and 31.3 cm in fat. The short wavelength
in tissue, less than a few millimeters, makes it possible to focus ultrasound energy in small
volumes at large depths. Because of the large impedance mismatch between soft tissue and
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air and between soft tissue and bone, these interfaces cause almost complete reflection of
the ultrasound energy. The anatomic locations where ultrasound can be applied are thus
limited. Ultrasound heating has an ablative solution also (see review on Thermal ablation).
The primary limitation of such systems is their inability to penetrate air and the difficulty in
penetrating bone (Habash et al., 2006).
2.4. Modes of application
Several methods of hyperthermia are currently being used in pre-clinical and clinical
practice. These have various subcategories and those are also subdivided further.
Traditionally clinical hyperthermia has been divided into three broad categories, namely, (1)
localized hyperthermia, (2) regional hyperthermia, and (3) whole-body hyperthermia. In
addition, we would like to discuss separately the nanoparticle-mediated hyperthermia as a
distinct type of use of hyperthermia, although it forms a local hyperthermia.
2.4.1 Local hyperthermia
In local hyperthermia, heat is applied to a small area restricted to the tumor. Different types
of energy may be used to apply heat, including microwave, radiofrequency, and ultrasound.
Local hyperthermia is performed with applicators of different kinds (waveguide, spiral,
current sheet) placed on the surface of superficial tumors with a contacting medium (bolus).
The resulting specific absorption rate (SAR) distribution is subject to strong physical
curtailment resulting in a therapeutic depth of only a few centimeters and is even further
limited in regions with an irregular surface, such as the head and neck area, or the
supraclavicular region (Habash et al., 2006). The penetration depth depends on the
frequency and size of the applicator. During local hyperthermia, the tumor temperatures are
increased to levels that are as high as possible, as long as the tolerance limits of the
surrounding normal tissues are not exceeded (van der Zee, 2002). Candidates for local
hyperthermia include chest wall recurrences, superficial malignant melanoma lesions, and
lymph node metastases of head and neck tumors. Depending on the tumor location, there
are several approaches to local hyperthermia.
2.4.1.1 External local hyperthermia
External local hyperthermia is used to treat tumors that are in or just below the skin.
Superficial lesions are the least difficult to heat adequately because of their accessibility and
proximity to external energy sources. Heat is usually applied using high-frequency energy
waves generated from a source outside the body (such as a radiofrequency or microwave
source). External applicators are positioned around or near the appropriate region, and
energy is focused on the tumor to raise its temperature. Electromagnetic techniques are
generally used for superficial tumors less than approximately 4 cm in depth, such as chest
wall recurrence of breast carcinoma, whereas ultrasound beams are useful for somewhat
deeper tumors up to approximately 6 cm deep.
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2.4.1.2 Intraluminal or endocavitary local hyperthermia
Intraluminal or endocavitary local hyperthermia may be used to treat tumors within or near
body cavities. Endocavitary antennas are inserted in natural openings of hollow organs.
These include (1) pulmonary (trachea, bronchus); (2) gynecological (cervix, uterus and
vagina); (3) genitourinary (prostate, bladder); and (4) gastrointestinal (esophagus, rectum).
Very localized heating is possible with this technique by inserting an endotract electrode into
lumens of the human body to deliver energy and heat the area directly. This type of thermal
therapy is used to achieve temperatures above 45°C to ablate tumors (see review Thermal
ablation).
2.4.1.3 Interstitial local hyperthermia
Interstitial local hyperthermia is used to treat tumors deep within the body, such as brain
tumors. This technique allows the tumor to be heated to higher temperatures than external
techniques. Under anesthesia, probes or needles are inserted into the tumor. Imaging
techniques, such as ultrasound, may be used to make sure the probe is properly positioned
within the tumor. This type of thermal therapy is used to reach temperatures above 45°C to
ablate tumors (see review Thermal ablation).
2.4.2 Regional hyperthermia
Regional hyperthermia attempts to heat moderately large volumes, such as the thorax or
pelvis, including the cancerous region as well as surrounding healthy tissue. The remainder
of the body is kept as close to normal temperature as possible. Various approaches may be
used to heat large areas of tissue. These techniques are intended to heat a large region at
depth and usually produce temperatures of approximately 39°C to 42°C throughout the
tumor and surrounding region, limited by power deposition in critical normal tissues. Deep
tissue approaches may be used to treat cancers within the body, such as cervical or bladder
cancer. External applicators are positioned around the body cavity or organ to be treated,
and microwave or radiofrequency energy is focused on the area to raise the temperature.
2.4.2.1 Deep regional hyperthermia
External applicators are positioned around the body cavity or organ to be treated, and EM
energy is focused on the area to raise its temperature. Deep regional hyperthermia is usually
performed using arrays of multiple applicators. An example of a recently developed
applicator is called HYPERcollar which comprises a phased-array of 12 RF antennas and
focuses heat onto the target while minimizing heating of adjacent critical tissues (Paulides et
al., 2007). The HYPERcollar was designed to enable deep heating of the head and neck
region, which contains many critical tissues and vessels with a large cooling capacity.
2.4.2.2 Regional perfusion hyperthermia
Regional perfusion hyperthermia is usually applied by perfusion of a limb, organ, or body

cavity with heated fluids and is mainly used perioperatively in combination with
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chemotherapy (Ceelen et al., 2000). Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is

a technique used to treat cancers within the peritoneal cavity (the space within the
abdomen that contains the intestines, stomach, and liver), including primary peritoneal
mesothelioma (Park et al., 1999) and stomach cancer (Kunisaki et al., 2006; Kerkar et al.,
2009). The combination of intraperitoneal chemotherapy used in the operating room with
hyperthermia has many different nomenclatures: heated intraoperative intraperitoneal
chemotherapy (HIIC), continuous hyperthermic peritoneal perfusion (CHPP), or
hyperthermic intraperitoneal chemotherapy (HIPEC). In this review, HIPEC is the designated
terminology. The term ‘intraperitoneal’ means that the treatment is delivered to the
abdominal cavity. The term ‘hyperthermic chemotherapy’ means that the solution
containing chemotherapy is heated to a temperature greater than normal body
temperature. During surgery, heated anticancer drugs flow from a warming device through
the peritoneal cavity. The peritoneal cavity temperature reaches 41–42°C. Cancer that has
spread to the lining surfaces of the peritoneal (abdominal) cavity from primary colorectal
cancer, ovarian cancer, gastric cancer, appendiceal cancer or from mesothelioma and
pseudomyxoma peritonei, known as peritoneal carcinomatosis, are very difficult to treat.
However, when these cancers are confined to the peritoneal cavity, HIPEC becomes an
option for candidate patients (Ceelen et al., 2008; Ceelen and Flessner, 2010). There are
three main methods of delivery of HIPEC into peritoneal cavity which are described
elsewhere (Helm, 2009) and in more detail (Esquivel et al., 2007). Before HIPEC is
administered, the surgeon using standard surgical methods will remove all visible tumors
that can be removed throughout the peritoneal cavity. This is known as cytoreductive
surgery. Following cytoreductive surgery, in the operative setting the surgeon will administer
HIPEC treatment. Depending on the type of cytotoxic drug, the duration of chemoperfusion
is between 30 and 90 minutes (Ceelen et al., 2008). An increasing number of centers are
initiating this multimodality therapy in ovarian cancer and colorectal cancer. Isolated limb
infusion (ILI) is a similar technique that has been used to combat cutaneous melanoma of
the extremities (Thompson and Kam, 2008). ILI involves drug administration (usually TNF-
alfa and/or melphalan) into a limb via percutaneously inserted catheters after vascular
isolation of the limb has been achieved with a tourniquet. The infused drug is circulated for a
set time via a simple extracorporeal circuit incorporating a heater to produce mild
hyperthermia.
2.4.3 Whole-body hyperthermia
Whole-body hyperthermia (WBH) raises the temperature of the entire body up to a fever-
range temperature of 39.5°C (i.e. moderate hyperthermia or fever-range hyperthermia) for
4-8 hours or to nearly 42°C for 1-2 hours (Jia and Liu, 2010). The tolerance of liver and brain
tissue, however, limits the maximum temperature for using WBH to 41.8–42.0°C, but this
temperature may be maintained for several hours. This type of systemic treatment uses
homogeneous heating all over the body, with no specific selection of the tumor. WBH
produces the most uniform tumor heating, regardless of tumor location within the body.
Hence WBH treatment acts differently from local/regional hyperthermia even at the same
temperature; in the systemic treatment the blood delivers the heath to the tumor, while in
the local/regional treatment the blood at normal body temperature cools the tumor.
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Two direct methods are mainly available to carry out systemic hyperthermia; the extra-
corporeal and the intra-corporeal treatments. The less frequently used extra-corporal blood
heating transports the blood in a continuous flow through an arterial outlet, pumping the
externally heated blood back to the patient. The other method is accomplished by non-
invasive means such as the enclosure of a patient in a radiant heat chamber with water-
filtered infrared or RF heat input. This non-invasive method rely on heating up the blood in
the capillary bed of the corium and sub cutis, which heats up the entire blood stream and in
this way the whole body. Water-filtered infrared-A (wIRA) radiation is a type of heat
radiation ideally suited to human skin. The application of wIRA distinguishes itself by its high
penetration, all the way into the capillary bed of the skin. With wIRA the interfering infrared-
B and the infrared-C is eliminated from the heat radiation. Thus a clearly higher radiation
power can be applied at a tolerable level than by applying unfiltered heat radiation. The
patient is sedated throughout the WBH procedure, which may last approximately one to
four hours. The patient reaches target temperature within approximately 30 minutes, is
maintained at 41.8°C, and experiences a one-hour cooling phase. Moderate or fever-range
whole body hyperthermia simulates a natural fever increasing the number and activity of
natural killer cells, T-helper cells and cytotoxic T-cells. Moderate WBH may also be used to
prevent recurrences and is used to treat metastatic cancer that has spread throughout the
body. WBH provides a possibility of synergy with conventional therapies. The disadvantages
of WBH are the significant systemic stress exerted by whole-body heating, the lack of
preferential tumor heating, and the fact that temperatures are limited to approximately
42°C because of thermosensitivity of critical tissues such as the heart, lung, liver, and brain.
Thus the thermal goals of systemic therapy are usually more modest than local or regional
heating techniques, and intended for activation of drugs or enhancement of immunologic
response. For a comprehensive review of the latest devices for WBH see Jia and Liu (2010).
2.4.4 Nanoparticle-mediated hyperthermia
The major problem of applied hyperthermia treatments is achieving a homogenous heat

distribution in the treated tissue (Habash et al., 2006). The currently available modalities of
hyperthermia are often limited by their inability to selectively target tumor tissue and,
hence, they carry a risk of collateral organ damage or they deposit heat in a localized
manner, which can result in under-treatment of a tumor. Nanotechnology-based cancer
therapy is a special form of interstitial thermotherapy with the advantage of selective heat
deposition to the tumor cells. This new therapy is one of the first applications of
nanotechnology in medicine and is based on heating of ferric oxide nanoparticles or
quantum dots in an external AC magnetic field. The technique consists of the localization of
magnetic particles or seeds within tumor tissue followed by exposure to an externally
applied magnetic field to cause them to heat (Moroz et al., 2002; Johannsen et al., 2010).
The method is also known as magnetic fluid hyperthermia (MFH) or nanohyperthermia.
Depending on the duration of treatment and the achieved intratumoral temperatures, the
tumor cells are either directly destroyed (see review Thermal ablation) or sensitized for
concomitant chemo or radiotherapy. The nanoparticles remain in place at the treatment
area, allowing for repeated treatments and the integration of multimodal therapy concepts.
Nanoparticle-mediated thermal therapies are being studied worldwide by using either a
radiofrequency field, an alternating magnetic field, or near-infrared light as a source of
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delivering energy. Different designs of nanoparticle structures (Krishnan et al., 2010; Huang
et al., 2011) or thermosensitive liposomes (Ponce et al., 2006; Koning et al., 2010) are in
development for energy delivery or as carriers for drug delivery.
2.5 Thermal dose, monitoring and treatment planning
2.5.1 Thermal dose definition
One of the most recognized control parameters for gauging the efficacy of hyperthermia is
temperature. Over the years, more than 20 of such parameters have been proposed (de
Bruijne et al., 2010). They range from simple temperature statistics (e.g. minimum
temperature, median temperature, temperature percentiles, etc.) to thermal isoeffect dose
parameters, which convert the time-temperature data into an isoeffect dose (Sapareto and
Dewey, 1984; Oleson et al., 1993). The randomized trial by Jones et al. (2005) was the first to
prescribe a thermal dose in human patients, using the CEM43°CT90 thermal dose parameter
(de Bruijne et al., 2010). CEM43°CT90 represents the thermal isoeffect dose expressed in
cumulative equivalent minutes (CEM) at a reference temperature of 43°C based on the low
end of the temperature distribution (T90). For a review of the background of the thermal
isoeffect dose concept, see Dewhirst et al. (2003).
The dosing and control particularly of deep heat transfer remains a complex issue. The
central issue concerning the dosimetric assessment of the absorption of EM energy by
biological tissues is how much is absorbed and where it is deposited. This is usually
quantified in terms of the specific absorption rate (SAR), which is defined as the rate at
which EM energy is absorbed by the tissue at a specific location per unit mass. SAR is
measured in W/kg. The SAR is determined not only by the incident electromagnetic waves
but also by the electrical and geometric characteristics of the irradiated subject and nearby
objects. It is related to the internal electric field strength as well as to the electric
conductivity and the density of tissues (Ziskin, 2005). In reality, tumors are far from
homogeneous, and their boundaries are not characteristic either. SAR distributions are
usually determined from measurements in human models, in animal tissues, or from
calculations. SAR values are of key importance when validating possible health hazards and
setting safety standards. Various methods are used to obtain point, planar, or whole-body
averaged SARs including the use of small electrical field probes or measurement of initial
rate of temperature rise in an irradiated object.
2.5.2 Temperature monitoring
Today, a major limitation of hyperthermia is the lack of detailed information available to

guide hyperthermia. In order to compare different treatments and to correlate the
treatment data with the clinical results, it is mandatory to know what temperatures are
reached in the target tissue volume. To ensure that the desired temperature is reached, but
not exceeded, the temperature of the tumor and surrounding tissue is monitored
throughout hyperthermia treatment. However, commonly available technologies do not
provide the temperature distribution throughout the tumor. If a tumor is too large for the
intended applicator, it is highly unlikely that 100% of the tumor will be adequately heated.
The need for sound thermometry measurements is reflected in the various quality assurance
Page 12 of 48
guidelines, i.e. Radiation Therapy Oncology Group (RTOG) and European Society for
Hyperthermic Oncology (ESHO) guidelines advise invasive thermometry and provide specific
guidelines for temperature registration (Hand et al., 1989; Dewhirst et al., 1990; Lagendijk et
al., 1998). Using local anesthesia, small needles or tubes are inserted with tiny
thermometers into the treatment area to monitor the temperature. Imaging techniques,
such as CT (computed tomography) or ultrasound may be used to make sure the probes are
properly positioned. During whole-body hyperthermia treatment, the esophageal, rectal,
skin and ambient air temperatures are monitored at 10-minute intervals. Small probes may
be inserted into the tumor under a local anesthetic to monitor the temperature of the
affected tissue and surrounding tissue. Heart rate, respiratory rate, and cardiac rhythm are
continuously monitored. A number of non-invasive thermometry techniques are under
investigation to allow both improved patient comfort and quantification of more complete
temperature distributions such as infrared thermography, fiberoptic sensors, computed
tomography, and magnetic resonance thermal imaging (MRTI) (Craciunescu et al., 2010).
2.5.3 Hyperthermia treatment planning
The time when hyperthermia can be applied must be considered carefully when opted for as
an adjuvant therapy. It is conventionally given either before or after another therapy, such
as radiotherapy. Most studies have been performed when radiotherapy has been chosen to
be given with hyperthermia. It was found that an increased therapeutic ratio could be
obtained if radiation was given before heat and an interval of 4 hours or more was allowed
(Overgaard, 1980). However, Moros et al. (2010) proposes to administer hyperthermia and
radiation simultaneously, rather than sequentially as it is conventionally done, for breast
cancer recurrence and others and found that heat induced radio-sensitization increases at
thermal doses which can be achieved in the clinic.
Another important issue is to determine which radiation dose-fractionation scheme should
be combined with hyperthermia. The optimum radiation dose-fractionation scheme has not
been defined yet. In practice, many institutions favor doses of approximately 4 Gy in case of
re-irradiation concurrently with hyperthermia for superficial tumors (van der Zee et al.,
2010). For deeper-seated lesions, in which there are more sensitive normal tissues,
conventional fractionation of 1.8 to 2 Gy has been the rule. Other issues include number of
hyperthermia treatments, target temperature and duration, and sequencing of the different
modalities. Further phase I and II trials are needed to help define the optimal thermal dose
and sequencing of hyperthermia with radiotherapy, including investigation of long-duration,
simultaneous radiotherapy plus hyperthermia. The type of treatment planning programs
that have already been developed for radiotherapy must be developed for more complex
requirements of both prospective and retrospective study of thermal dosimetry in clinical
thermal therapy. Since hyperthermia is usually applied in combination with radiotherapy
(see 2.6.2), chemotherapy (see 2.6.3), or both (see 2.6.4) the dose and treatment of the
other modality will also influence the clinical outcome.
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2.6 Mechanisms of synergies - Hyperthermia in combination with other therapies
2.6.1 Hyperthermia alone
The effectiveness of hyperthermia treatment is related to the temperature achieved during

the treatment, as well as the length of treatment and cell and tissue characteristics. Early
clinical studies using hyperthermia for the treatment of small, superficial neoplasms have
shown that hyperthermia alone, using multiple 30 – 60 minutes hyperthermia sessions, has
limited efficacy (e.g. Stewart, 1984). Hyperthermia by itself may result in shrinkage and
sometimes complete eradication of tumors, however, these results may not last, and the
tumors may come back. Clinical studies evaluating whole-body hyperthermia are primarily in
the form of uncontrolled clinical trials. The study populations were generally small and were
heterogeneous with respect to disease, site, stage and prior therapy. Today, hyperthermia is
almost always used with other forms of cancer therapies as it provides a possibility for
synergy with different actions of conventional therapies.
2.6.2 Hyperthermia and radiotherapy
Hyperthermia is considered to be one of the most potent radiosensitizers (Lindner and Issels,
2011). The primary mechanism of radiation therapy is the generation of free oxygen radicals
by ionizing radiation, which in turn attacks the DNA of the tumor cells. However cells low in
oxygen and pH range or in S-phase, as is often the case for cancers, are relatively radio-
resistant (Dewhirst et al., 2005). This is where hyperthermia may be a supplemental aid. Due
to the heating of the tissue, blood flow increases, resulting in higher oxygen enrichment in
the affected tissue. These effects on blood flow and tumor oxygenation may make the
cancer cells more susceptible to radiation therapy. Another important effect is the inhibition
of the cancer cells' inherent DNA repair mechanisms as a result of the release of heat-shock
proteins by the heat. Hyperthermia increases cytotoxic radiation effects, in particular by
interfering with the cellular repair system as a result of the denaturing of the DNA.
The synergistic effects of hyperthermia combined with radiation have been investigated and
reported to yield higher complete and durable responses than radiation alone (e.g. van der
Zee et al., 2000). Hyperthermia today is probably the most effective support to radiation
therapy. It has been reported by many clinical trials (see 3.2) that hyperthermia therapy has
been shown to substantially improve local control of cancer, tumor clinical response, and
survival rates when added to radiation treatments. It yields considerable therapeutic gain
compared to radiation alone in treating various cancerous tumors (Jones et al., 2007).
However, clinical experience has largely been limited to treatment of recurrent, metastatic
superficial melanomas, chest wall recurrence of breast cancer, cervical cancer and lymph
node metastases from head and neck cancers. Tumor depth is a critical factor when
combining radiation therapy and hyperthermia. In-vivo studies have shown that the effect of
radiotherapy can be increased by hyperthermia by a factor 1.2 to 5 (Horsman and
Overgaard, 2007). However, not all studies have shown increased survival in patients
receiving the combined treatments (Vasanthan et al., 2005). Systems and techniques have
been reviewed to deliver simultaneous thermoradiotherapy of breast cancer (Moros et al.,
2010). The synergy between heat and radiation, often expressed as thermal enhancement
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ratios, is highest when the two modalities are given simultaneously. When heat precedes
radiation, the synergy is lost when the time interval between the two modalities increases.
Despite many positive studies and comprehensive reviews, hyperthermia is still not widely
accepted as a therapy that can be combined with radiotherapy.
2.6.3 Hyperthermia and chemotherapy
The rationale for the combination of cytotoxic drugs with hyperthermia is based on
experimental and clinical evidence that heat increases killing of cells by direct thermal
toxicity and shows thermal enhancement of drug efficacy (Issels, 2008). This is because
hyperthermia is able to increase cell membrane permeability, which is favorable for the
penetration of chemotherapeutic drugs into tissues and absorption by the tumor. When the
pore size of cell membranes increase in response to heating, the intracellular drug
concentration is also elevated (Ponce et al., 2006). In addition, hyperthermia selectively
increases the size of fenestrations, conduits of the drug in tumor vessels, while it does not
cause this effect in normal tissues (Ponce et al., 2006). Some other physiology-related
features would also make a combination of heat and drugs more attractive. Drugs whose
rate-limiting reaction is primarily chemical (i.e., not involving enzymes) would, on
thermodynamic grounds, be expected to be more efficient at higher temperatures. The rates
of alkylation of DNA, or of conversion of a nonreactive species to a reactive one, can be
expected to increase as the temperature increases (Kampinga, 2006). Also, increased DNA
damage, decreased DNA repair, and reduced oxygen radical detoxification may have
cytotoxic effects as a result of the heat. Concentration of agents that are not normally toxic
at normal body temperature can become cytotoxic at 39°C, and in some cases, hyperthermia
may overcome some types of drug resistance.
A number of clinical studies indicate that elevated cell tissue temperature, induced by EM
energy absorption, significantly enhances the effectiveness of chemotherapy in the
treatment of malignant tumors in the human body without increasing the infused amount of
drug (e.g. Falk and Issels, 2001). Moderate or even mild hyperthermia (39°C) enhances cell
killing in vivo of a number of chemotherapeutic agents, such as mitomycin C, cisplatin,
doxorubicin, and bleomycin. Supra-additive cytotoxic effects were observed mainly in
combination with alkylants and platinum derivatives. It has been shown that hyperthermia
brings about a significantly stronger effect compared to applying chemotherapy only (e.g.
Issels, 2006). In combination with chemotherapy, the type of drug, dose, temperature, and
time of administration all play a role in determining the effect of treatment. Liposomes have
been identified as one of the promising carriers for therapeutic agents to improve drug
delivery in the treatment of cancer. Hyperthermia combined with temperature-sensitive
liposomes would allow for better control over the release of encapsulated drugs at the
disease site.
The microscopic action of chemotherapy, however, is different for local/regional and

systemic hyperthermia. The reaction of the given pharmaceutics for the local treatment
mainly supports a reaction deeper in the tissue while systemic treatment is near the
capillaries. Whole body hyperthermia is used in combination with chemotherapy for
treatment of advanced cancers especially metastases in different organs, e.g. in the liver,
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bones or lungs. The chemotherapy is started at a temperature of about 41°C. Very often it is
possible to use lower doses of chemotherapy thus possibly reducing side effects. For
patients showing intolerances for specific drugs, for example when they have renal or liver
insufficiency or an insufficient blood composition, the same results may be achieved by the
combination of decreased chemo-dose and hyperthermia (Wiederman et al., 1993). Tumors
or metastases resistant to chemotherapy can also be treated with a combination treatment
of chemotherapy and whole body hyperthermia.
2.6.4 Hyperthermia and radiochemotherapy
There is a growing literature on trimodality studies combining hyperthermia with

radiotherapy and chemotherapy for head and neck, breast, esophageal, and rectal cancers.
Both radio- and chemotherapies mainly act in the vessel neighborhood, because of their
higher activity in oxygen-rich tissues and via blood-delivered drug diffusion, respectively.
When hyperthermia is applied in combination with radiotherapy and chemotherapy, the
dose and treatment scheme of the other modality will also influence the clinical outcome.
An extensive review on the combination of hyperthermia with radiochemotherapy was
published by Falk and Issels (2001). Thermal radiochemosensitization has more beneficial
effects due to the multiple synergies (Bergs et al., 2007).
2.6.5 Integration of hyperthermia with therapies under development
2.6.5.1 Immunotherapy and hyperthermia
Hyperthermia might be effective in the enhancement of anti-tumor immune responses

(Overgaard et al., 2009; Franckena et al., 2009). Its use as an adjunct to cancer
immunotherapy is supported by an increasing amount of research data. Both pre-clinical and
clinical data results have demonstrated improved anti-tumor immune responses with the
addition of mild hyperthermia (Tanaka et al., 2005; Issels et al., 2006; Guo et al., 2007;
Knippertz et al., 2011; Matsumoto et al., 2011). The molecular mechanisms responsible for
the improved immune reactivity observed in the presence of hyperthermia include the
generation of heat-shock proteins (HSPs), the activation of antigen presenting cells and
changes in lymphocyte trafficking (Appenheimer et al., 2005; Skitzki et al., 2009).
A preclinical study evaluated the use of hyperthermia combined with intra-tumoral injection
of dendritic cells (DCs) to treat melanoma (Tanaka et al., 2005). This study aimed to assess
the proposed benefits of in situ tumor antigen loading of DCs in the presence of local
stimulating factors elicited by hyperthermia. A significant inhibition of tumor growth was
noted, with concomitant migration of injected DCs to tumor-draining lymph nodes and
priming of cytotoxic T-lymphocytes (CTLs) (Tanaka et al., 2005). Similar findings were
obtained in a small clinical study using this treatment strategy (Guo et al., 2007). Patients
with advanced melanoma were treated with intra-tumoral injections of immature DCs with
or without adjuvant local hyperthermia. The addition of hyperthermia extended the time to
tumor progression and improved T-lymphocyte priming (Guo et al., 2007). In a study using a
murine prostate cancer model, localized hyperthermia was combined with intra-tumoral
injection of DCs (Mukhopadhaya et al., 2007). Tumors treated with a combination of
Page 16 of 48
hyperthermia and intra-tumoral DC injections exhibited significant growth inhibition

compared with controls. Matsumoto et al. (2011) explored the feasibility of combining mild
hyperthermia and DC application for squamous cell carcinoma (SCC) in vitro and in vivo. A
more suppressive effect of tumor growth was observed, and cytotoxic T cell infiltration was
significantly increased by adding hyperthermia. Collectively, these findings support the use
of hyperthermia activating anti-tumor immune responses.
2.6.5.2 Gene therapy and hyperthermia
The combination of hyperthermia with gene therapy, in which hyperthermia induces

transgene expression, represents a promising strategy (Huang et al., 2000; Lohr et al., 2000;
Walther and Stein, 2009). In order to treat cancer effectively, the genetic material must
exert its effect only on tumor or tumor-associated cells, not on normal cells, and must not
eliminate the body’s immune response that is critical in fighting cancer. Different promoters
have been used for construction of viral and non-viral vectors and were tested in numerous
gene therapy studies for heat-inducible gene expression (Huang et al., 2000; Gerner et al.,
2000; Ohtsuru et al., 2001). Successful combination of hyperthermia and HSP-promoter-
mediated gene therapy in advanced breast cancer patients has been reported (Ohtsuru et
al., 2001). Hyperthermia also improved the results of the HSP-promoter gene therapy by
inducing local HSP production and by enhancing the local rate of release from liposome
(Gaber et al., 1996). It was shown that this combination therapy was highly selective for
mammary carcinoma cells. These studies demonstrated that hyperthermia can efficiently
induce transgene expression in vitro and in vivo. Furthermore, these studies showed anti-
tumoral efficacy of the combined action of hyperthermia and heat-responsive gene therapy.
Next to hyperthermia’s role in increasing and speeding transgene production directly at the
site, where needed to enhance therapeutic efficacy, hyperthermia would be expected to
help in opening up the pores of tumor blood vessels so that more liposomes reach the
tumors and deliver their DNA content to tumor cells. Siddiqui et al. (2009) studied the role of
hyperthermia in vitro and in vivo in an attempt to achieve higher transfection rates of viral
vectors. However, improvements in intra-tumoral adenoviral spread in response to
hyperthermia were not consistently observed in a mouse tumor model using two
quantitative endpoints of gene expression. Despite the fact that hyperthermia has long
entered clinical practice as therapeutic modality and heat-responsive vectors have been
largely improved, showing their effectiveness in vitro and in vivo, currently no clinical trial
for heat-responsive gene therapy is underway.
3. Does it work?
3.1 Introduction
Many research studies are being conducted to evaluate the efficacy improvements of
hyperthermia. Numerous clinical trials have studied hyperthermia in combination with
radiation therapy and/or chemotherapy or other modalities. These studies have focused on
the treatment of many types of cancer. Many of these studies have shown a significant
reduction in tumor size when hyperthermia is combined with other treatments. Table 1
reviews examples of recent outcomes of hyperthermia combination therapy for different
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types of cancer. The purpose of this section is to summarize and evaluate the clinical efficacy
of hyperthermia combined with other therapies for each anatomical tumor location.
Evidence for its efficacy comes from published research studies and clinical trials. The main
focus is on phase II and III randomized controlled clinical trials. The clinical value of
hyperthermia in addition to other treatment modalities has been shown in many
randomized trials. Over one hundred clinical trials are registered in the ClinicalTrials.gov
(access September 2011, conditions: cancer; interventions: hyperthermia). The clinical
objective is to achieve tumor regression in a controlled fashion. Significant improvement in
clinical outcome has been demonstrated for tumors of the bladder, breast, cervix,
esophagus, head and neck, melanoma, rectum, and for soft tissue sarcoma. The diversity of
the clinical trials can be observed from the diversity of the applied methods. A direct
comparison of divergent technical solutions (for example whole-body treatment with RF-
ablation in the liver) is not possible. At present, several other studies of the use of
hyperthermia in recurrent rectal cancer, anal cancer, peritoneal metastases of ovarian
cancer, pancreatic cancer and prostate cancer are under development and/or close to being
started (van der Zee and Overgaard, 2009).
An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and

ClinicalTrials.gov databases was undertaken in August 2011. In vitro and animal studies, as
well as case reports and abstracts have been omitted including studies published before
2005, however, review studies generally go further back in time. Treatments of patients and
technologies have evolved over the years and now often consist of different adjuvant
chemotherapy and/or radiotherapy implementations. Case reports have been omitted
mainly because they are based on an individual patient’s profile hence results cannot be
generalized, nevertheless RCT acknowledges their scientific value, however limited. Thus
these selection criteria would benefit the rationale for rating the efficacy of hyperthermia
based on what is available in clinical practice today.
3.2. Evidence-based results for using hyperthermia per anatomical location
3.2.1 Bladder cancer
Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive

bladder cancer (NMIBC), the search for better therapeutic options continues. One of the
developing treatments for high-risk NMIBC is the combination of intra-vesical chemotherapy
and hyperthermia, called chemohyperthermia. During the last 15 years, the combined
regimen has been tested in different clinical settings.
A systemic review has been performed to evaluate the efficacy of chemohyperthermia as a

treatment for NMIBC (Lammers et al., 2011). The primary end point was time to recurrence.
Secondary end points included time to progression, bladder preservation rate, and adverse
event rate. A total of 22 studies met inclusion criteria and underwent data extraction. Based
on three clinical studies with control groups, of which one was a randomized trial,
recurrence was seen 59% less after chemohyperthermia than after taking mitomycin C
alone. Due to short follow-up, no conclusions could be drawn about time to recurrence and
progression. The overall bladder preservation rate after chemohyperthermia was 87.6%. This
Page 18 of 48
rate appeared higher than after mitomycin C alone, but valid comparative studies were
lacking. The adverse effects were higher with chemohyperthermia than with mitomycin C
alone, but this difference was not statistically significant. The authors of the systemic review
concluded that published data suggest a 59% relative reduction in NMIBC recurrence when
chemohyperthermia is compared with mitomycin C alone. Chemohyperthermia also appears
to improve bladder preservation rate. However, due to a limited number of randomized
trials and to heterogeneity in study design, definitive conclusions could not be drawn. The
authors further notify that chemohyperthermia may become a standard therapy for high-
risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy,
and in cases for which Bacillus Calmette-Guérin treatment is contraindicated.
Colombo et al. (2011) presents long-term efficacy data of intravesical thermochemotherapy

vs. chemotherapy alone with mitomycin-C (MMC) randomly administered to 83 patients
with intermediate-/high-risk NMIBC as an adjuvant treatment after complete trans-urethral
resection. The 10-year disease-free survival rate for thermochemotherapy and
chemotherapy alone were 53% and 15%, respectively. Bladder preservation rates for
thermochemotherapy and chemotherapy alone were 86% and 79%, respectively. The high
rate (53%) of patients who were tumor-free 10 years after treatment completion, as well as
the high rate (86%) of bladder preservation, confirms the efficacy of this adjuvant approach
for NMIBC at long-term follow-up, even in patients with multiple tumors.
The aim of another study by Halachmi et al. (2011) was to evaluate retrospectively the
clinical data of patients with T1G3 NMIBC who underwent complete transurethral resection
(TURT) followed by hyperthermia and chemotherapy (mitomycin C) treatment. A total of 51
T1G3 patients were available for analysis. Median follow-up time of tumor-free patients was
18 months (range 2-49 months). Seventeen patients (33.3%) had tumor recurrence and 4 of
them progressed to muscle invasive disease. The median time to recurrence was 9 months
(range 2-31 months). Here as well the authors concluded that chemohyperthermia can be an
effective adjuvant treatment option after TURT to prevent recurrence in patients with T1G3
NMIBC. The progression rate after this treatment was low (7.9%).
3.2.2 Breast Cancer and chest wall recurrences
Patients who suffer superficial recurrences of breast cancer, be it in their chest wall
following mastectomy, or in their breast after breast conservation, typically have poor
clinical outcomes (Zagar et al., 2010a). There is no accepted standard of care in treating
superficial recurrences of breast cancer. The goal of utilizing hyperthermia in breast cancer
and chest wall recurrences is to increase response rates in order to prolong disease-free and
overall survival. Most reported studies are single institution series or anecdotal case reports.
The overall body of evidence suggests that local external superficial hyperthermia, when
used as part of a multi-modal regimen, may aid in increasing local tumor response and
greater duration of local control. Patients with persistent and/or recurrent breast cancer and
chest wall tumors have significantly benefited when hyperthermia has been added to their
radio- and/or chemotherapy regimens (Jones et al., 2005; 2007; van der Zee et al., 2010;
Wahl et al., 2008; Welz et al., 2005). However, this does not consistently translate into
increased survival rates (Jones et al., 2005; Wahl et al., 2008). In 2007 McCormick wrote that
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despite significant research efforts in multiple studies over the past 25 years, convincing
results for adopting this therapy as standard care are still lacking.
The 2011 National Comprehensive Cancer Network (NCCN) Breast Cancer Clinical Practice
Guidelines in Oncology include consideration of the addition of hyperthermia to irradiation
for localized recurrences/metastasis. There is indeed a substantial literature regarding the
combined use of hyperthermia and radiotherapy for the superficial recurrences of breast
cancer. Most of it is retrospective in nature, but there are several larger phase III
randomized trials that show an improved rate of clinical complete response in patients
treated with both modalities (Zagar et al., 2010b). While there is heterogeneity among the
study results, a series with strict quality assurance demonstrated a statistically significant
increase in local tumor response and greater duration of local control with the addition of
hyperthermia to radiation compared to radiation alone (Jones et al., 2005). No differences in
overall survival have been demonstrated. A recent multi-institutional review of repeat
irradiation of chest wall and breast for recurrent breast cancer revealed that repeat
radiotherapy is feasible for such patients (Wahl et al., 2008).
A more recent review of Zagar et al. (2010b) concludes that in a select group of patients, the
addition of hyperthermia to radiotherapy increases the eradication of local tumor, with a
modest increase in largely self-limited toxicity. With rigorous thermal dosimetry and careful
treatment technique, the addition of heat to radiotherapy can result in long-term local
control of breast cancer chest wall recurrences (Zagar et al., 2010b). The most recently
reported phase III trial of radiotherapy with or without hyperthermia was performed by
Jones et al. (2005). Of the 122 patients enrolled, 108 patients were deemed heatable and
were randomized. Of those patients, 65% had disease in their breast or chest wall. Overall,
the complete response (CR) rate was 66.1% for patients treated with both heat and
radiotherapy, versus 42.3% in the arm which received radiotherapy only. A higher frequency
of thermal burns was recorded related to hyperthermia. Van der Zee et al. (2010) performed
a large study on re-irradiation combined with hyperthermia in superficial (depth limited to
40 mm from the skin surface) breast cancer recurrences using a custom built multi-
applicator multi-amplifier system. They concluded that it is feasible to achieve CR rates of
65% to 90% (depending on size of tumor) in breast cancer recurrences when re-irradiation is
combined with hyperthermia. In another study conducted by Oldenborg et al. (2010) on 78
patients with loco-regional recurrent breast cancer in previously radiated areas, it was
observed that re-irradiation plus hyperthermia following minimization of tumor burden lead
to a high rate of local control compared to historical series, albeit with significant toxicity.
Simultaneous superficial thermoradiotherapy of breast cancer has proven to be feasible and
safe (Moros et al., 2010).
The addition of hyperthermia to radiotherapy and chemotherapy in cases of chest wall

recurrence has been reported previously in only a few studies. The addition of hyperthermia
to preoperative radiochemotherapy has been shown to increase CR rates more so than
chemotherapy alone (Zagar et al., 2010). However, they conclude that randomized trials
need to be performed that look at hyperthermia and chemotherapy versus hyperthermia
and chemoradiotherapy or chemoradiotherapy alone, in the neoadjuvant setting to see if
hyperthermia adds an advantage. A number of drugs such as liposomal doxorubicin and
Page 20 of 48
paclitaxel have been applied in combination with hyperthermia in a phase I/II study
demonstrating their feasibility and tolerance (Vujaskovic et al., 2010).
3.2.3 Esophageal cancer
The prognosis of esophageal cancer remains dismal, with a 2-year overall survival after
surgery alone of 33-44% (Hulshof et al., 2009). A phase I study investigated the feasibility of
external deep loco-regional hyperthermia in localized primarily operable carcinoma of the
thoracic esophagus and gastro-esophageal junction in 31 patients (Albregts et al., 2004).
Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP
and etoposide) was evaluated. Since it was concluded from this phase I study that
hyperthermia was feasible in esophageal cancer, a phase II study was started combining
loco-regional hyperthermia with a chemotherapy (paclitaxel and carboplatin) plus moderate-
dose radiotherapy in a neo-adjuvant setting (Hulshof et al., 2009). All patients who
completed the planned neo-adjuvant treatment had a R0 esophageal resection. The survival
rates at one, two and three years were 79%, 57% and 54% respectively. The authors
conclude that preoperative chemoradiation combined with regional hyperthermia resulted
in excellent loco-regional tumor control and good overall survival. However, they also admit
that it cannot be concluded from this study whether hyperthermia or the new
chemoradiation schedule accounts for the outcome.
Treatment options for patients with primary malignant melanoma of the esophagus (PMME)
are very limited. For medically or technically inoperable patients, there are no curative
options. The first results on patients with PMME have been described in a case report
(Hulshof et al., 2010). Two patients with a large obstructive primary malignant melanoma of
the esophagus were treated with a combination of external radiotherapy and hyperthermia.
Both patients developed a complete local tumor regression, both clinically and
endoscopically, without signs of local progression or late toxicity until the end of follow up.
3.2.4 Gynecological cancers
Franckena and van der Zee (2010) have reviewed the available literature on the use of
various modalities of hyperthermia combined with radiation for various types of
gynecological cancers. Hyperthermia for gynecologic cancers can be applied systematically
(whole-body hyperthermia), invasively (intraperitoneal, interstitial or intracavitary) or
locoregionally. Radiation and hyperthermia has been researched for two main indications in
gynecologic oncology: cervix and vaginal cancer. The most widely used form of hyperthermia
for gynecological malignancies is loco-regional hyperthermia.
3.2.4.1 Cervical cancer
In a Cochrane review, Lutgens et al. (2010) assessed whether adding hyperthermia to

standard radiotherapy for locally advanced cervix carcinoma (LACC) has an impact on (1)
local tumor control; (2) survival; and (3) treatment related morbidity. The randomized
controlled trials (RCTs) compared radiotherapy alone versus combined hyperthermia and
radiotherapy in patients with LACC. Between 1987 and 2009 the results of six RCTs were
Page 21 of 48
published, and used for the review (Chen et al., 1997; Datta et al., 1987; Harima et al., 2001;
Sharma et al., 1991; van der Zee, et al., 2000; Vasanthan et al., 2005). Various modalities
were used to deliver the energy for hyperthermia treatment. A major drawback of the
Cochrane review is that the sequencing of radiotherapy and hyperthermia and the interval
between radiotherapy and hyperthermia differed between and within the selected studies
analyzed. The results of the analysis with respect to the endpoints studied, i.e. complete
response rate following treatment, local recurrence, overall survival and treatment related
toxicity grade 3 to 4, indicated a significant improvement of local (pelvic) tumor control and
overall survival for the combined treatment modality whereas acute and late toxicity was
not significantly different between both treatment groups. Complete tumor response at the
end of treatment in the pooled data analysis including 267 study patients yields a
significantly better treatment outcome following the combined treatment modality. Local
recurrence as endpoint in the pooled data analysis including 264 study patients yields a
significantly reduced local recurrence rate. Overall survival as endpoint in the pooled data
analysis including 264 study patients yields a significantly better survival for the combined
treatment group. The authors conclude that the limited number of patients available for
analysis, methodological flaws and a significant over-representation of patients with FIGO
stage IIIB prohibited drawing definite conclusions regarding the impact of adding
hyperthermia to standard radiotherapy. However, they also report that the available data do
suggest that the addition of hyperthermia improves local tumor control and overall survival
in patients with locally advanced cervix carcinoma without affecting treatment related grade
3 to 4 acute or late toxicity.
Technologies and methodologies evolve and thus studies based on more recent data may
provide a better overview for assessing efficacy of hyperthermia for advanced cervical
cancer. The beneficial effects of loco-regional hyperthermia along with radiation for patients
with inoperable cervix cancer are confirmed by a recent update of the largest randomized
trial (Franckena et al., 2008) and a large follow-up study (Franckena et al., 2009) in an
unselected group of patients. Franckena et al. (2008) evaluated the long-term results of the
Dutch Deep Hyperthermia Trial after 12 years of follow-up. The Dutch Deep Hyperthermia
Trial showed that combining radiotherapy with hyperthermia improved three-year local
control rates of 41–61%, as reported in an earlier study. From 1990–1996, a total of 114
women with loco-regionally advanced cervical carcinoma were randomly assigned to
radiotherapy or radiotherapy and hyperthermia. The primary end point was local control.
Secondary end points were overall survival and late toxicity. At the 12-year follow-up, local
control remained better in the radiotherapy and hyperthermia group (37% versus 56%).
Survival was persistently better after 12 years: 20% (radiotherapy) and 37% (radiotherapy +
hyperthermia). The difference in the cumulative incidence of grades 3–5 radiation-induced
toxicities in both groups of patients was not statistically significant. The authors reported
that radiotherapy and hyperthermia should be considered for patients with locally advanced
cervical cancer and even more so if they are not suited to receive chemotherapy. This was
also the conclusion of a recent review (Franckena and van der Zee, 2010). Interestingly, a
significant correlation between hyperthermia dose and clinical response was found in a large
group of patients with cervix cancer treated with local/regional hyperthermia along with
radiation (Franckena et al., 2009).
Page 22 of 48
A combination that is still under clinical evaluation is hyperthermia concurrently applied with
radiation and chemotherapy. In a multi-center phase I/II prospective feasibility study,
Westermann et al. (2005) studied the efficacy of the combination of hyperthermia,
radiotherapy and cisplatin modalities in previously untreated patients with cervical
carcinoma. The endpoint was the number of patients who were able to complete treatment,
defined as full-dose radiotherapy, at least four cisplatin courses, and at least four
hyperthermia courses. At least four courses of chemotherapy were received by 97% of
patients, and at least four courses of hyperthermia treatment were received by 93% of
patients. Toxicity was fully comparable to that described for chemoradiotherapy alone. The
disease-free survival rate at 2 years (from the day of registration in the study) was 71.6%,
and the overall survival rate at 2 years was 78.5%. The authors reported that based on this
study, an international, randomized, phase III trial of chemoradiotherapy with or without
hyperthermia has been launched.
3.2.4.2 Ovarian cancer
Overall outcome for women with epithelial ovarian cancer remain relatively poor, and
superior methods of treatment are needed (Helm, 2009; 2010). Even after optimal
cytoreduction followed by adjuvant chemotherapy, most patients with stage III disease will
experience a recurrence (Ceelen, 2009; Leitao and Chi, 2009). In an attempt to improve the
unfavorable clinical outcome of relapsed ovarian cancer, hyperthermia has been applied in
experimental settings for advanced stages of the disease with concomitant systematic
chemotherapy. A prospective phase I/II study of regional abdominal hyperthermia has been
performed, combined with systemic chemotherapy in ovarian cancer relapse patients in
order to evaluate outcome, efficacy and tolerance (Fotopoulou et al., 2010). The study
indicates that hyperthermia can be safely combined with platinum and non-platinum agents
in heavily pre-treated patients with relapsed ovarian cancer.
A review by Helm (2009) discusses the role that hyperthermic intra-peritoneal

chemotherapy (HIPEC) could play in improving outcomes for women with epithelial ovarian
cancer. As we have seen (see 2.4.2.2), intraperitoneal hyperthermia involves the
introduction of heated fluid to the abdomen and is mainly used perioperatively in
combination with chemotherapy. The rationale for hyperthermic drug administration is
based mainly on thermal enhancement of the cytotoxicity of many cytostatic drugs,
including the alkylating agents and the platinum compounds (Issels, 2008). The addition of
HIPEC to cytoreductive surgery for recurrent epithelial ovarian cancer has been reported in
many non-randomized studies cumulatively, including a large number of cases (Table 7,
Ceelen et al., 2009; Table 3, Helm 2009). The studies are heterogeneous and difficult to
evaluate and compare among themselves and with series reporting cytoreductive surgery
alone for recurrent disease (Helm, 2009). In another study, Helm et al. (2010) proposed that
HIPEC is a viable additional treatment option for patients with invasive epithelial ovarian
cancer and may extend life in selected groups. Ceelen et al. (2009) reported a phase II multi-
modal protocol consisting of extensive cytoreduction followed by HIPEC in patients with
recurrent, heavily pre-treated ovarian cancer. The objective of this phase II study was to
assess the safety and efficacy of extensive cytoreduction and HIPEC in a cohort of patients.
The authors conclude that in selected patients with pre-treated recurrent ovarian cancer,
Page 23 of 48
cytoreduction combined with HIPEC may provide a meaningful overall survival with accepted
morbidity. Optimal results, however, are achieved in patients with a macroscopically
complete resection and biologically favorable disease. All studies warrant further study in
randomized controlled trials (Ceelen et al., 2009; Fotopoulou et al., 2010, Helm et al., 2010).
3.2.4.3 Vaginal cancer
Aktas et al. (2007) evaluated the supplementary value of adding hyperthermia to

radiotherapy in patients with primary vaginal cancer. This is the first report and so far the
only one of the application of combined radiotherapy and hyperthermia in the treatment of
primary vaginal cancer. The authors evaluated 39 patients with vaginal carcinoma who were
treated with radiotherapy. Of the 39 patients, 23 had a FIGO stage II tumor and 8 stage III.
The criterion to apply hyperthermia in addition to radiotherapy was a stage III tumor with a
diameter of more than 4 cm. The 5-year overall survival rate in the whole group of patients
was 63%. For stage II tumors it was 59% and for stage III tumors 56%. The 5-year survival for
FIGO stages I and IV were 83% and 50%, respectively. The unexpected lack of difference
between 5-year overall survival rates for stage II and III tumors found by them may be
related to the addition of hyperthermia to radiotherapy in the majority of patients with
stage III tumors. These results are suggestive for a beneficial effect of hyperthermia for large
size tumors (Aktas et al., 2007; van der Zee et al., 2008).
3.2.5 Head and neck cancer
Until recently, the application of hyperthermia in the head and neck region was limited to
superficial regions, mostly lymph nodes, because of the lack of deep-heating equipment for
this region. The development of the HYPERcollar applicator system (see 3.4.2.1) has bridged
this gap by providing the technology to enable deep heating of the head and neck region,
which contains many critical tissues and vessels with a large cooling capacity (Paulides et al.,
2007). The first clinical experiences were presented in a study by Paulides et al. (2010).
Three patient cases (thyroid, oropharynx and nasal cavity) were analyzed with a focus on the
technology involved. The study demonstrated that the focused heating of tumors in the
head and neck region is feasible. The phase III study by Hua et al. (2011), which studied the
influence of intra-cavitary hyperthermia, provides clinical data supporting the rationale to
continue research into the benefit of hyperthermia in the treatment of tumors in the
nasopharynx. In this study, 180 patients with nasopharyngeal cancer were randomized to
receive radiation either with or without intra-cavitary hyperthermia. Local external
microwave hyperthermia was delivered using a commercially available device. The complete
response rate in the two arms (radiotherapy plus hyperthermia versus conventional
radiotherapy) was 95.6% and 81.1%, respectively. The results from Hua et al. confirm the
benefit from hyperthermia when added to radiation for this deeply located site in the head
and neck region (Paulides and Van Rhoon, 2011). Equally important was the observation that
no increase in early or late toxicity was induced. Another prospective randomized study
performed between 2005-2009 by Huilgol et al. (2010) on the combination of hyperthermia
and radiotherapy in the treatment of locally advanced head and neck cancer has shown a
survival advantage and better response rate when hyperthermia is added to radiotherapy.
Page 24 of 48
3.2.6 Mesothelioma
Most studies in the current literature on mesothelioma have relatively small patient
samples; therefore, the clinical implications of these reports are limited. To our knowledge
the largest collaborative effort to demonstrate clinical outcomes of patients with peritoneal
mesothelioma who were treated by a combined strategy is from Yan et al. (2009). In a multi-
institutional registry study, they evaluated cyto-reductive surgery combined with
hyperthermic intra-peritoneal chemotherapy (HIPEC, see 2.4.2.2) for diffuse malignant
peritoneal mesothelioma (DMPM), which represents one fourth of all mesotheliomas. The
study included 405 patients with DMPM. The primary end point was overall survival and the
secondary end point was evaluation of prognostic variables for overall survival. The median
follow-up period was 33 months (range, 1 to 235 months). 79% of patients had epithelial
tumors, 6% of patients had positive lymph nodes. The mean peritoneal cancer index was 20.
46% of patients had complete or near-complete cytoreduction and 92% of patients received
HIPEC. 31% of patients had grades 3 to 4 complications. The overall median survival was 53
months (1 to 235 months), and 1-, 3- and 5-year survival rates were 81%, 60% and 47%,
respectively. Four prognostic factors were independently associated with improved survival
in the multivariate analysis: epithelial subtype, absence of lymph node metastasis,
completeness of cytoreduction scores of CC-0 or CC-1, and HIPEC. The data suggest that
cytoreductive surgery combined with HIPEC achieved prolonged survival in selected patients
with DMPM.
3.2.7 Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC) comprises at least 80% of all lung neoplasm and the long-
term prognosis for advanced stages (IIIB/IV) which are present in 75% of new cases is poor
(Vertrees et al., 2005). The addition of hyperthermia to radiotherapy or chemotherapy is
another effort to combat NSCLC. There are rare reports that demonstrate the advantage of
combining hyperthermia with radio- or chemotherapy for the treatment of advanced NSCLC.
Mitsumori et al. (2007) conducted a multi-center prospective randomized trial to evaluate
whether the combination of regional hyperthermia and radiotherapy improved the rate of
local control compared to that obtained by radiotherapy alone. A total of 80 patients with
locally advanced NSCLC were randomized to receive either standard radiation therapy alone
or radiation therapy combined with hyperthermia. The primary endpoint was the local
response rate. The secondary endpoints were local progression-free survival and overall
survival. The median follow-up period was 204 days for all patients and 450 days for
surviving patients. There were no significant differences between the two arms with regard
to local response rate or overall survival rate. However, local progression-free survival was
better in the radiation and hyperthermia arm. Toxicity was generally mild and no grade 3
late toxicity was observed in either arm. The authors reported that this study failed to show
any substantial benefit from the addition of hyperthermia to radiotherapy in the treatment
of locally advanced NSCLC. The quality of this study, however, is compromised by variations
in actual treatment and an excessive amount of missing data.
A phase II randomized trial was designed to evaluate the therapeutic efficacy and feasibility
of hyperthermia in combination with chemotherapy for patients with advanced NSCLC (Shen
Page 25 of 48
et al., 2011). Eighty patients with advanced NSCLC were divided into two groups. One group
of patients was treated by regional hyperthermia in combination with the regimen of
gemcitabine and cisplatin, the other group of patients were treated with chemotherapy
alone. The clinical benefit response showed a significant difference however not the
response rate. The authors concluded from this study that hyperthermia in combination with
chemotherapy is a safe, well tolerated, and effective therapeutic modality for patients with
NSCLC and that addition of hyperthermia improved quality of life.
3.2.8 Prostate cancer
No consensus on optimal therapy for advanced prostate cancer exists and even though
hormonal therapy and radiotherapy are standards, different groups have included
hyperthermia associated with radiotherapy to increase its efficiency (Baronzio et al., 2009).
Baronzio et al. compared 5 studies to verify if hyperthermia ameliorates the best classical
therapy in use, i.e. radiotherapy plus androgen ablation, for advanced prostate cancer. From
this analysis, the authors conclude that no amelioration can be obtained adding
hyperthermia. They further notify that the possible mechanism which can explain this failure
is androgen resistance induced by hyperthermia as demonstrated by Pajonk et al. (2005). In
their opinion patients eligible for hyperthermia treatment in association with radiotherapy
are those who have developed androgen resistance and are hormone refractory.
More recent research however proved otherwise. Long term results have been reported
from a phase II study that assessed the efficacy of trans-rectal ultrasound hyperthermia plus
radiation with or without androgen suppression for the treatment of locally advanced
prostate cancer (Hurwitz et al., 2011). The study was designed to assess improvement in the
2-year disease-free survival rate compared with the short-term androgen suppression arm in
Radiation Therapy Oncology Group (RTOG) study 92-02. Thirty-seven patients were enrolled
in this study. The absolute rate of disease-free survival was the primary study end point. A
significant benefit was noted with the addition of hyperthermia in this patient population
compared prospectively with the study-designed control group of patients who were treated
on the short-term androgen suppression arm of RTOG 92-02, 84% and 64% respectively. The
current results provide further support to the hypothesis that hyperthermia may be
beneficial for the treatment of locally advanced prostate cancer. The authors conclude that
hyperthermia combined with radiation for the treatment of locally advanced prostate cancer
appeared to be promising, however, only a phase III study can provide conclusive evidence
of efficacy. Several recent pilot studies have evaluated whether hyperthermia using
magnetic nanoparticles (magnetic fluid hyperthermia, see 2.4.4) can be used for minimally
invasive treatment of prostate cancer (reviewed in Krishnan et al., 2010). These results will
be discussed in a review on Thermal ablation.
3.2.9 Rectal and colorectal cancer
3.2.9.1 Rectal cancer
In patients with advanced rectal cancer, loco-regional recurrence remains a major problem
and a major cause of mortality as well as a source of metastasis to distant organs.
Preoperative chemoradiation therapy followed by a total meso-rectal excision is considered
Page 26 of 48
the standard treatment of choice based on a German randomized control trial (Sauer et al.,
2004). Better operating techniques, further improvements in local control and survival have
been made possible by the additional use of adjuvant radiotherapy. In line with these
preoperative treatment developments, the use of hyperthermia in combination with
radiotherapy was researched more than a decade ago.
In a Cochrane Review, De Haas-Kock et al. (2009) conducted a systematic review of the

literature to study the additional value of hyperthermia if added to radiotherapy in advanced
rectal cancer, with respect to pathological complete responses, overall survival and toxicity
in rectal cancer therapy. Criteria for considering studies for this review included the outcome
measures studied including: overall survival (OS) at 2, 3, 4 and 5-year; local tumor recurrence
at 2 and 3 years; severe acute tissue toxicity and severe late tissue toxicity. Severe toxicity is
defined as grade 3-4 toxicity and complete tumor response (CR) at 2 months. CR is defined
as disappearance of clinical symptoms or as tumor free margins, i.e. microscopically
complete (R0) resections, in operated patients. Only phase II and III randomized controlled
clinical trials (RCTs) were included in the analysis. Six RCTs published between 1990 and
2007 were identified (Berdov et al., 1990, 1996; Kakehi et al., 1990; You et al., 1993; Trotter
et al., 1996; van der Zee et al., 2000). A total number of 520 patients were treated, 258 with
radiotherapy only (RT group) and 262 with radiotherapy and hyperthermia (RHT group). The
type of interventions included any regimen of pelvic radiotherapy given concurrently or not
with a specific hyperthermia regimen. The studies included hyperthermia treatment that
was administered regionally, intracavitary or interstitially. After two years, overall survival
was significantly better in the RHT group, but this difference disappeared after a longer
period (3, 4 and 5 year OS). The chance to develop a CR was significantly higher in the
combined treated patient group. Due to limited data the authors were not able to draw firm
conclusions about acute or late toxicity. In this review of the available studies the authors
reported that the overall quality of studies published is poor, prohibiting definitive
conclusions regarding the beneficial effect of hyperthermia added to standard radiotherapy.
However, the review shows that adding hyperthermia to radiation in locally advanced and
recurrent rectal cancer, can lead to higher short term local/pelvic control rates and a short
term survival benefit. The Cochrane review’s final statement is that further studies are
needed to compare chemoradiation versus thermoradiation versus chemoradiation plus
hyperthermia in well selected/conducted and quality controlled randomized trials.
Other more recent studies not included in the Cochrane review indicated that neoadjuvant
radiochemotherapy combined with hyperthermia has beneficial effects. Milani et al (2008)
reported results of a multimodal salvage therapy including radiochemotherapy (fluorouracil)
and regional hyperthermia in 24 preirradiated patients with recurrent rectal cancer. The
median time interval between prior radiotherapy and the onset of local recurrence was 34
months. The primary endpoint was local progression-free survival, secondary endpoints
were overall survival, symptom control, and toxicity. The median local progression-free
survival was 15 months with a median follow-up of 27 months. The overall 1-year and 3-year
survival rates were 87% and 30%, respectively. The authors concluded that
radiochemotherapy combined with hyperthermia is an efficient salvage therapy showing
high efficacy with acceptable toxicity and can be recommended as treatment option for this
unfavorable group of pre-irradiated patients with local recurrence of rectal cancer. Maluta et
Page 27 of 48
al. (2010) reported from a phase II study that pre-operative chemoradiotherapy combined
with regional hyperthermia yields acceptable toxicity as well. A more recent study
determined the impact of hyperthermia on preoperative radiochemotherapy for locally
advanced rectal cancer (Kang et al., 2011). 235 patients with locally advanced rectal cancer
were treated with concurrent preoperative radiochemotherapy with or without
hyperthermia. The authors withdraw from taking any conclusions due to the fact that
temperature measurements were not taken in all patients with hyperthermia. They state
that hyperthermia seemed to increase the response of the primary tumor and lymph nodes
to preoperative radiochemotherapy in patients with locally advanced rectal cancer, and
patients with downstaging showed better survival rates.
3.2.9.2 Colorectal cancer
In the last decades, multimodality therapy encompassing surgery and HIPEC has been
proven to provide a significant benefit in selected patients with peritoneal carcinomatosis
(Ceelen et al., 2008). A systematic review of relevant studies was conducted by Yan et al.
(2006) on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal
chemotherapy for patients with peritoneal carcinomatosis from colorectal carcinoma. Two
randomized controlled trials, one comparative study, one multi-institutional registry study,
and 10 most recent case-series studies were evaluated. The level of evidence was low in 13
of the 14 eligible studies. The median survival varied from 13 to 29 months, and 5-year
survival rates ranged from 11% to 19%. Patients who received complete cytoreduction
benefited most, with median survival varying from 28 to 60 months and 5-year survival
ranging from 22% to 49%. The overall morbidity rate varied from 23% to 44%, and the
mortality rate ranged from 0% to 12%. The evidence suggested that cytoreductive surgery
combined with perioperative intraperitoneal chemotherapy is associated with an improved
survival, as compared with systemic chemotherapy for peritoneal carcinomatosis from
colorectal carcinoma.
Verwaal et al. (2008) conducted an 8-year follow-up of a randomized trial comparing
systemic chemotherapy alone with cytoreduction followed by hyperthermic intraperitoneal
chemotherapy and systemic chemotherapy in patients with peritoneal carcinomatosis of
colorectal cancer. Progression-free and disease-specific survival were analyzed and the long-
term results were studied in more detail to evaluate efficacy and toxicity. The median
progression-free survival was 7.7 months in the control arm and 12.6 months in the HIPEC
arm. The median disease-specific survival was 12.6 months in the control arm and 22.2
months in the HIPEC arm. The 5-year survival was 45% for those patients in whom a R1
resection was achieved. The randomized trial shows that cytoreduction followed by HIPEC
does significantly add survival time to patients affected by peritoneal carcinomatosis of
colorectal origin. For a selected group, there is a possibility of long-term survival. Elias et al.
(2009) performed as well a retrospective comparison of a group of patients who underwent
cytoreduction and HIPEC with a matched group who received systemic chemotherapy
containing oxaliplatin or irinotecan. A significant survival advantage was found in favor of
cytoreduction and HIPEC in patients with peritoneal cancer from colorectal cancer (median
overall survival 23.9 months versus 62.7 months).
Page 28 of 48
3.2.10 Skin cancer and skin metastases of various primary tumors
A multicenter randomized trial by the European Society for Hyperthermia Oncology (ESHO)
investigated the value of hyperthermia as an adjuvant to radiotherapy in the treatment of
malignant melanoma (Overgaard et al., 2009). The study describes the results of a previous
ESHO report (ESHO 3-85) (Overgaard et al., 1995) but contains a more detailed analysis of
parameters related to the outcome of the previous study and a description of the quality of
the hyperthermia treatment. Previous experimental and clinical work by Overgaard formed
the basis of the treatment schedule prescribed in ESHO 3-85 (Overgaard, 1981; 1986). A
total of 134 metastatic of recurrent malignant melanoma lesions in 70 patients were
randomized to receive radiotherapy alone or each fraction followed by hyperthermia. The
endpoint was persistent complete response in the treated area. Overall, the study showed
that the combined treatment resulted in significantly better complete response and local
control rates than radiotherapy alone. The complete response rate was 35% and 65% in the
radiotherapy alone and the combined arm, respectively, and local control probability after
two years and longer 28% and 46%. Especially tumors <4cm which received combined
treatment had a much greater response.
The NCCN Guidelines (Version 1.2012) on melanoma has included hyperthermic isolated
limb perfusion or infusion as one of the treatment options for patients with unresectable in-
transit metastases (category 2B).
3.2.11 Soft tissue sarcomas
Soft tissue sarcomas (STS) are a heterogeneous group of tumors can affect almost all
anatomical sites (Stahl et el., 2009). Adult patients with newly diagnosed primary STS of
large size (≥5cm) are at risk for developing local recurrence and distant metastasis despite
surgical tumor resection (Lindner and Issels, 2011). Neoadjuvant chemotherapy combined
with regional hyperthermia is a multimodality treatment scheme which has been under
investigation in prospective clinical trials for several years and shows encouraging results in
patients with locally advanced high-risk STS (Stahl et al., 2009; Schlemmer et al., 2010; Issels
et al., 2010; Lindner and Issels, 2011).
Schlemmer et al. (2010) reported data from a phase II trial examining the efficacy of
multimodality treatment with neoadjuvant chemotherapy, hyperthermia, surgery, radiation
and postoperative thermochemotherapy in adult patients with high-risk sarcomas of the
extremities that were not completely resectable. 47 patients were prospectively treated
with a treatment plan of etoposide, ifosfamide and doxorubicin combined with regional
hyperthermia followed by surgery, radiation and adjuvant chemotherapy. The multimodality
treatment in this trial revealed that response to neoadjuvant thermochemotherapy predicts
long term local-failure-free survival for patients with high-risk extremity sarcomas and led to
limb preservation in 79% of patients.
The European Society for Hyperthermic Oncology (ESHO) and European Organization for
Research and Treatment of Cancer (EORTC) - Soft Tissue and Bone Sarcoma Group (STBSG)
conducted a multicenter, randomized phase III study to assess the efficacy and safety of
adjuvant chemotherapy with regional hyperthermia in patients with localized high-risk STS
(Issels, et al., 2010). Patients were enrolled with primary or recurrent disease. Patients were
Page 29 of 48
randomly assigned to either chemotherapy consisting of etoposide, ifosfamide, and

doxorubicin (EIA) combined with regional hyperthermia (n=169) or to EIA alone (n=172). The
BSD-2000 hyperthermia system (BSD Medical Corporation, Salt Lake City, UT, USA) was used.
All patients received comparable local tumor treatment including surgery and radiotherapy.
The primary outcome was local progression-free survival (LPFS), defined as the time from
randomization to confirmed local progression, relapse, or death, whichever occurred first
and irrespective of any occurrence of distant metastases. Secondary endpoints were
disease-free survival (DFS), overall survival (OS), tumor response after induction therapy,
treatment toxicity, and long-term complications. DFS was defined as the time from
randomization to confirmed local failure, distant metastases, or death due to disease or
treatment, whichever occurred first. At 2 years, the primary endpoint of local progression-
free survival was achieved in 76% of the hyperthermia group versus 61% of the
chemotherapy-alone group. Secondary endpoints were also significantly improved by the
addition of hyperthermia. The disease-free survival was nearly doubled with 32 versus 18
months and the response rate was more than doubled in the combined treatment arm. The
authors report that whether a similar benefit will be seen in lower risk patients, and whether
the safety profile will be the same, and hence the tradeoff between benefit and harm
worthwhile, remains to be established. However, the role of etoposide remains questionable
and might be omitted in future protocols (Lindner and Issels, 2011).
In a phase II study with 39 children (median age 5.2 years) primarily for extracranial non-
testicular germ cell tumors, 12 patients with soft tissue sarcomas and three patients with
chondrosarcomas had been enrolled. The thermochemotherapy applied consisted of
ifosfamide, etoposide, and cisplatin and regional hyperthermia. In combination with
hyperthermia, a response of 73% was reported (Wessalowski et al., 2003).
In another study, reirradiation and hyperthermia for radiation-associated sarcoma (RAS) in

the thoracic region was examined (de Jong et al., 2011). RAS is defined as the appearance of
a sarcoma inside an area previously irradiated with a dose of 25 to 80 Gy, a latency interval
of at least 3 years, and a histology clearly distinct from the initial neoplasm for which the
radiotherapy was applied. RAS is a very rare disease with a poor prognosis. Because RAS
arises by definition in previously irradiated areas, options for full-dose primary or
postoperative reirradiation are limited. 16 patients with RAS were treated with reirradiation
and hyperthermia. The response rate for 12 patients was 75%, six patients remained free of
local failure until last follow-up (8-68 months). The high response rate and the possibility of
durable control suggest that this treatment of reirradiation plus hyperthermia for RAS is
promising.
4. Is it safe?
4.1. Does hyperthermia have any complications or side effects?
Hyperthermia is mostly applied within a department of radiation oncology under the

authority of a radiation oncologist and a medical physicist. Hyperthermia is usually
implemented as part of a multimodal, oncological treatment strategy, i.e., in combination
with radiotherapy or chemotherapy. The majority of hyperthermia treatments are applied
Page 30 of 48
using external devices, employing energy transfer to tissues by EM technologies. Evaluation

of human exposure risk to EM sources or the corresponding heat is a difficult task because it
involves many physical, biological, and chemical variables. Guidelines for human exposure to
EM fields are generally called maximum permissible exposure (MPE) values, or reference
levels. Guidelines recommending limitations in RF exposure have been continually evolving
for over a decade. Many countries have developed guidelines by either adopting or adapting
the recommendations of major organizations such as the International Commission on
Non−Ionizing Radiation Protection (ICNIRP). It should be mentioned that based on the long
history of EM exposure in humans, it is reasonably certain that exposures below MPE values
have no credible reported adverse health effects and are medically safe (Habash et al., 2003;
Feychting et al., 2005).
Most normal tissues are not damaged during whole-body hyperthermia (WBH) if the
temperature remains under 43°C. However, due to regional differences in tissue
characteristics, higher temperatures may occur in various spots. This can result in burns,
blisters, or pain (Falk and Issels, 2001; Kapp et al., 2000; van der Zee et al., 2000). WBH is
often uncomfortable for the patient due to these temperature gradients. The overheated
area must be monitored continuously in the process (i.e. to avoid sweat accumulation; sweat
can heat up excessively and result in blisters on the skin). The subcutaneous fat absorbs four
times the amount of energy as the underlying tissues, which can cause problems of
temperature-limiting hot spots and increased incidence of skin burns. However, the safe
treatment of using hyperthermia could be shown by documented near-eye cases, when the
tumor disappeared by the hyperthermia treatment, while the eye remained unhurt and
intact from the treatment (van der Zee et al., 2010).
WBH can be applied only to patients in good health. When combined with drugs, the first
step must evidently be to demonstrate its safety (van der Zee, 2002). The toxicities
associated with WBH may be significant, therefore, careful patient selection and supportive
care are essential. Some people are particularly susceptible to the adverse effects of heat,
especially the elderly, who are at increased risk of coronary thrombosis in these
circumstances, but also infants and people with certain medical conditions and/or who are
taking certain medications (Goldstein et al., 2003). WBH may also cause cardiac and vascular
disorders, but these effects are uncommon (van der Zee, 2000; Kapp et al., 2000; Wust et al.,
2002). Diarrhea, nausea, and vomiting are commonly observed after WBH (Kapp et al.,
2000). A number of studies have documented the adverse effects of hyperthermia on the
normal adult testis in human (e.g. Mieusset et al., 1995) with a temporary period of partial
or complete infertility (e.g. Jannes et al., 1998).
Further studies are in progress using more extensive thermometry and third-generation
heating equipment with significantly improved planning and real-time control of heating
patterns. These trials should establish the safety and efficacy of hyperthermia in a larger
number of disease sites to expand the clinical utility of hyperthermia in the management of
cancer.
Page 31 of 48
4.2 Hyperthermia and metastasis
Local hyperthermia causes changes in the tumor microvasculature including increased

perfusion and changes in endothelial gap size (Kong et al., 2000; Reinhold, 1988).
Consequently, this may cause tumor cell shedding. The question, however, of whether local
hyperthermia increases the risk for metastasis is difficult to answer in clinical trials unless
the primary therapy has high probability for local control. The question of enhanced
metastases with hyperthermia has rarely been examined carefully in human clinical trials
where local or regional hyperthermia has been used, however, because many patients in
such series already had metastatic disease or had tumors with high likelihood for
development of them anyway. The conclusion that can be drawn regarding this issue is that
there is no evidence that local-regional hyperthermia causes an increase in metastases.
When whole-body hyperthermia is used, the issue is not resolved.
4.3 Risks involved in combining hyperthermia with other therapies
Hyperthermia is generally applied to tumors in combination with radiotherapy or

chemotherapy to improve local control. Toxicity with the addition of hyperthermia and
radiotherapy is said to be manageable (Zagar et al., 2010). In the most recently reported
clinical phase III trial of radiotherapy with or without hyperthermia for superficial tumors,
thermal burns occurred in 45% of patients randomized to hyperthermia plus radiotherapy,
versus 5.7% in the radiotherapy alone group (Jones et al., 2005). Nearly half of the burns in
the combined modality arm were first degree, with only three patients experiencing third-
degree burns (Jones et al., 2005). Another point that needs to be taken into account is that
cells may develop a resistance to subsequent heat following previous heat treatment
(Franckena et al., 2010; Dings et al., 2011). This condition is known as thermotolerance
(Habash et al., 2006). In radiotherapy, a standard treatment regimen consists of a six week
course of radiation doses. If one would like to apply hyperthermia with each of these
radiation treatments, this thermotolerance would certainly negatively interfere with the
effectiveness of the treatment. Haveman et al. (2005) indicated in an overview that there
are no clear experimental data pointing out an increase in adverse effects specific to the
central nervous system after localized or whole-body hyperthermia as a result of combined
treatment with chemotherapy. Whether toxicity from chemotherapy is enhanced when
applying hyperthermia may depend on the sequence of the two modalities, and on which
tissues are heated. It is known from applying perfusion techniques that tissue swelling, blood
clots, bleeding, and other damage to the normal tissues in the perfused area can occur;
however, most of these side effects are temporary. The peritoneal damage by HIPEC (see
2.4.2.2) is not caused by the hyperthermia but by the peritoneal perfusion with saline
solution containing anticancer drugs (Shido et al., 2000).
4.4 Exclusion criteria for using hyperthermia
In some instances hyperthermia cannot be used on patients. Locoregional deep

hyperthermia cannot be used for patients with electronic cardiac pacemakers (van der Zee
et al., 2010) since it is not possible to guarantee that the electronics of the pacemaker will
not be destroyed, resulting in functional disruptions. In addition, patients who have tumors
Page 32 of 48
in the direct vicinity of metal implants such as joint prostheses, braces, etc. are difficult to
treat since the metals can heat up excessively under the influence of hyperthermia. Tumor
position, region and power levels of the locoregional deep hyperthermia must then be
estimated and tailored accordingly.
5. Concluding remarks
Hyperthermia is an emerging therapy method in oncology. It has been indicated in

laboratory and clinical studies as an effective modality of cancer treatments, showing
significant improvements in clinical responses for a subset of patients when used in
combination with other treatment methods such as radio- and/or chemotherapy. In
summary, clinical studies have shown the following therapeutic gains from hyperthermia for
certain tumor types: improvement in survival rates; increased remission rates; reduced
morbidity; reduction in tumor size; improved palliation and quality of life. Exposing tumors
to hyperthermic conditions has been shown to be a powerful adjuvant to radiotherapy as
demonstrated by recent clinical trials for chest wall recurrences of breast cancer (Jones et
al., 2010; van der Zee et al., 2010); locally advanced cervical cancer (Franckena et al., 2009;
Franckena and van der Zee, 2010); advanced head and neck cancer (Paulides et al., 2010;
Hua et al., 2011), locally advanced prostate cancer (Hurwitz et al., 2011); and malignant
melanoma (Overgaard et al., 2009) when compared with radiotherapy alone. Further, a
combination of chemotherapy and hyperthermia has been found to improve outcome for
non-muscle-invasive bladder cancer (Lammers et al., 2011); recurrent ovarian cancer (Ceelen
et al., 2009; Helm et al., 2010); and soft tissue sarcomas (Issels et al., 2010).
Although the efficacy of hyperthermia has been established for some years when used as an
adjunct to radiation and/or chemotherapy, it has yet to enter routine clinical practice. In
addition, hyperthermia still faces many challenges in oncology. We do not understand
clearly the underlying mechanisms, the possible risks and safety issues, and the limits of its
applications. Some trials continue to research hyperthermia in combination with other
therapies such as immunotherapy for the treatment of different cancers. Other studies focus
on improving hyperthermia techniques. For hyperthermia to become an established
treatment modality, much work is needed to better understand and exploit the biology of
heat in combination with radiotherapy, chemotherapy or novel therapies; improve the
equipment used for performing, monitoring and planning hyperthermic treatments; and
further define appropriate thermal dose goals and clinical applications.
This review concludes that hyperthermia combined with radiotherapy and/or chemotherapy
may provide useful local supportive or palliative effects. The clinical exploitation of
hyperthermia was and is still hampered by various challenges including the high degree of
interdependency between physiology and biology, technical and clinical limitations, and
standardization. Quality hyperthermia requires the coordinated efforts of physicists,
technicians, nurses, and physicians. However, these resources are not available at all
facilities. Patients who might benefit from this technology should be referred to facilities
that have modern equipment and expertise in this area.
Page 33 of 48
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Page 46 of 48
6.2 Books
Hyperthermia in Cancer Treatment: A Primer. Baronzio GF, Hager ED (Eds.), 2010

The Official Patient's Sourcebook on Hyperthermia: A Revised and Updated Directory for the
Internet Age, ICON Health Publications, 2006
Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and
Supporting Measures (Cancer Growth and Progression), Boris R. Minev (Editor), 2011
6.3 Professional Societies/Organizations
Deutsche Gesellschaft für Onkologie (www.dgo-info.de)

European Society for Hyperthermic Oncology (ESHO) (www.esho.info)
Hyperthermie in Nederland (www.hyperthermie.nl)
Interdisziplinäre Arbeitsgruppe (www.hyperthermie.org)
International Clinical Hyperthermia Society (www.hyperthermia-ichs.org)
National Comprehensive Cancer Network (NCCN) (www.nccn.org)
Society for Thermal Medicine (www.thermaltherapy.org)
7. Table
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Table 1. Examples of recent studies (reviews, clinical trials) for hyperthermia combined treatment
Therapy Tumor type Patients (n) Drug type Study Results Author (year)
non-muscle-invasive bladder systematic

C-HT 987 MMC 59% less recurrence vs. CT alone Lammers et al., 2011
cancer review
CR 65% to 90% depending on

RT + HT breast cancer recurrences 1144 - review van der Zee et al., 2010
tumor size vs. 32% RT alone
superficial breast cancer and

RT + HT 761 - review CR 66.1% vs. 42.3% RT alone Zagar et al., 2010
chest wall recurrence
local control 56% vs. 37% RT

RT + HT advanced cervix cancer 114 - phase III Franckena et al., 2008
alone, OS 37% vs. 20%
CR (T2 patients) 97.1% vs. 79.5%

RT + HT nasopharyngeal cancer 180 - research Hua et al., 2011
RT alone
CRS + diffuse malignant peritoneal cisplatin, doxorubicin, mitomycin,

405 review OS (medium) 53 months Yan et al., 2009
HIPEC mesothelioma paclitaxel, other
RT + HT prostate cancer 37 - phase II DFS 84% vs. 64% RT alone Hurwitz et al., 2011
RCT + HT rectal cancer recurrence 24 5-fluorouracil phase II OS 1y 87%, 3y 30% Milani et al., 2008
RT + HT malignant melanoma 70 - phase III 65% vs. 35% RT alone Overgaard et al., 2009
CT + HT soft tissue sarcoma 341 etoposide, ifosfamide, doxorubicin phase III LPFS 76% vs. 61% CT alone Issels et al., 2010
C-HT: chemohyperthermia; CRS: cytoreductive surgery; CT: chemotherapy; DFS: disease-free survival; HIPEC: hyperthermic intraperitoneal chemotherapy; LPFS: local progression-
free survival; MMC: mitomycin C; RCT: radiochemotherapy; RT: radiotherapy
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Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2011;1(2):1-48.

Hyperthermia in Cancer Treatment

2. What is it? ............................................................................................................................ 4

3. Does it work? ....................................................................................................................... 16

5. Concluding remarks .............................................................................................................31

Keywords: chemohyperthermia, continuous hyperthermic peritoneal perfusion,

2.2 Principles of hyperthermia

Hyperthermia causes numerous subtle changes in tissue physiology. An increase in

2.3 Mechanisms of heating

2.3.1 Thermal conduction

2.3.2 Electromagnetic power deposition

2.3.2.1 Radiative hyperthermia

2.3.2.2 Magnetic induction hyperthermia

2.3.3 Ultrasound power deposition

2.4. Modes of application

2.4.1 Local hyperthermia

2.4.1.1 External local hyperthermia

2.4.1.2 Intraluminal or endocavitary local hyperthermia

2.4.1.3 Interstitial local hyperthermia

2.4.2 Regional hyperthermia

2.4.2.1 Deep regional hyperthermia

2.4.2.2 Regional perfusion hyperthermia

Regional perfusion hyperthermia is usually applied by perfusion of a limb, organ, or body

chemotherapy (Ceelen et al., 2000). Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is

2.4.3 Whole-body hyperthermia

2.4.4 Nanoparticle-mediated hyperthermia

The major problem of applied hyperthermia treatments is achieving a homogenous heat

2.5 Thermal dose, monitoring and treatment planning

2.5.1 Thermal dose definition

2.5.2 Temperature monitoring

Today, a major limitation of hyperthermia is the lack of detailed information available to

2.5.3 Hyperthermia treatment planning

2.6 Mechanisms of synergies - Hyperthermia in combination with other therapies

2.6.1 Hyperthermia alone

The effectiveness of hyperthermia treatment is related to the temperature achieved during

2.6.2 Hyperthermia and radiotherapy

2.6.3 Hyperthermia and chemotherapy

The microscopic action of chemotherapy, however, is different for local/regional and

2.6.4 Hyperthermia and radiochemotherapy

There is a growing literature on trimodality studies combining hyperthermia with

2.6.5 Integration of hyperthermia with therapies under development

2.6.5.1 Immunotherapy and hyperthermia

Hyperthermia might be effective in the enhancement of anti-tumor immune responses

hyperthermia and intra-tumoral DC injections exhibited significant growth inhibition

2.6.5.2 Gene therapy and hyperthermia

The combination of hyperthermia with gene therapy, in which hyperthermia induces

An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and

3.2. Evidence-based results for using hyperthermia per anatomical location

3.2.1 Bladder cancer

Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive

A systemic review has been performed to evaluate the efficacy of chemohyperthermia as a

Colombo et al. (2011) presents long-term efficacy data of intravesical thermochemotherapy

3.2.2 Breast Cancer and chest wall recurrences

The addition of hyperthermia to radiotherapy and chemotherapy in cases of chest wall

3.2.3 Esophageal cancer

3.2.4 Gynecological cancers

3.2.4.1 Cervical cancer

In a Cochrane review, Lutgens et al. (2010) assessed whether adding hyperthermia to

3.2.4.2 Ovarian cancer

A review by Helm (2009) discusses the role that hyperthermic intra-peritoneal

3.2.4.3 Vaginal cancer

Aktas et al. (2007) evaluated the supplementary value of adding hyperthermia to

3.2.5 Head and neck cancer