Publications (15)0 Total impact
ABSTRACT: Direct intraperitoneal (IP) installation of anticancer agents for the treatment of patients with peritoneal carcinomatosis
or sarcomatosis has pharmacological advantages compared to intravenous systemic therapy in terms of local drug concentrations
(Table 1). The ratio of antineoplastic agent in the dialysate compared to the levels in the blood is 18-1,000 times greater,
depending on the drug (Table 2).1 In a pharmacological study comparing intravenous versus intraperitoneal infusion of carboplatin the 24 hr platinum AUC in
the peritoneal cavity was 280 times higher when carboplatin was administered with IP route.2 In addition, pharmacological studies showed, that IP infusion is a pharmacologically more reasonable route for systemic chemotherapy
of carboplatin. The peritoneal space/plasma barrier provides dose-intensive therapy.
12/2005: pages 218-226;
ABSTRACT: Radiofrequency ablation is used for the treatment of a variety of neoplasms including: osteoid osteoma, hepatocellular carcinoma,
renal cell carcinoma, bronchopulmonary carcinoma, parathyroid adenoma;1 hepatic and retroperitoneal metastases from a variety of primary tumors. The size of the coagulation zone is a crucial factor,
as only a complete coagulation of the tumor including a sufficient safety zone inhibits local recurrence. Thus many efforts
have been made to enlarge the coagulation zone using multiprobe arrays, saline perfusion, internal cooling, bipolar technique,
pulsed application or a combination of these mentioned techniques. Tumors up to 5 cm can now be effectively treated, taking
inclusion and exclusion criteria into account. Lately published data suggests that RF ablation is far more than an electro-physical
tool to generate a thermal tumor destruction, it also induces a significant activation of tumor-specific T lymphocytes.
Percutaneous, image-guided, tumor ablation using thermal energy sources such as radiofrequency (RF) have received increasing
attention as promising techniques for the treatment of focal malignant diseases. Often these therapies can still be used when
more invasive surgical techniques are no longer feasible due to concomitant disease or tumor localisation. Several studies
showed an impressive long term survival for patients with primary and secondary malignant tumors of the liver2 comparable with the data published for surgical resection.3 Unfortunately large prospective, randomised studies are missing. Potential benefits of percutaneous tumor ablation include:
decreased cost and morbidity; the possibility of performing the procedure on outpatients and, the possibility of treating
patients who would not be considered candidates for surgery due to age, comorbidity or disease spread. Additionally, recent
studies support the idea that RFA induces a tumorspecific T-cell activation.4
An important limitation of RF tumor ablative techniques was the extent of coagulation that could be produced with a single
RF application, i.e., the tumor size which could be practically treated in a single session.5 As many tumors show an advanced size at the time of their detection either the use of multiple treatment probes, multiple
treatment sessions, or both was required. A major focus of research has therefore been on the development of techniques to
achieve single session, large-volume tissue necrosis in a safe and readily accomplished manner.
CT scan of a liver colorectal carcinoma metastases before treatment.
After preliminary animal studies,6–10 radiofrequency ablation has been used for the treatment of a variety of neoplasms including: osteoid osteoma, hepatocellular
carcinoma, renal cell carcinoma, bronchopulmonary carcinoma, parathyroid adenoma;1 hepatic and retroperitoneal metastases from a variety of primary tumors. The procedures are generally performed using thin
(14–21 gauge), partially insulated electrodes which are placed under imaging guidance (CT, MRI, or ultrasound) into the tumor
to be ablated (see Fig. 1). When attached to an appropriate radiofrequency generator, the RF current flows from the exposed
tip of the RF needle, through the bio tissue of the human body, either to a neutral grounding pad (monopolar application)
or to a second inserted RF needle (bipolar technique).
Using monopolar technique, a large dispersive electrode (grounding pad) is usually placed on the patient’s back, belly or
thigh. A second needle electrode is used, instead of the grounding pad, for bipolar ablation. Current passing through tissue
leads to ion agitation, which is converted into heat by friction. The process of cellular heating induces cellular damage.
The amount of damage is a function of temperature and time. For example, a coagulation necrosis is achieved applying 70°C
for less than 1 second or 50°C for about 200 seconds.
Several approaches have been made to increase the diameter of coagulation necrosis achieved by RF ablation techniques.11 These include: (1) the use of multiprobe, hooked, and bipolar needle arrays; (2) intraparenchymal injection/infusion of saline
prior to and/or during RF application; (3) internally cooled RF electrodes; and (4) algorithms for current application which
maximize energy deposition but avoid tissue boiling, charring or cavitation.
12/2005: pages 190-198;
ABSTRACT: Hyperthermia (HT) is a promising method for cancer treatment when combined with radiotherapy or chemotherapy. The molecular
mechanisms of anti-tumoral efficacy of HT are not well understood. Besides its direct cytotoxic effect on tumor cells, HT
injures the normal microvasculature and, in particular, tumor vessels. This effect on microvasculature represents an important
mechanism of tumor growth inhibition exerted by HT.
Recently, many studies have been made to understand the effects of HT on tumor vessels and, in particular, on new vessel formation
that occurs during tumor progression. The tumor vasculature develops in a process known as angiogenesis that consists of the
formation of new blood vessels from preexisting ones. Angiogenesis is essential for tumor progression and, without blood vessels,
tumors can not grow beyond a critical size or metastatize to another organ.
HT above 42°C inhibits endothelial cell (EC) differentiation on capillary-like structures both in vitro and in vivo. At least
three distinct mechanisms have been described to be involved in angiogenesis inhibition by HT: direct cytotoxicity on proliferating
ECs, down-modulation of vascular endothelial growth factor (VEGF) production by tumor cells and induction of the plasminogen
activator inhibitor-1 (PAI-1) expression. These data indicate that inhibition of angiogenesis exerted by heat shock could
represent an important mechanism of tumor control in clinical HT and could suggest a new rationale for a combined cancer therapy
based on HT associated with anti-angiogenic molecules.
12/2005: pages 92-98;
ABSTRACT: A high level of body temperature (43°C) is needed for effective use of whole body hyperthermia. Such a high level hyperthermia
can only be safely used taking into account a theory of developing post-aggressive hyperproteolysis.1,2 Besides the control of proteolysis, it is also necessary to apply total phentanyl anesthesia, high-frequency lung ventilation
and a high rate of heating.3 Clinical application of this method allows inducing the apoptosis of malignant cells, decreasing the viral load in HIV and
HCV-infected patients and also causing a general sanitary effect. Use of water immersion makes the technology noninvasive
and “physiological”. Application of this whole body hyperthermia technology reduces ventilation time and complications.4–7
12/2005: pages 227-236;
ABSTRACT: Solid tumours tend to have a more acidic and hypoxic microenvironment than normal tissue. This hostile microenvironment results
from a disparity between oxygen supply and demand of the tumor tissue. Overcoming hypoxia tumor induces a new vascular supply.
This new vasculature is however inefficient and chaotic. It perpetuates the factors that have stimulated its induction. This
review focuses on these processes and peculiarly on angiogenesis, tumor vascular morphology, hypoxia, pH, and the metabolic-vascular
events induced or following tumour tissue heating. The various mechanisms that either modulate tumor microenvironments or
blood perfusion during hyperthermia are described, providing also the many clinical modalities that may enhance or sensitize
cancer cells to heat.
12/2005: pages 67-91;
ABSTRACT: Locoregional hyperthermia can be differentiated into external, interstitial and endocavitary hyperthermia. Different heat
delivery systems are available: antennae array, capacitive coupled, and inductive devices. Depending on localization and size
of the tumour different methods and techniques can be applied: superficial, intratumoral (thermoablation), deep hyperthermia,
endocavitary, and part-body hyperthermia. Randomized clinical trials have been performed mostly with electromagnetic applicators
for superficial hyperthermia in combination with radiotherapy, deep hyperthermia with and without radiation, and endocavitary
hyperthermia in combination with chemotherapy and radiotherapy. In randomized clinical trials it could be demonstrated, that
loco-regional deep hyperthermia with antennae array or capacitive coupled hyperthermia devices may increase response rate,
disease free survival and overall survival of patients with cancer in combination with radiotherapy or chemotherapy without
increasing the toxicity of standard therapies.
12/2005: pages 167-182;
ABSTRACT: In this overview we describe surgical procedures and hyperthermic-isolated limb perfusion techniques for the treatment of
in transit metastases from melanoma and sarcoma of the limbs. We also briefly analyze the rationale of limb perfusion. The
procedures are divided, for teaching purposes, in three phases (surgical procedure, perfusion time, reconstructive phase).
Finally we present a brief summary of our results obtained in the treatment of sarcoma and melanoma. We have performed 91
limb perfusions on 86 patients (5 patients have been treated twice). We obtained an objective response on 93.6% of patients
with in-transit metastases from melanoma (45.5% presented a complete response and 48.1% a partial response). About sarcoma
of limbs, we reached an objective response on 80% of patients. Side effects have been mild and not life threatening (e.g.,
edema of the limb, leukopenia and a compartment syndrome)
12/2005: pages 208-217;
ABSTRACT: Carcinoma of the prostate has been included in the top five big killer neoplasms. The management of advanced disease is still
a problem in oncology. Starting from the beginning of the eighties, hyperthermia has been associated to radiotherapy with
the aim to increase the local control.
This issue summarizes the indication, technical modality and results of the combined treatment, both as radical and salvage
12/2005: pages 183-189;
ABSTRACT: Hyperthermia is a medical heat-treatment, widely used in various medical fields and has a well-recognized effect in oncology.
It is an ancient treatment. However, when making hyperthermia we are limited by numerous biological, physical/technical and
physiological problems. The word hyperthermia means increased temperature by heating of tumors. This relatively simple, physical-physiological
method has a phoenix-like history with some bright successes and many deep disappointments. Why is this enigma? What do we
have in hand? Answers lie in the applied techniques.
12/2005: pages 27-59;
ABSTRACT: Tumour cells are selectively inhibited by hyperthermia (41–42.5°C) in the same conditions where normal cells are not damaged.
At higher temperature, also normal cells are injured. In spite of the large number of reports on the cytotoxic effect of hyperthermia
the mechanisms of heat cytotoxicity are yet unclear. It appears plausible that concomitant phenomena, triggered by heat and
related each other, may be involved. The major points on this subject are the following:
DNA, RNA synthesis, DNA repair mechanism and cell respiration are affected;
Tumour cell membranes are damaged as it is demonstrated by alteration of their permeability and the effect of empty liposomes;
DNA polymerase-β, a key enzyme in multi-step repair system, should be involved;
Dilation of mitochondria cristae and dissociation of poliribosomes were observed;
Heat shock proteins should be involved;
Heat appears to increase the flux of oxygen free radicals mediating in part the cytotoxicity.
12/2005: pages 110-118;
ABSTRACT: Inadequate thermal dose received by the tumor can cause failures in hyperthermic treatments. 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 volume. From the total three-dimensional temperature, it is possible to deduce the “thermal dose”, which is
defined as what part of the body had which temperature for how long during a treatment. The actual temperature/heat-dose distribution
in the tissue is one of the most important factors which determines the effectiveness of hyperthermic treatment.
In order to calculate the resulting temperature profile given a spatial power deposition, we need a thermal model and a method
to solve the heat transfer equation. In living tissue the heat transfer equation includes not only the conductive term, but
also the convective and the metabolic ones.
There are no practical methods to evaluate the total temperature distribution in the target volume during treatment. In the
clinical practice thermocouples are inserted inside the treated volume to generate a temperature sampling that represents
the total temperature profile. Methods of magnetic resonance imaging can be used to obtain a complete temperature profile.
12/2005: pages 19-26;
ABSTRACT: The interest in clinical hyperthermia (HT) was maximum in eighties and decreases during nineties of the last century but now,
thank to possibility of heat deeply and to measure the temperature not invasively the interest is growing another time. On
the other hand the biology of HT, clearly established during seventies, is now discussed with particular attention to the
Heat alone can be used as a cytotoxic agent. Results from 14 studies about lesions treated with HT alone reported complete
response (CR) rate of 13% and overall response (OR) rate of 51%; the response time was short.
HT alone can obtain results similar to some drugs employed as monochemotherapy. The result depends strictly from the possibility
to obtain a good quality geometrical heat and to prescribe a sufficient number of heat session. The recommendation of the
International Consensus meeting on HT held in 1989 was that results of heat alone should be used as a reference for such combinations.
We performed from 1983 to 1996 some studies concerning the association of HT and radiations (RT). The most important results
were the 90% and 75% of OR and CR for chest wall recurrences (the majority of them pretreated with radiotherapy); the data
obtained were similar to results of multicentric Italian data obtained in 212 lesions treated in 10 radiotherapy centres.
In the Overgaard, Myerson and van der Zee reviews about numerous studies the therapeutic enhancement ratio for patients treated
with the association versus patients treated with radiotherapy alone is for the great majority of studies between 1.5 and
From 22 randomized studies we found in 15 a statistically significant advantage for patients treated with the association
of HT and RT or radiochemotherapy versus patients treated with RT or chemotherapy alone. We would emphasise that the two American
studies by RTOG (Radiation Therapy Oncology Group) are inconclusive because of sub-optimal technical way of HT.
The use of interstitial HT permits heat delivery to a well-defined volume which is frequently inaccessible to external local
or deep HT. Interstitial HT uses placement into the treatment-planned volume of multiple microwave or radiofrequency antennas.
Intracavitary HT associated with radiation therapy and/or chemotherapy is under study from about 20 years, in particular for
the carcinoma of the oesophagus. Several hundred patients have been treated in phase I-II studies in the far East: all reports
showed good treatment tolerance and a lack of significant late complications but most of the reports are based on small number
of patients and not provide sufficient information.
A strong biological rationale exists for the use of local HT and systemic chemotherapy in patients with superficial tumors.
Superficial metastases are often associated with additional occult distant metastases that warrant systemic treatment. Preliminary
results employing cisplatinum and bleomycin with local HT revealed high response rate even in tumors located in previously
irradiated sites: the better results were obtained in the treatment of breast carcinoma, head and neck and malignant melanoma.
The most important prognostic factors affecting the response to HT are RT or heat dose: some of them may be more important
than others in the clinical application, e.g., the temperature and total heating time, and, when HT is done in association
with RT, radiation dose.
The great challenge for HT in the next future is to provide adequate heating to the full tumor volume, in particular for deep
seated tumors. Radiation Therapy Oncology Group (RTOG) studies demonstrated that 42°C minimum temperature not were obtained
for most tumors; now some devices will ultimately lead to better minimum temperature not only for superficial tumors but also
for deep seated lesions. Another way to ameliorate HT in clinical setting will be the possibility to measure the temperature
not invasively by means of magnetic resonance (MR) or ultrasound (US).
12/2005: pages 119-127;
ABSTRACT: The observation that cancer patients who experienced a feverish period after surgery survived significantly longer than patients
without fever and the fact that spontaneous tumor remission was observed mostly after a fever period was the rationale for
the artificial induction of fever (“fever therapy”). The history and rationale for fever therapy are presented and the immunological
basis for endo- and exotoxin-induced tumor regression are discussed on the basis of nearly 800 citations of research literature.
The effects and clinical research of different biological inductors of hyperthermia like Coley’s Toxin (MBV), Propioni Bacteria,
Corynebacterium parvum, Bacillus Calmette Guerin (BCG), OK-432, Staphylococcus protein A and Streptokinase are described.
Though the biological effects of fever on tumors are well characterized and interesting biological and immune ological results
are obtained, and some clinical observational studies and small randomized trials show very promising results, larger controlled
GCP-conform trials are still lacking. In combination of moderate and extreme whole body hyperthermia with chemotherapy, radiotherapy
or immunotherapy with monoclonal antibodies significant improvement in outcome of the treatment of cancer patients is to be
expected. The toxicities of active “fever therapy” or passive “fever-range whole body hyperthermia” are tolerable.
12/2005: pages 276-337;
ABSTRACT: Although nanoparticles have been already applied on patients in clinical trials, generally nanotechnology in medicine is regarded
rather a vision than a realistic option. Progress in this field arises particularly from the combination of molecular biology
and nano(bio) technology. From the viewpoint of entrepreneurs nanotechnology is only a tool to develop new products, however
nanotechnology itself is not a product. We developed a new cancer treatment platform technology termed MagForce Nanotherapy,
in which nanotechnology has the potential to cause a revolution in tumor therapy.
12/2005: pages 60-63;
ABSTRACT: Recent developments in thermal ablation and perfusion hyperthermia have expanded the treatment options of patients with certain
cancers. Initially thermal ablation was applied to liver tumor; later its application has been extended to focal malignancies
confined in other organs such as: breast, kidney, adrenal glands, pancreas, bone, and lung. Metastases to localized organs,
such as liver, lung, and pleura are a common event. The inoperable tumors (primary or metastatic) are generally treated by
systemic chemotherapy; however toxicity is very high. Some clinicians have developed regional therapies to reduce this toxicity.
Perfusional therapy permits a higher concentration of antineoplastic agents in the tumor target. Furthermore the combination
of hyperthermia with appropriate antineoplastic agents has demonstrated enhancement of the single therapy and reduction of
toxicity. Lung, pleura and liver perfusion in combination with hyperthermia, will briefly be described here. This review is
not exhaustive; its purpose is to illustrate the applications that we hope will become routine in cancer therapy in the near
12/2005: pages 338-360;
Sapienza University of Rome
Policlinico di Monza
Institute for Cancer Research and Treatment