- Hyperthermia + Radiotherapy
- Hyperthermia + Chemotherapy
- Hyperthermia + Radiochemotherapy
- The Future
The science behind Hyperthermia
Hyperthermia is a therapeutic application of heat utilized to raise, in a controlled manner, the temperature of certain organs and tissues in a range between 41�C and 45�C. In oncology it is used to increase the temperature of a region of the body affected by cancer in order to contrast the progression of the tumor.
Hyperthermia therapy has been developed in oncology based on the fact that, with respect to normal tissue cells, tumor cells are more sensitive to temperatures in the range between 40�C and 45�C. The efficacy of heat on tumors can be related to the peculiar combination of hypoxia, nutrient deficiency and acidosis characterizing tumor cells (Hildebrandt et al., 2002; Engin K. et al., 1996; Dewey et al., 1994; Streffer et al., 1987; Giovannella et al 1977; Strom et al., 1977).
However in most cases adequate heating of the whole tumor at moderate temperature is difficult to obtain, thus hyperthermia application as a single oncologic treatment modality may be limited. On the other hand many clinical studies on a variety of tumor types have demonstrated synergistic effects of hyperthermia with traditional oncologic treatments such as chemotherapy and radiotherapy. It has been found that hyperthermia can significantly enhance radiotherapy and chemotherapy effects making it a potent adjuvant treatment in cancer therapy.
In many circumstances Hyperthermia has certainly turned out to be an efficient approach, whose potential should be further exploited. Many biological and clinical studies have shown hyperthermia effects to be:
- Damaging DNA and proteins;
- Causing several protein accretion;
- Inducing oxidative damage on cell and mitocondrial membrane;
- Inducing in some extent tumour-immunogenicity through HSPs stimulation;
- Inhibiting DNA repair following CH and/or RT;
- Enhancing rates of interaction of several anticancer drugs with their target;
- Increasing drug release in situ;
- Giving back, to some extent and under certain conditions, drug sensitivity to drug resistant cells;
- Being rather a safe therapy with rare of little entity, or none at all
Mechanisms of heat citotoxicity
In vitro studies have been really useful in enhancing some aspects of heat cytotoxic effects.
DNA synthesis damage and protein denaturation.
The phases in which the assembly of new replicons and the reorganization of nascent DNA into mature chromatin occur, have turned out to be the most heat-sensitive phases (Warters et al., 1988).
During the S-phase, chromosome damage is observable, as a result of a dysfunction of the replication apparatus (Iliakis et al., 2004).
During the G1 phase, it has been observed that heat cytotoxicity occurs in a rapid mode instead of the more common slow mode.
The rapid mode prevails during the first few days post-heating, and it is characterized by cell detachment and inhibited rates of protein, RNA, and DNA synthesis.
The slow death mode becomes evident after the cells have fully recovered from the heat-induced inhibition of macromolecular synthesis and cell detachment has ceased (Vidair et al., 1988).
In particular, after having been heated, cells recover from their cell cycle delay and progress through the cycle into G2, although at that stage many of them appear to have a fragmented centrosome which would lead to multinucleated cells. This defragmentation of the cell's centrosomes is attributed to the heat-induced disorganization of pericentriolar material. (Vidair et al., 1993). A further observation of interest in phases which follow heating is the cell growth of several proteins (Chu et al., 1993; Vanderwaal et al., 2004).
The membrane structure and mitochondria of tumor cells suffer from the oxidative damage caused by hyperthermia. Tumor cells are much more exposed to this sort of damage as their reductive efficiency is reduced because of their metabolic characteristic(Mondov� et al., 1969.)
Heat shock proteins induction and tumor-specific immunogenicity
When cells are subjected to heat shock, they answer by synthesizing a specific group of proteins (heat shock proteins-HSPs).
HSPs behave as chaperons and they are responsible for the thermoresistance that overcomes after repeated heat exposures.
In addition to this, a very interesting observation has been made on HSPs in cancer therapy: they can induce tumor-specific immunogenicity.
It has been recently observed that these molecules allow the expression of an array of peptides, including antigenic peptides chaperoned by them and able to produce an immune response (Srivastava et al., 2005; Castelli et al., 2001).
Hyperthermia as a support for traditional anticancer therapy
Hyperthermia therapy (HT) has, for a long time, been utilized as a support to traditional Radiotherapy (RT), to Chemotherapy (CT) and to a combination of both (Triple Modality, or TM).Combining HT with CT or RT can increase the extent of short and long term success of anticancer therapy. It has also been observed that HT allows clinicians to reduce doses of anticancer drugs and RT administered to patients (Falk and Issels 2001). The reduction of the doses helps, consequently, the reduction of anticancer therapy side effects.
Randomized clinical trials overview
HT combined with RT and/or CT enhances the Complete Response by a factor of 1.4 to 4.6
Several randomized clinical trials on the use of hyperthermia as a adjuvant therapy to radiotherapy and/or chemotherapy or in triple modality have shown significant results. They are listed in the following table.
|Referencies||Tumour type||Treatment modality||Patients (lesions)||Endpoint||Effect with HT||Effect without HT|
|Valdagni et al., 1993||Lymphnodes of head & neck tumours||RT+/-HT||41 (44)||CR
|Overgaard et al.,1995||Melanoma||RT+/-HT||70 (138)||CR rate
2-yr local control
|Vernon et al., 1996||Breast||RT+/-HT||306||CR||59%||41%|
|EL Jones et al., 2005||Breast||RT+/-HT||108||CR
|Sneed et al., 1998||Glioblastoma multiforme||RT+/-HT postoperative||68||Median survival
|Van der Zee et al.,2000||Bladder, cervix and rectum||RT+/-HT||358||CR
|Van der Zee et al.,2000||Cervix||RT+/-HT||114||CR
|Frankena et al., 2008 (follow up)||Cervix||RT+/HT||114||Local control
|Datta et al.,1997||Cervix||RT+/-HT||64||CR||55%||31%|
|Harima et al., 2001||Cervix||RT+/-HT||40||CR||85%||50%|
|Berdov et al.,1990||Rectum||RT+/-HT preoperative||115||5-yr survival||36%||7%|
|Kakehi et al.,1990||Rectum||RT+/-HT||14||Response||100%||20%|
|You Q-S et al.,1993||Rectum||RT+/-HT preoperative||122||CR||23%||5%|
|Strotsky et al., 1991||Bladder||RT+/-HT preoperative||102||3-yr survival||94%||67%|
|Wang et al., 1996||Oesophagus||RT+/-HT||125||3-yr survival||42%||24%|
|Egawa et al., 1989||Various superficial||RT+/-HT||92||Response||82%||63%|
|Colombo et al.,1996||Bladder||CT+/-HT preoperative||52||CR||66%||22%|
|Colombo et al., 2003||Bladder||CT+/-HT postoperative||83||2-yr relapse free survival||82%||38%|
|Colombo et al., 2010 (Follow up)||Bladder||CT+/-HT postoperative||83||10-yr disease-free survival||53%||15%|
|Issels et al., 2010||Soft tissue� sarcoma||CT+/-HT||341||Response
2-yr local progression
2-yr overall survival
4-yr overall survival
|Kitamura et al.,1995||Oesophagus||RT+CT+/-HT||66||CR||25%||6%|
|Sugimachi et al.,1992||Oesophagus||RT+CT+/-HT preoperative||53||Palliation||70%||8%|