Pii: s0302-4598(99)00073-2

Eva Nilsson a,), Henrik von Euler b, Jaak Berendson a, Anders Thorne c Ingemar Naslund d, Anne-Sofie Lagerstedt b, Kristina Narfstrom b, Jerker M. Olsson e a Department of Chemical Engineering and Technology, Applied Electrochemistry, Royal Institute of Technology ( b Department of Small Animal Clinical Sciences, Swedish UniÕersity of Agricultural Sciences ( c Department of Surgery, Huddinge UniÕersity Hospital, Karolinska Institutet, SE-141 86 Huddinge, Sweden Radiumhemmet , Karolinska Hospital, SE-171 76 Stockholm, Sweden e Department of Immunology, Microbiology, Pathology and Infection Diseases, DiÕision of Pathology, Huddinge UniÕersity Hospital, Karolinska Institutet, Received 23 September 1999; received in revised form 20 October 1999; accepted 28 October 1999 Abstract
EChT of tumours implies that tumour tissue is treated with a continuous direct current through two or more electrodes placed in or near the tumour. The treatment offers considerable promise of a safe, simple and relatively noninvasiveanti-tumour therapy for treatment of localised malignant as well as benign tumours. Although more than 10 000 patients have been treatedin China during the past 10 years, EChT has not yet been universally accepted. The reason for this is the lack of essential preclinicalstudies and controlled clinical trials. Uncertainties regarding the destruction mechanism of EChT also hinder the development of anoptimised and reliable dose-planning methodology. This article reviews the collected Chinese and occidental experiences of theelectrochemical treatment of tumours, alone and in combination with other therapies. The current knowledge of the destructionmechanism underlying EChT is presented along with different approaches towards a dose planning methodology. In addition, we discussour view of different important parameters that have to be accounted for, if clinical trials are to be initiated outside of China. q 2000Elsevier Science S.A. All rights reserved.
Keywords: Cancer; Direct current; Dose planning; Electrochemical treatment Ž 1. Introduction
of clinical data from China. It is now appropriate to onceagain review the subject.
This article intends to give an overview of the experi- plies that tumour tissue is treated with a continuous direct ences of the last three decades of electrochemical treat- current through two or more electrodes placed inside the ment of tumours and combination therapies. The present tumour or in its close vicinity. Reports on the anti-tumour knowledge of the destruction mechanism underlying EChT effect of low-level direct current date back to the end of is reviewed, along with different approaches towards a the 19th century 1 . However, the interest of its underly- reliable dose planning. Finally, we discuss our view of ing mechanism and possible therapeutic use waned until different important parameters that have to be accounted 1959, when Humphrey and Seal reported encouraging for, if clinical trials are to be initiated also outside of results with sarcoma tumours in mice 2 . Following this, a number of workers applied EChT in both animal tumourmodels and small-scale clinical studies. A short review on 2. Experiences from the electrochemical treatment of
the application of direct current in the treatment of tu- mours was presented in 1991 3 . Since then, many inter-esting studies have been published, including a vast amount 2.1. Pioneering clinical studies by Nordenstrom ) Corresponding author. Tel.: q46-8-790-65-06; fax: q46-8-10-80-87.
is considered to be a pioneer in the treatment of tumours E-mail address: [email protected] ŽE.
with direct electric current and combination therapies in 0302-4598r00r$ - see front matter q 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 3 0 2 - 4 5 9 8 Ž 9 9 . 0 0 0 7 3 - 2 E. Nilsson et al.r Bioelectrochemistry 51 ( primary lung cancers by applying current between twoplatinum wire electrodes. The anode was placed centrally An EChT project, based on the experiences of Norden- in the tumour and the cathode approximately twice the and supported by the Chinese government, was tumour diameter away from the anode. The applied voltage initiated in China in 1987. Experimental and clinical data was about 10 V. The patients were treated under local were rapidly gathered for 2 years, and in 1989, the electro- anaesthesia, and they were seldom uncomfortable during chemical treatment of tumours was approved by a commit- the treatment. A preliminary trial on five patients was tee of experts, organised by the Ministry of Public Health published in 1978 4 , and in his book 5 , written in 1983, in China, to be used throughout the entire country 11,12 .
reported the results from the treatment of 26 Professor Xin Yu-Ling and co-workers at The China–Japan lung tumours in 20 patients. Many of these patients were, Friendship Hospital in Beijing were assigned to organise for various reasons, unsuitable for surgical, radiotherapeu- postgraduate courses, and up to 1998, more than 2000 tic, or chemotherapeutic treatment. The average delivered physicians have been trained in EChT.
The clinical experience of EChT in China was interna- of tumour diameter. Regression was obtained in 12 out of tionally presented at The First Conference of the Interna- 26 tumours and no signs of regrowth were detected after a tional Association for Biologically Closed Electric Circuits 2–5-year follow-up period. There was no reported lethal in Medicine and Biology, held in 1993 in Stockholm, outcome of the therapy, although tumours with a diameter Sweden. A large amount of clinical material, covering larger than 3 cm did not respond well to the treatment.
more than 2000 cases of various tumour types, both benign as well as malignant, and treated during the period be- and local pain during the treatment.
tween 1987 and 1992, was discussed at this conference and thoroughly discussed possible destruction subsequently published 13 . During this period, Xin and mechanisms behind EChT, such as extreme pH changes, his collaborators modified Nordenstrom’s electro-osmotic transport of water and the effect of current ment methodology. Instead of placing an anode in the on transmembranous ionic transport 5,6 . He also pointed tumour and a cathode far away from the tumour, they out that most tumours possess an excess of fixed elec- inserted a number of anodes into the centre of the tumour tronegative charges on their surfaces and therefore only the and the same number of cathodes just outside the tumour anode should be placed inside the tumour so as to prevent the spreading of micrometastases during treatment. How- The number of publications found in international jour- nals, concerning the clinical results from China, are cur- results when he placed the cathode in the tumour.
rently quite limited. However, a recent report 14 suggests et al. 8 and Ekborg et al. 9 , investigated that EChT provides a safe, simple, and effective comple- the effects of a combined, simultaneous therapy of EChT mentary treatment for patients with lung neoplasms, who and the chemotherapeutic agent, adriamycin . The purpose are neither suitable for surgery nor responsive to chemo- was to influence the distribution of the electropositively or radiotherapy. Of the 386 patients treated for lung can- charged adriamycin by means of the electric field. When infused into the tumour via an anodic electrode, the elec- tropositively charged adriamycin could, by electrophoresis, survival rates were approximately 85, 60 and 30% after 1, be dispersed uniformly into the surrounding tissue. Alter- 3 and 5 years, respectively. Furthermore, tumours larger natively, adriamycin could be concentrated within the tu- than 8 cm in diameter had poorer prognoses than those mour region when applied intravenously and when the with a diameter measuring 4–8 cm. In this study, Xin et al.
cathode was placed in the tumour. Using these techniques, had again modified their electrode placement technique the authors hoped to minimise the systemic side effects of and both anodes and cathodes were now placed inside the chemotherapy. Beneficial effects were obtained in a pre- tumours, with anodes in the centre and cathodes in the liminary study of 14 patients with large lung cancers, periphery. This modification did not only protect the nor- which were incurable by conventional methods 8 .
mal tissue from destruction, but was also shown to en- One of the latest articles by Nordenstrom hance the therapeutic effect. It was stated that the tumour colleagues reports positive results from the electrochemical tissue-killing diameter around each electrode was about 3 treatment of a patient with breast cancer 10 . Mammogra- cm, and thus, the distance between electrodes should not phy, repeated at 6 monthly intervals in the 2 years after exceed 3 cm. Typical treatment parameters were 6–8 V, treatment, could not discern any trace of tumour remnants.
40–80 mA and a coulomb dosage of 100 Crcm of tumour The authors also proposed a combination therapy between an extensive electrochemical pretreatment and a restricted A second international symposium in 1998 on the elec- surgical operation. Ideally, the electrochemical treatment trochemical treatment of cancer was held in Beijing, China, would kill undetected tumour foci and hence, post-oper- and it was reported that the treatment had been established in 1260 hospitals throughout China. Furthermore, more E. Nilsson et al.r Bioelectrochemistry 51 ( months efficacy of EChT. Objective remissions in 3802 cases of superficial malignant tumours treated with EChT in China, 1987–1997 12 . Responses were determined by direct measurement. CR s complete response, PR s partial response, NC s no change, PD s progressive disease than 10 000 patients, with various kind of tumours, have These circumstances must be taken into consideration when been treated during the previous 10 years, indicating a comparing the efficacy of EChT to that of conventional tremendous clinical experience of the method 12 . For anti-tumour therapies in occidental countries.
patients with neoplasms, who were neither suitable for According to the data collected from 156 of the hospi- curative surgery nor responsive to chemo- or radiotherapy, tals, 8240 patients, up until 1997, were treated with EChT, EChT was considered as an effective complementary treat- where 7642 of them suffered from malignant tumours and ment. In the cases of lung, liver, and esophageal cancer, the remaining 598 had benign tumours. About half of the the presented results indicated substantially lower mortal- ity rates compared to the available statistics in occidental countries 15 . The 5-year survival rate for lung cancer treated with EChT was 39%, while the western figure is 14%. The corresponding values for cancer in the liver are ment was 47–100% for the superficial neoplasms. Skin 15% and 5%. Moreover, patients with noncurative cancer, oral cancer, and parotid carcinoma demonstrated esophageal cancer, treated with EChT, demonstrated a the highest response rates, while malignant melanoma 5-year survival rate of 13%, which is similar to corre- responded markedly less. The effectiveness for treatment sponding data reflecting the survival rate in all patients of visceral cancer, measured by X-ray, ultrasonography or suffering from this neoplasm in western countries. How- computertomography, was approximately 70%, where la- ever, randomised and controlled clinical trials are yet to be ryngeal carcinoma tended to respond better to EChT than performed in China, and the characterisation and follow-up other visceral tumours. The corresponding values for pa- rate of patients, as well as the classification of the tumours, tients suffering benign tumours was 76–99% ŽTable are only presented sparingly in the available reports 12 .
and data showed that patients with haemangioma andthyroid tumours were cured to a great extent from theirdiseases. The results indicate that the short-term therapeu- tic effectiveness are more favourable for benign tumours and superficial cancers, such as those originating from Objective remissions in 3840 cases of visceral malignant tumours treated with EChT in China, 1987–1997 12 . Responses were determined byX-ray, ultrasonography, or computertomography. CR s complete re- sponse, PR s partial response, NC s no change, PDs progressive dis- months efficacy of EChT. Objective remissions in 598 cases of benign tumours treated with EChT in China, 1987–1997 12 .
Responses were determined by direct measurements, ultrasonography, or computertomography. CR s complete response, PR s partial response, 3840 1056 28 1705 44 709 19 370 10 2761 72 E. Nilsson et al.r Bioelectrochemistry 51 ( Long-term efficiency of EChT determined as the 1–5-years survival rate in 3802 cases of superficial malignant tumours treated in China, 1987–1997 12 skin, oral cavity, thyroid and parotid gland. Electrochemi- suffering from benign tumours are presented in Table 6, cal therapy was, in general, less effective on visceral and as expected, the 5-year survival rate was high, in neoplasms compared to superficial cancers, with the excep- accordance with the short-term results ŽTable .
tion of melanoma and fibrosarcoma. The effectiveness of The electrode placement technique had once again been EChT on both malignant and benign tumours decreased modified by Xin 12 . Anodes and cathodes were placed with increasing tumour size, but this relationship was less alternately, 2 cm apart, throughout the tumour volume.
Typical electrical treatment parameters were 6–8 V and The long-term survival rate of superficial and visceral 50–80 mA. Different coulomb dosages were given depend- malignant tumours, as well as benign tumours, is shown in ing on the type of tumour. For example, solid malignant Tables 4–6. Among patients with superficial neoplasms tumours were given a dosage of 80–100 Crcm of tumour and benign tumours, the survival figures are virtually in diameter, while benign hemangioma, which is rich in agreement with the short-term results. The 5-year survival electrolytes, was treated with 30–40 Crcm of tumour rate of superficial malignant tumours varied from 0% to In addition to the results shown by the figures, a domyosarcoma had dismal prognoses. Moreover, 60–80% number of tumour diagnoses and macro- and microscopic of patients suffering from skin cancer and oral cancer photographic documentation of a great number of cases, survived for more than 5 years. The survival rate after 5 before and after treatment, clearly demonstrated that de- years of visceral malignant tumours varied from 13% to struction or reduction of malignant as well as benign tumours was achievable in patients. It was concluded from esophageal and liver cancer sufferers Žapproximately the conference, that patients with malignant tumours of but the figures were less dismal for lung cancer patients less than 8 to 10 cm diameter who were unsuitable for and markedly better for patients suffering from surgery or were nonresponsive to radiorchemotherapy, and along with those with benign tumours, may benefitfrom EChT. However, it was clearly pointed out thatEChT was a local therapy, and that it should be combined Table 5Long-term efficiency of EChT determined as the 1–5-years survival ratein 3840 cases of visceral malignant tumours treated in China, 1987–1997w Long-term efficiency of EChT determined as the 1–5-years survival rate in 598 cases of benign tumours treated in China, 1987–1997 12 3840 3284 86 2618 68 1574 41 1121 29 837 22 E. Nilsson et al.r Bioelectrochemistry 51 ( with surgery, radio-, chemo- andror immunotherapy. Fur- therapy, both in experimental colon carcinoma tumours in thermore, EChT was contraindicated in late stage cancer rats 21 and in a lung tumour patient 22 . In the former wire electrodes, either copper or platinum, placed about 10 2.3. Occidental studies in animals and patients mm apart in the centre of the tumour. The combinedtreatment resulted in tumour growth inhibition and in 75% Several research groups in Europe, North America and of the cases the tumours disappeared. In the group that Japan have applied EChT in many different in vivo tumour received only radiotherapy, 75% of the tumours remained.
models and in a few clinical case studies, in parallel with The authors hypothesised that the inflammatory reaction work and the clinical activities in China.
around the electrolytic lesion leads to increased blood flow Several different approaches for the application of current and higher oxygenation of the tumour, and thereby made have been employed, including different electrode shapes, materials and configurations as well as different current David et al. 23 treated hamster melanoma tumours Schauble et al. 16 evaluated the effect of three differ- consecutive days. A needle electrode made of either stain- ent current levels Ž3, 0.5 and 0.001 mA, 1 hrday for 4 less steel or platinum–iridium alloy was placed in the days on the growth of melanoma tumours in tumour and served as either the anode or cathode. The hamsters. A stainless steel point electrode was placed in counter electrode, made of aluminum foil, was applied to the tumour, as either anode or cathode, and a planar wire the skin of either the abdomen or left side of the hamster.
mesh electrode was applied to the skin of the chest.
Tumour growth reduction was obtained in all treatment Tumour growth was inhibited and metastases were re- groups, irrespective of electrode material or polarity.
duced. The effects were most pronounced with the anodic treatment by which the two higher currents produced growth of implanted lung carcinoma in mice. Two plat- Habal 17 treated hepatoma tumours in rats with a inum wire electrodes were placed parallel to one another small direct current Ž0.4–0.6 mA, 10–24 into the tumour. Morris et al. 25 made a similar study, implanted power source 18 . A point-shaped platinum but used larger tumours and current Ž20 mA, 15 min, one anode was placed in the centre of the tumour and a plate treatments . These two studies showed that the stainless steel cathode was placed on the surface of the EChT treatment was able to lessen tumour burden. More- power unit, which was in turn attached to normal tissue.
over, the treatment did not increase the presence of metas- The power sources were implanted after different times tasis or the growth rate in the unaffected fraction of the following the tumour implant, and it was found that tu- mour growth retardation only occurred when the treat- Heiberg et al. 26 applied different constant voltages ments were started at an early stage. Moreover, tumour 2.5–12.5 V and coulomb dosages 30–50 Crcm growth was enhanced when the treatment was started at an mour on colon adenocarcinoma in mice, by means of two early stage and was then discontinued.
gold needles placed parallel to each other within the Samuelsson et al. tested EChT as a possible method for tumour. All the treated tumours showed significant volume the destruction of tumours, especially lung metastases. One study 19 compared the results from the electrolytic treat- ment of colon adenocarcinoma tumours in rats with those 30 , in a series of papers, studied the effect of direct obtained by surgery and came to the conclusion that the efficiency of the treatments were approximately equal.
mours in mice. Their studies involved both single Ž30–90 min and repetitive treatments, as well as different elec- applied by two torpedo-shaped platinum electrodes, with trode configurations and materials ŽPt, Pt–Ir, Au, Ag, Ti, an anode placed in the centre of the tumour and a cathode positioned at the tumour surface. In one of the trials, more with one electrode placed in the tumour and a second than 50% of the animals treated with either EChT or placed subcutaneously in healthy tissue. Another electrode surgery were devoid of tumours when killed 7 months configuration, the so-called ‘‘field configuration’’, in- after inoculation. The EChT treatment did not seem to volved two electrodes placed in healthy tissue on opposite sides of the tumour. Tumour growth retardation was ob- A subsequent article by the same research team reported tained in all experiments, irrespective of electrode material a 60–80% tumour mass reduction from treatments Ž80 mA, and configuration. The anti-tumour effect depended pro- 2–4 h of five lung tumours in four patients 20 . In these portionally on the current level, and cathodic treatments treatments, the current was applied by two or three plat- exhibited a better effect than anodic treatments 28,30 .
inum electrodes, all placed in the tumour. Samuelsson et The best effect was achieved in a study on melanoma al. also studied the effect of EChT with subsequent radio- tumours using a multiple-array electrode Žthree Pt–Ir cath- E. Nilsson et al.r Bioelectrochemistry 51 ( odes placed in the tumour and two anodes placed subcuta- EChT in animals and humans, either as a single type of therapy 41 or in combination with chemo- or radiother- regression with a cure rate of 40% after 4 months.
apy 42–46 . In one article 47 , published in The Euro- The same research team has also published papers pean Journal of Surgery, Matsushima et al. reviewed their describing EChT in combination with other anti-tumour alone, and in combination with systemic chemotherapy followed by systemic bleomycin treatment on fibrosar- coma tumours in mice. Current was passed between two platinum–iridium needle electrodes placed outside of the tumour. The combined treatment was found to be more platinum electrodes placed in the tumour. More than 70% effective than either treatment acting alone. Other works of the tumours showed regression, and in two of the cases, concern the effects of EChT in combination with different where only EChT was used, complete regression was immunomodulators, such as tumour necrosis factor ŽTNF- 36 . These combination therapies indicated poten- tial beneficial effects in fibrosarcoma and melanoma tu- carcinomas in mice. The animals were placed on a copper mours in mice. In a recent study, Miklavcic plate electrode, while a gold wire was placed inside the investigated the immune response in mice after electro- tumour and used as either the anode or cathode. The chemical treatment, where the electrodes were placed on results showed that the volume of tumour destruction, opposite sides of a sarcoma tumour. EChT was found to be obtained at a given coulomb dosage, was significantly less efficient in immunodeficient mice than in immuno- greater due to anodic than cathodic treatment. Further- competent mice, and the authors concluded that the effec- more, the study revealed a linear relationship between the tiveness of low-level direct current strongly depends on the volume of regression induced in the tumour, and the ˇ ˇ et al. 38 investigated the effect of Chou et al. 49 treated implanted fibrosarcoma tumours in mice and rats with a constant voltage load ŽF 10 current was applied by two-needle platinum–iridium elec- configurations. Two to five platinum wire electrodes were trodes, placed on opposite sides of the tumour. Tumour inserted into the mice tumours whereas four to seven growth retardation was obtained in both tumour models.
electrodes were used in the rat tumour treatments. All of An almost complete absence of staining with Patent Blue the treated tumours showed regression, although in many dye, in the SA-1 tumours, suggested that tumour growth of the animals the tumours recurred. After multiple treat- delay resulted from prolonged vascular occlusion. How- ments, the best mouse tumour cure rate was 59%, after 3 ever, the LPB tumours decreased only slightly in tumour months, and was 75% for the rats after 6 months.
staining, thus indicating a less effect of vascular damage.
Jarm et al. 39 reported a continuation of the perfusionstudies on SA-1 tumours, using a rubidium extraction 3. Destruction mechanisms
technique. Tumour perfusion was found to decrease bymore than 50% following treatment, and it was not until Many studies have been dedicated to the investigation three days later that partial reperfusion occurred. The of the underlying destruction mechanisms of EChT. Sev- dynamics of these perfusion changes correlated well with eral contributory factors seem to be involved in tissue the reported tumour growth data. The authors concluded, destruction, although their respective roles are not yet fully for this particular tumour model, that vascular occlusion understood. Early in 1959, Humphrey and Seal 2 hypoth- could be the main anti-tumour mechanism.
esised that direct current therapy would change the tu- et al. 40 treated 12 melanoma skin tumours mour’s inherent negative bioelectrical potential Žvoltage in five patients, where a steel needle cathode was inserted into the tumour and three or four self-adhesive plate causes an anti-tumour effect. This hypothesis was later anodes were placed on the skin, 30–40 mm from the edges of the lesion. All of the patients, with one exception, effects due to current flow were once suggested as a possible destruction mechanism, but this has now been with systemic chemo- andror immunotherapy. The treat- ruled out by both experimental measurements 23,26,29 ments resulted in tumour mass reduction in all of the and theoretical calculations 23,27 .
Most people involved in recent research agrees that the primary tissue destruction, obtained in the electrodes’ close A number of papers have been published in Japanese vicinity is caused by the toxic species produced in the language journals that describe the anti-tumour effect of electrochemical reactions during electrolysis. The electro- E. Nilsson et al.r Bioelectrochemistry 51 ( chemical reactions occurring in the electrolysis of aqueous The pH values down to 1 have been detected in tissue saline solutions are well documented, and the current yield adjacent to the anode 29 , while a pH as high as 13 has of the different reactions strongly depends on the choice of been measured near the cathode 53 . At these unphysio- electrode material and operating conditions 50 . If the logical conditions, vital proteins become denatured and anode material is electrochemically soluble Že.g., precipitate 5,53,56 . The extreme pH conditions in the the major part of the anodic current will consist of metal vicinity of the electrodes have also been predicted in dissolution. A small amount of the anodic current is trans- several theoretical studies 57–61 . Furthermore, in a re- ferred by the oxidation and reduction of certain species cent study on mammary tissue in rats, von Euler et al. 54 already dissolved in the tissue. Some dissolvable metals found a correlation between pH and the size of anodic and silver form a nonconducting compound on the anode cathodic lesions produced by platinum–iridium electrodes.
surface, which may cause current fluctuations. In cases Several authors have identified chlorine 5,53,62 and where the anode material is made of a metal that can be hydrogen 5,53 evolving from the anode and cathode site, passivated, such as platinum, metal dissolution is negligi- ble. Passivity is caused by the formation of a thin content of organically bound chlorine in anodic lesions, electron-conducting oxide film that acts as a barrier to the produced around platinum electrodes in the lungs of pigs, anodic metal dissolution reaction. The main reactions, in and found it to be significantly elevated compared with these cases, are decomposition of water and oxidation of healthy tissue. They concluded that chlorine, through its oxidative properties, is the main agent responsible for thetissue destruction obtained in EChT treatments. Their con- clusions were contradicted by the works of Berendson and Simonsson 57 , and Berendson and Olsson 58 , which presented several estimations of the spreading of chlorine There are also several anode materials, including gold and and hydrogen ions in tissue surrounding a platinum elec- stainless steel, which do not belong to any of the cate- trode. The calculations indicated that the acidified zone gories mentioned above. Gold is only passive within a very around the anode is significantly larger than the chlori- narrow potential interval, while the metal dissolution reac- nated zone and thereby determines the extent of tissue tion substantially increases at potentials above and below this potential interval 51 . Stainless steel behaves as a It has been suggested that the extreme pH condition in passive metal when no current is applied, while it dissolves the vicinity of the electrodes causes electrocoagulation and due to local surface attacks when an anodic current is thereby causing the shutdown of blood flow to the tumour 64,65 . This mechanism could possibly explain the anti- The cathode material is protected against electrochemi- tumour effect obtained in EChT studies where the elec- cal dissolution by the applied cathodic current, and the trodes are placed outside the tumour. Miklavcic major electrochemical reaction in all cases is the decompo- and Jarm et al. 39 tested this hypothesis and obtained sition of water into molecular hydrogen and hydroxyl ions: promising results on fibrosarcoma tumours in mice. Tu- mour blood perfusion was measured following treatment with two-needle platinum–iridium electrodes, placed on Species produced at the anode and cathode are mainly opposite sides of the tumour. In one experiment 39 , the transported to the surrounding tissue by diffusion due to relative tissue perfusion of the tumours was found to concentration gradients, and by migration Žcharged due to the potential gradient. At the anode, the reaction The production of toxic electrolytic products may not products, which can be locally destructive, are different fully explain the anti-tumour effects obtained in EChT metal ions, hydrogen ions and various species containing studies. A series of in vitro studies with direct current, on oxygen and chlorine. Hydroxyl ions and molecular hydro- both malignant and normal cells, has showed that the gen are the destructive reaction products at the cathode.
electric field itself influences both survival and prolifera- The electrochemical reaction products may also react with tion of the cells 36,66–70 . Batista et al. 66,67 and Sersa organic and inorganic tissue constituents, to potentially et al. 36 carried out in vitro studies with currents in the form new toxic products. Chlorine, for example, reacts mA range. Their experiments resulted in an inhibition of with water to form hypochlorous acid, chloride, and hydro- cell proliferation. Other authors report both stimulating and gen ions. Other types of secondary reactions may include suppressing effects on cell proliferation, in studies with an increase of intermediate toxic radicals, to which tumour cells are assumed to be more sensitive to than normal cells The mechanism by which the electric field affects cell growth and survival has not yet been elucidated but is The presence of extreme local pH changes in tissue most probably a complex process. The electric field causes surrounding the electrodes, during and after EChT treat- ment has been confirmed in many studies 5,29,53–55 .
towards the cathode, and consequently, the tissue sur- E. Nilsson et al.r Bioelectrochemistry 51 ( rounding the anode dehydrates while oedema is obtained Another approach towards a reliable dose planning around the cathode 5,71 . Charged substances, dissolved methodology is the use of physicochemical simulation or suspended in tissue, migrate in the electric field and models. Such models are based on a set of physico- accumulation of ions and charged tissue constituents are chemical differential equations that describe the transport obtained at certain and different locations in the electric and reaction processes occurring at the electrodes during field. The electric field influences the ion exchange across EChT. By solving these equations, concentration profiles the cell membranes and thereby the conditions for many of substances dissolved in tissue, and the potential profile essential enzyme-regulated reactions 5 . The possibility of within the tissue itself, can be simulated as a function of direct current in inducing an immune response or enhanc- time. Hence, together with knowledge of the underlying ing the toxicity of immune cells has also been discussed destruction mechanism, the model can be used to predict the tumour destruction produced through EChT.
Several physicochemical simulation models of EChT have been proposed in the literature. Cvirn et al. 59 4. Dose planning
calculated the spreading of the alkaline zone around a A dose planning methodology is a prerequisite for spherical cathode while Berendson and Simonsson 57 reproducible and predictable treatment results. When Nor- and Berendson and Olsson 58 studied the spreading of first started his clinical work, few guidelines hydrogen ions and molecular chlorine around spherical and existed to an optimal choice of treatment parameters and planar platinum anodes. In both works, the authors stated an arbitrary dose of 100 Crcm of tumour diameter was that the calculations must be considered as preliminary chosen 5 . Xin adopted this preliminary dose unit and estimations, since the influence of the potential field on based on their clinical experiences, later adapted the electrode kinetics and the spreading of ions were ne- coulomb dose depending on the type of tumour Ž30–100 glected. In two recently published articles 60,61 , Nilsson et al. developed a mathematical model of the processes In order to develop an optimised dose planning method- occurring around a spherical platinum anode. Tissue was ology, several authors have systematically investigated the treated as a sodium chloride solution containing a bicar- dose–response relationship between the applied current, bonate buffer system, and in contrast to the other models, treatment time, coulomb dosage and tissue destruction.
it included both electrode kinetics and transport due to Samuelsson et al. 55 treated normal lung and liver tissue, migration in the electric field. A promising correlation was in rabbits, with different coulomb dosages Ž2.5–40 obtained when comparing their simulated pH profiles with found a linear relationship between the volume of tissue those, and lesion sizes, found experimentally 54,55 .
destruction around the anode, and coulomb dosage. Griffin et al. treated both mouse mammary carcinomas 48 and normal rat livers 64 with different currents Ž1–5 m .
5. Discussion
treatment times. The relationship between the volume ofprimary tissue destruction and coulomb dosage Ž2–27 A common method of characterising different EChT around both anode and cathode was also found to be linear treatments, as has been mentioned above, is the amount of in this case. Moreover, no differences could be detected coulombs that has been transferred between the between the biological effects obtained at lower and higher electrodes. It is our opinion that other parameters, such as currents at a given coulomb dosage. Robertson et al. 72 current density, time, electrode geometry and electrode configuration, also play important roles in the effect of the livers, and came to the same conclusions.
While the above data supports the hypothesis that The current density at the surface of a passivated metal, coulomb dosage is a reliable dose parameter, other workers acting as an anode, determines the yield of the electro- have reported the opposite. Von Euler et al. 54 treated chemical reactions, i.e., oxygen evolution and chlorine normal mammary tissue in rats and obtained significant formation. Tissue adjacent to the anode at low current differences in lesion sizes when using currents of 1 and 5 densities becomes saturated with chlorine, and chlorine mA at constant coulomb dosage 5 C , Yen et al. 68 produced subsequently is lost to the surroundings 73 .
studied the growth retardation and survival of human KB Secondary reactions of chlorine with tissue play important cells after electrochemical treatment and found that the roles as hydrogen ion generators, and the contribution of cytotoxicity of EChT is related not only to coulomb dosage, these reactions to the acidification of tissue, around the but also to the way by which the coulomb dosage was anode, increases with decreasing current density 73 .
delivered. Treatments with low current and longer treat- The current density also determines the electric field ment times resulted in lower cell viability, compared to strength and thereby influences the transport of ionic treatments with higher current and shorter treatment time.
species around the electrodes. The fact that the spreading Xin et al. 14 reported analogous results from clinical of hydrogen ions occurs in an electric field implies that a higher spreading rate occurs compared to the situation E. Nilsson et al.r Bioelectrochemistry 51 ( where a dilute solution of hydrochloric acid is infused into compared to that of a visceral tumour. The reaction prod- tissue, in the absence of an electric field. In the latter case, ucts in a superficial tumour, formed at the electrodes, the transport rate of hydrogen ions is determined by the would be confined by the presence of an outer boundary effective diffusion coefficient of hydrochloric acid, while surface, which would enhance the toxic effect of the in EChT, transport is determined by the migration rate of the hydrogen ion. A similar reasoning is valid for the Several authors have suggested the benefit of combin- transport of hydroxyl ions from the cathode, although this ing EChT with other established treatment methods. Elec- transport is lower than that of hydrogen ions.
trochemical treatment in combination with chemotherapy The applied voltage is carefully noted as a treatment 32 or radiotherapy 44 was shown to be more effective parameter in some of the published studies. It is important than either treatment acting alone. Moreover, immunologi- to observe that the thermodynamic potential difference cally related compounds, such as TNF-a , IFN-a and IL-2, between the anode and the cathode, the so-called Nernst’s used in combination with EChT were found to enhance the potential difference, is about 2 V due to the anodic reac- effect of the electrochemical treatment 33–36 . TNF-a tions, oxygen and chlorine formation, and the hydrogen gave massive necrosis after treatment, whereas the effec- evolution reaction at the cathode. In addition to this poten- tiveness of IL-2 differed significantly depending on the tial difference, one must consider the total electrochemical tumour strain. It was also found that the efficiency of polarisation at the electrodes and the ohmic losses in the EChT was less in immunodeficient mice compared to tissue. Both these losses depend strongly on the geometri- immunocompetent mice, thus indicating that the effective- cal shape and the configuration of the electrodes, which ness of the treatment strongly depends on the host’s im- implies that the voltage between the anodes and cathodes is individual for every treatment set-up.
We propose two other combination therapies in addition The transferred charge during treatment, given in to those suggested in the literature. EChT could be used to coulombs, is a measure of the amount of chemical reaction pretreat inaccessible parts of a tumour, or decrease the products formed at the electrodes. However, the effect of a volume of a large tumour, before the remainder is removed specified coulomb dose is not always consistent. For ex- by surgery. EChT may also serve as a complement to ample, if the applied current is sufficiently low, buffering radiotherapy in the treatment of large tumours. The limita- systems in the tissue may counteract the pH changes at the tions of radiotherapy in effectively achieving tumour con- electrodes, and consequently, no acidification or alkalisa- trol in the centre of a large tumour is mainly due to the tion is obtained. Thus, the number of coulombs corre- fact that a large portion of the cells might be hypoxic sponds to the amount of reaction products formed at the because of an impaired blood supply and high intratu- electrodes during a treatment but does not directly describe moural pressure. A good oxygenation of the tissue will result in the development of more oxygen radicals and The destructive reaction products, formed at the elec- further DNA damage during radiotherapy 74 . In addition, trodes during the electrochemical treatment, give rise to peripheral parts of the tumour might periodically become both immediate cell death and long-term effects to the hypoxic by the shunting of blood 75 . Hence, a possible surrounding tissues. The extreme pH conditions in the combination therapy could involve an initial stage using vicinity of the electrodes causes an instant coagulative EChT, placing the anode in the centre of the tumour, necrosis, while secondary changes such as decreased per- followed by radiotherapy. In this case, EChT would act fusion of tumours cause hypoxia and a diminished nutri- both as an independent therapy and as an efficient oxy- tional level. In addition, it has been demonstrated that the genating pretreatment to radiotherapy. In order to avoid the electric field itself influences both the survival and prolif- chlorinating part of the anodic process, an anode with a eration of the cells. It is of great interest to distinguish if surface coating that promotes oxygen evolution Že.g., irid- there is a difference in these responses between tumour oxide could be used. Moreover, if the tumour is cells and normal cells. To deal with this and other related situated in a very sensitive organ, one may consider plac- topics, further in vitro studies must be done. An in vitro ing the cathode in a main vein instead of in normal tissue environment enables a unique possibility to study the cells’ response to different treatments, and also to isolate single The clinical experience of EChT in China indicates that factors created during EChT, which could be harmful to this method is a safe and simple anti-tumour therapy for the cells. Through initiating histopathological and molecu- treatment of localised malignant as well as benign tu- lar biological studies, one may discern between injuries on mours. Although more than 10 000 patients have been cell membranes and cell nuclei, and possibly decide if treated in China during the past 10 years, EChT has not yet been universally accepted. There is a need for further According to the Chinese clinical experience, EChT essential preclinical studies and reliably controlled clinical exhibited more promising effects on superficial than vis- trials for the method to be applied outside of China. In ceral tumours. A possible explanation to these experiences addition, further systematic investigations of the destruc- is that the buffer capacity of a superficial tumour is lower tion mechanisms behind EChT should be done. Some E. Nilsson et al.r Bioelectrochemistry 51 ( promising dose-planning models have been reported in the 14 Y.L. Xin, F. Xue, B. Ge, F. Zhao, B. Shi, W. Zhang, Electrochemi- literature and these physicochemical simulation models cal treatment of lung cancer, Bioelectromagnetics 18 Ž 15 L.A.G. Ries, C.L. Kosary, B.F. Hankey, B.A. Miller, L. Clegg, B.K.
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19 L. Samuelsson, Electrolysis and surgery in experimental tumours in This research group is grateful for the financial support given to the research program by the Swedish Cancer pulmonary tumors by electrolysis, Radiologe 23 Ž Society. The continued work will be dedicated to the commemoration of our dear colleague, the late professor Electrolysis with different electrode materials and combined with Daniel Simonsson, who was the scientific leader of this irradiation for treatment of experimental rat tumours, Acta Radiol.
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