Key words
breast cancer - metastasis - mammary
Schlüsselwörter
Mammakarzinom - Metastasierung - Mamma
Fundamentals and Technical Requirements of Electrochemotherapy
Fundamentals and Technical Requirements of Electrochemotherapy
Electrochemotherapy is a combination of electroporation and low-dose chemotherapy.
The first clinical
(phase I/II) studies were already being carried out at the beginning of the 1990s
[1]. Thus far, this innovative technology has established itself mainly in the dermatological
field. New study results, however, have been able to prove the treatmentʼs high degree
of effectiveness
when used for gynaecological tumours, with electrochemotherapy now being increasingly
employed in the
field of gynaecology as a result.
Electrochemotherapy utilises the phenomenon of electroporation. By applying an external
electric field,
the membrane potential of the cell can be changed. At a sufficiently high intensity,
this results in
changes in the structure of the membrane. This can cause small “pores” in the membrane,
which in turn
make the membrane permeable to molecules which would otherwise be unable to penetrate
it. In this way,
the increased permeability can allow cytostatic agents to cross the cell membrane
and then enter into
the cytosol by diffusion. The increased permeability also allows the cytostatic to
reach the cytosol at
much higher concentrations, leading to increased cytotoxicity [2]. As
electroporation is limited to the tumour-affected area, there is no increase in systemic
toxicity caused
by the chemotherapeutic agent, resulting in the good tolerability of this method.
The permeability of
the cell membrane, however, does not persist for an unlimited period, and is suspended
once again a few
minutes after the electrical impulse ([Fig. 1]) [3].
Fig. 1 Schematic representation of electrochemotherapy: Phase 1: Injection of the cytostatic:
bleomycin (i. v./intratumoural) or cisplatin (intratumoural); Phase 2: high-frequency
electroporation results in a permeable cell membrane and the cytostatic agent reaches
up to 10 000
times higher concentrations in the tumour cell; Phase 3: reversible poration, the
cell membrane
closes and the cytostatic drug accumulates in the tumour cell (courtesy of IGEA, Carpi,
Italy).
Practical Implementation and Technical Requirements
Practical Implementation and Technical Requirements
Electrochemotherapy is performed using an electrical impulse generator, the Cliniporator™
(IGEA, Carpi,
Italy). The device is shown in [Fig. 1] and consists of a console unit, a
power supply unit for supplying the current and an applicator for placement on the
skin. The
Cliniporator™ allows for electroporation by means of the generation of an electrical
low and an
electrical high voltage impulse, which are applied to the tumour cells using specific
electrodes. This
makes possible the transfer of intracellular substances or molecules which would not
normally be able to
pass through the cell membrane. The emitted impulse lasts 100 µs. The number of impulses
varies between
1–20 and their amplitude between 100–1000 volts. The frequency used is between 1–5000 Hz.
During
implementation, both the applied voltage and the corresponding current curve are shown
on the display in
real-time, thus allowing for the effectiveness of each individual electroporation
to be seen on the
monitor.
Prior to the start of the impulse generation, a low-dose cytostatic – usually bleomycin
at a dosage of
15 mg/m2 – is administered intravenously over one minute. Following a recommended time
interval of 8 minutes, the administration of the electrical impulses begins. Special
electrodes are used
to generate an electrical field around the tumour. The cell membrane then opens and
the cytostatic agent
is able to accumulate in the cell at a high concentration. Different needle electrodes
and plate
electrodes are used depending on the size, depth and shape of the tumour ([Fig. 2]) [3]. The procedure is performed under local anaesthesia,
regional anaesthesia or general anaesthesia, depending on the location of the tumour.
In the case of
large surfaces, painful muscle contractions are to be expected: as a result, it is
wise to carry out the
procedure under general anaesthesia. The best results are obtained when the impulse
is applied within 25
minutes following administration of the chemotherapeutic agent [3], [4], [5].
Fig. 2 Cliniporator and electrodes for carrying out electrochemotherapy (courtesy of IGEA,
Carpi, Italy).
Cytotoxic Agents Used
Several cytotoxic agents have been tested in preclinical studies (e. g. doxorubicin,
daunorubicin,
paclitaxel, etoposide, bleomycin and cisplatin, etc.). In principle, following electroporation,
the
anti-tumour effect of cisplatin is increased between 1.1 and 80 times, and is increased
several thousand
times in the case of bleomycin [6]. On the basis of these studies, bleomycin
and cisplatin proved to be the optimal substances in terms of their effects [6]. Cytotoxic agents can be administered both intravenously and intratumourally [3]. With respect to response rates, there was no significant difference found
between intratumoural and intravenous administration of cisplatin and bleomycin ([Fig. 3]).
Fig. 3 Objective response rate of tumours treated with intravenous or intratumoural (i. v.
or
i. t.) bleomycin and intratumoural (i. t.) cisplatin. ORR: “overall response”, NR:
“no response”
(courtesy of IGEA, Carpi, Italy).
Bleomycin
Bleomycin is an anti-cancer antibiotic from the group of glycopeptides with minimal
myelotoxic effect
[7]. In the case of bleomycin, it is important to note that it is
primarily excreted renally, and that it is rendered inactive by the enzyme bleomycin
hydrolase. This
enzyme is present in all cells of the human body, however the concentration of the
enzyme is reduced
in skin cells and in alveolar epithelial cells in the lung.
The administration of bleomycin can cause subacute or chronic interstitial plasmacytic
pneumonia,
which can also lead to interstitial fibrosis in the worst case. Pulmonary toxicity
is reported in
approximately 10 % of patients and approximately 1 % of patients develop a pulmonary
fibrosis from
the bleomycin-induced nonspecific pneumonitis; this can also be fatal in the worst
case [8]. Risk factors that promote pulmonary fibrosis include advanced age,
pre-existing pulmonary disease, smoking, renal insufficiency, previous radiotherapy
of the lung,
increased oxygen concentration in the air inhaled, etc. [9] (bleomycin
drug information sheet).
A connection has been established between bleomycin administration and pulmonary toxicity.
Therefore,
a bleomycin dose of 400 IU/m2 should not be exceeded.
It is also important that ⅔ of the bleomycin dose administered is excreted unchanged
in the patientʼs
urine. In conclusion, patients with impaired renal function have greatly increased
plasma
concentrations when standard doses are administered. Therefore, patients with moderately
reduced
renal function (glomerular filtration rate [GFR] 10–50 ml/minute) should receive only
75 % of the
usual dose at normal dose intervals, while patients with severe renal impairment (GFR
< 10 ml/minute) should receive 50 % of the usual dose at normal dose intervals. No
dosage
adjustment is necessary in patients with a GFR > 50 ml/minute (bleomycin drug information
sheet).
An overdose can cause hypotension, fever, an increase in pulse, difficulty breathing
and general
symptoms of shock. It is important to note that there is no specific antidote and
that bleomycin
cannot be dialysed.
In the case of respiratory problems, the patient should be treated with corticosteroids
and
broad-spectrum antibiotics.
How does bleomycin work at cellular level?
At DNA level, bleomycin leads to DNA strand breaks and inhibits the DNA-dependent
polymerase. This
leads to the fragmentation of the DNA [10].
The effect of bleomycin remains unchanged despite the effect of electroporation: cell
death is
induced by means of DNA breakages, similar to diffusion through non-permeable membranes.
In the case
of non-electroporated cells, the uptake of bleomycin is limited.
In electrochemotherapy, both intratumoural and intravenous bleomycin administration
are possible.
Intratumoural administration is recommended in cases in which a small number of metastases
(< 7)
and small nodules (< 20 mm in diameter) are present [3], [6], [11], [12].
Dosing in intratumoural administration is dependent on tumour volume. In [Table
1], the corresponding doses from the SOP are shown. The number of metastases to be
treated
must of course be determined in advance.
Table 1 Dosing of intratumoural bleomycin and intratumoural cisplatin
according to the tumour volume (Mir et al. 2006).
|
Tumour volume (V = ab2π/6)
|
< 0.5 cm3
|
0.5–1 cm3
|
> 1 cm3
|
|
Bleomycin dosage concentration 1 000 IU/ml
|
1 ml (1 000 IU)/cm3 of tumour
|
0.5 (500 IU)/cm3 of tumour
|
0.25 (250 IU)/cm3 of tumour
|
|
Carboplatin dosage concentration 2 mg/ml
|
1 ml (2 mg)/cm3 of tumour
|
0.5 ml (1 mg)/cm3 of tumour
|
0.25 ml (0.5 mg)/cm3 of tumour
|
Studies have demonstrated that the response of cutaneous metastases in the intratumoural
administration of bleomycin alone is significantly worse (31 %) than the response
in the case of the
administration of a combination of intratumoural bleomycin and electroporation (78 %)
[12] ([Fig. 4]).
Fig. 4 Response rate of cutaneous metastases in intratumoural bleomycin therapy alone vs.
combination therapy consisting of intratumoural bleomycin and simultaneous electroporation
(courtesy of IGEA, Carpi).
If several, larger metastases (> 20 mm in diameter) are present, the intravenous administration
of
bleomycin is recommended. In this case, the dosage of bleomycin should be 15 mg/m2 or
18–27 IU/m2. For intravenous administration it should be dissolved in 5 or 10 ml
(max. 50 ml), so that it can be administered within one minute. The dosage is comparable
to
conventional chemotherapy. However, as it is only administered once, the total dose
is generally
regarded as low. Electrochemotherapy treatment, however, can also be repeated several
times if
necessary. The cumulative bleomycin dose of 400 IU/m2 must not be exceeded, however, due
to the danger of pulmonary fibrosis. It is also important, in the case of conscious
sedation or
general anaesthesia, that the FiO2 chosen by the anaesthesiologist is as low as possible
due to the increased risk of pulmonary fibrosis in the case of hyperoxia.
The intravenous administration of bleomycin has been proven in practice, while intratumoural
administration has not.
Cisplatin
Cisplatin works exactly like bleomycin at DNA level. Unlike bleomycin, however, cisplatin
leads to
the cross-linking of DNA, thus destroying their structure and rendering them inoperative.
The result
is that the cell subsequently initiates apoptosis.
90 % of cisplatin is excreted renally (tubular and glomerular). Prior to the start
of and during
treatment renal function, electrolytes, blood count and hearing should be investigated,
as well as
hepatic and neurological functions. In order to avoid serious kidney damage, attention
should be
paid to adequate hydration. Forced diuresis should never be performed using loop diuretics,
as this
increases the risk of renal tubular injury and increased ototoxicity. Should forced
fluid retention
prove necessary, for example in the case of fluid retention ≥ 1000 ml, mannitol must
be
administered.
Two hours after administration, more than 90 % of cisplatin will have bound to plasma
proteins.
Therefore, cisplatin can only be dialysed in the first 2 hours following administration
(cisplatin
drug information sheet).
Cisplatin may be administered as part of an intravenous chemotherapy treatment in
doses up to
100 mg/m2 BSA, depending on the treatment regimen. These high doses cannot be
achieved in electrochemotherapy, due to the fact that, in contrast to bleomycin, cisplatin
should
only be administered intratumourally, and not intravenously. The expected side effects
of
electrochemotherapy are therefore considered to be minor ([Table 1]).
Cisplatin should also only be administered in the case of a small number (< 7) of
small metastases
(< 20 mm in diameter). The dosing is shown in [Table 1]. The number of
metastases to be treated must also be determined in advance in the case of cisplatin
use.
Indication Studies
General
The method is suitable for patients with cutaneous or subcutaneous metastases who
have already
exhausted the possibilities of surgery and radiation therapy and who are no longer
strong candidates
for surgery or chemotherapy treatment. The method is generally suitable for all solid
tumours. The
application is palliative, with the objectives of relieving tumour-associated symptoms
and improving
quality of life. These are ensured by a short treatment time, the rapid action of
the
electrochemotherapy and simple after-care.
In 2003, the ESOPE project (European Standard Operating Procedures for Electrochemotherapy)
[3] was founded. The aim of this project was to confirm the efficacy of
electrochemotherapy in cutaneous and subcutaneous metastases as part of an international,
multi-centre prospective study, and to develop standardisation of the method. The
endpoints of the
study were response rate according to WHO criteria, and response rate taking into
account the tumour
type, size, location, etc. In addition, the side effects and toxicity of the therapy
were also to be
investigated within the framework of the project. A total of 41 patients with cutaneous
and
subcutaneous metastases with a tumour size < 3 cm were included in the study. The
study showed
that electrochemotherapy was effective in both melanomas and non-melanomas, with a
complete
remission rate of 74 % and a partial remission rate of 11 % according to the WHO criteria.
The local
tumour control rate 5 months after treatment was between 73–88 % [3], [13]. Another study of 52 patients with varying tumour
types published in 2008 showed that 50 % of patients were in complete remission 1 month
after
electrochemotherapy treatment. Partial remission was observed in 46 % of patients
and no response
was observed in 4 %. The response was objectivised according to RECIST criteria. 94 %
of patients
surveyed in this study indicated an improvement in their quality of life after receiving
electrochemotherapy [14]. A further Danish and English study of 52
patients showed a complete remission rate of 68 % and a partial remission rate of
18 % for cutaneous
metastases < 3 cm, corresponding to 8 and 23 % for metastases > 3 cm [15].
In 2012, Mali et al. published a review which aimed to further strengthen the effects
of
electrochemotherapy. A total of 44 previously published studies (1993–2011) of 413
patients and 1894
tumours were analysed. Patients with malignant melanomas, breast cancer and head and
neck tumours
were all included in the study. It was noted that, regardless of tumour type, electrochemotherapy
showed a complete remission rate of 59.4 % and an objective response rate of 84.1 %
[16].
Breast cancer
In the case of breast cancer, recurrences in the thoracic wall area following a mastectomy
have been
reported with an incidence of 5–40 % [17], [18], [19]. It is also known that approximately 10–15 % of all
breast cancer patients develop a locoregional recurrence within 10 years following
a mastectomy and
radiation therapy. In fact, in the case of most patients, this occurred after 2–3
years [20], [21], [22] in
the form of numerous cutaneous and subcutaneous nodules in the area of the thoracic
wall. If these
are left untreated, they often lead to ulceration, bleeding, pain, etc. The quality
of life of
affected patients is thus significantly reduced.
Once the treatment options of surgery and radiation therapy have been exhausted, the
possibilities of
local tumour control are limited. If the cutaneous metastases do not respond well
to chemotherapy,
miltefosine or electrochemotherapy are the only remaining options. Topical chemotherapy
with
miltefosine was not a possibility as this method was withdrawn from the market and
is no longer
available in Germany. Furthermore, studies also showed only a moderate success rate
for this
preparation when used for cutaneous metastases. The overall response rate for miltefosine
is only
33 %. In addition, topical chemotherapy does not possess a low side effect profile,
as a severe
grade 3 or grade 4 toxic skin reaction occurs during the therapy in more than ⅓ of
patients treated
[23]. Because of its low side effects, electrochemotherapy is
therefore an appropriate therapy for patients who have exhausted all other treatment
options.
The studies published to date are very promising: in a phase II study published in
2012, 19 of 35
patients (54.3 %) with an unresectable chest wall recurrence were in complete remission
2 months
after electrochemotherapy, while 13 patients (37.1 %) were in partial remission and
3 patients
(8.6 %) did not respond to treatment. Electrochemotherapy was performed an average
of two times in
this study. Using this method, it was possible to achieve a tumour control rate of
81 % over the
observation period of 3 years [24]. In another phase II study of 12
patients, the data is somewhat more sobering. This study showed complete and partial
remission rates
of 8 %. Stable disease was noted, however, in 75 % of patients, and a progression
was observed in
8 % [25]. The Benevento study of 12 elderly patients (mean age 76, 11
females, 1 male) published in 2012 shows significantly better response rates: using
electrochemotherapy, it was possible to achieve a complete remission rate of metastases
of 75.3 %
and a partial remission rate of 17 % [4].
In 2011, Sersa et al. published a review that examined the response rate of electrochemotherapy
for
breast cancer thoracic wall recurrences. A total of eight studies were analysed. It
was noted that
the response rate was 89 % and the complete remission rate stood at 59 % [26]. These results are encouraging, considering that the treatments were carried out
in
different centres and the tumours treated were of varying sizes and expansions [26].
Summary of the Advantages and Disadvantages of Electrochemotherapy
Summary of the Advantages and Disadvantages of Electrochemotherapy
Advantages
The method is suitable for patients with severe co-morbidity and/or patients of an
advanced age who
have already exhausted all other treatments. Electrochemotherapy can be used to treat
painful,
bleeding and weeping metastases, as well as large lesions up to a depth of 4 cm. Furthermore,
the
implementation of electrochemotherapy can also result in the prevention of large scars
and can also
potentially result in preserved function e.g. of the arm in the case of severe lymphedema.
On the
whole, the quality of life of patients is improved by this procedure. The procedure
is associated
with a short hospital stay of 2–3 days. The side effects are minor and most patient
do not require
analgesics. In most cases, only a temporary reddening of the skin and the injection
sites of the
electrodes were visible in the area of the treated thoracic wall. Muscular fasciculation
in terms of
muscle aches is rare.
Local tumour control is possible with the aid of electrochemotherapy. Furthermore,
in contrast to
radiotherapy, for example, repeatability is possible in the case of this method.
The favourable cost-benefit ratio makes this method attractive.
Disadvantages
The procedure is performed under general anaesthesia and is associated with common
anaesthesia-related risks. The use of intravenous bleomycin can result in the development
of
pulmonary fibrosis, particularly as this treatment is administered to patients who
have previously
received radiation therapy and who are comorbid, older, etc. A pulmonary function
test should
therefore be carried out prior to the procedure. During anaesthesia, the anaesthetist
should select
the lowest possible FiO2 in order to minimise the risk of pulmonary fibrosis. The
electrode used during electrochemotherapy is a disposable instrument which is not
particularly
inexpensive. In the case of extensive electrochemotherapy in particular, the formation
of large
ulcers is possible due to increased tumour decomposition. As the use of electrochemotherapy
is not
curative but palliative, it is very likely that the treatment will have to be repeated,
as the
metastases become progressive over time.
Individual Experiences
[Fig. 5] shows a 75 year-old patient with breast cancer cutaneous metastases
in the area on the right of the thoracic wall which has been extensively pre-treated.
The lesions have
been present since 2009, and have been growing over the course of time. The patient
has already
undergone radiotherapy and further radiation therapy is no longer possible. The lesions
on the thoracic
wall are inoperable and there is no longer a chemotherapeutic option as the patient
has already received
7 courses of chemotherapy. Electrochemotherapy was performed on the patient when the
patient was
experiencing a great deal of suffering caused by pain, itching and bleeding from the
ulcerated
metastases. [Fig. 5 a] shows the patient preoperatively. The results 1 week
and 1 month after electrochemotherapy are shown in [Figs. 5 b] and [c].
Fig. 5 a to c Result after electrochemotherapy (individual experience). Patient with
numerous cutaneous metastases in the thoracic wall area due to known breast cancer.
The patient
complained of itching, pain and bleeding from the metastasis shown above. a shows the patient
prior to chemotherapy. Figure b shows the patient 1 week after electrochemotherapy. It can
clearly be seen that the ulcerating metastases have become necrotic in places, and
are also
significantly smaller. Figure c shows the patient 4 weeks after the procedure. After 4 weeks,
the metastases have regressed further.
Conclusions for Clinical Practice
Conclusions for Clinical Practice
Electrochemotherapy is a promising method for the treatment of cutaneous and subcutaneous
metastases in
the local/locoregional recurrence of breast cancer in the palliative situation.
This innovative treatment improves the quality of life of patients and contributes
to local tumour
control. The side effects are minor, depending on the size of the area being treated.
These are redness
in the treated area of the thoracic wall, which can also lead to persistent skin changes
(hyperpigmentation of the skin) and muscular fasciculation in this area.
