Abstract:
AC electric fields at particular frequencies and field strengths have been shown to be effective for destroying rapidly proliferating cells such as cancer cells. The effectiveness of such fields is improved when the field is sequentially switched between two or more different directions. The effectiveness of such fields can be improved even further by choosing the rate at which the field is switched between the various directions.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of application 11/537,026, filed Sep. 29, 2006, which claims the benefit of U.S. provisional application No. 60/723,560, filed Oct. 3, 2005. Each of the above-identified applications is incorporated herein by reference. 
     
    
     BACKGROUND 
       [0002]    U.S. Pat. Nos. 6,868,289 and 7,016,725, each of which is incorporated herein by reference, disclose methods and apparatuses for treating tumors using AC electric fields in the range of 1-10V/cm, at frequencies between 50 kHz and 500 kHz, and that the effectiveness of those fields is increased when more than one field direction is used (e.g., when the field is switched between two or three directions that are oriented about 90° apart from each other). Those alternating electric fields are referred to herein as Tumor Treating Fields, or TTFields. 
       SUMMARY OF THE INVENTION 
       [0003]    The effectiveness of TTFields in stopping the proliferation of and destroying living cells that proliferate rapidly (e.g., cancer cells) can be enhanced by choosing the rate at which the field is switched between the various directions. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0004]      FIG. 1  is a schematic representation of two pairs of insulated electrodes that alternately apply TTFields to target region. 
           [0005]      FIG. 2  shows examples of waveforms that are suitable for switching the fields that are applied between the electrodes on and off. 
           [0006]      FIG. 3  depicts the changes in growth rate of a glioma cell culture treated with alternating electric fields switched between two directions at different switching rates. 
           [0007]      FIG. 4  is a graph of tumor volume vs. time for fields that were switched between two directions at different switching rates. 
           [0008]      FIG. 5  is a block diagram of a system for generating the TTFields in different directions. 
           [0009]      FIG. 6  illustrates a preferred waveform for driving the electrodes. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0010]    Since electric fields sum as vectors, two or more fields with different directions cannot be applied simultaneously at a given location. Instead, the different field directions must be applied sequentially, by applying a first field in one direction for a certain period of time t 1 , and then applying a second field in another direction for a period t 2 . During t 2  the first field is not active and during t 1  the second field is inactive. When this cycle is repeated over and over, the result is that sequential field pulses of changing directions are applied in a cyclic manner. 
         [0011]    The inventor has determined that that the effectiveness of TTFields for destroying proliferating cells in tissue culture as well as malignant tumors in experimental animals is dependent on the rate of switching between the various directions of which the fields are applied. In a set of experiments, TTFields were applied to the tissue cultures or experimental animals by means of two pairs  11 ,  12  of insulated electrodes that alternately apply TTFields  15 ,  16  normal to each other, shown schematically in  FIG. 1 . The waveforms applied were 100-200 kHz alternating fields modulated to stay On and Off for half cycle durations ranging from 10 ms to 1000 ms. 
         [0012]      FIG. 2  shows two examples of waveforms that are suitable for modulating the AC signals that were applied between the electrodes: a first pair A of 50% duty cycle waveforms  21 ,  22  time shifted with respect to each other such that one is on when the other is off, and a second pair B of 50% duty cycle waveforms  23 ,  24  that is similar to the first set of waveforms, but switched at twice the frequency. Note that each set of waveforms consists of two 50% duty cycle square waves that are shifted in phase by one half cycle with respect to each other. 
         [0013]      FIG. 3  depicts the results of one set of experiments by plotting the changes in growth rate of a glioma cell culture (F98) treated with 200 kHz alternating electric field waveforms switched between two directions at different switching rates. Experimental data was also obtained for the case where the field was applied continuously in one direction only. (Note that the control baseline of 100% is for the case when no field was applied.) The data shows that some switching frequencies are more effective than others for reducing the proliferation of glioma tumor cells in culture. The highest effectiveness was found when the half cycle duration was 50 ms (with a similar Off duration) waveform. However, the effectiveness differences in the range of 250 ms to 50 ms were small. Within this range, the cell proliferation rate is reduced to about half of what it is when either a continuous field was applied, or when a 1000 ms half cycle duration waveform is used. 
         [0014]      FIG. 4  is a graph of tumor volume vs. time for a set of experiment, and it shows the effect of 200 kHz TTFields on Vx2 carcinoma growth in vivo, when the fields were applied in two different directions at different switching rates. In the experiment, tumors from the carcinoma line Vx2 were inoculated under the kidney capsule in rabbits. As expected, the tumor size increases with time during the 4 week follow up period in the control, non-treated, group of rabbits (curve  31 ). The growth rate was slower when the fields were applied in different directions with a switch in direction every 1000 ms (curve  32 ); and the growth rate was even slower when the field&#39;s direction was switched every 250 ms (curve  33 ) or every 50 ms (curve  34 ). Thus, we see that the effectiveness of the treatment is significantly higher for waveform having half duty cycle durations of between 50 and 250 ms, as compared with 1000 ms half cycles. 
         [0015]    Based on the above, the following approach is recommended for tumor treatment with TTFields: Treatment should be carried out with at least two field directions, such that each pair of electrodes is activated for On periods of a duration that is preferably between 50 and 250 ms, interposed by Off periods of a similar duration. The TTFields basic alternation frequency (which corresponds to the carrier frequency in an amplitude modulation system) should preferably be in the range of 50-500 kHz, and more preferably in the range of 100-200 kHz. The field intensity is preferably at least 1 V/cm, and more preferably between 1 and 10 V/cm. 
         [0016]      FIG. 5  is a block diagram of a system for generating the TTFields in different directions by driving a first electrode pair  11  and a second electrode pair  12  that are positioned about a target. An AC signal generator  41  generates a sinusoid, preferably between 100-200 kHz, and a square wave generator  43  generates a square wave that resembles the wave  21  shown in  FIG. 2 . Preferably the output of the square wave is high between 50 and 250 ms and low for an equal amount of time in every cycle, although duty cycles that deviate from 50% may also be used. An inverter  44  inverts this square wave, thereby providing the second wave  22  shown in  FIG. 2 . The amplifiers  42  amplify the sinusoid when their control input is in one state, and shut off when their control input is in the other state. Since the control input for the two amplifiers are out of phase, the amplifiers will alternately drive either the first electrode pair  11  or the second electrode pair  12  to generate either the first field  15  or the second field  16  in the target region. Of course, persons skilled in the relevant arts will recognize that a wide variety of other circuits may be used to alternately drive either the first or second pair of electrodes. For example, a suitable switching circuit may provided to route the output of a single amplifier to either the first or second pair of electrodes in an alternating manner, with the switching controlled by a single square wave. 
         [0017]    As explained in U.S. Pat. No. 6,868,289, insulated electrodes are preferred for in vivo applications. Preferably, care should be taken to avoid overheating of the tissues by the capacitive currents and dielectric losses in the insulated electrodes. It is also preferable to avoid the generation of spikes during the switching process. This can be done, for example, by carrying out the switching itself while the AC signal is turned off and immediately afterwards turning the signal on. The rate of turning the field on t 3  and off t 4  should preferably be done at a rate that is slow relative to the reciprocal of the field frequency (i.e., the period t 5 ), and fast relative to the half cycle duration tl, t 2 , as seen in  FIG. 6  for waveform  61 . An example of a suitable turn-on rate t 3  and turn-on rate t 4  is to reach 90% of the steady-state values within about 1-5 ms. Circuitry for implementing this slow turn on may be implemented using a variety of approaches that will be apparent to persons skilled in the relevant arts, such as using a slow-rising control signal to drive an accurate AM modulator, or by driving a gain control of the amplifier with a square wave and interposing a low pass filter in series with the gain control input. 
         [0018]    While examples of the invention are described above in the context of F98 glioma and Vx2 carcinoma, the switching rate may be optimized for other cancers or other rapidly proliferating cells by running experiments to determine the best switching rate, and subsequently using that switching rate to treat the problem in future cases.