On the Possibility to Use the Charge Imbalance in Patients Undergoing Radiotherapy: A New Online, In Vivo, Noninvasive Dose Monitoring System

Round 1

Reviewer 1 Report

Please, read attached file.

Comments for author File: Comments.pdf

Author Response

1. English concerns
   1. We revised the English of the whole paper
2. Content concerns
   1. The authors agreed with the referees and changed the sentence according
   2. We think this is a misunderstanding: we have not a “water chamber” but a “water tank” i.e. a box of plastic filled with water. This is the same box used to perform the absolute dosimetry where the ionisation chambers are immersed. We decided to the test our detector immerging it in water (that somehow simulates the human body) as any conventional dosimeter. The important difference is that while in the conventional case the detector is exposed directly to the beam, in our case we irradiated only the water and the electrode collected the signal from the charge released in water.
   3. The authors do not understand what the Referee means saying “the number of tests in setting (a). We will then try to comment. As far we understand the referees affirm that the reported tests are not exhaustive. This is somehow correct. The reported are a preliminary set of tests aiming at demonstrating the proof-of-principle of the approach. We performed these tests using the water as a conductive medium. The results demonstrate an optimal linearity with the absorbed dose, a good independence with the dose rate and with the temperature and position of the detector as respect the beam incidence. Of course a more complete characterisation is ongoing. In particular we are changing the material and we are performing measurements also changing the beam energy to verify potential difference with a different stopping power. These tests are ongoing, as well.
      Regarding the statistical significance. We think that the results reported were made with a sufficient statistical robustness (ten or five measurements repeated measurements per each investigated point) The same degree of accuracy cannot be reached for the in-vivo test, as only one irradiation can be used, of course.
      The authors added, in the “Conclusions and perspectives” section some comments on the statistical robustness of the data and on the needed future tests and characterisations needed for a deeper characterisation of of the system.
   4. See point c. We added a comment stating that in-vivo data are not sufficiently robust and that additional tests are needed in order to reach an aprpriate statistical confidence.

Reviewer 2 Report

The authors describe an innovative system for real time in vivo dosimetry of charged particle radiotherapy treatments based on the collection of electric charge entering the patient by an electrode in contact with the patient’s skin. This finding could have important implications as routine delivery check of clinical treatments, especially as it is placed outside of the beam entrance path. I have following comments:

- This measurement system captures a surrogate of the entrance dose delivered to the patient’s skin surface. How did you define this skin dose, e.g. how was the 4 Gy nominal dose measured in the phantom experiments, and how was the 1366 cGy defined in the patient experiment?

- Please explain more in detail the performed normalization of the electrode output signal using the reference beam emission monitor signal. Does this mean that the entire nA signal in Figure 2 is corrected online, and if so by which value? The authors state that the measurement system provides a relative dose measurement, why is the correction using a reference signal then required?

- Was any lag time observed between the reference signal (machine output) and the electrode signal captured? This could be important for potential online decisions based on your measurements in future applications.

- The measured accumulated charge is dependent on the field size, and so a correction factor will have to be applied to estimate the skin dose in clinical applications. In clinical practice however intensity-modulated proton therapy (IMPT) is often used nowadays. How would you envisage to measure such treatments?

 

Minor comments:

Title: meaning ‘imbalance’?

p.3 l.71 “all devices can be positioned on patient’s skin”, but higher it was mentioned that this is ”not suitable” for the silicon and diamond detectors?

p.9 l.181 60 MeV instead of 62 MeV for this experiment?

p.8 “0.39 nC/Gy” was obtained here, but “0.47 nC/Gy” was obtained from the experiment on page 10. What was causing this difference between the experiments?

p.10 l.196 “Each curve corresponds to a nominal dose of 4 Gy”: meaning that 5 bursts of 4 Gy were given during the time sequence depicted in Figure 2? Was the charge integrated throughout this whole time sequence or was it integrated per burst?

p.10 l.210 “analysed”

p.11 l.231 “sketch”

p.12 What were the beam energy and field size of the clinical treatment experiment?

Figure 2 What are the drops in the signal caused by? Could they be the reason for the lower nC/Gy sensitivity obtained when compared to the calculation?

Figure 4 Should state 15 Gy/min as in the text instead of 16 Gy/min?

Author Response

Reviewer 2

1. This measurement system captures a surrogate of the entrance dose delivered to the patient’s skin surface. How did you define this skin dose, e.g. how was the 4 Gy nominal dose measured in the phantom experiments, and how was the 1366 cGy defined in the patient experiment?

When we say we release the dose of 4 Gy, we mean that a dose of 4 Gy is released in the entrance region of the Bragg peak. In this sense the system acts exactly like a Faraday cup for dosimetric purposes. A Faraday Cup, in fact, collect a charge (that is the charge transported by the beam) and this charge is then transformed in absorbed dose at the entrance point.

1. 1. In our case the dose at the entrance is measured using a PTW Markus Chamber and following the IAEA 398 dosimetric protocol. We position the Marcus at the entrance point of the Bragg peak, and we perform there the reference dosimetry.
   2. In the case of patient irradiation, we position the Markus chamber in the middle of the Spread Out Bragg Peak and 1366 Gy is the dose measured there. This is also the total dose released in one treatment session. In the case of patient irradiations, we did not calculate the dose from the Electrode system as this would include a detailed knowledge of the energy spectra. What we demonstrated is that, in different days, for the same dose released to the patient, the system response was quite similar. This demonstrates the possibility of an its use as beam monitoring.

2. Please explain more in detail the performed normalization of the electrode output signal using the reference beam emission monitor signal. Does this mean that the entire nA signal in Figure 2 is corrected online, and if so by which value? The authors state that the measurement system provides a relative dose measurement, why is the correction using a reference signal then required?
   The Referee correctly addressed this point, and, in fact, this is a paper error. We corrected the sentence stating that the SEM represents a “reference” signal directly proportional to the primary proton beam.
   By the way, we will better explain the point raised up:
   1. The signal in Figure 2 is not normalised. It represents the current read by the electrode immersed in water. The y-axis reports, in fact, directly an absolute value in nano Ampere.
   2. The SEM signal, that is, for example, reported in Figure 7, represents a measure of the beam fluence. It is important as it helps us to understand if a change in the electrode current is related to an intrinsic problem of the detector or it is connected to an effective variation of the beam.
3. Was any lag time observed between the reference signal (machine output) and the electrode signal captured? This could be important for potential online decisions based on your measurements in future applications.
   There is a lag-time between the electrode and SEM (reference) signal. This is due to the different gains of the I-V converter. The signals from the Electrode are, in fact, much lower than the reference signal. For them is then necessary a high-gain I-V converter that, inevitably, make the response in a time slower.
4. The measured accumulated charge is dependent on the field size, and so a correction factor will have to be applied to estimate the skin dose in clinical applications. In clinical practice, however intensity-modulated proton therapy (IMPT) is often used nowadays. How would you envisage to measure such treatments?
   In this paper we are only considering the case of a fixed, not changing in time beam. No-modulated intensity is considered. Moreover, the system can only measure the total charge that reach the patient skin while it cannot determine the energy or the spatial distribution of this charge. Dedicated studies for rapidly changing current will be by the way performed in the next future.

 

Minor comments

1. Title: meaning ‘imbalance’?
   “Imbalance” means “not in equilibrium”. When a charge enters in the patient, if the patient is isolated, a disequilibrium in charge occurs, indeed. The patient will become “more positive” and it will start to conduct current if connected to an electrometer.
2. 3 l.71 “all devices can be positioned on patient’s skin”, but higher it was mentioned that this is ”not suitable” for the silicon and diamond detectors?
   We agree with the Reviewer: this sentence is misleading and we will remove it.
3. 9 l.181 60 MeV instead of 62 MeV for this experiment?
   62 MeV is the proton beam energy as extracted from the cyclotron: it is the nominal energy of the beam. 60 MeV in the proton energy at the irradiation point. We corrected the text explicitly emphasizing this difference.
4. 8 “0.39 nC/Gy” was obtained here, but “0.47 nC/Gy” was obtained from the experiment on page 10. What was causing this difference between the experiments?
   Firstly, there is an error in the second value reported that is not 0.467 nC/Gy but 0.367 nC/Gy. The difference between these two values is around 7%.

These two values are derived in a different way: the first is derived as the slope of the response-dose response fit of Figure 4. The second one is derived considering only the value of released dose of 4 Gy. Somehow the first value is  more realistic spanning a wider dose range. The second was chosen as always, the 4 Gy value was our reference at the beginning of each irradiation.

5. 10 l.196 “Each curve corresponds to a nominal dose of 4 Gy”: meaning that 5 bursts of 4 Gy were given during the time sequence depicted in Figure 2? Was the charge integrated throughout this whole-time sequence or was it integrated per burst?
   Each of the plotted burst correspond to a dose of 4 Gy released at the entrance of the monochromatic Bragg peak. We integrated each curve and calculated the average charge under each curve. The average value was considered.
6. 10 l.210 “analysed”
   Corrected
7. 11 l.231 “sketch”
   Corrected
8. 12 What were the beam energy and field size of the clinical treatment experiment?
   We added two sentences in the text to clarify these points.
9. Figure 2 What are the drops in the signal caused by? Could they be the reason for the lower nC/Gy sensitivity obtained when compared to the calculation?
   We thanks the Reviewer for this comment.
   The drops of Figure 2 are due to the proton beam instabilities. We normalised the detector response to the beam response (signal acquired by the SEM detector). This procedure should, in principle, minimise the effects on the detector sensitivity. By the way, as the Reviewer correctly argued, these instabilities could result in a lower detector sensitivity as the two I-V converter and amplifiers (used for the SEM and detector) are not the same and they respond differently when huge beam time variations occur.
   We added a comment to the Figure to underline this aspect.
10. Figure 4 Should state 15 Gy/min as in the text instead of 16 Gy/min?
    The correct dose rate used was 16 Gy/minutes so we corrected the text
    Thank you to the reviewer for this comment

Round 2

Reviewer 1 Report

See attached file.

Comments for author File: Comments.pdf

Author Response

All the corrections were accepted except for the "MOSFET" as we already added the meaning of the acronym  during the first review

Reviewer 2 Report

The authors clarified some methodological aspects of the study. The manuscript is now suitable for publication.

Author Response

We thanks the reviewer for the work.