Multimodality proton therapy treatment planning system

Abstract

To provide a proton therapy treatment planning system.SOLUTION: A plan comprises combining N fractions including irradiation of volumes including tumoral cells and / or healthy cells at a conventional dose deposition rate defined as a dose rate CDR<1Gy / s and irradiation of them at an ultra-high dose deposition rate defined as a dose rate HDR≥1Gy / s. An equivalent healthy fraction dose (Dmhij) defined as a sum Dmhij=Dchij+αDhhij does not exceed a maximum equivalent healthy fraction dose (Dmh0ij), for preserving the healthy cells after each fraction j, where Dchij is a conventional healthy fraction dose and Dhhij is a high rate healthy fraction dose (Dhhij). A total equivalent healthy dose (DmhTi) delivered to and cumulated in a volume of a healthy tissue (3hi) at the end of N fractions defined as DmhTi=ΣDmhij=Σ(Dchij+αDhhij) does not exceed a maximum equivalent healthy dose (DmhT0i) for preserving the healthy cells.SELECTED DRAWING: Figure 5a

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a treatment planning system (TPS) for generating a plan for treating a target tissue, including tumor cells, with a charged particle beam, preferably a proton beam, which meets certain clinical criteria to ensure that tumor cells are destroyed or killed while protecting healthy cells adjacent to the tumor cells at the end of the treatment. The TPS builds the plan by combining sessions or fractions with conventional dose deposition rate (CDR) and / or ultra-high dose deposition rate (HDR) according to criteria specific to the present invention. The plan thus generated ensures effective treatment of tumor cells while reducing the rate of damage to healthy cells adjacent to the tumor cells. [Background technology]

[0002] 2. Background of the Invention Radiation therapy with particles or waves, such as electron beams, proton beams, heavy ion beams, X-rays, gamma rays, etc., has become an essential means for treating patients suffering from tumors. Such radiation damages both tumor cells and healthy cells, and therefore a major challenge in cancer treatment is to define a plan that ensures effective destruction or death of tumor cells while sparing as much as possible healthy cells, especially those adjacent to tumor cells. Such plans must satisfy multiple, often competing, parameters and are therefore highly complex. Therefore, treatment planning systems are generally computer-generated.

[0003] The first criterion that a treatment plan must meet is to ensure that at the end of treatment, a total target dose (DmtT) equal to or greater than the minimum target dose (DmtT0) effective to destroy / kill tumor cells has been delivered to the tumor cells that form the target.

[0004] The second criterion to be met by the treatment plan is to minimize the destruction of healthy cells adjacent to the tumor cells. No matter how precise the dose deposition in a volume containing tumor cells, a radiation beam that reaches this volume containing tumor cells almost inevitably passes through healthy cells and delivers dose to healthy cells there, surrounded by or contained in that volume. Different radiations deposit their energy in different patterns. For example, as illustrated in FIG. 1, X-rays deposit most of their energy near the level of the epidermis, and the deposited energy decreases with depth. Thus, healthy tissues located upstream of the target volume of tumor cells receive a higher dose than the tumor cells of the target volume. In contrast, protons deposit most of their energy near the end of their beam path, forming a so-called Bragg peak. By superimposing multiple beamlets with respective Bragg peaks of unequal depths, it is possible to define a sum of individual Bragg peaks (SOBP) that spans the entire depth of the volume of tumor cells or a portion of that volume. Thus, healthy cells located upstream of the tumor cell volume passed by the proton beam receive a lower dose than tumor cells within this volume. As a result, proton therapy is suitable for depositing high doses in deep tumors.

[0005] To minimize destruction of healthy cells adjacent to tumor cells, the total dose (DhTi) received by the healthy cells (i) must not exceed the maximum tolerated dose. The maximum tolerated dose that a healthy cell can (relatively) safely receive in one session can be substantially lower than the minimum target dose (DmtT0) required to destroy tumor cells, so that the total target dose (DmtT) can be delivered to the tumor cells in one or more fractions (or sessions).

[0006] Thus, the treatment plan may include delivering a predetermined total target dose (DmtT) of radiation to all tumor cells in N sessions or fractions j, where N≧1 and each fraction j delivers a target fractional dose (Dmtj) to the tumor cell volume. If N=1, the entire predetermined total target dose is delivered in a single session. If N>1, the predetermined total target dose is delivered to a number of fractions, possibly different tumor cell volumes, so that all tumor cells receive an accumulated target dose equal to the predetermined total target dose (DmtT) required to kill all tumor cells at the end of the Nth session. The number of fractions N depends on the nature of the healthy tissues, which determines the maximum fractional dose they can safely receive in fractions. This also depends on the type of radiation used and the position of the healthy cells relative to the tumor cells. These parameters at least partially determine the dose deposited in healthy cells traversed by a radiation beam intended to deposit the target fractional dose (Dmtj) in a volume containing tumor cells.

[0007] It has been observed that tumor cells have a longer recovery time than healthy cells to recover from damage sustained after radiation fractionation, allowing treatment regimens to span several fractions and be spread out over a period of days and weeks. (a) Healthy cells receive a fractionated dose low enough to protect them, (b) the tumor cells receive a total target dose, integrated over N fractions, at least equal to the minimum target dose (DmtT); (c) the recovery time between two successive divisions is sufficient to allow substantial recovery for healthy cells, but not for tumor cells; Treatment plans can ensure that at the end of treatment, all tumor cells have been destroyed while sparing most healthy cells.

[0008] The maximum fractional dose and the maximum total dose acceptable to healthy cells can be defined in relation to the normal tissue probability of injury (NTCP), which defines the probability that a given tissue will develop injury when exposed to radiation. Values ​​of borderline doses of radiation resulting in a given value of NTCP for selecting organs are available in the literature. For example, (Non-Patent Document 1) lists in Table 3 on page 171 several doses that result in 50% of NTCP developing 5 years after treatment symptoms, as defined in the last column for several organs. The volume 1 / 3 to 3 / 3 in Table 3 indicates the fraction of the total volume of the corresponding organ irradiated. Alternatively, medical personnel may have other sources, such as referring to personal experience or other experimental data, to determine the borderline dose.

[0009] Historically, radiotherapy treatment plans involved delivering radiation doses to treated cells at conventional dose deposition rates (CDR) of less than 1 Gy / s. With rare exceptions, current radiotherapy facilities deliver dose rates close to 0.1 Gy / s, and most clinical protocols involve daily delivery of N target fraction doses (Dmtj) of 2-15 Gy that accumulate to reach a total target dose (DmtT), which often exceeds the tolerance limits of normal tissues located in the radiation field, thereby damaging normal tissues along with tumor cells. In recent years, it has been observed that the same dose (D) has different effects on healthy cells, but not on tumor cells, when deposited at conventional dose deposition rates (CDR) or ultra-high dose deposition rates (HDR). HDR can be an order of magnitude or more, greater than the conventional dose deposition rates (CDR) typically applied. For example, U.S. Patent No. 6,399,433 describes a computer-implemented method and system for generating treatment plans for use in external beam radiation therapy to treat patients in need of radiation therapy. The treatment plans described in U.S. Patent No. 6,399,433 do not take into account dose deposition rates, let alone ultra-high dose deposition rates.

[0010] The deposition of charge at ultra-high dose deposition rate (HDR) is also called FLASH radiotherapy (=FLASH-RT). It has been experimentally demonstrated in animals and various organs that the deposition of ultra-high doses at HDR can significantly spare healthy tissues compared to the conventional deposition of the same dose at CDR, while tumor cells respond equally or even better to the deposition of HDR than to the deposition of CDR. For example, it has been reported that FLASH-RT induces a dramatic reduction in the incidence of pulmonary fibrosis, memory loss after brain irradiation, and small intestinal necrosis in mice, while maintaining the antitumor effect unchanged. This sparing of certain normal tissues has already been confirmed in large animals and in patients with cutaneous lymphoma treated with FLASH-RT. However, many treatment centers do not have equipment in place that can deliver doses at HDR within times on the order of milliseconds or seconds, or that can be modified to deliver only HDR with a very limited field size.

[0011] There remains an unsolved problem of generating new and more effective treatment regimens that enhance tumor cell killing while sparing as much healthy tissue as possible using existing equipment. The discovery that tumor cells and healthy cells respond differently to radiation doses deposited at ultra-high dose rates (HDR) provides an additional tool to enhance the efficacy of treatment regimens. For example, US Pat. No. 5,399,366 describes a treatment regimen for treating tumors by subjecting cancer patients to radiation at ultra-high dose rates and administering a therapeutic agent. The treatment regimen provides the dual benefit of protection of normal tissues in addition to anti-tumor activity when combining a therapeutic agent with radiation at ultra-high dose rates to treat cancer patients. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] US Patent Application Publication No. 2012 / 0136194 [Patent Document 2] International Publication No. 2019018813 [Non-patent literature]

[0013] [Non-Patent Document 1] Kehwar, J. Cancer Res. Ther., Sept. 2005, 1 (3), 168 Summary of the Invention [Means for solving the problem]

[0014] The present invention proposes a treatment planning system (TPS) for generating a plan for treating a target tissue, including tumor cells, with a charged particle beam, preferably a proton beam, the plan comprising a combination of N fractions (N≧1), each fraction comprising: Irradiating a volume containing tumor cells and / or healthy cells with a conventional dose deposition rate (CDR), defined as a dose rate CDR<1 Gy / sec, and / or Irradiating a volume containing tumor cells and / or healthy cells with a very high dose deposition rate (HDR), defined as a dose rate HDR ≥ 1 Gy / sec Includes.

[0015] By carefully combining the selection of the doses deposited in the CDR and HDR to the tumor cells and / or healthy tissue, an optimal regimen can be achieved that efficiently kills tumor cells while sparing much of the healthy tissue. These and other advantages of the present invention are described in more detail in the following sections.

[0016] Summary of the Invention The object of the present invention is achieved by a treatment planning system (TPS) for generating a plan for treating a target tissue comprising tumor cells surrounded by healthy cells forming healthy tissue and / or surrounded within a circumferential surface that also surrounds the healthy cells, with a charged particle beam, preferably a proton beam, the plan consisting of N fractions of irradiation, where N≧1, and the plan comprises the following criteria: (C1) At the end of N fractions, all tumor cells in the target tissue (3t) must have received a total target dose (DmtT) equal to the sum of the target fraction doses (Dmtj) received in each fraction (i.e., DmtT = ΣDmtj), and the total target dose is at least equal to the minimum target dose (DmtT0) to kill the tumor cells, i.e., DmtT = ΣDmtj ≧ DmtT0; (C2) At the end of N divisions, all healthy cells (3hi) of the healthy tissue surrounding or enclosed within the peripheral surface (C2.1) the healthy fraction dose (Dhij) received in each fraction j does not exceed a predefined threshold for protecting healthy cells at the end of fraction j; and (C2.2) The total health dose (DhTi) received and accumulated at the end of N fractions does not exceed a predefined threshold for protecting healthy cells at the end of N fractions of treatment. Thus, each person must have received a total health dose (DhTi) equal to the sum of the health fraction doses (Dhij) received in each fraction j (i.e., DhTi = ΣDhij).

[0017] The TPS is configured to define N fractions that involve irradiating a volume containing tumor cells and / or healthy cells with a conventional dose deposition rate (CDR), defined as a dose rate CDR<1 Gy / sec.

[0018] According to the present invention, the plan for treating is configured to include irradiating a volume containing healthy cells and preferably also tumor cells with a very high dose deposition rate (HDR), defined as a dose rate HDR≧1 Gy / sec.

[0019] At the end of N fractions, the total target dose (DmtT) delivered and accumulated to the target tissue volume is defined to satisfy criterion (C1) as the sum over N fractions j of the target fraction doses (Dmtj) delivered to the target tissue in each fraction DmtT = ΣDmtj = Σ(Dctj + Dhtj) ≧ DmtT, where the target fraction dose (Dmtj) delivered during fraction j is the conventional target dose (Dctj) ​​delivered to that volume at the conventional dose deposition rate (CDR) during fraction j, the high-rate target dose (Dhtj) delivered to that volume with a very high dose deposition rate (HDR) during fraction j; It is defined as the sum of

[0020] The healthy fraction dose (Dhij) delivered to a volume of healthy cells in healthy tissue (3i) during fraction j is given by: the conventional healthy fractionated dose (Dchij) delivered to that volume at the conventional dose deposition rate (CDR), and High-rate healthy fractionated dose (Dhhij) delivered to that volume with a very high dose deposition rate (HDR) and The sum of these is equal to Dhij=Dchij+Dhhij.

[0021] The gist of the present invention is to Conventional healthy fractionated dose (Dchij) and - The product of the equivalence factor (α) and the high-rate health fraction dose (Dhhij) The TPS is configured to ensure that the equivalent healthy fractionated dose (Dmhij) as the sum Dmhij = (Dchij + αDhhij) of all the fractions j does not exceed the maximum equivalent healthy fractionated dose (Dmh0ij) for protecting healthy cells after each fraction j (i.e. Dmhij ≦ Dmh0ij), and therefore satisfies criterion (C2.1), where the maximum equivalent healthy fractionated dose (Dmh0ij) corresponds to the dose deposited to healthy cells due to the conventional dose deposition rate (CDR) alone and is less than or equal to the maximum healthy conventional fractionated dose (Dch0ij) that results in a given probability of damage occurring (NTCP0i) to healthy cells (i.e. Dmh0ij ≦ Dch0ij).

[0022] The gist of the invention is also that the TPS is configured to ensure that the total equivalent health dose (DmhTi) delivered and integrated to a volume of healthy tissue at the end of N fractions is defined as the sum over N fractions j of the equivalent healthy fraction doses (Dmhij), DmhTi = ΣDmhij = Σ(Dchij + αDhhij), where α ≦ 1, preferably α > 0.5, where the total equivalent health dose (DmhTi) is defined as The maximum equivalent health dose (DmhT0i) for protecting healthy cells is not exceeded (i.e., DmhTi≦DmhT0i), and therefore criterion (C2.2) is met, where the maximum equivalent health dose (DmhT0i) corresponds to the dose accumulated in healthy cells due to the conventional dose deposition rate (CDR) alone, and is less than or equal to the maximum healthy conventional dose (DchT0i) that results in a given probability of injury (NTCP0i) in healthy cells (3hi), (i.e., DmhT0i≦DchT0i).

[0023] The equivalent healthy fractionated dose (Dmhij) and the total equivalent healthy dose (DmhTi) are defined as the equivalent doses that result in an equivalent or lower probability of injury (NTCP0i) in healthy cells as if the healthy fractionated dose (Dhij) and the total healthy dose (DhTi), respectively, had been accumulated in healthy cells only at the conventional dose deposition rate (CDR).

[0024] In one embodiment of the present invention, in division j, If a volume of healthy tissue is irradiated only with the conventional dose deposition rate (CDR), then Dmhij = Dchij ≤ Dch0ij for that volume in that fraction, or If a volume of healthy tissue is irradiated with very high dose rates (HDR) only, then Dmhij = αDhhij ≤ Dch0ij and Dhhij ≤ Dhh0ij for that volume in that fraction, where Dhh0ij is the maximum high-rate healthy fraction dose delivered with HDR only in a single fraction j that must not be exceeded to protect healthy cells of the healthy tissue (3i), or When a healthy tissue volume is irradiated with both conventional dose deposition rate (CDR) and very high dose deposition rate (HDR), Dmhij=Dchij+αDhhij≦Dch0ij and Dhij=Dchij+Dhhij <Dhh0ijとなる。

[0025] The equivalent coefficient α does not necessarily have to be a constant. For example, α can be expressed as follows: is a constant, preferably equal to 1 / k, where k=1.2 to 1.5 (i.e. α=1 / k, k=1.2 to 1.5), preferably α<0.9, more preferably α<0.85, most preferably α<0.7, or Depends on the HDR fraction of the dose deposited at very high doses (HDR), xH=Dhhij / (Dchij+Dhhij), and varies between 1 / k for xH=1 (i.e., only HDR) and 1 for xH=0 (i.e., only CDR) It can be either of the following.

[0026] The values ​​of the border quantities Dch0ij and Dhh0ij as well as DchT0i and DhhT0i that must not be exceeded to protect healthy cells can be determined in different ways: Dch0ij and DchT0i can be predefined by medical personnel (clinicians) or can be defined in the literature; on the other hand, Dhh0i and DhhT0i can be: For a given value of HDR, either predefined by a medical professional or defined in the literature, or For a given value of HDR, it is defined as Dhh0ij = k Dch0ij and Dhh0Ti = k DchT0i, respectively, where k is in the range 1.2 to 1.5 (i.e. k = 1.2 to 1.5), or Defined by a pre-established curve of the Nosocomial Damage Probability (NTCP) of healthy tissue as a function of dose and dose rate, where Dhh0ij and DhhT0i are defined as the doses delivered by the HDR alone that have the same NTCP as the doses Dch0ij and DchT0i delivered by the CDR alone, respectively? It can be either of the following.

[0027] For example, the maximum healthy conventional dose (DchT0i) and the maximum healthy high fraction dose (DhhT0i) at the end of N fractions can be defined as follows to select healthy tissue:

[0028] [Table 1]

[0029] In one embodiment, during the N fractions, all healthy tissue located upstream of the circumferential surface is irradiated only at a conventional dose deposition rate, where: In each fraction j, the healthy dose fraction (Dhij) deposited in the healthy tissue (equal to the conventional healthy dose fraction (Dchij)) does not exceed the maximum healthy conventional dose fraction (Dch0ij); At the end of N fractions, the total health dose (DhTi) (equal to the conventional health dose (Dchi)) deposited in said healthy tissues does not exceed the maximum health conventional dose (Dch0Ti); Healthy cells are located upstream of the peripheral surface when the charged particle beam defined in the TPS traverses said healthy cells before penetrating the peripheral surface.

[0030] In one embodiment, all healthy tissue downstream of the circumferential surface is irradiated with only a very high dose deposition rate, where: the healthy fraction dose (Dhij) deposited in the healthy tissue in each fraction j (equal to the high-fraction healthy fraction dose (Dhhij)) does not exceed the maximum high-fraction healthy fraction dose (Dhh0ij); At the end of N fractions, the total health dose (DhTi) deposited in said healthy tissue (equal to the high rate health dose (DhhTi)) does not exceed the maximum health conventional dose (Dch0Ti); When the charged particle beam intersects said healthy cells only after exiting the peripheral surface, the healthy cells are located downstream of the peripheral surface.

[0031] In a preferred embodiment, one or more of the divisions of the plan comprises the following steps, performed in any order: ·A first charged particle beam or a group of charged particle beams parallel to a first direction, each formed by various beamlets ○In each or part of one or more divisions, at least 90%, preferably at least 95%, more preferably at least 99% of the tumor cells of the target tissue (3t) receive the conventional target dose per fraction (Dctj) ○In each or part of one or more divisions, a conventional healthy dose per fraction (Dchij) (i.e., Dchij < Dch0ij) lower than the maximum conventional healthy dose per fraction (Dch0ij) is delivered to healthy tissue (3hi) surrounding and enclosed within the outer peripheral surface such that a first step of delivering the conventional dose at a conventional dose accumulation rate (CDR) is performed ·After the first step, by a second charged particle beam or a group of charged particle beams parallel to a second direction that is the same as or different from the first direction ○A high-rate target dose per fraction (Dhtj) is delivered to the target tissue in each or part of one or more divisions such that 100% of the tumor cells of the target tissue receive the dose per fraction at a conventional rate (CDR) and / or a high dose rate (HDR) ○A high-rate healthy dose per fraction (Dhhij) is delivered to healthy tissue surrounding and within the outer peripheral surface in each or part of one or more divisions such that the equivalent healthy dose per fraction (Dmhij = Dchij + αDhhij) delivered to all healthy cells at both a conventional rate (CDR) and a high dose rate (HDR) does not exceed the maximum conventional healthy dose per fraction (Dch0ij) (i.e., Dmhij ≤ Dch0ij) such that a second step of delivering a high rate dose at a high dose rate accumulation (HDR) is performed and includes

[0032] The second charged particle beam or the group of charged particle beams can be selected so as not to overlap with the first charged particle beam or the group of charged particle beams in any healthy tissue surrounding or within the outer peripheral surface.

[0033] In an alternative preferred embodiment, the plan is ·At least 90%, preferably at least 95%, more preferably at least 99% of the tumor cells in the target tissue are delivered the conventional target fraction dose (Dctj), ·To the healthy tissue (3hi) surrounding and enclosed within its outer periphery, a conventional healthy fraction dose (Dchij) lower than the maximum healthy conventional fraction dose (Dch0ij) (i.e., Dchij < Dch0ij) is delivered, ·So that 100% of the tumor cells in the target tissue receive the fraction dose at the conventional rate (CDR) and / or the high rate (HDR), a high rate target fraction dose (Dhtj) is delivered to the target tissue in each or some of the one or more fractions, ·So that the equivalent healthy fraction dose (Dmhij = Dchij + αDhhij) delivered to all healthy cells at both the conventional rate (CDR) and the high rate (HDR) does not exceed the maximum conventional healthy fraction dose (Dch0ij) (i.e., Dmhij ≤ Dch0ij), a high rate healthy fraction dose (Dhhij) is delivered to the healthy tissue surrounding and within its outer periphery in each or some of the one or more fractions Including a single charged particle beam (PB) or a beam group parallel to the first direction, formed by beamlets.

[0034] The outer periphery may include an uncertain volume defined as an area that defines an uncertain region and includes both tumor cells and healthy cells mixed in different ratios. In this case, the TPS is ·The total healthy dose (DhTi = DchTi + DhhTi) is greater than the minimum target dose (DmtT0) and lower than the maximum high rate healthy dose (DhhT0i) (i.e., DmtT0 < DhTi < DhhT0i), ·The total equivalent healthy dose (DmhTi = DchTi + αDhhTi) delivered at the end of N fractions is lower than the maximum healthy conventional dose (DchT0i) of the healthy tissue (3hi) present in the uncertain region (i.e., DmhTi < DchT0i), The equivalent healthy fraction dose (Dmhij=Dchij+αDhhij) delivered in each fraction j is lower than the maximum healthy conventional fraction dose (DchT0ij) of the healthy tissue (3hi) present in the uncertainty region (i.e., DmhTi <DchT0i) Such a method may include delivering a total health dose (DhTi) to the entire uncertainty volume at the end of N fractions.

[0035] The TPS of the present invention can define as a charged particle beam a proton beam, which can be delivered in single scattering mode or heavy scattering mode or by pencil beam scanning (PBS).

[0036] The invention also relates to a computer-implemented method, preferably implemented by using a treatment planning system (TPS) as defined above, for generating a plan for treating a target tissue (3t) comprising tumor cells surrounded by healthy cells and / or surrounded within a circumferential surface also surrounding healthy cells forming a healthy tissue (3hi), where the subscript i indicates a type of healthy tissue (3hi), with a charged particle beam, preferably a proton beam, the plan consisting of N fractions of irradiation, where N≧1, and the plan comprises the following criteria being met: (C1) At the end of N fractions, all tumor cells in the target tissue (3t) must have received a total target dose (DmtT) equal to the sum of the target fraction doses (Dmtj) received in each fraction (i.e., DmtT = ΣDmtj), and the total target dose is at least equal to the minimum target dose (DmtT0) to kill the tumor cells, i.e., DmtT = ΣDmtj ≧ DmtT0; (C2) At the end of N divisions, all healthy cells (3hi) of the healthy tissue surrounding or enclosed within the peripheral surface (C2.1) the healthy fraction dose (Dhij) received in each fraction j does not exceed a predefined threshold for protecting healthy cells at the end of fraction j; (C2.2) The total health dose (DhTi) received and accumulated at the end of N fractions does not exceed a predefined threshold for protecting healthy cells at the end of N fractions of treatment. Thus, each person must have received a total health dose (DhTi) equal to the sum of the health fraction doses (Dhij) received in each fraction j (i.e., DhTi = ΣDhij).

[0037] The method includes the following steps. irradiating a volume containing tumor cells and / or healthy cells in N fractions with a conventional dose deposition rate (CDR), defined as a dose rate CDR<1 Gy / sec; irradiating a volume containing healthy cells and preferably tumor cells in N fractions with a very high dose deposition rate (HDR), defined as a dose rate HDR ≥ 1 Gy / sec, whereby At the end of N fractions, the total target dose (DmtT) delivered and accumulated to the volume of target tissue (3t) is defined to satisfy criterion (C1) as the sum over N fractions j of the target fraction doses (Dmtj) delivered to the target tissue (3t) in each fraction DmtT = ΣDmtj = Σ(Dctj + Dhtj) ≧ DmtT0, where the target fraction dose (Dmtj) delivered during fraction j is the conventional target dose (Dctj) ​​delivered to that volume at the conventional dose deposition rate (CDR) during fraction j, ○ High-rate target dose (Dhtj) delivered to that volume with ultra-high dose deposition rate (HDR) during fraction j and It is defined as the sum of

[0038] The healthy fraction dose (Dhij) delivered to a volume of healthy cells in healthy tissue (3i) during fraction j is given by: the conventional healthy fractionated dose (Dchij) delivered to that volume at the conventional dose deposition rate (CDR), ○ High-rate healthy fractionated dose (Dhhij) delivered to that volume with a very high dose deposition rate (HDR) and The sum of these is equal to Dhij=Dchij+Dhhij.

[0039] The method is: Conventional healthy fractionated dose (Dchij) and ○ The product of the equivalence factor (α) and the high-rate health fraction dose (Dhhij) the equivalent healthy fractionated dose (Dmhij), defined as the sum Dmhij = (Dchij + αDhhij), after each fraction j does not exceed the maximum equivalent healthy fractionated dose (Dmh0ij) for protecting healthy cells (Dmh0ij) (i.e. Dmhij ≦ Dmh0ij), and therefore satisfies criterion (C2.1), where the maximum equivalent healthy fractionated dose (Dmh0ij) corresponds to the dose deposited in healthy cells by the conventional dose deposition rate (CDR) alone and is less than or equal to the maximum healthy conventional fractionated dose (Dch0ij) that results in a given probability of injury (NTCP0i) to healthy cells (3hi), (i.e. Dmh0ij ≦ Dch0ij).

[0040] The method also includes ensuring that a total equivalent health dose (DmhTi) delivered and integrated to a volume of healthy tissue (3hi) at the end of N fractions is defined as a sum over N fractions j of equivalent healthy fraction doses (Dmhij), DmhTi = ΣDmhij = Σ(Dchij + αDhhij), where α < 1, preferably α > 0.5, where the total equivalent health dose (DmhTi) is the total equivalent health dose delivered to healthy tissue (3hi) at the end of N fractions. The maximum equivalent health dose (DmhT0i) for protection is not exceeded (i.e. DmhTi≦DmhT0i) and therefore criterion (C2.2) is met, the maximum equivalent health dose (DmhT0i) corresponds to the dose accumulated in healthy cells due to the conventional dose deposition rate (CDR) alone and is less than or equal to the maximum healthy conventional dose (DchT0i) that results in a given probability of injury (NTCP0i) in healthy cells (3hi) (i.e. DmhT0i≦DchT0i).

[0041] The equivalent healthy fractionated dose (Dmhij) and the total equivalent healthy dose (DmhTi) are the equivalent doses that result in a lower probability of injury (NTCP0i) in healthy cells (3hi) than if the healthy fractionated dose (Dhij) and the total healthy dose (DhTi) were accumulated in healthy cells using the conventional dose deposition rate (CDR) alone. [Brief description of the drawings]

[0042] [Figure 1a]1 shows the energy deposition in tissue as a function of penetration depth (z) of the X-ray (XR) and proton beamlets, which together form the sum of individual Bragg peaks (SOBP) spanning the entire depth of the tumor (3). [Figure 1b] A cross section parallel to the proton beam direction through target cells including tumor cells is shown. [Figure 1c] The corresponding SOBP is shown. [Figure 2a] Shown is a target tissue (3t) containing tumor cells surrounded by healthy cells (3hi) and / or enclosed within a peripheral surface that also surrounds healthy cells (3hi). [Figure 2b] 2(a) illustrates a cross section of the target tissue along a plane (x,z) parallel to the charged particle beam. [Diagram 3] Shown is a portion of a treatment plan divided into N fractions referenced to healthy tissue (3hi), where each fraction includes the delivery of a given dose (Dhij) at conventional rates (CDR) and / or ultra-high rates (HDR) that accumulate to a total equivalent healthy dose (DmhTi) at the end of the Nth fraction. [Figure 4a] NTCP contours are shown as a function of the deposited dose (D) and dose deposition rate (DR) in healthy tissue. [Figure 4b] NTCP as a function of the dose (D) deposited in healthy tissues in the CDR (open circles) and HDR (filled circles). [Figure 4c] The principle of equivalent healthy fractionated dose (Dmhij=Dchij+αDhhij) is shown. [Figure 5a] Dmhij (=Dchij+αDhhij) is illustrated as a function of Dhij (=Dchij+Dhhij) for dose accumulation assuming only CDR (=“Dhhij=0(CDR)”), only HDR (=“Dchij=0(HDR)”), and linear (=“(1)”) and nonlinear (=“(4)”) accumulation modes that mix the dose accumulated in CDR Dch1ij with the remaining dose accumulated in HDR. [Figure 5b] We plot Dh0ij as a function of xH for four choices of α = f(xH) shown in Fig. 5(c). [Figure 6] A treatment plan is shown that includes a dose (D) deposition profile as a function of penetration depth (z) and a dose deposition rate (DR) as a function of the same penetration depth. [Figure 7] The principle of equivalent health dose (DmhTi = DchTi + αDhhTi) is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Detailed Description The present invention relates to a treatment planning system for generating a plan for treating a target tissue (3t) with a charged particle beam. An example of a target tissue is illustrated in Figures 1(b), 2(a) and 2(b) including tumor cells surrounded by healthy cells and / or within a circumferential surface that also surrounds the healthy cells, where the healthy cells form the healthy tissue (3hi) and the subscript i indicates the type of healthy tissue (3hi). Due to the complexity of the multi-parameter treatment to be planned, the TPS generally comprises a computer or processor configured to optimize the nature and number of beams or beamlets required to meet a given criterion. The beam properties include the type of charged particle, the intensity of the beam, the dose deposited, the dose deposition rate, the beam direction, the number and frequency of splits, etc. The charged particles are preferably protons, since the dose deposition profile is one that includes a Bragg peak as illustrated in Figures 1(a) and 1(c). The charged particle beam can be delivered in a single or heavy scattering mode or by pencil beam scanning (PBS). As shown in FIG. 3, the plan consists of N fractions of shots, where N≧1, and the TPS needs to optimize the nature and number of beam shots to meet the following criteria: (C1) All tumor cells in the target tissue (3t) must have received a total target dose (DmtT) at the end of N fractions equal to the sum of the target fraction doses (Dmtj) received in each fraction (i.e., DmtT = ΣDmtj), and the total target dose is at least equal to the minimum target dose (DmtT0) to kill the tumor cell, i.e., DmtT = ΣDmtj ≧ DmtT0. (C2) All healthy cells (3hi) of healthy tissue surrounding or enclosed within the peripheral surface (C2.1) the healthy fraction dose (Dhij) received in each fraction j does not exceed a predefined threshold for protecting healthy cells at the end of fraction j; (C2.2) The total health dose (DhTi) received and accumulated at the end of N fractions does not exceed a predefined threshold for protecting healthy cells at the end of N fractions of treatment. Thus, at the end of N fractions, one must have received a total health dose (DhTi) equal to the sum of the health fraction doses (Dhij) received in each fraction j (i.e., DhTi = ΣDhij).

[0044] Although the FLASH effect is now widely recognized by those skilled in the art, the chemical mechanism underlying the FLASH effect is not yet clearly understood. Several different theories have been developed. For example, it has been proposed that ultra-high dose deposition rates of FLASH-RT significantly reduce the killing of cells circulating in the bloodstream, suggesting that the threshold dose deposition rate at which CDR and HDR are distinguished may depend on one cycle of blood circulation time. In humans, it has been reported that the threshold dose deposition rate for the appearance of the FLASH effect is about 1 Gy / s. It has also been proposed that the organic peroxyl radical ROO·, formed by the addition of O2 to primary carbon-centered radicals, may play an important role in radiation-induced injury. In another example, it has also been reported that the FLASH effect can be explained by the competition between radiation-induced oxygen deficiency and the rediffusion of oxygen from capillaries. The present invention is not bound by any of these or other theories, but is based on experimental evidence that the FLASH effect actually exists. The present invention was developed based on the following observations: (O1) Tumor cells are killed similarly regardless of the dose deposition rate (DR). (O2) A given probability of normal tissue damage (NTCP0i) in healthy tissue (3hi), which must not be exceeded, is reached at a lower dose deposited at the conventional dose deposition rate (CDR) than at the ultra-high dose deposition rate (HDR), as shown in Figures 4(a) to 4(c). (O3) Tumor cells in the target tissue (3t) have a longer recovery time than healthy tissue exposed to an identical radiation dose, regardless of the dose deposition rate.

[0045] To meet the above criteria, and as illustrated in FIG. 3, the TPS of the present invention comprises: Irradiating a volume containing tumor cells and / or healthy cells with a conventional dose deposition rate (CDR), defined as a dose rate with a CDR < 1 Gy / sec, and / or Irradiating a volume containing tumor cells and / or healthy cells with a very high dose deposition rate (HDR), defined as a dose rate of HDR ≥ 1 Gy / sec Combine N divisions including

[0046] Based on the above observation (O1), the total target dose (DmtT) delivered and accumulated to a volume of target tissue (3t) at the end of N fractions is defined to satisfy criterion (C1) as the sum over N fractions j of the total target fraction doses (Dmtj) delivered to the target tissue (3t) in each fraction. The target fraction dose (Dmtj) delivered during fraction j is: the conventional target dose (Dctj) ​​delivered to that volume at the conventional dose deposition rate (CDR) during fraction j, the high-rate target dose (Dhtj) delivered to that volume with a very high dose deposition rate (HDR) during fraction j; This can be expressed as DmtT = ΣDmtj = Σ(Dctj + Dhtj) ≧ DmtT0, which satisfies the criterion (C1).

[0047] The healthy fraction dose (Dhij) delivered to a volume of healthy cells in healthy tissue (3i) during fraction j is given by: the conventional healthy fractionated dose (Dchij) delivered to that volume at the conventional dose deposition rate (CDR), ○ High-rate healthy fractionated dose (Dhhij) delivered to that volume with a very high dose deposition rate (HDR) and The sum of these is equal to Dhij=Dchij+Dhhij.

[0048] Based on the above observation (O2) that a given NTCP0i for healthy cells, which should not be exceeded, is reached with a lower conventional healthy dose (Dchij) accumulated in the CDR than in the HDR, the equivalent healthy fractionated dose (Dmhij) is defined as: Conventional healthy fractionated dose (Dchij) and ○ The product of the equivalence factor (α) and the high-rate health fraction dose (Dhhij) The sum of Dmhij = Dchij + αDhhij is defined as

[0049] The equivalent healthy fractionated dose (Dmhij) is defined as the equivalent dose that would produce an equal or lower probability of injury (NTCP0i) in healthy cells (3hi) as if the healthy fractionated dose (Dhij) had been deposited in healthy cells only by the conventional dose deposition rate (CDR). This definition is a direct consequence of the observation (O2) above.

[0050] To satisfy the above criterion (C2.1), the equivalent healthy dose fraction (Dmhij) must not exceed the maximum equivalent healthy dose fraction (Dmh0ij) to protect healthy tissues after each fraction j (i.e., Dmhij≦Dmh0ij). The maximum equivalent healthy dose fraction (Dmh0ij) corresponds to the dose deposited in healthy tissues only by the conventional dose deposition rate (CDR) and is less than or equal to the maximum conventional healthy dose fraction (Dch0ij) that results in a given probability of injury (NTCP0i) in healthy tissues (3hi) (i.e., Dmh0ij≦Dch0ij). Dmh0ij may be smaller than Dch0ij to allow a safety margin in cases where the equivalence factor α for a particular healthy tissue (3hi) is not specified with sufficient certainty or precision.

[0051] To meet the above criterion (C2.2), the total equivalent health dose (DmhTi) delivered and accumulated to a volume of healthy tissue (3hi) at the end of N fractions is defined as the sum over N fractions j of the equivalent healthy fraction doses (Dmhij), DmhTi = ΣDmhij = Σ(Dchij + αDhhij) (α ≦ 1, preferably α > 0.5). The total equivalent health dose (DmhTi) must not exceed the maximum equivalent health dose (DmhT0i) to protect healthy cells at the end of N fractions (i.e. DmhTi ≦ DmhT0i).

[0052] The total equivalent health dose (DmhTi) is defined as the equivalent dose that results in an equivalent or lower probability of injury (NTCP0i) in healthy tissues (3hi) as if the total health dose (DhTi) had been deposited in healthy tissues only with the conventional dose deposition rate (CDR). This definition is a direct consequence of the observation (O2) above. The maximum equivalent health dose (DmhT0i) is less than or equal to the maximum conventional health dose (DchT0i) that corresponds to the dose deposited in healthy tissues only with the conventional dose deposition rate (CDR) and results in a given probability of injury (NTCP0i) in healthy tissues (3hi) (i.e. DmhT0i≦DchT0i). Again, DmhT0i can be smaller than DchT0i to allow a safety margin in cases where the equivalence factor α for a particular healthy tissue (3hi) is not specified with sufficient certainty or precision.

[0053] Observation (O2): Health dose Dhij(NTCP0i) is a function of dose accumulation rate (DR) Figures 4(a)-4(c) graphically illustrate the dependence of the healthy dose (Dhij) required to reach a given NTCP for a given healthy tissue (3hi) during treatment of fraction j on the dose deposition rate (DR). It should be noted that the expression "healthy dose" is used herein as an abbreviation for "dose delivered to healthy cells" and should not be understood as a dose beneficial to cell health. According to criteria (C2.1) and (C2.2), a "healthy dose" must be such that it limits as much as possible the damage to healthy cells traversed by the beam of charged particles while at the same time killing tumor cells of the target tissue (3t) by the same beam.

[0054] Figure 4(a) shows the NTCP contour plotting the dose deposition rate (DR) as a function of the healthy dose (Dhij) for NTPC values ​​with probabilities between 10% and 100%. If we assume that the value of NTCP that must not be exceeded during treatment of fraction j, NTCP0i, corresponds to a 50% probability of injury, then the dose to the left of the NTCP contour, shown in the shaded area and labeled (0.5), can be deposited with the corresponding dose deposition rate. It can be seen that the dose (D) that defines the NTCP contour = 50% strongly depends on the rate at which the dose is deposited.

[0055] FIG. 4(b) is a direct result of FIG. 4(a), where the white dots aligned with the vertical axis DR=1 Gy / sec in FIG. 4(a) indicate the dose (Dhij) required to reach a given NTCP at the dose rate in FIG. 4(b), and it is noted that a sigmoid curve of white dots was obtained. 3 By repeating the same procedure with the black dots aligned in Gy / s, it is noted that a sigmoid curve of black dots is obtained in Fig. 4(b).Assuming NTCP0i=50% as in Fig. 4(a), we obtain the corresponding shaded regions showing the dose that can be deposited in healthy cells in healthy tissue (3hi) with these two deposition rates.

[0056] The NTCP contours in Figures 4(a) and 4(b) define the dose (Dhij) required to reach a given NTCP if the entirety of each dose is delivered at the corresponding dose deposition rate (DR). In other words, in one embodiment of the present invention, the volume of healthy tissue (3hi) during fraction j is When irradiated using only conventional dose deposition rates (CDR), the equivalent health dose fraction (Dmhij) must be equal to the conventional health dose fraction (Dchij) (i.e., Dmhij=Dchij) but less than or equal to the maximum conventional health dose fraction (Dch0ij) for that volume in fraction j (i.e., Dmhij=Dchij≦Dch0ij), or When only ultra-high dynamic range (HDR) is used, The equivalent health fraction dose (Dmhij) is equal to the product of the equivalence coefficient (α) and the high-rate health fraction dose (Dhhij) (i.e., Dmhij = αDhhij), but must be less than or equal to the maximum conventional health fraction dose (Dch0ij) (i.e., Dmhij = αDhhij ≦ Dch0ij), The fractional healthy fraction dose (Dhhij) must be less than or equal to the maximum fractional healthy fraction dose (Dhh0ij) for that volume in that fraction (i.e., Dhhij≦Dhh0ij), where Dhh0ij is the maximum fractional healthy fraction dose delivered with HDR alone during a single fraction j that must not be exceeded to protect healthy cells in healthy tissue (3i).

[0057] However, the present invention may include a fraction j that combines doses deposited at both conventional dose deposition rates (CDR) and very high dose deposition rates (HDR). At both conventional dose deposition rates (CDR) and very high dose deposition rates (HDR), the equivalent health dose fraction (Dmhij) is equal to the sum of the conventional health dose fraction (Dchij) and the product of the equivalence factor α and the high rate health dose fraction (Dhhij) (i.e., Dmhij=Dchij+αDhhij), but must be less than or equal to the maximum conventional health dose fraction (Dch0ij) (i.e., Dmhij=Dchij+αDhhij≦Dch0ij).

[0058] This is illustrated in Fig. 4(c), where the black dots marked "Dchi1" are the doses accumulated in healthy cells by CDR, and the white dots marked "Dhhi1" are the doses accumulated in the same healthy cells by HDR during the same fractionation j = 1. Note that in the example of Fig. 4(c), Dchi1 < Dmhi1 < Dch0ij < Dhhi1 < Dhi1 < Dhh0ij. Strictly speaking, the present invention is satisfied as long as Dmhij < Dch0ij, and Dhij is necessarily smaller than Dhh0ij. Note that Dhij can be equal to Dhhij only when Dhhij is necessarily smaller than Dhij or when Dchij = 0 (i.e., accumulation by HDR only). The healthy fraction dose (Dhij) can be above or below Dch0i as long as the equivalent healthy fraction dose (Dmhij) is below Dch0i. Contrary to what might be intuitively expected, as in the example of Fig. 4(c), the healthy fraction dose Dhij = Dchij + Dhhij can be substantially larger than the maximum conventional healthy fraction dose (Dch0ij).

[0059] The maximum conventional healthy fraction dose (Dch0ij) is generally a predefined threshold given by the clinician as a criterion (=criterion (C2.1)) for constructing a treatment plan that protects healthy cells at the end of fraction j. The healthy fraction dose (Dhi1) is larger than Dch0ij, but surprisingly meets criterion (C2.1). This is possible because the equivalent healthy fraction dose ("αDhhi1") of the dose (Dhhi1) deposited only at the ultra-high rate is only a part of the high-rate healthy fraction dose (Dhhi1) actually deposited at HDR, as determined by the equivalence factor α. This corresponding equivalent healthy fraction dose is shown in Figure 4(c) by the shaded dot labeled "αDhhi1" and is obtained by multiplying the dose Dhhi1 by the equivalence factor α. The equivalent healthy fraction dose (Dmhi1) is shown by the dashed line and is a simple sum, Dmhi1=Dchi1+αDhhi1. In the example of Figure 4(c), it can be seen that the equivalent healthy dose fraction (Dmhi1) is smaller than the maximum conventional healthy dose fraction (Dch0ij), and therefore the fraction j=1 shown therein satisfies the criterion (C2.1). To protect healthy tissue (3i), care must be taken to ensure that the total health dose (Dhi1) does not exceed the maximum healthy dose fraction (Dh0ij), which will be explained subsequently.

[0060] As illustrated in FIG. 4(c), in many cases, the minimum target fractional dose (Dmt0j) required to kill tumor cells in the volume irradiated during fraction j can be included in Dch0ij and Dhh0ij. A major advantage of the present invention is that radiation therapy can be performed by depositing a given fractional dose in a volume containing tumor cells and healthy cells with a combined deposition rate (Dhi1=Dmt1) of CDR and HDR that kills tumor cells during fraction j=1. This is because the target fractional dose (Dmt1) is larger than the minimum target fractional dose (Dmt0j), and at the same time, the healthy fractional dose (Dhi1) is such that the total equivalent healthy fractional dose (Dmhi1) is smaller than the maximum healthy conventional fractional dose (Dch0ij), thus protecting the healthy cells contained in the irradiated volume. In summary, a volume containing both tumor cells and healthy cells can be defined as: To kill tumor cells in the volume, Dchij+Dhhij=Dhij=Dmtj>Dmt0j, To protect healthy cells within the volume, Dchij+αDhhij=Dmhij≦Dch0ij. Provided that, it can be treated by accumulating split doses (Dhij=Dmtj) in both CDR and HDR.

[0061] It will be clear to one skilled in the art that the above description of FIG. 4(c) for partition j=1 applies mutatis mutandis to any partition j (i.e., the subscript “1” can be replaced by “j”).

[0062] Equivalent coefficient α For example, the value of the equivalence factor α for dose deposition at very high dose deposition rates (HDR) can be determined by establishing the NTCP curve as a function of dose (Dhij) and dose deposition rate (DR) as illustrated in Figures 4(a)-4(c). At sufficiently high dose deposition rates, the dose (Dhh0ij) resulting in a given NTCP0i becomes independent of dose rate, and the factor α becomes substantially constant (i.e., the right vertical portion of the solid curve in Figures 4(a), 4(c) and 7) and can be defined as equal to 1 / k, where k=1.2-1.5 (i.e., α=1 / k, k=1.2-1.5), preferably α<0.9, more preferably α<0.85, and most preferably α<0.7.

[0063] Figure 5(a) illustrates various examples of the relationship between the equivalent healthy dose fraction (Dmhij) and the healthy dose fraction (Dhij). The solid lines show the relationship between the accumulation in only CDR, labeled "Dhhij=0(CDR)", and the accumulation in only HDR, labeled "Dchij=0(HDR)". Considering that Dmhij=Dchij+αDhhij and Dhij=Dchij+Dhhij, it follows that In the case of CDR alone, Dhhij=0, and therefore Dmhij=Dhij, defines a line with a slope of 1, labeled “Dhhij=0(CDR)” in Figure 5(a), which intersects with the horizontal dashed lines Dmhij=Dch0ij and Dhij=Dch0ij at a value that must not be exceeded in order to protect healthy tissue (3hi); With HDR alone, Dchij=0, and therefore Dmhij=αDhhij, defining a straight line with slope α=1 / k, labeled “Dchij=0(HDR)” in Figure 5(a), that intersects with the horizontal dashed lines Dmhij=Dch0ij and Dhij=Dhh0ij at values ​​that must not be exceeded in order to protect healthy tissue (3hi).

[0064] For treatment plans that include dose deposition at both conventional rates (CDR) and ultra-high rates (HDR), the relationship between Dmhij and Dhij is contained between the two straight lines in FIG. 5(a) with slope 1 (= “Dhhij=0(CDR)”) and slope α=1 / k (= “Dchij=0(HDR)”). If the conventional health dose (Dchij) deposited in the volume during a treatment fraction is fixed as Dch1i (i.e. Dchij=Dch1i=constant), then Dchij=Dch1i+αDhhij, where Dhhij is free to vary from 0 (CDR only) to any positive value. If the total dose is deposited only at CDR (i.e. Dhhij=0), then Dchij=Dhij=Dch1i, which is the beginning of the curve relating Dmhij and Dhij.

[0065] By defining the HDR fraction as xH = Dhhij / (Dchij + Dhhij), ranging from xH = 0, which defines accumulation in CDR only, to xH = 1, which defines accumulation in HDR only, and defining the fraction of the healthy dose fraction (Dhij) accumulated in HDR as Dmhij = Dch1i + αDhhij, it can also be expressed as Dmhij = (1 + xH(α-1))Dhij as a function of Dhij. The maximum healthy dose (Dh0ij) that can be accumulated in healthy cells of healthy tissue (3hi) as a function of xH can be determined by equating Dmhij = Dch0ij = (1 + xH(α-1))Dh0ij, which is represented graphically in Figure 5(b) and for different values ​​of α, depending on whether and how the value of α varies as a function of xH as illustrated in Figure 5(c).

[0066] In one embodiment of the present invention, labeled (1) in FIG. 5(c), the equivalence coefficient α is independent of the HDR ratio (xH=Dhhij / (Dchij+Dhhij)). The HDR ratio (xH) can also be expressed as xH=1-Dch1i / Dhij. Naturally, if the equivalence coefficient α is independent of xH, it is also independent of Dhij. Thus, the relationship Dchij=Dch1i+αDhhij is defined by a straight line with a slope α=1 / k starting at the point Dmhij=Dhij=Dch1i. This embodiment is illustrated in FIGS. 5(a) and 5(b) by the corresponding dashed line labeled "1," showing the linear relationship between Dmhij and Dhij (see FIG. 5(a)) starting at the point Dmhij=Dhij=Dchi1, and the nonlinear relationship between Dch0ij and xH (see FIG. 5(b)).

[0067] In alternative embodiments, the equivalence factor α depends on the HDR fraction of the dose deposited at very high rates (HDR), xH=Dhhij / (Dchij+Dhhij), and varies between α=1 / k for xH=1 (i.e., HDR only) and α=1 for xH=0 (i.e., CDR only). By way of example, three such embodiments are illustrated in FIG. 5(c). · The short dashed line (2) defining the linear relationship between α and xH, α=(1 / k−1)xH+1, this embodiment being illustrated in FIG. 5(b) by the corresponding short dashed line (2). · Polynomial relationship between α and xH, α=(1 / k-1)xH 2 A long dashed line (3) defines +1, and this embodiment is illustrated in FIG. 5(b) by the corresponding long dashed line (3). The second polynomial relationship between α and xH, α=(1-1 / k)xH 2 +2(1 / k-1)xH+1, this embodiment is illustrated in Figures 5(a) and 5(b) by the corresponding dotted line labeled "(4)". Figure 5(a) shows the non-linear relationship between Dmhij and Dhij at conventional healthy fraction doses Dchij=Dch1ij=constant, starting at Dhij=Dmhij=Dch1ij and crossing at a value of Dhij=Dhi0ij(4) with a predefined threshold (Dch0ij) indicated by a horizontal dashed line at Dmhij=Dch0ij that must not be exceeded to protect healthy tissue (3hi).

[0068] Whether the equivalence coefficient α depends on the HDR ratio xH or not depends mostly on the type of healthy tissue (3hi) involved, and the skilled person knows where to find or how to evaluate this information. The horizontal axis (Dhij) of FIG. 5(a) shows that by using either HDR alone or in combination with CDR, a dose (Dhij) substantially higher than a certain threshold defined by the clinician at the maximum conventional healthy fraction dose (Dch0ij) can be delivered without exceeding a certain NTCP0i value specified to protect the health of a given healthy tissue (3hi). FIG. 5(b) shows how the maximum healthy dose (Dh0ij) increases above Dch0ij as the value of xH increases (i.e. as the contribution of Dhhij in the radiation treatment increases). This is very interesting for the following reasons: In treatment planning, the aim is to reduce the dose deposited in healthy tissues compared to the dose deposited in tumor cells, which is not always feasible in practice. For example, when an irradiated volume contains both tumor cells and healthy cells, substantially equal doses are deposited in both tumor cells and healthy cells, such that the target fractional dose (Dmti) is substantially equal to the healthy fractional dose (Dhij) (i.e., Dmtj≒Dhij). In most cases, the minimum target fractional dose (Dmt0j) required to kill tumor cells in the volume in fraction j is higher than the maximum conventional healthy fractional dose (Dch0ij) (i.e., Dmt0j>Dch0ij). These two competing conditions (i.e., Dmtj≒Dhij and Dmt0j>Dch0ij) make it very difficult to kill tumor cells while sparing healthy cells contained in the volume within a given value of NTCP0i (i.e., the case of Dmt0j>Dch0ij is problematic).Since the tumor cell death rate at a given dose is practically independent of the dose accumulation rate (see observation (O1) above), and since the NTCP of healthy cells at the same dose decreases at a high accumulation rate (see observation (O2) above), it is possible to deposit a target fractionated dose (Dmti) higher than the maximum conventional healthy fractionated dose (Dch0ij) and still maintain it within a given range of NTCP0i values ​​required to spare healthy tissue (3hi).

[0069] The window that defines the dose that can be deposited in the volume in fraction j for which values ​​of NTCP≦NTCP0i are obtained spans from Dch0ij to Dhh0ij. If the total dose (Dmti) is deposited only in the CDR, the target fraction dose (Dmtj) cannot exceed the maximum conventional healthy fraction dose (Dch0ij) that defines the lowest boundary of the window. This situation represents the state of the art with the problems mentioned above when Dmt0j>Dch0ij. Combining deposition in both CDR and HDR results in an increase in the maximum healthy dose (Dh0ij) as the HDR fraction xH increases, as illustrated in Fig. 5(b) according to the dependence of xH on α.

[0070] The highest tolerable dose (Dhij) that can be "safely" deposited in healthy tissue in fraction j is the maximum high-health fraction dose (Dhhij) that can be deposited if the entire target fraction dose (Dmtj) is deposited with HDR (i.e., with xH=1). As a given target fraction dose (Dmtj) required to kill tumor cells in a volume in fraction j increases, it becomes more difficult to deposit the entire dose (Dmti) with HDR alone. This is mainly due to machine limitations that may not be able to deposit more than a given dose in a given time, on the order of milliseconds to seconds. Combining CDR and HDR to deposit the entire target fraction dose (Dmtj) in a given fraction j can generate treatment plans that are implementable on existing machines, where the total dose deposited in the volume (Dmtj≒Dhij) can be equal to or greater than the minimum target fraction dose (Dmt0j) required to kill tumor cells in the volume in fraction j.

[0071] As shown in FIGS. 5(a) to 5(c) by the mixed straight line marked with "(1)", when the equivalent coefficient α = 1 / k ≠ f(xH) and is a constant, the dose up to the maximum value (Dhi0ij(1)) can be accumulated in healthy cells within a predetermined NTCP0i range. As shown in FIG. 5(a) by the dotted curve marked with "(4)", when the equivalent coefficient α = f(xH), α = 1 at Dhhij = 0 and α = 1 / k at Dhhij = 1, the dose up to the maximum value (Dhi0ij(4)) can be accumulated in healthy cells within a predetermined NTCP0i range. Therefore, the maximum dose value that can be accumulated in the volume containing healthy cells is defined as Dch0ij < Dhi0ij(4) < Dhi0ij(1) < Dhh0ij as follows.

[0072] Assuming that the maximum dose value that can be accumulated in the volume containing both tumor cells and healthy cells is higher than the minimum target dose per fraction (Dmt0j), it is possible to normally perform irradiation fractions that kill tumor cells while preserving healthy cells contained in the irradiated volume within a predetermined NTCP0i range.

[0073] Maximum dose and minimum dose The treatment plan must meet several criteria including the following. (C1) DmtT = ΣDmtj ≧ DmtT0, where DmtT is the total target dose required to kill tumor cells in the volume during fractionation, and DmtT0 is the minimum target dose integrated over N fractions to kill all tumor cells contained within the outer peripheral surface. (C2.1) Dmhij = Dchij + αDhhij ≦ Dch0ij, where Dmhij is the equivalent healthy dose per fraction and Dch0ij is the maximum conventional healthy dose per fraction that should not be exceeded during fractionation to protect healthy cells (see FIG. 4(c)). (C2.2) DmhTi = ΣDmhij = Σ(Dchij + αDhhij) ≦ DchT0i, where DmhTi is the equivalent health dose, where DchT0i is the maximum conventional health dose integrated over N fractions j that must not be exceeded to protect healthy cells (see Figure 7).

[0074] Criteria (2.1) and (2.2) (C2.1) Dhij=Dchij+Dhhij≦Dh0ij, where Dhij is the healthy fraction dose and Dch0ij is the maximum healthy fraction dose that must not be exceeded during a fraction to protect healthy cells (see FIG. 5(a)); (C2.2) DhTi = ΣDhij = Σ(Dchij + Dhhij) ≦ DhT0i, where DhTi is the health dose accumulated over N fractions j and DhT0i can also be expressed as the maximum health dose accumulated over N fractions j that must not be exceeded to protect healthy cells.

[0075] In order to ensure that the treatment kills the tumor cells contained within the outer surface at the end of N fractions, the minimum target dose (DmtT0) must be exceeded. If the tumor cells belong to the same tissue or organ as the healthy cells (3hi) located within or adjacent to the outer surface, the minimum target dose (DmtT0) is likely to be higher than the maximum conventional healthy dose (DchT0i) that must not be exceeded in order to spare said healthy cells with the same properties as the tumor cells. Naturally, this is a pitfall that at first glance seems unavoidable, since it seems impossible to determine a dose that is high enough to kill the tumor cells and low enough to spare the healthy cells adjacent to the tumor cells. The minimum target dose (DmtT0) is generally predefined by the medical personnel who define the criteria (C1).

[0076] As can be seen in Figure 5(a), the maximum healthy dose fraction Dh0ij is included between the maximum conventional dose fraction (Dch0ij) and the maximum high-fraction dose fraction (Dhh0ij), i.e. Dch0ij < Dh0ij < Dhh0ij, and depends on the HDR ratio xH = Dhhij / (Dchij + Dhhij). In one embodiment, the maximum healthy dose fraction Dh0ij can be expressed as Dh0ij = Dch0ij + (1 - α) Dhhij (xH), where α may or may not vary with xH, and is the high-fraction healthy dose fraction at the value of xH such that Dhhij (xH) is Dmhij = Dch0ij.

[0077] Similarly, the maximum health dose DhT0i is included between the maximum conventional health dose (DchT0i) and the maximum high-percentage health dose (DhhT0i), i.e. DchT0i≦DhT0i≦DhhT0i, and depends on the HDR ratio xH. In one embodiment, DhT0i can be expressed as DhT0i=DchT0i+(1−α)DhhTi(xH), where α may or may not vary with xH, and is the high-percentage health dose at the value of xH such that DhhTi(xH) is DmhTi=DchT0i.

[0078] The maximum conventional healthy fraction dose (Dch0ij) and maximum conventional healthy dose (DchT0i), which define the fraction dose and total cumulative dose accumulated only in CDR resulting in a certain NTCP0i that must not be exceeded to protect healthy cells, used to define criteria C2.1 and C2.2, can be predefined by medical professionals or defined in literature. For example, Table 1 shows the values ​​of DchT0i for several organs / tissues diagnosed 5 years after radiotherapy with a value of NTCP0i=50%, taken from Table 3 on page 170 of (Non-Patent Document 1). These values ​​are representative of the values ​​that medical professionals can use as reference to define the value of DchT0i.

[0079] [Table 2]

[0080] The maximum high-rate healthy fractionated dose (Dhh0ij) and maximum high-rate healthy dose (DhhT0i) that can be used in the present invention and define the fractionated dose and total accumulated dose accumulated only in HDR resulting in a given NTCP0i that must not be exceeded to protect healthy cells are: For a given value of HDR, either predefined by a medical professional or defined in the literature, or For a given value of HDR, it is defined as Dhh0ij=k Dch0i and Dhh0Ti=k DchT0i, respectively, where k is included between 1.2 and 1.5 (i.e. k=1.2-1.5), or It can be either: - defined by a pre-established curve of the Nominal Threshold Value (NTCP) of healthy tissue (3hi) as a function of dose and dose rate, as illustrated in Figures 4(a)-4(c) and 7, where Dhh0i is defined to be the dose that has the same NTCP as Dch0i.

[0081] For example, the value of DhhT0i can be estimated by multiplying the value of DchT0i given in Table 1 by a coefficient k=1.5. The corresponding results are given in Table 2.

[0082] [Table 3]

[0083] Local distribution of dose deposition in CDR and HDR For a given irradiation device with limited capability to deliver a given dose at a given ultra-high rate (HDR), the FLASH effect properties can be exploited by selecting the volume of the target tissue (3t) to be treated in fraction j according to the presence and location of healthy cells relative to the volume in order to optimize the HDR ratio xH=Dhhij / (Dchij+Dhhij) of the doses deposited in CDR and HDR, respectively. In an embodiment where the charged particles are protons, all healthy tissue (3hi) located upstream of the circumferential surface is irradiated only with the conventional dose deposition rate during N fractions. This is possible thanks to the dose deposition profile of the proton beam, which includes a low deposition that increases locally to form a Bragg peak. This is represented graphically in Figures 1(b) and 1(c) and is represented by a cylinder to take into account the width of the proton beam, so that the healthy tissue (3hi) traversed first by the proton beam receives a low dose that can be "safely" deposited in the CDR within a given value of NTCP0i. Of course, the following criteria must be met in addition: The healthy fraction dose (Dhij) deposited in the healthy tissue in each fraction j does not exceed the maximum conventional healthy fraction dose (Dch0ij); At the end of N fractions, the total health dose (DhTi) deposited in said healthy tissues does not exceed the maximum conventional health dose (Dch0Ti).

[0084] When the TPS-defined charged particle beam crosses the healthy cell before penetrating the peripheral surface, the healthy cell is located upstream of the peripheral surface. Similarly, when the TPS-defined charged particle beam crosses the healthy cell for the first time after leaving the peripheral surface, the healthy cell is located downstream of the peripheral surface. If the corresponding NTCP is ≦NTCP0i, the dose is "safely" deposited in the healthy cell.

[0085] In contrast, all healthy tissue (3hi) located downstream of the peripheral surface may be irradiated at least partially, preferably only with a very high dose deposition rate, where: The healthy fraction dose (Dhij) deposited in the healthy tissue in each fraction j does not exceed the maximum high-rate healthy fraction dose (Dh0ij); At the end of N fractions, the total healthy dose (DhTi) deposited in said healthy tissues does not exceed the maximum conventional healthy dose (Dch0Ti).

[0086] Figure 6 illustrates an example of the distribution of the dose (D) and dose deposition rate (DR) deposited in fraction j in the penetration depth (z) of the proton beam. The dose (D) defines a portion of the low dose deposited in healthy cells of healthy tissue (3hi) located upstream of the tumor cells of the target tissue (3t), followed by the type of SOBP illustrated in Figures 1(a) and 1(c), which spans the entire depth of the target tissue (3t) and drops off sharply downstream of the target tissue (3t). Cells located adjacent to the downstream end of the circumferential surface along the proton beam direction are of greatest concern, as they may receive high doses (D) at the end of the Bragg peak and may include healthy cells located within the circumferential surface or mixed with tumor cells in the uncertainty zone (3z) formed by the healthy tissue (3hi) outside the circumferential surface. Therefore, if the dose (D) deposited along the beam path is deposited at various deposition rates (DR), it is preferable to deposit it at CDR at the upstream and part upstream of the circumferential surface and to increase it as the beam penetrates deeper closer to the downstream end of the circumferential surface and passes through it until it reaches HDR. If healthy cells are present in the volume, the deposition rate at which the dose (D) deposited in the volume exceeds the maximum conventional healthy fractional dose (Dch0ij) should be at least partially HDR. In the example of FIG. 6, healthy tissue may be exposed to a dose higher than Dch0ij, especially in the downstream part of the circumferential surface and in the uncertainty region (3z) located immediately downstream of the circumferential surface. It is important to deposit such dose at least partially HDR in order to satisfy criteria (C2.1) and (C2.2).

[0087] Uncertain area (3z) The peripheral surface surrounding the tumor cells of the target tissue (3t) may not form a clear interface separating the tumor cells inside it from the healthy cells outside it, but instead may form an interface layer that defines an uncertainty zone (3z) that contains both tumor cells and healthy cells in different ratios. As the uncertainty zone (3z) is the most sensitive area when irradiating with a proton beam, the uncertainty zone (3z) is shown in the downstream part of the peripheral surface as described above in Figs. 2(a), 2(b) and 6. However, it is clear that such uncertainty zone (3z) may be located anywhere along the peripheral surface or even within the mass of the target tissue (3t) if there are islands of healthy cells surrounded within the peripheral surface, as shown in Figs. 2(a) and 2(b). In order to reduce the undesirable side effects of radiation treatment, preferably all healthy cells should be spared, even if they are healthy cells included in the uncertainty zone. However, these healthy cells are particularly difficult to preserve because they are exposed to the same radiation dose as the tumor cells, which must be at least equal to the minimum target fraction dose (Dmt0j). Therefore, most clinicians to date may prioritize the destructive destruction of tumor cells at the expense of any healthy cells contained within the same irradiated volume, rather than attempting to preserve the healthy cells at the risk of leaving the tumor cells activated. In a preferred embodiment, the TPS includes delivering a total uncertain dose (DuTi) throughout the uncertainty region (3z) at the end of N fractions. If healthy cells are spared, the maximum value of DuTi is dictated by the protection of the healthy cells. In these conditions, the total uncertain dose DuTi is equal to the total healthy dose (DhTi), and it can be stipulated that the following conditions apply to any irradiated volume that contains healthy cells contained within the uncertainty region, such as, but not limited to, islands of healthy cells enclosed within the outer peripheral surface, as illustrated in Figures 2(a) and 2(b), or healthy cells exposed to the same radiation dose as the tumor cells contained within the irradiated volume. In this case, as shown in FIG. · The total health dose (DhTi = DchTi + DhhTi) is greater than the minimum target dose (DmtT0) and lower than the maximum high-dose health dose (DhhT0i) (i.e., DmtT0 < DhTi < DhhT0i), where DchTi and DhhTi are the conventional health dose and high-dose health dose respectively accumulated by CDR and HDR integrated over N divisions j. · The total equivalent health dose (DmhTi = DchTi + αDhhTi) delivered at the end of N divisions is lower than the maximum conventional health dose (DchT0i) of healthy tissue (3hi) existing in the uncertainty region (i.e., DmhTi < DchT0i). · It is preferable that the equivalent health split dose (Dmhij = Dchij + αDhhij) delivered in each division j is lower than the maximum conventional health split dose (DchT0ij) of healthy tissue (3hi) existing in the uncertainty region (i.e., DmhTi < DchT0i).

[0088] Multi-step treatment plan In one embodiment of the present invention, one or more splits of the treatment plan each include a first step of delivering a conventional dose at a conventional dose accumulation rate (CDR) by a first charged particle beam or a group of charged particle beams parallel to a first direction, each formed by various beamlets. Referring to FIG. 1(a), this corresponds to delivering all the beamlets labeled "Dchij" in the first step. The conventional dose is · In each or a part of one or more splits, a conventional target split dose (Dctj) is delivered to at least 90%, preferably at least 95%, more preferably at least 99% of the tumor cells of the target tissue (3t). · In each or a part of one or more splits, a conventional health split dose (Dchij) lower than the maximum conventional health split dose (Dch0ij) (i.e., Dchij < Dch0ij) is delivered to the healthy tissue (3hi) surrounding and enclosed within the outer peripheral surface.

[0089] This first (conventional) step is followed or preceded by a second step of delivering a high rate dose with a very high dose deposition rate (HDR) by a second charged particle beam or group of charged particle beams parallel to a second direction, which may be the same as or different from the first direction. With reference to FIG. 1(a), this corresponds to delivering a beamlet labeled "Dhhij" in the second step. The high rate dose is A high-rate target fractionated dose (Dhtj) is delivered to the target tissue (3t) in each or a portion of one or more fractions such that 100% of the tumor cells in the target tissue (3t) receive a fractionated dose at a conventional rate (CDR) and / or a very high rate (HDR); In each or a portion of one or more fractions, a high rate healthy fraction dose (Dhhij) is delivered to healthy tissue (3hi) surrounding and within the peripheral surface such that the equivalent healthy fraction dose (Dmhij=Dchij+αDhhij) delivered to all healthy cells at both the conventional rate (CDR) and the ultra-high rate (HDR) does not exceed the maximum conventional healthy fraction dose (Dch0ij) (i.e., Dmhij≦Dch0ij).

[0090] The first pass with a conventional dose is to paint the area enclosed within the perimeter with a large brush, then paint the edges of this area with a thinner brush, ensuring that all of the area adjacent to and within the perimeter is colored, while no color is visible outside the perimeter. The first and second passes can be performed in any order.

[0091] To ensure that healthy cells do not receive a healthy fraction dose (Dhii) accumulated over the first and second steps in fraction j that does not exceed the maximum healthy fraction dose (Dh0ij), the treatment plan may ensure that the second charged particle beam or group of charged particle beams does not overlap with the first charged particle beam or group of charged particle beams in any healthy tissue (3hi) surrounding or within the peripheral surface during the same fraction.

[0092] Single-step treatment planning In an alternative embodiment of the present invention, one or more fractions of the treatment plan involve a single charged particle beam (PB) or beam group parallel to a first direction, formed by beamlets, · The conventional target dose (Dctj) is delivered to at least 90%, preferably at least 95%, more preferably at least 99% of the target cells of the target tissue (3t), · A conventional healthy dose (Dchij) lower than the maximum conventional healthy dose (Dch0ij) (i.e., Dchij < Dch0ij) is delivered to the healthy tissue (3hi) surrounding and enclosed within the outer surface, · A high-dose target dose (Dhtj) is delivered to the target tissue (3t) in each or some of the one or more fractions such that 100% of the tumor cells of the target tissue (3t) receive the dose at a conventional rate (CDR) and / or a high dose rate (HDR), · A high-dose healthy dose (Dhhij) is delivered to the healthy tissue (3hi) surrounding and within the outer surface in each or some of the one or more fractions such that the equivalent healthy dose (Dmhij = Dchij + αDhhij) delivered to all healthy cells at both the conventional rate (CDR) and the high dose rate (HDR) does not exceed the maximum conventional healthy dose (Dch0ij) (i.e., Dmhij ≤ Dch0ij).

[0093] The difference between this single-step treatment plan and the multi-step treatment plan described above is that all the beamlets of fraction j are delivered within the scope of a single irradiation step instead of two steps for the multi-step treatment plan. Referring to FIG. 1(a), this is a single step, meaning that the beamlets labeled "Dchij" and the beamlets labeled "Dhhij" are all delivered within the scope of the same irradiation beam, which is modulated to change the dose accumulated as a function of the penetration depth (z).

[0094] Figure 3 shows N fractions, each of which includes accumulations at conventional fractionation (Dchij) (shaded bars) and at high fractionation (Dhhij) (white bars). The HDR ratio xH = Dhhij / (Dchij + Dhhij) can vary substantially from one fraction to another. Each conventional fractionation and high fractionation must meet the following criteria: The total target dose (DmtT) (DmtT = ΣDmtj = DctT + DhtT = Σ(Dctj + Dhtj)) accumulated over N fractions must be greater than a predefined minimum target dose (DmtT0), i.e. DmtT > DmtT0, where DctT and DhtT are the accumulated conventional and high-rate target doses in the CDR and HDR, respectively, accumulated over N fractions j. The total equivalent health dose (DmhTi) accumulated over N fractions (DmhTi = ΣDmhij = DchTi + αDhhTi = Σ(Dchij + αDhhij)) must be lower than the specified maximum conventional health dose (DchT0i) (i.e. DmhTi > DchT0i).

[0095] According to the multi-step treatment plan, the conventional dose (Dchij) in each fraction j (see the shaded bars in Fig. 3) is accumulated in a first step, followed by the accumulation at high rate dose (Dhhij) in the second step. According to the single-step treatment plan, all beamlets accumulating doses at both CDR and HDR are delivered in a single shot, and the properties of successive beamlets (including accumulation rate) vary with the depth (z) of the corresponding Bragg peak.

[0096] overview A treatment plan for treating a target tissue containing tumor cells with a charged particle beam, preferably a proton beam, must meet certain clinical criteria to ensure that, at the end of the treatment, the tumor cells are killed while sparing the healthy cells adjacent to the tumor cells. (1) killing tumor cells, (C1) The total target dose (DmtT) delivered to the entire volume contained within the outer circumferential surface must exceed the minimum target dose (DmtT0), i.e., DmtT = ΣDmtj ≧ DmtT0; (2) Preserving healthy cells, (C2.1) The accumulated healthy fraction dose (Dhij) in a fraction j cannot exceed the maximum healthy fraction dose (Dh0ij), i.e. Dhij = Dchij + Dhhij ≤ Dh0ij; (C2.2) The health dose (DhTi) accumulated over N fractions j cannot exceed the maximum health dose (DhT0i) accumulated over N fractions j, i.e. DhTi = ΣDhij = Σ(Dchij + Dhhij) ≦ DhT0i.

[0097] When healthy cells are adjacent to tumor cells, they may receive the same dose as the tumor cells. If the dose received is sufficient to kill tumor cells, it may also be sufficient to kill healthy cells, which is of course undesirable. The present invention exploits the FLASH effect observed at ultra-high dose deposition rates (HDR) by combining conventional irradiation at a specific volume of CDR and FLASH irradiation at HDR in a treatment plan.

[0098] Criterion (C1) is met by ensuring that the total target dose DmtT=DctT+DhtT is greater than the minimum target dose (DmtT0).

[0099] Criterion (C2.1) is met by ensuring that the healthy dose fraction (Dhij=Dchij+Dhhij) is lower than the maximum healthy dose fraction (Dh0ij). This criterion is met if the equivalent healthy dose fraction (Dmhij=Dchij+αDhhij) does not exceed the maximum conventional healthy dose fraction (Dch0ij), i.e., Dmhij=Dchij+αDhhij≦Dch0ij. The equivalent healthy dose fraction (Dmhij) is the dose, deposited at least in part in the HDR, that results in the same value of the probability of injury occurrence (NTCP0i) as if the same dose had been deposited in the CDR alone.

[0100] Criterion (C2.2) is met by ensuring that the total health dose (DhTi = DchTi + DhhTi) is less than the maximum total health dose (DhT0i). This criterion is met if the equivalent health dose (DmhTi = DchTi + αDhhij) does not exceed the maximum conventional health fraction dose (DchT0i), i.e., Dmhij = Dchij + αDhhTi ≦ DchT0i. The equivalent total health dose (DmhTi) is the accumulated dose, deposited at least partially in HDR over N fractions, that results in the same value of the probability of injury occurrence (NTCP0i) as if the same dose had been deposited only in CDR.

[0101] According to the above treatment plan, if the healthy fraction dose (Dhij) accumulated in healthy cells at fraction j is greater than the minimum target dose (DmtT0) required to kill both tumor cells and healthy cells contained within the volume irradiated at fraction j, by combining the accumulation at CDR and the accumulation at HDR to obtain the advantages of the FLASH effect, a pitfall that would otherwise seem inescapable is resolved. This pitfall is resolved even in the worst-case scenario where both tumor cells and healthy cells receive the same radiation dose (Dmtij = Dhij), and thus both criteria (C1) and (C2.1) are satisfied. The same conclusion applies to the entire treatment at the end of N fractions, such that if the total healthy dose (DhTi) accumulated in healthy cells after N fractions is at least partially accumulated at HDR, the total healthy dose (DhTi) can be greater than the minimum target dose (DmtT0) required to kill tumor cells within the outer perimeter surface and lower than the maximum total healthy dose (DhT0i) required to spare healthy tissue (3hi). Here again, this seemingly inescapable pitfall is resolved even in the worst-case scenario where both tumor cells and healthy cells receive the same radiation dose, and thus both criteria (C1) and (C2.2) are satisfied. The case where Dhij = Dmtj and DhTi = DmTt after N fractions is referred to as the "worst-case scenario", which is an attempt to reduce the dose (Dhij) delivered to healthy cells and maximize the dose (Dmtj) delivered to tumor cells by the treatment plan such that in most cases, Dhij < Dmtj when healthy cells are outside the outer perimeter surface and DhTi < DmTt after N fractions.

[0102] The treatment plan generated by the TPS of the present invention and preferred embodiments thereof can be realized in a method for treating a target tissue (3t) comprising tumor cells surrounded by healthy cells and / or surrounded within a circumferential surface that also surrounds the healthy cells, by a charged particle beam, preferably a proton beam, where the healthy cells form a healthy tissue (3hi), the subscript i indicating the type of healthy tissue (3hi), and the method comprises N fractionated irradiations, where N≧1 satisfies the following criterion: (C1) All tumor cells in the target tissue (3t) must have received a total target dose (DmtT) at the end of N fractions equal to the sum of the target fraction doses (Dmtj) received in each fraction (i.e., DmtT = ΣDmtj), and the total target dose is at least equal to the minimum target dose (DmtT0) to kill the tumor cell, i.e., DmtT = ΣDmtj ≧ DmtT0; (C2) All healthy cells (3hi) of healthy tissue surrounding or enclosed within the peripheral surface (C2.1) the healthy fraction dose (Dhij) received in each fraction j does not exceed a predefined threshold for protecting healthy cells at the end of fraction j; (C2.2) The total health dose (DhTi) received and accumulated at the end of N fractions does not exceed a predefined threshold for protecting healthy cells at the end of N fractions of treatment. Thus, at the end of N fractions, one must have received a total health dose (DhTi) equal to the sum of the health fraction doses (Dhij) received in each fraction j (i.e., DhTi = ΣDhij). " The method is o Irradiating a volume containing tumor cells and / or healthy cells with a conventional dose rate (CDR), defined as a dose rate with a CDR < 1 Gy / sec, and / or Irradiating a volume containing tumor cells and / or healthy cells with a very high dose rate (HDR), defined as a dose rate HDR ≥ 1 Gy / sec Combine N divisions including At the end of N fractions, the total target dose (DmtT) delivered and accumulated to the volume of target tissue (3t) is defined as the sum over N fractions j of the target fraction doses (Dmtj) delivered to the target tissue (3t) in each fraction, DmtT = ΣDmtj = Σ(Dctj + Dhtj) ≧ DmtT0, satisfying criterion (C1), where the target fraction dose (Dmtj) delivered during fraction j is the conventional target dose (Dctj) ​​delivered to that volume at the conventional dose deposition rate (CDR) during fraction j, ○ High-rate target dose (Dhtj) delivered to that volume with ultra-high dose deposition rate (HDR) during fraction j and It is defined as the sum of The healthy fraction dose (Dhij) delivered to a volume of healthy cells of healthy tissue (3i) during fraction j is the conventional healthy fractionated dose (Dchij) delivered to that volume at the conventional dose rate (CDR), ○ High-rate healthy fractionated dose (Dhhij) delivered to that volume at very high dose rate (HDR) and The sum of Dhij=Dchij+Dhhij is equal to The equivalent fractionated healthy dose (Dmhij) is Conventional healthy fractionated dose (Dchij) and ○ The product of the equivalence factor (α) and the high-rate health fraction dose (Dhhij) The sum of Dmhij = (Dchij + αDhhij) is defined as After each fraction j, the maximum equivalent healthy fraction dose (Dmh0ij) for protecting healthy cells is not exceeded (i.e., Dmhij≦Dmh0ij), thus satisfying criterion (C2.1), where the maximum equivalent healthy fraction dose (Dmh0ij) corresponds to the dose deposited in healthy cells at the conventional dose rate (CDR) alone and is less than or equal to the maximum healthy conventional fraction dose (Dch0ij) that results in a given probability of injury (NTCP0i) in healthy cells (3hi) (i.e., Dmh0ij≦Dch0ij); The total equivalent health dose (DmhTi) delivered and accumulated to a volume of healthy tissue (3hi) at the end of N fractions is defined as the sum over N fractions j of the equivalent healthy fraction doses (Dmhij), DmhTi = ΣDmhij = Σ(Dchij + αDhhij) (α ≦ 1, preferably α > 0.5), where the total equivalent health dose (DmhTi) is the maximum equivalent healthy dose to protect healthy tissue at the end of N fractions. The healthy dose (DmhT0i) is not exceeded (i.e. DmhTi≦DmhT0i) and therefore criterion (C2.2) is met, where the maximum equivalent healthy dose (DmhT0i) corresponds to the dose accumulated in healthy cells at the conventional dose rate (CDR) alone and is less than or equal to the maximum healthy conventional dose (DchT0i) that results in a given probability of injury (NTCP0i) in healthy cells (3hi) (i.e. DmhT0i≦DchT0i).

[0103] The equivalent healthy fractionated dose (Dmhij) and the total equivalent healthy dose (DmhTi) are the equivalent doses that result in the same or lower probability of injury (NTCP0i) in healthy cells (3hi) as if the healthy fractionated dose (Dhij) and the total equivalent healthy dose (DhTi) were deposited in healthy cells at the conventional dose rate (CDR) alone. [Explanation of symbols]

[0104] Reference Description 3hi Healthy tissuei 3t target tissue 3z uncertainty region D Dose Dch0ij Maximum conventional healthy fractionated dose DchT0i Maximum conventional health dose accumulated over N fractions j Dchi1 Conventional healthy fraction dose for fraction j=1 Dchij Conventional Health Split Dose DchTi Conventional health dose accumulated over N fractions j DctT Conventional target dose Dctj Conventional target fractionated dose Dh0ij maximum healthy fractional dose Dhi0ij(1) Maximum healthy fractional dose (α=constant) Dhi0ij(2) Maximum healthy fractional dose (α=f(xH) is linear) Dhi0ij(3) Maximum healthy fractional dose (α=f(xH) is parabolic) Dhi0ij(4) Maximum healthy fractional dose (α=f(xH) is parabolic) Dhhi1 High-rate healthy fraction dose for fraction j=1 Dhhij high rate health split dose Dhh0ij Maximum High Rate Healthy Fractionated Dose DhhT0i Maximum High Health Dose DhhTi High Rate Health Dose Dhi1 Healthy fraction dose for fraction j=1 Dhij Dhij=Dchij+Dhhij, Healthy split dose DhTi DhTi = ΣDhij = Σ(Dchij + Dhhij), the total health dose accumulated over N fractions j Dhtj High-rate target fractionated dose DhtT High Rate Target Dose DhT0i Maximum total health dose accumulated over N fractions j Dmh0ij Maximum equivalent fractionated dose for health Dmhi1 Equivalent health fraction dose for fraction j=1 Dmhij Dmhij=Dchij+αDhhij, equivalent healthy fractionated dose DmhTi DmhTi = ΣDmhij = Σ(Dchij + αDhhij), the total equivalent health dose accumulated over N fractions j Dmt0j Minimum target fraction dose Dmtj Dmtj=Dctj+Dhtj, target fractionated dose DmtT DmtT=DctT+DhtT, total target dose DmtT0 Minimum target dose DR Dose accumulation rate (or accumulation rate) k CDR / HDR proportionality constant at very high dose rates, (k=1 / α) CDR Conventional Dose Accumulation Rate HDR Ultra-high dose accumulation rate NTCP Probability of normal tissue damage NTCP0i Maximum NTCP value in healthy tissue (3hi) PB Proton Beam S skin SOBP Bragg peak sum x,y Vector defining the plane perpendicular to the beam at depth (z) xH HDR ratio=Dhhij / (Dchij+Dhhij) X-ray z penetration depth Z0 Z=0(skin) Zn Deepest part of outer surface α Equivalent coefficient (Dmhij=Dchij+αDhhij)

Claims

1. A treatment planning system (TPS) for generating a plan for treating a target tissue (3t) with a charged particle beam, preferably a proton beam, the target tissue (3t) being defined by a circumferential surface, the target tissue (3t) comprising tumor cells surrounded by the circumferential surface, the circumferential surface being at least one of a circumferential surface surrounded by healthy cells, a circumferential surface surrounding healthy cells, and a circumferential surface surrounded by and surrounding healthy cells, the healthy cells forming healthy tissue (3hi), subscript i indicating a type of healthy tissue (3hi), the plan consisting of N fractions of irradiation, where N>=1, and the plan satisfying the following criteria: (C1) at the end of the N fractions, all tumor cells in the target tissue (3t) must have received a total target dose (DmtT) equal to the sum of the target fraction doses (Dmtj) received in each fraction (i.e., DmtT=ΣDmtj), and the total target dose is at least equal to the minimum target dose (DmtT0) to kill the tumor cells, i.e., DmtT=ΣDmtj≧DmtT0; (C2) At the end of the N divisions, all healthy cells (3hi) of the healthy tissue surrounding or enclosed within the peripheral surface are (C2.1) the healthy fraction dose (Dhij) received in each fraction j does not exceed a predefined threshold to protect the healthy cells at the end of said fraction j; and (C2.2) A patient must receive a total health dose (DhTi) equal to the sum of the health fraction doses (Dhij) received in each fraction j, so that the total health dose (DhTi) received and accumulated at the end of the N fractions does not exceed a predetermined threshold for protecting the healthy cells at the end of the N fraction treatment (i.e., DhTi = ΣDhij). " The TPS is Irradiating a volume containing tumor cells and / or healthy cells with a conventional dose deposition rate (CDR), defined as a dose rate CDR < 1 Gy / sec, and / or Irradiating a volume containing tumor cells and / or healthy cells with a very high dose deposition rate (HDR), defined as a dose rate HDR ≥ 1 Gy / s, and generating said plan combining N splits including: At the end of N fractions, the total target dose (DmtT) delivered and integrated to the volume of the target tissue (3t) is defined to satisfy criterion (C1) as the sum over the N fractions j of the target fraction doses (Dmtj) delivered to the target tissue (3t) in each fraction DmtT = ΣDmtj = Σ (Dctj + Dhtj) ≧ DmtT0, and the target fraction dose (Dmtj) delivered during fraction j is the conventional target dose (D) delivered to said volume at the conventional dose deposition rate (CDR) during said fraction j; and a high-rate target dose (Dhtj) delivered to said volume with a very high dose deposition rate (HDR) during said fraction j; and It is defined as the sum of The healthy fraction dose (Dhij) delivered to a volume of healthy cells of healthy tissue (3i) during fraction j is the conventional healthy fractionated dose (Dchij) delivered to said volume at the conventional dose deposition rate (CDR); a high rate healthy fractionated dose (Dhhij) delivered to said volume with a very high dose deposition rate (HDR); The sum of Dhij = Dchij + Dhhij is equal to - Equivalent health fraction dose (Dmhij) is The conventional healthy fractionated dose (Dchij), ○ It is defined as the sum Dmhij = (Dchij + αDhhij) of the product of the equivalence coefficient (α) and the high-rate health fraction dose (Dhhij), the equivalent healthy dose fraction (Dmhij) does not exceed the maximum equivalent healthy dose fraction (Dmh0ij) for protecting the healthy cells after each fraction j (i.e. Dmhij≦Dmh0ij) and therefore satisfies criterion (C2.1), the maximum equivalent healthy dose fraction (Dmh0ij) corresponds to the dose accumulated in the healthy cells only by the conventional dose deposition rate (CDR) and is less than or equal to the maximum healthy conventional dose fraction (Dch0ij) that results in a given probability of injury (NTCP0i) for the healthy cells (3hi) (i.e. Dmh0ij≦Dch0ij); the total equivalent health dose (DmhTi) delivered and accumulated to a volume of healthy tissue (3hi) at the end of N fractions is defined as the sum over the N fractions j of the equivalent healthy fraction doses (Dmhij), DmhTi = ΣDmhij = Σ(Dchij + αDhhij), where α < 1, preferably α > 0.5, said total equivalent health dose (DmhTi) does not exceed the maximum equivalent health dose (DmhT0i) for protecting said healthy cells at the end of the N fractions (i.e. DmhTi ≦ DmhT0i) and therefore meets criterion (C2.2); The equivalent healthy fractionated dose (Dmhij) and the total equivalent healthy dose (DmhTi) are equivalent doses that cause a probability of injury (NTCP0i) in healthy cells (3hi) that is equal to or lower than the probability of injury (NTCP0i) when the healthy fractionated dose (Dhij) and the total equivalent healthy dose (DhTi) are accumulated in the healthy cells only at the conventional dose accumulation rate (CDR), The maximum equivalent healthy dose (DmhT0i) corresponds to a dose accumulated in a healthy cell by the conventional dose deposition rate (CDR) alone and is smaller than the maximum healthy conventional dose (DchT0i) that results in a predetermined probability of injury (NTCP0i) in the healthy cell (3hi) (i.e., DmhT0i<DchT0i); Treatment Planning System (TPS).

2. During split j, the volume of healthy tissue (3i) is If a volume of healthy tissue (3i) is irradiated only with the conventional dose deposition rate (CDR), then Dmhij=Dchij≦Dch0ij for said volume in said fractions; if a volume of healthy tissue (3i) is irradiated with very high dose rate (HDR) only, Dmhij=αDhhij≦Dch0ij and Dhhij≦Dhh0ij for said volume in said fraction, where Dhh0ij is the maximum high-rate healthy fraction dose delivered with HDR only in a single fraction j that must not be exceeded in order to protect the healthy cells of said healthy tissue (3i), or If a volume of healthy tissue (3i) is irradiated with both conventional dose deposition rate (CDR) and very high dose deposition rate (HDR), then Dmhij=Dchij+αDhhij≦Dch0ij and Dhij=Dchij+Dhhij<Dhh0ij; 2. The treatment planning system (TPS) of claim 1 .

3. The equivalent coefficient α is is a constant, preferably equal to 1 / k, where k=1.2-1.5 (i.e. α=1 / k, k=1.2-1.5), preferably α<0.9, more preferably α<0.85, most preferably α<0.7, or Depends on the HDR fraction of the dose deposited at very high doses (HDR), xH = Dhhij / (Dchij + Dhhij), and varies between 1 / k for xH = 1 (i.e., HDR only) and 1 for xH = 0 (i.e., CDR only) 3. The treatment planning system (TPS) of claim 2, wherein:

4. Dch0ij and DchT0i are predefined by a medical professional or defined in the literature, and Dhh0i and DhhT0i are predefined by a medical professional or defined in the literature for a given value of the HDR, or For a given value of said HDR, it is defined as Dhh0ij = k Dch0i and Dhh0Ti = k DchT0i, respectively, where k is comprised between 1.2 and 1.5 (i.e. k = 1.2 to 1.5), or o defined by a pre-established curve of normal tissue probability (NTCP) of the healthy tissue as a function of dose and dose rate, where Dhh0ij and DhhT0i are defined as the doses delivered with HDR only that have the same NTCP as the doses Dch0ij and DchT0i delivered with CDR only, respectively? Either A treatment planning system (TPS) according to claim 2 or 3.

5. configured to generate the plan for treatment such that during the N fractions, all healthy tissue located upstream of the circumferential surface is irradiated only at conventional dose deposition rates; the healthy fraction dose (Dhij) deposited in the healthy tissue in each fraction j does not exceed the maximum healthy conventional fraction dose (Dch0ij); and At the end of the N fractions, the total healthy dose (DhTi) deposited in the healthy tissues does not exceed the maximum healthy conventional dose (Dch0Ti); A healthy cell is located upstream of the peripheral surface when a charged particle beam defined in the TPS traverses the healthy cell before penetrating the peripheral surface. A treatment planning system (TPS) according to any one of claims 2 to 4.

6. configured to generate the plan for treatment such that all healthy tissue downstream of the circumferential surface is irradiated only with a very high dose deposition rate; the healthy fraction dose (Dhij) deposited in the healthy tissue in each fraction j does not exceed the maximum high-rate healthy fraction dose (Dhh0ij); and At the end of the N fractions, the total healthy dose (DhTi) deposited in the healthy tissues does not exceed the maximum healthy conventional dose (Dch0Ti); A healthy cell is located downstream of the peripheral surface when a charged particle beam defined in the TPS intersects the healthy cell only after exiting the peripheral surface. A treatment planning system (TPS) according to any one of claims 2 to 5.

7. One or more of the partitions of the plan are performed according to the steps of: by a first charged particle beam or a group of charged particle beams parallel to a first direction, each of which is formed by a different beamlet, in each or a portion of said one or more fractions, a conventional target fractionated dose (Dctj) ​​is delivered to at least 90%, preferably at least 95%, more preferably at least 99% of said tumor cells in said target tissue (3t); and In each or a portion of the one or more fractions, a conventional healthy fractionated dose (Dchij) that is lower than the maximum healthy conventional fractionated dose (Dchij) (i.e., Dchij<Dchij) is delivered to the healthy tissue (3hi) surrounding and enclosed within the peripheral surface. a first step of delivering a conventional dose at a conventional dose deposition rate (CDR) such that After the first step, a second charged particle beam or group of charged particle beams parallel to a second direction, which may be the same as or different from the first direction, a high-fraction target fractionated dose (Dhtj) is delivered to the target tissue (3t) in each or a portion of the one or more fractions such that 100% of the tumor cells in the target tissue (3t) are conventionally and / or very high-fractionally (CDR, HDR) fractionated; and In each or a portion of the one or more fractions, a high-rate healthy fraction dose (Dhhij) is delivered to the healthy tissue (3hi) surrounding and within the peripheral surface such that the equivalent healthy fraction dose (Dmhij=Dchij+αDhhij) delivered to all healthy cells both conventionally and with very high rates (CDR, HDR) does not exceed the maximum conventional healthy fraction dose (Dch0ij) (i.e. Dmhij≦Dch0ij). a second step of delivering a high rate dose at an ultra-high dose deposition rate (HDR) such that 7. A treatment planning system (TPS) according to any one of claims 1 to 6, comprising, in any order:

8. 8. The treatment planning system (TPS) of claim 7, wherein the second charged particle beam or group of charged particle beams does not overlap with the first charged particle beam or group of charged particle beams in any healthy tissue (3hi) surrounding or within the outer peripheral surface.

9. - a conventional target fractionated dose (Dctj) ​​is delivered to at least 90%, preferably at least 95%, more preferably at least 99% of the target cells of the target tissue (3t); a conventional healthy fractionated dose (Dchij) lower than the maximum healthy conventional fractionated dose (Dchij) (i.e. Dchij<Dchij) is delivered to the healthy tissue (3hi) surrounding and enclosed within the peripheral surface; - a high-fraction target fractionated dose (Dhtj) is delivered to the target tissue (3t) in each or a portion of the one or more fractions such that 100% of the tumor cells in the target tissue (3t) are conventionally and / or very high-fraction (CDR, HDR) fractionated dose; and A high-rate healthy fractionated dose (Dhhij) is delivered to the healthy tissue (3hi) surrounding and within the peripheral surface in each or a portion of the one or more fractions such that the equivalent healthy fractionated dose (Dmhij=Dchij+αDhhij) delivered to all healthy cells both conventionally and very high-rate (CDR, HDR) does not exceed the maximum conventional healthy fractionated dose (Dch0ij) (i.e., Dmhij≦Dch0ij). A treatment planning system (TPS) according to any one of claims 1 to 4, comprising a single charged particle beam (PB) or a group of beams parallel to a first direction, formed by beamlets such that:

10. the outer circumferential surface includes an uncertainty volume that defines an uncertainty region (3z) that is defined as a region that contains both tumor cells and healthy cells in different proportions; The TPS is The total health dose (DhTi=DchTi+DhhTi) is greater than the minimum target dose (DmtT0) and less than the maximum high-rate health dose (DhhT0i) (i.e. DmtT0<DhTi<DhhT0i); and the total equivalent health dose (DmhTi = DchTi + αDhhTi) delivered at the end of N fractions is lower than the maximum health conventional dose (DchT0i) of the healthy tissue (3hi) present in the uncertainty region (i.e. DmhTi < DchT0i); and The equivalent healthy fraction dose delivered in each fraction j (Dmhij = Dchij + αDhhij) is lower than the maximum healthy conventional fraction dose (DchT0ij) of the healthy tissue (3hi) present in the uncertainty region (i.e. DmhTi < DchT0i). and delivering a total health dose (DhTi) to the entire uncertainty volume at the end of the N fractions such that A treatment planning system (TPS) according to any one of claims 2 to 9.

11. A treatment planning system (TPS) according to any one of claims 1 to 10, wherein for selecting healthy tissue (3hi), the maximum healthy conventional dose (DchT0i) at the end of the N fractions is defined as follows: 【Table 1】

12. A treatment planning system (TPS) according to any one of claims 1 to 11, wherein for the selection of healthy tissue (3hi), the maximum high-rate healthy dose (DhhT0i) at the end of the N fractions is defined as follows: 【Table 2】

13. A treatment planning system (TPS) according to any one of claims 1 to 12, wherein the charged particle beam is a proton beam delivered in single or heavy scattering mode or by pencil beam scanning (PBS).

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