# US 12,214,218 B2 · Perfusion modulated tumor dose sculpting with single dose radiotherapy

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- Number: US 12,214,218 B2
- Document ID: US12214218B2
- Status: Granted
- Kind: B2
- Application number: 17/631,152
- Filed: 2020-07-30
- Published: 2022-09-22
- Granted: 2025-02-04
- Earliest claimed: 2019-07-31
- Assignees: Memorial Sloan Kettering Cancer Center; Fundação D. Anna de Sommer Champalimaud e Dr. Carlos Montez Champalimaud
- Applicants: Memorial Sloan Kettering Cancer Center; FundaçãO D. Anna De Sommer Champalimaud E Dr. Carlos Montez Champalimaud
- Inventors: Richard Kolesnick; Zvi Fuks; Carlo Greco
- Web page: https://patentgrep.com/patent/US12214218B2

## CPC

- A61N 5/1031: {using a specific method of dose optimization}
- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61N 2005/1087: {Ions; Protons}
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present disclosure provides methods and systems for treating tumors with radiotherapy, wherein a first dose of radiation is administered to a first sub-volume of the tumor and a second dose of radiation is administered to a second sub-volume of the tumor.

## Claims

### Claim 1

A method of treating a tumor in a subject in need thereof, said tumor comprising:
a total planning target volume (PTVTOTAL) comprising the tumor's total volume, wherein the PTVTOTAL comprises a first planning target sub-volume (PTVHD) and a second planning target sub-volume (PTVPMDS), wherein the PTVPMDS comprises at least 5% of the tumor's total volume;
wherein the method comprises delivering a radiation dose to each of the PTVPMDS and PTVHD, wherein the dose of radiation delivered to the PTVPMDS is lower than the dose of radiation delivered to the PTVHD, and
wherein the dose of radiation delivered to the PTVPMDS is insufficient to treat the tumor when delivered to the entirety of the PTVTOTAL, optionally wherein:
the method reduces incidence of local relapse compared to fractionated radiotherapy methods, or
the tumor is adjacent to a dose limiting organ at risk (OAR), optionally wherein the OAR is a serial OAR, or
the radiation is delivered from a radiation source comprising a radioactive element selected from the group consisting of radioactive cesium, iridium, iodine, cobalt, and combinations thereof, or
the radiation is delivered from a radiation source selected from the group consisting of an x-ray emitter, an electron beam emitter, a proton beam emitter, and a linear accelerator.

### Claim 2 (depends on 1)

The method of claim 1, wherein the PTVHD comprises at least 60% of the PTVTOTAL or wherein the PTVHD comprises at least 60% of the tumor's total volume.

### Claim 3 (depends on 1)

The method of claim 1, wherein the PTVPMDS comprises 40% or less of the PTVTOTAL or wherein the PTVPMDS comprises at least 5% of the PTVTOTAL.

### Claim 4 (depends on 1)

The method of claim 1, wherein the dose of radiation delivered to the PTVHD is at least 18 Gy, at least 19 Gy, at least 20 Gy, at least 21 Gy, at least 22 Gy, at least 23 Gy, at least 24 Gy, at least 25 Gy, at least 26 Gy, or between about 22 Gy and about 25 Gy; or
wherein the dose of radiation delivered to the PTVPMDS is less than about 23 Gy, less than about 18 Gy, less than about 12 Gy, between about 12 Gy and 23 Gy, or between about 12 Gy and 18 Gy; or
wherein the dose of radiation delivered to the PTVPMDS is at least 10% lower than the dose of radiation delivered to the PTVHD, or is between about 10% and about 50% lower than the dose of radiation delivered to the PTVHD, or is at least 50% lower than the dose of radiation delivered to the PTVHD; or
wherein the dose of radiation delivered to the PTVHD and the dose of radiation delivered to the PTVPMDS are delivered in the same treatment session or are delivered simultaneously in the same treatment session.

### Claim 5 (depends on 1)

The method of claim 1, wherein the dose of radiation delivered to 99% of the PTVPMDS is at least 20% lower than the dose of radiation delivered to 99% of the PTVHD or wherein the dose of radiation delivered to 95% of the PTVPMDS is at least 20% lower than the dose of radiation delivered to 95% of the PTVHD.

### Claim 6 (depends on 1)

The method of claim 1, wherein the method further comprises administering a radio-sensitizing agent to the subject prior to delivering the radiation to the subject, optionally wherein
the radio-sensitizing agent is an ASMase/Ceramide activating agent selected from a vector comprising a polynucleotide encoding the ASMase protein, an anti-angiogenic agent (AAA), a composition comprising ceramide, a recombinant ASMase protein, a ceramidase antagonist, and a sphingosine kinase antagonist; or
the radio-sensitizing agent is an ASMase/Ceramide activating agent selected from a protein kinase C (PKC) activator, TNF-alpha, an agent that downregulates or inhibits the expression and/or activity of caveolin-1 (CAV1), CD95 (Fas/APO-1), lipopolysaccharide (LPS), Palmitic acid (PA), lysobisphophatidic acid (LBPA), and phosphatidylinositol (PI); or
the radio-sensitizing agent is selected from the group consisting of fluoropyrimidine, gemcitabine, a platinum analog such as cisplatin, NBTXR3, Nimoral, trans sodium crocetinate (TSC), NVX-108, misonidazole, metronidazole, tirapazamine, vandate, nitroimidazole alkylsulfonamides, ATR inhibitor AZD6738, taxane containing at least 2 electron-affinic radiosensitizing functional groups, 2-carboxyaldehyde pyridine thiosemicarbazone compound or prodrug thereof, substituted diamines containing 2-4 electron-affinic radiosensitizing functional groups, lanthanide-based nanoparticles, platinum complexes with one radiosensitizing ligand, indazolpyrrolotriazines, anthraquinones, and monomethyl auristatin e (mmae) and derivatives thereof, or
the sensitizing agent is selected from the group consisting of a fluorocarbon, a halogenated nucleoside or its analog, a poly-(ADP-ribose)-polymerase (PARP) inhibitor, a histone H3 demethylase inhibitor, and a histone deacetylase (HDAC) inhibitor.

### Claim 7

A system comprising:
a) a radiation source; and
b) an electronic device, the electronic device including at least a memory and a processor operatively coupled to the memory and configured to execute instructions stored on the memory, the processor configured to:
i) define a total planning target volume (PTVTOTAL) comprising the tumor's total volume, wherein said PTVTOTAL comprises a first planning target sub-volume (PTVHD) and a second planning target sub-volume (PTVPMDS), wherein the PTVPMDS comprises at least 5% of the tumor's total volume;
ii) define a radiotherapy treatment plan for said PTVTOTAL; and
iii) send, to the radiation source, a signal indicative of an instruction to deliver radiation doses to the PTVTOTAL, wherein the dose of radiation delivered to the PTVPMDS is less the dose of radiation delivered to the PTVHD;
wherein the dose of radiation delivered to the PTVPMDS is insufficient to treat the tumor when delivered to the entirety of the PTVTOTAL, optionally wherein
the tumor is adjacent to a dose limiting organ at risk (OAR), optionally wherein the OAR is a serial OAR.

### Claim 8 (depends on 7)

The system of claim 7, wherein the radiation source is selected from the group consisting of an x-ray emitter, an electron beam emitter, a proton beam emitter, and a linear accelerator or wherein the radiation source comprises a radioactive element selected from the group consisting of radioactive cesium, iridium, iodine, cobalt, and combinations thereof.

### Claim 9 (depends on 7)

The system of claim 7, wherein the PTVHD comprises at least 60% of the PTVTOTAL or wherein the PTVHD comprises at least 60% of the tumor's total volume.

### Claim 10 (depends on 7)

The system of claim 7, wherein the PTVPMDS comprises 40% or less of the PTVTOTAL or wherein the PTVPMDS comprises at least 5% of the PTVTOTAL.

### Claim 11 (depends on 7)

The system of claim 7, wherein the dose of radiation delivered to the PTVHD is at least 18 Gy, at least 19 Gy, at least 20 Gy, at least 21 Gy, at least 22 Gy, at least 23 Gy, at least 24 Gy, at least 25 Gy, at least 26 Gy, or between about 22 Gy and about 25 Gy; or
wherein the dose of radiation delivered to the PTVPMDS is less than about 23 Gy, less than about 18 Gy, less than about 12 Gy, between about 12 Gy and 23 Gy, or between about 12 Gy and 18 Gy; or
wherein the dose of radiation delivered to the PTVPMDS is at least 10% lower than the dose of radiation delivered to the PTVHD, or is between about 10% and about 50% lower than the dose of radiation delivered to the PTVHD, or is at least 50% lower than the dose of radiation delivered to the PTVHD; or
wherein the dose of radiation delivered to the PTVHD and the dose of radiation delivered to the PTVPMDS are delivered in the same treatment session or are delivered simultaneously in the same treatment session.

### Claim 12 (depends on 7)

The system of claim 7, wherein the dose of radiation delivered to 99% of the PTVPMDS is at least 20% lower than the dose of radiation delivered to 99% of the PTVHD or wherein the dose of radiation delivered to 95% of the PTVPMDS is at least 20% lower than the dose of radiation delivered to 95% of the PTVHD.

### Claim 13 (depends on 7)

The system of claim 7, further comprising:
an imaging device configured to capture one or more images of the tumor,
wherein the processor is configured to define the PTVTOTAL based at least in part on the one or more images of the tumor captured by the imaging device, optionally wherein
the electronic device and the radiation source are included in a single machine; or
the electronic device is in communication with the radiation source via a network; or
wherein the imaging device and the radiation source are included in the same machine; or
wherein the imaging device and the electronic device are included in the same machine; or
wherein the imaging device is in communication with the electronic device via a network.

### Claim 14

A method of treating a tumor in a subject in need thereof comprising:
defining, at a processor, a total planning target volume (PTVTOTAL) of the tumor;
dividing, at the processor, the PTVTOTAL of the tumor into at least a first planning target sub-volume (PTVHD) and a second planning target sub-volume (PTVPMDS), wherein the PTVPMDS comprises at least 5% of the tumor's total volume;
sending, from the processor and to a radiation source, a signal associated with a perfusion modulated dose sculpting (PMDS) radiotherapy plan; and
delivering, from the radiation source, a dose of radiation to each of the PTVHD and the PTVPMDS based on the PMDS radiotherapy plan,
wherein the dose of radiation covering 95% of the PTVPMDS is lower than the dose of radiation covering 95% of the PTVHD and wherein the dose of radiation covering 95% of the PTVPMDS is lower than the dose of radiation covering 95% of the total PTV required to treat the tumor, optionally wherein
the method reduces incidence of local relapse compared to fractionated radiotherapy methods or
the tumor is adjacent to a dose limiting organ at risk (OAR), optionally wherein the OAR is a serial OAR.

### Claim 15 (depends on 14)

The method of claim 14, wherein the PTVHD comprises at least 60% of the total PTVTOTAL or wherein the PTVHD comprises at least 60% of the tumor's total volume.

### Claim 16 (depends on 14)

The method of claim 14, wherein the PTVPMDS comprises 40% or less of the PTVTOTAL or wherein the PTVPMDS comprises at least 5% of the PTVTOTAL.

### Claim 17 (depends on 14)

The method of claim 14, wherein the dose of radiation delivered to 95% of the PTVHD is at least 18 Gy, at least 19 Gy, at least 20 Gy, at least 21 Gy, at least 22 Gy, at least 23 Gy, at least 24 Gy, at least 25 Gy, at least 26 Gy, or between about 22 Gy and about 25 Gy, or
wherein the dose of radiation delivered to 95% of the PTVPMDS is less than about 23 Gy, less than about 18 Gy, less than about 12 Gy, between about 12 Gy and 23 Gy or between about 12 Gy and 18 Gy; or
wherein the dose of radiation delivered to 95% of the PTVPMDS is at least 10% lower than the dose of radiation delivered to 95% of the PTVHD or is between about 10% and about 50% lower than the dose of radiation delivered to 95% of the PTVHD, or is at least 50% lower than the dose of radiation delivered to 95% of the PTVHD; or
wherein the dose of radiation delivered to 95% of the PTVPMDS is at least 10% lower than the dose of radiation delivered to 95% of the PTVTOTAL required to treat the tumor, is between about 10% and about 50% lower than the dose of radiation delivered to 95% of the PTVTOTAL required to treat the tumor, or is at least 50% lower than the dose of radiation delivered to 95% of the PTVTOTAL required to treat the tumor; or
wherein the doses of radiation are delivered to the PTVHD and the PTVPMDS in the same treatment session or are delivered to the PTVHD and the PTVPMDS simultaneously in the same treatment session.

### Claim 18 (depends on 14)

The method of claim 14, wherein sending the signal from the processor to the radiation source includes sending the signal via a network, or wherein the processor is included in an electronic device having at least the processor and a memory and wherein the electronic device and the radiation source are included in a single machine.

### Claim 19 (depends on 14)

The method of claim 14, further comprising:
capturing one or more images of the tumor via an imaging device; and
sending, from the imaging device and to the processor, data associated with the one or more images;
wherein the processor is configured to define the PTVTOTAL based at least in part on the data associated with the one or more images of the tumor, optionally wherein
the imaging device and the radiation source are included in the same machine; or
wherein the processor is included in an electronic device having at least the processor and a memory, and wherein the electronic device and the imaging device are included in a single machine; or
the imaging device is in communication with the electronic device via a network.

### Claim 20

A method of defining a perfusion modulated dose sculpting (PMDS) radiotherapy plan for treating a tumor in a subject in need thereof, the method comprising:
defining, at a processor, a total planning target volume (PTVTOTAL) of the tumor;
dividing, at the processor, the PTVTOTAL of the tumor into at least a first planning target sub-volume (PTVHD) and a second planning target sub-volume (PTVPMDS), wherein the PTVPMDS comprises at least 5% of the tumor's total volume;
defining a dose of radiation for each of the PTVHD and the PTVPMDS; and
defining the PMDS radiotherapy plan for treating the tumor wherein the dose of radiation covering 95% of the PTVPMDS is lower than the dose of radiation covering 95% of the PTVHD and wherein the dose of radiation covering 95% of the PTVPMDS is lower than the dose of radiation covering 95% of the total PTV required to treat the tumor.