Perfusion modulated tumor dose sculpting with single dose radiotherapy

1. A method of treating a tumor in a subject in need thereof, said tumor comprising:

a total planning target volume (PTV TOTAL ) comprising the tumor's total volume, wherein the PTV TOTAL comprises a first planning target sub-volume (PTV HD ) and a second planning target sub-volume (PTV PMDS ), wherein the PTV PMDS comprises at least 5% of the tumor's total volume;

wherein the method comprises delivering a radiation dose to each of the PTV PMDS and PTV HD , wherein the dose of radiation delivered to the PTV PMDS is lower than the dose of radiation delivered to the PTV HD , and

wherein the dose of radiation delivered to the PTV PMDS is insufficient to treat the tumor when delivered to the entirety of the PTV TOTAL , 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.

2. The method of claim 1 , wherein the PTV HD comprises at least 60% of the PTV TOTAL or wherein the PTV HD comprises at least 60% of the tumor's total volume.

3. The method of claim 1 , wherein the PTV PMDS comprises 40% or less of the PTV TOTAL or wherein the PTV PMDS comprises at least 5% of the PTV TOTAL .

4. The method of claim 1 , wherein the dose of radiation delivered to the PTV HD 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 PTV PMDS 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 PTV PMDS is at least 10% lower than the dose of radiation delivered to the PTV HD , or is between about 10% and about 50% lower than the dose of radiation delivered to the PTV HD , or is at least 50% lower than the dose of radiation delivered to the PTV HD ; or

wherein the dose of radiation delivered to the PTV HD and the dose of radiation delivered to the PTV PMDS are delivered in the same treatment session or are delivered simultaneously in the same treatment session.

5. The method of claim 1 , wherein the dose of radiation delivered to 99% of the PTV PMDS is at least 20% lower than the dose of radiation delivered to 99% of the PTV HD or wherein the dose of radiation delivered to 95% of the PTV PMDS is at least 20% lower than the dose of radiation delivered to 95% of the PTV HD .

6. 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.

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 (PTV TOTAL ) comprising the tumor's total volume, wherein said PTV TOTAL comprises a first planning target sub-volume (PTV HD ) and a second planning target sub-volume (PTV PMDS ), wherein the PTV PMDS comprises at least 5% of the tumor's total volume;

ii) define a radiotherapy treatment plan for said PTV TOTAL ; and

iii) send, to the radiation source, a signal indicative of an instruction to deliver radiation doses to the PTV TOTAL , wherein the dose of radiation delivered to the PTV PMDS is less the dose of radiation delivered to the PTV HD ;

wherein the dose of radiation delivered to the PTV PMDS is insufficient to treat the tumor when delivered to the entirety of the PTV TOTAL , optionally wherein

the tumor is adjacent to a dose limiting organ at risk (OAR), optionally wherein the OAR is a serial OAR.

8. 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.

9. The system of claim 7 , wherein the PTV HD comprises at least 60% of the PTV TOTAL or wherein the PTV HD comprises at least 60% of the tumor's total volume.

10. The system of claim 7 , wherein the PTV PMDS comprises 40% or less of the PTV TOTAL or wherein the PTV PMDS comprises at least 5% of the PTV TOTAL .

11. The system of claim 7 , wherein the dose of radiation delivered to the PTV HD 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 PTV PMDS 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 PTV PMDS is at least 10% lower than the dose of radiation delivered to the PTV HD , or is between about 10% and about 50% lower than the dose of radiation delivered to the PTV HD , or is at least 50% lower than the dose of radiation delivered to the PTV HD ; or

wherein the dose of radiation delivered to the PTV HD and the dose of radiation delivered to the PTV PMDS are delivered in the same treatment session or are delivered simultaneously in the same treatment session.

12. The system of claim 7 , wherein the dose of radiation delivered to 99% of the PTV PMDS is at least 20% lower than the dose of radiation delivered to 99% of the PTV HD or wherein the dose of radiation delivered to 95% of the PTV PMDS is at least 20% lower than the dose of radiation delivered to 95% of the PTV HD .

13. 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 PTV TOTAL 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.

14. A method of treating a tumor in a subject in need thereof comprising:

defining, at a processor, a total planning target volume (PTV TOTAL ) of the tumor;

dividing, at the processor, the PTV TOTAL of the tumor into at least a first planning target sub-volume (PTV HD ) and a second planning target sub-volume (PTV PMDS ), wherein the PTV PMDS 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 PTV HD and the PTV PMDS based on the PMDS radiotherapy plan,

wherein the dose of radiation covering 95% of the PTV PMDS is lower than the dose of radiation covering 95% of the PTV HD and wherein the dose of radiation covering 95% of the PTV PMDS 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.

15. The method of claim 14 , wherein the PTV HD comprises at least 60% of the total PTV TOTAL or wherein the PTV HD comprises at least 60% of the tumor's total volume.

16. The method of claim 14 , wherein the PTV PMDS comprises 40% or less of the PTV TOTAL or wherein the PTV PMDS comprises at least 5% of the PTV TOTAL .

17. The method of claim 14 , wherein the dose of radiation delivered to 95% of the PTV HD 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 PTV PMDS 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 PTV PMDS is at least 10% lower than the dose of radiation delivered to 95% of the PTV HD or is between about 10% and about 50% lower than the dose of radiation delivered to 95% of the PTV HD , or is at least 50% lower than the dose of radiation delivered to 95% of the PTV HD ; or

wherein the dose of radiation delivered to 95% of the PTV PMDS is at least 10% lower than the dose of radiation delivered to 95% of the PTV TOTAL required to treat the tumor, is between about 10% and about 50% lower than the dose of radiation delivered to 95% of the PTV TOTAL required to treat the tumor, or is at least 50% lower than the dose of radiation delivered to 95% of the PTV TOTAL required to treat the tumor; or

wherein the doses of radiation are delivered to the PTV HD and the PTV PMDS in the same treatment session or are delivered to the PTV HD and the PTV PMDS simultaneously in the same treatment session.

18. 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.

19. 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 PTV TOTAL 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.

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 (PTV TOTAL ) of the tumor;

dividing, at the processor, the PTV TOTAL of the tumor into at least a first planning target sub-volume (PTV HD ) and a second planning target sub-volume (PTV PMDS ), wherein the PTV PMDS comprises at least 5% of the tumor's total volume;

defining a dose of radiation for each of the PTV HD and the PTV PMDS ; and

defining the PMDS radiotherapy plan for treating the tumor wherein the dose of radiation covering 95% of the PTV PMDS is lower than the dose of radiation covering 95% of the PTV HD and wherein the dose of radiation covering 95% of the PTV PMDS is lower than the dose of radiation covering 95% of the total PTV required to treat the tumor.