Treatment Modalities AB 25% Flashcards
Define sentinel lymph node (SLN)
first node identifiable after peritumoral injection of a radioactive marker and subsequent scintigraphy
if SLN is negative, other LN in the chain likely to be negative
Most common scintigraphic SLN mapping technique?
Injection of methylene blue with use of gamma probe in the operating room to detect the LN with greatest radioactivity
What % of cutaneous MCT were found to have a different SLN than the atomic local LN using SLN mapping?
42%
What is indirect lymphography?
injection of a contrast agent in the periphery of the tumor with serial or real time imaging to follow contrast uptake –> first contrasting node I/D with imaging –> then vital dye (methylene blue) is injected intraop in the same location as the contrast for visual confirmation of the SLN
What is the preferred type of agent for lymphography? CT lymphography?
lipid soluble to permit longer imaging
- CT lymphography is using same technique with CT pre-op. A 2021 study showed that viscosity did not affect uptake but massaging did
Success rate of lymphography?
96.6% for solid tumors
What can be combined with indirect lymphography?
Near infrared fluorescence; although not a great test NIF alone failed in 20% of tumors when combined 40% agreement
in this study 95% of tumors were low grade/grade II with 95% found have mets HN2-3
What can hinder the ability of technetium 99/methylene blue scintigraphy in cutaneous MCT?
surgical scar tissue from previous sx
- 63% different than regional LN
- early mets in 56%
What is the sensitivity of FNA w/ cytology for LN?
compared to histo after FNA
sn:
- carcinoma 100%
- sarcoma 67%
- melanoma 63%
- MCT 75%
- other round cell 100%
sp ranged from 83-96%
non-diagnostic in 25%
What can reduce surgery time when performing lympadenectomy?
ultrasound guided placement of an anchor wire or methylene blue compared to blind
SLN enhancement patterns (homogenous, peripheral, heterogeneous) during computed tomography lymphagiograph can predict metastatic status?
no
What can enhance the the sn of preoperative computed tomography lymphography?
combining with intraopterate SLN maps with near infrared fluoresce and indocyanine green
What is a promising technique for SLN mapping that does not require AX for MCT?
contrast enhanced ultrasound with microbubbles
SLN mapping detection, correspondance, and prevalence in dog head and neck cancers that have clinically normal LN?
- SLN detected in 83% which did not correspond to the regional LN in 52%
- 42% ended up being metastatic
FYI in this paper radiopharmaceutical and blue dye sn ~89%, sp 100%
Complication rate following SLN biopsy guided by y-probe and meth blue?
24% post op 92% of which were lymphodema
high BW higher likelihood
What is lymphotropic nanoparticle MRI?
- use of paramagnetic iron nanoparticles for imaging metastatic LN with MRI
- nanoparticles phagocytized by Macs then localized to LN where they create suspectibilty artifact
- overall Sn 64%, Sp 95%, accuracy 90%
- excluding MCT Sn 86%, sp 96%, ac 94%
What is a cost effect technique for SLN mapping?
intratumoral iohexole then rads 90% MCT SLN detected
What is the difference between autologous and allogenic bone marrow transplant?
autologous - stem cells harvested from self = self donor, cures 33-40%
allogenic - stem cells harvest from an immune matched related or unrelated donor, cures 89%
Plasma nucleosome concentrations can be used for ____ in hematopoietic malignancies
- LSA, AML, MM
- can be used to for treatment monitoring and disease progression
- sig higher at diagnosis and PD then when in remission
- highest [ ] dogs had sig shorter PFS than dogs with lower nucleosome [ ]
Thermographic assessment of normal skin vs soft tissue tumors in cats revealed that higher temperatures were found in malignant tumors vs benign. What is the Sn and Sp?
- Sens 76%
- Spec 80%
How can liquid biopsy (cfDNA) using next gen sequencing % detection based on disease status?
- 32% early stage cancer
- 48% preclinical dogs
- 84% advanced stage cancer
- dogs with diagnosis of cancer were enrolled
Sn, sp, and PPV screening vs aid in dx liquid biopsy?
- SN 61.5%, SP 97.5%
- PPV screening 75%, PPV aid in DX 97.7%
- LSA, HSA, HS, and malignant melanoma most likely circulating
- STS, OSA, MST least likely
Searchlight DNA genomic diagnostic assay (Vidium) % of diagnostic clarity and prognostic clarity?
- DX 54%
- therapeutic/prognostic 69%
- Clinically useful in 86% of cases overall
Is sternal lymphadenopathy a neg prognostic indicator for dogs presenting with hemoabdomen?
no- but may be predictive of shorter OST in HSA and 19 other splenic malignancies
What are coated platelets?
a subset of activated plt generated by dual stimulation of thrombin and convulxin found to be elevated in dogs with solid tumors compared to healthy controls
Which 5 microRNAs have been associated with splenic mass (HSA or hematoma) vs healthy controls?
miR-214-3p,
- 452
-494-3p
-497-5p
-543
Circulating macrophage like cells may indicate?
severe inflammation, HS, or non HS cancer
albumin blood to effusion ratio associated with cancer?
> 0.6
Is there a difference in using 22-g vs 25-g needles for FNA?
No - does not affect ability to make dx
- 25 associated with less blood contamination but more trauma
SDMA 10x upper limits of normal without concurrent azotemia in a dog may be suggestive of?
LSA
3x in cats
sig higher in LSA than non tumor controls
Wilm’s tumor protein 1 might be able to help differentiate?
- higher in mesothelial hyperplasia than carcinoma
- negative in carcinoma as was desmin (in all but one)
- still not definitive
What is the overall disagreement on any variable between 1st and 2nd opinion histopathology?
- overall disagreement 49.5%
- complete (change in tumor type or malignancy) 15.6%
- Partial (subtypes, grades, margin, MC) 33.9%
- major (resulting in alteration of tx) 38.5%
- most commonly sought 2nd d/t atypical/poorly differentiated tumor 31.2% or discordant clinical picture 24.8%
- With any form of disagreement natural history favored 2nd option 33.3%
IHC for lymphangiosarcoma v. hemangiosarcoma
- Lymphangiosarcoma – PROX1, LYVE-1
- HSA (and lymphangio) – Factor VIII-related antigen, CD31
Re-classification of telangiectatic OSA and HSA
vWF staining – 20% OSA reclassified as HSA
Non-specific immunotherapy & examples
- strategies that augment general T-cell responses
e.g.
- cytokines (IL-2)
- immunological adjuvants (TLR agonists)
- agents that targets immunomodulatory molecules (check point inhibitors)
Specific immunotherapy & examples
- activation and enhancement of the # of Tcells that can recognize TAAs
e.g.
- Tumor associated proteins (Oncept)
- autologous and allogenic tumor (Torigen)
- adoptive cell therapies (CAR T cells, Elias)
Active immunotherapy
- stimulates the body’s own immune system to recognize and attack cancer cells or pathogens
- Oncept - need immune response to respond
Passive immunotherapy
- administration of pre-formed immune components, such as antibodies, to directly target cancer cells or pathogens
- moAbs, cytokines
Limitations of immunotherapy
- failure d/t immunosuppressive microenvironment established by tumors and ability to avoid elimination
- variable response rates with limited efficacy in some individuals/tumor types
- cost
- can result in auto-immune side effects
- delayed response
- need for specialized equipment (CAR T cells)
- resistance
- limited predictive biomarkers for response
Advantages of immunotherapy
- may improve other therapies (RT, chemo)
- may spare normal cells
- can result in memory (best with potent adjuvants e.g. CpG motifs)
- personalized medicine
- variation in SE from typical therapies
Liposomal clodronate therapy to eliminate MDSc can enhance the tumor response to chemotherapy with which cancer?
malignant histiocytosis
Principles to consider when using immunotherapy?
- Target: are there specific Ag to the tumor cells, TAAs, or check points expressed that can be targeted
- Tumor type: some tumor types are immunogenic (melanoma) and likely to respond while others are considered “cold” and unlikely to respond
- Tumor burden: may be best used after cytoreduction, larger heterogenous tumors may be not respond, mets may or may not respond based on immunogenicity, combination therapies may be best
In which phase of the cell cycle are cells most radiosensitive?
G2/M
In which phase of the cell cycle are cells most radio resistant?
S
How is gemcitabine a radio sensitizer?
Inhibition of ribonucleaotide reductase and DNA polymerase
What is the relationship between paclitaxel and radiation?
- Paclitaxel cell survivors accumulate in G2/M phase of the cell cycle = radiosensitive phase
- Paclitaxel targets p53 mutant while RT is more sensitive to p53 wild type
What are radiosensitizers?
compounds or agents that enhance the sensitivity of cancer cells to radiation therapy, making them more susceptible to radiation-induced cell death
Major benefits of radiosensitization?
- eliminate resistant cells (CSCs)
- inhibit repopulation
- Enhanced cell killing
- selective action - can sometimes
- synergism
- potential for lower RT dose
- TX of radio resistant tumors
Major cons of radiosensitization?
- off target effects - non selective
- resistance
- increased toxicity
- limited evidence
Which drug class has been used to specifically overcome hypoxia in tumors with radiosensitization?
- azoles (e.g.nimorazole, metronidazole) - fix damage produced by free radicals
- tirapazamine
- high doses required, too toxic including neurotoxicity in people
Drugs with some degree of synergy with RT?
ipilimumab
sorafenib
sunitinib
Rituximab
Erlotinib
Etoposide
Paclitaxel
Methotrexate
Hydroxyurea
Temozolomide
CCNU
Drugs with mild synergy with RT?
Bevacizumab
5 FU
Cisplatin/carbo
Drugs with moderate RT synergy?
PARP inhibitors
Cetuximab
Mitomycin C
ActinomycinD
Drugs with significant RT synergy?
Gemcitabine
Dox
DTIC
Mechanisms that result in clinical resistance to RT?
- hypoxia
- induced DNA repair ability
- increased levels of glutathione or free radical scavenging compounds
How can drugs influence that survival curve?
- the curve may be displaced downward by the amount of cell kill
- the shoulder on the curve may be lost representing an inability to repair from DNA damage
- the slope of the exponential part of the curve may change indication sensitization or protection
(Fig 17-13 T&H pg 422)
List radio protectors
amifostine (WR-2721) decreased the amount of RT damage to normal cells
MOA of radiosensitizers?
- typically additive
- target hypoxic cells
- increase O2 delivery
- decreased O2 consumption
Differences between SRT & IMRT?
SRT:
- 6-24 Gy/fx
- GTV = CTV
- mm margins
- CT/MR/PET-CT for planning
- strictly enforced spatial accuracy
- immobilization devices, resp management
- Palliative or curative intent
IMRT:
- 2.5-4.2 Gy/fx
- GTV<CTV<PTV , tumor may not have sharp boundaries
- cm margins
- CT planning
- moderate spatial accuracy
- immobilization techniques, minimal need for resp management
- Palliative or curative intent
What does SRT require?
- A tumor for targeting, cannot use in microscopic disease or surgical scar
- tx planning and administration that will provide dramatic drop off between the tumor and surrounding normal tissues
- a method of stereotactically verifying patient positioning
Result - normal late responding structures are spared through dose avoidance rather than be administering small dose per fraction like IMRT
Difference between IMRT and 3D-CRT?
3D-CRT - computerized plan where you set beam parameters, direction, etc and the computer calculates the dose = forward planning
IMRT- computerized plan where the desired dose is first determined then the computer calculated the ideal beam setup and multi leaf collimation movement
Tomotherapy
- form of IMRT that uses CT scanner built into the machine to deliver radiation in a helical manner while simultaneously obtaining CT images = LINAC + tomotherpay unit = cone beam
- adaptive planning
What is the difference between brchytherapy, plesiotherapy, and teletherapy?
Brachy - local RT delivered to tumor, cavity, etc via catheter implantation
Plesio - superficial RT e.g. strontium 90, low enevery beta RT
tele - external beam RT
Many linacs can produce electron beams which can be used for therapy. In which clinical scenarios are electrons the ideal tx?
superficial tumors
Dmax ~ 2cm, penetrates up to 5 cm on 6 MeV machine
What is the difference between the Compton and photoelectric effect? which dominates at 10 MV?
Photoelectric - electron ejection from solid/liquid surface
Compton - scattering of a photon by charged particle (e-) –> decreased energy/increased wavelenght dominates at 10 MV
Given the curve with different energies, what would be the best tx option for superficial tumors?
electrons
RT histogram shows higher dose to left eye than left lens?
OS blind, cataract
left lens high dose would be a cataract - is it blind due to the cataract ? idk this is dumb
Why do you add bolus with RT?
allows dose build up to occur before reaching the skin so superficial tumors can receive maximum dose
Linear energy transfer (LET)
- a measure of the density of ionizations along a radiation beam
- Higher LET radiations (particles: carbon, argon, alpha particles, protons, and neutrons) produce greater damage in a biologic system than lower LET radiations (electrons, gamma rays, x-rays)
What is true of high LET sources?
- require cyclotron (protons)
- higher relative biologic effectiveness
- less wasted dose (shoulder) per fraction
- better normal tissue appearing effects with few AE
Why is there increased survival with splitting RT dose?
repair
Sr90 treatment
- pure B emitter
- decays to yttrium
- superficial <2 mm deep
- delivers 100-200 Gy/fx
Dose volume histogram
Be able to assess and explain implications on normal/tumor tissues, recurrence, and morbidity
Color wash
Be able to assess and explain implications on normal/tumor tissues, recurrence, and morbidity
- same if contouring image given
Standard fractionated protocol, goals, indications, toxicity?
- 2.7-4 Gy 3-5x/week total 42-57 Gy
- improve outcome/tumor control, limit late toxicity by delivering lower dose per fraction tissues have time to repair
- various indications e.g. microscopic disease control
- acute>late
Accelerated RT protocols goals, indications, toxicity?
- reducing overall treatment time by giving more than 1 dose per day (same dose divided in 2)
- improve tumor control has been seen with head and neck cancers in people
- allows less time for repair to may result in enhanced late effects some of which could be fatal
- acute effects will be common
Coarse fractionated RT protocols goals, indications, toxicity?
- eg. 6 Gy x 6 aka hypofractionated protocol that has curative intent
- higher dose per fraction, smaller # of fractions, lower overall dose
- minimize acute AE, late AE more likely
- tumors with low a/b ratio e.g. melanoma
When is a 5% probability of late effects acceptable? 1%?
5% - patient will not live without treatment and will likely not live long enough to develop late AE
1% - sensitive structures (spinal cord) where a late affect would result in paralysis
Palliative vs definitive RT?
- definitive going for the cure with various protocols (SRT vs coarse vs standard)
- palliative providing pain relief, minimizing AE, cost, and time commitments typically 6-10Gy x 1-6 fx once or twice weekly
- do not require strict adherence to RT biologic principles as patients should not live long enough to experience late effetcs
Reirradiation goals, toxicity, indications?
- retreat recurrent tumors or new tumors along previously treated sight
- have to carefully considered is there was a positive response initially and which tissues (late vs acute responding) are in the area. IN general, early responders recover and tolerate treatment better than late
- have seen with brain tumors and SRT, nasal tumors, repeated palliative treatment
Which cells are sensitive to the late effects of RT?
vascular endothelial cells
Late responding tissues
Steeper = late responding tissues
What causes acute and chronic RT AE?
ACUTE/early responding:
- damage to rapidly dividing tissues repaired by stem cells
- high a/b
LATE/chronic responding:
- vascular damage and loss of parenchymal cells
- low a/b
How can use reduce acute and late RT AE?
ACUTE:
- longer duration of tx
- hyperfractionation
- overall tx time important and fx size
Chronic:
- decrease total dose
- hypofractionation
- total dose important
Why is there interest in hypofractionated protocols?
- some tumors have low a/b ration (melanoma) IMRT more precise or SRT
- less acute AE on tumor vasculatur
- reoxygenation
Wide shoulder RT curve =
Lower ability for tumor to repair sublethal dame, low alpha beta
BLUE LINE = WIDE SHOULDER
How does I-131 work?
SQ/IV/oral radiopharmaceutical that travels to the thyroid gland and releases beta particles (electrons) and gamma particles (photons) then excreted in urine/feces (3-5d)
I-131 uses?
Thyroid tumors - 2 mCi or can calculate based on T4/T3/TSH levels
What are disadvantages of I-131?
cost, availability, hospitalization, toxicosis, hypothyroidism, public health
What is Sm-153?
Samarium - radionuclide with anti-tumor properties and pain relief in bone tumors
Owners perception of QOL following RT?
92% happy 88% would tx again
Does RT improve neurologic signs in cats with brain tumors?
Yes
- ~42 Gy in 22 cats
- all but one had improved neuro signs 95.5%
- 55.7% free of progressive signs at 1 yr
- MST ~ 17 mo
Should you stop Palladia if you intend to deliver hypofractionated full abd RT?
Yes - increased rates of D+, hyperemia, and V+
- hyporexia often severe
- sig dif from just receiving one therapy at a time
Describe palliative inten QUAD protocol
- 3.5-4 fx given over 2-4 days for total dose of 14-16 Gy = 1 cycle
- 3 cycles rx in 1 month intervals for Toal of 42-48 Gy
- 25% PR, 67% SD for mix of nasal & oral tumors
- MPFS 7 mo
- 3% high grade acute toxicity
- 29% low grade late toxicity
- # of QUAD cycles, CB, and response duration associated with PFS
What % of dogs experience critical weight loss during RT?
~5.5%
Effects of local irradiation on circulating lymphocytes in dogs receiving fx therapy
- sig decrease in mean lymph count between pre and mid tx with increase in neut:lymph
- 33.5% sig lymphopenia
- lymph count correlated with volume irradiated:body weight
Response of thyroid tumors to I-131?
- 35.5% mostly PR
- MST 27 mo (no mets), 1 year (with mets)
- RT RR 70-100%
- Palladia 26-26%
DLT sm-153
neutropenia and thrombocytopenia
Sm-153 response rate
~50-60% improvement in pain
Chemical ablation
focuses on intralesional injection (usually ethanol) into the tumor
Hyperthermic ablation techniques
radiofrequency ablation
microwave ablation
high-intensity focused ultrasound
laser
- can be used percutaneously, during surgery, etc
Hypothermic ablation techniques
cryoablation
How does radiofrequency ablation work? Described tumors?
RFA electrode entered into the tumor –> electrical current –> ionic agitation –> generation of heat –> coagulation and cellular necrosis
- prostatic carcinoma
- parathyroid masses to manage hyperCA
Microwave ablation MOA? Benefit over radiofrequency? Tumors treated?
- electromagnetic energy to cause friction and heat –> coagulative necrosis
- higher intratumoral temperatures with faster ablation, less char, less pain, no grounding pads needed which can cause burns
- liver , pulmonary mets, renal carcinoma
MOA cryoablation? Tumors treated?
- causes cell death by forming ice crystals within cells
- nasal adenocarcinoma, head & neck tumors
Platinum impregnated beads recent use, AE, RR?
STS in dogs:
- mild and did not need additional sx: seroma, swelling, discharge
- ocal disease-free rates 1, 2, and 3 years after surgery were 70%, 70%, and 58%
% of dogs who receive Stelfonta CR after first dose?
- 75% with resolution of the MCT by 28 days
-no recurrence in 93% of dogs at 84 days
increased to 87% with two treatments
What is stelfonta’s efficacy dependent on?
area of the wound (tissue deficit) after slough of the necrotic tumor relative to pretreatment tumor volume
causes oncolysis, stimulation of acute inflammatory response and increased permeability of tumor vasculature
When does tumor slough occur after stelfonta? Time to heal?
- 3 to 14 days max day 7
- Wound area after tumor slough in general was related to pretreatment tumor volume
- 28-42 days most by 2nd intention, 5 needed bandaging
When does stelfonta failure most commonly occur?
-11% recurrence at 1 year
- all within 6 mo and predominately in first 12 weeks 71%
MOA of stelfonta?
-activator of protein kinase C/C1
- caspase/gasdermin E-dependent pyroptopic pathway
- acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum dysfunction (leading to unfolded protein responsemt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis
- promote activation of the integrated stress response together with the release/externalization of DAMPs damage-associated molecular patterns (HMGB1, ATP, calreticulin) characteristics indicative of immunogenic cell death
RR of stelfonta for high grade MCT?
- 56% CR to at least 84 days after their first or second treatment
- 50% tumor free at 2 years
- additional injection resulted in second CR in 3 dogs
(unclear how they knew high grade - appear presumptive +/- cyto grading)
Which tumors has steflonta been used for in horses?
Sarcoid disease free at 93 days
SCC decease free at 189 days
Photodynamic therapy MOA?
- Photosensitzer administered, taken up preferentially by cancer, cells, light activation, cell death by apoptosis, ROS formation
- PDT damages and restricts tumor microvasculature and causes local inflammation to stimulate immune response
Drugs used in photodynamic therapy?
Prodrugs – 5-ALA and MTHPC
Cancers treated with photodynamic therapy?
- SCC of nasal planum, urinary tumors in dogs, equine sarcoids
- superficial tumors, minimally invasive, minimal tox
MTHPC photodynamic tx in cats – effectiveness? Side effects?
Flickinger et al 2018
- IV inj of mTHPC and 4 hr later 652 nm light delivered w diode laser
- ORR was 84% (CR 61%, PR 22%) w mean PFI of 35 mo (med not reached) and MST of 40 mo
- Tumor stage – invasiveness yielded highly sig worse outcome
- All patients w invasive tumors showed progression at <6 mo
- Larger lesions assoc w inferior control and treatment intensity and tumor location did not influence response and duration
ALA photodynamic therapy in cats w nasal SCC – ORR? Relapse? Chance of new lesions?
- ORR in 2 separate studies – 96% and 85%
- 51% recurred within median of 157 d in 1 study, and 63.6% recurred within median of 21 weeks in other
BSA under doses? over doses?
- under doses large dogs
- over doses small dogs; receive more drug/kg
What is the issue with BSA dosing?
K (constant) and a (exponent) are incorrect and do not account for variations in breeds
or
a because a linear component such as body length is lacking
BSA formula dogs
10.1 x weight (kg) ^2/3 / 1000
BSA formula cats
10 x weight (kg)^2/3 / 1,000
When might BSA dosing actually be appropriate?
- If drug is eliminated intact by GF or degraded non enzymatically and eliminated with GFR being the rate limiting step
- If ithe rate and extent of drug distribution is equivalent for all breeds or is correlated to metabolic rate
What else affects drug dosing variability?
- enzymatic degradation/distribution may not be the same amongst breeds
- concurrent drugs can affect metabolism
- disease state may affect metabolism
Cell-kill hypothesis
a given dose of chemotherapy kills a constant proportion of tumor cells rather than a constant number
What are the key components of the cell kill hypothesis?
1) Dose response relationship between the concentration of a chemotherapeutic agent and its cytotoxic effect on cancer cells
- In general, higher doses of chemotherapy are expected to result in greater cancer cell kill
2) Logarithmic cell kill - each dose kills a % of cells
3) Cellular kinetics - effectiveness depends on the kinetics of the tumor
- e.g. fast growing with high proliferation rate are more susceptible to chemo
4) Fractional Cell Kill - fraction killed with each tx
- e.g. 90% kill rate (1 log kill) with each tx cycle then after 3 cycles ~99.9% of cancer cells eradicated
5) TX schedule - timing and frequency important
What is the Goldie Coleman Hypothesis?
a mathematic model that predicts that tumor cells mutate to a resistant phenotype at a rate dependent on their intrinsic genetic instability. The probability that a cancer would contain drug-resistant clones depends on the mutation rate and the size of the tumor. According to this hypothesis, even the smallest detectable cancers would contain at least one drug-resistant clone; therefore, the best chance of cure would be to use all effective chemotherapy drugs; in practice, this has meant using two different non-cross-resistant chemotherapy regimens in alternating cycles
use multimodal tx at FIRST treatment - first is best chance bc otherwise breed the resistant clones
What are the key aspects of the Goldie Coldman hypothesis?
1) Tumor heterogeneity
2) Tumor sensitivity: follows a distribution curve, with some cells being highly sensitive to the drug and others being relatively resistant
3) Drug resistant sub populations
- e.g. CSCs
4) Selection pressure & emergence of resistant colones: exposure to a chemo will result in mutations to resist in a population of cells
What are the clinical implications of the Goldie Coldman hypothesis?
- treat with multiple effective drugs that work through different MOA and have different mechanisms of resistance
- treat in the lowest disease setting where tumors are least heterogenous
What does the Gompertzian Growth Model assume?
Initially tumors grows exponentially then declines over time.
1) Exponential growth decline: the rate of growth of the population (or tumor) decreases exponentially over time. This means that as the population (or tumor) increases in size, the rate of increase gradually slows down.
2) Logarithmic growth: the decline in growth rate is assumed to follow a logarithmic curve, where the rate of decrease is proportional to the size of the population (or tumor) at any given time.
3) Asymptotic limit: the model predicts that growth eventually reaches a plateau or asymptotic limit, where the population (or tumor) size stabilizes and ceases to increase further. This reflects the finite resources available to support growth and the constraints imposed by the environment.
What are the clinical implications of Gompertzian Growth?
microscopic or small tumors are more likely to be in exponential phase (rapidly dividing) and more sensitive to chemotherapy
- treat early in lowest disease setting
If time for a solid tumor to doubling time is constant, what type of growth does this imply?
Gompertzian - exponential growth
followed by plateau
What is the therapeutic index?
ratio between the toxic dose and therapeutic dose for a drug
abstract for chemo bz MTD used
Define MTD
dose that represents the highest dose of a given drug that can be administered w/ few p experiencing unacceptable or irreversible AEs
Define biologically effective dose
dose based on measured response to a putative target or surrogate that is related to the MOA of the agent
What is dose intensity?
- measure of dose per unit of time
- allows comparison between protracted and compacted dosing schedules
Example of dose intensity
comparing q1 week vs q3 week scheduling to determine whether the total dose of the drug or the dose intensity relates to toxicity or therapeutic outcome
What is therapeutic gain?
- combination of two drugs or a drug with RT for improved tumor response relative to increased normal tissue toxicity
- additive or synergistic
Define dose density
- Giving same dose of a chemotherapy more frequently to kill cells in the rapid growth phase
- e.g. 2 vinc weeks in COP
AKA Norton-Simon model
What is the mechanism of action of bortezomib (Velcade)?
Bortezomib MOA is by proteasome inhibition
Forms of somatic afferent stimulation to relieve pain?
acupuncture needling, laser, and electroacupuncture
MOA of acupuncture?
nerve fiber stimulation begins at the needle-tissue interface –> local alterations in cytokines/inflammatory mediators –> normalization of circulation and immune function in the surrounding tissue –> agitation of connective tissue –> activation of somatic and autonomic nerve fibers that fire to CNS
In addition to propriospinal signaling, what changes does acupuncture induce?
- neuronal firing patterns in the limbic system, cerebellum, cortex, and brainstem
- affects mood, autonomic function and pain
Acupuncture and nausea
- study compared maropitant, acepromazine, saline, and acupuncture following dose of morphine in 222 healthy dogs
- maropitant was associated with lower vomiting incidence compared to controls
- ace and electroacupuncture prevented an increase in nausea following morphine
Human literature on acupuncture that could be extrapolated
- 3-armed, randomized, prospective clinical trial, women with high-grade mammary carcinoma who were treated with high-dose myeloablative chemotherapy were assigned to 1 of 3 groups: antiemetic alone, antiemetic with electroacupuncture, and antiemetic with acupuncture at a nontherapeutic location Women in the antiemetic with electroacupuncture treatment group had significantly fewer vomiting episodes
- Women with uterine cancer received therapeutic or non therapeutic acupuncture and WBC monitoring. Total WBC count higher and decreased grade 2-4 neutropenia in the acupuncture group. May help pv serious neutropenia
What else might acupuncture be useful for?
Pain- however limited research with randomized clinical studies to report use
AE and contraindications of acupuncture
- inflamed skin
- bleeding disorders
- pregnant animals (can induce premature labor)
- do not place in tumor or infected site - seeding
- pace makers
- rare risk of migrating needles
MOA of laser therapy?
tissues exposed to photons from light emitting diodes (LEDs) –> stimulation of cellular function (supports endogenous processes of cell division and proliferation)
WHY cancer is generally considered a contraindication for laser therapy
Physiologic processes of laser therapy?
phagocytosis, vasodilation, regeneration of lymphatic and blood vessels, increased enzyme activity at wound edges, fibroblast stimulation and proliferation, increased ATP and DNA synthesis
Role of laser therapy in vet oncology?
Oral mucositis treatment (phase III randomized double blind placebo controlled study showed reduced severity and pain scores with no AE)
When is laser therapy considered contraindicated in the cancer patient?
- at tumor site (unknown safe distance or wavelength)
- systemic cancers such as LSA
Benefits of massage/physical therapy?
- animals with acute or chronic illness exhibit heightened sympathetic tone –> maladaptive changes
- therapy increased parasympathetic tone which diminishes sympathetic tone
- counteracts peripheral vasoconstriction, inflammation, m. tension, spinal cord wind up and pain
When to use massage/physical therapy in cancer patients?
recovering from surgery, post-op or chemo induced ileus
Risks/AE/contraindications of massage/physical therapy?
- OSA, skeletal mets, spinal instability
- avoid over implants to deliver chemo, fragile previously RT sites
- hypercoagulation could induce emboli
- bleeding disorders
When are anti-oxidants recommended?
prior to cancer development to avoid oxidative damage- not helpful and counterproductive once cancer has developed and p undergoing chemo that causes oxidative damage to cancer cells
Which nutritional supplement has some scientific support for use in LSA?
- Polyunsaturated omega-3 fatty acids supplementation (EPA and DHA)
- study compared dogs undergoing chemo for LSA either receiving placebo diet or diet high in omega3
- dogs with omega 3 had sig longer DFI and ST
- study concerning because not clear about patient selection and randomization so may include bias
Which substrate has altered metabolism in cancer patients?
CHO - cancer cells can use as energy source
- high fat or protein diet may be more beneficial but no evidence to support
Cori cell cycle hypothesis?
- neoplastic tissue, like skeletal m., undergo regeneration of glucose from lactate through hepatic resythesis of glucose
- contributes increase in resting energy requirements
- study comparing dogs with LSA and healthy contraindicates this as there was no difference in RER between groups nor after removal of tumor burden within the cancer group
- Similar study for solid tumors OSA, high grade MCT
What may result in insulin resistance in dogs with LSA?
IL-6 aberrant influence on glucose metabolism
% of cats with LSA or solid tumors that have BCS < 5/9?
56%
- associated with ST in LSA, BSA >5 sig longer ST 16.9 mo vs 3.3 mo
Which AA can inhibit cancer cells by altering cell cycle progression?
Arginine - could improve outcomes in 1 study but realistically have to feed 100 mg/kg BW for improvement. Unpalatable and could result in AA dysregulation
Dose of fish oil dog?
45 mg EPA and 25 mg DHA per kg (e.g. 1 tsp/BW)
The addition of fatty acids to the diet may alter the intracellular signaling events specifically of which pathways?
-arachidonic acid release pathways
- may transform to inert eiconsanoids via 5-LOX –> LTB4, 5-oxo-ETE results in autocrine/paracrine activation
or
COX –> PGe2 –> proinflammitory LTB4, 12-HETE, 5-HETE
RT paradigm in relation to omegas?
omegas may be oxidized to a greater extent during RT leading to increased membrane compromise and cell death
Is vitamin A (retnoic acid) recommended for tx of cancer?
NO - can result in discordant effects on nuclear signaling with different heterodimers. Some cause proliferation of cells while others diminish proliferation
% of pet owners who incorporate non traditional feeding patterns after cancer diet in pet? Begin supplementation?
- > 50%
- 39%
mAbs target & general MOA?
extracellular domain of RTKs –> pv GF from binding, promote internalization of RTK and degradation, or induce immune response against the cancer cell
Small molecule inhibitors general MOA?
block ATP binding site of kinase acting as reversible or irreversible competitive inhibitors–> in the absence of ATP kinase is unable to phosphorylate itself for downstream signaling –> disrupting of survival/growth –> cell death
What is allosteric inhibition?
when small molecule inhibitor works by pv necessary protein-protein interaction
How does Verdinexor (Laverdia) work?
inhibits XPO-1 - forces retention of tumor suppressors p53, p21, RB, FOXO, NFkB to stay in cell and result in death
reversible, selective inhibitor of nuclear export (SINE) - it is selectively cytotoxic for cells with genomic damage (i.e. for tumor cells).
laverdia RR and DLT
- 35% RR (mostly long term SD) for LSA
- TTP 30-37 d ( 7-244 range)
- DLT hyporexia
subset of patients that responded well for a long time
how is verdinexor metabolized
The primary metabolism of LAVERDIA-CA1 in vitro and in vivo is thought to be inactivation by glutathione (GSH) conjugation. Therefore, administration of LAVERDIA-CA1 with drugs which undergo substantial GSH conjugation (e.g., acetaminophen) should be minimized.
verdinexor - laverdia AEs
The most common adverse reactions across all dose groups included: anorexia, vomiting, diarrhea, weight loss and lethargy.
also thrombocytopenia
PLN in one dog
Which is the most important DNA meythyltransferase in cancer?
DNMT1 - inhibited by 5-azacytidein and decitabine
How do demethylating agents (e.g. 5-aza work)?
- incorporate into DNA and inhibit DNMT activity
- DNMT hypermethylates regions that normally code for tumor suppressors in cancer
What are the issues with DNMT inhibitors?
- long term genome wide hypomethylation –> decreased chromosome stability –> tumorigenic rearrangements
- trigger reactivation of genes promoting more aggressive metastatic phenotype
5-aza upregulates?
urokinase like plasminogen activator = enzyme important for tumor invasion and metastasis –> enhanced metastatic potential in breast cancer
FDA approved HDAC inhibitors for cutaneous T cell LSA in people?
vorinostat and romidepsin
vorinostat has been shown to have efficacy against OSA cell lines
Proteosome inhibitor with in vitro and in vivo effects in canine melanoma and OSA cells?
bortezomib - has established dose and tolerable from golden retrieve muscular dystrophy study
Which is a molecular target that has the potation to interrupt a wide variety of pathways important in cancer?
Heat shock protein 90
What molecules and processes are targeted by heat shock 90 inhibition?
- Invasion and migration - urokinase-plasminogen activator, FAK phosphorylation
- cell cycle progression - cyclin D3, cdk4
- Signal transduction- akt, kit, Raf,EGF, Jun, HER, lyn, Src, IGF, PDGF, Met, BCR-abl, etc
- hypoxic response/angiogenesis - Hif1, VEGF, Glut1, NO synthase
- anti-apoptosis- wild tyle and mutant p53, survivin
- Cell senescence - telomerase
MOA of bortezomib?
Proteasome inhibitor
Consequences of proteasome inhibition?
- NFkB activation –>decreased proliferation, survival, invasion, angiogenesis
- apoptosis via p53, Bax, tBID, Smac, JNK, NOXA
- Signal transduction via MKP1 phosphatase –> decreased MAPK signaling
- Oncogenic transformation
- Unfolded protein response
- Chemo/RT sensitivity
What does HDAC inhibition result in?
- HDACs maintain chromatin in condensed form normally
- HDAC induction can lead to transcriptional repression in cancer negatively regulating tumor suppressors
- Inhibition results in decreased angiogenesis via VHL and HIF1, enhance apoptosis of tumor and endothelial cells
What does PARP normally do?
“nick sensor” that signals presence of DNA damage and facilitates repair
What is the MOA of SAHA (suberoylanilide hydroxamic acid)?
HDACi
MOA of HDACi?
Increased transcription by preventing histone deacetylation and gene silencing; Ex. valproic acid, vorinostat
PARPi for BRCA mutant breast cancer?
olaprarib, rucaparib, niraparib
lethal in brca deficient cells that are normally repaired by BER
Indirect inhibitors of angiogenesis?
anti-HER2 (Herceptin) and cetuximab
- neutralization of their oncogenic targets leads to a dramatic reduction in VEGF production
What are endogenous proteins that inhibit blood vessel growth? Use as anti-angiogenesis?
angiostatin, endostatin, thrombospodins
- ## thrombospodin mimetic (ABT-526, etc) response or SD in solitary tumors and LSA (takes ~ 60d)
What drug targets tumor endothelial cells?
phage vector delivering tumor necrosis factor (RGD-A_TNF) to AV integrins –>PR in 2/14 dogs with tumors, SD in 6/14
What does effective gene therapy rely on?
Ability to introduce genes efficiently into target cells in vivo or the delivery of genes to autologous cells and subsequent transfer back to the patient
List viral vectors for gene therapy
- retrovirus (oncovirus)
- retrovirus (lentivirus);safer and more efficient in non dividing cells
- adenovirus or Aden-associated viruses
List non-viral vectors for gene therapy
- naked DNA
- particle bombardment (gene gun)
- liposome/DNA conjugates
- ligand/DNA conjugates
Advantage of viral vectors?
- ability to infect cells and our ability to exploit replicative capacity
- use replication defective viruses to overcome concern of natural infection
Most common method of viral system for gene therapy delivery?
local via intramural injection
- avoids rapid removal by immune system
- limited ability to tx metastatic disease
Limitations of plasmid delivery?
- inefficient
- diluted by cell devision
- bacterial sequences in plasmids (unmethylated CpG) can be recognized by immune system via TLR9
- encode ABX resistant genes
Strategies to provide targeted gene therapy while sparing normal tissue?
- transduction targeting - surface modification of a virus to allow entry and/or delivery to cells via specific receptors
- e.g. adenoviral vectors via modification to coxsackie and adenovirus receptor (CAR) gives cellular tropism and/or the use of adaptors that can ablate native CAR based tropism and target the virus for an alternate cellular molecule (e.g. diabodies - transcriptional targeting - ID certain genes only expressed by cancer cells (e.g. prostate specific Ag TAA)
- Replication-competent oncolytic viruses - ONYX-015 only replicates in cells difficeint in p53
What is the risk with retroviruses gene therapy?
The virus is permanently in the genome
What is a gene gun?
Delivers naked DNA encoated on gold particles directly into tumor
How are cytokines utilized in gene therapy?
Direct immune system towards humoral or cell mediated response
What is the future of gene therapy?
gene repair via CRISPR or TALENS
What is gene silencing?
Delivery and use of siRNA molecules to cancer cells to ablate the deleterious effects of activated oncogenes
- no vet studies but human trials using delivery with gold nanoparticles
What is gene-directed prodrug therapy?
delivery of a suicide gene (viral or bacterial enzyme) to cancer cells that has the ability to concert a non toxic prodrug to an active compound inside the cell
What is cytokine directed gene immunotherapy?
codeliver of cytokine (in vet med IL-2) genes to cancer cells to incite local immune response
What is CAR (Chimeric Antigen Receptor) T-cell therapy?
- use of autologous T (CD8) that are engineered to recognize and kill tumor cells bearing specific Ag
- achieved through cellular medication of the chimeric Ag receptor to redirected T cells
- combines the specificity of a moAb with proliferative and cytotoxic ability of CD8 T cell
- in dogs CD20 directed CAR T cell demonstrated feasibility with only modest response
bragg peak
