Lecture 9: Overview of Chemotherapy principles

 Define adjuvant versus neo-adjuvant chemotherapy, curative versus palliative therapy, and supportive care; discuss
treatment goals and expected benefits
o Adjuvant chemotherapy – given AFTER surgery, to prevent cancer relapses. You got the tumor out with surgery
and has NEGATIVE margins, but will kill small volume of malignant cell left after surgical resection.
 FREE OF CANCER ALREADY, only handle small amount of cells
 Can cure patients who would otherwise die of relapse: lung, breast, colorectal, testicular, ovarian,
bladder
 Prostate is not here.. it does not get adjuvant
o Neo-adjuvant chemotherapy: given BEFORE surgery to downstage the cancer
 Allows resection of locally-advanced tumors or organ-sparring approaches
 Breast, lung, rectal, GI (resection locally-advanced) – GI spare the sphincter
 Head and neck, bladder, esophageal (organ-sparing)
o Chemo-radiotherapy: tough, but can cure
 Chemo: sensitized cells to radiation
 Severe mucositis is common, may need feeding by G tube or IV
 Tx-associated deaths 
o Curative therapy
 Acute leukemias, lymphomas, testicular cancers, childhood solid tumors – need chemo, radiation,
surgery
 Small cell carcinoma – if only one lung is infected
o Palliative chemotherapy: for non-curable metastatic solid tumors
 Could be good for lung, breast/prostate, colorectal: for slower-growing tumors
 Goals: prolong life and/or delay symptoms, palliative existing symptoms and improve QOL
 Discuss problems with chemotherapy (narrow therapeutic index, development of resistance)
o Problems with chemotherapy
 Low therapeutic index: close to 1, effective dose/toxic dose – most always have side effects
 Limited activity in non-cycling cell: limited effect on cancer stem cells (divide once every few months)
 Emergence of resistance – can’t rid of every single cell
 Low response rates of single agents – even with most targeted therapies
 Describe the general mechanisms of action of DNA damaging agents, anti-metabolites, microtubule inhibitors, and
topoisomerase inhibitors, and where they act in the cell cycle
o DNA damaging agents (G0)
 Alkylators (cyclophosphamide, platinum compounds)
 Good for slow growing cancer, even if the cells are just
resting
o Antimetabolites (S) – inhibitor DNA synthesis
 (antifolates, purine and pyrimidine analogs)
 Good for cells that cycle faster
o Microtubule inhibitors (M)
 (vinca alkaloids, taxanes)
 Good for mitosis
o Iopoisomerase inhibitors (irinotecan, anthracyclins, etoposide)
 Single strand break – die in checkpoint after mitosis , dsb –
can kill the cell immediately
o Other:
 bleomycin, hydroxyurea
o Target therapies

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 Describe principal mechanisms of resistance and ways to overcome them
o Impaired transport
o Loss of activating enzyme
o Over-expression of metabolic enzyme – get rid of the drugs faster
o Mutation of cellular target protein (microtubules are the target of the taxane, which wouldn’t work anymore)
o Over-expression of drug efflux pump (MDR) – cannot figure out how to inhibit this pump
 Multiple drug resistance (MDR)
 ATP-binding cassettes, and it is highly expression in kidney and liver
 Gets rid of all chemotherapy that comes from plants or other stuff
 Frequently over-expressed in cancer cells
 Drugs affected: Vinca alkaloids, taxanes, topo inhibitors
o Enhanced DNA repair – reduced sensitivity
o Defects in Apoptotic signaling – so no p53, overexpression BCL-2, mutant EGFR, even if
your DNA dies
o Overcome resistance
 Combine agents with different MOA, sequential/alternating chemotherapy
 Dose-intensity: maximal cell kill before develop resistance
 Give it quickly in a row, then you can have downstream stroke
 Sensitize cell with targeted agents (or radiation) – EGFR or VEGF inhibitor
 Exploit synergistic actions: Taxanes and platinum compounds
 If pt asks if you can test which drugs will their tumor be sensitive to, it is hard because in vivo sensitivity
is different than in vitro sensitivity
 Discuss common toxicities of chemotherapy, and ways to reduce them
o Nausea, vomiting (GI and CNS toxicity) – day 1-2
o Mucositis, diarrhea – day 1-2, mucosa gets thin and sore
o Alopecia: day 7-14
o Myelosupression!!! (nadir WBC / plt , 10-14 days after
administration), may be dose-limiting
 Important for pt to know, like when to come to the ER
when they have a fever
o Immunosuppression (weeks after)
o Chest radiation: can develop CAD at the age of 30
 CHF is the worst!!! So never combine it
o Minimize toxicity
 Monitor labs (renal): look at heart (ECHO)
 Hydration (help renale), anti-emetics, hematopotietic growth factors
 Understand tumor growth kinetics; explain the rationale for combination
chemotherapy and “dose intensity”; describe factors that influence
chemotherapy dosing
o Depends on Body surface area, or weight, adjust for renal and/or
hepatic function, if bone marrow reserve (if they had chemo before),
if hepatitis, etc, other meds
o Performance status (how healthy is this patient already) and age of pt
o Goals: palliative vs curative
 Avoid chemo in ECOG 3 or 4
 Understand the immunosuppressive properties of chemotherapy agents
o Organ transplantation
o Rheumatologic disease (RA, SLE)
o MS
o Psoriasis
o Autoimmune hemolysis and ITP (cyclophosphamide, vincristine, rituximab)

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Lecture 10: Cancer Pharmacology
 Immunosuppression
o Long term lymphocytes suppression – more susceptible to herpes virus , takes couple of months to develop
o WBC decrease, neutrophil decrease so susceptible to bacteria, takes a couple of weeks
 Discuss representative chemotherapy agents of each class with their mechanisms of action, principle causes of
resistance, general clinical applications, major toxicities and ways to reduce toxicities:
 DNA Damaging agents
o Alkylators
 Cyclophosphamide (Uses: breast cancer and lymphoma)
 Melphalan (Myeloma, stem cell preparation)
 MOA: covalent bonds with DNA bases, so then you get excision, and then interstrand links and repair
enzymes are overwhelmed and create breaks
 If p53 is present, cells become more sensitive, but p53 deficit cells are not resistant
 Cell cycle independent response!!! Cell does not have to be dividing
 MOR:
 Mucous membrane toxicity can be reduced by giving THIOLS
 Increased DNA repair activity
 Mutant p53, resistant to apoptosis
 Can give higher doses to overcome resistance
 Toxicities
 Hemoorhagic cystitis – excreted in the bladder, while it is still active, so if you do not hydrate
enough, bladder will turn into mush, so you must overhydrate people
o Must give thiols if you give high doses
 High mutagenitiy
o Platinum compounds:
 Cisplatin (lung, testicular), carboplatin (lung), oxaliplatin
(colorectal)
 Used as radiation sensitizers
 MOA: binds directly to the DNA, very mutagenic
 Cell cycle independent cytotoxicity
 MOR: high expression of DNA excision repair enzymes
 Toxicities: ALWAYS GIVE FLUIDS
 Antimetabolites (methotrexate, AraC, 5’FU)
o Antifolates (Metrotrexate)
 MOA: inhibit dihydrofolate reductase (DHFR)
 Lack of reduced folates – which is important for purine de nove synthesis
 You can rescue with Leukovorin (product of the inhibitor) –you can protect the main cells
 Used for leukemia, lymphomas, immunosuppression
 MOR: Gene amplification of DHFR, or mutation of DHFR
 Toxicities: Pulmonary toxicity (pneumonitis), hepatic toxicity (cirrhoisis)
o Purine (use for hematologic malignancies: RAPIDLY DIVIDING ONES)
o Pyrimidine analogs(cytosine arabinoside, 5’fluorouracil, Gemcitabine)
 Ara-C
 Incorporated into DNA so you cannot elongate anymore
 MOR: deletion of activating enzyme or overexpress metabolic enzyme to break it down
 Toxicity: Liver and CNS toxicity, cannot use > 65
 Clinical: lymphoma and leukemia
 Gemcitabine: Go into DNA and leads to inhibition of DNA synthesis
 Toxicities: Flu-like syndrome (fevers), edema, Clinical use: Pancreatic cancer
 5’FU
 Works only in the presence of leukovorin, OPPOSITE OF METROTREXATE
 Toxicities, diarrhea, skin toxicity (hand-foot)
 Clinical use: Colorectal/GI malignanites, radiation sensitization

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 Microtubule inhibitors
o vinca alkaloids – block tubulin polymerization
 Vincristine (need to give IV!! ONLY IV)
 Neurotoxicity, AND WILL BE SUPER BAD IF
YOU MISS AND IT GOES INTO THE TISSUE
 Clinical use: leukemias, lymphomas
o Taxanes- cannot disassemble (-taxel)
 Very insoluble – and need to be bound to albumin)
 Toxicities: hypersensitivity reactions!! To the solvent of the drug
 Neurotoxicity
 Clinical use: lung, breast, prostate, USE THIS A LOT
 Topoisomerase inhibitors
o MOA: prevent resealing of DNA
o TopoI: Tecans (irinotecan)
 Toxicities: Severe diarrhea (like cholera), clinical use: colorectal cancer
o TopoII: anthracyclins, etoposide – can immediately kill, even non-dividing cell
 Anthracycline: doxorubicin (blue)
 MOA: stuck in the DNA
 Toxicity: cardiac toxicity (generates free radicals) - CHF, severe skin toxicity if not given IV
 Clinical use: Lymphoma, leukemias, breast cancer
o Good for radiation prep, because radiation causes DNA damage so its extra
 Etopside: VP-16
 Toxicities: secondary leukemia! (risk > 2%)
 Clinical use: Lung and testicular cancer
 Other: bleomycin, hydroxyurea
o Bleomycin: causes oxidative damage, lead to DNA strange breaks
 Toxicity: 1/3 gets pulmonary toxicity, shock
 Clinical use: testicular (PVB), Hodgkin’s disease (ABVD)
o Hydoxyurea
 MOA: ribonucleotide reductase inhibitors
 Toxicity: myelosuppression (quickly reversible) – die from sepsis
 Clinical use: sickle cell anemia, myeloproliferative diseases

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Lecture 11: Cancer Pharmacology III: Target agents and other
emerging therapies

 Review key signaling pathways targeted by anti-cancer drugs,

and the need to individualize therapy
o
 Review molecular profiling of cancers and its significance for
targeted therapies (e.g. Her2, EGFR, Ras, B-Raf, estrogen
receptor)
o Only around 125 driver genes, rest of the mutations are
passenger mutations that don’t really do much to cell
fate/growth/survival, only do 12 PATHWAYS
 Most solid cancer are caused by 2-8 mutations that
happen over 20-30 years
o For Lynch cancer, with lots of mutations, they have a lot of
things that can be target with immunotherapy
o Pediatric cancers do not have many mutations,not many things can target
o Ethnic: lung adenocarcinomas: nonsmokers, LOTS of their tumors have
EGFR mutations
 Caucasians have 15% likely to have EGFR
 Mutated EGFR in adenocarcinomas, woman, non-smokers (35%)
and east Asians (75%)
 Understand small molecule kinase inhibitors: mechanism of action, resistance,
major toxicities, and clinical applications
o EGFR inhibitors: erlotinib/lapatinib
 LUNG AND BREAST
 Mutation in the tyrosine kinase domain that keeps it on, so then these drugs inhibit TK
 For lapatinib: it also targets Her2, which is on the heart as well so if you block Her2, you get cardiac
toxicity
 Mutations in kinase domain predict whether or not these drugs will work
 All metastatic non small cell lung cancer should be tested
 EGFR inhibitors better than standard chemo for EGFR mutant
lung cancer, but after this you don’t have any good drugs
o ALK inhibitors: Alectinib
 In 5% of lung metastatic cancers, is because of translocation
chromosome: detect by FISH
 ALK is major driver of the disease, can treat metastatic disease
 Toxicity
o SPECIFIC TK INHIBITOR imatinib/desatinib
 Imatinib (first gen): CML, GIST
 Targets: BCR-abl, C-kit,
 GIST: 3% of GI malignancies
 Ping pong balls under mucosa – benign for a long time
 After surgical resection, then do imatinib
o sunitinib/sorafinib – Target VEGFR receptor : dirty
 Without NO, then you get HTN
 Risk: thrombosis risk because HTN + TED (thromboembolic
disease), bleeding and GI perforation
 If patient has ulcer, if you put them on VEGFR, then the
blood vessels that is trying to heal the ulcer, will bleed
 Targets renal cell carcinoma and hepatocellular
 Usually disease stabilizes, but renal cell might help a little more

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 o B-Raf/MEK inhibitors: Vemurafenib: only bind to mutated B-raf inhibitor
 found in 50% of melanoma, or some GI
 metastatic: improved overall disease, and adjuvant therapy
 Doesn’t inhibit wild type B-RAF, but normal tumors w/o this mutation, will overgrow so that’s bad..
 Resistance: wild type b-raf/ras mutation
 Toxicity: skin squamous cell cancer can increase
 Not a solution, and immunotherapy is better than this. Because it helps at 6 months, but at 1 year, it’s the
same
 Understand the use of antibodies for cancer therapy: their targets,
resistance, toxicities, and clinical applications
o Retuximab – need to test first of HepB
 For non-hodkin’s lymphoma
o Trastuzumab – for breast cancer
o Bevacizumab – Target VEGF
o cetuximab – EGFR receptor: for colon, head and neck
 used by itself to do radiation sensitizer
 Can also be chemo sensitization: colorectal cancer
o Infusion reacetions to antibodies
 Very frequent, Little one: stop, and cool it down
 Anaphalyaxis: stop and never start again
 Look for hives, angioedema,
bronchospasms
 Tx: Stop, saline if hypotention, Epi if bronchospasm or severe hypotention, give diphenhydramine and
hydrocortisone. If minor reaction, can start with slower infusion
 Discuss use of hormonal agents in breast and prostate ca.: targets, resistance, toxicities, and clinical applications
o Breast cancer (50% estrogen responsive, ER+)
 Can use selective estrogen receptor modulators (tamaoxifen) – SERMS
 Aromatase inhibitors: ANastrozole
 Inhibit converstion of androstenedione and testerosterone  estrone and estradiol
o Tissue specific, anti-estrogenic in breast, and pro-estrogenic in uterus and bone
o It is good for the bone, does not cause osteoporosis
o Can cause uterine cancer (2-3x), and uterine bleeding, and thromboembolic events!!!
 Toxicity: hot flashs, and osteoporosis (like menopause)
 Used in ER+ breast cancer (first choice!)
o Postmenopausal: adjuvant therapy
o Premenopausal: adjuvant therapy + ovarian suppression
o Prostate (90% angrogen-responsive)
 GnRH agonists: Leuprolide, Goserelin
 Induce initial surge in LH/FSH, followed by receptor downregulate, then inhibit GnRH
o Suppression of gonadal estrogen
or testosterone production
 Toxicities: initial disease flare (use AR or
ER blocker for the initial LH/FSH flare)
o Osteroprosis
 Use in pre-menopausal ER+breast cancer
(with tamoxifen or aromatase) – for ovarian
suppresion
 AR blocks: Enzalutamine
 Competitive inhibitor of androgen binding
 Toxicities: Gynecomastia, and can decrease
seizure threshold
 Use together with GnRH angonists
 Androgen synthesis inhibitors
 SERMs, aromatase inhibitors, GnRH-agonists, androgen receptor blocking agent

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Lecture 12: integrated approaches to cancer therapy: how do we evaluate
and treat the four most common cancers?

 Review the importance of staging for treatment selection (therapeutic

principles for early stage, locally advanced, and metastatic disease)
o If cancer is in one organ, cut it out with local N1 node – can
check with sentinel
o If cancer is too big, shrink it first with chemo and XRT (neo-
adjuvant)
 Cisplatin, 5’fu, paclitaxel as radio-sensitizers
o High risk of recurrence ( bad gene, Large tumor, Nodes)
 Use XRT to reduce local recurrence
 Adjuvant chemo to reduce systemic recurrence
o If cancer has metastasized to other organs, use chemo and/or targeted agents to control – rarely cure/surgery
 Childhood and prostate can be cured in metastatic
o For the four major cancers: the first nodal station is: Cut out together with The tumor!
 Breast: Axilla, 2nd is supraclavicular nodes
 Lung: Hilar nodes, 2nd is suptraclavicular nodes and mediastinal nodes
 Colon: Mesenteric nodes,
 Rectum: perirectal nodes,
 If 2nd is affected, then that means you cannot cure locally, and it has spread
 Chemo-radiotherapy is the hopes of curing if it is local
 Discuss the main principles of combined modality treatment
o Chemotherapy agents as radiation sensitizers
o Neo-adjuvant chemo/radiation therapy to “debulk” tumors prior to surgery
o Adjuvant radiation therapy to reduce local recurrence after surgery
o Adjuvant chemotherapy to reduce systemic/metastatic recurrence after surgery
 Breast Cancer Treatment
o Early/Localized disease
 Small tumor – few lymph nodes, resect both
 Do lumpectomy + sentinel nodes, and make sure margins are clean, and if they are not, go
back and make it clear
 Do radiation therapy after to decrease local recurrence
 Larger Tumor, nodes (T3-4, N1-2) – downstage with neo-adjuvant chemo before surgery
 Is this good or bad kind of cancer, do genetics,, gene expression
 High risk of release (bad gene or + nodes) – use adjuvant chemo and/or hormonal therapy
 Adrianmycin/cyclophosphamide +/2 taxane
 Trastuzumab x 1 year – if her2+
 Aromatase inhibitor x 10 years if ER+, if pre-menopausal, use GnRH agonist +
Tamoxifen/aromatase inhibitor
o Metastatic (live 5-10 years)
 ER+ - hormonal therapy
 Use aromatase inhibitor, Tamoxifen and other agents (GnRH agonist if premenopausal)
 Her2+ - use Anti-Her2 ab or TKI+ chemo
 Lapatinib – small molecular inhibitors, use more than one antibody against Her2
 Triple negative – chemo (no ER+ PR+ or HER2+)
 Cis/carboplatin + Taxene, if BRCA1/2 mutant, many other chemo agents

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 Non-small cell lung cancer treatment (die in 1-3 years)
o Small tumor/hilar nodes – reset, and adjuvant (but 50% relapse and die anyways)
 Lung cells are more resistant
o Larger TU: upper tumor in upper load: give neo-adjuvant chemo=XRT followed by surgery
o N2 (mediastinal nodes) – not resectable – use Radiation and chemo (cisplatin/VP16)
 Later surgery = controversial
o Metastatic disease (3 kinds of lung cancer, 3 kinds of breast cancer)
 Chemo/target agent?
 EGFR + mutation – osimertinib
 ALK translocation – alectinib
 PDL1 expression high – immunotherapy (interaction between T cells and cancer cell)
 No target – use platninum doublet
o After resesction – Adjuvant chemotherapy after resection is good! – 5-7% CURED
o Note: most people relapse, surgery is not that good, most people will die, you can do adjuvant chemo, might
help
 Colorectal cancer treatment (half of people alive at 2 years)
o Small-large tumor/local node – resect, and if there is positive nodes, use adjuvant chemo (5FU’leucovorin)
o Rectal cancer: Surgery is harder to do, and difficult to resect completely, and it can go into the wall
 Neo-adjuvant chemo-xrt f/b surgery f/b adjuvant chemo
 Don’t want to get the sphincter or if it goes through the wall
o Metastatic disease
 5FU/leucovorin + oxaliplatin
 VEGF inhibitor (bavacizumab) – improves responses
 Anti-EGFR ab (cetruximab) – only if wild type Ras/B-raf
 Somewhere between breast and lung cancer… half of people alive after 2 years
 Immunotherapy – only if microsatellite-instable
 Prostate Cancer treatment
o T1-2, No – surgically resectable, no evidence that adjuvant chemo/adt helps
 XRT if cannot resect
o T3, or N1 – difficult to resect completely so use XRT + androgen deprivation
 Surgery + Adjuvant ADT I/- XRT
o Metastatic disease- ADT +/- chemo
 GNRH agonist
 Add AR blocker, or AD inhibitor
 Add docetaxel to GnRH agonist for high volume disease
o Metastatic
 High volume – least four bone metastatis – do chemo and androgen deprivation therapy
 Low volume – only ADT, no difference if you do chemo at 5 years, it is the same
 Understand the influence of performance status and co-morbidities on cancer prognosis and therapy
o

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 Explain supportive care during chemotherapy: anti-emetics,
appropriate use of growth factors, antibiotic prophylaxis
o Anti-emetic therapy
 1- always give 30 min before chemo
 2- moderate nausea
 3 – if you take cisplatin or something
 4 – REALLY HAVE A HARD TIME
o Anticipatory nausea – smell hospital, or see doctor, get anxiety, especially kids – should premediate with
benzo
o Growth factors – Granulocyte colony-stimulating factors (G-CSF)
 7-10 days is the lowest, so start at 24-48 hours after the last chemo agent
 Indications: chemo with 20% chance of febrile neutropenia, previous episode of neutropenia, or
severe neutropenia without fever
 Does not help if patient is already neutropenic or infected
o EPO stimulating agents (ESA)
 Increased mortality in breast, lung, lymphoid, cervical, head/neck, DO NOT DO
 Increased risk of thromboembolic disease
 Highest risk if hx of thrombembolis, hypercoagulatility
o Antibiotic prophylaxis
 Give if high risk of profound,prolonged neutropenia and you cant get to them
 Intestive chemo for AML/ALL, lymphoproliferative disorder
 Risk: develop resistence, hypersensitivity, toxicity
 Discuss iv access devices
o Vascular access
 Lots of IV, blood draws – run out of veins
 Use PICC line catheter – go to SVC, or port a cath and can stay for years – risk is the lowest
 Risk: blood vessel injury, pneumothorax, bleeding, arrhythmia, air embolism , infection,
contact dermatitis, line occlusion

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Lecture 13: Oncologic Emergencies

Discuss the clinical presentation and treatment of oncologic

emergencies:

 Tumor lysis syndrome (TLS)

o Caused by massive tumor cell lysis  release K+ ,
Phosphate, nucleic acids
 Nucleic acid  uric acid  hyperuricemia AKI
o Risk factors; High tumor cell proliferation rate, chemo-
sensitivity large tumor burden
 Predisposing clinical features: pretreatment
problems with stuff, urine, dehydration,
nephropathy, increased K+, PO4, low Ca, High uric
acid
o Clinical Presentation: cervical lymphadenopathy, significant
cervical and axillary lymphadenopathy, splenomegaly
 Nausea, vomiting, seizure, cardiac dysrhythmia,
syncope
o Treatment: IV hydration (keep constantly), lower the uric acid
level (allopurinol and rasburicase), monitor fluid and
electrolyte status, dialysis
 Goal: flush everything out!
 Allopurinol doesn’t get rid of the uric acid,
rasburicase does but it is more expensive
 Note:
The cardiac dysrhythmia and neuromuscular
irritability- the HYPERKALEMIA is the most
DANGEROUS part – can lead to sudden death
 Do continuous cardiac monitor, monitor K+
 Spinal cord compression
o Mechanism: tumor invades the epidural space, compresses thecal sac, edema  ischemia+ infarction
o Causes: in 5% of cancer patients in the 5 years before death
 Usually from metastatic tumor in vertebral bodies
 most common in lung, breast, multiple myeloma
 Highest incidence in multiple myeloma, lymphoma, prostate
o Clinical Presentation: constipation, progression back pain, frequent urination, hx of cancer treated with surgery,
legs are weakly diffuse, diminished session in lower extremities and hyperreflexia 3+ at knees and ankles
 Normal labs, tender at the perfusion
 Pain!!!!, severe pain, precedes neurologic symptoms by 7 weeks
 Motor, sensory findings, bowel and bladder dysfunctional are a late finding
o Management: MRI, give steroids to decrease edema (consider the increased glucose so you try to help patient
with lucid dreams)
 Primary endpoint = ability to walk
 Do surgery + radiation
 Increased intracranial pressure
o Primary brain tumors, metastatic malignancy  edema, headache, nausea, vomiting, confusion, could herniate
o Do: urgent brain imaging
o Tx: steroids, decrease the edema, and if there is lots, you can do surgery
 Surgery + radiation
 Pericardial tamponade
o Rare cancer emergency
o Accumulation of pericardial fluid under pressure, decreased stroke volume, increased back pressure
o Tx: drain fluid immediately
o Effusion without tamponate – metastatic malignancy (breast, lung, lymphoma, or because of radiation/chemo)
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 Intestinal and urinary obstruction
o Intestinal
 Colon cancer, metastatic malignancies – if you get obstructed, then you will probably die very soon
 CT scan  nasogastric decompression surgical/GI evaluation – try to get rid of obstruction
o Urinary: find it with ultrasound, CT (Acute renal failure, hydronephrosis)
 Tx: malignancy: radiation/chemo
 Because of pelvic tumor: prostate, cervix, met from nodes, which
obstruct the ureteral area
 Neutropenic fever (including typhlitis)
o Fever with low neutrophil count
o Depends on degree and duration of neutropenia, and signs of infection
might be low
o This is URGENT TREATMENT! Cannot deal with infections
o Management
 Broad spectrum antibotics immediately (gram+ and – bacteria)
o Prevention: after you give chemo, put the prophylactic growth factors
(promote more growth)
o Typhlitis – necrotizing process of the cecum – happens because of poor arterial perfusion and theres lots of
colonic bacteria
 This happens especially when people are neutropenic, and have breakdown of gut mucosa because of
chemo
 Sx: abdominal pain, decreased bowel sounds, fever, diarrhea
 CT: thickening of the bowl wall, could lead to sepsis and bowel perforation and hemorrhage
 Tx: NG suction, bowel rest, antibiotics
 Hypercalcemia – Covered under paraneoplastic syndromes
o
 SIADH/severe hyponatremia - Covered under paraneoplastic syndromes
o
 Superior cava syndrome is covered in the lung cancer case discussion
o

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Lecture 14: Radiation Oncology: Radiation biology and principles of radiation therapy
 Def: Treatment of benign and malignant disease in adults and children with ionizing radiation
 NOT radiologists
o Radiology = low energy x-ray to image tumor
o Rad Onc = high energy x-ray to treat tumor
 1800s – first time used to treat cancer
 Describe physical properties of differing types of RT
o Primary mode of treatment: use photons (energy, gamma,xrays)
 Very short wavelength, so high frequency, cannot be stopped by lead apron, doesn’t do anything
 It doesn’t matter if its solid tissue or soft, same effect
o Produces free radicals, that cause DNA damage in a tumor cell – they do not repair as well as normal cells
o 2/3 of damage is indirect (through ROS), 1/3 of damage directly Damage dna
 Cancer cells divide more than normal cells, so the more it divides (during S and G2 phase), the more
sensitive it is
 Understand why different types of radiation are used, and the consequences
o Repopulation – how fast do normal tissues recover vs cancer cells (give some recovery – 6 hoursish), that’s how
long it takes for normal cells recovering
 When cancers are recovering, they become immune to radiation
 Need to get all the radiation done in a short amount of time
o Repair: because cancer cells repair less, this is effective
o Redistribution/reassortment: G2/M phase are the most sensitive to IR, but this is shortest part of cell cycle
 Therfore you need fractionated radiotherapy
o Oxygenation: hypoxic cells are more radioresistent because you need the O2 to create the free radicals
 Therefore you need fractionated radiotherapy
o Different particles
 Electrons:– treat superficial cancers like melanoma or breast
 Protons: mass and charge – diffusion is high, so it will spare a lot of tissue,
especially for cues
 Skin sparing, and good for deep tissue and they attenuate quickly
 Neutrons: high charge, high mass – more potent, but higher side effe
 Neurons do not attenuate quickly
 Principles of external therapy and brachytherapy
o External therapy: uses linear accelerator to direct a beam from outside the body
o Brachytherapy: prostate and cervical cancer
 Inserts radioactive source inside the body inside a carrier
 Can be directly injected into body as a pill or liquid tagged to another
substance
 Giving iridium 192, half life is quick, low dose = long time
 Used to use cesium for a long time – low dose rate: get procedures with therapy
 1/r^2 = attenuation of brachytherapy – therefore it is great because the radioactivity attenuates very quickly
 Cannot treat all things, only works if the radiation is next to the cancer, so therefore, you cannot
treat most things with brachycardia
 Insert the radiation right inside the tumor – can treat like lip cancer, … lots of fun radiation and
sticks of catheters
 Good for kids, because anything exposed to radiation will not grow anymore, which is bad
 Understand basic dosimetric parameters (dose, volume, fractionation) and how that affects tumor and normal tissue
response
o Radon – in soil, Atmosphere protects against radiation so higher levels are exposed to more radiation
o Smokers – get exposed to more radiation because there are trace levels of radioactive lead and stuff
o Conventional treatment: 180cGy/day
o Fractionation is important because it givens the
normal cells time to heal, reoxygenate, helping cells
move through the cell cycle
 Number of fraction depends on the type of
cancer
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 o Sterotactic radiosurgery – radioablavtive doses in single fractions
o Total dose and dose/fraction will determine what the general response is
o The smaller the target, the higher amount of radiation it can tolerate. This is opposed to large tumors, surrounded
by sensitive tissue and abdominal sarcoma
 Understand basic principles of resistance and sensitization
o Some drugs, like taxoles, cisplatin, nitroimadazoles, and tirapazamine are radiation sensitizers and can be given
beforehand
 Understand radiotherapeutic modalities
o 2dD: square radiation bean in the region with tumor
o 3D conformal: use linear accelerator software to shape the beam to the tumor in 3D
o Intensity Modulated Radiation Therapy (IMRT) – different intensities of radiation at different parts of the beam
 Good for sparing of the heart and lung during radiation
o Image Guided Radiation Therapy – good for organs that move or when tumors shrink
 Uses imagers on radiation delivery device to make sure tumor and organs are correctly placed
o Respiratory gating: good for liver and lung radiosurgery when the target organs move with respiration
 Understand multimodality therapy
o Radiation recall, lots of adrianmycin, vermurafenib, PD1-1, do not work well with radiation + chemo
o Some chemo and drugs make you more sensitive to radiation
 Review basic treatment strategies for common tumors
o
 Understand the short and long term toxicities
o Acute (4-6 weeks): irritation of skin, mucosal surfaces,
nausea
o Late: after therapy – lifelong: fibrosis of tissue,
narrowing of vessels, edema, poor healing
 Review the role of radiation in palliative therapy

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Lecture 15: Tumor Immunology
 1. Discuss the immune response to malignant cells
o Spontaneous regression of cancer: MAGIC, some immune cells kill cancer
o Tumor immunology – study of what happens when immune cells and tumor cells localize to common place
o Tumor surveillance = natural, often clinically silent process in which body’s immune cells eliminate nascent
cancer cells – want to prove this exists
 1. Immune suppressed mice and humans have more cancers
 2. People with cancer have tumor-specific T cells
 3. Cancers that have increased infiltrating memory CD8+ T cells and decreased infiltrating FOXP3+ T-
regs harbor a better prognosis. Cancers with Th1 gene signature also have better prognosis
 the CD8/Treg ratio, if higher, the patient will do better
 Th1 = CD8 cells
o Tumor immunotherapy – treating cancer using immune modulatory approaches; direct translation of tumor
immunology
o Now, included in the hallmarks of cancer, is that it has to evade immune cells
o Responses:
 Inflammation induced cancers = immune cells function to facilitate tumor progression, or co-opt
inflammatory signals so they can grow
 Other immune cells perform tumor surveillance – and they undergo elimination
 2. Explain why the immune response alone is not sufficient to limit the spread of malignancies
o Do not have robust proliferating capacity, cannot keep with tumor cells, NK cannot grow fast enough
o Cancer immunoediting = the immune system kills all the tumor cells through tumor surveillance. However,
some tumors have antigenic cells, and others don’t, and the immune system will kill the antigenic cells, and not
many of the immunogenic
 By the time we see the immunogenic cells, it is cancer, and it has learned to evade the immune system,
which has happened over many years
 3. Describe the types of immune cells and molecules that promote or inhibit tumor formation
o Inflammation and cancers = cancers are wounds
that do not heal
 Inflammation = immune cells + non-immune
cells interacting with NF-kB (transcription
factor) – IL6, etc to promote inflammatory
response
 KO NF-kB in immune cell, or non-
immune cell, reduces the incidence
of colon cancer
 Immune cells: innate: macrophages, DC,
neutrophils, mast cell, non immune= trumor
 4. Discuss the types of tumors that are associated with an inflammatory process
o Colon cancer = aspirin reduces colon cancer risk by 22%
o Chronic inflammation = chronic hepatitis – more likely to get hepatitis cancer
o Gastric cancer, cervical cancer
 5. Discuss how the NF-κB pathway can promote tumor formation
o Induces inflammatory gene signature
 6. Discuss the prognostic value of examining tumor infiltrating leukocytes
 1. Immune suppressed mice and humans have more cancers
 2. People with cancer have tumor-specific T cells
 3. Cancers that have increased infiltrating memory CD8+ T cells and decreased infiltrating FOXP3+ T-
regs harbor a better prognosis. Cancers with Th1 gene signature also have better prognosis
 the CD8/Treg ratio, if higher, the patient will do better
 Th1 = CD8 cells
 7. Explain how adaptive immunity plays a role in tumor immunology
o Th-1 promotes anti-tumor, Th-2 and Treg = promote tumor formation

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 8. Describe two molecular characteristics of tumors that make
them immunogenic
o Needs to break tolerance!
o Antigen
 Mutate proteins (ribosomal protein)
 Ectopic expression of protein (cancer – testis)
 Overexpressed maybe
 Tissue specific proteins (melanoma)
o Immune specific cells
o Usually presents on MHC I (because they are from inside the
cell) and interacts with CD8
 If no MHCI, NK cells will kill you
 And also maybe express NKG2D ligands
 Which is expressed – im stressed and damaged please kill me
 9. Describe three molecular characteristics of tumors that allow them to escape immune rejection
o T cells are activated by 2 signals
 1. Present with antigen
 2. Co-stimulation – activated CD28 to stop suicide
 3. Cytokine secretion
o Method 1: Tumor cells can lose MHC
o Method 2: Also doesn’t express signal 2.
 Some are adhesion molecules, do not have B7, so if
you have signal 1, but no Signal 2, will just kill the
naïve T cells
 Usually the naïve t cells jump around from lymph
node to lymph node, but since tumor cells create so
much inflammation, they draw the naïve t cells,
which get activated, but then start to suicide and then
die because no signal 2
 So now you can use vaccine that has signal
1 and signal 2. So this creates effector cells so they do not need it anymore
o Method 3: Cancer cells typically have 10-50 mutations in their genome- which determines the response to
immune therapy
 Lots of mutation, may still not respond because they could lose the antigens, but generally they do have it

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 10. Discuss the principles behind the various forms of immune therapy, including passive antibody transfer, adoptive
cellular therapy, engineered T cells (CAR-T), vaccination, and checkpoint blockade.
o Mutated antigen vaccine – specific for one person
o Prostate cancer vaccine – tissue specific and are germline encoded
o Mutations = passenger and driver
 Passenger = mutations that are not important for the cancer
 Generally not shared between mutations
 Driver = actually the activating mutations in oncogene or inactivating mutation in tumor suppressor
 Generally shared between patients: like a Ras mutation
o Types of immune therapy
 Passive transfer of antibody!!!!
 Have tumor antigen, make an antibody, and do ADCC, and complement (MAC attack) can kill
tumor cells
o 4 function of antibodies: ADCC, Complement, phagocytosis, neutralization
 aka rituximab (anti-CD20) – treat B cell malignancies
 Transfer T cell
 Biopsy – Grow the T cells (already specific for tumor, and then give back to the patient) – tumor
infiltrating therapy (TIL therapy) – maybe limited in the patient
 Can also grow the Cancer, and make antibodies against it
 Chimeric antigen receptor – CAR receptor: it is antibody binding region
 Put the Signal 1, signal 2, in one high affinity receptor on the T cell
 In order to make this, you take T cells from the blood,
 These immune side effects are THE WORST because they so effective
 CLL, ALL, HL, NHL – response rate of 90% :O SHOOKETHHH
 THEY ARE BOTH CD4 AND CD8 cells, so you do a ratio of these
 Give IL-2, or IFNa to stimulate T cells and NK cells
 Vaccines to activate naïve T cells
 Give cytokines
 Block inhibitory molecules: CHECKPOINT BLOCKADE
 CTLA4 – Normally expressed to turn off signal 2
so you don’t get overactivation after an infection
 This grabs B7 away
 KO CTLA4 = autoimmunity
 So therefore, if you make antibodies to to
CTLA4, then the T cells can stay activated
 PDL1 also turns off the response
o Tumor cells also have PDL1 and turns
off the T cells, so if you have anti-
PDL1, it cannot turn off
 11. Discuss the efficacy of the immune therapies described above
(examples: melanoma, renal cell carcinoma, lung cancer)
o PDL1 – super effective against melanoma
o PD1 and CTLA4 – 53% response rate!
 PD1 and CTLA are checkpoint
o Also works in colon cancer – works best in MMR defect
 Case study
o Patient with melanoma gave two kidneys 16 years after being cancer
free. The recipients all got melanoma. Maybe because they had less
T cells, less immune suppression because of the rejection drugs, or
maybe its because the surgery is an inflammatory process which facilitated the tumor growth

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