6 - Principles of Cancer Chemo

Question 1

what are the goals of cancer therapy?

Answer 1

• patient cure – for lifetime
• patient management – over years
• extension of survival – over months
  
  • when we can’t cure or manage –> can only slow the progression of CA
  • must determine if side-effects is worth it to prolong life for a few months

Question 2

list the cancer chemotherapy drug classes

Answer 2

alphabetical order:

Question 3

what are the 3 diff’t uses of chemotherapy?

Answer 3

• adjuvant chemotherapy
• primary therapy
• preparative therapy

Question 4

what is the gold standard for chemotherapy?

Answer 4

SURGERY and RADIATION

(“cut” or “burn” out the cancer)

Question 5

adjuvant therapy:

define, purpose

Answer 5

• when chemotherapy is used as ADJUNCT to other treatments
• purpose: clear remaining tumor cells
  
  • cells are not recognized and left behind at site of operation/ outside the scope of the radiation tx –>
  • if tumor has metastasized, the cancer chemo is useful at those distant sites

Question 6

primary therapy:

purpose

Answer 6

• used for disseminated tumor
• ideal when surgery and radiation is contraindicated

Question 7

preparative therapy:

purpose, ex

Answer 7

• when surgery and/or radiation is contraindicated due to tumor size
  
  • use chemotherapy first to reduce tumor size
  • THEN followed by surgery and radiation
• Gastrointestinal stromal tumors (GIST); colorectal cancer; osteogenic sarcoma

Question 8

what are the benefits/ results of cancer chemotherapy?

Answer 8

• subtantial success; several types of tumors are curable
• dec childhood cancer mortality rate:
  
  • from 3/4 to now only 1/5!
• breast CA in postmenopausal women
  
  • 98% survival rate w/ localized tumor
  • 84% survival rate if it’s regional

Question 9

what is the SEER data base?

Answer 9

• Surveillance, Epidemiology, and End Results
• from National Cancer Institute

Question 10

why are people still dying of colon cancer?

Answer 10

• routine colonoscopies reduce cancer rate
  
  • polyps removed before they become cancerous
  • tumors identified at an early stage before clinical presentation
• BUT 55% of those who should have colonoscopies don’t (due to preparation for the colonoscopy)

Question 11

what are examples of refractory tumors?

Answer 11

• pancreatic CA: usually in survival mode (can be in management mode if very lucky)
• metastatic melanoma: deadly (basal or squamous cell carcinomas are excised and they’re not as much of a concern)
• brain CA: we don’t have good agents to tx brain CA (due to BBB)
• breast CA:
  
  • triple negative (ER-, PR-, Her2-): we don’t have a great therapy
  • premenopausal women: do not respond as well to the treatments as postmenopausal women do – so breast exams/mammograms are critical

Question 12

targeted radiation:

define, benefits

Answer 12

• repeated, short, intense exposure (daily/biweekly) –> focus on tumor
  
  • MUST be done M-F, every day for 5 weeks
  • Distance/travel logistics affects patient compliance
• benefits: less damage to surrounding tissue

Question 13

monoclonal antibodies:

define

Answer 13

develop monoclonal antibodies to “tumor-specific proteins” and to proteins necessary for vascular support

(typically, end in -mab)

Question 14

targeted therapy:

define

Answer 14

• development of drugs which inhibit specific proteins
• especially involved in signal transduction
• Inhibitors: INIB indicates inhibitor and targets tyrosine kinase

Question 15

personalized therapy:

define

Answer 15

• genetic profiling of tumors
• determine expression levels of “invasive” genes

Question 16

immunotherapy:

define

Answer 16

• use of immune systems to target and destroy cancer cells
• promising new treatment protocol

Question 17

what are the major disadvantages of cancer chemotherapy?

Answer 17

• in cancer chemo, we lose the specificity of action of drugs, which are selective against bacterial infection
• tumor cells are derived from the pt’s own body, and thus very similar to normal cells and hard to distinguish from self (effectively, 95% of the proteins are identical to the other normal cells of the body)

Question 18

with cancer chemo, what can we take advantage of?

(remember: these parameters can affect BOTH tumor and normal cells –> leading to side effects)

Answer 18

• cell cycle characteristics
  
  • proliferating vs. non-proliferating cells
• biochemical pathways
  
  • artificial substrates
  • metabolism of drugs – at times can not administer drugs in active form - need to be converted to active form by cellular metabolic pathways
• modification of cellular macromolecules:
  
  • DNA damaging agents
• perturbation of cell functions
  
  • altered gene expression
  • altered transcription
  • disruption of cell structure

Question 19

how many cells are needed to cause a tumor?

what are the implications of this?

Answer 19

• only one; a single cell can cause a tumor
• therefore, for a true cure/cell cure –> we need to remove every single cell

Question 20

what affects the presence/absence of symptoms of cancer?

implications of this?

Answer 20

depends on the number of tumor cells;

• need 10⁹-10¹⁰ cells to experience symptoms
• below this level, life is “normal”

Therefore, to obtain significant benefit, we have to reduce the number of tumor cells below that level

Question 21

repetitive treatment with the same drug kills an equals

(NUMBER/ FRACTION) of cells?

Answer 21

repetitive tx w/ the same drug kills an EQUAL FRACTION OF CELLS, NOT an equal number of cells

Question 22

what is the Skipper Hypothesis?

Answer 22

concept stating that repetitive tx w/ the same drug kills an EQUAL FRACTION OF CELLS, NOT an equal number of cells

Question 23

based on the skipper hypothesis, what mathematical relationship will result?

Answer 23

• a first order logarithmic relationship
• more doses needed than if the relationship was linear
• (talk in terms of “logarithmic kill”)

Question 24

Gompertzian Growth:

define and describe

Answer 24

• describes the complex pattern of tumor growth
• graph:
  
  • linear at first –> flattens off –> achieves steady state
  • growth fraction declines
  • older cells become separated from circulation and nutrient supply –> they die off

Question 25

describe tumor cell growth

Answer 25

• growth starts w/ a single cell
  
  • increases to 10⁹ when detection and possibly sxs can occur
  • by this stage, growth fraction has already fallen drastically
• thus, conditions for chemotherapy which are best at high growth fractions are unfavorable at time of probably diagnosis

Question 26

what is a fatal population of tumor cells?

Answer 26

10¹² cells is fatal

Question 27

how do you determine treatment schedules?

Answer 27

• devise tx schedules using the long-kill hypothesis
• three modalities of tx illustrated:
  
  • uppermost curve: “single agent therapy”
    
    • tx is given infrequently; involves repetitive doses of 2 log kills
    • result is manifested in prolongation of survival –> recurrence of sxs b/w therapies –> tumor cell regrowth exceeds tumor cell kill –> eventually fatal
  • middle curve: “drug resistance does not develop” –> a “cure” results –> tx continues long after the clinical evidence of the tumor disappear
    
    • more intensive; tx is begun earlier
    • combination chemotherapy by itself; an alternative approach
  • bottom curve: “most effective approach”
    
    • surgery or perhaps radiation is feasible and is used to remove the primary tumor
    • are faced w/ a smaller number of cells that are needed to be killed (log-kill hypothesis)
    • eradicate remaining tumor cells which may comprise small metastases