BIO 302 - Exam 3 - Local Treatment of Cancer PowerPoint

Question 1

Goals of Cancer Treatment DEPEND ON THE ASSESSMENT OF THE PATIENT’S DISEASE

Treatment strategy depends on what 4 things?
The overall treatment strategy depends on?

______ means eliminating ALL cancer cells (without killing the patient).
The ______ the number of cancer cells at any phase of therapy, the better the outcome.

Answer 1

• the patient
• the tumor type
• the stage of the cancer
• other prognostic factors

The intention to cure or not to cure.
Cure / fewer

Question 2

Treatments are used in combination to achieve multiple different mechanisms of tumor kill/damage simultaneously

No tumor is uniformly sensitive to any given treatment due to ______ ______.

Treatment approach and goal may change over the course of the patient’s disease as the cancer evolves / progresses

Answer 2

clonal heterogeneity

Question 3

What are the 5 overarching principles to localized therapy?

Cl
Da
Pref
Li
Pot

Answer 3

• Close monitoring for complications and/or toxicities of therapies must be part of the treatment plan.
• Damage to normal cells and tissues should be minimized.
• Preferences should be respected.
• Limitations should be determined.
• Potential benefit should outweigh potential harms

Question 4

Localized therapy is, by definition, limited to FOCAL areas of the body.
Delivery is aimed at and directed to circumscribed foci to include:
*
*
*

Answer 4

• The cancer itself
• A pre-defined rim (“margin”) of normal tissue around the cancer where microscopic tumor cells may be lurking.
• The rest of the body is not exposed to the therapy or its side effects.

Question 5

What are the 3 types of ablasions?
T
H
Z

Answer 5

Targeted, Hemi (half) ablation (destruction) & Zonal ablation

Question 6

Systemic therapy is delivered to ______ ______ ______.
Typically via ______ ______.
Rare exception: radiation of the entire body (followed by ______ ______ ______).
Delivery is aimed at treatment of all cancers cells throughout the body.

The normal cells of the body are subjected to equal exposure to the therapy and side effects are inevitable.

Systemic therapy may be use in combination with local therapy.

Answer 6

the entire body / the blood stream /
bone marrow transplantation

Question 7

Treatment with curative intent
R
Min
Max TR
TR

Answer 7

Remove/kill all tumor cells
Minimize damage to normal tissues
Maximize therapeutic ratio (TR)
TR = tumor response/normal tissue response

Question 8

Non-curative Treatment
Pro
Red
Treat
Assist
Rest
Pall

Answer 8

Prolongation of life if cure cannot be achieved
Reduction or elimination of signs and symptoms
Treatment of complications of continued tumor growth
Assist in providing therapeutic convenience and comfort
e.g.., intravenous chemotherapy access catheter
Restoration of form or function from disease or therapy
Palliation with no expectation of cure to improve quality of life

Question 9

Surgical oncology: Types of Cancer surgery

C
De
Dia

Pal
Pre
R
S

Answer 9

Curative
Debulking (cytoreductive)
Diagnostic

Palliative
Preventive
Reconstructive / plastic surgery
Supportive (catheter placement)

Question 10

Cancer surgery for cure

Answer 10

Treatment for localized disease and regional spread
Rare exceptions: e.g., limited liver metastasis in colon cancer
Physical removal of ALL detectible cancer

Question 11

Cancer Surgery techniques

Answer 11

Cold knife: surgeon and scalpel
Laser surgery
(CO2; argon; Ng-YAG – neodymium: yttrium-aluminum-garnet lasers):
Photoablation (vaporization or burning of tissue), coagulation, sterilization
Lasers plus light-sensitizing drugs (photodynamic therapy / PDT)
Electrocautery: high-frequency electrical current (burn)
Cryosurgery: cold ablation
Liquid nitrogen
Ultra-cold probe

Question 12

What is Neo-adjuvant therapy?

What is the aim?

Answer 12

Chemotherapy or radiation BEFORE surgery
Aim: “Shrink” tumor to improve technical probability of successful removal of all disease and biological probability of reducing tumor viability

Question 13

What is Adjuvant therapy?

What is the aim?

Answer 13

Chemotherapy or radiation AFTER surgery
Aim: Kill tumor cells left behind – detectible or not
Radiation if tumor cells are present at the surgical resection margin
Chemotherapy if systemic risk of recurrence (metastatic disease appearing after surgery) is high

Question 14

Principles of oncologic surgery (1)

(1)

(2)

Answer 14

(1*) Remove the entire tumor, respecting the anatomy.
* Anatomy may allow local excision with an adequate margin.
* “Margin” = rim of normal tissue around visible tumor.
* Anatomy (blood supply, innervation, functional connection to other organ systems) may require removal of poles, lobes, or entire organs to fully excise the tumor.

(2*) Remove the regional lymph nodes (both diagnostic and therapeutic)
* If tumor invades an adjacent organ, that organ is also resected along with its regional lymph nodes

Question 15

Principles of oncological surgery (2)

(3)

(4)

Answer 15

(3*) Leave no detectible tumor behind (margins should be free of tumor macroscopically and microscopically)
* Verification of complete excision requires pathological examination of the resection specimen margins.

(4*) Options for a “positive margin” include:
* Post-operative radiation: timing crucial while surgical wound heals.
* Break-down of surgical wound may be life-threatening
Re-operation may be required.

Question 16

Principles of oncological surgery (3)

(5)

(6)

Answer 16

(5*) Preserve function and anatomy when possible
* Only if it does not compromise the chance of surgical cure
* Resect as little as possible but as much as you must

(6*) Attempt curative excision only when the tumor type, the stage and the tumor site permit
* Tumor type: glioblastoma multiforme (GBM)
* Stage: generally, all stage IV
* Site: brain stem
* Heroic and not easy to realize due to competition for organs:
* Liver transplantation as treatment for hepatocellular carcinoma, intrahepatic bile duct carcinoma (cholangiocarcinoma)
* Heart transplantation for cardiac sarcoma, lymphoma

Question 17

Classification of surgery:
R0 –
R1 –
R2 –

Answer 17

Classification of surgery:
R0 – no tumor at margins
R1 – microscopic at margin
R2 – macroscopic tumor at margin

Question 18

Surgical removal may be precluded by:
T
L
M
P

Answer 18

Type of disease (e.g., leukemia is not a “surgical disease”)
Location of disease (e.g. brain stem) or size
Metastatic spread of disease
Pattern of tumor growth (highly infiltrative – cannot completely remove)

Question 19

Complications of surgery related to anatomical site and tissue function

Answer 19

Disfigurement
Disablement
Emotional distress for patient and family
Loss of bowel control
Bladder incontinence
Loss of speech
Loss of taste

Question 20

Tissue conserving surgery

Answer 20

Minimizing amount of normal tissue removed
Understanding the impact of amount of surrounding tissue removed on local recurrence and overall survival
Read about Dr. Bernard Fisher and breast cancer

Question 21

When is tissue conserving surgery
NOT justifiable???

Question 22

Advances in cancer surgery

Answer 22

(1) Robotic, optically enhanced micro-dissection
Laparoscopy vs. laparotomy - avoiding “open” surgery of body cavities – laparoscopic or thoracoscopic surgery
Avoiding damage to vital structures in anatomic site that affect function after surgery

(2) Sentinel lymph node surgery
Indicator of likelihood that removal of all regional lymph nodes is necessary or not

(3) Intra-operative consultation
“Frozen section” for diagnosis or margin examination

(4) Intra-operative radiation
Greater precision in targeting tissue at risk for cancer persistence

Question 23

Guidelines for surgical candidacy from outcomes research:

Answer 23

Co-morbidities (other diseases)
Anatomical location (“inoperable”)
Stage
Performance status of patient

Question 24

ECOG (Eastern Cooperative Oncology Group) Score

Answer 24

Researchers worldwide consider the ECOG Performance Status Scale when planning cancer clinical trials to study new treatments. This numbering scale is one way to define the population of patients to study in the trial and guide physicians who enroll patients into those studies. It is also a way for physicians to track changes in a patient’s level of functioning as a result of treatment during the trial.

Question 25

Why oncological surgery works

Answer 25

(1) If removed “early” in the evolution of the cancer (before metastasis has occurred), ALL clones and sub-clones are simultaneously, completely removed

(2) The heterogeneity, complexity, molecular biology, evolutionary principles of disease progression are all irrelevant

(3) Collateral damage to patient’s normal cells and tissues can be controlled with good technique and enabling technology

Question 26

Other Ablative therapy

Answer 26

(1) Electrodessication (cautery)

(2) Cryosurgery (freezing): for cancers arising in or spread to skin, cervical, eye, prostate, pancreas, lung, kidney, bone
Tissue destruction: -10 to -120°C
Malignant cell kill: -40 to -50°C

(3) PDT (photodynamic therapy)
Radiation sensitizing agent attuned to a specific laser wavelength is administered systemically
After 24-72 hr the agent is gone from most normal cells but retained by tumor cells
Laser exposure creates ROS that kill the cancer cells.

(4) Laser therapy: focused narrow beam of high-intensity light of a single wave length
Uses primary for superficial tumors at a body surface
External surface tumors: non-melanoma skin cancers
Internal surface tumors: trachea, esophagus, stomach, colon
Advantages
Less bleeding than surgery (closes down blood vessels)
Active sterilization of the operative field
High precision
Often used in conjunction with other therapeutic approaches (surgery, chemotherapy, radiation therapy)

Question 27

Cancer Radiotherapy (XRT) overview (1)

Answer 27

• Treatment for localized disease and regional spread
• May be used alone or before or after surgery
• Use of ionizing radiation (x-rays, electrons, protons) to kill tumor cells
• Radiationis energy that comes from a source and travels through space and may be able to penetrate various materials.

Electromagnetic radiation (no mass; travels in waves)
Particulate radiation (high-speed particles)

Question 28

Cancer Radiotherapy (XRT) overview (2)

Answer 28

• Ionizing radiation is radiation with enough energy that it can remove tightly bound electrons from the orbit of an atom, causing the atom to become charged or ionized.
• Ultraviolet light, X-rays, gamma-rays, and all particleradiationfrom radioactive decay areionizing.
  Near ultraviolet, visible light, infrared, microwave, radio waves are all non-ionizing radiation.
• All types of ionizing radiation are caused by unstable atoms, which have either an excess of energy or mass (or both). In order to reach a stable state, they must release that extra energy or mass in the form of radiation.

Question 29

Types of energy and atomic particles used in radiation therapy (XRT)

Radiation therapy delivers biologically-damaging physical energy to kill cancer cells.

Electrons (______ charge, ______ mass – tiny package of energy) generated in a linear accelerator used for ______ ______ ______.

Photons (______ charge, ______ mass – tiny package of energy): most common ______.

______ (high-energy photons) produced by colliding electrons with atoms of a metal in a ______ ______.
______ ______ (super-energetic photons) from radioactive decay of atomic nuclei.

Protons: ______ charged nuclear particles with 1836-times the mass of an electron.

Answer 29

negative / little / superficial ((e.g., skin) cancers.

no / no / XRT

X-rays / linear accelerator

Gamma rays

Protons: Positively

Question 30

Radiation therapy

Answer 30

Treatment for localized disease and regional spread
Can be used with non-curative intent to treat complications
Can be used in a preventative mode (“sterilize” microscopic disease)
About HALF of all cancer patients receive XRT in their treatment
Also kills / damages normal cells in radiation field
Increases risk of secondary cancer

Question 31

Radiation therapy delivery methods

Teletherapy: __________.
Brachytherapy: __________.

• Systemic radiation therapy delivers ______ ______, such as ______, or an antibody joined to a radioactive substance via the blood – but becomes localized to a site within the body – for specific uptake in cancer cells.

Patient becomes temporarily radioactive (hours to days)
* Total body irradiation (TBI) in otherwise lethal doses for preparation for bone marrow transplantation.

Answer 31

• Teletherapy-radiation source is outside the patient
• Brachytherapy- radiation source is placed inside the patient in the form of radioactive seeds or wires

radioactive elements / iodine

Question 32

The leading reason for failure of effectiveness is?

Answer 32

failure to eradicate all of the tumor within treatment fields

Question 33

Cancer Radiotherapy (XRT) overview

Answer 33

(1) Killing is nonspecific (unrepaired DNA damage causing apoptosis) and will affect both normal and cancer cells

(2) Therefore, XRT delivery of all types is designed to limit the amount of collateral damage to normal tissue as much as possible without compromising the therapeutic dose to the cancer.

(3) Works through DNA damage, either directly or indirectly (through induction of ROS)

Apoptosis follows when damage is unrepaired

Question 34

Radiation therapy

Answer 34

Dose measured in Gray or GY
The amount of radiation energy absorbed by 1kilogram of human tissue
Predominant form of cell death occurs at mitosis
Requires a dose of ~ 2 Gy
Interphase death through apoptosis
Involves events controlled by tumor suppressor genes: gatekeepers
Can occur at low doses of radiation
Cells not in cell cycle are harder to treat
Non-dividing or rarely dividing cells requires very high doses
~ 100 Gy can cause loss of cell function and death

Question 35

Importance of Cell cycle (slide 40)

Question 36

FACTORS AFFECTING RADIATION SENSITIVITY

Answer 36

The cell type(s) involved:
Cells with high mitotic rate are sensitive
Stem cells
Cancer cells
Cells with low mitotic rate are resistant
Brain cells
Muscle cells
The repair and re-population capacity of the tissue following injury

Question 37

What is Brachytherapy?

Introduced through the skin or via a body cavity (e.g., the vagina)
Low dose (permanent): implanted “seeds” remain in place permanently (Rx is several months).
High dose (temporary): radioactive wires inserted under ultrasound guidance (several minutes)

Most often used to treat cancers of what 6 things?

Answer 37

Placement of radioactive sources within the body.

head and neck, breast, cervix, prostate, rectum, and eye.

Question 38

Dividing a total dose into several fractions (“______”) spares normal tissues and increases damage to tumor.

Answer 38

fractionation

Question 39

Fractionation in XRT (1)

Answer 39

The purpose of conventional fractionation is to INCREASE total radiation dose to the tumor while preserving normal tissue function
Single high doses of radiation do not allow a therapeutic differential between tumor and critical normal tissues; dose fractionation does

Question 40

Fractionation in XRT (2)

Answer 40

Tumors are generally irradiated with 2Gy dose per fraction delivered daily to over a 6 week time period to a specified total dose
For curative intent, total dosage depends on tumor type
The typical dose for a carcinoma ranges from 60 to 80Gy
The typical dose for a lymphoma is 20 to 40 Gy

Question 41

Efficacy of fractionation is based on the 4 R’s:

Answer 41

Repair of sublethal damage
Repopulation
Reassortment of cells within the cell cycle
Reoxygenation

Question 42

What is reoxygenation?

Answer 42

• Cells of solid tumors are relatively deficient in oxygen due to disorganized and insufficient tumor vasculature
• Tumor hypoxic environment is 2-3-fold more resistant to radiation damage than a normal oxygen environment
• Hypoxic cells require more radiation to kill
• Oxygen is a potent radio-sensitizer: increases the effectiveness of radiation by also increasing DNA-damaging reactive oxygen species

Question 43

Strategies to in crease oxygen in tumor:
*
*
*
*
*

______ allows tumors to re-oxygenate between doses and tumor shrinkage itself reduces ______ areas.

Answer 43

• High pressure oxygen tanks
• Hyperthermia (vessel dilatation to deliver more blood)
• Blood substitutes to increase O2-carrying capacity
• Hypoxic cell radiosensitizer drugs: e.g., metronidazole
• Hypoxic cytotoxins: e.g., tirapazamine

Fractionation / hypoxic

Question 44

What is Re-population?

Answer 44

(1) regeneration of the surviving cell fraction
(2) Has the net effect of making tumors more resistant
(3) Determines the length and timing of therapy course
(4) Known as the “schedule”

Aim: hit them again before they can regenerate
Rapidly proliferating tumors regenerate faster

Question 45

Redistribution

Position in cell cycle at time of radiation determines ______.
Cells are most resistant in ___, ___, and ___phases.
Cells are most radiosensitive in the___phase.

Rapidly cycling cells like ______, ______ are more sensitive.
Slower cyclers like ______ ______, ______ are resistant.

______ redistributes cells in cell cycle.

Allows tumor cells that were in a radio-resistant phase during one treatment to cycle into a sensitive phase for next treatment.

Answer 45

sensitivity / G0, G1, and S/ M / mucosa, skin / connective tissue, brain / Fractionation /

Question 46

Time scales of the 4 r’s

Relative speed of the event:
Repair of sublethal damage =
Reoxygenation and Redistribution =
Repopulation =

Answer 46

Repair of sublethal damage = FAST
Reoxygenation and Redistribution = MODERATE
Repopulation = SLOW

Question 47

Basics of Radiation Sensitivity

Answer 47

(1) Cell type
* Normal stem cells are sensitive
* Normal brain, muscle cells are resistant
* Tumor types differ in radiation sensitivity

(2) Growth fraction (percentage of cells in the cell cycle)
* Cycling cells are sensitive
* Highly proliferate tumor cells are sensitive

(3) Repair capability (ability to survive damage)

Question 48

The bottom line

Cells are killed
Cells survive without damage
Cells survive but are damaged
Damaged normal tissues repair/scar
Fast: skin
Slow: spinal cord
Complications determined by tissue type involved and the severity of damage
Radiation may predispose to new cancer formation
Ionizing radiation is an initiator and a progressor

Question 49

Planning XRT for the patient (1)

Treatment planning begins with” simulation”.
Detailed imaging scans show the configuration of the tumor.
The area selected for treatment usually includes the whole tumor plus a small amount of adjacent normal tissue.
Regional lymph nodes also may be treated
The normal tissue is radiated for two main reasons:
Body movement (unintentional)
Microscopic spread (intentional)

Question 50

Planning XRT for the patient (2)

During simulation and treatments, it is necessary to ensure that the patient will be in exactly the same position.
Body molds, head masks, or other devices hold a patient still.
Temporary skin marks or tattoos used for precise patient positioning.
After simulation, the radiation oncologist determines:
The exact area that will be treated
The total radiation dose that will be delivered to the tumor
The allowed dose for the normal tissues around the tumor
The safest angles (paths) for radiation delivery

Question 51

The TYPE of radiation therapy prescribed by a radiation oncologist depends on many factors, including:

Answer 51

The type of cancer
The size of the cancer
The cancer’s location in the body
How far into the body the radiation needs to travel
How close the cancer is to normal tissues that are radiation sensitive
The patient’s general health and medical history (previous radiation)
Whether the patient will have other types of cancer treatment
Other factors, such as the patient’s age and other medical conditions

Question 52

Complications of radiation therapy

Answer 52

Little correlation between short- and long-term toxicities

(1) Short-term
* Bone marrow suppression
* Mucositis
* Dermatitis

(2) Long-term (these limit the total dose that can be given)
* Delayed damage to organs or tissues within the radiation field: can be debilitating with severe effects on quality of life (all patients)
* Impaired development (pediatric patients)
* Teratogenesis (women irradiated during pregnancy).
* Carcinogenesis (all patients, but especially those younger than 15)

Question 53

Take home messages

Cancer therapies now cure about 65% of all cancers (including skin cancers)
Surgical resection (physical removal) is first line treatment for most local and regional stage cancers and may be combined with adjuvant or neo-adjuvant radiation or chemotherapy to improve surgical success and long-term outcome
Surgery is likely to be curative only in localized (non-metastatic) disease
Radiation therapy kills cells nonspecifically through DNA damage and does not distinguish normal from abnormal cells
Radiation therapy increases risk of secondary cancers
Normal tissue complications of XRT can be severely debilitating and can impact effectiveness of therapy
Ablative therapies do not address tumor complexity but are aimed at physical removal/elimination of tumor cells