25 Neoplasia 4 Flashcards
Describe the principal modalities of tumor treatment, including roles, advantages, disadvantages, and common side effects of:
a) surgery
- Objective:
- Regional ? may also be removed (?)
- If intention is palliative: ?
- For some tumors, surgery alone can be ?
- ? may be given prior to surgery
- Margin = zone of ? surrounding the tumor
- Definition of an adequate margin depends on ?
- Performed for ? tumors
- Side effects: 4
- Objective: Achieve local control
- Regional lymph nodes may also be removed (locoregional control)
- If intention is palliative: may remove tumor to relieve symptoms
- For some tumors, surgery alone can be curative
- Chemotherapy may be given prior to surgery: decrease size of tumor to facilitate removal (= neoadjuvant chemotherapy) - has implications for diagnosis/evaluation of resection specimen
- Margin = zone of non-malignant tissue surrounding the tumor
- Definition of an adequate margin depends on tumor type
- Performed for solid (non-hematologic) tumors
- Side effects: pain (perioperative, longterm) // loss of function // disfigurement // Changes/damage to surrounding normal structures
Describe the principal modalities of tumor treatment, including roles, advantages, disadvantages, and common side effects of each:
b) radiotherapy
-Like surgery, is a ? therapy
-? hits cells -> formation of ? -> interact with ? -> ? breaks -> cell dies when it tries to ?
-Two types:
-?: Most common method // Radiation beam produced by external radiation source, beam directed over chosen treatment area // Given in fractions, typically over weeks
-?: Radioactive source placed directly on/in patient (wires or pellets) // Allows delivery of high dose radiation to the tumor with a lower dose to surrounding tissue // continuous delivery of radiation over a few days
-? = susceptibility of a tumor to the effects of radiation
-? can act as a radiation sensitizer
-There is an ? to the total amount of radiation that can be given
-Can be ? or ? (eg pain from bone metastases)
-Side effects:
- Acute: 2
- Late: 4
b) radiotherapy
-Like surgery, is a locoregional therapy
-radiation hits cells -> formation of free radicals -> free radicals interact with DNA -> DNA strand breaks -> cell dies when it tries to divide
-Two types:
External Beam Radiotherapy: Most common method // Radiation beam produced by external radiation source, beam directed over chosen treatment area // Given in fractions, typically over weeks
Brachytherapy: Radioactive source placed directly on/in patient (wires or pellets) // Allows delivery of high dose radiation to the tumor with a lower dose to surrounding tissue // continuous delivery of radiation over a few days
-Radiosensitivity = susceptibility of a tumor to the effects of radiation
-Chemotherapy can act as a radiation sensitizer
-There is an upper limit to the total amount of radiation that can be given
Can be curative or palliative (eg pain from bone metastases)
Side effects:
- Acute: seen in high-turnover tissues such as skin/gut epithelium (hair loss, erythema)
- Late: Pulmonary fibrosis // transverse myelitis // radiation nephritis // mutagenesis (cells mutated but not killed -> secondary cancers)
Erythema multiforme is a skin reaction that can be triggered by an infection or some medicines.
Describe the principal modalities of tumor treatment, including roles, advantages, disadvantages, and common side effects of:
chemotherapy
-? treatment, unlike surgery or radiotherapy
-? that are toxic to normal and cancer cells but moreso to cancer cells
- Generally are more active against ?
- Variety of targets: 1. ? damage DNA via ? ? ? that bind to DNA and by forming ? ? (alkylating agents and platinum analogs (“platins”) 2. Interfere w/ ? ? (antimetabolites, topoisomerase II inhibitors) 3. Interfere with ? assembly and disassembly (taxanes and Vinca alkaloids**
- Administration?
- Commonly use a combination of drugs to achieve ? and reduce ?
- Can be ? in intent
- Mode of delivery?
- Side effects: 6
chemotherapy
-Systemic treatment, unlike surgery or radiotherapy
-Cytotoxic agents that are toxic to normal and cancer cells but moreso to cancer cells
- Generally are more active against rapidly proliferating cells i) Normal tissues that rapidly divide experience the most toxicity (Bone marrow, GI tract mucosal lining, hair follicles ets
- Variety of targets: 1. Directly damage DNA via electrophilic reactive intermediates that bind to DNA and by forming DNA crosslinks (alkylating agents and platinum analogs (“platins”) 2. Interfere w/ DNA synthesis (antimetabolites, topoisomerase II inhibitors) 3. Interfere with microtubule assembly and disassembly (taxanes and Vinca alkaloids**
- Administered in cycles with recovery time (for normal tissues) in between
- Commonly use a combination of drugs to achieve greater efficacy and reduce resistance
- Can be palliative in intent
- Mode of delivery? Can be oral; most IV
- Side effects: Emesis // Mucositis // diarrhea // infertility (esp alkylating agents) // bleeding // infections etc
Describe the principal modalities of tumor treatment, including roles, advantages, disadvantages, and common side effects of:
HORMONAL THERAPY
-For ?-responsive cancers: ?, ?. ? // can be used in ? therapy
-? therapy in prostate cancer
-? therapy for breast cancer
-Tumor must express ? for therapy to be effective
-Works slower than ? but is given continuously
-Side effects: 8
HORMONAL THERAPY
-For hormone-responsive cancers: prostate, breast, uterus
/ can be used in adjuvant therapy, palliation
-Anti-androgen therapy in prostate cancer
-Anti-estrogen therapy for breast cancer
-Tumor must express Hormone receptor for therapy to be effective
-Works slower than chemotherapy but is given continuously
-Side effects:
1. Menopause-like symptoms
2. Bone density loss
3. Blood clots
4. endometrial cancer
5. mood disorders
6. changes in serum lipids
7. Loss of muscle mass and insulin resistance for anti-androgens
Describe:
-Tumor vaccines:
?: HPV, Hepatitis B
?
-Monoclonal Antibodies: mAbs
Antibodies that ? proteins expressed by ? cells
can be conjugated to a “?” (eg ?)
? ? ? therapy
-CAR (chimeric antigen receptor)-T-Cell adoptive immunotherapy
Genetically modified T-Cell which combines ? with ?
Greatest success is use of CAR-T against ?, ? or ? ? malignancies
-Tumor vaccines:
prophylactic: HPV, Hepatitis B
Therapeutic
-Monoclonal Antibodies: mAbs
Antibodies that bind to and inhibit function of proteins expressed by cancer cells
can be conjugated to a “payload” (eg radioisotope)
Immune Checkpoint Blockade therapy
-CAR (chimeric antigen receptor)-T-Cell adoptive immunotherapy
Genetically modified T-Cell which combines T-cell signaling apparatus with antibody specific for target of choice
-Greatest success is use of CAR-T against aggressive, refractory or relapsed B-cell malignancies
What are the four broad categories of Immunotherapy?
- Bacillus Calmette-Guerin (BCG)
- Tumor vaccines:
prophylactic: HPV, Hepatitis B
Therapeutic - Antibodies that bind to and inhibit function of proteins expressed by cancer cells (monoclonal antibodies: mAbs)
-can be conjugated to a “payload” (eg radioisotope)
-Immune checkpoint blockade therapy -
CAR (chimeric antigen receptor)-T-Cell adoptive immunotherapy
-Genetically modified T-Cell which combines T-cell signaling apparatus with Antibody specific for target of choice
-Greatest success is use of CAR-T against aggressive, refractory or relapsed B-Cell malignancies
Treatment resistance
Tumors are (heterogeneous/homogeneous)?
Tumors are heterogeneous
Even within the same tumor from the same patient, tumor cells might be subtly or even dramatically different. And there can be very important implications of this type of heterogeneity.
- One implication is that more-sophisticated tools will be needed to characterize patients’ cancers and guide their treatment.
- Pathological examination of tumors often relies on needle biopsy, a procedure in which small samples of cells are extracted from a tumor for analysis. However, if doctors are dealing with a highly heterogeneous cancer, the tiny fraction of cells in the biopsy may not be representative of the entire tumor mass— which means important disease features might be missed.
Describe mechanisms of tumor resistance to treatment.
Treatment Resistance:
- ? vs ?
- Multiple potential mechanisms:
- Decreased ? of drugs ? or increased ? -> Ultimately: decreased ?
- Accelerated ? of drug
- Increased ? capacity
- Modification of ?
Treatment Resistance:
Intrinsic vs Acquired (emerges during tx)
Multiple potential mechanisms:
- Decreased transport of drug into or increased efflux of drug out of cells -> decreased accumulation of drug
- Accelerated inactivation or impaired activation of drug
- Increased DNA repaire capacity
- Modification of cellular targets (by quantitative decrease or by mutation
Describe ways in which dev’ts in treatment can impact the clinical lab
Have known for some time that:
- Certain mutations have ? significance
- Certain mutations made a ? more or less susceptible to certain ? regimens
As treatments become increasingly “personalized”, the number of ? or ? the lab is asked to evaluate increases to determine ?
Treatments carry both ? and ?
Trend towards being asked to ?
Have known for some time that:
- Certain mutations have prognostic significance
- Certain mutations made a malignancy more or less susceptible to certain chemotherapeutic regimens
As treatments become increasingly “personalized”, the number of mutations or markers the lab is asked to evaluate increases to determine eligibility for tx
Treatments carry both benefits and risks
- Which patients will benefit from a particular tx
- Are particular patients at risk of increased harm
Trend towards being asked to do more with less
- eg in lung cancers, expected to confidently diagnose malignancy, classify histologic subtype and perform molecular testing with one small biopsy
In most situations, a biopsy is the only way to definitively diagnose cancer. In the laboratory, doctors look at cell samples under the microscope.
What are two different intents for tumor treatment?
- Curative - generally willing to tolerate more side effects of treatment
- Palliative - Can’t cure but aim to improve quality/quantity of life
What is Adjuvant therapy?
Objective?
Therapy given in conjunction with the primary modality of treatment
- Most often chemotherapy and/or radiation as adjucts to surgery
- Objective: Eradicate microscopic tumor cells that may have been left behind following primary treatment
What is External Beam Radiotherapy?
One of the two types of Radiotherapy
External Beam Radiotherapy:
- Most common method //
- Radiation beam produced by external radiation source,
- beam directed over chosen treatment area //
- Given in fractions, typically over weeks
Brachytherapy: Radioactive source placed directly on/in patient (wires or pellets) // Allows delivery of high dose radiation to the tumor with a lower dose to surrounding tissue // continuous delivery of radiation over a few days
What is Brachytherapy?
One of the two types of Radiotherapy:
Brachytherapy:
- Radioactive source placed directly on/in patient (wires or pellets) //
- Allows delivery of high dose radiation to the tumor with a lower dose to surrounding tissue //
- continuous delivery of radiation over a few days
One of the two types of Radiotherapy
External Beam Radiotherapy:
- Most common method //
- Radiation beam produced by external radiation source,
- beam directed over chosen treatment area //
- Given in fractions, typically over weeks
What are three potential targets of chemotherapy?
1. Directly damage DNA via ? that ? to DNA and by forming ? (alkylating agents and platinum analogs (“platins”)
2. Interfere w/ ? (antimetabolites, topoisomerase II inhibitors)
3. Interfere with ? assembly and disassembly (taxanes and Vinca alkaloids**
- Directly damage DNA via electrophilic reactive intermediates that bind to DNA and by forming DNA crosslinks (alkylating agents and platinum analogs (“platins”)
- Interfere w/ DNA synthesis (antimetabolites, topoisomerase II inhibitors)
- Interfere with microtubule assembly and disassembly (taxanes and Vinca alkaloids**
What is the target of chemotherapy agents such as alkylating agents and platinum analogs?
- Directly damage DNA via electrophilic reactive intermediates that bind to DNA and by forming DNA crosslinks (alkylating agents and platinum analogs (“platins”)
What is CTLA-4
-Type of ? therapy
-CTLA-4 (?)
Negative ? (?) receptor on ?
When it binds its ligand ? on ? cells, inhibits ? funtion
Anti-CTLA-4 antibody ipilimumab approved for ?
—ipilimumab blocks ? -> Block ? ? -> Decreased ?
-Side effects tend to be ?-related (skin rash, colitis, etc)
-Current no marker to predict ?
-CTLA-4 (cytotoxic T-lymphocyte antigen-4)
-Type of immune checkpoint blockade therapy
Negative costimulatory (inhibitory) receptor on T-cells
When it binds its ligand B7 on antigen-presenting cells, inhibits T-cell funtion
Anti-CTLA-4 antibody ipilimumab approved for melanoma
—ipilimumab blocks CTLA-4 binding -> Block inhibitory signal -> Decreased immune tolerance (allows T-cell killing of tumor cell)
-Side effects tend to be immune-related (skin rash, colitis, etc)
-Current no marker to predict benefit
Immunotherapy drugs called immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells
What is PD-1?
- PD-1 = ?
- Type of ? therapy
- ? receptor on ? cells
- Ligands are ? and ? which are upregulated in many tumors
- Binding of PD1 with ? -> inhibits ?
- Pembrolizumab is a ? against PD-1
- Side effects: ? // ? (less frequent than ipilimumab)
- Testing for ? now being done in alberta for advanced ? carcinoma
What is PD-1?
- PD-1 = Programmed death-1
- Type of Immune checkpoint blockade therapy
- Inhibitory receptor on T cells
- Ligands are PD-L1 and PD-L2 which are upregulated in many tumors
- Binding of PD1 with PD-L1/2 -> inhibits T-cell activation
- Pembrolizumab is a monoclonal antibody against PD-1
- Side effects: immune related // severe colitis (less frequent than ipilimumab)
- Testing for PD-L1 now being done in alberta for advanced Non small cell lung carcinoma
PD-L1 binds to PD-1 and inhibits T-cell killing of tumor cell
Block PD-L1 or PD-1 allows T-cell killing of tumor cell
