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What are the goals of chemotherapy?
- To cure malignancy
- To improve cure rates (adjuvant therapy)
- To spare organ function (along with radiation)
- To Palliate Symptoms
What is an alkylating agent?
- There are 2 types, an alkane which is a hydrocarbon chain with only C-C and C-H bonds.
- The other type is an alkyl group which is an Alkane that is missing a hydrogen molecule giving it an unpaired e- so it is very reactive.
What is an anti metabolite?
- A molecule similar to an essential metabolite that blocks that metabolite's utilization
- When used in chemotherapy it implies inhibition of the synthesis of DNA, RNA, or protein.
What are naturally occurring agents?
- Anti cancer agents found in nature that inhibit cell replication and need little to no synthetic modification.
- Usually derived from fungi(antibiotics) or plants(plant alkyloids)
What are the chemotheraputic alkylating agents that are Nitrogen Mustard derived?
What are the chemotheraputic alkylating agents that are classified as Nitrosureas?
What are the chemotheraputic alkylating agents that are classified as "other"?
What are the anti metabolite chemotheraputic agents?
What are the naturally occurring fungal derived chemotheraputic agents?
What are the plant derived chemotheraputic agents?
- Vinca Alkaloids
- Misc- platinum derived, and I-Asparaginase
What are some of the similarities between antimicrobials and anti neoplastic drugs?
- Inhibition of DNA synthesis (like Quinilones inhibiting DNA gyrase)
- Inhibition of mitotic spindle function
- Undermine growth regulation (target ribosomes)
- Acquire resistance
- Anti neoplastics carry much more risk than antibiotics
What is the Log Kill principle?
- Effective chemo doses kill a constant fraction of tumor cells so as the number of cells decreases so does the number killed with each dose.
- Complete killing does not occur.
What is needed to kill the cells left after chemo treatment?
Immunologic mechanisms, or possibly apoptosis of those cells
When is chemotherapy most effective?
- When the tumor cells are actively replicating (cell cycling)
- Usually only a small percentage of tumor cells are cycling
The cell cycle is controlled by Cyclin Dependent Kinases. What proteins control the CDKs?
- P14arf- indirectly by blocking MDM2 which Blocks P53 which in turn does not stimulate P21 formation allowing progression
What happens when P53 is mutated?
Cells with damaged DNA are allowed to complete the cell cycle.
What is Compertzian growth?
- As tumors grow rapidly they outstrip their blood supply and may decrease their growth fraction decreasing chemo effectiveness.
- As tumors shrink and the growth fraction increases chemo may become more effective.
What happens in the different phases of the cell cycle?
- G1 the cell is making the machinery to replicate DNA
- S phase is where the DNA is replicated
- G2 is where the synthesis of mitotic machinery happens
- G0 is the time between mitosis and the beginning of G1
What drugs inhibit mitotic spindle synthesis?
Vinca Alkaloids and Taxanes
What drugs inhibit DNA synthesis?
What drugs work in G0 (cell cycle non specific)?
- Platinum compounds
- These are said to be radiomimetic because they cause DNA damage in non cycling cells
What are the properties of alkylators?
- Action is due to the bonding of alkyl groups to intracellular molecules
- They generate highly reactive positively charged intermediates
- Combine with nucleophilic groups (- charge) like amino, phosphate, sulfhydryl, or hydroxyl groups
- Can have 1 or 2 functional groups
- Usually first line- cause vesicles
What are some adverse effects of alkylators?
- Secondary malignancies like AML
- Toxicity worse in patients with defective DNA repair genes like ataxia telangiectasia and xeroderma pigmentosa since the drugs cause single or double stranded breaks.
How is resistance to alkylators developed?
- Decreased transport across cell membranes
- Gene amp of efflux genes
- Increased intracellular thiol concentration- thiols neutralize alkylation
- Increased enzymatic detox of reactive intermediates
- Alteration in DNA repair enzymes- gene mutation
What are the properties of Nitrosureas?
- Fat soluble so can cross BBB
- Prolonged bone marrow suppression
- Easily degraded
- Used in melanoma and brain tumors commonly
- Streptozocin is used in islet tumors
What is Dacarbazine?
- An alkylator that is not often used, causes prolonged marrow suppression
- Has some action in melanoma
- Busulfan(CML) and Procarbazine(Hodgkin's and brain tumors) also aren't used any more.
What are the nitrogen mustard alkylators active on?
- Part of MOPP protocol for Hodgkin's treatment
Which alkylator is used on low grade lymphomas?
- Well absorbed orally and active on slowly progressing malignancies like CLL
What is Melphalan?
- Alkylator used in multiple myeloma
- Given in high dose bone marrow transplant protocol
- Some activity in breast and ovarian cancer
What is cyclophosphamide?
- Alkylator that is well absorbed orally
- Widely used
- Active intermediates (phosphoramide mustard)
- Good for breast cancer, lymphomas and leukemias
- Causes myelosuppression
What is ifosfamide?
- An alkylator used in testicular cancer, sarcomas, and lung cancer
- Intermediate is acrolein which can cause hemorrhagic cystitis destroying the bladder
- Can use MESNA to inactivate Acrolein
What is Mesna?
- Inactivates Acrolein by giving a free thiol group
- Acrolein comes from ifosfamide and cyclophosphamide
What is DTIC?
An alkylator used in melanoma as well as in the ABVD protocol for Hodgkin's
What are the toxicities associated with alkylator use
- Marrow suppression usually after use, recovery in 7-10 days
- Happens more often and for longer with nitrosureas
- Hemorrhagic cystitis due to acrolein- forced hydration so it does not sit in bladder along with MESNA
- Can cause secondary malignancies due to sub lethal DNA damage
What are the toxicities of Busulfan and Procarbazine?
- Busulfan- Interstitial fibrosis
- Procarbazine- antabuse effect
What are the common properties of anti metabolites?
- Most active during DNA synth
- Inhibit DNA RNA and protein synth
What are the families of anti metabolites?
- Anti folates- methotrexate
- Pyrimidine analogues- 5-FU, ARA-C
- Purine Analogues- 6-MP, 5-TG
- Urea Analogues- Hydroxyurea
What is Methotrexate?
- Anti folate anti metabolite that blocks dihydrofolate reductase by competing with oxidized folate
- DHFR reduces folate for Thymidylate synthetase which uses it to convert uridine monophosphate to thymidine monophosphate.
- It is not metabolized- half life based on renal clearance
- Weak acid that is soluble at alkaline pH
- Does not cross BBB
What are the mechanisms of resistance to Methotrexate?
- Increased production of DHFR by gene amp
- Decreased affinity of DHFR for methotrexate (mutation)
- Decreased uptake by gene amp
- More active if polyglutamated- cancer cells often can't do this.
What are the common clinical uses of methotrexate?
- Non Hodgkin's Lymphoma
- Cutaneous T cell lymphoma
- Lung and breast cancer
- Intrathecal- spinal cord chemo
- Causes marrow suppression, rash, mucositis, Hepatotoxicity with chronic use, pulmonary tox
What is a special characteristic of methotrexate?
- Collects in pleural effusions and ascitic fluid
- Then slowly released
What are other antifolate drugs?
- Pemetrexed- used for mesothelioma and lung cancer
- Raltitrexed- used for colorectal and breast cancer
What is Leucovorin and what is it used for?
- Used to rescue tumor cells
- As tumor shrinks GF (cells in mitosis) goes down making MTX less effective
- Rescuing the tumor cells brings the GF back up so you can hit with MTX again
- Very dangerous, must be timed right
What are the dna bases?
- Pyrimidines are thymine (uracil in RNA), cytosine
- Purines are guanine and Adenine
What is 5-FU
- Anti pyrimidine (C T U) drug, looks just like uracil but with fluorine at position 5
- Converted to F-Dump which competes with DeoxyUridine MonoPhosphate for Tymidylate synthetase stopping formation of dTMP a precursor to dTTP a dna base
- 5f-UMP gets incorporated into RNA acting as a false pyrimidine.
What are the mechanisms of resistance to 5-FU?
- Decreased activation of 5-FU (decreased PRPP with allopurinol use)
- Increased activity of TS (gene amp)
- Reduced drug sensitivity of enzyme (mutation)
What is 5-FU used for?
- Colorectal cancer (non metastatic) - enhanced by addition of reduced folate that makes a complex allowing for another bond between F-Dump and TS completely blocking it
- Breast cancer- used as adjuvant
- GI malignancies
What are the toxicities associated with 5-FU use?
- Mostly GI (mucositis)
- Skin- sun sensitivity and venous discoloration
What are other pyrimidine analogues?
- Cytosine Arabinoside(ARA-C
- Capecitabine- pro drug converted to 5-FU in liver then to active drug in liver and tumor cells- oral admin, mimics 5-FU- tox= hand foot syndrome
What is ARA-C?
- A pyrimidine analogue that is incorporated into DNA, inhibits DNA pol and DNA elongation
- Resistance due to- increased activity of cytidine deaminase(inactivates drug)
- Decreased activity of deoxycytidine kinase(activates drug
- Decreased affinity of DNA pol for ARA-C- mutation
What is ARA-C used for?
- AML treatment
- Causes severe BM suppression
- GI mucositis
- Unusual neuro tox- cerebellar dysfunction
What is gemcitabine?
- A cytoisine analogue
- Similar structurally to ARA-C
- Anti tumor activity against variety of tumors
- Key in treatment of pancreatic cancer- but still not great
What are the Purine analogues?
- 6-MP and 6-TG
- Work by inserting into DNA activated by HGPRT
- This blocks DNA synth
- Most important point of attack is the reaction of glutamine and 5-phosphoribosyl-1-pyrophosphate (PRPP) to form ribosyl-5- phosphate, the first committed step in DNA synthesis
What are the properties of 6-MP and 6-TG?
- Metabolized to deoxynucleotides and incorporated into DNA
- Active during DNA synth
- Resistance due to decreased activity of HGPRT- mutation, and increased drug degradation
- Used for leukemia
- Cause myelosuppression, mucositis, diarrhea, nausea, and vomiting
What is the significance of allopurinol?
- Decreases 5-FU activity by inhibiting PRPP which converts 5-FU to Fdump
- Increases activity of purine analogues by inhibiting PRPP which is needed for activation
What is Fludarabine?
An adenosine analogue with activity in low grade lymphoma
What is hydroxyurea?
- Unique anti metabolite that is an analogue of urea
- Blocks ribonucleotide reductase which is needed to make ribonucleotides into deoxyribonucleotides
- Blocks DNA synth
- Active in CML
- Causes myelosuppression, nausea, vomiting, and diarrhea
What are the major types of antibiotics?
- Anthracyclines- doxorubicin, Danorubicin, Idarubicin, epirubicin
- Anthracenedione- ,mitoxantrone
- Come from various strains of soil fungi like streptomyces
What is the mechanism of action of the Anthracycline Doxorubicin?
- Intercalates between DNA and RNA base pairs blocking synthesis
- Inhibits Topoisomerase 2 causing DNA strand breakage
- Generates oxygen and hydroxyl free radicals causing DNA breakage and membrane damage
- Resistance mediated by MDR membrane assoc p-glycoprotein (an efflux pump)
What are the therapeutic used for anthracyclines?
- Doxorubicin used in Non Hodgkin's lymphoma with cyclophosphomide, vincristine, and prednisone
- Also in breast cancer, sarcomas, and other tumors
- daunorubicin used in AML
- Idarubicin used in hematologic malignancy
- Epirubicin used in same manner as doxorubicin
What are the toxicities of anthracyclines?
- Cardiac- free radicals have affinity for cardiac muscle
- Result is dose dependent cardiomyopathy
- Worse with HT or other after load stress
- Aggravated by radiation
- Synergistic with other drugs like herceptin
- Can use cardio protective drugs to prevent
- Marrow suppression
- Severe nausea and vomiting
- Secondary malignancy
What is Mitoxantrone?
- An Anthracinedione
- Similar to anthracycline but less active and less toxic
- Used in frail patients
What is Dactinomycin?
- Antibiotic that works by intercalation
- Activity in pediatric tumors like wilms tumor
- Causes myelosuppression, severe vesicant
What is Mitomycin-C?
- Antibiotic that works by causing potent cross linking similar to alkylators
- Possible preferential activity in hypoxic conditions
- MDR mediated by p glycoprotein
- Used in anal cancer with 5-FU and radiation to spare anal function
- Can also be used for intra vesicle Rx for superficial bladder cancer
- Tox- TTP, often fatal
What is Bleomycin?
- Antibiotic used to treat recurrent pleural infections, causes inflammation making the pleura stick together.
- Intercalates in DNA
- Produces single and double stranded breaks
- ONLY drug that works predominantly in G2resistance is MDR mediated by p- glycoprotein
- Works on Testicular cancer
- Hodgkin's as part of ABVD protocol
- Tox: free radical is directly toxic to lung
- Must monitor pulmonary function
- Can cause acute anaphylaxis
What are the Vinca alkaloids?
- Vincristine, Vinblastine, Vindesine, and Vinorelbine
- Derived from periwinkle plant
What are the alkaloid esters?
- Paclitaxel and docetaxel
- Derived from the yew tree
What are the podophlotoxins?
Etoposide and Teniposide
What are quinolone alkaloids?
Irinotecan and Topotecan
What are the properties of vinca alkaloids?
- Bind to tubulin and cause depolymerization of microtubules preventing spindle formation and thus mitosis.
- MDR mediated by p glycoprotein
- Tox: peripheral neuropathy since MT is similar to neural sheath
- Dose dependent
- Sensory neuropathy is often reversible but motor is not
- Used in Hodgkins, NHL, Lung cancer, Glioma, and Breast cancer (vinorelbine)
What are the properties of the Taxanes?
- Bind tubulin enhancing MT formation, preventing spindle dissociation stopping mitosis
- Paclitaxel used in ovarian cancer
- Active in breast and lung cancer
- Tox: Marrow, allergies, myalgia, arthralgia, neurologic, skin (thin fragile nails
What are the properties of podophyllotoxins?
- Emetic, cathartic, antihelminthic.
- Inhibit DNA topoisomerase 2 thus inhibiting DNA and RNA synthesis- cell cycle specific
- Works in testicular cancer, small cell lung cancer, NHL, and some others
What are the properties of camptothecins?
- Inhibit topoisomerase 1 blocking DNA synth and killing the cell
- Irinotecan used in metastatic colon cancer- causes excessive diarrhea, also has cholinergic effect requiring atropine
- Topotecan- used mostly in small cell lung and ovarian cancer- causes myelosuppression
What are the properties of the miscellaneous anti cancer agents?
- Cisplatinum, Carboplatinum, and Oxaliplatinum
- Heavy metals
- Can mould shape
- Act as alkylators
- Neuro toxic
- cisplatinum has nephrotoxicity
- carboplatinum causes myelosuppression
- Oxaliplatinum causes cold intolerance
What is cisplatinum?
- Platinum complex with 2 Cl- and 2 H3N groups
- Curative for most germ cell tumors
- Works well for lung, breast, and unknown primary cancers
- Carboplatinum has the same spectrum but less nephro tox
- Oxaliplatinum has unique activity in colon cancer
How do you prevent nephro and neuro toxicity from platinum use?
- Nephrotoxicity: parenteral and oral hydration
- Use mannitol(volume expander) to force diuresis
- Replace K+ and magnesium
- Use Amifostine- a compound that picks up cisplatin metabolites from the tissues
- Neurotoxicity: Ca and magnesium infusions are somewhat protective
- Cold induced neuropathy prevented by avoidance of cold things.
What is L- Asparaginase?
Anti cancer drug from pig serum that inhibit leukemia cells by hydrolyzing circulating asparagine- this inhibits tumor growth because most tumors have low asparagine synthetase activity. So protein synthesis is inhibited.
What are the major classes of anti hormonal therapy?
- Anti Estrogenic- Tamoxifen, aromatase inhibitors, progestins, and LHRH analogues
- Anti Androgenic- Receptor block (flutamide/biclutamide) LHRH analogues
What are the properties of Tamoxifen?
- Blocks the estrogen receptor- given orally
- Tox: Thromboembolic disease
- Endometrial cancer
- Hot flashes
- Faslodex is an irreversible blocker of the ER
What is Aminogluthemide?
An aromatase inhibitor that is very toxic and requires steroid use at same time
What are the third gen aromatase inhibitors?
- Anastrozole, Letrozole, and Exemestane
- Tox is caused by estrogen withdraw- osteoporosis, hot flashes, and arthralgia.
- Aromatase inhibitors more active in post menopausal than tamoxifen
When does tamoxifen work best?
- Post menopausal because ER is up reg to combat low estrogen levels
- Has an anti estrogen effect on the breast but estrogen effect in the uterus
- Aromatase inhibitors only used in post menopausal when adrenal is making the estrogen
What is the toxicity of flutamide and biclutamide?
hot flashes, impotence, and andropause
What is the purpose of LHRH analogues?
- Pituitary inhibition
- Leuprolide and goserelin- work by decreasing pituitary release of LH and FSH leading to decreased estrogen and testosterone prod
- Work for prostate and breast cancers
- Cause flare effect and impotence
What are the properties of corticosteroid therapy in cancer?
- Cause malignant lymphocytes to lyse.
- Work in Hodgkin's and NHL
- Also used in supportive care as anti nauseant, appetite stimulant, reduction of cerebral edema, and analgesic
- Tox: fluid retention, glucose intolerance, proximal myopathy, insomnia, immunosuppression, increased appetite, skin changes, and stress ulcers.
What is targeted therapy?
- Drugs that block cancer growth/spread by blocking specific molecules that the tumor cells need
- Tyrosine Kinases, EGF receptors, VEGF receptors, and m-TOR are usual targets
What are the tyrosine kinase inhibitors?
- Receptor and non receptor associated- they block signal transduction
- Iapatinib- used in breast cancer blocks EGFR(her 2 assoc)
- Gefitinib and erlotinib block EGFR(non her2 assoc) both used for non small cell lung ca
- Sunitiniband Sorafanib block VEGF
- Imatinib and Nilotinib work for GIST and CML- Block product of mutated oncogene(non receptor assoc)
What is imatinib?
- TK inhibitor that blocks activity of the protein produced by BCR-Abl oncogene in CML
- Used for CML and GI stromal tumors ( expressing c-kit TK)
- Mutation of BCR-Abl confers resistance
- Tox: Diarrhea, Myalgia, and fluid retention
What are monoclonal antibodies to EGFR?
- Trastuzumab- has cardio tox,
- Indicated in Her-2/neu over expressing breast ca
- Cetuximab- used in Sq cell, head and neck Ca, and wild type K-Ras colon cancer
- Panitunumab- also used in Wt K-Ras colon cancer
What are monoclonal antibodies to VEGFR
- Bevacizumab- used mainly in colon cancer
- Causes poor wound healing
What are monoclonal antibodies to CD20 and CD 52 lymphocyte receptors?
- CD20- rituxumab- used for B cell lymphoma
- CD52- alemtuzumab- also for B cell lymphoma
What is the action of M-TOR inhibitors?
- They block the proteosome so cells cannot degrade proteins.
- Inhibited by bortezomib
- Have activity in multiple Myeloma and mantle cell lymphoma
What is the mechanism of action of Interferon?
- Interferes with tumor cell replication
- Activity in melanoma, renal cell carcinoma, hairy cell leukemia, T cell lymphoma, and early stage CML
- Tox: predictable- flu like symptoms, myelosuppression, and hepatotoxicity.
What are the mechanisms of resistance to chemo?
- Increased expression of target proteins
- Increased DNA repair
- Failure of drug to enter cell or rapid efflux- mediated by MDR gene
- Inability of drug to penetrate tumor- large tumors with hypoxic areas
- Target proteins no longer available
- Target alteration
- Formation of trapping agent
- Decrease in activation of pro drug
What are some strategies to prevent resistance to chemo?
- Combination therapy
- Dose intensity- give high doses killing the tumor before resistance can occur- does not work in ep tumors, only for leukemia and lymphoma
- Agents that reverse resistance
What is adjuvant therapy?
- Chemotherapy given along with the primary therapy to increase cure rates
- Used in treatment of early stage breast cancer, colon cancer, and osteosarcoma
- Application of compertzian growth principles
What is induction chemotherapy?
- Attempt to induce complete response in sensitive tumors.
- Used in treatment of most acute leukemia, Hodgkin's disease, NHL, and testicular cancer
- Give high dose of several drugs, often requires a month and hematologic support
What is consolidation and maintenance chemotherapy?
- Use of a higher dose of subsequent chemo to consolidate induced response and then maintain response with a lower dose
- Used in acute leukemias
- Usually given right after induction
- often need support with antibiotic prophylaxis
What is neoadjuvant therapy?
- Chemotherapy given before the primary therapy to reduce cell numbers making the primary treatment more effective
- Used in advanced but local breast/rectal cancer
- Typical drugs used in breast- FAC, FEC-100, Taxanes, A.I.s
- 5-FU + radiation in anal
What is palliative chemotherapy?
- Chemo with primary goal of improving quality of life, extending life is secondary.
- Used in most cancers
- - Examples: glioma – temozolomide
- - Head and neck – platinum
- - Lung – gemcitabine
- - Breast – vinorelbine
- - Pancreas – gemcitabine
- - Colon - capecitabine
What are the common toxicities of chemotherapy?
- Nausea and Vomiting
- Skin Changes
What are the characteristics of chemo induced alopecia?
- It is predictable
- Commonly happens with anthracyclines, taxanes, and some alkylators
- Usually 3 weeks after 1st cycle
- Hair still grows but is brittle
- When hair comes back it is often a different texture.
- Variation of drugs, avoidance of concurrent toxins
What are the characteristics of chemo induced nausea and vomiting?
- Worse in young
- Common with platinum, anthracyclines, IV nitrogen, Mustard derived alkylators
- Psychological component
- Used to be main cause of premature discontinuation of chemo
- Prevent with light meals, amnesics, and multiple drugs
- Use HT-3 inhibitors
- Anti histaminics,
- Anti dopamines
- Tranquilizers, steroids, and THC
What are the characteristics of myelosuppression?
- Very impt, biggest cause of death
- White count drops in 7-10 days, plates later, red cell drop 1%/day
- Often get mucositis creating ideal infection environment.
- Hygiene impt, avoid crowds, report fever or chills ASAP, broad spectrum antibiotics if fever with low absolute neutrophils
- Consider fungal if fever persists
- Give CSF after subsequent doses to support
What is CSF support?
- Colony stimulating factors- granulocyte CSF used prophylactically, decreases infection related hospitalization/death but causes bone pain
- EPO- increases RBC
What are the characteristics of mucositis?
- usually seen with antimetabolites
- Usually at Nadir blood count
- Painful: dysphagia and diarrhea leading to malnutrition and electrolyte imbalance
- Assoc with yeast infection big cause of sepsis
- Give mouth care, pre chemo dental check
- Good hydration, mouth wash with anesthetic
- Occasional feeding tube req
What are the characteristics of skin tox in chemo?
- leakage of IV drugs like alkylators from veins
- Antimetabolites can cause discoloration but not vesicles
- Nail changes- mainly taxanes
- Capecitabine- hand-foot syndrome
- acneiform rash common with targeted therapy like EGFR inhibitors and steroids
What is the treatment for skin toxicity?
- If extravisation discontinue infusion
- Elevate/ ice limb
- Give anti histamines and anti inflammatory agents
- Keep close eye on pt for extension of rxn
- Consult plastics
- For hand-foot- reduce dose, gloves, skin emollients
- Acneiform rashes give topical antibiotics/steroids
What are the characteristics of subacute neurologic toxicity?
- Common with Vinca Alkyloids, taxanes, and platinum
- Sensory is the most common deficit- reversible
- Motor deficit usually late to show- usually irreversible
- Autonomic deficit- often GI constipation, unpredictable
What are the characteristics of sub acute cardiotoxicity?
- Common with anthracyclines, 5-FU, and high dose cyclyophosphamide
- Anthracycline- dose dep cardiomyopathy mediated by free radical intermediate. HT and radiation exacerbate, can be prevented with cardio protective agent. herceptin can make it lethal
- 5-FU- unpredictable coronary spasm, seen with capecitabine as well
- cyclophosphamide is direct cardiac tox
What steps are taken to prevent cardio toxicity?
- Monitor dose ( anthracycline dep on cumulative dose)
- Baseline and follow cardiac ejection fraction, drop>10%= discontinuation usually
- Avoid concurrent cardio tox like trastuzumab or radiation
- cardio protective agents
What are the characteristics of sub acute nephrotoxicity?
- common with cis- platinum, Mitomycin-C, and cyclophosphamide
- Cicplatinum is a dose dep prox tubule tox- can partially prevent with hydration and amifostine
- MitomycinC- can cause TTP w/renal failure, likely free radical mediated, unpredictable and irreversible
- Cyclophosphamide- acrolein mediated cystitis
- Prevented with MESNA and hydration
What are the characteristics of sub acute pulmonary toxicity?
- Common with bleomycin, gemcitabine, busulfan
- Bleo- free radical intermediate interacts with heme assoc iron in pulmonary interstitium. Tox can be cumulative, must follow pulm function tests
What are the characteristics of hematologic toxicity?
- Common with all alkylators and anthracyclines
- Presents with myelodysplasia, myelofibrosis, leukemia, andTTP
- Mediated by sub lethal DNA damage
What are the long term toxicities assoc with chemotherapy?
- Accelerated aging
- CNS- memory loss
- Fatigue- may be reversed with exercise and better sleep
- Chronic pain- less common- similar to fibromyalgia: possible response to better sleep, exercise, antidepressants, and neuropathic drugs
- Acceleration of osteoporosis, muscle loss
- Secondary malignancies- leukemia, lymphoma, lung and bladder cancer common
What are the effects of chemotherapy on pregnancy?
- Variable, all agents increase risk of adverse outcomes in 1st trimester
- Should delay chemo if possible
- 2nd and 3rd trimester can use most agents except antimetabolites
- Need for chemo usually NOT an indication for abortion
What are the characteristics of Thromboembolic disease due to chemo?
- Cancer is thrombogenic
- Some antihormonal agents like tamoxifen are thrombogenic
- Chemo is less predictable regarding thrombosis
- 5-FU and Cisplatinum are vasoactive
- ALL pts high risk
What are the effects of chemotherapy on sex?
- Negative impact on libido, anxiety/depression
- Nausea, mucositis, fatigue
- Dysfunction most common with anti hormonals like LHRH agonists, androgen/estrogen receptor block, and estrogen synth inhibitors
What effects does chemo have on bones?
- Corticosteroids, aromatase inhibitors, LHRH agonists, and most other chemo agents accelerate osteoporosis
- aromatase inhibitors and adjuvant chemo may cause arthralgias (primary reason for discontinuation of aromatase inhib)
What are the effects of chemotherapy on gonadal function?
- Stop ovulation and azoospermia- common with alkylators and topoisomerase inhibitors- effects vary with age and sex
- Males- Hodgkin's treated with MOPP usually sterile, testicular cancer treated with BEP often ok Should consider sperm bank
What are the effects of chemo on the female gonads?
- alkylators cause anovulation- can recover usually if under 30yo
- Premature menopause
- Maintain contraception
- Consider BCP during chemo
- Consider HRT in non responsive tumors
What effects do anti inflammatories have on chemotherapy?
- Use the same carrier prtn as most chemo agents causing increase of relative dose of many
- Can increase chemo induced mucositis
- Increase bleeding risk
What are the effects of anti infectives on chemotherapy?
- Use same carrier
- Increase risk of fungal infection
What are the effects of anti gout medication on Chemotherapy?
- Could inhibit drug activation- allopurinol inhibits 5-FU
- Could increase drug effect- colchicine on vincas
- allopurinol on 6-MP
What are the effects of diuretics on chemotherapy?
- Increase risk of renal dysfunction like when using platinum
- HCTZ and cyclo/5-FU can cause prolonged neutropenia
What effects do anti convulsants have on chemotherapy?
decrease efficacy due to induction of liver metabolism with irinotecan
What effects do anti coagulants have on chemotherapy?
- warfarin and 5-FU/ capecitabine/ etoposide/ carboplatinum/ paclitaxel/ gemcitabine
- Same carrier protein leading to increased bleeding