Therapeutics 523 Final Overview III
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What are the major class SEs of alkylating agents?
- secondary leukemias
What are the 3 categories of alkylating agents and the drugs that fall into each?
- Nitrogen mustards: bendamustine, cyclophosphamide, ifosfamide
- Triazenes: temozolomide
- Platinum Agents: carboplatin, cisplatin, oxaliplatin
What are the class SEs of antimetabolites?
What are the 3 categories of antimetabolites and what drugs fall into each category?
- Folate antagonists: methotrexate, pemetrexed, pralatrexate
- Purine analogues: fludarabine
- Pyrimadine analogues: capecitabine, cytarabine, fluorouracil, gemcitabine
What are the class SEs of antimicrotubules?
- peripheral neuropathy
- Low N/V potential
What are the 4 categories of antimicrotubules and what drugs fall into each?
- Vinca alkaloids: vincristine, vinorelbine
- Taxanes: cabazitaxol, docetaxel, paclitaxel
- Epothilones: ixabepilone
- Misc: eribulin
What are the class SEs of Enzyme Inhibitors?
- cardiac tox (anthracyclines)
What are the 3 categories or enzyme inhibitors and what drugs fall into each category?
- Topoisomerase I Inhibitors: irinotecan
- Topoisomerase II Inhibitors (anthracyclines): daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone
- Epipodophyllotoxins: etoposide
Name the 7 monoclonal antibodies discussed in class. What do each of them target?
- ofatumumab - CD20(+) antigen
- rituximab - CD20(+) antigen
- alemtuzumab - CD52(+) antigen
- bevacizumab - VEGF receptors
- cetuximab - EGFR
- panitumumab - EGFR
- trastuzumab - EGFR
What are the 9 targeted therapies discussed in class? What do they each target? How can they be grouped?
- Dasatinib - BCR-ABL oncogene in Ph+ CML cell lines
- Imatinib - BCR-ABL oncogene in Ph+ CML cell lines
- Nilotinib - BCR-ABL oncogene in Ph+ CML cell lines
- Erlotinib - tyrosine kinase inhibitor
- Lapatinib - tyrosine kinase inhibitor w/in EGFR+ breast cancer cells
- Everolimus - mTOR
- Pazopanib - multi tyrosine kinase inhibitor of VEGF, PDGF, FGFR and Kit receptors
- Sorafenib - Inhibits multiple kinases (tyrosine and Raf). Inhibits angiogenesis by internally blocking activation of VEGF and PDGF receptors
- Sunitinib -Inhibits multiple kinases (tyrosine and Raf). Inhibits angiogenesis by internally blocking activation of VEGF and PDGF receptors
- Group 1 treats leukemias (dasa, ima, nilo)
- Group 2 treats solid tumors (erlo, lapa)
- Group 3 treats renal cell carcinoma (ever, pazo, sora, suni)
Name 4 misc antineoplastic agents discussed in class
- All-trans retinoic acid
- Arsenic trioxide
What is the difference between a protooncogene, oncogene and tumor suppressor gene?
- Protooncogenes are normal genes that oncogenes develop from
- Oncogenes develop from protooncogenes and have important roles in all phases of carcinogenesis
- Tumor suppressor genes regulate and inhibit inappropriate cellular growth and proliferation (loss or mutation results in loss of control over normal cell growth)
What is angiogenesis and what receptors are responsible for it?
- the formation of new blood vessels
- VEGFR, EGFR, PDGFR
What do each of the numbers on the ECOG scale represent, and what does a pt's performance status determine about the chemo treatment?
- 0 - fully active. can carry out all pre-disease activity
- 1 - restricted in strenuous activity but can do light/sedentary work
- 2 - out of bed > 50% of the time; can care for self but not do work activity
- 3 - in bed > 50% of the time; limited self-care capabilities
- 4 - bedridden; cannot self care; completely disabled
- PS 0-1: candidate for chemo
- PS 2: may be chemo candidate, but less aggressive regimen
- PS 3-4 best supportive care
Give specific examples of oncogenes and what types of cancer they are associated with
- EGFR: ErbB-1 (HER-1) assoc with colon CA; ErbB-2 (HER-2) assoc with breast CA; HER-3 and HER-4 not drug targets
- BCR-ABL: occurs in CML
- K-RAS: assoc with lung and colon CA
Give specific examples of tumor suppressor genes
- p53 - mutated in 53% of cancers
- BRCA1 and BRCA2 - test for mutations in these genes in pts at risk for breast cancer
What are the 4 steps of carcinogenesis?
- Initiation - exposure to carcinogens
- Promotion - environment altered to favor growth of mutated cells (reversible process!)
- Conversion/transformation - mutated cell becomes cancerous
- Progression - tumor invasion into local tissue and metastasis
At what WBC count, ANC, and platelet count is it considered "safe" to administer chemo?
- WBC >/= 3000
- ANC >/= 1500
- Platelets >/= 100,000
What are the screening guidelines for detection of cancer?
- Breast: breast exam q 1-3 years after age 20; mammogram annually after age 40
- Colon and Rectum: colonoscopy q 10 years starting at age 50
- Prostate: PSA and DRE annually after age 40
- Uterus: pap annually beginning 3 years after the start of vaginal intercourse and no later than 21 years
What are the major toxicities associated with cisplatin and carboplatin?
oto and nephro
What is a major toxicity assoc with doxorubicin?
What is a major toxicity assoc with bleomycin?
What is a major toxicity assoc with cyclophosphamide?
hemorrhagic cystitis (bladder tox)
What is a major toxicity assoc with 5-FU, 6-mercaptopurine, and MTX?
bone marrow suppression
What is a major SE assoc with the vinca alkaloids?
Which drugs are responsible for delayed N/V and which med do we always give with them?
- cisplatin, carboplatin, cyclophosphamide, doxorubicin
- always need aprepitant
Which 3 chemo meds are considered to have high emetogenic potential?
What agents are used as the standard of care for moderate/highly emetogenic chemo?
- a benzodiazepine prn (for anticipatory n/v)
- a 5HT3 antagonist
- aprepitant (for delayed n/v)
- a prn agent for breakthrough n/v
What are the 5HT3 receptor antagonists used for CINV?
What are the NK1 receptor antagonists used in CINV?
What corticosteroids are used in CINV?
What agents may be used for breakthrough n/v in CINV?
What is the prophylactic pre-chemo CINV regimen for pts with moderately emetogenic chemo?
- Day 1: 5HT3 antag + dexamethaxone (with select regimens, add aprepitant)
- Days 2 and 3: dexamethasone for 2-3 days and aprepitant for select regimens
What is the prophylactic pre-chemotherapy antiemetic CINV regimen for pts with highly emetogenic chemo?
- Day 1: 5HT3 antagonist + dexamethaxone + aprepitant
- Days 2&3: aprepitant + dexamethasone x 3-4 days
Laboratory definition of tumor lysis syndrome
- 2 or more of these lab changes within 3 days before or 7 days after chemo:
- hyperuricemia >/= 8
- hyperkalemia >/= 6
- hyperphosphatemia >/= 1.45
- hypocalcemia </= 1.75
Clinical definition of TLS
- lab evidence plus:
- renal insufficiency
- cardiac arrhythmias/sudden death
TLS risk factors
- tumor type - lymphomas, leukemias, solid tumors with high proliferative rate and rapid treatment response
- tumor burden - bulky disease (> 10 cm), elevated LDH (lactate dehydrogenase), elevated WBC (>250,000)
- renal fxn - preexisting renal failure, oliguria
- elevated baseline uric acid (> 7.5)
Treatment options for prevention of TLS for low, intermediate, and high risk patients
- Low risk (WBC < 50,000) - clinical judgement and close monitoring
- Intermediate risk (Diffuse large b-cell lymphoma, WBC 50,000-100,000 for ALL or 10,000-50,000 for AML) - hydration + allopurinol
- High risk (burkitt's lymphoma, WBC > 100,000 for ALL or > 50,000 for AML) - hydration + rasburicase
MOA of allopurinol
- inhibits xanthine oxidase leading to inhibition of uric acid formation
- does not reduce existing uric acid
MOA of rasburicase
transforms uric acid into allantoin which is highly soluble and can be easily excreted
Which form of iron can be absorbed?
the ferrous form (Fe+2) - this is the reduced form of ferric iron (Fe+3)
Meds that can cause iron-deficiency anemia
- cause inadequate GI iron absorption - antacids, H2 blockers, PPIs, TCs
- cause blood loss - ASA, alcohol, NSAIDs, steroids
s/s of iron-deficiency anemia
- hair loss
- koilonychia (spoon nails)
Treatment of iron deficiency anemia
- 325 mg ferrous sulfate PO QID
- or 200 mg elemental iron PO QD in in 2-3 divided doses
- Duration - 3-6 mo after the anemia has resolved
How much elemental iron is in a 325 mg tab of ferrous sulfate?
In iron deficiency anemia which lab findings are low and which are high?
- Hemoglobin and hematocrit are low (hypochromic)
- MCV is low (microcytic)
- Serum Iron is low
- % Transferrin Saturation and serum ferritin are both low
- TIBC is high (more binding sites open)
What techniques may be used to administer Iron Dextran?
- it is parenteral
- IM - use z-track technique
- IV - bolus, or if diluted infuse over 1-6 h
- must do test dose because there's a BBW for anaphylactic rxns
What meds may cause vitamin B12 deficiency anemia?
- H2 blockers
B12 deficiency anemia may be d/t pernicious anemia, which is lack of _______
Aside from general s/s of anemia, what 2 categories of s/s does vitamin b12 deficiency anemia exhibit?
What are the lab findings in Vitamin B12 deficiency anemia?
Everything is low except MCV (it is macrocytic)
What do homocysteine and methylmalonic acid have to do with Vitamin B12 deficiency anemia?
they are useful tests to identify this type of anemia. the levels are elevated.
What is the treatment for Vitamin B12 deficiency anemia - initial and maintenance?
- B12 supplementation
- Oral: initial is 1000-2000mcg PO qd x 1-2 weeks; maintenance is 1000mcg PO qd
- Parenteral: initial is 1000mcg IM daily or qod for 1-2 weeks; maintenance is 1000mcg IM q 1-3 months
- Intranasal: only for maintenance; Nascobal is 500mcg in one nostril once weekly; CaloMist is 25mcg in each nostril QD
- Length of treatment: often lifetime
What meds can lead to inadequate dietary absorption of folic acid?
- folic acid antagonists - MTX, pentamidine, trimethoprim, triamterene, 5-FU, hydroxyurea, pyrimethamine
- interference with absorption - phenytoin, phenobarbital, primidone
What is the difference in the s/s between vitamin b12 deficiency anemia and folic acid deficiency anemia?
with folic acid deficiency anemia there are no neurologic or psychiatric sx
What are the lab findings in folic acid deficiency anemia?
all are low except MCV (it is high - macrocytic)
What it the treatment for folic acid deficiency anemia?
1 mg of folic acid PO qd for at least 4 months. Lifetime if underlying cause can't be corrected.
What must be ruled out before treating for folic acid deficiency anemia?
vitamin B12 deficiency anemia - if we treat the wrong one, the pt could get better, but not any neurologic sx they might have
What are common causes of anemia of chronic disease?
- chronic infx
- chronic inflamm
What are the lab findings for anemia of chronic disease?
- Hemoglobin and hematocrit are low
- serum iron is low
- transferrin saturation is low
- reticulocyte count is low
- TIBC is low or normal
- MCV is normal - normocytic
- Serum ferritin is normal or high
What lab findings help distinguish between iron deficiency anemia and anemia of chronic disease?
- TIBC: it's low or normal in ACD and high in iron-def
- Serum Ferritin: it's normal or high in ACD and low in iron-def
What is the treatment for anemia of chronic disease?
- treat the underlying cause
- RBC transfusions
- iron supplementation
- erythropoiesis-stimulating agents (ESAs) - epoetin alfa (epogen, procrit) and darbepoetin alfa (aranesp)
When should erythropoiesis-stimulating agents be used in anemia of chronic disease and why?
- only use when pt is getting chemo and the prognosis is not cure
- the BBW is for serious CV and thrombolytic events, increased risk of tumor progression or recurrence, and increased mortality
What ANC value indicates that a pt is neutropenic?
- < 1000 with predicted decrease to less than 500
- < 500 cells/mm3 is severe neutropenia
How is ANC determined?
ANC = WBC x [(segs/100)+(bands/100)]
What is the most significant clinical finding that suggests and infx in neutropenic patients?
- Detection of fever
- single oral temp of > 101 or temp of >100.4 for at least 1 hour
When should empiric antibiotics be initiated in a neutropenic pt?
immediately or asap upon detection of fever
What are the pt characteristics of a febrile neutropenic pt in the High Risk category? The Low Risk?
- pt is hospitalized at onset of fever
- significant comorbidities or clinicaly unstable
- anticipated prolonged or severe neutropenia
- hepatic or renal insufficiency
- pneumonia or other complex infx at time of onset
- alemtuzumab use
- uncontrolled/progressive cancer
- mucositis (grade 3-4)
- Low Risk:
- Outpt at onset of fever
- no assoc acute comorbid illness
- anticipated short duration of severe neutropenia
- good performance status
- no hepatic or renal insufficiency
High risk febrile neutropenic pts should receive empiric antibiotics where and by what route?
- in an inpatient facility
What are the most common fungal infx in febrile neutropenic cancer patients?
Is prophylactic or empiric antifungal therapy for febrile neutropenic pts recommended?
What meds can be used in febrile neutropenic pts with influenza A or B infx?
- oseltamivir or zanamivir
- NOT amantadine or rimantadine
What agents should be used as prophylactic antivirals in febrile neutropenia pts and why?
- for Herpes and varicella, use acycloir or valacyclovir
- for CMV use ganciclovir or valganciclovir
- use because these viruses have potential for viral reactivation in neutropenic pts
Which febrile neutropenic pts are at high risk for developing PCP infx? What prophylactic therapy should be used for them?
- those on alemtuzumab or fludarabine
- use TMP/SMX, pentamidine or atovaquone
Why is it important for empiric antimicrobial therapy for febrile neutropenia pts to include meds with significant G(-) coverage?
to cover Pseudomonas
What is the algorithm for empiric therapy for pts with neutropenic fever?
- If low risk, oral tx is cipro + amox/clav
- If low risk , IV tx is cefepine, ceftazidime or carbapenem monotx or an AG + either an anti-psa pen or cefepime, ceftazidime, or carbapenem (2 drugs)
- If high risk and vanco is not needed, monotx with cefepime, ceftazidime or carbapenem. or 2 drug tx with and AG plus either an anti-psa pen or cefepime, ceftazidime, or carbapenem
- If high risk and vanco is needed, use vanco plus cefepime, ceftazidime, or carbapenem
- Reassess after 3-5 days
When is vanco added to empiric therapy for febrile neutropenia pts?
- if the facility has high incidence of pen-resistant orgs
- when the pt has a catheter-related infx, a SSTI, previous colonization, previous FQ prophylaxis
How often should the neutropenic pt be evaluated, regardless of the clinical situation?
at least once daily
If a previously febrile neutropenic pt is afebrile within the 1st 3-5 days of treatment what should be adjusted in the treatment?
- if high risk and no etiology identified, continue the current abx
- if low risk and no etiology identified, change to cipro + amox/clav (adult) or cefixime (child)
- then discharge
- if the etiology is identified, adjust to the most appropriate tx
If a febrile neutropenia pt has a persistant fever during the first 3-5 days of treatment and no etiology is identified, how should we proceed with the treatment?
- Reassess on days 3-5
- can continue the initial abx - if no change in pts condition, consider stopping vanco
- can change the abx if the disease is progressing or if the criteria for vanco are met
- can add an antifungal with or without changing the abx if febrile through d 5-7 and resoution of neutropenia is not imminent (echinocandin)
Algorithm for duration of antibiotic therapy for febrile neutropenia pts
- if pt is afebrile by days 3-5 and the ANC is > 500 for 2 day in a row, stop abx 48 hours after they are both afebrile and the ANC is over 500
- if pt is afebrile by d 3-5 and the ANC is less than 500 by day 7, if the pt was initially low risk, stop when they've been afebrile for 5-7 days; if they were initially high risk, continue abx
- If the pt has a persistant fever and an ANC >/= 500, stop 4-5 d after the ANC is over 500 then reassess
- If the pt has a persistant fever and the ANC is < 500, continue abx for 2 weeks, then reassess, then stop if no disease and the condition is stable
Should empiric therapy for febrile neutropenia pts include antifungals and antivirals?
no, unless there is clinical suspicion or presentation of these infx
What is another name for myeloid growth factors?
colony stimulating factors
3 ways to manage neutropenia in the oncology patient
- 1. decrease chemo dose
- 2. increase chemo cycle interval
- 3. prevention - admin of a myeloid growth factor (colony stimulating factor)
What is primary prophylaxis with myeloid growth factors? When is primary prophylaxis with myeloid growth factors indicated? When would it be given?
- use of myeloid growth factor before the pt has any neutropenia
- it is indicated for chemo regimens with a 20% or greater risk of febrile neutropenia
- the MGF would be given with the 1st chemo cycle
Describe secondary prophylaxis in the oncology pt with regard to myeloid growth factors
- this is starting the MGF(CSF) after neutropenia has occurred
- it is to prevent recurrent neutropenia
- it would be added into later chemo cycles
When is the use of myeloid growth factors in chemotherapy pts considered treatment rather than prophylaxis?
this is when the MGF are started at the same time antibiotics are started to treat existing febrile neutropenia
Individual pt risk factors that along with a moderate or low risk of febrile neutropenia indicate the need for prophylaxis with myeloid growth factors
- age > 65
- co-morbidities (diabetes, CVD, liver disease, renal dysfxn)
- presence of active infx or open wounds
- poor performance status (ECOG 2,3, 4)
- decreased immune fxn
What are the 3 myeloid growth factors available?
When in relation to chemotherapy should MGFs be given?
no sooner than 24 hours after completion of the chemo and no later than 72 hours after
What is the dose and duration of treatment of each MGF used?
- filgrastim - 5mcg/kg/d SQ/IV daily - continue until ANC >/= 2000
- pegfilgrastim - 6 mg SQ once per chemo cycle - only use once per cycle - bone marrow recovers in 10-11 days
- sargramostim - 250 mcg/m2/d SQ/IV daily - continue until ANC >/= 1500
What is the MOA of the myeloid growth factors?
stimulate proliferation and differentiation of hematopoetic cells in the granulocyte lineage (sargramostim also the macrocyte line)
How are the myeloid growth factors eliminated?
- filgrastim and sargramostim are eliminated by the kidneys
- pegfilgrastim is eliminated by neutrophil endocytosis
What mechanisms are associated with hypercalcemia of malignancy?
- increased Calcium abs from GIT
- decreased renal excretion of calcium
- stimulation of osteoclastic resorption from bone
What is the equation for corrected calcium?
Corrected Ca = measured calcium + 0.8(4-albumin)
what are clinical s/s of hypercalcemia of malignancy?
- GI: severe N/V
- GU: renal failure
- Neuro: confusion, lethargy
What are the goals of treatment of hypercalcemia of malignancy?
- restore intravascular volume
- enhance calcium excretion
- block tumor-mediated bone resorption
Algorithm for managing hypercalcemia of malignancy
- if symptomatic OR Ca+2 > 14 or life-threatening sx: give 0.9% NaCL @ 200-300 ml/h + calcitonin 1-4 IU/kg SQ q6h x 8 doses + bisphosphonate
- if the Ca+2 level is < 14, encourage oral fluids, increase sodium intake, increase ambulation
- Monitor: calcium, phosphorous, potassium, BUN, SCr, albumin, fluid status
What is the MOA of NaCl in hypercalcemia of malignancy?
- expands intracellular volume
- increases renal excretion of Ca+2
What is the MOA of diuretics in hypercalcemia of malignancy?
inhibit calcium reabsorption by kidney
What is the MOA of calcitonin in hypercalcemia of malignancy?
- inhibit osteoclastic bone reabsorption
- increase renal excretion of calcium
What is the MOA of bisphosphonates in hypercalcemia of malignancy? What are 2 bisphosphonates used?
- inhibit osteoclast bone reabsorption
- inhibit bone crystal dissolution
- pamidronate disodium, zoledronic acid
What is the MOA of glucocorticoids in hypercalcemia of malignancy?
- increase urinary calcium excretion
- decrease intestinal calcium absorption
What is the MOA of plicamycin in hypercalcemia of malignancy?
- antineoplastic agt
- inhibits RNA synthesis of osteoclasts
- used in refractory pts
What are the antiestrogens used in breast cancer?
- toremifene (for advanced disease)
- fulvestrant (for advanced disease)
What aromatase inhibitors are used in breast cancer? What is their MOA?
- MOA - block aromatase from converting androgens (from adipose tissue) to estrogens
- Note: only used in post-menopausal females
What genetic factors contribute to breast cancer?
- BRCA-1 and BRCA-2 are tumor suppressor genes. Mutations in either of these is assoc with and increased risk of breast and ovarian cancer
- HER-2/neu (EGFR2) is a proto-oncogene. Its overexpression is associated with more aggressive disease and poor prognosis. Targeted by lapatinib and trastuzumab.
Which meds are used for risk reduction in breast cancer?
- Tamoxifen - for pre- or post- menopausal
- Raloxifene - only for menopausal
What is LCIS and DCIS and what is the treatment for them?
- they are non-invasive carcinomas (breast cancer)
- for LCIS (lobular carcinoma in situ) use observation + tamoxifen or raloxifene
- for DCIS (ductal carcinoma in situ) surgery +/- radiation therapy + tamoxifen (if ER positive)
What are ER and PR in regard to breast cancer? Why are they important?
- ER - estrogen receptor
- PR - progesterone receptor
- important because being ER/PR positive is a good sign
What are ILC and IDC in regard to breast cancer?
- invasive lobular carcinoma
- invasive ductal carcinoma
What is the treatment strategy for invasive carcinomas in breast cancer?
- Early stage (I, IIA, IIB): surgery +/- radiation +/- adjuvant therapy (chemo +/- endocrine therapy)
- Locally Advanced (Stage IIIA, IIIB, IIIC): if operable, surgery + adjuvant therapy; if inoperable, neoadjuvant chemo then surgery then radiation then chemo +/- endocrine therapy
- Metastatic (advanced)(Stage IV): endocrine therapy OR chemotherapy plus bisphosphonates (for pts with bony metastases) - no role for surgery or radiation
In breast cancer treatment, when is endocrine therapy started?
after completion of chemotherapy (not concurrently)
What endocrine therapy is indicated for pre-menopausal women with early stage or locally advanced breast cancer?
- tamoxifen x 5 years
- OR tamoxifen x 5 years then aromatase inhibitor x 5 years (if post menopausal at end of tamoxifen therapy)
What endocrine therapy is indicated for post-menopausal women with early stage or locally advanced breast cancer?
- aromatase inhibitor x 5 years
- OR tamoxifen x 2-3 years then aromatase inhibitor to complete 5 years total
- OR tamoxifen x 5 years then aromatase inhibitor x 5 years
- OR tamoxifen x 5 years
What drugs are consistently used in adjuvant chemotherapy regimens for early stage and locally advanced breast cancer?
always have either docetaxel or doxorubicin
What biomarkers are routinely tested for in non-small cell lung cancer and what is their significance?
- EGFR mutations - pts with these have a better response to erlotinib and gefitinib (positive response to TKIs)
- K-ras oncogene - pts with k-ras mutations do not respond to TKIs
What are the recommended 1st line regimens for advanced NSCLC?
- Bevacizuab + paclitaxel + carboplatin (for non-squamous, EGFR negative, NO CNS mets)
- Cetuximab + vinorelbine + cisplatin (for squamous or non-squamous)
- Erlotinib (for non-squamous, EGFR positive, K-ras negative)
- Platinum based regimens (for those who aren't candidates for bevacizumab or cetuximab) - Cisplatin + one of these: pemetrexed, paclitaxel, gemcitabine, docetaxel, vinorelbine, paclitaxel OR Carboplatin plus one of these: gemcitabine, docetaxel, pemetrexed
- Non-platinum based regimen (gemcitabine + docetaxel)
- All of these regimens are 4-6 cycles
Treatment strategies for small-cell lung cancer
- Limited - (etoposide + cisplatin) or (etoposide + carboplatin)
- Extensive - (etoposide + cisplatin) or (Etoposide + carboplatin) or (irinotecan + cisplatin) or (irinotecan + carboplatin)
Maintenance therapy for NSCLC
single agent pemetrexed, erlotinib or docetaxel (only for non-squamous)
Second line therapy for NSCLC
single agents: docetaxel, pemetrexed, erlotinib
third line therapy for NSCLC
Contraindication for use of bevacizumab
Can pemetrexed be used for both squamous and non-squamous cell lung cancer?
no, only for non-squamous
What lifestyle factors increase the risk of colorectal cancer? Which decrease the risk?
- increase risk:
- alcohol intake
- type 2 DM
- obesity and physical inactivity
- western diet
- decrease risk:
- ASA and NSAID use
- Calcium and Vitamin D
- postmenopausal hormone use
Clinical risk factors for colorectal cancer
- Chronic inflammatory diseases (ulcerative colitis, Crohn's)
- Genetic conditions (Familial adenomatous polyposis FAP - risk is 100%; Hereditary nonpolyposis colon cancer HNPCC - risk is around 70%)
Which meds are used in chemoprevention and are beneficial in FAP?
Does the size of the tumor influence prognosis in colon cancer?
- the stage of the tumor determines survival and risk of disease recurrence - based on depth of tumor in bowel wall and presence or absence of lymph nodes
What are the important biomarkers in colon cancer?
- K-ras - predict lack of response to cetuximab or panitumumab
- BRAF gene also indicates lack of response to cetuximab or panitumumab
- MMR gene mutation or modification predicts lack of response from 5-FU therapy
General treatment strategies for colorectal cancer
- Stage IIA, IIB, IIIA, IIIB, IIIC: surgery + adjuvant chemo
- Stage IV: neoadjuvant and adjuvant chemo if isolated mets; if disseminated, chemotherapy for advanced disease
- Adjuvant chemo regimens -
- 5-FU + leukovorin
- FLOX (5-FU (IV bolus) + leukovorin + oxalaplatin)
- FOLFOX (same as above, but the 5-FU is IV continuous infusion)
Chemo regimens for advanced (disseminated) or recurrent disease in colon cancer
- FOLFOX +/- bevacizumab
- CapeOx +/- bevacizumab
- FOLFIRI +/- bevacizumab
- capecitabine +/- bevacizumab
- 5-FU + leukovorin +/- bevacuzumab
- FOLFOX +/- cetuximab or panitumumab
- FOLFIRI +/- cetuximab or panitumumab
If a tumor has a KRAS mutation, what meds is it insensitive to?
panitumumab and cetuximab
What racial group is at highest risk for prostate cancer?
What is the major source for circulating androgens?
testes and adrenal glands
Normal growth and differentiation of the prostate depends on _______
What symptoms are seen in localized prostate cancer? In locally invasive? In advanced disease?
- localized: asymptomatic
- locally invasive: uretal dysfxn, frequency, hesitancy, dribbling, impotence
- advanced disease: back pain, cord compression, lower-extremety edema, pathologic fractures, anemia, weight loss
What are the screening exams for prostate cancer?
- PSA (norm is less than 4 ng/ml)
What factors can elevate and decrease PSA levels in a pt?
- finasteride, dutasteride, and androgen receptor blockers can decrease PSA
- DRE, ejaculation, acute urinary retention, acute prostatitis, prostate ischemia, prostatic infarction, BPH can increase PSA
Describe the pattern of tumors and the grades on the gleason scale for prostate cancer
- Grade 1: glands are small, well formed, closely packed
- Grade 2: well-formed glands, larger with more tissue in between
- Grade 3: recognizable glands but darker cells, some are beginning to invade surrounding tissue
- Grade 4: few recognizable glands - many cells invading surrounding tissue
- Grade 5: no recognizable glands
What type of prostate cancer can be cured by surgery or radiation therapy?
What is the basis for the treatment of advanced prostate cancer?
hormonal manipulation to decrease circulating androgens
Why is Finasteride controversial in the prevention of prostate cancer? What is its MOA? When should it be offered?
- it can decrease the risk of prostate cancer, but in those who took it and then still developed the cancer it was more aggressive
- MOA is 5-alpha reductase inhibition
- it should be offered in men > 50 with BPH
What are the 3 luteinizing hormone-releasing hormone agonists (LH-RH agonists) used in prostate cancer? What is their MOA?
- leuprolide, triptorelin, goserelin
- MOA - downregulation of pituitary receptors and decrease in testosterone production
- also known as androgen ablation therapy
What prostate cancer medication is associated with tumor flare? What is it?
- Tumor flare is an expected SE of LH-RH agonists.
- Initially LH and FSH are stimulated, leading to bone pain and increased urinary sx.
- Usually resolves within 2 weeks.
What are the antiandrogens used in prostate cancer and what is their MOA? When should they be used?
- MOA - inhibit testosterone binding to androgen receptor - inhibit cell division
- flutamide and bicalutamide should only be used in combo with LH-RH agonists
- Nilutamide should only be used in combo with orchiectomy
What SEs are assoc with antiandrogens?
- hot flashes
- LFT abnormalities
- breast tenderness
What are androgen synthesis inhibitors used for in prostate cancer? Which meds are androgen synthesis inhibitors?
- they are used in refractory cases
When is chemotherapy used in prostate cancer? What regimens are used?
- in refractory cases
- docetaxel + prednisone q 3 weeks
- mitoxantrone + prednisone q 3 weeks
- cabazitaxel + prednisone
What medication is used for immunotherapy in prostate cancer?
What are bisphosphonates used for in prostate cancer? What is their clinically important benefit? Give examples of bisphosphonates.
- supportive care
- they decrease skeletal events and complications
- zoledronic acid, alendronate, pamidronate
What agent can be used in NSCLC that is EGFR mutation positve and K-ras mutation negative?
- no benefit to combining with chemo - use as monotx
What is the first-line treatment for prostate cancer?
LH-RH agonists (leuprolide, triptorelin, gosrelin)
What is the definition of acute leukemia?
the presence of at least 20% leukemic blasts in the bone marrow or blood (normal is less than 5%)
The CNS and testes may serve as sanctuary sites in which type of leukemia?
- CNS involvement is also possible with AML (M4 and M5 subtypes)
What population is typically affected in AML? APL? ALL? CML? HL? NHL?
- AML - older adults
- APL - any age (subtype of AML - diagnosis usually betw 15-60 y.o.)
- ALL - bimodal distribution
- CML - older adults
- HL - bimodal distribution
- NHL - any age
Name a few distinguishing features of AML
- Auer Rods
- Gum hypertrophy (common with M4 and M5 subtypes)
- infiltration of gingivae, skin, soft tissues, or meninges (common with M4 and M5 subtypes)
What is the induction therapy for pts with AML?
- 7+3: cytarabine continuous infustion standard dosing for 7 d + anthracycline (daunorubicin or idarubicin) for 3 d
- HiDAC: high-dose cytarabine + anthracycline (dauno or ida) for 3 d
SEs of cytarabine
- cerebellar toxicity (slurred speech, nystagmus, dysmetria) with high-dose
- Conjunctivitis/keratitis with high-dose
SEs of anthracyclines
- cardiac tox
- urine discoloration (red-orange with daunorubicin, doxorubicin, idarubicin; blue-green with mitoxantrone)
Supportive care for AML
- Myelosuppression: RBC and platelet transfusions, myeloid growth factors
- TLS: allopurinol, rasburicase, hydration
- Infection: antifungals (fluconazole), antivirals (acyclovir), antibiotics (bactrim)
- Cerebellar tox: with HiDAC only - neurologic assessments and monitor
- Conjunctivitis/keratitis: with HiDAC only - saline or steroid eyedrops
- Antiemetics, good oral care
Treatment of CNS leukemia
- provide CNS therapy if CT/MRI or LP is positive at diagnosis
- Concurrently with induction therapy, give intrathecal chemotherapy (methotrexate +/- cytarabine 2x/wk, then q week x 4-6 wk)
- If pt receiving HiDAC, can defer until induction therapy is done
APL is a subtype of which type of leukemia?
- It is the M3 subtype of AML
- it is the most curable of all AML subtypes
What mutation is seen in 95-100% of the cases of APL?
PML-RAR fusion protein
Clinical presentation characteristic of APL. Why is it counterintuitive?
- severe coagulopathy characterized by disseminated intravascular coagulation (DIC)
- even though this is a clotting problem, the pt is actually at risk of bleeding because all the pt's clotting factors are used up
Induction therapy for APL
- ATRA (all-trans retinoic acid) + anthracycline (daunorubicin, idarubicin) +/- cytarabine
- ATRA + arsenic trioxide (As2O3)
SE of ATRA
- APL differentiation syndrome (aka retinoic acid syndrome) - fever, rapidly rising WBC, fluid retention, pulmonary infiltrates
- use steroids as prophylaxis/treatment
- note - arsenic trioxide can cause APL differentiation syndrome too
Which chemo meds cause QT prolongation?
- arsenic trioxide
Supportive care for APL
- Coagulopathy and bleeding: platelet transfusions
- APL differentiation syndrome: dexamethasone prophylaxis
- QT prolongation: avoid other QT prolonging meds and monitor lytes
- Myeloid Growth Factors are NOT recommended
What supportive care that is common in leukemia is not recommended for use in APL?
myeloid growth factors
Which factor in ALL gives a very poor prognosis for adults?
What are some characteristic features in the presentation of ALL?
- testicular enlargement (testes can serve as sanctuary site)
- Chloromas (small blue-green collections of leukemia cells underneath the skin)
Induction therapy for ALL
- any combo of these:
Which ALL patients require CNS prophylaxis? What is the regimen?
- all ALL patients
- intrathecal chemo - MTX +/- cytarabine or triple therapy with hydrocortisone
What purine analog is part of the initial therapy of T-cell ALL?
Ph(+) ALL therapy should include what type of med?
What med used to treat ALL is fatal if given intrathecally?
What medication needs MESNA as adjuvant therapy and why?
cyclophosphamide - to help reduce hemorrhagic cystitis
Supportive care for ALL
- Myelosuppression: RBC transfusion, platelet transfusion, myeloid growth factors
- TLS: allopurinol, rasburicase, hydration
- Infection: antivirals (acyclovir), antibiotics (bactrim)
- Methotrexate: must give leukovorin with high dose MTX; alkalinize urine with sodium bicarb to prevent kidney ppt
- Cyclophosphamide - MESNA to prevent hemorrhagic cystitis
What mutation is commonly associated with CML?
- the philly chromosome (Ph)
- abnormal fusion protein BCR-ABL
Describe the clinical course of CML
- 1. chronic phase - less than 10% blasts - asymptomatic
- 2. accelerated phase - 10-29% blasts - subclinical presentation
- 3. blast phase - > 30% blasts - similar to acute leukemia
What is a distinguishing characteristic in the clinical presentation of CML?
What is the treatment of CML?
TKIs are 1st line (imatinib, dasatinib, nilotinib)
- Chronic phase: imatinib dasatinib or nilotinib
- Accelerated phase: dasatinib or nilotinib
- Blast phase: TKI plus AML or ALL induction therapy (or TKI alone is ok too)
Supportive care for CML
- Myelosuppression: hold med until ANC and platelets are high enough; RBC transfusions
- Diarrhea: supportive care
- GI upset: take with food and water, divide dose
- Rash: steroids
What symptoms are the hallmark of lymphomas?
- B symptoms:
- drenching night sweats
- weight loss (>10% of body weight)
What are the 2 classifications of Hodgkin's Lymphoma and and how are they determined?
- Classical and Lymphocyte-Predominant
- Classical has Reed-Sternberg cells and Lymphocyte-predominant does not
Clinical presentation of Hodgkin's Lymphoma
- systemic B symptoms
- chronic pruritis
- extranodal involvement
Chemo treatment options for Classical Hodgkin's Lymphoma
- ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine (1st line)
- Stanford V: doxorubicin + bleomycin + vinblastine + mechlorethamine + etoposide + vincristine + prednisone
- BEACOPP: for high risk disease because very toxic and may cause secondary cancers
- MOPP: obsolete
3 types of chromosomal translocations in Non-Hodgkin's Lymphoma
- Burkitt's lymphoma
- follicular B cell lymphoma
- mantle cell lymphoma
this is a lymphoproliferative disorder characterized by the accumulation of non-functional B-cells with bone marrow/blood involvement
- if there is nodal involvement, it is called SLL (small lymphocytic leukemia)
Clinical presentation of CLL
- often asymptomatic in early stages
- B symptoms
- autoimmune disease
- richter transformation (goes from being indolent to being aggressive)
Treatment of CLL
- Asymptomatic early stage: managed with observation and supportive care
- symptomatic or high-risk disease: combo of cyclophosphamide, fludarabine, rituximab
Treatment of autoimmune cytopenias associated with CLL
What vaccinations should the CLL patient receive
- annual influenza
- pneumococcal q5years
- avoid live vaccines
What type of lymphoma are follicular and diffuse large b cell lymphoma?
What is the difference between follicular lymphoma and diffuse large b-cell lymphoma in terms of survival and treatment response?
- Follicular lymphoma is fairly benign and has a long survival prognosis with or without treatment. It is responsive to treatment, but pts rarely cured.
- DLBCL is aggressive and is fatal within weeks to months if therapy not initiated. Responsive to treatment and many are cured.
What is the treatment of follicular lymphoma?
- chemo +/- radiation
- Rituximab-based regimens:
- bendamustine + rituximab
- fludarabine + rituximab
- radioimmunotherapy with Zevalan or Bexxar
What is the treatment for Diffuse Large B-cell Lymphoma?
- RCHOP +/- radiation
- EPOCH + rituximab
Which chemo meds cause hemorrhagic cystitis?
cyclophosphamide and ifosphamide
What chemo med can cause dose-limiting thrombocytopenia?
What chemo med can cause sensory neuropathy that is precipitated by cold beverages?
What is the dose-limiting toxicity of methotrexate? What other therapies must be given when using high-dose MTX?
- myelosuppression and mucositis are dose-limiting
- with high-dose, must give leukovorin to prevent toxicity and must alkalinize urine to prevent precipitation in the kidneys
What premedications are necessary with pemetrexed? Why?
- vitamin B12
- folic acid
- to decrease myelosuppression
What premedications are necessary with pralatrexate and why?
premedicate with B12 and folic acid to decrease hemotologic toxicity and mucositis
What med is the oral prodrug of 5-FU?
When using HiDAC, what must be used because of the high-dose cytarabine?
dexamethasone eyedrops to decrease conjunctivitis/keratitis
Why is 5-FU combined with leukovorin in colon CA?
to increase cytotoxicity
What chemo med has dose-limiting diarrhea as a SE?
irinotecan - treat with loperamide
what is the lifetime dose of daunorubicin?
900-1000 mg/m2 (400 if pt has had prior chest irradiation)
What is the lifetime dose of doxorubicin?
450-500 mg/m2 (250 if prior chest irradiation)
What is the correlation between epirubicin and CHF risk?
the risk increases rapidly with doses over 900 mg/m2
which anthracycline has a lower CHF risk than the others?
What is the dose-limiting SE of etoposide?
- can cause secondary leukemias
What mab causes impaired wound healing?
which chemo meds cause QT prolongation?
- arsenic trioxide
What chemo med causes hand-foot syndrome?
What chemo med causes a yellow discoloration of the skin?
what is the dose-limiting toxicity and the max lifetime dose of bleomycin?
- pulmonary toxicity
- 450 mg (not based on BSA)
What chemo meds require prophylaxis for hypersensitivity reactions? What meds are used for this?
- docetaxel, cabazitaxol, paclitaxel
- for docetaxel and cabazitaxol use dexamethasone (+/- diphenhydramine +/- H2 antagonist)
- for paclitaxel, use all 3 of the above agents
What would you like to do?
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