1. The following material is intended for MSKCC internal medicine housestaff teaching purposes
only. The slides were updated for the LibGuide in 2011-2012.
2. Develop a framework for understanding
chemotherapeutic agents
Review basic chemotherapy principles
Discuss some common chemotherapeutic agents and
side effects
3. Surgery
In localized disease, surgery is often the most effective and
definitive curative therapy
May also play a role in metastatic disease
Solitary brain metastases
Resectable liver or lung lesions
Palliation
Radiation
Cure or control of localized disease
Palliation
Systemic Chemotherapy
4. Adjuvant Chemotherapy: Used after surgery to reduce
the risk of disease recurrence
Operates under the assumption that micro-metastases
exist and not removed by surgery
Sometimes surgery is useful to “debulk” the amount of
tumor cells
Neo-adjuvant chemotherapy: Used prior to surgery in
order to eliminate micrometastatic disease
Useful to shrink tumors for anatomic preservation
(larynx, anal sphincter)
5. Cure of cancer: Ultimate goal of chemo is
CURE, though that requires elimination of every last
neoplastic cell
As an adjunct to surgery
As an adjunct to radiation
Curative chemotherapy alone
Long-term control of cancer
Using Gleevec in CML
Hormonal therapy for breast/prostate cancer
Palliation of symptoms of cancer
6. Main Barriers:
Re-growth of tumor cells
Chemotherapy Toxicities
Cell-Cycle Specific
Resistance
7. Cancer stem cells: cells that are reversibly not in cycle are capable of
replenishing tumor cells physically removed or damaged by radiation
and chemotherapy
8. Tumor growth follows a
Gompertzian growth curve:
growth fraction of a tumor starts
at 100% and declines
exponentially over time and with
tumor burden
Tumor size increases slowly, goes
through an exponential
phase, and slows again as the
tumor reaches the size at which
limitation of nutrients occur
Efforts to treat the tumor results
in an increase in the growth
fraction and an increase in growth
rate
9. The Log-Kill Hypothesis
A given dose kills a
constant proportion of a
cell population rather
than a constant number
of cells, usually by three
orders of magnitude
If 109 leukemia cells x
99.999% kill (5-log kill)
After a dose of
chemotherapy, then 104
cells will still remain
Will be induced to grow
again -> 105 or 106 cells
before long
11. Some Definitions:
Therapeutic Index: ratio of the amt that causes the
therapeutic effect versus the amt that causes toxicity
Dose Limiting Toxicity (DLT): a dose that yields
greater toxicity than is acceptable in practice
Maximal Tolerated Dose (MTD) : dose just lower than
DLT, usually the dose suitable for phase II trials
12. Tumors consist of cells that are either actively dividing
or not dividing at the moment
Drugs are sometimes effective only in a particular
phase of the cell cycle. Other drugs kill tumor cells in
both dividing and resting phases of the cell cycle
13.
14. Antimetabolites – S phase
Topoisomerase Inhibitors – S and
G2 phase
Mitotic Spindle Inhibitors – M and
G2 phase
15. Tumor heterogeneity
Efflux pumps
Increased rate of DNA repair
Changes in the drug sensitivity
of a target enzyme
Decreased activation of pro-drugs (precursors)
Inactivation of anticancer drugs by enzymes
16. What is the solution to killing resting cells and
overcoming limitations with killing on a constant
fraction of cells?
CYCLES of chemotherapy
Recruitment
Initially use a cell-cycle nonspecific (CCNS) drug to
achieve initial log kill recruits resting cells to start
dividing subsequently use cell-cycle specific (CCS)
against dividing cells
17. Minimize toxicities:
Perfuse tumor locally (hepatic pump)
Hydration / diuresis
Leucovorin rescue with MTX
Pulse Therapy
Intermittent treatment with very high doses of a
drug that’s too toxic to be used continuously
Stem cell rescue (BMT) allows for high doses of
chemo that would otherwise kill the patient
G-CSF (Neupogen, Neulasta)
18. Combination Therapy
Target tumor cells that are not equally sensitive to a
single drug
Prevents/slows development of resistant cell lines
20. Kill both resting (non-dividing cells) as well as cells in
replication
Though dividing cells often more susceptible
Alkylating agents
Platinum agents
Antitumor antibiotics
Steroids
Kill non-dividing cells
23. Mechanism
Add alkyl groups and covalently bind to DNA bases
Leads to cross-linking of DNA strands, abnormal base
pairing, and breaks in the DNA
No discrimination between resting or dividing cells
Decreased transcription, translation, protein synthesis
DNA damage -> apoptosis
• Nitrogen Mustards • Nitrosureas
– Mechlorethamine – Carmustine (BCNU)
– Cyclophosphamide – Lomustine (CCNU
– Ifosfamide – Streptozocin
– Chlorambucil • Alkylsulfonates
– Melphalan – Busulfan
24. Toxicities
Myelosuppression
Alopecia
Mucositis
Pulmonary toxicity
Can cause secondary neoplasms many years later
(particularly leukemia)
25. Used in breast, lymphoma, myeloma, BMT, rheumatic
diseases
Metabolized by P450 then further break down to
phosphoramide mustard and acrolein
Clinical issues: (aside from myelosuppression, secondary
malignancies, sterility)
Acrolein irritates bladder causing hemorrhagic cystitis
Must hydrate patients
Give mesna (2-Mercaptoethane sulfonate Na) which binds acrolein
Patients must be on PCP prophylaxis due to high rates of
immunosuppression and PCP infection, in particular
26. Melphalan
Used prominently in Multiple Myeloma, BMT
Busulfan
Used in transplant prep regimens
Pulmonary toxicity
27. Similar to alkylating agents: cause cross-links in DNA
Used in: lung, head & neck, testicular cancers
Cisplatin – extremely toxic, but efficacious
Carboplatin – developed as a less toxic alternative
28. Toxicities:
Nausea & vomiting (the most emetogenic drug)
Neurotoxicity: stocking/glove paresthesias, weakness
Nephrotoxicity
Ototoxicity
Clinical Issues:
Watch out for aminoglycosides with similar toxicity
May require more antiemetics, hydration
Hypomagnesemia, hypocalcemia
29. Mechanism
Produced by bacteria that naturally provide chemical defenses
against other hostile microorganisms
Intercalate into DNA directly -> disrupt transcription & replication
Also generate free radicals that damage DNA
Drugs:
Anthracyclines (also inhibits topoisomerase II)
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
Bleomycin
Mitomycin
30. Toxicities & Clinical Issues
Myelosuppression
Cardiotoxicity
Cardiac tissue low in superoxide dismutase & catalase, so
susceptible to oxidative damage
Heart failure may be seen decades afterwards
Dose-dependent
Get echocardiogram or MUGA prior to therapy
Extravasation injury
Dexrazoxane is antidote (may be cardioprotective)
31. 35 yo F with early-stage breast cancer
Treated with lumpectomy & XRT
ER/PR positive
Her2 negative
SLN biopsy negative
Oncotype DX shows HIGH RISK
The patient receives adjuvant treatment with hormonal
treatment and AC-T
Adriamycin
Cyclophosphamide
Taxol
Is subsequently started on tamoxifen
32. 4 years later, the patient has anemia &
thrombocytopenia
Work-up reveals AML
Is poor-risk, due to likelihood that this is therapy-
related
Adriamycin
topo-isomerase II inhibitor; typically 1-5 years post-tx
Cyclophosphamide
alkylating agent; typically 5-10 years post-tx
Taxol
33.
34. Stop the infusion
Assess site for signs of extravasation
o Redness
o Swelling
o Pain
o Decreased range of motion
o Change in sensation
o Change in skin temperature
Elevate the extremity
Contact the attending physician for plan of
care and to obtain antidote orders as
indicated
Apply cold or warm pack as outlined in
MSKCC guidelines
Consider topical or systemic antibiotics as
needed
Plastic Surgery evaluation as outlined below
35. Antimetabolites – S phase
Topoisomerase Inhibitors – S and G2 phase
Mitotic Spindle Inhibitors – M and G2 phase
36. Mechanism
Compounds with
structural similarity to
precursors of purines or
pyrimidines
Compounds that
interfere with purine or
pyrimidine synthesis
Causes DNA damage
indirectly, through mis-
incorporation into
DNA, abnormal DNA
synthesis
37. CO2 +
PRPP Glutamine
ATP
Carbamoyl
IMP phosphate
AMP -> GMP -> UMP dUMP
ATP GTP
Thymidylate
synthase
Xanthine UTP dTMP
Uric acid CTP
39. Toxicities
Myelosuppression
Stomatitis
Diarrhea
Not associated with second malignancies
40. Folic acid analog that competitively inhibits the enzyme
dihydrofolate reductase, thereby inhibiting the conversion of
dihydrofolate to tetrahydrofolate .
Without the ability to replenish a supply of reduced
folates, purine & pyrimidine synthesis is interrupted
Can be sequestered in third-space collections
Uses: Leukemia, lymphoma, breast cancer,
head & neck cancers, rheumatologic diseases,
gestational trophoblastic disease
Crosses the blood-brain barrier,
so is useful in CNS disease
41. Toxicities:
Myelosuppression, Hepatoxicity, Nephrotoxicity, Hypersensiti
vity pneumonitis, encephalopathy, rash
Clinical Issues:
- Often given intrathecally for leptomeningeal disease
- At high doses, can penetrate the blood-brain barrier and is
useful in the prophylaxis or treatment of CNS disease
- May need to avoid in ascites
- Metabolized to insoluble form at physiologic pH, so must
alkalinize the blood & urine to eliminate
- Leucovorin started 24 hours afterward moderate or high doses
of methotrexate to “rescue” normal cells
Lippincott’s Pharmacology. Ed.
Harvey & Champe. 2000.
42. Toxicities: Myelosuppression
Hepatoxicity
Clinical Issues:
- Doesn’t penetrate blood-brain barrier, so often given
intrathecally for CNS disease
- May need to avoid in ascites
- Metabolized to insoluble form at physiologic pH, so must
alkalinize the blood & urine to eliminate
- Leucovorin used to “rescue” normal cells
Lippincott’s Pharmacology. Ed.
Harvey & Champe. 2000.
43. Supportive Medications
Pre-dose:
Infuse 1 liter D5W + 100 mEq sodium bicarbonate over 4 hours
Urine output should be >150 ml/hour and urine pH >7.5 ( ≥ 7 for
patients on neurology service) prior to the start of the high-dose
methotrexate. Notify MD/NP if these criteria are not met.
For continuous infusions:
Infuse D5W + 50 mEq sodium bicarbonate/ liter @150 ml/hour
throughout infusion
Post-dose
Infuse D5W + 50 mEq sodium bicarbonate/ liter @150 ml/hour x 72
hours
Sodium bicarbonate tablets 1300 mg PO x 1 or 50 mEq in 25 ml D5W
IV x 1 for each urinalysis with pH less than 7.5
Obtain specific order from Attending MD/NP for dose and schedule
of Leucovorin
44. 56 year-old male with DLBCL and leptomeningeal involvement.
Admitted Feb 2011 for high-dose methotrexate…
45. Thorough evaluation failed to reveal other causes of renal failure, and this
was attributed to MTX nephrotoxicity.
The patient temporarily required hemodialysis.
46. Teaching Points:
It is important to monitor urine pH, urine output, renal
function and daily methotrexate levels in patients receiving
high-dose methotrexate.
Inform any covering individual (e.g. night float) that a patient
has received methotrexate, and clearly sign out the need to
follow up any urinalyses.
Service attending should be notified about drops in urine pH
or oliguria associated with high-dose methotrexate.
47. Pyrimidine analog with fluorine
Inhibits thymidilate synthase, so inhibits conversion of
dUMP to dTMP
Uses: Colon, gastric,
pancreatic
Toxicities:
N/V/D, alopecia
Hand-foot syndrome
48. Clinical issues:
Vasospasm – more with infusional administration than
with bolus
- discontinue drug
- consider a CCB
50. • Capecitabine (Xeloda):
Used in breast, colon cancers
oral drug converted to 5-FU
Still has concern for vasospasm
• Gemcitabine:
Analog of cytidine
• Cytarabine (Ara-C):
Analog of cytidine
Used in AML, ALL
Clinical issue: conjunctivitis
For high dose therapy (> 2000 mg/m2/day):
Dexamethasone eye drops 0.1%; administer 2 drops to each eye 6 hours before
infusion and continue every 6 hours until 24 hours post therapy.
51. Mechanism (natural products)
Topoisomerase I: creates SS breaks allowing for
unwinding of DNA strand
Topoisomerase II: creates DS breaks through which
another
Interference with DNA’s capacity to unwind and allow
for normal replication or transcription
Toxicities
Myelosuppression
Mucositis
Secretory diarrhea
52. Topoisomerase I
Camptothecin
Topotecan
Irinotecan
From Camptotheca
Chinese ornamental
tree
53. Topoisomerase II
Etoposide
From Podophyllum
Peltatum (American
Mayapple)
54. Clinical issues:
Used in FOLFIRI regimen (colon cancer)
Patients may develop a severe diarrhea, often
requiring hospitalization and intensive
fluid resuscitation
- Still look for infectious causes
55. Mechanism
Plant alkaloids or derived from natural products
Microtubules form the mitotic spindle, which allows for
migration of the chromosomes and cell division
Toxicities
Peripheral nerve damage (glove-and-stocking
neuropathy, paralytic ileus, paresthesias, jaw pain)
Extravasation injuries
56. Vinca Alkaloids
blocks assembly of
microtubules
Vincristine
“Oncovin” – the “O” in CHOP
Bad neuropathy, extravasation injury
Vinblastine
57. Taxanes
prevents microtubule disassembly
bark of Pacific Yew Tree (Taxus Brevifolia)
paclitaxel (Taxol)
Breast cancer, Ovarian cancer
Docetaxel (Taxotere)
Clinical issues:
HYPERSENSITIVITY
NEUTROPENIA
Peripheral neuropathy
58. 1) Each drug should be active when used alone against
the particular cancer
2) Drugs should have different mechanisms of action
3) Cross-resistance between drugs should be minimal
4) Drugs should have different toxic effects
59. Non-Hodgkin’s Lymphoma
CHOP
(Cyclophosphamide, Doxorubicin, Vincristine, Predniso
ne)
An alkylating agent, an anthracycline, a vinka alkaloid, and a
steroid
Cyclophosphamide: Hemorrhagic cystitis (need IVF &
UA); PCP
Doxorubicin: Extravasation injury; Cardiotoxicity
Vincristine: Extravasation injury; Neuropathy
60. Colon Cancer
FOLFIRI - Leucovorin (FOL), 5-FU (F), Irinotecan (IRI)
An antimetabolite, synergistic agent, topoisomerase inhibitor
5-FU: Hand-foot syndrome & cardiotoxicity/vasospasm
Irinotecan: Bad diarrhea
61. Standard chemotherapy regimens are given every 3-4
weeks, in order to allow healthy cells to recover
between cycles (blood counts, mucosa)
However, given Gompertzian growth curve, during this
3-week break, the smaller number of tumor cells are
already rapidly-dividing again
By administering the same doses, but on a 2-week
interval, we can catch the tumor cells in this early
rapid growth phase
Concerns about toxicity & marrow suppression have
been mediated by growth factors, etc.
Hinweis der Redaktion
Requires clear margins; often micrometastatic disease present
As an adjunct to surgeryAdjuvant chemotherapy: to eliminate micrometastatic diseaseNeoadjuvant chemotherapy: to improve chances of clean margins or to preserve anatomic structures (sphincter; larynx; breast)As an adjunct to radiationHead and neck cancerCurative chemotherapy aloneLeukemiaMetastatic germ cell tumors Gestational trophoblastic disease
Recruit resting cells into growth phase; kill additional cells with each round
Analogs of nucleotides & intermediates will either inhibit enzymes, or be incorporated into RNA/DNA causing transcription to halt
Hydroxyurea – inhibits ribonucleotide reducatase
Hand-foot = palmar-plantar erythrodysesthesia: chemo diffuses out of small capillaries in hands, soles; worse w friction and heat