The document discusses principles of chemotherapy, including common agents and their mechanisms of action, side effects, and clinical considerations. It covers conventional chemotherapy drugs like alkylating agents, antimetabolites, and antitumor antibiotics, as well as their uses in treating cancers and managing side effects. The goal of chemotherapy is to cure cancer through eliminating all cancer cells, achieving long-term disease control, or palliating cancer symptoms.

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

10.  Infections
 Myelosuppression
 Organ failure
 Debilitation
 Etc…

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

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

19.  Conventional
chemotherapy agents
 Cell Cycle Non-Specific
 Cell Cycle Specific
 Hormonal therapies
 Targeted agents
 Biologic therapies

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

22.  Nitrogen Mustards  Lomustine (CCNU
 Mechlorethamine  Streptozocin
 Cyclophosphamide
 Ifosfamide  Alkylsulfonates
 Chlorambucil  Busulfan
 Melphalan
 Nitrosureas
 Carmustine (BCNU)

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

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

38.  Pyrimidine analogs
 Methotrexate
 5-Fluorouracil
 Capecitabine
 Cytarabine (ara-C)
 Gemcitabine
 Purine analogs
 Fludarabine
 6-Mercaptopurine
 Hydroxyurea

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

49. Clinical issues:
Leucovorin is synergistic

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.