General Principles

• Factors influencing cancer:

  • Sex

  • Age

  • Race

  • Genetics

  • Environmental carcinogens

• Environmental carcinogens may be the most important

• Chemical carcinogens: implicated in human and animal cancer--

  • Constituents in tobacco

  • Azo dyes

  • Aflatoxins

  • Benzene

• Most carcinogens appear mutagenic based on the Ames test.

• Herpes and papilloma group DNA viruses and type C RNA viruses: implicated in animal cancer.

• Oncogenic RNA viruses contain reverse transcriptase capability, allowing integration of viral genomic information into the whole cell.

• HTLV-1,a particular human T cell leukemia virus, appears implicated in oncogenesis.

• Certain genes appear to cause oncogenic transformation -- oncogenes.

• Tumor suppressor genes, when damaged or lost, may cause neoplastic disease.

Cellular Considerations

• Transformed cells proliferate abnormally, forming local tumors.

  •  Tumors may contain a sub population of cells (tumor stem cells) that only divide repeatedly but also metastisize to remote sites.

• Cancer treatment may involve surgery, radiation, and/or chemotherapy.

• In 1998, about half of patients with cancer can be cured with drug treatment contributing in about 17% of cases.

•  Cancer chemotherapy can be curative even in metastatic disease. For example:

  • Testicular cancer

  • Diffuse large cell lymphoma

  • Hodgkin's disease

  • Choriocarcinoma

  • Certain childhood tumors:

    • Acute lymphoblastic leukemia

    • Burkett's lymphoma

    • Wilms' tumor

    • Embryonal rhabdomyosarcoma

• Certain cancers are more resistant to current treatment (current drug treatment may be effectively palliative):

  • Lung cancer

  • Colon cancer

• Cancer Cell Burden:

  • Widespread cancer may correspond to a cell burden of 10^12.

  • Clinical remission and symptomatic improvement may require killing 99.9% of tumor cells.

    •  Even with 99.9% cell kill, 10 ^ 9 cells remain (nine "logs" remaining)

      • Some of these remaining cells may be resistant or may not be accessible to chemotherapeutic agents (central nervous system)

      • Successful chemotherapy must ultimately target (tumor stem cells).

      • By comparison, a three "log" kill may be curative for bacterial infections, since host resistance factors can eliminate residual disease,unlike the situation in treating cancer.

    • To achieve the objective of total cancer cell kill, several approaches are used:

      • Combination therapy

        • Drugs with differing toxicity profiles

        • Drugs with differing mechanisms

        • Drugs with synergistic action

        • Chemotherapy in combination with surgical and radiation intervention.

      • Combination Chemotherapy Curative:

        • Testicular cancer

        • Lymphoma

      • Combination Chemotherapy -- palliative treatment for many other tumors.

• Dosing Principles

  • Drugs: more effective in combination (may be synergistic)

  • More effective if drugs do not share common mechanisms of resistance.

  • More beneficial if drugs do not overlap in major toxicities.

  • Drugs should be in administered near their maximum individual doses

  • Drugs should be administered as frequently as possible -- to maximize dose intensity (dose per unit time) limiting tumor regrowth.

  • Desirable: maximum cell kill with each treatment cycle, using the highest those possible, repeating doses as frequently as tolerable.

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• Myelosuppression

  • Myelosuppression: most common dose limiting toxicity

    • Leukopenia

    • Thrombocytopenia

    • Anemia

  • Neutropenia increases infectious complication risk

    • Neutrophil counts less than 10^9/L with fever

      • Parenteral antibiotics (broad-spectrum)

      • Hematopoietic growth factors may shorten the length of neutropenia

        • Granulocyte colony stimulating factor

        • Granulocytes-macrophage colony stimulating factor

    • Thrombocytopenia: less likely to be dose limiting than leukopenia

      • Risk for hemorrhage due to low platelets (spontaneous intracranial bleeding may occur)

      • Serious thrombocytopenia is usually seen only with very intense chemotherapy protocols (acute leukemia).

    • Anemia: transfusions not usually required, except with high-dose chemotherapy protocols

     

    Reference:   Slapak, C.A., and Kufe, D.W. Principles of Cancer Therapy : In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 523-537.

• Nausea/Vomiting

  • Nausea and vomiting: major side effects of cancer chemotherapy

    • Vomiting: two medullary centers

      • Vomiting center

        • Stimulated by CTZ output (CTZ = Chemoreceptor Trigger Zone)

        • Stimulated by cerebral input (visual/olfactory) and

      • chemoreceptor trigger zone (CTZ)

        • Directly stimulated by toxins or drugs.

        • Neurotransmitters(e.g. dopamine) stimulate the vomiting center

      • Not all chemotherapeutic drugs are equally emetogenic:

        • Most severe: cisplatin (Platinol)

        • Severe:

          •  Dacarbazine (DTIC)

          •  Doxorubicin (Adriamycin, Rubex, Doxil)

          •  Mechlorethamine

        • Relatively mild-- antimetabolites:

          • Methotrexate

          • Flurouracil (5-FU)

  • Major goal: prevention of nausea and vomiting

    • Antiemetic: regular regimen

    • Antiemetic administration should error on the side of more aggressive rather than insufficient (particularly for first administration)

  • Antiemetics

    • Major Tranquilizers

      • Phenothiazines:

        • Most widely used:

          • Mechanism of action: anti-dopaminergic; and anti-serotoninergic effects

          • As monotherapy: effective for only mild emetogenic agents, such as Flurouracil (5-FU)

        •  Chlorpromazine (Thorazine)

        •  Prochlorperazine (Compazine)

• Dopamine Antagonists

  • Metoclopramide (Reglan):

    • Dopamine antagonist (centrally and peripherally)

    • Parenteral administration: effectively reduces nausea and vomiting associated with the most emetogenic chemotherapeutic drugs

    • Metoclopramide, in high doses, can cause extrapyramidal side effects; often administered with an antihistamine (diphenhydramine (Benadryl)) or a benzodiazepine (lorazepam (Ativan)).

• Serotonin Antagonists:

  • Ondansetron (Zofran); Granisetron

  • 5 HT₃ blockers

  • Centrally acting: CTZ

  • Peripherally acting: vagus nerve

  • Effective in treating nausea and vomiting due to cisplatin (Platinol)

  • No dystonic reactions (by contrast to metoclopramide)

  Cannabinoids

  • Dronabinol

    • Available in oral formulation

    • Effective against milder moderate emetogenic agents or protocols

    • Significant mood alteration; including dysphoric reactions.

• Other Agents:

  • Used in combination with other agents:

    • High-dose glucocorticoids (dexamethasone);used for short periods, typically with metoclopramide.

    • Benzodiazepines (sedatives): may be useful for patients with anticipatory nausea and vomiting; may also be beneficial for amnestic properties.

    • Antihistamines: some anti-nausea properties -- useful to prevent dystonic reactions associated with phenothiazines or metoclopramide (Reglan).

• Alopecia

  • Alopecia: Hair loss due to chemotherapy drugs-- extremely distressing for certain patients.

  • Mechanism of effect: cytotoxic action of anticancer drugs on the hair follicle.

  • After completion of treatment, hair usually returns to pre-treatment levels; texture and color may be different

  • Agents that cause the most significant hair loss:

    • Cyclophosphamide (Cytoxan)

    • Dactinomycin (Cosmegen)

    • Doxorubicin (Adriamycin, Rubex, Doxil)

    • Paclitaxel (Taxol)

    • Vincristine (Oncovin)

  • ref:  Slapak, C.A., and Kufe, D.W. Principles of Cancer Therapy : In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 523-537.

• Stomatitis

  • Stomatitis: oral mucosal inflammation:Major Complication of Cancer Chemotherapy

  • Oral ulcers: poor nutrition/dehydration

  • Ulcers may become infected

  • Basically all chemotherapy drugs can cause stomatitis

  • No means to prevent stomatitis, except management of dose.

  • Risk of infection can be decreased with meticulous oral hygiene

  • Pain relief:

    • Topical oral anesthetics:viscous lidocaine

    • Capsaicin may be beneficial

  • ref: Slapak, C.A., and Kufe, D.W. Principles of Cancer Therapy : In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 523-537.

• Anticancer drugs: selective toxicity

  • Cancers that are rapidly dividing are most vulnerable to chemotherapeutic agents

    • These neoplasms have a high percentage of dividing cells -- large growth fraction

  •  Normal tissues that divide rapidly are also damaged by the chemotherapeutic agents: side effects associated with chemotherapy are often do to effects of drugs on such normal tissues:

    • Toxicity: bone marrow suppression (marrow cells are rapidly dividing)

    • Toxicity: alopecia (hair follicle cells are rapidly dividing)

    • Toxicity: GI disturbances-- nausea and vomiting (gastric mucosal cells are rapidly dividing)

    • Some of these toxicities, such as bone marrow suppression,may be dose limiting.

  •  Some cancers are slowly dividing (examples: colon and lung carcinoma) -- a characteristic that makes successful chemotherapy difficult.

• Anticancer chemotherapy: drug resistance

  • Types of resistance:

    •  Primary if resistance is present prior to first drug exposure

      • Examples:

        • Colon cancer

        • Non-small cell lung cancer

    •  Acquired if resistance develops to single drug after treatment;

      •  Usually associated with an increased expression of tumor cell genes

      •  May be a multidrug-resistant phenotype

        • Often due to increased expression of MDRI gene (coding for a cell surface glycoprotein involve been drug transport (efflux))

      •  Overexpression of the multidrug resistance-associated protein (NPR) may cause resistance-examples: Anthracyclines,Vinca alkaloids, epipodophyllotoxins

      •  Changes in topoisomerase II (repairs DNA damage caused by antitumor drugs)

  • Drug-resistant tumor cells may be selected by exposure to single agent, low-dose chemotherapy:

  •  Examples of mutations leading to drug resistance:

    •   Single agent: deletion of activating enzyme -- deoxycytidine kinase for cytosine arabinoside

    •   Multiple agents: Overexpression of drug efflux pump.

    •   Genetic change: loss of p53 suppressor oncogene -- may lead to resistance

    •   Genetic change: mutation of p53 or overexpression of bcl-2 gene (translocated in nodular non-Hodgkin's lymphoma) inactivates apoptosis (programmed cell death))

  Single-Agent Drug Resistance (adapted from Table 86-4*,p. 533)

  Defective Transport	Methotrexate	Folate transporter
  Defective Transport	Cytarabine (ARA-C)	Nucleoside transporter
  Defective Transport	Mechlorethamine (Mustargen)	Choline transporter
  Decreased Activating Enzyme Activity	Cytarabine (ARA-C)	Deoxycytidine kinase
  Decreased Activating Enzyme Activity	Mercaptopurine (Purinethol)	HGPRT
  Increased Drug Inactivation	Bleomycin (Blenoxane)	Bleomycin hydrolase
  Increased Drug Inactivation	Cyclophosphamide (Cytoxan)	Aldehyde dehydrogenase
  Increased Drug Inactivation	Cytarabine (ARA-C)	Cytidine deaminase
  Increased Target Enzyme	Fluorouracil (5-FU)	Thymidylate synthase
  Increased Target Enzyme	Methotrexate	Dihydrofolate reductase
  Increased Target Enzyme	Pentostatin (Nipent)	Adenosine deaminase

  Alteration in Target	Fluorouracil (5-FU)	Thymidylate synthase
  Alteration in Target	Hydroxyurea (Hydrea)	Ribonucleotide reductase
  Alteration in Target	Vincristine (Oncovin)	Tubulin

  Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911.

  *Slapak, C.A., and Kufe, D.W. Principles of Cancer Therapy : In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 523-537.

  Calabresi, P. and Chabner, B.A. Chemotherapy of Neoplastic Diseases. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1225-1232.

• Combination Therapy: Combination chemotherapeutic protocols: Principles

  1. Each drug: independent activity against the specific tumor

  2. Each drug: different mechanism of action (targeting different steps along a pathway)

  3. No cross-resistance among the drugs in the protocol (rationale: Tumor cell subpopulation resistant to one drug, would not be resistant to another drug in the combination protocol

  4. Each drug: different dose limiting toxicity

  •  Following high-dose chemotherapy or chemotherapy with radiation therapy, severe myelosuppression may occur:

    • Bone marrow transplantation may be used

    • If bone marrow transplantation is part of theprotocol, the most favorable relationship between cell kill and drug dose has been observed with:

      • Alkylating agents (busulfan; cyclophosphamide)

      • Use of alkylating agents as part of the myeloablative protocol results in higher tumor cell kill.

    • Autologous bone marrow transplant: patient's bone marrow or peripheral blood stem cells:

      • Isolated

      • Cryopreserved

      • Infused back into patients following high-dose chemotherapy

    • Allogenic bone marrow transplant: Bone marrow from an appropriate donor re-constitutes the patient's immune system

      • Following allogenic transplantation, immune mechanisms contribute to control of malignant disease (graft-vs.-tumor effect)

    •  Bone marrow transplantation -- Most Effective:

      • When tumors are initially responsive to chemotherapeutic agents

      • Acute leukemia

      • Hodgkin's disease

      • Non-Hodgkin's lymphoma

      • Testicular carcinoma

    •  Bone marrow transplantation -- Least Effective:

      • Epithelial-derived cancer

        • Non-small cell lung carcinoma

        • Colorectal cancer