General Principles of Cancer Therapy

Chapter 30 General Principles of Cancer Therapy



October 21, 1997. 1st year resident S. B. Cho M.D.



I. Biologic Factors




1. Cell Kinetic Concepts




A. Patterns of Normal Growth




  • Static cells ; relatively well differentiated cells, rarely undergo cell division
    (striated muscles & neurons)



  • Expanding cells ; characterized by the capacity to proliferate under special stimuli
    (liver or kidney)



  • Renewing cells ; in a constantly proliferative state, (bone marrow, epidermis,
    gastro-intestinal mucosa)



  • Static cells, rarely seriously injured by drug therapy.

    renewing cells : usually injured



B. Cancer cell growth




  • The tumor cell growth => disruption in normal cellular brake mechanisms
  • Cell proliferation ; same as in normal tissues
  • Failure of regulated balance between cell loss & cell proliferation



C. Gompertzians Growth



  • As a tumor mass increases, the time required to double the tumors volume also
    increases



D. Doubling Time




  • The time that it takes for the mass to double in size



  • Relatively fasting doubling time ; embryonal tumors, lymphomas, malignant
    mesenchymal tumors (20 ~ 40 days).



  • Relatively slow doubling times ; adenocarcinoma, squamous carcinoma (50 ~ 150
    days)



  • Metastases => generally have faster doubling time than primary lesions



  • If it is assumed that exponential growth occurs early in a tumor history & that a
    tumor starts from a single malignant cell

    1mm mass ; undergone 20 doubling times

    5mm mass ; undergone 27 doubling times (first visualized an X-ray film)

    1cm mass ; undergone 30 doubling times



  • With current clinical techniques : most tumors recognized late in their growth &
    metastasis may well have occurred long before there is evidence of the primary
    lesion



    In late stages of tumor growth, a very few doubling in tumor mass have a
    dramatic impact on the size of the tumor.



E. Cell Cycle



  • The generation time ; the duration of the cycle form M phase to M phase
    variation occurs in all phases of the cell cycle, => greatest during the G1 period



  • Two major factors affect the rate at which tumors grow : growth fraction & cell
    death




    • The growth fraction ; the number of cells in the tumor mass that are actively
      undergoing cell division


    • Marked variations in growth fraction ; 25 - 90 %


    • In the past ; human tumors contained billions of cells, all growing slowly

      In actuality ; only a small fraction of cells with in a tumor mass are rapidly
      proliferating



  • Factors that alters tumor growth



    • Cytotoxic chemotherapy
    • Hormones
    • X-ray therapy
    • Alterations in oxygen & vascular supply
    • Immunologic therapies



II. Chemotherapy




A. Differential Sensitivity



1. Therapeutic Index



  • Therapeutic index ; a ratio of the doses at which therapeutic effect & toxicity occur

    => The net effect of a chemotherapeutic agent


  • Most chemotherapeutic agent

    => the window of toxicity is narrow


2. Cell cycle-Specific Versus Cycle non-specific Drugs



    ·Table. 30.2 - 30.3



3. Log Kill Hypothesis



  1. Chemotherapeutic agents => first order kinetics

    ; Killing a constant fraction of cells rather than a constant number



  2. Single chemotherapeutic agents => 2 ~ 5 logs or cell kill

    1kg ; 1012 cells => single use is unlikely to be curative =>need for intermittent

    courses of chemotherapy & multiple drug or combination chemotherapy



  3. Cure rate => significantly improved if small tumors present



  4. 101 ~ 104 cell mass => too small for clinical detection;



  5. Basis for using adjuvant chemotherapy in early stages of disease



4. Drug Resistance & Tumor Cell Heterogenicity



  • A variety of cellular mechanism is involved


    a. Increased activation

    b. Decreased activation of drugs

    c. Increased drug efflux

    d. Resist normal drug uptake

    e. Altered specificity to an inhibiting enzyme or increased production of the target
    enzyme



5. Dose Intensity



  • Dose intensity = Drug (mg) 1Surface area (M2) / Time (week)



  • Bone morrow transplantation ; with advanced, refractory ovarian Cancer

    -- peripheral stem cell transplantation



  • Granulocyte - macrophage colony stimulating factor (GM -CSF)




B. Pharmacologic Factors Influencing Treatment



1. Drug Effect = Drug concentration x Duration of Exposure (C X T)


2. Route of Administration & Absorption



  • Orally, intravenously, intramuscularly intra-arterially.


  • Intraperitoneal => slower clearance than plasma clearance

    ; an increased concentration of the drug in the pleural & peritoneal cavity



C. Principles of Combination Chemotherapy



1. Limitations of Single-Drug Therapy



  • Toxicity
  • Adoptive mechanisms allow cell survival & eventual regrowth of resistant tumor
    cells


2. Combination Chemotherapy Mechanisms



  • Cell cycle - nonspecific agents only => tumor regrowth


  • By using cell cycle

    specific agent => only the cells coming into cell cycle will be affected


  • By using combinations or sequences of two agents, log kill can be enhanced in
    tumors


3. Drug Resistance



  • With combination regimen => drug resistance cells can be reduced


4. Drug Interaction



  • Synergic ; increased anti-tumor activity & decreased toxicity
  • Additive ; enhanced anti-tumor activity equivalent to the sum of both agents acting
    singly
  • Antagonize ; producing a lesser therapeutic effects




D. Remission




  1. Complete Remission ; the complete disappearance of all objective evidence of tumor
    as well as the resolution of all signs & symptoms referable to the tumor



  2. Partial Remission : > 50% reduction in the size of measurable lesions along with
    some degree of subjective improvement & absence of any new lesions during
    therapy.




E. Dose Adjustment




  • Table 30.4 - 30.5



F. Drug Toxicity



1. Hematologic Toxicity



  1. Acute granulocytopenia ; 6 ~ 12 days after administration => recovery, 21 ~ 24days
    Acute thrombocytopenia ; 4 ~ 5 days => recovery ; after white cell count returns
    to base line



  2. Granulocytopenia



    • < 500/mm3 => 5days or longer ; at high risk of rapidly fatal sepsis
    • Prophylactic & empirical use of broad-spectrum antibiotics

      => has significantly decreased the incidence of life-threatening infections
    • Temperature ; checked every 4 hours
    • G-CSF, GM-CSF ; shortens duration of granulocytopenia, not thrombocytopenia



  3. Thrombocytopenia




    • < 20,000/mm3 => at risk of spontaneous hemorrhage

      (acute gastrointestinal or intracranial hemorrhage)
    • 6 ~ 10 units transfusion per 2 ~ 3days
    • > 50,000/mm3 with active bleeding, peptic ulcer disease, surgical procedure
    • 1hr after transfusion => platelet count does not increase

      => HLA-matched platelet is needed


2. Gastrointestinal Toxicity



  1. Mucositis



    • 3 ~ 5 days earlier than the myelosuppression
    • Can be confused with candidiasis or herpes simplex infection



  2. Candidiasis



    • Oral candidiasis ; chlorthrimazide (10 mg five times daily)
    • Esophageal candidiasis ; 7 day amphotericin B



  3. Mucocutaneous herpes simplex



    • IV Acyclovir
    • Topical anesthetics IV fluids, hyperalimentation



  4. Mucositis in lower GI tract



    • bowel perforation, hemorrhage necrotizing enterocolitis




  5. Necrotizing Enterocolits



    • Watery or bloody diarrhea, abdominal pain, sore throat, nausea, vomiting, fever
      ,abdominal tenderness & distention
    • Most cases => associated with clindamycin use & C. difficile

    • C. difficle infection => oral vancomycin 125mg four times daily for 10 ~ 14 days



3. Immunosuppression



  • The magnitude & duration of the immunosuppression

    =>vary with the dose & schedule of drug administration
  • Does not persist after therapy ; complete restoration after 2-3 days



4. Dermatologic Reactions



1) Skin necrosis & sloughing

  • Extravasation (doxorubicin & actinomycin D)
  • Immediate removal of IV line, local infiltration of corticosteroid, ice park therapy
    four times a day for 3 days elevation of the affected limb


2) Alopecia

  • Most common side effect
  • Paclitaxel & cyclophosphamide
  • Always reversible
  • Hair growth => 10 days to several weeks after treatment


3) Generalized allergic skin reactions

  • Skin pigmentation (bleomycin)
  • Photosensitivity reactions, transverse banding or nail loss, folliculitis

    (actinomycin D, methotrexate)
  • Radiation recall reactions (doxorubicin)



5. Hepatic Toxicity



  • Modest elevations in transaminase, alkaline phosphatase, and bilirubin level

    => resolve soon after treatment
  • Methotrexate => hepatic fibrosis, cirrhosis


6. Pulmonary Complications



  • Interstitial pneumonitis ; blemomycin, nitrosoureas
  • Discontinuation of drug & supportive care


7. Cardiac Toxicity




  1. Doxorubicin ; The risk increases with the total cumulative dose => 500mg/m2
  2. Left ventricular ejection fraction check
  3. Paclitaxel & cyclophosphamide
  4. Radionuclide cardiac scintigraphy

    => should performed for early detection of cardiac compromise


8. Genitourinary Toxicity



  1. Cisplatin => renal tubular toxicity ; azotemia & magnesium wasting


  2. Methotrexate => precipitate in renal tubule ; oliguric renal failure

    prevention => maintenance of high urine volume & alkalinization of urine


  3. Cyclophosphamide => chronic hemorrhagic cystitis, vigorous hydration & diuresis


  4. Treatment


  • Discontinuation of drugs & volume expansion to increase glomerular filtration
  • Hyperuricemia, hypomagnesemia correction
  • Short-term peritoneal dialysis or hemodialysis,
  • Mesna => by inactivating the toxic metabolite, acrolein

    => prevent hemorrhagic cystitis caused by cyclophosphamide, Ifosfamide



9. Neurotoxicity




  1. Cisplatin



    • Ototoxicity, peripheral neuropathy, retrobulbar neuritis & blindness
    • High dose cisplatin => delayed peripheral neuropathy sensory impairment, loss of
      proprioception, motor strength => generally preserved.



  2. Paclitaxel ; peripheral neuropathy

    Paclitaxel + Cisplatin chemotherapy => can potentiate the neuropathy



  3. 5-FU ; cerebellar toxicity



  4. Hexamethylmelamine ; peripheral neuropathy & encephalopathy.



10. Vascular & Hypersensitivity Reactions




  1. Anaphylaxis : cyclophosphamide, doxorubicin, cisplatin, iv. melphalan, high close of
    methotrexate

  2. Bleomycin : marked fever reactions, anaphylaxis, Raynauds phenomenon, chronic
    scleroderma - like reaction

  3. Paclitaxel : hypersensitivity reaction
    <-- Dexamethasone, diphemhydramine, clmetidine 30 minutes before administration


11. Second Malignancies



  1. Alkylating agent (especially melphalan) : more than 1 year of usage => risk of
    acute non-lymphocytic leukemia is increased

  2. Commonly occurs after successful therapy.

  3. Other chemotherapeutic agent alone & Radiation therapy alone => little risk

  4. Risk factors




    • Extensive radiation therapy + combination chemotherapy
    • Prolonged alkylating agent therapy (longer than l year)
    • Prolonged maintenance therapy
    • Age at initial Treatment older than 30 years


12. Gonadal Dysfunction




  • Chemotherapeutic agent (esp. alkylating agent) => azoospermia, amenorrhea


  • Short-term intensive chemotherapy particularly with anti-metabolites, vinca alkaloids,
    antitumor antibiotics => less injury to the reproductive system

    ex) testicular cancer, acute leukemia, GTD, ovarian germ cell malignancy


  • Chemotherapy in Pregnancy

    : risk of congenital abnormalities increased in first trimester especially with
    antimetabolite & alkylating agent


13. Metabolic Abnormalities




  1. Syndrome of inappropriate ADH secretion



    • With vinca alkaloid chemotherapy
    • Symptom ; altered mental status, confusion, lethargy, seizure, coma
    • Laboratory findings ; hyponatremia, hypertonic urine



  2. Tumor lysis syndrome



    • Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia
    • Prevention : Maintenance of high urine output & high urinary PH(>7.0) prophylactic
      use of the xanthine oxidase inhibitor (allopurinal)


G. Anti-neoplastic Drugs



  • Table 30.6


1. Alkylating Agents



  • Usually bind to the N-7 position of guanine => interfere with accurate base pairing,
    cross-link DNA => single & doable-stranded break => results in DNA & RNA,
    protein synthesis
  • All alkylating agents => similar mechanism => cross-resistance can occur


2. Anti-tumor Anti-biotics




  1. Natural products from fungi

  2. Action mechanism



    • Inserted between DNA base pairs
    • Formation of tree radicals => damaging DNA, RNA, proteins
    • Metal ion chelation & alteration of tumor cell membranes



  3. Anthracyclines, Bleomycin


3. Anti-metabolites



  • Interacts with vital intracellular enzymes => inactivation or frauclulent products
    incapable of normal intracelluar function


  • More disruptive to actively proliferating cells => cell-cycle specific



  • Methotrexate ; folate antagonist

    Hydroxyurea ; Ribonucleotide reductase inhibitor

    5 - FU ; pyrimidine antagonists


4. Plant Alkaloids




  • Vincristine & Vinblastine

    => binding to microtubular proteins

    => inhibition of microtubular proteins & destruction of the mitotic spindle

    => arrested in mitosis



  • Paclitaxel

    => binds of microtubules & polymerization & stabilization



  • Etoposide (VP-16)

    => Causing single-stranded DNA breaks