Introduction to Chemotherapy

Question 1

What are the goals of chemotherapy, and what are some general principles?

Answer 1

• The most successful approach to cancer therapy is a multi-modality approach, using surgery, radiotherapy and/or chemotherapy
  
  • The role of each of these modalities varies in different cancers
  • Since the introduction of chemotherapy more than 50 years ago, the prognosis for patients with many types of cancer has improved dramatically
• For example, in pediatrics < 30% of children with cancer survived in the 1960s when therapy included surgery with or without radiotherapy
• Today > 80% of children with cancer are cured, which in large part is a direct result of the incorporation of anticancer drugs into treatment regimens
  
  • Of course this is not entirely due to chemotherapy as newer surgical techniques, newer methods of delivering radiotherapy, improved imaging modalities and improved supportive care measures have also been developed
• The goal of chemotherapy can be cure or palliation (symptom control) for patients with recurrent cancers, extremely widespread cancers or other significant morbidities that prevent intensive treatment
  
  • If we are to achieve cure, we must kill all or most cancer cells with anticancer therapy, possibly with the help of the immune system
  • Alternatively, differentiation of cancer cells can contribute to cure
• In order to develop drugs that kill cancer cells we must exploit differences between cancer cells and normal host cells
• For most cytotoxic drugs this means attacking dividing cells

Question 2

What are the preclinical studies of chemotherapy drug therapy.

Answer 2

• In vitro screening of agents:
  
  • The strategy to identify agents that kill cancer cells generally begins with in vitro screening of agents against tumor cell lines
  • High-throughput screening can be done to test many agents or a targeted approach can be used to test an agent that is known to have activity directed against a specific molecular defect that is found in cancer cells
  • The endpoint of such experiments is generally cell viability or the ability to kill cancer cells, the ability to reduce proliferation of cancer cells or the ability to induce differentiation
• In vivo screening of agents:
  
  • Agents that show in vitro activity may be tested using in vivo xenograft experiments, in which human tumor cells are injected into nude/immunodeficient mice
  • The mice are then treated with a single agent or a combination of agents and in vivo response and survival can be assessed
  • If there is pre-clinical evidence of activity then clinical trials may be conducted using the agent in humans

Question 3

What are the different phases of clinical trials for chemotherapy agents?

Answer 3

• Phase I studies:
  
  • Phase I studies are usually designed as dose escalation studies to define toxicity (including identification of the dose limiting toxicity [DLT]) and determine the maximal tolerated dose (MTD)
  • For the most part these studies are conducted in patients with multiply recurrent cancers for whom there is no known effective therapy
• Phase II studies:
  
  • Once the MTD is established then response rates are evaluated in small cohorts of patients with specific types of tumors in phase II studies
  • Response is usually quantified as a CR (complete response; tumor gone), PR (partial response; > 25-30% reduction), SD (stable disease; < 25-30% smaller to < 25-30% larger) or PD (progressive disease; > 25-30% larger)
  • Generally, the CR + PR rate is used to determine the response rate
• Phase III studies:
  
  • If a promising response rate is seen in phase II, then the agent may be tested in front-line therapy as part of a multi-agent chemotherapy regimen
  • A randomized trial represents a powerful approach, comparing the experimental regimen with a regimen that is considered the standard

Question 4

What is combination chemotherapy?

Answer 4

• Chemotherapy regimens usually include multiple agents
  
  • These regimens are referred to as combination chemotherapy
• The scientific rationale for combination chemotherapy is to overcome inherent drug resistance to individual agents and delay or even prevent development of acquired drug resistance in tumors that are initially responsive to chemotherapy
• Anticancer agents that are included in a regimen should have:
  
  • single agent activity against the tumor to be treated
  • different mechanisms of action
  • different toxicities
• Effective doses and schedules of administration can then be used

Question 5

What is the difference between adjuvant and neoadjuvant therapy?

Answer 5

• Adjuvant therapy:
  
  • Adjuvant therapy refers to administration of chemotherapy after surgical resection or radiotherapy when the tumor burden is small
  • Indeed, chemotherapy seems most effective for many cancers when there is not evidence of overt or gross disease
  • In this setting, chemotherapy effectively eliminates micro-metastatic tumor deposits
  • Based on tumor growth kinetics a smaller burden of tumor cells would be expected to have a larger fraction of proliferating cells (the targets of cytotoxic agents) and a lower probability that resistant cells are present
  • The concepts of combination chemotherapy and adjuvant therapy are summarized by the Goldie-Coleman hypothesis, which states that the chance of cure will be maximized if all active drugs are given simultaneously in the adjuvant setting when the tumor burden is small
• Neoadjuvant therapy:
  
  • Neoadjuvant therapy refers to administration of chemotherapy before the tumor is removed by surgery or treated with radiotherapy
  • Neoadjuvant therapy provides potential advantages, including the fact that:
    
    • it avoids chemotherapy treatment delays
    • it may shrink the tumor and therefore make surgical resection easier or even possible
    • it allows one to make an assessment of chemotherapy sensitivity either based on a reduction in tumor size radiographically or based on necrosis detected histologically following resection of the tumor
  • Neoadjuvant chemotherapy is sometimes followed by adjuvant chemotherapy to maximize chances for cure

Question 6

What is the benefit of maximizing chemotherapy doses?

Answer 6

• When possible, agents are used at the maximal tolerated dose (MTD)
• This is the dose that in theory will provide the greatest cell kill with acceptable toxicity
  
  • Oncologists are reluctant to reduce doses in part because most chemotherapeutic agents have steep dose-response curves
  • This means that a small decrease in dose may result in a large decrease in cell kill
• We can assess dose intensity by calculating a dose rate, which is the dose of an agent delivered over time (eg. mg/M2/week)
  
  • Dose rate can be increased by increasing the drug dose (dose escalation) or decreasing the time interval between doses (interval compression)

Question 7

What are common chemotherapy toxicities, and how are they assessed?

Answer 7

• Cytotoxic chemotherapeutic agents have a low therapeutic index (effective dose:toxicity ratio) and therefore may have severe or life-threatening toxicity
  
  • Oncologists must assess risk-benefit ratios when studying and using toxic regimens
  • A clear benefit of a regimen is the potential for cure
  • Risks include severe toxicity as well as recurrence, which is often fatal
• Common/important acute toxicities of cytotoxic chemotherapy regimens: Since chemotherapeutic agents are designed to kill dividing cells, common toxicities affect normal cells that are also dividing at the time that chemotherapy is administered
  
  • These normal cells include:
    
    • bone marrow stem cells, which are precursors of red cells, white cells, and platelets
    • mucosal epithelial cells lining the gastrointestinal tract
    • precursor hair cells
  • Therefore, important common acute toxicities include myelosuppression, mucositis and alopecia
    
    • Because of neutropenia patients are at risk for bacterial and fungal infections
  • Tumor lysis syndrome is a result of rapid tumor cell kill usually in the setting of T-cell or B-cell leukemia/lymphoma
    
    • As the tumor cells die, they release their contents, including uric acid, potassium and phosphorus into the blood, which can cause kidney failure and cardiac arrhythmias
• Supportive care measures: Supportive care measures to prevent or reduce toxicity are essential for administration of dose intensive chemotherapy regimens
  
  • Myeloid growth factors (eg. G-CSF) are used to raise the neutrophil count more rapidly following chemotherapy
  • Transfusions of red cells or platelets can be given
  • Hydration and pain medications are given for severe mucositis
  • Antibiotics are sometimes administered prophylactically and empiric administration of broad-spectrum antibiotics in the setting of fever and neutropenia following chemotherapy is standard
  • Many agents cause nausea/vomiting, for which anti-emetics are routinely administered
  • Hydration together with either allopurinol (xanthine oxidase inhibitor that prevents production of uric acid) or rasburicase (catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive more soluble and therefore less harmful metabolite) are administered for tumor lysis syndrome
• Toxicity grading: The NCI has established criteria for grading the severity of acute toxicities called the Common Terminology Criteria for Adverse Events (CTCAE)
  
  • Toxicities are graded from 1-5
  • Many chemotherapy protocols define specific chemotherapy dose reductions based on the CTCAE toxicity grade
• Long term effects of chemotherapy: Some of the important long-term consequences of specific chemotherapy regimens include:
  
  • infertility caused by alkylating agents
  • organ dysfunction, including cardiomyopathy caused by:
    
    • anthracyclines
    • pulmonary fibrosis caused by bleomycin or BCNU
    • renal tubular dysfunction caused by cisplatin or ifosfamide
  • secondary leukemia or myelodysplasia caused by alkylating agents or etoposide
    
    • Etoposide induces leukemia, which is associated with abnormalities of the MLL locus at 11q23 and alkylating agents cause leukemias and myelodysplasia, which are associated with abnormalities of chromosomes 5 and/or 7 (monosomy or long arm deletions)

Question 8

What is the pharmacology of therapy?

Answer 8

• Pharmacokinetics:
  
  • “Pharmacokinetics” refers to what the body does to the drug
  • This includes the absorption, distribution, metabolism and excretion (ADME) of the agent
  • In practical terms for the oncologist, pharmacokinetics are used to determine drug dose, route of administration and schedule
• Pharmacodynamics:
  
  • “Pharmacodynamics” refers to what the drug does to the body
  • Pharmacodynamics describe the relationship between the concentration of a drug and an effect, which can be efficacy or toxicity
  • For example, pharmacodynamic measurements can be used to determine whether a given dose of a protein kinase inhibitor actually inhibits protein kinase activity in vivo
• Pharmacogenetics:
  
  • “Pharmacogenetics” refers to how the genome affects the drug and its metabolism
  • For example, polymorphisms in certain enzymes involved in the metabolism of an agent may affect toxicity and dosing
    
    • eg. Thioguanine methyltransferase [TPMT] detoxifies mercaptopurine. TPMT deficiency as a result of inherited inactive polymorphic TPMT variants significantly increases myelosuppression during therapy with mercaptopurine

Question 9

What are the different classes of chemotherapy agents?

Answer 9

• Anticancer agents are classified as cytotoxic or targeted.
• Cytotoxic agents:
  
  • Cytotoxic agents have non-selective mechanisms of action that generally affect dividing cells (both normal and cancer cells) by interfering with the synthesis or function of DNA or RNA
  • Some agents are S-phase specific (eg. antimetabolites)
  • Classes of cytotoxic agents include:
    
    • alkylating agents
    • antimetabolites
    • antibiotics
    • plant products
    • miscellaneous agents
• Targeted agents:
  
  • Targeted agents have more selective mechanisms of action
  • Some classes of targeted agents include small molecule protein kinase inhibitors and monoclonal antibodies
• Drug resistance:
  
  • Drug resistance represents an important limitation to the use of chemotherapy
  • There are several mechanisms that cause drug resistance
  • Some mechanisms are drug specific and others affect multiple drugs simultaneously, which is referred to as multidrug resistance (MDR)
  • A well described mechanism for MDR is overexpression of P-gp (P-glycoprotein), MRP (multidrug resistance protein) or other drug efflux pumps, which cause resistance to anthracyclines, dactinomycin, etoposide, irinotecan, topotecan, vincristine and other drugs

Question 10

What are some major alkylating agents and their pharmacologies?

Answer 10

• General mechanism: Alkylating agents cause covalent bonding of alkyl groups with DNA, RNA and proteins
  
  • Some of these drugs have two functional groups and are referred to as bifunctional alkylating agents, which cause intra-strand or inter-strand cross-linking of DNA
  • This leads to damage to the DNA template and induces apoptosis
• Classes: Nitrogen mustards, nitrosoureas and platinum compounds
• Select toxicities of alkylating agents:
  
  • The DLT is myelosuppression
  • Dose-dependent infertility represents a significant long-term toxicity
  • Leukemia/myelodysplasia is a rare and important long-term toxicity, generally occurring 5-7 years following therapy and characterized by abnormalities of chromosomes 5 and/or 7
• Nitrogen mustards (eg. cyclophosphamide, ifosfamide):
  
  • Cyclophosphamide and ifosfamide cause alkylation and cross-linking
  • These are prodrugs that are activated by hepatic microsomes
  • Their metabolism is complex and includes active metabolites (hydroxylation) and metabolites that cause toxicity (acrolein metabolite associated with hemorrhagic cystitis)
  • These agents are used to treat leukemia/lymphoma and solid tumors
  • Cyclophosphamide is used in stem cell transplant preparative regimens
• Nitrosoureas (eg. lomustine [CCNU], carmustine [BCNU]):
  
  • Nitrosoureas are lipid soluble bifunctional alkylating agents
  • Because these agents are lipid soluble, they penetrate the blood brain barrier and are used to treat brain tumors
  • An important dose-dependent toxicity of BCNU is pulmonary fibrosis
• Platinum compounds (eg. cisplatin, carboplatin, oxaliplatin):
  
  • Platinum compounds coordinate the heavy metal platinum and are considered non-classical alkylating agents, causing platination (analogous to alkylation), which cross-links DNA. Cisplatin causes nephrotoxicity and ototoxicity
  • Carboplatin and oxaliplatin cause myelosuppression
  • Oxaliplatin also causes neurotoxicity
  • These agents are used to treat solid tumors

Question 11

What are some major antimetabolites and their pharmacologies?

Answer 11

• General mechanism:
  
  • Antimetabolites are S-phase specific agents that inhibit synthesis of nucleic acids and their building blocks or are incorporated into DNA or RNA resulting in a defective product
  • These drugs are structural analogs of vital cofactors or intermediates in the biosynthetic pathways of DNA or RNA
  • Most are prodrugs that require metabolic activation within target cells
• Classes:
  
  • folate analogs
  • purine analogs
  • pyrimidine analogs
• Folate analogs (e.g. methotrexate):
  
  • Methotrexate is a structural analog of folate, which is a cofactor for the synthesis of purines and thymidine
  • Methotrexate inhibits dihydrofolate reductase, which converts dihydrofolate to tetrahydrofolate
  • In order to prevent toxicity, leucovorin (an analog of tetrahydrofolate) is given approximately 24 hours after high dose methotrexate in order to rescue normal cells from the inhibition of dihydrofolate reductase
  • Methotrexate is used for lymphoid leukemia/lymphoma and osteosarcoma
• Purine analogs (e.g. mercaptopurine, thioguanine):
  
  • Purine analogs are incorporated into DNA and inhibit de novo purine synthesis
  • Thiopurine methyltransferase (TPMT) regulates metabolism of these agents
  • There are many polymorphic variants, some of which have decreased activity
  • Homozygosity for variants with absent activity is associated with significant myelosuppression, requiring dose reductions (an example of pharmacogenetics)
  • These agents are used to treat leukemia/lymphoma
• Pyrimidine analogs (e.g. cytarabine, gemcitabine):
  
  • Pyrimidine analogs are incorporated into DNA and inhibit DNA polymerase
  • These agents are used to treat leukemia/lymphoma and solid tumors

Question 12

What are antibiotics used for chemotherapy and their pharmacologies?

Answer 12

• General mechanism:
  
  • Antibiotics are natural products isolated from the microbial broth of soil micro-organisms (eg. Streptomyces) that:
    
    • bind DNA by intercalation between bases, which induces topoisomerase-II strand breaks
    • cause free radical formation, leading to oxidative stress.
• Classes/Agents:
  
  • Anthracyclines
  • Dactinomycin
  • Bleomycin
• Anthracyclines (e.g. doxorubicin, daunomycin):
  
  • Anthracyclines intercalate into DNA and cause free-radical formation
    
    • An important but rare side effect is cardiomyopathy caused by free radical-induced cardiac myocyte damage
    • The risk of cardiomyopathy depends on the total cumulative dose of anthracycline and perhaps the peak concentration during administration
  • Dexrazoxane is a chelator that may reduce the risk of cardiac toxicity
    
    • These agents are used to treat leukemia/lymphoma and solid tumors.
• Dactinomycin:
  
  • Dactinomycin intercalates into DNA and blocks transcription
  • Dactinomycin rarely causes sinusoidal obstruction syndrome, which is characterized by hepatomegaly, RUQ pain, weight gain, jaundice and thrombocytopenia
    
    • It is used to treat solid tumors
• Bleomycin:
  
  • ​Bleomycin causes free radical formation
  • An important dose-related toxicity is interstitial pneumonitis
  • It is used to treat Hodgkin lymphoma and germ cell tumors

Question 13

What are plant products used in chemotherapy and their pharmacologies?

Answer 13

• General mechanism:
  
  • These are natural or semisynthetic compounds derived from plants
  • They have complex structures and metabolism and a variety of mechanisms account for their anticancer activity
• Classes/Agents:
  
  • camptothecins (Camptotheca acuminata tree)
  • epipodophyllotoxins (mandrake plant)
  • vinca alkaloids (periwinkle plant)
  • taxanes (yew tree)
• Camptothecins (e.g. topotecan, irinotecan):
  
  • Camptothecins are semisynthetic analogs of natural plant products that inhibit topoisomerase-I, causing DNA strand breaks
  • Irinotecan is prodrug that is activated to SN-38
  • The UGT1A1 enzyme detoxifies SN-38 by glucuronidation to SN-38G
  • Individuals with a specific polymorphism in the promoter region of the UGT1A1 enzyme (the UGT1A1*28 polymorphism) have reduced enzyme activity and enhanced toxicity (myelosuppression and diarrhea) (another example of pharmacogenetics)
  • A reduced dose is given to these individuals
  • Diarrhea occurs when SN-38G is de-glucuronidated back to SN-38 in the gut by gut bacteria
  • Antibiotics can be given to kill the gut bacteria and prevent diarrhea
  • These agents are used to treat solid tumors
• Epipodophyllotoxins (e.g. etoposide):
  
  • Etoposide (VP-16) is a semisynthetic analog of a natural plant product that inhibits topoisomerase-II, leading to DNA strand breaks
  • A rare but serious late toxicity is secondary leukemia
  • These myeloid leukemias generally occur with a latency of about 30 months and contain rearrangements of a gene call MLL (mixed lineage leukemia) at 11q23.
• Vinca alkaloids (e.g. vincristine):
  
  • Vincristine binds the tubulin protein and inhibits mitotic spindle formation
  • The dose limiting toxicity is peripheral neuropathy
  • It is used to treat leukemia/lymphoma and solid tumors

Question 14

What are miscellaneous agents used in chemotherapy and their pharmacologies?

Answer 14

• Examples of miscellaneous anticancer agents include asparaginase and retinoids
  
  • Asparaginase is an enzyme produced by bacteria (usually E. coli) that depletes the amino acid asparagine by converting it to aspartic acid and ammonia and therefore disrupts protein synthesis
    
    • It is used in induction therapy for acute lymphocytic leukemia
• Retinoids are related to vitamin A and function as differentiating agents
  
  • All-trans retinoic acid is used during induction therapy for promyelocytic leukemia and the isomer 13-cis retinoic acid is used to treatment neuroblastoma in the setting of minimal residual disease

Question 15

What are targeted therapies for chemotherapy and their pharmacologies?

Answer 15

• Two of the most commonly used classes of targeted agents include protein kinase inhibitors and monoclonal antibodies
  
  • Protein kinase inhibitors (e.g. imatinib, dasatinib):
    
    • Protein kinases are enzymes that transfer the terminal phosphate of ATP to tyrosine, serine and threonine residues
    • Phosphorylation leads to activation of signal transduction pathways that regulate a variety of cellular process, including growth, differentiation, adhesion, metabolism and apoptosis
    • Cancer cells sometimes show constitutive activation of kinases due to mutation, overexpression or translocations
    • Small molecule inhibitors selectively inhibit these aberrant kinases
    • Imatinib and dasatinib target the constitutively activated Bcr-Abl kinase as well as other kinases and are used in the therapy of CML
• Monoclonal antibodies (e.g. rituximab):
  
  • Monoclonal antibodies are antibodies that are directed against cell surface proteins
  • Rituxumab is a widely used monoclonal antibody that is directed against CD20, which is expressed on the surface of B-cells and is used to treat B-cell lymphomas
• Targeted agents are generally used together with cytotoxic anticancer agents
  
  • Roles for many targeted agents are still under investigation