Cancer and Chemotherapy Overview Part 1

Benign

- Surface epithelium: papilloma

- Glandular epithelium: adenoma

- Fibrous: Fibroma

- Bone: Osteoma

- Smooth muscle: Leiomyoma

- Striated muscle: Rhabdomyoma

- Fat: Lipoma

tissue of origin + "-oma;" slow growing, non-invasive, non-cancerous

Malignant

rapid, uncontrolled growth, invasive, fatal without treatment

Carcinoma (surface epithelium)

- Glandular: adenocarcinoma

Malignant tumor of epithelial tissue

Sarcoma

- Fibrous: Fibrosarcoma

- Bone: Osteosarcoma

- Smooth muscle: Leiomyosarcoma

- Striated muscle: Rhabdomyosarcoma

- Fat: Liposarcoma

Malignant tumor of connective tissue

In situ

Abnormal cells are present but have not invaded tissue yet- not normally considered cancerous but may become cancerous

Lesion

An area of abnormal tissue; typically, an area of concern that needs to be biopsied

Localized

Cancer is confined to the primary site/tissue. No evidence of spread to other regions

Metastasis

- aka distant

Spreading of cancer to a different part of the body from the primary (starting) tumor location

Regional

Cancer has spread to nearby lymph nodes surrounding tissues near the site of the primary tumor

Neoadjuvant

Treatment given before the primary therapy (usually surgery) as a first step to shrink a tumor to make the surgery more effective

Adjuvant

Treatment given after the primary therapy (usually surgery) or concurrent with other therapy (i.e. radiation or surgery) to eradicate residual disease and decrease recurrence

Biopsy

Excision of tissue for microscopic examination to determine if it is cancerous; used to make definitive diagnosis

Induction

Systemic therapy administered to eradicate cancer cells to individual complete remission (CR)

Remission

Disappearance of disease

Consolidation

Therapy used after induction therapy once CR is achieved to "clean up" and prevent recurrence

Maintenance therapy

Administered after consolidation therapy to prevent recurrence

Recurrence

Cancer has returned after a period during which it could not be detected

Curative

Intent is to achieve disease resolution, complete remission, and prevent cancer recurrence

Palliative

Intent to relieve symptoms of cancer and improve quality of life

- can also be used to reduce or control the side effects of cancer treatment

- care includes management of psychological, social, and/or spiritual problems

Disease control

Intent to stop or slow the progression of disease and reduce disease symptoms as long as possible

1. Workup: physical exam, biopsy, imaging tests, lab tests, tumor markers

2. Staging: may dictate prognosis and treatment selection [TNM]

- Tumor: extent (size) of primary tumor

- Node: number of nearby lymph nodes near the primary tumor that also have cancer

- Metastasis: has the cancer spread to other areas of the body

3. Tumor Markers

- May be detected in the serum, plasma, or other bodily fluid that indicates the presence of cancer cells

- Allows cancer detection without directly accessing the tumor or examining the tumor cells

Cancer diagnosis

0: Fully active, able to carry on all pre-disease performance without restriction

1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work

2: Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours

3: Capable of only limited self-care; confined to bed or chair more than 50% of waking hours

4: Completely disabled; cannot carry on any self-care; totally confined to bed or chair

5: Dead

Assessment of Performance Status (PS): Eastern Cooperative Oncology Group (ECOG)

PRONTO Method

Person: age, performance status, comorbidities, treatment goals

Regimen: medication schedule

Organ function: renal and hepatic function

Numbers: labs

Toxicities: expected SEs and management

Order Entry

Pharmacist's role in the safety and efficacy of antineoplastics

1. Loss of suppression: patient may have tumor suppressor genes that make them susceptible to cancer

- loss of programmed cell death, loss of negative growth signals

- TP53

- BRCA1, BRCA2

2. Cell proliferation: exposure to carcinogens leads to active oncogenes that increase positive growth factor signals

- EFGR, HER-2, BRAF

Describe the two-hit theory of cancer causation

Asparaginase

Interferons

Steroid hormones

Which medications affect the G1 phase of the cell cycle?

Antimetabolites: Folate antagonists, Purine analogs

Topoisomerase I & II Inhibitors: Anthracyclines

Which medications affect the S phase of the cell cycle?

Topoisomerase II Inhibitors

Which medications affect the G2 phase of the cell cycle?

Antimicrotubule Agents: Taxanes, Vinca alkaloids

Which medications affect the M phase of the cell cycle?

Antitumor Antibiotics: Bleomycin, Mitomycin

Which medications affect multiple phases of the cell cycle?

Alkylating Agents: Nitrogen mustards, Nitrosureas, Platinum analogs

Which medications work indepedently from the cell cycle?

• Myelosuppression

• Hepatotoxicity

• Nephrotoxicity

• Teratogenicity

• Cardiotoxicity

• Pulmonary toxicity

Toxicities requiring dose adjustment

• Mucositis

• Diarrhea

• Constipation

• Xerostomia: typically due to radiation

• Nausea and vomiting

Toxicities requiring symptomatic management

Grade 1: Asymptomatic or mild

Grade 2: Minimal, local, or noninvasive intervention indicated

Grade 3: Severe or medically significant, but not life-threatening

Grade 4: Life-threatening, urgent intervention indicated

Grade 5: Death related to AE

Common Terminology Criteria for Adverse Events (CTCAE) Grading Scale

Prevent cell replication by damaging DNA

- not cell-cycle specific

Alkylating agents MOA

• Myelosuppression

• Nausea/Vomiting

• Gonadal toxicity

• Secondary malignancy risk (leukemia) due to damage to bone marrow cells

- risk is higher 5 -10 years after treatment

Classwide toxicities of the alkylating agents

Cyclophosphamide

Ifosfamide

Melphalan

Bendamustine

Mechlorethamine

Which alkylating agents are nitrogen mustards?

Carmustine (BCNU)

Lomustine (CCNU)

Which alkylating agents are nitrosureas?

Procarbazine

Dacarbazine

Temozolomide

Which alkylating agents are non-classical?

Busulfan, Thiotepa

Which alkylating agents are classified as "other"?

1. Hemorrhagic cystitis (high doses)

- use MESNA at high doses

2. Cardiotoxicity

3. Immunosuppression

4. SIADH

Key toxicities of Cyclophosphamide [alkylating agent; nitrogen mustard]

1. Available PO and IV

2. Use with MESNA at high doses to protect from hemorrhagic cystitis

3. Delayed n/v at high doses

4. Administer with adequate hydration

Pearls of Cyclophosphamide [alkylating agent; nitrogen mustard]

1. Hemorrhagic cystitis

- use with MESNA at most doses

2. Neurotoxicity, Encephalopathy

Key toxicities of Ifosfamide [alkylating agent; nitrogen mustard]

1. Neurotoxicity

2. Pulmonary toxicity (delayed effect)

3. Facial flushing

4. Pain and burning at the injection site

5. N/V

6. Myelosuppression

Key toxicities of Carmustine [alkylating agent; nitrosurea]

1. Myelosuppression

2. N/V

3. Delayed effects: pulmonary toxicity and nephrotoxicity

Key toxicities of Lomustine [alkylating agent; nitrosurea]

Platinum structure causes bifunctional cross-linking

MOA of the platinum analogs (alkylating agents)

- Cisplatin, Carboplatin, Oxaliplatin

- Nephrotoxicity

- Ototoxicity

- Peripheral neuropathy

- Myelosuppression

Classwide SEs of the platinum analogs (alkylating agents)

- Cisplatin, Carboplatin, Oxaliplatin

1. Nephrotoxicity

- Prevention with Amifostine

2. Ototoxicity

3. High emetogenicity (N/V)

4. Electrolyte depletion: K, Mg, Na

Key toxicities with Cisplatin [alkylating agent; platinum analog]

1. Prevention of Nephrotoxicity with Amifostine

2. BSA dosing

3. Limit dose to ≤100 mg/m2 per cycle

4. Provide adequate hydration

Pearls of Cisplatin [alkylating agent; platinum analog]

Myelosuppression

- Other toxicities: neuropathy, acute and delayed N/V, nephrotoxicity

Carboplatin is generally less toxic than Cisplatin, except for which toxicity?

Calvert

Carboplatin [alkylating agent; platinum analog] is dosed using the ____ formula to account for renal function

Dose (mg) = AUC * (CrCl or GFR + 25 ml/min)

- use Cockcroft Gault equation for CrCl

- use ADJUSTED BW for CrCl when BMI ≥25

- Minimum SCr = 0.7

- Minimum GFR/CrCl: 125 ml/min

Calvert formula for Carboplatin dosing

1. Pulmonary toxicity

2. Sinusoidal obstructive syndrome (SOS)

3. Hyperpigmentation

Key toxicities of Busulfan [alkylating agent]

1. Available PO or IV

2. PK-dosing to minimize toxicity

Pearls for Busulfan [alkylating agent]

Interfere with DNA and RNA by substituting for the natural building blocks of RNA and DNA; causes the inability of DNA to make copies, and the cell cannot reproduce

- Cell cycle specific: S-phase

- Commonly used to treat: leukemias, breast and ovarian cancers, the intestinal tract, and others

MOA of antimetabolites

Myelosuppression

Mucositis

Diarrhea

Classwide SEs of the antimetabolites

1. Myelosuppression

2. Hepatotoxicity

Key toxicities of Mercaptopurine (6MP) [antimetabolite; purine analog]

1. PO; can be taken with or without food

2. Pharmacogenomic considerations

3. DDI with Allopurinol: Allopurinol increases serum concentrations of 6MP, which can lead to life-threatening bone marrow suppression

Pearls of Mercaptopurine (6MP) [antimetabolite; purine analog]

1. Myelosuppression

2. Immunosuppression

3. Neurotoxicity

- irreversible at doses >40 mg/m2/day x 5 days

Toxicities of Fludarabine [antimetabolite; purine analog]

1. Irreversible neurotoxic syndrome at doses >40 mg/m2/day x 5 days

2. Requires renal dose adjustments

Pearls of Fludarabine [antimetabolite; purine analog]

1. Mucositis

2. Myelosuppression

3. Chemical conjunctivitis

- prevent using steroid eye drops

4. Cerebellar toxicity

5. Fever, rash

Toxicities of Cytarabine (AraC) [antimetabolite; pyrimidine analog]

1. Available IV, IT, SC

2. May use steroid eye drops to prevent conjunctivitis

Pearls of Cytarabine (AraC) [antimetabolite; pyrimidine analog]

Radition sensitizer

- makes cancer cells more sensitive to radiation

- more effective but higher risk of toxicity

Gemcitabine [antimetabolite; pyrimidine analog] is a ____

1. Myelosuppression

2. Flu-like symptoms

3. Thrombotic microangiopathy

4. Pulmonary toxicity

Toxicities of Gemcitabine [antimetabolite; pyrimidine analog]

1. Hand-foot syndrome

2. Myelosuppression

3. Diarrhea

4. Coronary vasospasm (presents as chest pain)

Toxicities of Fluorouracil (5-FU) and Capecitabine [antimetabolite; pyrimidine analog]

myelosuppression and diarrhea

Which toxicities are seen with bolus dosing of 5-FU?

Leucovorin

_____ enhances the response of 5-FU [antimetabolite; pyrimidine analog]

DPYD testing

_____ testing is required when using Fluorouracil (5-FU) and Capecitabine [antimetabolite; pyrimidine analog]

Capecitabine

Oral 5-FU prodrug that's taken within 30 min after a meal

1. Mucositis

2. Myelosuppression

3. Nephrotoxicity

4. Hepatotoxicity

5. Neurotoxicity

6. Chemical arachnoiditis: chronic inflammatory condition of the arachnoid mater (a membrane surrounding the spinal cord)

Toxicities of Methotrexate (MTX) [antimetabolite; antifolate]

1. Routes: IV, IT, PO

2. Leucovorin can reduce toxicity (rescue)

3. Glucarpidase for enzymatic reversal: used for rapid reversal and toxicity

Pearls of MTX [antimetabolite; antifolate]

1. Myelosuppression

2. Hand-foot syndrome

Toxicities of Pemetrexed [antimetabolite; antifolate]

1. Folic acid and B12 are given to reduce toxicity

2. Dexamethasone x 3 days can minimize cutaneous reactions

Pearls of Pemetrexed [antimetabolite; antifolate]

1. Hydration

2. Urine alkalization (sodium bicarbonate): target urine pH >7

3. Leucovorin rescue

4. MTX level monitoring

Concurrent interventions for high-dose MTX [antimetabolite; antifolate]

• Penicillins

• Sulfamethoxazole/trimethoprim

• NSAIDs

• PPIs

• Ciprofloxacin

DDIs with MTX to avoid

Disrupt microtubule function

- prevents cell division

- M-phase specific

MOA of antimitotics (vinca alkaloids, taxanes)

intrathecally

Vincristine and Vinblastine [antimitotic; vinca alkaloid] are fatal if given by which route?

2 mg

MAX dose of Vincristine [antimitotic; vinca alkaloid]

1. Peripheral neuropathy

2. Constipation: paralytic ileus

3. Jaw pain

4. SIADH

5. Vocal cord paresis

Toxicities of Vincristine [antimitotic; vinca alkaloid]

1. Fatal if given intrathecally

2. CYP3A4 substrate

3. Extravasation: use warm compress and hyaluronidase

4. Max dose: 2 mg

Pearls of Vincristine [antimitotic; vinca alkaloid]

warm compress and hyaluronidase

Management of extravasation with Vincristine and Vinblastine [antimitotic; vinca alkaloid]

1. Neutropenia

2. Peripheral neuropathy

3. Hypersensitivity reactions

- Premedicate with Dexamethasone + H1RA + H2RA

Toxicities of Paclitaxel [antimitotic; taxane]

Premedicate with Dexamethasone + H1RA + H2RA

Premedicate with _____ prior to admnistering Paclitaxel [antimitotic; taxane]

1. Fluid retention

- premedicate with a corticosteroid to prevent

2. Neutropenia

3. Peripheral neuropathy

Toxicities of Docetaxel [antimitotic; taxane]

Corticosteroid

Premedicate with ____ prior to administration of Docetaxel [antimitotic; taxane]

Induce DNA strand breaks to unwind double-helix structure and allow transcription/replication

- result in single and double strand breaks

MOA of Topoisomerase Inhibitors

- Topoisomerase I: irinotecan, topotecan, camptothecin

- Topoisomerase II: etoposide, doxorubicin, epirubicin

1. Diarrhea

2. Cholinergic syndrome

Toxicities of Irinotecan [topoisomerase I inhibitor]

Atropine 0.4 mg for early diarrhea (within 24h)

Loperamide 4 mg followed by 2 mg after each loose stool (or every 4 hours) for late diarrhea

Management of diarrhea with Irinotecan [topoisomerase I inhibitor]

UGT1A1

Which testing is done with Irinotecan [topoisomerase I inhibitor]?

Cephalosporins (such as cefixime or cefpodoxime)

_____ allow for higher doses of irinotecan by acting as an antibiotic prophylactic to reduce severe, delayed-onset diarrhea, which is the primary dose-limiting toxicity

1. Myelosuppression

2. Secondary AML

3. Hypotension if infused too quickly

4. Hypersensitivity reactions

Toxicities of Etoposide [topoisomerase II inhibitor]

1. Hypotension with faster infusion rates

2. IV to PO (1:2)

Pearls of Etoposide [topoisomerase II inhibitor]

Intercalation of the drug molecule between DNA base pairs by inhibition of topoisomerase II and by steric obstruction

MOA of Anthracyclines

1. Cardiotoxicity: especially at Doxorubicin equivalents >450 mg/m2)

- monitor LVEF

- Dexrazoxane to ameliorate

2. Extravasation

- use cold compress

- Dexrazoxane to ameliorate

3. N/V

4. Myelosuppression

Key toxicities of Anthracyclines

- Doxorubicin, Daunorubicin, Idarubicin, Epirubicin

450 mg/m2

What is the recommended lifetime exposure to Doxorubicin [anthracycline]?

Dexrazoxane

What can be given to ameliorate cardiotoxicity and extravasation with Doxorubicin?

≥300 mg/m2

When should Dexrazoxane be started for cardiotoxicity with Doxorubicin?

bodily fluids

- reddish discoloration

Anthracyclines can cause discoloration of ____

inhibits synthesis of DNA; binds to DNA leading to single- and double-strand breaks; inhibit RNA and protein synthesis to a lesser extent

MOA of antitumor antibiotics

1. Pulmonary toxicity

- Risk increases with higher cumulative doses, especially doses >400 units

2. Cutaneous effects

3. Fever within 48 hours of the dose

Toxicities of Bleomycin [antitumor antibiotic]

≥30

Single doses of Bleomycin [antitumor antibiotic] ≥____ units may lead to rapid pulmonary fibrosis