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Cancer Chemotherapy
Işıl Özakca Gündüz 2019-2020 Fall Semester
Types of cancer:
1. Carcinoma: A category of types of cancer that develop from epithelial cells. Adenocarcinoma (breast, colon, prostate) is a type of carcinoma.
2. Sarcoma: A cancer that arises from transformed cells of connective tissue (bone, cartilage, vascular) origin.
3. Leukemia: A group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells.
4. Lymphoma: A group of blood cancers that develop from lymphocytes (T- and B-cells). The two main categories of lymphomas are Hodgkin’s and non-Hodgkin lymphomas.
5. Multiple myeloma: A cancer of plasma cells, a type of white blood cell which normally produces antibodies.
6. Melanoma: Atype of cancer that develops from the pigment-containing cells known as melanocytes.
7. Brain and spine tumors: They can be benign & malign.
Cancer treatment:
1. Surgery
2. Radiation therapy
3. Chemotherapy
4. Immunotherapy
5. Targeted therapy
6. Hormon therapy
7. Stem cell therapy
Chemotherapy vs Targeted therapy?
Abnormal activation of growth factor receptors, Dysregulations in intracellular signaling pathways, Problems with DNA repair and apoptosis.
Monoclonal antibodies
They kill the tumor cells by blocking the function of surface receptors.
Generally they are specific for a receptor subtype.
Their t1/2 values are extremely long, so they can be applied intervally.
Abnormal activation of growth factor receptors, Dysregulations in intracellular signaling pathways, Problems with DNA repair and apoptosis.
Small molecules
They act on tumor cells through inhibition of intracellular enzymatic functions by entering into the cell.
Generally they target more than one enzimatic region.
Their t1/2 values are between 12 and 24 hours and they should be taken orally everyday.
Monoclonal antibodies which act on epidermal growth factor
receptors (EGFR) are generally effective on head, neck and
colon cancers.
Small molecules such as erlotinib act on tyrosine kinase
activity of EGFR. (non-small cell lung cancer)
Imanitib, Dasatinib, Nilotinib: Inhibitors of BCR-ABL kinase.
FDA approved for the treatment of chronic myeloid leukemia and GI stromal tumors.
BCR-ABL tyrosine kinase mutation (Philadelphia chromosome).
They are effective all cancer types in which this mutation has been seen.
Philadelphia
chromosome:
İmatinib has high absorbtion rates when applied orally.
Its bioavailability reduces in neutral gastric pH (antacid and H2 blockers!) but food intake did not affect the bioavailability.
Plasma peak values can be seen in 2-4 hours. 400-600mg/day.
Metabolized by CYP3A4. Ketoconazole, rifampicin, simvastatin!!!
Adverse effects are GI problems, periferal edema, myelosuppression and hepatotoxicity.
Dasatinib, very similar to imatinib (bioavailability, interactions, metabolism, advers effects).
Recommended dose is 140mg/day (70mgX2).
Nilotinib has an oral bioavailalibity around 30%. Recommended dose is 800mg/day (400mgX2).
t1/2 is around 17 hours. Reaches the plasma peak values at the 8th day.
Similar to the imatinib and dasatinib in terms of metabolism, drug interactions and adverse effects.
Erlotinib: EGFR tyrosine kinase inhibitor.
FDA aproved in the treatments of advanced primer or metastatic non-small cell lung cancer (150mg/day) and pancreas cancer (100mg/day, +gemcitabine).
Adverse effects include;
1. Diarrhea, acne-like skin rashes, anoreksia, fatigue,
2. Renal failure, thrombosis, hemolitic anemia, hand and foot syndrome.
Bioavailability reduce with food intake (1h before/2h after).
Using with PPIs reduce the bioavailability to 50%.
Metabolized by CYP3A4!! Smoking!
Warfarin-INR control is required.
Sorafenib:
FDA approved for the treatment of advanced renal cell cancer (RCC), advanced hepatocellular cancer (HCC) and repeated locally or metastatic, progressive, differentiated thyroid carcinoma (DTC).
Metabolized by CYP3A4: Warfarin!!
Attention to the usage ofgrapefruit juice and St John’s wort.
Frequently seen adverse effects include hypertension, bleeding disorders and fatigue.
In 30-50% of the patients skin rashes and hand and foot reactions can be seen.
Sunitinib:
Treatment of the advanced renal cell cancer and GI stromal tumors. It can be used especially in conditions with resistance to imanitib.
Metabolized by CYP3A4: Warfarin!!
Attention to the usage ofgrapefruit juice and St John’s wort.
Frequently seen adverse effects include hypertension, bleeding disorders and fatigue.
Also cardiac dysfunction can be seen.
The expression of EGFR is increased in colorectal cancer, head and neck canceri NSCLC and pancreas
cancer.
The activation of EGFR can lead to cell growth, proliferation, invasion, metastas and angiogenesis.
On the other hand, the EGFR signaling pathway inhibit the cytotoxic activity of several cancer therapy (pharmacologic and radiotherapy) and
support the development of drug resistance.
Chimeric (human&mouse) monoclonal antibody. G1 isotype.
Target is the extracellular domain of EGFR.
Compared with erlotinib, even they have similar targets and similar adverse effect profile, their antitumor activity are different.
Therapeutic usage:
• Treatment of head and neck cancers combined with radiotherapy,
• Treatment of EGFR-positive metastatic colorectal cancers as monotherapy or combined with
irinotecan.
Adverse effects: Acne-like skin rashes, pruritus, hypomagnesemia, infusion-related hypersensitivite reactions.
Cetuximab:
Human monoclonal antibody. G2 isotype.
Target is extracellular domain of EGFR.
It is used in the treatment of metastatic colorectal cancers as monotherapy or combined with other agents.
Adverse effects: Acne-like skin rashes, pruritus, hypomagnesemia, infusion-related hypersensitivite reactions.
Panitumumab:
Humanized monoclonal antibody.
Target is extracellular domain of HER2/neu.
In the treatment of HER2/neu-overexpressed metastatic breast cancer after the chemotherapy completed as monotherapy or combined with paclitaxel.
Trastuzumab:
Chimeric monoclonal antibody.
Target is the CD20 antigen located on the surface of B- lymphocytes.
CD20 take place in the beginning of cell cycle and differentiation. In Non-Hodgkin lymphoma it is only expressed in B-cells and not found in other cells.
Therapeutic usage:
• Lymphoma
• Chronic lymphocytic leukemia Very slow infusion rate!!
Hypotension, bronchospasm, angioedema can be seen.
After first dose, fever can be seen. Premedication should be applied.
In first 24-hour after first infusion tumor lysis syndrome can be observed: Hyperkalemia, hypocalsemia,
hyperurisemia and acute renal failure.
Rituximab:
Recombinant humanized monoclonal antibody. Target is all forms of VEGFA.
It can stop renal cell cancer when used alone. With cytotoxic chemotheraupeutics, colorectal, lung and breast cancer can be treated effectively.
Adverse effects: Vascular defects and bleeding risk. Delay in wound healing. Hypertension and proteinürea. Increase in arterial trombotic events.
Bevacizumab:
Stage I-II, number of lymph nodes 1-3:
6 cycle cyclophosphamide-methotrexate-fluorouracil (CMF protocole), 6 cycle fluorouracil-epirubicin-cyclophosphamide (FAC protocole),
4 cycle doxorubicin-cyclophosphamide+6 cycle fluorouracil-epirubicin-cyclophosphamide (FEC protocole) Tamoxifen: in postmenopousal women. Monotherapy or in addition to cytotoxic chemotherapy.
5 years of continous treatment after the surgery.
At the end of 5-years, an additional 2.5 years of treatment certainly with an aromatase inhibitor (anastrozole).
Current available protocol: Tamoxifen (2-3 years)+aromatase inhibitor (totally 5 years) Stage III-IV:
Chemotherapyi+hormonal therapy.
Aromatase inhibitors are FDA-approved as the first-line therapy in hormon receptor-positive advanced breast cancer cases.
If hormonal therapy works, in addition to cytotoxic treatment trastuzumab should be in the protocol.
Antracyclins (doxorubicin, epirubisin), taxans (paclitaxel, dosetaxel), microtubule inhibitors, cyclophophamide, methotrexate, cisplatine.
At the end of 10 months partial remission, at the end of 15 months complete remission can be reached.
Breast cancer:
Tamoxifen: Selective estrogen receptor modulator (SERM). Works as an estrogen receptor antagonist with estrogenic activity. Has indication for pre- and postmenopausal women. Endometrial cancer, risk of
thromboembolic complications, hypercalcemia, bone pain.
Can be used for prophylaxis in the women with high risk.
Raloxifen: SERM. Has indication at the treatment of invasive breast cancer seen in postmenopausal women and at the treatment of postmenopausal osteoporosis. Arthralgia, myalgia.
Fulvestrant: Estrogen antagonist. Applied i.m. in the treatment of hormone-positive metastatic breast cancer. Has indication in the patients with tamoxifen-resistant breast cancer.
Aromatase inhibitors: Aromatase is responsible from the synthesis of estrogen especially in liver, adipose tissue, skin and breast tissue.
Peripheral aromatization is important especially in postmenapausal women, so aromatase inhibitors are more effective in these cases.
Anastrozole and letrozole: They do not induce any predisposition to endometrial cancer. First-line drugs in the treatment of
postmenapausal women. Totally block the estrojen synthesis.
Activation when orally taken. Metabolized by liver.
Exemestane: Irreversible aromatase inhibitor. Approved for the
treatment of advanced breast cancer in postmenapausal women. Dose adjustment should be done in patients with renal failure. Nausea,
fatigue, hot flush, alopecia, dermatitis can be seen.
Prostate cancer:
Second type of cancer giving response to hormonal manipulations.
Therapeutic approach for the metastatic prostate cancer is prevention of testosterone synthesis by surgical or chemical ways.
Previously bilateral orchiectomy or estrogen treatment were preferred as a treatment option, but today luteinizing hormone-released hormone/gonadotropin-releasing hormone (LHRH/GnRH) analogs/+ antiandrogens are used.
LHRH/GnRH analogs:
Leuprolide, goserelin: Mediate desensitizasyon by stimulating GnRH in
hypothalamus and inhibit the release of FSH and LH. They reduce the synthesis of both estrogen and androgen.
Effective as orchiectomy in the treatment of prostate cancer treatment. Also can be used in advanced breast cancer treatment in premenapausal women.
Leuprolide: SR, sc enjection ve im injection.
Goserelin: only im injection.
Impotency, hot flush and exacerbation of tumor can be seen as adverse effects. But the incidence of these effects are rare compared to estrogen treatment.
Antiandrogens:
Flutamide, bicalutamide, nilutamide: Synthetic antiandrogens used in the treatment of prostate cancer. They compete with androgen and prevent the translocation to the nucleus.
They remove the inhibitor effect of testosterone on gonadotropine secretion and lead to increase the serum LH and testosterone levels. Because of their stimulator effect on LH and testosteron, antiandrogens should be applied combined with leuprolide/goserelin.
Taken by orally, excreted by kidneys.
Gynecomastia and GI disturbances are adverse effects. Also with flutamide hepatic insufficiency and with nilutamide ocular problems can be seen.
Abiraterone, Enzalutamide:
Orally used in the treatment of metastatic castration-resistant prostate cancer.
Abiraterone is generally applied with prednisolone to suppress the testosterone synthesis by inhibiting CYP17 enzyme.
Hepatotoxicity, hypertension, hypokalemia, fluid retantion, artralgia, myalgia, hot flush and diarrhea can be seen.
Enzalutamide is indicated in metastatic prostate cancer patients who was taken docetaxel previously. Inhibit the coupling of androgen to its own receptor and nuclear translocation. Fatigue, back aches and fluid retention. Drug interactions!! CYP3A4, 2C9, 2C19!!
>100 type has been identified 30-40 anogenital
15-20 oncogenic: HPV 16 and HPV 18 (Cervical cancer) Nononcogenic types: HPV 6 and HPV 11 (Wart)
Cancer types caused by HPV:
HPV types which are classified as “high risk” can induce cancer.
• Cervical cancer: Especially HPV16 and 18 are responsible from the 70% of all cases.
• Anal cancer: Especially HPV16. 95% of all cases are HPV-originated.
• Oropharynx cancers (pharinx, palate, base of the tongue and tonsils): 70% of the cases are HPV-related. According to the records in USA, more than half of the diagnosed cases are associated with HPV16.
• Rare cancers: 65% of vaginal cancers, 50% of vulvar cancers and 35% of penil cancers are associated with HPV (esp. HPV16).
High risk HPV types are responsible from the 5% of the whole cancer cases seen in the world.
