Downloaded 52 times
Uploaded byStuart Solomon Winkler
Introduction to Chemotherapy in a Gyn/Onc Context
This document provides an overview of chemotherapy principles and agents used in the treatment of gynecologic cancers, covering tumor cell growth mechanisms, pharmacokinetics, and the various toxicity profiles of chemotherapy drugs. It lists and details common regimens and chemotherapeutic agents, including their mechanisms of action, usage, and toxicity, while also offering insights and trivia for medical professionals. Overall, it serves as a comprehensive resource for understanding chemotherapy in a gynecological oncology context.
More Related Content
Similar to Introduction to Chemotherapy in a Gyn/Onc Context
Introduction to Chemotherapy in a Gyn/Onc Context
- 1. Chemotherapy in a GynOncology Context Stuart S. Winkler, MD Wake Forest Baptist Health
- 2. Objectives Review principlesof tumor cell growth and inhibition with chemotherapy Discuss the mechanism of action and toxicities of chemotherapy agents used to treat gynecologic cancers Discuss common chemotherapy regimens used in the treatment of gynecologic cancers and the evidence behind the regimens Review tidbits that might pop up on CREOGs Learn trivia for dinner parties (with other OB/GYNs)
- 3.
- 4. Principles of chemotherapy:the target Kill the neoplastic cells without killing the native cells Cells in normal tissues are either: Static Expanding Renewing Neoplastic cells exhibit a loss of cell control mechanisms Cell division is not more rapid Overgrowth is due to loss of cell-cycle regulation and failure of apoptosis
- 5.
- 6. Tumor cell growth Gompertzian growth: as tumor mass increases, the time required for tumor mass to double also increases Laird, A.K. Laird, Dynamics of tumour growth, Br. J. Cancer 18 (1964), pp. 490–502.
- 7. Tumor cell growth Palpable tumors are already “large” and correspond to the flat portion of this curve Tumors reach 1 cm after about 30 doublings (10^9) Doubling times for clinically detectable gynecologic cancers differ widely, from 1 month for some embryonal cancers to 6 months for adenocarcinomas Chemotherapy used in the adjuvant setting works on a lower volume of tumor cells on the left side of the curve.
- 8. Principles of chemotherapy: pharmacokinetics Most chemotherapy agents operate in a context of first- order kinetics The effect of chemotherapy is seen when the active drug is in contact with the neoplastic cell This is affected by Prodrug conversion (e.g. Ifosfamide) Solubility (binding) Dose (AUC) Tissue accessibility (delivery) Active transport vs simple diffusion Elimination mechanisms
- 9. Principles of chemotherapy:the bullet Most CT drugs have a very narrow therapeutic window (effective but with tolerable toxicities) Dosing is critical Weight-based: mg/kg Area under curve: the total drug exposure over time, expressed in mg/(mL x min), also called the definite integral Calvert formula: target AUC x (GFR + 25) Body surface area: m2 = 𝑤𝑒𝑖𝑔ℎ𝑡 × ℎ𝑒𝑖𝑔ℎ𝑡/60
- 10. Log kill hypothesisand chemotherapy schedules A constant proportion of cells are killed with each cycle of chemo, not a constant number Effective treatment requires cyclic administration and often multiple agents to: Maximize killing of tumor cells Vary toxicity profile Deter development of tumor resistance
- 11.
- 12.
- 13. Chemotherapy Agents • Antimetabolites •Alkylating agents • Antitumor antibiotics • Plant-derived agents • Hormonal agents • Monoclonal antibodies, targeted therapy
- 14. Chemotherapy Agents • Antimetabolites •Methotrexate • Gemcitabine • Fluorouracil • Pemetrexed
- 15. Methotrexate Mechanism: dihydrofolatereductase inhibition leading the thymidine depletion, inhibits synthesis of purines Usage: GTD Regimens: PO, IV, IM, IT; single agent for low risk GTD; given as part of EMA-CO for high risk GTD Toxicity: myelosuppression, nephrotoxicity, elevated liver enzymes, mucositis Fun fact: Sidney Farber
- 16. Gemcitabine (Gemzar) Mechanism:nucleoside analog; phosphorylated intracellularly to active metabolite which inhibits ribonucleotide reductase inhibit DNA synthesis; also incorporates into DNA resulting in strand breaks Usage: EOC, sarcoma; radiosensitization Regimens: 800-1000 mg/m2 weekly (3 of 4, or 2 of 3) Toxicity: myelosuppression (thrombocytopenia), nephrotoxicity (rarely hemolytic uremic syndrome); flu-like syndrome
- 17. Chemotherapy Agents • Antimetabolites •Alkylating agents • Antitumor antibiotics • Plant-derived agents • Hormonal agents • Monoclonal antibodies, targeted therapy
- 18. Chemotherapy Agents • Alkylatingagents • Cyclophosphamide • Ifosfamide • Cisplatin • Carboplatin • Oxaloplatin • Chlorambucil • Hexamethylmelamine • Melphalan
- 19. Cyclophosphamide Mechanism: pro-drugconverted to active 4-OH cyclophosphamide enters cell and intercalates DNA Usage: EOC, GTD, endometrial Regimens: IV; Mesna given during high-dose regimens Toxicity: pancytopenia (leukopenia), N/V, alopecia, hemorrhagic cystitis, SIADH Fun fact: mustard gas
- 20. Ifosfamide (IFEX) Mechanism:pro-drug converted to active drug in liver (saturable) Usage: cervix, EOC, endometrial sarcoma Regimens: IV; daily slow infusions for 3-5 days; Mesna given during high-dose Toxicity: pancytopenia, N/V, alopecia, hemorrhagic cystitis, CNS toxicity
- 21. Cisplatin Mechanism: covalentbonds formed between G-G in DNA and platinum atom distorting the DNA helix Usage: EOC, GC, GTD, endometrial, cervix, vulva Regimens: IV or IP, q3w; weekly for radiosensitization Toxicity : neuropathy, myelosuppression (anemia), N/V, nephrotoxicity Fun fact: none
- 22. Carboplatin Mechanism: similarto cisplatin Usage: EOC, GC, GTD, endometrial, cervix, vulva Regimens: IV; q3w, dosed as AUC Toxicity : thrombocytopenia, hypersensitivity Fun fact: first cisplatin analog to be approved
- 23. Platinum resistance Mostimportant compound in GYN cancers Platinum sensitive: > 6 months Platinum resistant: < 6 months Platinum refractory: progress on therapy Mechanisms CTR-1 transporter: regulates cisplatin influx Increased intracellular glutathione inhibits adducts Nucleoside excision repair
- 24. Chemotherapy Agents • Antimetabolites •Alkylating agents • Antitumor antibiotics • Plant-derived agents • Hormonal agents • Monoclonal antibodies, targeted therapy
- 25. Chemotherapy Agents • Antitumorantibiotics • Doxorubicin • Liposomal doxorubicin • Bleomycin • Dactinomycin • Mitomycin C
- 26. Doxorubicin (Adriamycin) Mechanism:inhibits topoisomerase-II; adriamycinone ring intercalates with DNA leading to multiple DNA double- strand breaks; quinone group leads to free radical formation Usage: endometrial, EOC, cervix, vulva Regimens: IV; bolus infusion every 3 weeks or weekly Toxicity: cardiotoxicity, myelosuppression (leukopenia, thrombocytopenia), alopecia, vesicant Fun fact: “red devil”
- 27. Vesicant injury Irritantvs. Vesicant In the event of extravasation: Stop drug Withdraw drug from line Elevate extremity Doxorubicin: topical dimethysulfoxide, cold compress Cisplatin: SC sodium thiosulfate, cold compress Taxol: SC hyaluronidase, cold compress Vincas, Etoposide: SC hyaluronidase, warm compress
- 28. Liposomal doxorubicin (Doxil) Mechanism: same as doxorubicin, but… Usage: EOC Regimens: IV; 40-50 mg/m2 monthly Toxicity: cardiotoxicity (less severe), myelosuppression (less severe), palmar-plantar erythrodysesthesia (more severe), acute infusion reaction
- 29. Bleomycin Mechanism: usescopper or iron as cofactor in creating superoxide free radicals leading to DNA damage Usage: germ cell Regimens: IV; dosage is expressed in units/m2, given weekly or twice weekly, intracavitary for effusions Toxicity: interstitial pneumonitis and pulmonary fibrosis, hyperpigmentation, fever, anaphylaxis
- 30. Actinomycin D Mechanism:phenoxazone ring intercalates at guanine residues which plug the minor groove on DNA Usage: GTD Regimens: IV; EMA-CO Toxicity: myelosuppression, alopecia, N/V
- 31. Chemotherapy Agents • Antimetabolites •Alkylating agents • Antitumor antibiotics • Plant-derived agents • Hormonal agents • Monoclonal antibodies, targeted therapy
- 32. Chemotherapy Agents • Plant-derivedagents • Vinca alkaloids • Etoposide • Topotecan • Paclitaxel • Docetaxel
- 33. Vincristine (Oncovin) and Vinblastine(Velban) Mechanism: binds to tubulin subunit leading to mitotic arrest by inhibition of the mitotic spindle Usage: germ cell tumors, GTD, EOC Regimens: IV; EMA-CO, Navelbine q1-2w Toxicity: myelosuppresssion (Vb), alopecia (Vc), neuropathy (Vc), constipation/ileus (Vc), vesicant Fun fact: derived from periwinkle
- 34. Etoposide (VP-16) Mechanism:inhibition of topoisomerase-2 activity Usage: GTD, EOC, GC, uterine sarcoma Regimens: IV, daily (germ cell) or PO (salvage EOC) Toxicity: Pancytopenia (leukopenia), N/V, alopecia, hypotension, vesicant, secondary leukemia Fun fact: derived from podophyllotoxin, produced by the mandrake or mayapple
- 36. Topotecan (Hycamtin) Mechanism:binds to topoisomerase I causing single strand DNA breaks Usage: EOC, cervical Regimens: IV or PO; daily x5 days q3w or weekly; ?IP Toxicity: myelosuppression (severe), alopecia Fun fact: Wani and Wall
- 37. Paclitaxel (Taxol) Mechanism:stabilizes microtubules Usage: EOC, endometrial Regimens: IV or IP; 175 mg/m2 every 3 weeks or 80 mg/m2 weekly (dose-dense) Toxicity: neurotoxicity (peripheral neuropathy), pancytopenia, alopecia, hypersensitivity reaction, bradycardia Fun fact: Pacific Yew
- 39. Taxol reaction Characterizedby hypotension, urticaria, bronchospasm, dyspnea, stridor Similar to type 1 hypersensitivity Severe enough to be dose-limiting and those with severe reactions should not be re-challenged Heavy premedication with H1 blockers, H2 blockers, and corticosteroids Treatment starts with: Stop infusion Give hydrocortisone 100 mg IV x1
- 40. Taxol reaction Furthertreatment based on presenting symptoms: Hives/flushing: Benadryl or Cimetidine Wheezing: Albuterol nebulizer Chest tightness: Hydrocortisone Stridor: 100% oxygen via face mask Bronchospasm: Epinephrine (0.3 mg SC q10m) Hypotension: Fluid, hydrocortisone, Benadryl, epinephrine
- 41. Docetaxel (Taxotere) Mechanism:similar to Taxol Usage: EOC Regimens: IV, q3w Toxicity: less neurotoxicity, more neutropenia Fun Fact: European yew
- 42. Chemotherapy Agents • Antimetabolites •Alkylating agents • Antitumor antibiotics • Plant-derived agents • Hormonal agents • Monoclonal antibodies, targeted therapy
- 43. Chemotherapy Agents • Hormonalagents • Megesterol acetate • Tamoxifen • Levonorgestrel IUD
- 44. Megesterol acetate (Megace) Mechanism: unknown, but may be due to down-regulation of estrogen receptors in tumor Usage: endometrial, ESS Regimens: 80 mg PO BID Toxicity: alopecia, Cushinoid faces, thromboembolism
- 45. Tamoxifen Mechanism: reversiblybinds ER receptor thereby decreasing estrogen-mediated protein synthesis Usage: EOC, ovarian stromal tumor Regimens: 20 mg PO BID Toxicity: thrombocytopenia, hot flushes, thromboembolism, endometrial polyps and CA
- 46. Chemotherapy Agents • Antimetabolites •Alkylating agents • Antitumor antibiotics • Plant-derived agents • Hormonal agents • Monoclonal antibodies, targeted therapy
- 47. Chemotherapy Agents • Monoclonalantibodies, targeted therapy • Bevacizumab • Olaparib
- 48. Bevacizumab (Avastin) Mechanism:inhibits binding of VEGF-A to its receptors thereby inhibiting angiogenesis Usage: EOC, cervical Regimens: IV, 15 mg/m2 q3w with standard treatment, maintenance Toxicity: hypertension, mucocutaneous bleeding, bowel perforation
- 49. Olaparib (Lynparza) Mechanism:poly ADP-ribose polymerase (PARP) inhibition leads to impairment of DNA repair mechanisms through synthetic lethality Usage: recurrent EOC (BRCA+) Regimens: PO monotherapy Toxicity: thrombocytopenia, N/V
- 50.
- 51. Olaparib (Lynparza) Mechanism:poly ADP-ribose polymerase (PARP) inhibition leads to impairment of DNA repair mechanisms through synthetic lethality Usage: recurrent EOC (BRCA+) Regimens: PO monotherapy Toxicity: thrombocytopenia, N/V Fun fact: most recent drug to be FDA approved for ovarian cancer
- 52. Objectives Review principlesof tumor cell growth and inhibition with chemotherapy Discuss the mechanism of action and toxicities of chemotherapy agents used to treat gynecologic cancers Discuss common chemotherapy regimens used in the treatment of gynecologic cancers and the evidence behind the regimens Review tidbits that might pop up on CREOGs Learn trivia for dinner parties (with other OB/GYNs)
- 53.
Editor's Notes
- #5 Static cells are well differentiated and don’t actively proliferate in adults (striated muscle, nerves) Expanding cells don’t proliferate but can when stressed (liver) Renewing cells are in constant cell division (GI mucosa, bone marrow) To understand this is to understand toxicities
- #6 It all starts with the cell cycle This cartoon is for the dividing cell that is not in G0 G1 is variable. The is the cell-repair phase. S is DNA synthesis G2 is short So how to do tumor cells grow?
- #7 Tumor cells grow by what has been termed “Gompertzian growth” Benjamin Gompertz, a nineteenth-century actuary, who uses this curve to describe birth rates, but Laird in the 1960s applied this curve to tumor growth. Initially the tumor grows exponentially until crossing the inflection point at 2 whereupon its growth decelerates. As the tumor grows its core lacks oxygen and becomes necrotic. When the rate of growth equals the rate of death (necrosis) tumor size remains constant
- #8 1 cm is typically about 30 doublings- this was derived mostly from breast These are just ballpark numbers to give you a sense of how tumors grow
- #9 First order kinetics which basically means that the effect is proportional to the drug concentration Active drug in contact with cell: Seems simple, but the use of Topotecan was stalled by about 15 years because, while they knew it was an extremely effective drug, no one could figure out how to make it soluable Prodrugs Most drugs bind to albumin. Drugs such as cisplatin, Taxol and etoposide are >95% albumin bound. This can increase toxicity in patients with poor nutritional status. Volume of distribution affects dosing: can dose as AUC (time x concentration), BSA in m2, mg/kg or mg per mg (as in Mesna). Tissue accessibility is affected by delivery (IV, IP, oral) and blood supply (decreased with radiaition) Active transport (platinum drugs) whereas some reach the cell by simple diffusion (5-FU)
- #10 As a general rule, drug toxicity correlated with the peak plasma concentration while efficacy is correlated with AUC. AUC is calculated for each individual drug. At least 3 different ways to calculate BSA. First invented by DuBois and DuBois, a married couple who published their formula in 1916. The Mosterllar formula is a much simpler, though slightly less accurate formula.
- #11 Finally the log kill hypothesis The principle of multiagent therapy
- #12 Chemotherapy kills a constant fraction, but not a constant number of cells
- #15 Most exert their effect in S-phase
- #16 S-phase. In vitro, it synchronizes tumor cells in S phase in 2-3 days. Charing Cross regimen 50 mg/m2 on day 1,3,5,7 alternating Folinic acid (Leukovorin) Single agent (Northwestern regimen) 20 mg/m2 IM for 5 days, repeat every 7 days or EMA-CO: etoposide, MTX, dactinomycin, cyclophosphamide and vincristine (oncovin) Nephrotoxicitiy can be avoided by alkalinizing the urine to prevent precipitation of metabolites in renal tubules. Amethopterin- developed by Sidney Farber after observation that supplementation of folic acid seemed to stimulate cancer growth in ALL (1948) Pemetrexed (Alimta) has been studied in a phase II trial as a treatment for recurrent platinum resistant ovarian cancer
- #17 Prodrug that is phosphorylated Acts synergistically with Cisplatin, especially is cisplatin is given 24 hours prior to Gemzar Dose limiting FLS is reduced when drug is given over 30 minutes as opposed to longer infusion
- #19 Most exert their effect in S-phase, but not cell-cycle specific All alkylating agents contain large positively charged alkyl groups that bind to negatively charged sites on DNA, most commonly at the N-7 site on guanine. These adducts lead to single or double strand breaks and cross links and change the tertiary structure of DNA
- #20 Prodrug activated in liver by p450. Not cell-cycle specific Pancytopenia is primarily leukopenia with little effect on platelets Acrolein is a breakdown product and alkylates bladder mucosa, bound by the sulfhydryl group on Mesna 1943- German air raid in Italy deployed nitrogen mustard bomb. Medical exams done on survivors showed a marked lymphoid and myeloid suppression. This lead to the development of the first chemotherapy agent– mustine.
- #21 Prodrug activated in liver. Less than 5% is albumin-bound. The hepatic microsomal activation of ifosfamide is saturable. At higher dose, inactive drug is excreted in the urine. This is the rationale for multi-day dosing. Acrolein is a breakdown product, bound by Mesna CNS toxicity (encephalopathy) is probably due to chloroacetalacetitde and affects 10-15% of patients, risk is increase with underlying dementia or low serum albumin. Methyline blue may help bind this.
- #22 Diamineplatinum distorts the DNA helix by up to 40 degrees. Extensively protein bound in the plasma with a long half life of about 5 days. Radiosenitizer– inhibits DNA repair by nonhomologous end joining and other unknown mechanisms, disregulates S-phase checkpoints. IP dosing for optimally debulked ovarian cancer is usually employed using the GOG-172 protocol of day 1 IV Taxol 135 mg/m2, day 2 IP Cisplatin 100mg/m2 given with up to 2 L of NS at body temperature to the point of abdominal dyscomfort and day 8 IP Taxol 60 mg/m2. Neurotoxicity (espically peripheral neuropathy and ototoxicity), autonomic neuropathies and retinopathy. Neuropathy is dose limiting and is likely due to accumulation of inorganic platinum in the DRG. It can be irreversible. Can be synergistic with Taxol. Nausea/vomiting is severenephrotoxicity (cumulative), electrolyte abnormalities (especially low magnesium and potassium). Nephrotoxicity requires aggressive hydration which can predispose to pulmonary edema. Does not cause significant alopecia.
- #23 Not cell cycle specific. Interestingly, while cisplatin is >95% albumin bound, carboplatin is less than 5% albumin bound. Much more reliant on renal excretion, so dosed with Calvert formula which takes into account GFR. Has a huge volume of distribution and not albumin-bound, so penetrates pleural effusions Can be given quickly over 15-30 minutes Thrombocytopenia is much more severe with carbo as opposed to cisplatin and nadir is usually about 21 days out. Usually the dose limiting toxicity. N/V less severe. Alopecia is less severe. Neuropathy can be mitigated by vitamin B6 (less severe). Not excreted in the renal tubules like cisplatin, so nephrotoxicity is less severe. Hypersensitivity is cumulative and incidence is about 25% after 6 cycles., primarily itching and erythema and happens in the first 3 days after administration– something we might get phone calls about. Amifostine (Ethyol) can reduce thrombocytopenia, neutralizes toxic metabolites and scavenges free radicals, but also increases half-life. Also, combination Carbo/Taxol is associated with less thrombocytopenia than is seen with Carbo alone– this is explained by the sigmoid maximum effect model. Oxaliplatin: another cisplatin analog. Used for GI cancers and has some use in mucinous cancers of the ovary
- #24 Some ovarian CA cells rapidly downregulate CTR-1 Glutathione interferes with DNA/cisplatin adducts, increased in some ovarian cancer cells. These is cell-line evidence that addition of a synthetic amino acid called BSO can inhibit glutathione production leading to restoration of drug sensitivity Nucleoside excision repair is the primary mechanism for cells to remove DNA/platinum adducts, and increased transcription of a key gene called ERCC1 has been demonstrated in platinum resistance All of these mechanisms provide targets for drugs or modifications of platinum. Focus of a huge amount of research.
- #27 Anthracycline. Topoisomerase regulates DNA supercoiling. Frequency of double strand breaks is proportional to the efficacy of the drug Superoxide free radicals undergo a redox reaction the leads to formation of hydrogen peroxide. Catalase neutralizes hydrogen peroxide. Cardiac muscle has very low levels of catalase. Cardiotoxicity (cardiomyopathy leading to CHF) is due to cumulative dose, risk is 3% with dose of 450 mg/m2, up to 40% with 700 mg/m2. Pre-existing cardiac disease predisposes. Drug should be stopped if EF decreases by more than 10%. Dexrazoxane has been FDA approved for reducing doxorubicin induced cardiomyopathy in breast CA patients. Photosensitive, so often kept in brown wrapping or paper bags. Palmar/plantar erythema (less severe) Leukopenia is usually dose limiting toxicity with nadir at 10-14 days. An ancestor of doxorubicin was discovered by French researchers in Italy in the late 1950s. It was isolated from a strain of Streptomyces and was found to have antitumor activity in mice. It was named Daunirubicin after the Daunians, who were a pre-Roman tribe that occupied the area where it was discovered. The “rubicin” part of the name comes from it’s red color. Another Streptomyces isolate was discovered near the Adriatic Sea and was thus named Adriamycin.
- #28 Irritant- tenderness or pain along vein with local erythema that does not result in permanent tissue damage Vesicant- leads to extensive tissue damage with ulceration and necrosis. DMSO Cold compress inhibits cytotoxicity Warm compress increases systemic absorption
- #29 Prolonged half-life and less affinity for RES. The drug is surrounded by a lipid bilayer that prolongs half life and protects the drug from detection by macrophages (pegylated) Not a vesicant. Mild nausea/vomiting. Rare alopecia. Doxil was developed to treat Kaposi sarcoma, but in the early 2000s was investigated for use in EOC. Hand foot syndrome can be dose limiting. The polyethylene glycol coating (proprietary stealth microsomes) results in preferential concentration of Doxil in tissues with increased microvascular permeability such as tumors and the skin (it was developed to treat Kaposi’s sarcoma). Following administration of Doxil, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m2 dosing every 4 weeks, 50.6% of patients treated with Doxil developed hand-foot syndrome. Most regimens call for 40 mg/m2. Acute infusion reactions in fewer than 10%, usually with first course.
- #30 G2 specific Derived as a fermentation product of Steptomyces verticillus (discovered in 1966). Weekly for BEP Pulm fibrosis: risk is increased with lifetime exposure >400 units. Monitor with DLCO (carbon monoxide diffusion capacity), stop if decrease >15%. Exposure to high concentrations of oxygen increases pulmonary toxicity, fever Anaphylaxis reported in 1-8% of patients, but most common with lymphoma patients
- #31 Also a fermentation product of Streptomyces As part of EMACO, given every 14 days. Other regimens describe daily administration
- #33 Up to this point, the chemo groups have shared mechanisms. The plant-derived group is a more of a potpourri group which is appropriate given that they are plant derived.
- #34 Vinca alkaloids Anti Microtubule agents arrest cells in M-phase Navelbine is a synthetic vincristine. Even though it rhymes with Gemciobine, it’s not an antimetabolite Leukopenia is dose limiting for Vinblastine From the rosy periwinkle from Madagascar
- #35 G2 arrest Inhibits topoisomerase by stabilizing the topoisomerase-2/DNA complex, leading to inhibition of DNA supercoiling and predisposing to single and double strand breaks. Also binds to tubulin like the vinca alkyloids, but this mechanism is unclear Dosing is frequent to take advantage of cell-cycle dependent cytotoxicity Can cause hypotension if given quickly Can cause secondary leukemia if total dose exceeds 2 gm Some naturopaths encourage people to eat mayapples for their cancer fighting properties
- #36 States that Mayapple can be used to fight cancer, but should only be used by experienced herbalists
- #37 TOPO-1 is the unzipper that allows DNA replication Derived from the Chinese Camptotheca tree Myelosuppression is severe, particularly neutropenia (80% with grade 4 in initial trials) that is not alleviated by G-CSF. Weekly schedule has less myelosuppression IP administration is under investigation, Isolated by Manusukh Wani and Monroe Wall who did their work at the natural products lab at the Research Triangle Institute in North Carolina. Together the discovered and developed two major chemotherapy agents. Camptothecin was isolated from the Chinese camptotheca tree. It was found to have marked in vitro activity against a mouse model of leukemia. The problem was that it was insoluble. It took them 15 years to solve this problem and develop the drug. This was developed into Topotecan almost 40 years later (1990s).
- #38 Binds to a different site on microtubules than the vinca alkyloids. Abraxane (albumin bound taxol)- better toxicity profile Taxol should be given prior to Platinum or else the half life is increased in the plasma. Taxol can be given over 3 hours or 24 hrs. Dose dense is given over 1 hr. GOG 111 published in 1996 compared cyclophosphamide/cisplatin with taxol/cisplatin in patients with suboptimal TRS (stage 3 and 4) and showed improved PFS and OS. Peripheral neuropathy due to the inhibition of microtubules in neuronal exons, so first effects are seen in the longest axons which is why it starts in hands and feet. Pancytopenia is worse with longer infusions (24 hr) Neurotoxicity is worse with shorter infusions (3 hr) Alopecia is severe, including accessory body hair. Typically occurs 14-21 days after first dose Extract of bark of Pacific Yew tree. The name Taxol comes from the genus “Taxus” brevifolia and the –ol for alcohol Back to Wani and Wall, Interestingly, Camptothecin almost interfered with the discovery of Taxol (B-1645). Arthur Barclay has brought them as sample of bark to analyze. Wall (who was the lab director) wanted to abandon the Taxol project because, after months of work, they weren’t able to isolate the active compound. The yield on the bark was very low. In fact, it took about 60 lbs of bark to make 1 gram of Taxol. Wani worked on isolating the active compound on his own time unbeknownst to Wall. Unlike plantinum, the structure is extremely complex.
- #40 The other difficult thing about Taxol (besides being scarce) was that it was extremely insoluable Like type 1 hypersensitivity, but it is actually most common during the first exposure (hence why we have to be there). Taxol is a finicky drug and is hard to dissolve into solution. The vehicle is Cremphor EL which is a castor oil derivative. This vehicle has been showed to react with mast cells and cause direct histamine release, therefore, sensitization is not required like for classic type 1 hypersensitivity reactions which require IgE. These reactions are similar to severe radiocontrast allergies. Premedication has decreased the incidence of hypersensitivity reaction to 2% down from about 20% in the original phase 1 trials.
- #41 Like type 1 hypersensitivity, but it is actually most common during the first exposure (hence why we have to be there). Taxol is a finicky drug and is hard to dissolve into solution. The vehicle is Cremphor EL which is a castor oil derivative. This vehicle has been showed to react with mast cells and cause direct histamine release, therefore, sensitization is not required like for classic type 1 hypersensitivity reactions which require IgE. These reactions are similar to severe radiocontrast allergies. Premedication has decreased the incidence of hypersensitivity reaction to 2% down from about 20% in the original phase 1 trials. Epinephrine is given 0.3-0.5 mg sc every 10 minutes
- #42 Docetaxel is semisynthetic and derived from the European yew which is more renewable. Taxol shortage is a concern in the future because the Yew tree grows very slowly. In one study comparing carbo/taxol to carbo/taxotere, grade 2 or greater neurotoxicity was 30% in the taxol group vs 11% in the taxotere group In most studies, outcomes are the same
- #46 Like Megace, Tamoxifen is cytostatic (not cytocidal) and the bond with the ER receptor is reversible when the drug is stopped. This is why patients are typically on Tamoxifen for years.
- #49 2014 received FDA approval for metastatic cervical CA.
- #50 FDA approved in 2014. Indicated as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with ≥3 prior lines of chemotherapy BRCA 1 and 2 are tumor suppressor genes because they help regulate repair of double stranded DNA breaks by homologous recombination. Patients who are BRCA+ lack this repair mechanism and their cells are prone to mutation. Poly ADP-ribose polymerase is an essential component in the repair of single-strand breaks. If inhibited, the random single-strand breaks or “nicks” that usually occur spontaneously cannot be repaired. With DNA replication, these are to double-strand breaks. In BRCA+ cells, where double strand breaks cannot be repairs, the cell undergoes apoptosis. This concept is known as synthetic lethality. This is really cool because it uses the BRCA mutation against itself.
- #51 BRCA 1 and 2 are tumor suppressor genes because they help regulate repair of double stranded DNA breaks by homologous recombination. Patients who are BRCA+ lack this repair mechanism and their cells are prone to mutation. Poly ADP-ribose polymerase is an essential component in the repair of single-strand breaks. If inhibited, the random single-strand breaks or “nicks” that usually occur spontaneously cannot be repaired. With DNA replication, these are to double-strand breaks. In BRCA+ cells, where double strand breaks cannot be repairs, the cell undergoes apoptosis. This concept is known as synthetic lethality.
- #52 FDA approved in 2014. Indicated as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with ≥3 prior lines of chemotherapy This is really cool because it uses the BRCA mutation against itself.