Uterine Cytotoxic Therapies

Episode Notes

1. Platinum-Agents

1. Mechanism: form adducts between DNA and their platinum atom; these covalent bonds between heavy metals and DNA disrupt the DNA double helix leading to strand breakage

2. Can cause an IgE-mediated hypersensitivity +/- anaphylactic reaction

1. pre-medicating with histamine receptor blockers and steroids can help mitigate this

3. Cisplatin

1. Used in combo w/ radiation or as single agent in second-line or subsequent therapy

2. Renally eliminated, undergoes little to no true metabolism

3. Dose depends on the route of administration, whether it is being used as a radiosensitizer, and whether it is being given as a monotherapy or combination therapy

4. Toxicities

1. Dose limiting: nephrotoxicity

2. Ototoxicity, neurotoxicity, autonomic dysfunction, nausea and vomiting

4. Carboplatin

1. Equal efficacy but less toxicity than cisplatin

2. Excretion highly dependent on GFR -> dosed by AUC

3. Remember paclitaxel must be given before carboplatin! Otherwise, significant myelosuppression can occur

4. Toxicities

1. Dose limiting: thrombocytopenia

2. Nephrotoxicity, nausea and vomiting, neurotoxicity (less than cisplatin)

3. Hypersensitivity reactions

2. Plant-Derived Agents

1. Paclitaxel

1. Derived from Western Yew Tree

2. Mechanism: binds to and stabilizes intracellular microtubules, inhibiting depolymerization

3. Low solubility and a large molecular weight; therefore, it requires a diluent to make it soluble, which is a combination of Cremophor EL and dehydrated alcohol

4. Toxicities

1. Dose limiting: Myelosuppression, particularly neutropenia

2. Alopecia

3. Peripheral neuropathy

4. Cardiovascular effects (bradycardia, Mobitz type II heart block, rarely Vtach or MI)

5. Arthralgias and myalgias

6. Hypersensitivity/anaphylactic reactions (actually a reaction to the diluent, Cremophor)

5. Abraxane

1. Albumin-bound paclitaxel

2. Does not require steroid premedication, so it can be a good option for patients with uncontrolled diabetes who cannot tolerate steroids

3. Very expensive

2. Doxetaxel

1. Semisynthetic analogue of paclitaxel

2. Mechanism: binds to and stabilizes intracellular microtubules, inhibiting depolymerization

3. Most commonly utilized when a patient has severe, pre-existing neuropathy limiting use of paclitaxel or when patients have severe anaphylactic reactions to paclitaxel

4. Toxcities

1. Much lower risk of peripheral neuropathy and much higher incidence of myelosuppression than paclitaxel

2. Cardiovascular effects of fluid retention

3. Serositis

3. Topotecan

1. Mechanism: inhibits topoisomerase I, thereby creating single stranded DNA breaks

2. Toxicities:

1. Dose limiting: myelosuppression (neutropenia)

2. Nausea and vomiting

3. Diarrhea

4. Mucositis

5. Alopecia

6. Rash

4. Vinca alkaloids (vincristine, vinblastin, vinorelbine)

1. Mechanism: inhibits microtubular polymerization thereby leading to mitotic arrest

2. Toxicities:

1. Similar to taxanes

5. Etoposide

1. More on this later

3. Antimetabolites

1. Mechanism: work by replacing normal substrates required to synthesize molecules necessary for metabolism, like DNA and RNA, leading to reduced cell proliferation and potential cell death

1. Thus, work best in cells/tumors that are rapidly proliferating

2. Gemcitabine

1. Mechanism: cytidine analog, but its effect is not limited to the S phase of the cell cycle, so it likely has other mechanisms by which it acts

2. Toxicities:

1. Myelosuppression

2. Thrombotic thrombocytopenic purpura (rare)

3. Radiation recall (rare):  an acute inflammatory reaction that occurs only in previously irradiated areas and is triggered by the administration of chemotherapeutic agents after radiation

4. Transaminitis, hematuria or proteinuria, pneumonitis, somnolence and headache

5. Patients not uncommonly experience flu-like symptoms with low-grade fevers 24 hours around infusion

4. Alkylating Agents

1. Mechanism: positively charged alkyl groups that bind to negatively charged sites on DNA.  They create DNA adducts that lead to single or double-stranded DNA breaks or cross links

1. can develop resistance to alkylating agents by overexpressing a heavy-metal chelator called metallothionein, which provides alternate targets for the alkylating agents, reducing efficacy.

2. Ifosfamide

1. Prodrug requires hepatic activation. 

2. Cleared renally, and patients with renal insufficiency are at risk for toxicity

3. Toxicities

1. Pathognomonic: hemorrhagic cystitis

1. Mesna and aggressive IV hydration should be given as a bladder protectant

2. Neurologic syndrome of somnolence, lethargy, ataxia, confusion, disorientation, dizziness, malaise, and even coma in severe cases

1. Due to metabolite, choracetaldehyde

2. Anecdote: methylene blue

3. Secondary hematologic malignancies

4. Myelosuppression

5. Nausea and vomiting

6. Alopecia

3. Trabectedin

1. Mechanism: incompletely understood; binds to the minor groove of DNA, bending the helix, which then alters transcription and DNA repair; also thought to alter the tumor microenvironment

2. Toxicities

1. Neutropenia, thrombocytopenia, nausea and vomiting, transaminitis, fatigue, and hypersensitivity reactions

2. Rhabdomyolysis (rare)

1. Check the creatinine phosphokinase (CPK) level with each cycle

3. Cardiac toxicity

1. Periodic echocardiograms recommended

5. Antitumor Antibiotics/Anthracyclines

1. Mechanism: work via DNA intercalation

1. Most are cell-cycle nonspecific

2. Doxorubicin

1. Mechanism: inhibition of topoisomerase II (thereby creating double-stranded DNA breaks), DNA intercalation, and formation of free radicals

2. Toxicities

1. Dose limiting: leukopenia

2. Cardiomyopathy

1. Thought to be due to the free radicals created by the compound, and the lack of catalase enzyme to neutralize them in cardiac muscle cells

2. Get an echo before therapy → at total lifetime dose of 300 mg/m2

3. Total lifetime doses of > 550 mg/m2 are associated with much higher rates of cardiomyopathy, and a lot of institutions have implemented a lifetime limit of doxorubicin to reduce the rates of cardiac disease, which is irreversible

3. Thrombocytopenia

4. Secondary hematologic malignancies

5. Vesicant injury

3. Pegylated liposomal doxorubicin

1. Toxicities

1. Dose limiting: Palmar-plantar erythrodysesthesia

2. Cardiotoxicity much less than doxorubicin

references

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