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Chemotherapy Side Effects

Notes

Chemotherapy Side Effects

Sections




Overview

Overview

  • Here, we'll address chemotherapy side effects.
  • Start a table.
  • Indicate that we'll address high yield side effects and common clinical side effects.

High Yield Side Effects

Overview

  • Let's begin with high yield chemotherapy side effects.

Cisplatin (Oto- & Nephrotoxicity), Carboplatin (Myelosuppression)

  • Show that for cisplatin, nephrotoxicity and ototoxicity are its primary side effects of interest.
  • Whereas for carboplatin, myelosuppression is its primary side effect.

Chemo Figure

  • We can create a human figure as a helpful mnemonic to remember these effects.
  • Starting from the top and going down, let's first address cisplatin-induced ototoxicity and nephrotoxicity.
  • Draw Ci (cisplatin) for the ears (ototoxicity) and the kidneys (nephrotoxicity).

Ototoxicity

  • For ototoxicity, draw an inner ear.
    • Show the semicircular canals, which are fundamental balance and spatial orientation, and the cochlea, which is key for hearing.
    • Show the respective components of the vestibulocochlear nerve emanating from each of them.
  • Specify that the ototoxcity stems from injury to cochlear structures, most notably toxicity to the hair cells of the organ of Corti.
    • Indicate the outer hair cells and inner hair cells.
    • As a simple heuristic think of the outer hair cells as modulators of sound wave nerve impulses and the inner hair cells as sound wave detectors.
  • Also indicate that toxicity can occur to the spiral ganglia (especially via demyelination).
  • Consider that the otoxicity presents with hearing loss without prominent dizziness or vertigo, which highlights that the injury is to the auditory component of the inner ear, rather than the vestibulocochlear nerve, itself.
  • Note that the toxicity is typically for high frequency range sounds, affects both ears, and is generally irreversible.
  • To date, there are no clear-cut ways to prevent cisplatin-induced ototoxcity.

Nephrotoxicity

  • Next, let's address cisplatin-induced nephrotoxicity.
  • In a quarter to a third of patients, cisplatin causes acute kidney injury (AKI).
  • Indicate that the proximal tubule renal epithelial cells undergo apoptosis and as well as direct necrosis from cisplatin toxicity.
  • It has been shown to have active accumulation within the kidney and cause apoptotic-induced cell death (interaction with death receptors); tissue necrosis; and mitochondrial means; as well as the endoplasmic reticulum (ER) stress pathway.

Organic cation transporter 2 (OCT 2)

  • Organic cation transporter 2 (OCT 2) is a key transporter in renal uptake of cisplatin.
    • Cimetidine is a competitive inhibitor of OCT2 reduces cisplatin renal epithelial cell accumulation and toxicity without significant reduction in anti-tumor effects.
    • In keeping with this, OCT knockout mice have reduced ototoxicity, as well.
  • On, the contrary, carboplatin is a poor OCT2 substrate, thus it doesn't demonstrate renal epithelial accumulation or nephrotoxicity.
  • Oxaliplatin, on the other hand, does have an affinity for OCT2 but also has affinity for efflux transporters, so it doesn't accumulate (this is the presumed reason for its lack of nephrotoxicity).
    • However, OCT2-mediated uptake of oxaliplatin is a key cause of its potential to produce peripheral neuropathy via dorsal root ganglion toxicity. As we'll see later, vinca alkaloids and taxanes are also key causes of peripheral neuropathy.

Myelosuppression

  • On the contrary, show that a key side of effect carboplatin is myelosuppression.
  • Along a pair of long bones (the femurs), indicate Ca (carboplatin).
  • Draw a long bone and show that whereas healthy bone marrow is teeming with red blood cells, white blood cells, and platelets, in myelosuppression the empty marrow is constituted with, for the most part, fat cells and stroma.
    • Naturally, myelosuppression produces neutropenia, anemia, and thrombocytopenia.
    • To counteract this, patients receive granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), as well as RBC and platelet transfusions, and chemotherapy treatment delays are incorporated into their regimen.
  • Interestingly, pre-treatment with trilaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor provides myeloprotection by arresting hematopoeietic stem cells and progenitor cells in G1, which has been demonstrated to protect them from certain chemotherapy toxicities.
    • Don't let this fact confuse us about platinum agents: they are considered cell cycle nonspecific (act in any stage of the cell cycle).

Bleomycin (Pulmonary Fibrosis)

Overview

  • Now, let's address bleomycin-induced pulmonary fibrosis.
  • Draw a pair of B's to represent the lungs.
  • Draw an axial cross-section through the lungs in chest CT modality (include the heart, pulmonary bronchi and vasculature, and the spine).

Pulmonary Fibrosis

  • Let's focus on the very basics of some imaging hallmarks of pulmonary fibrosis:
    • First, just show some general irregular reticulation: a network of irregular lines of opacification, from fibroblast proliferation and dense collagen deposition.
    • Next, show honeycombing, which refers to clustered pockets of cystic dilated air-filled spaces.
    • Then, show ground glass opacity, a more diffuse opacity from patchy alveolar septal thickening.
  • It's helpful to consider that bleomycin has such a propensity to cause pulmonary fibrosis that it is used to create mouse models for the disease.
  • It occurs in ~ 5 to 15 percent of patients who receive bleomycin.

Pneumonia & Pulmonary Edema

  • For reference, also show pneumonia, a more opaque consolidation and pulmonary edema, which has greater opacity, as well, and is gravity dependent.
  • Note that bleomycin can cause other pulmonary manifestations and note that there are numerous other chemotherapies than can lead to pulmonary disease (especially pneumonia and pulmonary edema).

Mitomycin, Methotrexate, Bevacicumab

Additional notable pulmonary offenders are:

  • Mitomycin, another potential inducer of pulmonary fibrosis.
  • Methotrexate, which can lead to interstitial and alveolar infiltrates, as well as pleural effusions.
  • Bevacicumab, which, notably, can cause pulmonary hemorrhage, presenting with hemoptysis.

**Doxorubicin & Trastuzumab (Cardiotoxicity)

  • Next, let's address cardiotoxicity from the anthracyclines, namely doxorubicin (the red devil), as well as trastuzumab, a monoclonal antibody.
  • Draw a D for the heart (for doxorubicin) and a T within it (for trastuzumab)
  • Show that these two chemotherapies can lead to dilated cardiomyopathy.
  • It classically and commonly taught that doxorubicin produces irreversible (type I) cardiotoxicity and trastuzumab produces reversible (type II) cardiotoxicity, but on deeper inspection each can do the opposite: aspects of anthracycline toxicity is reversible and some of the cardiotoxicity from trastuzumab can be irreversible.
  • Note that doxorubicin is commonly referred to as the red devil due to its color and potential for cardiotoxicity.

Pathogenesis

  • The cardio-pathology from anthracyclines is multifactorial, it's helpful to consider that, in part, it stems from the same pathogenesis as with neoplastic cells: DNA damage and free radical-induced apoptosis. We address the mechanism of action of doxorubicin in detail, separately.
  • Trastuzumab cardiotoxicity likely involves antibody-mediated cytotoxicity or cell death directly related to its primary mechanism of action: the inhibition of HER2 signaling pathways.

Mitoxantrone (Blue-Discoloration)

  • While we are on the topic of anthracyclines, let's show that mitoxantrone, which is an anthracene (similar to an anthracycline), is less cardiotoxic but, notably, can cause blueish discoloration to the sclera, nails, and urine.
  • It's primary dose-limiting side effect, however, is myelosuppression.

**Cyclophosphamide (Hemorrhagic Cystitis)

Overview

  • Now, let's address cyclophosphamide-induced hemorrhagic cystitis (also include the related drug ifosfamide).
  • Draw a bladder as a Cy (cyclophosphamide).

Hemorrhagic Cystitis

  • Show that cyclophosphamide can induce hemorrhagic cystitis: hemorrhage from diffuse bladder inflammation; it occurs through various pathological mechanisms.

Acrolein

  • As one important component of this pathogenesis, indicate that acrolein is a toxic urinary metabolite of cyclophosphamide that accumulates in the bladder.

MESNA

  • In order to prevent acrolein toxicity, indicate that we administer MESNA (M-E-S-NA for 2-mercaptoethanesulfonate sodium) as a pre-treatment, so it's on-board when the cyclophosphamide is given as a way to bind up the acrolein; it acts as a sulfhydryl (aka thiol) donor which bonds to and clears acrolein.
  • It's important to understand that MESNA doesn't treat the hemorrhagic cystitis, itself (it doesn't help heal the damaged bladder) but rather it acts as a preventative of the damage by neutralizing acrolein.

Vincristine & Paclitaxel (Peripheral Neuropathy

Overview

  • Next, let's address chemotherapy-induced neuropathy (CIPN).
  • In the chemo figure distal UEs mark V (vincristine) and in the feet mark P (paclitaxel).

Peripheral Neuropathy

Key Causes

  • Let's list five notable examples:
    • Vincristine, of the vinca alkaloids – they prevent microtubule polymerization.
    • Paclitaxel, of the taxanes – they prevent microtubule depolymerization (produce overpolymerization).
    • Oxaliplatin, as well as cisplatin of the platinum agents (remember cisplatin it is an OCT2 substrate and OCT2 has an affinity for uptake in the dorsal root ganglion).
    • Bortezomib, a proteasome inhibitor.
    • Thalidomide, which is, amongst other things an antiangiogenic, IL-6 inhibitor.

Stocking-Glove Distribution

  • Draw a figure and show that CIPN produces a classic "stocking-glove" distribution of sensory loss/pain/paresthesias that manifests in a "dying-back" progression.

Toxicity to Dorsal Root Ganglion, Nerve Endings, & Subcellular Components

  • Next, draw a spinal cord and show injury at the dorsal root ganglion, which houses the sensory neurons. Sensory symptoms predominate, at least in part, because the dorsal root ganglion lacks a nervous system barrier (like the brain does (ie, the blood-brain barrier), which makes it particularly vulnerable to toxins because it: it isn't protected from the systemic vasculature in the way other major nervous system structures are.
  • Now, draw a nerve and show direct neurotoxicity at the nerve endings, the distal nerve terminals.
  • Also, illustrate that toxicity to some notable cellular components along the nerve axon are proposed to produce the neuropathy. They include microtubules (remember that vinca alkaloids and taxanes are microtubule inhibitors); mitochondria, which have their own DNA; and ion channels.
  • Unfortunately, no clear-cut CIPN preventative or treatment has been discovered, as of 2022.

Common Side Effects from Chemotherapy

Overview

  • Let's now turn to some common side effects that occur with chemotherapies, in general, so we can anticipate what our patients might experience.

Constitutional

  • Constitutional (nonspecific) symptoms of fatigue, loss of appetite, weight loss (although steroids can increase weight) and loss of libido.

Gastrointestinal

  • Gastrointestinal symptoms of nausea and vomiting, as well as constipation (slowing of bowel motility) and diarrhea (hyperactive bowels).

Dermatologic

  • Dermatologic symptoms of mucositis, rash, alopecia (hair loss), and dry skin and nail changes.

Neurologic/Psychiatric

  • Neurological/Psychiatric symptoms of chemo brain, which is a common term for decreased memory and concentration secondary to chemotherapy, mood changes, and, as discussed, chemotherapy-induced peripheral neuropathy.

Obstetric

  • Obstetric issues include infertility and teratogenicity of chemotherapies (thalidomide, for example, which was found to cause limb truncations in the fetus).

Genitourinary

  • Genitourinary symptoms primarily of cystitis, which presents with complaints of pain with urination (dysuria), increased frequency, and urgency or hesitancy.

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