Chemotherapy extravasation refers to the accidental leakage of chemotherapy drugs from the intended vein into surrounding tissues during the administration process. This can lead to damage to the surrounding tissues and may cause various complications. Extravasation can occur due to factors such as improper placement of the intravenous (IV) catheter, infiltration of the drug into the surrounding tissue, or issues with the vascular system. Chemotherapy drugs are potent and can be toxic, so when they leak into the surrounding tissues, they may cause irritation, inflammation, and tissue damage. The severity of the complications depends on factors such as the type and amount of chemotherapy drug, the location of extravasation, and the patient's overall health.
Healthcare professionals involved in administering chemotherapy are trained to prevent extravasation and to promptly recognize and manage it if it occurs. Immediate actions may include stopping the infusion, aspirating any residual drug from the affected site, and applying appropriate measures to minimize tissue damage. In some cases, antidotes or specific treatments may be administered to counteract the effects of the extravasated drug.
Highlighting a crucial aspect, the primary objective in managing chemotherapy extravasation is swift localization or dispersion of the leaked agent. The decision between localization and dispersion hinges on the specific chemotherapeutic agents involved. Utilizing a cold compress facilitates the constriction of local blood vessels, thereby aiding in localizing tissue damage. Conversely, a warm compress serves to disperse the chemotherapeutic agent into the surrounding tissues. The secondary goal is to neutralize the localized chemotherapeutic or dilute the agent, facilitating absorption and subsequent metabolism.
I will discuss some common chemotherapy agents that may cause extravasation. The first treatment goal we will discuss is localizing and neutralizing it. This would be for a vesicant like doxorubicin or an irritant like cisplatin. Localizing would occur by using a dry cold compress, and only doxorubicin has an antidote that can neutralize it: Dimethyl sulfoxide (DMSO) or Dexrazoxane. Another treatment goal for a vesicant like Vincristine would be to disperse and dilute it. Dispersing would occur by using a dry warm compress and diluting it with hyaluronidase. The final treatment goal for a nonirritant drug like Cyclophosphamide would be to monitor for mild inflammation and apply a dry cold compress.
Every instance of extravasation necessitates comprehensive documentation and reporting. Documentation serves a multifaceted role, encompassing the provision of an accurate chronological record, safeguarding the healthcare professionals involved, collecting data on extravasations, and pinpointing practice deficiencies. Additionally, reporting adverse drug reactions and medication errors to the appropriate authorities is a proactive measure by pharmacists to avert future occurrences. The information provided from reported incidents can serve as valuable educational tools, enabling a systematic review of the underlying mechanisms contributing to such events. The adherence to local procedures and protocols is crucial for the prompt identification, management of extravasation, and the prevention of consequential tissue damage.
While chemotherapy extravasation is a serious concern, advancements in medical practices and increased awareness have contributed to improved prevention, early detection, and management of this complication in cancer treatment.
Tecvayli is the first-of-its-kind treatment for multiple myeloma. It is a bispecific antibody that works by binding to both multiple myeloma cells and your t-cells to help your immune system recognize the multiple myeloma cells and destroy them. Tecvayli is for adults with multiple myeloma who have already received at least 4 treatment regimens and whose cancer has come back or did not respond to prior treatment. Tecvayli is approved under accelerated approval based on response rate, it is not fully approved.
Multiple myeloma is a blood cancer that develops in plasma cells in the bone marrow—the soft, spongy tissue at the center of your bones. In healthy bone marrow, normal plasma cells make antibodies to protect your body from infection.
For Providers & Patients:
Tecvayli is administered via subcutaneous injection only. For all first time patients, there is step up dosing. Due to the risk of cytokine release syndrome and immune effector cell associated neurotoxicity syndrome, patients should be hospitalized for 48 hours after administration of all doses within the step up dosing schedule for close monitoring.
To reduce the risk of CRS, these are the following pretreatment medications that should be administered before each dose of the step up dosing schedule and the first treatment dose: Corticosteroid (oral or IV dexamethasone 16mg), IV or oral diphenhydramine, and oral or IV acetaminophen 650mg to 1000mg.
The risk of CRS is high as shown in clinical trials when it occurred in 72% of patients who received Tecvayli at the recommended dose. This risk does not take away from the benefits of the drug as it can be managed at the bedside. Clinical signs and symptoms of CRS include but are not limited to, fever, difficulty breathing, chills, dizziness or lightheadedness, fast heartbeat, headache, and elevated liver enzymes. Due to the risk of CRS and neurologic toxicity, there is a black box warning by the FDA. This drug is only available through a restricted program known as REMS (risk evaluation mitigation strategy). REMS requires prescribers to be certified with the program by enrolling and completing training. Prescribers must counsel patients receiving Tecvayli about the risk of CRS and neurologic toxicity. Like other medications used to treat cancer, there are risks. The benefits outweigh the risks.
Tecvayli causes the release of cytokines that may suppress activity of cytochrome P450 enzymes, resulting in increased exposure of CYP substrates. Monitor for toxicity or concentration of drugs that are CYP substrates where minimal concentration changes may lead to serious adverse reactions (1).
Hepatotoxicity may occur. Patients should report symptoms that may indicate liver toxicity, such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
The most common side effects include fever, pain in joints, tiredness and weakness, nausea, headache, and diarrhea. These can be managed by your doctor with proper care.
Tecvayli has not been studied in pregnant women. There is an embryo-fetal toxicity. Advise patients of reproductive potential to use effective contraception during treatment with Tecvayli and for 5 months after the last dose.
Doxorubicin is an anticancer medication that is categorized as an anthracyclines. Doxorubicin is the first liposomal encapsulated anticancer drug that received clinical approval against malignancies including solid tumors, transplantable leukemias, and lymphomas. Initially, in the quest to find anticancer components from soil-based microorganisms, a strain called Streptomyces peucetius was discovered. It produced bright red pigment and was found to be very effective against mouse tumors. The compound was named daunorubicin and was utilized to treat acute leukemia and lymphoma. However, due to its fatal cardiac toxicity, genetic modifications were performed on the strain to produce doxorubicin. Unfortunately, doxorubicin still exhibited cardiotoxicity despite being more effective than daunorubicin.
Although the exact mechanism of action of doxorubicin is unclear due to its complexity, it is believed that the mechanism of action for this medication is that chemical components are able to intercalate with the DNA base pairs of the body. When this happens, the DNA strands will break, which ultimately will inhibit both the DNA as well as the RNA synthesis. Overall, that means it will prevent the cancer cells from going. Furthermore, other clinical researchers have found that doxorubicin can also inhibit the enzyme called topoisomerase II. Similarly, it can cause the DNA to break and allow for apoptosis to occur. Apoptosis is also known as cell death which shows that the cancer cells will die. Lastly, another mechanism of action that is seen with doxorubicin is when it is combined with iron which promotes a free radical oxidative event that damages the DNA. Thus, ceases the DNA synthesis.
Doxorubicin can be used as a treatment for different types of cancers. It may be beneficial to use for acute lymphoblastic leukemia, breast cancer, endometrial carcinoma, and even for Hodgkin lymphoma. This medication is typically given intravenously. For acute lymphoblastic leukemia, the dose is typically 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7. This is typically given in combination with cyclophosphamide, vincristine, and dexamethasone as well as alternating cycles with high dose of the methotrexate and cytarabine. On the other hand, for breast cancer with a CAF based regimen, the dose is given as 30 mg/m2 on days 1 and 8 for every 28 days for a total of 6 cycles. This regimen will also administer cyclophosphamide and fluorouracil together as well.
It is important to note that Doxorubicin may cause several heart related issues. Typically, before administering the Doxorubicin, a health care professional will administer an ECHO test to monitor the normal functions of the patient’s heart. The most common side effect seen with doxorubicin is headache, nausea, and some chest pain as well. The cardiotoxicity that is associated with doxorubicin is classified as either acute or chronic. The major concern is that it is dose-limiting. Some risk factors that can increase the risk of cardiotoxicity include current or past heart disease, older age, and the cumulative dose received. Those with acute doxorubicin induced cardiotoxicity may exhibit symptoms of rhythm disturbances, abnormal electrocardiographic changes, acute, reversible reduction in left-ventricular ejection fraction. Cardiotoxicity from doxorubicin treatment manifests as chronic complication and leads to congestive cardiomyopathy. It is important to note that the toxicity is related to the peak plasma doxorubicin concentration and the lifetime total dose administered to the patient. Although historically, cumulative doses of doxorubicin below 450 mg/m2 rarely exhibit cardiomyopathy, studies show that CHF from doxorubicin can still occur at lower doses and with greater frequency. Other studies report incidences of cardiac myopathy at 3% of cumulative dose of 400 mg/m2, at 7% at 55 mg/m2, and 18% at 700 mg/m2.
Recently, there have been new formulations of doxorubicin being developed, including stealth liposomes, doxorubicin-loaded polymer-lipid hybrid nanoparticles, and liposomal doxorubicin formulations. The efficacies and safety profiles still need further testing in order for them to be available in the market to be incorporated into treatment procedures. Overall, although doxorubicin is an excellent medication to be used in certain types of cancer, healthcare professionals should still exhibit caution before the utilizing this medication due to the cardiotoxic profile.
References:
“Doxorubicin.” Lexicomp. 11/06/2021.
Johnson-Arbor K, Dubey R. Doxorubicin. [Updated 2021 Aug 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459232/
Rivankar S. An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther. 2014;10(4):853-858.
Vincristine is an example of an anticancer drug. It is categorized as a vinca alkaloid for anticancer drugs that is used for various types of both adult and pediatric cancers. It is derived from the plant Catharanthus roseus. The mechanism of action for Vincristine is inhibiting the microtubule formation of the mitotic spindle during the DNA formation. By doing so, it allows the dividing and replicating cancer forming cells to stop continuously growing. Ultimately, the cancer cells die down and the cancer will stop spreading throughout the body.
Vincristine is typically administered intravenously. There are different doses that a patient can be on depending on the regimen that is best preferred for the patient by the healthcare professional. For instance, if a patient is on a hyper-CVAD regimen, this will include taking Vincristine 2 mg on days 4 and 11, along with other anticancer medications; like cyclophosphamide, mesna, doxorubicin, and dexamethasone. This will then be followed by a maintenance treatment of Vincristine 2 mg to be taken once monthly for 2 years (typically, in combination with a tyrosine kinase inhibitor as well). On the other hand, with a CALGB 8811 regimen, the induction phase will include 2 mg to be taken on days 1,8,15, and 22 as a 4 - week treatment cycle. Additionally, depending on the patient's progress, the provider can also start the patient on other phases, like the maintenance phase or the intensification phase.
It is important to note that Vincristine is only to be administered intravenously over a period of time. And quite similarly to other anticancer drugs that are to be administered via IV, the administrator should be very careful of drug leakage from the vein. If the drug happens to leak from the vein and spreads out, it can cause tissue damage. Thus, it is vital that patients should be aware of the symptoms that can follow. This includes burning, pain, or even, redness at the injection sites. Patients should also be aware of other side effects like muscle weakness or pain. However, the main side effect of vincristine is neurotoxicity. It is a dose-limiting side effect that causes neuropathy at peripheral and symmetric sensory motors. The symptoms of peripheral neuropathy include muscle weakness, areflexia, neuropathic pain and sensory loss. Other side effects from vincristine include syndrome of inappropriate antidiuretic hormone secretion, myelosuppression, and alopecia. Vincristine can also cause autonomic polyneuropathy which leads to orthostatic hypotension and constipation.
For vincristine induced peripheral neuropathy (VIPN), one of the common side effects of vincristine, it affects the distal neurons of the lower limbs, which are the longer neurons. These symptoms may develop after few administrations of vincristine but will mostly disappear within a few months of discontinuation. However, some children experience long term side effects from VIPN such as permanent loss of deep tendon reflexes and decreased motor functions. Unfortunately, diagnosis of VIPN is difficult due to its different clinical presentations. Furthermore, the difficulty increases in young children because they are unable to properly describe their complaints. Hence, a diagnostic tool called CTCAE has been developed to assess the degree of VIPN. The limitation with CTCAE is that it has a floor and ceiling effects when assessing VIPN. To address this issue, other diagnostic tools that can replace CTCAE have been studied, although there is no gold standard for VIPN assessing. With regard to the mechanism of VIPN, studies were mostly done in adult patients instead of children, and previous studies were unable to find an association between age and VIPN.
Vincristine is an anticancer medication, categorized under the drug class of vinca alkaloids. It is used in cancers found in adults and children. Although this medication is given often to treat many types of cancers some of which include leukemia and Hodgkin’s lymphoma, healthcare professionals should be aware of the possible side effects it can cause, as with all other chemotherapy agents. Among the numerous side effects that vincristine can potentially cause, vincristine induced peripheral neuropathy is very frequently encountered and leads to suboptimal dosing from a therapeutic point of view. This side effect is difficult to diagnose and may have devastating effects on children. Furthermore, it has been found that the quality of life of children with VIPN is deprived, even after the completion of vincristine therapy. Therefore, the use of vincristine should be based on benefit versus risk profile.
References:
“Vincristine.” Lexicomp, 11/02/2021.
van de Velde ME, Kaspers GL, Abbink FCH, Wilhelm AJ, Ket JCF, van den Berg MH. Vincristine-induced peripheral neuropathy in children with cancer: A systematic review. Crit Rev Oncol Hematol. 2017 Jun;114:114-130. doi: 10.1016/j.critrevonc.2017.04.004. Epub 2017 Apr 6. PMID: 28477739.
It is important to understand the specific mechanisms of drugs even when they are of the same category. A good example of this phenomenon is with the use of Selective Estrogen receptor modulators, or SERMs. Selective Estrogen receptor modulators (SERMs) are used for different disease states depending on the drug chosen. Selective Estrogen receptor modulators are non steroidal antiestrogens that compete with estrogen for the estrogen receptor. The two used in therapy include Tamoxifen (Soltamox) and Raloxifene (Evista). Both medications are administered orally to patients. Raloxifene prevents and treats osteoporosis by mimicking the effects of estrogen to increase the bone mineral density (BMD). It also decreases the risk of developing invasive breast cancer by blocking the effects of estrogen on breast tissue. Raloxifene is unique in that it has positive effects in the skeletal system but does not affect breast and endometrial tissue negatively. In other words, it is an antagonist in uterine and endometrial tissue and breast tissue but an agonist in bone tissue which decreases bone resorption and bone turn over, increasing the bone mineral density (BMD) and decreasing fracture incidence. Therefore, Raloxifene runs a lower risk in patients developing endometrial cancer which increases three to four fold in patients taking Tamoxifen. However, the use of Raloxifene runs the black box warning risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). If a woman has had a past medical history of deep vein thrombosis or pulmonary embolism, they should not be taking Raloxifene. There is increased risk of stroke in post menopausal women, benefit vs risk of treatment in these patients should be assessed. Similar to a woman going through menopause, common Raloxifene side effects include hot flashes, joint pain and sweating. Hot flashes can cause flushing of the skin and medications like gabapentin and venlafaxine can be used to manage these hot flashes. Tamoxifen is the medication more used for active breast cancer therapy as it can be used in the treatment of metastatic breast cancer in males and females since it is competitively binding to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is also an adjuvant treatment of breast cancer following surgery and radiation. It can also reduce the risk of invasive breast cancer in women that are at a high risk. It can also be used off label to treat endometrial cancer and ovarian cancer. Like Raloxifene, it also has hot flashes as a side effect, in addition to fatigue, vaginal discharge and mood swings. Unlike Raloxifene, Tamoxifen has a black boxed warning of uterine malignancies because it is not antagonist in the uterine tissue. Tamoxifen also has a warning of pulmonary embolism and stroke, but is less of a risk compared to Raloxifene’s. Raloxifene is used more so in the risk reduction of breast cancer in post menopausal women with osteoporosis whereas Tamoxifen is used for the prevention of breast cancer in high risk patients as well as the treatment of breast cancer due to it’s mechanism of action.
References:
• Tamoxifen and Raloxifene Package Insert
• Lexicomp Online®, Hudson, Ohio: Lexi-Comp, Inc; October 23, 2020
5-Fluorouracil (5-FU) is an agent used in chemotherapy to treat a wide variety of cancers. It can be used both systemically and topically. Some systemic cancers 5-FU treats are gastric adenocarcinoma, pancreatic adenocarcinoma, breast carcinoma, and colorectal adenocarcinoma, among others. Topical use of 5-FU treats basal cell carcinomas, cutaneous metastatic lesions from melanoma, keratoacanthomas, and treatment-resistant vitiligo when other treatments are either not tolerated or non-efficacious. Other dermatologic uses of 5-FU also include the reduction of keloids and hypertrophic scars. 5-FU works by entering cells and then converting to fluorodeoxyuridine monophosphate (FdUMP). FdUMP then couples with the enzyme thymidylate synthase (TS), thereby inhibiting the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, and depletion of this compound results in an imbalance of nucleotides. This then leads to double-stranded breaks in DNA by an enzyme known as the endonuclease. In addition to inhibition of thymidylate synthase, 5-FU also serves as an analog which incorrectly incorporates RNA and DNA. The overwhelming damage of DNA repair machinery caused by these mechanisms ultimately results in cell death of rapidly proliferating cells. The most common adverse effect reported in patients receiving systemic 5-FU treatment was diarrhea. Other common adverse effects include vomiting, nausea, and dehydration. More concerning side effects that require monitoring include neutropenia, pyrexia, pulmonary embolism, thrombocytopenia, and leukopenia. Patients experiencing adverse effects from 5-FU can be given uridine triacetate. The mechanism of toxicity reversal is due to the high concentrations of uridine delivered by uridine triacetate that competes with 5-FU metabolites for binding sites in the body.
Fluorouracil, also known as 5-FU, is a chemotherapeutic medication used to treat various malignancies such as gastric, pancreatic, breast, and colorectal cancer. In addition, it can be used topically to treat dermatological conditions including multiple actinic or solar keratosis. 5-FU is converted to fluorodeoxyuridine monophosphate which forms a complex with the enzyme thymidylate synthase. Thymidylate synthase is inhibited so the synthesis of thymidine, a nucleoside necessary in DNA replication, is blocked. There will be DNA breaks and eventually cell death. Topically, 5-FU has a selective cytotoxic effect on thymidylate synthase so it has a selective cytotoxic effect for the actinic skin but it doesn’t affect the normal skin. Randomized clinical trials have proven that chemopreventive treatment using 5% 5-FU topically can reduce the rate of squamous cell carcinoma in high risk individuals. One of the most common side effects patients experience with this drug systemically is diarrhea. 5-FU enters the brain through passive diffusion and there have been accounts of patients who experienced long term side effects of cognitive impairment. Psychological and behavioral tests have shown that 5-FU has a negative effect on memory and cognition. When applied topically, side effects include localized skin irritation, erythema, and eczematous skin reactions. A contraindication with receiving fluorouracil is if a patient has a documented deficiency of the enzyme dihydropyrimidine dehydrogenase, which is responsible for degrading 5-FU to biologically inactive metabolites. If there is a deficiency of this enzyme, it can lead to life-threatening toxicity of fluorouracil. Uridine triacetate, which competes with 5-FU metabolites for binding sites, can be given for toxicity reversal within four days of treatment when a patient is experiencing severe adverse effects from 5-FU. Fluorouracil is in the pregnancy category risk and can cause fetal harm if administered during pregnancy. Breastfeeding is also a contraindication for systemic 5-FU. There have been mechanisms of resistance such as alteration of enzyme activity or influx and efflux pump that lead to decreased efficacy of 5-FU with certain malignancies.
References
Casale J, Crane JS. Fluorouracil. [Updated 2019 Dec 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549808/
Wigmore PM, Mustafa S, El-Beltagy M, Lyons L, Umka J, Bennett G. Effects of 5-FU. Adv Exp Med Biol. 2010;678:157-164. doi:10.1007/978-1-4419-6306-2_20
While melanoma is not the most common cancer in the world, it is by far the most deadly with only 16% of patients diagnosed with melanoma surviving it. In addition, melanoma cases are rising at an alarming rate with an almost 8x increase between 1970 and 2009. Pembrolizumab was the first anti-PD-1 (programmed death receptor) antibody to be approved by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma. Pembrolizumab binds to the PD-1 receptor and inhibits it from interacting with PD-L1 and PD-L2 (programmed death ligand). This binding results in the activation of T-cell–mediated immune responses against tumor cells which results in decreased tumor growth. The recommended dosage of pembrolizumab is 2 mg/kg which should then be administered as an intravenous infusion over 30 minutes every 3 weeks. A study was conducted in an attempt to test the effectiveness of Pembrolizumab. Of the 21 patients with an objective response to pembrolizumab, 1 patient achieved a complete response and 20 patients achieved a partial response. Of these 21 patients, three had disease progressions after the initial response to pembrolizumab therapy. The remaining 18 patients had ongoing responses after the initial response to therapy. It should also be noted that Pembrolizumab has side effects which resulted in its discontinuation in around 9% of all the patients studied. Some of the more notable side effects include, but are not limited to, immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated nephritis, immune-mediated hyper/hypothyroidism, and renal failure.
References
Raedler LA. Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma. Am Health Drug Benefits. 2015;8(Spec Feature):96-100.
Pembrolizumab, with the brand name Keytruda, is a monoclonal antibody used to treat numerous oncologic conditions including melanoma, non-small and small cell lung cancer, classical hodgkin lymphoma, etc. It is also used as an off label for triple-negative, early stage breast cancer and malignant pleural mesothelioma. Its mechanism of action is binding to the programmed cell death protein 1(PD-1) receptor and blocking its interaction with PD-L1 and PD-L2. Some tumors have a high number of PD-1L which can suppress immune system responses. The PD-1 receptor is an immune checkpoint that helps prevent the immune system from attacking itself. When the ligand and PD-1 meets, T cell functions become inhibited but when pembrolizumab blocks PD-1 receptor, T cells are able to function and kill. Pembrolizumab is for intravenous use and it is usually given as a 200 mg infusion over 30 minutes every three weeks. Some adverse reactions include immune-related skin reaction, immune-related colitis, immune-mediated hepatitis, etc. since it is an antibody. Pembrolizumab can cause fetal harm so females with the potential to become pregnant should be advised. A pregnancy test would be done before a patient starts this drug. Patients who receive this drug should be closely monitored for their renal and liver function, infusion reaction, increase in their blood glucose. A drug interaction of pembrolizumab is axitinib in the category C risk since it can enhance the hepatic effects. Another drug interaction is with thalidomide analogs in the category X risk because pembrolizumab can enhance the toxic effect.
References
Flynn JP, Gerriets V. Pembrolizumab. [Updated 2020 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546616/
Chemotherapy Extravasation Management
Chemotherapy extravasation refers to the accidental leakage of chemotherapy drugs from the intended vein into surrounding tissues during the administration process. This can lead to damage to the surrounding tissues and may cause various complications. Extravasation can occur due to factors such as improper placement of the intravenous (IV) catheter, infiltration of the drug into the surrounding tissue, or issues with the vascular system. Chemotherapy drugs are potent and can be toxic, so when they leak into the surrounding tissues, they may cause irritation, inflammation, and tissue damage. The severity of the complications depends on factors such as the type and amount of chemotherapy drug, the location of extravasation, and the patient's overall health.
Healthcare professionals involved in administering chemotherapy are trained to prevent extravasation and to promptly recognize and manage it if it occurs. Immediate actions may include stopping the infusion, aspirating any residual drug from the affected site, and applying appropriate measures to minimize tissue damage. In some cases, antidotes or specific treatments may be administered to counteract the effects of the extravasated drug.
Highlighting a crucial aspect, the primary objective in managing chemotherapy extravasation is swift localization or dispersion of the leaked agent. The decision between localization and dispersion hinges on the specific chemotherapeutic agents involved. Utilizing a cold compress facilitates the constriction of local blood vessels, thereby aiding in localizing tissue damage. Conversely, a warm compress serves to disperse the chemotherapeutic agent into the surrounding tissues. The secondary goal is to neutralize the localized chemotherapeutic or dilute the agent, facilitating absorption and subsequent metabolism.
I will discuss some common chemotherapy agents that may cause extravasation. The first treatment goal we will discuss is localizing and neutralizing it. This would be for a vesicant like doxorubicin or an irritant like cisplatin. Localizing would occur by using a dry cold compress, and only doxorubicin has an antidote that can neutralize it: Dimethyl sulfoxide (DMSO) or Dexrazoxane. Another treatment goal for a vesicant like Vincristine would be to disperse and dilute it. Dispersing would occur by using a dry warm compress and diluting it with hyaluronidase. The final treatment goal for a nonirritant drug like Cyclophosphamide would be to monitor for mild inflammation and apply a dry cold compress.
Every instance of extravasation necessitates comprehensive documentation and reporting. Documentation serves a multifaceted role, encompassing the provision of an accurate chronological record, safeguarding the healthcare professionals involved, collecting data on extravasations, and pinpointing practice deficiencies. Additionally, reporting adverse drug reactions and medication errors to the appropriate authorities is a proactive measure by pharmacists to avert future occurrences. The information provided from reported incidents can serve as valuable educational tools, enabling a systematic review of the underlying mechanisms contributing to such events. The adherence to local procedures and protocols is crucial for the prompt identification, management of extravasation, and the prevention of consequential tissue damage.
While chemotherapy extravasation is a serious concern, advancements in medical practices and increased awareness have contributed to improved prevention, early detection, and management of this complication in cancer treatment.
References:
https://www.aaha.org/aaha-guidelines/oncology-configuration/implementation-toolkit/chemotherapy-extravasation-management/
https://www.uspharmacist.com/article/management-of-chemotherapy-extravasations
TECVAYLI: Teclistamab-cqyv
Tecvayli is the first-of-its-kind treatment for multiple myeloma. It is a bispecific antibody that works by binding to both multiple myeloma cells and your t-cells to help your immune system recognize the multiple myeloma cells and destroy them. Tecvayli is for adults with multiple myeloma who have already received at least 4 treatment regimens and whose cancer has come back or did not respond to prior treatment. Tecvayli is approved under accelerated approval based on response rate, it is not fully approved.
Multiple myeloma is a blood cancer that develops in plasma cells in the bone marrow—the soft, spongy tissue at the center of your bones. In healthy bone marrow, normal plasma cells make antibodies to protect your body from infection.
For Providers & Patients:
Tecvayli is administered via subcutaneous injection only. For all first time patients, there is step up dosing. Due to the risk of cytokine release syndrome and immune effector cell associated neurotoxicity syndrome, patients should be hospitalized for 48 hours after administration of all doses within the step up dosing schedule for close monitoring.
To reduce the risk of CRS, these are the following pretreatment medications that should be administered before each dose of the step up dosing schedule and the first treatment dose: Corticosteroid (oral or IV dexamethasone 16mg), IV or oral diphenhydramine, and oral or IV acetaminophen 650mg to 1000mg.
The risk of CRS is high as shown in clinical trials when it occurred in 72% of patients who received Tecvayli at the recommended dose. This risk does not take away from the benefits of the drug as it can be managed at the bedside. Clinical signs and symptoms of CRS include but are not limited to, fever, difficulty breathing, chills, dizziness or lightheadedness, fast heartbeat, headache, and elevated liver enzymes. Due to the risk of CRS and neurologic toxicity, there is a black box warning by the FDA. This drug is only available through a restricted program known as REMS (risk evaluation mitigation strategy). REMS requires prescribers to be certified with the program by enrolling and completing training. Prescribers must counsel patients receiving Tecvayli about the risk of CRS and neurologic toxicity. Like other medications used to treat cancer, there are risks. The benefits outweigh the risks.
Tecvayli causes the release of cytokines that may suppress activity of cytochrome P450 enzymes, resulting in increased exposure of CYP substrates. Monitor for toxicity or concentration of drugs that are CYP substrates where minimal concentration changes may lead to serious adverse reactions (1).
Hepatotoxicity may occur. Patients should report symptoms that may indicate liver toxicity, such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
The most common side effects include fever, pain in joints, tiredness and weakness, nausea, headache, and diarrhea. These can be managed by your doctor with proper care.
Tecvayli has not been studied in pregnant women. There is an embryo-fetal toxicity. Advise patients of reproductive potential to use effective contraception during treatment with Tecvayli and for 5 months after the last dose.
References:
https://www.tecvayli.com/how-tecvayli-works?utm_source=google&utm_medium=cpc&utm_campaign=GO-USA-ENG-PS-Tecvayli-BC-PH-RN-DTC&utm_content=Teclistamab&utm_term=teclistamab+tecvayli&gclid=CjwKCAiA0PuuBhBsEiwAS7fsNc-eShnaeY7xCQ8sjeVPr2Wz0mt24orxo2SVVe9tP9roRZNoD-GFhRoCTHwQAvD_BwE&gclsrc=aw.ds
Doxorubicin:
Written by: Jae Chang and Hillary Pham
Doxorubicin is an anticancer medication that is categorized as an anthracyclines. Doxorubicin is the first liposomal encapsulated anticancer drug that received clinical approval against malignancies including solid tumors, transplantable leukemias, and lymphomas. Initially, in the quest to find anticancer components from soil-based microorganisms, a strain called Streptomyces peucetius was discovered. It produced bright red pigment and was found to be very effective against mouse tumors. The compound was named daunorubicin and was utilized to treat acute leukemia and lymphoma. However, due to its fatal cardiac toxicity, genetic modifications were performed on the strain to produce doxorubicin. Unfortunately, doxorubicin still exhibited cardiotoxicity despite being more effective than daunorubicin.
Although the exact mechanism of action of doxorubicin is unclear due to its complexity, it is believed that the mechanism of action for this medication is that chemical components are able to intercalate with the DNA base pairs of the body. When this happens, the DNA strands will break, which ultimately will inhibit both the DNA as well as the RNA synthesis. Overall, that means it will prevent the cancer cells from going. Furthermore, other clinical researchers have found that doxorubicin can also inhibit the enzyme called topoisomerase II. Similarly, it can cause the DNA to break and allow for apoptosis to occur. Apoptosis is also known as cell death which shows that the cancer cells will die. Lastly, another mechanism of action that is seen with doxorubicin is when it is combined with iron which promotes a free radical oxidative event that damages the DNA. Thus, ceases the DNA synthesis.
Doxorubicin can be used as a treatment for different types of cancers. It may be beneficial to use for acute lymphoblastic leukemia, breast cancer, endometrial carcinoma, and even for Hodgkin lymphoma. This medication is typically given intravenously. For acute lymphoblastic leukemia, the dose is typically 50 mg/m2 on day 4 of Courses 1, 3, 5, and 7. This is typically given in combination with cyclophosphamide, vincristine, and dexamethasone as well as alternating cycles with high dose of the methotrexate and cytarabine. On the other hand, for breast cancer with a CAF based regimen, the dose is given as 30 mg/m2 on days 1 and 8 for every 28 days for a total of 6 cycles. This regimen will also administer cyclophosphamide and fluorouracil together as well.
It is important to note that Doxorubicin may cause several heart related issues. Typically, before administering the Doxorubicin, a health care professional will administer an ECHO test to monitor the normal functions of the patient’s heart. The most common side effect seen with doxorubicin is headache, nausea, and some chest pain as well. The cardiotoxicity that is associated with doxorubicin is classified as either acute or chronic. The major concern is that it is dose-limiting. Some risk factors that can increase the risk of cardiotoxicity include current or past heart disease, older age, and the cumulative dose received. Those with acute doxorubicin induced cardiotoxicity may exhibit symptoms of rhythm disturbances, abnormal electrocardiographic changes, acute, reversible reduction in left-ventricular ejection fraction. Cardiotoxicity from doxorubicin treatment manifests as chronic complication and leads to congestive cardiomyopathy. It is important to note that the toxicity is related to the peak plasma doxorubicin concentration and the lifetime total dose administered to the patient. Although historically, cumulative doses of doxorubicin below 450 mg/m2 rarely exhibit cardiomyopathy, studies show that CHF from doxorubicin can still occur at lower doses and with greater frequency. Other studies report incidences of cardiac myopathy at 3% of cumulative dose of 400 mg/m2, at 7% at 55 mg/m2, and 18% at 700 mg/m2.
Recently, there have been new formulations of doxorubicin being developed, including stealth liposomes, doxorubicin-loaded polymer-lipid hybrid nanoparticles, and liposomal doxorubicin formulations. The efficacies and safety profiles still need further testing in order for them to be available in the market to be incorporated into treatment procedures. Overall, although doxorubicin is an excellent medication to be used in certain types of cancer, healthcare professionals should still exhibit caution before the utilizing this medication due to the cardiotoxic profile.
References:
“Doxorubicin.” Lexicomp. 11/06/2021.
Johnson-Arbor K, Dubey R. Doxorubicin. [Updated 2021 Aug 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459232/
Rivankar S. An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther. 2014;10(4):853-858.
Vincristine:
Written by: Hillary Pham and Jae Chang
Vincristine is an example of an anticancer drug. It is categorized as a vinca alkaloid for anticancer drugs that is used for various types of both adult and pediatric cancers. It is derived from the plant Catharanthus roseus. The mechanism of action for Vincristine is inhibiting the microtubule formation of the mitotic spindle during the DNA formation. By doing so, it allows the dividing and replicating cancer forming cells to stop continuously growing. Ultimately, the cancer cells die down and the cancer will stop spreading throughout the body.
Vincristine is typically administered intravenously. There are different doses that a patient can be on depending on the regimen that is best preferred for the patient by the healthcare professional. For instance, if a patient is on a hyper-CVAD regimen, this will include taking Vincristine 2 mg on days 4 and 11, along with other anticancer medications; like cyclophosphamide, mesna, doxorubicin, and dexamethasone. This will then be followed by a maintenance treatment of Vincristine 2 mg to be taken once monthly for 2 years (typically, in combination with a tyrosine kinase inhibitor as well). On the other hand, with a CALGB 8811 regimen, the induction phase will include 2 mg to be taken on days 1,8,15, and 22 as a 4 - week treatment cycle. Additionally, depending on the patient's progress, the provider can also start the patient on other phases, like the maintenance phase or the intensification phase.
It is important to note that Vincristine is only to be administered intravenously over a period of time. And quite similarly to other anticancer drugs that are to be administered via IV, the administrator should be very careful of drug leakage from the vein. If the drug happens to leak from the vein and spreads out, it can cause tissue damage. Thus, it is vital that patients should be aware of the symptoms that can follow. This includes burning, pain, or even, redness at the injection sites. Patients should also be aware of other side effects like muscle weakness or pain. However, the main side effect of vincristine is neurotoxicity. It is a dose-limiting side effect that causes neuropathy at peripheral and symmetric sensory motors. The symptoms of peripheral neuropathy include muscle weakness, areflexia, neuropathic pain and sensory loss. Other side effects from vincristine include syndrome of inappropriate antidiuretic hormone secretion, myelosuppression, and alopecia. Vincristine can also cause autonomic polyneuropathy which leads to orthostatic hypotension and constipation.
For vincristine induced peripheral neuropathy (VIPN), one of the common side effects of vincristine, it affects the distal neurons of the lower limbs, which are the longer neurons. These symptoms may develop after few administrations of vincristine but will mostly disappear within a few months of discontinuation. However, some children experience long term side effects from VIPN such as permanent loss of deep tendon reflexes and decreased motor functions. Unfortunately, diagnosis of VIPN is difficult due to its different clinical presentations. Furthermore, the difficulty increases in young children because they are unable to properly describe their complaints. Hence, a diagnostic tool called CTCAE has been developed to assess the degree of VIPN. The limitation with CTCAE is that it has a floor and ceiling effects when assessing VIPN. To address this issue, other diagnostic tools that can replace CTCAE have been studied, although there is no gold standard for VIPN assessing. With regard to the mechanism of VIPN, studies were mostly done in adult patients instead of children, and previous studies were unable to find an association between age and VIPN.
Vincristine is an anticancer medication, categorized under the drug class of vinca alkaloids. It is used in cancers found in adults and children. Although this medication is given often to treat many types of cancers some of which include leukemia and Hodgkin’s lymphoma, healthcare professionals should be aware of the possible side effects it can cause, as with all other chemotherapy agents. Among the numerous side effects that vincristine can potentially cause, vincristine induced peripheral neuropathy is very frequently encountered and leads to suboptimal dosing from a therapeutic point of view. This side effect is difficult to diagnose and may have devastating effects on children. Furthermore, it has been found that the quality of life of children with VIPN is deprived, even after the completion of vincristine therapy. Therefore, the use of vincristine should be based on benefit versus risk profile.
References:
“Vincristine.” Lexicomp, 11/02/2021.
van de Velde ME, Kaspers GL, Abbink FCH, Wilhelm AJ, Ket JCF, van den Berg MH. Vincristine-induced peripheral neuropathy in children with cancer: A systematic review. Crit Rev Oncol Hematol. 2017 Jun;114:114-130. doi: 10.1016/j.critrevonc.2017.04.004. Epub 2017 Apr 6. PMID: 28477739.
It is important to understand the specific mechanisms of drugs even when they are of the same category. A good example of this phenomenon is with the use of Selective Estrogen receptor modulators, or SERMs. Selective Estrogen receptor modulators (SERMs) are used for different disease states depending on the drug chosen. Selective Estrogen receptor modulators are non steroidal antiestrogens that compete with estrogen for the estrogen receptor. The two used in therapy include Tamoxifen (Soltamox) and Raloxifene (Evista). Both medications are administered orally to patients. Raloxifene prevents and treats osteoporosis by mimicking the effects of estrogen to increase the bone mineral density (BMD). It also decreases the risk of developing invasive breast cancer by blocking the effects of estrogen on breast tissue. Raloxifene is unique in that it has positive effects in the skeletal system but does not affect breast and endometrial tissue negatively. In other words, it is an antagonist in uterine and endometrial tissue and breast tissue but an agonist in bone tissue which decreases bone resorption and bone turn over, increasing the bone mineral density (BMD) and decreasing fracture incidence. Therefore, Raloxifene runs a lower risk in patients developing endometrial cancer which increases three to four fold in patients taking Tamoxifen. However, the use of Raloxifene runs the black box warning risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). If a woman has had a past medical history of deep vein thrombosis or pulmonary embolism, they should not be taking Raloxifene. There is increased risk of stroke in post menopausal women, benefit vs risk of treatment in these patients should be assessed. Similar to a woman going through menopause, common Raloxifene side effects include hot flashes, joint pain and sweating. Hot flashes can cause flushing of the skin and medications like gabapentin and venlafaxine can be used to manage these hot flashes. Tamoxifen is the medication more used for active breast cancer therapy as it can be used in the treatment of metastatic breast cancer in males and females since it is competitively binding to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is also an adjuvant treatment of breast cancer following surgery and radiation. It can also reduce the risk of invasive breast cancer in women that are at a high risk. It can also be used off label to treat endometrial cancer and ovarian cancer. Like Raloxifene, it also has hot flashes as a side effect, in addition to fatigue, vaginal discharge and mood swings. Unlike Raloxifene, Tamoxifen has a black boxed warning of uterine malignancies because it is not antagonist in the uterine tissue. Tamoxifen also has a warning of pulmonary embolism and stroke, but is less of a risk compared to Raloxifene’s. Raloxifene is used more so in the risk reduction of breast cancer in post menopausal women with osteoporosis whereas Tamoxifen is used for the prevention of breast cancer in high risk patients as well as the treatment of breast cancer due to it’s mechanism of action.
References:
• Tamoxifen and Raloxifene Package Insert
• Lexicomp Online®, Hudson, Ohio: Lexi-Comp, Inc; October 23, 2020
5-Fluorouracil (5-FU) is an agent used in chemotherapy to treat a wide variety of cancers. It can be used both systemically and topically. Some systemic cancers 5-FU treats are gastric adenocarcinoma, pancreatic adenocarcinoma, breast carcinoma, and colorectal adenocarcinoma, among others. Topical use of 5-FU treats basal cell carcinomas, cutaneous metastatic lesions from melanoma, keratoacanthomas, and treatment-resistant vitiligo when other treatments are either not tolerated or non-efficacious. Other dermatologic uses of 5-FU also include the reduction of keloids and hypertrophic scars. 5-FU works by entering cells and then converting to fluorodeoxyuridine monophosphate (FdUMP). FdUMP then couples with the enzyme thymidylate synthase (TS), thereby inhibiting the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, and depletion of this compound results in an imbalance of nucleotides. This then leads to double-stranded breaks in DNA by an enzyme known as the endonuclease. In addition to inhibition of thymidylate synthase, 5-FU also serves as an analog which incorrectly incorporates RNA and DNA. The overwhelming damage of DNA repair machinery caused by these mechanisms ultimately results in cell death of rapidly proliferating cells. The most common adverse effect reported in patients receiving systemic 5-FU treatment was diarrhea. Other common adverse effects include vomiting, nausea, and dehydration. More concerning side effects that require monitoring include neutropenia, pyrexia, pulmonary embolism, thrombocytopenia, and leukopenia. Patients experiencing adverse effects from 5-FU can be given uridine triacetate. The mechanism of toxicity reversal is due to the high concentrations of uridine delivered by uridine triacetate that competes with 5-FU metabolites for binding sites in the body.
References
Casale, J. (2019, December 28). Fluorouracil. Retrieved August 13, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK549808/
Wigmore PM, Mustafa S, El-beltagy M, Lyons L, Umka J, Bennett G. Effects of 5-FU. Adv Exp Med Biol. 2010;678:157-64.
Fluorouracil, also known as 5-FU, is a chemotherapeutic medication used to treat various malignancies such as gastric, pancreatic, breast, and colorectal cancer. In addition, it can be used topically to treat dermatological conditions including multiple actinic or solar keratosis. 5-FU is converted to fluorodeoxyuridine monophosphate which forms a complex with the enzyme thymidylate synthase. Thymidylate synthase is inhibited so the synthesis of thymidine, a nucleoside necessary in DNA replication, is blocked. There will be DNA breaks and eventually cell death. Topically, 5-FU has a selective cytotoxic effect on thymidylate synthase so it has a selective cytotoxic effect for the actinic skin but it doesn’t affect the normal skin. Randomized clinical trials have proven that chemopreventive treatment using 5% 5-FU topically can reduce the rate of squamous cell carcinoma in high risk individuals. One of the most common side effects patients experience with this drug systemically is diarrhea. 5-FU enters the brain through passive diffusion and there have been accounts of patients who experienced long term side effects of cognitive impairment. Psychological and behavioral tests have shown that 5-FU has a negative effect on memory and cognition. When applied topically, side effects include localized skin irritation, erythema, and eczematous skin reactions. A contraindication with receiving fluorouracil is if a patient has a documented deficiency of the enzyme dihydropyrimidine dehydrogenase, which is responsible for degrading 5-FU to biologically inactive metabolites. If there is a deficiency of this enzyme, it can lead to life-threatening toxicity of fluorouracil. Uridine triacetate, which competes with 5-FU metabolites for binding sites, can be given for toxicity reversal within four days of treatment when a patient is experiencing severe adverse effects from 5-FU. Fluorouracil is in the pregnancy category risk and can cause fetal harm if administered during pregnancy. Breastfeeding is also a contraindication for systemic 5-FU. There have been mechanisms of resistance such as alteration of enzyme activity or influx and efflux pump that lead to decreased efficacy of 5-FU with certain malignancies.
References
Casale J, Crane JS. Fluorouracil. [Updated 2019 Dec 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549808/
Wigmore PM, Mustafa S, El-Beltagy M, Lyons L, Umka J, Bennett G. Effects of 5-FU. Adv Exp Med Biol. 2010;678:157-164. doi:10.1007/978-1-4419-6306-2_20
While melanoma is not the most common cancer in the world, it is by far the most deadly with only 16% of patients diagnosed with melanoma surviving it. In addition, melanoma cases are rising at an alarming rate with an almost 8x increase between 1970 and 2009. Pembrolizumab was the first anti-PD-1 (programmed death receptor) antibody to be approved by the US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma. Pembrolizumab binds to the PD-1 receptor and inhibits it from interacting with PD-L1 and PD-L2 (programmed death ligand). This binding results in the activation of T-cell–mediated immune responses against tumor cells which results in decreased tumor growth. The recommended dosage of pembrolizumab is 2 mg/kg which should then be administered as an intravenous infusion over 30 minutes every 3 weeks. A study was conducted in an attempt to test the effectiveness of Pembrolizumab. Of the 21 patients with an objective response to pembrolizumab, 1 patient achieved a complete response and 20 patients achieved a partial response. Of these 21 patients, three had disease progressions after the initial response to pembrolizumab therapy. The remaining 18 patients had ongoing responses after the initial response to therapy. It should also be noted that Pembrolizumab has side effects which resulted in its discontinuation in around 9% of all the patients studied. Some of the more notable side effects include, but are not limited to, immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated nephritis, immune-mediated hyper/hypothyroidism, and renal failure.
References
Raedler LA. Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma. Am Health Drug Benefits. 2015;8(Spec Feature):96-100.
Khoja L, Butler MO, Kang SP, Ebbinghaus S, Joshua AM. Pembrolizumab. J Immunother Cancer. 2015;3:36.
Pembrolizumab, with the brand name Keytruda, is a monoclonal antibody used to treat numerous oncologic conditions including melanoma, non-small and small cell lung cancer, classical hodgkin lymphoma, etc. It is also used as an off label for triple-negative, early stage breast cancer and malignant pleural mesothelioma. Its mechanism of action is binding to the programmed cell death protein 1(PD-1) receptor and blocking its interaction with PD-L1 and PD-L2. Some tumors have a high number of PD-1L which can suppress immune system responses. The PD-1 receptor is an immune checkpoint that helps prevent the immune system from attacking itself. When the ligand and PD-1 meets, T cell functions become inhibited but when pembrolizumab blocks PD-1 receptor, T cells are able to function and kill. Pembrolizumab is for intravenous use and it is usually given as a 200 mg infusion over 30 minutes every three weeks. Some adverse reactions include immune-related skin reaction, immune-related colitis, immune-mediated hepatitis, etc. since it is an antibody. Pembrolizumab can cause fetal harm so females with the potential to become pregnant should be advised. A pregnancy test would be done before a patient starts this drug. Patients who receive this drug should be closely monitored for their renal and liver function, infusion reaction, increase in their blood glucose. A drug interaction of pembrolizumab is axitinib in the category C risk since it can enhance the hepatic effects. Another drug interaction is with thalidomide analogs in the category X risk because pembrolizumab can enhance the toxic effect.
References
Flynn JP, Gerriets V. Pembrolizumab. [Updated 2020 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546616/
Pembrolizumab (Lexi-drugs). Hudson, OH: Lexicomp. Updated 8/6/20. Assessed 8/10/20.