The Ultimate Guide to Oncology Pharmacy for the Non-Oncologist
Oncology pharmacy is hard.
Like, really hard.
You get a 3 - 5 week module during school. Maybe you have an APPE rotation. But there's just too much. Too many types of cancers. Too much history that explains how we got to where we are. Too much rapidly-evolving literature. Too many drugs (and dozens more coming out every year).
I mean really, can you distill one of the most complex topics in medicine down to a few weeks worth of lectures?
Can you somehow package it into a single blog post and call it "The Ultimate Guide to Oncology Pharmacy for the Non-Oncologist?"
I'm sure as hell gonna try.
I probably don't have to tell you, but this sucker is gonna be lengthy. Yet it will still only scratch the surface.
I'd set aside a solid 30 minutes plus to read it...or you can bookmark and read it in chunks.
But when you're done, you will know just about everything you need to know for oncology pharmacy. Unless you're actually an oncology pharmacist (in which case you will laugh at me for leaving so much out).
The focus is going to be on supportive care. Things that show up frequently in cancer patients like CINV and anticoagulation. Why? Because on the NAPLEX and in day-to-day practice, that's what you'll come across.
The NAPLEX recognizes that unless you're a specialist, you won't need to know how to adjust the carboplatin dose for someone that experienced neutropenia on their last cycle....
But you will encounter patients with hypercalcemia. Or patients who are taking colony stimulating factors.
And don't worry! (Please stop worrying). We're also going to cover the dose-limiting toxicities of the popular cytotoxic chemo agents.
These are the "worst of the worst" side effects that stop us from using higher doses of a given drug (hence the "dose-limiting").
Dose limiting toxicities also make wonderful NAPLEX questions...so we just can't leave them out.
To make things even easier for you, we also made an Oncology Cheat Sheet.
Here's an outline of what we're going to cover:
- Clinical Pearls for Cytotoxic Chemotherapy
- Clinical Pearls for Targeted/Biologic Agents
- Chemotherapy-Induced Nausea and Vomiting (CINV)
- Colony Stimulating Factors
- Anticoagulation in Cancer Patients
- Tumor Lysis Syndrome
- Febrile Neutropenia
Buckle up. Let's get started.
Chemotherapy Clinical Pearls
First, some background. Why does chemotherapy have all those awful side effects? When most of us imagine a "cancer patient" we imagine someone that's withered and frail. They don't have hair. They're pale. They're always in the hospital.
What's going on here?
Treating a cancerous cell is a tough job for a drug. It's nothing like treating a bacterial infection. With bacteria, the drug has to kill a prokaryotic cell. This makes it pretty easy to not kill your eukaryotic cell.
But with cancer, chemotherapy has to somehow kill only the cancerous cell. This cell (for the most part) looks just like every other cell in your body.
And so classic cytotoxic chemotherapy doesn't do a very good job at discriminating. The best it can do is target rapidly dividing cells. Uncontrolled cell growth is the hallmark of cancer, so we use drugs that stop some part of the cell division process.
Lot's of healthy cells in your body rapidly divide under normal conditions. Your bone marrow. Your hair. The lining of your GI tract.
This is where most of the side effects of classic chemotherapy come from. Anemia. Hair loss. Sores/ulcers in the mouth and esophagus (mucositis). Nausea and vomiting.
In that regard, many of the side effects "make sense." They're unfortunate. But they at least have some rhyme and reason to them.
Most of the classic chemotherapy agents can be broken down into two categories:
- Cell Cycle Specific
- Cell Cycle Non-specific
Basically, some drugs only target cells in the S-phase of cell division. Or the M-phase, etc. They target some specific part of the cell cycle.
And some drugs do not specifically target any phase of the cell cycle.
In my opinion (and at the risk of angering people who are smarter than me), it's not that important to memorize which chemo agents are cell cycle specific. Especially if you're not an oncology specialist.
The take home here is that the chemo regimens we created back in the day were designed to target different phases of the cell cycle. This gave us a synergistic effect and prevented resistance.
As we'll see in the next section, today the focus on new drugs is on targeted therapies. We've found a few ways to more selectively target cancer cells. Targeted therapies are usually better tolerated. And because they target specific receptors or proteins on a tumor cell, they don't focus on the cell cycle at all.
And so there is less of a focus on which drugs are cell cycle specific or not.
Moving on, let's get to them clinical pearls.
For starters, let's talk dosing really quick.
Most chemo agents are dosed on your Body Surface Area (BSA). This is some fantasy ratio of your height and your weight that helps to standardize dosing. It helps make the dose of a drug less sensitive to outliers (like extreme obesity, or an amputee).
BSA doses are based on the m2 of surface area of your body. If nothing else, this will help you weed out some multiple choice answers on a test. Most doses for parenteral (IV, SubQ, IM, etc) will be in the form "X milligrams per m2."
For example, you might give 85mg/m2 of oxaliplatin to a patient whose BSA is 2.0. In this case, their final dose would be 170mg.
Easy enough, right? Just don't make the mistake of using the patient's weight instead of their BSA in the dose calculation (yes, I did that once on a test in pharmacy school).
There are a few different ways of calculating BSA...but a commonly accepted one is the Mosteller formula. It says that:
Of course there are some exceptions. Some drugs have a flat dose, which stays the same no matter the patient's size.
And then there's carboplatin....
Carboplatin gets it's own spot because it's dosing is unique. It's dosed via "The Calvert Formula" and it's the only drug in existence (to my knowledge) dosed this way.
You dose carboplatin based on the amount of exposure (AUC) you're hoping to achieve. AUC? Area Under the Curve? That thing you learned back in calculus and then forgot completely about?
Carboplatin's AUC is largely determined by kidney function, so we use CrCl as a proxy. All carboplatin doses start with the CrCl.
The Calvert Formula is:
Dose = (CrCl + 25)(AUC)
That 'AUC' in the Calvert Formula is the target AUC you're shooting for. It usually ranges from 2 - 7 (depending on what you're treating).
Remember that AUC is determined by "amount going in" and "amount going out." Our amount going in is the "dose." Our amount going out is (CrCl +25).
Carboplatin is mostly cleared by the kidney (CrCl), but there is also some "extra-renal" clearance that happens outside of the kidney. This is where the "25" modifier comes in.
So again, that equation is:
Dose = (CrCl + 25)(AUC)
Carboplatin doses always start with your target AUC and then you use that to figure out the actual milligram dose.
We've got a patient with CrCl of 75. And we're targeting 5AUC.
Dose = (75 + 25)(5)
Dose = 500mg.
Pretty simple right? Just remember that carboplatin is the only drug dosed off of AUC...so look for that on test questions.
Alright, so what about those promised dose-limiting toxicities?
There are several iterations out there of a drawing called "Chemo Man."
A google search will show you a lot of variations. My favorite one comes from Pharmacology Weekly. Apparently, they don't seem to exist anymore. But thanks to the miracle of time travel via the Wayback Machine, we can still use their excellent resources.
I was alerted to using the Wayback Machine thanks to some very helpful tl;dr pharmacy readers, so let's all give a collective "Thanks!" to Andy and Ben.
And let's all also give some appreciation to the creators of Pharmacology Weekly...wherever they are today. It's really a shame their site is no longer active because it was truly great. Anyway, here is a link to their fantastic Antineoplastic Man.
I really don't have much to add to Antineoplastic Man, honestly. It does a great job at hitting the dose-limiting toxicity for most of the commonly-used cytotoxic agents.
If you memorize that you will be more than covered for Dose Limiting Toxicities.
I will instead focus on 3 important toxicities you need to know for the NAPLEX.
- Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) - Cardiac toxicity
- Ifosfamide and Cyclophosphamide - Hemorrhagic cystitis
- Cisplatin - Renal and ototoxicity
Why am I singling out those 3? Because each of them has an "antidote." Or a specific agent to manage/prevent the toxicity.
These cytoprotective agents are as follows:
- Anthracyclines - Dexrazoxane
- Ifosfamide/Cyclophosphamide - Mesna
- Cisplatin - Amifostine
Now it's not that these "cytoprotective agents" are necessarily always used. For example, there's plenty of literature that suggests that although dexrazoxane lowers the risk of cardiac toxicity, it also lowers the treatment efficacy of the anthracyclines.
And honestly, I've never seen amifostine used (it's used to prevent cumulative renal toxicity from cisplatin and to help manage some of the side effects of radiation).
On the other hand, Mesa is REQUIRED if you're giving ifosfamide (I'd remember that if I were you...). And it's also frequently used with higher doses of cyclophosphamide.
Anyway...it's a good idea to know these cytoprotective agents for the NAPLEX. They aren't always used clinically, but if you can match them with the drug they are used to protect against you'll be fine.
As a final bonus clinical pearl, all of the anthracyclines are bright red in color. And (just like rifampin) can cause urine, tears, and other secretions to look like Kool Aid.
And there is a lifetime dosing limit (again, in mg/m2) for each anthracycline to limit cardiac toxicity.
Clinical Pearls for Targeted/Biologic Therapies
I'll spare you the history lesson, but starting with imatinib [Gleevec], we launched a huge turning point in cancer treatment.
We shifted from cytotoxic chemotherapies to targeted molecular therapies.
We went from "kill all of the things" to "kill just this one thing."
On the whole, this makes cancer treatment much more tolerable. But it also introduces a new range of side effects. To be clear, these new targeted agents have plenty of side effects.
But compared to cytotoxic chemo, most of their side effects are more tolerable.
The bulk of all new targeted therapies fall into two categories...
- Monoclonal Antibodies (IV administration)
- Tyrosine Kinase Inhibitors (PO administration...usually)
Monoclonal antibodies are confusing on the surface, but they're not that bad once you get to know them. Thanks to an established nomenclature, the name of the drug actually tells you quite a lot about it.
We've already written an entire post about this. You can check that out here, and I'll give the CliffsNotes below.
For starters, they all end in the suffix -mab. So any drug you see that ends in -mab is a monoclonal antibody.
We make -mabs through a process of refining antibodies from a 'source' and distilling them down until we are left with many, many copies of the same antibody.
It's kind of like The Clone Wars that you heard about in Star Wars saga.
Actually, it's exactly like that.
Anyway, the 'source' for these antibodies are usually human, mouse, or some Frankenstein combination of human and mouse.
No matter what, can you guess what the main side effect of -mab administration is?
Infusion reactions. Lots of them.
Even with fully human source antibodies, your body may detect them as foreign proteins. And your immune system tends to go ape-shit when you inject foreign proteins into the body.
So while you may not get hair loss and CINV with -mabs, you might get anaphylaxis or SJS.
The pre-medications for -mabs are reflective of this. You will usually see some cocktail of acetaminophen, diphenhydramine, and possibly a steroid like methylprednisolone ordered 30 minutes before -mab administration. You may even see a prn order for meperidine for rigors.
Keep that in mind on a test. If you see a pre-medication regimen that includes ondansetron, dexamethasone, and aprepitant to be given before a -mab, that answer choice is probably wrong.
And to be clear, -mabs have other side effects. Just because they are more targeted than cytotoxic chemotherapy does not mean that they don't have side effects.
For example, trastuzumab [Herceptin] is an antibody directed at the HER2 receptor. It's often used in breast (and more recently in some stomach) cancers. However, trastuzumab has up to a 34% rate of cardiotoxicity.
Or bevacizumab [Avastin], an antibody directed at VEGF. It can cause hypertension, proteinuria, and even GI perforation.
So while -mabs are generally better tolerated than cytotoxic chemo...they are far from choir boys in terms of adverse effects.
Here's a quick run down of the risk of infusion reaction (in order) based on the type of -mab (again, our -mab post explains this nomenclature in detail)
- -momab: Highest risk
- -mumab: Lowest risk
There are exceptions, of course. A recently approved drug, daratumumab [Darzalex] has an astounding 48% risk of infusion reaction.
But following the general guidelines above will cover you for most scenarios.
The management of infusion reactions usually starts with stopping the infusion and administering IV steroids and/or Benadryl. From there, the infusion can be restarted at half the rate it was running at previously.
If the patient reacts again, then you will most likely not re-challenge them with the drug. You'll have to try another therapy.
With -mabs, you are at the highest risk of infusion reaction the first couple of times you receive the drug. If you've not reacted for a few treatments, you're most likely not going to react this time.
And because it's just oh so good, here is Pharmacology Weekly's excellent rendition of FABio to help you learn your -mab toxicities.
Tyrosine Kinase Inhibitors (TKIs)
Tyrosine Kinase Inhibitors were the original targeted therapy (via the aforementioned imatinib). They stop cancerous cells on a genetic level by inactivating certain cell signaling cascades.
It was discovered a while back that tyrosine kinases act like a sort of "on-off" switch for whatever protein or signal their gene codes for.
And that sometimes these on-off switches can mutate and become stuck in the "on" position. Basically, the cell is unable to shut the factory down. And uncontrolled growth is like, the definition of cancer.
Editor's Note: For further background reading on the history of TKIs and cancer treatment in general, check out The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee and The Philadelphia Chromosome by Jessica Wapner. Both are seriously fantastic reads.
In full disclosure, tl;dr pharmacy will earn a small commission if you purchase through either of these links. This does not affect your purchase price, but it does help support us in running the site. Thanks!
So finding a way to inhibit tyrosine kinase creates a pretty effective tumor missile.
Further, TKIs work at a different site than the -mabs we've already talked about. For example, trastuzumab might bind to and block a HER2 receptor on the surface of a cell...
...but the TKI lapatinib enters the cell and shuts it down from there.
It binds on the cytoplasmic side of the receptor and stops HER2 from activating.
This is an effective way to target a uncontrolled growth. And it's pretty specific to cancer cells. At least compared to cytotoxic chemotherapy.
So TKIs aren't going anywhere. There will be more of them in the coming years. We've currently got TKIs that inhibit VEGF, BCR-ABL, EGFR, and a bunch of other biomarkers for cancer.
Most TKIs are given PO, but not all. This is an added bonus because it further simplifies treatment. Patients don't have to spend half of their day in an infusion clinic every couple of weeks.
Of course, it's not all a bed of roses with TKIs. They have skeletons in their closet too.
At the end of the day, they target many of the same pathways as our -mabs. They just do it at different steps in the chain. So there is some overlap with the side effects.
TKIs can form nasty acneiform rashes. Some progressing to SJS. This is often treated with topical steroids and a 6 week course of doxycycline.
In fact, it's probably easiest for you to remember that every TKI can cause rash and diarrhea. Those 2 side effects are pretty much ubiquitous with TKIs.
There is also the risk of drug interactions...particularly with acid-suppressing agents.
In fact, proton pump inhibitors are contraindicated with several TKIs. For these drugs, you can use H2RAs. But you must separate the dosing (take the TKI 2 hours before or 10 hours after the H2RA).
Here's a short run down of common toxicities with each TKI target:
- EGFR - Skin rash. Diarrhea. Occasional mucositis
- HER2 - Skin rash. Diarrhea. Left ventricular dysfunction
- VEGF - Hypertension. Proteinuria. Impaired wound healing. Increased risk of VTE
- BCR-ABL - Cytopenias. Occasional hypothyroidism
Do you want an Oncology Cheat Sheet?
It's got all you need to know for the NAPLEX. It's a great way to prepare for an APPE rotation. Keep it on hand when you're practicing and you'll know what to monitor.
It packs a ton of information in a single page. Dose limiting toxicities, renal and hepatic dosage adjustments, emetogenic potential, likelihood of hair loss, infusion reactions, and much more.
Chemotherapy-Induced Nausea and Vomiting (CINV)
In one of tl;dr pharmacy's earliest posts, we broke down the basics of CINV. You can check that out for more details. This will be a quick and dirty summary.
Your job when selecting a CINV regimen is to determine the emetogenic potential (i.e. likelihood of inducing vomiting) of the chemo you are giving. You also need to determine the risk of delayed emesis (vomiting that initiates or continues 24 hours after treatment) because you need to cover that too.
Luckily, lots of really smart people have already done this for you.
ASCO and NCCN both have CINV guidelines. Note: You'll need to create a login for the NCCN guidelines. But it's free, and they don't spam your email. They have a guideline for everything cancer-related under the sun, so you're highly encouraged to join.
The institution you end up practicing in will also have it's own version of CINV guidelines.
The point is, it's already been established what chemo regimens are highly emetogenic...
Which produce delayed CINV...
And how to prevent and treat CINV (hint: it's much easier to prevent than it is to treat).
They are meant to be tweaked, of course. For example, if your patient develops refractory nausea from a "moderately emetogenic" regimen, you're not going to tell them to grow a pair and man up.
You're going to give them the extra medication support that they need.
Here is a bare bones summary of current CINV best practices:
- Minimal emetogenic risk - no prophylaxis necessary
- Low emetogenic risk - dexamethasone 8 mg OR any first generation 5HT3 antagonist
- Moderate emetogenic risk - 5HT3 antagonist + dexamethasone. If patient develops severe/refractory emesis after previous cycle(s), add an NK1 antagonist. If there is any risk of delayed emesis, continue dexamethasone daily for a few days (usually to Day 4) or give palonosetron as your 5HT3 antagonist (it's got a super long half life and will cover patients for about 5 days)
- Severe emetogenic risk - NK1 antagonist + 5HT3 antagonist + dexamethasone
- For anticipatory nausea/vomiting - benzodiazepines (usually lorazepam because it will not accumulate in liver or renal failure)
- For breakthrough nausea/vomiting - we're kind of in no man's land here. You use what works and what makes sense given your patient's medical history and other medications. You commonly see (in no particular order): olanzapine, prochlorperazine, promethazine, metoclopramide, dronabinol (and depending on what state you live in, dronabinol's more 'natural' cousin).
And here's a few more random clinical pearls for CINV...
There's a nice new combination pill called [Akynzeo] which contains netupitant (an NK1 antagonist) and palonosetron (our only second generation, super long acting 5HT3 antagonist). It is a single PO dose that will cover both severe emetogenic risk and delayed CINV with ease. You will still use dexamethasone with Akynzeo, but you will not need any other NK1 or 5HT3 antagonists.
For a long time, aprepitant [Emend] was the only NK1 antagonist. It can be given IV (as fosaprepitant) for a single 150 mg dose per regimen. It's also given PO as a 3 day regimen (120 mg, 80 mg, 80mg). Of note, it has a drug interaction with dexamethasone which is compensated for by decreasing the dexamethasone dose by ~50%.
More recently, rolapitant [Varubi] has entered the fray. It's different than Emend because it's given PO x 1 dose and doesn't have a drug interaction with dexamethasone.
Otherwise, all NK1 antagonists (aprepitant, rolapitant, netupitant) are considered therapeutically equivalent.
All first generation 5HT3 antagonists (i.e. everything except for palonosetron) are also considered equally efficacious. Select them based on formulary preference and dosing convenience (there are ODTs and patch formulations that are better for patients with difficulty swallowing).
It's worth noting that all first generation 5HT3 antagonists (ondansetron, granisetron, dolasetron, etc...) are associated with QT prolongation. QT prolongation is an opportunity area for pharmacists because it usually only manifests when several QT prolonging agents are on board.
If your patient is at risk for QT prolongation, you can use...
Palonosetron [Aloxi]. This second generation 5HT3 antagonist is not associated with QT prolongation. As an added bonus, a single dose will cover your patient for about 5 days. In practice, we tend to use this only when we need to because it is considerably more expensive than every 1st generation agent. But it definitely has a place in therapy.
And finally, for CINV, you can actually use any steroid. We just tend to use dexemethasone. It's the best studied, and it has no mineralocorticoid activity. So high doses are unlikely to result in fluid retention.
Colony Stimulating Factors
Next up we have colony stimulating factors. Remember from somewhere about 1000 words ago that chemotherapy can absolutely torch the bone marrow.
The cytotoxic agents all target fast growing cells, and that means your white blood cells, your platelets, and your red blood cells can sustain heavy losses after each cycle.
This creates all sorts of problems.
Low WBCs open your patients up to infections. Low platelets introduce a bleeding risk. And low RBCs leave your patients feeling anemic and tired.
So, as loving health care professionals, we try to mitigate these risks. We try to prevent (or at least manage) them.
Most importantly, we aim to keep the WBCs (and specifically the neutrophils) in check. There's an entire section later in this post dedicated to neutropenic fever, so I won't spoil the surprise for you here. But suffice it to say (for now) that low neutrophils = low immune system.
Cancer patients are prone not only to the same infections that hamper all of us, but also to things that only cause infections in "immunocompromised" people. Things like TB, CMV, PCP and so on.
Further, many chemo regimens require a patient to keep a permanent central line in place. Mix this with frequently being in and out of health care facilities and you get a risk of super bugs like MRSA and Pseudomonas.
Granulocyte Colony Stimulating Factors (G-CSF)
Granulocyte is a fancy way of saying "neutrophils." The package insert lists off 5 or 6 indications, but at the end of the day it's simple...
We give these to either prevent or treat neutropenia (and all that's associated with neutropenia).
So if a patient's ANC (absolute neutrophil count) dips too low after a particular cycle of chemo, we'll give a G-CSF to help correct it (and start giving them prophylactically after the next cycle).
If the patient is receiving a chemo regimen that's expected to drop the ANC, we'll give a G-CSF prophylactically ahead of time.
How do you choose a G-CSF? Once again, it's convenience and formulary preference.
Here's a quick break down:
- filgrastim [Neupogen] - 5 - 10 mcg/kg/day daily SubQ or IV
- filgrastim-sndz [Zarxio] - biosimilar (i.e. generic) for Neupogen. The same dosing applies
- tbo-filgrastim [Granix] - It's kind of like a biosimilar for Neupogen...but technically it obtained it's own FDA approval before the biosimilar program existed (so you cannot call it a biosimilar). It is not FDA approved for as many indications as Neupogen or Zarxio, but it is used in practice for all of the same things. For what it's worth, CMS has assigned the same J-code to Neupogen, Zarxio, and Granix. This basically means that CMS considers them interchangeable. The dosing is the same among all 3 agents.
- pegfilgrastim [Neulasta], [Neulasta Onpro] - 6 mg SubQ once per cycle of myelosuppresive chemotherapy.
- sargramostim [Leukine] - 250 mcg/m2/day daily SubQ or IV. Leukine is actually a GM-CSF (it stimulates both granulocytes and macrophages). It's primarily used for stem cell/bone marrow transplants, although it also has an indication for AML.
There are very few FDA-approved biosimilars at the time of this writing. We've written about the other one here.
G-CSFs (and GM-CSFs) are pretty well tolerated, but here's a few quick clinical pearls...
For testing purposes, note the subtle differences in dosing.
Neupogen is mcg/kg and it's daily...
Leukine is mcg/m2 daily...
Neulasta is a flat dose in mg and it's only given once per cycle...
You can weed out multiple choice answers with this information.
We don't start any of these (except the Neulasta Onpro) until 24 - 72 hours after chemotherapy. Why? If we give them before or during chemotherapy, all of the neutrophils they stimulate are going to be killed by the chemo.
The Neulasta Onpro is a new, "on-body injector" that the nurse can stick on the patient in the infusion room the same day of chemotherapy. It auto-injects itself 27 hours later.
This saves the patient from returning to the infusion center a day or two later for Neulasta. Of note, the patient cannot shower while wearing Onpro.
One of the primary side effects of G-CSFs is bone pain (which makes sense given their mechanism). Somewhat strangely, we can use antihistamines (typically loratadine) to help manage this pain.
The main "really bad thing" to watch out for is splenic rupture. G-CSFs (and GM-CSFs) can clog up your spleen. A ruptured spleen can be fatal. There's also a small risk of anaphylaxis and other injection site reactions.
Erythropoietin Stimulating Agents
Erythropoietin Stimulating Agents (ESAs) are the same concept as G-CSFs, except they stimulate red blood cell (RBC) production.
But listen up, cause this is important...
There is very strict usage criteria with ESAs in cancer patients. There is an entire REMS program called ESA APPRISE that breaks down the essential info.
UPDATE: The ESA APPRISE program has been discontinued as of April 2017. It's not because the risks of using ESAs in oncology don't exist, but because the FDA felt that prescribers were adequately informed about the risks.
The majority of ESA usage is in chronic kidney disease (CKD). Your kidneys supply your body with erythropoietin, and as their ability declines with time you get less erythropoietin.
Less erythropoietin = less RBCs (which means anemia, poor oxygenation, etc...). So it is very common to use an ESA in kidney failure.
Much less common is ESA use in cancer. As it turns out, ESAs are associated with an increased risk of death and tumor progression in cancer patients. They are only indicated for chemotherapy-induced anemia.
That means the patient must have very recently had (or currently be receiving) chemotherapy.
Additionally, ESAs are only for palliative chemo. If the treatment goal is "cure," ESAs cannot be used. ESAs are never used prophylactically. They are also not used for AML or CML. And you only treat to an Hgb of 10.
Alright, got all of that? Good.
ESAs come in a couple of flavors.
- Epoetin alfa [Procrit], [Epogen] is dosed in units. It's usually given several times per week.
- Darbepoetin [Aranesp] is dosed in micrograms. It's usually given once every 1 - 2 weeks.
Therapeutically, all of the above are considered equally efficacious. Cost, convenience, and formulary will (again) drive your decision in terms of which to use.
As for a couple of clinical pearls...
You won't see an increase in Hgb/Hct for about 2 - 6 weeks. These are not drugs that work overnight. It takes time...and consistent use is key to achieving an increase. And even then, the benefits may be modest.
There are several risks associated with use. Most notably, hypertension, stroke and venous thromboembolism (VTE).
You'll find the general goal for ESAs is to decrease blood transfusions. We don't treat to a "normal" Hgb. We typically stop around 10 or 11.
This helps to mitigate some of the unpleasant side effects...as well as the unpleasant cost of ESAs.
And for your next round of "drug trivia," or for you HIV buffs, ESAs also carry an indication for zidovudine-induced anemia.
Their use here is pretty rare. We typically just switch patients from zidovudine to something else. But the indication is there, living as a remnant from an age where zidovudine was the only HIV drug.
Platelet Stimulating Agents
Last up, we have the platelets. It's a very rare day that you will see these used in chemotherapy. But for the sake of completeness, we're gonna include them here.
Platelet stimulating agents are used primarily in patients with idiopathic thrombocytopenia purpura (ITP). And even then, they're not first line agents.
We typically start with steroids or immune suppressants and graduate up to IVIG or even plasmapheresis (which is sort of like dialysis, but it filters the antibodies from your blood).
Platelet stimulating agents are added on only for refractory symptomatic treatment.
All of that is to say...
These are never going to be your first line treatment choices on a test. And relating to cancer, we tend to just use good ole fashioned platelet transfusions instead of exposing the patient to another drug that stimulates cell growth.
Anyway, as for the drugs...
- Oprelvekin [Neumega] - The only platelet stimulating agent that has an FDA-approved indication for chemotherapy-induced thrombocytopenia. It's an IL-11 stimulator that stimulates megakaryocyte stem cells (which then go on to make platelets). It's usually dosed at 50 mcg/kg SubQ daily.
- Eltrombopag [Promacta] - This is unique because it's given PO. It's a thrombopoetin receptor stimulator, which directly stimulates platelet production. It starts at 50 mg PO daily for adults and is dose-adjusted to keep the platelets above 50 (max dose of 75 mg daily).
- Romiplostim [NPlate] - Similar to Promacta, except that it is a SubQ injection. But it is also a thrombopoetic receptor stimulator. It's starting dose is 1 mcg/kg once weekly and it's also dose-adjusted to keep platelets above 50 (max dose of 10 mcg/kg)
And for some clinical pearls...
These drugs all stimulate platelets...so there is an inherent clotting risk with all of them. Make sure to monitor your patient for signs of clotting.
Also, the formulation of Neumega is derived from E. coli, so there is a decent risk of anaphylactic infusion reactions. These will most likely occur on the first cycle.
And finally, these drugs just may not work for your patient. The general rule of thumb is that if there is no effect on platelet count after 4 weeks to discontinue use.
Anticoagulation in Cancer Patients
Patients with cancer have a relatively high risk of developing a clot. In fact, DVTs and PEs are some of the leading causes of morbidity and mortality in cancer patients.
So we often find ourselves in a position where we need to treat a blood clot in cancer patients. But are all anticoagulants considered equal in cancer?
Low Molecular Weight Heparins (LMWH) such as enoxaparin and dalteparin are far and away the anticoagulants of choice in cancer patients. Nothing has ever beat them in a head to head trial.
So, if at all possible, look to use Lovenox or similar in your cancer patients. How long do you have to treat?
For the first clot, it's pretty similar to how we manage a DVT/PE in a patient without cancer. We'll follow the standard 3 - 6 month treatment with therapeutic doses of LMWH.
However, if the patient continues getting clots (cancer by itself induces a hypercoagulable state), then they may need to go on lifelong therapeutic anticoagulation.
And even though this means injecting themselves once or twice a day with enoxaparin, that is the gold standard.
Of course, if your patient is unable or unwilling to inject themselves, can you use something else? What about one of those fancy "oral" anticoagulants?
Almost universally, warfarin is not recommended in cancer patients. There are way too many drug interactions. And way too many other things (diet, exercise, etc...) also have an impact on warfarin. So we really try to avoid it in cancer.
New Oral Anticoagulants (NOACs) circumvent many of the drug and food interactions with warfarin.
And they are starting to gain some traction for VTE prophylaxis in cancer patients as well. In treatment, the general consensus is that they can work, but they have a considerably higher bleeding risk.
Certainly, they are better than no anticoagulation. So as always, you'll have to tailor your clinical decisions to your patient.
As a quick warning for anticoagulation and cancer patients. Remember that many of the cytotoxic chemotherapy agents jam up your platelets (and hgb/hct). So you need to closely monitor and watch out for bleeds. Especially when counts hit their low point (nadir) after each cycle.
The nadir is different for each chemo regimen, but it's usually somewhere around 7 - 14 days after treatment. After hitting that low point, the counts are expected to recover.
And as a reference point, our usual "Oh shit!" level is when the platelets fall below 50k. At that point we need to consider temporarily holding (or at least reducing the dose) of any anticoagulation to mitigate the bleed risk.
And also remember...LMWH is contraindicated in dialysis and needs to be dose adjusted in renal failure. So if your patient fits either of those criteria be on the lookout.
Hypercalcemia of Malignancy
Certain solid tumors (breast and lung) and some blood tumors (multiple myeloma) put a patient at risk for hypercalcemia.
It's partially due to the cancerous cells themselves which tend to pump out calcium. But it's mostly due to the fact that breast, lung and myeloma cells like to metastasize to the bone where they cause resorption.
Multiple myeloma cells also create a bunch of immature "plasma cells" which clog up the kidneys (which can further cause renal failure and calcium accumulation).
However it happens, hypercalcemia is something that must be monitored in cancer patients.
Here's how we treat it...
For starters, we don't usually treat asymptomatic hypercalcemia. If the patient isn't showing symptoms (thirst, confusion, weakness, nausea/vomiting, diarrhea, etc...) there's no need to do anything drastic.
If the patient is asymptomatic, we just try not to make the problem worse. Avoid thiazide diuretics, calcium supplements or antacids. Make sure to monitor renal function to ensure the calcium level doesn't get worse.
And for our symptomatic patients?
First we hydrate with saline. This will cause a relative dilution of the serum Ca level and help reduce symptoms. Of course, we don't want the patient to get volume overloaded either...
So if the patient's kidneys can handle it, we sometimes give furosemide along with the hydration.
This is worth noting because it's one of the rare instances you'll be giving both a diuretic and hydration (they're sort of opposing ideas).
As an added bonus, the furosemide (or really any loop diuretic) will also help to remove some of the serum calcium.
Just remember that loop diuretics can contribute to acute renal failure, so use them with caution if your patient already has compromised kidney function.
If you're interested, you can read more about fluid management here.
Second, we'll usually go to calcitonin. It's not incredibly effective at lowering calcium, per se. But it works quickly. And when symptoms are present that's a good thing.
As a quick reminder, our formulation of calcitonin is derived from salmon...so watch out for salmon/fish allergies.
Next, we'll jump to either the bisphosphonates (use IV here, not PO) or denosumab.
To jog your memory, denosumab is that weird RANKL inhibitor that you learned about in your osteoporosis lecture.
These remove a lot more calcium from the serum compared to calcitonin. But they take longer to work and they aren't anywhere near as safe.
Now, for some clinical pearls...
Bisphosphonates are contraindicated in renal failure. The most common IV formulation used in cancer is zoledronic acid (though pamidronate is also popular). Both must be renally adjusted, or avoided altogether once the CrCl dips below 30 ml/min.
If your patient has renal issues, denosumab is a better choice. There is no recommended renal adjustment, though you will have to keep an eye on the calcium level because it will profoundly lower it. You do have to worry about infusion and hypersensitivity reactions with denosumab as well.
This next part is NAPLEX fodder...
Both denosumab and zoledronic acid are used for oncologic indications and for osteoporosis. The oncologic indications are hypercalcemia of malignancy and the reduction of skeletal events in patients with bone metastases.
However, the dosing, and associated brand names are different. Here's a quick summary:
- Zoledronic acid
- [Reclast] - Osteoporosis. 5 mg IV once per year. No dosage adjustment...it's either 5 mg or nothing (don't administer below CrCl of 30 ml/min).
- [Zometa] - Oncology indications. 4 mg IV once per month. There is a range of dose adjustments starting at CrCl of 60. And again, you don't administer with CrCl < 30 ml/min.
- [Prolia] - Osteoporosis. 60 mg SubQ once every six months. No renal adjustment.
- [Xgeva] - Oncology indications. 120 mg SubQ once per month. No renal adjustment
When giving either bisphosphonates or denosumab every month, it's usually to prevent skeletal events from bone metastases. Of course, those bone mets can also cause hypercalcemia, so you're kind of killing two birds with one stone.
If you'd like additional information, here's a nice update on hypercalcemia of malignancy.
Tumor Lysis Syndrome
Everything's going great. You've got a new Burkitt's Lymphoma patient. You run a whole bunch of genetics and cytology studies and give them some chemo. Your job here is done. Time to smile and congratulate yourself for being so awesome, right?
Certain tumors have a high "tumor burden." Basically, there are a shit-ton of tumor cells floating around.
When the chemo kills all of those cells, their inner contents spill out into the patient's cytoplasm. And what lives inside our cells? Potassium, phosphate, and uric acid.
This can lead to a medical emergency known as Tumor Lysis Syndrome (TLS).
The high potassium levels cause heart arrhythmias. The uric acid and phosphate crystallize in the kidneys and cause acute renal failure. This further raises the potassium because the body can't clear it.
Just all around bad times.
Most of the time you'll see it with leukemia or lymphoma patients. But it's not completely unheard of to see it with large/aggressive solid tumors (e.g. lung) as well.
So what do we do about it?
The first rule of Tumor Lysis Syndrome is to prevent it before you treat it.
The second rule of Tumor Lysis Syndrome is to prevent it before you treat it.
So, just like CINV, neutropenia, and neutropenic fever (below), we'll try to prevent TLS in our high risk patients.
First we hydrate the daylights out of them. We'll start this hours before starting chemotherapy and we're shooting for urine outputs in the 100 - 200 ml/hr range.
Second, we'll sometimes give something to lower the uric acid level preemptively. Usually, that 'something' is allopurinol. The same allopurinol you've seen in gout.
Xanthine oxidase inhibition = lowered uric acid levels.
On the other hand, if we're dealing with an incredibly high risk patient (who also happens to have good insurance), we may skip the allopurinol and go straight to rasburicase [Elitek]. Rasburicase is an enzyme that chops up uric acid into its metabolic byproducts.
Chopped up uric acid = lowered uric acid levels.
Elitek may be a new drug for you, so here's some deets:
- Patients who may have G6PD deficiency (African Americans and Southeastern Asians) need to have G6PD levels checked. Elitek will cause hemolysis if G6PD levels are low
- Dosed 0.2 mg/kg IV daily for up to 5 days
- May cause anaphylaxis
And what if your poor patient ends up with TLS?
For starters, they just bought themselves a trip to the ICU. They'll need frequent cardiac and electrolyte monitoring.
If you haven't already given them rasburicase, now would be a good time. Other than that the name of the game is supportive care.
Keep their kidneys, heart, and electrolyte levels happy, and they'll make it through.
Last but not least, no discussion of oncology pharmacy is complete without mentioning neutropenic fever.
As we've learned, chemotherapy can destroy white blood cells (and especially neutrophils). And those neutrophils are a critical component of your immune system.
Normally, when you are sick your body lets you know it. You might be achy, or just feel general malaise.
But when you barely have any neutrophils, your body doesn't do that. The only way your body can "tell you" that you're sick is to give you a fever.
Enter neutropenic fever.
Neutropenic fever is one of only a handful of oncologic emergencies. It is one of the most important things to warn your patient about when they go home after getting chemotherapy.
"If you get a fever, go straight to the ER."
Time is critical with neutropenic fever. With no immune system, a "normal" UTI or pneumonia or cellulitis quickly becomes sepsis...
And sepsis quickly becomes septic shock...
And septic shock quickly becomes death...
So it goes.
So what actually defines neutropenic fever (also known as febrile neutropenia)? Here's what the IDSA says...
- single PO temp of >/= 38.3 C (101 F)
- sustained PO temp of 38.0 C (100.4 F) for 1 hour
- of note, axillary or rectal tempertures are discouraged
- absolute neutrophil count (ANC) < 500 cells/mm3, or an expected decrease to < 500 in the next 48 hours
- Profound Neutropenia
- ANC < 100 cells/mm3
- a manual reading of the blood smear is required to confirm this count (it's that low)
Patients are further stratified into high or low risk based on the Multinational Association for Supportive Care in Cancer (MASCC) score.
In short, according to the MASCC score, high risk patients get IV antibiotics. Low risk patients get PO antibiotics.
In practice (at least in my experience), basically everyone with febrile neutropenia gets IV antibiotics. Most patients have several co-morbidities and it's better to be safe than sorry.
So...how do we treat febrile neutropenica?
First, 2 sets of peripheral blood cultures from separate sites should be taken. This way the offending organism can be identified and antibiotics streamlined
Next, we give broad spectrum antibiotics...and we cover for Pseudomonas. Cefepime is a great choice. Pip/Tazo is a great choice (though you usually don't need the anaerobic coverage).
If the patient has an access point such as a central line or a catheter in place, you should also cover for MRSA (with vancomycin).
For more information on antibiotics that cover the resistant bugs, check out our post here.
We also give supportive care for blood pressure (if the patient is developing septic shock). This pretty much follows the Surviving Sepsis algorithm.
- Start with a fluid bolus (usually normal saline)
- Then add pressors in a stepwise manner until goal blood pressure is achieved. Norepinephrine is the pressor of choice in septic shock.
Once the blood cultures have provided an organism, streamline the antibiotic therapy down to specifically target the offending pathogen.
If fever persists in the patient for no apparent reason, antifungal coverage may be added.
Antibiotic treatment should continue until the ANC rises above 500 cells/mm3.
Febrile Neutropenia Prophylaxis
In certain high risk patients (such as leukemia or lymphoma), we may provide prophylaxis for an expected neutropenia.
Most frequently, that will consist of either ciprofloxacin or levofloxacin for the bacteria. In addition, we sometimes add acyclovir or valacyclovir for HSV prophylaxis. And fluconazole for antifungal coverage.
Once again, prophylactic coverage is given until the ANC gets above 500.
If you made it this far...pat yourself on the back. Go get yourself some ice cream. Or a glass of wine. Or whatever tickles your fancy.
You are now prepared to tackle anything that oncology throws at you (unless you become a specialist or something silly like that).
You're prepped for the NAPLEX, that APPE rotation, or the random AML patient who gets admitted when you're working on a Saturday night. They got nothing on you.
Ain't nothin' gonna break your stride
Nobody's gonna slow you down
And yes, for the record, I just ended a 7300 word post on oncology pharmacy with lyrics from an 80's pop song.
Do you want an Oncology Cheat Sheet?
It's got all you need to know for the NAPLEX. It's a great way to prepare for an APPE rotation. Keep it on hand when you're practicing and you'll know what to monitor.
It packs a ton of information in a single page. Dose limiting toxicities, renal and hepatic dosage adjustments, emetogenic potential, likelihood of hair loss, infusion reactions, and much more.