Before I launch into further comments, a brief disclaimer: not all of this is evidence-based, but based on experience and what patients tell me when I ask them.  I will also say that there are two major areas to discuss here-palliative care as a new specialty, and the difficult conversations we face when things don’t go as we wish.

The Docs

Physicians are major contributors to the resistance in two major ways: 1. misperceptions of palliative care, and 2. reluctance to have the difficult conversations.  On the subject of misperceptions, physicians think of palliative care as only for patients at the end of their lives, or only when all anti-cancer treatments have been exhausted.  This deprives patients and their families of services that could help them at any point in the course of their disease and places the onus on patients and families to hear about palliative care.  There has been a some research to confirm this.  Most recently, the Center to Advance Palliative Care hired a polling company to do a “consumer report” on palliative care .  During the course of this report, they polled physicians on their understanding, and what do you know-they thought palliative care was only for patients at the end of life and that is the only time they refer.  In a study by Keating and colleagues of over 4000 physicians who care for patients with cancer, 65% said that they would discuss prognosis if they saw a patient with a 4-6 month prognosis and only 26% would discuss (not recommend) hospice.  Interestingly, while cancer specialists (medical, surgical, radiation oncologists) were more likely to discuss prognosis, non-cancer specialists were more likely to discuss DNR, hospice, and site of death (where a patient preferred to die).

The reluctance to have difficult conversations when treatments aren’t working is a more complex issue, I think.  On a very basic level, who wants to have difficult conversations?  Many avoid these conversations as much as possible.  We all get that “feeling” in our stomachs when we have to do something stressful-nausea combined with heartburn combined with butterflies.  The stakes are high, and it’s very emotional for all.  Multiple studies have demonstrated that there is only minimal training in these communication skills during the formal years (medical school, residency).  A mentor of mine in palliative care would say to me, “Competence is a great stress reliever.”  Physicians, just like most human beings, tend to avoid things that they aren’t good at.  Better education on this topic and these skills would help.  Just think, business school students get all sorts of classes on negotiations and tough conversations to prep them for the hard conversations, like when they have to fire someone, or when they have to tell their board of directors the venture failed.  Why not have more rigorous education for physicians-in-training who will be having conversations about prognosis and dying.  I’ll also say that discussions like these do take time, and sometimes it is just faster and easier not to talk about such hard topics.  Unfortunately, procrastination is not suitable for patient care, especially for patients who have serious illnesses.

What Patients Say

Similar to physicians, there is a lack of understanding of what palliative care is.  Most people think it is for patients on hospice.  CAPC’s report revealed that of 800 random adults surveyed, 70% were not at all knowledgeable of palliative care.  I get that question all the time: What is palliative care?  Is it rehab?  Is it hospice?  That same report also revealed that once the participants were educated about palliative care, 95% agreed that it is important for patients and families with serious illness be informed about palliative care.  92% said that they would be likely to consider palliative care for a loved one if they had a serious illness and that it should be made available at all hospitals.  Basically, when most folks here about palliative care, they think it’s a good thing to have.  We all need to continue to educate the public and each other about palliative care.

Things become more complicated when we look at why patients resist discussing care that is solely palliative, i.e. when cure is not achievable and anti-cancer treatments are no longer effective.  To pull back the curtain on what I do, physicians often call on our palliative care service to help facilitate these tough discussions when communication is not going well.  Ultimately, I still think that most of the heavy lifting in having needs to come from the physicians-studies have shown that patients are interested in speaking with their physicians about advance care planning (who is the patient’s surrogate decision-maker, what to do when treatments don’t work, how they want to spend their time if prognosis is limited, etc), but won’t bring it up first.  This should be something physicians bring up as part of comprehensive patient care.  For those times when more treatment is not necessarily better care, patients tell me it is very difficult not to “do something” at the cancer, even if they are told it will not work.  This makes sense, but as in all fields of medicine, we have found that sometimes, less is more-that better outcomes don’t always come from more drugs, more procedures.

The question of hope comes up a lot in these discussions.  Hope is a complex thing, not just one-dimensional.  Hope doesn’t exist only when there is treatment going on, but I think many view it this way and fiercely adhere to that view.  And of course, the hope for cure, for long life, is an important hope, but the inter-workings of human emotion and psyche go beyond that.  There are often lots of different hopes (hopes for being pain-free, hopes for spending time with family, hopes for not having to hang out so much in a hospital, etc).  Chris Feudtner, a pediatrician and medical ethicist, wrote a moving perspectives article in the New England Journal of Medicine a few years ago that I have found helpful, basically urging us all not to underestimate or limit what hope exists.

The Hard Part of Palliative Care

I can tell you that in these tough circumstances when the treatment doesn’t go how we want, when the diagnoses are devastating, we all have the same prelude to everything we do: “I wish that things were different…”  That being said, palliative care is there for patients, families and clinicians as we face tough times.

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What exactly is “early palliative care”?  What exactly was happening in those visits?  Could it be replicated?  I’m a palliative care doctor, and I’ve been trying to figure this out myself.

In a separate article earlier this year, Jennifer Temel (a thoracic oncologist) and her colleagues took a closer look at what was happening in those visits. In general, they noted that palliative care consultation teams provide support through a number of ways, including symptom management, decision-making, education regarding illness, coping (for both patients and families), and planning ahead. In their article “Components of Early Outpatient Palliative Care Consultation in Patients with Metastatic Nonsmall Cell Lung Cancer”, they found that out of all the services that palliative care consultation provides, there were three particular areas that were emphasized in these outpatient visits: symptom management, patient and family coping, and understanding of illness. They also found that for those patients who reported a lower quality of life, the palliative care clinicians spent more time on symptom management during their visits. The clinicians did not know about any of the scores the patients reported.

On the surface, this makes some sense, particularly in thinking about improved quality of life and mood. The outcome of longer survival with palliative care is not as simple to explain. Indulge me here, as I go through a thought experiment with each of these content areas–symptom management, coping, and illness understanding—and seeing how they could lead to increased survival.

Imagine having pain under better control: one would be more mobile and more functional. One can imagine that if a patient was having a lot of troublesome symptoms, these may be a barrier to continuing a particular therapy. For example, if a patient was receiving chemotherapy but was so miserable from symptoms they wanted to stop—maybe not even side effects directly of the chemotherapy, but other symptoms (pain, fatigue, etc.). Aggressive symptom management may then enable a patient to continue their therapy.

In considering patient and family coping, I can imagine that if coping could be strengthened, this may lead to lower stress. There have been some studies on metastatic breast cancer patients in support groups and some survival benefit associated (as compared to similar patients not in a support group).

Illness understanding is an intriguing content area to contemplate. Why would understanding the illness better lead to longer survival? Perhaps patients may make decisions more deliberately if they have a resource like palliative care to assist them in the decision-making process.

Overall, the visits weren’t all about death and dying, a common misconception of palliative care. The bottom line? Early palliative care is still a black box, but one that has been opened! Stay tuned…

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qa-dr-lacouture-on-skin-hair-nail-side-effects-of-treatment-transcript

This was really all audio without associated slides, so no figures or video version for this one.

Thanks again to LUNGevity Foundation for their partnership with GRACE in this program and the podcast. I hope it’s helpful.

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Below you’ll find the audio and video versions of the podcast, as well as a pdf file of the transcript and figures that go with it.

dr-lacouture-on-skin-hair-nail-side-effects-of-treatment-audio-podcast

dr-lacouture-on-skin-hair-nail-side-effects-of-treatment-transcript

dr-lacouture-on-skin-hair-nail-side-effects-of-treatment-figures

The live podcast was followed by a lively question and answer session, and we’ll have that podcast available shortly.

Thanks to Dr. Lacouture for not only doing the live presentation but for taking the time to re-record a version he was happier with to offer to people as a resource.  And thanks, as always, to LUNGevity Foundation for partnering with us to make this series of live programs and podcasts possible.

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What is a DVT and what is a PE?

DVT stands for deep vein thrombosis. “Thrombosis” is the doctorly word for, “clot,” and the deep veins are the larger veins of the legs and arms.

DVTs can disrupt the flow of blood from an extremity (arm or leg) causing swelling and pain. This is most commonly a leg, although it can happen in the arms, especially when there are larger IV lines in place (such as a PICC or PORT). However, the true danger of DVTs is their propensity to spread. Just as the spreading of cancer has a name (metastasis) the spreading of clot has a name—embolus.

Blood from the extremities flows into a big vein called the vena cava. As the diagram above shows, blood from the vena cava (including any clots it caries) travels to the right side of the heart, where it is then pumped out to the arteries of the lungs (pulmonary arteries). These vessels branch as they reach towards the edges of the lung and as they do so, they get smaller and smaller. When blood clots spread from the deep venous system to the lungs via this path, this is called a, “pulmonary embolus,” or “PE.” The clot will get lodged once it arrives in a vessel too small for its continued passage.

By blocking off the flow of blood to the lung, a PE deprives part of the lung of oxygen, causing it to die. This is very much like a heart attack, but in the lung. Once lung tissue dies, it cannot be regenerated and is thus lost forever. While this, “lung attack,” is going on, the most common symptoms are shortness of breath and chest pain. PEs can also cause the heart not to work well, and can even cause death.

Causes of DVT

There are many causes of DVT and sometimes more than one is at play. Among these are:

· Damage to the lining of a blood vessel (this lining is also known as, “vascular endothelium.” There are many cause for this type of damage including venous access lines like a PICC and the damage caused by a high-fat diet and lack of exercise)

· Stasis (including not moving around secondary to surgery or a long airplane trip)

· Surgery

· Inherited predispositions

· Smoking

· Obesity

· Hormonal influences (pregnancy, hormone replacement therapy, birth control pills)

· Some medications

· Nephrotic kidney disease (the kind where protein is lost in the urine, including anti-clotting proteins)

The astute observer will note that I left off one of the most important causes of DVT and PE—cancers. One of the best studies to look at clots in cancer patients was published in 2009 by Wun and White in Cancer Investigations.

There are several important themes to this table that are echoed through similar studies. First, thrombosis (clotting) is very common in cancer. Second, more advanced cancers cause more clotting than more local cancers. Finally, lung cancer is one of the most prothrombotic cancers. Also of note, the risk of clotting goes up, not down with chemo, even when the chemo works well to control the cancer.

Diagnosis—Physical Examination and Symptoms

The major symptoms of DVT are leg pain and swelling. In my opinion, almost any new leg swelling in a lung cancer patient should prompt evaluation for DVT, because it is so common and cause so many problems. Doctors often consider DVT more likely to be the cause of swelling if only one extremity is swollen. I agree with this, but note that I’ve diagnosed bilateral DVT in many lung cancer patients with swelling of both ankles.

When your doctor squeezes your ankles at physical examination, he/she is mostly looking for swelling. Another physical examination sign of DVT is a positive, “Homen’s sign.” In this test, the doctor bends your ankle towards your head—if this hurts, the sign is considered positive. While I do this test, it’s so-so in predicting for presence or absence of DVT.

Diagnosis—Medical Tests

Before getting to the tests that do work, I’ll get out of the way discussion of a blood test that I consider less useful in lung cancer patients, but worth mentioning because it is frequently done. D-Dimer is a blood test for clots. In non-cancer patients, a negative D-dimer is very predictive for absence of clot. However, lung cancer tends to elevate D-Dimer and so it’s really hard to find a lung cancer patient (even those without clots) with a negative D-Dimer.

So, let’s move on to good tests. The best test for DVT is an ultrasound of the legs. They’re called, “Doppler studies,” or, “LENIs” (lower extremity, non-invasive). The ultrastenographer places the ultrasound probe over the deep veins of the leg. Normal veins are easily compressible. However, clots are hard and if present, will cause the ultrastenographer to be unable to compress the vessel. In my hospital (and many others) if the test is negative, the ultrastenographer tells the patient. If it’s positive, the ultrastenographer sends the patient back to my office, and we address it together (more to come, in “treatment” below).

When a patient presents with shortness of breath, chest pain, or other symptoms that make the oncologist concerned for PE, we will test for it. The most commonly used test for PE is the CT angiogram, or CTA for short. In this test, CT contrast is rapidly administered so that it can light up the vessels of the lung. If any spot inside the vessels is dark instead of being lit up by the dye, this will be because clot is present. It looks like this:

The CTA is the preferred test for PE at most institutions. It is fast, easy, and readily available at any hour of the day or night. My favorite thing about the CTA is that it can also diagnose things other than PE because it images the whole lungs and heart. For example, if a patient with lung cancer comes to the ER with shortness of breath, a CTA might be ordered to evaluate for PE. Even if a PE isn’t present, the CTA might find compression of an airway by cancer, pleural effusion, pneumonia, or one of a myriad of other possible causes. However, CTA is not the right test for every patient. Its major limitation is the need for contrast dye, which can be a problem for patients with allergies or kidney problems. In this case, the doctor might order a V/Q scan. The, “V” stands for “ventilation” and the, “Q” for perfusion. When everything is working right, these should be matched—blood should flow maximally to places of maximal air exchange. With PE, these will be mismatched. Unfortunately, there are many other causes of V/Q mismatch and so back when this test was in common use, the most common answer was, “indeterminate” and resident physicians carried around cheat-sheets that combined pre-test probability of PE based on symptoms together with the test results to get a final probability of PE.

The mainstay of clot treatment, both DVT and PE, are blood thinners. The body has complicated chemical cascades that remodel clots by simultaneously breaking down clots while rebuilding them. Blood thinners work by blocking some part of the rebuilding part, shifting the balance towards breaking down. Perhaps the most commonly used blood thinner in the US for lung cancer patients is lovenox. Lovenox is given as a shot twice a day. The need for self-injection and high cost are the major disadvantages of lovenox and related drugs such as arixtra. Their advantages are data for superior efficacy in cancer patients, and drug levels that are easy to get right without the need for a lot of blood tests. Lovenox can be used both in the hospital and at home, at the same doses.

The major alternative to lovenox is the blood-thinner pill Coumadin (warfarin). The major advantages of Coumadin are that it is cheap and that it is oral. However, I must be honest that while it is in common use both in the US and the rest of the world, it is one of my least favorite medicines. Coumadin has a lot of food and drug interactions. If you change your meds, your diet, or even look at your pills the wrong way, Coumadin drug levels will be off. When levels are low, the risk of clotting increases and when they are too high the risk of bleeding increases. Therefore, to use Coumadin correctly, blood tests (the test is called INR or PT) should be done very frequently. Finally, in the first few days it is started, Coumadin is actually pro-coagulant, and so must be used together with another blood thinner like lovenox or a heparin drip.

A new class of drugs have been developed called, “direct thrombin inhibitors” or DTIs. The only one FDA approved in the US is dagibatran. It is not yet indicated for DVT/PE, but I look forward to the day when it is—I’d love to be able to offer my patients a pill to thin their blood whose levels are always right. I’ve been actively trying to encourage the manufacturers of these pills to study them further in lung cancer patients—let’s keep our fingers crossed!

I also recommend compression stockings to patients who have had a DVT. They can reduce the incidence of complications after a DVT (called post-thrombotic syndrome).

Finally, there are two less commonly used therapies that I’d at least like to mention. The first is an IVC filter. The IVC is the big vein that carries blood from the lower part of the body back to the heart. The idea of the filter is that it will catch any clots that try to travel (embolize) to the lung. This device makes a huge amount of common sense, but isn’t nearly as good as it sounds. In fact, IVC filters are very controversial. They can be great for stopping a DVT from turning into a PE if there’s some reason that you can’t use blood thinners, like right after major surgery or trauma or if the platelet count is super low. And, they work well for a few months. However, after that time, especially in patients already prone to clots like lung cancer patients, they actually increase the risk of new DVTs. I occasionally use them when in a bind, but feel that they are generally used too much. I also feel that when placed, most of them should be removed after the tough situation has passed, typically within a few months. The second less-common therapy is thrombolysis. These are clot-busting drugs. Their best use is with the worst life-threatening PEs—the ones that cause the heart to have trouble pumping well. While these drugs work great to break up clots, their major problem is that they cause bleeding—bad bleeding. One newer use of these drugs is to use fancy catheters to deliver smaller doses of the drug right to the site of the clot (“catheter-directed thrombolysis). I’ve used this some in patients whose clots don’t improve on a blood thinner alone and have had some good results, but do not consider it the standard therapy for the average patient.

Every blood thinner increases the risk of bleeding. Therefore, it is wise for the oncologist to monitor platelet counts carefully while on chemo. As a patient, it is wise for you to consider wearing an alert bracelet that you are taking a blood thinner. If you should have any trauma like a car accident, it will be important for anyone caring for you to know that you are on a blood thinner.

A final word must be made regarding duration of anticoagulation. The minimum anticoagulation period after a clot for a lung cancer patient is 3 months. However, in my opinion (and, forgive, me, I’m very opinionated because I’ve spent a lot of time thinking about clots in lung cancer patients) the optimal duration for a patient with metastatic lung cancer is life-long. The reasons is that the cause of the clot never goes away—while metastatic disease can sometimes be controlled for a long time, the cancer is still there in the body secreting its pro-inflammatory chemicals and the patient may still need chemo, which increases the risk further. While I do worry about bleeding in my patients on anticoagulation, I worry more about clotting. The reason is simple—if a patient bleeds, I can replace the blood. However, I cannot replace tissue that dies because of lack of blood flow, and the incidence of death from clots is very real. Lifelong anticoagulation is not right for every patient with lung cancer and a DVT or PE. However, for the motivate patient who isn’t super bothered by the shots, and has no contraindication, I think that lifelong anticoagulation is the best thing to do.

Prevention

It makes great sense to try low doses of blood thinners in lung cancer patients who have never had a clot and it is has been tried. So far, there’s no great evidence that this is the right thing to do. So, as a patient, I recommend keeping mobile, keeping hydrated, and watching out for leg swelling. And, as I was pretty frank about above, I believe that the best prevention against a new clot in a patient who has already had one is lifelong, full-dose anticoagulation, ideally with lovenox or a similar agent.

For More Information

For more information about clots, I recommend http://www.clotconnect.org/ . I know and work with the people running the site, have reviewed it, and think that it’s great.

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For this particular patient, I argued for consideration of surgery, on the premise that while the long term success rate of about 9% in this situation, based on the surgical literature, was better than an essentially 0% chance of success without it, and that this person was relatively young and fit.  Even if his cancer recurred after surgery, he would prefer to have had the opportunity, and I felt it was likely he’d tolerate the surgery far better than most patients.  Though his cancer recurred several months after surgery, despite my giving him additional chemotherapy in the adjuvant setting, neither of us felt regret for trying.

Something similar can be said for many of our treatments in oncology.  There are many treatments, curative or palliative, that offer only a small window of potential success, but which are the attractive strategy in many cases where the alternative is resignation to a disappointing result. Another physician noted to me, “Don’t forget that when the bad guy with a gun on the top of a cliff is about to shoot the hero of the story, the hero always takes his chances and jumps off“.  Slim odds are better than no odds.

I agree with that mentality, at least to a point.  In many cases in cancer care, the more aggressive approach still provides no meaningful chance for benefit, and it can often be associated problematic side effects that are only reasonable to accept when that treatment isn’t truly futile.  And the resignation of not pursuing anti-cancer treatment isn’t just settling for no benefit: there can be great comfort in focusing on symptomatic management as well as having family and friends along with the patients work on acceptance and mutual support.  More treatment just for the sake of more treatment isn’t valuable, but I can definitely understand why slim odds and an absence of proof would still provide enough hope to lead them to favor a more challenging approach.

I’m interested in whether this analogy feels apt or not to people living with cancer, as well as other related thoughts you may have.

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Preventing F & N

There are three basic ways to prevent febrile neutropenia. When appropriate, a regimen with a smaller chance of causing F & N can be chosen. There are two other options: the use of drugs to bring the neutrophil count up, and prophylactic (preventative) antibiotics.

There are two drugs in common usage for lung cancer that can raise the neutrophil count. The first is called neupogen and the second neulasta. I’ve linked to the Amgen page on neulasta because I think that it’s actually pretty helpful. Granted, it’s there to sell more neulasta, but in trying to do so, the page on blood counts makes two very valid points about low blood counts: they can cause direct problems by causing infection, and they can interfere with needed chemotherapy.

How do these drugs work? As we discussed above, the bone marrow is a factory for making blood cells, including the subtype of white blood cells we’ve been talking about—neutrophils. Neupogen and neulasta send an artificial signal to the bone marrow to make more neutrophils, hurry up and get them ready, and release them into the blood. Neuopgen is given every day until the counts have recovered, typically a week or two. Neulasta is a long-acting drug that you only need to give once.

Both drugs, when utilized, are typically started 24 hours after chemotherapy. The package insert for both says that they shouldn’t be used for 14 days before chemotherapy. The reason for this is theoretical—doctors fear that if they send the bone marrow a signal for the blood-making stem cells to divide while chemo is still around, they will risk poisoning these stem cells, actually making the problem worse. This makes a lot of sense, but is it true? While coming back the next day is only a minor nuisance for some of my patients, for others it represents a significant hardship. What do the data say?

As usual, they are not definitive. Four randomized studies compared same day neulasta administration to the usual 24 hours post administration. Studies were done in patients with breast cancer, Non-Hodgkin’s lymphoma, NSCLC and ovarian CA. Overall, there was no clear harm from giving the neulasta the same day:

As a result of this study, I became less dogmatic about always using neulasta the day after chemo. If a patient has to drive several hours to come to my infusion room and there is no option for administration closer to home, I talk to them about same-day neulasta. But, I don’t do so without some schpilkas. Neutropenia duration was actually longer in the breast study and the lymphoma study with same day dosing. This is important, because risk of F&N goes up with neutropenia duration. Further, none of these studies looked at patients for long followup. Did the same-day groups have more problems with counts in future cycles? We don’t know. My practice, when possible, remains to give the neulasta the next day.

Who should get prophylactic neulasta? While the drug can prevent febrile neutropenia, it can also cause side effects. The patient product information sheet lists all kinds of side effects, but I prefer patient-reported information. Patients most commonly complain of bone pain and a flu-like syndrome. Plus, there’s the inconvenience of having to come to the doctors office the day after chemo, a minor nuisance for some but a big problem for others. Both ASCO (American Society of Clinical Oncology) and NCCN (national comprehensive cancer network) guidelines recommend neulasta prophylaxis when the risk of febrile neutropenia reaches 20% and I think that this guideline is very reasonable.

Now, on to things that don’t work. Preventative antibiotics are rarely used in lung cancer patients. The reason is that the duration and severity of neutropenia with lung cancer regimens is just not deep or long enough to justify the risk of antibiotic side effects and the risk of antibiotic resistance. There are certainly specific cases where I consider it, but routine prophylactic antibiotics would be more likely to harm than to help the average lung cancer patient. Patients often ask about cloistering themselves at home to try to avoid infections while they are neutropenic. Neither data nor my experiences suggest that this works. The biggest reason is that infections with F&N in lung cancer regimens are largely from bugs that are everywhere, rather than from bugs that you specifically pick up from someone. It makes sense to practice good hand hygiene, and to avoid people who are actively sick. It’s unclear that avoiding your healthy grandchildren will help you to live a day longer (unless their mischief is so bad that it shortens your life!) There’s a very important caveat to what I’m saying—while it applies well to lung cancer and head/neck cancer regimens, none of this is true for hematologic cancers (leukemia, lymphoma, bone marrow transplant patients) and is not oriented even towards patients with other solid cancers who get more intensive regimens (such as sarcoma). This conversation is very head/neck and lung centered because, at the time of writing, GRACE is an exclusively head/neck and lung cancer site.

Treatment of febrile neutropenia

In the doctor’s office or hospital, the doctor will look for a source of infection. This workup typically includes history taking (questions that could point to a source, such as, “Does it burn when you pee?” and “Are you coughing?”), physical examination, imaging, and cultures of urine and blood. If a source can be found, then the antibiotic regimen can be tailored to the bug in question. If not, broad-spectrum antibiotics that are active against most suspected bugs are given. If the suspected source is a line (such as a PICC) then strong consideration must be given to removing it.

The use of neupogen and neulasta to treat febrile neutropenia has not been studied nearly as much as their use to prevent infections. A meta-analysis suggested that their use can shorten length of hospitalization and time to recovery of neutrophil counts, but not survival. NCCN recommends consideration of these drugs if certain risk factors are present. I’ve re-ordered them from the NCCN’s list into the order in which they influence my thinking:

· Sepsis (a severe inflammatory syndrome associated with infection)

· Pneumonia

· Invasive fungal infection

· Neutropenia expected to be more than 10 days in duration

· Severe neutropenia (absolute neutrophil count < 100/mcl)

· Hospitalization at the time of fever

· Other clinically documented infections

· Age > 65 years

· Prior episode of febrile neutropenia

Can any patient with febrile neutropenia be managed at home? Most patients hate being admitted to the hospital. Beyond being unpleasant, admission to the hospital can interfere with sleep, reduce contact with loved ones, and be a great place to catch resistant bugs. To me, the following factors make me more comfortable with considering outpatient treatment of F&N:

· Known or strongly suspected source

· Reliable patient (especially including willingness to go the ER for any worsening)

· Presence of reliable partner (ability to monitor patient, willingness to insist on ER trip if things get worse)

· Patient does not seem super sick—this is a combination of what my patient tells me, my physical examination (especially vital signs) and my gut feeling

· Short expected duration of neutropenia (biggest factor is regimen and current timing from regimen, but patient history with counts also matters)

· Mild severity of neutropenia (counts aren’t super low)

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Febrile Neutropenia, Part I: The side effect of chemotherapy your doctor (probably) worries about the most Introduction I have asked many patients what side effect of chemotherapy they fea...

I have asked many patients what side effect of chemotherapy they fear the most. The most common answer is nausea, very closely followed by fatigue (or its cousins such as feeling, “blah,” or the consequences of fatigue such as not being able to do things). I’ve never asked the question of another oncologist, but I suspect that over half would respond, “F&N.”

F & N is not, “fresh and natural,” nor is it, “fries and nutella.” Rather, it’s, “febrile neutropenia.” What is this? Basically, it’s a fever, potentially indicating infection, at a time when blood counts are low.

As a patient, the most important thing to know if you should get a fever while on chemotherapy is to take it seriously. This should be seen as a top medical emergency prompting a visit to the ER and/or a call to your doctor. The reason is that the infections associated with febrile neutropenia can be extremely serious, and can progress quickly. This is not the time to spare your doctor a wake-up phone call in the middle of the night or to spare your partner having to get up and go to the ER. While these infections can be serious, when headed off quickly with IV antibiotics, most patients recover quite well. While definitions of fever vary, 100.4 Fahrenheit is a reasonable threshold.

But why should chemotherapy make blood counts low at all? Tumors grow through division of the cells that compose them. Chemotherapy works by killing rapidly dividing cells. Most cells in the adult body do not divide, and so are less affected by chemotherapy than cancer cells. However, there are a few places in the human body where cells normally divide and are thus affected by chemotherapy—the bone marrow is one of these places. The bone marrow is a factory where special cells called stem cells divide to make all the different kinds of blood cells. Chemotherapy temporarily lowers blood counts by shutting down the blood cell factory in the marrow. Occasionally, chemotherapy can even completely kill one of those stem cells, permanently reducing the speed at which the factory can produce cells. This is why following many cycles of chemotherapy, count recovery can become increasingly sluggish.

Types of blood cells

There are three basic types of cells in human blood: Platelets, red blood cells (aka erythrocytes), and white blood cells.

In adults, these cells are mostly made in the bone marrow.

Platelets help control bleeding by starting the formation of clots. A normal platelet count is 150,000 to 400,000. We rarely talk about platelets in lung cancer care because even at their lowest, most patients have enough to share with friends and neighbors. Hematologists (blood doctors) argue about how many platelets patients need. But, very roughly, most patients will not spontaneously bleed with more than 10,000 platelets, can tolerate minor trauma or surgery with >50,000, and can tolerate brain surgery with >100,000. It is rare for lung cancer regimens to bring platelet counts lower than 100,000, with one notable exception—gemcitabine containing regimens.

Red blood cells carry oxygen to the tissues of the body, including the heart, lungs, and brain. When red blood cell counts are low, this is called anemia. Patients vary greatly in how low this count can go before they have symptoms such as fatigue and shortness of breath. The two biggest factors in determining how well a patient can tolerate anemia are how fast the count fell (with greater tolerance for slower falls) and the patient’s other medical problems (particularly heart problems and lung problems).

What are neutrophils?

Finally, we get to the counts that we will focus on here—the white blood cell count. White blood cells fight infection. When the white blood cell count is low, patients are more prone to infections and if they get infected it is more likely to be serious. There are several kinds of white blood cells. Perhaps the most important kind is neutrophils. Neutrophils are the marines of the immune system. They are the first on the scene to fight infection and you cannot fight infection properly without them. They are sometimes referred to as “polys,” which is short for polymorphonuclear neutrophils, or “PMNs.” When the neutrophil count is low, this is called, “neutropenia.”

Lung cancer chemotherapy

On average, the neutrophil count is at its lowest between day ten and day fourteen after chemotherapy.

Chemotherapy regimens vary in their propensity to cause F & N. I’ve compiled for you below some of the most commonly used lung cancer and head/neck regimens, their rate of neutropenia, and their rate of F & N in major studies.

NSCLC Regimens

Regimen                                 Study               Rate gr 3-4 neut.      Rate of F&N

SCLC Regimens

Regimen                             Study              Rate gr 3-4 neut.       Rate of F&N

Head and Neck Cancer Regimens

Regimen                                    Study                    Rt gr 3-4 neut.    Rate of F&N

When considering risk of febrile neutropenia, the data mostly address the regimen itself.  While it’s true that the regimen is a huge factor in the probability of developing febrile neutropenia, the patient is also an important factor.  Prior treatment with chemotherapy and radiation increase risk.  Other factors that increase risk include age, other medical problems, advanced cancer, performance status, infection, open wounds, recent surgery, kidney function, and liver function.

Part two will follow within a few days.  It will cover prevention of F&N and its treatment once it happens.

Related posts:

Febrile Neutropenia, Part II: Prevention and Treatment Preventing F & N There are three basic ways to prevent febrile neutropenia...

1) Most patients don’t suffer much as their cancer progresses and as they transition through the dying process.

2) This process is quite variable from one person to another, but we typically have a good idea of what a patient’s leading problems will be weeks to months before a person is experiencing a more rapid decline.

3) Engaging hospice services/palliative care can help guide expectations and generally manage many of the problems effectively by anticipating them, rather than waiting until very late to accept palliative care.

While I would never want to romanticize or minimize the challenges of the dying process, I find that the majority of my patients experience a controlled decline in which they really don’t suffer.  The most common pattern I see is that someone with a progressing cancer will slow down, eat less, begin to lose weight more steadily, and just gradually become less and less active.  They no longer go out on walks, then leave the house less often, then spend more time alternating between sleeping and getting up in a chair, then eventually get to a point where they are sleeping most of the time and are pretty much bed-bound.  They have less interest in eating, which is sometimes frustrating to the patient but often more so to the family and supporters of the person, who may pressure the patient to force down food that they have little or no appetite for (the danger is that some patients describe distress from the unyielding pressure from well-intentioned but nagging loved ones).  Soon, they are sleeping more and more, to the point that they eventually sleep all of the time and are no longer communicative; this is followed by irregular breathing, more prolonged pauses between breaths (called agonal breathing, though it isn’t uncomfortable for the person, just a reflex — the last phase of the dying process), and then they stop breathing. It’s important to remember that this common pathway of progression isn’t a lack of will on the part of the person with progressing cancer: they would eat and be more active if they could, but the cancer pours out toxic proteins that mediate this inexorable process.

It’s true that some patients have pain, or a terrible cough, or shortness of breath, agitation, and other problems, but I would say that most of the time, we have signals that these are going to be issues for a long while before the later stages, and it’s advisable to deal with them as aggressively as possible before these symptoms become a crisis.  Secondly, I most commonly see problems emerge when people (patients and/or their doctors) are very resistant to enlisting hospice support, which typically does a very good job of addressing symptoms proactively, before they become a crisis, and also being able to provide the comfort of helping patients and families/caregivers to understand what to expect in the near future.  Just as on a plane, turbulence is much easier to understand if you know to expect it, what it represents, and how you’ll get through it.

About 20 years ago, I spent some time in medical school doing home visits with the very compassionate and thoughtful Medical Director of a Boston hospice.  I asked him about his feelings on euthanasia, and he told me that he didn’t actually feel that it was a pressing need in almost any cases.  Specifically, he noted that it was most common for people to fear two things about dying: being alone in being in pain.  Though being a primary caregiver is a very hard job, it is a great blessing to have someone there to help as a caregiver to a terminally ill patient — something that even attentive medical care can’t substitute for.  That care and the ability to ensure that people aren’t alone is incredibly helpful.  But a medical team today can usually do a good job to minimize the physical suffering of the process — to relieve pain and other symptoms.  And most of the time, what we see is a patient gradually withdrawing and eventually passing comfortably.

Related posts:

Why Not Palliative Care? Some thoughts on resistance… I consider GRACErs a very enlightened bunch regarding of palliative care, but outsid...

What is Hospice: Fact and Fiction Hospice is both an organization and a philosophy of care. It was first conceptualize...

Hoarseness

Introduction

Thank you to cross-bearer for asking about hoarseness. Hoarseness is any change in voice quality. Most commonly, it is experienced as decreased volume with increased strain. It’s a common problem in lung cancer patients, so common that we’ve discussed it over 40 times in the forums and so I think that it may be time for a proper post discussing it.

There are many causes of hoarseness in the lung cancer patient. Many of these also happen in people without lung cancer, but all are more common in our circles either because of effects of the cancer itself, side effects of cancer treatments, or both.

Normal speech

Speech is produced in the voice box, or larynx.

External view of Larynx

Here’s a cartoon of the larynx from inside.

View of larynx (voicebox) from NPL or larygoscopy

Vocal cord inflammation

In general, there are many causes of hoarseness. We’ll start with causes of larynx (vocal cord) inflammation, otherwise known as laryngitis, that can also occur in non cancer patients. First is voice overuse. If you’ve ever yelled a lot at a ballgame, you may already be familiar with this one. Similarly, infections of the larynx by viruses and bacteria are not uncommon. Cancer patients, especially those receiving chemotherapy (and thus having low blood counts) are particularly prone to fungal infections (thrush). This is the same thrush that can be seen in the mouth. When a patient has both thrush in the mouth plus another symptom lower down (sore throat or hoarse voice) I always consider the possibility that the fungal extension extends lower than I can see.

Thrush

Thrush can be treated with antifungals such fluconazole.

There are also a variety of non-malignant sources of inflammation that can affect the vocal cords such as noncancerous growths and noncancerous inflammatory conditions.

Larynx Cancer

Larynx cancer is cancer of the vocal cords. It is a type of head and neck cancer, which has such a close biologic relation to lung cancer that I consider it a brother more than a cousin. Head and neck cancers are mostly squamous cell—the same cell type found in a little under half of lung cancer. The major causative factor of larynx cancer is tobacco, with some contribution from alcohol consumption. The HPV virus that we have recently discovered to be an important cause of tonsil cancer does not seem to be a major cause of squamous cell carcinoma of the larynx. Obviously a cancer of the vocal cords impairs their function. We’ve started covering head and neck cancer on GRACE and you can find more information about it here.

Lung cancer

The brain controls the muscles of the body through wires called nerves. The nerve connecting the brain to the vocal cords is called the recurrent laryngeal nerve.

Lung cancer most commonly causes hoarseness by pressing on on the recurrent laryngeal nerve. Also, the surgeon may sometimes accidentally (or unavoidably) cut this nerve while cutting a lung cancer out.

A reasonable person might wonder how this can be. After all, the brain is above the vocal cords and the lung is far below—so how can lung cancer push on this nerve? Well, it turns out that the recurrent laryngeal nerve takes a funny path. It branches off the larger vagus nerve, travels under the aorta in the AP window, an area of the left lung commonly involved with lung cancer, and travels back up to the voice box. Interestingly, those who believe in evolution use this indirect path as an argument in favor of evolution while creationists insist that the design is, in fact, intelligent. We’ll leave that question aside—enough people have made themselves hoarse yelling about it.

Evaluation of hoarseness—the importance of NPL

By far, the most important test to evaluate hoarseness is NPL. NPL stands for nasopharyngolaryngoscopy. In this procedure, an ENT doc sprays some numbing medicine into the nose, and then passes a thin tube in. This thin tube passes to the back of the throat and down to the larynx, where the ENT can see the vocal cords. If there is something abnormal present, like, cancer or thrush, he/she can see it. As you speak, the ENT can see if one or both cords fail to move. You can see a picture of the scope itself here and the cartoon view of the cords above is what the ENT sees.

Treatment of hoarseness

Many of the treatments of hoarseness address the root cause. For example, if there is a fungal infection, you give an antifungal. If the patient is yelling too much at baseball games, you introduce him to cricket (am I right that you don’t yell at cricket matches?) If there is impingement of the recurrent laryngeal nerve leading one cord to not move, there is treatment available beyond just treating the cancer.

The root problem when the recurrent laryngeal nerve is dysfunctional is that the cord on that side doesn’t move. It therefore can’t come towards the middle of the airway to enable proper sound production. There are several procedures that are all variants on the same basic idea—they move the dysfunctional cord toward the middle of the airway so that when the other side moves, it comes close enough to make a good seal. This is called medialization.

Injection is typically done with the patient awake.

It can be done with a variety of materials, such as teflon, fat, collagen, hyaluronic acid, calcium hydroxyapatite gel, and polydimethylsiloxane gel. Each of these materials has its advantages and disadvantages, although typically the ENT will counsel the patient as to which material is right for them. Injections can be done with local numbing medicine, sparing the risks and discomforts of sedation. The video below shows the procedure, as well as what NPL looks like. I can’t promise that your ENT will play the “Peanuts” theme song while restoring your voice.

Video of injection

When surgery is used, some kind of implant is put in to push the dysfunctional cord towards the functional one. Again, there are a variety of materials that can be used for the implant and I defer to the ENT surgeons to counsel individual patients regarding which material is right for them. I found a utube video of the surgery. The narration is a bit technical and the images are not for those with a weak stomach, but it does give the basic idea of what is done.

medialization laryngoplasty video

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