Kelly R. Reveles, PharmD, PhD

When we talk about patients who are immuno-suppressed or have dysregulated gut microbiomes, and they get 

] and then get it again, what’s the syndrome of recurring 

? What’s your affinity for this? Is this a disease you like to treat? Or does it drive you crazy?

This is 1 of the most frustrating aspects of this infection. We hope that when someone comes in with pneumonia, we can treat with a round of antibiotics. But when I see a patient, I must tell them that there’s a chance that this infection may come back. After a first episode of 

infection, I tell my patient they have about a 20% chance that it’s going to come back.

 I want you to see the numbers people quote. You say 20%. What do you guys say?

I’d say between 20% and 30%, depending on overall risk factors that they have for recurrence after the first infection.

 Usually 20% to 25%. It’s going to depend on what they were treated with in the first place, though. We can get to that later, but I usually say about a quarter because that’s a nice round number.

Maybe I’m more generous. I say about 30%.

It slowly increases over time. After they get a second infection—if they’re in that 20% who got a second infection—they probably have a higher chance of getting it again. I’ll say about 40% or so. If they did get another infection after that, then they have about a 60% chance of getting it again. I consider them having a greater chance in a flip of a coin than getting 

. That’s what I call the vicious cycle of occurrence that we see thrown around, and it’s written in papers all the time. The reason is those individuals may have been treated with antibiotics or other agents to the point where they have lost resilience in the gut biodiversity and the microbiome. 

will flourish in that environment. Although we’re throwing the antibiotics to diminish the vegetative forms, we’re not addressing the spores that are present in this dysbiotic state. As Dr Khanna had mentioned, 

 is very good at producing its own bacteriocins or chemicals that suppress the recovery of that biodiversity. 

is extremely efficient at camping out and remaining inside a person’s gastrointestinal tract.

Is this where diet plays a role? Should you eat more complex fibers?

Early on you want to maintain the best balance inside of the gastrointestinal tract that you can. But over time, you reach this point of no return, which is that vicious cycle of recurrence because the microbiota have been shifted in such a way that you’ve lost the ability for colonization resistance to come back on its own. As we were talking about earlier, in treating 

 appropriately, the first go-round has an incredible impact on the risk of a subsequent recurrence. We’ll talk about IDSA [Infectious Diseases Society of America] guidelines in a few, and we’ll talk about why there have been shifts over the last decade or so in order for us to optimize treatment to treat our patients adequately and optimally the first time around because that gives them the best chance of success.

Let’s jump into that. What’s the best treatment for the initial phase, and what’s the best treatment for the second?

It’s interesting when you use the word 

Chosen specifically. There was a reason for that.

infection, I look at many things. I make an accurate diagnosis. They have the risk factors, they have symptoms, they have a test to confirm that this person does have 

infection. After all that housekeeping stuff is done, I start looking at what does this patient have that’s going to increase this person’s risk of recurrence? If I see a person who has an increased risk of recurrent 

by risk factors such as increasing age, immunosuppression, having a severe infection, getting other concomitant antimicrobial therapy at the same time—meaning they have the pneumonia still being treated and they have 

at the same time—then I look at the IDSA guidelines. I think about using a microbiome-sparing therapy, such as fidaxomicin for a period of about 10 days, or sometimes they use the extended regimen for about 25 days—the same number of capsules. But I try to use that in a patient who has the increased risk of recurrence. Cost is an issue. Availability is an issue. If either of those is an issue, then you must flip to vancomycin. If you have someone who doesn’t have these traditional risk factors for recurrent infection, then you can use vancomycin. This is the second-best treatment in most situations for the first infection. Again, it’s a 10-day course.

 I agree with Dr Khanna completely. The brand-new hot-off-the-press IDSA guidelines do recommend fidaxomicin as our first-line treatment for initial 

in severe and nonsevere cases. Using traditional dosing, we typically do twice a day for 10 days. But for recurrences, there are some great data with the extended-pulse dosing that you mentioned, where you essentially do a full dose twice a day for 5 days and then every other day for 20 days. The study that evaluated that regimen showed 1 of the lowest recurrence rates that we’ve ever seen in 

studies. That’s a potential option for recurrence.

We mentioned oral vancomycin. Oral vancomycin used to be our go-to antibiotic for treating 

,but it just wipes the gut microbiome. There are interesting studies show that when we take oral vancomycin, not only does it kill our gram-positive microbes, which it’s aimed to do, but because there’s such complex interplay among all our microbes in our gut, you can lose gram-negative bacteria as well. It’s interesting, which is why microbiome-sparing therapies like fidaxomicin can help to prevent future recurrences.

Dr Khanna, you mentioned cost. What’s underappreciated is just how much a recurrence can cost. We’re talking $10,000 to $12,000 to treat a patient who recurs in the hospital, and those initial drug acquisition costs with fidaxomicin can feel a little scary and give us some heartburn. But if you look at the cost-effectiveness, when looking through at least 1 or 2 recurrences, fidaxomicin is cost-effective in those settings.

Carl, how do you feel about that strategic approach for 

It’s important because if you step back and think about it, the treatment for 

is the risk factor for its recurrence. One of those major phyla that we spoke about was 

. In particular, a specific group of bacteria, 

, are reduced by the presence of vancomycin. We were using this treatment to suppress 

, but at the same time, we’re suppressing the colonization resistance. That’s what sets patients up for sometimes failure, because it’s a race against time as to what can reconstitute itself first after vancomycin has stopped.

win out, or will the colonization resistance come back? It’s hit or miss. We don’t know who that’s going to happen for appropriately. We want our patients to do well, but we’ve just given them an antibiotic that hurts them. Using an agent that can spare the rest of the gram-negatives—

 like fidaxomicin—makes the most sense. It’s 1 of the reasons the IDSA decided to state that fidaxomicin should be preferred slightly over vancomycin. You can use either 1, but there’s that caveat that you should prefer to use fidaxomicin for this reason. It makes more sense biologically to use an agent that will spare your floor because the floor is so important in managing the pathophysiology of this particular infection.

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Shared insight on the prevalence of recurring Clostridioides difficile infection and management strategies. 

Identification and Management of Recurrent C Difficile Infection

I’m going to put you on the spot for a little bit, but you are a PharmD, so I might as well ask, when we’re talking about duration of therapy, for an uncomplicated UTI [urinary tract infection], how many days?

How about a community-associated pneumonia?

It’s really fun to have this conversation because from an infectious disease perspective, a lot of us were trained that duration of therapy for health care-associated pneumonia should be 14 days. It’s a hard transition, but the science here is clear that for most cases, 7 days is a phenomenal choice. Then the other question is on selection of antibiotics. The traditional teaching is, oh, avoid clindamycin. I might argue that now, it’s fluoroquinolones, but where do you stand on that? What’s your drug of the day that you’re worried about?

 I will tell you; I don’t have strong feelings about fluoroquinolones and I’ll tell you why. We have some data microbiome studies that show that the disruption of the microbiome following fluoroquinolones is probably not quite as impactful compared to some of our other more broad-spectrum agents. We did see a significant increase in 

incidence in the 2000s related to the epidemic 027 strain and likely related to this big increase in fluoroquinolone prescribing, both in the inpatient and outpatient setting. That’s where we got scared about fluoroquinolones and thinking that they were associated with 

, which I do think they are, particularly the 027 strain. But to me, carbapenems and our beta-lactamase inhibitor combinations are probably our big drivers. If you think about where those agents are typically used, they’re going to be in patients who are really sick and hospitalized patients, since they’re IV [intravenous] therapies, and patients who often will have underlying conditions. For using carbapenems, they are likely having other multidrug-resistant organisms. These patients are already at high risk for poor outcomes, are already hospitalized, so have increased risk for 

exposure, and then you add on these big guns that are going to wipe out your gut. Those are the ones that I tend to worry about the most.

That’s right, there’s a context-dependency here.

Because the alternative story is if you look at the UK [United Kingdom] and their attempts to restrict fluoroquinolone use in the outpatient setting. What you’re driving at is stewardship in the right environment, and looking at need in both the outpatient setting, skilled nursing facility setting, long-term acute care, hospitalized patients. Each of these areas has a unique reality, and how to optimize for each of those is a different story. A topic that is also interesting is understanding the impact of other nonantibiotic-type medications, like PPIs [proton pump inhibitors] and others. How important is that? As an ID [infectious disease] guy, I’m going to say it’s all about the antibiotics, but is that right? Are there other things I need to think about, and how impactful are those sort of dynamics?

Yes, we do know that there are other medications or even procedural exposures that increase the risk for 

I would say gastric acid suppressants are up there in terms of one of our other medication classes that we’re more worried about. We’ve seen in epidemiological studies that there’s an association between both PPI use and H2 [histamine 2] blockers in 

 in PPI users. A little bit less among H2 blocker users. For a long time, we just assumed there were changes in the gastrointestinal pH, and we now have studies to support that. Our group did a study a couple of years ago where we took an older, healthy adult population, and we gave them just 2 weeks of low-dose omeprazole, and then we characterized their microbiome diversity and composition from the pre-PPI exposure to post-PPI and looked at those changes. It was interesting. We didn’t see any major changes in diversity, but we did see a compositional shift in the abundance of different bacterial taxa, particularly at the phylum and family levels. We saw changes that we often see in 

like a reduction in certain firmicutes, phyla, and bacteroidetes. It’s a lead into potential mechanistic association between the microbiome, proton pump inhibitors, and 

: It is a paper I refer to, so nicely done. Thank you very much. It’s one of the ones that goes to the fellows. The other comment here to talk about is, Carl, you deal with patients who receive stem cell transplants and now heart transplants. What is that impact of immune suppression on this?

 infections, it causes the infection by releasing a toxin in certain individuals. One has a second barrier of protection, which is the immune system, so the body is capable of making antibodies that can neutralize the toxin. If you were to lose some of those protective functions of your microbiota and 

decides to produce a toxin, one can neutralize that toxin. If you have both arms knocked out, you have loss of colonization resistance and loss of immunity, then that’s the perfect storm. You’re going to have an infection. In those patients who are critically ill or patients who are elderly, they’ll lose the ability to mount these robust immunoglobulin responses against toxin A or toxin B and develop a 

 infection. The immunity is extremely important. At some point, we can talk about some of the therapies that we use for 

 infections that can address this in certain individuals who are sick or immunosuppressed.

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Experts review the impact that medications, antibiotic or otherwise, may have on the development of Clostridioides difficile infection.

Impact of Therapies on Clostridioides Difficile Infection Development

One of the things that is helpful to understand is, among the spectrum of disease between health care-associated and community-onset cases, are there subsections of these groups of patients that are at higher risk for either developing disease or really bad outcomes?

 Yes, from a healthcare-associated standpoint, we are typically looking at patients who have already come into the hospital, they already have underlying illnesses. Maybe they’re in intensive care for a critical illness. Those patients are going to be the ones who we really worry about in terms of high mortality rates. There are some data to suggest that for patients in the ICU [intensive care unit], mortality may be as high as 37%, in critically ill patients with 

. So again, really severe outcomes. Now, community-associated 

 has been a little bit tricky. Of course, antibiotic exposure can potentially increase risk. We think that maybe an increased use of gastric acid suppressants among our outpatients may have contributed to that increase in community-associated cases. But as a general rule of thumb, our community-associated patients tend to have better outcomes and tend to have less severe disease compared to our health care-associated cases.

Any comment on patients in nursing homes?

I’ll add to that. Nursing homes are notorious to harbor patients with 

 infection. There have been outbreaks reported. Also, patients in nursing homes are exposed to antibiotics frequently, are exposed to PPIs [proton pump inhibitors] frequently. The incidence has been stable, but you do see high, stable incidence in patients in nursing homes, and they tend to have adverse outcomes in a similar manner to the hospital-acquired patient population, where they tend to get admitted to the hospital fairly frequently with 

 infection. I’d like to add one more thing to what Kelly said. In terms of the community-acquired patient population, there’s a small group, roughly about 20%, who have not been exposed to antibiotics. From a clinician’s standpoint, if you’re seeing someone who’s a little younger, because community-acquired patients are younger, who comes with chronic diarrhea lasting over several days to weeks, and they don’t have antibiotic exposure and there is no other explanation for the diarrhea, do consider 

 infection in today’s world because you could be missing that if you’re only looking for the hospitalized patient who’s had antibiotics. Because studies after studies are showing that 

 is out in the community in younger patients who may not have even received antibiotics.

What are you seeing in that realm, if any at all?

 really comes from. A lot of these places such as hospital care centers or nursing homes are just reservoirs where 

 exists. But as I was mentioning before, 

 is a ubiquitous organism, and it’s in the environment. In order for these patients in the community to get a

infection, they have to pick it up from somewhere. They may be picking it up from the food supply. They may be picking it up after being in the same local environment as someone who had

, who was discharged from the hospital. It’s difficult to predict which patients are going to be truly harboring or being colonized by 

in the community, but we know that it can range anywhere from 3% to 6% inside of the community. It’s just a matter of setting up the right sort of perfect storm.

We mentioned that antibiotics are a big risk factor for developing 

, but we can’t forget about the role of the diet that we mentioned earlier and what are a lot of the patients in the community consuming? Are they eating a healthy diet that nourishes the microbiome and supporting the protective mechanisms of colonization resistance from firmicutes and bacteroidetes? Are they consuming things that we never thought about before, such as complementary alternative medicines, things that are over the counter, like herbs and supplements and special kinds of teas, that also we know have some antibacterial activity? There are a lot of different things to consider when we see this increase slowly happening inside of the community, and it’s an active area of investigation that is important for us to understand, just given the numbers of what we’re seeing rise inside of the community. Of course, the patients inside of the hospital are just naturally sicker, and they tend to do worse than our patients who are in the community who can function and be in the community, so they have more of a reserve. They may have more resilience in their microbiome to attenuate the disease in the community.

How do we think about the interplay between exposure to 

 spores, antimicrobial stewardship, and this diet change? How do these things balance out?

Jim, in my mind, what I think about is, what’s the highest risk factor? Apart from that, what are modifiable and nonmodifiable risk factors? The highest risk factor, as we all know, is antimicrobial exposure. Antimicrobial stewardship is where you get your best bang for the buck, especially if you’ve got a patient population who’s getting frequent antibiotics, maybe for reasons that are not completely clear. People getting antibiotics for viral infections, which we’ve seen recently in the pandemic. That’s one part of it. Then I think about what are modifiable versus nonmodifiable risk factors? Increasing age is a risk factor for 

 that is nonmodifiable, sometimes hospitalization is nonmodifiable, and other disease states, those are nonmodifiable. You have to work around them, but antibiotics and antibiotic exposure probably is the most important modifiable risk factor that we have around for 

It’s important to note that not all antibiotics are created equal, and when we think of

risk, we tend to think of antibiotics that are going to have the biggest impact on our gut microbiome. It’s going to be related to spectrum activity, pharmacokinetics, are we getting concentrations in the gut, and then total exposure. Clindamycin has been our prototypical antibiotic to increase 

 for us because it has broad anaerobic coverage, high concentrations in the gut. But there are definitely several other classes of antibiotics that we know are associated with increased risk, like the carbapenems, our later-generation cephalosporins, our third and fourth generation. Some of our extended-spectrum beta-lactamase inhibitors like piperacillin/tazobactam, which just about everybody in the hospital gets nowadays, ampicillin/sulbactam, and then fluoroquinolones. Again, coming back, although a single dose can increase our risk for

, it’s cumulative antibiotics exposure that predominantly increases risk, the total duration of therapy, total number of different antibiotics, and dosing frequency as well.

On the duration of antibiotic question, the traditional teaching that we’ve heard is 7 days is kind of your cutoff. If you can keep it less than 7, your risk of 

 is [less] than more than 7. How would you react to that?

: From a stewardship standpoint nowadays, we are looking to see how short of a duration of therapy can we treat a patient with, to where we still optimize outcomes but limit duration of therapy just for this reason, to help not only prevent 

but the development of antimicrobial resistance. It totally depends on the patient. We have uncomplicated UTIs [urinary tract infections] that can be treated for a few days and be OK. But then we get some more complicated infections or septic patients with bacteremia where we need longer durations of therapy. It’s just that balance of treating the patient. Although we say antibiotics are modifiable, they are still critical for treating infection. It’s just a matter of, can we potentially use alternative antibiotics that pose a lower risk for 

and/or decrease our duration of therapy without affecting patient outcomes?

An overview of the risk factors that contribute to the development of Clostridioides difficile infection in various health care settings.

Who Is at Risk for Developing Clostridioides Difficile Infection?

: The costs of diagnostic, treatment, and end-of-life phases for advanced squamous cell carcinoma of the head and neck (SCCHN) are unknown, particularly after the approval of the first biologic agent for treatment, cetuximab. We aimed to characterize costs for each of the 3 disease phases and total cost of care for patients with advanced SCCHN before and after the approval of cetuximab.

: Retrospective, observational, cohort study.

: This was a retrospective analysis of the PharMetrics Choice insurance claims database. Patients 20 years or older with International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes suggestive of advanced SCCHN between March 1, 2003, and March 1, 2008, were included. Patients were divided into 2 cohorts by date of diagnosis: a “prebiologic” period and a “postbiologic” period. Descriptive statistics were used to summarize baseline patient characteristics, monthly and total medical costs, and cost drivers. The Mann-Whitney U test was used to compare medical costs between segments and cohorts.

: A total of 365 patients with SCCHN met the study criteria. Median monthly medical costs were: diagnosis ($2199), treatment ($4161), end-of-life ($6614), and total ($4167). Total medical costs were driven primarily by outpatient costs (23%), inpatient costs (18%), and the cost of radiation therapy (16%). In the treatment segment, median monthly costs were significantly lower in the prebiologic era compared with the postbiologic era ($3301 vs $4381; P = .0024).

: Median total costs exceeded $4000 per month for patients with SCCHN, driven primarily by the end-of-life segment. The median monthly costs of the treatment segment increased by approximately $1000 following cetuximab’s approval.

Head and neck cancers account for approximately 3% of all cancer diagnoses and 2% of cancer-related deaths in the United States.

 In 2015, an estimated 45,780 Americans were diagnosed with head and neck cancers, of which 90% were of squamous cell histology.

Currently, the estimated 5-year survival rate for all patients diagnosed with squamous cell carcinoma of the head and neck (SCCHN) is 60%. Of those diagnosed with SCCHN, 60% are diagnosed with locally or regionally advanced disease, generally denoting a poorer prognosis.

Fortunately, recent data from the American Cancer Society demonstrate a steady annual decrease in SCCHN mortality of approximately 2% for women. Mortality in men has since stabilized.

The decrease in mortality is likely attributable to advances in the management of head and neck cancers.

 The National Comprehensive Cancer Network clinical practice guidelines recommend combined modality therapy for patients diagnosed with locally or regionally advanced disease.

Currently, first-line recommendations include combining radiation therapy with chemotherapy (eg, cisplatin) or with biologic therapy.

 Cetuximab is a biologic therapy, an epidermal growth factor receptor inhibitor approved in 2006 for use in patients with locally or regionally advanced SCCHN in combination with radiation therapy.

Second-line options include surgery, radiation (if not previously given), or systemic therapy with various single-agent chemotherapeutic options: cisplatin, carboplatin, docetaxel, cetuximab, or fluorouracil.

With the rising cost of cancer care in the United States, new therapies must be critically evaluated in regard to their economic value. Multiple factors, including extent of care, advancements in diagnostic capabilities, and increases in cancer prevalence rates, have contributed to this rise in recent years.

 The growing use of newer drug therapies, such as biologic agents, is often cited as one of the primary drivers of increasing cancer costs.

 However, available cost analyses of head and neck cancers have been limited to time periods preceding approval of these newer treatment modalities.

Differing patterns of care across disease segments (ie, diagnosis, treatment, end-of-life) make it difficult to quantify the costs of managing specific cancers

; however, a longitudinal evaluation of incidence-based direct medical costs for specific cancers can be used to estimate long-term costs for managing patients with cancer.

 The objective of this study was to describe the segmented (diagnosis, treatment, end-of-life) and total direct medical costs associated with the management of SCCHN.

This was a retrospective, observational, cohort study utilizing data from a private payer claims database (PharMetrics Choice) spanning the period from September 1, 2002, through March 1, 2010. The study was approved by the institutional review board at the University of Texas Health Science Center at San Antonio.

The PharMetrics database is an integrated patient-level database of pharmacy and medical claims from more than 90 commercial health plans in the United States. The database is representative of commercially insured patients across the United States and captures various claims rendered, such as laboratory and diagnostic tests, outpatient physician visits, hospitalizations, outpatient clinic visits, and pharmacy-related costs.

The PharMetrics Choice database (derived from the PharMetrics database) excludes claims for carve-outs, patients who lack integrated pharmacy and medical benefits, plans that have failed to submit data for the previous 2 years, and plans that lack membership tables. In 2010, more than 55 million patients were included in the PharMetrics Choice database.

All patients 20 years or older and enrolled in an eligible health plan for more than 1 day between March 1, 2003, and March 1, 2008, (the enrollment period) were considered for initial sampling. Individuals with advanced or locally advanced SCCHN were identified using an algorithm developed for use with healthcare claims data (Figure 1).

Diagnosis of new SCCHN cases was determined by the presence of at least 1 inpatient or 2 outpatient claims suggestive of head and neck malignancies at sites with a high proportion of squamous cell histology. These claims were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 140.X to 148.X, 161.X, 195.0, and 196.0. The date of the first claim for SCCHN was assigned as the index date.

Eligible patients were required to have 6 months of continuous enrollment preindex date and 24 months of continuous enrollment postindex date to account for patient progression through all segments of disease. Additionally, patients were required to have claims and procedure codes indicative of receipt of therapy for squamous cell histology and recurrent and/or advanced disease (ie, stage II, III, IV). Patients with another primary malignancy, as evidenced by at least 1 inpatient or 2 outpatient claims, were excluded.

Variables evaluated at the time of the index date included patient age, sex, geographic region, and National Cancer Institute (NCI) Comorbidity Index score. This score was derived from the Charlson Comorbidity Index and numerically represents the risk of impending mortality according to the presence of various chronic diseases at the time of cancer diagnosis.

 Additional data, such as race, ethnicity, tobacco and alcohol use, and human papilloma virus status, were not reported for the study population due to a lack of reporting of such information in the claims database.

Patients were followed from the index date until patient death, end of continuous enrollment, or end of the study period (March 1, 2010). Patient follow-up was evaluated in total and as segments (ie, diagnosis, treatment, and end-of-life). These 3 disease segments were derived from prior published studies evaluating the economic burden of cancer across phases of care.

The diagnosis segment was defined as the period 90 days immediately preceding the index date plus the time until the receipt of active treatment, identified as claims for surgery, radiation therapy, biologic therapy, or chemotherapy.

The treatment segment consisted of all claims identified following the initiation of active treatment until the study's end or the start of the end-of-life segment. The end-of-life segment was defined as the period 90 days preceding death. As reporting of mortality in healthcare claims is limited, we used a previously published algorithm for identifying deaths within insurance claims databases.

Patients with claims ending prior to the study end (March 1, 2010) and coding of a “likely fatal event” (eg, hospitalization, hospice, emergency department [ED], resuscitation, or cardiac arrest) within 30 days of the last date of active enrollment were considered to have died. Those patients who did not experience a likely fatal event during the study period would have remained in the treatment phase and not experienced the end-of-life phase.

The primary outcome was direct medical costs of SCCHN from the payer perspective, according to the specific disease segment: diagnosis, treatment, and end-of-life. Cost estimates were based on direct medical costs paid and included total reimbursed amounts and all paid medical and pharmacy claims.

Claims for hospitalization, ED visits, outpatient physician visits, outpatient treatments, skilled nursing care, hospice direct costs, radiation therapy, and drug costs made during the follow-up period were included. Costs were reported as monthly costs for each segment. Secondary outcomes included total monthly cost, cost per disease segment and total cost, percentage of costs for individual claims, and cost comparison among the prebiologic and postbiologic cohorts.

The approval of new treatments allowed stratification across 2 time periods. Patients were categorized into cohorts surrounding the approval of the biologic agent, cetuximab. Patients with an index date between March 1, 2003, and February 28, 2006, were assigned to the prebiologic cohort whereas patients with an index date on or following March 1, 2006, were assigned to the postbiologic cohort. Costs were compared among individuals according to prespecified cohort.

Additionally, those patients who experienced all segments of care (ie, diagnosis, treatment, and end-of-life) were assessed separately. This analysis was performed to evaluate costs incurred in patients with a likely fatal event, as these costs may differ from those for patients experiencing only the first 2 of the 3 segments of care associated with advanced SCCHN. These patients were referred to as the “full-care” group.

Categorical data were reported as numbers and percentages. Data were compared using the 

2 method. Continuous data were reported using descriptive methods and compared across cohorts using the Mann-Whitney U test. All costs were adjusted to 2009 US dollars based on the medical services component of the Consumer Price Index and were presented as medians and interquartile ranges (IQRs).

All statistical analyses were conducted using JMP version 9.0 (SAS Corporation; Cary, North Carolina).

Initial sampling identified 38,601 patients with head and neck malignancies. A total of 365 patients met the study inclusion criteria for SCCHN: 100 in the prebiologic period and 265 in the postbiologic period (Figure 1). The eAppendix (available at www.ajpb.com) describes patient demographics for the study population in composite and among the prebiologic and postbiologic cohorts. Patients were predominately male (78%), with a median age of 57 years. The mean NCI Comorbidity Index score was 0.53 (SD = 1.04).

The median duration of follow-up after the index date for all patients with SCCHN was 30.1 months (eAppendix), predominated by the treatment segment (median = 27.3 months). Overall, the total median cost incurred for patients with SCCHN was $110,793 (IQR, $73,769-$156,836) (Table 1). The median cost for care of patients with SCCHN incurred in this study was $4167 per month over the follow-up period.

The end-of-life segment was associated with the highest monthly cost (median = $6614; IQR, $3172-$17,158), followed by the treatment segment (median = $4161; IQR, $2540-$7915); however, total costs (median = $99,247; IQR, $63,117-$142,653) were highest in the treatment segment due to the longer duration of follow-up. The diagnostic segment incurred the lowest total (median = $6341; IQR, $2749-$11,121) and monthly (median = $2199; IQR, $1077-$4677) costs.

Outpatient clinic visits, radiation, and inpatient therapy costs were the 3 main cost drivers, representing 23%, 18%, and 16% of total medical costs, respectively. During the treatment segment, outpatient visits (23%) were the primary cost driver (

Radiation therapy, when combined with intensity-modulated radiation therapy (IMRT), accounted for 39.5% of the total costs incurred. Composite oncology drug (chemotherapy plus cetuximab) claims accounted for 7% of treatment costs, with chemotherapy accounting for 2.6% and biologics 4.4%. Surgery accounted for only 0.6%.

Patient characteristics were similar for prebiologic and postbiologic cohorts, with the exception of geographic region (P <.0036) (eAppendix). The overall duration of diagnostic and end-of-life segments (if present) were similar, with median durations of 2.8 and 2.9 months, respectively (Table 2). Patients in the prebiologic period had a significantly longer median duration of treatment, resulting in a longer observation period compared with the postbiologic period (29.1 vs 26.8 months; P = .0023).

Median monthly costs in the treatment segment were increased in the postbiologic cohort compared with the prebiologic cohort ($3301 vs $4381; P = .0024), whereas costs in the diagnostic and end-of-life segments were not statistically different (Table 2). Total monthly costs were higher in the postbiologic cohort compared with the prebiologic cohort ($3236 vs $4421; P = .0006). Medical claims between cohorts remained unchanged, with the exception of IMRT (8% vs 14%; P <.0001), chemotherapy (4% vs 2%; P = .001), and cetuximab (0% vs 4%; P <.0001) use.

Twelve percent of patients (n = 44) in this study were included in the full-care group: 14 prebiologic patients and 30 postbiologic patients. Baseline characteristics of patients in the full-care group were similar to patients in the non—full-care group: median age (58.5 vs 57 years; P = .0943), percentage male (81.8% vs 77.8%; P =.5521), and mean NCI comorbidity index score (0.73 vs 0.50; P = .1476). Full-care patients in the prebiologic and postbiologic cohorts had similar baseline characteristics.

Median monthly costs in the full-care group according to segment were: diagnostic segment ($1733; IQR, $660-$3614), treatment segment ($8265; IQR, $3946-$17,851), and end-of-life segment ($6614; IQR, $3172-$17,157). Total median costs for the follow-up period were $122,041 (IQR, $73,582-$168,461), with the highest proportion of costs incurred in the treatment segment ($89,281; IQR, $46,598-$121,067).

In comparing prebiologic and postbiologic cohorts, median monthly costs and median total costs were similar across all disease segments. The total median monthly cost for the follow-up period ($7817; IQR, $4053-$12,243) was higher compared with the non—full care group, ($3889; IQR, $2549-$6757; P = .0002).

To our knowledge, this is the first study to characterize the segmented direct medical costs of SCCHN across disease segments during the era of biologic therapy. The results of this study illustrate the economic impact of SCCHN across different segments of care and capture the impact of cetuximab by evaluating the time surrounding the approval of this agent.

Earlier studies evaluated the cost of head and neck cancers utilizing data from the 1990s.13,14 In a study by Lang et al, the economic cost of SCCHN in patients 65 years or older used data collected from the Surveillance, Epidemiology, and End Results database.

The study results demonstrated a significant increase in the median cost of SCCHN compared with controls ($1428 vs $446 per month; P < .001), with most costs incurred from hospitalization. The investigators found that patients with regional and distant disease had higher average costs ($2059-$2547); however, chemotherapy and radiation accounted for only 8% and 10% of regional and distant disease costs, respectively.

In comparison, the median cost of care of patients with SCCHN incurred in this study was $4167 per month over the follow-up period. When converted to 2009 dollars, the median cost per month incurred for advanced-stage disease in the study by Lang et al

 would be approximately $3300, which is comparable with the costs incurred in our study.

Although our study is the first to our knowledge to evaluate the segmented costs of SCCHN, other studies have conducted similar analyses in other malignancies.

 Song et al evaluated the costs incurred for metastatic colorectal cancer during the era of biologic therapy.

Articles

The cost of squamous cell cancer of the head and neck is driven primarily by the end-of-life phase. Treatment costs increased following the approval of cetuximab.