FDG-PET/CT In the Evaluation of Persistent Febrile Neutropenia in Cancer Patients

What is the significance of this project? The significance is two fold: (1) the serious
nature of the clinical condition that it addresses, and (2) in the potential ease and safety
by which this approach could be translated to clinical practice. Although there have been
many advances in treatment modalities related to febrile neutropenia, it still remains a
common complication of cancer therapy and accounts for the majority of
chemotherapy-associated deaths (Sipsas 2005). The broad-spectrum therapeutic management of
febrile neutropenia is often "shotgun" in its approach, without a clear source to allow
target-specific therapy. The subpopulation of patients with febrile neutropenia that present
the greatest problem is that with persistent febrile neutropenia > 5 days despite broad
spectrum antibiotics, and without an identifiable source of infection. As noted previously,
however, the definition of persistence is changing in medical practice. Currently medical
professionals are ordering diagnostic imaging studies such as CT scans earlier due to the
need to localize a site of infection and use the most appropriate antibiotic therapy.
Without a target, multi-drug antibiotic therapy in these patients can continue for many
weeks. The drugs are often toxic, with substantial side effects. Hospitalization is
extended. The cost of broad spectrum hospital course of antibacterial and antifungal drugs
is in the range of multiples of $10,000, and the cost of extended hospitalization to treat
an unknown infection in a patient with persistent febrile neutropenia may be multiples of
$100,000. Chemotherapy may be suspended or discontinued, with risk of development of
chemo-resistant tumor cells. Conventional imaging methods are limited in evaluation of
febrile neutropenia due to lack of anatomic changes. The lack of sufficient white cells to
mount an inflammatory reaction compromises detection of sites of infection by radiography or
CT.

Because white cell number is severely reduced, the use of labeled white cell scans is often
precluded. If FDG-PET/CT can provide a likely anatomic site for targeted antibiotic therapy
in this specific high risk population, it is possible that morbidity/mortality from
infection and antibiotic side effects may be minimized, hospitalization days may be reduced,
and effective anti-cancer therapy may be continued without interruption. Although FDG-PET/CT
is not cheap, the ultimate result may be highly cost-effective.

Our oncologist and infectious diseases co-investigators predict that a tissue diagnosis can
be obtained in at least 80% of all FDG-PET/CT or CT findings that are suspicious for
infection in children and 50% in adults. This confirmatory tissue diagnosis will serve as
the "gold standard" to assess the effectiveness of FDG-PET/CT in finding a source of
infection.

Additional confirmatory factors will include clinical response to targeted therapy and
resolution of associated radiographic or CT findings. The data will be evaluated to address
the following questions, which are the sub-aims of the funded proposal:

1. How effective is FDG-PET/CT in identifying sites of infection in patients with febrile
neutropenia without an obvious cause?

2. To what degree does FDG-PET/CT improve detection of sites of infection over CT alone?

3. What FDG-PET/CT imaging variables best predict the presence of infection at a specific
site (e.g. standardized uptake value [SUV], concomitant abnormality on CT)?

4. Can the magnitude of uptake of FDG measured by an SUV at sites of infection predict the
identity of the infective agent (bacterial vs. fungal vs. viral)?

5. Does magnitude of uptake at sites of infection correlate with absolute neutrophil count
(ANC)?

6. Can a clinical scoring system be developed to identify a population of patients in whom
FDG-PET/CT is likely to be most efficacious in identifying sites of infection?

This pilot data will be used to determine whether there is sufficient support for, and to
aid in the design of, a large, prospective, multi-center clinical trial to establish the
cost-effectiveness and efficacy of FDG-PET/CT in evaluation of febrile neutropenia, compared
to patients who are managed by conventional methods.

Pediatric patients:

All pediatric subjects will be recruited from Intermountain Primary Children's Medical
Center (PCMC). At any point in time, there are 6-10 inpatients at PCMC who are being
treated as in-patients for febrile neutropenia. Each day, 2-3 new patients with febrile
neutropenia are admitted or transferred to PCMC from hospitals and clinics across the
intermountain area. Approximately 3-5 patients per week will be eligible for inclusion in
this study (having high-risk persistent febrile neutropenia without an obvious cause). The
target for this study is to recruit a minimum of 1-2 pediatric patients per month to the
protocol. Therefore, the eligible pediatric patient population should be more than
sufficient to meet this goal. Most of these patients are >10 years of age. The vast
majority are adolescents and teenagers, because pediatric patients at highest risk for
febrile neutropenia are those on high dose methotrexate for high risk leukemia and
lymphomas that target adolescents and teenagers. Leukemics constitute the largest
percentage of these patients. To be eligible for inclusion, subjects must be admitted for
treatment as in-patients for febrile neutropenia, with an absolute neutrophil count (ANC)
< 500 cells/mm3, in whom a fever persists without obvious source despite 5 days of broad
spectrum antibiotics. Typically, pediatric patients in this category will have been
treated with IV Fortaz (ceftazidime). We will also study patients that do not meet the
older definition of persistent (> 5 days) fever who for medical reasons an advanced
imaging study (typically CT scans) is now medically indicated for localization of a
possible site of infection. These patients will have a fever and be neutropenic, however
they may not have been febrile for > 5 days. Medical imaging is indicated sooner than the
typical 5 days due to the patients condition and need to localize a site of infection.

Exclusion criteria will include inability to undergo a FDG-PET/CT scan without conscious
sedation, medical instability that would preclude safe transport to the PET center in the
Huntsman Cancer Hospital (PCMC does not have a PET scanner), and a fasting serum glucose >
200 mg/dl. A negative pregnancy test will be required in post-menarche females prior to
inclusion.

Adult patients:

All adult subjects will be recruited from the Huntsman Cancer Hospital, patients will be
recruited from the general oncology service. As for the pediatric patients, those
considered eligible will include those with a documented fever > 5 days despite IV
antibiotics, an ANC < 500 cells/mm3, and in patient treatment as a high risk patient. We
will also study patients that do not meet the older definition of persistent (> 5 days)
fever who for medical reasons an advanced imaging study (typically CT scans) is now
medically indicated for localization of a possible site of infection. These patients will
have a fever and be neutropenic, however they may not have been febrile for > 5 days.
Medical imaging is indicated sooner than the typical 5 days due to the patients condition
and need to localize a site of infection. On average, 5-6 patients per week are admitted
to the Huntsman Cancer Hospital with the diagnosis of high risk persistent febrile
neutropenia. At any one time, there are typically 3-4 adult in patients on the ward with
the diagnosis of persistent febrile neutropenia. Of these, approximately 2-3 patients per
week will be eligible for inclusion in this study (having persistent febrile neutropenia
without an obvious cause). The target for this study is to recruit a minimum of 1-2 adult
patients per month to the protocol. Therefore, the eligible adult patient population
should be more than sufficient to meet this goal. As with the pediatric population, the
majority of these patients have leukemia and lymphoma (50:50). Adult patients may also
have multiple myeloma. In these patients, the typical duration of neutropenia is 3-4
weeks. Typically, the initial workup of the adult patients with febrile neutropenia is a
chest X-ray, CBC, urinalysis, peripheral and central line blood culture, and additional
studies only as directed by symptoms. Initial in-patient treatment for high risk patients
is typically with IV meropenem and ceftazidime. If fever persists beyond 5 days without
specific localizing signs or symptoms, antibacterials may be changed or added, and
antifungals are started (typically amphotericin B or caspofungin), typically persisting
until the white count returns to 1000 cell/mm3. Additional imaging studies are not done on
a consistent basis for the adults with persistent high-risk febrile neutropenia. Extended
imaging is typically done only as symptoms dictate. Typically, a source of infection is
found in only 40-50% of patients with febrile neutropenia at our institutions as well as
from the literature (Chaimberlain 2005; Hughes 2002; Roguin 1996). In the persistent
febrile neutropenia patient despite further and more comprehensive evaluation and
assessment a source is identified in only about an additional 10% of these patients.

As with pediatric patients, adult exclusion criteria will include inability to undergo a
FDG-PET/CT without conscious sedation, medical instability, a fasting serum glucose > 200
mg/dl, and pregnancy. A negative pregnancy test will be required of all females of
reproductive potential prior to inclusion.

Of note, patients from the bone marrow transplant unit will be eligible to participate in
this pilot study,. Many of these patients are placed on prophylactic antifungal agents at
the time of presentation of neutropenia and fever. This may cause a drug-induced fever in
a certain percentage of recipients. For this reason, the clinical picture is clouded
however the patients may still have an occult infection. Bone marrow transplant patients
will be included in the study as this is an exploratory study and the information gained
from assessing the ability of FDG-PET/CT to localize sites of infection in neutropenic,
febrile bone marrow transplant patients will be valuable.