FDG-PET/CT In the Evaluation of Persistent Febrile Neutropenia in Cancer Patients
FDG-PET/CT In the Evaluation of Persistent Febrile Neutropenia in Cancer Patients
Patients must be currently treated at the Huntsman Cancer Institute or Intermountain Primary
 Children's Medical Center to be eligible for this study.

 Although there have been many advances in the assessment and treatment of infections
 responsible for febrile neutropenia in cancer patients, it still remains a common
 complication of cancer therapy and accounts for the majority of chemotherapy-associated
 deaths. This National Cancer Institute (NCI) funded proposal using the R-21 Quick-Trials
 Exploratory Grant mechanism is to conduct an exploratory/pilot project in a group of patients
 with persistent febrile neutropenia to provide critical information that will support the
 concept, and aid in the design, of a larger multi-center clinical trial. The ultimate goal of
 our interdisciplinary team of oncologists, infectious diseases experts, imagers, and
 biostatisticians is to conduct a prospective, multi-center trial to establish the utility and
 cost-effectiveness of PET/CT using the widely available glucose analogue
 [18F]fluoro-2-deoxy-D-glucose (FDG) in identifying sites of infection in cancer patients with
 persistent febrile neutropenia without an obvious identifiable source thus improving targeted
 therapy.
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.