Purpose/Objective(s)[18F]F-MISO PET is an established hypoxia imaging surrogate, and a prognostic and predictive marker of overall survival in head and neck squamous cell cancers. We utilized long-term follow-up data to assess whether pretreatment focal FMISO uptake can predict location of local tumor recurrences.Materials/MethodsOutcomes for 11 HN SCC patients on an FMISO-PET imaging study treated at the University of Washington between January 2005 and September 2006 were retrospectively reviewed. Original treatment plans were fused with pre-treatment FMISO scans and follow-up CT demonstrating first recurrence. Prescription dose was 70 Gy for all but one prescribed to 66 Gy. All patients received concurrent chemotherapy. Maximal SUV in the FMISO uptake region was determined, and contours by threshold segmentation at 75%, 80%, 85%, and 90% of SUVMax were formed. Volumes of FMISO contours, overlap with recurrence volume and original GTV volume were calculated.ResultsOf 11 patient analyzed, with median follow-up of 51 months (range, 3-68 months), four are alive and seven have died. Seven had local recurrence or progression, with 5 in the primary GTV area, and two in the nodal region. Of those recurrences/progression areas, 6/7 overlapped with the FMISO75% uptake contour, with mean overlap volume of 9.04 mL (range, 3.71-37.17 mL), encompassing a mean of 33.8% (range, 13-80.8) of the recurrence volume. 6/7 also had overlap between FMISO80% contour and 5/7 had overlap with the FMISO85% and FMISO90% contour. Mean percent overlap between the recurrence areas and FMISO uptake increased in areas of highest uptake, with 31% at FMSIO75%, 34% at FMISO80%, 36% at FMISO85%, and 40% at FMISO90%. Conversely, mean percentage overlap between FMISO uptake and initial GTV decreased in areas of highest uptake, with 41.2% for FMISO75%, 44.3% for FMISO80%, 26% for FMISO85%, and 15% for FMSIO90%.ConclusionsIn previous studies, FMISO uptake was shown to predict for overall survival and local recurrence. In this study, we found that pre-treatment areas of highest FMISO uptake could predict the location of subsequent tumor recurrence, with areas of higher thresholds uptake overlapping with a higher percentage of recurrence area. The areas of higher threshold of uptake were also less likely to have been encompassed by the original GTV contour. Radiation boost to the FMISO uptake volume may improve local control, and has been previously shown by our group to be dosimetrically feasible. These results lend support for a Phase II trial to investigate the impact of a subvolume boost in a prospective manner. Purpose/Objective(s)[18F]F-MISO PET is an established hypoxia imaging surrogate, and a prognostic and predictive marker of overall survival in head and neck squamous cell cancers. We utilized long-term follow-up data to assess whether pretreatment focal FMISO uptake can predict location of local tumor recurrences. [18F]F-MISO PET is an established hypoxia imaging surrogate, and a prognostic and predictive marker of overall survival in head and neck squamous cell cancers. We utilized long-term follow-up data to assess whether pretreatment focal FMISO uptake can predict location of local tumor recurrences. Materials/MethodsOutcomes for 11 HN SCC patients on an FMISO-PET imaging study treated at the University of Washington between January 2005 and September 2006 were retrospectively reviewed. Original treatment plans were fused with pre-treatment FMISO scans and follow-up CT demonstrating first recurrence. Prescription dose was 70 Gy for all but one prescribed to 66 Gy. All patients received concurrent chemotherapy. Maximal SUV in the FMISO uptake region was determined, and contours by threshold segmentation at 75%, 80%, 85%, and 90% of SUVMax were formed. Volumes of FMISO contours, overlap with recurrence volume and original GTV volume were calculated. Outcomes for 11 HN SCC patients on an FMISO-PET imaging study treated at the University of Washington between January 2005 and September 2006 were retrospectively reviewed. Original treatment plans were fused with pre-treatment FMISO scans and follow-up CT demonstrating first recurrence. Prescription dose was 70 Gy for all but one prescribed to 66 Gy. All patients received concurrent chemotherapy. Maximal SUV in the FMISO uptake region was determined, and contours by threshold segmentation at 75%, 80%, 85%, and 90% of SUVMax were formed. Volumes of FMISO contours, overlap with recurrence volume and original GTV volume were calculated. ResultsOf 11 patient analyzed, with median follow-up of 51 months (range, 3-68 months), four are alive and seven have died. Seven had local recurrence or progression, with 5 in the primary GTV area, and two in the nodal region. Of those recurrences/progression areas, 6/7 overlapped with the FMISO75% uptake contour, with mean overlap volume of 9.04 mL (range, 3.71-37.17 mL), encompassing a mean of 33.8% (range, 13-80.8) of the recurrence volume. 6/7 also had overlap between FMISO80% contour and 5/7 had overlap with the FMISO85% and FMISO90% contour. Mean percent overlap between the recurrence areas and FMISO uptake increased in areas of highest uptake, with 31% at FMSIO75%, 34% at FMISO80%, 36% at FMISO85%, and 40% at FMISO90%. Conversely, mean percentage overlap between FMISO uptake and initial GTV decreased in areas of highest uptake, with 41.2% for FMISO75%, 44.3% for FMISO80%, 26% for FMISO85%, and 15% for FMSIO90%. Of 11 patient analyzed, with median follow-up of 51 months (range, 3-68 months), four are alive and seven have died. Seven had local recurrence or progression, with 5 in the primary GTV area, and two in the nodal region. Of those recurrences/progression areas, 6/7 overlapped with the FMISO75% uptake contour, with mean overlap volume of 9.04 mL (range, 3.71-37.17 mL), encompassing a mean of 33.8% (range, 13-80.8) of the recurrence volume. 6/7 also had overlap between FMISO80% contour and 5/7 had overlap with the FMISO85% and FMISO90% contour. Mean percent overlap between the recurrence areas and FMISO uptake increased in areas of highest uptake, with 31% at FMSIO75%, 34% at FMISO80%, 36% at FMISO85%, and 40% at FMISO90%. Conversely, mean percentage overlap between FMISO uptake and initial GTV decreased in areas of highest uptake, with 41.2% for FMISO75%, 44.3% for FMISO80%, 26% for FMISO85%, and 15% for FMSIO90%. ConclusionsIn previous studies, FMISO uptake was shown to predict for overall survival and local recurrence. In this study, we found that pre-treatment areas of highest FMISO uptake could predict the location of subsequent tumor recurrence, with areas of higher thresholds uptake overlapping with a higher percentage of recurrence area. The areas of higher threshold of uptake were also less likely to have been encompassed by the original GTV contour. Radiation boost to the FMISO uptake volume may improve local control, and has been previously shown by our group to be dosimetrically feasible. These results lend support for a Phase II trial to investigate the impact of a subvolume boost in a prospective manner. In previous studies, FMISO uptake was shown to predict for overall survival and local recurrence. In this study, we found that pre-treatment areas of highest FMISO uptake could predict the location of subsequent tumor recurrence, with areas of higher thresholds uptake overlapping with a higher percentage of recurrence area. The areas of higher threshold of uptake were also less likely to have been encompassed by the original GTV contour. Radiation boost to the FMISO uptake volume may improve local control, and has been previously shown by our group to be dosimetrically feasible. These results lend support for a Phase II trial to investigate the impact of a subvolume boost in a prospective manner.

2554 Background: PR104 is a nitrogen mustard pre-prodrug activated by hypoxia or the reductase AKR-1C3. When activated, PR104 exerts cytotoxicity through DNA crosslinking. Preclinical studies support combining PR104 with G or D. The MTD of single agent Q3wk PR104 is 1100 mg/m2 with dose-limiting toxicity (DLT) of neutropenia. Methods: Patients (pts) for which treatment with single agent G or D was considered reasonable were eligible. PR104 was combined with either G (800 mg/m2) or D (60 or 75 mg/m2) in 4 separate groups. Grp A received PR104 + G on days 1 and 8; Grp B received PR104 + D (60 mg/m2) on day 1; Grp C received PR104 + D (60 mg/m2) on day 1 with GCSF; Grp D received PR104 + D (75 mg/m2) on day 1 with GCSF. All groups were retreated on a 21 day cycle. Plasma pharmacokinetics was assessed with cycle 1. At selected sites tumor hypoxia was evaluated with F18-fluoro-misonidazole positron emission tomography (FMISO-PET). Results: 42 pts: 23 F/19 M; median age 61 (range 27-87); median of 2 prior chemotherapy regimens (range 0-3); NSCLC (10 pts), pancreatic and prostate (4 pts each), sarcoma and melanoma (3 pts each), and other solid tumors (18 pts) received a median of 3 treatment cycles (range 1-23). Grps A (6 pts) and B (6 pts), defined MTDs for PR104 at ≤200 mg/m2 with myelotoxicity as DLT. Grp C (21 pts) defined an MTD of 770 mg/m2 for PR104. The DLTs in 2/6 pts at 1,100 mg/m2 were grade 4 thrombocytopenia and grade 3 fatigue. Two pts had a partial response (nasopharyngeal and H&N cancer) and 10 pts (5 with NSCLC) had stable disease (≥6 cycles). Grp D (6 pts restricted to ≤1 prior chemotherapy) received PR104 at 770 mg/m2 + D at 75 mg/m2 with GCSF, no DLT were observed. PR104 was rapidly converted to the alcohol PR104A and further metabolized to the glucuronide PR104G and the cytotoxic hydroxylamine PR104H. Tumor hypoxia was detectable in 11/17 baseline scans. Conclusions: The MTD ofPR104 with G or D in the absence of concomitant GCSF is ≤200 mg/m2. With GCSF, PR104 can be administered at a dose of 770 mg/m2 (70% of its single agent MTD) with D (60 or 75 mg/m2). A randomized phase II trial of PR104 + D (60mg/m2) with GCSF was initiated in relapsed NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Proacta Proacta Proacta Proacta

Purpose To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels. Materials and methods Testicular uptake and retention of 131I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54±11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using 131I-tositumomab. Time–activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy. Results The absorbed dose to the testes showed considerable variability (range=4.4–70.2 Gy). Pretherapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction [4.6±1.8 nmol/l (pre-RIT) vs. 3.8±2.9 nmol/l (post-RIT), P<0.05]. Patients receiving higher radiation doses to the testes (≥25 Gy) showed a greater reduction [4.7±1.6 nmol/l (pre-RIT) vs. 3.3±2.7 nmol/l (post-RIT), P<0.05] compared with patients receiving lower doses (<25 Gy), who showed no significant change in total testosterone levels. Conclusion The testicular radiation absorbed dose varied highly among individual patients. Patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.

3575 Background: PR-104 is a prodrug with selective toxicity to hypoxic tumor cells. In these cells, PR-104 forms a nitrogen mustard alkylator causing DNA crosslinks. Preclinical data suggest additive efficacy for PR-104 combined with G or D. This study defines the toxicities, maximum tolerated dose (MTD) and pharmacokinetics (PK) of PR-104 in combination with either G or D, with or without GCSF. Methods: Patients (pts) had cancer for which G or D was considered reasonable treatment by the physician. All cohorts (>3 pts) received a fixed dose of G (800 mg/m2) or D (60 mg/m2) with escalating or de-escalating doses of PR-104 administered IV every 3 weeks (wks): Grp A=PR-104 (starting at 275 mg/m2) + G on days 1 and 8; Grp B=PR-104 (starting at 400 mg/m2) + D on day 1. Grp C=PR-104 (starting at 200 mg/m2) + D on day 1 with prophylactic GCSF. PK was assessed for cycle 1. At U.S. sites, tumor hypoxia was evaluated by positron emission tomography (PET) using F-18-fluoro-misonidazole (FMISO). Results: To date, 23 pts have been dosed: median age 62 yrs (range 30–85); 12 male (52%); median of 2 (range 0–3) prior chemotherapy regimens. Grp A: At 275 mg/m2, 2 DLTs in 3 pts: grade (gd) 4 thrombocytopenia (1pt) and gd 4 thrombocytopenia/gd 4 neutropenic fever (1pt). Non-DLT toxicity included gd 3/4 neutropenia (2 pts). At 140 mg/m2, no DLT in 6 pts. The PR-104 MTD was 140 mg/m2. Grp B: At 400 mg/m2, 2 DLTs (gd 4 neutropenic fever) in 3 pts. At 200 mg/m2, 2 DLTs (gd 3 neutropenic fever) were observed. The PR-104 MTD was <200 mg/m2 with D. Grp C: At 200 (3 pts) and 400 mg/m2 (3 pts), the most frequent adverse events were neutropenia (17%), fatigue (14%), vomiting (14%), headache (12%), nausea (12%), thrombocytopenia (10%) and anemia (8%). Four pts had stable disease: NSC lung (11 cycles), ovarian (7 cycles) breast and melanoma (6 cycles). The maximum plasma concentration of G was 69 ± 38 umol/L; the AUC of D was 3098 ± 2613 ng.h/mL. Tumor hypoxia was detectable in 8/10 pts. Conclusions: The MTD of PR-104 + G is 140 mg/m2. The MTD of PR-104 + D is < 200 mg/m2. Both are less than the single agent MTD of 1100 mg/m2. GCSF allows dose escalation of PR-104 + D (currently accruing at 550 mg/m2). FMISO PET detected tumor hypoxia in a majority of pts. PR-104 does not appear to significantly alter the PK of G or D. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Proacta, Inc. Proacta, Inc. Proacta, Inc.

Purpose The majority of patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL) are older than 60 years, yet they are often denied potentially curative high-dose therapy and autologous stem-cell transplantations (ASCT) because of the risk of excessive treatment-related morbidity and mortality. Myeloablative anti-CD20 radioimmunotherapy (RIT) can deliver curative radiation doses to tumor sites while limiting exposure to normal organs and may be particularly suited for older adults requiring high-dose therapy.

Animal studies have shown that hypoxic tumors are more invasive, likely to metastasize, and resistant to radiation therapy. However, evidence from human studies is mixed, presumably owing to widely different methods for measuring hypoxia. It has been postulated that the selective delivery of higher doses of radiation therapy to more radioresistant cells would improve control rates. However, continued dose escalation, even to limited volumes, needs to be justified given the significant associated morbidity. [F-18] fluoromisonidazole (FMISO) PET allows for the imaging of cells with a clinically important level of hypoxia. Our objective was to evaluate whether there is increased local failure in patients who have higher volumes of hypoxic tumor and whether this translates to a compromise in disease-specific survival and overall survival. From April 1994 to April 2006, 88 patients with biopsy-demonstrated head and neck cancer were enrolled in an institutional review board–approved protocol. All patients underwent routine laryngoscopy, contrast-enhanced computed tomography, chest X-ray, and routine laboratory evaluation to determine staging. In addition, an FMISO PET was performed before initiation of treatment. For this analysis, patients were then broken down into two groups on the basis of whether they had a lower or higher volume of quantified hypoxic tumor. A retrospectively determined cutoff of < or = 5 mL of total tumor volume exhibiting a tumor/blood ratio of ≥1.2 was used. Primary survival analyses were performed using the Kaplan-Meier method. Secondary analyses to determine the independence of the prognostic effect was via a Cox multivariate hazards model. Seventy-eight of the 88 patients met the inclusion criteria for this study. Median follow-up times were 3 years and 2.3 years for the non-failing cohort and the entire group, respectively. The 5-year overall survival (OS) for the entire group was 51%. When comparing the groups with low vs. high hypoxic tumor volumes, corresponding actuarial 5-year rates of OS, disease-specific survival (DSS), freedom from local regional failure, and freedom from distant metastases were 81% vs. 24% (p = 0.02), 80% vs. 27% (p = 0.02), 78% vs. 59% (p = 0.44), and 87% vs. 64% (p = 0.11), respectively. On Cox multivariate analysis, FMISO hypoxic volume >5 mL (p = 0.04), higher FDG PET Max SUV (p = 0.04), and higher stage (p = 0.05) independently predicted for a lower DSS. No single factor maintained independent significance as a predictor for OS, although FMISO hypoxic volume >5 mL showed a strong trend (p = 0.079). Similarly, FMISO hypoxic volume >5 mL did not independently predict for a higher local or regional failure. Greater than 5 mL of hypoxia within a tumor volume is a significant predictor for poor 5-year OS and DSS. For DSS, this parameter is independent of the predictive values gained from overall stage, T stage, grade, primary site, and FDG PET. Both local regional failure and metastatic failure appear to contribute to DSS, although these parameters did not individually meet significance. Thus, continued study on how specific regions of local failure correspond to regions of initial hypoxic volume is needed before utilizing hypoxic tumor volumes as a target for dose escalation.

LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, has been found to radiosensitize various human cancer cells. However, its potential to act as an effective therapeutic agent is diminished by its toxicity levels. The purposes of this study were to determine the mechanism by which LY294002 radiosensitizes.Cell growth curves and clonogenic assays were performed with increasing LY294002 exposure times proximate to the radiation dose. Protein levels of downstream PI3K effectors were analyzed. Detection of phosphorylated histone H2AX (γH2AX) was used to identify DNA double-strand breaks at various time points post-radiation.LY294002 significantly radiosensitized HeLa cervical cancer cells when administered for just 12 h following radiation. Cell growth curves also decreased with brief LY294002 application. DNA double-strand breaks are typically repaired within 2–6 h following radiation. Interestingly, at 48, 72, and 96 h post-irradiation, γH2AX was still significantly elevated in cells radiated in combination with LY294002. Protein expressions of ATM and ATR downstream effectors showed no differences among the treated groups, however, DNA-PK activity was significantly inhibited by LY294002.These results lead us to conclude that the central mechanism by which LY294002 radiosensitizes is via DNA-PK inhibition which induces DNA double-strand break repair inhibition. We are currently investigating radiosensitization induced by DNA-PK-specific inhibition in efforts to find a less toxic, yet equally effective, chemotherapeutic agent than LY294002.

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.

Purpose: To investigate the use of [F‐18] fluoromisonidazole (FMISO) PET and intensity modulated radiation treatment (IMRT) planning to escalate the dose to hypoxic subvolumes in patients with advanced head and neck tumors. Method and Materials: Seventy‐three patients with head and neck cancer underwent FMISO‐PET scans, with fifty‐three of them also undergoing FDG‐PET scans as part of ongoing research studies. An initial treatment plan used a PTV defined with a 0.5‐cm margin around physician‐defined primary GTVs and affected nodal systems. The prescription dose is 70 Gy to the PTV and 50 Gy to the affected nodes, while sparing the spinal cord, mandible, and parotid glands. Physician‐defined regions of enhanced FMISO signal were used to define boost volumes on coregistered FMISO‐PET/CT images. The boost plan prescription dose to the hypoxic subvolumes is an additional 10 Gy. Results: Initial results from example treatment plans for two head and neck cancer patients are as follows (average over patients): to the PTV V100 = 87.2%, Dmin = 6081 cGy, D10 = 7303 cGy and to the nodal system V100 = 95.9%, Dmin = 4764 cGy, D10 = 5280 cGy. The IMRT boost plan yields V100 = 95.1%, Dmin = 979 cGy, D10 = 1012 cGy to the hypoxic PTV. The critical structures of interest received the following dose distributions from the composite IMRT plans: cord D1 = 3890 cGy, left (contralateral) parotid gland D1 = 1965 cGy, right parotid gland D1 = 4907 cGy (same side as primary tumor), and mandible D5 = 6220 cGy. Conclusion: We demonstrate the feasibility of directing dose‐escalated IMRT to hypoxic subvolumes in head and neck cancer using coregistered FMISO‐PET and CT images. Ongoing research and patient studies are expected to provide conclusive information on the clinical role of this procedure.

Background. 2-deoxy-2[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) imaging can be registered with CT images and can potentially improve neck staging sensitivity and specificity in patients with head and neck squamous cell cancer. The intent of this study was to examine the use of registered FDG-PET/CT imaging to guide head and neck intensity modulated radiotherapy (IMRT) planning.Methods. Twenty patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx underwent FDG-PET and contrast-enhanced CT imaging of the head and neck before neck dissection surgery, Combined FDG-PET/CT images were created by use of a nonrigid image registration algorithm. All IMRT plans were theoretical and were not used for treatment. We prescribed 66 Gy in 30 fractions to FDG-avid CT abnormalities and nodal zones directly involved with disease, without prophylactic coverage of uninvolved neck levels. Matched CT-guided IMRT plans designed according to the specifications of Radiation Therapy Oncology Group (RTOG) H-0022 were available for comparison. We investigated the feasibility of FDG-PET/CT-directed IMRT dose escalation in five patients with FDG-avid disease located away from critical normal structures. After 66 Gy, FDG-avid disease with 0.5-cm margins was boosted in 220 cGy increments until dose-limiting criteria were reached.Results. Elimination of prophylactic coverage to FDG-PET/CT-negative neck levels markedly reduced mean dose (Dmean) to the contralateral parotid gland (p < .001) and Dmean to the laryngeal cartilage (p = .001). No FDG-PET/CT-directed plan missed pathologically verified nodal disease. During the dose escalation exercise, we successfully increased the dose to 95% of the planning target volume (PTV95%) to a mean of 7490 cGy (range, 7153-8098 cGy).Conclusions. We demonstrate early proof of the principle that FDG-PET/CT-guided IMRT planning can selectively target and intensify treatment of head and neck disease while reducing critical normal tissue doses. Routine clinical use of such planning should not be engaged until the accuracy of FDG-PET/CT is fully validated. Future directions, including refinement of treatment to gross disease and radiologically uninvolved neck nodal levels, are discussed. (c) 2005 Wiley Periodicals, Inc.

OBJECTIVE To confirm that high pretreatment uptake of 2-deoxy-2[(18)F]fluoro-d-glucose (FDG) detected by positron emission tomography (PET) measured at the primary head and neck squamous cell carcinoma (HNSCC) and at metastatic nodal disease predicts poor outcomes for HNSCC. DESIGN AND PATIENTS We enrolled 63 consecutive patients with a histological diagnosis of HNSCC (including tumors of the oral cavity, oropharynx, larynx, and hypopharynx) from September 2000 through June 2003, into a prospective institutional imaging trial. Fifty-four patients (86%) underwent a baseline FDG-PET scan before curative treatment and were eligible for analysis. RESULTS A primary tumor standardized uptake value (SUV) of greater than 9.0 predicted inferior local recurrence-free survival (P = .02) and disease-free survival (P = .03). Nodal SUV dichotomized according to the cohort median of 6.1 did not predict for either disease outcome (P = .71 and P = .98, respectively). On proportional hazards analysis, local recurrence and disease event hazard ratios for a primary tumor SUV of 9.0 or greater remained significant or at borderline significance when adjusted for nodal SUV or other clinical covariates. CONCLUSIONS Our findings support an association between baseline primary tumor FDG SUV and HNSCC outcomes. In contrast, nodal FDG SUV was not predictive. Primary tumor FDG SUV is a promising prognostic factor and may establish the need for intensified locoregional therapy in individual patients. Multi-institutional imaging trials and further characterization of the biology responsible for elevated FDG uptake in HNSCC will be necessary to confirm the prognostic utility of FDG-labeled PET.

BACKGROUND Accurate baseline staging is necessary to appropriately treat head and neck squamous cell carcinoma. [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) is valuable for locoregional staging of primary head and neck disease. The effectiveness of FDG-PET for the detection of distant metastatic or synchronous disease remains unproven. OBJECTIVE To investigate the utility of FDG-PET extended into the abdomen (extended-field FDG-PET) for wide-field staging of head and neck tumors. METHODS This is a prospective institutional study of 35 consecutive patients diagnosed with American Joint Committee on Cancer (AJCC)-defined stage II-IV squamous cell carcinoma of the oral cavity, oropharynx, or larynx between September 2000 and June 2002. Thirty-three patients (94%) were eligible for analysis. All patients were routinely staged with chest radiography, liver function tests, and extended-field FDG-PET. Chest or abdominal computed tomographic scans were used as corroborative studies and were obtained only when one of the above tests indicated distant disease. RESULTS Of 33 patients, 7 (21%) had evidence of distant disease by extend-field FDG-PET-4 with metastases and 3 with synchronous primary cancers of the aerodigestive tract. [F-18]-fluorodeoxyglucose PET detected hepatic, bone, gastrointestinal, and mediastinal disease not identified by chest radiography or liver function tests. Two of the 7 patients with FDG-avid distant disease had false-negative staging by all other tests, including computed tomography. CONCLUSIONS Extended-field FDG-PET is feasible and may improve staging of primary head and neck squamous cell carcinoma. Use of staging FDG-PET must be explicitly described in reports from centers engaged in prospective research to facilitate comparison with historical results.

Purpose/Objective: Image localization of head and neck squamous cell carcinoma lags behind current techniques to deliver precise radiation dose with IMRT. This prospective study examined the addition of FDG-PET imaging information to standard CT imaging for both regional neck staging and IMRT treatment planning for patients with intermediate to advanced stage head and neck disease. Materials/Methods: We enrolled fifty-two patients with stage II–IV squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx to an institutional imaging protocol between 9/2000 and 2/2003. All patients underwent FDG-PET and contrast-enhanced CT imaging of the head and neck. FDG-PET and CT images were fused with a non-rigid image registration algorithm developed at the University of Washington. Of these patients, sixteen went on to immediate neck dissection surgery. Neck dissection specimens were subdivided into nodal zones intraoperatively, and histopathologic findings were correlated with blinded FDG-PET/CT image interpretations. IMRT treatment planning was then conducted with preoperative image sets of these sixteen patients utilizing an ADAC Pinnacle3 planning system. All IMRT plans were theoretical and were not used for treatment. Control IMRT plans were designed according to the specifications of the RTOG H-0022 protocol using CT scan information alone. Sixty-six Gy and 54 Gy were prescribed to high risk and prophylactic coverage volumes, respectively, in 30 fractions. Test IMRT plans were then designed with the guidance of co-registered FDG-PET/CT imaging. Sixty-six Gy in 30 fractions were prescribed to FDG-avid CT abnormalities and nodal zones directly involved with disease. Test plans did not incorporate prophylactic coverage to uninvolved sites. Results: FDG-PET/CT imaging detected 13/13 heminecks and 21/22 nodal zones found to be positive by dissection pathology (100% and 95% sensitivity, respectively). Negative predictive values for FDG-PET/CT were 100% (9/9) and 98% (57/58) for heminecks and nodal zones, respectively. Analysis of side-by-side IMRT planning comparisons for CT and FDG-PET/CT-guided plans is ongoing. Data from nine paired plans confirmed smaller mean treatment volumes sizes (502.1 cc vs. 290.6 cc, p <0.001 by t-testing). We achieved improved dose homogeneity for tumor volumes in FDG-PET/CT-guided plans: mean PTV D5% values decreased from 7225 cGy in control plans to 6926 cGy in test plans. Elimination of prophylactic coverage markedly improved IMRT dosimetric parameters to parotid glands and skin. Unlike CT-guided plans, contralateral parotids could be spared (Dmean <26 Gy) with FDG-PET/CT guidance in all tested cases. Complete analysis will be forthcoming at the time of presentation. Conclusions: Co-registered FDG-PET and CT imaging information can provide precise disease localization in the head and neck region. FDG-PET/CT imaging promises to improve head and neck IMRT planning by directing treatment away from normal tissues towards FDG-avid disease. Future work will focus on confirmation of FDG-PET/CT staging accuracy, as well as dose escalation to metabolically imaged tumor volumes.