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Non-specific targets such as DNA and microtubules have been the mainstay of cancer therapeutics and the most effective clinical agents until a decade ago. Advances in genetics, molecular and cellular biology over the past decade led to the development of a new generation of agents that are far more specific and effective. In contrast to progress seen with therapeutic agents, general monitoring targets such as proliferation imaging are just gaining momentum and targeted imaging is still in its infancy. In these paradoxical times, this review assesses the role of proliferation imaging in monitoring the efficacy of targeted therapeutics.

Purpose: Fluoropyrimidines like 1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl)-thymine (FMAU) and 3'-deoxy-3'-fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study., Methods: Retention of [(3)H]FLT and [(3)H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1-beta-D: -arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively., Results: FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r (2) = 0.88, p = 0.006). FMAU phosphorylation correlated with increased TK2 activity (r (2) = 0.87, p = 0.0002)., Conclusion: FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.

Purpose: Imaging tumor proliferation with 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and positron emission tomography is being developed with the goal of monitoring antineoplastic therapy. This study assessed the methods to measure FLT retention in patients with non-small cell lung cancer (NSCLC) to measure the reproducibility of this approach., Experimental Design: Nine patients with NSCLC who were untreated or had progressed after previous therapy were imaged twice using FLT and positron emission tomography within 2 to 7 days. Reproducibility (that is, error) was measured as the percent difference between the two patient scans. Dynamic imaging was obtained during the first 60 min after injection. Activity in the blood was assessed from aortic images and the fraction of unmetabolized FLT was measured. Regions of interest were drawn on the plane with the highest activity and the adjacent planes to measure standardized uptake value (SUV(mean)) and kinetic variables of FLT flux., Results: We found that the SUV(mean) obtained from 30 to 60 min had a mean error of 3.6% (range, 0.6-6.9%; SD, 2.3%) and the first and second scans were highly correlated (r(2) = 0.99; P < 0.0001). Using shorter imaging times from 25 to 30 min or from 55 to 60 min postinjection also resulted in small error rates; SUV(mean) mean errors were 8.4% and 5.7%, respectively. Compartmental and graphical kinetic analyses were also fairly reproducible (r(2) = 0.59; P = 0.0152 and r(2) = 0.58; P = 0.0175 respectively)., Conclusion: FLT imaging of patients with NSCLC was quite reproducible with a worst case SUV(mean) error of 21% when using a short imaging time.

Increased cellular proliferation is an integral part of the cancer phenotype. Several in vitro assays have been developed to measure the rate of tumor growth, but these require biopsies, which are particularly difficult to obtain over time and in different areas of the body in patients with multiple metastatic lesions. Most of the effort to develop imaging methods to noninvasively measure the rate of tumor cell proliferation has focused on the use of PET in conjunction with tracers for the thymidine salvage pathway of DNA synthesis, because thymidine contains the only pyrimidine or purine base that is unique to DNA. Imaging with 11C-thymidine has been tested for detecting tumors and tracking their response to therapy in animals and patients. Its major limitations are the short half-life of 11C and the rapid catabolism of thymidine after injection. These limitations led to the development of analogs that are resistant to degradation and can be labeled with radionuclides more conducive to routine clinical use, such as 18F. At this point, the thymidine analogs that have been studied the most are 3'-deoxy-3'-fluorothymidine (FLT) and 1-(2'-deoxy-2'-fluoro-1-beta-d-arabinofuranosyl)-thymine (FMAU). Both are resistant to degradation and track the DNA synthesis pathway. FLT is phosphorylated by thymidine kinase 1, thus being retained in proliferating cells. It is incorporated by the normal proliferating marrow and is glucuronidated in the liver. FMAU can be incorporated into DNA after phosphorylation but shows less marrow uptake. It shows high uptake in the normal heart, kidneys, and liver, in part because of the role of mitochondrial thymidine kinase 2. Early clinical data for 18F-FLT demonstrated that its uptake correlates well with in vitro measures of proliferation. Although 18F-FLT can be used to detect tumors, its tumor-to-normal tissue contrast is generally lower than that of 18F-FDG in most cancers outside the brain. The most promising use for thymidine and its analogs is in monitoring tumor treatment response, as demonstrated in animal studies and pilot human trials. Further work is needed to determine the optimal tracer(s) and timing of imaging after treatment.

Purpose: Under Medicare's Coverage with Evidence Development policy, positron emission tomography (PET)/computed tomography (CT) and PET became covered services for previously noncovered cancer indications if prospective registry data were collected. The National Oncologic PET Registry (NOPR) was developed to meet these coverage requirements and to assess how PET affects care decisions., Methods: The NOPR collected questionnaire data from referring physicians on intended patient management before and after PET. After 1 year, the cohort included data from 22,975 studies (83.7% PET/CT) from 1,178 centers. The numbers of scans performed for diagnosis of suspected cancer (or unknown primary cancer), initial cancer staging, restaging, and suspected cancer recurrence were approximately equal. Prostatic, pancreatic and ovarian cancers represented approximately 30% of cases., Results: If PET data were not available, the most common pre-PET plan would have been other imaging. In these patients, the post-PET strategies changed to watching in 37% and treatment in 48%. In patients with planned biopsy before PET, biopsy was avoided in approximately 70%. If the pre-PET strategy was treatment, the post-PET strategy involved a major change in type in 8.7% and goal in 5.6%. When intended management was classified as either treatment or nontreatment, the post-PET plan was three-fold more likely to lead to treatment than nontreatment (28.3% v 8.2%; odds ratio = 3.4; 95% CI, 3.2 to 3.6). Overall, physicians changed their intended management in 36.5% (95% CI, 35.9 to 37.2) of cases after PET., Conclusion: This large, prospective, nationally representative registry of elderly cancer patients found that physicians often change their intended management on the basis of PET scan results across the full spectrum of its potential uses.

Unlabelled: The rationale was to develop recommendations on the use of (18)F-FDG PET in breast, colorectal, esophageal, head and neck, lung, pancreatic, and thyroid cancer; lymphoma, melanoma, and sarcoma; and unknown primary tumor. Outcomes of interest included the use of (18)F-FDG PET for diagnosing, staging, and detecting the recurrence or progression of cancer., Methods: A search was performed to identify all published randomized controlled trials and systematic reviews in the literature. An additional search was performed to identify relevant unpublished systematic reviews. These publications comprised both retrospective and prospective studies of varied methodologic quality. The anticipated consequences of false-positive and false-negative tests when evaluating clinical usefulness, and the impact of (18)F-FDG PET on the management of cancer patients, were also reviewed., Results and Conclusion: (18)F-FDG PET should be used as an imaging tool additional to conventional radiologic methods such as CT or MRI; any positive finding that could lead to a clinically significant change in patient management should be confirmed by subsequent histopathologic examination because of the risk of false-positive results. (18)F-FDG PET should be used in the appropriate clinical setting for the diagnosis of head and neck, lung, or pancreatic cancer and for unknown primary tumor. PET is also indicated for staging of breast, colon, esophageal, head and neck, and lung cancer and of lymphoma and melanoma. In addition, (18)F-FDG PET should be used to detect recurrence of breast, colorectal, head and neck, or thyroid cancer and of lymphoma.

Unlabelled: The kinetics of 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated., Methods: Ten patients with brain (n = 4) or prostate (n = 6) tumors were imaged using (18)F-FMAU PET (mean dose, 369 MBq). Sixty-minute dynamic images were obtained; this was followed by whole-body images. Mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) of each tumor were determined as the mean over 3 planes of each time interval. For kinetic analyses, blood activity was measured in 18 samples over 60 min. Samples were analyzed by high-performance liquid chromatography at 3 selected times to determine tracer metabolites. FMAU kinetics were measured using a 3-compartment model yielding the flux (K1 x k3/(k2 + k3)) (K1, k2, and k3 are rate constants) and compared with TRR measurements. TRR was calculated as the tumor (18)F-FMAU uptake area under the curve divided by the product of blood (18)F-FMAU AUC and time. A similar analysis was performed using muscle to estimate (18)F-FMAU delivery., Results: SUVmean measurements obtained from 5 to 11 min correlated with those obtained from 30 to 60 min (r(2) = 0.92, P < 0.0001) and 50 to 60 min (r(2) = 0.92, P < 0.0001) due to the rapid clearance of (18)F-FMAU. Similar results were obtained using SUVmax measurements (r(2) = 0.93, P < 0.0001; r(2) = 0.88, P < 0.0001, respectively). The measurement of TRR using either blood or muscle activity over 11 min provided results comparable to those of 60-min dynamic imaging and a 3-compartment model. This analysis required only 5 blood samples drawn at 1, 2, 3, 5, and 11 min without metabolite correction to produce comparable results., Conclusion: Tissue retention ratio measurements obtained over 11 min can replace flux measurements in (18)F-FMAU imaging. The SUVmean and the SUVmax in 5-11 min images correlated well with those of images obtained at 50-60 min. The quality of the images and tissue kinetics in 11 min of imaging makes it a desirable and shorter tumor imaging option.

Unlabelled: FIAU is of interest as a potential reporter probe to monitor herpes simplex virus thymidine kinase (HSV-tk) gene expression and bacterial infections. This study investigates the biodistribution, metabolism, and DNA uptake of 1-(2'-deoxy-2'-(18)F-fluoro-beta-d-arabinofuranosyl)-5-iodouracil ((18)F-FIAU) in normal dogs., Methods: Four normal dogs were intravenously administered (18)F-FIAU. A dynamic PET scan was performed for 60 min over the upper abdomen; this was followed by a whole-body scan for a total of 150 min on 3 dogs. The fourth dog was not scanned and was euthanized at 60 min. Blood and urine samples were collected at stipulated time intervals and analyzed by high-performance liquid chromatography to evaluate tracer clearance and metabolism. Tissue samples collected from various organs were analyzed to evaluate tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. Nondecay-corrected time-activity curves were used for residence time calculation and absorbed dose estimation., Results: At 60 min after injection, unmetabolized FIAU radioactivity in blood and urine samples was greater than 78% and 63%, respectively, demonstrating resistance to metabolism. The tissue-to-muscle ratio derived from image and tissue analysis showed a slightly higher uptake in proliferating organs (mean tissue-to-muscle values: small intestine, 1.97; marrow, 1.70) compared with nonproliferative organs (heart, 1.07; lung, 1.06). A high concentration of activity was seen in the bile (mean, 23.02), demonstrating hepatobiliary excretion of the tracer. Extraction analysis of tissue samples showed that >62% of the activity in the small intestine, 74% in marrow, and <21% in heart, liver, and muscle was incorporated into DNA., Conclusion: These results demonstrate that FIAU is resistant to metabolism and moderately incorporates into DNA in proliferating tissues. These results suggest that incorporation into the DNA of normal tissues may need to be considered when FIAU is used to track reporter gene activity. Studies in humans are needed to determine whether imaging properties differ in patients and are altered as a result of metabolism changes affected by gene therapies.

Objective: The purpose of this article is to review the recent expansion of Medicare coverage for 18F-FDG PET for certain cancer indications under the Centers for Medicare & Medicaid Services' new Coverage with Evidence Development (CED) policy and to describe the specific operational mechanics of the National Oncologic PET Registry (NOPR)., Conclusion: The NOPR will make possible a more accurate assessment of the actual influence of PET on patient management across a wide spectrum of cancer indications. By linking access to PET for virtually all Medicare beneficiaries to the collection of clinically valuable evidence, the NOPR represents the cutting edge of the CED approach.

Objectives: To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial., Patients and Methods: Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0-2 and adequate renal, hepatic and bone marrow function., Results: Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39-75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0-9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89-1.76) to 1.12 (SUV min-max 0.55-1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months., Conclusion: The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.

Unlabelled: Our objective was to determine whether human prostate cancer xenografts in mice can be localized by PET using 64CuCl2 as a probe (64Cu PET)., Methods: Athymic mice bearing human prostate cancer xenografts were subjected to 64Cu PET, followed by quantitative analysis of the tracer concentrations and immunohistochemistry study of human copper transporter 1 expression in the tumor tissues., Results: Human prostate cancer xenografts expressing high levels of human copper transporter 1 were well visualized on the PET images obtained 24 h after injection but not on the images obtained 1 h after injection. PET quantitative analysis demonstrated a high concentration of 64CuCl2 in the tumors in comparison to that in the left shoulder regions (percentage injected dose per gram of tissue: 3.6 +/- 1.3 and 0.6 +/- 0.3, respectively; P = 0.004), at 24 h after injection., Conclusion: The data from this study suggested that locally recurrent prostate cancer might be localized with 64Cu PET using 64CuCl2 as a probe.

This work highlights the explosion and evolution of positron emission tomography (PET) for use in oncology research and clinical practice. 2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET is important in the staging of cancer, estimation of prognosis, and for its ability to predict therapeutic outcome. A number of new imaging agents are under development and may find a place in oncology when studies prove their utility. This scientific overview includes a review of the development of a number of thymidine analogs, such as 18F-3'-deoxy-3'-fluorothymidine (FLT) and 18F-1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-thymine (FMAU), including chemical structure variations; their application in a variety of tumors; and the role of various kinetic models for understanding cellular proliferation. The greatest unmet need for PET is in further developing and validating its use in the measurement of treatment response.

Purpose: FAU (1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl) uracil) can be phosphorylated by thymidine kinase, methylated by thymidylate synthase, followed by DNA incorporation and thus functions as a DNA synthesis inhibitor. This first-in-human study of [F-18]FAU was conducted in cancer patients to determine its suitability for imaging and also to understand its pharmacokinetics as a potential antineoplastic agent., Methods: Six patients with colorectal (n = 3) or breast cancer (n = 3) were imaged with [F-18]FAU. Serial blood and urine samples were analyzed using HPLC to determine the clearance and metabolites., Results: Imaging showed that [F-18]FAU was concentrated in breast tumors and a lymph node metastasis (tumor-to-normal-breast-tissue-ratio 3.7-4.7). FAU retention in breast tumors was significantly higher than in normal breast tissues at 60 min and retained in tumor over 2.5 h post-injection. FAU was not retained above background in colorectal tumors. Increased activity was seen in the kidney and urinary bladder due to excretion. Decreased activity was seen in the bone marrow with a mean SUV 0.6. Over 95% of activity in the blood and urine was present as intact [F-18]FAU at the end of the study., Conclusions: Increased [F-18]FAU retention was shown in the breast tumors but not in colorectal tumors. The increased retention of FAU in the breast compared to bone marrow indicates that FAU may be useful as an unlabeled antineoplastic agent. The low retention in the marrow indicates that unlabeled FAU might lead to little marrow toxicity; however, the images were not of high contrast to consider FAU for diagnostic clinical imaging.

More and more hybrid PET/CT machines are being installed in medical centers across the country as combining computer tomography (CT) and positron emission tomography (PET) provides powerful and unique means in tumor diagnosis. Visual inspection of the images is a tedious and error-prone task and in many clinics the attenuation-uncorrected PET images are not examined by the physician, potentially missing an important source of information, especially for subtle tumors. We are developing a computer aided diagnosis software prototype that simultaneously processes the CT, attenuation-corrected PET, and attenuation-uncorrected PET volumes to detect tumors in the lungs. The system applies optimal thresholding and multiple gray-level thresholding with volume criterion to extract the lungs and to detect tumor candidates, respectively. A fuzzy logic based approach is used to reduce false-positive tumors. The remaining set of tumor candidates are ranked according to their likelihood of being actual tumors. We show the preliminary results of a retrospective evaluation of clinical PET/CT images.

Background: Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer., Methods: The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1,000 mg/m(2) over 100 minutes, cisplatin 35 mg/m(2) I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days., Results: Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6-7.6 months). The probability of survival at 6 months was 46% (90% CI, 27-62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients., Conclusions: The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.

Purpose: [18F]3'-deoxy-3'-fluorothymidine (FLT) is a thymidine analog developed for imaging tumor proliferation with positron emission tomography (PET). To quantitatively assess images, the blood activities of FLT and its glucuronidated metabolite were measured and its kinetics analyzed. This study sought to limit the number of blood samples needed to measure FLT retention., Methods: Total FLT activity was measured from 18 venous samples obtained over the first hour and dynamic imaging performed on 33 patients (average dose 350 MBq/mmol). The 5-, 10-, 30- and 60-min samples were analyzed to measure the fraction of activity in FLT and its glucuronide. HPLC analysis was compared against a two-step column (Sep-Pak) and metabolic rates measured using full and limited sampling. Probenecid (2 g, oral) was given to two patients to determine whether imaging of the liver improved., Results: At 60 min, 74% of the blood activity was unmetabolized (range 57-85%). HPLC and Sep-Pak gave comparable results (r=0.97; average difference 2.1%). For kinetic analysis, eight venous samples were sufficient to accurately measure total activity; for metabolite analysis, a single sample at 60 min yielded data with mean errors of 2.2%. The metabolic rate correlated with average SUV (r2=0.85; p=0.0002). An aorta input function gave kinetic results comparable to venous blood (r2=0.82). Probenecid did not improve imaging of the liver., Conclusion: Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.

Unlabelled: This study reports on the biodistribution and radiation estimates of 1-(2'-deoxy-2'-(18)F-fluoro-1-beta-d-arabinofuranosyl)-5-bromouracil ((18)F-FBAU), a potential tracer for imaging DNA synthesis., Methods: Three normal dogs were intravenously administered (18)F-FBAU and a dynamic PET scan was performed for 60 min over the upper abdomen followed by a whole-body scan for a total of 150 min. Blood samples were collected at stipulated time intervals to evaluate tracer clearance and metabolism. Tissue samples of various organs were analyzed for tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. The radiation dosimetry of (18)F-FBAU was evaluated using the MIRD method., Results: At 60 min after injection, blood analysis found >90% of the activity in unmetabolized form. At 2 h after injection, (18)F-FBAU uptake was highest in proliferating tissues (mean SUVs: marrow, 2.6; small intestine, 4.0), whereas nonproliferative tissues showed little uptake (mean SUVs: muscle, 0.75; lung, 0.70; heart, 0.85; liver, 1.28). Dynamic image analysis over 60 min showed progressive uptake of the tracer in marrow. Extraction studies demonstrated that most of the activity in proliferative tissues was in the acid-insoluble fraction (marrow, 83%; small intestine, 73%), consistent with incorporation into DNA. In nonproliferative tissue, most of the activity was not found in the acid-insoluble fraction (>84% for heart, muscle, and liver)., Conclusion: These results demonstrate that (18)F-FBAU was resistant to metabolism, readily incorporated into DNA in proliferating tissues, and showed good contrast between organs of variable DNA synthesis. These findings indicate that (18)F-FBAU may find use in measuring DNA synthesis with PET.

Background: Building on results from Southwest Oncology Group trial 8905, this trial was designed to compare low-dose continuous infusion (LDCI) of 5-fluorouracil (5-FU) versus intermittent high-dose infusion (HDI) of 5-FU in disseminated colorectal cancer (CRC) for evidence of survival advantage based on dose intensity. A companion trial was funded to assess molecular parameters associated with fluoropyrimidine response or resistance and toxicity from these treatments., Patients and Methods: Eligibility included histologic diagnosis of disseminated CRC, measurable or evaluable disease, no previous therapy for metastatic disease, performance status of 0-2, and adequate renal, hepatic, cardiac, and hematologic function. Stratification factors were measurable versus evaluable disease, performance status of 0/1 versus 2, presence versus absence of adjuvant therapy, and presence versus absence of previous surgery and enrollment on the companion trial. Patients were randomized to receive (1) LDCI 5-FU 300 mg/m(2) per day for 28 days every 5 weeks or (2) HDI 5-FU 2,600 mg/m(2) for 24 hours each week., Results: Between April 1995 and May 1999, 730 patients were accrued (LDCI arm, n = 360; HDI arm, n = 370). Of these, 708 eligible patients were assessable for survival and 690 for toxicity. Median survival for both groups was 13 months. Toxicity was mild; < 10% of patients in both arms had grade > 4 events. There were 8 study-related deaths (1%). Less than 10% of patients were enrolled in the companion trial., Conclusions: Increasing 5-FU dose intensity yields no survival advantage beyond that achieved with LDCI 5-FU. This study confirms the favorable toxicity profile of infusional 5-FU. Because no preferential benefit was observed for either infusion schedule, the more convenient weekly schedule should be considered for 5-FU-based combination regimens for disseminated CRC.

Unlabelled: We imaged DNA synthesis in vivo with PET and (18)F-1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU), which is phosphorylated by thymidine kinases and incorporated into DNA., Methods: We produced (18)F-FMAU and injected the tracer into 5 normal dogs and studied them by imaging or biodistribution for up to 2.5 h. The pharmacokinetics of FMAU in blood and urine were determined using high-performance liquid chromatography analysis. At the end of each study, selected tissues were removed to measure the total activity retained in these tissues. In addition, the selected tissues were extracted by acid precipitation, by which the macromolecules can be precipitated to determine the radioactivity of (18)F-FMAU incorporated into DNA., Results: Imaging and tissue analysis showed increased activity in the lymph nodes, stomach, small intestine, and bone marrow, with mean standardized uptake values of 1.4, 1.6, 2.3, and 3.9, respectively, because of varying degrees of increased cell proliferation. In contrast, (18)F-FMAU was distributed with tissue-to-muscle ratios of approximately 1.0 in nonproliferative organs such as lung, liver, and kidneys. Analysis of the tissue extracts using acid precipitation demonstrated that 88% of activity in marrow and 65% of activity in small intestine was acid precipitated. However, more than 90% of activity in the nonproliferating tissues such as heart and lungs was in the supernatant. Increased activity was seen in the heart because of a high level of thymidine kinase 2 and in the gallbladder because of excretion. Analysis of blood and urine demonstrated that more than 95% of activity was present as intact (18)F-FMAU at the end of the studies., Conclusion: The results showed that (18)F-FMAU was selectively retained in DNA of the proliferating tissues and was resistant to degradation. These features indicate that (18)F-FMAU might be an alternative to (11)C-thymidine for imaging DNA synthesis in normal tissues and tumors.

Purpose: FMAU (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine) is a thymidine analog that can be phosphorylated by thymidine kinase and incorporated into DNA. This first-in-human study of [18F]FMAU was conducted as a pilot in patients to determine its biodistribution and suitability for imaging DNA synthesis in tumors using positron emission tomography (PET)., Methods: Fourteen patients with diverse cancers (brain, prostate, colorectal, lung, and breast) were imaged with [18F]FMAU. We obtained dynamic PET images for 60 min and a whole-body image. Blood and urine samples were analyzed by high-performance liquid chromatography to measure metabolites and clearance., Results: Active tumors in the breast, brain, lung and prostate were clearly visualized with standardized uptake values (SUVs) of 2.19, 1.28, 2.21, and 2.27-4.42, respectively. Unlike with other tracers of proliferation, low uptake of [18F]FMAU was seen in the normal bone marrow (SUV(mean) 0.7), allowing visualization of metastatic prostate cancer (SUV 3.07). Low background was also observed in the brain, pelvis, and thorax, aside from heart uptake (SUV 3.36-8.78). In the abdomen, increased physiological uptake was seen in the liver (SUV 10.07-20.88) and kidneys (SUV 7.18-15.66) due to metabolism and/or excretion, but the urinary bladder was barely visible (SUV(mean) 2.03). On average, 95% of the activity in the blood was cleared within 10 min post injection and an average of 70% of the activity in the urine was intact FMAU at 60 min post injection., Conclusion: Tumors in the brain, prostate, thorax, and bone can be clearly visualized with FMAU. In the upper abdomen, visualization is limited by the physiological uptake by the liver and kidneys.

Introduction: The purpose of this study was to determine the recommended phase II dose (RPTD) of the combination of cyclophosphamide and liposomal doxorubicin (Doxil)., Patients and Methods: Eligibility criteria included: a diagnosis of non-hematologic cancer with no conventional effective therapy, normal renal, liver and bone marrow function, and ECOG performance status of 0-2. Both drugs were administered intravenously on day 1 of a 21-day cycle. The following doses (mg/m2) of Doxil and cyclophosphamide were tested: 30/500, 40/600, and 48/600., Results: Thirty-seven patients with a median age of 62 years (male:female 21:16) received 119 cycles of Doxil and cyclophosphamide. Hand-foot syndrome and mucositis were the dose limiting toxicities for this combination. Other major toxicities included neutropenia. The side effects to the combination were cumulative. The RPTD of Doxil and cyclophosphamide was 48 mg/m2 and 600 mg/m2, respectively. Three patients with adenocarcinoma of the stomach, fibrosarcoma of the stomach and renal cell carcinoma showed objective antitumor responses., Conclusion: The toxicity profile of the combination of Doxil/cyclophosphamide differs significantly from that of non-liposomal doxorubicin plus cyclophosphamide. Major toxicities of the combination include the hand-foot syndrome, stomatitis and neutropenia.

PET cellular proliferation imaging has its roots in a long history of in vitro cellular proliferation studies to characterize cancer and in the understanding of the biology of thymidine incorporation into DNA gained from these studies. PET imaging represents the logical translation of the in vitro work to measure in vivo tumor proliferation. Preclinical studies of [11C]-thymidine and other PET-labeled thymidine analogues set the stage for early clinical studies that provided very promising results. Recent progress in the application of [18F]-FLT, a clinically practical PET thymidine analogue, to patient studies sets the next stage for clinical PET cellular proliferation imaging. Further mechanistic studies of the imaging agents and well-designed clinical trials will be important in moving PET proliferation imaging into what is likely to be a significant role in the care of cancer patients by providing a quantitative measure of tumor response to cytotoxic or cytostatic therapy.

Background: The current study was designed to evaluate the antitumor activity and toxicity of capecitabine and oxaliplatin in previously untreated patients with advanced colorectal carcinoma. The primary endpoint of the study was to determine the objective response rate, and a secondary endpoint was to measure the time to disease progression., Methods: A 2-stage trial was planned with an accrual goal of 35 patients. The treatment included oxaliplatin given at a dose of 130 mg/m2 on Day 1 of each 3-week cycle. Initially, capecitabine at a dose of 2000 mg/m2/day in 2 divided doses was given on Days 1-14 of each cycle, but this was reduced to a dose of 1500 mg/m2/day because of toxicity. Patients were followed by computed tomography scans every two cycles to evaluate treatment response, and toxicity was monitored., Results: The first 13 patients on the trial received the higher dose of capecitabine. Although 5 responses (38.5%) were noted, 5 patients were hospitalized with diarrhea and dehydration. This toxicity led to a decrease in the dose of capecitabine to 1500 mg/m2/day and an additional 35 patients were treated. At the lower dose, the partial response rate was 37.1% (95% confidence interval [95% CI], 21.5-55.1%). The estimated median progression-free survival was 6.9 months (95% CI, 4.4-8.2 months). At the lower dose, four patients were hospitalized with diarrhea/dehydration (with one death reported), one with febrile neutropenia, and one with ventricular fibrillation. Overall, Grade (according to version 2.0 of the National Cancer Institute Common Toxicity Criteria) 3-4 diarrhea was reported to develop in 20% of those patients treated at the capecitabine dose of 1500 mg/m2/day compared with 62% of patients treated at the dose of 2000 mg/m2/day., Conclusions: The combination of oxaliplatin and capecitabine is an active and convenient regimen for the treatment of patients with advanced colorectal carcinoma and should be compared with other front-line regimens as therapy for disease., (Copyright 2003 American Cancer Society.)

Purpose: To evaluate the efficacy and safety of reteplase for central venous catheter (CVC) occlusion in patients with cancer., Materials and Methods: An open-label, single-arm, prospective study was conducted. Reteplase (0.4 U) was instilled into each catheter lumen with a dwell time of 30 minutes in patients with cancer with a dysfunctional CVC. If the function of the catheter was not restored in 30 minutes, an additional dwell time of 30 minutes was allowed (a total of 60 minutes possible dwell time for the first dose). A second dose was repeated at 60 minutes after the first dose if catheter function was not restored (a total of 120 minutes for up to two doses). The primary efficacy outcome was the restoration of CVC function., Results: Of 139 patients who received reteplase, the first-attempt success rate after a 30-minute dwell time was 66.9%. The cumulative success rates at 60, 90, and 120 minutes were 88.5%, 94.7%, and 94.7%, respectively. The variation of patient age, catheter age, CVC occlusion age, CVC type, number of lumen, or occlusion type was not associated with the efficacy of reteplase. There were no treatment-associated adverse events reported during the study period., Conclusion: Reteplase at 0.4-U dosing per catheter lumen is an effective and safe alternative that rapidly restores the patency of occluded CVCs in patients with cancer.

Purpose: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer, Patients and Methods: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 x 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis., Results: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication., Conclusion: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

An efficient and reliable synthesis of 2'-deoxy-2'-[(18)F]fluoro-beta-D-arabinofuranosyl nucleosides is presented. Overall decay-corrected radiochemical yields of 35-45% of 4 analogs, FAU, FMAU, FBAU and FIAU are routinely obtained in >98% radiochemical purity and with specific activities of greater than 3 Ci/micromol (110 MBq/micromol) in a synthesis time of approximately 3 hours. When approximately 220 mCi (8.15 GBq) of starting [(18)F]fluoride is used, 25 -30 mCi (0.93 -1.11 GBq) of product (enough to image two patients sequentially) is typically obtained.

We have studied the biodistribution of [(18)F]FAU [(1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil], which previous work has shown is incorporated into DNA and functions as an inhibitor of DNA synthesis. It is being tested as a potential antineoplastic agent and imaging agent for PET. We have produced [(18)F]FAU and injected the tracer into 3 normal dogs and imaged them for up to 4 hours and removed tissues along with blood and urine samples for HPLC and activity analysis. The results showed that [(18)F]FAU evenly distributed to most of organs. In sharp contrast to our prior experience with thymidine and its analogs, marrow had less retention of [(18)F]FAU than the non-proliferating tissues., (Copyright 2002 Elsevier Science Inc.)

Positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been shown to be a highly sensitive diagnostic tool to stage, restage, and monitor the progress of various neoplasms. A number of physiological and non-neoplastic conditions, however, also may be associated with focal accumulation of FDG and can cause false-positive results. This work reports a 52-year-old man who had marked FDG accumulation in carcinoid tumor of the distal ileum. The tumor was resected. A follow-up FDG-PET scan one and a half years later revealed intense FDG accumulation in the abdominal periaortic region, suggesting recurrent malignancy. Computerized tomography (CT) of the abdomen showed soft tissue mass surrounding the aorta. Fine-needle aspiration biopsy of the periaortic soft tissue confirmed benign retroperitoneal fibrosis. This case shows that retroperitoneal fibrosis can cause intense FDG accumulation giving false impression of malignancy. In interpretation of whole-body FDG-PET, various physiological and benign causes of FDG accumulation must be considered in order to avoid pitfalls. The authors have reviewed the literature and discussed association of carcinoid tumor and retroperitoneal fibrosis.

We have developed 3'-deoxy-3'-[F-18] fluorothymidine ([F-18]FLT) as an agent to image cellular proliferation with PET. Recent work has demonstrated that [F-18]FLT is stable to degradation and produces high contrast images of proliferating tissues and tumors. To increase our understanding for the use of this agent we have explored the kinetics of [F-18]FLT clearance from the blood and uptake into tissues in normal and tumor bearing dogs. The results indicate that [F-18]FLT is readily modeled in canines with a three-compartment model, with parameter k(3) representing phosphorylation by thymidine kinase. During the first 60 minutes, little loss was measured from the phosphorylated compartment, therefore parameter k(4) could not be differentiated from zero. The extraction of marrow from normal dogs was consistent with this model and demonstrated retention of phosphorylated [F-18]FLT. It is concluded that [F-18]FLT produces images of the DNA synthetic pathway by phosphorylation via thymidine kinase. This pathway can be readily modeled using a three-compartment model.