Heiko Schöder

Intensity of 18Fluorodeoxyglucose Uptake in Positron Emission Tomography Distinguishes Between Indolent and Aggressive Non-Hodgkin’s Lymphoma

PURPOSE (18)Fluorodeoxyglucose positron emission tomography (FDG PET) is widely used for the staging of lymphoma. We investigated whether the intensity of tumor FDG uptake could differentiate between indolent and aggressive disease. MATERIALS AND METHODS PET studies of 97 patients with non-Hodgkins lymphoma who were untreated or had relapsed and/or persistent disease and had not received treatment within the last 6 months were analyzed, and the highest standardized uptake value (SUV) per study was recorded. Correlations were made with histopathology. RESULTS FDG uptake was lower in indolent than in aggressive lymphoma for patients with new (SUV, 7.0 +/- 3.1 v 19.6 +/- 9.3; P < .01) and relapsed (SUV, 6.3 +/- 2.7 v 18.1 +/- 10.9; P = .04) disease. Despite overlap between indolent and aggressive disease in the low SUV range (indolent, 2.3 to 13.0; aggressive, 3.2 to 43.0), all cases of indolent lymphoma had an SUV <or= 13. A receiver operating characteristic (ROC) analysis demonstrated that the SUV distinguished reasonably well between aggressive and indolent disease (area under ROC curve, 84.7%), and an SUV > 10 excluded indolent lymphoma with a specificity of 81%. With a higher cutoff for the SUV, the specificity would have been higher. CONCLUSION FDG uptake is lower in indolent than in aggressive lymphoma. Patients with NHL and SUV > 10 have a high likelihood for aggressive disease. This information may be helpful if there is discordance between biopsy and clinical behavior.

Diagnostic and Prognostic Value of [18F]Fluorodeoxyglucose Positron Emission Tomography for Recurrent Head and Neck Squamous Cell Carcinoma

PURPOSE: Patients with recurrent head and neck squamous cell carcinoma (HNSCC) present a diagnostic and therapeutic challenge. We evaluated the diagnostic accuracy and prognostic value of [18F]fluorodeoxyglucose positron emission tomography (PET) in this patient population. PATIENTS AND METHODS: We performed a retrospective review of 143 patients with previously treated HNSCC who underwent 181 PET scans at our institution from May 1996 through April 2001 to detect recurrent disease. Disease recurrence within 6 months was used as the gold standard for assessing true disease status at PET. RESULTS: With equivocal sites considered positive, the sensitivity and specificity of PET for detecting recurrence overall were 96% and 72%, respectively. PET was highly sensitive and specific at regional and distant sites. At local sites, sensitivity was high, but specificity was lower because of false-positive findings. One fifth of all false-positive PET scans occurred at sites of known inflammation or infection. The a...

Risk-Adapted Dose-Dense Immunochemotherapy Determined by Interim FDG-PET in Advanced-Stage Diffuse Large B-Cell Lymphoma

PURPOSE In studies of diffuse large B-cell lymphoma, positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) performed after two to four cycles of chemotherapy has demonstrated prognostic significance. However, some patients treated with immunochemotherapy experience a favorable long-term outcome despite a positive interim FDG-PET scan. To clarify the significance of interim FDG-PET scans, we prospectively studied interim FDG-positive disease within a risk-adapted sequential immunochemotherapy program. PATIENTS AND METHODS From March 2002 to November 2006, 98 patients at Memorial Sloan-Kettering Cancer Center received induction therapy with four cycles of accelerated R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by an interim FDG-PET scan. If the FDG-PET scan was negative, patients received three cycles of ICE (ifosfamide, carboplatin, and etoposide) consolidation therapy. If residual FDG-positive disease was seen, patients underwent biopsy; if the biopsy was negative, they also received three cycles of ICE. Patients with a positive biopsy received ICE followed by autologous stem-cell transplantation. RESULTS At a median follow-up of 44 months, overall and progression-free survival were 90% and 79%, respectively. Ninety-seven patients underwent interim FDG-PET scans; 59 had a negative scan, 51 of whom are progression free. Thirty-eight patients with FDG-PET-positive disease underwent repeat biopsy; 33 were negative, and 26 remain progression free after ICE consolidation therapy. Progression-free survival of interim FDG-PET-positive/biopsy-negative patients was identical to that in patients with a negative interim FDG-PET scan (P = .27). CONCLUSION Interim or post-treatment FDG-PET evaluation did not predict outcome with this dose-dense, sequential immunochemotherapy program. Outside of a clinical trial, we recommend biopsy confirmation of an abnormal interim FDG-PET scan before changing therapy.

Quantitation of respiratory motion during 4D-PET/CT acquisition

We report on the variability of the respiratory motion during 4D-PET/CT acquisition. The respiratory motion for five lung cancer patients was monitored by tracking external markers placed on the abdomen. CT data were acquired over an entire respiratory cycle at each couch position. The x-ray tube status was recorded by the tracking system, for retrospective sorting of the CT data as a function of respiration phase. Each respiratory cycle was sampled in ten equal bins. 4D-PET data were acquired in gated mode, where each breathing cycle was divided into ten 500 ms bins. For both CT and PET acquisition, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to their respiratory phases. The respiratory periods, and average amplitude within each phase bin, acquired in both modality sessions were then analyzed. The average respiratory motion period during 4D-CT was within 18% from that in the 4D-PET sessions. This would reflect up to 1.8% fluctuation in the duration of each 4D-CT bin. This small uncertainty enabled good correlation between CT and PET data, on a phase-to-phase basis. Comparison of the average-amplitude within the respiration trace, between 4D-CT and 4D- PET, on a bin-by-bin basis show a maximum deviation of approximately 15%. This study has proved the feasibility of performing 4D-PET/CT acquisition. Respiratory motion was in most cases consistent between PET and CT sessions, thereby improving both the attenuation correction of PET images, and co-registration of PET and CT images. On the other hand, in two patients, there was an increased partial irregularity in their breathing motion, which would prevent accurately correlating the corresponding PET and CT images.

Clinical Utility of 18F-FDG PET/CT in Assessing the Neck After Concurrent Chemoradiotherapy for Locoregional Advanced Head and Neck Cancer

For patients with locoregional advanced head and neck squamous cell carcinoma (HNSCC), concurrent chemoradiotherapy is a widely accepted treatment, but the need for subsequent neck dissection remains controversial. We investigated the clinical utility of 18F-FDG PET/CT in this setting. Methods: In this Institutional Review Board (IRB)–approved and Health Insurance Portability and Accountability Act (HIPPA)–compliant retrospective study, we reviewed the records of patients with HNSCC who were treated by concurrent chemoradiation therapy between March 2002 and December 2004. Patients with lymph node metastases who underwent 18F-FDG PET/CT ≥ 8 wk after the end of therapy were included. 18F-FDG PET/CT findings were validated by biopsy, histopathology of neck dissection specimens (n = 18), or clinical and imaging follow-up (median, 37 mo). Results: Sixty-five patients with a total of 84 heminecks could be evaluated. 18F-FDG PET/CT (visual analysis) detected residual nodal disease with a sensitivity of 71%, a specificity of 89%, a positive predictive value (PPV) of 38%, a negative predictive value (NPV) of 97%, and an accuracy of 88%. Twenty-nine heminecks contained residual enlarged lymph nodes (diameter, ≥1.0 cm), but viable tumor was found in only 5 of them. 18F-FDG PET/CT was true-positive in 4 and false-positive in 6 heminecks, but the NPV was high at 94%. Fifty-five heminecks contained no residual enlarged nodes, and PET/CT was true-negative in 50 of these, yielding a specificity of 96% and an NPV of 98%. Lack of residual lymphadenopathy on CT had an NPV of 96%. Finally, normal 18F-FDG PET/CT excluded residual disease at the primary site with a specificity of 95%, an NPV of 97%, and an accuracy of 92%. Conclusion: In patients with HNSCC, normal 18F-FDG PET/CT after chemoradiotherapy has a high NPV and specificity for excluding residual locoregional disease. In patients without residual lymphadenopathy, neck dissection may be withheld safely. In patients with residual lymphadenopathy, a lack of abnormal 18F-FDG uptake in these nodes also excludes viable tumor with high certainty, but confirmation of these data in a prospective study may be necessary before negative 18F-FDG PET/CT may become the only, or at least most-decisive, criterion in the management of the neck after chemoradiotherapy.

Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma

Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11:14) translocation results in enhanced cyclin D1 expression and cyclin D1-dependent kinase activity to promote cell-cycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-deoxy-3[(18)F]fluorothymidine (FLT) positron emission tomography (PET) to study tumor metabolism and proliferation, respectively, in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein (Rb) phosphorylation and markers of proliferation and apoptosis. Substantial reductions in the summed FLT-PET maximal standard uptake value (SUV(max)), as well as in Rb phosphorylation and Ki-67 expression, occurred after 3 weeks in most patients, with significant correlations among these end points. Five patients achieved progression-free survival time of > 1 year (range, 14.9-30.1+ months), with 1 complete and 2 partial responses (18% objective response rate; 90% confidence interval, 5%-40%). These patients demonstrated > 70%, > 90%, and ≥ 87.5% reductions in summed FLT SUV(max) and expression of phospho-Rb and Ki67, respectively, parameters necessary but not sufficient for long-term disease control. The results of the present study confirm CDK4/6 inhibition by PD0332991 at a well-tolerated dose and schedule and suggest clinical benefit in a subset of MCL patients. This study is registered at www.clinicaltrials.gov under identifier NCT00420056.

2-[18F]Fluoro-2-Deoxyglucose Positron Emission Tomography for the Detection of Disease in Patients with Prostate-Specific Antigen Relapse after Radical Prostatectomy

Experimental Design: Retrospective cohort study in 91 patients with prostate-specific antigen (PSA) relapse following prostatectomy, imaged with 2-[18F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in a tertiary care cancer center between February 1997 and March 2003. Comparison was made with magnetic resonance imaging (n = 64), bone scan (n = 56), and computed tomography (n = 37). The standard of reference included biopsy or clinical and imaging follow-up. We calculated sensitivity and specificity of PET and correlated PET findings with PSA values, other clinical parameters, and conventional imaging, when available. Results: PET was true positive in 28 of 91 (31%) patients, showing isolated disease in the prostate bed (n = 3) or metastatic disease with (n = 2) or without (n = 23) simultaneous disease in the prostate bed. In detail, PET identified lesions in the prostate bed (n = 5, all true positives), bones (n = 22; 20 true positives, 2 false positives), lymph nodes (n = 7; 6 true positives, 1 likely false positive), and one liver metastasis. Mean PSA was higher in PET-positive than in PET-negative patients (9.5 ± 2.2 versus 2.1 ± 3.3 ng/mL). PSA of 2.4 ng/mL and PSA velocity of 1.3 ng/mL/y provided the best tradeoff between sensitivity (80%; 71%) and specificity (73%; 77%) of PET in a receiver operating curve analysis. Combination with other clinical parameters in a multivariate analysis did not improve disease prediction. There were only two patients in whom other imaging studies showed isolated local recurrence or metastatic disease. Conclusions: FDG-PET detected local or systemic disease in 31% of patients with PSA relapse referred for this test. There is a link to tumor burden and tumor biology in that the probability for disease detection increased with PSA levels.

Effects of Long-term Smoking on Myocardial Blood Flow, Coronary Vasomotion, and Vasodilator Capacity

BACKGROUND The effect of long-term smoking on coronary vasomotion and vasodilator capacity in healthy smokers is unknown. METHODS AND RESULTS Myocardial blood flow (MBF) was quantified with [13N]ammonia and positron emission tomography (PET) at rest, during cold pressor testing (endothelium-dependent vasomotion), and during dipyridamole-induced hyperemia in 16 long-term smokers and 17 nonsmokers. MBF at rest did not differ between the 2 groups. Cold induced similar increases in rate-pressure product (RPP) in smokers and nonsmokers. However, MBF increased only in nonsmokers and was, during cold, higher than in smokers (0.91+/-0.18 versus 0.78+/-0.14 mL x g(-1) x min(-1), P<0.05). MBF normalized to the RPP (derived from the ratio of MBF ([milliliters per gram per minute] to RPP [beats per minute times millimeters of mercury] times 10000) declined in smokers but remained unchanged in nonsmokers (0.86+/-0.10 versus 0.72+/-0.11, P=0.0006, and 0.99+/-0.25 versus 0.96+/-0.27, P=NS). The hyperemic response to dipyridamole and the myocardial flow reserve did not differ between the 2 groups. In a multiple regression model adjusted for age, sex, serum lipid levels, years of smoking, and pack-years, years of smoking was the strongest predictor of the normalized blood flow response to cold (P<0.001), followed by the HDL/LDL ratio. CONCLUSIONS The normal hyperemic response to dipyridamole in long-term smokers indicates a preserved endothelium-independent coronary vascular smooth muscle relaxation, whereas the abnormal response to cold suggests a defect in coronary vasomotion likely located at the level of the coronary endothelium. Its severity depends on the total exposure time to smoking.

PET Monitoring of Therapy Response in Head and Neck Squamous Cell Carcinoma

In the Western world, more than 90% of head and neck cancers are head and neck squamous cell carcinomas (HNSCCs). The most appropriate treatment approach for HNSCC varies with the disease stage and disease site in the head and neck. Concurrent chemoradiotherapy has become a widely used means for the definitive treatment of locoregionally advanced HNSCC. Although this multimodality treatment provides higher response rates than radiotherapy alone, the detection of residual viable tumor after the end of therapy remains an important issue and is one of the major applications of 18F-FDG PET. Studies have shown that negative 18F-FDG PET or PET/CT results after concurrent chemoradiotherapy have a high negative predictive value (>95%), whereas the positive predictive value is only about 50%. However, when applied properly, FDG PET/CT can exclude residual disease in most patients, particularly patients with residual enlarged lymph nodes who would otherwise undergo neck dissection. In contrast to other malignancies, data are limited on the utility of 18F-FDG PET for monitoring the response to induction chemotherapy in HNSCC or for assessing treatment response early during the course of definitive chemoradiotherapy. The proliferation marker 18F-3′-deoxy-3′fluorothymidine is currently under study for this purpose. Beyond standard chemotherapy, newer treatment regimens in HNSCC take advantage of our improved understanding of tumor biology. Two molecules important in the progression of HNSCC are the epidermal growth factor receptor and the vascular endothelial growth factor (VEGF) and its receptor VEGF-R. Drugs attacking these molecules are now under study for HNSCC. PET probes have been developed for imaging the presence of these molecules in HNSCC and their inhibition by specific drug interaction; the relevance of these probes for response assessment in HNSCC will be discussed. Hypoxia is a common phenomenon in HNSCC and renders cancers resistant to chemo- and radiotherapy. Imaging and quantification of hypoxia with PET probes is under study and may become a prerequisite for overcoming chemo- and radioresistance using radiosensitizing drugs or hypoxia-directed irradiation techniques and for monitoring the response to these techniques in selected groups of patients. Although 18F-FDG PET/CT will remain the major clinical tool for monitoring treatment in HNSCC, other PET probes may have a role in identifying patients who are likely to benefit from treatment strategies that include biologic agents such as epidermal growth factor receptor inhibitors or VEGF inhibitors.

Pattern of Prostate-Specific Antigen (PSA) Failure Dictates the Probability of a Positive Bone Scan in Patients With an Increasing PSA After Radical Prostatectomy

PURPOSE Physicians often order periodic bone scans (BS) to check for metastases in patients with an increasing prostate-specific antigen (PSA; biochemical recurrence [BCR]) after radical prostatectomy (RP), but most scans are negative. We studied patient characteristics to build a predictive model for a positive scan. PATIENTS AND METHODS From our prostate cancer database we identified all patients with detectable PSA after RP. We analyzed the following features at the time of each bone scan for association with a positive BS: preoperative PSA, time to BCR, pathologic findings of the RP, PSA before the BS (trigger PSA), PSA kinetics (PSA doubling time, PSA slope, and PSA velocity), and time from BCR to BS. The results were incorporated into a predictive model. RESULTS There were 414 BS performed in 239 patients with BCR and no history of androgen deprivation therapy. Only 60 (14.5%) were positive for metastases. In univariate analysis, preoperative PSA (P = .04), seminal vesicle invasion (P = .02), PSA velocity (P < .001), and trigger PSA (P < .001) predicted a positive BS. In multivariate analysis, only PSA slope (odds ratio [OR], 2.71; P = .03), PSA velocity (OR, 0.93; P = .003), and trigger PSA (OR, 1.022; P < .001) predicted a positive BS. A nomogram for predicting the bone scan result was constructed with an overfit-corrected concordance index of 0.93. CONCLUSION Trigger PSA, PSA velocity, and slope were associated with a positive BS. A highly discriminating nomogram can be used to select patients according to their risk for a positive scan. Omitting scans in low-risk patients could reduce substantially the number of scans ordered.