Post-treatment Positron Emission Tomography Scans Research Articles

Outcome of Locally Advanced Esophageal Cancer Patients Treated With Perioperative Chemotherapy and Chemoradiotherapy Followed by Surgery.

Perioperative chemotherapy (P-CT) or neoadjuvant chemoradiation (C-RT) followed by surgical resection is the standard of care for locally advanced esophageal cancer (LAEC). We present an institutional review and outcome of patients with LAEC treated with neoadjuvant C-RT or P-CT followed by surgery. Patients were identified through the Manitoba Cancer Registry. Overall survival (OS), recurrence-free survival (RFS), and time to recurrence (TTR) were compared using proportion hazard regression analysis. Metabolic and pathologic response rates were compared by the Fisher exact test. Sixty-seven patients were treated with C-RT and 32 with P-CT. Fifty-two percent of the patients had pretreatment and posttreatment positron emission tomography scans before surgery. Ninety-five percent of the patients in C-RT and 91% in P-CT had a partial metabolic response or stable disease. Sixty-one percent of C-RT and 34% of P-CT patients had tumor regression grade (TRG) 0 to 1; 39% of C-RT and 66% of P-CT had TRG 2 to 3 (P=0.018). Median OS was 37 and 18 months for patients with TRG 0 to 1 and 2 to 3, respectively (P=0.013, hazard ratio [HR]=1.96). Three-year OS was 43% versus 37% (P=0.37, HR=1.30), RFS was 34% versus 26% (P=0.87, HR=0.96), and median TTR was 30 versus 13 months (P=0.07, HR=0.59) for C-RT and P-CT, respectively. C-RT was associated with a higher degree of pathologically tumor regression. Patients with major tumor regression had a better outcome than those with minimal to poor response. There was a trend toward improved TTR with C-RT but no difference in OS or RFS.

Patient Outcomes With Dose Escalation Using Modern Radiotherapy Techniques: A Retrospective Review of Anal Cancer Treated at a Large Academic Institution Between 2010 and 2016

Introduction: The use of modern radiotherapy techniques (MRTs) has contributed to reduced treatment-related toxicities through better avoidance of normal structures and dose tapering, and has enabled the delivery of higher doses continuously. The purpose of this study was to review retrospectively (1) outcomes for anal cancer treated at BC Cancer (Canada) using MRT, and (2) the utilization and effect of dose escalation on cancer-related outcomes.Methods: Patients between 2010 and 2016 with biopsy-proven anal cancer, aged >18 years, and treated with primary curative-intent chemoradiation using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) were included. Primary end points included overall survival (OS), relapse-free survival (RFS), and colostomy-free survival (CFS). Kaplan-Meier curves were created for prognostic factors, as well as dose escalation (>54 Gy vs. ≤54 Gy). Univariate and multivariate analyses were performed to evaluate predictors of the outcome.Results: A total of 273 patients were assessed. The median age was 61 years with 70% being female, 6% HIV positive, and 68% with locally advanced cancer (T3-4, or node positive). The median follow-up time was 41.3 months. Time from diagnosis to treatment was 60 days, and treatment duration 42 days. Dose escalation was prescribed for 22, of whom 15 were locally advanced cases. A total of 97% completed their radiation, including all who were dose-escalated; 11% required unplanned treatment breaks, with over half of breaks <5 days. More than 90% completed at least half of their chemotherapy; 41% had pre-treatment, and 34% post-treatment positron emission tomography (PET) scans. For primary tumor response, 88% were complete and 10% partial; 23% relapsed, with 15% locoregional, 5% distant, and 3% both, and 12% had salvage surgery. The colostomy rate was 15%, with 4% pre-treatment, 10% relapse related, and only 1% treatment-toxicity related. On univariate analysis, male sex was associated with a higher risk of death (p=0.02) and relapse (p=0.041). Non-squamous histology was consistently a strong predictor of all outcomes (OS, p=0.0089; RFS, p<0.0001; CFS, p<0.0001) as was advanced T stage (OS, p=0.0075; RFS, p=0.0019; CFS, p=0.0099), and node positivity (OS, p=0.0014; RFS, p=0.001; CFS, p=0.0071). Age, HIV status, grade, longer treatment times (>42-day median), and lack of a pre- or post-treatment PET scan were not associated with the outcome. Dose escalation beyond 54 Gy was not significant, even among locally advanced tumors. On multivariate analysis, non-squamous histology (OS, p=0.043; RFS, p<0.001; CFS, p=0.01), T4 (OS, p=0.049; RFS, p=0.026; CFS, p=0.042) and node positivity (OS, p=0.05; RFS, p=0.006) remained significant predictors of the outcome, although node positivity was no longer significant for CFS (p=0.10).Conclusion: BC Cancer outcomes for anal cancer treated with MRTs are comparable to what has been previously reported. Unplanned breaks were notably few, and short. Treatment-related colostomies were rare. Dose-escalated regimens were infrequently prescribed, appeared tolerable, but more often required a break. Prospective trials are needed to clarify efficacy of such regimens.

FDG PET based prediction of response in head and neck cancer treatment: Assessment of new quantitative imaging features.

Introduction18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is now a standard diagnostic imaging test performed in patients with head and neck cancer for staging, re-staging, radiotherapy planning, and outcome assessment. Currently, quantitative analysis of FDG PET scans is limited to simple metrics like maximum standardized uptake value, metabolic tumor volume, or total lesion glycolysis, which have limited predictive value. The goal of this work was to assess the predictive potential of new (i.e., nonstandard) quantitative imaging features on head and neck cancer outcome.MethodsThis retrospective study analyzed fifty-eight pre- and post-treatment FDG PET scans of patients with head and neck squamous cell cancer to calculate five standard and seventeen new features at baseline and post-treatment. Cox survival regression was used to assess the predictive potential of each quantitative imaging feature on disease-free survival.ResultsAnalysis showed that the post-treatment change of the average tracer uptake in the rim background region immediately adjacent to the tumor normalized by uptake in the liver represents a novel PET feature that is associated with disease-free survival (HR 1.95; 95% CI 1.27, 2.99) and has good discriminative performance (c index 0.791).ConclusionThe reported findings define a promising new direction for quantitative imaging biomarker research in head and neck squamous cell cancer and highlight the potential role of new radiomics features in oncology decision making as part of precision medicine.

RISK STRATIFICATION BASED ON NCCN‐IPI AT THE TIME OF DIAGNOSIS IN COMBINATION WITH POST‐TREATMENT PET‐CT SCAN FOR THE TREATMENT OF NODAL PERIPHERAL T‐CELL LYMPHOMA

Background: Nodal peripheral T-cell lymphomas (PTCLs) consist of PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+), and ALCL-ALK−. Clinical assessments before and after treatment are essential to predict survival in nodal PTCL. However, limited data are available regarding the prognostic significance of National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) as a pre-treatment clinical tool and post-treatment PET-CT scan indicating tumor viability in patients with nodal PTCL. The primary aim was to establish a risk model for nodal PTCL based on NCCN-IPI and post-treatment PET-CT scan. Method: In this retrospective, multicenter, cohort study, patients were eligible if they were diagnosed with nodal PTCL from Jan 2005 to June 2016, received systemic chemotherapy, and had the results of PET-CT scan at the time of diagnosis and at the end of treatment, which was assessed using 5-point Deauville score. The study excluded ALCL-ALK+. Results: A total of 396 patients were screened. Seventy patients were excluded from the analysis: unavailable pre- or post-treatment PET scans, no systemic treatment, uncertain histology, and ALCL-ALK+. Thus, 326 patients were analyzed. The median age was 61 years (range, 18–86) and 209 (64%) were male. PTCL-NOS (N = 172, 53%) was the most common subtype, and AITL (N = 111, 34%) and ALCL-ALK− (N = 43, 13%) followed. Patients were categorized into low (N = 42, 13%), low-intermediate (LI, N = 108, 33%), high-intermediate (HI, N = 136, 42%), and high (N = 40, 12%) risk groups according to the NCCN-IPI. Based on the Deauville criteria, post-treatment PET-CT scan was scored as 1 (N = 130, 40%), 2 (N = 47, 14%), 3 (N = 60, 18%), 4 (N = 27, 8%), and 5 (N = 62, 19%). Because the number of progression in Deauville score 3 (40/60, 67%) was significantly different from score 2 (21/47, 45%; P = 0.023) and 4 (24/27, 89%; P = 0.030), we categorized patients into 3 groups: Deauville score 1–2, 3, and 4–5. With a median follow-up of 54.7 months (IQR, 30.2–84.5), 5-year PFS rate was 35.7% (95% CI, 30.0–41.4), and OS rate was 47.1% (95% CI, 40.8–53.4). NCCN-IPI risk and post-treatment PET-CT scan were independently associated with PFS in multivariate analysis (for LI NCCN-IPI, hazard ratio [HR] 1.615, 95% CI 0.838–3.113; HI NCCN-IPI, HR 3.063, 95% CI 1.626–5.769; high NCCN-IPI 4.475, 95% CI 2.231–8.977; P < 0.001: for post-treatment Deauville score 3, HR 1.895, 95% CI 1.281–2.801; score 4–5, HR 6.916, 95% CI 4.948–9.667; P < 0.001). We stratified patients into 5 groups based on risk of progression: low (low NCCN-IPI and Deauville score 1–2), INT-1 (low NCCN-IPI and score 3, or LI NCCN-IPI and score 1–2), INT-2 (HI NCCN-IPI and score 1–2), high (high NCCN-IPI and score 1–2, or LI to high NCCN-IPI and score 3), and very high (score 4–5). The risk model showed a strong association with PFS and OS (Figure 1). Keywords: peripheral T-cell lymphomas (PTCL); positron emission tomography (PET); prognostic indices.

Prognostic value of post treatment PET scan in small cell lung cancer.

e20013 Background: In most lymphomas, improving patient outcome rely on an assessment of response to therapy. Functional imaging with 18-fluoro-deoxyglucose (FDG) positron emission tomography (PET) increases sensitivity and specificity of disease assessment, predicts outcome and directs future therapies. Lately, PET-scan is more utilized in small cell lung cancer (SCLC) both for initial staging and to assess response to therapy. However, limited data in the literature have evaluated the prognostic value of post-therapy response on PET-scan in SCLC. Methods: This is a retrospective chart-review of SCLC patients who received their first-line chemotherapy between January-2007 and December-2013. Inclusion criteria included complete data on age, sex, race, cancer stage, histologic grade, chemotherapy, radiotherapy, and PET images pre- and post-therapy. CR was defined as either 100% drop in FDG uptake on post-therapy PET-scan. Results: Fifty patients met the inclusion criteria, and served as the basis for this study. 46% had Limited Stage Small Cell Lung Cancer (LS-SCLC), and 54% had Extensive stage small cell lung cancer (ES-SCLC). All were treated with platinum-based chemotherapy in addition to concurrently radiation therapy for the LS-SCLC group. Eleven patients out of the whole cohort achieved CR. Using COX regression model, we evaluated the correlation between achieving CR on post-therapy PET-scan and survival outcome. We found that achieving CR was significantly correlated with worse outcome in ES-SCLC group (HR = 2.70; 95%CI: 1.26-5.81; p = 0.01). While, in the whole cohort and LS-SCLC group, P-value was not statistically significant, nevertheless achieving CR indicated unfavorable outcome (HR = 1.18; 95%CI: 0.51-2.69; p = 0.49) and (HR = 1.99; 95%CI: 0.77-5.13; p = 0.15) respectively. Conclusions: Unlike lymphomas, achieving CR on post-therapy PET-scan in SCLC was associated with worse survival outcome. This might indicate that in aggressive small cell lung cancer, despite excellent response to first-line therapy, the prognosis is still dismal. These results suggest that further prospective studies are warranted to identify the prognostic rule of post-therapy PET-scan in SCLC patients particularly those with ES-SCLC.

Usefulness of Positron Emission Tomography in Patients with Syphilis: A Systematic Review of Observational Studies.

Background:Diagnosis of syphilis is difficult. Follow-up and therapy evaluation of syphilitic patients are poor. Little is known about positron emission tomography (PET) in syphilis. This review was to systematically review usefulness of PET for diagnosis, disease extent evaluation, follow-up, and treatment response assessment in patients with syphilis.Methods:We searched PubMed, EMBASE, SCOPUS, Cochrane Library, Web of Science, ClinicalTrials.gov, and three Chinese databases (SinoMed, Wanfang, and CNKI) for English and Chinese language articles from inception to September 2016. We also collected potentially relevant studies and reviews using a manual search. The search keywords included the combined text and MeSH terms “syphilis” and “positron emission tomography”. We included studies that reporting syphilis with a PET scan before and/or after antibiotic treatment. The diagnosis of syphilis was based on serological criteria or dark field microscopy. Outcomes include pre- and post-treatment PET scan, pre- and post-treatment computed tomography, and pre- and post-treatment magnetic resonance imaging. We excluded the articles not published in English or Chinese or not involving humans.Results:Of 258 identified articles, 34 observational studies were included. Thirty-three studies were single-patient case reports and one study was a small case series. All patients were adults. The mean age of patients was 48.3 ± 12.1 years. In primary syphilis, increased fluorodeoxyglucose (FDG) accumulation could be seen at the site of inoculation or in the regional lymph nodes. In secondary syphilis with lung, bone, gastrointestinal involvement, or generalized lymphadenopathy, increased FDG uptake was the most commonly detected changes. In tertiary syphilis, increased glucose metabolic activity, hypometabolic lesions, or normal glucose uptake might be seen on PET. There were five types of PET scans in neurosyphilis. A repeated PET scan after treatment revealed apparent or complete resolution of the asymmetry of radiotracer uptake.Conclusion:PET is helpful in targeting diagnostic interventions, characterizing disease extent, assessing nodal involvement, and treatment efficacy for syphilis.

Application of single- and dual-energy CT brain tissue segmentation to PET monitoring of proton therapy

The purpose of this work was to evaluate the ability of single and dual energy computed tomography (SECT, DECT) to estimate tissue composition and density for usage in Monte Carlo (MC) simulations of irradiation induced β+ activity distributions. This was done to assess the impact on positron emission tomography (PET) range verification in proton therapy.A DECT-based brain tissue segmentation method was developed for white matter (WM), grey matter (GM) and cerebrospinal fluid (CSF). The elemental composition of reference tissues was assigned to closest CT numbers in DECT space (DECTdist). The method was also applied to SECT data (SECTdist). In a validation experiment, the proton irradiation induced PET activity of three brain equivalent solutions (BES) was compared to simulations based on different tissue segmentations. Five patients scanned with a dual source DECT scanner were analyzed to compare the different segmentation methods. A single magnetic resonance (MR) scan was used for comparison with an established segmentation toolkit. Additionally, one patient with SECT and post-treatment PET scans was investigated.For BES, DECTdist and SECTdist reduced differences to the reference simulation by up to 62% when compared to the conventional stoichiometric segmentation (SECTSchneider). In comparison to MR brain segmentation, Dice similarity coefficients for WM, GM and CSF were 0.61, 0.67 and 0.66 for DECTdist and 0.54, 0.41 and 0.66 for SECTdist. MC simulations of PET treatment verification in patients showed important differences between DECTdist/SECTdist and SECTSchneider for patients with large CSF areas within the treatment field but not in WM and GM. Differences could be misinterpreted as PET derived range shifts of up to 4 mm. DECTdist and SECTdist yielded comparable activity distributions, and comparison of SECTdist to a measured patient PET scan showed improved agreement when compared to SECTSchneider.The agreement between predicted and measured PET activity distributions was improved by employing a brain specific segmentation applicable to both DECT and SECT data.

18F-FDG PET predicts pathological response to preoperative chemoradiotherapy in patients with primary rectal cancer: a meta-analysis

The aim of this study was to assess the performance of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in predicting pathological response to preoperative chemoradiotherapy (CRT) in patients with primary rectal cancer. Potentially relevant articles were searched in the databases of PubMed and Embase from January 1990 to September 2013. The Quality Assessment for Diagnostic Accuracy Studies criteria was employed to assess the quality of all of the included studies. The pooled sensitivity and specificity were calculated, and the area under the curve of the summary receiver operating characteristic curve was obtained. Subgroup analysis was conducted to explore the sources of heterogeneity. Thirty-one eligible studies involving 1527 patients were ultimately included in the meta-analysis. Four main quantitative or qualitative parameters [response index (RI), post-treatment maximum standardized uptake value (SUVmax-post), visual response (VR) and the percentage change in total lesion glycolysis (TLG) before and after CRT (deltaTLG%)] related to PET or positron emission tomography/computed tomography (PET/CT) were assessed for the prediction of histopathological response. The pooled sensitivities of these four parameters were comparable and were 74, 74, 75 and 78%, respectively (P>0.05). The pooled specificity of deltaTLG% was higher than that of the other three parameters (RI, SUVmax-post and VR) and was 81, 66, 64 and 67%, respectively (P<0.05). The results from subgroup analysis showed that the RI and SUVmax-post had higher specificity in predicting tumor regression grade (TRG) than complete pathological response (pCR) [RI, 71 vs. 59% (P=0.0275); SUVmax-post, 72 vs. 61% (P=0.0178)].The diagnostic sensitivity and specificity of the RI and SUVmax-post when the post-treatment PET or PET/CT scan was performed at two different time points (during CRT and after the completion of CRT) were 82 vs. 72% (P=0.0630) and 78 vs. 63% (P=0.0059), respectively. 18F-FDG PET could be a potentially powerful non-invasive tool for predicting pathological response; the related parameters RI and SUVmax-post may be more suitable for the prediction of TRG than pCR. The current data also suggested that the optimum post-treatment 18F-FDG PET scan could be carried out during CRT.

Pre-SBRT metabolic tumor volume and total lesion glycolysis to predict survival in patients with locally advanced pancreatic cancer receiving stereotactic body radiation therapy.

189 Background: Though prior studies have demonstrated the prognostic value of pre- and post-treatment positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer is yet to be established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiotherapy (SBRT). Methods: Thirty-two patients with LAPC received up to 3 doses of gemcitabine, followed by SBRT 6.6 Gy in 5 daily fractions, 33 Gy total, on a prospective clinical trial. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using an in-house software. Disease measurability was assessed at a threshold based on the liver standard uptake value (SUV) using the equation Livermean + (2 * Liversd). Median values of PET parameters were used as cutoffs when assessing their prognostic potential through univariate and multivariate Cox regression analyses. Results: Of the 32 patients in this study, the majority were male (N=19, 59%), 65 years or older (N=21, 66%), and had tumors located in the pancreatic head (N=27, 84%). Twenty-seven patients (85%) received induction gemcitabine prior to SBRT per protocol. Median overall survival for the entire cohort was 18.8 months (95% CI, 15.7-22.0). An MTV of 26.8 cm3 or greater (HR 4.46, 95% CI 1.64 to 5.88, p &lt; 0.003) and TLG of 70.9 cm3 or greater (HR 3.08, 95% CI 1.18 to 8.02, p &lt; 0.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19 to 22.21, p=0.029) and TLG (HR 3.34, 95% CI 1.07 to 10.48, p=0.038) remained independent prognostic factors for overall survival in separate multivariate analyses. Conclusions: Pre-SBRT MTV and TLG yield prognostic information on overall survival in patients with LAPC and may assist in tailoring therapy. Clinical trial information: NCT01146054.

ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early‐stage, nonbulky Hodgkin lymphoma

Patients with early-stage, nonbulky classic Hodgkin lymphoma (cHL) undergo intensive posttreatment radiologic surveillance despite having a low risk of disease recurrence. The current study attempted to evaluate the risk of disease recurrence and the value of radiologic surveillance in patients treated with the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone who achieved a complete remission (CR) as noted on posttreatment positron emission tomography (PET). Forty-seven patients who underwent therapy with interim and/or posttreatment PET scans were evaluated for disease recurrence during ≥ 24 months of follow-up. Their presenting characteristics and imaging results were assessed and interpreted in relation to clinical outcome. All 47 patients were eligible for analysis. The majority of patients were female (35 patients) with a median age of 28 years (range, 17 years-65 years.). The nodular sclerosing subtype was the predominant histology (41 patients). A total of 34 patients were staged with IIA disease, 6 with IA disease, 6 with IIB disease, and 1 with IIEA disease (lung) (according to Cotswolds modification of the Ann Arbor staging system). All patients completed 6 cycles of planned ABVD therapy and achieved a CR. Two had a positive PET scan (1 interim scan and 1 posttreatment scan); both were biopsy-proven sarcoidosis. Two patients developed disease recurrence at 7 months and 24 months, respectively, after negative interim and posttreatment imaging. One case of recurrence was identified through surveillance imaging and the other was identified simultaneously by the patient and surveillance scan. A total of 45 patients experienced a durable CR; 21 had additional unscheduled imaging/workup during surveillance to investigate symptoms or imaging signs of concern. Because of a low risk of disease recurrence, posttreatment radiologic surveillance appears to be unnecessary in patients with early-stage, nonbulky (CD20 negative) cHL who achieve a PET-detected CR with the ABVD combination alone. This will reduce cumulative radiation exposure and health care costs in a predominantly young patient population.

Image Change Detection Using Paradoxical Theory for Patient Follow-Up Quantitation and Therapy Assessment

In clinical oncology, positron emission tomography (PET) imaging can be used to assess therapeutic response by quantifying the evolution of semi-quantitative values such as standardized uptake value, early during treatment or after treatment. Current guidelines do not include metabolically active tumor volume (MATV) measurements and derived parameters such as total lesion glycolysis (TLG) to characterize the response to the treatment. To achieve automatic MATV variation estimation during treatment, we propose an approach based on the change detection principle using the recent paradoxical theory, which models imprecision, uncertainty, and conflict between sources. It was applied here simultaneously to pre- and post-treatment PET scans. The proposed method was applied to both simulated and clinical datasets, and its performance was compared to adaptive thresholding applied separately on pre- and post-treatment PET scans. On simulated datasets, the adaptive threshold was associated with significantly higher classification errors than the developed approach. On clinical datasets, the proposed method led to results more consistent with the known partial responder status of these patients. The method requires accurate rigid registration of both scans which can be obtained only in specific body regions and does not explicitly model uptake heterogeneity. In further investigations, the change detection of intra-MATV tracer uptake heterogeneity will be developed by incorporating textural features into the proposed approach.

Decreased microglial activation in MS patients treated with glatiramer acetate

Activated microglia are thought to be an important contributor to tissue damage in multiple sclerosis (MS). The level of microglial activation can be measured non-invasively using [(11)C]-R-PK11195, a radiopharmaceutical for positron emission tomography (PET). Prior studies have identified abnormalities in the level of [(11)C]-R-PK11195 uptake in patients with MS, but treatment effects have not been evaluated. Nine previously untreated relapsing-remitting MS patients underwent PET and magnetic resonance imaging of the brain at baseline and after 1 year of treatment with glatiramer acetate. Parametric maps of [(11)C]-R-PK11195 uptake were obtained for baseline and post-treatment PET scans, and the change in [(11)C]-R-PK11195 uptake pre- to post-treatment was evaluated across the whole brain. Region-of-interest analysis was also applied to selected subregions. Whole brain [(11)C]-R-PK11195 binding potential per unit volume decreased 3.17% (95% CI: -0.74, -5.53%) between baseline and 1 year (p = 0.018). A significant decrease was noted in cortical gray matter and cerebral white matter, and a trend towards decreased uptake was seen in the putamen and thalamus. The results are consistent with a reduction in inflammation due to treatment with glatiramer acetate, though a larger controlled study would be required to prove that association. Future research will focus on whether the level of baseline microglial activation predicts future tissue damage in MS and whether [(11)C]-R-PK11195 uptake in cortical gray matter correlates with cortical lesion load.

Advanced Insights Into the Biology of Malignant Lymphomas

This Journal of Clinical Oncology Review Series deals with some of the newest scientific advances that provide insight into the biology of malignant lymphomas and offers a future pathway for the development of targeted therapies. As described by Nogai et al, recent studies of tumor tissue from patients with diffuse large B-cell lymphoma have demonstrated heterogeneity in the gene expression profiles that has resulted in the classification of these lymphomas into at least three different categories: germinal center B-cell lymphoma, activated B-cell lymphoma, and mediastinal B-cell lymphoma. The remaining lymphomas are currently classified as other, and remain heterogeneous. Different signaling pathways seem to be activated in each of these different categories. Furthermore, specific activating mutations have been detected, particularly in the activated B-cell lymphomas. These activated pathways have been shown to be critical for the survival of these lymphoma cells and are therefore likely targets for successful future intervention. In contrast, in Hodgkin’s disease, the role of the tumor microenvironment has been shown to have significant prognostic importance. InteractionswiththeReed-Sternbergcellandthesurroundinginflammatory infiltrate are critical for the pathogenesis of Hodgkin’s lymphoma. This is discussed in detail in the article by Steidl et al. Several areas of great clinical controversy are also described in this series of articles. Transformation of indolent lymphomas to diffuse large B-cell lymphomas is a critical event that requires intensive successful intervention to prevent a fatal outcome. As discussed by Montoto and Fitzgibbon, many questions remain about the biology and treatment of this process. Is it prevented or delayed by early therapeutic intervention? What is the histology and natural history of recurrence after successful treatment for transformation? The biology, diagnosis, and appropriate treatment of the highly proliferative, aggressive non-Hodgkin’s lymphoma in the adult patient have been controversial for many years. Classic Burkitt’s lymphoma is relatively easy to diagnose. However, many tumors demonstrate histologic features of both Burkitt’s lymphoma and diffuse large B-cell lymphoma. The so-called double-hit lymphomas fall into this category. In the newest classification, these have been called gray-zone lymphomas, as discussed by Salaverria and Siebert. Perhaps no new diagnostic test has had more impact on the treatment of malignant lymphomas than the positron emission tomography (PET) scan that is now in widespread use. In this Review Series, Cheson provides a detailed review of the data regarding the usefulness of PET scans in different histologies. In addition, the use of interim and post-treatment PET scans has become relatively common. The value of these scans in predicting ultimate therapeutic benefit may vary greatly depending on both the timing of the scan and the histology of the lymphoma. Three new approaches to treatment are discussed in extensive detail in the Review Series. Chakraverty and MacKinnon describe the development of the reduced-intensity allogeneic stem-cell transplantation that has made allogeneic transplantation available to many patients who previously did not have a match or were too old to survive the procedure. Despite the failure of the randomized trials of anti-idiotype therapy to provide significant benefit for patients with follicular lymphoma, new approaches are being developed, as described by Brody et al. As information regarding the importance of the tumor microenvironment in regulating the growth of malignant lymphoma increases, the potential for successful immunotherapy also increases. In the treatment of patients with malignant lymphoma, there has never been a time when more novel therapeutics are being developed. What are the rational targets? What are the features of a novel agent that make it likely to succeed? How can we move forward with a rational plan for the development of the most important of these agents? This subject is also addressed extensively in the article by Mahadevan and Fisher. Finally, as we become more successful and a greater number of patients survive longer, the long-term impact of treatments becomes more of a problem for the cancer survivor and his or her physician. General guidelines for the follow-up of patients who have been treated for malignant lymphomas is proposed by Ng et al; however, much more study is necessary. In summary, we hope that this Journal of Clinical Oncology Review Series will provide the reader with information that is useful in the day-to-day management of these patients as well as a framework with which to understand the future biologic and treatment advances that we all believe will dramatically change the prognosis of patients with malignant lymphomas in the next decade.

Value of [18F]Fluorodeoxyglucose Positron Emission Tomography in the Management of Follicular Lymphoma: The End of a Dilemma?

Background[18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a powerful tool for the imaging of various lymphomas. Despite its high FDG avidity, there is little data on PET in follicular lymphoma (FL). In this work, we present findings concerning PET at staging and posttreatment evaluation in FL. Patients and MethodsA total of 181 PET scans were evaluated in 117 patients with FL in a retrospective study. Positron emission tomography—based results were compared with conventional staging in 82 patients. Posttreatment PET evaluation was performed in 99 patients; there were comparable progression-free survivals of PET-positive and PET-negative patients. ResultsPositron emission tomography showed more involvement than computed tomography (CT) with clinical examination in 41 of 82 patients (50%), less in 11 of 82 (13%); the same extension was found in 27 of 82 patients (33%), and 3 patients revealed discordant foci visible on PET only and lymphadenopathy without PET activity (P < .001). Including the results of trephine biopsy, PET finally upstaged FL in 15 of 82 patients (18%), which was projected in change of treatment strategy. There were 73 of 99 negative posttreatment PET scans; 54 of 73 PET-negative patients (74%) remain in complete remission (median follow-up, 27 months); 19 (26%) of them relapsed with median of 12 months. Fourteen of 20 (70%) PET-positive patients relapsed with a median of 4.5 months regardless of findings on CT and subsequent therapy. The difference in relapse rates between PET-positive and PET-negative patients is statistically significant (P < .001). ConclusionPositron emission tomography at staging is able to substantially change treatment strategy in an important proportion of patients with FL. Persisting PET positivity after treatment predicts for a high risk of an early relapse and can identify patients with poor prognosis.

Prognostic significance of (18) F-fluorodeoxyglucose positron emission tomography after treatment in patients with limited stage small cell lung cancer

7591 Background: Small cell lung cancer (SCLC) represents 15%-25% of all lung cancers. Despite favorable response rates after initial treatment, SCLC is likely to recur and long term prognosis is dismal. The ability to accurately measure response to therapy is critical in order to determine which patients might benefit from further treatment and which patients might be spared additional treatment and the potential for additional treatment-related side effects. After treatment, functional imaging with (18) F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) alone or in combination with computerized tomography (CT) may help distinguish between necrotic or fibrous tissue and residual disease, and thus be a useful tool in guiding further treatment and prognosis. Methods: This study was a retrospective chart review of patients with SCLC treated between January 1, 1992, and July 31, 2007. Results: A total of 21 patients with limited stage SCLC were identified as having a PET scan after treatment. The median duration between the last chemotherapy to PET scan was 37 days (13 to 125 days). PET scan results were positive in 11 (52.4%) patients and negative in 10 (47.6%). Median follow-up for all patients was 36.8 months, ranging from 6.8 to 65.9 months. Median survival time for all patients was 19.2 months (95% confidence interval [CI], 10.2 to >65.8 months). The estimated median survival time for PET negative patients was higher than the PET positive patients (29.2 vs. 10.3 months, P = 0.09). Estimated median progression-free survival for all patients was 8.1 months (95% CI, 4.3 to 11.9 months). Only about 5% of patients with SCLC treated in this time period underwent post-treatment PET scans. Conclusions: From this study, we conclude that post-treatment PET/PET-CT scanning has prognostic significance and currently post-treatment PET scanning may be underutilized. No significant financial relationships to disclose.

Thymic 18F-fluorodeoxyglucose uptake on positron emission tomography scanning after doxorubicin, bleomycin, vincristin and dacarbazine chemotherapy and highly-active antiretroviral therapy in HIV-associated Hodgkin's disease in an adult

Positron emission tomography (PET) scanning is being increasing used to stage disease and monitor response to therapy in lymphoma patients [1]. More recently, it has been used as a prognostic tool to predict disease recurrence after chemotherapy [2,3]. PET-positive residual mass with standardized uptake value (SUV) > 3 after chemotherapy is associated with recurrence rate of 60–80% [4,5] PET imaging has a high sensitivity and specificity of 86% and 96%, respectively, and, in many centres, treatment recommendations were made solely on the basis of PET results for diagnosis of recurrence without confirmatory tissue diagnosis. This is the first report of a patient in whom anterior mediastinal PET positivity was due to thymic reconstitution after successful chemotherapy for HIV-related Hodgkin's disease and highly-active antiretroviral therapy (HAART) rather than disease relapse. A 26-year-old HIV-infected man presented with a 3-month history of night sweats, fevers and generalised lymphadenopathy. He had been diagnosed with HIV infection 2 years previously. His CD4 count was 330 cells/μl and his HIV RNA load was 12 000 copies/ml. A computed tomography (CT) scan showed a large anterior mediastinal mass measuring 10 × 6 cm with further enlarged nodes seen in the right para-tracheal, sub-carinal, right hilar, retroperitoneal and inguinal regions. Biopsy of the mediastinal mass was performed and the histological examination showed large cells with Reed–Sternberg morphology and expressing both CD30 and CD15, establishing the diagnosis of classical Hodgkin's lymphoma, nodular sclerosis subtype. Bone marrow aspirate and trephine showed no evidence of bone marrow involvement. The patient was staged as stage IIIb. Treatment with doxorubicin, bleomycin, vincristin, and dacarbazine (ABVD) was started. He was also treated with HAART using efavirenz 600 mg daily, emtricitabine 200 mg daily, and tenofovir 245 mg daily in an attempt to maintain and/or improve his immune status while undergoing chemotherapy treatment. His HIV RNA became undetectable (<50 copies/ml) and the CD4 cell counts remained reasonably stable during the chemotherapy treatments. A CT scan after six cycles of chemotherapy showed a residual anterior mediastinal mass measuring 7 × 4 cm but this was shown not to take up fluorodeoxyglucose (FDG) on PET scanning (Fig. 1a).Fig. 1: Positron emission tomography (PET)–computed tomography (CT) scan performed 1 month after the completion of chemotherapy showed residual anterior mediastinal mass which was, however, not fluorodeoxyglucose (FDG)-avid (a). Another CT–PET scan was performed 16 months after the completion of chemotherapy and it showed increased FDG uptake with an SUV of 3.2 (arrow) in the anterior mediastinum, consistent with disease relapse (b). Biopsy of the mediastinal mass that was positive on FDG–PET 16 months after the completion of chemotherapy was performed but the histological examination showed regenerated thymus with a lobular architecture and containing morphologically normal cortex, medulla, and Hassall's corpuscles (c); original magnification × 45).The patient continued to receive HAART and maintained good virological control. Sixteen months later, he presented with enlarged 1.0 cm axillary lymph node and a CT–PET scan was requested to exclude disease recurrence. His CD4 count was 600 cells/μl and HIV RNA remained undetectable. On this CT–PET scan, there was now an increased uptake detected in the anterior mediastinum with an SUV of 3.2, suggesting disease relapse (Fig. 1b; arrow). Mediastinoscopic biopsy was requested to confirm disease progression with the view of high-dose chemotherapy and peripheral blood stem cell transplantation. To our surprise, the histology revealed normal regenerating thymic tissue with no evidence of lymphoma (Fig. 1c). In our patient, the PET positivity in the mediastinum after chemotherapy in a HAART patient with HIV-associated Hodgkin's lymphoma is the result of T-cell immune reconstitution in a functional thymus gland. Initiation of HAART in HIV-infected patients is associated with immune reconstitution of T cells and this is correlated with thymus volume increase and generally occurs in patients with initial low CD4 counts and/or rising CD4 counts [6–8]. The thymic reconstitution is also associated with increased thymic metabolism, which is reflected by increased FDG uptake detected by PET [9]. Interestingly, in our patient, the number of CD4 cell was high prior to treatment. It is possible that HAART in combination with transient lymphopenia induced by chemotherapy could have triggered the thymic reconstitution. In conclusion, this is the first case to report on the occurrence of FDG-avid uptake in functional thymic tissue in a HAART patient with HIV-associated Hodgkin's lymphoma previously treated with chemotherapy. Our case illustrates the importance of verification of PET findings by a biopsy. It is also important to consider this differential diagnosis in HIV-infected patients treated with HAART and chemotherapy if a post-treatment PET scan shows increased mediastinal uptake.

Correlation of Molecular Response as Measured by 18-FDG Positron Emission Tomography With Outcome After Chemoradiotherapy in Patients with Esophageal Carcinoma

To determine whether 18-fluorodeoxyglucose positron emission tomography (PET) computed tomography scans predict the pathologic complete response and disease-free and overall survival in patients with esophageal carcinoma undergoing definitive or preoperative chemoradiotherapy. The records of patients with esophageal carcinoma presenting for definitive or preoperative treatment and undergoing pre- and post-treatment 18-fluorodeoxyglucose PET-computed tomography scans were retrospectively reviewed. The histologic type, T stage, and nodal status were the variables investigated to determine a relationship with the baseline standardized uptake value (SUV) of the primary tumor at diagnosis. We also attempted to determine whether a relationship exists between the percent decrease in SUV and a pathologic complete response, overall and disease-free survival. A total of 81 patients, 14 women and 67 men, underwent 18-fluorodeoxyglucose PET-computed tomography scanning before treatment and 63 also had post-treatment scans. T stage and tumor location predicted in univariate, but not multivariate, analysis for the initial SUV. Of the patients with a postchemoradiotherapy SUV of <2.5, 66% had tumor in the surgical specimen and 64% of patients had positive lymph nodes at surgery that were not imaged on the postchemoradiotherapy PET scan. A trend existed for post-treatment SUV and the days from radiotherapy to surgery to predict for a pathologic complete response (p = 0.09 and p = 0.08, respectively). The post-treatment SUV predicted for disease-free survival in the definitive chemoradiotherapy group (p = 0.01). A correlation was found between the depth of tumor invasion and the baseline SUV. The post-treatment SUV predicted for disease-free survival in the definitive chemoradiotherapy group. Caution should be exercised in using post-treatment PET scans to determine the necessity for surgical resection.

Value of Positron Emission Tomography in Staging Ocular Adnexal Lymphomas and Evaluating Their Response to Therapy

An observational case series to assess the value of positron emission tomography (PET) in staging ocular adnexal lymphomas and evaluating their response to therapy. The clinical records of 16 consecutive patients with ocular adnexal lymphoma for whom pretreatment and posttreatment PET scans and corresponding computed tomography (CT) and magnetic resonance imaging (MRI) scans were available were compared. Pretreatment PET scans demonstrated fluorine 18-fluorodeoxyglucose (FDG) positive lesions in 15 orbits of 12 patients. In 1 patient with low-grade follicular lymphoma of the orbit, PET revealed an additional focus of lymphoma in the deltoid muscle that was missed on clinical examination and conventional radiography. All of the posttreatment PET scans showed complete resolution of FDG uptake, suggesting good response to therapy. However, posttreatment CT and MRI scans demonstrated residual masses in 3 patients. PET is valuable for initial staging of ocular adnexal lymphomas and may be a good adjunct to conventional imaging in evaluation of response to therapy.

1094: The Influence of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography (PET) on the Clinical Management of Patients With Head and Neck Cancer

1094: The Influence of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography (PET) on the Clinical Management of Patients With Head and Neck Cancer

The Role of Positron Emission Tomography Scans in the Management of the N‐Positive Neck in Head and Neck Squamous Cell Carcinoma After Chemoradiotherapy

The objective of this study was to determine the sensitivity, specificity, and predictive value of 18-fluorodeoxyglucose positron emission tomography (PET) in predicting residual cervical metastatic disease in patients with N-positive necks undergoing curative radiotherapy and chemoradiotherapy for squamous cell carcinoma (SCC) of the upper aerodigestive tract. The authors studied a prospective case series of patients (2003-2005) of patients undergoing radiotherapy and chemoradiotherapy for advanced head and neck SSC. Study entry criteria included N-positive neck disease, a complete response to treatment at the primary tumor site, posttreatment PET scan (8-12 weeks after completion of treatment), followed by salvage neck dissection. The posttreatment PET scan neck findings were correlated to the salvage neck dissection pathology report. The sensitivity, specificity, and predictive values of the PET scan to predict residual cervical metastatic disease after curative chemoradiotherapy were calculated. Twenty-one neck dissections (pretreatment N1 = 5, N2a = 2, N2b = 8, N3 = 6) were entered into the protocol. Four (19.0%) of the 21 neck specimens were positive for residual cervical metastatic disease, whereas the remaining 17 (80.9%) specimens demonstrated no residual carcinoma. The overall sensitivity and specificity were 75.0% and 64.7%, respectively. The positive predictive value was 33% and the negative predictive value was 91.7%. Although the role of posttreatment neck dissection remains controversial, the surgeon must rely on clinical examination and imaging studies. Our practice has been to perform planned staged neck dissections on all N2 and N3 necks, as well as N1 necks with an incomplete response to treatment. Based on this small prospective study, it appears that PET imaging lacks adequate sensitivity and specificity to reliably predict the presence of residual cervical metastatic disease after completion of chemoradiotherapy. With a negative predictive value of 91.7%, however, a negative PET scan appears to be a reliable predictor of the absence of residual tumor.