Amir H. Khandani

Incorporating Bevacizumab and Erlotinib in the Combined-Modality Treatment of Stage III Non–Small-Cell Lung Cancer: Results of a Phase I/II Trial

PURPOSE Bevacizumab and erlotinib have been shown to improve survival in stage IV non-small-cell lung cancer (NSCLC). This phase I/II trial was designed to incorporate these agents with induction and concurrent chemoradiotherapy in stage III NSCLC. PATIENTS AND METHODS Patients received induction chemotherapy (carboplatin area under the curve [AUC] 6, paclitaxel 225 mg/m(2), and bevacizumab 15 mg/kg on days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly with bevacizumab 10 mg/kg every other week for four doses) and thoracic conformal radiation therapy (TCRT) to 74 Gy. In the phase I portion, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, Tuesday through Friday, during TCRT. Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3 to 6 weeks later for six cycles. RESULTS Forty-five eligible patients were enrolled. The objective response rates to induction and overall treatment were 39% (95% CI, 24% to 55%) and 60% (95% CI, 44% to 75%), respectively. The median progression-free and overall survival times were 10.2 months (95% CI, 8.4 to 18.3 months) and 18.4 months (95% CI, 13.4 to 31.7 months), respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with one patient with grade 3 tracheoesophageal fistula), which was often prolonged. Consolidation therapy with bevacizumab and erlotinib was not feasible. CONCLUSION The use of bevacizumab and erlotinib as administered in this trial is not recommended given the lack of an efficacy signal and the substantial risk of esophageal toxicity.

Use of yttrium-90 microspheres in patients with advanced hepatocellular carcinoma and portal vein thrombosis.

PURPOSE Patients with portal vein thrombosis (PVT) and hepatocellular carcinoma (HCC) have limited treatment options because of increased disease burden and diminished hepatic perfusion. Yttrium-90 ((90)Y) microspheres may be better tolerated than chemoembolization in these patients. The present study reviews the safety and efficacy of (90)Y microspheres in HCC with major PVT. MATERIALS AND METHODS A retrospective review of HCC with main (n = 10) or first-branch (n = 12) PVT treated with (90)Y microspheres (N = 22) was conducted. Cancer of the Liver Italian Program (CLIP) scores ranged from 2 to 5, with 18% of patients having a score of 4 or greater. Imaging response at 8-12 was based on Response Evaluation Criteria In Solid Tumors. Overall survival (OS) was estimated by the Kaplan-Meier method. RESULTS A total of 32 microsphere treatments (26 glass, six resin) were administered to 22 patients. Common grade 1/2 toxicities included abdominal pain (38%), nausea (28%), and fatigue (22%). Four posttreatment hospitalizations occurred, all less than 48 hours in duration. One death occurred 10 days after therapy. The partial response rate was 8% and progressive disease was seen in 42% of patients. Stable disease was achieved in 50% of treatments. Median OS was 7 months from initial treatment. Patients with Child-Pugh class A disease had a median OS of 7.7 months; those with class B/C disease had an OS of 2.7 months (P = .01). Median OS for patients with CLIP scores of 2/3 was 7 months, versus 1.3 months for those with scores of 4/5 (P = .04). CONCLUSIONS Yttrium-90 microspheres are tolerated in patients with HCC and major PVT. Compared with chemoembolization, rates of severe adverse events appear low. Radiographic response rates are low. The median OS of 7 months is promising and warrants further study versus systemic therapy.

Lung cancer presenting with a solitary colon metastasis detected on positron emission tomography scan

The patient is a 60-year-old man with a history of tobacco use (80 pack-years) who presented with a history of a cough of several months’ duration, occasionally productive of bloodtinged sputum. As part of the evaluation of these symptoms, a chest x-ray was performed, which revealed hilar fullness. As a result of this finding a computed tomography (CT) scan was performed, which revealed a left upper lobe mass surrounding the left main stem bronchus to the level of the carina, and the pulmonary artery without evidence of mediastinal lymphadenopathy. The patient was evaluated by the thoracic surgery service and determined to be unresectable. A positron emission tomography (PET) -CT scan was performed, which revealed increased [18]fluorine fluorodeoxyglucose (FDG) uptake in the left hilar mass, and focally increased uptake in the ascending colon (Fig 1), and no increased uptake in the mediastinal lymph nodes. The differential diagnosis for the focal area of increased FDG uptake in the colon was abscess, adenomatous polyps, hamartomatous adenoma, colonic primary, and metastatic lesion. The patient had a colonoscopy performed 2 years before presentation, which did not reveal any evidence of malignancy. A repeat colonoscopy was performed, which revealed a mass in the ascending colon (Fig 2), and biopsy revealed squamous cell carcinoma consistent with a lung primary. The patient’s clinical stage changed from stage III (T4N0M0) to histologic stage IV, and the patient’s treatment plan changed from chemoradiotherapy with curative intent to chemotherapy. In patients with clinical stage III disease, PET scanning will detect extrathoracic metastases in approximately 25% of patients. Patients who are being considered for surgical resection or chemoradiotherapy with extrathoracic areas of increased FDG uptake detected on PET scan should have a pathologic evaluation of the suspected lesions. A pathologic evaluation of solitary lesions is especially important. A recent retrospective review of patients with non–small-cell lung cancer (NSCLC) found that solitary extrapulmonary lesions were observed on PET-CT imaging in 21% of patients, and 46% of the lesions were either another malignancy, benign tumors, or inflammatory conditions. Previously the colon was not considered a frequent site of metastases for NSCLC; however, PET scanning may reveal a higher incidence of colonic metastases than previously suspected. The optimal management of patients with a solitary lesion detected on PET scan is unclear. Data exist that a proportion of patients with solitary brain or adrenal metastasis may experience prolonged survival with resection of both the primary and solitary metastatic lesion. Whether long-term survival is possible with resection of lung primary and solitary visceral metastasis is not known.

Glut1 and Glut3 expression in lymphoma and their association with tumor intensity on 18F-fluorodeoxyglucose positron emission tomography

ObjectiveTo evaluate the expression of glucose transporters (Gluts) 1 and 3 in Hodgkin and nonHodgkin lymphoma and to assess the association between their expression and the tumor intensity on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). MethodsAll 31 lymphoma patients in whom the histologic diagnosis was made and who had also undergone a prechemotherapy PET scan at our institution between June 2001 and December 2005 were included in this retrospective study. The percentage of tumor cells in the various lymphoma subtypes was estimated by comparison of hematoxylin and eosin stain with a lineage-associated immunohistochemical stain on the same block of tissue. Tissue specimens were stained with Glut1 and Glut3 antibodies. The percentages of Glut1+ and Glut3+ cells in the entire cell population (lymphoma cells and nonlymphomatous cells) and among the lymphoma cells were estimated. FDG PET images were reviewed and the tumor intensity was assessed by calculating the maximum standard uptake value (SUVmax). Correlation coefficients between SUVmax and the percentage of Glut1+ and Glut3+ cells in the entire cell population were calculated. ResultsIn all 31 cases, tumors were visible on FDG PET and positive for Glut1 and Glut3. The correlation between the percentage of Glut1+ cells and SUVmax was statistically significant across all 31 cases (r = 0.73, P<0.0001, 95% confidence interval: 0.50–0.86) and across the 25 cases of nonHodgkin lymphoma (r = 0.71, P<0.0001, 95% confidence interval: 0.44–0.87). There was no statistically significant correlation between the percentage of Glut3+ cells and SUVmax. More importantly, in 16 of 31 cases (52%), only nonlymphomatous, benign cells expressed Glut1 or Glut3. ConclusionIntensity of lymphoma on FDG PET is likely associated with Glut1 expression. The nonlymphomatous, benign cells may play an important role in visualization of lymphoma on FDG PET.

A Pilot Study of Early 18F-FDG PET to Evaluate the Effectiveness of Radiofrequency Ablation of Liver Metastases

OBJECTIVE The objective of our study was to collect pilot data about the use of FDG PET within hours after radiofrequency ablation (RFA) of liver metastases. CONCLUSION Total photopenia on early PET can potentially be regarded as a macroscopic tumor-free margin; focal uptake can be regarded as macroscopic residual tumor.

Positron Emission Tomography in Renal Cell Carcinoma: An Imaging Biomarker in Development

Positron emission tomography (PET) has revolutionized cancer imaging. The current workhorse of molecular imaging, fluorodeoxyglucose (FDG) PET is used in the majority of malignant tumors with a few exceptions. Renal cell carcinoma (RCC) is one of those exceptions because of its variable uptake of FDG, although this variable uptake may actually be an asset in predicting response to some targeted agents, as will be discussed later. Beyond FDG, there is only scattered information in the literature on the use of PET in RCC. The purpose of this review is to summarize the current status of PET usage in RCC and point out its potentials and future directions. We will start with a brief overview of the demographics, molecular pathogenesis, and evolving treatment strategies in RCC because this information is essential for better understanding of uptake of various PET radiotracers in this cancer and their indications. This will be followed by discussing the role of PET in characterization of indeterminate renal masses, in staging and restaging of RCC, and, finally, in predicting and monitoring therapy response. Each of these 3 areas of PET usage will include the relevant radiotracers currently in use or in development.

Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell-Renal-Cell-Carcinoma: Proof-of-Concept Study

Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone.

Primary renal cell carcinoma: relationship between 18F-FDG uptake and response to neoadjuvant sorafenib.

ObjectiveThe objective of this study was to collect preliminary data on the predictive value of pretherapy 18F-fluorodeoxyglucose positron emission tomography in primary renal cell carcinoma (RCC) patients undergoing neoadjuvant therapy with sorafenib. MethodsAs part of a clinical trial to assess the safety and feasibility of using neoadjuvant sorafenib in patients with RCC, 26 patients [19 with clear cell RCC (ccRCC), seven with non-clear cell RCC (non-ccRCC)] underwent 18F-fluorodeoxyglucose positron emission tomography with concurrent computed tomography (CT) before commencing sorafenib therapy and 17 (13 ccRCC, four non-ccRCC) of them also at the end of sorafenib therapy. The maximal standard uptake value at baseline (SUVbase) and its change from baseline after therapy (SUVdiff and SUVrel) were recorded and correlated with therapy response, measured as percentage size change on CT, using Spearman’s rank and Pearson’s correlation coefficients. ResultsSUVbase and size change on CT showed a strong inverse correlation (Spearman’s rank correlation coefficient=−0.72, P=0.0003; Pearson’s correlation coefficient=−0.64, P=0.002) in ccRCC. There was no statistically significant correlation in non-ccRCC (Spearman’s rank correlation coefficient=0.67, P=0.098; Pearson’s correlation coefficient=0.46, P=0.32). In neither group was there a statistically significant correlation between change in SUV and size after commencement of treatment. All findings were limited by the small number of samples included in this analysis. ConclusionPrimary ccRCC tumors with lower SUVbase are more likely to respond to neoadjuvant sorafenib, whereas this trend was not observed for non-ccRCC tumors.

Extracardiac abnormalities on rubidium-82 cardiac positron emission tomography/computed tomography.

BackgroundThe role of rubidium-82 (82Rb) in recognizing extracardiac diseases is minimally investigated. The aim of this study was to evaluate the frequency and incremental added value of extracardiac findings on 82Rb cardiac positron emission tomography/computed tomography (PET/CT) studies. MethodThe study included all consecutive patients who were referred from July 2008 to June 2010 for 82Rb cardiac PET/CT to our institution. A blinded reader reviewed the images retrospectively to assess abnormal extracardiac PET findings. ResultsImages of 406 patients (142 men; 264 women) with a mean age±standard deviation of 59.72±12.93 years (range: 18–91 years) were reviewed. Incidental extracardiac abnormalities were found in 67 of 406 patients (16.5%). Among them, eight patients had malignant etiologies (1.9%). ConclusionIncidental extracardiac findings were present in a significant portion of patients undergoing 82Rb cardiac PET/CT studies. Although most of the extracardiac findings on 82Rb cardiac PET/CT studies represented clinically known pathologies, these incidental findings on routine 82Rb cardiac PET/CT scans may have a significant clinical impact on a small number of patients, and offer the referring physician the chance to obtain additional clinically relevant information.

Positron Emission Tomography and Stage Migration in Head and Neck Cancer

IMPORTANCE Since 2001, there has been a rapid adoption of positron emission tomography (PET) for diagnosis and American Joint Committee on Cancer (AJCC) staging of head and neck cancer (HNC) without data describing improved clinical outcomes. OBJECTIVE To determine the association between increased use of PET and stage and/or survival for patients with HNC in the managed care environment. DESIGN, SETTING, AND PARTICIPANTS Adult patients diagnosed as having HNC (n = 958) from 2000 to 2008 at 4 integrated health systems were identified via tumor registries linked to administrative data. The AJCC stage distribution, patient and treatment characteristics, and survival between pre-PET era (2000-2004) vs PET era (2005-2008) and use of PET vs no use of PET during the PET era were compared. The AJCC stages were categorized to represent localized (stage I or II), locally advanced (stage III, IVA, or IVB), and metastatic (stage IVC) disease. INTERVENTIONS Treatments were determined by billing codes for surgery, radiation treatment, and chemotherapy. MAIN OUTCOMES AND MEASURES The primary outcome for this study was the use of PET. Secondary outcomes included treatment received and 2-year survival. A logit model estimated the effects of PET on diagnosis of locally advanced disease. Kaplan-Meier estimates described overall survival differences between PET and non-PET. Cox regression evaluated the association of PET on survival in patients with locally advanced disease. RESULTS An association between PET and locally advanced disease was found (odds ratio, 2.86 [95% CI, 1.90-4.29) (P < .001). Two-year overall survival for patients with locally advanced disease with and without PET was 52% and 32%, respectively (P = .004), but there was no difference for all stages (P = .69). On Cox proportional hazard regression, PET had no association with survival in patients with locally advanced disease (hazard ratio, 1.208 [95% CI, 0.778-1.877]) (P = .40). CONCLUSIONS AND RELEVANCE The increasing use of PET among patients with HNC is associated with a greater number of patients with higher-stage disease and a dilution of the population with higher-stage disease with patients who have a better prognosis. Thus, the improved survival in patients with locally advanced disease likely reflects selection bias and stage migration. Further research on PET use among patients with HNC is necessary to determine if it results in improved treatment for individual patients.