Colette Zwarthoed

Positron Emission Tomography (PET) in Oncology

Since its introduction in the early nineties as a promising functional imaging technique in the management of neoplastic disorders, FDG-PET, and subsequently FDG-PET/CT, has become a cornerstone in several oncologic procedures such as tumor staging and restaging, treatment efficacy assessment during or after treatment end and radiotherapy planning. Moreover, the continuous technological progress of image generation and the introduction of sophisticated software to use PET scan as a biomarker paved the way to calculate new prognostic markers such as the metabolic tumor volume (MTV) and the total amount of tumor glycolysis (TLG). FDG-PET/CT proved more sensitive than contrast-enhanced CT scan in staging of several type of lymphoma or in detecting widespread tumor dissemination in several solid cancers, such as breast, lung, colon, ovary and head and neck carcinoma. As a consequence the stage of patients was upgraded, with a change of treatment in 10%–15% of them. One of the most evident advantages of FDG-PET was its ability to detect, very early during treatment, significant changes in glucose metabolism or even complete shutoff of the neoplastic cell metabolism as a surrogate of tumor chemosensitivity assessment. This could enable clinicians to detect much earlier the effectiveness of a given antineoplastic treatment, as compared to the traditional radiological detection of tumor shrinkage, which usually takes time and occurs much later.

Prognostic value of bone marrow tracer uptake pattern in baseline PET scan in Hodgkin Lymphoma: results from an International Collaborative Study

PET/CT-ascertained bone marrow involvement (BMI) constitutes the single most important reason for upstaging by PET/CT in Hodgkin lymphoma (HL). However, BMI assessment in PET/CT can be challenging. This study analyzed the clinicopathologic correlations and prognostic meaning of different patterns of bone marrow (BM) 18F-FDG uptake in HL. Methods: One hundred eighty newly diagnosed early unfavorable and advanced-stage HL patients, all scanned at baseline and after 2 adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) courses with 18F-FDG PET, enrolled in 2 international studies aimed at assessing the role of interim PET scanning in HL, were retrospectively included. Patients were treated with ABVD × 4–6 cycles and involved-field radiation when needed, and no treatment adaptation on interim PET scanning was allowed. Two masked reviewers independently reported the scans. Results: Thirty-eight patients (21.1%) had focal lesions (fPET+), 10 of them with a single (unifocal) and 28 with multiple (multifocal) BM lesions. Fifty-three patients (29.4%) had pure strong (>liver) diffuse uptake (dPET+) and 89 (48.4%) showed no or faint (≤liver) BM uptake (nPET+). BM biopsy was positive in 6 of 38 patients (15.7%) for fPET+, in 1 of 53 (1.9%) for dPET+, and in 5 of 89 (5.6%) for nPET+. dPET+ was correlated with younger age, higher frequency of bulky disease, lower hemoglobin levels, higher leukocyte counts, and similar diffuse uptake in the spleen. Patients with pure dPET+ had a 3-y progression-free survival identical to patients without any 18F-FDG uptake (82.9% and 82.2%, respectively, P = 0.918). However, patients with fPET+ (either unifocal or multifocal) had a 3-y progression-free survival significantly inferior to patients with dPET+ and nPET+ (66.7% and 82.5%, respectively, P = 0.03). The κ values for interobserver agreement were 0.84 for focal uptake and 0.78 for diffuse uptake. Conclusion: We confirmed that 18F-FDG PET scanning is a reliable tool for BMI assessment in HL, and BM biopsy is no longer needed for routine staging. Moreover, the interobserver agreement for BMI in this study proved excellent and only focal 18F-FDG BM uptake should be considered as a harbinger of HL.

Interim FDG-PET Imaging in Lymphoma

In the present article, the authors reviewed the rationale of FDG-PET/CT performed at an interim time point during therapy (iPET), focusing on the transition from standard, anatomical assessment of tumor shrinkage with CT to document a chemotherapy response, to the use of functional imaging with PET to assess chemosensitivity of the individual tumor. The prognostic or predictive role of iPET in different lymphoma subsets has been reviewed, with particular emphasis on early and advanced-stage Hodgkin lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, extranodal natural killer/T-cell lymphoma, and primary mediastinal B-cell lymphoma. A large body of evidence exists in most lymphoma subtypes stressing the role of iPET for early chemotherapy response during first-line chemotherapy treatment, but an increased number of reports have recently been published focusing on the role of iPET in relapsed or refractory lymphoma to predict treatment outcome. Varying patterns of FDG uptake was observed across various lymphoma entities; hence, interpretation of FDG-PET scans should be in the context of the tumor architecture and the prevalence of cellular population, in particular, neoplastic vs non-neoplastic inflammatory cells present in tissue microenvironment. In the second part of the article, the authors reviewed the iPET-response adapted clinical trials and the clinical benefits of this strategy compared to standard non-PET adapted therapy. In particular, the authors extrapolated the reproducibility of FDG-PET image interpretation and the feasibility of a timely treatment adaptation based on FDG-PET results in daily clinical practice. This is essential for the reader, as the iPET-adapted strategy has become the standard of care in both early- and advanced-stage Hodgkin lymphoma, and, in the future, probably this strategy will be expanded to primary mediastinal B-cell lymphoma, follicular lymphoma, and peripheral T-cell lymphoma.

Iodinated contrast agents perturb iodide uptake by the thyroid independently of free iodide

Perturbation of thyroid iodide uptake is a well-documented side effect of the use of iodinated contrast media (ICM) administered intravenously. This side effect is thought to be mediated by free iodide in ICM formulations, but this hypothesis has never been formally proven. The aim of the present study was to assess the validity of this hypothesis. Methods: We used mass spectrometry analysis to quantify free-iodide contamination in ICM. Established cell lines expressing the Na/I symporter (NIS) were used to quantify the effect of ICM on iodide uptake. SPECT/CT was used to measure the in vivo uptake of 99mTc-pertechnetate and 123I in 2 NIS-expressing mouse tissues, thyroid and salivary glands. Scintiscans of ICM-naïve and ICM-administered patients were compared. Immunohistologic and Western blot analyses were performed to evaluate NIS protein expression in these organs. Results: Although free iodide was present in ICM formulations, in vitro uptake of iodide by NIS-expressing cells was not significantly affected by ICM. In mice, intravenous or sublingual administration of ICM led to a reduction in radiotracer uptake by the thyroid, accompanied by a dramatic reduction in NIS protein expression in this tissue. In the salivary glands, neither radiotracer uptake nor NIS protein expression was affected by ICM. The thyroid-selective effect of ICM was also observed in humans. Administration of potassium iodide as a source of free iodide led to a diminution of 99mTc-pertechnetate uptake in both mouse thyroid and mouse salivary glands. Altogether, these data rule out a direct intervention of free iodide in the perturbation of thyroid uptake and suggest a direct and selective effect of ICM on the thyroid. Conclusion: We demonstrated that ICM reduce thyroid uptake of iodide independently of free iodide. This effect is due to a specific and dramatic decrease in NIS expression in thyrocytes. These data cast serious doubt on the relevance of measuring urinary iodide concentration to evaluate the delay between ICM administration and radioiodine therapy in patients with differentiated thyroid carcinoma. Finally, the ability of ICM to perturb iodide uptake in the thyroid may be used in radioprotection.

PET Response-Adapted Treatment in Hodgkin Lymphoma

The present review will focus on the issue of interim PET scan intended as surrogate test for chemosensitivity in Hodgkin lymphoma (HL). When performed early during treatment, PET scan is able to predict the final treatment outcome with variable accuracy, depending on HL tumour burden. In early-stage disease, interim PET shows a very high sensitivity and negative predictive value, while specificity and positive predictive value are only moderate, due to a substantial number of false-positive studies. In advanced-stage disease, a better positive predictive value has been reported, at the partial expense of the negative predictive value, which proved suboptimal, due to a non negligible percentage (5–10 %) of cases experiencing treatment failure despite a negative interim PET scan. The latter transformed, in the last decade, from a simple imaging technique to a prognostic tool indissoluble from HL therapeutic strategy. As a consequence, several PET response-adapted strategies have been proposed in clinical trials; some of them already concluded, while others are still ongoing. In early-stage lymphoma, two phase II trials explored whether treatment de-escalation by omitting involved-field radiation could be safely offered in interim PET-negative patients, without compromising the treatment efficacy, with opposite conclusions. In advanced-stage disease, most trials have been addressed to explore the efficacy of escalating treatment in interim PET-positive patients after few courses of ABVD treatment, while two others are still ongoing aimed at assessing treatment de-escalation in patients with a negative interim PET scan after two courses of BEACOPP escalated.