Anna Borra

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.

Role of PET in Lymphoma

Opinion Statement18 F-2-deoxy-d-glucose positron emission tomography (FDG-PET), combined with a multidetector helical CT (PET/CT) has emerged, in the past decade as one of the most important prognostic tool for lymphoma management. Besides proving as the only imaging technique able to recapitulate all the information yielded by the standard radiological staging and restaging, it provided new essential information for chemosensitivity assessment and radiotherapy planning. In lymphoma staging, functional imaging (FI) by PET/CT was shown to be more accurate than conventional radiological (anatomical) imaging to detect nodal and extranodal involvement, whereas in posttreatment restaging it showed a superior predictive value on treatment outcome. In Hodgkin lymphoma (HL), FI concurred to delineate a new paradigm of therapy in which PET is considered an essential tool to guide physician’s choice on treatment intensity and modality. In fact, PET proved very useful for: 1) assessing chemosensitivity early during treatment to predict final therapy outcome; 2) managing a residual mass, detected by CT scan in up to two thirds of patients at the end of chemotherapy; and 3) planning radiotherapy in early-stage disease when conformal radiotherapy fields are used to spare toxicity to adjacent tissues. The early chemosensitivity assessment is the underpinnings of a new therapeutic strategy in HL, aimed at minimizing treatment-related toxicity while maintaining treatment efficacy. Several clinical trials are currently underway to test this hypothesis. In diffuse, large, B-cell lymphoma (DLBCL), PET/CT proved very useful: 1) in lymphoma staging, leading to upward stage migration in one third of the patients; and 2) to identify patients benefiting from consolidation radiotherapy for FDG-avid, single mass or limited–extension disease. Different to HL, the role of interim PET in DLBCL remains controversial. In follicular lymphoma (FL) preliminary studies PET/CT proved useful, in baseline staging to predict time to treatment in patients in which a watchful observation without treatment (watch and wait) was chosen as therapeutic approach treatment. In FL end-of-treatment PET/CT proved the most powerful prognostic tool to predict long-term treatment outcome.

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.

Peripheral Blood CD34+ Percentage at Hematological Recovery after Chemotherapy Is a Good Early Predictor of Harvest: A Single-Center Experience

Several algorithms for early prediction of poor-mobilizing patients after chemotherapy and granulocyte colony-stimulating factor administration have been proposed. They generally define peripheral blood cut-off levels of CD34+ cells at a fixed day after starting chemotherapy, mostly with cyclophosphamide. To define an algorithm for early addition of plerixafor regardless of the chemotherapy regimen used, we retrospectively analyzed 280 chemomobilization attempts in 236 patients treated at our institution between 2002 and 2012. In multivariate analysis, CD34+ absolute count and CD34+ percentage upon total leukocyte count at day 1 (defined as the first day in which leukocytes reached a value > 1 × 10(9)/L) were the only factors able to predict a total harvest ≥ 2 × 10(6) CD34+/kg. In patients with day 1 CD34+ lower than 20/μL, the CD34+ percentage was a more reliable predictor of stem cell harvest in the following days than CD34+ absolute count. Upon definition of the best CD34+ cut-off value for identification of poor-mobilizing patients, an algorithm was set up to guide plerixafor administration. It was prospectively validated in 20 patients in 2013 with encouraging results in terms of low incidences of both mobilization failure and plerixafor use. Large prospective trials that define the most cost-effective strategy for just-in-time rescue plerixafor are warranted.

Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity: A translational18F-FDG PET/CT observation

The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min−1 × g−1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min−1 × g−1, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min−1 × g−1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

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.

Functional Imaging in Hodgkin Lymphoma

Hodgkin lymphoma (HL) has become a curable malignancy with more than 90 % of patients alive and 80 % considered cured after a minimum follow-up of 6 years. These results have been obtained by a combination of factors influencing treatment outcome in different ways. These can be briefly summarised: (a) a high chemo- and radiosensitivity of the tumour, (b) an increasing accuracy of staging procedures, and (c) different treatment strategies tailored to well-defined categories of patients with a different risk of treatment failure.