Markus Dietlein

Use of Positron Emission Tomography for Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma

PURPOSE To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial

BACKGROUND The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkins lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. METHODS In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkins lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. FINDINGS Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. INTERPRETATION Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkins lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING Deutsche Krebshilfe and the Swiss Federal Government.

Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a multicentre study

n=222) and the group with negative radioiodine scan (n=166), respectively. Specificity was 90% in the whole patient group. Sensitivity and specificity of WBS were 50% and 99%, respectively. When the results of FDG-PET and WBS were considered in combination, tumour tissue was missed in only 7%. Sensitivity and specificity of MIBI/Tl were 53% and 92%, respectively (n=117). We conclude that FDG-PET is a sensitive method in the follow-up of thyroid cancer which should be considered in all patients suffering from differentiated thyroid cancer with suspected recurrence and/or metastases, and particularly in those with elevated thyroglobulin values and negative WBS.

Guidelines for radioiodine therapy of differentiated thyroid cancer

IntroductionThe purpose of the present guidelines on the radioiodine therapy (RAIT) of differentiated thyroid cancer (DTC) formulated by the European Association of Nuclear Medicine (EANM) Therapy Committee is to provide advice to nuclear medicine clinicians and other members of the DTC-treating community on how to ablate thyroid remnant or treat inoperable advanced DTC or both employing large 131-iodine (131I) activities.DiscussionFor this purpose, recommendations have been formulated based on recent literature and expert opinion regarding the rationale, indications and contraindications for these procedures, as well as the radioiodine activities and the administration and patient preparation techniques to be used. Recommendations also are provided on pre-RAIT history and examinations, patient counselling and precautions that should be associated with 131I iodine ablation and treatment. Furthermore, potential side effects of radioiodine therapy and alternate or additional treatments to this modality are reviewed. Appendices furnish information on dosimetry and post-therapy scintigraphy.

Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma

In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.

Fluorine-18 fluorodeoxyglucose positron emission tomography and iodine-131 whole-body scintigraphy in the follow-up of differentiated thyroid cancer

Abstract.Metastases of differentiated thyroid cancer may show different uptake patterns for fluorine-18 fluorodeoxyglucose and [131I]NaI. FDG positron emission tomography (PET), iodine-131 whole-body scintigraphy (131I WBS) and magnetic resonance imaging were performed in 58 unselected patients, and spiral computed tomography (CT) of the lung in 25 patients. Thirty-eight patients presented with papillary carcinomas, 15 patients with follicular carcinomas and five patients with variants of follicular carcinoma. Primary tumour stage (pT) was pT1 in 3, pT2 in 19, pT3 in 11 and pT4 in 25 cases. For the detection of metastases, FDG PET was found to have a sensitivity of 50%, 131I WBS a sensitivity of 61%, and the two methods combined a sensitivity of 86%. When FDG PET was limited to patients with elevated thyroglobulin (Tg) levels and negative 131I WBS, the sensitivity of this algorithm was 82%. Of the 21 patients with lymph node metastases, seven presented with FDG uptake but no iodine uptake. In four of them, a second FDG hot spot appeared in a lymph node metastasis of normal size. Five of the seven patients underwent surgery. None of the eight patients with pulmonary metastases smaller than 1 cm exhibited FDG uptake, while five of them had iodine uptake. All had positive results on spiral CT. In conclusion, FDG PET cannot be substituted for 131I WBS. If the Tg level is elevated and 131I WBS is negative, FDG PET can be used to detect lymph node metastases and complements anatomical imaging. A spiral CT of the lung is useful to exclude pulmonary metastases before planning a dissection of iodine-negative lymph node metastases.

Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results

Abstract. Decision analysis is used here to establish the most cost-effective strategy for management of potentially operable non-small cell lung cancers (NSCLCs). The strategies compared were conventional staging (strategy A), dedicated systems of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) in patients with normal-sized (strategy B) or in patients with enlarged mediastinal lymph nodes (part of strategy C), and FDG-PET followed by exclusion from surgical procedures when both computed tomography (CT) and PET were positive for mediastinal lymph nodes (strategy D) or when PET alone was positive (strategy E). Based on published data, the sensitivity and specificity of FDG-PET were estimated at 0.74 and 0.96 for detecting metastasis in normal-sized mediastinal lymph nodes, and at 0.95 and 0.76 when these lymph nodes were enlarged. The calculated probability of up-staging to M1 by using PET was 0.05. The costs quoted correspond to the cost reimbursed in 1999 by the public health provider in Germany. The incremental cost-effectiveness ratio (ICER) of strategy B was much more favourable (143 EUR/LYS; LYS = life year saved) than the ICER of strategy C (36,667 EUR/LYS). In strategy B, the use of PET did not raise the overall costs because the costs of PET were almost balanced by a better selection of patients for beneficial cancer resection. The exclusion from biopsy confirmation in strategies D and E led to cost savings that did not justify the expected reduction in life expectancy. In sensitivity analyses, the ICERs of strategy B were robust to the pretest likelihood of N2/N3, to penalized test parameters of PET and to reimbursement of PET. However, the ICER of strategy B would be raised to 28,000 EUR/LYS through use of thoracic PET without whole-body scanning. To conclude, the implementation of whole-body PET with a full ring of detectors in the preoperative staging of patients with NSCLC and normal-sized lymph nodes is clearly cost-effective. However, patients with nodal-positive PET results should not be excluded from biopsy.

Fluorine-18 fluorodeoxyglucose positron emission tomography in medullary thyroid cancer : results of a multicentre study

Abstract. The aim of this study was to evaluate the clinical use of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in medullary thyroid cancer (MTC) on the basis of comparison with findings obtained using indium-111 pentetreotide (SMS), pentavalent technetium-99m dimercaptosuccinic acid (DMSA), technetium-99m sestamibi (MIBI), computed tomography (CT) and magnetic resonance imaging (MRI). One hundred FDG-PET examinations in 85 patients (40 males, 45 females) with elevated tumour marker levels and/or pathological findings on other imaging methods were evaluated retrospectively. Eighty-two patients were examined after total thyroidectomy, and the remaining three patients prior to surgery. Overall, 181 lesions could be identified with at least one of the imaging techniques. Fifty-five lesions were confirmed histologically. FDG-PET detected 123 of 181 sites, which is a lesion detection probability of 68%. In the 55 cases with histological confirmation, we found 32 true positive, 3 false positive, 11 true negative and 9 false negative lesions using FDG-PET, resulting in a sensitivity of 78% and a specificity of 79%. Sensitivity and specificity were, respectively, 25% and 92% for SMS, 33% and 78% for DMSA, 25% and 100% for MIBI, 50% and 20% for CT and 82% and 67% for MRI. Compared with morphological techniques and functional imaging methods with single-photon emitters, FDG-PET showed the highest lesion detection probability for MTC tissue, with a high sensitivity and specificity. It is concluded that FDG-PET is a useful method in the staging and follow-up of MTC.

Whole-body positron emission tomography using 18F-fluorodeoxyglucose for initial staging of patients with Hodgkin's disease

Abstract. An accurate initial staging of patients with Hodgkins disease (HD) is important for the evaluation of clinical stage and risk factors, which are crucial for the choice of an appropriate treatment. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful for detecting active tumor tissue in patients with lymphoproliferative diseases and may contribute to conventional staging methods in patients with HD. Twenty-two patients who presented with newly diagnosed HD underwent conventional staging methods including computed tomography (CT) as well as FDG PET. Lesions apparent in FDG PET and CT were correlated to each other. Seventy-seven lesions were observed either in PET or CT or in both. In 48 (62%) lesions PET and CT were both positive. In 20 (26%) sites, PET was positive and CT negative. Of 22 patients (18%) 4 were upstaged due to these positive PET findings, and as a result one patient received a different therapeutic regimen. PET failed to detect nine (12%) CT-positive sites in six patients. Statistically, these data are reflected by a sensitivity for PET and CT of 88% and 74%, respectively. Specificity of both imaging modalities was 100%. PET can contribute valuable information as an additional staging examination and led to an upstaging in some patients with primary HD. However, PET should not be used as the only imaging modality as it failed to detect CT-positive, active tumor regions in some cases.

Comparison of [18F]DCFPyL and [68Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with Relapsed Prostate Cancer

PurposeGallium-68 (Ga-68)-labeled tracers for imaging expression of the prostate-specific membrane antigen (PSMA) such as the [68Ga]Ga-PSMA-HBED-CC have already demonstrated high potential for the detection of recurrent prostate cancer. However, compared to Ga-68, a labeling with fluorine-18 (F-18) would offer advantages with respect to availability, production amount, and image resolution. [18F]DCFPyL is a promising F-18-labeled candidate for PSMA-positron emission tomography (PET) imaging that has been recently introduced. In the current study, we aimed to compare [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL for clinical use in biochemically relapsed prostate cancer.ProceduresIn 14 selected patients with PSA relapse of prostate cancer, [18F]DCFPyL PET/X-ray computed tomography (CT) was performed in addition to [68Ga]Ga-PSMA-HBED-CC PET/CT. A systematic comparison was carried out between results obtained with both tracers with regard to the number of detected PSMA-positive lesions, the standardized uptake value (SUV)max and the lesion to background ratios.ResultsAll suspicious lesions identified by [68Ga]Ga-PSMA-HBED-CC were also detected with [18F]DCFPyL. In three patients, additional lesions were observed using [18F]DCFPyL PET/CT. The mean SUVmax in the concordant [18F]DCFPyL PSMA-positive lesions was significantly higher as compared to [68Ga]Ga-PSMA-HBED-CC (14.5 vs. 12.2, p = 0.028, n = 15). The mean tumor to background ratios (n = 15) were significantly higher for [18F]DCFPyL compared to [68Ga]Ga-PSMA-HBED-CC using kidney, spleen, or parotid as reference organs (p = 0.006, p = 0.002, p = 0.008), but no significant differences were found using the liver (p = 0.167) or the mediastinum (p = 0.363) as reference organs.Conclusion[18F]DCFPyL PET/CT provided a high image quality and visualized small prostate lesions with excellent sensitivity. [18F]DCFPyL represents a highly promising alternative to [68Ga]Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer.