The German evidence-based guidelines for Hodgkin’s lymphoma

This report reviews aspects of the German evidence-based guidelines for Hodgkin’s lymphoma relevant to radiation oncologists. Stage-adapted treatment is discussed with the focus on radiotherapy. Up-to-date literature citations provide an overview of current recommendations.     

Quality control of involved-field radiotherapy for patients with early stage Hodgkin’s lymphoma based on a central prospective review

Purpose

Based on experience in trials HD10 and HD11 (1998–2003), the radiotherapy reference center of the German Hodgkin Study Group (GHSG) continued their central prospective radiation oncological review in trials HD13 and HD14. The purpose of this analysis was to identify the impact of this procedure on radiotherapeutic management and to compare findings with former trials.

Methods

Between 2003 and 2009, 1,710 patients were enrolled in the HD13 trial (early favorable stages) and 2,039 patients in the HD14 trial (early unfavorable stages). All patients received a total of 30?Gy involved-field (IF) radiotherapy within a combined modality approach.

Results

For patients in HD13, there was a correction of disease involvement in 847/1,518 patients (56%), and for patients in HD14 in 1,370/1,905 patients (72%). Most discrepancies were observed in the lower mediastinum (19.2%), infraclavicular (31.7%), upper cervical (12.7%), and supraclavicular (10.8%) lymph nodes. This resulted in a change of disease stage in 241 (7%) patients and a shift into another study protocol in 66 (2%) patients. Due to the incorrect lymph node documentation of the participating study centers, the IF radiotherapy volume had to be enlarged in 1,063/3,423 patients (31%) and reduced in 244/3,423 patients (7.1%). These findings are comparable to the results of the quality control in the trials HD10 and HD11 (2,611 patients reviewed).

Conclusion

Central review of the diagnostic imaging and clinical findings of Hodgkin’s lymphoma patients shows a considerable number of discrepancies compared with the local evaluation. Thus, meticulous evaluation of all imaging information in close collaboration between the radiation oncologist and diagnostic radiologist is mandatory.     

Characterizing bone marrow involvement in Hodgkin’s lymphoma by FDG-PET/CT

Purpose

Fluoro-deoxyglucose positron emmission tomography combined with computed tomography (FDG-PET/CT) is superior to iliac bone marrow biopsy (iBMB) for detection of bone marrow involvement (BMI) in staging of Hodgkin’s lymphoma (HL). The present study aims to characterize the patterns and distribution of BMI in HL as determined by FDG-PET/CT.

Methods

Reports of FDG-PET/CT studies performed for staging of HL were reviewed. BMI was defined as positive iBMB and/or foci of pathological FDG uptake in the skeleton that behaved in concordance with other sites of lymphoma in studies following chemotherapy. Number of FDG uptake foci, their specific location in the skeleton and the presence of corresponding lesions in the CT component of the study, and stage according to the Ann Arbor staging system, were recorded.

Results

The study included 473 patients. iBMB was performed in 336 patients. Nine patients had positive iBMB (9/336, 3 %). Seventy-three patients (73/473, 15 %) had FDG-PET/CT-defined BMI. The BM was the only extranodal site of HL in 52/473 patients (11 %). Forty-five patients had three or more foci of pathological skeletal FDG uptake (45/73, 62 %). Sixty-four patients (64/73, 88 %) had at least one uptake focus in the pelvis or vertebrae. In 60 patients (60/73, 82 %), the number of skeletal FDG uptake foci without corresponding CT lesions was equal to or higher than the number of foci with morphological abnormalities.

Conclusion

FDG-PET/CT demonstrated BMI in 15 % of patients with newly diagnosed HL. Diagnosis of BMI in HL by FDG-PET/CT was more sensitive than iBMB with potential upstage in 11 % of patients. The most common pattern of FDG-PET/CT BMI was multifocal (at least three foci) skeletal FDG uptake, with at least one focus in the pelvis or vertebrae and no corresponding CT lesions.     

Early therapy monitoring with FDG-PET in aggressive non-Hodgkin’s lymphoma and Hodgkin’s lymphoma

This study was designed to determine the value of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the early assessment of therapy response in lymphoma patients. We studied 20 patients with pathologically proven lymphoma, including 17 patients with aggressive non-Hodgkins lymphoma and three patients with Hodgkins lymphoma. All patients underwent whole-body FDG-PET imaging at baseline and after 1–2 cycles of chemotherapy. PET images were analysed visually and quantitatively by calculating the standardised uptake value (SUV). In each patient, we measured the SUV of the tumour demonstrating the highest FDG uptake at baseline study and the SUV of the same tumour after 1–2 cycles of therapy. The achievement of complete response was assessed on the basis of a combination of clinical findings and the results of conventional imaging modalities. Follow-up of progression-free survival (PFS) was obtained for the validation of PET data. Of the 20 patients, ten achieved complete remission at the completion of chemotherapy and the other ten did not respond to chemotherapy. Of the ten responders, four are still in remission (PFS 24–34 months) while the other six have relapsed (PFS 8–16 months). For the prediction of 24-month clinical outcome, visual analysis of PET after 1–2 cycles showed high sensitivity (87.5%) and accuracy (80%) but low specificity (50%). Comparison with the baseline SUVs revealed that the responders showed a significantly greater percent reduction in SUV after 1–2 cycles of therapy as compared with the non-responders (81.2%±9.5% vs 35.0%±20.2%, P<0.001). In addition, using 60% reduction as a cut-off value, the responders were clearly separated from the non-responders, with the exception of one non-responder. In conclusion, when performed early during chemotherapy, FDG-PET may be predictive of clinical outcome and allows differentiation of responders from non-responders in cases of aggressive lymphoma.     

Manifestation of Hodgkin’s lymphoma in an adrenal myelolipoma

Adrenal myelolipomas are benign tumors histologically consisting of fat and bone marrow. The computed tomography findings of Hodgkins lymphoma manifested in an adrenal myelolipoma are described. This collision tumor constellation has not been reported previously.     

Checkpoint inhibitors and radiation treatment in Hodgkin’s lymphoma

Background

Patients with classical Hodgkin’s lymphoma (cHL) have a good prognosis even in advanced stages. However, combined chemo- and radiotherapy, as the standard of care, is also associated with treatment-related toxicities such as organ damage, secondary neoplasias, infertility, or fatigue and long-term fatigue. Many patients suffer from this burden although their cHL was cured. Therefore, the efficacy of immune checkpoint inhibitors like anti-PD1/PD-L1 antibodies in the treatment of solid cancers and also in HL offers new options. A remarkable and durable response rate with a favorable toxicity profile was observed in heavily pretreated cHL patients.

Methods

Planning to perform prospective randomized clinical trials in the content of radio-immune treatment in patients with Hodgkin’s lymphoma (HL), we transferred the results of preliminary clinical studies and basic research in clinical relevant study concepts.

Results

Based on these promising early phase trial data, the German Hodgkin Study Group (GHSG) will investigate innovative treatment regimens in upcoming phase II trials.

Conclusion

The therapeutic efficacy and potential synergies of anti-PD1 antibodies in combination with chemo- or radiotherapy will be investigated in various settings of HL.

     

Early interim 18F-FDG PET in Hodgkin’s lymphoma: evaluation on 304 patients

Purpose

The use of early (interim) PET restaging during first-line therapy of Hodgkin??s lymphoma (HL) in clinical practice has considerably increased because of its ability to provide early recognition of treatment failure allowing patients to be transferred to more intensive treatment regimens.

Methods

Between June 1997 and June 2009, 304 patients with newly diagnosed HL (147 early stage and 157 advanced stage) were treated with the ABVD regimen at two Italian institutions. Patients underwent PET staging and restaging at baseline, after two cycles of therapy and at the end of the treatment.

Results

Of the 304 patients, 53 showed a positive interim PET scan and of these only 13 (24.5%) achieved continuous complete remission (CCR), whereas 251 patients showed a negative PET scan and of these 231 (92%) achieved CCR. Comparison between interim PET-positive and interim PET-negative patients indicated a significant association between PET findings and 9-year progression-free survival and 9-year overall survival, with a median follow-up of 31?months. Among the early-stage patients, 19 had a positive interim PET scan and only 4 (21%) achieved CCR; among the 128 patients with a negative interim PET scan, 122 (97.6%) achieved CCR. Among the advanced-stage patients, 34 showed a persistently positive PET scan with only 9 (26.4%) achieving CCR, whereas 123 showed a negative interim PET scan with 109 (88.6%) achieving CCR.

Conclusion

Our results demonstrate the role of an early PET scan as a significant step forward in the management of patients with early-stage or advanced-stage HL.     

Role of [18F]-FDG-PET/MDCT in evaluating early response in patients with Hodgkin’s lymphoma

PURPOSE: The authors evaluated the prognostic role of 18-fluoro-fluorodeoxyglucose positron emission tomography/multidetector computed tomography ([(18)F]-FDG PET/MDCT) in treating patients with Hodgkin's lymphoma (HL). MATERIALS AND METHODS: We retrospectively evaluated 132 patients with HL studied with PET/MDCT before the start of chemotherapy (CTX) for staging purposes and again after two CTX cycles with [doxorubicin (Adriblastin), bleomycin, vinblastine, dacarbazine (ABVD_] (interim PET/MDCT), at least 30 days after the end of the last CTX cycle and/or 3 months after the end of radiotherapy, if delivered (final PET-MDCT). RESULTS: Interim PET-MDCT was negative in 104/132 patients (79%), and their final PET-MDCT showed complete remission in 102/104 (98%) of cases, with disease recurrence/persistence in two (2%). In the remaining 28 (21%) patients, interim PET-MDCT revealed an early response in 68% of cases and chemoresistance with disease progression in 32% of cases; in these 28 patients, final PET-MDCT showed a lack of response to treatment in 43% of cases (43%) and complete remission in 57% of cases. Statistical analysis of these data showed that interim PET-MDCT had a negative predictive value of 98% and a positive predictive value of 42%, with values of sensitivity, specificity and diagnostic accuracy of 85.7%, 86.4% and 86.4%, respectively. CONCLUSIONS: Interim PET-MDCT has a reliable prognostic role in diagnosis and treatment of patients with HL, as it helps predict which patients are more likely to achieve a complete response at the end of treatment. PET/MDCT may also lead to a change in treatment, with reduced treatment-related toxic effects and significantly reduced total costs.     

Multicenter evaluation of different target volume delineation concepts in pediatric Hodgkin’s lymphoma

Background and purpose

In pediatric Hodgkin’s lymphoma (PHL) improvements in imaging and multiagent chemotherapy have allowed for a reduction in target volume. The involved-node (IN) concept is being tested in several treatment regimens for adult Hodgkin’s lymphoma. So far there is no consensus on the definition of the IN. To improve the reproducibility of the IN, we tested a new involved-node-level (INL) concept, using defined anatomical boundaries as basis for target delineation. The aim was to evaluate the feasibility of IN and INL concepts for PHL in terms of interobserver variability.

Patients and methods

The INL concept was defined for the neck and mediastinum by the PHL Radiotherapy Group based on accepted concepts for solid tumors. Seven radiation oncologists from six European centers contoured neck and mediastinal clinical target volumes (CTVs) of 2?patients according to the IN and the new INL concepts. The median CTVs, coefficient of variation (COV), and general conformity index (CI) were assessed. The intraclass correlation coefficient (ICC) for reliability of delineations was calculated.

Results

All observers agreed that INL is a feasible and practicable delineation concept resulting in stronger interobserver concordance than the IN (mediastinum CI_INL?=?0.39 vs. CI_IN?=?0.28, neck left CI_INL?=?0.33; CI_IN?=?0.18; neck right CI_INL?=?0.24, CI_IN?=?0.14). The COV showed less dispersion and the ICC indicated higher reliability of contouring for INL (ICC_INL?=?0.62, p?<?0.05) as for IN (ICC_IN?=?0.40, p?<?0.05).

Conclusion

INL is a practical and feasible alternative to IN resulting in more homogeneous target delineation, and it should be therefore considered as a future target volume concept in PHL.     

Value of PET/CT versus PET and CT performed as separate investigations in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma

Purpose The aim of this study was to assess the clinical benefit of combined [¹⁸F]FDG PET/CT in patients with malignant lymphoma as compared to separately performed PET and CT. Methods Overall, 100 patients with Hodgkin’s disease (HD) or non-Hodgkin’s lymphoma (NHL) were included in this study. Co-registered PET/CT with [¹⁸F]FDG and contrast medium was performed in 50 consecutive patients with NHL (n=38) or HD (n=12) for initial staging (IS) (n=12) or re-treatment staging (RS) (n=38). Another 50 patients with NHL (n=32) or HD (n=18) underwent separate PET and CT investigations within a time frame of 10 days for IS (n=22) or RS (n=28). Lymphoma involvement was separately evaluated for seven different regions in each patient. Each patient had clinical follow-up evaluation for >6 months. PET and CT data were analysed separately as well as side-by-side or in fused mode. Results In the PET/CT group, region-based evaluation for lymphoma involvement suggested a sensitivity/specificity of 85%/91% for CT, 98%/99% for PET and 98%/99% for PET/CT. In the PET and CT group, region-based evaluation showed a sensitivity/specificity of 87%/80% for CT, 98%/99% for PET and 98%/100% for PET and CT read side by side. Conclusion PET was superior to CT alone and was improved further by side-by-side reading of both examinations. However, no significant difference was observed between PET/CT and separate PET and CT imaging in patients with lymphoma. Christian la Fougère and Walter Hundt contributed equally to this work.     

Primary EBV-positive Hodgkin’s lymphoma of the CNS under azathioprine treatment

Background

Retrospective and prospective cohort studies suggest that central nervous system involvement occurs in approximately 0.5?% of patients with advanced Hodgkin’s lymphoma. The isolated primary intracranial manifestation of Hodgkin’s lymphoma is an extremely rare finding, with few cases reported in the literature. Little is known about the optimal treatment and prognosis of these tumors. Here, we present a case report with a review of the literature.

Case presentation

A 47-year-old Caucasian man with persistent frontal headache and unspecific vertigo for half a month was diagnosed with nodular space-occupying lesions in the cerebellum. His medical history included multiple sclerosis, which was treated for 20 years with the immunosuppressive drug azathioprine. Further staging revealed no additional lesions suspected of being malignant. The patient underwent total tumor resection. Immunohistopathological examination showed Epstein–Barr virus-associated classic Hodgkin’s lymphoma. Diagnostic bone marrow punction excluded lymphoma involvement of the bone marrow. The patient had no B symptoms. Consequently, the patient was classified as having stage I_EA disease according to the Modified Ann Arbor Classification of Hodgkin Lymphoma and received systemic chemotherapy followed by radiation therapy for the former cerebellar tumor region. He was in complete clinical remission atthe last follow-up 9 months after the initial diagnosis.

Conclusion

This case report and literature review suggest that multimodal treatment leads to a remarkable clinical outcome in Hodgkin’s lymphoma with intracranial involvement.     

Can treatment of pediatric Hodgkin’s lymphoma be improved by PET imaging and proton therapy?

Background and purpose

To explore a new positron emission tomography (PET)-based target concept for pediatric Hodgkin’s lymphoma (PHL).

Patients and methods

For 10 patients, the planning target volume PTV1 was based on initial CT tumor extension and PTV2 on anatomy-related PET-positive lymph node levels after chemotherapy. The treatment techniques investigated (prescribed dose 19.8 Gy) comprised opposed-field (2F), intensity-modulated photon (IMXT), and single-field (PS) proton techniques. Treatment concepts were compared concerning dose-volume histogram (DVH) parameters and organ-equivalent doses (OED).

Results

The median PTV1 and PTV2 were 902?±?555 cm³ and 281?±?228 cm³. When using PTV2 instead of PTV1 for all techniques, the D_2% of the heart was reduced from 14 to 9 Gy and the D_mean of the thyroid from 16.6 to 2.7 Gy. Low- (20%), median- (50%), and high-dose volumes (80%) were reduced by 60% for the heart and bones using PTV2. PS reduced the high-dose volume of the lungs and the heart by up to 60%. IMXT increased the low-dose volumes and OED. PTV2 reduced OED by 54?±?10% for all organs at risk.

Conclusion

PTV2 has a high impact on the treated volume and on sparing of organs at risk. The combination of an adaptive target volume definition with protons could contribute to future PHL treatment concepts.     

Decreased brain FDG uptake in patients with extensive non-Hodgkin’s lymphoma lesions

Objective  

Faint brain [¹⁸F]fluoro-2-deoxyglucose (FDG) uptake has sporadically been reported in patients with FDG-avid large or diffusely extended tumors. The purpose of this study was to investigate whether there is a correlation between massive tumor uptake and decreased brain uptake on FDG positron emission tomography/computed tomography (PET/CT).