Cardiotoxicity of mediastinal radiotherapy.

AIM: To explore available recent literature related to cardiotoxicity following mediastinal radiation. BACKGROUND: Radiotherapy-related heart injury is well documented, with no apparent safety threshold dose. The number of long-term cancer survivors exposed to mediastinal radiotherapy at some point of their treatment is increasing. Heart dosimetric parameters are of great importance in developing a treatment plan, but few data are available regarding radiosensitivity and dose-volume constraints for specific heart structures. MATERIALS AND METHODS: In October 2018, we identified articles published after 1990 through a PubMed/MEDLINE database search. The authors examined rough search results and manuscripts not relevant for the topic were excluded. We extracted clinical outcomes following mediastinal radiotherapy of childhood cancers, lymphoma, medulloblastoma, thymic cancers and hematopoietic cell transplantation survivors and evaluated treatment planning data, whenever available. RESULTS: A total of 1311 manuscripts were identified in our first-round search. Of these manuscripts, only 115 articles, matching our selection criteria, were included. CONCLUSIONS: Studies uniformly show a linear radiation dose-response relationship between mean absorbed dose to the heart (heart-Dmean) and the risk of dying as a result of cardiac disease, particularly when heart-Dmean exceeds 5 Gy. Limited data are available regarding dose-volume predictors for heart substructures and the risk of subsequent cardiac toxicity. An individual patient's cardiotoxicity risk can be modified with advanced treatment planning techniques, including deep inspiration breath hold. Proton therapy is currently showing advantages in improving treatment planning parameters when compared to advanced photon techniques in lymphoma, thymic malignancies, malignant mesothelioma and craniospinal irradiation.

Patterns of failure of diffuse large B­cell lymphoma patients after involved-site radiotherapy.

PURPOSE: Radiotherapy (RT) in combination with chemoimmunotherapy is highly efficient in the treatment of diffuse large B­cell lymphoma (DLBCL). This retrospective analysis evaluated the efficacy of the treatment volume and the dose concept of involved-site RT (ISRT). PATIENTS AND METHODS: We identified 60 histologically confirmed stage I-IV DLBCL patients treated with multimodal cytotoxic chemoimmunotherapy and followed by consolidative ISRT from 2005-2015. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Univariate analyses were performed by log-rank test and Mann-Whitney U­test. RESULTS: After initial chemoimmunotherapy (mostly R­CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), 19 (36%) patients achieved complete response (CR), 34 (64%) partial response (PR) or less. Excluded were 7 (12%) patients with progressive disease after chemoimmunotherapy. All patients underwent ISRT with a dose of 40 Gy. After a median follow-up of 44 months, 79% of the patients remained disease free, while 21% presented with failure, progressive systemic disease, or death. All patients who achieved CR after chemoimmunotherapy remained in CR. Of the patients achieving PR after chemotherapy only 2 failed at the initial site within the ISRT volume. No marginal relapse was observed. Ann Arbor clinical stage I/II showed significantly improved PFS compared to stage III/IV (93% vs 65%; p ≤ 0.021). International Prognostic Index (IPI) score of 0 or 1 compared to 2-5 has been associated with significantly increased PFS (100% vs 70%; p ≤ 0.031). Postchemoimmunotherapy status of CR compared to PR was associated with significantly increased PFS (100% vs 68%; p ≤ 0.004) and OS (100% vs 82%; p ≤ 0.026). Only 3 of 53 patients developed grade II late side effects, whereas grade III or IV side effects have not been observed. CONCLUSION: These data suggest that a reduction of the RT treatment volume from involved-field (IF) to involved-site (IS) is sufficient because no marginal failures occurred. The concept of IS will likely reduce the risk for late sequelae of RT.

Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF). PATIENTS AND METHODS: For 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared. RESULTS: 3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique. CONCLUSIONS: In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.

Radiation doses to mediastinal organs at risk in early-stage unfavorable Hodgkin lymphoma- a risk stratified analysis of the GHSG HD17 trial.

Introduction: The German Hodgkin Study Group (GHSG) HD17 trial established the omission of radiotherapy (RT) for patients with early-stage unfavorable Hodgkin lymphoma being PET-negative after 2 cycles of BEACOPP escalated plus 2 cycles of ABVD. This patient group reveals heterogeneity in characteristics and disease extent which prompted us to perform a decisive dosimetric analysis according to GHSG risk factors. This may help to tailor RT individually balancing risks and benefits. Methods: For quality assurance, RT-plans were requested from the treating facilities (n= 141) and analyzed centrally. Dose-volume histograms were scanned either paper-based or digitally to obtain doses to mediastinal organs. These were registered and compared according to GHSG risk factors. Results: Overall, RT plans of 176 patients were requested, 139 of which had dosimetric information on target volumes within the mediastinum. Most of these patients were stage II (92.8%), had no B-symptoms (79.1%) and were aged < 50 years (89.9%). Risk factors were present in 8.6% (extranodal involvement), 31.7% (bulky disease), 46.0% (elevated erythrocyte sedimentation rate) and 64.0% (three involved areas), respectively. The presence of bulky disease significantly affected the mean RT doses to the heart (p=0.005) and to the left lung (median: 11.3 Gy vs. 9.9 Gy; p=0.042) as well as V5 of the right and left lung, respectively (median right lung: 67.4% vs. 51.0%; p=0.011; median left lung: 65.9% vs. 54.2%; p=0.008). Significant differences in similar organs at risk parameters could be found between the sub-cohorts with the presence or absence of extranodal involvement, respectively. In contrast, an elevated erythrocyte sedimentation rate did not deteriorate dosimetry significantly. No association of any risk factor with radiation doses to the female breast was found. Conclusion: Pre-chemotherapy risk factors may help to predict potential RT exposure to normal organs and to critically review treatment indication. Individualized risk-benefit evaluations for patients with HL in early-stage unfavorable disease are mandatory.

Brentuximab vedotin plus AVD followed by involved-node radiotherapy in a patient with classic Hodgkin lymphoma following gray zone lymphoma after autologous stem-cell transplantation failure.

BACKGROUND: No consensus has been reached yet concerning treatment strategies for a sequential classic Hodgkin lymphoma (CHL) following gray zone lymphoma (GZL). Prognosis of GZL after a failed autologous hematopoietic stem-cell transplantation (auto-HCT) is poor and treatment strategy is very limited. As yet there are limited data showing clinical outcomes of brentuximab vedotin (BV) for GZL, especially for sequential CHL after GZL. CASE PRESENTATION: We report a case of CHL following primary refractory GZL after a failed auto-HCT and showed favorable response to first-line CHL-directed chemoradiotherapy consisting of BV plus doxorubicin, vinblastine, and dacarbazin (AVD) followed by irradiation. The sequential cases with an early evolution, whose diagnosis of second lymphoma was made within a year, have been recently reported very poor survival shorter than a year. Whether a sequential CHL following GZL should be treated as a primary or relapsed disease has not been clearly elucidated. Our patient showed favorable response to first-line CHL-directed chemoradiotherapy without allogenic hematopoietic stem-cell transplantation and has in continuous remission for 2 years. CONCLUSIONS: The management of our case could help for physicians to make better treatment decisions and provide insights for further exploration in future studies.

Involved node radiation therapy in the combined modality treatment for early-stage Hodgkin lymphoma: Analysis of relapse location and long-term outcome.

BACKGROUND AND PURPOSE: Involved node radiation therapy (INRT) in the combined modality treatment for early-stage Hodgkin lymphoma (ESHL) has reduced the irradiated volume dramatically. Limiting the irradiated volume further based on initial disease bulk, 18F-fluoro-deoxy-glucose (FDG)-avidity, or residual computed tomography (CT) abnormality after chemotherapy seems attractive. In a cohort of patients treated with INRT a meticulous pattern-of-relapse analysis was performed to examine these options. MATERIAL AND METHODS: Patients treated for ESHL in our institution from 2005 to 2014 who achieved complete remission with chemotherapy were included. Patient characteristics, treatment details and clinical outcome were registered. For relapsed patients, rigid co-registration of the positron emission tomography/computed tomography-scans from the time of diagnosis and at relapse was done to visually assess the relapse location relative to initial involvement and, if irradiated, the irradiated volume. Size and maximum Standardized Uptake Value of the initial node(s) with later relapse, and residual CT abnormalities after chemotherapy in those locations were measured. RESULTS: We included 182 patients. Twelve (6.6%) patients relapsed, five in previously involved nodes (two irradiated, three not irradiated). Relapses did not occur preferentially in initially bulky disease, in lymph node(s) with the highest FDG-uptake, or in residual CT abnormalities after chemotherapy. CONCLUSIONS: Modern treatment with brief chemotherapy and limited radiotherapy provides excellent long-term disease control in ESHL. Neither bulk, high FDG-uptake, nor residual CT abnormality after chemotherapy could predict initially involved lymph nodes with a high risk of relapse.

Involved Node, Site, Field and Residual Volume Radiotherapy for Lymphoma: A Comparison of Organ at Risk Dosimetry and Second Malignancy Risks.

AIMS: Recent radiotherapy guidelines for lymphoma have included involved site radiotherapy (ISRT), involved node radiotherapy (INRT) and irradiation of residual volume after full-course chemotherapy. In the absence of late toxicity data, we aim to compare organ at risk (OAR) dose-metrics and calculated second malignancy risks. MATERIALS AND METHODS: Fifteen consecutive patients who had received mediastinal radiotherapy were included. Four radiotherapy plans were generated for each patient using a parallel pair photon technique: (i) involved field radiotherapy (IFRT), (ii) ISRT, (iii) INRT, (iv) residual post-chemotherapy volume. The radiotherapy dose was 30 Gy in 15 fractions. The OARs evaluated were: breasts, lungs, thyroid, heart, oesophagus. Relative and absolute second malignancy rates were estimated using the concept of organ equivalent dose. Significance was defined as P < 0.005. RESULTS: Compared with ISRT, IFRT significantly increased doses to lung, thyroid, heart and oesophagus, whereas INRT and residual volume techniques significantly reduced doses to all OARs. The relative risks of second cancers were significantly higher with IFRT compared with ISRT for lung, breast and thyroid; INRT and residual volume resulted in significantly lower relative risks compared with ISRT for lung, breast and thyroid. The median excess absolute risks of second cancers were consistently lowest for the residual technique and highest for IFRT in terms of thyroid, lung and breast cancers. The risk of oesophageal cancer was similar for all four techniques. Overall, the absolute risk of second cancers was very similar for ISRT and INRT. CONCLUSIONS: Decreasing treatment volumes from IFRT to ISRT, INRT or residual volume reduces radiation exposure to OARs. Second malignancy modelling suggests that this reduction in treatment volumes will lead to a reduction in absolute excess second malignancy. Little difference was observed in second malignancy risks between ISRT and INRT, supporting the use of ISRT in the absence of a pre-chemotherapy positron emission tomography scan in the radiotherapy treatment position.

Involved site radiation therapy for the treatment of early-stage Hodgkin lymphoma in adolescents and young adults.

Radiation therapy technology has permitted the development of new treatment planning techniques. Involved field, involved node, and involved site radiotherapy fields are discussed and compared. Indications for and implications of combined modality therapy are examined, particularly as pertinent to the adolescent and young adult population.

Risk- and response-adapted strategies for the management of Hodgkin lymphoma.

Therapy for Hodgkin lymphoma (HL) is associated with excellent long-term survival rates, of 80% of more. Extended follow up has described late treatment-related toxicities, principally secondary malignancies, cardiovascular disease and infertility. Given the young age of many patients, there is a desire to offer a more personalised approach, correlated to individual tumour biology that enables treatment de-escalation in low risk patients to reduce toxicity, and treatment intensification in high risk patients to reduce treatment failure. Contemporary therapeutic strategies have involved risk assessment based on staging and clinical factors. The use of functional imaging with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) as a predictive tool to identify early non-responders has been well validated and outperforms the risk stratifying International Prognostic Score (IPS). HL has particularly high FDG-avidity (97-100%), with FDG-PET scanning reflecting metabolic activity and acting as a surrogate biomarker for chemosensitivity. International consensus on the methods of reporting and interpreting FDG-PET scans has enabled their use to be standardised and reproducible. Given that primary therapy fails for 15-20% of patients, the use of combined FDG-PET and computerised tomography (FDG-PET/CT) to provide a response-adapted strategy to guide management is under investigation in numerous prospective clinical trials. They aim to determine whether early response scanning can be used to directly modulate subsequent therapy, through intensifying or abbreviating chemotherapy regimens and/or omitting radiotherapy. Integrated multi-modality imaging and advanced conformal planning techniques have led to the emergence of radiotherapy strategies such as involved-node radiation (INRT) that aim to optimise treatment volumes and maintain efficacy whilst lowering toxicity. Study groups have incorporated these modalities in trial designs to assess whether a PET-directed, individualised approach can become the new standard of care.

Reduction of the treated volume to involved node radiation therapy as part of combined modality treatment for early stage aggressive non-Hodgkin's lymphoma.

BACKGROUND AND PURPOSE: This retrospective study investigated whether focused involved node radiation therapy (INRT) can safely replace involved field RT (IFRT) in patients with early stage aggressive NHL. PATIENTS AND METHODS: We included 258 patients with stage I/II aggressive NHL who received combined modality treatment (87%) or primary RT alone (13%). RT consisted of a total dose of 30-40 Gy in 15-20 fractions IFRT or INRT. We compared survival, relapse pattern, radiation-related toxicity and quality of life for both RT techniques. RESULTS: Type of RT was not related to the outcome in either the uni- or multivariate survival analysis. Relapses developed in 59 of 252 patients (23%) of which 47 (80%) were documented as distant recurrence only. Failure of the INRT technique was noted in one patient. There was no significant difference in acute radiation-related toxicity between RT-groups but IFRT showed a significantly higher incidence of higher grade toxicities. Patients treated with INRT had a significantly better physical functioning and global quality of life compared to the IFRT group. CONCLUSIONS: Given the retrospective nature of this study, no solid conclusions can be drawn. However, in view of the equivalent efficacy and more favorable toxicity profile, the replacement of IFRT by INRT in combination with chemo-(immuno)-therapy looks very attractive for patients with early stage aggressive NHL.