Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

Challenges in Treating Childhood Infratentorial Ependymoma: A Low- and Middle-Income Country Experience.

PURPOSE: Patients and physicians in low- and middle-income countries (LMICs) face challenges owing to limited expertise and suboptimal access to appropriate diagnostic and treatment modalities. We report our experience in treating posterior fossa ependymoma (PFE) at MAHAK, a charity organization in Iran whose radiation oncology department is the only one exclusively dedicated to childhood cancer in the whole country. METHODS AND MATERIALS: Pediatric patients with PFE referred to MAHAK between November 2008 and January 2016 were identified. Details on investigations and management done before referral were collected. Management at MAHAK and patient outcomes were analyzed. RESULTS: Of 80 patients diagnosed as having ependymoma, 54 with PFE were identified. Forty-three patients received adjuvant radiation therapy, and 11 were irradiated initially after recurrence. At a median follow-up of 5.1 years (range, 0.3-9.7 years), the latter group had the worst outcome, with a 5-year overall survival (OS) rate of 27% (95% CI, 7%-54%). Patients who started radiation therapy within 77 days after initial surgery had a better outcome compared with those who started later (5-year OS: 74% vs 32%; P = .05). Compliance with follow-up recommendations was poor. Only 22% of the patients had at least 2 IQ test assessments, and 50% showed some decline over time. Three cases of growth hormone deficiency were detected, but none of the patients received replacement therapy. CONCLUSIONS: Access to pediatric neurosurgery, anesthesia, and timely radiation therapy are among the most challenging obstacles to be overcome in LMICs. Our series confirmed that chemotherapy is not an appropriate option for delaying radiation therapy, especially in young children. The importance of long-term follow-up should be acknowledged by the parents and medical team.

A Quality Control Study on Involved Node Radiation Therapy in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 Trial on Stages I and II Hodgkin Lymphoma: Lessons Learned.

PURPOSE: Involved node radiation therapy (INRT) was introduced in the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi H10 trial, a large multicenter trial in early-stage Hodgkin Lymphoma. The present study aimed to evaluate the quality of INRT in this trial. METHODS AND MATERIALS: A retrospective, descriptive study was initiated to evaluate INRT in a representative sample encompassing approximately 10% of all irradiated patients in the H10 trial. Sampling was stratified by academic group, year of treatment, size of the treatment center, and treatment arm, and it was done proportional to the size of the strata. The sample was completed for all patients with known recurrences to enable future research on relapse patterns. Radiation therapy principle, target volume delineation and coverage, and applied technique and dose were evaluated using the EORTC Radiation Therapy Quality Assurance platform. Each case was reviewed by 2 reviewers and, in case of disagreement also by an adjudicator for a consensus evaluation. RESULTS: Data were retrieved for 66 of 1294 irradiated patients (5.1%). Data collection and analysis were hampered more than anticipated by changes in archiving of diagnostic imaging and treatment planning systems during the running period of the trial. A review could be performed on 61 patients. The INRT principle was applied in 86.6%. Overall, 88.5% of cases were treated according to protocol. Unacceptable variations were predominately due to geographic misses of the target volume delineations. The rate of unacceptable variations decreased during trial recruitment. CONCLUSIONS: The principle of INRT was applied in most of the reviewed patients. Almost 90% of the evaluated patients were treated according to the protocol. The present results should, however, be interpreted with caution because the number of patients evaluated was limited. Individual case reviews should be done in a prospective fashion in future trials. Radiation therapy Quality Assurance tailored to the clinical trial objectives is strongly recommended.

Telomere and Centromere Staining Followed by M-FISH Improves Diagnosis of Chromosomal Instability and Its Clinical Utility.

Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10-4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.

Repeated courses of low-dose 2 × 2 Gy radiation therapy in patients with indolent B-cell non-Hodgkin lymphomas.

PURPOSE: In patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL), one course of low-dose radiotherapy (LD-RT) 2 × 2 Gy is emerging as new option of therapy in palliative setting. Efficacy of LD-RT when repeated remains to be determinate. This study aims to assess the efficacy of repeated LD-RT given in patients with indolent B-NHL. MATERIALS AND METHODS: All consecutive adult patients who received two or more courses of LD-RT 2 × 2 Gy for indolent B-NHL at Gustave Roussy institution, during the period 1990-2015 were retrospectively investigated. RESULTS: Thirty-three patients received two or more courses of LD-RT for indolent B-NHL during the study period. The median age was 57 (range 37-80) years, histological types were distributed among follicular lymphoma (n = 24 pts; 73%), marginal-zone lymphoma (n = 6 pts; 18%), and primary cutaneous follicle center lymphoma (n = 3 pts; 9%). The median number of low-dose radiation therapy courses given per patients was 2 (range 2-6). The overall response rates following the first and the second course of LD-RT were 96% and 88%, respectively (P = .31). The 1- and 2-years local control rates following the first courses of LD-RT were 94% (CI 95: 86-100) and 94% (CI 95: 86-98); and were 91% (CI 95: 82-100) and 88% (CI 95: 77-100) following the second course of LD-RT (P = .39). CONCLUSION: The repeated courses of LD-RT offered similar efficacy compare with the first course in patients with indolent B-NHL. LD-RT repeated is a simple, easy to give, and non-toxic asset that could be investigated as treatment option in patients with indolent B-NHL.

Erratum: Cuceu, C., et al. Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability. Cancers 2018, 10, 233.

The authors wish to make the following corrections to this paper [...].

Establishment and Characterization of a Reliable Xenograft Model of Hodgkin Lymphoma Suitable for the Study of Tumor Origin and the Design of New Therapies.

To identify the cells responsible for the initiation and maintenance of Hodgkin lymphoma (HL) cells, we have characterized a subpopulation of HL cells grown in vitro and in vivo with the aim of establishing a reliable and robust animal model for HL. To validate our model, we challenged the tumor cells in vivo by injecting the alkylating histone-deacetylase inhibitor, EDO-S101, a salvage regimen for HL patients, into xenografted mice. Methodology: Blood lymphocytes from 50 HL patients and seven HL cell lines were used. Immunohistochemistry, flow cytometry, and cytogenetics analyses were performed. The in vitro and in vivo effects of EDO-S101 were assessed. Results: We have successfully determined conditions for in vitro amplification and characterization of the HL L428-c subline, containing a higher proportion of CD30-/CD15- cells than the parental L428 cell line. This subline displayed excellent clonogenic potential and reliable reproducibility upon xenografting into immunodeficient NOD-SCID-gamma (-/-)(NSG) mice. Using cell sorting, we demonstrate that CD30-/CD15- subpopulations can gain the phenotype of the L428-c cell line in vitro. Moreover, the human cells recovered from the seventh week after injection of L428-c cells into NSG mice were small cells characterized by a high frequency of CD30-/CD15- cells. Cytogenetic analysis demonstrated that they were diploid and showed high telomere instability and telomerase activity. Accordingly, chromosomal instability emerged, as shown by the formation of dicentric chromosomes, ring chromosomes, and breakage/fusion/bridge cycles. Similarly, high telomerase activity and telomere instability were detected in circulating lymphocytes from HL patients. The beneficial effect of the histone-deacetylase inhibitor EDO-S101 as an anti-tumor drug validated our animal model. Conclusion: Our HL animal model requires only 10³ cells and is characterized by a high survival/toxicity ratio and high reproducibility. Moreover, the cells that engraft in mice are characterized by a high frequency of small CD30-/CD15- cells exhibiting high telomerase activity and telomere dysfunction.

Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability †.

Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL.

The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes.

Background: We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. Materials and Methods: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT) was also assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes. Our findings were reproduced in HL cell lines. The highest levels of TA were expressed in CD30-/CD15- cells. Small cells were identified with ALT and TA. Hodgkin and Reed Sternberg cells contained high levels of PML bodies, but had very low hTERT expression. There was a significant correlation between overall survival (p < 10-3), event-free survival (p < 10-4), and freedom from progression (p < 10-3) and the presence of an ALT profile in lymph nodes of EBV+ patients. Conclusion: The presence of both types of TMMs in HL lymph nodes and in HL cell lines has not previously been reported. TMMs correlate with the treatment outcome of EBV+ HL patients.

Comparison of 36 Gy, 20 Gy, or No Radiation Therapy After 6 Cycles of EBVP Chemotherapy and Complete Remission in Early-Stage Hodgkin Lymphoma Without Risk Factors: Results of the EORT-GELA H9-F Intergroup Randomized Trial.

PURPOSE: While patients with early-stage Hodgkin lymphoma (HL) have an excellent outcome with combined treatment, the radiation therapy (RT) dose and treatment with chemotherapy alone remain questionable. This noninferiority trial evaluates the feasibility of reducing the dose or omitting RT after chemotherapy. METHODS AND MATERIALS: Patients with untreated supradiaphragmatic HL without risk factors (age ≥ 50 years, 4 to 5 nodal areas involved, mediastinum-thoracic ratio ≥ 0.35, and erythrocyte sedimentation rate ≥ 50 mm in first hour without B symptoms or erythrocyte sedimentation rate ≥ 30 mm in first hour with B symptoms) were eligible for the trial. Patients in complete remission after chemotherapy were randomized to no RT, low-dose RT (20 Gy in 10 fractions), or standard-dose involved-field RT (36 Gy in 18 fractions). The limit of noninferiority was 10% for the difference between 5-year relapse-free survival (RFS) estimates. From September 1998 to May 2004, 783 patients received 6 cycles of epirubicin, bleomycin, vinblastine, and prednisone; 592 achieved complete remission or unconfirmed complete remission, of whom 578 were randomized to receive 36 Gy (n=239), 20 Gy of involved-field RT (n=209), or no RT (n=130). RESULTS: Randomization to the no-RT arm was prematurely stopped (≥20% rate of inacceptable events: toxicity, treatment modification, early relapse, or death). Results in the 20-Gy arm (5-year RFS, 84.2%) were not inferior to those in the 36-Gy arm (5-year RFS, 88.6%) (difference, 4.4%; 90% confidence interval [CI] -1.2% to 9.9%). A difference of 16.5% (90% CI 8.0%-25.0%) in 5-year RFS estimates was observed between the no-RT arm (69.8%) and the 36-Gy arm (86.3%); the hazard ratio was 2.55 (95% CI 1.44-4.53; P<.001). The 5-year overall survival estimates ranged from 97% to 99%. CONCLUSIONS: In adult patients with early-stage HL without risk factors in complete remission after epirubicin, bleomycin, vinblastine, and prednisone chemotherapy, the RT dose may be limited to 20 Gy without compromising disease control. Omitting RT in these patients may jeopardize the treatment outcome.

Transmission of Induced Chromosomal Aberrations through Successive Mitotic Divisions in Human Lymphocytes after In Vitro and In Vivo Radiation.

The mechanisms behind the transmission of chromosomal aberrations (CA) remain unclear, despite a large body of work and major technological advances in chromosome identification. We reevaluated the transmission of CA to second- and third-division cells by telomere and centromere (TC) staining followed by M-FISH. We scored CA in lymphocytes of healthy donors after in vitro irradiation and those of cancer patients treated by radiation therapy more than 12 years before. Our data demonstrate, for the first time, that dicentric chromosomes (DCs) decreased by approximately 50% per division. DCs with two centromeres in close proximity were more efficiently transmitted, representing 70% of persistent DCs in ≥M3 cells. Only 1/3 of acentric chromosomes (ACs), ACs with four telomeres, and interstitial ACs, were paired in M2 cells and associated with specific DCs configurations. In lymphocytes of cancer patients, 82% of detected DCs were characterized by these specific configurations. Our findings demonstrate the high stability of DCs with two centromeres in close proximity during cell division. The frequency of telomere deletion increased during cell cycle progression playing an important role in chromosomal instability. These findings could be exploited in the follow-up of exposed populations.

Early Positron Emission Tomography Response-Adapted Treatment in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial.

Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments. Methods We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)-stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS). Results Of 1,950 randomly assigned patients, 1,925 received an ePET-361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. Conclusion In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.

Interobserver delineation uncertainty in involved-node radiation therapy (INRT) for early-stage Hodgkin lymphoma: on behalf of the Radiotherapy Committee of the EORTC lymphoma group.

BACKGROUND AND PURPOSE: In early-stage classical Hodgkin lymphoma (HL) the target volume nowadays consists of the volume of the originally involved nodes. Delineation of this volume on a post-chemotherapy CT-scan is challenging. We report on the interobserver variability in target volume definition and its impact on resulting treatment plans. MATERIALS AND METHODS: Two representative cases were selected (1: male, stage IB, localization: left axilla; 2: female, stage IIB, localizations: mediastinum and bilateral neck). Eight experienced observers individually defined the clinical target volume (CTV) using involved-node radiotherapy (INRT) as defined by the EORTC-GELA guidelines for the H10 trial. A consensus contour was generated and the standard deviation computed. We investigated the overlap between observer and consensus contour [Sørensen-Dice coefficient (DSC)] and the magnitude of gross deviations between the surfaces of the observer and consensus contour (Hausdorff distance). 3D-conformal (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans were calculated for each contour in order to investigate the impact of interobserver variability on each treatment modality. Similar target coverage was enforced for all plans. RESULTS: The median CTV was 120 cm3 (IQR: 95-173 cm3) for Case 1, and 255 cm3 (IQR: 183-293 cm3) for Case 2. DSC values were generally high (>0.7), and Hausdorff distances were about 30 mm. The SDs between all observer contours, providing an estimate of the systematic error associated with delineation uncertainty, ranged from 1.9 to 3.8 mm (median: 3.2 mm). Variations in mean dose resulting from different observer contours were small and were not higher in IMRT plans than in 3D-CRT plans. CONCLUSIONS: We observed considerable differences in target volume delineation, but the systematic delineation uncertainty of around 3 mm is comparable to that reported in other tumour sites. This report is a first step towards calculating an evidence-based planning target volume margin for INRT in HL.

Concurrent Etoposide, Steroid, High-dose Ara-C and Platinum chemotherapy with radiation therapy in localised extranodal natural killer (NK)/T-cell lymphoma, nasal type.

PURPOSE: Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen. METHODS: An induction phase with two upfront courses of CCRT delivering a 40Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2-3 cycles of ESHAP chemotherapy alone. RESULTS: Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3-4 haematological toxicity. The main non-haematological grade 3-4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%. CONCLUSIONS: With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type.

Coronary stenosis risk analysis following Hodgkin lymphoma radiotherapy: A study based on patient specific artery segments dose calculation.

BACKGROUND AND PURPOSE: The dose effect-effect relationship for cardiac diseases following radiotherapy suffers from uncertainties. Three dimensional coronary artery (CA) dose calculation after mediastinal Hodgkin lymphoma radiotherapy was performed, using the patient's coronary CT angiography (CCTA), and the relationship between the coronary arteries' radiation doses and the risk of stenosis was estimated. MATERIALS AND METHODS: Radiotherapy simulation CT scans and CCTAs of patients treated for a mediastinal Hodgkin lymphoma were used to merge thoracic and detailed cardiovascular anatomies. Radiation treatment parameters were used to estimate CA radiation doses. Twenty-one patients without coronary stenosis (controls) were matched with twelve patients with stenosis (cases). CA segments were considered as sub-volumes of interest. Radiation doses to stenotic segments were compared with those received by normal segments (from cases and controls) using a logistic regression. RESULTS: In eleven cases out of twelve, the highest of the coronary dose distribution was on a damaged segment. Logistic regression with CA segments yielded an odds ratio associated with the risk of coronary stenosis of 1.049 per additional gray with the CA segment median dose (95% confidence interval, 1.004-1.095; p-value <0.05). CONCLUSION: The CA segment dose significantly increased the risk of stenosis on the segment. Such personalized CA dose calculations on larger cohorts are expected to improve the understanding of the cardiovascular radiation dose-effect relationship.

Role of FDG-PET in the implementation of involved-node radiation therapy for Hodgkin lymphoma patients.

PURPOSE: This study examines the role of (18)F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) in the implementation of involved-node radiation therapy (INRT) in patients treated for clinical stages (CS) I/II supradiaphragmatic Hodgkin lymphoma (HL). METHODS AND MATERIAL: Patients with untreated CS I/II HL enrolled in the randomized EORTC/LYSA/FIL Intergroup H10 trial and participating in a real-time prospective quality assurance program were prospectively included in this study. Data were electronically obtained from 18 French cancer centers. All patients underwent APET-computed tomography (PET-CT) and a post-chemotherapy planning CT scanning. The pre-chemotherapy gross tumor volume (GTV) and the postchemotherapy clinical target volume (CTV) were first delineated on CT only by the radiation oncologist. The planning PET was then co-registered, and the delineated volumes were jointly analyzed by the radiation oncologist and the nuclear medicine physician. Lymph nodes undetected on CT but FDG-avid were recorded, and the previously determined GTV and CTV were modified according to FDG-PET results. RESULTS: From March 2007 to February 2010, 135 patients were included in the study. PET-CT identified at least 1 additional FDG-avid lymph node in 95 of 135 patients (70.4%; 95% confidence interval [CI]: 61.9%-77.9%) and 1 additional lymph node area in 55 of 135 patients (40.7%; 95% CI: 32.4%-49.5%). The mean increases in the GTV and CTV were 8.8% and 7.1%, respectively. The systematic addition of PET to CT led to a CTV increase in 60% of the patients. CONCLUSIONS: Pre-chemotherapy FDG-PET leads to significantly better INRT delineation without necessarily increasing radiation volumes.

Dependence of coronary 3-dimensional dose maps on coronary topologies and beam set in breast radiation therapy: a study based on CT angiographies.

PURPOSE: In left-side breast radiation therapy (RT), doses to the left main (LM) and left anterior descending (LAD) coronary arteries are usually assessed after delineation by prior anatomic knowledge on the treatment planning computed tomography (CT) scan. In this study, dose sensitivity due to interindividual coronary topology variation was assessed, and hot spots were located. METHODS AND MATERIALS: Twenty-two detailed heart models, created from heart computed tomography angiographies, were fitted into a single representative female thorax. Two breast RT protocols were then simulated into a treatment planning system: the first protocol comprised tangential and tumoral bed beams (TGs_TB) at 50 + 16 Gy, the second protocol added internal mammary chain beams at 50 Gy to TGs_TB (TGs_TB_IMC). For the heart, the LAD, and the LM, several dose indicators were calculated: dose-volume histograms, mean dose (Dmean), minimal dose received by the most irradiated 2% of the volume (D2%), and 3-dimensional (3D) dose maps. Variations of these indicators with anatomies were studied. RESULTS: For the LM, the intermodel dispersion of Dmean and D2% was 10% and 11%, respectively, with TGs_TB and 40% and 80%, respectively, with TGs_TB_IMC. For the LAD, these dispersions were 19% (Dmean) and 49% (D2%) with TGs_TB and 35% (Dmean) and 76% (D2%) with TGs_TB_IMC. The 3D dose maps revealed that the internal mammary chain beams induced hot spots between 20 and 30 Gy on the LM and the proximal LAD for some coronary topologies. Without IMC beams, hot spots between 5 and 26 Gy are located on the middle and distal LAD. CONCLUSIONS: Coronary dose distributions with hot spot location and dose level can change significantly depending on coronary topology, as highlighted by 3D coronary dose maps. In clinical practice, coronary imaging may be required for a relevant coronary dose assessment, especially in cases of internal mammary chain irradiation.