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Involved-Site Image-Guided Intensity Modulated Versus 3D Conformal Radiation Therapy in Early Stage Supradiaphragmatic Hodgkin Lymphoma
International Journal of Radiation Oncology*Biology*Physics
Image-guided intensity modulated radiation therapy (IG-IMRT) allows for margin reduction and highly conformal dose distribution, with consistent advantages in sparing of normal tissues. The purpose of this retrospective study was to compare involved-site IG-IMRT with involved-site 3D conformal RT (3D-CRT) in the treatment of early stage Hodgkin lymphoma (HL) involving the mediastinum, with efficacy and toxicity as primary clinical endpoints.
Methods and Materials
We analyzed 90 stage IIA HL patients treated with either involved-site 3D-CRT or IG-IMRT between 2005 and 2012 in 2 different institutions. Inclusion criteria were favorable or unfavorable disease (according to European Organization for Research and Treatment of Cancer criteria), complete response after 3 to 4 cycles of an adriamycin- bleomycin-vinblastine-dacarbazine (ABVD) regimen plus 30 Gy as total radiation dose. Exclusion criteria were chemotherapy other than ABVD, partial response after ABVD, total radiation dose other than 30 Gy. Clinical endpoints were relapse-free survival (RFS) and acute toxicity.
Forty-nine patients were treated with 3D-CRT (54.4%) and 41 with IG-IMRT (45.6%). Median follow-up time was 54.2 months for 3D-CRT and 24.1 months for IG-IMRT. No differences in RFS were observed between the 2 groups, with 1 relapse each. Three-year RFS was 98.7% for 3D-CRT and 100% for IG-IMRT. Grade 2 toxicity events, mainly mucositis, were recorded in 32.7% of 3D-CRT patients (16 of 49) and in 9.8% of IG-IMRT patients (4 of 41). IG-IMRT was significantly associated with a lower incidence of grade 2 acute toxicity (P=.043).
RFS rates at 3 years were extremely high in both groups, albeit the median follow-up time is different. Acute tolerance profiles were better for IG-IMRT than for 3D-CRT. Our preliminary results support the clinical safety and efficacy of advanced RT planning and delivery techniques in patients affected with early stage HL, achieving complete response after ABVD-based chemotherapy.
This study reports the outcomes of a cohort of patients affected with stage IIA mediastinal Hodgkin lymphoma (HL) who were treated with an adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) regimen followed by involved-site intensity modulated radiation therapy (IMRT) (n=41). Results were compared with those for a cohort of patients treated with 3-dimensional conformal RT (n=49). Relapse-free survival rates were excellent for both groups, and acute toxicity was lower for IMRT. These results support the clinical safety of involved-site IMRT after ABVD in limited stage HL.
Major changes in treatment strategy of early stage Hodgkin lymphoma (HL) lead to excellent outcomes, with relapse-free and overall survival rates exceeding 90% after combined modality therapy, consisting of brief chemotherapy followed by involved-field RT (1), (2), (3), and (4). Long-term survivors are at risk for the development of late toxic effects secondary to chemotherapy, RT, or the combination of both (5) . Mediastinum is involved in the majority of stage I - II HL patients (60%) and is probably the most critical presentation in terms of potential radiation-induced late morbidity. Late effects following thoracic irradiation consist mainly of cardiac toxicity (coronary artery disease, myocardial dysfunction, damage to valvular structures, pericardial fibrosis) (6) and secondary malignancies (mainly represented by breast and lung cancer) (7) . The incidence and severity of late toxicities depend strongly on radiation treatment parameters (total dose, fraction size, treated volumes, dose to surrounding healthy tissues), as well as on quality and quantity of chemotherapy (8) . As a consequence, current clinical protocols focus mainly on treatment intensity minimization in order to avoid late and severe toxic effects. In the field of RT, these efforts recently translated through several years of clinical research (3), (9), and (10) into innovative strategies reducing radiation doses (20 Gy in low-risk patients) and volumes (ie, involved nodal RT). Outside of clinical trials still investigating the safety of involved nodal RT, the classic involved fields (designed according to anatomical boundaries) (11) were progressively replaced by “involved-site” RT (ISRT) concept (12) , after the advent of computed tomography (CT) simulation and 3-dimensional (3D) contouring. The combination of advanced systems for radiation planning and delivery may allow selectively encompassing the clinical target volumes (CTV) while substantially reducing dose to nontarget tissues, and this may have an impact on late toxic effects directly related to thoracic irradiation (mainly cardiac). On the other hand, although the advantages of IMRT include a tight conformal dose distribution and a steep dose gradient, target definition and treatment delivery verification may need even more attention than in conventional RT, considering the potential risk of tumor geographic miss.
Several comparative planning studies have shown that IMRT may result in better planning target volume (PTV) coverage and sparing of organs at risk (OAR), with both IF and IN volumes, and especially in unfavorable mediastinal presentations (bulky disease, involvement of the anterior mediastinum) (13), (14), (15), (16), (17), (18), and (19). This gain could be obtained at the price of a larger amount of normal tissues receiving low doses. Conversely, to the best of our knowledge, there is weak evidence for clinical outcomes (tumor control and acute toxicity) after combined modality treatment with involved-site RT delivered through advanced beams modulation.
The aim of the present study was to retrospectively analyze a series of stage IIA HL patients homogenously selected for clinical characteristics, treated with chemotherapy plus involved-site RT in 2 institutions, with either 3D-CRT or IG-IMRT. The primary study end point was assessment of the efficacy of involved-site IG-IMRT versus 3D-CRT in terms of disease control; the secondary objective was to compare the incidence of acute toxicity between the 2 different treatment techniques.
Methods and Materials
The clinical data of 105 patients affected with stage IIA HL and mediastinal involvement, treated between January 2005 and December 2012 with combined modality therapy in 2 institutions were retrospectively analyzed. All patients had a diagnosis of classic HL. Study inclusion criteria were adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) chemotherapy for 3 to 4 cycles, complete response after chemotherapy, ISRT volumes, and RT dose of 30 Gy delivered with conventional fractionation. Patients treated with chemotherapy regimens other than ABVD or receiving doses higher than 30 Gy were excluded in order to avoid biases in outcome evaluation. Bulky disease was defined as the maximum width of the mediastinal mass exceeding one-third of the intrathoracic diameter at the T5-T6 interspace or tumor diameter exceeding 10 cm in at least 1 direction. Ninety patients fulfilled the inclusion criteria.
All patients without risk factors according to European Organization for Research and Treatment of Cancer (EORTC) criteria received 3 standard ABVD therapy cycles on days 1 to 15 every 28 days; patients with unfavorable prognostic factors received a total of 4 ABVD cycles. Radiation therapy was scheduled for all patients within 6 weeks from the end of chemotherapy.
Radiation therapy technique
Clinical target volumes were outlined on the treatment planning CT scan on the basis of prechemotherapy tumor volume, taking into account response to chemotherapy and displacement of normal tissues. Prechemotherapy positron emission tomography-CT scan was used to improve target contouring, as was image fusion with simulation CT (deformable registration software). In some clinical presentations, and when optimal imaging was available, the CTV results were similar to the volumes defined as “involved nodal” RT but actually corresponded, both for 3D-CRT and IG-IMRT, to the current definition of ISRT (12) . Lungs, thyroid, breasts, heart, and coronary ostia were defined as OAR and delineated on CT datasets; for the breast glandular tissue, we used a standard window (0) and width (500) level. The heart was defined from the auricles to the tip of the organ, including thus all cardiac chambers. In both centers, margins from CTV to PTV were isotropically expanded to 10 to 12 mm for 3D-CRT and to 8 mm for IG-IMRT. Image guidance protocols consisted of daily kilovoltage or megavoltage cone beam CT. Patient plans and treatment used either a thermoplastic mask for head and shoulders fixation, with arms along the body or with arms up, using specific devices.
Forty-nine patients were treated with 3D-CRT, delivered with 2 opposed parallel anteroposterior fields; prescription dose was 30 Gy to the isocenter, according to International Commission on Radiation Units and Measurements guidelines. Forty-one patients were treated with IG-IMRT: 23 patients with volumetric modulated arc therapy (VMAT) in 1 center and 18 patients with helical tomotherapy (HT) in the other.
IG-IMRT has been used since 2008 in the center using HT and since 2010 in the center using VMAT; therefore, all patients treated before those years were given 3D-CRT, whereas afterwards, the choice between 3D-CRT and IG-IMRT was made for each patient, considering clinical presentation and specific needs related to dosimetric plan evaluation.
VMAT was planned by MonacoTM treatment-planning system (Elekta, Stockholm, Sweden), with radiobiological dose optimization based on Monte Carlo dose calculation. Details about VMAT optimization process, both for planning and delivery, have been published elsewhere (15) . Briefly, the VMAT solution we used for treating patients used multiple noncoplanar arcs with the aim of reducing exposure to lung and breast tissue while maintaining heart sparing. Tomotherapy planning was performed using a Hi-Art HT treatment planning system (Accuray Inc, Sunnyvale,CA), based on a superposition/convolution calculation algorithm. Either by means of radiobiology functions defined by Monaco or by Hi-Art HT treatment planning systems, plans were optimized in order to spare OAR as much as possible (particularly lungs, breasts, and heart). Dose constraints are shown in Table 1 .
|Coronary ostia||Dmean||20 Gy|
Abbreviations: Dmean = mean dose; HT = helical tomotherapy; PTV = planning target volume; VMAT = volumetric modulated arc therapy; Vx% = percentage of the target volume receiving X Gy.
Toxicity and survival
All patients were seen weekly during radiation treatment, every 3 months during the first year, and then once every 6 months. Acute toxicity was scored according to Radiation Therapy Oncology Group (RTOG) scoring criteria. Relapses were defined as the clinical or radiological appearance of new disease sites outside radiation fields or the regrowth of initially involved lymph nodes on CT scans and/or positron emission tomography scans. Relapse-free survival was calculated using the Kaplan-Meier method, starting from the time of diagnosis. Follow-up time was calculated by using reverse Kaplan-Meier method.
The log-rank test was used to test the differences in relapse-free survival probability, whereas the Pearson χ2 test was used to compare the 2 groups in terms of acute toxicity incidence.
The clinical features of the 90 patients are summarized in Table 2 . The 2 groups are balanced for different characteristics such as median age, bulky disease, number of involved sites, favorable versus unfavorable risk profile, and anatomical involvement at diagnosis.
|Characteristic||All||3D-CRT ∗||IG-IMRT ∗|
|No. of patients||90||49 (54.4%)||41 (45.6%)|
|Male||44 (48.9%)||21 (42.9%)||23 (56.1%)|
|Female||46 (51.1%)||28 (57.1%)||18 (43.9%)|
|Ann Arbor stage|
|IIA||90 (100%)||49 (100%)||41 (100%)|
|Bulky||15 (16.7%)||7 (14.3%)||8 (19.5%)|
|No. of involved sites|
|<4||83 (92.2%)||45 (91.8%)||38 (92.7%)|
|≥4||7 (7.8%)||4 (8.2 %)||3 (7.3%)|
|Favorable||67 (74.5%)||38 (77.6%)||29 (70.7%)|
|Unfavorable||23 (25.5%)||11 (22.4%)||12 (29.3%)|
|Mediastinum alone||5 (5.6%)||1 (2%)||4 (9.7%)|
|Mediastinum and cervical area||74 (82.2%)||41 (83.7%)||33 (80.5%)|
|Mediastinum and cervical and axillary areas||11 (12.2%)||7 (14.3%)||4 (9.8%)|
∗ Values are numbers (percentages), except where noted.
Abbreviations: 3D-CRT = 3-dimensional conformal RT; EORTC = European Organization for Research and Treatment of Cancer; IG-IMRT = image-guided intensity modulated RT.
The median follow-up time was 42 months globally, 54.2 months for 3D-CRT (range, 11.8-103.7 months), and 24 months for the IG-IMRT group (range, 6.1-99 months).
The 3-year relapse-free survival rates were 97.8% and 100% for 3D-CRT and IG-IMRT, respectively ( Fig. 1 , log-rank = 0.389). Two relapses occurred, 1 in the 3D-CRT group (combined relapse, with in-field and out-of-field component, at 16 months) and 1 in the IG-IMRT group (out-of-field, at 36 months). Failures were observed in patients affected with unfavorable disease (1 for bulky disease and >4 involved sites; 1 for >4 involved sites). Overall survival was 100%, as both patients received salvage chemotherapy plus autologous stem cell transplantation, achieving a continuous complete remission.
Table 3 summarizes the type and grade of radiation-induced acute toxic events in all patients. The most frequent grade 2 toxicity was mucositis/dysphagia, occurring in 12 (24.5%) and 4 patients (9.8%) in the 3DCRT and IG-IMRT groups, respectively. Two cases of grade 2 skin reactions and 2 cases of grade 2 radiation pneumonitis were recorded in the 3D-CRT group. The differences in occurrence of grade 2 toxicity between patients treated with 3D-CRT and those with IG-IMRT were statistically significant (Pearson χ2 = 4.09, P=.043).
|Grade 1||1 (2.0%)||-|
|Grade 2||2 (4.1%)||-|
|Grade 1||4 (8.2%)||1 (2.4%)|
|Grade 2||2 (4.1%)||-|
|Grade 1||13 (26.5%)||11 (26.8%)|
|Grade 2||12 (24.5%)||4 (9.8%)|
Abbreviations: 3D-CRT = 3-dimensional conformal RT; IG-IMRT = image-guided intensity modulated RT; RTOG = Radiation Therapy Oncology Group.
While IMRT is widely accepted for the treatment of some solid tumors, it is still not regarded as a standard option in hematological malignancies. IMRT has been thought to be less useful in lymphomas because of the lower prescribed doses, generally below the tolerance dose of normal tissues; the fear of late effects secondary to low-dose exposure of larger volumes of normal tissues in young patients; and the theoretical increased risk of geographic miss, as the dose gradients are steeper around the target volumes.
Several published studies investigated the dosimetric profiles of IMRT compared to those of 3D-CRT and showed significantly better PTV coverage (measured parameters: V90, V95, conformity index) and/or a significantly better sparing effect of different OAR in the mediastinum (measured parameters: mean, high, intermediate and low dose volumes) (13), (14), (15), (16), (17), (18), and (19). In particular for heart, coronary arteries, breast, thyroid gland, and lungs, a significant reduction in the mean doses and in the volumes receiving higher doses have been documented, with consequential improvements of known predictors of radiation-induced toxicity such as V20 in both lungs. This sparing effect is believed to play a role in potentially reducing the incidence of late effects such as coronary artery disease or myocardial dysfunction following thoracic irradiation, especially in patients where the classical 3D approach (anteroposterior-posteroanterior [AP-PA] opposed fields) would result in a significantly higher cardiac exposure. All studies globally obtained parallel results and have been confirmed both for the traditional involved fields (13), (14), and (15) and for the more recent new concept of involved node RT (16), (17), and (18). The clinical interpretation of the above-mentioned data is complex, due to the high variability in target definition (IF, IN, advanced diagnostic imaging, and other factors) and in planning solutions (static IMRT with different beams arrangements, dynamic IMRT, volumetric modulated techniques, constraints for OAR and their prioritization in terms of penalties, different algorithms for dose calculation). Moreover, image guidance systems were not used in all series, and the margins for PTVs were widely variable. The risk of geographic marginal miss potentially related to the steeper dose gradient achievable with IMRT can be presently reduced through the use of image guidance delivery, which in our opinion should be an integral part of the IMRT approach in order to improve the accuracy other than the conformity of the radiation treatment.
There is also an important open issue regarding the potential increase in the risk of second malignancies with IMRT, secondary to the peculiar dose distribution and the possible higher integral dose. IMRT has been shown to increase the volume of normal tissues receiving lower doses (for example V5 in both lungs). The currently available data for the risk of radiation-induced secondary tumors are only theoretical (purely based on radiobiological modeling) and somehow controversial, with studies showing no differences between 3D-CRT and dedicated IMRT solutions (20) and others indicating a potential increased risk (21), (22), and (23), especially for breast and lung cancer (interestingly, in 1 report, contradictory results are presented according to the use of 2 different models, that is, linear versus nonlinear  ). It must be noted that these experimental hypotheses have been developed starting from datasets including different disease presentations in a very few patients, with variable optimization parameters for OAR, and conclusions for IMRT should not be generalized on the basis of these findings.
In the present study, we aimed to provide clinical data for the use of IMRT with image guidance techniques (IG-IMRT) in limited stage HL patients, deliberately choosing to focus on clinical results (relapse-free survival rate and acute toxicity profile), without reporting dosimetric findings (already well described in several scientific reports) or discussing second malignancy risk modeling. The study was designed as a retrospective analysis of a homogeneous cohort of patients treated with involved-site IG-IMRT with 2 different technical approaches (VMAT and HT), in comparison with a control arm of patients treated in the same institutions with involved-site 3D-CRT.
All patients treated before 2008 were given 3D-CRT, whereas afterwards, the choice between 3D-CRT and IG-IMRT was made for every single patient, considering clinical presentation and specific needs related to plan dosimetric evaluation. The term ISRT was recently introduced (12) but actually corresponds exactly to the volumes we used to treat since the introduction of 3D planning in both institutions. A reduction in RT volumes from the conventional involved-field RT toward a modified approach only including involved nodal areas has been previously investigated in high-quality retrospective studies, without any influence on the relapse pattern (10) and (24). To our knowledge, only 2 retrospective single-institutional studies have addressed the clinical role of IMRT in early stage HL. Paumier et al (25) analyzed a heterogeneous cohort of 50 patients treated with involved node RT using either IMRT (n=32) or deep inspiration breath hold 3D-CRT (n=18). The number of ABVD cycles was 4 to 6, with a median prescribed dose of 40 Gy. The 5-year overall survival and progression-free survival rates for the IMRT group were 95% and 91%, respectively, with a median follow-up time of 59.9 months. As underlined by the authors, the heterogeneity in patient selection and the relatively high doses used in IMRT were explainable by clinical characteristics of their clinical cohort (cases of relapsed/refractory disease, a new radiation technique, final data on low doses unavailable at the time of recruitment). Bulky disease was present in 37.5% of IMRT patients. That study, which was not intended as a comparison between IMRT and deep inspiration breath hold 3D-CRT technique, provides us, however, with important information regarding the clinical efficacy of IMRT in mediastinal HL in a patient cohort with an adequate follow-up time. Lu et al retrospectively analyzed a cohort of 52 patients affected with mediastinal stage I-II HL treated with a combination of 4 to 6 ABVD cycles followed by 30 to 40 Gy involved field IMRT (step-and-shoot technique) (26) . Patient characteristics were heterogeneous (4-6 ABVD cycles, different response to chemotherapy, different total dose), and the median follow-up time was 36.3 months, with 44.2% of bulky disease. Three-year local control, overall and progression-free survival rates were 97.9%, 100%, and 96%, respectively. Acute tolerance profile was acceptable, with 2 patients experiencing grade 3 toxicity (mucositis and leukopenia) and 5 grade 2 mucositis (9.6%). The second most frequent toxic event was skin reactions (46.2% grade 1 and 5.8% grade 2).
In our study, we defined strict inclusion criteria in order to investigate a homogeneous population and to minimize confounding factors typical of retrospective evaluations (complete response after 3-4 ABVD chemotherapy cycles, 30 Gy as total radiation dose, involved site approach); the percentage of favorable clinical characteristics was markedly high (approximately 70%). This aspect, together with the limited follow-up time, should explain the excellent tumor control achieved until now in both groups. The pattern of acute toxicity was comparable to that reported by Lu et al (26) , with mucositis being the most common toxic event; few grade 2 events were recorded in the IG-IMRT group (9.8%). We did not observe any case of xerostomia and only 2 cases of grade 2 radiation pneumonitis (in the 3D-CRT group). The differences in incidence and severity of acute effects between the 3D-CRT and IG-IMRT groups reached statistical significance (P=.043).
We are not currently able to provide data for late toxic effects because of limited follow-up time. In treating early stage HL patients, a minimal late toxicity represents the most important clinical end point and this cohort will be followed by closely monitoring late potential treatment-related morbidities. In the near future, several trials will investigate the role of new drugs and response-adapted therapeutic strategies in early stage HL, all them designed to minimize treatment-related toxicity, and some including modern RT approaches.
As there is no single proven best planning and delivery RT technique, every patient should be individually assessed and treatment plans compared and the corresponding dose-volume histogram, together with specific clinical needs and priorities. According to what was recently stated by Specht et al (12) on behalf of the International Lymphoma Radiation Oncology Group (ILROG), in certain situations, 3D-CRT still represents the best choice because of the smaller volume of irradiated normal tissues, albeit to the full prescription dose. In others, IMRT may be preferred, offering a significantly better sparing of critical normal structures, albeit at the price of larger volumes of normal tissues receiving low doses.
In early-stage HL patients who are candidates for highly conformal radiation therapy, involved-site IG-IMRT is safe and effective in the setting of ABVD-based combined modality treatment.
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∗ Department of Oncology, University of Torino, Torino, Italy
† Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia, Italy
‡ Hematology, Città della Salute e della Scienza, Torino, Italy
§ Hematology, University of Torino and Città della Salute e della Scienza, Torino, Italy
‖ Hematology Unit, ASMN Hospital IRCCS, Reggio Emilia, Italy
∗ Reprint requests to: Andrea Riccardo Filippi, MD, Department of Oncology, University of Torino, Via Genova 3, 10126 Torino, Italy. Tel: 39 011 6705352
Conflict of interest: none.
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