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

doi:10.1016/j.clon.2015.03.005

Clinical Oncology

Volume 27, Issue 7, July 2015, Pages 401-410

https://doi.org/10.1016/j.clon.2015.03.005 Get rights and content

Highlights

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Modern lymphoma radiotherapy techniques reduce radiation exposure of normal organs.
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Second malignancy modelling predicts this will reduce the absolute excess second malignancy rate.
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The calculated second malignancy rate is similar for involved sites and involved node radiotherapy.

Abstract

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.

Introduction

Radiotherapy continues to play a major role in the curative treatment of Hodgkin and non-Hodgkin lymphomas [1], [2], [3]. Survivorship studies have highlighted the prevalence of late treatment-related complications, with cardiac toxicity and second malignancies being the most common cause of non-lymphoma deaths in Hodgkin lymphoma survivors [4], [5], [6], [7], [8]. This has been a driving factor in attempts to limit the volume of irradiated tissue without compromising cure rates. The advent of combined modality treatment had previously led to a shift in practice from extended field radiotherapy techniques to involved field radiotherapy (IFRT) [9], [10]. Some recent studies have shown the safety of further reductions in field sites [11], [12], [13].

In 2006, Girinsky et al. [14] proposed a major change in practice, which was subsequently incorporated into the EORTC-GELA guidelines [15], with the concept of involved node radiotherapy (INRT) in order to reduce the risk of radiotherapy-induced toxicity. INRT is based on treating only initially involved lymph nodes and excluding adjacent uninvolved nodal areas. This version of INRT required the acquisition of a pre-chemotherapy FDG-positron emission tomography-computed tomography scan in the radiotherapy treatment position, with subsequent rigid co-registration to the post-chemotherapy planning computed tomography scan.

In most centres, pre-chemotherapy positron emission tomography-computed tomography scans are not carried out in the radiotherapy treatment position with immobilisation devices as required for INRT; in addition, lymphoma masses regress during chemotherapy, leading to anatomical and positional changes, leading to uncertainties in the reconstruction of the pre-chemotherapy disease extent. In order to account for these difficulties, the UK National Cancer Research Institute (NCRI) Lymphoma Radiotherapy Group developed guidelines for a concept termed ‘involved site radiotherapy’ (ISRT) to address this issue [1]. This version of ISRT includes an additional margin of 1.5 cm craniocaudally in the direction of lymphatic spread from the pre-chemotherapy extent of nodal disease. Subsequently, the International Lymphoma Radiation Oncology Group (ILROG) has subsequently published guidelines on the use of ISRT for Hodgkin [2] and nodal non-Hodgkin [3] lymphoma, recommending a contoured additional margin to account for uncertainties in defining the pre-chemotherapy gross tumour volume (GTV); the size of the clinical target volume (CTV) varies according to the degree of uncertainty in contouring. The ILROG guidelines for Hodgkin lymphoma also include the concept of irradiating a residual mass rather than the pre-chemotherapy extent of disease after a full course of chemotherapy for advanced disease [2]. Similarly, the ILROG guidelines for nodal non-Hodgkin lymphoma include the concept of treating a residual mass with positron emission tomography-avidity following full-course chemotherapy for advanced-stage aggressive non-Hodgkin lymphoma [3].

The aim of this study was to quantify the dosimetric differences and calculated second malignancy risks between different treatment techniques of IFRT, ISRT, INRT and treatment of residual masses in a series of patients who had received mediastinal radiotherapy.

Section snippets

Patients

Fifteen consecutive patients who had received radiotherapy to the mediastinum for histologically proven lymphoma were retrospectively selected from records. Eligibility included (i) histologically proven lymphoma, (ii) radiotherapy delivered as consolidation after first-line chemotherapy, (iii) positron emission tomography-computed tomography staging before radiotherapy. All patients were immobilised with a five-point thermoplastic mask with arms by sides and extended neck position and

Patient Characteristics

Fifteen consecutive patients who had received mediastinal radiotherapy were identified; 10 were female. The median age was 43 (range 19–64) years old. Ten had a diagnosis of classical Hodgkin lymphoma with three stage I, four stage II and three stage III disease; all had received six cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy and radiotherapy was delivered as consolidation treatment. Four patients had a diagnosis of mediastinal B cell lymphoma and one

Discussion

Although a reduction in the size of the target volume might be expected to reduce toxicity, there is a possibility of an increased risk of marginal or out-of-field failures. There is no randomised trial evidence comparing the previous standard of IFRT with either INRT or ISRT. Reassuringly, evidence is now accumulating that INRT is effective without an excess of marginal treatment failures [24], [25], [26]. Maraldo et al. [12] reported a retrospective cohort of 97 patients with early Hodgkin

Conflict of Interest

The authors have no conflict of interest to declare.

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This increase may range from 1.1 to 8.2 times depending upon the organ site in respect to primarily irradiated area [99]. The decrease of the treatment volume from involved-field to involved-node radiation therapy for Hodgkin lymphoma can also lead to lower probabilities for developing secondary malignancies [111]. Wedged-field irradiations may influence the out-of-field organ doses and the respective probability of carcinogenesis.
Innovations in cancer treatment have contributed to the improved survival rate of these patients. Radiotherapy is one of the main options for cancer management nowadays. High doses of ionizing radiation are usually delivered to the tumor site with high energy photon beams. However, the therapeutic radiation exposure may lead to second cancer induction. Moreover, the introduction of intensity-modulated radiation therapy over the last decades has increased the radiation dose to out-of-field organs compared to that from conventional irradiation. The increased organ doses might result in elevated probabilities for developing secondary malignancies to critical organs outside the treatment volume. The organ-specific dosimetry is considered necessary for the theoretical second cancer risk assessment and the proper analysis of data derived from epidemiological reports. This study reviews the methods employed for the measurement and calculation of out-of-field organ doses from exposure to photons and/or neutrons. The strengths and weaknesses of these dosimetric approaches are described in detail. This is followed by a review of the epidemiological data associated with out-of-field cancer risks. Previously published theoretical cancer risk estimates for adult and pediatric patients undergoing radiotherapy with conventional and advanced techniques are presented. The methodology for the theoretical prediction of the probability of carcinogenesis to out-of-field sites and the limitations of this approach are discussed. The article also focuses on the factors affecting the magnitude of the probability for developing radiotherapy-induced malignancies. The restriction of out-of-field doses and risks through the use of different types of shielding equipment is presented.
Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lymphoma Radiation Oncology Group Guidelines
2020, International Journal of Radiation Oncology Biology Physics
Involved node radiation therapy for lymphoma was introduced with the aim of using the smallest effective treatment volume, individualized to the patient’s disease distribution, to avoid the potentially unnecessary normal tissue exposure and toxicity risks associated with traditional involved field radiation therapy. The successful implementation of involved node radiation therapy requires optimal imaging and precise coregistration of baseline imaging with the radiation therapy planning computed tomography scan. Limitations of baseline imaging, changes in patient position, and anatomic changes after chemotherapy may make this difficult in routine practice. Involved site radiation therapy (ISRT) was introduced by the International Lymphoma Radiation Oncology Group as a slightly larger treated volume, intended to allow for commonly encountered uncertainties. In addition to imaging considerations, the optimal ISRT treatment volume also depends on disease histology, stage, nodal or extranodal location, and the type and efficacy of systemic therapy, which in turn influence the distribution of macroscopic and potential subclinical disease. This article presents a systematic overview of ISRT, updating key evidence and highlighting differences in the application of ISRT across the lymphoma clinical spectrum.
Probability of carcinogenesis due to involved field and involved site radiation therapy techniques for supra- and infradiaphragmatic Hodgkin's disease
2019, Physica Medica
Citation Excerpt :
Additionally, they found that the risk of esophageal cancer remains constant for IFRT and ISRT technique. Murray et al. [21] compared the second malignancy risk after mediastinal HL radiotherapy, with different target volume definition techniques (IFRT, ISRT, INRT, residual volume radiotherapy). They reported that for a 25-year old patient, ISRT leads to substantial cancer risk reduction for lung, thyroid and breast, compared to IFRT.
To estimate the second cancer risk associated with Hodgkin Lymphoma (HL) radiotherapy at supradiaphragmatic or infradiaphragmatic region, using the involved field (IFRT) and the involved site radiotherapy (ISRT).
IFRT and ISRT treatment plans were created for twenty HL patients. Three dimensional plans (3DRT) were employed for all patients. The organ equivalent dose (OED) and lifetime attributable risk (LAR) for organs at risk were estimated with mechanistic, plateau and bell-shaped model. Estimated risk values were compared with nominal risk of unexposed population.
For supradiaphragmatic radiotherapy, the mean OED range was 0.63–8.53 Gy and 0.63–7.26 Gy for IFRT and ISRT, respectively. The corresponding range for infradiaphragmatic radiotherapy was 0.18–7.64 Gy and 0.80–4.95 Gy. The LAR for cancer induction in the partially in field organs at risk after IFRT was 0.5%–8.0% and 0.2%–9.3% at supradiaphragmatic and infradiaphragmatic regions, respectively. The corresponding risk after ISRT method was 0.5%–5.2% and 0.9%–6.0%. Estimated cancer risk for breast, lung, thyroid, colon and rectal with ISRT was found significantly reduced compared to IFRT. The risk of secondary malignancies for lung, mouth, pharynx, rectum and colon was assessed more than 1.2 times higher than nominal risk for IFRT. The respective risk using ISRT was above nominal only for pharyngeal cancer.
ISRT compared with IFRT, results in decreased second cancer risk in most organs considered. Second cancer probability with IFRT was higher than the nominal risk for certain organs, while for ISRT remains higher only for pharyngeal cancer.
Balancing risk and benefit in early-stage classical Hodgkin lymphoma
2018, Blood
Citation Excerpt :
Patients treated with CMT had a significantly longer time to disease progression (8-year time to progression, 93% vs 87%; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.78), but no overall survival (OS) difference was detected. Subgroup analyses indicated that those patients with early-stage favorable disease achieving a complete response by CT scan after 2×ABVD might not need consolidating IFRT.22 Also evaluating omission of RT without PET stratification, a large retrospective US National Cancer Database analysis and a recent Cochrane meta-analysis compared sole chemotherapy with CMT, showing poorer progression-free survival (PFS) without RT.23,24 The results are limited by the short follow-up, potentially missing reports on RT-associated morbidity and mortality.
With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2×ABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4×ABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2×BEACOPP_escalated) followed by 2×ABVD improved 5-year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [¹⁸F]fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2×ABVD and an excellent outcome after 4×ABVD, whereas in those with a positive interim PET, 2×BEACOPP_escalated improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT-associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti–programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients.
Benefit from the inclusion of radiation therapy in the treatment of patients with stage III classical Hodgkin lymphoma: A propensity matched analysis of the Surveillance, Epidemiology, and End Results database
2017, Radiotherapy and Oncology
Citation Excerpt :
The variability of these results is likely due to the large heterogeneity in these studies regarding patient population, systemic therapies, length of follow up, and assessed outcomes. Additionally, a wide variety of RT techniques, treatment volumes, field designs, treatment schedules, and doses have been used and accepted as standard of care over the past several decades, and provider-to-provider interpretation of these recommendations varies [21,22]. Antiquated techniques and excessive RT doses may compromise survival due to late appearing adverse effects in a disease with a generally favorable long-term outcome.
While stage III and IV classical Hodgkin lymphoma (HL) patients are often combined and defined as “advanced stage,” there are significant differences in disease distribution and burden between the two stages. This may obscure advantages of radiotherapy (RT) in a combined modality therapy strategy in stage III disease due to the relative lack of benefit in stage IV patients.
We queried the Surveillance, Epidemiology, and End Results (SEER) database, restricting our search to patients with stage III classical HL diagnosed from 2004 to 2012, to examine the difference in overall and cause-specific survival (OS and CSS) between patients who did or did not receive RT.
Patients treated with RT had improved OS and CSS relative to those treated without RT (5-year OS 91.6% with RT compared to 71.4% without RT, HR = 0.34, p < 0.001) and CSS (5-year OS 95.4% with RT compared to 84.7% without RT, HR = 0.32, p < 0.001). A benefit in OS and/or CSS was seen in all patient subgroups except for older adults (>64 years).
These data support at least a cautionary approach to omitting RT from treatment strategies for patients with advanced stage HL.
Late Cardiac Toxicity After Mediastinal Radiation Therapy for Hodgkin Lymphoma: Contributions of Coronary Artery and Whole Heart Dose-Volume Variables to Risk Prediction
2017, International Journal of Radiation Oncology Biology Physics
Mediastinal radiation therapy (RT) for Hodgkin lymphoma (HL) is associated with late cardiotoxicity, but there are limited data to indicate which dosimetric parameters are most valuable for predicting this risk. This study investigated which whole heart dosimetric measurements provide the most information regarding late cardiotoxicity, and whether coronary artery dosimetry was more predictive of this outcome than whole heart dosimetry.
A random sample of 125 HL patients treated with mediastinal RT was selected, and 3-dimensional cardiac dose-volume data were generated from historical plans using validated methods. Cardiac events were determined by linking patients to population-based datasets of inpatient and same-day hospitalizations and same-day procedures. Variables collected for the whole heart and 3 coronary arteries included the following: Dmean, Dmax, Dmin, dose homogeneity, V5, V10, V20, and V30. Multivariable competing risk regression models were generated for the whole heart and coronary arteries.
There were 44 cardiac events documented, of which 70% were ischemic. The best multivariable model included the following covariates: whole heart Dmean (hazard ratio [HR] 1.09, P=.0083), dose homogeneity (HR 0.94, P=.0034), male sex (HR 2.31, P=.014), and age (HR 1.03, P=.0049). When any adverse cardiac event was the outcome, models using coronary artery variables did not perform better than models using whole heart variables. However, in a subanalysis of ischemic cardiac events only, the model using coronary artery variables was superior to the whole heart model and included the following covariates: age (HR 1.05, P<.001), volume of left anterior descending artery receiving 5 Gy (HR 0.98, P=.003), and volume of left circumflex artery receiving 20 Gy (HR 1.03, P<.001).
In addition to higher mean heart dose, increasing inhomogeneity in cardiac dose was associated with a greater risk of late cardiac effects. When all types of cardiotoxicity were evaluated, the whole heart variable model outperformed the coronary artery models. However, when events were limited to ischemic cardiotoxicity, the coronary artery–based model was superior.

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¹: These authors have contributed equally.

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

Highlights

Abstract

Aims

Materials and methods

Results

Conclusions

Introduction

Section snippets

Patients

Patient Characteristics

Discussion

Conflict of Interest

Clin Oncol (R Coll Radiol)

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Ann Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

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