Contemporary Radiation Therapy in Combined Modality Therapy for Hodgkin Lymphoma

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  • 1 From the Department of Radiation Oncology & Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins Hospital, Baltimore, Maryland.

The advent of effective combination chemotherapy markedly changed the management of Hodgkin lymphoma, establishing combined modality therapy as the standard of care for most patients with this disease. In response, significant interest has been shown in refining the delivery of radiation in the combined modality setting such that toxicity is minimized while still preserving disease control. An understanding of the way in which radiation treatment fields, prescription dose, and advanced technology have evolved to accomplish these goals is critical. Moreover, fluency in the clinical literature exploring contemporary questions, such as the omission of radiation and response-based treatment, is equally important. Knowledge of these topics will yield both an appreciation of the value of radiation in the combined modality setting and the ability to better customize treatment regimens to individual patients.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/65996; and 4) view/print certificate.

Release date: May 13, 2015; Expiration date: May 13, 2016

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Explain the role of advanced radiation planning techniques in the treatment of patients with HL

  • Summarize the potential toxicities associated with the use of conventional RT

  • Discuss the data from clinical trials that have evaluated the feasibility of omission of RT based on mid-treatment PET imaging

Historically, radiation therapy (RT) alone was the backbone of management for Hodgkin lymphoma (HL). Despite high tumor control rates with RT alone, large treatment fields were required that included uninvolved lymph nodes at risk. As a result, patients incurred late toxicities that contributed to morbidity and mortality, in particular secondary malignancies and cardiovascular disease.13 However, the HL treatment paradigm dramatically shifted with the ability to target subclinical disease using modern combination chemotherapy. Effective systemic agents launched the era of combined modality therapy, which has remained the standard of care for a large proportion of patients with HL, as reflected in national guidelines.46

In the setting of combined modality therapy, critical questions have been raised regarding the optimal administration of RT. Observations linking RT-related late toxicities to both the RT dose and the volume of normal tissue irradiated have sparked investigators to explore avenues to reduce the intensity of therapy in order to minimize the risk of toxicity while still preserving oncologic efficacy.3,710 Technological advances in RT planning and delivery have also provided innovative solutions for minimizing the radiation exposure of normal tissue.

This article reviews the rapidly evolving nature and continued importance of RT for patients with HL, even in the setting of effective systemic therapy. Important considerations surrounding modern field design, prescription dose, and the implementation of advanced radiation planning techniques are explored, and treatment regimens that have omitted RT, including recent strategies that alter therapy based on mid-treatment imaging, are critically assessed.

Optimizing the Delivery of RT

Radiation Field Size

Historically, single-modality radiation was administered as extended-field RT (EFRT), such as a “mantle field” or “inverted Y,” which involved prophylactic treatment of uninvolved lymph node regions. With the advent of modern chemotherapy, involved-field RT (IFRT), in which only the clinically involved lymph node group or groups are treated, became the standard radiation technique based on randomized trial data supporting the use of IFRT over an EFRT approach when chemotherapy is included in the treatment regimen. In the German Hodgkin Study Group (GHSG) HD8, early-stage patients with unfavorable features were randomized to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy with either EFRT or IFRT to 30 Gy, with a 10-Gy boost to bulky disease in both arms.11 No difference was seen in disease control or survival, and patients in the EFRT arm experienced higher rates of toxicity, including secondary cancers in certain subgroups.12

De Bruin et al13 further explored the impact of field size on the long-term risk of secondary breast cancer in 782 HL survivors treated with supradiaphragmatic RT with various field designs. Secondary breast cancer risk was directly compared between patients with HL who underwent mantle field radiation, which includes irradiation of the axilla in addition to mediastinal lymph nodes, versus patients with HL who underwent mediastinal radiation alone. On multivariate analysis, patients treated with mantle field radiation experienced nearly a 3-fold increase in the secondary breast cancer risk when compared with those treated with mediastinal radiation alone.13 The dramatic variation in secondary breast cancer risk based on field size highlights the association between axillary node irradiation and risk of secondary breast cancer. The study illustrates a key concept that radiation-related toxicities must be interpreted in the context of the field size that was used. The strong link between field size and toxicity is the basis for enthusiasm surrounding further refinements in treatment fields, as described herein.

Predicated on observations that the initially involved lymph nodes are at greatest risk for relapse, the EORTC–Groupe d’Etude des Lymphomes de L’Adulte (GELA) introduced involved-node RT (INRT), in which only sites of initial macroscopic disease are targeted.14,15 Although the INRT technique offers further reduction in field size, optimal pretreatment imaging with an 18FDG-PET scan is critical, because considerable evidence has shown the ability of PET to detect occult disease not present on CT.16 Furthermore, INRT requires that the prechemotherapy PET imaging be obtained in the treatment position to facilitate fusion with the simulation scan. After simulation, prechemotherapy CT and PET gross tumor volumes are defined using the fused prechemotherapy imaging and reconciled with the postchemotherapy extent of disease, from which a clinical tumor volume is constructed that accounts for tumor shrinkage and displacement of nearby structures.17

However, it is a common scenario that prechemotherapy imaging is not available and/or was not performed in the treatment position. Therefore, both the International Lymphoma Radiation Oncology Group and the UK National Cancer Research Institute have developed guidelines for volume delineation in this scenario.18,19 Involved-site RT (ISRT) is similarly used to target the initially involved lymph nodes but allows for a potentially larger margin based on the uncertainty introduced by the lack of prechemotherapy imaging or inability to fuse such imaging.18,19 Figure 1 illustrates how ISRT can substantially reduce the volume of tissue irradiated when compared with IFRT.

Ultimately, long-term follow-up will be important to understand how the reduction in field sizes using ISRT and INRT translates in terms of the development of late toxicities. Importantly, initial data on the use of smaller field sizes have suggested that clinical outcomes are not sacrificed. Paumier et al,20 for example, reported a 92% 5-year progression-free survival (PFS) in patients with early-stage HL treated with INRT as per EORTC-GELA guidelines. Similarly, Filippi et al21 reported a 3-year relapse-free survival of 99% in patients with stage IIA disease using an ISRT technique.

Radiation Dose

Randomized controlled data have also confirmed the feasibility of lowering the radiation prescription dose in certain settings. The GHSG HD10 used a 2 x 2 design to randomize patients to either 2 or 4 cycles of ABVD chemotherapy with either 20 or 30 Gy IFRT. Neither 5-year freedom from treatment failure nor overall survival differed based on number of chemotherapy cycles or radiation dose.22 Notably, the GHSG definition of favorable disease differs from those of the EORTC, NCCN, and National Cancer Institute of Canada (NCIC), which are summarized in Table 1. As such, it is important that patients meet the GHSG definition of favorable disease when applying the results of GHSG HD10.4 In the unfavorable early-stage population, GHSG HD11 used a 2 x 2 design to randomize patients to 4 cycles of either ABVD or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) followed by either 20 or 30 Gy of

Figure 1
Figure 1

Comparison of treatment volumes between (A) involved-field radiation therapy (IFRT) and (B) involved-site radiation therapy. Patient has stage I disease with paratracheal and prevascular involvement. An IFRT approach would include treatment of the mediastinum, bilateral hila, and bilateral supraclavicular lymph nodes. Standard borders for an IFRT approach would include C5-C6/top of larynx superiorly, a 1.5-cm margin on the postchemotherapy transverse extent of disease laterally, and 5 cm below the carina/2 cm below the prechemotherapy extent of disease inferiorly.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 5; 10.6004/jnccn.2015.0077

IFRT. In the setting of BEACOPP, 20 Gy was not inferior to 30 Gy, but inferiority of 20 Gy could not be excluded in the setting of ABVD.23 Taken together, in patients meeting GHSG favorable disease criteria, 2 cycles of ABVD chemotherapy followed by 20 Gy IFRT can be considered a standard of care, whereas in patients with unfavorable disease, 4 cycles of ABVD followed by 30 Gy can be considered a standard regimen, with a higher number of chemotherapy cycles and/or radiation dose depending on number of risk factors, initial bulk, and response to treatment.

Table 1

Definitions of Unfavorable Risk Factors by Specific Cooperative Group

Table 1

Advanced Planning Technology

Advanced planning technology also serves as another tool for reducing normal tissue exposure. Intensity-modulated RT (IMRT), for example, takes advantage of complex beam arrangements to create steep radiation dose gradients outside of the target volume, increasing the conformality of the treatment plan and reducing dose to surrounding structures. The potential for IMRT to decrease the dose to the heart and lungs in the setting of mediastinal RT has been demonstrated and is illustrated in Figure 2.2426 Nevertheless, use of IMRT should be individualized to the specific patient. As also shown in Figure 2, IMRT plans can sometimes expose a larger volume of normal tissue to low doses of radiation compared with conventional treatment plans because of the use of multiple beams with IMRT, an issue that could impact the long-term risk of secondary malignancies.27 However, innovative solutions for maintaining the steep dose gradient of IMRT while minimizing low-dose exposure are being investigated.26

Figure 2
Figure 2

Comparison of dose distributions using (A) anterior-posterior/posterior-anterior technique and (B) intensity-modulated radiation technique. The clinical tumor volume is outlined in purple; the volume receiving the prescription dose is highlighted red.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 5; 10.6004/jnccn.2015.0077

Techniques to manage respiratory motion during treatment, such as the deep inspiration breath hold (DIBH), have also proved instrumental in lowering the radiation exposure of normal tissue. During inspiration, the separation between tumor and key normal structures, such as the heart, coronary arteries, and lungs, is generally increased. DIBH takes advantage of this change in anatomy with inspiration. With the DIBH technique, patients are coached to take repeated deep inspirations during treatment with the assistance of a spirometer, and radiation is only administered during periods of deep inspiration. Dosimetric analysis has confirmed a decreased mean dose to key thoracic structures with use of DIBH when compared with free-breathing, particularly in the context of IMRT.24

Proton therapy may also provide additional dosimetric benefit, given its ability to reduce exit dose. In a prospective phase II trial of proton therapy using INRT for patients with mediastinal HL, the mean heart and lung doses were significantly reduced, compared with 3-dimensional conformal and IMRT plans.28 Favorable early oncologic outcomes were also recently reported.29 Ultimately, long-term follow-up will be needed to better appreciate the value of proton therapy and identify which patients may benefit most from its use.

Omission of RT

Combined Modality Therapy Versus Chemotherapy Alone

Although advances in field design, prescription dose, and planning techniques have significantly reduced the radiation exposure of normal tissue, concerns regarding late radiation toxicities have prompted investigators to explore whether omission of RT from the treatment regimen is feasible. As such, several trials have compared combined modality therapy with chemotherapy alone, some of which are outlined in Table 2. Reconciling the results of these studies can be difficult because of varying inclusion criteria and treatment techniques. Nevertheless, these studies provide valuable insight into the merits of RT.

Specifically, randomized comparisons of combined modality therapy with chemotherapy alone generally show higher rates of relapse with omission of RT. As an example, the EORTC-GELA H9-F trial examined 619 patients with early-stage favorable

Table 2

Randomized Controlled Trials Comparing Combined Modality Therapy With Chemotherapy Alone

Table 2
disease who had achieved a complete response after 6 cycles of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) chemotherapy. After chemotherapy, patients were randomized to observation, IFRT to 20 Gy, or IFRT to 36 Gy. Although no difference was seen in 4-year event-free survival between the 2 IFRT arms (20 Gy, 84% vs 36 Gy, 87%), patients in the observation arm experienced a significantly lower 4-year event-free survival of 70% (P<.001).30 Similarly, in the NCIC-ECOG HD6 trial, 405 patients with early-stage disease were randomized to 4 to 6 cycles of ABVD chemotherapy alone versus subtotal nodal irradiation with either no or 2 cycles of ABVD chemotherapy. With long-term follow-up, patients in the combined modality arm (which used now-antiquated EFRT techniques) experienced a trend toward improved 12-year freedom from disease progression compared with those in the chemotherapy-alone arm (92% vs 87%; P=.05), with “unfavorable” patients experiencing a statistically significant difference in freedom from disease progression (94% vs 86%; P=.01).31 Notably, patients in the combined modality arm experienced worse overall survival (87% vs 94%; P=.04). However, interpretation of the survival results is unclear given an excess of mortality from “other” causes, including Alzheimer disease, suicide, and drowning, in the combined modality arm. As such, the best interpretation of this trial is uncertain, particularly because it compared chemotherapy alone with a treatment approach that is no longer used.

In fact, some data have suggested a survival decrement from RT omission. Recently, a systematic Cochrane review investigated the omission of RT from combined modality therapy. The analysis included 5 unconfounded trials (Table 3) and demonstrated significantly decreased hazard ratios (HRs) for both tumor control (HR, 0.41; 95% CI, 0.25–0.66) and overall survival (HR, 0.40; 95% CI, 0.27–0.61) in patients receiving combined modality therapy.32 Furthermore, 2 recent analyses using datasets from the SEER program and the National Cancer Data Base have also suggested decreased overall survival in patients with early-stage HL treated with chemotherapy alone, although both reports are subject to the standard criticisms of observational data sets that lack granular details.33,34

Nevertheless, the variation in survival outcomes and availability of effective salvage therapy support the viability of a chemotherapy-alone strategy in patients likely to experience morbidity from RT late effects. However, this approach must balance the toxicity of an increased number of chemotherapy cycles and a higher need for salvage therapy, which often requires intensive chemotherapy, higher doses of RT, and/or stem cell transplantation. On this note, it is important to recognize the contribution of chemotherapy to late toxicity. Cardiac and pulmonary toxicities, for example, may occur in patients treated with doxorubicin and bleomycin, respectively, whereas secondary malignancies are relevant for

Table 3

Characteristics of Trials Included in Cochrane Meta-Analysis Examining Combined Modality Therapy Versus Chemotherapy Alone

Table 3
several agents, most frequently in the form of leukemia.3538 Although sparing radiation may be an appropriate goal in a female patient younger than 30 years whose disease burden necessitates that a large volume of breast tissue would receive a moderate radiation dose because of the location of nodal involvement, such considerations may be less applicable to an older man with significant cardiac comorbidities for whom limitating the dose of anthracycline may be an important goal. Because late radiation toxicity develops decades after delivery, the current knowledge base is informed by mature follow-up of therapy delivered in the 1980s or 1990s with radiation fields that are no longer used.

It is also important to note that the aforementioned studies predominantly focused on patients with early-stage nonbulky disease. For early-stage bulky disease, combined modality radiation remains a standard treatment option.4 In advanced-stage disease, the optimal application of RT is less clear. UK Lymphoma Group LY09 randomized patients to ABVD versus 2 multidrug chemotherapy regimens, and consolidation radiation was recommended, although not mandated, to sites of initially bulky or residual disease. In an exploratory analysis, patients treated with consolidative radiation after chemotherapy experienced improved event-free survival despite having more adverse features.39 Nevertheless, the extent of disease in these patients can raise concerns regarding field size, and as such, limiting treatment to patients with one or a few sites of initially bulky or residual disease may be prudent. Furthermore, incorporation of mid-treatment metabolic imaging may help guide decisions in the advancedstage population, as noted herein.

Response-Based Therapy

Several reports have illustrated the prognostic value of 18FDG-PET imaging when obtained after only 2 to 3 cycles of chemotherapy. As such, enthusiasm has been shown for using mid-treatment PET to guide both the provision and omission of RT, a strategy that has been effective in the pediatric population.40 In advanced-stage HL, encouraging results have been reported with the selective use of RT in patients with residual PET-avid masses after therapy with BEACOPP, which has been incorporated into the ongoing HD18 trial.41,42 Evidence also supports the use of RT in advanced-stage patients with positive mid-treatment PET imaging results in the setting of ABVD chemotherapy.43 Whether PET response can be used to omit RT in early-stage patients is unclear. In the EORTC-GELA H10 trial, patients with early-stage HL were randomized to either standard combined modality therapy or an experimental arm that tailored treatment based on PET response after 2 cycles of ABVD. In the experimental arm, patients with a negative mid-treatment PET result received chemotherapy alone, with the specific number of cycles based on risk factors. At first interim analysis, however, 16 events of progression were seen in the experimental arm versus 7 in the standard arm, and based on these results, the data monitoring committee declared that it was unlikely that the experimental arm would experience a noninferior outcome, leading to early closure of this arm of the study.44 The United Kingdom National Cancer Research Institute RAPID trial also explored the value of interim PET imaging for dictating the administration of RT in patients with stage I/II disease without B symptoms or mediastinal bulk. Patients with a negative PET scan after 3 cycles of ABVD were randomized to IFRT versus no further therapy (NFT). The trial was designed as a noninferiority study and powered to exclude a 7% difference in PFS between arms. At a median follow-up of 45.7 months, 3-year PFS was similar between the IFRT and NFT arms (IFRT, 93.8 vs NFT, 90.7%). However, the 95% CI for the difference in PFS exceeded the prespecified noninferiority boundary of 7% (risk difference, –3.1%; 95% CI, –10.7% to 1.4%).45 Furthermore, because several patients randomized to the IFRT arm did not actually receive RT, a secondary per-protocol analysis was performed, which showed a significant improvement in PFS with IFRT (3-year PFS rate, 97% vs 91.7%; HR, 2.39 in favor of IFRT; P=.03). The results of this trial therefore remain open to interpretation, because clinicians must balance the similarity in PFS on intent-to-treat analysis with the inability to statistically prove noninferiority of response-based RT omission and the larger difference in PFS on per-protocol analysis. Taken together, these studies highlight the evolving understanding of how to best incorporate mid-treatment response assessment into decision-making. Nevertheless, the omission of RT based on mid-treatment PET imaging should remain investigational until longer-term follow-up and the results of additional ongoing trials exploring this question become available (ClinicalTrials.gov identifier: NCT00736320).

Conclusions

The efficacy of modern chemotherapy for patients with HL has triggered an exciting transformation in the administration of RT for this disease. The availability of conformal treatments administered at reduced doses and delivered to a smaller target volume that has been delineated by more accurate imaging should continue to decrease toxicity for patients with HL. Nevertheless, although minimization of toxicity is an important goal, it is crucial that enthusiasm for reducing radiation volume and intensity not lead to its widespread abandonment, a trend suggested in a recent analysis of SEER data.33 Although chemotherapy alone may be feasible and appropriate in certain settings, RT continues to provide an important local control benefit and its omission may compromise oncologic outcomes. Ongoing work to better define which populations derive the most benefit, using both pretreatment predictive factors and mid-treatment response assessment and using smaller treatment fields tailored to the initially involved disease extent, will allow a more individualized approach regarding the provision of radiation and the optimal dose and field design.

The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education, has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education Accreditation & Program Operations, has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships.

Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships.

Hema Sundar, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.

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Correspondence: Stephanie A. Terezakis, MD, Department of Radiation Oncology & Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 North Broadway, Suite 1440, Baltimore, MD 21231-2410. E-mail: stereza1@jhmi.edu

Supplementary Materials

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    Comparison of treatment volumes between (A) involved-field radiation therapy (IFRT) and (B) involved-site radiation therapy. Patient has stage I disease with paratracheal and prevascular involvement. An IFRT approach would include treatment of the mediastinum, bilateral hila, and bilateral supraclavicular lymph nodes. Standard borders for an IFRT approach would include C5-C6/top of larynx superiorly, a 1.5-cm margin on the postchemotherapy transverse extent of disease laterally, and 5 cm below the carina/2 cm below the prechemotherapy extent of disease inferiorly.

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    Comparison of dose distributions using (A) anterior-posterior/posterior-anterior technique and (B) intensity-modulated radiation technique. The clinical tumor volume is outlined in purple; the volume receiving the prescription dose is highlighted red.

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