Radiotherapy in younger patients with advanced aggressive B-cell lymphoma—long-term results from the phase 3 R-MegaCHOEP trial: the additive value of radiation therapy in the management of patients with lymphoma

Introduction

Although radiation therapy (RT) has an important historical role in the management of patients with lymphoma, as systemic management has improved, the role of RT in this disease requires refinement for successful modern management of the lymphoma relative to tumor control and normal tissue outcome. The carefully crafted paper offered by colleagues in the German Lymphoma Alliance (GLA) offers insight into the role of RT in modern patient care of patients with aggressive B-cell lymphoma.

The strength of the study crafted by the GLA

Dr. Oertel and the GLA are to be commended for their recent analysis evaluating R-MegaCHOEP (4 cycles of high-dose chemotherapy followed by autologous stem cell transplant) high-dose chemotherapy with autologous bone marrow transplant and conventional immunochemotherapy including R-CHOEP (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone) (1). The trial was well designed and executed. It addressed an important point concerning the role of intensive therapy in patients with potentially aggressive non-Hodgkin lymphoma and associated known high-risk features predicting for tumor recurrence. Although not uniformly imbedded in clinical trials evaluating patients with lymphoma, RT was permitted on this study for consolidation therapy and management. Extranodal lesions and lesions measuring ≥7.5 cm in isolation or as a single conglomerate of lymph nodes were considered conditions for consolidation RT assuming the patient had a complete remission, unconfirmed complete remission, or a partial remission to systemic therapy. For this trial RT was considered a study requirement with a central RT reference panel used to develop a treatment plan for each patient undergoing RT as consolidation therapy. The mediastinum, mesentery, and retroperitoneum were common sites treated with RT with tissues including the liver, kidney, adrenal glands, and bone marrow not considered targets for intentional RT. A radiation dose of 3,600 cGy in 180 cGy and 200 cGy fractions was recommended for management. Radiation oncologists involved in the study reviewed the information post therapy to determine protocol deviations, including patients with bulk disease not treated with RT and those who were treated without specific protocol associated indication or with disease progression. Of 103 patients treated with RT due to the presence of bulk disease, 101 were treated per protocol. Of important note, only one patient not qualifying for therapy underwent RT in contrast to 40 patients assigned to RT who did not receive it. Twenty-one of these patients had extranodal involvement and 19 had bulk disease. One of the many strengths of this study is reporting the study deviations and how this sub-group fared with management. In total, 261 patients were available for analysis and of this group 120 underwent RT with the most frequent areas treated being the mediastinum, mesentery, and retroperitoneum. Each target volume contains an area of normal tissue consequence; therefore, risk was associated with toxicity to patients potentially influencing study outcome. Toxicity risk likely influenced site investigators in not moving forward with RT as well as patients with insufficient response to initial management. For all patients on study, there was statistical improvement for event-free survival with the use of RT and for patients with bulk disease in particular, there was a statistical advantage in event-free survival, progression-free survival, and overall survival in patients receiving RT. Modern RT can be applied with exact position with image guidance; therefore, it is not unusual for the investigators to report no significant additive acute sequelae as conformal avoidance strategies can be generated in RT for lymphoma in all disease sites including the head/neck, thorax, abdomen-pelvis, and extremities. Perhaps more importantly, the investigators reported no increase in second malignancies which is often one of the primary arguments used to not offer RT. The diligence and commitment to science by the GLA investigators is to be applauded as they have permitted the facts to drive the narrative.

The importance of the study by the GLA

The investigators are also to be applauded in accepting RT as a study question. This is an important study question as investigators often drive studies towards intensification of chemotherapy and omit the use of RT assuming RT has no advantage beyond local control of disease. This is an unfortunate perception yet continues to resonate with multiple senior investigators with influence in the protocol management of patients with lymphoma and liquid disease. As RT is not drug, it can be applied in a strategic manner to many if not all sites of original disease with dose augmentation to sites where response to anatomic and metabolic imaging is incomplete. In similar circumstances on clinical trials involving non-Hodgkin lymphoma, the application of RT is often at the discretion of the investigator with limited guidelines for normal tissue dose volume constraints. Often protocols are written in this manner to facilitate accrual. This has merit at a fundamental level including cost; however, to answer the primary study question it is often assumed RT would not influence primary study questions or study outcome. We have made this mistake in the past; however, once we learn that RT has a favorable impact on patient survival, it is difficult to acquire data from investigator sites including images to answer secondary and tertiary trial questions. Therefore, in writing study guidelines, data acquisition and management including collection of imaging and RT treatment objects need to be included in all trials, especially those with the potential of altering clinical practice. The GLA investigators remained committed to the science and reported outcome with 10-year follow-up. The data is invaluable, and all credit goes to the GLA investigative team for generating strong clinical science despite the potential controversy in the outcome of the study.

The investigators have opened the door and identified the importance of the study question, and it is now of equal importance that we follow their lead and offer protocol-based quality assurance strategies to ask next generation questions and improve upon their already excellent effort in defining the role of RT in this disease. There have been multiple similar circumstances in previous studies and if we apply these experiences thoughtfully to the current situation, we can work to avoid our mistakes of the past. Protocol 8725 conducted by the National Cancer Institute (NCI)’s former Pediatric Oncology Group (POG) group evaluated patients who today would be considered to have intermediate and high-risk Hodgkin lymphoma. In this study patients received eight cycles of hybrid chemotherapy with RT randomized to 50% of the patients in a 1:1 fashion. All sites of disease at presentation required RT to be protocol compliant. Although protocol imaging and RT treatment objects were acquired on study, the objects were only reviewed for compliance after the study was completed. Study investigators found deviations in 30% of RT cases, largely driven by exclusion of areas of original disease by site investigators. This had direct influence of the outcome of the clinical trial. In the primary publication, the lead investigator indicated that outcomes were not influenced by RT, and this is accurate if you include the entire study population (2). A closer evaluation of the data revealed, however, that if patients were treated with RT to protocol guidelines and all sites of involvement at disease presentation were included in the RT treatment fields, patients had a statistically significant improvement in survival. The emergence of this data generated a new strategy in the management of radiation oncology quality assurance for clinical trials as studies were now required to include peer review of objects prior to the initiation of treatment to make certain that both response to treatment and application of RT were compliant with protocol guidelines (3-12). The process increased the confidence that the results of the study could be trusted and applied to clinical management. Although digital tools for data transfer were nascent, the decision by cooperative group leadership was to move forward and review RT treatment objects pre-therapy in near real time for compliance to study. This strategy was incorporated into the next iteration of trials for Hodgkin lymphoma. Children’s Oncology Group (COG) 9426 was a risk adaptive trial and the first trial to adjust therapy based on response to anatomic and metabolic imaging. The trial included what would be considered today as early-stage favorable patients. If there was an early response to chemotherapy, patients would discontinue chemotherapy after two cycles and receive 2,100 cGy RT to sites of original involvement. Although there was excellent compliance for the RT component of the study, there was a 50% discordance between site and central retrospective review of imaging response indicating the importance of moving image interpretation into the real time review process. Intermediate risk Hodgkin lymphoma study COG AHOD0031 (the clinical trial which evaluated dose-intensive response based chemotherapy and radiation therapy for children/adolescents with intermediate risk Hodgkin lymphoma: a report from the Childrens Oncology Group) became the study which broke the glass ceiling in simultaneous real time review of multiple imaging and RT treatment objects including outcome imaging and became one of the most successful trials in risk adaptive management of patients with Hodgkin lymphoma. This study accrued over 1,700 patients with data collected including longitudinal metabolic and anatomic imaging and RT treatment objects allowing outcome analysis and review of post therapy normal tissue treatment correlates as well as patterns of failure. Patients were treated with chemotherapy for two cycles and updated image sets were reviewed to determine if the patient had a rapid or slow early response to chemotherapy. This would invite a change in therapy with rapid early response patients moving to two additional cycles of chemotherapy and those with a slow early response would move to a more protracted course of chemotherapy followed by involved field RT. After four cycles of chemotherapy, rapid early response patients would be re-evaluated with additional imaging and if found to be in complete response, they would be randomized to no further treatment or involved field RT. Outcome imaging was acquired including anatomic and metabolic positron emission tomography to assess status post therapy. The data acquired and managed from this study has generated multiple manuscripts evaluating multiple additional study components not uniformly anticipated at the time of activation of the clinical trial (3). Because of the rigor applied to data management for the current study, the GLA group has been able to publish strong clinical data and provide evidence that the data management is secure, and we can trust the outcome of the study. Again, this could not be accomplished without the diligent efforts of the GLA clinical trial management group which is reflected in the strength of the study.

How the study outcome can shape future clinical investigation

We now need to build upon the strength of the study and optimize how to apply RT in this disease. There are patients who will not require RT and at the moment, this would appear to include patients with more limited tumor burden at presentation and those who exhibit rapid and excellent response to initial therapy. Patients with more extended tumor burdens at presentation coupled with those who have medical co-morbidities which preclude traditional application of chemotherapy are candidates to include RT into their care plans. These populations merit study investigation as treatment strategies for these patients remain less well defined. Today, there are many therapy options including traditional chemotherapy, biomarker driven therapy, and immunotherapy including chimeric antigen receptor therapy known as CAR-T. Despite the volume of therapies available to patients with cancer, with rare exception, successful primary management of the patient at the time of presentation remains the best indicator of favorable and durable outcome. This suggests that the role of RT in this disease has relevance in selected circumstances and it would be helpful in protocol management to better define how RT would be applied relative to both radiation dose to disease and the volume of disease to treat. Today, protocols in Hodgkin lymphoma are designed both to treat all sites of disease at presentation and in selected studies, treat areas of limited response without intentional treatment of all disease sites at presentation. To study the role of RT with rigor for lymphoma protocol management, protocols need to be specific about both target volume and dose. Normal tissue dose volume constraints for protocol compliance would need to be written to accommodate all potential sites of disease at presentation in a manner similar to pediatric protocols including rhabdomyosarcoma, Ewing’s disease, and neuroblastoma as the site of origin of disease and disease involvement can be in any body location. Therefore, investigators in this disease need to be fluent in defining disease contours and RT dose/volume constraints in all body regions. This approach to protocol management has been applied to multiple clinical trials including real time review if protocol objects to ensure compliance. The approach will improve our understanding of how RT should be applied in these patients from both a dose and volume perspective (4-12).

Modern RT guidelines can be easily applied to protocol management in this disease. Volumetric RT treatment planning is important for patients with this disease as this permits the development of dose volume histograms to measure outcome relative to normal tissue treated between patients both on individual studies and patients on different protocols. Treatment planning in four dimensions is extremely important as motion can affect target location during therapy in the thorax, abdomen, and pelvis. Image guidance, including optical tracking, is essential for treatment reproducibility on a daily basis and guidelines for use need to be imbedded into each study to ensure that treatment is being reproduced accurately. Protons should also be permitted on study as in all disease areas, including the thorax, there is an advantage to sparring normal tissue with the use of particle therapy. Radiation dose painting can be applied with asymmetric fractionation as a single composite plan with tissues of intermediate risk defined as disease sites at presentation with response to chemotherapy and areas of high risk defined as sites with more limited response to chemotherapy which may require a higher radiation dose for disease control (13,14).

Pre-treatment review of imaging and RT treatment objects has evolved into a nimble and efficient mechanism to ensure that RT treatment plans meet study guidelines prior to the patient being treated. Objects can be transferred through multiple digital media in real time to permit same day review of objects for study compliance. This has become important in studies of all disease areas. It is increasingly important in the protocol management of lymphoma in order to treat disease sites at presentation with dose painting and volume titration relative to response to initial chemotherapy management and for protocols that limit treatment areas based on tumor bulk at presentation and response to chemotherapy. The RT quality assurance process limits study deviations and generates confidence that the results of the study can be applied directly into clinical practice. The GLA has provided such confidence in their review process recognizing the deviations on study centered on investigator concern for the application and addition of RT to patient care. However, through the diligence of review provided by the GLA, they have shown that the concern of second malignancies was not influenced by the addition of RT to the treatment portfolio, thus removing one of the concerns investigators would identify as a reason not to move forward with RT as part of the therapy care plan.

Conclusions

This is an important paper, and the therapy community expresses gratitude and appreciation to the GLA for addressing this topic and publishing the data in a clear and rigorous manner. The paper will initiate conversation and dialogue between providers and have direct impact with influence on patient care and outcome.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-138/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-138/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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