Radiotherapy in the Modern Treatment of Hodgkin Lymphoma

Abstract

Radiation therapy (RT) has long been an important part of the history of curative treatment for Hodgkin Lymphoma since the pioneering work of Vera Peters, MD and Henry Kaplan, MD. The contemporary role of radiation therapy in the management of patients with early-stage favorable and unfavorable disease, advanced disease, and relapsed/refractory disease will be explored. Seminal clinical trials that highlight the critical role of RT in local control and progression-free survival will be reviewed. The interest in combined modality therapy (CMT) (combination of chemotherapy and RT) will be explored as well as the use of CMT with emphasis on cost effectiveness, age and sex, and risk profile including secondary malignancy and cardiac toxicity compared with chemotherapy alone. Contemporary radiation treatment volumes, techniques, and doses will be discussed as modern strategies to mitigate late toxicities while maintaining efficacy.

CURRENT TREATMENT PARADIGM AND RADIATION THERAPY

Radiation therapy (RT) has long been an important part of the Hodgkin Lymphoma (HL) treatment. Large multi-institutional trials have found ∼80% to 90% of relapses occurr at the original site of disease when RT is omitted.^1,2 These trials support the use of RT to improve progression-free survival (PFS). The contemporary role of RT is for patients with early-stage disease and in relapsed/refractory HL receiving high-dose therapy (HDT) and autologous stem cell transplant (ASCT).

Risk stratifications have been proposed by groups including the German Hodgkin study group (GHSG), National Comprehensive Cancer Network (NCCN), and European Organization for Research and Treatment of Cancer (EORTC) for HL. Each group has identified risk factors for HL relapse that have resulted in allocation to early and advanced stage groups. Early-stage HL is further subdivided into favorable and unfavorable risk groups.

Early Stage

Current guidelines for early-stage favorable and unfavorable risk patients havestandard of care recommendations dictating treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)×2 cycles followed by an interim PET scan. Early-stage favorable patients who have an interim PET complete response (CR), Deauville 1-3, receive consolidative RT to a dose of 20 or 30 Gray. Early-stage favorable risk patients who remain PET positive on interim PET scan, Deauville 4 or 5, receive 2 additional cycles of ABVD followed by a restaging PET CT, and if subsequently achieve a CR would receive RT to 30 Gray. Early-stage unfavorable patients who achieve a PET CR after 2 cycles of ABVD receive 2 additional cycles of ABVD followed by RT to 30 Gray or an additionally 4 additional cycles of AVD. Early-stage unfavorable risk patients that remain positive on interim PET receive an additional 2 cycles of systemic treatment and if restaging PET is negative go on to receive either 2 more additional cycles of systemic therapy or RT to 30 Gray. If restaging PET demonstrates a Deauville of 4, then the patient receives RT to 36 to 40 Gray.

Advanced Stage and Relapse/Refractory Disease

RT is reserved for advanced-stage patient who remain positive on interim PET or end-of-treatment PET. When used in this setting, RT improves PFS.³

RT can be delivered in the pretransplant or post-transplant setting predicated on the goal of treatment without interfering with the plan for High Dose Therapy and Autologous Stem Cell Transplant (HDT/ASCT). Pretransplant RT has the goal of cytoreduction to sites of persistent disease after second-line systemic treatment. Post-transplant RT targets areas of residual disease, which is frequently a smaller volume. Our institutional experience of RT for primary refractory or salvage refractory diffuse large B-cell Lymphoma receiving HDT/ASCT is to use twice daily RT delivered over 10 days in the pretransplant setting to sites of persistent disease.

CONSCIENTIOUS RADIATION THERAPY AND DE-ESCALATION TRIALS

The prognosis for early-stage Hodgkin lymphoma patients is excellent. Given this, it is necessary to consider the risks and benefits of any given therapy and its subsequent association with long-term chronic toxicities. Thus, attempts have been made to avoid local RT to prevent late toxicities and complications.⁴

The HD.6 trial demonstrated that progression-free survival (PFS) at 12 years was improved in patients with early-stage Hodgkin Lymphoma who received combined modality therapy (CMT) with subtotal nodal radiation with or without 2 cycles of ABVD, compared with ABVD alone. Unfortunately, CMT resulted in inferior 12-year overall survival (OS) rates compared with ABVD alone.⁵ This worse OS in the setting of improved PFS was attributed to increased cardiovascular events and secondary cancers from RT and elevated concern regarding the utilization of radiation in this patient population. Notably, the radiation volumes, technique, and doses do not accurately reflect current RT management, which has significantly improved since that time.

Additional trials on unfavorable early-stage patients have demonstrated that escalated chemotherapy alone is noninferior to CMT for those with a negative interim PET scan. For example, GHSG HD17 demonstrated that for patients with unfavorable disease who achieved a CR after 2 cycles of Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Procarbazine, and Prednisolone (escalated BEACOPP) and ABVD, that addition of 30 Gray consolidative RT did not significantly impact PFS (difference of 2.2%) and did not meet a preset noninferiority margin of 8%.⁶ In the setting of unfavorable risk disease treated with chemotherapy intensification consolidation RT may not be warranted.

With these data and the associated concern for RT induced side effects, there was a decrease in the utilization of RT.⁷ In conjunction, multiple trials in the PET-adapted era have compared CMT to chemotherapy alone for early-stage Hodgkin Lymphoma patients. Many of these sought to determine the necessity of consolidative RT in the setting of interim PET negativity after initial chemotherapy, as well as dose intensification of additional systemic therapy if interim PET is positive.

RENEWED FOCUS ON COMBINED MODALITY THERAPY

Clinical Trials

The RAPID trial conducted in the United Kingdom randomized nonbulky early-stage patients who were found to have CR after 3 cycles of ABVD on interim PET to no further therapy versus consolidative RT. Patients who were interim PET positive went on to receive a fourth cycle of ABVD followed by 30 Gray of consolidative RT. The 3-year PFS rate for patients with a CR who underwent CMT compared with chemotherapy alone exceeded the predefined noninferiority boundary on intention to treat analysis at 97.1% and 90.8%, respectively, which was statistically significant (P=0.02, Table 1).¹⁰

TABLE 1.

Seminal Trials Resulting in Improved PFS Outcomes With the Addition of Consolidative Radiation Therapy in the PET Adapted Era

References	Hogkin group	PET timing	PET negative rate (%)	Design	Outcome
RAPID8	Favorable	ABVD×3	75	PET− : IFRT vs. no IFRT PET+ : ABVD×1 + IFRT 30 Gray	3y PFS RT: 97.1% No RT: 90.8%
H10F9	Favorable	ABVD×2	87	PET− : ABVD×2 PET+ : BEACOPPesc ×2 + INRT 30 Gray	5y PFS RT: 99% No RT: 87.1%
					10y PFS RT: 98.8% No RT: 85.4%
H10U1	Unfavorable	ABVD×2	78	PET− : ABVD ×4 PET+ : BEACOPPesc ×2 + INRT 30 Gray	5y PFS RT: 92.1% No RT: 89.6%
					10y PFS RT: 91.4% No RT: 86.5%
HD162	Favorable	ABVD×2	—	Arm1: IFRT 20 Gray Arm 2: PET− : No RT, PET+ : IFRT 20 Gray	5y PFS RT: 94.2% No RT: 86.7%

The EORTC/LYSA H10 studies included both favorable (H10F cohort) and unfavorable (H10U cohort) early-stage patients who were randomized to treatment predicated on interim PET versus treatment without PET restaging. Like the RAPID trial, patients in the H10F cohort experienced improved progression-free survival after CMT than chemotherapy alone with an additional cycle of ABVD after a negative interim PET scan. Five-year PFS in the CMT arm was 99% compared with 87.1% for the chemotherapy alone arm; however, there was no difference in OS. H10U patients underwent 4 cycles of ABVD followed by an interim PET assessment. Those found to have CR either went on to complete CMT or complete 6 total cycles of ABVD. The 5-year PFS in the CMT arm was 92.1% vs 89.6% in the ABVD alone arm (Table 1). This increase in PFS was considered quite modest and the authors felt this challenged the use of RT for patients with unfavorable early-stage disease. The 5-year H10 data further revealed that for those with PET-positive disease after 2 cycles of ABVD, chemotherapy intensification with escalated BEACOPP provided a significant improvement in overall survival at 90.6% compared with ABVD×4 total cycles at 77.4%. Notably, all patients who were interim PET positive received consolidative RT to 30 Gray. The dose escalation arm had an OS benefit approaching significance.¹¹

Recently, 10-year follow-up data was released for the H10 trials. The H10F cohort who completed CMT maintained a 10-year PFS of 98.8%, stable from the reported 5-year PFS of 99%. Those who completed ABVD alone had a 10-year PFS of 85.4%, which was slightly decreased from the reported 5-year PFS of 87.1%. The CMT arm had 2 total relapses, and the chemotherapy alone arm had 24 total relapses. Nineteen of these 24 relapses (79%) in the ABVD alone arm were at the original sites of disease. The H10U cohort mirrored these results with unfavorable risk patients who were interim PET negative and underwent CMT obtaining a 10-year PFS of 91.4% compared with 86.5% in the chemotherapy alone arm. The CMT arm had 11 total relapses with the chemotherapy alone arm having 22 relapses, 20 (91%) of which occurred in the original site of disease. The difference in PFS between the CMT and chemotherapy alone H10U groups increased over time favoring CMT. The PFS difference increased from 2.5% at year 5 to 5% at year 10 (Table 1).¹ These data for complete responders are further corroborated by the H10U patients with PET⁺ disease on interim assessment, where significance was lost in the escalated BEACOPP intensification arm compared with ABVD alone, at 10 years. This leads to a concern that chemotherapy intensification with escalated BEACOPP delays recurrence rather than decreasing the long-term risk of recurrence. These 10-year data help mitigate concern that RT simply delays relapse and further confirms the importance of local control given the likelihood of original site relapse.

Congruent with these studies, the GHSG HD16 trial found that CMT had a significantly improved 5-year PFS compared with ABVD monotherapy at 94.2% and 86.7%, respectively (P=0.04), in favorable patients who had a CR on interim PET analysis. In addition, the dose of consolidative RT utilized in this trial was 20 Gray (compared with previously utilized 30 Gray) and thus gives rise to the feasibility of RT dose de-escalation while maintaining excellent local control (Table 1).² The authors of this study concluded that with this finding, response-adapted RT is not possible, and should be offered even to favorable stage patients with a CR.

Salvage Therapy and Cost Effectiveness

Patients who experience relapsed or refractory disease often go on to complete salvage therapy with HDT/ASCT. This is a physically and financially toxic treatment modality with a significant impact on patient and institutional cost burden. In an elegant study by Smith and colleagues, a Markov model was developed predicated on the findings of the HD16 trial to simulate 1 million early-stage Hodgkin Lymphoma patient treatments as per the trial results. The analysis revealed that for patients with early-stage Hodgkin lymphoma, CMT compared with PET-directed therapy had a significant reduction in associated treatment cost. In addition, quality-adjusted life years (QALY) were identical between the 2 groups.¹²

Young Age and Female Sex are Not Necessarily Contraindications

One of the primary considerations and discussion points with patients for providing consolidative RT is patient age and sex. Radiation carries a risk of secondary malignancy as well as cardiac disease above that of the baseline population, thus earlier exposure confers higher risk of developing these rare but significant radiation induced toxicities.¹³ As Hodgkin Lymphoma often involves the mediastinum, RT fields frequently involve normal lung and heart tissue, as well as breast tissue in female patients, making breast cancer a particular concern. A study by Jones and colleagues utilized age, sex, smoking status, and organ at risk (OAR) data from the UK RAPID trial to produce a microsimulation model at the individual-patient level, for those who completed CMT versus chemotherapy alone. Importantly, the model incorporated the risk of developing secondary malignancy and cardiac disease predicated on previous epidemiological studies investigating RT associated risk with each of these outcomes. Even when accounting for these aforementioned RT induced toxicities, the gain in QALY significantly favored CMT compared with chemotherapy alone. Surprisingly, QALY improvement was greater the younger the patient age at the time of treatment. An additional important aspect of the findings was that there was no difference in secondary malignancy risk attributable to gender. This model also delineated excess relative risk (ERR) per Gray for heart disease and secondary malignancy at various patient ages. ERR for heart disease for patients <28 years, 28 to 36 years, and >36 years was 0.2, 0.088, and 0.042, respectively. ERR for breast cancer for patients <19 years, 20 to 24 years, 25 to 29 years, 30 to 34 years, and >34 years was 0.257, 0.097, 0.057, 0.043, and 0.03, respectively. QALY favored chemotherapy alone if patients required very large RT fields covering bilateral neck and mediastinum as well as significantly for current and former smokers, highlighting the importance of patient selection and discussion on whom should be recommended for CMT.¹⁴ This study correlates with previous data demonstrating smoking dramatically compounds the effects of chemotherapy and RT induced toxicities.¹⁵ It is important to note that the RAPID trial utilized involved field RT (IFRT), which is larger than contemporary involved site RT (ISRT). In addition, the radiation was delivered mostly with the 3D technique compared with the currently utilized intensity modulated RT (IMRT), which is a much more conformal technique. Finally, the RAPID trial did not incorporate deep inspiration breath hold (DIBH), which dramatically reduces heart and lung dose. Thus, the risk of these long-term toxicities is likely even further reduced when utilizing contemporary RT treatment modalities.

Chemotherapy and Radiation Therapy Risk Comparisons

Hodgkin Lymphoma survivors have a 3.2-fold increased risk of coronary heart disease, 6.8-fold increased risk of heart failure, and a cumulative cardiovascular disease risk of about 50%.¹⁶ While RT is not without added risk and a long-term cardiac toxicity profile, the same holds true for chemotherapy as well. For example, each component of CMT, including anthracycline-containing chemotherapy regimens such as ABVD and radiation, independently contributes to increased risk of cardiac disease in Hodgkin Lymphoma patients.⁸ An analysis of 9 EORTC-LYSA trials found an increase in hazard ratio of 1.015/Gy of radiation and 1.077/50 mg/m² dose of anthracycline (1 cycle). The increase conferred by an additional 50 mg/m² was similar to that imparted by the heart receiving 5 Gray radiation.¹⁶ Analysis of the RAPID trial data determined that absolute increase in risk of cardiac related mortality is <1% if mean heart dose is kept below the very manageable 10 Gy, and is just 0.1% and 0.03% if mean dose is 0.5 - 1 Gray and <0.5 Gray, respectively.⁹ This is an important consideration to take into account, especially if the patient has nonbulky disease far from the heart with likely mean heart dose ∼1 Gy utilizing contemporary treatment techniques.

Secondary malignancy risk is a late side effect of RT that remains of great concern in the patient and provider psyche given the long latency period to development¹⁷ and the lack of mature contemporary trial data. Previously ubiquitous mantle field/total nodal RT volumes were historically preferred, which exposed large amounts of normal tissue (including breast, lung, and heart) to often >40 Gray of radiation. An NCI-SEER-based analysis published in 2002 (encompassing the era of these large RT fields) determined the actuarial risk of solid tumor 25 years after Hodgkin treatment to be a shocking 19.3% for males and 24.8% for females.¹⁸ Another study found a 30-year cumulative incidence of secondary malignancy in Hodgkin survivors to be 33.2% when the expected incidence was 9.6%, with the most common being female breast cancer.¹⁹ This notion of radiation and secondary cancer risk remains pervasive even in a very different contemporary RT treatment milieu, which likely substantially decreases the risk. In addition, just as with cardiac toxicity, the contribution to secondary malignancy risk is made by both chemotherapy and RT, independent from one another. It has been shown that 200 mg/m² doxorubicin (i.e., 4 cycles of ABVD) cumulatively has a 1.5-fold increased risk of breast cancer with another 1.18-fold increase in risk for every additional 100 mg/m² (i.e., 2 cycles ABVD).²⁰ Congruently, acute myeloid leukemia/MDS often occurs 12 to 36 months after initial treatment of HL and has been associated with an increased number of BEACOPP cycles received.¹⁶

Another toxicity to remain cognizant is peripheral neuropathy which is associated with vinblastine as well as brentuximab and can persist for decades.²¹ As such, peripheral neuropathy is more prevalent in Hodgkin patients compared with the general population and has an impact on health-related quality of life.²² This can be particularly impactful on elderly and frail patients with ambulation/balance issues and thus could be a patient population where CMT could be considered.

Fertility is also impacted by Hodgkin chemotherapy regimens with up to 50% of women developing premature menopause before age 40 if they received 4 cycles of ABVD during their treatment course.²³ Congruently, secondary analysis of the HD21 trial found that fewer cycles of chemotherapy (4 vs. 6) is better for fertility preservation and patients >30 years are impacted the most.⁸ For relapsed/refractory patients requiring HDT/ASCT, the chemotherapy utilized for induction often includes alkylating agents. The alkylating agents in the BEAM regimen (comprised carmustine, etoposide, cytarabine, and melphalan) have been shown to be deleterious to gonadal function with 32% of women unable to return to normal menses post-treatment.²⁴ Considering these data, if fertility preservation is the goal, minimizing chemotherapy exposure and increasing PFS through CMT may be preferred.

Taken together, the patient goals, age, performance status, disease stage and location, and comorbidities should be taken into consideration when discussing available treatment options.

YESTERDAY, TODAY, AND TOMORROW: INCREASING THE THERAPEUTIC RATIO

The preponderance of RT associated cardiovascular and secondary malignancy risk is based on outdated techniques and are no longer directly applicable to modern treatments.^15,16 Modern analyses have been conducted, which show a substantial decrease in radiation dose to OARs and a subsequent decrease in risk of associated longer-term sequalae. For example, breast cancer risk mitigation as a function of decreased RT volume²⁵ and cardiovascular protection with a reduction in RT volumes from historical large fields to only the involved lymph node.²⁶ A separate study found no excess long-term mortality in early-stage Hodgkin patients treated with ABVD and more modern limited field radiotherapy with a median follow-up of 16 years. The only patients with significant excess mortality were those who developed progression after 5 years, thus conferring added importance on local control and PFS.²⁷ Various RT delivery and planning strategies are currently utilized that help facilitate this improved toxicity profile.

Radiation Therapy Fields

One of the most notable examples is how RT treatment fields have substantially decreased in volume. This evolution and timeline is depicted in Figure 1. Historically, patients were treated with large fields such as total nodal fields and mantle field volumes to doses of 40 to 45 Gray. When PET-adapted therapy became available, it was no longer required to cover the uninvolved nodal basin prophylactically, and thus treatment volumes decreased. First volumes decreased to involved field RT or IFRT (nodal disease plus involved nodal basin) and then continued to evolve and shrink further to the currently utilized involved site/involved nodal fields (ISRT/INRT, only the area involved with disease with a margin) treated to doses of 20 to 30 Gray. These contemporary volumes are significantly smaller treatment fields thereby substantially decreasing the radiation dose to normal tissue. With these obvious advantages in mind, the NCCN, European Society for Medical Oncology (ESMO), and the International Lymphoma Radiation Oncology Group (ILROG) guidelines specify utilization of ISRT/INRT for the treatment of adult lymphomas.²⁸

FIGURE 1.

Evolution and timeline of radiation therapy for the treatment of Hodgkin Lymphoma. The translucent gray color is representative of the radiation volume. IFRT indicates involved field radiation therapy; ISRT/INRT, involved site radiation therapy/involved node radiation therapy.

IMRT/VMAT and DIBH

IMRT with daily image guidance via cone beam CT is now often utilized over the 3D technique for RT delivery when it is found to be dosimetrically advantageous. Myriad studies have demonstrated a significant decrease in mean dose to OARs when utilizing IMRT (and the related technique, volume modulated arc therapy or VMAT), due to improvement in conformality.^29–31 This allows physicians to shape the dose to maintain adequate target coverage while avoiding critical OARs. This is especially true when the OARs are not immediately adjacent to the tumor. However, mean dose is not the only metric by which treatment acceptability is assessed, as IMRT increases the low dose spillage to uninvolved tissues.³⁰ Maximum benefit of IMRT/VMAT is often seen with concurrent use of DIBH. Studies have shown DIBH can decrease the mean dose to lungs, heart, and breast tissue by 17% to 21%, ∼30%, and 5% to 16%, respectively, predicated on RT planning technique used.³²

Dose De-Escalation

Recent trials have also demonstrated that further toxicity mitigation through dose reduction of consolidative RT is feasible. The aforementioned GHSG HD16 trial used 20 Gray consolidative RT compared with 30 Gray, without any impact on local control or PFS benefit.² This was confirmed in other trials including GHSG HD7, HD10, and HD11 trials, even with long-term follow up.^33,34 Dose de-escalation is a simple yet incredibly effective and viable method of decreasing normal tissue exposure to radiation. The only limitation has been the concern of response and durability of that response, which has been lessened by the results from the heretofore mention trial outcomes.

Protons

Dose to normal tissue structures may be further decreased by utilizing of another advanced technology: proton therapy. Compared with photons, the physics of particle therapy allow for significantly decreased exit dose distal to the target structure, thereby decreasing overall integral dose to OARs.³⁵ Studies have shown proton therapy can spare dose with even more efficiency than photon-based IMRT therapy when treating mediastinal Hodgkin disease.³⁶ This technology can also allow for the treatment of larger disease volumes and extended RT fields while maintaining safe OAR constraints.³⁷ In addition, DIBH when utilized in combination with proton therapy, has been shown to further reduce dose to all OARs when compared with photon/DIBH based planning, which has already been shown to provide significant dosimetric benefits.³⁸ Unfortunately, proton therapy is not widely available due to significant facility costs. As it becomes less expensive and more ubiquitous, proton therapy will provide an additional means to decrease radiation dose to off-target tissues and further mitigate late treatment side effects.

Modern Radiotherapy in Action

A recent study by Pinnix and colleagues demonstrated that when all these contemporary RT treatment techniques are utilized, including field size reduction with ISRT, heart and lung sparing with DIBH, dose de-escalation to 20 Gray, all delivered through highly conformal IMRT/VMAT, the doses to OARs can be dramatically improved compared with historical averages. In this cohort of 42 favorable early-stage patients with CR on interim PET, the mean heart dose was 0.8 Gray.³⁹ This dose is far below a study that found a 2 to 6 fold increase in cardiac events if patients received a mean heart dose >15 Gray compared with survivors who did not receive RT⁴⁰ and is also well below the mean heart dose constraint set for lymphoma of 4 Gray. The Pinnix study also reported an impressive reduced mean right and left breast dose of 0.1 Gray. To put this into perspective, this is a fraction of previous breast exposure of sometimes >40 Gray with mantle or larger treatment fields. This study demonstrates the progress that has been made and highlights the work that remains to further decrease the late effects of RT, while maintaining therapeutic efficacy. Figure 2 is comprised of 3 separate studies that when taken together demonstrate how decreasing RT field size, modern delivery technique, and dose de-escalation result in very low OAR doses (specifically the breast and heart), with cardiac toxicity profile comparable to or less than an extra cycle of ABVD.^21,39,41,42 The progressive decrease in OAR doses that is demonstrated by these data is an exemplar of how modern RT continues to evolve in a never-ending pursuit of safer, efficacious treatments for patients with Hodgkin Lymphoma.

FIGURE 2.

Field and technique Impact on OAR mean dose. Bar graph demonstrated the impact of field type and radiation technique on 2 critical OARs: heart and breast tissue. Red dotted line demarcating the equivalent increased cardiac disease risk of 50 mg/m² anthracycline chemotherapy or 5 Gray radiation.²¹ IFRT indicates involved field radiation therapy, ISRT, involved site radiation therapy; MFRT, Mantle Field Radiation Therapy. Ω=Data from work completed by Koh et al⁴¹ utilizing the 3D radiation technique. ∑=Data from work completed by Murray et al⁴² utilizing the 3D radiation technique. π=Data from work completed by Sprecht et al³⁹ utilizing volume modulated arc therapy (VMAT) planning and deep inspiration breath hold technique (DIBH).