Abstract
Treatment for stage II bulky Hodgkin lymphoma with B symptoms is controversial, with patients treated using either early-stage or advanced disease treatment paradigms, varying greatly by institution. We reviewed patients with stage IIB bulky disease at our institution treated primarily with combined-modality therapy and found that these patients had generally excellent outcomes when treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by consolidative radiation and superior outcomes when compared to advanced-stage patients. Furthermore, outcomes have improved over time, likely as a result of the reduction of treatment-associated toxicities.
Background:
Treatment of stage IIB bulky Hodgkin lymphoma(HL) is controversial, with treatment varying by institution. We evaluated patients with IIB bulky disease treated with combined-modality therapy at our institution by describing their longterm outcomes.
Patients and Methods:
We identified 149 consecutive patients with stage IIB bulky HL treated between 1971 and 2012. Clinical, pathologic, and treatment characteristics were extracted from medical records. Actuarial overall survival (OS) and relapse-free survival (RFS) were calculated by the Kaplan-Meier method. Independent factors associated with these outcomes were identified by a multivariate Cox regression model. Outcomes were further compared against comparison groups of both advanced-stage and stage IIB patients treated between 1971 and 2009.
Results:
The 8-year OS rate for patients with stage IIB bulky disease who received combined-modality ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and radiation was 88.8%; the 8-year RFS rate was 76.8%. On multivariate analysis, age < 40 years (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.14-0.57; P = .001), receipt of ABVD (vs. MOPP [mechlorethamine, vincristine, procarbazine, prednisone]; HR, 0.32; 95% CI, 0.10-0.88; P = .028), and radiation dose ≥ 30.1 Gy (HR, 0.25; 95% CI, 0.11-0.65; P = .006) were associated with improved OS. Cardiac events (n = 11) and secondary malignancies (n = 11) only occurred in patients treated before 1995. A subgroup analysis demonstrated significantly improved survival in IIB bulky versus advanced-stage patients (8-year OS, 73.4% vs. 57.4%; P = .008). Improved outcomes in patients with in IIB bulky disease were especially evident in the modern era (> 1995; P = .004).
Conclusion:
Patients with stage IIB bulky HL had excellent outcomes after combined-modality therapy. Treatment strategies have changed substantially over time, with concomitant improvements in disease outcomes and long-term toxicities.
Keywords: B symptoms, Bulky, Chemotherapy, Hodgkin lymphoma, Radiation
Introduction
Over the past half century, treatment strategies for Hodgkin lymphoma (HL) have undergone major changes, most of which reflect tailoring the choice of therapy based on risk factors at presentation. A central goal of more recent strategies has been to avoid unnecessary long-term adverse effects, as this disease typically presents in young patients. Radiotherapy and chemotherapy have both evolved in order to reduce toxicity while maintaining high cure rates, especially for patients with early-stage disease.1-6 Although advanced-stage disease is generally considered to require more aggressive therapy, one group of patients are in an intermediate zone in terms of ideal treatment: those who have stage II disease with both B symptoms and bulky disease. Most large international studies have excluded such patients from the early unfavorable group, instead grouping them with advanced-stage disease.7 Yet in practice and according to published guidelines, patients with stage IIB bulky disease can be managed using an early-stage treatment paradigm with combined-modality treatment consisting of chemotherapy followed by consolidative radiation.8 This discrepancy has created confusion in delineating the optimal treatment strategy for IIB bulky patients.
We reviewed our institutional experience with patients with stage IIB bulky disease to evaluate whether this group of patients can be appropriately stratified and treated with combined-modality treatment, similar to early-stage patients, by describing their long-term clinical outcomes and by comparing them to both advanced-stage (stage III or IV disease) and stage IIB patients. A secondary objective was to examine the influence of treatment era on outcomes in the stage IIB bulky HL population.
Methods and Materials
Study Cohort
The appropriate institutional review board approved this retrospective analysis. Upon review of 1600 patients with pathologically proven HL treated at our institution, we identified 149 consecutive patients with stage IIB bulky disease treated between 1971 and 2012 with complete clinical, pathologic, and treatment characteristics available for review. We also identified a comparison group of 126 consecutive patients who had advanced-stage (III or IV) disease and 201 patients with stage IIB HL treated in a similar era, between 1971 and 2009.
Covariates
Pretreatment variables extracted from medical records included age, sex, disease stage, and presence of B symptoms and bulky disease. Bulky disease was defined as > 10 cm in greatest diameter on axial slices in the computed tomography era or by a mass larger than one-third of the mediastinum on a posteroanterior chest x-ray in the pre—computed tomography era. Disease was staged on the basis of the Ann Arbor system. In every case, the diagnosis of HL had been confirmed by histologic or immunophenotypic examination of excisional or core needle biopsy specimens, and all cases had been examined by flow cytometry immunophenotyping or by immunohistochemical analysis of fixed, paraffin-embedded tissue sections.
For temporal trends analyses, 2 eras were compared, with patients diagnosed before and during 1995 versus after 1995. This cut point was based on the historical shift in treatment at our institution away from MOPP (mechlorethamine, vincristine, procarbazine, prednisone) to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) as standard chemotherapy, and from extended-field radiotherapy to limited fields.
Outcomes
Overall survival (OS), disease-specific survival (DSS), relapse-free survival (RFS), and progression-free survival (PFS) were abstracted from the medical record and were defined according to published guidelines regarding the reporting outcomes in HL.9 Time to event was calculated from date of pathologic diagnosis. Patients who survived were censored at the last date of follow-up. Patterns of failure were also collected. Common treatment-associated long-term complications, including cardiac events and secondary malignancies, were also identified.
Statistical Analysis
In patients with stage IIB bulky disease, unadjusted actuarial OS, DSS, and RFS curves were calculated by the Kaplan-Meier method. Independent predictors of OS were identified by a multivariate Cox regression analysis. We then conducted secondary analyses comparing long-term OS and DSS outcomes in our cohort of patients with stage IIB bulky disease with our comparison groups of patients with either advanced-stage (stage III and IV) or IIB disease. For this secondary analysis, all patients (stages IIB through IV) must have been diagnosed before 2010 to ensure at least a minimum of 5 years of follow-up. All statistical analysis were performed by JMP 11 (SAS Institute, Cary, NC) and Stata 13 (StataCorp, College Station, TX).
Results
Patient Characteristics
In 149 patients with stage IIB bulky HL, the median age was 27 years (range, 11-67 years), and 53% were male. Median follow-up time was 6.8 years (range, 0.6-38.8 years). Patients treated with chemotherapy were most frequently treated using ABVD (49.0%; median number of cycles, 6; range, 4-8 cycles). Most patients received radiation (92.6%), and of these patients, 17% (n = 25) were treated with radiation alone. Table 1 summarizes the baseline patient characteristics.
Table 1.
Baseline Patient and Treatment Characteristics of Stage IIB Bulky Hodgkin Lymphoma (n = 149)
| Characteristic | Value |
|---|---|
| Follow-up time for living patients (years), median (range) | 6.8 (0.6-38.8) |
| Age at Diagnosis (Years) | |
| Median (range) | 27 (11-67) |
| ≤40 | 119 (79.9) |
| >40 | 30 (20.1) |
| Sex | |
| Male | 79 (53.0) |
| Female | 70 (47.0) |
| Year of Diagnosis | |
| ≤1995 | 78 (52.4) |
| >1995 | 71 (47.7) |
| Chemotherapy | |
| None | 25 (17.0) |
| ABVD | 72 (49.0) |
| MOPP | 29 (19.7) |
| Other | 21 (14.3) |
| Unknown | 2 (1.3) |
| Radiotherapy | |
| No | 11 (7.4) |
| Yes | 138 (92.6) |
| Radiation Dose (Gy) | |
| <30.1 | 11 (7.4) |
| ≥30.1 | 121 (81.2) |
| Unknown | 6 (4.0) |
Data are presented as n (%) unless otherwise indicated.
Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; MOPP = mechlorethamine, vincristine, procarbazine, and prednisone.
Temporal Trends
The treatment paradigm for patients with stage IIB bulky disease changed substantially between the pre-1995 treatment era compared to the era after 1995. After 1995, patients were significantly more likely to be treated with ABVD (87.3% vs. 12.8%; P < .0001) and combined-modality therapy (87.3% vs. 65.4%; P < .0001). Table 2 lists additional treatment characteristics by era.
Table 2.
Treatment Stratification of Patients With Hodgkin Lymphoma (n [ 149) by Treatment Era
| Characteristic | ≤ 1995 (n = 78) |
> 1995 (n = 71) |
P |
|---|---|---|---|
| Chemotherapy | |||
| None | 25 (32.1) | 0 (0) | <.0001 |
| ABVD | 10 (12.8) | 62 (87.3) | |
| MOPP | 27 (34.6) | 2 (2.8) | |
| Other | 14 (18.0) | 7 (9.9) | |
| Unknown | 2 (2.6) | 0 (0) | |
| RT | |||
| None | 2 (2.6) | 9 (12.7) | <.0001 |
| RT only | 25 (32.1) | 0 (0) | |
| RT and chemotherapy | 51 (65.4) | 62 (87.3) |
Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; MOPP = mechlorethamine, vincristine, procarbazine, and prednisone; RT = radiotherapy.
Long-Term Clinical Outcomes
In all patients with stage IIB bulky disease (n = 149), 8-year OS was 74.6% and 8-year DSS was 77.6%. Patients aged < 40 years at diagnosis had significantly better outcomes than those ≥ 40 years old (8-year OS: 80.4% vs. 51.1%; P = .002; Figure 1A). Patients with stage IIB bulky disease who received ABVD had significantly better OS (8-year OS 88.8%; P = .001; Figure 1B) than did those treated with MOPP (8-year OS 65.5%) or with any other type of chemotherapy (8-year OS 78.7%). Finally, we examined the influence of radiation dose on outcomes and found that patients treated with doses ≥ 30.1 Gy had improved OS (8-year OS 78.1%) than did those who received < 30.1 Gy (8-year OS 45.5%; P = .009; Figure 1C).
Figure 1. Survival of Patients With Stage IIB Bulky Hodgkin Lymphoma. (A) OS for Patients With Stage IIB Bulky Disease Stratified According to Age (P =.002). (B) OS for Patients With Stage IIB Bulky Disease Stratified According to Chemotherapy Received (P = .001). (C) OS for Patients With Stage IIB Bulky Disease Stratified According to Radiation Dose (P = .009).
Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; MOPP = mechlorethamine, vincristine, procarbazine, and prednisone; OS = overall survival.
On multivariate analysis, age ≤ 40 years remained associated with improved OS (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.14-0.57; P = .001; Table 3), as did receipt of ABVD chemotherapy (vs. MOPP: HR, 0.32; 95% CI, 0.10-0.88; P = .028) and radiation dose ≥ 30.1 Gy (HR, 0.25; 95% CI, 0.11-0.65; P = .006). Multivariate analysis also showed that receipt of ABVD chemotherapy was associated with improved OS compared to radiation alone (HR, 0.13; 95% CI, 0.04-0.35; P < .0001).
Table 3.
Cox Regression Analyses for Covariates of Interest With Respect to Overall Survival in Patients With Stage IIB Bulky Hodgkin Lymphoma (n = 149)
| Covariate | Univariate Analysis | Multivariate Analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | |
| Male (vs. female) | 1.36 | 0.77-2.46 | .3 | |||
| Diagnosis >1995 (vs. ≤1995) | 0.34 | 0.13-0.73 | .005 | |||
| Relapse (vs. no relapse) | 7.18 | 3.09-17.92 | <.0001 | |||
| Age <40 (vs. ≥40) | 0.38 | 0.20-0.74 | .006 | 0.28 | 0.14-0.57 | .001 |
| ABVD (vs. any MOPP) | 0.31 | 0.12-0.77 | .01 | 0.32 | 0.10-0.88 | .028 |
| ABVD (vs. RT alone) | 0.19 | 0.07-0.45 | .0001 | 0.13 | 0.04-0.35 | <.0001 |
| Radiation dose ≥30.1 Gy (vs. <30.1 Gy) | 0.35 | 0.17-0.87 | .026 | 0.25 | 0.11-0.65 | .006 |
Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; CI = confidence interval; HR = hazard ratio; MOPP = mechlorethamine, vincristine, procarbazine, and prednisone; RT = radiotherapy.
Patterns of Relapse
We next examined whether survival was affected by the occurrence of relapse. Among patients with stage IIB bulky disease, 27 (22.9%) had a documented relapse (8-year RFS 76.8%; Supplemental Figure 1). Of the 27 patients who experienced relapse, 7 were treated with chemotherapy, 8 with salvage radiation, and 9 both; 3 did not receive salvage treatment. Twelve patients had undergone stemcell transplantation as a component of their salvage therapy. Five of the 27 patients who experienced a relapse developed a secondary malignancy, which was a higher proportion than the 6 patients with secondary malignancy in the remainder of the stage IIB bulky cohort.
Comparison of Advanced-Stage and Stage IIB Disease
In order to determine whether patients with stage IIB bulky disease had different outcomes from patients with advanced-stage disease, we next directly compared both groups. To do this, we only included consecutively treated patients through 2009 to ensure a minimum of 5 years of follow-up for each patient cohort. In the subgroup analyses of patients with stage IIB bulky disease (n = 125) compared to advanced-stage patients (n = 126), patients with stage IIB bulky disease demonstrated longer OS and DSS (Figure 2). Eight-year OS for the stage IIB bulky disease group was 73.4% compared to 57.3% for those with advanced disease (P = .009, Figure 2A). Eight-year DSS for the stage IIB bulky group was 76.3% versus 60.9% for advanced disease (P = .0468, Figure 2B). Even accounting for treatment era, this pattern remained. In the pre-1995 era, 8-year OS and DSS was 66.5% and 70.3%, respectively, for patients with IIB bulky disease compared to 59% and 61.6% for advanced-stage disease (P = .137 and P = .406, respectively, Figure 3). In the post-1995 era, these differences were more apparent and were statistically significant, with 8-year OS and DSS of 88.4% for both end points in patients with stage IIB bulky disease compared to 53.9% and 59.5% in patients with advanced-stage disease (P = .005 and P = .011, respectively, Figure 3). Unsurprisingly, overall disease outcomes in patients diagnosed before 1995 were inferior to outcomes diagnosed after 1995.
Figure 2. Survival by Disease Stage. (A) OS According to Disease Stage (P = .009). (B) DSS according to Disease Stage (P = .0468).
Abbreviations: DSS = disease-specific survival; OS = overall survival.
Figure 3. Survival by Year of Therapy. (A) OS According to Disease Stage up to 1995 (P =.137). (B) DSS According to Disease Stage up to 1995 (P = .406). (C) OS According to Disease Stage After 1995 (P = .005). (D) DSS According to Disease Stage After 1995 (P = .011).
Abbreviations: DSS = disease-specific survival; OS = overall survival.
Given the dramatic differences in outcomes between patients with stage IIB bulky disease and patients with advanced-stage disease in the post-1995 era, we next compared PFS between these groups to determine whether the improved outcomes referenced above translated into decreased relapse and progression. In the post-1995 era, 3-year PFS for patients with stage IIB bulky disease was 80.2% versus 48.1% for patients with advanced-stage disease (P = .0002, Supplemental Figure 2). In total, 30 patients with advanced-stage disease (61.2%) developed a relapse, compared to 10 patients with stage IIB bulky disease (21.3%, Supplemental Table 1). Patients with advanced-stage disease were also more likely than patients with stage IIB bulky disease to experience relapse after salvage therapy (38.8% vs. 10.6%). Supplemental Table 1 provides additional details regarding salvage therapy in this cohort.
The above results suggest that IIB bulky disease in the modern era has improved outcomes relative to patients with advanced-stage disease and may have similar outcomes to early unfavorable disease. To expound on this finding, we next directly compared outcomes between patients with stage IIB bulky disease (n = 125) and patients with IIB disease (n = 201) using a method similar to the comparison between patients with stage IIB bulky disease and patients with advanced-stage disease. The 8-year OS for the IIB bulky group was 73.4% compared to 79.6% for the IIB group (P = .865, Supplemental Figure 3). The 8-year DSS for the stage IIB bulky group was 76.3% compared to 81.1% for the IIB group (P = .98). Consequently, there was no difference in outcomes between these 2 groups. A caveat to this comparison is that patients with stage IIB bulky disease often receive an intensified regimen of chemotherapy; however, given the above data, future trials may test whether fewer cycles of chemotherapy can be provided to patients with stage IIB bulky disease without compromising outcome.
Long-Term Complications
Because long-term follow-up information was available for the patients with IIB bulky disease, we also examined late adverse events as a result of treatment, ie, cardiac events and secondary malignancies. The incidence of documented cardiac events was 7.4% (11 patients; Table 4). There were no cardiac events among patients who received ABVD chemotherapy. Eleven patients (7.4%) experienced a documented secondary malignancy. Specific secondary malignancy histologies are listed in Supplemental Table 2. Median time to secondary malignancy was 20.3 years (range, 3.0-35.2 years). We also assessed the location of the secondary malignancies in relation to the prior radiation field and found that 7 of those malignancies were within the original radiation field, 1 was out of field, radiation records could not be located for 2 patients, and 1 patient developed leukemia. All 11 patients who developed a secondary malignancy and 11 patients who developed a cardiac event were diagnosed and treated for their disease before 1995.
Table 4.
Long-Term Complications Among 149 Patients With Stage IIB Bulky Hodgkin Lymphoma
| Complication | Value |
|---|---|
| Cardiac Events | |
| Yes | 11 (7.4) |
| No | 138 (92.6) |
| Cardiac Events by Year | |
| ≤1995 | 11 (100) |
| >1995 | 0 (0) |
| Secondary Malignancy | |
| Yes | 11 (7.4) |
| No | 137 (92.6) |
| Time to secondary malignancy (years), median (range) | 20.3 (3.0-35.2) |
| Secondary Malignancy by Year | |
| ≤1995 | 11 (100) |
| >1995 | 0 (0) |
Data are presented as n (%) unless otherwise indicated.
Discussion
To our knowledge, this is the first report to describe long-term outcomes for patients with stage IIB bulky HL. Because our institutional experience spanned several decades, our report is unique in highlighting the temporal changes in treatment paradigm, both for chemotherapy regimens and radiation for such patients. We found that outcomes for patients with stage IIB bulky disease were excellent. This was particularly true for patients treated in the more modern era (after 1995) with combined-modality ABVD and limited-field radiation.
Although our finding of an 88.8% 5-year OS rate for patients with stage IIB bulky disease after combined-modality treatment with ABVD was lower than the 95% 5-year OS reported in HD11,7 it still compares favorably when taking into consideration that the inclusion for criteria HD11 excluded those with stage IIB bulky disease.7 Additionally, outcomes for patients with stage IIB bulky disease at our institution still exceeded outcomes of patients with advanced-stage disease and were quite similar to the clinical outcomes of patients with stage IIB disease. Our findings are difficult to compare directly with those in the literature because most cases of stage IIB bulky HL are grouped with either early unfavorable stage disease per the 2014 criteria of the National Comprehensive Cancer Network (http://www.nccn.org/about/nhl.pdf) or advanced-stage HL per the German Hodgkin Study Group (GHSG) criteria.7 However, our data demonstrate that these cases can be adequately treated with combined-modality ABVD chemotherapy plus consolidative radiation, which can produce outcomes similar to those for patients with early unfavorable disease.
Our decades-long study period allowed us to compare outcomes for patients who received MOPP-based chemotherapy with those for patients who received ABVD-based chemotherapy, and to show how outcomes improved over time after the use of alkylating agents (eg, MOPP) and extended-field radiation were abandoned. Our results are consistent with the published literature on HL in that, first, abandoning extended-field radiation in favor of limited radiation fields improved outcomes, presumably by gaining back those patients who would have died as a result of the long-term adverse effects of extended-field radiation2,3,6,10-14; and second, replacing MOPP-based chemotherapy with ABVD also showed similar survival rates with the attendant decrease in long-term adverse effects, resulting in overall improved outcomes.5
Indeed, we found that all of the cardiac events and secondary malignancy in our series occurred in patients treated before 1995. Although this effect may also be explained by lead-time bias, given the extended follow-up in this patient population, no events were observed in patients treated after 1995, and long follow-up is available for at least some of the patients in this latter group. Therefore, we hypothesize that cardiac events likely stemmed from the long-term toxicity associated with extended-field radiation, while the second malignancies were likely caused by both MOPP chemotherapy and extended-field radiation. Consequently, treatment of patients with stage IIB bulky disease has changed considerably, evolving from extended-field radiation alone to combined-modality therapy with ABVD and limited radiation fields, and outcomes may have followed suit. This is also consistent with recently presented findings showing a decreased risk of second malignancy among patients treated in the modern era.15,16
This study did have weaknesses, chief among them its retrospective nature, with the attendant biases inherent in this type of investigation. Another caveat is that we are unable to provide a comparison of patients with stage IIB bulky disease treated with ABVD alone because this has not been the standard of care at our institution. We also were unable to compare differing cycles of ABVD, given the small number of patients who received fewer than 6 cycles. Future studies may seek to directly compare outcomes in these groups to confirm our reported findings. Prospective studies are also needed to validate our findings that suggest that patients with stage IIB bulky HL may optimally benefit from a combined-modality approach.
Conclusion
This study reports the long-term outcomes for stage IIB bulky HL, a clinical entity often categorized as advanced-stage disease, and demonstrates that these patients have excellent outcomes when treated with combined-modality therapy, especially in the modern era.
Supplementary Material
Clinical Practice Points.
There is controversy whether to categorize and treat stage IIB bulky HL as early unfavorable disease as per national guidelines or as advanced-stage disease as per the GHSG trials.
This report reviews our institutional experience with stage IIB bulky HL and shows overall excellent outcomes with combined-modality therapy.
Outcomes were superior to advanced-stage patients treated during a similar era, and outcomes have improved with the adoption of less toxic chemotherapy and smaller radiation fields.
Future studies should evaluate whether further de-escalation of chemotherapy and radiation dose can be achieved without compromising disease control in this population.
Acknowledgment
Supported in part by Cancer Center Support (Core) Grant CA016672 to The University of Texas MD Anderson Cancer Center.
Footnotes
Disclosure
The authors declare that they have no conflict of interest.
Supplemental Data
Supplemental tables and figures accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clml.2015.07.633.
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