In Western countries, only approximately 5–10% of patients with Hodgkin disease have lymphocyte-predominant Hodgkin disease (LPHD), and the remaining 90–95% of patients have classic Hodgkin disease (CHD).1–3 Due to the rarity of LPHD, optimal treatment remains unclear. Patients with LPHD have different patterns of presentation, gender and age distribution, and likelihood of occult abdominal disease than patients with CHD.4–8 Patients with LPHD tend to be young men with early-stage disease and few risk factors, e.g., they typically lack constitutional symptoms and present with fewer than four involved lymph node regions.6 LPHD tends to occur in peripheral lymph nodes; unlike CHD, it rarely involves hilar or mediastinal lymph nodes.4, 7 Paraaortic lymph node and splenic involvement also is seen less commonly in patients who have LPHD compared with patients who have CHD.4, 9, 10
The use of systemic therapy is well accepted for patients with advanced-stage LPHD; however, the role of systemic therapy in patients with early-stage LPHD remains unclear.11 This is due in part to the fact that there is very little information in the literature on results with systemic therapy for patients with early-stage LPHD. The National Comprehensive Cancer Network practice guidelines11 state that radiotherapy alone is the generally accepted approach in the United States for such patients, based in part on the paucity of published results on chemotherapy-based or antibody-based approaches.
Because it is unlikely that a Phase III clinical trial will be conducted exclusively in patients with early-stage LPHD, we decided to perform a retrospective analysis of our results. The purpose of this study was to examine recurrence free survival (RFS), overall survival (OS), and patterns of failure in patients with early-stage LPHD who were treated with radiotherapy alone or with chemotherapy followed by radiotherapy.
MATERIALS AND METHODS
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- MATERIALS AND METHODS
The European Organization for Research and Treatment of Cancer-Groupe d'Etude des Lymphomes de l'Adulte (EORTC-GELA) criteria define patients with very favorable (VF) Hodgkin disease if they are women age 16–39 years and have nonbulky, Ann Arbor12 Stage IA disease; the lymphocyte-predominant or nodular sclerosis subtype; and an erythrocyte sedimentation rate (ESR) < 50 mm per hour.13 Patients with Hodgkin disease are classified into the favorable (F) prognostic group if they are age 16–49 years and have nonbulky, Stage I–II disease; an ESR < 50 mm per hour with no B symptoms or an ESR < 30 mm per hour with B symptoms; and fewer than 4 involved lymph node regions. Between 1963 and 1996, there were 48 consecutive patients age 16–49 years (median, 28 years) with Ann Arbor Stage I (n = 30 patients) or Stage II (n = 18 patients), EORTC-GELA VF (n = 5 patients) or F (n = 43 patients) LPHD who underwent radiotherapy alone or chemotherapy followed by radiotherapy on prospective studies at The University of Texas M. D. Anderson Cancer Center.14, 15 Twelve of these patients were not included in our previous report on LPHD that involved patients age 5–76 years with all stages of disease who underwent treatment between 1960 and 1992.4 Tissue biopsy specimens were reviewed from every patient by pathologists at The University of Texas M. D. Anderson Cancer Center. Informed consent for treatment was obtained from all patients.
The diagnostic criteria for LPHD used in this study included the following: 1) lymphocytic (L) and histiocytic (H) variants of Reed–Sternberg cells; 2) small, mature lymphocytes constituted > 90% of background cells; 3) some nodular architecture present; and 4) reactivity of L and H Reed–Sternberg cells for CD20.1, 16, 17 In many patients, additional immunostains were done, including CD15, CD30, and CD45, to arrive at the final diagnosis. Features that excluded the diagnosis included 1) frequent classic Reed–Sternberg cells; 2) frequent nonlymphoid (eosinophils, neutrophils, and plasma cells) inflammatory background cells; 3) extensive fibrosis; and 4) reactivity of Reed–Sternberg cells for CD15, and nonreactivity for CD20.5
Nodular architecture was defined as the presence of rounded zones of small lymphocytes that were detectable on light microscopic examination of hematoxylin and eosin-stained slides. Specimens with focal nodularity that accounted for at least 10% of the involved tissue were classified as nodular.5, 18 Diffuse architecture was defined as effacement of nodal architecture with only 1–9% of the architecture showing nodularity by routine histologic or immunologic stain. Patients with specimens that were entirely diffuse were diagnosed with T-cell-rich B-cell lymphoma and were excluded from the study. Classification of nodular vs. diffuse architecture was not assigned in 10 patients (21%), because diagnostic material was no longer available for review.
A comparison of patient characteristics for the two treatment groups is presented in Table 1. Patients with Stage I disease tended to be treated more often with radiotherapy alone. The two treatment groups had similar percentages of VF LPHD (11% of patients in the radiotherapy alone group vs. 9% of patients in the chemotherapy and radiotherapy group) or F LPHD (89% of patients in the radiotherapy alone group vs. 91% of patients in the chemotherapy and radiotherapy group; P = 1.00). Eleven patients received a median of 3 cycles (range, 1–3 cycles) of induction chemotherapy either with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP; n = 6 patients) or with mitoxantrone, vincristine, vinblastine, and prednisone (NOVP; n = 5 patients).15
Table 1. Characteristics of Patients with Very Favorable or Favorable Lymphocyte-Predominant Hodgkin Disease According to the European Organization for Research and Treatment of Cancer-Groupe d'Etude des Lymphomes de l'Adulte Criteria
|Characteristic||No. of patients treated with radiotherapy alone (%)||No. of patients treated with chemotherapy and radiotherapy (%)||P value|
| I||26 (70)||4 (36)||0.07|
| II||11 (30)||7 (64)||—|
| A||36 (97)||10 (91)||0.41|
| B||1 (3)||1 (9)||—|
| Nodular||28 (76)||8 (73)||0.42|
| Diffuse||1 (2)||1 (9)||—|
| Unspecified||8 (22)||2 (18)||—|
| No||24 (65)||9 (82)||0.46|
| Yes||13 (35)||2 (18)||—|
| Female||7 (19)||1 (9)||0.66|
| Male||30 (81)||10 (91)||—|
| 16–39||32 (87)||10 (91)||1.00|
| 40–49||5 (13)||1 (9)||—|
|EORTC-GELA prognostic group|
| Very favorable||4 (11)||1 (9)||1.00|
| Favorable||33 (89)||10 (91)||—|
The median radiotherapy dose delivered to macroscopic disease was the same in both treatment groups: 40 grays (Gy) given in daily fractions of 2.0 Gy over 28 days. The extent of radiation therapy was categorized as follows: involved field (IF), treatment of only the involved lymph node region, as defined by the Ann Arbor staging system12; regional (R), treatment of more than the involved lymph node region but less than one side of the diaphragm; mantle (M), treatment of the lymph node regions above the diaphragm; subtotal lymph node irradiation (STNI), mantle, splenic, and paraaortic irradiation or treatment of the lymph node regions below the diaphragm; and total lymph node irradiation (TNI), mantle irradiation and treatment of lymph node regions below the diaphragm. Field sizes for patients who were treated with radiotherapy alone were IF, R, M, STNI, and TNI in 14%, 38%, 19%, 24%, and 5% of patients, respectively. Field sizes for patients who were treated with chemotherapy followed by radiotherapy were IF, R, M, STNI, and TNI in 9%, 9%, 9%, 73%, and 0% of patients, respectively.
The two-tailed Fisher exact test and a two-sided Pearson chi-square test were used to compare treatment groups in terms of patient characteristics. Kaplan–Meier analysis19 was used to calculate RFS and OS as a function of time. The log-rank test20 was used to compare the resulting curves.
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- MATERIALS AND METHODS
The median follow-up was 9.3 years (range, 2.7–34.4 years), and 98% of patients were observed for ≥ 3.0 years. The RFS rate for patients with EORTC-GELA VF and F LPHD was similar for patients who received radiotherapy alone and patients who received chemotherapy and radiotherapy (10-year rates: 77% and 68%, respectively; P = 0.89) (Fig. 1). The OS rate also was similar for the two treatment groups (10-year rates: 90% vs. 100%, respectively; P = 0.43) (Fig. 1). The RFS and OS rates in terms of histologic subtype are presented in Figure 2. The median duration of follow-up was similar for patients who received radiotherapy alone (9.8 years) and patients who received chemotherapy and radiotherapy (8.8 years). The patterns of first recurrence are presented in Table 2. Patterns of recurrence were similar for the two treatment groups, i.e., chemotherapy did not reduce the risk of recurrence outside of the radiotherapy fields.
Figure 1. Recurrence free survival (A) (P = 0.89) and overall survival (B) (P = 0.43) for very favorable and favorable patients with lymphocyte-predominant Hodgkin disease who were treated either with radiotherapy alone or with chemotherapy followed by radiotherapy.
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Figure 2. Recurrence free survival (A) and overall survival (B) for very favorable and favorable patients with nodular (n = 36 patients), diffuse (n = 2 patients), or unspecified (n = 10 patients) lymphocyte-predominant Hodgkin disease who were treated either with radiotherapy alone or with chemotherapy followed by radiotherapy.
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Table 2. Patterns of First Recurrence in Terms of the Treatment Delivered
|Treatment||No. of patients with recurrent disease (%)|
|None||In field only||Out of field only||In and out of field||Total|
|Radiotherapy alone||28 (76)||2 (5)||7 (19)||—||37 (100)|
|Chemotherapy and radiotherapy||7 (64)||—||3 (27)||1 (9)||11 (100)|
|Total||35 (73)||2 (4)||10 (21)||1 (2)||48 (100)|
The RFS and OS rates for patients who had Stage I disease compared with patients who had Stage II disease are presented in Figures 3 and 4. The addition of MOPP or NOVP chemotherapy did not affect the RFS or OS rate significantly.
Figure 3. Recurrence free survival for patients with Stage I (A) (P = 0.34) or Stage II (B) (P = 0.85) lymphocyte-predominant Hodgkin disease who were treated either with radiotherapy alone or with chemotherapy followed by radiotherapy.
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Figure 4. Overall survival for patients with Stage I (A) (P = 0.53) or Stage II (B) (P = 0.85) lymphocyte-predominant Hodgkin disease who were treated either with radiotherapy alone or with chemotherapy followed by radiotherapy.
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Twelve patients with LPHD had recurrences. Ten of these patients remain free of disease after receiving chemotherapy with cyclophosphamide, vinblastine, procarbazine, and prednisone alternated with doxorubicin, bleomycin, dacarbazine, prednisone, and lomustine (CVPP/ABDIC); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or MOPP chemotherapy with or without radiotherapy.
No patients were diagnosed with myelodysplastic syndrome or acute myeloid leukemia after treatment. One patient developed three neoplasms 5 years after undergoing radiotherapy alone: a Clark level III malignant melanoma and a pleomorphic neurofibroma within the radiotherapy fields and a squamous cell carcinoma of the penis outside of the radiotherapy fields. The melanoma and squamous cell carcinoma both were excised, and the neurofibroma is being observed.
Hypothyroidism developed in 9 of 32 patients (28%) who received neck irradiation and was treated effectively with levothyroxine. There were no patients with severe or life-threatening, nondisease-related complications.
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- MATERIALS AND METHODS
Lymphocyte-predominant Hodgkin disease usually has a nodular growth pattern with or without diffuse areas: It is rarely purely diffuse.21 Although some groups6, 8, 18 have observed late recurrences in patients with nodular LPHD, other groups22–24 have not. In the current study, the histologic subtype of LPHD was not specified in 21% of patients; in addition, diffuse architecture was confirmed in only 4% of patients (Table 1). Consequently, there was inadequate statistical power to determine whether histologic subtype significantly affected RFS. The histologic subtype of LPHD does not appear to affect overall survival.4, 18
There was a low incidence of second malignancies in this study. The incidence of second malignancies, particularly solid tumors, would be expected to increase with longer follow-up.25
The European Task Force on Lymphoma Project on LPHD reported an analysis of 219 patients with this particular histology pooled from 17 European and American centers.6 A significant finding from that study was that 27% of patients with recurrent LPHD suffered multiple recurrences compared with only 5% of the patients with lymphocyte-rich CHD. This finding raised the issue of how to minimize treatment for patients with LPHD given the high salvage and survival rates despite multiple recurrences. Diehl et al.6 have suggested that a watch-and-wait approach may be appropriate for patients with early-stage LPHD in an effort to delay treatment-related cardiac toxicity and second malignancies without compromising overall survival. A watch-and-wait strategy for patients with nodular LPHD is being studied as part of the EORTC-GELA H9 trial.
A wide range of field sizes was treated in our study, reflecting the fact that the optimal radiotherapy field size in patients with VF or F LPHD remains controversial. Because less than 33% of deaths among patients with Stage I–II LPHD are due to Hodgkin disease, compared with 50% of deaths among patients with CHD,5 and because LPHD uncommonly involves the paraaortic lymph nodes or the spleen on presentation,4, 9, 10 some groups26, 27 have suggested that mantle radiotherapy alone is the preferred treatment for patients with VF or F LPHD.7, 28 For example, Backstrand et al.28 in Boston have suggested that mantle irradiation alone may be preferable from a quality-of-life standpoint and may reduce the risk of solid tumors compared with STNI. The National Comprehensive Cancer Network Practice Guidelines also recommend limited-field radiotherapy.11 In contrast, Ha et al.4 have recommended STNI for patients with VF or F LPHD based on the excellent recurrence free survival rate and the low incidence of second malignancies that were observed with this approach (surviving patients were followed for a median of 12.3 years). Only approximately 5% of patients with VF disease have LPHD; the remaining VF patients have nodular sclerosis Hodgkin disease. The EORTC-GELA H7 trial involved mantle irradiation alone in 40 patients with VF disease.29 Based on the 6-year RFS rate of only 73%, the mantle irradiation alone arm was closed, and epirubicin, bleomycin, vinblastine, and prednisone (EBVP) chemotherapy followed by involved-field radiotherapy was recommended. However, the EORTC-GELA H7 trial (and the subsequent EORTC-GELA H8 trial) did not have adequate statistical power to address the role of mantle irradiation alone in patients with VF LPHD. Unfortunately, the current study also did not have adequate statistical power to address the question of radiotherapy field size in patients with VF LPHD.
The 10-year RFS and OS rates for patients with LPHD who were treated with radiotherapy alone were 77% and 90%, respectively (Fig. 1). Regula et al.18 obtained similar results (10-year RFS and OS rates: 76% and 82%, respectively) in patients with LPHD, most of whom had Stage I–II disease that was treated with radiotherapy alone. In accordance with these findings, Bodis et al.5 reported 10-year RFS and OS rates of 80% and 93%, respectively, in patients with LPHD.
We are not aware of any other articles that specifically address results with chemotherapy followed by radiotherapy in patients with Stage I–II LPHD. Like the EORTC-GELA H8-F trial, three cycles of induction chemotherapy were administered in our study. The 5-year RFS rates for the patients with LPHD who received radiotherapy alone compared with patients who received chemotherapy followed by radiotherapy were 89% and 82%, respectively (P = 0.89) (Fig. 1). Approximately 400 patients with LPHD combined would have been required to detect a 7% difference in the 5-year RFS rate with a two-sided significance level of 0.05 and a power of 0.90.30 The 5-year OS rates for the patients with LPHD who were treated with radiotherapy alone or with chemotherapy followed by radiotherapy both were 100% (Fig. 1). Consequently, even more patients would have been required to detect a significant difference in the OS rate.
The EORTC-GELA H731 (n = 333 patients) and H832 (n = 543 patients) Phase III clinical trials randomized patients with F Hodgkin disease to receive EBVP chemotherapy or MOPP/ABV chemotherapy, respectively, followed by IF radiotherapy versus STNI alone. The National Cancer Institute of Canada Clinical Trials Group HD.6 study will randomize 450 patients with F Hodgkin disease to receive 1) ABVD chemotherapy followed by STNI, 2) STNI alone, or 3) ABVD chemotherapy alone. Approximately 25 patients with LPHD have been enrolled on each of these trials, which will provide additional information regarding the role of chemotherapy in patients with F LPHD.
The malignant cell population in LPHD consistently expresses high levels of the CD20 antigen, whereas only 20% of all Reed–Sternberg cells in CHD are CD20 positive.33 The Cologne group recently reported four complete responses and one partial response in five patients with recurrent LPHD who were treated with the anti-CD20 monoclonal antibody, rituximab, for salvage.34 Similarly, the Stanford group recently reported six complete responses and three partial responses at restaging 6 weeks after rituximab was delivered to nine evaluable patients with LPHD.35 Longer follow-up and larger studies will help to clarify the role of antibody-based approaches in patients with LPHD.
In conclusion, the delivery of three cycles of MOPP or NOVP induction chemotherapy did not significantly affect RFS or OS in patients with VF and F LPHD, although the statistical power was limited, and these two chemotherapeutic regimens have been replaced by newer approaches, such as EBVP. Clinical trials are underway to help define the role of a watch-and-wait strategy or systemic therapy, including anthracycline (epirubicin or doxorubicin), bleomycin, and vinblastine-based chemotherapy or antibody-based approaches, in patients with F LPHD. Pending the results of these trials, we believe that radiotherapy alone remains the generally accepted approach in the United States for such patients.11