Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin's lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG)

L. Nogová1,*, T. Reineke1, H. T. Eich2, A. Josting1, H. K. Müller-Hermelink4, K. Wingbermühle1, C. Brillant1, A. Gossmann3, J. Oertel5, M. V. Bollen6, R.-P. Müller2, V. Diehl1, A. Engert1 for the GHSG

1 Clinic I for Internal Medicine, 2 Clinic of Radiotherapy and 3 Department of Radiology of University Hospital Cologne; 4 Insitut for Pathology of University Wuerzburg; 5 Campus Virchow Klinikum, Berlin; 6 University Hospital Heidelberg, Heidelberg, Germany and the German Hodgkin Lymphoma Study Group (GHSG)

* Correspondence to: Dr L. Nogová, First Department of Internal Medicine, University Hospital Cologne, Kerpenerstr. 62, 50924 Cologne, Germany. Tel: +49-221-478-6033; Fax: +49-221-478-6459; E-mail: lucia.nogova{at}uk-koeln.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Since there are no randomized studies, the treatment of choice for patients with early stage lymphocyte-predominant Hodgkin's lymphoma (LPHL) remains unclear. We thus reviewed all LPHL cases registered in the database of the German Hodgkin Study Group (GHSG) and compared the different treatment approaches, such as extended field (EF), involved field (IF) radiation and combined modality (CM) treatment for LPHL stage IA patients.

Patients and methods: One hundred and thirty-one patients with LPHL in clinical stage IA without risk factors were analyzed. Forty-five patients were treated with EF radiotherapy, 45 patients with IF radiation and 41 patients received CM treatment. The median follow-up was 78 months in the EF group, 40 months after CM and 17 months after IF, respectively.

Results: A total of 129 patients achieved complete remission (CR and CRu): 98% after EF radiotherapy, 100% after IF radiation and 95% after CM. With a median follow-up of 43 months there were 5% relapses and only three patients died. Toxicity of treatment was generally mild with most events observed after CM.

Conclusion: In terms of remission induction IF radiotherapy for stage IA LPHL patients is as effective as EF or CM treatment. However, longer follow-up is needed before final conclusion as the optimal therapy.

Key words: combined modality treatment, extended field radiotherapy, involved field radiotherapy, lymphocyte-predominant Hodgkin's lymphoma


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Lymphocyte predominant Hodgkin's lymphoma (LPHL) is rare accounting for 3%–8% of all Hodgkin's lymphoma (HL) cases in Western countries [1Go]. Histological, LPHL is characterized by a mixture of few Reed Sternberg-like cells and atypical ‘lymphocytic and histiocytic’ (L&H) or ‘popcorn’ cells in a background composed mostly of small B lymphocytes. In addition, there are fewer T cells compared with classical Hodgkin's lymphoma (cHL). L&H cells usually express the B-cell marker CD20 and lack expression of CD15 and CD30, the characteristic markers for cHL [2Go].

The clinical course of early stage LPHL is generally moderate with slowly progressive lymphadenopathy often preceding the diagnosis for many years [1Go, 3Go, 4Go]. The general prognosis is favorable, and only a few patients in early stages die of their disease [1Go, 5Go, 6Go]. The European Task Force on Lymphoma project found that treatment of LPHL with radiotherapy, chemotherapy or combined modality using standard protocols developed for the treatment of HL can lead to complete remission (CR) in more than 95% of patients. However, survival and freedom from treatment failure (FFTF) are substantially worse in advanced stage patients compared with early stage patients [1Go]. Thus, patients in advanced stages and those in early stages with unfavorable risk factors should be treated similar to cHL [1Go, 5Go].

In contrast, early stage LPHL patients without risk factors might be sufficiently treated with reduced intensity programs having less severe side-effects. Analyses performed by the European Organization for Research and Treatment of Cancer (EORTC) suggested that although the HL-related death rate in patients treated for HL decreases during the years after diagnosis, the overall mortality is higher compared with the general population, largely due to cardiac failures and secondary cancers [7Go]. Consequently, new standard approaches for patients with LPHL in early stages without risk factors are needed to avoid side-effects of standard treatment programs.

Unfortunately, clinical studies for patients with LPHL in clinical stage IA are lacking. We thus reviewed the German Hodgkin Study Group (GHSG) database for all LPHL CS IA cases without risk factors and compared the results of different treatment approaches (EF versus IF radiation versus CM treatment). Here we report that IF radiotherapy is as effective as EF radiotherapy or CM treatment in terms of remission induction.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
A total of 131 patients in CS IA without risk factors such as large mediastinal mass, extranodal involvement, erythrocyte sedimentation rate (ESR) ≥50 and massive spleen involvement from three study generations (HD4, HD7 and HD10) were included in this retrospective analysis.

To be eligible for the German Hodgkin Group trials, patients aged between 16 and 75 years (for HD4 between 16 and 60 years) had to have biopsy-proven LPHL at diagnosis, adequate organ function as defined by a creatinine clearance >60 ml/min, serum transaminases less than three times normal, bilirubin <2 mg/dl, left ventricular ejection fraction >0.45, forced expiratory volume in first-second (FEV1) or diffusion capacity of carbon monoxide (DLCO) >60% of predicted, WBCs ≥3500/µl, hemoglobin level ≥8 g/dl, and platelets ≥100 000/µl. Patients were required to test negative for antibodies against the human immunodeficiency virus and to be free of active infections. All patients signed informed consent based on the Institutional Review Board Guidelines.

As shown in Table 1, patients were randomized between 40 and 30 Gy EF plus 10 Gy IF in the HD4 trial, patients in HD7 between 30 Gy EF plus 10 Gy IF and 2x doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 30 Gy EF with an additional 10 Gy IF. In the fourth study generation (HD10), a more flexible strategy was chosen, including 30 Gy IF radiotherapy or CM treatment (randomized between 2x ABVD + IF and 4x ABVD + IF). All patients with LPHL in clinical stage IA without risk factors were included in this retrospective analysis.


View this table:
[in this window]
[in a new window]
 
Table 1. GHSG clinical trials for early stage LPHL patients

 
Staging procedures
The extent of disease was assessed by chest X-ray, abdominal ultrasound, computed tomography, bone scintigraphy and bone marrow biopsy. Since 1998 a central prospective radiotherapy review has been performed for all LPHL patients with the individual radiotherapy plan being assessed by the radiotherapy reference center in Cologne.

Response definition
According to GHSG criteria, CR was defined as the disappearance of all clinical and radiographic evidence of disease for at least 3 months. Partial response (PR) was defined as greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease lasting at least 3 months. Any response less than PR were considered as treatment failure.

Statistics
FFTF was calculated from the date of diagnosis until progression, relapse and death from any cause or to the last follow-up information. Overall survival (OS) was measured from the date of diagnosis until death from any cause or to the last follow-up. Demographics and disease characteristics were summarized using descriptive statistics. OS and FFTF rates were estimated according to the method of Kaplan and Meier [8Go]. All statistical analysis was performed using SAS 8.2.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
A total of 131 patients were analyzed retrospectively. Of those, 45 patients received EF radiotherapy, 45 had IF radiotherapy and 41 patients were treated with CM (2–4x ABVD plus EF/IF radiotherapy). The median age of patients was 35 years in the EF group, 41 years in those treated with IF and 39 years in the CM group. The lower median age in the EF group resulted in part from the different age limit in the HD4 study (upper limit 60 years). Twenty-two per cent of women and 78% of men received EF radiotherapy, 22% and 78% IF radiotherapy and 27% and 73% of women and men received CM, respectively (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 2. Patient characteristics

 
The median follow-up differed between the treatment modalities and was 78 months for those patients treated with EF, 40 months for CM treatment and 17 months for IF, respectively. Median observation for all patients was 43 months (Table 2).

Acute toxicity
We observed 2.2% cases of WHO grade 3 acute toxicity in patients treated both with EF and with IF radiotherapy, respectively, and 39% in those treated with CM. The most frequently observed WHO 3 toxicities included leucopenia, dysphagia, mucositis, nausea, infection, hair loss, gastroenterological and pulmonal toxicity. A total of 9.8% of patients developed acute toxicity WHO grade 4 after CM. The observed WHO 4 toxicities were leucopenia, gastroenterological complications, urosepsis, hair loss, pain and dyspnea at rest. No patients treated with EF or IF radiotherapy experienced WHO grade 4 toxicity.

Response
A total of 129/131 patients (99%) achieved CR/CRu: 98% patients after EF, 100% after IF and 98% after CM (ABVD + IF/EF). There were a total of 5% relapses (9% after EF radiation, 2% after IF radiation and 2% after combined therapy (Table 3).


View this table:
[in this window]
[in a new window]
 
Table 3. Response to treatment after first-line therapy in stage IA LPHL patients

 
Events
So far, two patients died after EF radiation. One patient died 6 years after therapy due to a gastric carcinoma. The other patient died 5 years after initial therapy due to a salvage-related toxicity. One patient died of a heart attack after CM (2x ABVD plus EF). There were four late relapses after EF radiotherapy, one late relapse after IF and one early relapse after CM treatment (2x ABVD plus IF). One patient developed an in-field relapse. The remaining relapses were on out-fielding sites. Except the patient with a gastric carcinoma, there was no other secondary malignancy observed (Table 3).

Survival
After a median observation of 43 months the FFTF rate was 95% and OS rate 99% for all patients (Figure 1). FFTF rates at 24 months were 100% for EF-RT, 92% for IF-RT and 97% for CM treatment (Figure 2). OS rates at 24 months were 100% for all treatment modalities. OS rates at a median follow-up of 78, 17 and 40 months, respectively, were 94% (95% confidence interval 86% to 100%) for EF-RT, 100% (95% CI 100%) for IF-RT and 96% (95% CI 90% to 100%) for CM (Figure 3).



View larger version (15K):
[in this window]
[in a new window]
 
Figure 1. FFTF and OS for stage IA LPHD patients.

 


View larger version (15K):
[in this window]
[in a new window]
 
Figure 2. FFTF according to different treatment at 24 months.

 


View larger version (15K):
[in this window]
[in a new window]
 
Figure 3. OS according to different treatment at median observation times.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We retrospectively analyzed 131 patients with LPHL in clinical stage IA without risk factors treated with different treatment modalities in clinical studies of the GSHG. The following findings emerged from this retrospective analysis. (1) The response was excellent with 99% of patients achieving CR/CRu and no differences between treatment groups (EF 98%, IF 100%, CM 98%). After a median observation of 43 months, FFTF and OS were 95% and 99%, respectively. (2) Toxicity of CM treatment was acceptable with 48.8% WHO grade 3/4 events (9.8% WHO grade 4). There were 2.2% WHO grade 3 toxicities, both after EF radiotherapy and IF radiotherapy. (3) Based on these data, IF radiotherapy might become the standard treatment for these patients.

Establishing a standard treatment for LPHL patients in early stages has been difficult. This is due to the low incidence of LPHL and very few events observed in early stages. As a result, treatment of early LPHL is rather heterogeneous including EF, IF, CM and more recently monoclonal antibodies.

An American group conducted an analysis on 36 LPHL patients with non-bulky IA or IIA supradiaphragmatic or subdiaphragmatic disease and suggested involved-field or regional radiotherapy alone as an adequate treatment in stage IA LPHL patients. The 5-year relapse-free and overall survival rates for the 20 patients with stage IA LPHL treated with IF or regional radiotherapy were 95% and 100%, respectively [9Go]. However, more patients with longer follow-up will help to clarify the risks of cardiac toxicity, solid tumors and late relapses that result from IF or regional radiotherapy, which appear to be low based on follow-up to date.

Hoskin et al. [10Go] recently published an analysis on 603 HL patients with clinical stage I and II treated with radiotherapy alone. Stage IA and IIA patients were randomized to receive IF or EF consisting of mantle or inverted Y fields alone. The treatment failure at 25 years for IA and IIA patients was 44% after EF and 54% after IF. The incidence of second malignancies was 21% after IF and 20% after EF. There were no significant differences in the causes of death between the randomized arms. The IF radiotherapy for stage IA and IIA HL patients results in a 11% greater risk of relapse compared with EF but had no impact on overall survival and risk of second malignancy at 25 years. However, this analysis included no separate data on LPHL IA patients [10Go].

Pediatric study groups reported non-randomized case studies with a small number of patients [11Go, 12Go] suggesting that a watch-and-wait strategy after initial lymph node surgery may also be an appropriate treatment. Pellegrino et al. [11Go] retrospectively analyzed 27 children (median age 10 years), most with localized LPHL, who received either standard treatment or were not treated beyond initial lymph adenectomy. With a median follow-up of 70 months, overall survival was 100% and overall event-free survival (EFS) was 69%. EFS was not significantly different between the two groups. Patients with residual mass after initial surgery had worse EFS if they did not receive additional treatment. Treatment in these cases thus reduces the number of relapses but has no impact on overall survival [11Go].

An American group of pediatric oncologists treated 15 children and adolescents (median age 11 years) with localized LPHL. Patients received a selected therapy: those with stage I diseases who were disease-free after excision of the involved lymph node were carefully followed without further treatment. Patients with incomplete resection in stages I or II were treated with a brief chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide and prednisone. All treated patients reached CR: one patient in stage II relapsed 6 years after the initial diagnosis [12Go].

These retrospective studies on small numbers of pediatric patients indicate promising results for early stage LPHL. Treatment of rather benign malignancies such as LPHL with low toxicity plays an important role, particularly in pediatric oncology, to avoid adverse events such as growth retardation, infertility, hypothyroidism, cardiopulmonary complications and second malignancies.

Therapy with monoclonal antibodies seems to be an option associated with low treatment-related toxicity and very little, if any, late adverse effects. The GHSG conducted a phase II trial to evaluate the chimeric monoclonal antibody rituximab in relapsed or refractory LPHL patients [13Go]. Fourteen adults with CD20+ Hodgkin's lymphoma at a median of 9 years after initial diagnosis received rituximab at standard doses once weekly for 4 weeks. The overall response was 86% with duration of response of 20+ months.

More recently, the Stanford group published their results on 22 adult patients with either untreated or previously treated LPHL who also received rituximab at standard doses [14Go]. The overall response rate in this study was 100%. However, with a short median follow-up of 13 months, nine patients had relapsed. Rituximab appeared to be less effective in patients with larger lymph nodes, stage III or IV disease and more than two involved nodal regions. Both the GHSG study and this trial showed little toxicity, good feasibility and suggest that rituximab might become a new treatment option for CD20+ HL patients. Another possible option would be to combine rituximab with cytotoxic drugs or radiotherapy in CD20+ HL.

Due to the very limited nature of LPHL stage IA, the patient cohort presented here is the largest. Although retrospective analyses are the only means to elucidate very rare diseases, the patients' follow-ups differ substantially. The median follow-up for patients in the present study varied between 17 and 78 months, respectively. Thus the information from this study on late adverse events and secondary malignancies has to be judged very carefully. In addition, other clinical events such as relapse or death are also difficult to compare. In fact due to the follow-up discrepancies, remission induction is the only valid parameter that can be shared between the three treatment modalities. Consequently, the major message from this analysis is that IF radiotherapy for stage IA LPHL patients is as effective in terms of remission induction as EF or CM treatment. Based on the data presented here, it might still be premature to draw final conclusions concerning IF as standard treatment for IA LPHL patients. However, the EORTC after their H7 trial (1998–93) have also adopted IF radiotherapy as routine treatment for stage IA LPHL patients [15Go].

Thus, IF radiotherapy seems to be emerging as the treatment of choice for stage IA LPHL patients, although conclusive longer follow-up data are required for final conclusions.


    Acknowledgements
 
The data were partly presented at the 39th annual meeting of the American Society of Hematology in San Diego, December 2003.

Supported in parts by the Deutsche Krebshilfe (German Cancer Aid), the BMBF (German Federal Ministry of Education and Research) and the Kompetenznetz Maligne Lymphome (Competence Network Malignant Lymphoma).

Received for publication April 2, 2005. Revision received June 1, 2005. Accepted for publication June 17, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Diehl V, Sextro M, Franklin J et al. Clinical presentation, course and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma project on lymphocyte-predominant Hodgkin's disease. J Clin Oncol 1999; 17: 776–783.[Abstract/Free Full Text]

2. Anagnostopoulos I, Hansmann ML, Fransilla K et al. European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunhistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 2000; 96: 1889–1899.[Abstract/Free Full Text]

3. Trudel MA, Krikorian JG, Neiman RS. Lymphocyte predominant Hodgkin's disease: a clinicopathologic reassessment. Cancer 1987; 59: 99–106.[ISI][Medline]

4. Pappa I, Norton AJ, Gupta RK et al. Nodular type of lymphocyte predominant Hodgkin's disease. Ann Oncol 1995; 6: 559–565.[Abstract]

5. Connors JM. Lymphocyte-predominant Hodgkin's lymphoma. In Schecter GP, Broudy VC, Williams ME (eds): Hematology 2001. American Society of Hematology Education Program Book. Washington, DC: American Society of Hematology 2001; 187–190.

6. Bodis S, Kraus MD, Pinkus G et al. Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease. J Clin Oncol 1997; 15: 3060–3066.[Abstract/Free Full Text]

7. Cosset JM, Henry-Amar M, Meerwaldt JH. Long-term toxicity of early stages of Hodgkin's disease therapy: The EORTC experience. Ann Oncol 1991; 2 (Suppl 2): 77–82.[ISI][Medline]

8. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Ass 1958; 53: 457–481.[ISI]

9. Schlembach PJ, Wilder RB, Jones D et al. Radiotherapy alone for lymphocyte predominant Hodgkin's disease. Cancer J 2002; 8: 377–383.[ISI][Medline]

10. Hoskin PJ, Smith P, Maughan TS et al. Long-term results of a randomised trial of involved field radiotherapy vs extended field radiotherapy in stage I and II Hodgkin lymphoma. Clin Oncol (R Coll Radiol) 2005; 17: 47–53.[Medline]

11. Pellegrino B, Terrier-Lacombe MJ, Oberlin O et al. Lymphocyte–predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection—a study of the French Society of Paediatric Oncology. J Clin Oncol 2003; 15: 2948–2952.[CrossRef]

12. Murphy SB, Morgan ER, Katzenstein HM, Kletzel M. Results of little or no treatment for lymphocyte-predominant Hodgkin disease in children and adolescents. J Pediatr Hematol Oncol 2003; 25: 684–687.[CrossRef][ISI][Medline]

13. Rehwald U, Schulz H, Reiser M et al. Treatment of relapsed CD20+ Hodgkin's lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood 2003; 101: 420–424.[Abstract/Free Full Text]

14. Ekstrand BC, Lucas JB, Horwitz SM et al. Rituximab in lymphocyte-predominant Hodgkin disease: results of phase 2 trial. Blood 2003; 101: 4285–4289.[Abstract/Free Full Text]

15. Raemaekers J, Kluin-Nelemans H, Teodorovic I et al. The achievements of the EORTC Lymphoma Group. European Organization for Research and Treatment of Cancer. Eur J Cancer 2002; 38 (Suppl 4): S107–S113.[Medline]





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
16/10/1683    most recent
mdi323v1
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Nogová, L.
PubMed
PubMed Citation
Articles by Nogová, L.