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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 37  |  Issue : 4  |  Page : 234-239

Treatment of early-stage Hodgkin’s lymphoma outcome ( Kuwait experience)


1 Department of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Medical Oncology, Lymphoma & Stem cell Transplantation Unit, Kuwait Cancer Control Center, Kuwait University, Kuwait
3 Department of Caner Statistics & Registry, Kuwait Cancer Control Center, Kuwait

Date of Submission30-May-2012
Date of Acceptance25-Jun-2012
Date of Web Publication21-Jun-2014

Correspondence Address:
Rehab S. ElHagracy
MD, Kuwait-Al-Jahra, Marzouk Elmetaeb Street, 3rd Floor, Flat 10 P.O. Box 5969, Kuwait

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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000419279.94780.52

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  Abstract 

Introduction

Treatment of early-stage classical Hodgkin’s lymphoma (HL) is changing targeting remission with reduced intensity.

Aim of the work

This study presents a review of treatment of earlystage I and II HL patients treated with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) with or without radiotherapy.

Materials and methods

Data were analyzed retrospectively from files of patients treated at the Kuwait cancer center from 2002 to 2010. The study included 105 patients divided as follows: group A, which included 34 patients treated by four cycles of ABVD, and group B, which included 71 patients treated by six cycles of ABVD.

Results

Unfavorable risk cases were 47 versus 77.4% in group A versus B. Radiotherapy was added to ABVD in 57.1% of patients; 35.3% of these patients were from group B. No significant difference in remission or relapse was noted between groups A and B (P=0.04). The 5-year overall survival (OS) for patients was 86%, with no difference between the two groups. Patients with B symptoms had significantly lower 5-year OS (73 vs. 92%; P=0.02). Although the presence of bulky disease and erythrocyte sedimentation rate 50 mm/h or more are associated with lower OS, the difference was not significant (P>0.05). Combined therapy yielded better 5-year OS (90.3%) than chemotherapy alone (80.4%), without significance (P=0.29). No cardiopulmonary toxicities or second malignancies were noted but hypothyroidism was evident after neck radiation. This indicates the good outcome of early-stage HL in general. Some prognostic factors could address treatment policy in terms of the presence of B symptoms, bulky disease, and high erythrocyte sedimentation rate.

Conclusion

Modification of therapy on the basis of novel prognostic factors may be of prospective interest.

Keywords: ABVD, early stage Hodgkin′s lymphoma, radiotherapy


How to cite this article:
ElHagracy RS, AlShemmari SH, Elbassmy A. Treatment of early-stage Hodgkin’s lymphoma outcome ( Kuwait experience). Egypt J Haematol 2012;37:234-9

How to cite this URL:
ElHagracy RS, AlShemmari SH, Elbassmy A. Treatment of early-stage Hodgkin’s lymphoma outcome ( Kuwait experience). Egypt J Haematol [serial online] 2012 [cited 2019 Dec 9];37:234-9. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/234/134970


  Introduction Top


Decades ago, treatment with local radiotherapy was the main stay of therapy for early stages of Hodgkin’s lymphoma (HL). Subsequent studies have reported better outcome with combination modalities of chemoradiotherapy1,2.

The long-term therapy-related toxicities including cardiac complications 3 and secondary malignancies 4 have been reported by researchers. The second malignant conditions occurred at an average rate of 1% per year for at least 30 years after treatment 5, and were 30–40% higher among women younger than 30 years of age who received thoracic radiotherapy and developed breast cancer in 25 years 6. Case–control studies have reported that reducing the radiation dose and field size would decrease the rate at which second malignant conditions occur 7,8.

The combination of radiotherapy and treatment with an anthracycline exerts an additive effect on the frequency of cardiovascular events 3. The increased risk of death from myocardial infarction persists for more than 25 years after thoracic radiotherapy 9.

Treatment of early-stage HL was tailored according to the prognostic factors. The prognosis of those patients was affected by the presence of systemic symptoms (i.e. fevers, night sweats, or significant weight loss), a high erythrocyte sedimentation rate (ESR), increase in the number of involved nodal sites, older age, and a large mediastinal mass 10,11.

A chemotherapy regimen consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with involved field radiotherapy showed greater efficacy in patients with early-stage HL and a favorable prognosis 2,10.

Several studies are ongoing to assess the possibility of reduction of chemotherapy cycles and radiotherapy dose in early-stage I or II HL targeted at achieving better disease control and minimizing the toxic effects of treatment. The study was carried by the German Hodgkin Study Group in 1998. A prospective, randomized, multicenter study on the treatment of favorable early-stage I or II HL found that two cycles ABVD are as effective as four cycles and a radiotherapy dose of 20 Gy involved field is as effective as 30 Gy dose 10.

The current study evaluated the treatment outcomes of early-stage HL.


  Patients and methods Top


The study is a retrospective population-based study that included 105 patients with early-stage HL I and II according to the Ann Arbor staging system 12 diagnosed between 2002 and 2010 who were analyzed in terms of the presenting picture, laboratory investigations, treatment modalities, and therapeutic outcome.

Bulky disease was defined as mass greater than one-third of the maximal intrathoracic diameter by plain chest radiography or greater than 10 cm by computed tomography (CT). Risk factors considered are nodal groups at least 4, bulky disease, B symptoms, high ESR (≥50 in the absence of B symptoms or 30 in the presence of B symptoms), and any extranodal site 13. Stage and remission evaluation was carried out by assessment of clinical history and examination, CT whole body, and by radionuclide scans [gallium-67 (67Ga)] or more recently, 18F-FDG-PET.

Overall survival (OS) time was calculated from the time of diagnosis to death secondary to the disease. All cases were universally primarily treated by an ABVD regimen at D1 and D14. Cases treated with alternative regimens or those who did not complete their treatment were excluded from the study (four cases). Follow-up time ranged from minimum 12 months up to 108 months.

According to the number of chemotherapy cycles, patients were further subdivided into group A, which included 34 patients treated with four or less ABVD cycles, and group B, which included 71 patients who were treated with six or more ABVD cycles. Among the patients of group A, three patients were treated by three cycles and two patients were treated by two cycles, whereas seven patients were treated by eight cycles and two patients were treated by five cycles in group B.

Data were analyzed using the statistical package for social science (SPSS Inc., Chicago, Illinois, USA) software computer program version 17. Data were described using mean and SD and frequencies according to the type of variables (quantitative or qualitative, respectively). The χ2-test was used to test the association between qualitative variables. Survival analysis was carried out by Kaplan–Meier analysis. A regression model was developed using a Cox regression model. Significance levels of the P value were as follows: P>0.05 insignificant, P⩽0.05 significant, and P⩽0.01 highly significant.


  Results Top


Patients’ characteristics and differences between the two groups are shown in [Table 1]

Out of 105 studied cases, there were 61 men and 44 women, with a male : female ratio of 1.3 : 1. Most of the patients were Kuwaitis 54 (51.4%); there were 15 Egyptians (14.3%) and the others were from heterogeneous countries (Saudi Arabia 5.7%, India 5.7%, Bangladesh 4.8%, Pakistan 3.8%, Syria 2.9%, Srilanka 2%, and 1% each from Canada, America, and Ceralion).
Table 1: Characteristic differences between patient groups

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Nodular sclerosis was the most frequent histopathological type, 70 cases (66.6%), followed by mixed cellularity [28 (26.6%)], lymphocyte rich [6 (5.7%)], and lymphocyte depleted [1 (0.9%)], respectively. The patients in group B were significantly younger (28.44±11.474) compared with those in group A (37.41±16.159) (P=0.005).

Sixteen patients out of 34 (47%) and 55 out of 71 (77.4%) of patients of groups A and B had an unfavorable prognosis (presence of any risk factors included bulky disease, more than three groups, high ESR more than 50 mm/h, B symptoms). Bulky disease was present in five patients (14.7%) of group A compared with 21 patients (29.6%) of group B. The most common presenting symptom was lymph-node swelling (63.8%) followed by B symptoms [25% (38)]. The presence of B symptoms was found in 17.6% (6) and 45.1% (32) of patients of groups A and B, respectively. Presentation by both lymph node swelling and B symptoms was evident in 20% of cases.

Stage II was most predominant among the patients in group A [61.8% (21)] and group B [90.1% (64)]. Significantly higher percentage of patients had stage II and B symptoms in group B compared with group A, whereas the presence of bulky disease or extra-nodal involvement was not significant between the two groups.

Significantly lower albumin, higher platelets count, ESR, and total leucocytic count were found in the patients in group B compared with those in group A. Although the lymphocyte count and lactate dehydrogenase level tended to be slightly higher among the patients in group B, the differences were not significant.

Treatment modalities and outcome of patients are shown in [Table 2]

Radiotherapy was delivered to a total of 60 (57.1%) patients, 28 out of 34 patients (46.6%) of group A and 32 out of 71 patients (53.3%) in group B to the bulky or initial disease sites; commonly radiated sites were cervical lymph node regions [32 (53.3%)] followed by the mediastinum in 25 (41.6%) of patients. Thirty-five patients received 36 Gy and the rest received 20 Gy. The high dose was used earlier before the recent reduction in the required radiotherapy dose.

Complete remission was achieved by 84 (80%) patients; in 15 (14.3%) patients, relapse was documented on follow-up and six patients (5.7%) showed residual disease and progression after therapy. Although group A is more favorable regarding risk factors; group A had no favorable outcome in comparison to group B.
Table 2: Treatment modalities and outcome between groups

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The mean relapse time was 4.3 months in the relapsed group A cases compared with 4.5 months in group B, without a significant difference (P=0.1). Thirteen patients were treated by high-dose chemotherapy, followed by ASCT: three from group A and 10 from group B.

Survival study

Six patients died because of relapse, four from group B and two from group A, whereas four patients died because of progressive disease, three from group B and one from group A.

Kaplan–Meier survival study yielded a 5-year survival rate of 86%, [Figure 1], without a statistically significant difference between groups A (85%) and group B (87%) (P=0.51). Although patients treated with combined modalities had better 5-year survival (90.3%) compared with patients treated with chemotherapy alone (80.4%), the difference was not significant (P=0.29).
Figure 1: 5-year overall survival for patients.

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The Cox regression model showed that only the presence of B symptoms had a significantly lower 5-year survival rate of 73% compared with 92% for those without B symptoms (P=0.02) [Figure 2]. However, the lower 5-year survival associated with the presence of bulky disease, 77% and ESR at least 50 mm/h (82%), was not significant compared with those without bulky disease (89%) or ESR less than 50 mm/h (89%; P=0.1, 0.5, respectively) [Figure 3] and [Figure 4]. There was no difference in survival between patients with >3 lymph node groups (92.1%) and those with ⩽3 lymph node groups (81.5%) (P=0.153).
Figure 2: 5-year overall survival and B symptoms.

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Figure 3: 5-year overall survival (OS) and bulky disease.

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Figure 4: 5-year overall survival (OS) and erythrocyte sedimentation rate level.

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No cardiopulmonary toxicities or secondary malignancies were detected in patients at the 5-year follow-up; however, 17 out of 32 patients who had radiotherapy to the neck were treated by thyroid replacement therapy for hypothyroidism.


  Discussion Top


Studies on the treatment of early-stage HL are aiming to resolve the debate on the essential number of chemotherapy cycles and whether radiotherapy should be combined with chemotherapy or whether an unfavorable risk group should considered as separate entity from the favorable group.

Identification of valuable prognostic markers will facilitate the choice of best treatment option and reduction of therapy intensity in the favorable arm or intensification for those with high-risk markers. This could reduce treatment-related toxicities. We attempted to assess treatment outcome in patients with early-stage classic HL who were treated by four versus six ABVD courses with or without radiotherapy. Six cycles of ABVD alone have been more commonly used for HL patients than four cycles.

Nodular sclerosis was the predominant form, followed by mixed cellularity similar to previous reports 14. Patients treated with six cycles had more risk factors compared with those treated with four cycles. The amount of chemotherapy required to achieve favorable results with a radiation-sparing approach is still questionable. Most of the studies used six cycles of ABVD, unless consolidated with radiotherapy, in which case fewer cycles are appropriate 2.

The Memorial Sloan-Kettering Cancer Center randomly assigned 152 patients with stages IA, IB, IIA, IIB, and IIIA disease to six cycles of ABVD with or without 36 Gy of consolidative involved or modified extended-field radiotherapy and found no difference in progression or OS at 5 years 11. However, a longer follow-up duration was required to detect radiotherapy-related toxicities. In another randomized trial, no difference in OS was found when radiation was excluded from the treatment of patients with nonbulky, limited-stage disease, although patients treated with combined modality therapy showed a 6% improvement in failure-free survival at 5 years compared with patients treated with radiotherapy alone 15. In the current study, radiotherapy was combined to treatment in 46.6% of patients treated by four cycles and 53.3% of patients treated by six cycles ABVD. The group of patients who received six courses had a more unfavorable risk as well more bulky disease. However, there was no significant 5-year survival benefit between those treated by chemotherapy alone compared with those who received combined model. However, multiple randomized-controlled trials have shown that combined therapy improves tumor control and OS in patients with early-stage Hodgkin’s lymphoma 16. The difference in previously used radiotherapy high doses compared to the recent reduction in doses is required.

A recent study reported that 92% of patients achieved remission with six cycles of ABVD for early-stage nonbulky HL without radiotherapy 14. The inclusion of bulky disease cases in our study could explain the lower remission recorded in our study. Moreover, relapse was more common among our group treated with six cycles of ABVD.

Treatment of early-stage HL with ABVD alone induced remission in 35% of patients by CT scan after two cycles; 82% of these patients had received a total of four cycles and the remaining 12% had received six cycles, with a 95% 5-year freedom from disease progression, compared with 81% for the patients not in radiographic remission after two cycles. Thus, it may be concluded that in the subset of patients in remission by CT scan following two cycles of ABVD, a total of four cycles may be sufficient. There was no difference in the 5-year EFS (87 vs. 85%) for favorable versus unfavorable patients treated only with chemotherapy 11.

A recent study has reported that the 5-year freedom from treatment failure for favorable early-stage patients treated with two or four ABVD cycles plus 20 or 30 Gy IFRT was equivalent in all four arms, with no significant differences in OS or progression-free survival except four cycles ABVD had significantly higher short-term toxicity compared with two cycles and 30 Gy compared with four cycles and a 20 Gy dose 10.

Interim PET was as accurate after two cycles as later during treatment and superior to CT scan at all times and a strong predictor factor for progression in regression analysis 17.

The 2-year failure-free survival rate for the patients with interim positive PET scans was 69%, as compared with 95% for those with negative PET. After the completion of the therapy course, the 2-year failure-free survival rate for patients with positive scans during chemotherapy and negative scans after chemotherapy was 92%, as compared with 96% for patients who had negative scans both during and after chemotherapy 18.

However, in another study, interim PET/67Ga was negative in most of the cases studied, including those who had later relapse 14. Our studied cases were evaluated by an interim PET/67Ga scan when possible but the treatment plan was not altered on obtaining negative results as the old guidelines required higher ABVD cycles and PET/67Ga was mostly carried out after four cycles if six were planned, but recently, PET has been carried out regularly after the second cycle of ABVD to assess the response. The role of early interim PET scans in tailoring of an individual patient’s therapy also remains unclear, and more clinical trials are required to use it as an indicator for treatment modification.

OS among our cases was 86%, with no significant increase in favor of patients treated by six cycles of ABVD (87 vs. 85%). There was no significant difference in OS reported between favorable and unfavorable (97 vs. 95%) early-stage HL considering age older than 40 years, ESR 50 or more, more than four nodal sites, and mixed cellularity and lymphocyte-depleted types as risk factors 11; however, our data showed that only the presence of B symptoms could affect patient's survival and not the nodal sites, high ESR ≥50 or bulky disease.

We found no cardiopulmonary toxicities, no solid tumors, no leukemia, or lymphoma at the 5-year follow-up; however, hypothyroidism is the main side effect in terms of neck-irradiated regions. Longer follow-up is required to evaluate latent complications as late and fatal complications of radiation therapy emerge close to the second decade after treatment including the development of secondary solid tumors, leukemia, and non-Hodgkin’s lymphoma 5–20 years after the initial treatment 19,20.

The goal of treating early-stage Hodgkin’s lymphoma is to reduce the intensity of curative therapy and to maintain disease control together with reducing short-term and long-term toxicity. These findings from recent studies 10–14 have shown good outcomes for these categories with reduced therapy intensity and less toxicity. The role of PET in guiding the treatment plan requires more studies. So far, early-stage HL has yielded a better outcome with less intensive regimens and development of new manometers to guide treatment selection is required to minimize toxicity in the long term and to achieve better cure including prognostic factors or PET findings.


  Acknowledgements Top


All authors have contributed equally toward the preparation of the manuscript, and all are responsible for all of the work. All authors agreed to the content of the manuscript and its submission to the International Hematology Journal.[20]

 
  References Top

1.Koontz BF, Kirkpatrick JP, Clough RW, Prosnitz RG, Gockerman JP, Moore JO, et al. Combined-modality therapy versus radiotherapy alone for treatment of early stage Hodgkin's disease: cure balanced against complications. J Clin Oncol. 2006;24:605–611  Back to cited text no. 1
    
2.Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med. 2007;357:1916–1927  Back to cited text no. 2
    
3.Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van ‘t Veer MB, Baaijens MH, de Boer JP, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109:1878–1886  Back to cited text no. 3
    
4.Hodgson DC, Gilbert ES, Dores GM, Schonfeld SJ, Lynch CF, Storm H, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol. 2007;25:1489–1497  Back to cited text no. 4
    
5.Franklin J, Pluetschow A, Paus M, Specht L, Anselmo AP, Aviles A, et al. Second malignancy risk associated with treatment of Hodgkin’s lymphoma: meta-analysis of the randomised trials. Ann Oncol. 2006;17:1749–1760  Back to cited text no. 5
    
6.Travis LB, Hill D, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst. 2005;97:1428–1437  Back to cited text no. 6
    
7.Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, Glimelius B, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst. 2002;94:182–192  Back to cited text no. 7
    
8.Van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van't Veer MB, Noordijk EM, et al. Role of radiation dose, chemotherapy and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst. 2003;95:971–980  Back to cited text no. 8
    
9.Swerdlow AJ, Higgins CD, Smith P, Cunningham D, Hancock BW, Horwich A, et al. Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst. 2007;99:206–214  Back to cited text no. 9
    
10.Engert A, Plütschow A, Eich HT, Lohri A, Dorken B, Borchmann P, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363:640–652  Back to cited text no. 10
    
11.Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Bezjak A, Wells WA, et al. Randomized comparison of ABVD chemotherapy with strategy that includes radiation therapy in patients with limited stage Hodgkin’s lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005;23:4634–4642  Back to cited text no. 11
    
12.Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin’s disease staging classification. Cancer Res. 1971;31:1860–1861  Back to cited text no. 12
    
13.Engert A, Eichenauer DA, Dreyling M. Hodgkin’s lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v168–v171  Back to cited text no. 13
    
14.Canellos GP, Abramson JS, Fisher DC, LaCasce AS. Treatment of favorable, limited-stage Hodgkin’s lymphoma with chemotherapy without consolidation by radiation therapy. J Clin Oncol. 2010;28:1611–1615  Back to cited text no. 14
    
15.Ng AK, Bernardo MP, Weller E, Backstrand KH, Silver B, Marcus KC, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol. 2002;20:2101–2108  Back to cited text no. 15
    
16.Herbst C, Rehan FA, Brillant C, Bohlius J, Skoetz N, Schulz H, et al. Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin’s lymphoma: a systematic review. Haematologica. 2010;95:494–500  Back to cited text no. 16
    
17.Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107:52–59  Back to cited text no. 17
    
18.Sher DJ, Mauch PM, Van Den Abbeele A, LaCasce AS, Czerminski J, Ng AK. Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin’s lymphoma: the importance of involved-field radiotherapy. Ann Oncol. 2009;20:1848–1853  Back to cited text no. 18
    
19.Franklin J, Pluetschow A, Paus M, Specht L, Anselmo AP, Aviles A, et al. Second malignancy risk associated with treatment of Hodgkin’s lymphoma: meta-analysis of the randomised trials. Ann Oncol. 2006;17:1749–1760  Back to cited text no. 19
    
20.Van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD, Vetter UA, et al. Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol. 2000;18:487–497  Back to cited text no. 20
    


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