Serap Yücel^1*, Zeynep Güral¹, Mustafa Bozkurt², Ayca İribaş³, Rejin Kebudi⁴, Fulya Ağaoğlu¹

¹Radiation Oncology Department, Acibadem University

²Medical Oncology Department, Acibadem University

³Radiation Oncology Department, Oncology Institute, Istanbul University

⁴Pediatric Oncology Department, Oncology Institute, Istanbul University

^*Corresponding Author: Serap Yücel, Radiation Oncology Department, Acibadem University.

Abstract
Objective: Historical assessment of HL treatment shows a successful model of combining therapies and achieving excellent outcomes. Centers with reporting epidemiologic knowledge, treatment schedules, and survival rates will make progress regarding their prognostic factors. So, we aimed to report treatment schedules and survival rates of pediatric Hodgkin lymphoma patients treated 20 years ago.

Methods and Materials: A single-center, retrospective study was performed on patients with pediatric Hodgkin lymphoma who underwent chemotherapy, radiotherapy, or both between 1988 and 2002. The demographic and clinical characteristics of the patients were recorded. Survival rates, including disease-free and overall, were calculated.

Results: There were 96 patients with a median age of 10 years. All stage I-II and IIIA patients who received combined or alone ChT and RT were in complete remission at the end of the RT, except one patient who did not receive RT was disease-free at the time of analysis. 5 and 10 years, disease-free survival rates were 95 % and 95 %. Also, for 5 and 10 years, overall survival rates were 99 % and 95 %.

Conclusion: HL has had higher survival rates with particularly effective treatment modalities over the years. So, in this study, pediatric HL patients also had been observed with high response rates and prolonged survival.

Keywords: Hodgkin Lymphoma, pediatric cancers, radiotherapy, chemotherapy

Introduction
With the advances in radiotherapy (RT) and chemotherapy (ChT), dramatic changes in treatment modalities in pediatric Hodgkin lymphoma (HL) have been observed for years. From the first description in 1832 by Thomas Hodgkin till the 1960s, HL was an incurable disease [1,2]. Later, Kaplan and his group defined classic extended field RT (EFRT) and high doses for HL, so RT had taken a significant part in treatment, and HL became one of the best curable diseases [2]. However, cure is often associated with substantial delayed effects of therapy, especially in children [3,4]. Stanford investigators reported the most severe growth retardation in children who had received more than 33 Gy [5]. RT techniques and doses were similar in children and adults. Successful results with ChT in patients who had relapsed prompted the first combined modality trials. The correlation between the size of radiation fields and late complications has been demonstrated in patients with early-stage unfavorable HL in a European trial [6]. This led to the concept of involved field RT (IFRT), and with effective ChT, IFRT was shown to be sufficient [6]. In the 1990’s doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were considered the standard ChT for HL treated with IFRT [7]. Later recurrences occurred in initially involved nodes treated with ChT alone. Patients have started treatments with the affected node RT (INRT) approach [8,9]. INRT is radiating specific lymph nodes initially involved and giving the mission of elimination of microscopic diseases. This approach increased the importance of pretreatment imaging technologies, and trials will report details of INRT soon. Pediatric HL trials recently focused on minimizing toxicity and improving survival rates by combining different treatment modalities and schedules. Data on prognostic factors influencing outcomes divide patients into groups and establish a new approach, risk-adapted therapy [10-13]. According to these factors that differ between institutions, favorable/unfavorable or low, intermediate, and high-risk groups have been defined, and treatment intensity is varied to limit late effects or increase survival rates.

Historical assessment of HL treatment shows a successful model combining therapies and achieving excellent outcomes. Centers with reporting epidemiologic knowledge, treatment schedules, and survival rates will make progress regarding their prognostic factors. So, pediatric HL patients treated at Istanbul University Oncology Institute were analyzed retrospectively since 1988 and aimed to report survival rates.

Results
Patients
96 pediatric patients treated between 1988 and 2002 were evaluated for analysis. Patient characteristics are summarized in (Table 1). Median age was 10 years (range 3-18 years), and a slight male predominance (male/female ratio, 2.7) was observed. According to WHO pathological classification, there were 47(49 %) patients with mixed cellularity, 39(41 %) with nodular sclerosis, 7(7 %) with lymphocyte predominance, and 3(3 %) with lymphocyte depletion. According to Ann Arbor classification, there were 57(59 %) patients with early-stage (stage I-II), and 21(22%) of these included B symptoms. Twenty-five (26 %) patients were presented with stage III, and 14(15 %) patients were given with stage IV disease.

Table 1: Patient characteristics

Table 2: Chemotherapy regimens

Table 3: Radiotherapy fields

Treatment outcome and response
Of the 96 patients with HL, two patients with stage IA did not have ChT and were treated only with RT. 44 of 94 patients with stage I-II and IIIA who received combined or alone ChT or RT were all in CR at the end of treatment, and all of them, except one patient who did not receive RT, were disease-free at the time of analysis. 20 of 31 patients with stage IB and IV had CR. 3 patients, one stage IV and two-stage II, had PD after ChT, and 2 stage II patients had CR with RT. Patients who had PR 29, and with RT, 24 had CR, and 5 had PR. 2 of these PR patients died due to progression. 1 stage IV patients with PD after ChT also died of the disease. Totally 10 of 96 patients did not receive RT, and the details of treatments were summarized in (Tables 2, 3 and 4).

On univariate analysis, age above 11 years, stage IIIB, and IV have significance for DFS. Stage was found to be the only factor for DFS on multivariate analysis. The entire group's 5-year and 10-year DFS and OS were 95 %, 95 %, 96 % and 95 %, respectively. 84 patients were alive without or with disease (Table 5). A total of 7 patients died to date at the analysis, but only 4 of them died because of progression. Of 3 of 7 patients, one was treatment-related death. The two patients died from non-disease-related factors. During the last follow-up, information on 5 patients needed to be included.

Table 4: The response rates of patients

Table 5: The status of patients

Discussion
HL comprises 6 % of childhood cancers with a range of 40 % among lymphomas, and for more than 40 years, treatment strategies geared to the specific problems in children with HL have been tested by different pediatric oncologic groups [20,21]. In these approaches, high priority was given to the reduction of late effects caused by RT and CT next to the goal of achieving high survival rates. Combined modality therapy results have been reported to improve outcomes such as relapse-free survival rates of 90 % to 95 % in patients with early-stage disease and 70 % to 90 % in patients with advanced-stage disease [22-24].

The other important sequence of studies is refining the extent of staging. Staging was reduced from systemic use of laparotomy to routine clinical stage [25]. When patients were to be treated by RT alone, a precise anatomic notation of the sites involved was critical to designing radiation portals. When all patients begin to receive CT, clinical staging has had successful treatment results. The clinical stage limits the potential immunosuppressive effects of splenectomy and other complications associated with staging laparotomy in patients with HL.

Strategies that have been used over the years to reduce side effects have included the following: reduction in the number of cycles of mustard, oncovin, procarbazine, and prednisone (MOPP), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered; reduction in the amount of radiation delivered; use of CT instead of RT; and the development of new combinations of CT drugs, with plans to use such combinations instead of MOPP or in alternation with MOPP [25,26]. MOPP, the first of the successful CT combination, is often associated with the development of amenorrhea in women, infertility in both sexes, and the occurrence of secondary leukemia [25,27-32].

In the 1990s, ABVD was considered the standard care for advanced HL and was replaced by MOPP treatment in combined therapy modality for early-stage HL [33]. RT has been a therapeutic mainstay for several decades, particularly for early-stage HL; nevertheless, high-dose RT is likely to produce skeletal growth retardation, thyroid dysfunction, cardiac diseases, and gonadal dysfunction when the relevant tissues are included in the treatment field. In addition, high- dose RT may contribute to the development of secondary malignancies. Radiation dose and area have been reduced by enhanced reliance on CT. Low-dose rather than standard dose (36-40 Gy) RT in children presumably reduces morbidity and long-term toxicity, such as growth disturbances and organ dysfunction. IFRT was as effective as EFRT in combined therapy approaches [34-36]. Risk-adapted combined-modality therapy is now the standard approach for children with Hodgkin’s disease, although risk categories vary slightly from one protocol to another. This approach aims to limit exposure to the most toxic agents among favorable risk patients while intensifying treatment among high-risk patients to improve disease control. So, patients with HL were divided into two or three groups based on factors shown to influence outcome by current trials [10-13]. According to these, favorable/unfavorable or low/intermediate/high-risk groups were defined. Mainly, agreement was supplied that low risk/bright patients include those with clinical stage I or II disease, no B symptoms or bulky nodal involvement, and disease in fewer than three nodal regions. Intermediate-risk conditions include bulky nodal involvement and sometimes stage IIIA disease, with criteria that vary from trial to trial. High-risk patients are those with background IIIB, IVA, and IVB disease.

Newer approaches advocate for early dose intensity to limit cumulative therapy using response-based paradigms. This means modifying treatment according to the response to the initial few cycles of CT and limiting toxicity by selecting patients who respond early to treatment and sparing them additional therapy. This is called response-adapted therapy. This approach was found safe and efficacious by preliminary results of prospective trials [11,13,37-40]. Some questions, like treatment strategy for slow responders, remain for response-adapted therapy. Ongoing studies may give a chance to define the outlines of this approach. Targeting molecular mechanisms specific to the Reed-Sternberg cell may allow for less toxic and more efficacious treatments.

For three decades, combined CT-RT has been preferred in most of the studies on childhood HL because combined modality is the precondition for reducing the radiation dose, reducing the radiation fields, shortening chemotherapy, omitting splenectomy and laparotomy, and thus, for optimizing the benefit/risk ratio between cure rates and late effects. This small sample study showed long-term high survival rates with all these effective ChT schemas and RT approaches.

Conflict of Interest: The author declares no conflict of interest.

References

1. Hodgkin (1832) On some morbid appearances of the absorbent glands and spleen. Med Chir Trans. 17: 68-114.
2. Kaplan HS (1971) Contiguity and progression in Hodgkin's disease. Cancer Res. 31(11): 1811-3.
3. Donaldson SS, Kaplan HS (1982) Complications of treatment of Hodgkin's disease in children. Cancer Treat Rep. 66(4): 977-89.
4. Mauch PM, Weinstein H, Botnick L, Belli J, Cassady JR (1983) An evaluation of long-term survival and treatment complications in children with Hodgkin's disease. Cancer. 51(5): 925-32.
5. Willman KY, Cox RS, Donaldson SS (1994) Radiation induced height impairment in pediatric Hodgkin's disease. Int J Radiat Oncol Biol Phys. 28(1): 85-92.
6. Ferme C, Eghbali H, Hagenbeek A, et al. MOPP/ABV hybrid and irradiation in unfavorable supradiaphragmatic clinical stages I-II Hodgkin’s disease. Comparison of three treatment modalities. Preliminary results of the EORTC-GELA H8U randomized trial in 995 patients. Blood. 2000; 96: A576.
7. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, et al. (1992) Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD or MOPP alternating with ABVD. N Eng J Med. 327(21): 1478-84.
8. Shahidi M, Kamangari N, Ashley S, Cunningham D, Horwich A (2006) Site of relapse after chemotherapy alone in stage I and II Hodgkin’s disease. Radiother Oncol. 78(1):1–5.
9. Girinsky T, van der Maazen R, Specht L, Aleman B, Poortmans P, et al. (2006) Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: Concepts and guidelines. Radiother Oncol. 79(3): 270-7.
10. Schellong G, Pötter R, Brämswig J, Wagner W, Prott FJ, et al. (1999) High cure rates and reduced lon-term toxicity in pediatric Hodgkin's disease: The German-Austrian multicenter trial DAL- HD-90. The German-Austrian Pediatric Hodgkin's Disease Study Group. J Clin Oncol. 17(12): 3736-44.
11. Rühl U, Albrecht M, Dieckmann K, Lüders H, Marciniak H, et al. (2001) Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: An interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys. 51(5): 1209-18.
12. Nachman JB, Sposto R, Herzog P, Gilchrist GS, Wolden SL, et al. (2002) Randomized comparison of low-dose involved-field raditherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol. 20(18): 3765-71.
13. Donaldson SS, Hudson MM, Lamborn KR, Link MP, Kun L, et al. (2002) VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial. J Clin Oncol. 20(14): 3081-7.
14. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the committee on Hodgkin’s disease staging classification. Cancer Res. 31(11): 1860-1.
15. Hudson MM, Onciu M, Donaldson SS. Hodgkin lymphoma. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 5th ed. Philedelphia: Lippincott Williams&Wilkins; 2005. p. 694-721.
16. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, et al. (1999) World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November. J Clin Oncol. 17(12): 3835-3849.
17. Kaplan EL, Meter P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc. 53(282): 457-481.
18. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, et al. (1977) Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 35(1): 1-39.
19. Cox DR (1972) Regression models and life tables. J R Stat Soc. 34(2): 187-220.
20. Pötter R (1999) Pediatric Hodgkin’s disease. Eur J Cancer. 35(10): 1466-76.
21. Buyukpamukcu M, Atahan L, Caglar M, Kutluk T, Akyuz C, et al. (1999) Hodgkin’s disease in Turkish children: Clinical characteristics and treatment results of 210 patients. Pediatr Hematol Oncol. 16(2): 119- 29.
22. Donaldson SS, Link MP (1987) Combined modality treatment with low dose radiation and MOPP chemotherapy for children with Hodgkin’s disease. J Clin Oncol. 5(5): 742-749.
23. Jenkin D, Doyle J, Berry M, Blanchette V, Chan H, et al. (1990) Hodgkin’s disease in children: Treatment with MOPP and low dose, extended field irradiation without laparotomy. Late results and toxicity. Med Pediatr Oncol. 18(4): 265-272.
24. Loeffler M, Brosteanu O, Hasenclever D, Sextro M, Assouline D, et al. (1998) Meta analysis of chemotherapy vs. combination treatment trials in Hodgkin’s disease: International Database on Hodgkin’s disease Overview Study Group. J Clin Oncol. 16(3): 818-829.
25. Olson MR, Donaldson SS (2008) Treatment of pediatric Hodgkin Lymphoma. Curr Treat Opti in Oncol. 9(1): 81-94.
26. Hodgson DC, Hudson MM, Constine LS (2007) Pediatric Hodgkin lymphoma: Maximizing efficacy and minimizing toxicity. Semin Radiat Oncol. 17(3): 230-242.
27. Dores GM, Metayer C, Curtis RE, Lynch CF, Clarke EA, et al. (2002) Second malignant neoplasms among long-term survivors of Hodgkin’s disease: A population-based evaluation over 25 years. J Clin Oncol. 20(16): 3484–3494. 
28. Hancock SL, Tucker MA, Hoppe RT (1993) Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA. 270(16): 1949–1955.
29. Straus DJ (2006) Treatment of early-stage nonbulky Hodgkin lymphoma. Curr Opin Oncol. 18(5): 432–436.
30. Swerdlow AJ, Barber JA, Hudson GV, Cunningham D, Gupta RK, et al. (2000) Risk of second malignancy after Hodgkin’s disease in a collaborative British cohort: The relation to age at treatment. J Clin Oncol. 18(3): 498–509.
31. van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD, et al. (2000) Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol. 18(3): 487–497.
32. Wolden SL, Lamborn KR, Cleary SF, Tate DJ, Donaldson SS (1998) Second cancers following paediatric Hodgkin’s disease. J Clin Oncol 16(): 536-544.
33. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, et al. (1992) Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 327(21): 1478–1484.
34. Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, et al. (2004) ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: Long-term results. J Clin Oncol. 22(14): 2835–2841.
35. Engert A, Schiller P, Josting A, Herrmann R, Koch P, et al. (2003) Involved-field radiotherapy is equally effective and less toxic compared with extendedfield radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: Results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 21(19): 3601–3608.
36. Noordijk EM, Carde P, Dupouy N, Hagenbeek A, Krol AD, et al. (2006) Combined-modality therapy for clinical stage I or II Hodgkin’s lymphoma: Longterm results of the European Organization for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol. 24(19): 3128–3135.
37. Donaldson SS, Link MP, Weinstein HJ, Rai SN, Brain S, et al. (2007) Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin’s disease. J Clin Oncol. 25(3): 332–337.
38. Dörffel W, Lüders H, Rühl U, Albrecht M, Marciniak H, et al. (2003) Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin’s disease in children and adolescents: analysis and outlook. Klin Padiatr. 215(3): 139–145.
39. Ruhl U, Albrecht MR, Lueders H, et al. Abstract at ASTRO, 46th annual meeting: The German multinational GPOH-HD 95 trial: Treatment results and analysis of failures in pediatric Hodgkins disease using combination chemotherapy with and without radiation. Int J Radiat Oncol Biol Phys 2004, 60:S131.
40. Landman-Parker J, Pacquement H, Leblanc T, Habrand JL, Terrier-Lacombe MJ, et al. (2000) Localized childhood Hodgkin’s disease: responseadapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low- dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol. 18(7): 1500–1507.