Annals of Oncology Advance Access originally published online on September 12, 2005
Annals of Oncology 2005 16(12):1936-1940; doi:10.1093/annonc/mdi401
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 European Society for Medical Oncology
Successful ambulatory treatment of Hodgkin's disease in Iranian children based on German-Austrian DAL-HD 85-90: single institutional results
Department of Pediatric Hematology and Oncology, Shohada Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran–Tajrish, Iran
* Correspondence to: Dr M. Alebouyeh, 53 Majlesi Street, Tehran 15959, Iran. Tel/Fax: +9821-224 00 844; E-mail: alebouyehm{at}yahoo.com
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResults and outcomeDiscussionReferences |
|---|
Background: Hodgkin's disease (HD) accounts for 7.5% of childhood malignancies in Iran. In order to minimize chemotherapy toxicity and avoid eventual hospitalization and psychological and financial burdens we have applied since 1988, for the first time in Iran, a treatment regimen based on subsequently revised DAL-HD 85-90 and later GPOH-HD 95 protocols.
Patients and methods: During the period 1988–2004, 40 children with HD received DAL/GPOH-HD-adapted treatment; 25 males (62.5%) and 15 females (37.5%) (male/female ratio 1.7; age 4–14 years, mean 8.8). Clinical evaluation and staging was performed in all patients. Constitutional symptoms: 24 patients were asymptomatic (A; 60%) and 16 had constitutional complaints (B; 40%). Staging was as follows: stage I; seven (17.5%); II, 11 (27.5%); III, 11 (27.5%); and IV, 11 (27.5%). Histopathology: 22 patients had mixed cellularity (MC; 55%), 13 nodular sclerosis (32.5%), four lymphocyte predominance (LP; 10%) and one patient lymphocyte depletion (2.5%). Stage IA and IIA patients (n = 15) received either OPA x2 (vincristine, prednisolone, doxorubicin) or OPPA x2 or OPEA x2 (vincristine, prednisolone, procarbazin and doxorubicin), the latter receiving etoposide instead of procarbazin, and applied to males. Stages IIB, IIIA/B and IV received OPPA x2, followed by CO(P)P x4 (cyclophosphamide, vicristine, prednisolone in alternate courses and procarbazin). Twenty nine patients (72.5%) received radiotherapy (20–25 Gy); four to the involved field (stage I), 25 to the upper mantel (stage II and also III with either residual or mediastinal mass) and three additionally to spleen and para-aortic lymph nodes. Eleven patients received only chemotherapy.
Results: All patients achieved complete remission (CR). Relapse occurred in eight patients (20%); seven stage IV (MC) and one stage IA (LP) with progression to IIIB. Salvage chemotherapy consisted of MOPP/ABVD hybrid; six patients achieved a second sustained remission and three patients died: two due to relapse and progressive disease and the third one in CR, owing to thrombocytopenic hemorrhage and foudroyant pneumonia. The achieved overall and event-free survival was 88.1% and 75.4%, respectively. Aside from minor acute toxicities, three patients demonstrated azoospermia at the age of 18 years and one of these patients suffered non-Hodgkin lymphoma as a second malignancy. HD occurred as a second malignancy in two patients with acute lymphoblastic leukemia. Both received appropriate treatment and are over 10 years in CR.
Conclusions: The DAL/GPOH-HD-based treatment approach proved to achieve long-term sustained cure even in children with advanced HD disease. The essentially outpatient diagnosis and treatment modus did not compromise the disease outcome, and was well tolerated and accepted by the patients and their parents. The employed drugs are easily available and affordable. This treatment approach is suitable for ambulatory use in developing countries. However, male infertility remains the major obstacle to procarbazin and cyclophosphamide use.
Key words: ambulatory treatment, childhood Hodgkin's, Iran, late effects, survival
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResults and outcomeDiscussionReferences |
|---|
Hodgkin's disease (HD) is a common malignancy in children and is curable in over 90% of cases [1
]. Since the mid-1970s there have been ever improving strategies to refine diagnostic and therapeutic approaches for children and adolescents afflicted with HD. This has resulted in universally adopted strategies, which encompass clinical instead of surgical staging, combined chemotherapy for all stages and low-dose involved field radiotherapy [1–4]. In long-time survivors of childhood HD, late effects of the combined modality treatment are still issues of major concern [1, 3–5].
HD accounts for 
7.5% of childhood malignancies in Iran [6]. In accordance with the improving diagnostic and therapeutic strategies, since the mid-1980s we have abandoned surgical staging in favor of clinical staging and adopted concurrently a risk-adapted chemotherapy regimen consisting of MOPP/ABVD (mustine, vincristine, procarbazine, prednisolone/doxorubicin, bleomycin, vinblastine, dacarbazine) and low-dose limited field radiotherapy [7]. This management was performed mostly on an inpatient basis. To spare patient/parental inconveniences and to reduce their financial burdens we have conducted, as a further step, the necessary diagnostic and therapeutic management of children with HD, whenever clinically justified and feasible, on an outpatient basis. To comply with these goals and owing to easy feasibility, low toxicity and excellent results, we have employed at our department since 1988, for the fist time in Iran, combined chemo-radiotherapy regimens, based on subsequently revised and improved German-Austrian DAL-HD 85-90 and later GPOH-HD guidelines [3, 8].
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResults and outcomeDiscussionReferences |
|---|
This study population consists of 40 children with previously untreated HD; 25 were males (62.5%) and 15 females (37.5%) (male/female ratio 1.7; age range 4–14 years, mean 8.8). All patients underwent thorough physical examination, blood testing and imaging procedures (X-ray, sonography, computed tomography scan and magnetic resonance imaging) as clinically indicated.
Constitutional symptoms
Twenty-four patients had no constitutional symptoms (A; 60%) and 16 had constitutional complaints (B; 40%).
Clinical staging
According to the Ann Arbor classification, seven patients had stage I (17.5%), 11 stage II (27.5%), 11 stage III (27.5%) and 11 stage IV (27.5%).
Histology subtypes
Diagnosis was made on biopsy materials obtained from accessible lymph nodes, using Rye's classification. Twenty-two patients had mixed cellularity (MC; 55%), 13 nodular sclerosis (NS; 32.5%), four lymphocyte predominance (LP; 10%) and one patient lymphocyte depletion (2.5%) (Table 1). The cohort includes the two patients who developed HD, one during and the other after treatment for acute lymphoblastic leukemia (ALL).
|
Treatment
The treatment comprised of ambulatory chemotherapy followed by radiotherapy. Stage IA and IIA patients (n = 15) received either two courses of OPA (n = 6) (vincristine, prednisolone and doxorubicin), or two courses of OPPA (n = 4) (vincristine, prednisolone, procarbazin and doxorubicin) or OPEA (n = 2) (vincristine, prednisolone, etoposide and doxorubicin), the latter being applied to males. Three stage IIA patients with sluggish response received additionally four courses of CO(P)P (cyclophosphamide, vicristine, prednisolone in alternate courses and procarbazin). Stages IIB, IIIA/B and IV received two courses OPPA, followed by four courses of CO(P)P. Twenty nine patients (72.5%) received reduced dose radiotherapy (20–25 Gy); four to the involved field (stage I), 25 to the upper mantel (stage II and also III/IV with either residual or mediastinal mass) and three additionally to spleen and para-aortic lymph nodes) (Table 2). Eleven patients achieving complete response (CR) post-chemotherapy did not receive radiotherapy (stage IA, one; IIB, one; IIIA, three; IIIB, two; and IVB, four).
|
|
Results and outcome |
|---|
|
TopAbstractIntroductionPatients and methodsResults and outcomeDiscussionReferences |
|---|
CR was achieved in all patients. Chemo- and radiotherapy was well tolerated. Acute drug toxicities were minor, with no indication for hospitalization. Eight patients suffered relapse (20%); seven stage IV (MC), and one stage IA (LP) had progression to stage IIIB. All patients received salvage chemotherapy as MOPP x3 /ABVD x3 hybrids. Six patients achieved a second sustained remission. Out of 11 non-irradiated patients only two had recurrent disease. Three patients deceased (7.5%): one male patient (stage IVB, MC) suffered three relapses and succumbed to the disease after 9 years, another patient (stage IIIA, MC) suffered relapse 23 months post-chemo-radiotherapy and deceased despite salvage chemotherapy and inverted Y radiotherapy (Table 3). The third patient, a teenage girl with stage IIA NS, developed post-chemotherapy (and shortly after beginning of upper mantel radiotherapy) acute thrombocytopenia, menorrhagia and foudroyant pneumonia, and deceased. For the whole cohort the 5- and 16-year overall survival (OS) was 94.4% and 88.1%, and the event-free survival (EFS) 79.2% and 75.4%, respectively (Table 2; Figure 1). The 16-year OS and EFS for stages IIIB and IV were 87.5% and 59%, respectively.
|
|
Complications and second malignancies
Three patients demonstrated azoospermia on routine examination at the age of 18 years. All of them had received procarbazin and cyclophosphamide as part of their treatment protocol.
Of these, one patient afflicted with HD (stage IIA, LP) at the age of 11 years developed an axillary mass 10 years after combined chemotherapy and upper mantel radiotherapy. The histological examination of the biopsy specimen revealed non-Hodgkin's lymphoma (NHL) and the patient was referred to the adult oncology department.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResults and outcomeDiscussionReferences |
|---|
Forty children with newly diagnosed HD have been treated with combined chemo-radiotherapy, based on adapted DAL-HD 85-90 and later GPOH-HD 95 guidelines, over a time span of 16 years. The management, consisting of chemotherapy with either OPA, OPPA (OPEA) or OPPA/COPP combined with low-dose radiotherapy, proved to be effective to achieve a high cure rate for all stages (OS 88.1% and EFS 75.4%) (Figure 1). In patients with stage IA and IIA disease, the combination of either OPA or OPPA (OPEA) and low-dose involved field radiotherapy were equally effective to induce complete, sustained remission. The 5-year OS and EFS in the group receiving OPEA/OPPA were compromised by two events (fatal foudroyant pneumonia in one and recurrent disease in another patient) (Table 2). Our results are on the whole less satisfactory as compared with those reported by DAL/GPOH-HD study groups of OS and EFS >90% for all stages [1
, 3, 5, 8]. However, one should consider the small study cohort, the high incidence of advanced disease (55% stage III and IV), the presence of constitutional symptoms (40%) and the prevalence of MC histology (55%). MC histology, as the prevalent histology subtype in developing countries, bulky tumor and splenic involvement are considered as poor prognostic factors for HD [9, 10]. In contrast, in affluent countries the NS subtype is prevalent, and according to a large scale study, NS2 and presence of B symptoms account for poor outcome in HD [11]. Poor socio-economic conditions, illiteracy, parental/medical negligence and late referral (up to 1 year) to specialized centers are adverse features that have additional impact on disease outcome, and are in concordance with our earlier report [12].
Azoospermia has been, in three patients so far studied, the major complication of any procarbazin- and cyclophosphamide-containing regimen. Procarbazin reduction has resulted in less gonadal damage, but its omission in higher HD stages will compromise the treatment outcome [3, 13, 14]. Substitution of procarbazin by etoposide as in OPEA might prevent male infertility, but one should consider in the long-run its carcinogenic potential in patients with HD, who are at a high risk for leukemia [14]. Further patients with advanced HD receiving OPEA have had more events as compared with OPPA [3]. Moreover, intravenous application of etoposide proved to be a hindrance for ambulatory treatment, especially for patients coming from rural areas. Reduction of cyclophosphamide dosage as in COPP/ABV hybrid has failed to prevent male infertility [15]. According to the GPOH-HD 2003 protocol, procarbazin in COPP will be replaced by dacarbazin in a randomized comparison, in order to prevent male infertility and early menopause in females [16]. To preserve male fertility, cryopreservations of either testicular specimens or sperm prior to chemotherapy commencement are currently under investigation [17]. Low-dose involved field radiotherapy (20–30 Gy) combined with chemotherapy did not have any adverse effect on the disease outcome [1–5, 18], although its omission in higher stages compromised the EFS [19]. A current GPOH-HD 2003 trial is aiming to omit radiotherapy for early stage patients who are in complete remission or are tumor-free by F18-fluorodeoxy-D-2-glucose positron emission tomography (FDG-PET) scan at the end of chemotherapy. Radiotherapy should be then given only to patients with residual or bulky tumor [16]. The goal is to avoid or minimize the risk of radiation-related second malignancies, but the interim results of these studies should be awaited. On the other hand, one should also consider the achieved long-time OS and disease-free survival in children with HD who were treated with chemotherapy alone [8, 20–23]. In our small cohort 11 stage I, II, III and IV patients achieved sustained CR by chemotherapy alone and only one patient suffered recurrent disease. Long-time survivors of childhood HD are at a significantly higher risk for developing second malignancies such as leukemia, NHL, radiation-associated solid tumors (e.g. breast and thyroid cancers) and cancers at various other sites. During the 16 years of treatment and follow-up we have observed only one case of NHL 10 years post-combined modality treatment in a patient with HD (stage IIA, LP). This and other late effects, occurring decades after diagnosis and treatment of HD, imply and underscore the importance of life-long follow-up and surveillance of these patients [24–26]. Acute immune thrombocytopenia is a well known complication of HD. All patients receiving doxorubicin and upper mantel radiotherapy have been scrutinized for cardiac and thyroid dysfunction. So far there has been neither evidence for such dysfunctions nor any other chemo- or radiotherapy-related long-term complications, e.g. growth impairment or secondary carcinomas. Of interest has been the development of HD as a second malignancy during and after completion of chemotherapy in two patients with ALL. HD as a second malignancy after ALL is an extremely rare event; however, one should be aware of this complication [27].
Owing to improved public health and medical services there is now a lower incidence of childhood and infectious diseases in most developing countries. Concurrently, childhood malignancies are gaining public health momentum. It is therefore worthwhile mentioning our efforts to tackle the problems relevant to childhood cancer management in Iran, which is a vast country with an old culture, scattered multi-ethnic population and deep-rooted traditions. There is a considerable socio-economic gap, poverty and still noticeable illiteracy, leading to unequal access to proper medical services. Oncology patients are often treated as having tuberculosis or toxoplasmosis, causing delayed referral to specialized pediatric oncology services. Therefore, it is difficult to manage children with malignancies in accordance with the standards as practiced in affluent countries. We have tried to overcome the persisting circumstantial problems, on one hand by establishing a trusting relation between parents and medical/nursing staff, assessing parental socio-economic status and basic needs, providing detailed information about the respective malignancy, its management, complications, prognosis and follow-up program, and on the other hand, relieving existing financial concerns have been achieved by covering all medical expenses and providing free accommodation in designated hostels. Furthermore, we have been offering free psychological counseling to patients and parents in need. By taking HD as an example, diagnostic and treatment approaches, acute and late effects and especially male infertility, which is an important issue in this case, have been discussed at length with parents and adolescent patients, who have given their consent for the proposed chemo/radiotherapy. Financial support, voluntary social workers and accommodation have been facilitated by a Tehran-based charitable society by the name MAHAK, and by private donations. This society, which was founded in 1990 by socially motivated physicians and individuals, has also had from the beginning a set goal of informing the public about childhood cancers and their management. These efforts and services have proved to encourage parent/patient compliance with the treatment modalities and long follow-ups, to change the general notion of public about childhood cancer and its curability and to solicit patients' compliance and public support for children suffering from cancer [28]. The conditions mentioned here apply, more or less, to all developing countries; therefore, next to public information and soliciting public support for the cause of children with malignancies, adoptation of protocols such as the DAL/GPOH-HD is well suited to achieve high cure rates in an ambulatory setting, and even limited access to radiotherapy facilities.
Received for publication March 18, 2005. Revision received June 12, 2005. Revision received July 11, 2005. Accepted for publication July 21, 2005.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResults and outcomeDiscussionReferences |
|---|
1. Schellong G. Pediatric Hodgkin's disease: treatment in the late 1990s. Ann Oncol 1998; 9: 115–119.
2. Oberlin O, Leverger G, Pacquement H et al. Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin disease. The experience of the French Society of Pediatric Oncology. J Clin Oncol 1992; 10: 1602–1608.
3. Schellong G. Treatment of children and adolescents with Hodgkin's disease: the experience of the German-Austrian Paediatric Study Group. Bailliere's Clin Haematol 1996; 9: 619–634.[CrossRef][Web of Science][Medline]
4. Donaldson S. A discourse: The 2002 Wataru W. Sutow Lecture. Hodgkin's disease in children-perspectives and progress. Med Pediatr Oncol 2003; 40: 73–81.[CrossRef][Web of Science][Medline]
5. Schellong G, Potter R, Bramswig J et al. High cure rates and reduced long 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 1999; 17: 3736–3744.
6. Alebouyeh M, Haddad-Deylami H, Vossough P. Childhood malignancies in Iran: a suvey based on MAHAK cancer registry. INCTR meeting, Brussels, Belgium 2003 (Abstract 36, INCTR, Institut Pasteur, 1180 Brussels, Belgium).
7. Dionet C, Oberlin O, Habrand JL et al. Initial chemotherapy and low-dose radiation in limited field in childhood Hodgkin's disease: results of joint cooperative study by the French Socierty of Pediatric Oncology (SFOP) and Hospital Saint-Louis, Paris. Int J Radiat Oncol Biol Phys 1988; 15: 341–346.[CrossRef][Web of Science][Medline]
8. Dorffel W, Albrecht M, Lueders H et al. Multi-national therapy study for Hodgkin's disease in children and adolescents GPOH-DH 95. Interim report after 2
years. Klin Padiatr 1998; 210: 212–219.[Web of Science][Medline]
9. Shankar AG, Ashley S, Radford M et al. Does histology influence outcome in childhood Hodgkin's disease? Results from the United Kingdom Children's Cancer Study Group. J Clin Oncol 1997; 15: 2622–2630.
10. Arya LS, Dinand V, Bakhshi S et al. Significance of splenomegaly in childhood Hodgkin disease. J Pediatr Hematol Oncol 2004; 26: 807–812.[Web of Science][Medline]
11. Dieckmann K, Potter R, Hofmann J et al. Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-1993HD 90. Int J Radiat Oncol Biol Phys 2003; 152: 21–23.
12. Alebouyeh M, Vossough P. Hodgkin disease in Iranian children. Eur J Pediatr 1993; 152: 21–23.[CrossRef][Web of Science][Medline]
13. van den Berg H, Furstner F, van den Bos C, Behrendt H. Decreasing the number of MOPP course reduces gonadal damages in survivors of childhood Hodgkin disease. Pediatr Blood Cancer 2004; 42: 210–215.[CrossRef][Web of Science][Medline]
14. Le Deley MC, Leblanc T, Shamsaldin A et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracycline: case–control study by Societe Francaisee d'Oncologie Pediatrique. J Clin Oncol 2003; 21: 1074–1081.
15. Hobbie WL, Ginsberg JP, Ogle SK et al. Fertility in males treated for Hodgkin's disease with COPP/ABV hybrid. Pediatr Blood Cancer 2005; 44: 193–196.[CrossRef][Web of Science][Medline]
16. Horholz D, Claviez A, Hasenclever D et al. The Concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease: evolution in the tradition of the DAL/GPOH studies. Klin Padiatr 2004; 216: 150–156.[CrossRef][Web of Science][Medline]
17. Brougham MF, Kelnar CJ, Sharpe RM, Wallace WH. Male fertility following childhood cancer: current concepts and future therapies. Asian J Androl 2003; 5: 325–337.[Web of Science][Medline]
18. Kaicker S, Kelly K. Pediatric Hodgkin's disease: current concepts in diagnosis and management. Indian Pediatr 2000; 37: 933–938.[Medline]
19. Dorffel W, Luders H, Ruhl U et al. 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 2003; 215: 139–145.[CrossRef][Web of Science][Medline]
20. Lobo Sanahuja F, Garcia I, Bararantes JC et al. Pediatric Hodgkin's disease in Costa Rica: twelve years experience of primary treatment by chemotherapy alone, without staging laparotomy. Med Pediatr Oncol 1994; 22: 398–403.[Web of Science][Medline]
21. Baez F, Ocampo E, Conter V et al. Treatment of childhood Hodgkin's disease with COPP or COPP/ABV (hybrid) without radiotherapy in Nicaragua. Ann Oncol 1997; 8: 215–216.
22. Sagar TG, Chandra A, Raman SG. Childhood Hodgkin disease treated with COPP/ABV hybrid chemotherapy: A progress report. Med Pediatr Oncol 2003; 40: 66–69.[CrossRef][Web of Science][Medline]
23. Hakvoort-Camme FGAJ, Buitendijk S, van den Heuvel-Eibrink M, Hahlen K. Treatment of pediatric Hodgkin disease avoiding radiotherapy: excellent outcome with the Rotterdam-HD-84-Protocol. Pediatr Blood Cancer 2004; 43: 8–16.[CrossRef][Web of Science][Medline]
24. Sankila R, Garwicz S, Olsen JH et al. Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. J Clin Oncol 1996; 14: 1442–1446.
25. Metayer C, Lynch CF, Clarke EA et al. Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol 2000; 18: 2435–2443.
26. Bhatia S, Yasui Y, Robison LL et al. High risk of subsequent neoplasms continue with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol 2003; 21: 4386–4394.
27. Ragusa R, Russo S, Villari L, Schiliro G. Hodgkin's disease as a second malignant neoplasm in childhood: report of a case and review of the literature. Pediatr Hematol Oncol 2001; 18: 407–414.[CrossRef][Web of Science][Medline]
28. Alebouyeh M. Pediatric hematology and oncology in Iran. Pediatr Hematol Oncol 2005; 22: 1–9.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||