Department of Pediatric Hematology and Oncology, Shohada Medical Center, Shaheed Beheshti University of Medical Sciences, TehranTajrish, Iran
* Correspondence to: Dr M. Alebouyeh, 53 Majlesi Street, Tehran 15959, Iran. Tel/Fax: +9821-224 00 844; E-mail: alebouyehm{at}yahoo.com
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Abstract |
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Patients and methods: During the period 19882004, 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 414 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 (2025 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
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Introduction |
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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
].
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Patients and methods |
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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).
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Results and outcome |
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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.
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Discussion |
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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 (2030 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.
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