it has become after the introduction of chemotherapy [ 14 ] and new radiation regimen [ 57 ] . but with increasing cure rates of mostly patients , late toxicities have been reported among survivors .
the long - term frequency of cardiopulmonary , gonadal , and neoplastic treatment complications has been alarming after mopp , mopp - like schedules , and irradiation .
in addition , subtotal nodal irradiation leads to an increased frequency of second malignancies ( solid tumor and leukemia ) .
the relative risk of the late effects is estimated as ranging from 2 to 6 [ 8 , 9 ] .
modern current therapy uses risk - adapted and risk - responded chemotherapy with restricted doses of alkylating agents , anthracyclines , and bleomycin and low - dose , involved - field ( node - field ) radiotherapy , with the identification of additional clinical and biologic risk factors in attempt to avoid treatment - associated toxicity while maintaining high cure outcomes .
recent study results demonstrate that patients with favourable disease are excellent candidates for therapy reduction .  
the optimal therapy program for patients with hl goes on to be discussed , and this study is representative of the original risk - adapted protocol spbhl-05 for therapy of the similar patients with the dual goals of reducing late adverse treatment effects while sustaining efficacy .
between january 2000 and july 2009 , previously untreated 60 patients less than 18 years old who had biopsy - proven hl were eligible . all patients were required to have clinical stage according to the modified ann arbor criteria [ 10 , 11 ] .
the clinical staging evaluation included medical history and physical examination , complete blood count , urinalysis , erythrocyte sedimentation rate , blood chemistry , chest x - ray , abdominal ultrasound , thoracic and abdominal computed tomography scan with contrast , bone marrow biopsy , and isotopic bone marrow , spleen , liver , and bone scans .
gallium scan was used to monitor response if need were . in induction chemotherapy , we used vbvp ( vinblastine , bleomycin , etoposide , and prednisone ) and abvd ( adriamycin , bleomycin , vinblastine , and dacarbazine ) schedules followed by consolidating radiotherapy .
vbvp was administered as follows : vinblastine 6  mg / m intravenously ( iv ) on days 1 and 8 , bleomycin 10  mg / m iv on day 1 , etoposide 100  mg / m iv on days 1 through 5 , and prednisone 40  mg / m orally on days 1 through 8 .
it gives a possibility to select patients on favourable , intermediate , and unfavourable risk groups . in the calculation of the prognostic index ( pi ) ,
several unfavorable factors are taken into account : the age of 10 years or more , 4 or more lymphatic zones involved ,
when any nodal mass more than 5  cm in diameter or / and  mediastinal bulky disease 
when the ratio of the largest transverse diameter of the mass to the transverse diameter of the thorax was at least 0,33 , biological 
b  stage that was defined by two or more of the following findings : erythrocyte sedimentation ratio 30  mm / h , fibrinogen 0,4  g / dl , serum albumin 4  g / dl , leukocytes 12  10/mm , and 2-globulin  12% of whole globulin count , systemic  b  symptoms ( fever , night sweats , or a weight loss of > 10% of the normal body weight ) , and stage iv disease .
these factors incorporated into the pi which was defined as the number of adverse factors present at diagnosis .
patients with pi = 02 ( favourable risk group ) received two vbvp , children with pi = 3 - 4 ( intermediate risk group ) were treated with two cycles of vbvp alternating with two cycles of abvd , and patients with pi = 5 - 6 ( unfavourable risk group ) were treated with three cycles of vbvp alternating with three cycles of abvd .
vbvp were repeated every 3 weeks and abvd repeated every 4 weeks as permitted by count recovery .
external beam radiation was delivered with megavoltage equipment  either a telecobalt or a linear accelerator .
patients who achieved complete response or 75% or greater reductions in all disease manifestation were administered 25  gy .
rt began 2 weeks after the completion of chemotherapy and was given in 1,8  gy fractions , five times per week .
patients who did not reach these status were administered 36  gy in 20 fractions during 4 weeks . in all patients , the fields
were limited to the involved sites , as defined by the initial clinical and radiologic examination ( involved - field irradiation 
petrov research institute of oncology . written informed consent of parents was required before therapy .
patients were evaluated for response after two , four , and six cycles in the chemotherapy arms and after completion of rt .
a cr was defined as the disappearance of any clinical and radiological evidence of active disease over a period of 4 weeks .
a partial remission ( pr ) was defined as a 50% or greater reduction in all disease manifestation compared with the initial involvement for at least 4 weeks .
progressive disease was defined as enlargement of measurable tumors by more than 25% or appearance of any new lesions .
stable disease was not satisfying the definition of cr , pr , or disease progression / relapse . restaging
was performed 2 weeks after the end of chemotherapy and 4 weeks after the end of irradiation . restaging consisted of a control and documentation of all initial disease manifestation by clinical methods including a physical examination , complete blood count , urinalysis , erythrocyte sedimentation rate , blood chemistry , chest x - ray , and abdominal ultrasound , computed tomography of the chest and abdomen . a bone marrow biopsy and isotopic bone marrow , spleen , liver , and
follow - up examination including medical history and physical examination , complete blood count and blood chemistry , chest x - ray , and abdominal ultrasound were performed within the first 2 years in 3-month interval , at years 35 in 6-month interval , and from year 5 once a year .
os was defined as the time from beginning of treatment to death , whether disease - related or not , or last follow - up examination .
efs was defined as the time from beginning of treatment to an adverse event ( relapse , disease progression , death in remission , and second malignancy ) or last follow - up examination .
os , efs and standard errors ( se ) were estimated by the methods of kaplan and meier .
test of statistical significance in the comparison of survival curves were calculated using the log - rank test .
actual treatment duration was calculated as a time between the first and final cytotoxic drug administration plus 14 days , representing the theoretical duration of last treatment cycle .
the total actual dose given represented the sum of all administered doses per square meter of body .
dose intensity was calculated by dividing the total actual dose in milligrams by total actual duration in days and subsequently expressed as the percentage of initially planned theoretical dose intensity .
six of the 60 ( 10% ) were less than 9 years , 54 ( 90% ) were 10 years of age or older .
twenty eight had stage iii and iv disease , while 32 had stage i and ii disease .
histological subtypes were lymphocyte predominance in 2 cases ( 3.3% ) , nodular sclerosis in 46 ( 76.7% ) , and mixed cellularity in 9 ( 15% ) ; three cases ( 5% ) were not subclassified .
thus , in the series about 90% had either nodular sclerosis or mixed cellularity , while only 3.3% had lymphocyte predominance .
twenty three patients ( 38.3% ) had one , two , or three sites of lymph node involvement , whereas 37 patients ( 61.7% ) had four or more sites of node involvement .
the distribution of prognostic groups , expressed as the pi , is listed in figure 2 .
fourteen patients ( 23.3% ) had none , one , or two adverse factors ( favourable risk group ) .
twenty five patients ( 41.7% ) had three or four adverse factors ( intermediate risk group ) .
twenty one children ( 35% ) had five or six adverse factors ( unfavourable risk group ) . after therapy , 57 ( 95% )
one child had stable disease , and one patient developed progressive disease after five cycles of chemotherapy . a cause of death after five cycles in one case was the accompanying intercurrent viral epiglottitis . with a median followup of 68 months ( range 7 to 115 months ) , the 5-year os is 91.3% ( se 3.7% ) , and the efs is 82.8% ( se 5.0% ) ( figure 3 ) .
of the 57 patients who received the protocol and achieved cr , 9 ( 15.8% ) relapsed at a median time of 50 months from initial diagnosis ( range , 6 to 104 months ) : seven relapsed patients initially were treated according to principles for unfavourable risk group , two others relapsed patients were treated according to principles for favourable and intermediate risk groups . according to the risk group division , 5-year os in the favourable and intermediate risk group
were 100% , efs were 92.9% and 90.7% , respectively , and os and efs in unfavourable risk group were 77.1% and 55.6% , respectively , ( table 2 ) .
the reasons for early termination of chemotherapy were progressive disease and death from viral infection .
decreasing dose - time intensity of schedules 25% was not significantly influences the outcomes ( figure 4 ) .
table 3 lists the acute toxicities associated with each chemotherapy regimen during the time the patient was on treatment .
the number cycles was administered to 254 ( 185 vbvp and 69 abvd ) .  
leukopenia and neutropenia were the most common haematologic toxicity with grade 1 - 2 in 13.8% and 12.5% , respectively , grade 3 - 4 in 6.2% and 4.4% , respectively , of the cycles .
hodgkin 's lymphoma has one of the best cure rates of all of childhood and adolescent malignancies . consequently
, ongoing studies aim at reducing treatment - related toxicity , including second tumors such as acute myeloid leukemia , non - hodgkin 's lymphoma , and solid tumors .
using the modern combination regimen , risk - adapted therapy models might be warrant the excellent cure rates of patients with hl and should help avoid overtreatment and reduce life - threatening toxicity in patients .
german - austrian hodgkin 's disease study ( dal - hd ) worked out the well - known risk - adapted treatment for hl .   the study was designed to reduce , step - by - step , loads of the treatment in low and intermediate risk group .
high - dose and extended - field irradiation were limited to involved - field irradiation at a dose of 2025  gy ( dal - hd 90 ) .
combined modality therapy schedule of the dal - hd study included induction chemotherapy ( oppa / oepa and copp regimens ) followed by radiotherapy .
variables were selected according to the stage of the disease and systemic  b  symptoms .
after stratification , similar strata were randomly assigned to treatment group tg1 ( early stages ) , tg2 ( intermediate stages ) , and tg3 ( advanced stages ) .
patients with stage ia , ib , and iia ( tg1 ) received two cycles ; children with stages iib and iiia ( tg2 ) received four cycles ; remaining patients with stages iiib and iv ( tg3 ) received six cycles .  
the total dose was 25  gy in tg1 and tg2 and 20  gy in tg3 .
a boost up to 35  gy total dose was given to sites with residual lymphoma .
eighty - three patients were treated using combined modality therapy schedule of the dal - hd study ( versions 87 and 90 ) between june , 1987 and february , 2000 in our clinic .
the median follow - up duration was 116 months ( range , 8 to 255 months ) .
seventy - two per cent of all patients received only two or four cycles ; 28% received six cycles .  
os of 5 years after diagnosis was 93.3% , whereas in dal - hd study , it was 98% ; as to efs , it came to 79.9% versus 86% , respectively . according to risk group division , os in
in tg2 , the contributions were 100% and 96.7% , and in tg3 they were 98% and 87% , respectively .
as for efs , the values in tg1 were 94% in dal - hd study and 84.4% in our investigation .
in tg2 , the contributions were 91% and 81.4% , and in tg3 , they were 93% and 72.7% , respectively
. there were fewer patients in tg1 ( 32.5% in the study and 48% in dal - hd study ) and more patients in tg2 ( 39.8% and 22.2% , resp . ) .
the number of patients in tg3 was approximately identical ( 27.7% and 29.9% , resp . ) .  
the proportion of the second tumors did not coincide in the studies , being 0.9%   and 3.6% , respectively .
we do not exclude further detection of second neoplasms because of the higher doses of alkylating agents and anthracyclines in tg2 and tg3 .  
overall , it may be conclude that the therapy regimen of the dal - hd study represented a risk - adapted treatment with high efficacy .
on the one hand , alkylating agents and anthracyclines causing late adverse sequels included in chemotherapy regimen of the dal - hd study .
the cumulative total dose of cyclophosphamide and procarbazine were 2000  mg / m and 6000  mg / m in tg3 , respectively , and the total dose of doxorubicin was 80  mg / m that were analogous to three cycles mopp or copp or abvd .  
on the other hand , in dal - hd study patients were selected according only two parameters : stage of the disease and  b  symptoms .   for these reasons , the new program spbhl-05 has been offered .
our protocol of risk - adapted therapy was extremely effective for disease control in patients from favourable and intermediate risk groups , but treatment results in unfavourable risk group have been less impressive .
treatment of children from unfavourable risk group resulted in inferior event - free and overall survival .
os in the favourable , intermediate and unfavourable risk group were 100% , 100% , and 77.1% , and efs were 92.9% , 90.7% , and 55.6% , respectively ; os were 100% , 100% and 77.1% , respectively .
our experience with protocol decreasing cumulative doses of alkylating agent and anthracyclines in combination low - dose involved - field radiotherapy showed excellent outcomes .
( 2 ) with a median followup of 68 months ( range 7 to 115 months ) , the 5-year os for all patients was 92.7% ( se 3.6% ) , and efs was 79.6% ( se 5.6% ) .
( 3 ) the study showed significantly improved complete remission rate , event - free survival , and overall survival for vbvp ( in favourable risk group ) or the sequential vbvp - abvd ( in intermediate risk group ) followed by radiotherapy .
although the followup was short and only 5-year result was available , there were no differences in survival rates between programs ( for example , dal - hd ) .
( 4 ) no patients developed second malignancies in our series , while 3 cases of second neoplasms occurred after the dal - hd .
while adequate for the purpose of examining the regimen , the median followup of approximately 5 years interrupted a more detailed comparison of the risk of second malignancy between two programs .
( 6 ) low - cumulative doses of potentially dangerous medicines were reached by using sequential vbvp - abvd .
( 7 ) own prognostic index included 6 adverse prognostic factors ( in dal - hd risk groups were selected according only to the stage of the disease and systemic  b  symptoms ) .
these results suggest that it is feasible to reduction alkylating agent and anthracyclines in children with hodgkin 's lymphoma , but this approach results in inferior disease control in those from unfavourable risk group .
stratification of patients on risk group according to own prognostic index is feasible and proven to be effective , but additional stratification is required in unfavourable risk group .
maybe stratification according to the prognostic score by d. hasenclever and v. diehl is needed in this group .
based on our results , it may be reflected that the spbhl-05 represents an effective risk - adapted and response - adapted treatment strategy for hodgkin 's lymphoma for children and adolescents .
 
 purpose . prospective analysis of the efficacy of the original protocol spbhl-05 was performed . 
 
 patients and methods . 
 sixty patients with hodgkin 's lymphoma ( hl ) aged less than 18 years old were treated in accordance with spbhl-05 from january 2000 , to july 2009 . in induction chemotherapy we used vbvp and abvd schedules followed by involved - field radiotherapy . 
 fourteen patients ( 23,3% ) with 02 adverse factors ( the favourable group ) received two cycles of chemotherapy ( vbvp ) , 25 children ( 41,7% ) with 3 - 4 unfavorable signs ( the intermediate group ) received two cycles of vbvp alternating with two cycles of abvd , 21 patient ( 35% ) who had 5 or more adverse prognostic factors ( the unfavourable group ) received three cycles of vbvp alternating with three cycles of abvd . results . with a median follow - up of 68 months , 
 overall survival ( os ) at 5 years is 91.3% , event - free survival ( efs ) is 82.8% . 
 os in the favourable and intermediate risk group were 100% , efs were 92,9% and 90,7% , respectively , os and efs in unfavourable risk group77,1% and 55,6% , respectively . 
 conclusion . 
 the identification of prognostic risk factors and using medicines with less prominent side effects would be of major importance in the development of new strategies of treatment for childhood 
 hl . 