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Keywords:

  • localized non-Hodgkin's lymphoma;
  • cyclophosphamide;
  • childhood

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

Summary. We have examined the outcome for children treated on two consecutive United Kingdom Children's Cancer Study Group studies of localized B-cell non-Hodgkin's lymphoma (NHL). The first study (NHL 8501; 1985–1989) included cyclophosphamide in the treatment regimen at a total cumulative dose of 4 g/m2 whereas the regimen in the succeeding study (NHL 9001; 1990–1996) did not include cyclophosphamide. Ninety children with confirmed B-cell NHL were treated in the two studies (NHL 8501, n = 33 and NHL9001, n = 57). With a median follow-up of 7·5 years, overall survival for localized B-cell NHL did not differ between the two regimens with observed 3-year survivals of 94%[95% confidence interval (CI) 80–98%] and 89% (95% CI 79–95%) respectively (P = 0·47). There was also no difference in the event-free survival between children treated on regimen NHL 8501 and NHL 9001 [91% (95% CI 76–97%) vs 84% (95% CI 73–92%) after 3 years; P = 0·34]. Although the difference in the number of failed remissions between NHL 8501 and 9001 (0/33 vs 6/57) approached statistical significance (P = 0·08, Fisher's exact test), there was no overall statistical difference between the treatment failures on either regimen (P = 0·34). Substantial long-term survival can be achieved for many children with localized B-cell NHL without the use of cyclophosphamide. Further studies are needed to identify whether all clinical or histopathological subgroups will benefit equally from the omission of cyclophosphamide.

Cyclophosphamide is an established chemotherapeutic agent for the treatment of both localized (Murphy stage I and II) and extensive B-cell non-Hodgkin's lymphoma (NHL). Excellent long-term overall survival rates and event-free survival (EFS) rates from localized B-cell NHL treated without the use of either radiotherapy or extensive surgery are observed (Murphy et al, 1983, 1989; Nachman, 1990; Link et al, 1997; Patte et al, 2001). However, late toxicity from cyclophosphamide, in the forms of reduced fertility and second malignancy, are well recognized (Byrne et al, 1987; Ben Arush et al, 2000; Kenney et al, 2001). Therefore, successful chemotherapy that does not contain an alkylating agent would be of great value in the treatment of localized NHL.

Between 1990 and 1996, the United Kingdom Children's Cancer Study Group (UKCCSG) undertook a study (NHL 9001) to evaluate whether a non-cyclophosphamide-containing regimen would be as effective as the previous chemotherapy regimen for the treatment of localized B-cell NHL. Here we present the results of this study and compare these with the subgroup of localized B-cell NHL treated in the NHL 8501 study, which preceded it and included cyclophosphamide.

Patients.  Eligible patients for both studies were aged between 0 and 15 years (inclusive) with localized (Murphy stage I or II) NHL. Any histological subtype was eligible for inclusion in the NHL 8501 study, whereas NHL 9001 was restricted to those with B-lineage disease. No patient had received either prior chemotherapy or radiotherapy, and informed consent was obtained before commencing treatment. Local ethical approval for the treatment of children in these studies was obtained at each participating centre.

Diagnosis. The diagnosis of NHL was based on both histopathological and immunopathological examination of biopsied tissue for all patients. In the NHL 8501 study, histological classification was according to the NHL Working Formulation (National Cancer Institute, 1982) whereas, for NHL 9001, the Kiel (Burkitt's; Lennert, 1975), Rappaport (undifferentiated; Rappaport, 1966) and the working formulation (small, non-cleaved) were used. For children treated on NHL 9001, immune markers confirming B-cell phenotype were required for all patients.

Central pathological review by an independent review panel was used in both studies. In addition to biopsy, the following investigations to confirm clinical stage were required: a chest radiograph, skeletal survey or bone scan as indicated, an abdominal ultrasound scan and either computerized topography (CT) or magnetic resonance imaging (MRI) for localized disease, a CT scan for nasopharyngeal primary, a full blood count, bone marrow aspiration and trephine, colony stimulating factor (CSF) cytology, and liver biochemistry.

Treatment.  Outlines of the treatment regimens NHL 8501 and NHL 9001 are shown in Tables IA and B, and II). Regimens NHL 8501 and NHL 9001 differed in that the former was given over 27 weeks (9-week induction and 18-week maintenance) with a cumulative dose of 4 g/m2 cyclophosphamide and 2·5 g/m2 methotrexate while, in the latter, treatment was given over 24 weeks with a cumulative dose of methotrexate of 4 g/m2 and absence of cyclophosphamide. The cumulative dose of anthracycline (doxorubicin) was the same (200 mg/m2) in each regimen.

Table I.  (A) UKCCSG NHL 8501 treatment regimen: induction.
(A) UKCCSG NHL 8501 treatment regimen: induction
Drug (daily dose in mg/m2 and route)Course Week1 012 23 344 55 676 8
Vincristine 1·5 i.v. on d 1      
Doxorubicin 50 i.v. on d 1        
Prednisolone 100 daily p.o. × 7 then tail over 3 d •••••••  •••••••     
Cyclophosphamide i.v. 1000 on d 1        
Methotrexate 500 i.v. on d 1 (over 1 h)       
Etoposide 150 i.v. on d 1       
Cytarabine 100 i.v. twice daily d 1–7       •••••••  
Thioguanine 75 p.o. d 1–7       •••••••  
Asparaginase 5000 iµ/m2 i.m. d 1–7       •••••••  
IT methotrexate dose based on age 5–12·5 mg    
(B) UKCCSG NHL 8501 treatment regimen: maintenance
Drug (daily dose in mg/m2 and route)Course WeekA 10 and 19B 13 and 22C 16 and 25
  1. A dot indicates the administration of a single dose of drug. i.v., intravenous; p.o., oral; i.m., intramuscular; i.t., intrathecal.

  2. A dot indicates the administration of a single dose of drug. s.c., subcutaneous; i.v., intravenous; p.o., oral.

Cyclophosphamide 1000 i.v. d 1   
doxorubicin 50 i.v. d 1   
Vincristine1·5 i.v. d 1   
Prednisolone 100 p.o. d 1–5 •••••  
Cytarabine150 i.v./s.c. d 1–5  ••••• 
Thioguanine 75 p.o. d 1–5  ••••• 
Etoposide150 i.v. d 1   
Methotrexate 500 i.v. d 1 (over 1 h)   
Table II.  UKCCSG NHL 9001 treatment regimen.
Drug (daily dose in mg/m2 and route)Course Week1 12 33 54 65 86 117 148 179 2010 23
  1. A dot indicates the administration of a single dose of drug. i.v., intravenous; p.o., oral; i.t., intrathecal; s.c., subcutaneous; b.d., bi-daily.

Vincristine 1·5 i.v. on d 1       
Doxorubicin 50 i.v. on d 1       
Prednisolone 100 p.o. d 1–5 ••••••••••      ••••••••••
Methotrexate 1000 i.v. on d 1 (over 6 h)       
Etoposide 200 i.v. on d 1         
Cytarabine 100 i.v. or s.c. b.d. d 1–5     ••••••••••    
Thioguanine 75 d 1–5 p.o.     ••••••••••    
IT methotrexate dose based on age 5–12·5 mg     

Statistics. Overall survival rates were estimated using the Kaplan–Meier method, taking the time from the date of diagnosis to date of either death from any cause or the last follow-up visit for patients who were still alive (Kaplan & Meier, 1958). The EFS rates were estimated using time from the date of diagnosis to date of relapse, progression or death; surviving event-free patients were censored at the date of last follow-up in clinic. Follow-up was complete up to December 2000.

NHL 9001 involved treatment reduction and, therefore, stopping rules were established mandating that the study should be stopped and the conclusion drawn that treatment led to a relapse rate of significantly more than 10% if 10 or more of the first 50 patients evaluated 1 year after diagnosis relapsed.

The percentiles for follow-up time were calculated by the reverse Kaplan–Meier method (Kaplan & Meier, 1958). Confidence intervals (CI) for EFS were calculated using Rothman's method (Parmar & Machin, 1995). Potential prognostic variables were tested individually in a Cox proportional hazard model using the change in log likelihood from the null model (Parmar & Machin, 1995).

Age (under 10 years: ≥ 10 years old) and site (abdominal: other) were subcategorized for survival analysis. Age was compared between protocols using the Mann–Whitney U-test. Tests for associations between categorical data used Fisher's exact test.

The statistical analysis was performed with the sas (statistical analysis system) statistical program (SAS Institute Inc, Cary, NC, USA).

Patients

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

Between 1985 and 1996, 147 children were treated for localized NHL. The median follow-up was 8·5 years (range 1·7–14·5 years). Of these, 74 were treated on the NHL 8501 study (August 1985 to December 1989) and 73 on the NHL 9001 study (July 1990 to March 1996). Study NHL 9001 was ended when a new International Co-operative Study French–American–British lymphome malins de Burkitt (FAB LMB) 96 opened; the number of relapses necessary to activate the stopping rule was never reached.

Central pathological review was available for 55 out of 74 (74%) patients in NHL 8501 of whom 33 had B-cell NHL. For the NHL 9001 study, central pathological review was available for 68 (93%) patients of whom the diagnosis of B-NHL was confirmed in 57 patients. There was no statistical difference in the overall survival between the group who had a diagnosis confirmed by central pathological review and the group that did not (P = 0·9). The results presented hereafter relate only to the group of 90 localized B-cell NHL patients from the two studies, which were confirmed by central pathological review.

Sixty-seven boys (44 treated on NHL 9001) and 23 girls (13 treated on NHL 9001) were treated for localized B-cell NHL. There was an excess of patients with Burkitt-like histology in NHL 9001 compared with NHL 8501 (45/57 vs 18/33 respectively; chi squared = 4·82; P = 0·028). There was no significant difference in either the distribution of stage (P = 0·23) or primary site in NHL 9001 compared with NHL 8501, and abdominal primaries were 11/33 (33%) and 26/57 (46%) respectively (P = 0·25). The overall median age was 9·1 years (range between 2·9 and 14·8 years), however, children treated on NHL 9001 were younger than those treated on NHL 8501: median 9·6 vs 8·4 years respectively (P = 0·045). Details of stage, site and histological subtype are shown in Tables III and IV.

Table III.  The stage and site distribution of the 90 localized B-NHL patients.
SiteProtocol
NHL 8501NHL 9001
Stage 1Stage 2Stage 1Stage 2
  1. GI, gastrointestinal.

GI tract ± associated nodes011026
Cervical nodes9683
Waldeyer's ring2077
Other head and neck nodes0002
Peripheral nodes0101
Other (including site unknown)3121
Total14191740
Table IV.  The histological classification of patients on studies NHL 8501 and NHL 9001.
Histological classificationNHL 8501NHL 9001
Burkitt-like/Burkitt's1845
B-cell lymphoblastic43
B centroblastic/centrocytic/follicular78
B cell/lineage not further classified41
Total3357

Treatment failure

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

All 33 children with B-NHL treated on regimen NHL 8501 achieved remission and there were no relapses on therapy. There were, however, three later relapses, with one patient surviving. Among the 57 children treated on regimen NHL 9001, six patients either failed to achieve a remission or relapsed on therapy, and there were nine relapses in total, of whom three survived. The difference in the number of failed remissions between NHL 8501 and 9001 (0/33 vs 6/57) approached statistical significance (P = 0·08, Fisher's exact test), however, there was no statistical difference between the treatment failures on either regimen (P = 0·34).

Most of the treatment failures on NHL 9001 were in children with Burkitt's or Burkitt-like histology but a comparison of EFS between the Burkitt's and Burkitt-like patients (18/33 on NHL 8501 vs 45/57 on NHL 9001) showed no statistically significant difference between the two regimens (log-rank test, chi squared = 1·579, P = 0·21).

Survival

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

With a median follow-up of 7·5 years and a range between 3·0 and 14·5 years (median 10·1 on NHL 8501 and 6·2 years on NHL 9001), overall survival for localized B-cell NHL on regimens NHL 8501 and NHL 9001 was 94% (95% CI 80–98%) and 89% (95% CI 79–95%) at 3 years respectively (P = 0·47). There was no difference in the EFS from localized B-cell NHL between children treated on regimen NHL 8501 and NHL 9001 [91% (95% CI 76–97%) vs 84% (95% CI 73–92%) after 3 years; P = 0·34].

Girls had better survival rate (0/23 relapses) compared with boys (12/67 relapses) (P = 0·03), and young age was associated with a poor survival rate (11/54 relapsed under 10 years compared with 1/36 over 10 years at diagnosis) that approached statistical significance (P = 0·08). Neither stage nor site of disease had a significant influence on survival.

There were no treatment-related deaths from regimen NHL 9001 but there were two from regimen NHL 8501 (one infection and one cavernous sinus thrombosis).

Late sequelae of treatment

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

With the long follow-up (median 8·5 years, range 1·7–14·5 years, interquartile range 6·2–10·2 years), no second malignancies were observed from either study group. The median age of survivors for patients treated on NHL 8501 was only 18·5 years and on NHL 9001 was 15·8 years, therefore, it is too early to perform a detailed assessment of fertility outcome.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

Localized NHL is now one of the most curable childhood malignancies, with long-term survival rates of over 90% reported in recent studies (Anderson et al, 1993; Link et al, 1997; Reiter et al, 1999; Patte et al, 2001). The UKCCSG studies NHL 8501 and NHL 9001, with 3 year overall survival rates of 94% (95% CI 80–98%) and 89% (95% CI 79–95%), respectively, compare favourably with previous studies. To our knowledge, this report is the first to document substantial EFS (84%; 95% CI 73–92%) in a national study using a regimen for the treatment of localized B-NHL that does not contain cyclophosphamide.

Cyclophosphamide has been included in all major studies of the chemotherapy of localized NHL and, to our knowledge, our report is the first indicating the comparable survival from a chemotherapy regimen for B-NHL without the use of an alkylating agent. The LMB 96 co-operative study superseded the UKCCSG study NHL 9001, and had the primary aim to verify that the EFS of LMB 89 would be maintained for group A patients (resected stage I and abdominal stage II) who received only two courses of COPAD (cyclophosphamide, vincristine, prednisolone and doxorubicin). A further aim was to establish that the EFS would not be substantially decreased by a reduction of treatment for LMB 89 group B patients (non-resected stage I and II). In LMB 96, the modification was randomized and consisted of a reduction of cyclophosphamide and/or the elimination of the last course of chemotherapy. The cumulative dose of cyclophosphamide in group A patients was 3 g/m2 and for group B patients was 5·8 g/m2,4·8 g/m2, 4·3 g/m2 or 3·3 g/m2, depending upon the randomization. It should be noted that in comparison with treatment with NHL 9001, patients treated as group B with stage I or II disease received more intense therapy. In LMB 89, 16/31 (52%) of stage I patients were treated as group B patients. Furthermore, even with the randomization to reduced therapy, patients in three of the four randomized arms of LMB 96 received more cyclophosphamide than in NHL 8501. LMB 96 closed in July 2001 and is awaiting analysis.

Assessment of the impact of alkylating agents alone on fertility is difficult, as multiagent chemotherapy is commonly employed. In the study from the Institute Gustav Roussy (Aubier et al, 1995), the relative risk of infertility for children (boys and girls) receiving ≤ 5 g/m2 cyclophosphamide as part of their chemotherapy regimen was 2·5. In our study, no systematic assessment of fertility has been made to date, although the increased relative risk from cyclophosphamide in protocol NHL 8501 (4 g/m2) will have been avoided in protocol NHL 9001.

During the follow-up period of this study, no child in either study developed a second malignancy. Secondary leukaemia following cyclophosphamide has a latent period of 3–8 years and, with median follow-up of 10 years on protocol NHL 8501, it would have been expected that most leukaemia caused by cyclophosphamide would have been detected.

Although there was no statistically significant difference in the overall relapse rates between studies NHL 8501 and 9001, caution must be exercised in the interpretation of these results, as a larger study might have uncovered a significantly worse outcome for at least a subgroup of those for whom cyclophosphamide was excluded.

There were significantly more patients classified as either Burkitt's or Burkitt-like in the NHL 9001 study. This may reflect developments in the classification of B-NHL or variability of classification as a result of diagnosis on histopathological grounds alone (Lones et al, 2000). Indeed it is now clear that Burkitt's and Burkitt-like NHL are distinct entities when examined immunohistochemically for the expression of B-cell lymphoma gene 6 (BCl 6) (Hutchison et al, 2000). The clear pathological distinction between subgroups of NHL would allow better risk stratification based on outcome. In our study, we were unable to determine any differences in survival between histological subgroups, but in the absence of clearly defined pathological groupings such differences would have been very difficult to interpret.

We have demonstrated that localized NHL may be successfully treated without cyclophosphamide and that no excess mortality results from this reduction in therapy. The apparently higher failure rate of NHL 9001 did lead to more treatment in a small percentage (approximately 10%) of patients who required both first- and second-line therapy. The implication for these patients would have been potentially higher doses of doxorubicin if they went on to receive NHL protocols 9002 or 9003. Refinement of the classification system of NHL in the light of biological studies is required to determine whether or not all subgroups of NHL respond equally favourably to reduced therapy.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References

The authors would like to acknowledge the clinicians in the following UKCCSG centres who enrolled patients on the studies: Aberdeen, St Bartholomew's, Belfast, Birmingham, Bristol, Cambridge, Cardiff, Dublin, Edinburgh, Glasgow, Great Ormond Street, Leeds, Leicester, Liverpool, Manchester, Middlesex, Newcastle, Nottingham, Oxford, The Royal Marsden, Sheffield, Southampton.

The authors would also like to thank the UKCCSG data centre and acknowledge the support given to the data centre by Cancer Research UK.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patients
  6. Treatment failure
  7. Survival
  8. Late sequelae of treatment
  9. Discussion
  10. Acknowledgments
  11. References
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