Treatment of children with Hodgkin's disease – Results of the German Pediatric Oncology Group

Annals of Oncology 3 (Suppl. 4): S73-S76, 1992. O 1992 Klutver Academic Publishers. Printed in the Netherlands.

Original article Treatment of children with Hodgkin's disease — Results of the German Pediatric Oncology Group G. Schellong, J. H. Bramswig & I. Hornig-Franz University Childrens Hospital, Department of Haematoiogy and Oncology, Miinster, Germany

with 6 cycles of chemotherapy: 2 x OPPA plus 4 x COPP in HD-82 and HD-87; 2 x OPA plus 4 x COMP (without PC, M = methotrexate) in HD-85, followed by IFI using 25 Gy (HD-82, HD-85) or 20 Gy (HD-87). Radiation doses to involved lungs and liver were 12-15 Gy. KME for event-free survival (survival) at 4.5 years were 88% (90%) in HD-82 (n = 50), 54% (100%) in HD-85 (n = 24) and 91% (95%) in HD-87 (n-58). 1 patient in HD-82 suffered MDS 6 years after beginning of therapy and died after ABMT. About 60% of the boys treated with 2 OPPA plus 4 COPP, but none of the girls (without pelvic irradiation) and none of the tested boys treated with 2 OPA plus 4 COMP showed gonadal dysfunction after puberty. It can be concluded that 2 x OPPA plus 4 x COPP combined with 25 or 20 Gy IFI is a highly effective treatment for advanced stages of HD, but causes testicular dysfunction in a considerable part of the boys. Thus, PC should be replaced by a drug which is as effective but does not impair testicular function. Event-free survival rates with OPA/COMP were disappointing. Identical conclusions can be drawn from the results with OPPA/COPP and OPA/ COMP in the intermediate risk group (stages IIB and II1A).

Hodgkin's disease in children presents very similar to the adult form. The response to radiation and chemotherapy is also not very different in children compared to young adults (up to 30-40 years). Nevertheless, pediatric oncologists left the therapeutic concepts of adult oncology and developed treatment strategies geared to the specific problems of children. These modifications were designed to reduce the long-term sequelae of high-dose and extended-field irradiation which are more severe in children, as well as the toxic late effects of chemotherapy. In Germany, four consecutive multicenter studies on childhood Hodgkin's disease were completed since 1978 |2-4|. At present, the 5th study is still open for patient entry. Six hundred sixty-seven children under age 16 were enrolled by 60 centers until September 1990. All studies were designed to reduce, step by step, the total dose and the extent of radiotherapy, as well as the toxicity of chemotherapy, in the context of a combined modality treatment concept for all stages. In addition, the invasive staging procedures and the indi-

cations for splenectomy were changed [5,6]. The most important results of the three completed studies HD82, HD-85, and HD-87 will be presented.

Key words: treatment of children, gonadal dysfunction, OPA, OPPA

Treatment group 1 includes stages IA, IB, and IIA, which comprises 50%-55% of all patients. In trial HD-82 staging laparotomy was mandatory, whereas splenectomy, following our intraoperative decisional strategy [6], was only performed in selected cases, namely 17% of the patients in this group. The following two studies HD-85 and HD-87 employed a new model of selective laparotomy [5] together with selective splenectomy. 35% of the patients were laparotomized, but only 6% in this group lost their spleen. Chemotherapy in trial HD-82 consisted only of 2 OPPA cycles (Fig. 1), whereby the patients received vincristin, prednisone, procarbazine and adriamycin. The subsequent radiotherapy was confined to the involved fields. The dose was 35 Gy (Fig. 1). In Fig. 2 the top curve represents event-free survival (EFS) in group 1 of HD-82 which counts 100 patients.

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Summary. Six hundred sixty-seven children under age 16 were enrolled in 4 consecutive studies in West Germany between 1978 and 1990. These trials were mainly designed to reduce the long-term sequelae of high dose extended-field irradiation as well as the late effects of chemotherapy, in the context of combined modality treatment for all stages. Treatment concepts and results of studies HD-82, HD-85 and HD-87 are presented here. Patients with stages IA/B and I1A were treated with 2 cycles of OPPA (HD-82, n-100) or OPA without procarbazine (HD-85, n - 53; HD-87, n - 104), followed by involved field irradiation (IFI) using 35 Gy (HD-82, HD-85) or 30 Gy (HD-87). Kaplan-Meier estimates (KME) for event-free survival (survival) at 4.5 years are 99% (100%) in HD-82, 85% (98%) in HD-85 and 88% (100%) in HD-87. Thus, 2 x OPPA is a highly effective chemotherapy eradicating occult microfoci in the non-irradiated adjacent fields, whereas 2 x OPA is less efficacious. Reduction of the radiation dose to 30 Gy (IFI) within the combined modality concept does not affect treatment outcome. About 30% of the boys treated with 2 x OPPA, but none of the girls and none of the boys treated without procarbazine (PC) showed elevated FSH-levels indicating gonadal dysfunction. No secondary leukemias and preleukemias were observed. Patients with the advanced stages 11IB and IVA/B (plus some patients with IIE B and IIIE A/B) were treated

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to the involved fields, within a combined modality concept using 2 cycles of OPA, does not affect treatment outcome.

PS/CS IA/B, IIA HD-82-Trial

HD-86-Trial

HD-87-Trial

Treatment group 2 includes stages IIB and IIIA and also stage IIE . In trial HD-82 laparotomy was done in all (without Proca/b Procifbmnt) (without Proc«rt>»iln«) patients, but only 45% were splenectomized. Chemotherapy consisted of 2 OPPA- plus 2 COPP-cycles (C = I IFHrr. 35Gy I I IF-Irr. 35Qv I IF-Irr. 30Ov IF- Involved ll*4da only cyclophosphamide). The dose of the involved field irraFig. I. Therapy for treatment group 1 in trials HD-82, HD-85 and diation was 30 Gy (Fig. 3). The event-free survival in 53 children treated with this protocol was 96% after 4'/2 HD-87. and 94% after 9 years (Fig. 4). Again we can conclude, that 2 cycles of OPPA plus 2 cycles of COPP are a The probability of EFS after 4'/2 years is 99%, and 98% highly effective chemotherapy eradicating occult after 9 years. The survival rate of this group is 100%. microfoci in apparently non-involved and non-irradiatWe concluded that in patients with early stage disease ed adjacent regions. Involved field irradiation with chemotherapy offering 2 cycles of OPPA is highly reduced doses is sufficient. About 45% of the boys effective and realiably eradiacates occult microfoci in treated with this chemotherapy revealed gonadal dysthe apparently non-involved adjacent regions which function after puberty, but none of the girls who did not receive no irradiation. Our endocrinological studies rereceive pelvic irradiation [1]. No secondary malignancy vealed gonadal dysfunction after puberty in about 30% has been observed in patients in first remission, so far. of the boys, but none of the girls, treated with 2 OPPA cycles. We concluded that testicular damage was due to procarbazine [1]. Secondary malignancies have not PS/CS IIEA, IIB, IIIA been observed in this group, so far. 2 x OPPA.

2 x OPA

2 x OPA

1

2 x OPPA

• 2 x COMP

2 x OPA (without Procarbazlna)

• 2 x COPP

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HD-87-Trial

2 x OPA (without Procarbazlrw)

• 2 x COPP

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HD-85-Trial

Fig. 1 Therapy for treatment group 2 in trials HD-82, HD-85 and HD-87.

Fig. 2. Probabilities for event-free survival in treatment group 1 (PS/CS IA/B, IIA) in trials HD-82, HD-85 and HD-87.

0.941SO-0.03 0.7&SO-0.08

In the following study HD-85 we omitted procarbazine without substitute (Fig. 1). The remission rate in 53 children was again 100%, but the rate of event-free survival after 4'/2 years dropped to 85% (Fig. 2). Testicular function in 16 patients after puberty was not affected. This finding supported our assumption that procarbazine had been responsible for the gonadal damage in the patients of trial HD-82 [1]. The next study HD-87 which included 104 children employed the same chemotherapy regimen, i.e. 2 cycles of OPA and no procarbazine. The radiation dose for the involved fields was reduced to 30 Gy (Fig. 1). The results show an EFS curve which is identical to the one achieved by HD-85 (Fig. 2). Due to an effective salvage therapy we have nevertheless obtained survival rates of 98% and 100% in both these studies so far. We may conclude that 2 OPA cycles without procarbazine are less effective than 2 OPPA cycles containing procarbazine. Reduction to 30 Gy of the radiation dose

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Fig. 4. Probabilities for event-free survival in treatment group 2 (PS/CS IIB, IIIA, II E A) in trials HD-82, HD-85 and HD-87.

In the following study HD-85 we omitted procarbazine and replaced it by methotrexate in COPP resulting in COMP (Fig. 3). The event free survival rate is significantly lower, with a probability of 55% after 47. years (Fig. 4). From these results it can be realized, that 2 cycles of OPA plus 2 cycles of COMP are significantly less effective than 2 cycles of OPPA plus 2 cycles of COPP. This trial was stopped prematurely and procar-

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HD-82-Trial 0.9ft SD-0.01 0.88:5 0.88:50-0.04 O.KtS OKtSD-O.M

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bazine was reintroduced in 2 of the 4 cycles, resulting in 2 cycles of OPA without and 2 cycles of COPP with procarbazine (Fig. 3). The radiation dose was reduced to 25 Gy. It is obvious, that treatment outcome in our strategy depends on how many of the 4 chemotherapy cycles contain procarbazine (Fig. 4). Reduction of the radiation dose to 25 Gy within the combined modality strategy used seems not to affect the results.

0.9USD-0.04 O.B&SO-O.OT

0.49:SO-0.10 W-S2: M-50. 7 •vent!. 2 LFU rt)-flS N-2< _ 1

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Fig. 6. Probabilities for event-free survival in treatment group 3 (PS/CS IIIB, IVA/B, II E B, IIIEA) in trials HD-82, HD-85 and HD-87.

The major conclusions from treatment groups 2 and 3 are as follows: 1. OPPA/COPP is a highly effective chemotherapeutic regimen for advanced stages. Combined with 20-30 Gy involved field irradiation, it has achieved the highest cure rates reported in the literature so far (not only in adults but also in children). The main long term effect is sterility in about 45%-60% of the male patients. The risk of secondary leukemia is negligible. PS/CS II E A/B, 1MB, IVA/B 2. At present, OPPA/COPP chemotherapy together with low dose involved field irradiation seems to be the optimal treatment for female children, HD-85-Trlal HD-87-Trlal HD-B2-Trlal adolescents and perhaps young adults with advanced stage disease. In our present study HD-90 2 x OPA 2 x OPPA (without Procartuzlne) we continue to follow this treatment concept in • A xCOMP 4 x COPP female patients. (M • MTX) 3. For male patients, we are challenged to find an _L appropriate drug to replace procarbazine in our 1 IFHrr. 26Gy I IFHrr, 25Qy I I IF-lrr. 20Gv treatment concept. We therefore try to apply etoIF- Involved IKK)! only poside instead of procarbazine in the OPPA Fig. 5. Therapy for treatment group 3 in trials HD-82, HD-85 and cycles (arriving at OEPA) in study HD-90.

HD-87.

In the HD-85 study we tried to eliminate procarbazine from the regimen and replaced it in the COPP cycles by methotrexate arriving at COMP (Fig. 5). The radiotherapy dose was left unchanged. The results were significantly less favorable than in HD-82. Only 83% of the patients achieved remission. The rate of event-free survival after 4'/2 years decreased to 54% (Fig. 6). Although we were still able to maintain the overall survival rate at 100% so far, the number of patients needing salvage therapy was too high, and we decided to stop the trial prematurely. Nevertheless, the fact deserved to be mentioned that OPA/COMP did not cause gonadal dysfunction. HD-87 reintroduced procarbazine, arriving at a chemotherapy identical to HD82 (Fig. 5). The radiation dose was reduced to 20 Gy. Looking at the event-free survival curve, it is apparent that the results of HD-82 were reproduced exactly. The curves of the 2 studies are superimposable (Fig. 6).

References 1. Bramswig JH, Heimes U, Heiermann E et al. The effect of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin's disease during childhood or adolescents. Cancer 1990; 65: 1298-1302. 2. Bramswig JH, Hornig-Franz I, Riepenhausen M et al. The challenge of Pediatric Hodgkin's disease - Where is the balance between cure and long-term toxicity? A report of the West German multicenter studies DAL-HD-78, DAL-HD-82 and DAL-HD85. Leukemia and Lymphoma 1990; 3: 183-93. 3. Schellong G, Bramswig JH, Schwarze EW et al. An approach to reduce treatment and invasive staging in childhood Hodgkin's disease: The sequence of the German DAL multicenter studies. Bull Cancer 1988; 75:41-51. 4. Schellong G, Hornig-Franz I, Schwarze EW et al. Risk factor adapted treatment of Hodgkin's lymphoma in childhood: Strategies and results of three consecutive multicenter studies in the Federal Republic of Germany. In Diehl V, Pfreundschuh M, Loeffler M (eds): New aspects in the Ireatment of Hodgkin's disease. Recent results in Cancer Research 1989; 117: 20513.

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Treatment group 3 includes stages IIIB and IV, but also some IIE B and IIIE patients. Chemotherapy generally consisted of 6 cycles. HD-82 prescribed OPPA for the first two, and COPP for the remaining four cycles (Fig. 5). Radiotherapy was given as involved field irradiation at a dose of 25 Gy. The involved extralymphatic organs were also irradiated (excluding the bone marrow). The dosage to lungs, liver and kidneys was 12-15 Gy (Fig. 5). The event free survival rates in 50 patients were 88% after 4'/2 years and 86% after 9 years (Fig. 6). Gonadal dysfunction after puberty occurred in about 60% of the boys treated with 2 OPPA plus 4 COPP, but in none of the girls who did not receive pelvic irradiation [1]. The cumulative rate of secondary ANLL after 12 years is 1% of patients in first remission.

12 ivints. 1 LFU

(C-87: H-5B. 3 tvinU

76 Schellong G, Lietzke S, Strauch S et al. Bedeutung sonographischer, computertomographischer und klinischer Befunde fur die Erkennung eines Abdominalbefalls beim Morbus Hodgkin im Kindesalter - Eine retrospektive statistische Analyse bei 145 Patienten der Therapiestudie DAL-HD-82. Klin Padiat 1986; 198:147-54. Schellong G, Waubke-Landwehr AK, Langermann HJ et al. Prediction of splenic involvement in children with Hodgkin's disease: significance of clinical and intraoperative findings - a

retrosf>ective statistical analysis of 154 patients in the German therapy study DAL-HD-78. Cancer 1986; 57: 2049-56. Correspondence to: Prof. Dr. G. Schellong Univ.-Kinderklinik Albert-Schweitzer-Str. 33 D-4400 Miinster, Germany

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