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Nowadays, childhood cancer patients survive much more often than they did 40 years ago. Therefore, the cure rates rise over 80%. Approximately 33,000 cured childhood cancer patients are documented by the German Childhood Cancer Registry (GCCR) for long-term follow-up in Germany. But does that mean, they are healthy, too? When compared to the normal population, it can be seen that morbidity and mortality are significantly higher among former childhood cancer patients. In two out of three survivors, the cancer and its treatments can lead to treatment-related late complications 30 years later; in about one-third, these late complications are classified as severe. A structured long-term follow-up is needed to detect and to treat new diseases early. The purpose of this position paper is to update the first position paper from 2007. Current developments are described, how appropriate aftercare structures and aftercare facilities should be planned, taking into account existing structures and increasing needs., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The MAHO studies for treatment of testicular germ cell tumors in childhood and adolescence registered between 1982 and 1/2001 260 patients (pts.). Aims of the studies were: 1. Delay of chemotherapy in YST of stage I A. 2. Delay of modified lymphadenectomy for staging in I A tumors. 3. Stepwise reduction of therapy in low stage tumors but increasing therapy in tumors of metastatic pattern. Standard therapy consisted of 4 courses of vinblastine, bleomycin and cisplatin. In stage II C or higher chemotherapy included cisplatin, VP 16 and bleomycin. As salvage therapy VP16, ifosfamide and cisplatin was given., Results: According to histology and stage only 75/260 pts. needed chemotherapy. Out of 140 pts. with YST 139 survived disease free according to a "watch and wait" policy. 16 of these patients (13 %) needed a delayed standard chemotherapy 6 - 60 weeks after orchiectomy. Patients with mature (40 pts.) and immature (19 pts.) teratoma were cured by orchiectomy alone. 59 pts. suffered from other malignant non-seminomatous tumors (EC, chorio, mixed tumors). 20 of these had a clinical stage I including 5 with a pathologic stage I A. 15 received adjuvant chemotherapy and all 20 pts. survived relapse-free. 22 pts. had stage II, 8 of these received salvage therapy in addition to standard chemotherapy, 21 of 22 pts. survived. 17 pts. had stage III or IV, 5 of these died despite receiving salvage therapy, 9 pts. survived in complete remission, 3 pts. had partial remission. Both patients with a seminoma (stage I) survived. In summary, the probability of disease free survival of 260 pts. is 97 % after a median observation time of 60 months., Conclusion: In alpha-fetoprotein producing YST tumors of clinical stage I A after semincastratio the "watch and wait" surveillance strategy is found to be optimal. Only about 13 % of these patients had to be treated by chemotherapy at a later time point and thus could be cured. For YST pts. of stages greater than stage I A and all other malignant testicular tumors in childhood effective chemotherapy exists with an overall cure rate of about 95 %. Local irradiation or staging lymphadenectomy is unnecessary.

Patients and Methods: According to previous literature incomplete tumor resection, coccygeal or ovarian primary site and immaturity are known risk factors for relapse in teratoma. To establish a risk score points are allocated for resection, primary site and histology in the following manner and added: incomplete resection 4 points, primary site coccyx 3 points, ovary 2 points, other site 1 point, histological grading 0-3 points. This score system is evaluated on 270 extracranial non-testicular teratoma cases collected between 1982 and 1995 in the MAKEI cooperative treatment protocols of the German Society of Pediatric Oncology and Hematology. Treatment was resection alone (230 patients) or resection followed by postoperative adjuvant chemotherapy (40 patients)., Results: Patients treated with surgery alone: 28/230 (12%) patients relapsed, 14/230 (6%) patients showed highly malignant histology (mostly yolk sac tumor) in relapse. Mortality in case of relapse was 6/28 (21%). Patients scoring > or = 6 points (n = 45) had a relapse rate of 21/45 (47%) resulting in a 23%-mortality (5/21). Patients scoring < 6 points (n = 185) had a 4%-relapse risk (8/185) resulting in 13%-mortality (1/8) (p < 0.01). Patients treated with surgery and adjuvant chemotherapy: 7/40 patients (18%) suffered a relapse, none of them showing malignant histology. Mortality rate in case of relapse was 3/7 (43%). Patients scoring > or = 6 points initially treated with adjuvant chemotherapy (n = 18) had a relapse rate of 7/18 (39%), compared to patients scoring < 6 points (n = 22), in whom no relapses occurred (p < 0.01). There were no highly malignant relapses in the group treated with adjuvant chemotherapy. Regardless of the scored points the difference in highly malignant relapse histology comparing the group treated with surgery and adjuvant chemotherapy to the group treated with surgery was statistically significant (p = 0.02)., Conclusion: The risk score system marks a high risk group including 63/270 (23%) of all evaluated extracranial non-testicular teratoma cases (scoring > or = 6 points). In this group 28/35 (80%) of relapses and 8/9 (89%) of tumor deaths occurred. For this high risk group a randomized trial will be suggested to evaluate the effect of adjuvant chemotherapy on the rate of malignant relapses. It should also be investigated, if adjuvant chemotherapy will influence relapse rate and mortality.

In this study treatment results in children and adolescents (n = 32) suffering from loco-regional abdominal relapses of germ cell tumors (GCT) (7 embryonal carcinoma, 17 Yolk sac tumors, 8 immature teratomas) aged from 1;0 to 23;3 years (mean = 10;11 years) were evaluated. In this pilot study 9 patients were treated with cisplatinum (40 mg/m2 on days 1 and 4), etoposide (100 mg/m2 on days 1 to 4), and ifosfamide (2000 mg/m2 on days 1 to 4) (PEI) +/- radiation in combination with regional deep hyperthermia (RHI). In sedation RHT was induced by non-invasive heat applicators (Sigma-40 and Sigma 60, BSD Medical Corporation, Utah, USA). In 7 out of these 9 patients with recurrent GCT a tumor response (5 CR, 2 PR, 1 SD, 1 PD) was found. In addition, in 2 patients a complete tumor resection could be achieved inspite of 2 previous incomplete tumor resections each. Five out of 9 patients are living event-free after an observation period ranging from 8 to 40 months (median = 15 months). Treatment results of this RHT study population were compared with treatment results in patients with recurrent GCT, who received conventional relapse therapy (chemotherapy/ surgery +/- radiation) alone. In this matched cohort 5 out of 23 patients are living event-free after an observation time ranging from 1 to 120 months (median = 8 months). According to Kaplan-Maier life table analysis, patients with relapse therapy combined with RHT have an event-free survival (EFS) of 0.41 +/- 0.33 whereas the matched cohort without RHT have an EFS of 0.16 +/- 0.25. The difference in treatment results of both groups is significant (Wilcoxon/p = 0.03). From the data presented in this study we conclude that children with loco-regional recurrences of extracranial non-testicular GCT have an unfavorable prognosis, unless local tumor control can be achieved. The additional application of RHT in combination with conventional therapy (PEI chemotherapy +/- radiation) can improve local tumor control and EFS in GCT patients with loco-regional recurrences. Therefore, based upon these results in the future MAKEI trial RHT will be applied to GCT patients with poor response to neoadjuvant chemotherapy alone as first line treatment.

Background: Secreting germ cell tumors are an invariably fatal subgroup within the malignant pediatric brain tumors. Thus in 1993, an international working group was initiated to establish a cooperative study for diagnostic and treatment of intracranial secreting germ cell tumors of the CNS. To pilot this protocol, since 1994 German and Italian patients are treated in accordance with the established guidelines., Methods: Regarding to the achieved consensus within the international protocol committee a characteristical diagnostic imaging (CT/MRI scan) of head and spine and a significant increase of tumor markers beta-HCG (> 50 IU/l) and/or AFP (> 25 ng/ml) are defined as sufficient diagnostic criteria. Additionally staging procedures include an initial CSF cytology. Treatment consists of 4 courses PEI: platinum (20 mg/m2 day 1-5), VP16 (100 mg/ m2 day 1-3), and ifosfamide (1.5 g/m2 day 1-5). Surgery of the residual tumor is administered after chemotherapy, if resection is possible, followed by craniospinal irradiation (30 Gy with tumor boost 24 Gy)., Results: Until September 96, 19 patients (16 boys and 3 girls) aged 8 to 19 years are registered and have finished their treatment. Seven children are diagnosed by elevated tumor markers. Six of 7 children with stereotactic fine needle biopsy and histology of germinoma have a significant marker increase as a specific characteristic for secreting non-germinomatous germ cell tumors. In 6 patients, the tumor is primarily resected, 2 children are biopsied. In 2 children spinal metastases are diagnosed initially. Tumor marker response is evaluated in 16 children. Thirteen of 16 patients show a clear marker normalization after 2 courses of PEI. One boy with a slight increase of the tumor marker after the 4th course developed an early spinal relapse and died. One girl showed a spinal recurrence during focal radiotherapy. She is still under relapse treatment. A significant decrease of tumor volume after chemotherapy is documented in 10/13 children, who have a definite signal tumor at start of therapy. In 3 children tumor volume does not change despite of marker normalization. Histology of these tumors is teratoma. One of these children died postoperatively because of tumor bleeding. 17/19 patients are alive, 16 of them are in complete remission with a median follow-up of 11 months., Conclusion: These results show a further significant increase of event-free survival (EFS 81%). The piloted chemotherapy is proven to be effective and the protocol is now open as an international SIOP CNS GCT study that is started in October 1996.

The treatment regimen of the ongoing cooperative study for non testicular germ cell tumors (MAKEI 89 of the German Society of Pediatric Oncology and Hematology), was stratified as in MAKEI 83 and 86 according to histology, localisation and stage. In the 1989 study, vinblastine was replaced by etoposide, resulting in a chemotherapeutic regimen of 3 to 4 courses BEP and 3 to 4 courses VIP in patients with stage I to IV. Total chemotherapy was reduced for 25%. In children under 1 year of age, bleomycin was omitted and bleomycin dose was reduced to 50%. In children up to 2 years because of two toxic deaths due to bleomycin who were registered in MAKEI 89 Pilot phase. Until Jan. 31, 1993, 230 patients were registered in the MAKEI 89 pilot study and the MAKEI 89 study, containing 186 protocol and 44 follow-up patients (patients with intracranial tumors are excluded for the review). 78 of the registered patients had a teratoma, 9 of these 78 patients suffered from a relapse. In 7 of 9 patients a lasting second remission has been achieved. 12 patients offered with germinoma. 1 of 12 patients had a recurrence but is in second remission. 47 patients had malignant non germinomatous germ cell tumors with an event free survival of 91 +/- 0.4%. 2 of the 47 patients relapsed and died. Toxicity was mainly hematologic without evidence of long term effects. Bleomycin induced pulmotoxicity (WHO grade IV) was documented in 1 protocol patient (see above). Nephrotoxicity with a grade III (WHO) decrease of creatinine clearance was found in 25% of the documented patients with a fast return to normal values after the end of therapy in most of the children. For the follow-up MAKEI 93 study, different topics are defined. 1. The value of chemotherapy for immature teratoma has to be discussed. 2. In invasive immature teratoma in children over 1 year of age, the effectiveness of chemotherapy should be proved. 3. Germinomas show high platinum sensitivity, therefore a platinum based chemotherapy has to be examined for this risk group. 4. The value of a wait and see strategy similar to the proved regimen in the French germ cell tumor protocol has to be verified in patients with stage I non germinomatous germ cell tumors. 5. An intensification of chemotherapy in patients with malignant stage III and IV non germinomatous germ cell tumors has to be examined as a new therapeutic approach for this risk group.

Germ cell tumors of the central nervous system are histological identical to the extracranial tumor sites. According to the localisation germ cell tumors of the CNS are different in symptoms, diagnostic approaches, kind and location of metastases and stratification of therapy. Since 1986 patients with intracranial germ cell tumors are registered in the ongoing study for non-testicular germ cell tumors (MAKEI) of the German Society of Pediatric Oncology and Hematology, and are treated in accordance to therapy guidelines for extracranial sites. In MAKEI 89 therapy strategy was revised with a reduction of radiotherapy and an increased cumulative cisplatinum dose from 200 mg/m2 to 400 mg/m2. Patients with germinoma receive after histologic diagnosis radiotherapy consisting of 30 Gy craniospinal irradiation and 15 Gy tumorboost. Malignant non-germinoma receive after diagnosis by tumor marker in CSF and/or serum 2 courses bleomycin 15 mg/m2 day 1-3, Etoposide 150 mg/m2 day 1 + 2 and cisplatinum 20 mg/m2 days 4-8 (BEP), continued by 2 courses Vinblastine 3 mg/m2 day 1 + 2, Ifosfamide 1500 mg/m2 days 1-5 and cisplatinum 20 mg/m2 days 1-5 (VIP), followed by 30 Gy craniospinal irradiation and 20 Gy tumor boost. In teratoma first line therapy is complete resection. In incomplete resected cases adjuvant chemotherapy according to histological grading is administered. Until 31st January, 1993 101 patients (pts) were registered, containing 69 protocol pts. Diagnosis in protocol pts was teratoma in 8 cases, 2 pts died postnatal because of extended disease, 2/8 pts relapsed, but were salvaged by chemotherapy. 40 pts offered germinomas.(ABSTRACT TRUNCATED AT 250 WORDS)

The cooperative therapy study MAKEI 83/86 included an examination of the prognostic value of the AFP in children and adolescents with extracranial non-testicular yolk sac tumors. The serum AFP values of 72 protocol- and follow-up-patients were documented at diagnosis and up to the ninth month of treatment. 32 of these patients had saccrococcygeal tumors, 27 had tumors of the ovary and 13 suffered from extragonadal germ cell-tumors. 4 children showed progressive disease under initial chemotherapy and 1 patient died of therapy, 10 of 72 patients relapsed. The AFP measurements were plotted on semilogarithmic charts. They were compared to the measurements of healthy children up to the age of 1 year. According to the development of the patients' AFP values compared to the reference curves the following classifications could be made: 1. Patients with a normal AFP-decrease id est 50% in less than or equal to 6 days during the 1st month of therapy: 48/72 patients 2. Patients with slow AFP-decrease: 17/72 patients 3. Patients with transient AFP-decrease: 5/72 patients 4. Patients with no AFP-decrease: 2/72 patients According to Kaplan-Meier life table analysis, patients with a normal AFP-decrease had an event-free survival of 89% +/- 4%, whereas all other patients showed an event-free survival of 63% +/- 10% (p less than 0.05). Regarding primary therapy id est tumor resection or preoperative chemotherapy an equal distribution of the patients among those with a normal and slow AFP-decrease was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficiency and toxicity of Carboplatin, a derivate of cisplatin in clinical use since 1981, was investigated in combination with VP16 in 11 children with recurrent or refractory tumors. 10 patients received therapy as outpatients without hydration. 160 mg/m2/day of Carboplatin were administered days 1 to 3, or days 1 to 5 as one hour infusion, combined with VP16 100 mg/m2/day, days 1 to 3, or days 1 to 5 as one hour infusion. One patient received Carboplatin, 600 mg/m2, as 24 hrs. continuous infusion in combination with VM26, 150 mg/m2/day as one hour infusion, 8 hours after Carboplatin. 9 of the treated children had measurable disease. 3 of 9 patients achieved a tumor response of more than 50% (partial remission). 5 of 9 children showed tumor response of less than 50% (stable disease). 1 out of 9 patients had progressive disease. 8 of 9 patients reported improvement or disappearance of clinical symptoms after the first course. All patients had severe myelosuppression with different times to recover. The WBC nadir was 14 days after Carboplatin/VP16. The nadir platelet counts occurred 21 days after therapy with fast recovery. Non-hematological side effects were minimal.