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© 2000 American Society for Clinical Oncology The United Kingdom Children’s Cancer Study Group’s Second Germ Cell Tumor Study: Carboplatin, Etoposide, and Bleomycin Are Effective Treatment for Children With Malignant Extracranial Germ Cell Tumors, With Acceptable ToxicityFrom the Birmingham Children’s Hospital, Birmingham; United Kingdom Children’s Cancer Study Group Data Centre and University of Leicester, Leicester; City Hospital, Nottingham; Medical School, Aberdeen; Institute of Child Health, Newcastle-upon-Tyne; and Royal Hospital for Sick Children, Bristol, United Kingdom. Address reprint requests to J.R. Mann, FRCP, Oncology Department, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom; email jill.mann{at}bhamchildrens.wmids nhs.uk.
PURPOSE: To evaluate carboplatin, etoposide, and bleomycin (JEB) in children with malignant extracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Malignant GCTs in children aged 0 to 16 years were excised without major morbidity or otherwise biopsied. Stage I testicular and some ovarian GCTs were resected and monitored with alpha-fetoprotein (AFP) ("watch-and-wait" approach). Patients with recurrent stage I disease and all other patients received JEB (etoposide 120 mg/m2 on days 1 through 3, carboplatin 600 mg/m2 on day 2, and bleomycin 15 mg/m2 on day 3). Courses were administered every 3 to 4 weeks until remission, and then two more courses were given. Chemotherapy toxicities were assessed using World Health Organization or Brock grading. RESULTS: Between January 1989 and December 1997, 192 patients were registered. Eight were excluded because either there was no histologic diagnosis (n = 3) or chemotherapy was given off-study (n = 5). The remaining 184 patients had germinoma (n = 20), malignant teratoma (n = 55), embryonal carcinoma (n = 1), yolk sac tumor (n = 107), or choriocarcinoma (n = 1). Forty-seven patients were treated with surgery alone, and 137 patients received JEB. The 5-year survival rate in March 1999 for all 184 patients was 93.2% (95% confidence interval [CI], 87.9% to 96.3%); for the 137 JEB-treated patients, it was 90.9% (95% CI, 83.9% to 95.0%), with an event-free survival rate of 87.8% (95% CI, 81.1% to 92.4%). The median follow-up after JEB treatment was 53 months (range, 0 to 109 months); the median number of courses was five (range, three to eight). Site, stage, and AFP level had prognostic significance. Nonfatal hematologic toxicity was common, but deafness and pulmonary and renal toxicities were rare. One child died of a thoracic tumor and bronchopulmonary dysplasia, and another died of acute myeloid leukemia. CONCLUSION: Conservative surgery, a watch-and-wait approach after complete excision, and JEB for those requiring chemotherapy produced high cure rates and few serious complications.
DURING THE LAST decade there have been reports of survival rates exceeding 75% in children with malignant germ cell tumors treated with platinum-containing regimens, from the United States,1-3 France,4,5 Germany,6-8 India,9 and Italy.10 Children with gonadal tumors have generally fared better than those with nongonadal primary tumors. However, a significant proportion of survivors have suffered deafness or renal toxicity attributed to cisplatin, and a few have developed bleomycin-induced lung fibrosis or etoposide-related leukemia.1,6,11,12 Although the 5-year survival rate was 84% in 33 patients treated with bleomycin, etoposide, and cisplatin (BEP) by the United Kingdom Children’s Cancer Study Group (UKCCSG), some degree of renal impairment was present in approximately 45% of survivors, deafness occurred in approximately 10%, and one child died of leukemia during the BEP chemotherapy.11 Bleomycin-induced lung fibrosis, or bleomycin lung, was also encountered before reduction of the bleomycin to one dose per cycle. In 1987, the substitution of carboplatin for cisplatin, to avoid renal toxicity and ototoxicity (ie, carboplatin, etoposide, and bleomycin [JEB]) was shown to be promising in children with malignant germ cell tumors.13 In the UKCCSG’s second germ cell tumor study (GCII), which opened in 1989, the aims were to maintain the high cure rates achieved with BEP in the first germ cell tumor study (GCI), to use JEB to reduce the chemotherapy-induced toxicity, and to minimize surgical morbidity. In this article, we describe the efficacy and toxicity of JEB in treating children with malignant extracranial germ cell tumors.
Patients Children less than 16 years old with biopsy-proven localized or metastatic malignant extracranial germ cell tumors were eligible, provided that no prior chemotherapy had been given. Patients with the following subtypes of germ cell tumor were included: germinoma, malignant teratoma, embryonal carcinoma, endodermal sinus tumor, and choriocarcinoma. Patients with mature or immature teratoma without malignant elements were not eligible. However, it was recognized that a small biopsy may have missed the malignant elements of large malignant teratomas. Therefore, patients with greatly elevated serum alpha-fetoprotein (AFP) levels but whose biopsies revealed only mature or immature teratoma were included.
Investigations
Staging
Histopathologic Classification A slightly modified version of Dehner’s classification16 was used and is described in Table 2. Histologic material from all cases was reviewed by a panel of three pediatric pathologists. Their diagnoses were used for this analysis.
Treatment All tumors were completely excised if this was possible without major morbidity; otherwise, biopsies were performed. Mutilating surgery, such as hysterectomy, was avoided. It was recommended that ovarian tissue, the vagina, and the uterus be preserved even if adherent to the tumor. In ovarian tumors, suspect tissue in the contralateral ovary was to be biopsied, with a view to second-look surgery after chemotherapy. Boys with stage I testicular tumors were treated by radical inguinal orchidectomy with high ligation of the spermatic cord and were monitored clinically and by AFP measurements. Neither retroperitoneal node biopsy nor dissection was performed. They were given JEB in the event of clinical recurrence or if serum AFP levels failed to fall appropriately or rose again. Boys with stage II to IV testicular tumors were given JEB chemotherapy after surgery, as initially were children with stage I to IV tumors at all other sites. However, it soon became customary, at the discretion of the investigator, for stage I ovarian tumors and rare stage I tumors arising in other sites to be treated with the same "watch-and-wait" policy after resection as used in stage I testicular tumor cases. It was recognized that the majority of malignant sacrococcygeal tumors would be unresectable at presentation; therefore, chemotherapy was to be given after biopsy. After completion of chemotherapy, all patients were re-evaluated and surgery was performed to resect any residual tumor as far as was possible without damaging structures such as the lumbosacral plexus. In sacrococcygeal cases, removal of residual mature/immature teratoma included removal of the coccyx. Infants with mature or immature teratomas were treated primarily by surgery, but JEB was given to those who went on to develop malignant yolk sac tumor recurrence. These children were included with the malignant teratoma group in the analyses.
Chemotherapy
Assessment of Chemotherapy Toxicity
Statistical Methods Survival time was defined as time from diagnosis to death; surviving patients were censored at the date of last follow-up. EFS was defined as time to first relapse or time to death; other patients were censored at the date of last clinical follow-up. The 95% confidence intervals (CIs) for probabilities of survival utilized the method of Rothman.25 In patients whose initial diagnosis was mature or immature teratoma but who developed yolk sac tumor recurrence, survival and EFS were calculated from the date of yolk sac tumor recurrence, with clinical stage and AFP level defined as those at that time.
Ethical Approval
Clinical Details and Histologic Classification Between January 1989 and December 1997, 192 patients were registered onto the study. Although theoretically ineligible because of their age, three 16-year-old patients who were registered were retained in the analyses because their tumors were similar to those in the younger teenagers (a boy with malignant teratoma of the testis, a girl with yolk sac tumor of the ovary, and a girl with dysgerminoma of the ovary). There were 112 girls and 80 boys. There were three children who, for clinical reasons, did not have a biopsy before treatment but were diagnosed on the basis of clinical features, radiology, and raised serum AFP levels (> 35,000, 800, and 144,000 kU/L). They had resection of residual immature or mature teratoma after completion of JEB chemotherapy. There were also four patients in whom pretreatment biopsy revealed only mature or immature teratoma but who had elevated serum AFP levels (2,890, 5,300, 28,810, and 67,031 kU/L). All seven of these children were classified as having malignant teratoma and were retained in the analyses. However, there were three patients whose pathology could not be reviewed and five who for various reasons were given nonprotocol chemotherapy (eg, one boy with embryonal carcinoma and another with seminoma of the testis were treated with adult protocols). All eight of these patients were excluded. Table 3 lists the sites of the tumors and their histologic diagnoses for the 184 patients who remained in the analyses. Included among the malignant teratoma group were seven patients who, after apparently complete resection of their congenital mature or immature sacrococcygeal teratomas, developed yolk sac tumor recurrence at 4, 12, 15, 20, 20, 28, and 32 months of age and one patient whose mature sacrococcygeal teratoma had been removed at 6 months of age and who developed yolk sac tumor recurrence at 37 months. Re-examination by the pathology panel of the original tumor from the neonate who developed recurrence at 28 months revealed that microfoci of yolk sac tumor had been present.
One girl treated surgically for dysgerminoma in one ovary subsequently developed dysgerminoma in the other, which after biopsy was treated successfully with JEB. In the survival analyses, only her first tumor was considered because the tumor in the second ovary was considered to be a second primary tumor.
Treatment Received, Site, Stage, and AFP and HCG Levels
Nineteen patients had elevated serum HCG levels; seven of them had normal AFP levels (six girls with ovarian germinoma and modestly raised HCG levels [13 to 159 IU/L; normal, < 10 IU/L] and one with ovarian choriocarcinoma and an HCG level of 320,500 IU/L). The other 12 patients with elevated HCG levels also had raised AFP levels (nine with ovarian or testicular malignant teratomas and single cases of ovarian embryonal carcinoma, germinoma, and yolk sac tumor). Further surgery after completion of JEB chemotherapy was undertaken in 45 cases because residual tumor was suspected on the basis of radiology. Three patients had had no initial surgery, 32 had had biopsy, six had had incomplete resection, and four had had apparently complete resection. No tumor or only necrotic or fibrous tissue was found in 24 patients, mature or immature teratoma was present in 19 patients, and viable malignant tumor was found in only two patients. The two children with viable tumor had no further treatment after complete resection of the tumor residuum.
Survival The overall survival rate for all 137 JEB-treated patients at 5 years was 90.9% (95% CI, 83.9% to 95%), and the 5-year EFS rate was 87.8% (95% CI, 81.1% to 92.4%). The median follow-up from the start of JEB chemotherapy was 53 months (range, 0 to 109 months), and the median number of JEB courses given was five (range, three to eight).
The EFS rates for JEB-treated patients, by site, stage, and histologic classification are listed in Table 5, which also shows EFS by AFP level in the children over the age of 1 year. Figure 1 shows EFS by stage and AFP level. Data were unavailable for stage in two cases and for pretreatment AFP level in five. Infants were excluded from the analysis of EFS by AFP level because of the normally higher AFP values in this age group. EFS was highly significant (P = .004) when analyzed according to AFP level less than 10,000 kU/L versus
Events Sixteen children suffered events after treatment with JEB. One child with a thoracic tumor died from this and bronchopulmonary dysplasia 28 days after starting chemotherapy, 14 children had recurrence of tumor, and one child developed myelodysplasia and then acute myeloid leukemia, from which she died. The karyotype of her leukemia was 47,XX,add(6)(q24-25),+8. There were a total of 10 deaths.
Treatment of Relapse After JEB
Prognostic Factors
Thirteen patients less than 1 year old, or with unknown AFP level or unknown stage, were not included in the multivariate analysis. None of them had an event. The low-risk group thus identified had none of the three risk factors and comprised children with a stage I or II sacrococcygeal/gonadal site and an AFP level less than 10,000 kU/L. These 26 patients (21%) had an EFS at 5 years of 100% (95% CI, 66% to 100%).
A high-risk group had two or all three of the strongest risk factors (ie, stage III or IV disease, AFP level
The intermediate-risk group had one or two risk factors (AFP level Only one of the 19 patients with an elevated HCG level suffered an event. This girl with ovarian malignant teratoma developed local recurrence of mature/immature components and then myelodysplastic syndrome and acute myeloid leukemia.
Toxicity of JEB The principal toxicities are listed in Table 7. There was only one treatment-related death from tumor and bronchopulmonary dysplasia in a girl with a thoracic yolk sac tumor who required ventilation at high pressures from diagnosis until her death 28 days after the start of her first and only course of JEB. All the other children reported to have pulmonary toxicity are now symptom-free; three had thoracic tumors, one had adenovirus infection, and one had collapse of the left lower lobe, making the contribution from chemotherapy hard to assess.
Treatment was modified in seven children because of an anaphylactic reaction to bleomycin (n = 1, vincristine was substituted), slow response (n = 2, one child was given Adriavac and the other was given etoposide with cisplatin), thoracic tumor and oxygen dependence (n = 1, vincristine was given instead of bleomycin for the first course), or myelotoxicity (n = 2, one child also had mild transient renal and pulmonary toxicities and was given Adriavac). The seventh child had severe myelotoxicity, so three cycles of BEP were given after three cycles of JEB had been given. She later developed myelodysplasia and died of acute myeloid leukemia, the karyotype of which was 47,XX,add(6)(q24-25),+8.
Since the introduction of cisplatin-containing chemotherapy, the survival rates for children with malignant testicular germ cell tumors, mostly yolk sac tumors, have approached 100%.1,7,26,27 They are high, ranging from 75% to more than 90% for malignant ovarian and nongonadal extracranial tumors.2,3,5,6,8-11 Therefore, as most children will become long-term survivors, attention in planning protocols is now turning to minimizing late effects. Cisplatin-induced ototoxicity was reported in 58% of children treated with various protocols at St Jude Children’s Research Hospital (Memphis, TN) between 1962 and198812 and in 10% of British children given BEP.11 Grade 3 and 4 ototoxicity has been reported in children treated with the Pediatric Oncology Group (POG)/Children’s Cancer Group (CCG) Intergroup protocol, especially in the high-cisplatin-dose cohort.2 Cisplatin-induced renal impairment has been reported by several groups, affecting approximately 45% of British survivors of BEP chemotherapy11 and approximately 25% of patients in the German Maligne Keimaelltumoren (MAKEI) 89 study.6 It is of particular concern in the high-cisplatin-dose cohort in the POG/CCG Intergroup study.2 The substitution of carboplatin for cisplatin in the UKCCSG’s GCII study has greatly reduced the occurrence of both oto- and nephrotoxicity, compared with the previous experience in the United Kingdom with BEP and reports from other groups. Only one child is currently reported to have severe deafness—as a result of middle ear hemorrhages—and none has significant renal toxicity. It is possible that a late-effects study of these patients that is currently being planned will reveal deafness or renal deficits that are at present undiagnosed; the results will be reported when available. Nevertheless, the initial evaluations are encouraging. Carboplatin is more myelotoxic than cisplatin, and myelotoxicity was the principal complication of the JEB therapy in GCII. It led to significant modification of the protocol in only three children, one of whom soon afterward developed myelodysplasia that progressed to acute myeloid leukemia. There were no cytopenia-related deaths. In a number of randomized trials in adults with metastatic testicular malignant germ cell tumors, carboplatin-containing combinations have been shown to be less effective than those containing cisplatin.28,29 The results in children treated in the French germ cell tumor TGM90 study, which incorporated carboplatin, were inferior to those of its predecessor, which included cisplatin.5 However, the carboplatin dose and dose-intensity in TGM90 were low, at 400 mg/m2 given every other course (ie, once every 6 weeks; the median dose was 1.2 g/m2 over 18 weeks for nonmetastatic cases and 2.5 g/m2 over 36 weeks for metastatic cases). The UKCCSG’s results with JEB, in which the carboplatin dose was 600 mg/m2 per course (ie, once every 3 to 4 weeks; the median cumulative dose was 3 g/m2 over 15 to 20 weeks), are more encouraging. They suggest that in children with malignant germ cell tumors, it is acceptable to substitute carboplatin for cisplatin as long as the dose is correct. Stratification of the cases for therapy in relation to risk factors by other groups makes direct comparisons of outcome difficult. However, our overall survival and EFS rates for JEB-treated patients of 90.9% and 87.8%, respectively, are similar to the best results of the other national groups. Even in stage IV cases, the EFS rate was 78%. As in the French series,30 an AFP level greater than 10,000 ku/L was the strongest prognostic factor. The highest-risk group in GCII seemed to be patients with an AFP level greater than 10,000 ku/L and stage III/IV disease, 27% of whom had events but in whom overall survival was still 85%. However, it is uncertain whether using a cisplatin-containing combination initially would significantly increase overall survival, even in the higher-risk patients, since in GCII, additional treatments rescued six of the 14 children who had recurrence after JEB. These relapsed patients had a variety of subsequent treatments that made them hard to evaluate. However, a standard intensive chemotherapy regimen incorporating cisplatin, vincristine, and ifosfamide is now in use for patients who relapse after JEB. In the United Kingdom, this strategy is preferred to the alternative of giving cisplatin-containing treatments to all the higher-risk patients, as this would certainly increase the incidence of ototoxicity and renal toxicity in the survivors. A valid comparison of efficacy and toxicity of cisplatin- and carboplatin-containing combinations in children with malignant germ cell tumors could only be undertaken on an international basis in order to accrue a sufficient number of patients. Discussions are currently in progress regarding possible international collaboration. Bleomycin-induced pulmonary dysfunction occurred in some of St Jude’s patients,12 and deaths from bleomycin lung were observed in the UKCCSG’s first germ cell tumor study (GCI).11 It was suggested that children might be more susceptible than adults to bleomycin lung damage, especially in the presence of renal impairment.11 Bleomycin treatments were therefore reduced to one per course both in the UKCCSG’s BEP protocol and in JEB chemotherapy. There have been no deaths in the United Kingdom caused by bleomycin lung in children given the reduced dose (unless bleomycin contributed to the death of the child with a thoracic tumor reported in this article). The planned late-effects study will determine whether any of the survivors have impaired pulmonary function. The German and Italian groups are substituting other agents for bleomycin.8,10 However, both groups have introduced ifosfamide, a nephrotoxic drug, although in the current MAKEI 96 protocol it is omitted in low-risk patients who receive cisplatin and etoposide rather than cisplatin, etoposide, and ifosfamide, and the number of cycles has been reduced to two for low-risk patients, three for intermediate-risk patients, and four for higher-risk patients. A number of trials have studied the effect of omitting bleomycin altogether from chemotherapy regimens given to adults with malignant germ cell tumors, and it seems that this omission may be safe in low-risk patients. Further randomized studies are required to clarify this recommendation.31 A Brazilian group has achieved encouraging results with just cisplatin and etoposide in children with extracranial malignant germ cell tumors, with 5-year survival rates of 92.3% for low-risk patients and 80.6% for high-risk patients.32 Secondary leukemia following chemotherapy has been reported only rarely in children with germ cell tumors,33,34 and as in adults, in some cases it may have arisen from the same stem cell as did the germ cell malignancy.35 The only case in the GCI study was in a girl with XY gonadal dysgenesis who developed acute myeloid leukemia during her BEP therapy. In the single case in the GCII study, the patient received three cycles of JEB and then three of BEP because of myelotoxicity; the patient developed myelodysplasia 2 years later and died of acute myeloid leukemia. Her leukemia’s karyotype did not show any abnormality of 11q23, which is generally seen in DNA topoisomerase II–associated leukemia.36 Among 1,132 children treated in the German malignant germ cell tumor trials between 1980 and 1998, of whom 442 received chemotherapy and 174 received chemo- and radiotherapy, six developed acute myeloid leukemia. No cases were seen in children treated only by surgery or radiotherapy, but the cumulative risk at 10 years was 1% for those who received chemotherapy and 4.2% for those who received chemotherapy and radiotherapy. In five of the children, the leukemia had cytogenetic abnormalities, and in four of them, these abnormalities were considered to be characteristic of therapy-related leukemia due to topoisomerase II inhibitors or alkylators.34 Thus, since etoposide-associated secondary acute myeloid leukemia is dose-related,37 it is clearly sensible to reduce the cumulative amount of etoposide given, if possible. However, it may not be desirable to omit etoposide altogether because it is probable that the benefit of etoposide-containing protocols may outweigh the risk of leukemia.38 As well as aiming to improve further the already high cure rates, all the major pediatric collaborative groups are modifying their protocols to avoid overtreatment and to minimize the use of drugs that have significant toxicities.5,8,10 There is now general agreement that a watch-and-wait policy is appropriate in patients with completely resected stage I gonadal tumors, regardless of histologic classification, and it is possible that the rare resectable nongonadal cases can be successfully managed similarly. The result is that a number of children will be spared chemotherapy altogether: in the GCII study, 51 patients with testicular tumors were observed after resection, and all 11 with recurrence are alive after JEB chemotherapy. Likewise, the three (of nine) ovarian watch-and-wait patients given JEB for recurrence are alive, as are all eight sacrococcygeal neonatal/infant patients with mature or immature teratomas given JEB for yolk sac tumor recurrence. In Germany, patients with mature and immature teratomas are currently being offered prophylactic chemotherapy if they are considered on the basis of a risk score to have a high risk (ie, about a 50:50 chance) of yolk sac tumor recurrence.39 Although the numbers in the United Kingdom are small, it seems probable that a watch-and-wait policy may achieve high cure rates for those who do develop recurrence and spare those who would not relapse unnecessary chemotherapy. Surgical morbidity is not reported in this article, although it is thought to be acceptable. It will be assessed in detail in the planned late-effects study. In conclusion, conservative surgery, a watch-and-wait policy after complete surgical excision, and JEB for those requiring chemotherapy have produced high cure rates in children with malignant germ cell tumors. There have been few serious chemotherapy-related complications.
The following UKCCSG centers contributed patients to this study (number in parentheses indicates number of patients): Aberdeen (4), Belfast (3), Birmingham (17), Bristol (8), Cambridge (2), Cardiff (7), Dublin (7), Edinburgh (8), Glasgow (7), Great Ormond Street London (23), Leeds (11), Leicester (6), Liverpool (9), Manchester (21), Newcastle-on-Tyne (12), Nottingham (6), Oxford (4), Royal Marsden London (7), Sheffield (8), Southampton (9), and St Bartholomew’s London (5).
The Cancer Research Campaign, London, United Kingdom, provided financial support for data management.
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Boshoff C, Begent RH, Oliver RT, et al: Secondary tumours following etoposide containing therapy for germ cell cancer. Ann Oncol 6: 35-40, 1995 39. Göbel U, Calaminus G, Blohm M, et al: Extra-cranial non-testicular teratoma in childhood and adolescence: Introduction of a risk score for stratification of therapy. Klin Pädiatr 209: 228-234, 1997[Medline] Submitted January 25, 2000; accepted June 16, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
10,000 kU/L; and tumor site, testis, ovary, sacrococcygeal region versus vagina/uterus, thorax, other. Variables were selected by a conditional forward stepwise approach, including those with a P value less than .20 and, finally, any significant interaction terms. 
