The UK Children's Cancer Study Group: Testicular malignant germ cell tumours 1979–1988

The UK Children’s Cancer Study Group: Testicular Cell Tumours 1979-1988 ByS.N.

Huddart,

J.R. Mann,

P. Gornall, D. Pearson,

A. Barrett,

F. Raafat,

J.M.

Malignant

Germ

Barnes, and K.R. Wallendsus

Birmingham, England 5 The United Kingdom Children’s Cancer Study Group (UKCCSG) malignant germ cell tumour (MGCT) studies were undertaken to establish standard protocols of investigation, staging, and treatment. The efficacy of new drug combinations and the value of serial measurements of serum alphafetoprotein (AFP) and human chorionic gonadotrophin (HCG) were evaluated. Following the initial surgery, staging of the tumour was performed using a variety of investigative approaches. In stage 1 testicular tumours, orchidectomy was performed. In more advanced tumours, and in stage 1 tumours that failed to show the expected decline in AFP or recurred, chemotherapy was used after appropriate surgery. Seventy-three boys, under 14 years of age, with testicular MGCTs have been entered into the UKCCSG studies since 1979. Serum AFP was measured preoperatively, or within 2 weeks of operation, in 70 boys. It was unequivocally elevated in 69. Monitoring by serial AFP measurement proved valuable in assessing response and in early detection of recurrence. HCG was measured in 45 boys, and was raised in three. Sixty-seven (91%) of the tumours were yolk sac (Teilum) tumours, four were immature teratoma, and two were mixed MGCTs. The only non-AFP producing tumour was an immature polydermal teratoma in a l-year-old boy. Serum HCG was raised in three boys with ‘yolk sac tumours, one with a mixed teratoma, and one 14year-old boy who had a mixed MGCT. The results of treatment were assessed on April 1, 1989 (median time from diagnosis, 3 years 4 months). Seventy-one boys were alive, 48 of whom had been cured by orchidectomy alone. The remaining 25 patients received chemotherapy. The initial chemotherapeutic regimen was with “low-dose” vincristine, actinomycin. and cyclophosphamide (LDVAC). but this was withdrawn in 1981 after it had been shown to be ineffective. Two boys who received LDVAC died. The remaining 23 boys were treated with various combinations of drugs and are alive with no evidence of disease. Excluding the two LDVAC cases, the survival rate is, therefore, 100%. There was no correlation between recurrence and initial AFP levels, nor whether HCG levels were raised or within normal limits. Q 1990 by W-6. Saunders Company.

A

LTHOUGH 60% to 75% of boys with testicular MGCTs have survived after radical orchidectomy alone, ts3 before 1979, when the UK Children’s Cancer Study Group (UKCCSG) studies began, reported cures after chemotherapy for metastatic testicular tumours in children were anecdotal.4-7 The combination of vinblastine, bleomycin, and cisplatin (PVB) that had proved successful in treating metastatic testicular tumours in young men* was reported to be too toxic for use in children.’ The UKCCSG malignant germ cell tumour (MGCT) studies were undertaken to (1) establish standard protocols of investigation, staging, and treatment with which future modifications could be compared; (2) study the efficacy of new drug combinations against tumours incompletely responding to, or recurring after, vincristine, actinomycin, and cyclophosphamide (VAC) treatment, and in children considered to have a poor prognosis; (3) study the value of serial measurements of serum alphafetoprotein (AFP) and Beta human chorionic gonadotrophin (HCG) in clinical management; and (4) test new drug combinations on newly diagnosed patients as they became available. In this paper the results in 73 patients studied since 1979 are reported. MATERIALS

AND

METHODS

Patients Children less than 16 years of age having biopsy-proven localised or metastatic MGCT being treated by members of the UKCCSG were eligible, provided no chemotherapy had been given. Investigations

From The Children’s Hospital, Birmingham, England; The Christie Hospital, Manchester, England: The Royal Hospital for Sick Children, Glasgow, Scotland; and the UKCCSG Ofice, Leicester, England. Supported in part by grants from the Cancer Research Campaign. London, England, and the Special Trustees of the Former United Birmingham Hospitals, Birmingham, England. Presented at the 36th Annual Congress of the British Association of Paediatric Surgeons, Nottingham, England, July I9-21,1989. Address reprint requests to S.N. Huddart. MD, The Childreris Hospital, Ladywood, Middleway. Birmingham B16 8ET. England. o 1990 by W.B. Saunders Company. 0022-3468/90/2504~007$03.00~0

Blood count, serum electrolytes, urea, creatinine, liver function tests, AFP and HCG, chest x-ray, skeletal survey and/or bone scan, bone marrow aspirate, and trephine and, where possible, computed tomography (CT) scanning or tomography of the lungs and CT of the liver and abdomen were recommended. CT scan of the abdomen and intravenous urography, rather than retroperitoneal lymph node dissection, were suggested to assess paraaortic lymph node status. Serum was taken for AFP and HCG measurement before surgery (or as soon as possible after), 5 days postoperatively, and weekly, until normal values were reached. Subsequent values were measured monthly for 2 years, every 3 months for 3 years, and at other times as indicated. The serum marker results were plotted on semilogarithmic charts to facilitate early detection of failed treatment, indicated, for example, by too slow a decline of AFP. When interpreting the results of AFP in infants, account was taken of the higher values present in this age group.“,”

406

Journal of Pediarric Surgery, Vol 25, No 4 (April), 1990: pp 406-410

INDEX WORDS:

Testis, germ cell tumours.

UKCCSG TESTICULAR TUMOURS

407

1979-1988 Table 2. Use of Staging investigations

Staging The British system of testicular tumour staging was used.” (I) Tumour confined to testis; (II) tumour confined to testis and retroperitoneal/abdominal lymph nodes; (III) supradiaphragmatic nodal disease (mediastinal and/or supraclavicular); and (IV) extralymphatic spread (liver, lung, bone, brain, skin, etc). Histopathology Review Histopathology review was undertaken by one of US (FR) in the 73 boys, using the system of Dehner.”

NO.

CXR

0

IVU

19

0

USS abdomen

19

2

CT lung

25

2

CT retroperitoneal

37

4

8M trephine

21

0

8M aspiration

30

0

2

2

20

1

52of

Lymphangiogram Bone scan

Treatment Complete excision via an inguinal approach was achieved in the majority of cases, although, disappointingly, 10 boys (13%) had an initial scrotal incision (usually because hydrocele had been suspected clinically). Chemotherapy was recommended for all patients, except those with stage 1 turnours, whose markers returned to normal values with the expected half-life of 5 days and remained normal. Radiotherapy was recommended only if there was residual disease after a full-course of chemotherapy, in which case 3,500 to 4,000 cGy in 4 weeks to as small a volume as possible was recommended.

Chemotherapy During the UKCCSG period of study, six regimens were used.14 “Low-dose” VAC (LDVAC) was abandoned after 2 years in favour of “high-dose” VAC (HDVAC) because responses were incomplete or of short duration. For patients considered to have a poor prognosis, physicians could add doxorubicin or give a modification of the PVB protocol described by Einhorn and Donahue'for metastatic testicular germ cell tumours in adults (cisplatin was given as a single dose, 100 mg/m’ on day 1, instead of 20 mg/m’ daily for 5 days, as used by Einhorn). Following three deaths from pneumonitis (in patients with tumours other than testicular) attributed to the bleomycin component of PVB, in 1983 we introduced BEPcisplatin, etoposide, bleomycin-which was based on a regimen used in adults at the Royal Marsden HospitaLI However, bleomycin was reduced to once per course in most patients. In 1986, carboplatin, etoposide, and bleomycin (JEB) was introduced in one centre and will form part of the next UKCCSG trial. RESULTS

Between January 1, 1979 and April 1, 1989,73 boys were registered from 17 centres. Ages ranged from 2 months to 14 years, with 55 under 2 years, 14 aged 2 to 4 years, and four aged over 4 years. At the time of diagnosis, 64 (88%) were stage 1, five (7%) were stage II, one (1%) was stage III, and three (4%) were stage IV. The site of the metastases are shown in Table 1. The use of staging investigations is shown in Table 2. Table 1. Sites of Metestatic

Spread

At Diacmosis

At Relapse

Rising AFP only (or AFP slow to fall)

No. Positive

68

PALN Biopsy

3

1

Liver scan

9

0

Abbreviations: CXR, chest x-ray; IVU, intravenous urogram: USS, ultrasound scan; CT, computed tomography; BM, bone marrow; PALN, paraaortic lymph node.

Ultrasonography of the abdomen demonstrated intraabdominal extension of the testicular tumour in one boy, and paraaortic lymphadenopathy in another. CT of the lungs showed metastases in two patients, whereas CT of the abdomen showed paraaortic nodes in three patients and a paraspinal mass in one. Lymphangiography was performed in only two patients and demonstrated involved nodes in both, but in these two cases, CT scan of the abdomen had already demonstrated enlarged lymph nodes. Paraaortic lymph node biopsy was only performed in three patients, and was positive in one. In two patients, nodes seen on CT scan were histologically benign. In the third, a boy entered into the trial in 1979, CT scan of paraaortic nodes was negative, but rising AFP levels and a previous scrotal orchidectomy prompted inguinal exploration and paraaortic dissection, in which one large malignant node.was excised. Congenital malformations were present in eight of the 73 patients (11%) (Table 3). Alphafetoprotein

AFP serum levels were examined within 2 weeks of surgery in 70 of 73 patients, and were raised in 69. HCG was measured in 46 of 73 and was raised in three. Table 3. Congenital Malformations Observed in Eight of 73 (11 %I Cases Case

Malformation

1

VSD

2

Odd facies, developmental delay, undescended left testis (contralateral), LIH VSD Bilaterat UDT

0

10

Lung/pleura

1

4

Down’s syndrome, UDT (ipsilateral)

Bone

1

0

Right leg and foot hypertrophy

Ratroperitoneal nodes

6

2

Liver

0

2

Other

3

0

Down’s syndrome

lleal polyp, possibly Peutz-Jagher svndrome Abbreviations: VSD, ventricular septal defect: LIH, left inguinal hernia; UDT, undescended testicle.

408

HUDDAAT

By plotting serial AFP levels on a semilogarithmic graph with a slope representing the expected rate of decline (taking t1/2 as 5 days”) it was possible to identify those patients who were not cured by surgery alone. Further investigations were then undertaken to try to locate residual or metastatic disease. No patient was found to have clinical or radiological evidence of metastases without also showing a rising AFP. As the study progressed, and confidence in serum AFP levels grew, 10 patients with initial stage 1 disease and no clinical or radiological evidence of recurrence, were treated with chemotherapy on the basis of rising AFP levels alone. All showed a subsequent decline in AFP levels (Fig 1) and have remained well. Due regard was placed on the normal values for AFP in a paediatric population” and the normal rate of decline, from high values at birth to adult levels by 1 year of age. One patient was identified who received a course of chemotherapy on the basis of an apparently slow decrease in AFP levels. Close analysis of the graph showed that the levels were probably normal for a boy of that age, and that the chemotherapy was probably unnecessary (Fig 2). For comparison, the AFP decline in another infant treated by orchidectomy alone is shown in Fig 3. The tumours were apparently typical endodermal sinus tumours of infantile type (yolk sac turnours) in 67 boys, and AFP was elevated in all 64 in whom it was measured; two boys also had increased HCG. One

ET AL

lCyear-old boy had mixed MGCT of adult-type histology (malignant teratoma intermediate [MTI]) and had increased AFP and HCG. Four boys had immature teratomas, in two the AFP was raised, in one the AFP was not measured within 5 weeks of surgery, and in the other the AFP was normal. One child had a gonadoblastoma containing an area of yolk sac elements. (He had no evidence of dysgenetic gonads and his karyotype showed a normal XY pattern). He had a high-AFP level. Monitoring

AFP/HCG

In stage I patients, successful treatment was always associated with a decline in AFP levels consistent with its half-life of 5 days. (Study of the slope of AFP decline in some of our patients with stage 1 tumours showed a mean half-life of 4.89 days (SD + 0.6, n = 27). AFP decreasing too slowly, not reaching normal levels, or increasing, always indicated inadequate tumour response and usually preceeded clinical or radiological evidence of treatment failure. In 10 boys, increasing AFP was the only evidence of failure to control the disease by orchidectomy, and in all of them chemotherapy was followed by a satisfactory decline of AFP. Radiotherapy

Only four boys received radiotherapy. Two (with initial stage 2 and 3 tumours, respectively), treated

Bleomycin Etoposide Cisplatin

Ill

1

1

lu

Ill

1

1

1

1

Orchidectomy 1,000,000 100,000 I

Expected rate of decline of AFP \ AFP LEVEL

1000

9 23 7

I

I SEPT

. Bwhadstaga 1 dis-

21 4 18 2 16 30 13 27 10 24 10 24 7 21 5 19

OCT

I

I NOV

1986

DEC

I JAN

I

I FEB

MAR 1987

APRIL

1 MAY

ease initially. diagnosed on the basis of increasing AFP level. There was a satisfactory decline of AFP after chemother-

aw.

409

UKCCSG TESTICULAR TUMOURS 1979- 1988

AFP LEVEL chemotherapy

I

4

5

6 AGE

7

(months)

Fig 2. Boy received chemotherapy at 6% months of age although AFP level was below the upper limit of normal.

unsuccessfully with LDVAC, were given 35 Gy radiotherapy to residual disease and both died. One boy received radiotherapy to paraaortic nodes that were incompletely excised at operation, and the fourth boy received 20 Gy to paraaortic nodes persistent after treatment with VAC and doxorubicin. Both these boys are well, with follow-up of 3 and 7 years, respectively.

diagnosed by a scrotal incision with the attendant risk of scrotal seeding. This may alter the histological stage of the tumour and lead to chemotherapy that would not have been otherwise necessary, although a study at the Royal Marsden Hospital has shown that scrotal incision does not appear to affect the prognosis in adult patients. l6 It is essential to obtain histological confirmation of clear resection margins, and presence or absence of vascular, lymphatic, tunica, and cord infiltration.” The initial staging should include AFP taken preoperatively, together with x-ray of the chest and CT scan of the chest, abdomen, and pelvis, where available. Lymphangiography did not prove to be necessary or helpful in managing these patients. The potential morbidity associated with paraaortic lymph node biopsy, especially if bilateral, is not considered to be justified by the information obtained. However, there are still some protocols, particularly in the US, in which lymph node dissection is used more freely as a staging investigation.‘8~23 We believe that sufficient information can be obtained by less aggressive methods, in particular by measurement of serum markers and by CT scan. This avoids the morbidity caused by a lymph node dissection9*24 and the stress of a major operation. The risk of ejaculatory failure (especially if dissection is bilateral) cannot now be justified in a paediatric population. Follow-up should be by clinical examination, regular chest x-ray, and AFP monitoring. When performed by radioimmunoassay, AFP has proven to be extremely valuable in the management of these patients.*’ FurAFP LEVEL

Additional Surgery

In 10 boys, the diagnosis was made by means of a scrotal incision. In only four of these was further surgery performed in an attempt to ensure complete clearance. Four of the 10 boys went on to receive chemotherapy, two because the AFP levels failed to decrease to normal values, one because AFP decreased and then increased again, and in the fourth, a 4-monthold child, the level was considered to be high (but was in fact normal for this age). All are alive and well at the end of the study period. DISCUSSION

The boys studied in this UKCCSG trial showed the usual preponderance of yolk sac tumours. These tumours behave in a different manner from adult testicular tumours and the prognosis, as demonstrated in this study, is excellent. Two thirds of these tumours may be cured by inguinal orchidectomy alone. It is disappointing that so many children in this study were first

10,000-

expected rate of decline of AFP 1000-

loo-

lo-

I

OP

I

,

1

2 MONTHS

3

4

POST-OP

Fig 3. Satisfactory decline in AFP level in boy with stage 1 disease cured by orchidectomy.

410

HUDDAAT

ther radiology is helpful when AFP levels indicate possible recurrence. Traditional staging of testicular tumours incorporating lymphangiography and/or paraaortic node dissections is relevant in adult patients who may require further surgery or radiotherapy. When chemotherapy is the mainstay of treatment of all but stage 1 tumours, and is effective, it is important to have markers of the presence of residual or recurrent disease.26 The precise site of tumour recurrence has not been found to be of major import in this study. Serum AFP is raised in the majority of paediatric patients, and provides a sensitive

ET AL

marker for tumour recurrence and response to treatment. ACKNOWLEDGMENT We thank K. Snow for the illustrations. We also thank the following UKCCSG members who entered patients in this study: A. Azmy, Dr C.C. Bailey, Dr F. Breatnach, Dr V. Broadbent, Dr S. Cartwright, Dr A.W. Craft, Dr S.I. Dempsey, Dr O.B. Eden, D. Gough, Dr J. Kingston, Dr I.J. Lewis, Dr J.S. Lilleyman, Professor J.S. Malpas, Dr J.R. Mann, Dr J. Martin, Professor T.J. McElwain, Dr P.H. Morris Jones, Dr M.G. Mott, Dr D. Pearson, Dr J. Pritchard, Dr M. Radford, Dr R.S. Shannon, Dr E.M. Simpson, and Dr M.C.G. Stevens.

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