PROGNOSTIC FACTORS IN ADVANCED NON-SEMINOMATOUS GERM-CELL TESTICULAR TUMOURS: RESULTS OF A MULTICENTRE STUDY

8 PROGNOSTIC FACTORS IN ADVANCED NON-SEMINOMATOUS GERM-CELL TESTICULAR TUMOURS: RESULTS OF A MULTICENTRE STUDY

Report from the Medical Research Council Working Party on Testicular Tumours* Multivariate analysis of prognostic factors for 458 patients with metastatic nonseminomatous germ-cell testicular tumours treated with chemotherapy between 1976 and 1982 in 6 British centres showed a 3-year survival rate of 75%. 3 prognostic groups with survival rates of 91%, 72%, and 47% could be identified by means of tumour volume, serum alphafetoprotein, and human chorionic gonadotropin concentrations. Patient age

Summary

and year in which the chemotherapy was given were additional variables independently related to outcome. Delay from first symptom to start of treatment was related to tumour volume and marker levels as well as survival time and is an important potentially reversible determinant of longterm survival. This study provides the basis for defining subgroups for future randomised trials and suggests that tumour volume and serum marker levels are important and complementary as prognostic indicators.

Introduction SEVERAL factors influence the prognosis of patients with advanced non-seminomatous germ-cell testicular tumours, including stage, tumour volume,I,2 and initial serum concentrations of alphafetoprotein (AFP) and human chorionic gonadotropin (HCG).3-5 Multivariate analysis of these and a number of other potentially useful prognostic indicators has been carried out on data from 458 patients treated in 6 British centres, all patients having received modern potentially curative chemotherapy. This collaborative investigation was undertaken to identify prognostic criteria for prospective randomised-treatment studies in which low-toxicity chemotherapy for goodprognosis patients and more effective chemotherapy for highrisk patients will be evaluated. Patients and Methods Criteria for

Entry to Study

All patients had histologically proven non-seminomatous testicular germ-cell tumours classified according to the criteria of the British Testicular Tumour Panel.6

Working Party members: Prof M J. Peckham (Chairman), Dr R T. D. Oliver (Secretary), Prof K D. Bagshawe, Prof J. P. Blandy, Dr R. B. Buchanan, Dr S. Dische, Prof W. Duncan, Dr L. S. Freedman, Mr W. F. Hendrv, Dr A Horwich, Dr W G. Jones, Dr S. Kaye, DrJ S. MacDonald, Mr J. E. Newsam, Dr E. S. Newlands, Dr C. Parkinson, Dr R. C B. Pugh, Dr G. Read, Dr G. Rusnn, Mr M R. G. Robinson, Dr K. Sikora, ProfJ. Smyth, Prof J. M. A Whitehouse, Dr P. Wttkmson, Dr C. J. Williams.

6 Goldfine C, Millar WA, Haddow JE. Amniotic fluid gel cholinesterase density ratios in fetal open defects of the neural tube and ventral wall. Br J Obstet Gynaecol 1983, 90: 238-40. 7. Peat

D, Brock DJH. Quantitative estimation of the density ratios of cholinesterase bands in human amniotic fluids. Clin Chim Acta 1984; 138: 319-24. 8. Brock DJH. Amniotic fluid tests for neural tube defects. Br Med Bull 1983; 39: 373-77. 9. Fambrough DM, Engel AG, Rosenberry TL. Acetylcholinesterase of human erythrocytes and neuromuscular junctions. homologies revealed by monoclonal antibodies Proc Natl Acad Sci USA 1982; 79: 1078-82. 10. Brock DJH, Sutcliffe RG Alphafetoprotein in the antenatal diagnosis of anencephaly

Staging and Patients

Tumour Markers

were

classification.7

clinically staged with the Royal Marsden Hospital

I. Lymphogram negative, no evidence of metastases. IM. No evidence of metastases but persistently elevated serum AFP and/or HCG levels. II Para-aortic-node metastases: A, metastases <2 cm diameter; B, metastases 2-5 cm diameter; C, metastases >5 cm diameter. III. Supradiaphragmatic and infradiaphragmatic-lymph-node involvement: abdominal status A, B, and C, as above. IV. Extralymphatic metastases’ abdominal status A, B, and C, as above. Lrrng status: L1 ::;3 metastases. L2, multiple, none >2 cm diameter. L3, multiple, one or more >2 cm diameter. Liver status: H+-liver involvement.

In this study small-volume disease included stages IM, IIA, IIB, IIIA, IIIB, IV ALl, IVAL2, IVBLI, IVBL2; large-volume disease, stages IIC, IIIC, IVCLI, and IVCL2 ; and very-large-volume disease, L3 pulmonary disease, liver involvement, central-nervoussystem spread, or bone metastases.

Analyses and

were

carried

out

with different concentrations of AFP

HCG, and in this series the best discriminant was obtained with

prechemotherapy AFP titres of >50 kU/1 and HCG titres of > 1000 IU/1, which were termed high. The cut-off levels were lower than those used m previous reports3,4 because few patients had an initial HCG of >50

000 IU/1.

Chemotherapy All patients had clinical evidence of metastatic tumour and received chemotherapy with vinblastine and bleomycin (VB), 65 patients.;’ cisplatin, vinblastine, and bleomycin (PVB), 179 bleomycin, etoposide, and cisplatin (BEP), 45 etoposide and cisplatin (EP), 11 patients;10 bleomycin, etoposide, vinblastine, and cisplatin (BEVIP), 64 patients; or the alternating multidrug (POMB/ACE) schedules employed at the Charing Cross Hospital (CX1, 34 patients; and CX2, 48 patients).4,11 12 patients received other types of chemotherapy as follows: cisplatin and vinblastine 3; cisplatin, etoposide, and vinblastine 2; etoposide, cyclophosphamide, and vincristine 1; etoposide, cisplatin 1; cyclophosphamide, vincristine, actmomycin D, and methotrexate 1; VB followed by PVB 1; cyclophosphamide, vinblastine, and bleomycin I;etoposide 1; and cisplatin 1.

patients;

patients;9

Patients 458 patients treated between January, 1976, and June, 1982 were included in the study. Of this group 108 (24%) have died. 89 of the 108 deaths were due to uncontrolled tumour, 11 were treatment related, and 8 resulted from mtercurrent disease (6 cardiovascular deaths, 1 encephalitis, and 1 due to infection). Of the 350 who were alive at last observation, 10 had been observed for less than 1 year, 98 for 1-2 years, 90 for 2-3 years, 77 for 3-4 years, 44 for 4-5 years, and 31 for more than 5 years. The median follow-up time since chemotherapy was just under 3 years, and the overall survival at 3 years was 75%. The number of patients contributed by each centre was as follows: the Royal Marsden Hospital, 197; Charing Cross Hospital, 82; Manchester, 69; London, St Bartholomew’s Hospital and Institute of Urology, 55; Leeds, 36; and Southampton, 19. The patient population of the 6 centres showed some variation in distribution with respect to marker levels and clinical stage, but these differences were not large. Thus the percentage of patients from each centre with abdominal masses of >5 cm was 43%, 33%, 20%, 38%, 36%, and 16%, respectively. The L3 patients were

and

spina bifida Lancet 1972; ii: 197-99. Report of the UK Collaborative Study

on Alpha-fetoprotein in relation to Neural-tube Defects. Amniotic fluid alpha-fetoprotein measurement in antenatal diagnosis of anencephaly and open spina bifida in early pregnancy. Lancet 1979; i: 685-88. 12. Brock DJH, Barlow RD, Wald NJ, et al. Fetal calf serum as cause of false positive amniotic fluid acetylcholinesterase gel tests. Lancet 1982; ii: 1044. 13 Norgaard-Pedersen B, Hangaard J, Bjerrum OJ. Quantitative enzyme antigen immunoassay of acetylcholinesterase in amniotic fluid. Clin Chem 1983; 29: 1061-64.

11. Second

9 TABLE

I-3-YEAR SURVIVAL RATES WITHIN DIFFERENT GROUPS OF

TABLE

II-3-YEAR

PATIENTS DEFINED BY CLINICAL STAGING FACTORS

SURVIVAL RATES WITHIN GROUPS OF PATIENTS

DEFINED BY AFP AND HCG MARKER LEVELS

*AFP>500

kU/1

or

&bgr;-HCG >1000

IU/1.

chemotherapy, and type of chemotherapy was collected on a single standardised form for each patient. Statistical Methods The methods used in this analysis have been based on calculation and plotting of survival curves;12 of survival in 2 or more groups by the logrank test;l2 and investigation of the contribution of several factors assessed simultaneously with the Cox regression method.13 Factors were investigated individually with the first 2 methods, and the combined effect of factors was analysed with the third test by means of a stepwise forward method for the 7 variables given in table IV and the 2 variables, volume and marker, given in tables I and n, respectively. The results of the Cox analysis were verified by stratified logrank tests. For ease of exposition the results are presented entirely in the framework of these simpler

comparison

*Includmg one patient

with para-aortic

status

unknown.

I

distributed as follows: 20%, 35%, 19%, 16%, 25%, and 16%, patients with high HCG titres, 14%, 29%, 27%, 34%, 11%, and 16%; and high AFP titres 25%, 20%, 17%, 14%, 22%, and 16%. 3 centres, Charing Cross, the Institute of Urology, and Manchester, had a greater proportion of high - HCG patients than the others (X2 =19-8, df= 5, p<0 . 005). The variations between centres are not large enough to make the combination of data meaningless.

Data Collection Information on 15 variables including stage, site and volume of metastases, serum marker levels, number of metastatic sites, age, duration of symptoms, previous irradiation, histology, year of first

Fig

I-Influence of tumour volume

on

survival.

analyses. Results Table I shows 3-year survival rates for patients subdivided according to sites of metastatic disease and tumour volume. Analysis for individual factors indicated that the most influential signs for a poor prognosis were para-aortic nodes

Fig 2-Survival by volume of disease and

serum

marker levels.

10 TABLE

III-3-YEAR SURVIVAL RATES WITHIN

GROUPS OF PATIENTS

TABLE

IV-3-YEAR SURVIVAL RATES WITHIN

>5 cm (C), bulky lung disease (L3), and liver or bone involvement. Survival curves for the combined staging groups subdivided into small, large, or very large tumour volume are shown in fig 1. The number of sites of metastases was also predictive of prognosis (table I). Table 11 shows 3-year survival rates according to the initial serum marker concentrations. The strongest predictor of a kU/1 or an HCG poor prognosis was an AFP level of >500 level of > 1000 IUII. Prediction of survival from markers was similar to that attained with tumour volume. In table III survival results have been analysed in terms of tumour volume and marker status. AFP does not add greatly to the prediction of prognosis afforded by tumour volume, but HCG was an important predictive factor within tumourvolume subgroups. When AFP and HCG are combined, the predictive power of marker levels is even better (fig 2). Table IV summarises the results for other factors. The most notable finding is the year-by-year improvement in survival from 1976 to 1982 (&khgr;2 = 15.2, df=l, p<0-001) (fig 3). Treatment patterns changed over this period as follows: in 1976-78 55% of patients received VB, 20% PVB, and 20% CXl; in 1979-80 only 3% received VB, 63% PVB, 57o CX1, 10% CX2, and 15% BEVIP; in 1981-82 no patient received VB or CX1, 22% received PVB, 26% BEP, 24% BEVIP, 19% CX2, and 7% EP. The improvements in treatment results over the whole period cannot be explained completely

by changing treatments.

patients’ length of symptoms not known. tAccording to the criteria of the British Testicular Tumour Panel. Histologies combined because of small numbers. 2-year survival rates given since 3-year rate is not available for 1981-82. MTC = mal1gnant teratoma undifferentiated; MTI=malignant teratoma intermediate; MTT=malignant teratoma trophoblastic; TD=teratoma * 10

differentiated.

Part of the improvement is probably due to the fact that between 1976 and 1978 only 40% of patients received cisplatinum and 20% etoposide, whereas by 1981-82 100% received cisplatinum and 78% etoposide. However, when the survival of patients treated with individual treatment schedules was compared, an improvement with time was also observed. Improvement of treatment results by year of first chemotherapy is not explained by changes in staging or marker distribution. Although the proportion of smallvolume and low-marker patients rose from 4307o and 53% in 1976-79 to 56% and 70%, respectively, in 1980-82, the logrank test for trend corrected for these differences still gave a statistically significant result (X 2 = 7.4, df= 5, p = 0-001). Further analysis of the factors included in table IV has been carried out taking clinical stage and serum marker levels into consideration. Age also emerged as an independent variable. The trend that prognosis is poorer with increasing age (more than 30 years) was statistically significant and not explained by differences in staging or marker distribution (logrank test for trend &khgr;2=4.4, df=l, p=0-04). There were more treatment-related deaths in the groups of patients over 30 years of age. Patients with a history of symptoms of greater than 3 months had a worse survival than those with a shorter history (p = 0 - 02). However, once stage and marker status are taken into account the influence of length of symptoms is no longer -

Fig 3-Survival by

year of chemotherapy.

GROUPS OF PATIENTS

DEFINED BY OTHER FACTORS

DEFINED BY CLINICAL STAGING AND MARKERS

11

significant (X== 1’ 4, df= 1, p 0 - 23), indicating that a longer history is associated with more advanced disease. Of 349 patients who had symptoms for less than 6 months, 54% (187) had small-volume disease and 65% (227) low markers. The corresponding proportions in the group of 99 patients with symptoms for greater than 6 months were 39% (39) and 51% (50). =

,

The smalldifferences between survival with the various

chemotherapy regimens were

not

changed substantially

on

introduction of staging and marker variables (X2= 3’ 7, df= 3, p=0’3). The relative efficiency of treatments cannot be assessed because of selection biases and the complexity of changes in treatment regimens during the period of analysis.

Discussion

3-year survival figure of 75% for the present series of patients is comparable to that from other series matched for era of treatment and demonstrates the important advance that The

has been made in the management of testicular cancer. As far as we are aware the present series of 458 patients treated with modern chemotherapy for metastatic testicular nonseminoma is the largest number to be analysed in depth to

identify prognostic subgroups. The main aim of this collaborative study was to define criteria for separating patients into low-risk and high-risk categories for prospective randomised clinical trials designed to investigate lower-toxicity chemotherapy and more effective chemotherapy, respectively. Tumour volume has been demonstrated to be of prognostic importance for radiotherapy 14 and chemotherapy. 1,2 These latter observations led to the development of the Royal Marsden Hospital staging classification, in which extent of disease and ‘’ tumour volume are combined.’ Since the development of accurate radioimmunoassays for AFP15 and HCGI6 both markers have been used extensively in the management of testicular cancer. More controversial, however, has been the prognostic importance of the extent of AFP and HCG elevation as a variable independent of tumour volume in terms of response to chemotherapy. The proportion of patients with raised AFP is related to clinical stage, 17 and serum AFP and HCG levels are higher when bulky metastases are present. 18 The present study shows a correlation between tumour volume and serum marker concentrations (table III). Germa-Lluch et al3 reported that AFP and HCG levels were more accurate prognostic indicators than tumour volume. In an update of these observations the value of AFP and HCG was confirmed, whereas tumour volume and clinical stage were found not to be prognostically important.4 The results of the present study suggest that clinical stage and serum markers are of roughly equal importance and are complementary to each other. The important observation that outcome improved with year of first chemotherapy may be explained by more appropriate use of chemotherapy and post-chemotherapy surgery. 19,20 Thus, comparison of current treatment results with earlier findings should be avoided, and the importance of treatment of patients in centres with adequate experience in the complexities of patient management realised.

staging classification combining tumour marker levels to the present population 180

By applying volume and

patients rate

are

a

allocated

to a

low-risk category with

a

survival

of 91%, 205 to an intermediate-risk category with a 72%

survival rate, and 73

to a

high-risk category

with

a

survival

rate of 47%. However, such a classification will not necessarily apply equally to other series. Because of the gradual improvement in treatment results between 1976 and 1982 the overall figures quoted above underestimate current survival figures. Thus, if patients treated from 1980 to 1982 are considered, the survival rates for these groups are 95%, 85%, and 5407o respectively. Bosl et al have arrived at a similar prognostic index by means of multivariate analysis with a combination of stage and marker levels.55 Age appears to be unrelated to any differences in staging or marker distribution and may be associated with the greater sensitivity of older patients to myelotoxic chemotherapy. However, whether the extra predictive power derived from this factor would merit the added complexity of any, classification which included it is doubtful. Though length of history as an independent variable does not give as good discrimination as tumour volume and marker levels, the fact that delay and extent of disease were directly correlated emphasises the need for more effort to be made in

encouraging early diagnosis. We thank the clinicians who referred patients to the centres participating in the study, and the laboratories where serum marker assays were carried out. We also thank Julie Butcher, who prepared the manuscript, and Lindsey Pegus for the art work. Data analysis was carried out by Dr L. S. Freedman and Ms Trials Office, Medical Research Council, Cambridge.

Correspondence

should be addressed

to

Hospital, Downs Road, Sutton, Surrey SM2

M. J. 5PT.

J. M. Barnes,

P., The Royal Marsden

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