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The international germ cell consensus classification: A new prognostic factor-based staging classification for metastatic germ cell tumours
Clinical Oncology(1997) 9:207-209 © 1997 The Royal College of Radiologists
Clinical Oncology
Editorial The International G e r m Cell Consensus Classification: A New Prognostic Factor-Based Staging Classification for Metastatic G e r m Cell Tumours G. M. Mead 1 and S. P. Stenning 2 aRoyal South Hants Hospital, Southampton, UK and 2MRC Clinical Trials Office, Cambridge, UK
Perhaps the most dramatic advance in clinical oncology in the last 20 years has been the achievement of cure rates exceeding 80% for patients with metastatic germ cell cancer. The early major advances in the treatment of these conditions were centred on individual institutions in the USA and Europe, each of whom devised their own widely differing staging classifications and advanced their own treatment approaches. As cure rates improved, a broad clinical management consensus emerged, based on chemotherapy with cisplatird etoposide + Neomycin, with postchemotherapy resection of residual masses for non-seminomatous germ cell tumours (NSGCT), and chemotherapy alone for advanced metastatic seminoma. A comparable consensus did not, however, emerge with regard to staging classifications. This is perhaps not surprising, as germ call cancers are a comparatively heterogeneous group of malignancies in which a wealth of measurable factors relate to prognosis. These malignancies may arise at gonadal or extragonadal sites; they commonly metastasize widely by either lymphatic and/or vascular routes. In addition, a characteristic feature of these cancers is the production of the tumour markers human chorionic gonadotrophic (hCG; from trophoblastic elements in seminoma or NSGCT), alpha-foetoprotein (AFP; from yolk sac tumour in NSGCT only) and lactate dehydrogenase (LDH; of uncertain pathogenesis). These markers not only correlate with prognosis but also provide a unique measure of response to treatment with chemotherapy. It rapidly became apparent when the above factors were analysed that staging classifications using conventional criteria (e.g. TNM) were quite unsuited to this malignancy, and that prognostic factor-derived classifications were likely to prove more informative and internationally applicable. In the UK, the Royal Marsden staging classification [l] has formed a basis for staging for many years. The original classification predominantly described the extent of spread, together with tumour bulk, but ignored the potential contribution of markers. This classification was modified by the inclusion of marker Correspondence and offprint requests to." Dr G. M. Mead, Department of Medical Oncology, Royal South Hants Hospital, Southampton SO14 0YG, UK.
and other data in two Medical Research Council
(MRC) studies [2,3]. These performed well in dividing patients into prognostic subgroups. Neither, however, including sufficient information on seminomas, extragonadal disease or LDH. The Indiana Group evolved a separate classification [4], again largely ignoring the contribution of serum markers. This divided the patient population into three groups, largely on the basis of disease extent and bulk. At the same time, the Memorial Hospital in New York [5] and Charing Cross Hospital in London [6] devised broadly comparable classifications, which placed heavy emphasis on the importance of tumour markers (AFP and hCG by Charing Cross, and hCG and LDH by the Memorial Hospital). The Memorial Hospital classification was of particular interest, as it sought to individualize the outlook for each patient. This was achieved by calculating a 'probability of complete remission (CR)' by the integration of marker data and comparatively simple data describing the extent of spread, into a complex formula. The large number of competing and conflicting classifications available in the literature [7,8] have, in recent years, served as a hindrance to collaboration and to the interpretation of international Phase II and III clinical trials. Germ cell cancers are comparatively rare and the results of small or, at best, moderatesized trials, as achievable by individual centres, were too often inconclusive. It became increasingly apparent that international collaboration was essential if large randomized trials, which are needed to provide statistically reliable and clinically meaningful results, were to be performed. The recent publication of an internationally agreed prognostic factor-based classification - the International Germ Cell Cancer Consensus Classification [9] - should bring this era to a close, and enable an international collaborative effort to cure all patients with this disease to proceed, also acting as a framework for clinicians reporting their results. This group comprised clinicians and statisticians from germ cell cancer treatment centres worldwide, who agreed to pool retrospective individual patient data. The patients who were eligible for this study were treated between 1976 and 1990 for metastatic germ cell tumours arising at any (extracranial) primary site. All patients received platinum-containing chemotherapy. A total of 5202 patients with NSGCT and 660
G. M. Mead and S. P. Stenning
208
Non-seminoma Mediastinal non-pulmonary primarysite or visceral mets or
Seminoma
high* [ markers?}
Non-pulmonaryvisceral mets?
I
I Intermediate* markers? ]
[ ,ow'markers ]
*High
intermediate
Low
AFP > 10 000 ng/m~ AFP > 1000 and < 10 000 ng/ml hCG > 50 000iu/I hCG > 5000 and < 50 000 lull LDH>10xN LDH> 1.5x N a n d < 10x N (N = upper limit of normal range)
AFP < 1000 ng/ml hCG < 5000iu/I LDH < 1.5 x N
Fig. 1. The International Germ Cell Consensus Classification.
with seminoma were included. The median posttreatment follow-up was 5 years. Extensive data were collected on presenting features and multivariate analyses sought to identify those most closely related to progression-free and overall survival. One of the central goals of the International Group was that any classification devised should be simple, robust, reproducible and relevant to future clinical trial objectives. The results of the analyses were striking. For NSGCT, the main adverse factors were: mediastinal primary site; the degree of elevation of each of the tumour markers AFP, hCG and LDH; and the extent of spread, which was most easily described by the presence of non-pulmonary visceral sites of metastatic disease (NPVM), such as liver, bone and brain. For seminoma, the predominant adverse feature was the presence or absence of NPVM. The International Group chose to divide the N S G C T population, using the above criteria, into three prognostic groups - good, intermediate and poor - which were considered clinically relevant, and for which different clinical trial approaches were needed. Sixty per cent of germ cell tumours (56% of NSGCT, 90% of all seminomas) were categorized as good prognosis, with a 5-year survival of over 90%, 26% of patients (28% of all NSGCT, 10% of all seminomas) were classified as intermediate prognosis, with a 5year survival of 79%; and 14% of patients (16% of NSGCT, no seminomas) were classified as poor prognosis, with less than 50% surviving for 5 years. The resulting classification (Fig. 1) was thus devised on the retrospective data set, but it was also
tested on a recently treated patient population (included in European clinical trials from 1990 to 1993) and was found to be robust. This classification will form the basis of the next T N M classification for testis tumours. The high cure rate achieved in patients with GCTs in the last 20 years represents a triumph of clinical empiricism. However, a proportion of these patients still die and efforts must continue to improve cure rates and reduce toxicity. Wherever possible, patients should be entered into clinical trials (within the UK, Usually sponsored by the MRC), which now use the International Germ Cell Classification as a basis for staging and therapy.
References 1. Peckham MJ, McElwain TJ, Barrett A, et al. Combined management of malignant teratoma of the testis. Lancet 1979;ii:267-70. 2. Medical Research Council. Prognostic factors in advanced nonseminomatous germ-cell testicular tumours: results of a multicentre study. Lancet 1985;i:8-12. 3. Mead GM, Stenning SP, Parkinson MC, et al. The second Medical Research Council study of prognostic factors in nonseminomatous germ cell tumours. J Clin Oncol 1992;10:85-94. 4. Birch R, Williams S, Cone A, et al. Prognostic factors for favourable outcome in disseminated germ cell tumours. J Clin Oncol 1986;4:400-7. 5. Bosl GJ, Geller NL, Cirrincoine C, et al. Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res 1983;43:3403-7. 6. Newlands ES, Bagshawe KD, Begent RHJ, et al. Current optimum management of anaplastic germ cell tumours of the testis and other sites. Br J Urol 1986;58:307-14.
The International Germ Cell Consensus Classification 7. Hitchins RN, Newlands ES, Smith DB, et al. Long-term outcome in patients with germ cell tumours treated with POMB/ACE chemotherapy: comparison of commonly used classification systems of good and poor prognosis. Br J Cancer 1989;59:236-42. 8. Bajorin D, Katz A, Chan E, et al. Comparison of criteria for
209 assigning germ cell tumour patients to 'good risk' and 'poor risk' studies. J Clin Oncol 1988;6:786-92. 9. International Germ Cell Cancer Collaborative Group (IGCCCG). The International Germ Cell Classification: a prognostic factor-based staging system for metastatic germ cell cancer. J Clin Oncol 1997;15:594-603.
Clinical Oncology
Editorial The International G e r m Cell Consensus Classification: A New Prognostic Factor-Based Staging Classification for Metastatic G e r m Cell Tumours G. M. Mead 1 and S. P. Stenning 2 aRoyal South Hants Hospital, Southampton, UK and 2MRC Clinical Trials Office, Cambridge, UK
Perhaps the most dramatic advance in clinical oncology in the last 20 years has been the achievement of cure rates exceeding 80% for patients with metastatic germ cell cancer. The early major advances in the treatment of these conditions were centred on individual institutions in the USA and Europe, each of whom devised their own widely differing staging classifications and advanced their own treatment approaches. As cure rates improved, a broad clinical management consensus emerged, based on chemotherapy with cisplatird etoposide + Neomycin, with postchemotherapy resection of residual masses for non-seminomatous germ cell tumours (NSGCT), and chemotherapy alone for advanced metastatic seminoma. A comparable consensus did not, however, emerge with regard to staging classifications. This is perhaps not surprising, as germ call cancers are a comparatively heterogeneous group of malignancies in which a wealth of measurable factors relate to prognosis. These malignancies may arise at gonadal or extragonadal sites; they commonly metastasize widely by either lymphatic and/or vascular routes. In addition, a characteristic feature of these cancers is the production of the tumour markers human chorionic gonadotrophic (hCG; from trophoblastic elements in seminoma or NSGCT), alpha-foetoprotein (AFP; from yolk sac tumour in NSGCT only) and lactate dehydrogenase (LDH; of uncertain pathogenesis). These markers not only correlate with prognosis but also provide a unique measure of response to treatment with chemotherapy. It rapidly became apparent when the above factors were analysed that staging classifications using conventional criteria (e.g. TNM) were quite unsuited to this malignancy, and that prognostic factor-derived classifications were likely to prove more informative and internationally applicable. In the UK, the Royal Marsden staging classification [l] has formed a basis for staging for many years. The original classification predominantly described the extent of spread, together with tumour bulk, but ignored the potential contribution of markers. This classification was modified by the inclusion of marker Correspondence and offprint requests to." Dr G. M. Mead, Department of Medical Oncology, Royal South Hants Hospital, Southampton SO14 0YG, UK.
and other data in two Medical Research Council
(MRC) studies [2,3]. These performed well in dividing patients into prognostic subgroups. Neither, however, including sufficient information on seminomas, extragonadal disease or LDH. The Indiana Group evolved a separate classification [4], again largely ignoring the contribution of serum markers. This divided the patient population into three groups, largely on the basis of disease extent and bulk. At the same time, the Memorial Hospital in New York [5] and Charing Cross Hospital in London [6] devised broadly comparable classifications, which placed heavy emphasis on the importance of tumour markers (AFP and hCG by Charing Cross, and hCG and LDH by the Memorial Hospital). The Memorial Hospital classification was of particular interest, as it sought to individualize the outlook for each patient. This was achieved by calculating a 'probability of complete remission (CR)' by the integration of marker data and comparatively simple data describing the extent of spread, into a complex formula. The large number of competing and conflicting classifications available in the literature [7,8] have, in recent years, served as a hindrance to collaboration and to the interpretation of international Phase II and III clinical trials. Germ cell cancers are comparatively rare and the results of small or, at best, moderatesized trials, as achievable by individual centres, were too often inconclusive. It became increasingly apparent that international collaboration was essential if large randomized trials, which are needed to provide statistically reliable and clinically meaningful results, were to be performed. The recent publication of an internationally agreed prognostic factor-based classification - the International Germ Cell Cancer Consensus Classification [9] - should bring this era to a close, and enable an international collaborative effort to cure all patients with this disease to proceed, also acting as a framework for clinicians reporting their results. This group comprised clinicians and statisticians from germ cell cancer treatment centres worldwide, who agreed to pool retrospective individual patient data. The patients who were eligible for this study were treated between 1976 and 1990 for metastatic germ cell tumours arising at any (extracranial) primary site. All patients received platinum-containing chemotherapy. A total of 5202 patients with NSGCT and 660
G. M. Mead and S. P. Stenning
208
Non-seminoma Mediastinal non-pulmonary primarysite or visceral mets or
Seminoma
high* [ markers?}
Non-pulmonaryvisceral mets?
I
I Intermediate* markers? ]
[ ,ow'markers ]
*High
intermediate
Low
AFP > 10 000 ng/m~ AFP > 1000 and < 10 000 ng/ml hCG > 50 000iu/I hCG > 5000 and < 50 000 lull LDH>10xN LDH> 1.5x N a n d < 10x N (N = upper limit of normal range)
AFP < 1000 ng/ml hCG < 5000iu/I LDH < 1.5 x N
Fig. 1. The International Germ Cell Consensus Classification.
with seminoma were included. The median posttreatment follow-up was 5 years. Extensive data were collected on presenting features and multivariate analyses sought to identify those most closely related to progression-free and overall survival. One of the central goals of the International Group was that any classification devised should be simple, robust, reproducible and relevant to future clinical trial objectives. The results of the analyses were striking. For NSGCT, the main adverse factors were: mediastinal primary site; the degree of elevation of each of the tumour markers AFP, hCG and LDH; and the extent of spread, which was most easily described by the presence of non-pulmonary visceral sites of metastatic disease (NPVM), such as liver, bone and brain. For seminoma, the predominant adverse feature was the presence or absence of NPVM. The International Group chose to divide the N S G C T population, using the above criteria, into three prognostic groups - good, intermediate and poor - which were considered clinically relevant, and for which different clinical trial approaches were needed. Sixty per cent of germ cell tumours (56% of NSGCT, 90% of all seminomas) were categorized as good prognosis, with a 5-year survival of over 90%, 26% of patients (28% of all NSGCT, 10% of all seminomas) were classified as intermediate prognosis, with a 5year survival of 79%; and 14% of patients (16% of NSGCT, no seminomas) were classified as poor prognosis, with less than 50% surviving for 5 years. The resulting classification (Fig. 1) was thus devised on the retrospective data set, but it was also
tested on a recently treated patient population (included in European clinical trials from 1990 to 1993) and was found to be robust. This classification will form the basis of the next T N M classification for testis tumours. The high cure rate achieved in patients with GCTs in the last 20 years represents a triumph of clinical empiricism. However, a proportion of these patients still die and efforts must continue to improve cure rates and reduce toxicity. Wherever possible, patients should be entered into clinical trials (within the UK, Usually sponsored by the MRC), which now use the International Germ Cell Classification as a basis for staging and therapy.
References 1. Peckham MJ, McElwain TJ, Barrett A, et al. Combined management of malignant teratoma of the testis. Lancet 1979;ii:267-70. 2. Medical Research Council. Prognostic factors in advanced nonseminomatous germ-cell testicular tumours: results of a multicentre study. Lancet 1985;i:8-12. 3. Mead GM, Stenning SP, Parkinson MC, et al. The second Medical Research Council study of prognostic factors in nonseminomatous germ cell tumours. J Clin Oncol 1992;10:85-94. 4. Birch R, Williams S, Cone A, et al. Prognostic factors for favourable outcome in disseminated germ cell tumours. J Clin Oncol 1986;4:400-7. 5. Bosl GJ, Geller NL, Cirrincoine C, et al. Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res 1983;43:3403-7. 6. Newlands ES, Bagshawe KD, Begent RHJ, et al. Current optimum management of anaplastic germ cell tumours of the testis and other sites. Br J Urol 1986;58:307-14.
The International Germ Cell Consensus Classification 7. Hitchins RN, Newlands ES, Smith DB, et al. Long-term outcome in patients with germ cell tumours treated with POMB/ACE chemotherapy: comparison of commonly used classification systems of good and poor prognosis. Br J Cancer 1989;59:236-42. 8. Bajorin D, Katz A, Chan E, et al. Comparison of criteria for
209 assigning germ cell tumour patients to 'good risk' and 'poor risk' studies. J Clin Oncol 1988;6:786-92. 9. International Germ Cell Cancer Collaborative Group (IGCCCG). The International Germ Cell Classification: a prognostic factor-based staging system for metastatic germ cell cancer. J Clin Oncol 1997;15:594-603.