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Risk-related adjuvant chemotherapy for stage I non-seminoma of the testis
Clinical Oncology (1991) 3:270--272 1991 The Royal College of Radiologists
Clinical Oncology
Original Article Risk-Related Adjuvant Chemotherapy for Stage I Non-Seminoma of the Testis G. Madej and A. Pawinski Unit of Chemotherapy, Maria Sklodowska-Cure Memorial Institute of Oncology, Warsaw, Poland
Abstract. Seventy-Two patients with stage I testicular non-seminoma presenting between January 1984 and December 1988 were managed either by adjuvant chemotherapy in the presence of histological adverse prognostic factors or by surveillance if none of these factors were present. The determining factors were vascular invasion, lymphatic invasion, involvement of the epididymis, involvement of the fete testis. Thirty patients were treated with three courses of platinum, vinblastine and bleomycin (PVB) and 42 were managed by surveillance. All 72 patients are alive and have been free of disease from 12-60+ months. One of 42 patients managed by surveillance relapsed 16 months after orchidectomy and he has been disease-free for 32+ months after chemotherapy. No relapses occurred in patients treated with adjuvant chemotherapy. The results confirm the suggestion by Peckham (Hoskin et al., 1986) that histopathological analysis of the primary tumour can provide the basis for subsequent management either by surveillance or chemotherapy. Keywords: Adjuvant chemotherapy; Non-seminoma; Testis
or by surveillance. The prognosis is excellent with all these management policies with a cure rate of approximately 95% (Fossa and Horwich, 1989). In patients managed by surveillance alone, the relapse rate is approximately 30% (Freedman et al., 1987). The early diagnosis of relapse leads to a very high success rate of chemotherapy with the advantage of reserving chemotherapy only for those with demonstrable need for treatment. Surveillance policies at the Royal Marsden Hospital (Hoskin et al. 1986), led to multicentre evaluation of surveillance by the Medical Research Council Testicular Tumour Working Party (Freedman et al., 1987). Both these studies found that the risk of relapse was higher if the primary tumour contained areas of vascular invasion, lymphatic invasion, and also if there was involvement of the epididymis of rete testis. These findings provide the basis for considering adjuvant chemotherapy in those patients who are at high risk of relapse. Since 1984, the Cancer Centre in Warsaw has pursued a policy of selective adjuvant chemotherapy in patients with one of these risk factors and we present the results of this policy.
MATERIALS AND METHODS INTRODUCTION
Modern combined treatment based on combination chemotherapy containing cisplatin and surgery allows the cure of approximately 80% of patients with widespread testicular cancers (Horwich, 1989). Patients without metastatic disease at presentation have been managed either with retroperitoneal node dissection, with radiotherapy, Correspondence and Offprint requests to: Dr. Grzegorz Madej, Unit of Chemotherapy, Maria Sklodowska-Cure Memorial Institute of Oncology, Warsaw, Poland.
A total of 72 patients aged 17-32 years (mean 21 years) with stage I testicular non-seminoma were managed at the Warsaw Cancer Centre between January 1984 and December 1988. In all cases, orchidectomy was performed through an inguinal incision. In 41 patients, preorchidectomy raised serum markers alphafetoprotein (AFP) and/or human chorionic gonadotrophin (HCB) fell to normal levels after orchidectomy. The pathology of resected tumour was reviewed in the Department of Pathomorphology of the Warsaw Cancer Centre according to the WHO classification. The primary
271
Risk-Related Adjuvant Chemotherapy for Stage 1 Non-Seminoma of the Testis Table 1. Patients' characteristics Absence of risk factors (surveillance) 42 patients
Embryonal carcinoma Teratocarcinoma Yolk sac tumour Chorioncarcinoma
2 24 8 8
Presence of risk factors (adjuvant chemotherapy) 30 patients Lymphatic invasion
Vascular invasion
Invasion of spermatic cord, epididymis or tunica abuginea
4 9 4 4
3 8 3 1
4 7 1 0
t u m o u r was examined histologically for evidence of vascular invasion, lymphatic p e r m e a t i o n and the local extent of the t u m o u r especially invasion of the epididymis or rete testis. In 30 of 72 patients, one of these factors was present and in 40 of 72 patients none were present (Table 1). T h e staging assessment in all cases include chest radiograph, c o m p u t e d axial t o m o g r a p h y of abdomen, m e a s u r e m e n t of serum tumour markers A F P and H C G , intr~/venous urography, serum test of liver and kidney function. Histological details were presented in Table 2. Patients with lymphatic or vascular invasion, infiltration of the tunica albuginea, epididymis or spermatic cord were treated with three courses of platinum, vinblastine and bleomycin (PVB) c h e m o t h e r a p y (Table 3). Patients with none of these factors were m a n a g e d by surveillance consisting of evaluation every m o n t h during Table 2. Primary tumour histology in 72 patients with stage I non-seminoma Histology (WHO classification)
Total Risk Risk number factors* factors* present absent
Tumour of one histological type Seminoma Spermatocytic seminoma Embryonal carcinoma 7 5 2 Yolk sac tumour 2 2 Polyembrioma teratoma Mature, with malignant transformation Chorioncarcinoma Tumours of more than one histological type Embryonal carcinoma with 38 14 24 teratoma (teratocarcinoma) Chorioncarcinoma and any other types 13 5 8 other combination 12 4 8 Total 72 30 42 *Lymphatic or vascular invasion, invasion of spermatic cord, epididymis or tunica albuginea.
the first year after orchidectomy, every 2 months the second year and every 3 months in the third year and thereafter every 6 months. Evaluations consisted of tumour m a r k e r assay and chest radiograph. CT scans were repeated 2 monthly in the first year, 4 monthly in the second year and 6 monthly in the third year.
RESULTS
The overall group of 72 patients followed from 1260+ months (median 28.4 months) after either orchidectomy or completion of chemotherapy, all are alive free of disease. The probability of 5-year survival was 96%. Of 30 patients with a high risk of relapse defined histologically and who were treated with three courses of PVB chemotherapy, no relapses occurred during follow-up of 14-60+ months (median 31 months). Of 72 patients m a n a g e d by surveillance and followed for 12-59+ months (median 31 months), there was one recurrence 16 months after orchidectomy. Recurrence was with lung metastases and he was treated with six courses of PVB achieving complete remission which at the time of analysis had lasted for 32+ months. Patients treated with three courses of PVB c h e m o t h e r a p y had toxicity assessment according to W H O criteria. T h e r e was no grade I I I or I V toxicity and in no patient was there delay in the timing of treatment or compromise of drug doses. Mild sideeffects included nausea, vomiting, alopecia and bone m a r r o w suppression.
DISCUSSION
Table 3. PVB programme of chemotherapy Cisplatin 100 mg/m2 Vinblastine 0.15 mg/kg Bleomycin 30 mg Cycle repeated every 21 days
i.v. i.v. i.v.
day 1 day 1 days 2, 9 and 16
Despite the high cure rate of patients with disseminated testicular non-seminoma, two general problems still occur. The first is the patient with advanced bulky disease when the cure rate falls to
272
less than 60% (MRC, 1985). Second, patients with stage I disease who have an excellent prognosis should have treatment of minimal morbidity. The identification of histological risk factors for recurrence enables the selective choice of appropriate treatment for each patient. Our results strongly confirm the findings that histological parameters can identify the high risk group of stage I patients (Hoskin et al., 1986; Freedman et al. 1987). They are similar to results published by Pont et al. (1990). They also indicate that three courses of adjuvant PVB prevents relapse. It has recently been demonstrated that two courses of adjuvant PVB prevent relapse in patients with pathological stage II nonseminoma who achieve complete remission by retroperitoneal lymphadenectomy (Williams et al., 1987). It would be appropriate in the future therefore to consider only two courses of adjuvant chemotherapy in high-risk clinical stage I patients and this forms the basis of a current Medical Research Council study.
G. Madej and A. Pawinski
References Fossa SD, Horwich A (1989). The staging and treatment of testicular cancer: management of stage I disease. In; Combination Therapy in Urological Malignancy. pp 174-189. Springer-Verlag, London. Freedman LS, Jones WG, Peckham MJ et al. (1987). Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchidectomy alone. Lancet i, 294-298. Horwich A (1989). Germ cell tumour chemotherapy. British Journal of Cancer, 59, 156--159. Hoskin P, Dilly S, Easton D et al. (1986). Prognostic factors in orchidectomy and surveillance: implication for adjuvant chemotherapy. Journal of Clinical Oncology, 4,1031-1036. Medical Research Council Working Party report on Testicular Tumours (Chairman MJ Peckham) (1985). Prognostic factors in advanced non-seminomatous germ cell testicular tumours; results of a multicentre study, Lancet, i, 8--11. Pont J. Kosak D et al. (1990). Risk-adapted treatment choice in stage I nonseminomatous testicular germ cell cancer by regarding vascular invasion in the primary tumour: a prospective trial. Journal of Clinical Oncology, 8, 16-20. Williams SD, Stablein DM, Einhorn LH et al. (1987). Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. New England Journal of Medicine, 317, 1433-1438.
Received for publication October 1990 Accepted May 1991
Clinical Oncology
Original Article Risk-Related Adjuvant Chemotherapy for Stage I Non-Seminoma of the Testis G. Madej and A. Pawinski Unit of Chemotherapy, Maria Sklodowska-Cure Memorial Institute of Oncology, Warsaw, Poland
Abstract. Seventy-Two patients with stage I testicular non-seminoma presenting between January 1984 and December 1988 were managed either by adjuvant chemotherapy in the presence of histological adverse prognostic factors or by surveillance if none of these factors were present. The determining factors were vascular invasion, lymphatic invasion, involvement of the epididymis, involvement of the fete testis. Thirty patients were treated with three courses of platinum, vinblastine and bleomycin (PVB) and 42 were managed by surveillance. All 72 patients are alive and have been free of disease from 12-60+ months. One of 42 patients managed by surveillance relapsed 16 months after orchidectomy and he has been disease-free for 32+ months after chemotherapy. No relapses occurred in patients treated with adjuvant chemotherapy. The results confirm the suggestion by Peckham (Hoskin et al., 1986) that histopathological analysis of the primary tumour can provide the basis for subsequent management either by surveillance or chemotherapy. Keywords: Adjuvant chemotherapy; Non-seminoma; Testis
or by surveillance. The prognosis is excellent with all these management policies with a cure rate of approximately 95% (Fossa and Horwich, 1989). In patients managed by surveillance alone, the relapse rate is approximately 30% (Freedman et al., 1987). The early diagnosis of relapse leads to a very high success rate of chemotherapy with the advantage of reserving chemotherapy only for those with demonstrable need for treatment. Surveillance policies at the Royal Marsden Hospital (Hoskin et al. 1986), led to multicentre evaluation of surveillance by the Medical Research Council Testicular Tumour Working Party (Freedman et al., 1987). Both these studies found that the risk of relapse was higher if the primary tumour contained areas of vascular invasion, lymphatic invasion, and also if there was involvement of the epididymis of rete testis. These findings provide the basis for considering adjuvant chemotherapy in those patients who are at high risk of relapse. Since 1984, the Cancer Centre in Warsaw has pursued a policy of selective adjuvant chemotherapy in patients with one of these risk factors and we present the results of this policy.
MATERIALS AND METHODS INTRODUCTION
Modern combined treatment based on combination chemotherapy containing cisplatin and surgery allows the cure of approximately 80% of patients with widespread testicular cancers (Horwich, 1989). Patients without metastatic disease at presentation have been managed either with retroperitoneal node dissection, with radiotherapy, Correspondence and Offprint requests to: Dr. Grzegorz Madej, Unit of Chemotherapy, Maria Sklodowska-Cure Memorial Institute of Oncology, Warsaw, Poland.
A total of 72 patients aged 17-32 years (mean 21 years) with stage I testicular non-seminoma were managed at the Warsaw Cancer Centre between January 1984 and December 1988. In all cases, orchidectomy was performed through an inguinal incision. In 41 patients, preorchidectomy raised serum markers alphafetoprotein (AFP) and/or human chorionic gonadotrophin (HCB) fell to normal levels after orchidectomy. The pathology of resected tumour was reviewed in the Department of Pathomorphology of the Warsaw Cancer Centre according to the WHO classification. The primary
271
Risk-Related Adjuvant Chemotherapy for Stage 1 Non-Seminoma of the Testis Table 1. Patients' characteristics Absence of risk factors (surveillance) 42 patients
Embryonal carcinoma Teratocarcinoma Yolk sac tumour Chorioncarcinoma
2 24 8 8
Presence of risk factors (adjuvant chemotherapy) 30 patients Lymphatic invasion
Vascular invasion
Invasion of spermatic cord, epididymis or tunica abuginea
4 9 4 4
3 8 3 1
4 7 1 0
t u m o u r was examined histologically for evidence of vascular invasion, lymphatic p e r m e a t i o n and the local extent of the t u m o u r especially invasion of the epididymis or rete testis. In 30 of 72 patients, one of these factors was present and in 40 of 72 patients none were present (Table 1). T h e staging assessment in all cases include chest radiograph, c o m p u t e d axial t o m o g r a p h y of abdomen, m e a s u r e m e n t of serum tumour markers A F P and H C G , intr~/venous urography, serum test of liver and kidney function. Histological details were presented in Table 2. Patients with lymphatic or vascular invasion, infiltration of the tunica albuginea, epididymis or spermatic cord were treated with three courses of platinum, vinblastine and bleomycin (PVB) c h e m o t h e r a p y (Table 3). Patients with none of these factors were m a n a g e d by surveillance consisting of evaluation every m o n t h during Table 2. Primary tumour histology in 72 patients with stage I non-seminoma Histology (WHO classification)
Total Risk Risk number factors* factors* present absent
Tumour of one histological type Seminoma Spermatocytic seminoma Embryonal carcinoma 7 5 2 Yolk sac tumour 2 2 Polyembrioma teratoma Mature, with malignant transformation Chorioncarcinoma Tumours of more than one histological type Embryonal carcinoma with 38 14 24 teratoma (teratocarcinoma) Chorioncarcinoma and any other types 13 5 8 other combination 12 4 8 Total 72 30 42 *Lymphatic or vascular invasion, invasion of spermatic cord, epididymis or tunica albuginea.
the first year after orchidectomy, every 2 months the second year and every 3 months in the third year and thereafter every 6 months. Evaluations consisted of tumour m a r k e r assay and chest radiograph. CT scans were repeated 2 monthly in the first year, 4 monthly in the second year and 6 monthly in the third year.
RESULTS
The overall group of 72 patients followed from 1260+ months (median 28.4 months) after either orchidectomy or completion of chemotherapy, all are alive free of disease. The probability of 5-year survival was 96%. Of 30 patients with a high risk of relapse defined histologically and who were treated with three courses of PVB chemotherapy, no relapses occurred during follow-up of 14-60+ months (median 31 months). Of 72 patients m a n a g e d by surveillance and followed for 12-59+ months (median 31 months), there was one recurrence 16 months after orchidectomy. Recurrence was with lung metastases and he was treated with six courses of PVB achieving complete remission which at the time of analysis had lasted for 32+ months. Patients treated with three courses of PVB c h e m o t h e r a p y had toxicity assessment according to W H O criteria. T h e r e was no grade I I I or I V toxicity and in no patient was there delay in the timing of treatment or compromise of drug doses. Mild sideeffects included nausea, vomiting, alopecia and bone m a r r o w suppression.
DISCUSSION
Table 3. PVB programme of chemotherapy Cisplatin 100 mg/m2 Vinblastine 0.15 mg/kg Bleomycin 30 mg Cycle repeated every 21 days
i.v. i.v. i.v.
day 1 day 1 days 2, 9 and 16
Despite the high cure rate of patients with disseminated testicular non-seminoma, two general problems still occur. The first is the patient with advanced bulky disease when the cure rate falls to
272
less than 60% (MRC, 1985). Second, patients with stage I disease who have an excellent prognosis should have treatment of minimal morbidity. The identification of histological risk factors for recurrence enables the selective choice of appropriate treatment for each patient. Our results strongly confirm the findings that histological parameters can identify the high risk group of stage I patients (Hoskin et al., 1986; Freedman et al. 1987). They are similar to results published by Pont et al. (1990). They also indicate that three courses of adjuvant PVB prevents relapse. It has recently been demonstrated that two courses of adjuvant PVB prevent relapse in patients with pathological stage II nonseminoma who achieve complete remission by retroperitoneal lymphadenectomy (Williams et al., 1987). It would be appropriate in the future therefore to consider only two courses of adjuvant chemotherapy in high-risk clinical stage I patients and this forms the basis of a current Medical Research Council study.
G. Madej and A. Pawinski
References Fossa SD, Horwich A (1989). The staging and treatment of testicular cancer: management of stage I disease. In; Combination Therapy in Urological Malignancy. pp 174-189. Springer-Verlag, London. Freedman LS, Jones WG, Peckham MJ et al. (1987). Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchidectomy alone. Lancet i, 294-298. Horwich A (1989). Germ cell tumour chemotherapy. British Journal of Cancer, 59, 156--159. Hoskin P, Dilly S, Easton D et al. (1986). Prognostic factors in orchidectomy and surveillance: implication for adjuvant chemotherapy. Journal of Clinical Oncology, 4,1031-1036. Medical Research Council Working Party report on Testicular Tumours (Chairman MJ Peckham) (1985). Prognostic factors in advanced non-seminomatous germ cell testicular tumours; results of a multicentre study, Lancet, i, 8--11. Pont J. Kosak D et al. (1990). Risk-adapted treatment choice in stage I nonseminomatous testicular germ cell cancer by regarding vascular invasion in the primary tumour: a prospective trial. Journal of Clinical Oncology, 8, 16-20. Williams SD, Stablein DM, Einhorn LH et al. (1987). Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. New England Journal of Medicine, 317, 1433-1438.
Received for publication October 1990 Accepted May 1991